Isocitrate dehydrogenase (IDH) inhibitors

Abstract

Disclosed are compounds that inhibit the conversion of α-KG to D-2-HG, pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof, and pharmaceutical compositions containing the compounds. The compounds and pharmaceutical compositions can effectively treat diseases associated with IDH, including cancer.

Description

[Technical Field]

[0001] The present disclosure relates to compounds that inhibit the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), such as D-2-HG, pharmaceutical compositions containing the compounds as an active ingredient, and the use of the compounds in the manufacture of medicaments for treating diseases associated with the conversion of α-KG to D-2-HG. [Background technology]

[0002] Isocitrate dehydrogenase (IDH) is an enzyme essential for cellular respiration in the tricarboxylic acid (TCA) cycle, catalyzing the oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (α-KG) and CO2. In humans, IDH exists in three isoforms, and IDH3 is a mitochondrial NAD+ dehydrogenase (NDH) isoform. + IDH1 catalyzes the third step of the citric acid cycle, converting ATP to NADH. IDH1 and IDH2 are isoforms that catalyze the same reaction outside the context of the citric acid cycle, using NADP as a cofactor instead of NAD. They are localized in the cytosol and peroxisomes or mitochondria, respectively.

[0003] Specific mutations in IDH1 have been found in several brain tumors, including astrocytomas, oligodendrogliomas, and glioblastoma multiforme. Mutations are found in almost all cases of secondary glioblastomas arising from low-grade gliomas, but rarely in primary glioblastoma multiforme. Patients with gliomas whose tumors harbor the IDH1-R132X mutation have longer survival times ["An integrated genomic analysis of human glioblastoma multiforme," Parsons, DW et al., Science, (2008); "Analysis of the IDH1 codon 132 mutation in brain tumors," Balss, J. et al., Acta Neuropathol, (2008); Bleeker, FE et al., "IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors," Hum Mutat, (2009)]. IDH1 and IDH2 mutations occur before p53 mutations, and loss of chromosome 1p / 19q is thought to be the initial event in gliomagenesis ["IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas", Watanabe, T. et al., Am J Pathol, (2009); "Mutational landscape and clonal architecture in grade II and III gliomas", Suzuki, H. et al., Nat Genet, (2015); "Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas", Brat, DJ et al., N Engl J Med, (2015)].Furthermore, IDH2 and IDH1 mutations have been observed in up to 20% of cytogenetically normal acute myeloid leukemia (AML) ["Recurring mutations found by sequencing an acute myeloid leukemia genome", Mardis, ER et al., N Engl J Med, (2009); "Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia", Thol, F. et al., Blood, (2010); "Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value", Abbas, S. et al., Blood, (2010); "The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3 / ITD status", Green, CL et al., Blood, (2010); "IDH1 mutations “Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia”, N Engl J Med, (2013)].IDH mutations are found in 75% of chondrosarcomas ["IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas, but not in other mesenchymal tumors", Amary, MF et al., J Pathol, (2011); "Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2", Amary, MF et al., Nat Genet, (2011)] and 10-23% of intrahepatic cholangiocarcinomas ["Frequent mutations of isocitrate dehydrogenase IDH1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping", Borger, DR et al., Oncologist, (2012); "Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas”, Wang, P. et al., Oncogene, (2012)], and some patients with angioimmunoblastic T-cell lymphoma and melanoma [“The consensus coding sequences of human breast and colorectal cancers”, Sjoblom, T. et al., Science, (2006)]. Currently, IDH1 and IDH2 are the metabolic enzyme genes most frequently mutated in human cancers.

[0004] These mutations result in alterations of amino acid residues essential for enzymatic activity (R132 in IDH1, R140, or R172 in IDH2), thereby preventing the IDH enzymes from catalyzing isocitrate to α-KG. At the same time, these IDH mutations acquire a novel catalytic activity that converts α-KG to D-2-HG. In tumor cells harboring these IDH mutations, D-2-HG accumulates to extremely high levels, inhibiting the function of α-KG-dependent enzymes. This leads to hypermethylation of DNA and histones, resulting in differential gene expression that can activate oncogenes and inactivate tumor suppressor genes. Ultimately, this can lead to the types of cancer described above ["The consensus coding sequences of human breast and colorectal cancers," Sjoblom, T. et al., Science, (2006)]. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, it is desirable to develop an inhibitor that inhibits the process of converting α-KG to D-2-HG. [Means for solving the problem]

[0006] In one aspect, the present disclosure provides a compound of formula (I):

[0007] [ka] or a pharmaceutically acceptable salt thereof (In the formula, Z 1 and Z 2 is independently selected from C and N; X is selected from the group consisting of aryl, heteroaryl, or saturated or partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, or saturated or partially unsaturated heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; Y is absent, bond, -CR 5 R 6 -, -O(CH2) n -, -N(R a )-, -S-, -S(=O)-, -S(=O)2-, -C(O)- and -C(O)N(R b )-selected from the group consisting of; W is selected from the group consisting of absent, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl are selected from the group consisting of one or more R 7 is optionally replaced by; R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, and alkoxy; R 2 is selected from the group consisting of halogen, hydroxyl, cyano and nitro; R 3is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl and alkoxyl; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl and alkoxyl; R 5 and R 6are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; R 7 is halogen, hydroxyl, cyano, nitro, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, -NR c R d and -C(O)R e wherein said alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl are independently selected from the group consisting of halogen, hydroxyl, cyano, alkyl, haloalkyl, alkoxyl, saturated or partially unsaturated cycloalkyl, —C(O)N(R c )(R d Optionally substituted with one or more groups independently selected from the group consisting of: R a , R b , R c and R dare each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, and alkoxyl; R e is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, and alkoxyl; m is 0, 1 or 2; n is 0, 1 or 2).

[0008] In another aspect, the present disclosure provides a compound of formula (Ia):

[0009] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1is alkyl optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, and alkoxy; R 2 , X, Y, W and m are defined as above) to provide.

[0010] In a further aspect, the present disclosure provides a compound of formula (Ib):

[0011] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is alkyl optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, and alkoxy; R 8 is a halogen, q is 1 or 2, and R 2 , X, Y, W and m are defined as above) to provide.

[0012] In another aspect, the present disclosure provides a compound of formula (Ic):

[0013] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 , R 8 , Y, W, m and q are defined as above) to provide.

[0014] In a further aspect, the present disclosure provides a compound of formula (Id):

[0015] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2, Y, W and m are defined as above) to provide.

[0016] In a still further aspect, the present disclosure provides a compound of formula (Ie):

[0017] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 , Y, W and m are defined as above) to provide.

[0018] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0019] In a further aspect, the present disclosure provides a method for treating a disease associated with the conversion of α-KG to D-2-HG, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0020] In another aspect, the present disclosure provides a method for inhibiting the conversion of α-KG to D-2-HG by using a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0021] In a further aspect, the present disclosure provides methods of inhibiting mutant IDH, wild-type IDH, or both by using a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows representative reactions catalyzed by wild-type and mutant IDH1 / 2. DETAILED DESCRIPTION OF THE INVENTION

[0023] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the scope of the claims. Those skilled in the art will recognize numerous methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs or contradicts with this application, including, but not limited to, defined terms, term usage, and described techniques, this application controls.

[0024] It will be appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0025] definition The definitions of specific functional groups and chemical terms are described in more detail below.For the purpose of this disclosure, chemical elements are identified according to the Periodic Table of Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein.In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987, the entire contents of each of which are incorporated herein by reference.

[0026] In various places in this disclosure, linking substituents are described. When a structure clearly requires a linking group, it is understood that the Markush variable listed for that group is the linking group. For example, when a structure requires a linking group and the Markush group definition for that variable lists "alkyl," it is understood that "alkyl" refers to a linking alkylene group.

[0027] As used herein, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valence of the substituted atom and results in a stable or chemically feasible compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, etc. Unless otherwise specified, an "optionally substituted" group may have suitable substitution at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. It will be understood by those skilled in the art that, where appropriate, substituents can themselves be substituted. Unless specifically indicated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0028] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom through which such substituent is bonded to the remainder of the compound of a given formula, such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0029] Any variable (e.g. R i When any radical R occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, a group R i When shown as substituted with a moiety, the group may have up to two R i and R at each occurrence may be optionally substituted with a moiety. i is R iAlso, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0030] As used herein, "C i~j " denotes a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point therebetween, where j is greater than i. For example, C 1~6 indicates a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, "C 1~12 " denotes 1 to 12, in particular 1 to 10, in particular 1 to 8, in particular 1 to 6, in particular 1 to 5, in particular 1 to 4, in particular 1 to 3 or in particular 1 to 2 carbon atoms.

[0031] As used herein, the term "alkyl," whether as part of another term or used independently, refers to a saturated, straight- or branched-chain hydrocarbon group. i~jThe term "alkyl" refers to an alkyl having i to j carbon atoms. In some embodiments, an alkyl group contains 1 to 12 carbon atoms. In some embodiments, an alkyl group contains 1 to 11 carbon atoms. In some embodiments, an alkyl group contains 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (i-butyl), 2-butyl (s-butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the like. 1~12 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. 1~6 Examples of "alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0032] Alkyl groups can be optionally substituted with substituents that independently replace one or more hydrogen atoms on one or more carbons of the alkyl group. Examples of such substituents include, but are not limited to, halogen, hydroxyl, cyano, nitro, azido, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxyl, haloalkyl, haloalkoxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylaryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphite, methylaminocarbonyl ... Examples of the alkyl group include carboxylate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, and saturated or partially unsaturated heterocyclyl. As described below, alkenyl, alkynyl, aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, and saturated or partially unsaturated heterocyclyl groups may also be similarly substituted.

[0033] As used herein, the term "alkenyl," whether used as part of another term or independently, refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon double bond, which may be optionally independently substituted with one or more substituents described herein, and which includes groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl (or vinyl), propenyl, butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.

[0034] As used herein, the term "alkynyl," whether used as part of another term or independently, refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon triple bond and optionally independently substituted with one or more substituents described herein. In some embodiments, alkenyl groups contain 2 to 12 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms. In some embodiments, alkenyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0035] As used herein, the term "alkoxy" or "alkoxyl," either as part of another term or used independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. i~j The term "alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 11 carbon atoms. In some embodiments, the alkoxy group contains 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1~12 Examples of "alkoxyl" include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy, neopentoxy, n-hexoxy, and the like.

[0036] As used herein, the terms "aryl" or "aromatic," whether used as part of another term or independently, refer to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, optionally independently substituted with one or more substituents described herein, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as used herein, are groups in which an aromatic ring is fused to one or more additional rings. In the case of polycyclic ring systems, only one of the rings need be aromatic (e.g., 2,3-dihydroindole), but all of the rings can be aromatic (e.g., quinoline). The second ring can also be fused or bridged. Examples of polycyclic aryls include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc. Aryl groups may be optionally substituted at one or more ring positions with one or more substituents as described herein.

[0037] As used herein, "cycloalkyl," "carbocyclyl," and "carbocycle" are interchangeable and, whether used as part of another term or independently, refer to monovalent saturated, partially unsaturated, or fully saturated mono- and polycyclic ring systems in which all ring atoms are carbon and contain at least three ring-forming carbon atoms, which may be optionally and independently substituted with one or more substituents described herein. In some embodiments, a cycloalkyl can contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, or 4 to 5 ring-forming carbon atoms. A cycloalkyl group can be saturated or partially unsaturated. Cycloalkyl groups can be optionally independently substituted with one or more substituents described herein.In some embodiments, cycloalkyl groups can be saturated cyclic alkyl groups.In some embodiments, cycloalkyl groups can be unsaturated cyclic alkyl groups, and contain at least one double bond or triple bond in their ring system.

[0038] In some embodiments, a cycloalkyl group can be a saturated or unsaturated monocyclic carbocyclic ring system, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0039] In some embodiments, cycloalkyl groups may be saturated or unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring systems that can be arranged as fused, spiro, or bridged ring systems. As used herein, the term "fused ring" refers to a ring system having two rings that share two adjacent atoms, the term "spiro ring" refers to a ring system having two rings that are connected through a single common atom, and the term "bridged ring" refers to a ring system in which two rings share three or more atoms. Examples of fused carbocyclyls include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl, and the like. Examples of spirocarbocyclyls include, but are not limited to, spiro[5.5]undecanyl, spiro-pentadienyl, spiro[3.6]-decanyl, and the like. Examples of bridged carbocyclyls include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.3]undecanyl, and the like.

[0040] As used herein, the term "cyano" refers to --CN.

[0041] As used herein, the term "halo" or "halogen" refers to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iodo).

[0042] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms independently replacing one or more hydrogen atoms on one or more carbons of the alkyl group.

[0043] As used herein, the term "heteroalkyl" refers to an alkyl having at least one of its carbon atoms replaced with a heteroatom selected from N, O, S, or P. A heteroalkyl can be a carbon or heteroatom group (i.e., the heteroatom can appear in the middle or at the end of the group), and can be optionally and independently substituted with one or more substituents described herein. The term "heteroalkyl" encompasses alkoxy and heteroalkoxy groups.

[0044] As used herein, the term "heteroalkenyl" refers to an alkenyl having at least one of its carbon atoms replaced with a heteroatom selected from N, O, S, or P. A heteroalkenyl can be a carbon or heteroatom group (i.e., the heteroatom can appear at the center or at the end of the group), which can be optionally and independently substituted with one or more substituents described herein.

[0045] As used herein, the term "heteroalkynyl" refers to an alkynyl having at least one of its carbon atoms replaced with a heteroatom selected from N, O, S, or P. A heteroalkynyl can be a carbon or heteroatom group (i.e., the heteroatom can appear at the center or at the end of the group), which can be optionally and independently substituted with one or more substituents described herein.

[0046] As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, or phosphorus, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0047] As used herein, the term "heteroaryl," whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms, and optionally independently substituted with one or more substituents described herein. Examples of heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl also includes groups in which an aromatic heterocycle is fused with one or more aryl, alicyclic, or heterocyclyl rings, and the group or point of attachment is on the aromatic heterocycle. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. In some embodiments, the term "5-10-membered heteroaryl" refers to a 5-6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus, or an 8-10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus. In certain embodiments, the term "5- to 12-membered heteroaryl" refers to a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus, or an 8- to 12-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur, or phosphorus.

[0048] As used herein, the term "heterocycle" or "heterocyclyl" refers to a saturated, partially unsaturated, or fully saturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, and one or more ring atoms are optionally and independently substituted with one or more substituents. In some embodiments, a heterocyclyl is a saturated heterocyclyl. In some embodiments, a heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, a heterocyclyl may contain any oxidized form of carbon, nitrogen, sulfur, or phosphorus, and any quaternized form of a basic nitrogen. "Heterocyclyl" also includes groups in which a heterocyclyl group is fused to a saturated, partially unsaturated, or fully saturated (i.e., aromatic) carbocyclic or heterocyclic ring. Heterocyclyl groups may be carbon- or nitrogen-bonded, where possible. In some embodiments, a heterocyclic ring is carbon-bonded. In some embodiments, a heterocyclic ring is nitrogen-bonded. For example, a group derived from pyrrole can be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked), and a group derived from imidazole can be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

[0049] In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spiro, and bridged ring systems are also included within this definition. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazole, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like. Examples of fused heterocyclyls include, but are not limited to, phenyl- or pyridinyl-fused rings, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolidinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl groups, etc. Examples of spiroheterocyclyls include, but are not limited to, spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclyls include, but are not limited to, morphanyl, hexamethylenetetraminyl, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), and the like.

[0050] As used herein, the term "hydroxyl" or "hydroxy" refers to an --OH group.

[0051] As used herein, the term "nitro" refers to the group --NO.sub.2.

[0052] As used herein, the term "partially unsaturated" refers to a group that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully saturated) moieties.

[0053] Unless otherwise specified, "IDH" or "wild-type IDH" refers to a normal IDH enzyme that catalyzes the conversion of isocitrate to α-KG. Exemplary normal IDH enzymes include:

[0054] Human IDH1 protein (NCBI accession number: O75874.2, SEQ ID NO: 1) 1 mskkisggsv vemqgdemtr iiwelikekl ifpyveldlh sydlgienrd atndqvtkda 61 aeaikkhnvg vkcatitpde krveefklkq mwkspngtir nilggtvfre aiickniprl 121 vsgwvkpiii grhaygdqyr atdfvvpgpg kveitytpsd gtqkvtylvh nfeegggvam 181 gmynqdksie dfahssfqma lskgwplyls tkntilkkyd grfkdifqei ydkqyksqfe 241 aqkiwyehrl iddmvaqamk seggfiwack nydgdvqsds vaqgygslgm mtsvlvcpdg 301 ktveaeaahg tvtrhyrmyq kgqetstnpi asifawtrgl ahrakldnnk elaffanale 361 evsietieag fmtkdlaaci kglpnvqrsd ylntfefmdk lgenlkikla qakl

[0055] Human IDH2 protein (NCBI accession number: P48735.2, SEQ ID NO: 2) 1 magylrvvrs lcrasgsrpa wapaaltapt sqeqprrhya dkrikvakpv vemdgdemtr 61 iiwqfikekl ilphvdiqlk yfdlglpnrd qtddqvtids alatqkysva vkcatitpde 121 arveefklkk ​​mwkspngtir nilggtvfre piickniprl vpgwtkpiti grhahgdqyk 181 atdfvadrag tfkmvftpkd gsgvkewevy nfpaggvgmg myntdesisg fahscfqyai 241 qkkwplymst kntilkaydg rfkdifqeif dkhyktdfdk nkiwyehrli ddmvaqvlks 301 sggfvwackn ydgdvqsdil aqgfgslglm tsvlvcpdgk tieaeaahgt vtrhyrehqk 361 grptstnpia sifawtrgle hrgkldgnqd lirfaqmlek vcvetvesga mtkdlagcih 421 glsnvklneh flnttdfldt iksnldralg rq

[0056] As used herein, the term "IDH mutation" refers to any mutation in an IDH enzyme that enables an "IDH mutation," "mutant IDH," or "mutated IDH" to catalyze the conversion of α-KG to D-2-HG. In some embodiments, a "mutant IDH" catalyzes both the conversion of α-KG to D-2-HG and the conversion of isocitrate to α-KG. Such mutations include, but are not limited to, R132H, R132C, R132G, R132L, R132S in IDH1; or R172K, R172M, R172W in IDH2.

[0057] compound In one aspect, the present disclosure provides a compound of formula (I)

[0058] [ka] or a pharmaceutically acceptable salt thereof (In the formula,

[0059] Z 1 and Z 2 is independently selected from C and N; X is selected from the group consisting of aryl, heteroaryl, or saturated or partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, or saturated or partially unsaturated heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl; Y is absent, bond, -CR 5 R 6 -, -O(CH2) n -, -N(R a )-, -S-, -S(=O)-, -S(=O)2-, -C(O)- and -C(O)N(R b )-selected from the group consisting of; W is selected from the group consisting of absent, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl are selected from the group consisting of one or more R 7 is optionally replaced by; R 1 is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, and alkoxy; R 2 is selected from the group consisting of halogen, hydroxyl, cyano and nitro; R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl and alkoxyl; R 4is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl and alkoxyl; R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl; R 7 is halogen, hydroxyl, cyano, nitro, alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, -NR c R d and -C(O)R ewherein said alkoxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl are independently selected from the group consisting of halogen, hydroxyl, cyano, alkyl, haloalkyl, alkoxyl, saturated or partially unsaturated cycloalkyl, —C(O)N(R c )(R d Optionally substituted with one or more groups independently selected from the group consisting of: R a , R b , R c and R d are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, and alkoxyl; R e is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, and alkoxyl; m is 0, 1 or 2; n is 0, 1 or 2) to provide.

[0060] In some embodiments, Z 1 is N.

[0061] In some embodiments, Z 1 is C.

[0062] In some embodiments, Z 2 is N.

[0063] In some embodiments, Z 2 is C.

[0064] In some embodiments, Z 1 is N and Z 2 is N.

[0065] In some embodiments, Z 1 is N and Z 2 is C.

[0066] In some embodiments, X is aryl, heteroaryl, or saturated or partially unsaturated heterocyclyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, and alkyl.

[0067] In some embodiments, X is selected from the group consisting of halogen-substituted aryl, unsubstituted heteroaryl, halogen-substituted heteroaryl, alkyl-substituted heteroaryl, or halogen-substituted saturated or partially unsaturated heterocyclyl.

[0068] In some embodiments, Y is a bond, -CR 5 R 6 -, -O(CH2) n -, -N(R a )-, -C(O)- and -C(O)N(R b)-.

[0069] In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0070] In some embodiments, W is absent, a 3-10 membered saturated or partially unsaturated cycloalkyl, a 3-10 membered saturated or partially unsaturated heterocyclyl, a 3-10 membered aryl, and a 3-10 membered heteroaryl, wherein the saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl are selected from the group consisting of one or more R 7 is optionally replaced by

[0071] In some embodiments, W is absent.

[0072] In some embodiments, W is

[0073] [ka] each of which is selected from the group consisting of one or more R 7 is optionally replaced by

[0074] In some embodiments, R 1 is selected from the group consisting of alkyl, alkenyl, and alkynyl, wherein said alkyl, alkenyl, and alkynyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, and alkoxy.

[0075] In some embodiments, R 1 is alkyl optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, and alkoxy.

[0076] In some embodiments, R 1is alkyl, optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, and alkoxy.

[0077] In some embodiments, R 1 is ethyl, optionally substituted with one or more groups independently selected from the group consisting of fluoro, hydroxyl, and methoxyl.

[0078] In some embodiments, R 2 is a halogen. In some embodiments, R 2 is fluoro, chloro, or bromo. In some embodiments, R 2 is fluoro or chloro. In some embodiments, R 2 is fluoro.

[0079] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0080] In some embodiments, R 2 is halogen and m is 0, 1, or 2. In some embodiments, R 2 is fluoro or chloro and m is 0, 1, or 2. In some embodiments, R 2 is fluoro or chloro and m is 0 or 1. In some embodiments, R 2 is fluoro and m is 0 or 1.

[0081] In some embodiments, R 3is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, and alkoxyl.

[0082] In some embodiments, R 3 is hydrogen or alkyl. In some embodiments, R 3 is hydrogen.

[0083] In some embodiments, R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, and alkoxyl.

[0084] In some embodiments, R 4 is alkyl. In some embodiments, R 4 is methyl, ethyl, propyl or butyl.

[0085] In some embodiments, R 5 and R 6are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partially unsaturated cycloalkyl, saturated and partially unsaturated heterocyclyl, aryl, and heteroaryl.

[0086] In some embodiments, R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxyl, and alkyl. 5 and R 6 is hydrogen.

[0087] In some embodiments, R 7 is halogen, hydroxyl, cyano, alkoxyl, alkyl, alkenyl, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl, -NR c R d and -C(O)R e wherein the alkoxyl, alkyl, alkenyl, haloalkyl, saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, heteroaryl is selected from the group consisting of halogen, hydroxyl, cyano, alkyl, haloalkyl, alkoxyl, saturated or partially unsaturated cycloalkyl, —C(O)N(R c )(R d ) is optionally substituted with one or more groups independently selected from the group consisting of:

[0088] In some embodiments, R 7is selected from the group consisting of halogen, hydroxyl, cyano, alkoxyl, alkyl, alkenyl, haloalkyl, and saturated or partially unsaturated cycloalkyl, wherein said alkoxyl, alkyl, alkenyl, haloalkyl, and saturated or partially unsaturated cycloalkyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, haloalkyl, and alkoxyl.

[0089] In some embodiments, R a , R b , R c and R d are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, and alkoxyl.

[0090] In some embodiments, R a , R b , R c and R d are each independently selected from the group consisting of hydrogen and alkyl.

[0091] In some embodiments, R e is selected from the group consisting of saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, wherein said saturated or partially unsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, carboxy, carbamoyl, alkyl, alkenyl, alkynyl, and alkoxyl. In some embodiments, R e is a saturated or partially unsaturated cycloalkyl.

[0092] In another aspect, the present disclosure provides a compound of formula (Ia):

[0093] [ka] (In the formula, R 1 is alkyl optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, and alkoxy; R 2 , X, Y, W and m are defined as above) to provide.

[0094] In another aspect, the present disclosure provides a compound of formula (Ic):

[0095] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 , R 8 , Y, W, m and q are defined as above) to provide.

[0096] In a further aspect, the present disclosure provides a compound of formula (Id):

[0097] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 , Y, W and m are defined as above) to provide.

[0098] In a still further aspect, the present disclosure provides a compound of formula (Ie):

[0099] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 , Y, W and m are defined as above) to provide.

[0100] In a further aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0101] [Table 1] JPEG0007776418000014.jpg219145JPEG0007776418000015.jpg223151JPEG0007776418000016.jpg219147JPEG0007776418000017.jpg229153JPEG0007776418000018.jpg221147JPEG0007776418000019.jpg218147JPEG0007776418000020.jpg219143JPEG0007776418000021.jpg226153JPEG0007776418000022.jpg225148JPEG0007776418000023.jpg226159JPEG0007776418000024.jpg219147JPEG0007776418000025.jpg223149JPEG0007776418000026.jpg210142JPEG0007776418000027.jpg220149JPEG0007776418000028.jpg207146JPEG0007776418000029.jpg205140JPEG0007776418000030.jpg217146JPEG0007776418000031.jpg212146JPEG0007776418000032.jpg215157JPEG0007776418000033.jpg208139JPEG0007776418000034.jpg211143JPEG0007776418000035.jpg204146JPEG0007776418000036.jpg209143JPEG0007776418000037.jpg198141JPEG0007776418000038.jpg196146JPEG0007776418000039.jpg195145JPEG0007776418000040.jpg195146JPEG0007776418000041.jpg203151JPEG0007776418000042.jpg196141JPEG0007776418000043.jpg187138JPEG0007776418000044.jpg196146JPEG0007776418000045.jpg205142JPEG0007776418000046.jpg185135JPEG0007776418000047.jpg196140JPEG0007776418000048.jpg210143JPEG0007776418000049.jpg166156.

[0102] The compounds provided herein are described with reference to both general formulas and specific compounds.In addition, the compounds of the present disclosure can exist in many different forms or derivatives, all of which are within the scope of the present disclosure.These include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, prodrugs, solvate forms, different crystalline forms or polymorphs and active metabolites.

[0103] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. Thus, the compounds of the present disclosure and their compositions may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the present disclosure are enantiopure compounds. In certain embodiments, a mixture of enantiomers or diastereomers is provided.

[0104] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The term "diastereomers" refers to a pair of optical isomers that are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities.

[0105] Furthermore, certain compounds as described herein may have one or more double bonds that can exist as either Z or E isomers, unless otherwise specified. The present disclosure also encompasses compounds as individual isomers substantially free of other isomers, or as mixtures of various isomers, such as racemic mixtures of enantiomers. In addition to the compounds themselves, the present disclosure encompasses compositions comprising one or more compounds.

[0106] As used herein, the term "isomer" includes all geometric and stereoisomers. For example, "isomer" includes cis and trans isomers, E and Z isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present invention. For example, a stereoisomer may, in some embodiments, be provided substantially free of one or more corresponding stereoisomers and may be referred to as "stereochemically enriched."

[0107] When a particular enantiomer is preferred, in some embodiments it may be provided substantially free of its counterpart, sometimes referred to as "optically enriched." "Optically enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be isolated from a racemic mixture by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, ELS Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, IN 1972).

[0108] The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerization, and cyclic forms in which a proton may occupy more than one position in a heterocyclic ring system (e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole). Valence tautomers include interconversions via rearrangement of some of the bonding electrons. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present disclosure that are identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0109] The compounds of the present disclosure also include prodrugs, active metabolic derivatives (active metabolites), active intermediates, and pharmaceutically acceptable salts thereof.

[0110] As used herein, the term "prodrug" refers to a compound or its pharmaceutically acceptable salt that, when metabolized under physiological conditions or converted by solvolysis, yields the desired active compound. Prodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, prodrugs are inactive or less active than the active compound, but may offer one or more advantageous operational, administration, and / or metabolic properties. For example, some prodrugs are esters of the active compound, and the ester group is cleaved during metabolism to yield the active drug. Some prodrugs are also enzymatically activated to yield the active compound or a compound that yields the active compound upon further chemical reaction. A prodrug may transition from the prodrug form to its active form in a single step, or may have one or more intermediate forms that may themselves be active or inactive. The preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.

[0111] As used herein, the term "metabolite," e.g., active metabolite, overlaps with the above-mentioned prodrug. Thus, such metabolites are pharmacologically active compounds or compounds that are further metabolized into pharmacologically active compounds, which are derivatives resulting from metabolic processes in the subject's body. For example, such metabolites can result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound or salt or prodrug. Among these, active metabolites are such pharmacologically active derivative compounds. For prodrugs, prodrug compounds are generally inactive or less active than metabolites. For active metabolites, the parent compound can be either an active compound or an inactive prodrug.

[0112] Prodrug and active metabolite can be identified by using conventional techniques known in the art.For example, see Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, supra.

[0113] As used herein, the term "active intermediate" refers to an intermediate compound during a synthesis process that exhibits the same or essentially the same biological activity as the final synthesized compound.

[0114] The compounds of the present disclosure can be formulated as or in the form of pharmaceutically acceptable salts. Unless otherwise specified, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0115] As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or the subject being treated therewith.

[0116] As used herein, the term "pharmaceutically acceptable salts," unless otherwise specified, includes salts that retain the biological effectiveness of the free acids and bases of a particular compound and are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, bis-, tris-, tetrakis-, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate the administration of higher drug concentrations.

[0117] Pharmaceutically acceptable salts include acid addition salts such as sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetate, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0118] Pharmaceutically acceptable salts also include base addition salts containing, for example, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc when an acidic functional group, such as a carboxylic acid or phenol, is present. See, for example, Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0119] Pharmaceutically acceptable salts can be prepared by standard techniques. The free base form of a compound can be isolated by dissolving it in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing an appropriate acid, and then evaporating the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0120] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide, etc. Representative examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, or tertiary amines, and cyclic amines such as hydroxyethylpyrrolidone, piperidine, morpholine, or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0121] It will be understood that the compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polymorphic forms), and that the present disclosure is intended to encompass all such forms.

[0122] As used herein, the term "solvate" or "solvate form" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent.Some compounds have a tendency to trap a certain molar ratio of solvent molecules in a crystalline solid phase, thereby forming a solvate.When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate.A hydrate is formed by combining one or more moles of water with one of the substances, where the water retains its molecular state as H2O.Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0123] As used herein, the terms "crystalline form," "crystalline form," "polymorphic form," and "polymorph" can be used interchangeably and refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Crystalline polymorphs of a compound can be prepared by recrystallization under different conditions.

[0124] The present disclosure is intended to include all isotopes of atoms in a compound. Isotopes of an element include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromide, or iodine in a compound of the present disclosure includes isotopes of these, including but not limited to: 1 H, 2 H, 3 H, 11 C. 12 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 127 I and 131 In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 Contains C.

[0125] Compound synthesis The synthesis of the compounds provided herein, including their pharmaceutically acceptable salts, is illustrated in the synthetic schemes in the examples.The compounds provided herein can be prepared using any known organic synthesis technology and can be synthesized according to any of numerous possible synthetic routes, and therefore these schemes are only illustrative and are not intended to limit other possible methods that can be used to prepare the compounds provided herein.In addition, the steps in the schemes are for better illustration and can be appropriately modified.The compound embodiments in the examples were synthesized in China for the purpose of investigation and possible submission to regulatory authorities.

[0126] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of more than one solvent.Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0127] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups.The need for protection and deprotection, and the selection of suitable protecting groups can be easily determined by those skilled in the art.The chemical properties of protecting groups can be found, for example, in TW Greene and PG M Buts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0128] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 The concentration of the compound can be monitored by infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), or mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem. 2004, Vol. 6 (No. 6), pp. 874-883, incorporated herein by reference in its entirety) and normal-phase silica gel chromatography.

[0129] For illustrative purposes, the following sets forth general synthetic routes for preparing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention. While specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be readily substituted to generate various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0130] Compounds of formula (I) can be synthesized as shown in Schemes AD.

[0131] General Scheme A: Synthesis of Compounds of Formula (I)

[0132] [ka]

[0133] General Scheme B: Synthesis of Compounds of Formula (I)

[0134] [ka]

[0135] General Scheme C: Synthesis of Compounds of Formula (I)

[0136] [ka]

[0137] General Scheme D: Synthesis of Compounds of Formula (I)

[0138] [ka]

[0139] Use of the compound In one aspect, the compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), or pharmaceutically acceptable salts thereof, are capable of inhibiting the conversion of α-KG to D-2-HG.

[0140] In some embodiments, compounds of the present disclosure can inhibit the conversion of isocitrate to α-KG. In some embodiments, compounds of the present disclosure can inhibit both the conversion of α-KG to D-2-HG and the conversion of isocitrate to α-KG. In some embodiments, compounds of the present disclosure can selectively inhibit the conversion of α-KG to D-2-HG but not the conversion of isocitrate to α-KG.

[0141] In another aspect, compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie), or pharmaceutically acceptable salts thereof, can inhibit mutant IDH. In some embodiments, compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie), or pharmaceutically acceptable salts thereof, can inhibit wild-type IDH. In some embodiments, compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie), or pharmaceutically acceptable salts thereof, can inhibit both mutant IDH and wild-type IDH. In some embodiments, compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie), or pharmaceutically acceptable salts thereof, can selectively inhibit mutant IDH but not wild-type IDH.

[0142] In some embodiments, compounds of the disclosure inhibit wild-type IDH and / or mutant IDH with an IC of 0.01-1000 μM, 0.01-500 μM, 0.01-100 μM, 0.01-80 μM, 0.01-50 μM, 0.01-40 μM, 0.01-30 μM, or 0.01-20 μM, 0.01-10 μM, 0.01-5 μM, or 0.01-1 μM, 0.01-0.5 μM, 0.01-0.1 μM, or 0.01-0.05 μM. 50 Inhibit by value.

[0143] As used herein, the term "selectively inhibits mutant IDH" means that a provided compound inhibits mutant IDH over wild-type IDH in at least one assay described herein. In some embodiments, compounds of the present disclosure are at least 2-500 times more selective for mutant IDH than wild-type IDH. In some embodiments, compounds of the present disclosure are at least 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, or at least 500-fold more selective for mutant IDH than wild-type IDH.

[0144] Pharmaceutical Composition The present disclosure provides pharmaceutical compositions comprising at least one compound disclosed herein.In some embodiments, pharmaceutical compositions comprise more than one compound disclosed herein.In some embodiments, pharmaceutical compositions comprise one or more compounds disclosed herein and pharmaceutically acceptable carriers.

[0145] Pharmaceutically acceptable carriers are conventional pharmaceutical carriers in the art, and can be prepared by methods well known in the pharmaceutical field. In some embodiments, the compounds disclosed herein can be mixed with pharmaceutically acceptable carriers to prepare pharmaceutical compositions.

[0146] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals, without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio. In some embodiments, pharmaceutically acceptable compounds, materials, compositions, and / or dosage forms refer to those approved by a regulatory authority (e.g., the U.S. Food and Drug Administration, the China Food and Drug Administration, or the European Medicines Agency) or those listed in a generally recognized pharmacopoeia (e.g., the United States Pharmacopoeia, the Chinese Pharmacopoeia, or the European Pharmacopoeia) for use in animals, more particularly humans.

[0147] The term "pharmaceutically acceptable carrier," as used herein, refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in the transport or transfer of a compound provided herein from one site, body fluid, tissue, organ (internal or external), or part of the body to another site, body fluid, tissue, organ, or part of the body. A pharmaceutically acceptable carrier can be a vehicle, diluent, excipient, or other material that can be used to contact animal tissue without excessive toxicity or adverse effects. Representative pharmaceutically acceptable carriers include sugars, starches, cellulose, malt, tragacanth, gelatin, Ringer's solution, alginic acid, isotonic saline, buffers, and the like. Pharmaceutically acceptable carriers that can be employed in the present disclosure include those generally known in the art, such as those disclosed in "Remington Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), incorporated herein by reference.

[0148] Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as cellulose acetate, ... (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) alcohols, such as ethyl alcohol and propane alcohol; (20) phosphate buffer solution; and (21) other non-toxic, compatible substances employed in pharmaceutical formulations, such as acetone.

[0149] Pharmaceutical compositions may contain, as needed, pharmaceutically acceptable auxiliary substances to approximate appropriate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.

[0150] The form of the pharmaceutical composition will depend on a number of criteria, including but not limited to the route of administration, the extent of the disease, or the dose to be administered.

[0151] The pharmaceutical compositions can be formulated for oral, nasal, rectal, transdermal, intravenous or intramuscular administration. Depending on the desired route of administration, the pharmaceutical compositions can be formulated in the form of tablets, capsules, pills, dragees, powders, granules, sachets, packets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants or suppositories.

[0152] Pharmaceutical compositions can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by employing procedures known in the art. In some embodiments, pharmaceutical compositions are formulated in sustained-release form. As used herein, the term "sustained-release form" refers to the release of an active agent from a pharmaceutical composition so that it becomes available for bioabsorption in a subject, primarily in the subject's gastrointestinal tract, over an extended period of time (sustained release), or at a specific site (controlled release). In some embodiments, the extended period can be about 1 to 24 hours, 2 to 12 hours, 3 to 8 hours, 4 to 6 hours, 1 to 2 days, or more. In certain embodiments, the extended period is at least about 4 hours, at least about 8 hours, at least about 12 hours, or at least about 24 hours. Pharmaceutical compositions can be formulated in tablet form. For example, the release rate of an active agent can be controlled not only by dissolution of the active agent in gastrointestinal fluid and subsequent pH-independent diffusion from the tablet or pill, but also by the physical processes of tablet disintegration and erosion. In some embodiments, polymeric materials such as those disclosed in "Medical Applications of Controlled Release," Langer and Wise (eds.), CRC Press, Boca Raton, Florida (1974); "Controlled Drug Bioavailability," Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105 can be used for sustained release. The above references are incorporated herein by reference in their entireties.

[0153] In certain embodiments, the pharmaceutical composition contains from about 0.01 mg to about 1000 mg (e.g., from about 0.01 mg to about 10 mg, from about 0.1 mg to about 10 mg, from about 1 mg to about 10 mg, from about 5 mg to about 10 mg, from about 5 mg to about 20 mg, from about 5 mg to about 30 mg, from about 5 mg to about 40 mg, from about 5 mg to about 50 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 50 mg to about 200 mg, from about 50 mg to about 300 mg, The compound provided herein may be administered in a dose of 50 mg to about 400 mg, about 50 mg to about 500 mg, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, about 500 mg to about 1000 mg, about 600 mg to about 1000 mg, about 700 mg to about 1000 mg, about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg. A suitable daily dosage per subject may be about 5 mg to about 500 mg, preferably about 5 mg to about 50 mg, about 50 mg to about 100 mg, or about 50 mg to about 500 mg.

[0154] In certain embodiments, the pharmaceutical compositions can be formulated in unit dosage form, with each dosage being about 0.01 mg to about 10 mg, about 0.1 mg to about 10 mg, about 1 mg to about 10 mg, about 5 mg to about 10 mg, about 5 mg to about 20 mg, about 5 mg to about 30 mg, about 5 mg to about 40 mg, about 5 mg to about 50 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 50 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 300 mg, about The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical carrier.

[0155] In some embodiments, the pharmaceutical composition comprises one or more compounds disclosed herein as a first active ingredient and further comprises a second active ingredient, which can be any anti-cancer agent known in the art. Representative examples of anti-cancer agents for treating cancer or tumors include, but are not limited to, cell signaling inhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, and panitumumab, etc.), mitotic inhibitors (e.g., paclitaxel, vincristine, and vinblastine, etc.), alkylating agents (e.g., cisplatin, cyclophosphamide, chlorambucil, and carmustine, etc.), metabolite antagonists (e.g., methotrexate, 5-FU, etc.), intercalating anticancer agents (e.g., cyclophosphamide, chlorambucil, and carmustine, etc.), and the like. These include anti-cancer agents (e.g., actinomycin, anthracyclines, bleomycin, and mitomycin-C), topoisomerase inhibitors (e.g., irinotecan, topotecan, and teniposide), immunotherapeutic agents (e.g., interleukins and interferons), and antihormonal agents (e.g., tamoxifen and raloxifene). In some embodiments, the second active agent is one or more of ibrutinib, venetoclax, imatinib mesylate, nilotinib hydrochloride, bosutinib, dasatinib, etoposide, fludarabine phosphate, ponatinib, vincristine sulfate, methotrexate, cyclophosphamide, lomustine, teniposide, temozolomide, fotemustine, carmustine, bevacizumab, picibanil, fluorouracil, melphalan, gemcitabine hydrochloride.

[0156] Methods for Treatment The present disclosure provides a method of treating a disease associated with IDH, comprising administering to a subject an effective amount of one or more compounds or pharmaceutically acceptable salts or pharmaceutical compositions disclosed herein.

[0157] As used herein, the term "subject" refers to an organism, tissue, or cell. A subject can include a human subject for medical purposes, such as diagnosis and / or treatment of an existing condition or disease, or a preventative treatment to prevent the occurrence of a condition or disease, or an animal subject for medical, veterinary, or development purposes. A subject can also include sample materials from tissue culture, cell culture, organ replication, stem cell production, etc. Suitable animal subjects include mammals and birds. The term "mammal," as used herein, includes, but is not limited to, primates, such as humans, monkeys, apes, etc.; bovine, such as cattle, oxen, etc.; ovine, such as sheep, etc.; caprine, such as goats, etc.; porcine, such as pigs, hogs, etc.; equine, such as horses, donkeys, zebras, etc.; felines, including wildcats and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, etc.; and rodents, including mice, rats, etc. The term "avian," as used herein, includes, but is not limited to, chickens, ducks, geese, quail, turkeys, and pheasants. In some embodiments, the subject is a mammal or a mammalian cell. In some embodiments, the subject is a human or a human cell. Human subjects include, but are not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Furthermore, a "subject" can include a patient suffering from or suspected of suffering from a condition or disease. Thus, the terms "subject" and "patient" are used interchangeably herein. A subject can also refer to a cell or collection of cells in laboratory or bioprocessing culture, in testing for viability, differentiation, marker production, expression, etc.

[0158] As used herein, the term "effective amount" of an active agent or drug delivery device refers to the amount necessary to elicit a desired biological response. As will be appreciated by those skilled in the art, the effective amount of an agent or device may vary depending on factors such as the desired biological endpoint, the agent being delivered, the composition of the encapsulation matrix, the target tissue, etc.

[0159] In some embodiments, one or more compounds disclosed herein or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof are administered parenterally or non-parenterally. In some embodiments, one or more compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions are administered orally, enterally, bucally, nasally, intranasally, transmucosally, epidermally, transdermally, cutaneously, intraocularly, pulmonary, sublingually, rectally, intravaginally, topically, subcutaneously, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcuticularly, intraarticularly, subcapsularly, subarachnoidally, intraspinally, or intracisternally.

[0160] The compound disclosed herein can be administered in pure form, in combination with other active ingredients, or in the form of pharmaceutical compositions of the present disclosure.In some embodiments, the compound disclosed herein can be administered to a subject in need thereof in combination with one or more anticancer drugs known in the art, simultaneously or sequentially.In some embodiments, administration is carried out once a day, twice a day, three times a day, or once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0161] In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with the conversion of α-KG to D-2-HG. In certain embodiments, the present disclosure provides the use of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with mutant IDH.

[0162] In certain embodiments, the disease associated with the conversion of α-KG to D-2-HG is a disease associated with mutant IDH, including cancer.

[0163] In particular, cancers include, but are not limited to, leukemia, glioblastoma, melanoma, chondrosarcoma, cholangiocarcinoma, osteosarcoma, lymphoma, lung cancer, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, stomach cancer, colon cancer, colorectal cancer, ovarian cancer, cervical cancer, brain cancer, esophageal cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, prostate cancer, nasopharyngeal cancer, or oral cancer. In some embodiments, the cancer is leukemia, glioblastoma, or cholangiocarcinoma.

[0164] The compounds of this disclosure, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof can be used in the prevention or treatment of any of the occurrence or development of diseases or conditions associated with the conversion of α-KG to D-2-HG in mammals, particularly humans. In some embodiments, the compounds of this disclosure, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof can be used in the prevention or treatment of any of the occurrence or development of diseases or conditions associated with mutant IDH in mammals, particularly humans.

[0165] In such situations, the present disclosure also provides methods for screening patients suitable for treatment with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another component (e.g., a second active component, e.g., an anticancer agent). The method includes sequencing a tumor sample from the patient and detecting the accumulation of D-2-HG in the patient, or detecting the mutation status of IDH in the patient. [Example]

[0166] The following further describes the general method of the present disclosure. The compounds of the present disclosure can be prepared by methods known in the art. The following illustrates the detailed preparation methods of the preferred compounds of the present disclosure. However, these do not limit the preparation methods of the compounds of the present disclosure in any way.

[0167] Synthesis Examples The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) or / and mass spectrometry (ESI). The NMR shifts (δ) were -6 The units were obtained as (ppm). 1 H-NMR spectra were recorded in dimethylsulfoxide-d6 (DMSO-d6) or CDCl3 on a Varian Mercury VX 400 spectrometer using tetramethylsilane (TMS) as an internal standard.

[0168] ESI-HRMS measurements were performed using a 1260-6230 TOF LC-MS mass spectrometer.

[0169] High performance liquid chromatography (HPLC) measurements were performed on an Agilent 1200 LC using a Phenomen C18 column (4.6 mm x 150 mm, 0.4 μm).

[0170] Thin-layer chromatography was performed using Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) were 0.15 mm to 0.2 mm. The silica gel plates used for separation and purification of the products by TLC were 0.4 mm to 0.5 mm.

[0171] The purification chromatography column uses silica gel as the carrier (200-300 mesh, manufactured by Yantai Huanghai Co.).

[0172] Known starting materials of the present disclosure can be synthesized by using or according to methods known in the art or can be purchased from Alfa Aesar, Langcaster, TCI, Aldrich, Bepharm and Scochem.

[0173] Unless otherwise specified, all reactions in the examples were carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of approximately 1 L. Hydrogenations were typically carried out under vacuum, filled with hydrogen, and repeated three times. Unless otherwise specified, reaction temperatures in the examples were ambient, ranging from 20°C to 30°C.

[0174] The progress of the reaction in the examples was monitored by TLC.The eluent system used in the reaction includes dichloromethane-methanol system and petroleum ether-ethyl acetate system.The volume ratio of the solvent was adjusted according to the different polarity of the compound.

[0175] The elution systems of column chromatography and TLC used for compound purification include dichloromethane-methanol and petroleum ether-ethyl acetate.The volume ratio of solvents is adjusted according to the different polarity of compounds.A small amount of alkaline or acidic agent, such as triethylamine and acetic acid, can be added for adjustment.

[0176] Abbreviations used in the following examples and elsewhere in this document are as follows:

[0177] [Table 2] JPEG0007776418000055.jpg220127 [Example]

[0178] 2-Ethyl-4-[[(1S)-1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethyl]amino]-3H-pyrrolo[3,4-c]pyridin-1-one (1)

[0179] This compound was prepared according to general scheme A. Specifically, the scheme is listed as follows:

[0180] Scheme 1:

[0181] [ka]

[0182] Step 1. 1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethanone (1b)

[0183] [ka] To a mixture of 1-methylindazol-5-ol (1a, 1 g, 6.75 mmol), 1-(3,4-difluorophenyl)ethanone (1.16 g, 7.42 mmol), and 18-crown-6 (178 mg, 0.67 mmol) in DMSO (20 mL) was added KCO (1.87 g, 13.5 mmol). The mixture was then stirred at 120 °C under N for 1 h. The mixture was poured into water (150 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was suspended in petroleum ether (60 mL) and stirred for 30 min. An off-white solid was formed. The solid was filtered, collected and dried in vacuo to give 1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethanone (1b, 1.7 g, 88.6% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.95 (s, 1H), 7.81 (dd, J = 2.0, 11.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 2.4, 8.8 Hz, 1H), 6.88 (t, J = 8.4 Hz, 1H), 4.12 (s, 3H), 2.58 (s, 3H). LC-MS: (ESI) m / z: 284.9 [M+H].

[0184] Step 2. N-[1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (1c)

[0185] [ka]

[0186] To a mixture of 1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethanone (1b, 1.7 g, 5.98 mmol) and (S)-2-methylpropane-2-sulfinamide (1.09 g, 8.97 mmol) in dry THF (30 mL) was added Ti(OEt) (2.73 g, 11.96 mmol). The mixture was then stirred at 70 °C under N for 16 h. The mixture was poured into a mixture of water (100 mL) and EtOAc (100 mL) under stirring. After stirring for 15 min, the mixture was filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, and filtered. The filtrate is concentrated and dried in vacuo to give N-[1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (1c, 2.3 g, 81.9% yield) as a brown oil, which is used directly for the next step. LC-MS: (ESI) m / z: 387.8 [M+H].

[0187] Step 3. (S)-N-((S)-1-(3-fluoro-4-((1-methyl-1H-indazol-5-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1d)

[0188] [ka]

[0189] To a solution of N-[1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (1c, 2.3 g, 5.94 mmol) in THF (40 mL) and HO (0.8 mL) was added NaBH (674 mg, 17.81 mmol) portionwise at −50° C. After stirring the mixture at −50° C. for 2 h, the mixture was warmed to 25° C. and stirred for 1 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by silica gel flash chromatography (petroleum ether / EtOAc = 1:1 (v / v)) to give (S)-N-((S)-1-(3-fluoro-4-((1-methyl-1H-indazol-5-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1d, 2.0 g, 82% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.90 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.20-7.18 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.96-6.90 (m, 1H), 4.53 (q, J = 6.4 Hz, 1H), 4.09 (s, 3H), 3.42 (br s, 1H), 1.52 (d, J = 6.4 Hz, 3H), 1.25 (s, 9H). LC-MS: (ESI) m / z: 389.9 [M+H].

[0190] Step 4. (1S)-1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethanamine (1e)

[0191] [ka]

[0192] To a mixture of (S)—N—((S)-1-(3-fluoro-4-((1-methyl-1H-indazol-5-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1d, 2.0 g, 5.13 mmol) in MeOH (20 mL) was added HCl / dioxane (4 M, 5 mL) dropwise. The mixture was then stirred at 25° C. for 2 h. The mixture was poured into water (100 mL) and basified to pH=9 with solid NaCO. The mixture was then extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and dried over NaSO. It is then filtered, concentrated, and dried in vacuo to give (1S)-1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethanamine (1e, 1.5 g, crude) as a brown oil, which is used directly for the next step. LC-MS: (ESI) m / z: 286.8 [M+H].

[0193] Step 5. 2-Fluoropyridine-4-carbonyl chloride (A-1b)

[0194] [ka]

[0195] To a solution of 2-fluoropyridine-4-carboxylic acid (A-1a, 10 g, 70.87 mmol) in SOCl (39 mL, 537.6 mmol), DMF (0.6 mL, 7.8 mmol) was added dropwise. The mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated and co-evaporated with DCM (2 × 100 mL) to give a yellow oil as 2-fluoropyridine-4-carbonyl chloride (A-1b, 13 g, 98.8% yield, 86% purity), which was used in the next step without purification.

[0196] Step 6. N-Ethyl-2-fluoro-pyridine-4-carboxamide (A-1c)

[0197] [ka]

[0198] To a solution of ethanamine (6.9 g, 84.09 mmol, HCl salt) and KCO (33.9 g, 245.3 mmol) in THF (150 mL) and HO (75 mL) was added 2-fluoropyridine-4-carbonyl chloride (A-1b, 13 g, 70.07 mmol, 86% purity) at 0-4 °C. The mixture was stirred at 0-4 °C for 2 h. The mixture was diluted with water (75 mL) and allowed to stand for 2 min. The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (75 mL), dried over NaSO, filtered, and concentrated to give a brown oil. The residue was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash column, elution with a 0–40% ethyl acetate / petroleum ether gradient at 80 mL / min) to afford N-ethyl-2-fluoro-pyridine-4-carboxamide (A-1c, 6.6 g, 56.2% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ: 8.31 (d, J = 5.2 Hz, 1H), 7.51-7.48 (m, 1H), 7.30-7.27 (m, 1H), 6.50 (br s, 1H), 3.55-3.45 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0199] Step 7. 2-Ethyl-4-fluoro-3-hydroxy-3H-pyrrolo[3,4-c]pyridin-1-one (A-1d)

[0200] [ka]

[0201] To a solution of N-ethyl-2-fluoro-pyridine-4-carboxamide (A-1c, 6.6 g, 39.42 mmol) in THF (200 mL) was added LDA (2 M in THF, 45 mL) dropwise at −65° C. under N2. The mixture was stirred at −65° C. for 30 min. DMF (16 mL, 208 mmol) was then added. The mixture was stirred at −65° C. for an additional 1 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and diluted with water (70 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (75 mL), dried over NaSO, filtered, and concentrated to give 2-ethyl-4-fluoro-3-hydroxy-3H-pyrrolo[3,4-c]pyridin-1-one (A-1d, 9.3 g, 98.9% yield, 82% purity) as a yellow solid, which was used in the next step without purification. 1 H NMR (400 MHz, CDCl3) δ: 8.37-8.35 (m, 1H), 7.52 (dd, J = 2.4, 4.8 Hz, 1H), 6.05 (s, 1H), 4.34 (br s, 1H), 3.82-3.74 (m, 1H), 3.54-3.46 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H).

[0202] Step 8. 2-Ethyl-4-fluoro-3H-pyrrolo[3,4-c]pyridin-1-one (A-1)

[0203] [ka]

[0204] To a solution of 2-ethyl-4-fluoro-3-hydroxy-3H-pyrrolo[3,4-c]pyridin-1-one (A-1d, 9.3 g, 39 mmol, 82% purity) in TFA (30 mL) and DCM (80 mL) was added EtSiH (16 mL, 100.17 mmol) at 0 °C. The solution was then stirred at 25 °C for 16 h. The mixture was slowly added to a stirred saturated NaHCO solution (800 mL) and then extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated to give a yellow oil. The residue was purified by flash silica gel chromatography (ISCO; 80 g SepaFlash Silica Flash column, elution with a 0–40% ethyl acetate / petroleum ether gradient at 60 mL / min) to give 2-ethyl-4-fluoro-3H-pyrrolo[3,4-c]pyridin-1-one (A-1, 6.3 g, 90.8% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 8.38-8.34 (m, 1H), 7.64 (dd, J = 2.8, 4.8 Hz, 1H), 4.49 (s, 2H), 3.72 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0205] Step 9. 2-Ethyl-4-[[(1S)-1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethyl]amino]-3H-pyrrolo[3,4-c]pyridin-1-one (1)

[0206] [ka]

[0207] A mixture of crude (1S)-1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethanamine (1e, 300 mg, 1.05 mmol), 2-ethyl-4-fluoro-3H-pyrrolo[3,4-c]pyridin-1-one (A-1, 758 mg, 4.21 mmol) and DIPEA (544 mg, 4.21 mmol) in NMP (4 mL) was stirred at 180 °C under N for 8 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered and concentrated to give a residue. The residue was purified by silica gel flash chromatography (EtOAc) to give crude 2-ethyl-4-[[(1S)-1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethyl]amino]-3H-pyrrolo[3,4-c]pyridin-1-one as a colorless gum, which was further purified by prep. HPLC (column: DuraShell 150 × 25 mm × 5 μm; mobile phase: water (0.05% HCl v / v)-ACN; B phase %: 22%-52%; flow rate: 25 mL / min) to give 2-ethyl-4-[[(1S)-1-[3-fluoro-4-(1-methylindazol-5-yl)oxy-phenyl]ethyl]amino]-3H-pyrrolo[3,4-c]pyridin-1-one (1, 122.0 mg, 23.7% yield, HCl salt) as a blue solid. 1 H NMR (400 MHz, CD3OD) δ: 7.98-7.91 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 2.0, 11.6 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.24-7.19 (m, 3H), 7.03 (t, J = 8.4 Hz, 1H), 5.15 (q, J = 6.4 Hz, 1H), 4.75-4.57 (m, 2H), 4.07 (s, 3H), 3.72 (q, J = 7.2 Hz, 2H), 1.74 (d, J = 6.4 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H). LC-MS: (ESI) m / z: 446.1 [M+H].

[0208] Synthesis of compounds 2-64 Generally, compounds 2-64 in Table 1 were prepared according to the procedure described in General Scheme A. The synthetic method was similar to Example 1. Data for compounds 2-64 are shown in Table 1 herein below.

[0209] [Table 3] JPEG0007776418000067.jpg204143JPEG0007776418000068.jpg204142JPEG0007776418000069.jpg205143JPEG00077764180 00070.jpg194142JPEG0007776418000071.jpg204143JPEG0007776418000072.jpg199143JPEG0007776418000073.jpg204141 JPEG0007776418000074.jpg199142JPEG0007776418000075.jpg200142JPEG0007776418000076.jpg199142JPEG00077764180 00077.jpg199142JPEG0007776418000078.jpg205143JPEG0007776418000079.jpg205143JPEG0007776418000080.jpg229142 [Example]

[0210] 2-Ethyl-4-[[(1S)-1-[3-fluoro-4-[[2-(trifluoromethyl)-4-pyridyl]oxy]phenyl]ethyl]amino]-3H-pyrrolo[3,4-c]pyridin-1-one (65)

[0211] Scheme 2:

[0212] [ka]

[0213] Step 1. Ethyl 6-hydroxy-5-methyl-pyrimidine-4-carboxylate (2)

[0214] [ka]

[0215] To a mixture of diethyl 2-methyl-3-oxobutanedioate (1, 30 g, 148.4 mmol) in EtOH (350 mL) was added EtONa (16.15 g, 237.4 mmol) and acetic acid formimidamide (21.6 g, 207.7 mmol) at 20 °C. The mixture was then stirred at 90 °C under N for 16 h. 2N HCl was added to the mixture to adjust the pH to 7, and then water (200 mL) was added to the mixture and extracted with EtOAc (3 × 200 mL). The organic layer was collected, washed with brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo to give the residue as a brown oil. The residue was purified by silica gel column chromatography eluting with (petroleum ether: EtOAc = 1:3) to give ethyl 6-hydroxy-5-methyl-pyrimidine-4-carboxylate (2, 6.0 g, 19.5% yield) as a yellow solid. 1 H NMR (400 MHz, CD3OD) δ: 8.09 (s, 1H), 4.40 (q, J = 7.2 Hz, 2H), 2.20 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H). LC-MS: (ESI) m / z: 182.9 [M+H].

[0216] Step 2. Ethyl 6-chloro-5-methyl-pyrimidine-4-carboxylate (3)

[0217] [ka]

[0218] To a solution of ethyl 6-hydroxy-5-methyl-pyrimidine-4-carboxylate (2, 1.0 g, 5.49 mmol) in EtOAc (50 mL) was slowly added oxalyl dichloride (1.44 mL, 16.47 mmol), followed by DMF (84 μL, 1.1 mmol). The mixture was then stirred at 80° C. under N for 2 hours. The mixture was cooled, ice water (50 mL) was added, and extracted with EtOAc (3×60 mL). The organic layer was collected, washed with brine (60 mL), dried over NaSO, filtered, and concentrated in vacuo to give the residue as a brown oil. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 4:1 (v / v)) to give ethyl 6-chloro-5-methyl-pyrimidine-4-carboxylate (3, 0.73 g, 61.2% yield) as a yellow oil. 1 H NMR (400 MHz, CD3OD) δ: 8.85 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H). LC-MS: (ESI) m / z: 200.8 [M+H].

[0219] Step 3: Ethyl 5-(bromomethyl)-6-chloro-pyrimidine-4-carboxylate (4)

[0220] [ka]

[0221] To a mixture of ethyl 6-chloro-5-methyl-pyrimidine-4-carboxylate (3, 0.73 g, 3.64 mmol), AIBN (60 mg, 0.36 mmol), and NBS (1.62 g, 9.10 mmol), 1,2-dichloroethane (30 mL) was dissolved, and the mixture was stirred at 100° C. for 12 hours under N. Water (50 mL) was added to the mixture, which was then extracted with EtOAc (3×50 mL). The organic layer was collected, washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give ethyl 5-(bromomethyl)-6-chloro-pyrimidine-4-carboxylate (4, 1.23 g, crude) as a brown oil. 1 H NMR (400 MHz, CD3OD) δ: 8.99 (s, 1H), 4.54-4.48 (m, 2H), 2.69 (s, 2H), 1.46-1.42 (m, 3H). LC-MS: (ESI) m / z: 278.9 [M+H].

[0222] Step 4: 4-Chloro-6-ethyl-5H-pyrrolo[3,4-d]pyrimidin-7-one (5)

[0223] [ka]

[0224] To a solution of ethyl 5-(bromomethyl)-6-chloro-pyrimidine-4-carboxylate (4, 1.18 g, 4.22 mmol), ethanamine hydrochloride (1.03 g, 12.66 mmol) in MeCN (40 mL) was added KCO (1.17 g, 8.44 mmol), and the mixture was stirred at 25 °C for 6 h under N. Water (50 mL) was added to the mixture, which was then extracted with EtOAc (3 × 50 mL). The organic layer was collected, washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give the residue as a brown oil. The residue was purified by silica gel flash chromatography (petroleum ether / EtOAc = 1:1) to give 4-chloro-6-ethyl-5H-pyrrolo[3,4-d]pyrimidin-7-one (5, 0.31 g, 29.7% yield) as a brown solid. 1 H NMR (400 MHz, CD3OD) δ: 9.15 (s, 1H), 4.66 (s, 2H), 3.75 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). LC-MS: (ESI) m / z: 197.9 [M+H].

[0225] Step 5: 6-Ethyl-4-[[(1S)-1-[3-fluoro-4-(4-methylphenoxy)phenyl]ethyl]amino]-5H-pyrrolo[3,4-d]pyrimidin-7-one (65)

[0226] [ka]

[0227] To a mixture of 4-chloro-6-ethyl-5H-pyrrolo[3,4-d]pyrimidin-7-one (5, 0.08 g, 0.4 mmol) and (1S)-1-[3-fluoro-4-(4-methylphenoxy)phenyl]ethanamine (129 mg, 0.53 mmol) in dioxane (4 mL) was added DIPEA (262 mg, 2.02 mmol), and the resulting mixture was stirred at 80 °C for 4 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine (20 mL), dried over Na SO , filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (column: DuraShell 150 × 25 mm × 5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 41%–61%, 10 min) to give 6-ethyl-4-[[(1S)-1-[3-fluoro-4-(4-methylphenoxy)phenyl]ethyl]amino]-5H-pyrrolo[3,4-d]pyrimidin-7-one (65, 30.3 mg, 18.2% yield) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ: 8.78 (s, 1H), 7.35 (dd, J = 2.0, 11.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.01 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 5.68 (q, J = 7.2 Hz, 1H), 4.56 (s, 2H), 3.70 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 1.69 (d, J = 6.8 Hz, 3H), 1.31 (t, J = 7.6 Hz, 3H). LC-MS: (ESI) m / z: 407.2 [M+H].

[0228] Synthesis of compounds 66 and 67 Generally, compounds 66 and 67 in Table 2 were prepared according to the procedure described in General Scheme B. The synthetic method was similar to Example 2. Data for compounds 66 and 67 are shown in Table 2 herein below.

[0229] [Table 4] [Example]

[0230] 2-Ethyl-4-[[(1S)-1-[3-fluoro-4-[4-(trifluoromethyl)phenyl]phenyl]ethyl]amino]-3H-pyrrolo[3,4-c]pyridin-1-one (68)

[0231] This compound was prepared according to general scheme C. Specifically, the scheme is listed as follows:

[0232] [ka]

[0233] Step 1. 4-Bromo-3-fluoro-N-methoxy-N-methyl-benzamide (C-1b)

[0234] [ka]

[0235] To a mixture of 4-bromo-3-fluorobenzoic acid (C-1a, 150 g, 0.68 mol) in DCM (1 L) and DMF (3 mL, 0.039 mol), (COCl) (66 mL, 0.75 mol) was slowly added dropwise at 0 °C. The reaction was stirred at 25–30 °C for 12 h. The mixture was cooled to 0–5 °C, and then N-methoxymethanamine hydrochloride (100 g, 1.03 mol) was added, followed by the slow addition of TEA (400 mL, 2.87 mol). The reaction was stirred at 25–30 °C for an additional 2 h. The mixture was filtered, and the filter cake was washed with DCM (2 × 200 mL). The mixture was diluted with water (800 mL) and extracted with DCM (3 × 300 mL). The combined organic layers were washed with 1.0 M HCl solution (2 × 500 mL), brine (500 mL), dried over NaSO, filtered, and concentrated. The resulting oil was cooled in a dry ice / EtOH bath until a solid formed. The mixture was diluted with petroleum ether (100 mL) and then filtered. The filter cake was collected and dried to give 4-bromo-3-fluoro-N-methoxy-N-methyl-benzamide (C-1b, 170 g, 94.7% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.60 (dd, J = 6.8, 8.4 Hz, 1H), 7.50 (dd, J = 2.0, 8.8 Hz, 1H), 7.41 (dd, J = 1.6, 8.4 Hz, 1H), 3.55 (s, 3H), 3.36 (s, 3H). LC-MS: (ESI) m / z: 261.9 / 263.9 [M+H].

[0236] Step 2. 1-(4-Bromo-3-fluoro-phenyl)ethanone (C-1c)

[0237] [ka]

[0238] To a solution of 4-bromo-3-fluoro-N-methoxy-N-methyl-benzamide (C-1b, 170 g, 0.65 mol) in THF (1.5 L) was added MeMgBr (3 M in ether, 325 mL) at 0-5 °C under nitrogen. The reaction was stirred at 0-5 °C for 3 h. The mixture was quenched with saturated NH4Cl solution (1 L) at 0-10 °C, and the mixture was extracted with EtOAc (3 × 600 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated. The resulting oil was cooled in a dry ice-EtOH bath until a solid formed. The mixture was diluted with petroleum ether (100 mL) and then filtered. The solid was collected and dried to give 1-(4-bromo-3-fluoro-phenyl)ethanone (C-1c, 121 g, 85.9% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.72-7.64 (m, 2H), 7.61 (dd, J = 2.0, 8.4 Hz, 1H), 2.59 (s, 3H).

[0239] Step 3. (S)-N-[1-(4-bromo-3-fluoro-phenyl)ethylidene]-2-methyl-propane-2-sulfinamide (C-1d)

[0240] [ka]

[0241] A mixture of 1-(4-bromo-3-fluorophenyl)ethanone (C-1c, 121 g, 0.56 mol), 2-methylpropane-2-sulfinamide (81 g, 0.67 mol), and Ti(OEt)4 (255 g, 1.12 mol) in THF (1 L) was stirred at 80 °C for 8 h. The mixture was poured into water (1 L) and then diluted with EtOAc (600 mL). The mixture was filtered, and the filter cake was washed with EtOAc (2 × 600 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 600 mL). The combined organic layers were washed with brine (800 mL), dried over NaSO, filtered, and concentrated to give (S)—N-[1-(4-bromo-3-fluoro-phenyl)ethylidene]-2-methyl-propane-2-sulfinamide (C-1d, 170 g, 95.2% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ: 7.68-7.59 (m, 2H), 7.53 (dd, J = 1.6, 8.4 Hz, 1H), 2.75 (s, 3H), 1.33 (s, 9H).

[0242] Step 4. N-[(1S)-1-(4-bromo-3-fluoro-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (C-1e)

[0243] [ka]

[0244] To a mixture of (S)-N-[1-(4-bromo-3-fluoro-phenyl)ethylidene]-2-methyl-propane-2-sulfinamide (C-1d, 160 g, 0.5 mol) in THF (1 L) and water (20 mL) was added NaBH (56.7 g, 1.50 mol) portionwise at -60 to -40 °C. The reaction was stirred at -60 to -40 °C for 3 h. The mixture was poured into saturated NH Cl solution (2 L), and the mixture was extracted with EtOAc (3 × 800 mL). The combined organic layers were washed with brine (800 mL), dried over Na SO , filtered, and concentrated. The resulting oil was dissolved in petroleum ether (300 mL) and allowed to stand at 15–20 °C for 12 h. The white precipitate was collected, washed with petroleum ether (2 × 50 mL), and dried to give the desired product (66 g) as a white solid. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3:1) to give the pure product (103 g) as a white solid: N-[(1S)-1-(4-bromo-3-fluorophenyl)ethyl]-2-methyl-propane-2-sulfinamide (C-1e, 103 g, 64% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.52 (dd, J = 7.2, 8.0 Hz, 1H), 7.14 (dd, J = 2.0, 9.2 Hz, 1H), 7.04 (dd, J = 2.0, 8.4 Hz, 1H), 4.55-4.48 (m, 1H), 3.41 (d, J = 2.4 Hz, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.24 (s, 9H). LC-MS: (ESI) m / z: 323.7 [M+H].

[0245] Step 5. (1S)-1-(4-bromo-3-fluoro-phenyl)ethanamine (C-1f)

[0246] [ka]

[0247] To a solution of N-[(1S)-1-(4-bromo-3-fluoro-phenyl)ethyl]-2-methyl-propane-2-sulfinamide (C-1e, 50 g, 155.17 mmol) in MeOH (250 mL) was added HCl / dioxane (4 M, 80 mL) at 20-25 °C, and the reaction was stirred for 2 h. The solvent was concentrated in vacuo, and the residue was diluted with water (300 mL). The mixture was extracted with EtOAc (3 × 150 mL). The organic layer was discarded. The aqueous layer was adjusted to pH = 7-8 with saturated NaHCO3 solution. The mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give (1S)-1-(4-bromo-3-fluoro-phenyl)ethanamine (C-1f, 30.1 g, 89% yield) as a colorless gum. 1 H NMR (400 MHz, CDCl3) δ: 7.48 (dd, J = 7.2, 8.0 Hz, 1H), 7.16 (dd, J = 2.0, 10.0 Hz, 1H), 7.02 (dd, J = 2.0, 8.0 Hz, 1H), 4.11 (q, J = 6.4 Hz, 1H), 1.36 (d, J = 6.8 Hz, 3H). LC-MS: (ESI) m / z: 200.7 / 202.7 [M+H].

[0248] Step 6. 4-[[(1S)-1-(4-bromo-3-fluoro-phenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (C-1)

[0249] [ka]

[0250] A mixture of (1S)-1-(4-bromo-3-fluoro-phenyl)ethanamine (C-1f, 20 g, 91.72 mmol), 2-ethyl-4-fluoro-3H-pyrrolo[3,4-c]pyridin-1-one (A-1, 50 g, 277.5 mmol) and DIPEA (48 mL, 275.58 mmol) in NMP (100 mL) was stirred at 170 °C for 6 h. The mixture was poured into water (800 mL) and then extracted with EtOAc (5 × 300 mL). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 3 / 1 to 1:1) to give 4-[[(1S)-1-(4-bromo-3-fluoro-phenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (C-1, 25 g, 72.1% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ: 8.20 (d, J = 5.2 Hz, 1H), 7.48 (dd, J = 7.2, 8.4 Hz, 1H), 7.17 (dd, J = 2.0, 9.6 Hz, 1H), 7.08 (dd, J = 2.0, 8.0 Hz, 1H), 7.06 (d, J = 4.8 Hz, 1H), 5.36 (quintet, J = 6.8 Hz, 1H), 4.41 (d, J = 6.8 Hz, 1H), 4.30-4.20 (m, 2H), 3.68 (q, J = 7.2 Hz, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H). LC-MS: (ESI) m / z: 377.8 / 379.8 [M+H].

[0251] Step 7. 4-[[(1S)-1-[4-(cyclopenten-1-yl)-3-fluoro-phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (35a)

[0252] [ka]

[0253] A mixture of 4-[[(1S)-1-(4-bromo-3-fluoro-phenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (C-1, 100 mg, 0.26 mmol), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (51 mg, 0.26 mmol), Pd(dppf)Cl.CHCl (22 mg, 0.026 mmol), and DIPEA (92 μL, 0.53 mmol) in 1,4-dioxane (1 mL) and HO (1 mL) was stirred at 85 °C for 2 h under N. The reaction mixture was added to HO (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phase was dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1 (v / v)) to give 4-[[(1S)-1-[4-(cyclopenten-1-yl)-3-fluoro-phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (35a, 50 mg, 51.6% yield) as a yellow oil. LC-MS: (ESI) m / z: 366.1 [M+H].

[0254] Step 8. 4-[[(1S)-1-(4-cyclopentyl-3-fluoro-phenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (35)

[0255] [ka]

[0256] A mixture of 4-[[(1S)-1-[4-(cyclopenten-1-yl)-3-fluoro-phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (35a, 50 mg, 0.14 mmol) and Pd / C (5 mg, 10 wt%) in MeOH (10 mL) was stirred at 25 °C for 20 min under a H atmosphere (15 psi). The reaction mixture was filtered to obtain a filtrate. The solvent was then removed under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 65%-85%, 9 min) to give 4-[[(1S)-1-(4-cyclopentyl-3-fluoro-phenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (35, 26.1 mg, 51.9% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 8.24 (d, J = 5.2 Hz, 1H), 7.24-7.19 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.08-7.02 (m, 2H), 5.38 (q, J = 6.8 Hz, 1H), 4.37 (d, J = 7.2 Hz, 1H), 4.28-4.16 (m, 2H), 3.67 (q, J = 7.2 Hz, 2H), 3.21 (q, J = 8.2 Hz, 1H), 2.10-1.99 (m, 2H), 1.86-1.76 (m, J = 5.2 Hz, 2H), 1.71-1.64 (m, 4H), 1.59 (d, J = 6.8 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). LC-MS: (ESI) m / z: 368.2 [M+H]. [Example]

[0257] 2-[4-[4-[(1S)-1-[(2-ethyl-1-oxo-3H-pyrrolo[3,4-c]pyridin-4-yl)amino]ethyl]-2-fluoro-phenyl]-2-pyridyl]-2-methyl-propanenitrile (69)

[0258] This compound was prepared according to general scheme C. Specifically, the scheme is listed as follows:

[0259] Scheme 4:

[0260] [ka]

[0261] Step 1. 4-[[(1S)-1-(4-bromo-3-fluoro-phenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (C-2)

[0262] [ka]

[0263] To a mixture of 4-[[(1S)-1-(4-bromo-3-fluorophenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (C-1, 0.05 g, 0.13 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (134 mg, 0.53 mol) in DMSO (2 mL), KOAc (26 mg, 0.26 mmol) was added at 20 °C. The mixture was purged with N three times, and Pd(dppf)Cl.CHCl (10.8 mg, 0.013 mmol) was added. The mixture was then purged with N three times again and stirred at 100 °C for 2 h under N. The reaction mixture (combined with another batch of 50 mg C-1 in dioxane and another batch of 50 mg C-1 in DMF) was added with water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was collected, washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give the residue as a brown oil. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 1:1) to give 2-ethyl-4-[[(1S)-1-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]amino]-3H-pyrrolo[3,4-c]pyridin-1-one (C-2, 0.1 g, 59.3% yield) as a brown gum. 1 H NMR (400 MHz, CDCl3) δ: 8.18 (d, J = 5.2 Hz, 1H), 7.71 (dd, J = 6.8, 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.09-7.04 (m, 2H), 5.35 (t, J = LC-MS: (ESI) m / z: 426.2 [M+H].

[0264] Step 2. 2-(4-Iodo-2-pyridyl)-2-methyl-propanamide (62a)

[0265] [ka]

[0266] A mixture of 2-(4-iodo-2-pyridyl)-2-methyl-propanenitrile (61b, 150 mg, 0.55 mmol) in concentrated H2SO4 (2 mL) was stirred at 20-25 °C for 12 h. The mixture was poured into water (20 mL) and adjusted to pH = 8 with saturated NaHCO3 solution. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give 2-(4-iodo-2-pyridyl)-2-methyl-propanamide (62a, 145 mg, 90.7% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 8.25 (d, J = 5.6 Hz, 1H), 7.80 (dd, J = 0.4, 1.6 Hz, 1H), 7.59 (dd, J = 1.6, 5.2 Hz, 1H), 6.62 (br s, 1H), 5.32 (br s, 1H), 1.64 (s, 6H). LC-MS: (ESI) m / z: 290.7 [M+Na].

[0267] Step 3. 2-[4-[4-[(1S)-1-[(2-ethyl-1-oxo-3H-pyrrolo[3,4-c]pyridin-4-yl)amino]ethyl]-2-fluoro-phenyl]-2-pyridyl]-2-methyl-propanamide (69)

[0268] [ka] To a mixture of 2-(4-iodo-2-pyridyl)-2-methyl-propanamide (62a, 60 mg, 0.21 mmol), 2-ethyl-4-[[(1S)-1-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]amino]-3H-pyrrolo[3,4-c]pyridin-1-one (C-2, 100 mg, 0.24 mmol), and NaCO (44 mg, 0.42 mmol) in dioxane (2 mL) and water (0.5 mL), Pd(dppf)Cl.CHCl (9 mg, 0.011 mmol) was added under nitrogen. The reaction was stirred at 90-100 °C for 2 h. The mixture was diluted with EtOAc (20 mL) and filtered through Celite. The filtrate was evaporated, and the residue was purified by prep-HPLC (column: DuraShell 150 × 25 mm × 5 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 14%–54%, 10 min) to give 2-[4-[4-[(1S)-1-[(2-ethyl-1-oxo-3H-pyrrolo[3,4-c]pyridin-4-yl)amino]ethyl]-2-fluoro-phenyl]-2-pyridyl]-2-methyl-propanamide (69, 47.2 mg, 49.5% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.64 (d, J = 5.2 Hz, 1H), 8.22 (d, J = 4.8 Hz, 1H), 7.56 (s, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.38-7.34 (m, 1H), 7.30 (dd, J = 1.6, 8.0 Hz, 1H), 7.23 (dd, J = 1.6, 12.0 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.82 (br s, 1H), 5.45 (quintet, J = 7.2 Hz, 1H), 5.29 (br s, 1H), 4.44 (d, J = LC-MS: (ESI) m / z 462.1 [M+H].

[0269] Synthesis of compounds 70-165 Generally, compounds 70-165 in Table 3 were prepared according to general Scheme C. The synthetic methods were similar to those in Example 3 or Example 4. Data for compounds 70-139 and 141-165 are shown in Table 3 below.

[0270] [Table 5] JPEG0007776418000102.jpg230146JPEG0007776418000103.jpg230146JPEG0007776418000104.jpg224147JPEG0007776 418000105.jpg229151JPEG0007776418000106.jpg230148JPEG0007776418000107.jpg232148JPEG0007776418000108.j pg228149JPEG0007776418000109.jpg225153JPEG0007776418000110.jpg218152JPEG0007776418000111.jpg234149JPE G0007776418000112.jpg235150JPEG0007776418000113.jpg221150JPEG0007776418000114.jpg233148JPEG00077764180 00115.jpg217151JPEG0007776418000116.jpg222145JPEG0007776418000117.jpg233148JPEG0007776418000118.jpg22 9147JPEG0007776418000119.jpg231147JPEG0007776418000120.jpg222150JPEG0007776418000121.jpg231148JPEG000 7776418000122.jpg232147JPEG0007776418000123.jpg218146JPEG0007776418000124.jpg229146JPEG00077764180001 25.jpg227149JPEG0007776418000126.jpg234149JPEG0007776418000127.jpg214149JPEG0007776418000128.jpg189143 [Example]

[0271] 3-[2-[[(1S)-1-(3-fluoro-4-phenoxy-phenyl)ethyl]amino]-4-pyridyl]benzonitrile (166)

[0272] This compound was prepared according to general scheme D. Specifically, the scheme is listed as follows:

[0273] Scheme 4:

[0274] [ka]

[0275] Step 1. 3-(2-fluoropyridin-4-yl)benzonitrile (166b)

[0276] [ka]

[0277] To a solution of 2-fluoro-4-iodopyridine (166a, 1.2 g, 5.38 mmol) in 1,2-dimethoxyethane (20 mL) under nitrogen was added (3-cyanophenyl)boronic acid (166a, 0.87 g, 5.92 mmol), Pd(PPh3)4 (186 mg, 0.16 mmol), and aqueous Na2CO3 solution (2 mol / L, 6 mL). The reaction mixture was heated at 80 °C for 12 h. The reaction mixture was diluted with ethyl acetate (100 mL) and water (30 mL). The separated aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was diluted with ethyl acetate (10 mL) and stirred for 30 min. The solid was isolated by filtration and dried to give 3-(2-fluoropyridin-4-yl)benzonitrile (166b, 0.69 g, 64.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.41 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.23 ​​(d, J = 8.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.82-7.73 (m, 2 H), 7.68 (s, 1 H). LC-MS: (ESI) m / z: 199.1 [M+H].

[0278] Step 2. 3-[2-[[(1S)-1-(3-fluoro-4-phenoxy-phenyl)ethyl]amino]-4-pyridyl]benzonitrile (166)

[0279] [ka]

[0280] (S)-1-(3-fluoro-4-phenoxyphenyl)ethanamine hydrochloride (166b1, 200 mg, 0.72 mmol) was added to saturated NaHCO3 solution (10 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was then extracted three times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the free base (S)-1-(3-fluoro-4-phenoxyphenyl)ethanamine, which was used in the next step. The above free base (S)-1-(3-fluoro-4-phenoxyphenyl)ethanamine and 3-(2-fluoropyridin-4-yl)benzonitrile (166b, 24 mg, 0.12 mmol) were mixed and heated at 160 °C for 5 hours. After cooling to room temperature, the crude product was purified by preparative TLC to give 3-[2-[[(1S)-1-(3-fluoro-4-phenoxy-phenyl)ethyl]amino]-4-pyridyl]benzonitrile (166, 22 mg, 44.4% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 8.18 (d, J = 5.2 Hz, 1H), 7.76 (s, 1H), 7.69-7.54 (m, 3H), 7.33-7.24 (m, 3H), 7.14-6.95 (m, 5H), 6.77 (dd, LC-MS: (ESI) m / z: 410.1 [M+H].

[0281] Synthesis of compounds 167-169 Generally, the synthesis methods for compounds 167-169 in Table 4 were similar to Example 5. Data for compounds 167-169 are shown in Table 4 herein below.

[0282] [Table 6] [Example]

[0283] 4-[[(1S)-1-[2,5-difluoro-4-[2-(1-fluoro-1-methyl-ethyl)-4-pyridyl]phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (102)

[0284] This compound was prepared according to Scheme 5, listed below.

[0285] Scheme 5:

[0286] [ka]

[0287] Step 1. 2-(4-Bromo-2-pyridyl)propan-2-ol (2)

[0288] [ka]

[0289] To a solution of methyl 4-bromopyridine-2-carboxylate (1.5 g, 23.14 mmol, 1 equiv.) in THF (100 mL), MeMgBr (3 M, 16.20 mL, 2.1 equiv.) was added dropwise at 0-4 °C under N2. The mixture was then stirred at 20-25 °C for 0.5 h. TLC (PE / EA = 3 / 1, R fA pH of 0.6 indicated the reaction was complete. The mixture was cooled to 0-4 °C and slowly quenched with saturated NH4Cl solution (30 mL). The mixture was diluted with water (50 mL), extracted with EtOAc (50 mL × 2), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 95 / 5 to 85 / 15). 2-(4-bromo-2-pyridyl)propan-2-ol (2, 2.5 g, 49.99% yield) was obtained as a pale yellow liquid. 1 H NMR (400MHz, CDCl3) δ: 8.36 (d, J = 5.2 Hz, 1H), 7.60-7.59 (dd, J = 0.4, 2.0 Hz, 1H), 7.40-7.38 (dd, J = 2.0, 5.2 Hz, 1H), 4.57 (s, 1H), 1.56 (s, 9H).

[0290] Step 2. 4-Bromo-2-(1-fluoro-1-methyl-ethyl)pyridine (3)

[0291] [ka]

[0292] To a solution of 2-(4-bromo-2-pyridyl)propan-2-ol (2, 1 g, 4.63 mmol, 1 equiv.) in DCM (30 mL), DAST (1.12 g, 6.94 mmol, N / A, 1.5 equiv.) was added dropwise at 0-4 °C. The mixture was then stirred at 0-4 °C for 1.5 h. TLC (PE / EA = 3 / 1, R f=0.8) indicated the reaction was complete. The mixture was poured into saturated NaHCO3 solution (100 mL), extracted with DCM (30 mL × 2), washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 98 / 2) (LCMS: ES9778-173-P1MA). 4-Bromo-2-(1-fluoro-1-methyl-ethyl)pyridine (3, 700 mg, 69.36% yield) was obtained as a yellow liquid. 1 H NMR (400MHz, CDCl3) δ: 8.36 (d, J = 5.2 Hz, 1H), 7.75 (t, J = 1.2 Hz, 1H), 7.38-7.36 (dd, J = 2.0, 5.2 Hz, 1H), 1.70 (d, J = 22.0 Hz, 6H). LC-MS: (ESI) m / z: 218.1 [M+H] + , t R = 0.809 minutes.

[0293] Step 3. 4-[[(1S)-1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (2A)

[0294] [ka]

[0295] A mixture of 4-[[(1S)-1-(4-bromo-2,5-difluoro-phenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (2B, 2 g, 5.05 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.20 g, 12.62 mmol, 2.5 equiv.), Pd(dppf)Cl.CHCl (412.20 mg, 504.76 μmol, 0.1 equiv.) and KOAc (990.76 mg, 10.10 mmol, 2 equiv.) in 1,4-dioxane (50 mL) was stirred at 100 °C for 2 h under N. LCMS (ES9799-190-P1A) showed that 4-[[(1S)-1-(4-bromo-2,5-difluorophenyl)ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one was completely consumed, and one major peak with the desired MS was detected. TLC (PE / EtOAc = 1 / 1) showed that no new spots were detected. The solvent was removed under reduced pressure to give the crude product. The crude product was purified by silica gel column (PE / EtOAc = 1 / 1) to give 4-[[(1S)-1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (2A, 2.2 g, crude) as a yellow oil, which was confirmed by LCMS. LC-MS: (ESI) m / z: 444.2 [M+H] + , t R = 0.817 minutes.

[0296] Step 4. 4-[[(1S)-1-[2,5-difluoro-4-[2-(1-fluoro-1-methyl-ethyl)-4-pyridyl]phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (102)

[0297] [ka]

[0298] 4-[[(1S)-1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (2A, 200 mg, 451.17 umol, 1 equiv.), 4-bromo-2-(1-fluoro-2-methyl-4-phenylpropan-2-yl)phenyl)ethylamino) ... in dioxane (6 mL) and HO (2 mL). A mixture of (fluoro-1-methyl-ethyl)pyridine (3, 130 mg, 596.15 μmol, 1.32 equiv.), Pd(dppf)Cl.CHCl (37 mg, 45.31 μmol, 0.1 equiv.), and NaCO (100 mg, 943.49 μmol, 2.09 equiv.) was degassed and purged with N three times, then the mixture was stirred at 90 °C for 1 h under a N atmosphere. LCMS (ES9778-175-P1LA) indicated the reaction was complete. The mixture was cooled and filtered through Celite. The Celite was washed with EtOAc (50 mL × 2). The filtrate was concentrated. The residue was purified by prep-HPLC (column: DuraShell 150 × 25 mm × 5 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 46-66%, 10 min) to give 4-[[(1S)-1-[2,5-difluoro-4-[2-(1-fluoro-1-methyl-ethyl)-4-pyridyl]phenyl]ethyl]amino]-2-ethyl-3H-pyrrolo[3,4-c]pyridin-1-one (102, 65.9 mg, yield 32.14%, purity 100%) as a pale yellow solid. LC-MS: (ESI) m / z: 455.1 [M+H] + , t R = 3.687 minutes. 1H NMR (400MHz, MeOD) δ: 8.53 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.69 (s, 1H), 7.44-7.42 (m, 1H),7.33-7.24 (m, 2H), 6.87 (d, J = 5.2 Hz, 1H), 5.57-5.52 (q, J = 6.8 Hz, 1H), 4.52-4.41 (m, 2H), 3.70-3.64 (q, J = 7.2 Hz, 2H), 1.68 (d, J = 22 Hz, 6H), 1.60 (d, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0299] Biological assays Test 1: Purification of wild-type and mutant IDH proteins Purification of IDH1 and IDH2 proteins The present disclosure provides methods for the expression and purification of mutant and wild-type recombinant IDH1 and IDH2 proteins in E. coli.

[0300] The pSJ3 plasmid containing the cDNA sequences encoding the full-length wild-type or mutant IDH1 protein (IDH1-R132H or IDH1-R132C), the partial IDH2 protein with the first 40 N-terminal amino acid residues deleted, the wild-type or mutant (IDH2-R140Q or IDH2-R172K) was transformed into the BL21 strain, and the IDH proteins were expressed overnight at 16°C in the presence of 0.5 mM IPTG. Using a six-tandem histidine tag fused to the expressed protein, the IDH proteins were purified using Ni Sepharose 4B (purchased from GE Lifescience) as described in the manufacturer's instructions. The eluted proteins were concentrated in TBS buffer using an Amicon 3,000 Da MWCO filter unit, and the final protein product was stored at -80°C in TBS solution containing 10% glycerol. Protein concentration was quantified using a Bradford kit (Shanghai Sangon).

[0301] Test 2: Biochemical assays for compound IDH inhibition and selectivity The present disclosure provides biochemical assays for detecting IDH inhibition and selectivity of compounds by directly detecting IDH enzymatic activity.

[0302] Figure 1 shows the reactions catalyzed by wild-type and mutant IDH1 / 2. The wild-type IDH enzyme uses NADP when catalyzing the α-KG production reaction. + The mutant IDH enzyme converts NADPH to NADP when catalyzing the D-2-HG production reaction. + Therefore, the activity of wild-type and mutant IDH1 / 2 could be measured by monitoring changes in NADPH levels, as NADPH is fluorescent (excitation 340 nm, emission 460 nm). By monitoring changes in NADPH levels during the reaction, enzyme activity could be rapidly and efficiently determined, and the IC value of the compound could be calculated. 50 could also be assayed.

[0303] Test compounds are prepared in 50 mM stock solutions in DMSO and stored at -20°C. For final use on the day of testing, each test compound stock is further diluted to give 100x stock solutions at concentrations of 400 μM, 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM, respectively (the concentration ranges for the 100x stock solutions are based on the estimated IC of the particular test compound). 50 (These will be adjusted to include

[0304] Inhibition of wild-type IDH1: To establish the reaction from isocitrate to α-KG catalyzed by wild-type IDH1 protein, purified wild-type IDH1 protein is first diluted to 2.7 nM in 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, 0.05 mg / ml BSA, and 107 μM isocitrate. 148 μL of the 2.7 nM wild-type IDH1 protein solution is mixed with 2 μL DMSO (vehicle control for test compounds) or a 100× stock solution of the test compounds described above, and incubated at room temperature for 1 hour. An extra reaction containing 148 μL of enzyme-free solution (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, 0.05 mg / ml BSA, and 107 μM isocitrate) and 2 μL DMSO is also set as a background control. Each reaction was then initiated by adding 50 μL of a 200 μM NADP+ solution prepared in 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, and 0.05 mg / ml BSA. A BioTek Synergy H1 microplate reader (BioTek Instruments Inc., Winooski, US) was employed to monitor NADPH fluorescence (excitation 340 nm, emission 460 nm) every 42 seconds for 15 minutes. The NADPH change rate was determined according to the linear phase of the fluorescence-time curve, and the results from the background control reaction were used as background subtraction to calculate the net NADPH change rate for other reactions. The net NADPH change rate from the vehicle control reaction was used as 100% enzyme activity, allowing the relative enzyme activity of reactions containing test compounds to be determined. A dose-response curve for each test compound was then constructed, and the corresponding IC 50 Calculate IC 50 The values ​​are used to assess the inhibition and selectivity of each test compound towards IDH enzyme activity.

[0305] Inhibition of mutant IDH1 (R132H or R132C): To assay the enzymatic activity of mutant IDH1 proteins, 25 nM IDH1-R132C or 50 nM IDH1-R132H protein solutions are prepared in 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, 0.05 mg / ml BSA, and 1.33 mM α-KG. 148 μL of 25 nM IDH1-R132C or 50 nM IDH1-R132H protein solution is mixed with 2 μL DMSO (vehicle control for test compounds) or a 100× stock solution of the test compound described above, and incubated at room temperature for 1 hour. An extra reaction containing 148 μL of enzyme-free solution (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, 0.05 mg / ml BSA, and 1.33 mM α-KG) and 2 μL DMSO was also set up as a background control. Each reaction was then initiated by adding 50 μL of an 80 μM NADPH solution prepared in 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, and 0.05 mg / ml BSA. A BioTek Synergy H1 microplate reader (BioTek Instruments Inc., Winooski, US) was used to monitor NADPH fluorescence (excitation 340 nm, emission 460 nm) every 42 seconds for 15 minutes. The NADPH change rate was determined according to the linear phase of the fluorescence-time curve, and the results from the background control reaction were used as background subtraction to calculate the net NADPH change rate for other reactions. The net NADPH change rate from the vehicle control reaction was used as 100% enzyme activity, allowing the relative enzyme activity of the reaction to which the test compound was added to be determined. A dose-response curve for each test compound was then constructed, and the corresponding IC 50 Calculate IC 50 The values ​​are used to assess the inhibition and selectivity of each test compound towards IDH enzyme activity.

[0306] Test 3: Cell-based assays for compound IDH inhibition and selectivity The present disclosure also provides a cell-based method for assaying the IDH inhibitory and selectivity of compounds in the human fibrosarcoma cell line HT1080 and the cholangiocarcinoma cell line HCCC9810, which harbor endogenous heterozygous IDH1 R132C and R132H mutations, respectively, and accumulate D-2-HG. The tumor-derived IDH mutations lost their normal activity of producing α-KG and acquired a new activity of producing D-2-HG. D-2-HG is a metabolite that is particularly elevated in tumor cells expressing mutant IDH1 or IDH2 proteins. When such mutant IDH-expressing tumor cells are treated with an effective IDH inhibitor, the synthesis of D-2-HG is blocked, and the D-2-HG concentration is reduced by an oxidation reaction catalyzed by endogenous D-2-HG dehydrogenase. Therefore, the IDH inhibitory activity and selectivity of compounds of the present disclosure could be assayed by the reduction of D-2-HG in cellular metabolites.

[0307] To perform the cell-based IDH inhibition assay, HT1080 and HCCC9810 cells (or other cell lines carrying different IDH mutations) are cultured in DMEM supplemented with 10% FBS. The cells are treated with various concentrations of the disclosed compounds. After 16 hours of treatment, the culture medium supernatant is removed, and cellular metabolites are extracted with 40% methanol and 40% acetonitrile in water (pre-cooled below -80°C) at 4°C for 1 hour. The extract supernatant is collected, and cell debris is removed by high-speed centrifugation. The resulting metabolites are analyzed for 2-HG and glutamic acid concentrations using an Agilent LC-MS system (model: 1290-6470). A HILIC-Z column (2.1 mm x 100 mm, 2.7 μm) is employed for HPLC. Mobile phase A is 15 mM CH3COONH4 and 0.3% NH3·H2O in water. Mobile phase B is 15 mM CH3COONH4 and 0.3% NH3·H2O in 90% MeCN / 10% H2O. A 19% solvent A and 81% solvent B isocitrate gradient method is used at a flow rate of 0.3 mL / min. D-2-HG is ionized in negative ion spray mode and detected via multiple reaction monitoring of the mass transition pairs at m / z = 147.0 / 128.9 and 147.0 / 85.1. Glutamate ions are ionized in ion spray mode and detected via negative multiple reaction monitoring of the mass transition pairs at m / z = 146 / 102 and 146 / 128, and their levels are used to normalize the 2-HG concentration. The activity of the cellular mutant IDH protein in the presence of different concentrations of each test compound can be expressed by the relative D-2-HG concentration to the negative control sample (i.e., cells treated with DMSO only), and is calculated as IC 50 Values ​​could be determined to assess the inhibition and selectivity of each test compound towards IDH enzyme activity.

[0308] Test 4: Metabolic stability assay in liver microsomes Liver microsomes from mice, rats (from Xenotech), dogs, monkeys, and humans (from Corning Inc.) are used to test the in vitro metabolic stability of compounds. All liver microsomes are stored at -60°C before use. Testosterone, diclofenac, and propafenone are used as controls.

[0309] Each test compound or control compound was diluted to 0.5 mg mL in PBS (100 mM, pH 7.4) with 3 mM MgCl . -1 The mixture is co-incubated with mouse, rat, dog, monkey, or human liver microsomes at a preset initial concentration of 1 μM in a 37°C water bath. The reaction is initiated by adding NADPH to a final concentration of 1 mM. The final volume of each reaction mixture is 0.2 ml, and all reactions are performed in duplicate. At each set time point (0, 5, 15, 30, and 60 min), a small aliquot (e.g., 20 μl) is transferred from the reaction to ice-cold internal standard (IS) containing acetonitrile to quench the reaction and precipitate the protein. After vortexing and centrifugation at 3700 rpm for 10 min, the supernatant is injected into the LC-MS / MS for analysis.

[0310] In vitro microsomal clearance was measured by the elimination half-life (T 1 / 2 ) is determined. Calculate the peak area ratio of each compound (test or control) to IS. Plot the Ln (% control) vs. incubation time (min) curve and calculate the slope of the linear fitting line. Calculate the drug elimination rate constant k (min -1 ), T 1 / 2 (min) and in vitro intrinsic clearance CL int (mL×min -1 ×mg -1 Protein) is calculated according to the following formula: k=-slope T 1 / 2 =0.693 / k CL int =k / C タンパク質 (In the formula, C タンパク質 (mg × mL -1 ) is the microsomal protein concentration in the incubation system).

[0311] Study 5: In vivo pharmacokinetic assay The pharmacokinetic properties of compounds of the present disclosure can be evaluated in ICR mice (male, 6-8 weeks, 20.0-25.3 g) by po or iv administration.

[0312] ICR mice were purchased from Vital River Laboratory Technology Co., Ltd. (Beijing, China) and housed in sturdy polypropylene cages with sterilized bedding in a room with 40%-70% humidity, 20-25°C, 10-20 air changes per hour, and a 12-hour light / dark cycle unless interrupted by testing activities. Mice were provided with sterile food and water from Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China). All animals were inspected upon receipt and allowed to acclimate for at least 3 days. Only those that appeared healthy were selected for testing based on overall health, body weight, or other relevant data as needed. Individual animals within each group were identified by ear notches.

[0313] Mice are fasted overnight before dosing but allowed free access to water at all times. Prior to dosing, each mouse is weighed and the actual dose volume for each mouse is calculated by using the following formula: Dose volume (mL) = [nominal dose (mg kg -1 ) / Dose concentration (mg mL -1 )] × animal weight (kg)

[0314] Actual body weight and actual dose volume will be recorded as appropriate.

[0315] For each test group, nine mice were used, and mice in different groups were administered 10 mg kg -1 A single p.o. dose of the test compound at 2 mg kg-1 A single intravenous dose of 100 mg / kg / day is administered to each mouse. Blood samples are collected into tubes containing EDTA-K2 at predetermined time points, e.g., 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours before or after administration. Blood samples from each mouse are collected at three intermittent time points, with three mice used for sampling at each time point. The collected samples are centrifuged at 5500 rpm for 10 minutes to obtain plasma samples, which are then analyzed by LC-MS / MS. Data on plasma drug concentration versus time are processed by linear regression analysis. All pharmacokinetic parameters are calculated using a non-compartmental model in WinNonlin 8.0.

[0316] Test 6: Inhibition of anchorage-independent growth of IDH mutant cells It is well established that anchorage-independent cell growth is a fundamental property of cancer cells, and the ability of anchorage-independent growth is closely related to the tumorigenic and metastatic potential of tumor cells in vivo.

[0317] Previous studies have shown that deletion of mutant IDH1 in HT1080 cells (harboring the endogenous IDH1-R132C mutation) has little effect on cell proliferation under normal culture conditions, but potently inhibits anchorage-independent growth of HT1080 cells ["D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth," Ma, S. et al., Oncotarget, (2015)]. Because IDH1 mutations promote 2-HG-induced tumorigenesis, anchorage-independent growth (cell colony formation in soft agar) can also be used as a convenient and valuable in vitro assay to measure the activity of compounds in tumor inhibition.

[0318] Tumor cell lines carrying an endogenous IDH1-R132X mutation, such as HT1080 (containing the IDH1-R132C mutation) or HCCC9810 (containing the IDH1-R132H mutation), are seeded on 0.35% agar (top agar layer) in an appropriate culture medium (e.g., DMEM with 10% FBS for HT1080 or HCCC9810 cells), with the test compound or DMSO on top of a 0.65% agar layer (bottom agar layer) in an appropriate culture medium (e.g., DMEM with 10% FBS for HT1080 or HCCC9810 cells). The test compound or DMSO is added to the top of the top agar layer to keep the agar layer moist. The final concentration of the test compound in the top agar layer or the medium above is usually equal to the IC50 tested in HT1080 cells. 50 The values ​​are higher than the normal values. The cells in the agar are cultured for approximately 4 weeks, and the medium containing the test compound or DMSO above the top agar layer is replaced weekly. At the end of the experiment, the soft agar plates are stained with crystal violet, and the cell colonies are imaged under a microscope for quantification. The difference in the number of colonies between the plates containing the test compound and DMSO reflects the inhibitory effect of the test compound on the anchorage-independent growth of IDH mutant cells.

[0319] Study 7: Inhibition of IDH mutations in tumors from HT1080 xenografted mice To test the inhibitory effect of test compounds on IDH mutations in tumors, HT1080 cells are first inoculated subcutaneously into BALB / c nude mice (5 million HT1080 cells per mouse). When the HT1080 tumor volume reaches approximately 200 mm 3When the 2-HG level reaches 100%, the mice are randomly divided into groups, and each group of mice is orally administered with the test compound. At different time points, such as 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration, a group of mice is sacrificed for blood and HT1080 tumor tissue. After homogenization and extraction, the 2-HG level in the tumor tissue is determined by LC-MS / MS, and the inhibitory ratio of the test compound to the IDH1-R132C mutant activity of producing 2-HG in HT1080 tumors at different time points after administration is calculated.

[0320] Actual example Example 1: Compounds inhibit the activity of IDH1 R132H and IDH1 R132C The IDH inhibitory activity of the compounds was evaluated according to Test 2 in the Biological Assays section. Each compound was tested in triplicate for inhibition of mutant IDH1 R132H and IDH1 R132C. IC values ​​of representative compounds against IDH1 R132H and IDH1 R132C were 50 The values ​​are shown in Table 5. As used in Table 5, "A" stands for IC 50 "B" indicates inhibitory activity against IDH1 R132H or IDH1 R132C at IC<0.1 μM, and "B" indicates IC<0.1 μM-0.5 μM. 50 "C" refers to the inhibitory activity against IDH1 R132H or IDH1 R132C at IC50 of 0.5 μM to 1 μM. 50 "D" refers to the inhibitory activity against IDH1 R132H or IDH1 R132C at IC 50 Refers to inhibitory activity against IDH1 R132H or IDH1 R132C at >1 μM.

[0321] [Table 7] JPEG0007776418000139.jpg239136JPEG0007776418000140.jpg234134JPEG0007776418000141.jpg232132 JPEG0007776418000142.jpg232132JPEG0007776418000143.jpg230133JPEG0007776418000144.jpg191139

[0322] Table 5 shows that compounds of the present disclosure exert good inhibition against mutant IDH1.

[0323] Example 2: Compounds inhibit the activity of IDH in cell-based assays The IDH inhibitory activity of the compound was evaluated in human Fibrosarcoma The cell line HT1080 was evaluated according to Test 3 in the Biological Assays section. Each compound was tested for IDH inhibition in triplicate. IC of representative compounds against IDH 50 The values ​​are shown in Table 6. As used in Table 6, "A" stands for IC 50 "B" indicates IDH inhibitory activity at IC<0.1μM, and "B" indicates an IC of 0.1μM to 0.5μM. 50 "C" indicates IDH inhibitory activity at IC of 0.5 μM to 1 μM. 50 "D" refers to IDH inhibitory activity at IC 50 Refers to IDH inhibitory activity at >1 μM.

[0324] [Table 8] JPEG0007776418000146.jpg23287JPEG0007776418000147.jpg24594JPEG0007776418000148.jpg24594 JPEG0007776418000149.jpg23992JPEG0007776418000150.jpg23790JPEG0007776418000151.jpg15292

[0325] As shown in Table 6, compounds of the present disclosure also exhibit good inhibition of mutant IDH1 in cell-based assays.

[0326] The foregoing description is considered merely as illustrative of the principles of the disclosure. Moreover, it is not desired to limit the invention to the precise construction and steps shown above, since numerous modifications and changes will be readily apparent to those skilled in the art. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the following claims.

[0327] The terms "comprise," "comprising," "include," "including," and "includes," when used in this specification and the claims that follow, are intended to specify the presence of stated properties, integers, components, or steps, but they do not exclude the presence or addition of one or more other properties, integers, components, steps, or groups thereof.

Claims

1. Compound of formula (Ie): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the ceremony Y is a bond; W is one or more R ７ is heteroaryl optionally substituted with R ２ is selected from the group consisting of halogen, hydroxyl, cyano, and nitro; R ７ is C １～６ Alkoxyl, C １～６ Alkyl, C ２～６ Alkenyl, C １～６ Haloalkyl, saturated or partially unsaturated C ３～６ Cycloalkyl, C ６～１２ Aryl, 5- to 10-membered heteroaryl, and —NR ｃ R ｄ wherein the alkoxyl, alkyl, alkenyl, saturated or partially unsaturated cycloalkyl, aryl, heteroaryl are independently selected from the group consisting of halogen, cyano, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, saturated or partially unsaturated C ３～６ optionally substituted with one or more groups independently selected from the group consisting of cycloalkyl; R ｃ and R ｄ is hydrogen or C １～６ is alkyl; m is 0, 1 or 2).

2. W is, 【Chemistry 2】 is a group containing a ring selected from the group consisting of each of which is one or more R ７ 2. The compound of formula (Ie) according to claim 1, optionally substituted by: or a pharmaceutically acceptable salt thereof.

3. R ２ 2. The compound of formula (Ie) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is halogen.

4. 2. The compound of formula (Ie) according to claim 1, wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof.

5. The compound is (S)-4-((1-(2,5-difluoro-4-(p-tolyloxy)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-((1-methyl-1H-indol-5-yl)oxy)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-(((1S)-1-(2,5-difluoro-4-((3,3,5-trimethylcyclohexyl)oxy)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-(((S)-1-(2,5-difluoro-4-(((1R,5S)-3,3,5-trimethylcyclohexyl)oxy)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-(((S)-1-(2,5-difluoro-4-(((1S,5S)-3,3,5-trimethylcyclohexyl)oxy)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(tert-butyl)pyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-cyclobutylpyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-cyclopropylpyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(cyclopropylmethyl)pyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(1-methyl-1H-pyrrol-3-yl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(oxetan-3-yl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(3-hydroxyoxetan-3-yl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-chloropyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2'-chloro-[2,4'-bipyridin]-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(3,3-difluorocyclobutyl)pyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-phenylpyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-([2,3′-bipyridin]-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(5'-chloro-[2,3'-bipyridin]-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-cyclopentylpyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(2-fluoropropan-2-yl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(2-hydroxypropan-2-yl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(tert-butyl)-5-fluoropyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(1,1-difluoroethyl)pyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(perfluoroethyl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(4-(tert-butyl)pyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(5-(tert-butyl)pyridin-3-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(6-(tert-butyl)pyrimidin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(tert-butyl)pyrimidin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-6-methylpyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-2-(4-(1-((2-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)amino)ethyl)-2,5-difluorophenyl)isonicotinonitrile; (S)-4-((1-(2,5-difluoro-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(tert-butyl)-5-methoxypyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(6-(tert-butyl)-3-methoxypyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(6-(fluoromethyl)-4-(2-fluoropropan-2-yl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(6-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-6-methoxypyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(6-(fluoromethyl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(1-(trifluoromethyl)cyclopropyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S,E)-4-((1-(2,5-difluoro-4-(4-(1,1,1-trifluorobut-2-en-2-yl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 4-(((1S)-1-(2,5-difluoro-4-(4-(5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)pyridin-2-yl)phenyl) (ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin ion-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-5-methylpyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(4-(tert-butylamino)-6-methylpyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(4-(tert-butoxy)-6-methylpyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(6-(2-fluoropropan-2-yl)pyrimidin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(1-fluorocyclopropyl)-6-methylpyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(2-(2-fluoropropan-2-yl)-5-methoxypyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(5-fluoro-4-(2-fluoropropan-2-yl)-6-methylpyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(3-fluoro-4-(2-fluoropropan-2-yl)-6-methylpyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-5-methoxypyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(5-chloro-4-(2-fluoropropan-2-yl)pyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(5-fluoro-4-(2-fluoropropan-2-yl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(tert-butyl)-5-hydroxypyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(5-(fluoromethyl)-2-(2-fluoropropan-2-yl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(6-(2-fluoropropan-2-yl)-2-methoxypyrimidin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(5-hydroxy-2-(trifluoromethyl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(1,1-dimethyl-1,3-dihydrofuro[3,4-c]pyridin-6-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-5-(methoxymethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-5-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(6-(tert-butyl)-5-methoxypyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(4-(tert-butyl)-5-methoxypyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(tert-butoxy)-5-methylpyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(4-(tert-butoxy)-5-chloropyridin-2-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(5-(2-fluoropropan-2-yl)-6-methoxypyridazin-3-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-2-(4-(4-(1-((2-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)amino)ethyl)-2,5-difluorophenyl)pyridin-2-yl)-2-methylpropanenitrile; (S)-4-((1-(2,5-difluoro-4-(6-fluoro-4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-6-hydroxypyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(6-hydroxy-4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(tert-butyl)pyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-(2-methoxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(2-(tert-butyl)pyridin-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-(2-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(4-(1-(tert-butyl)-1H-imidazol-4-yl)-2,5-difluorophenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-5-(methoxymethoxy)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-((1-(2,5-difluoro-4-(4-(2-fluoropropan-2-yl)-5-hydroxypyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-6-(4-(1-((2-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)amino)ethyl)-2,5-difluorophenyl)-4-(2-fluoropropan-2-yl)nicotinonitrile; (S)-4-((1-(2,5-difluoro-4-(5-hydroxy-4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; and (S)-4-((1-(2,5-difluoro-4-(5-methoxy-4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)amino)-2-ethyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of formula (Ie) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a compound according to claim 5 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

7. Use of a compound of formula (Ie) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, or a compound according to claim 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, in the manufacture of a medicament for treating a disease characterized by accumulation of D-2-HG in a patient, wherein the disease is preferably cancer.

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