Tricyclic phthalazinone PARP inhibitors and methods of use

Abstract

The present disclosure relates to a compound of formula I, or a pharmaceutically acceptable salt and / or solvate thereof, and to compositions containing such compounds and their use, 【Chemical 1】 TIFF2025523385000067.tif68170 wherein X 1 is H, F, or Cl, and X 2 is NH or N-R 3 wherein R 1 and R 2 one of which is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl, and the remaining one of R 1 and R 2 is aryl, heteroaryl, or non-aromatic heterocyclyl, and R 3 is alkyl, cycloalkyl, alkenylenyl, and non-aromatic heterocyclyl. In particular, the present disclosure has demonstrated that the compounds of the present disclosure penetrate the central nervous system and enable the treatment of central nervous system cancers.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of Provisional Patent Application No. 63 / 350,366, filed on June 8, 2022, which is hereby incorporated by reference in its entirety for all purposes.

[0002] The present technology relates to compounds, compositions, and methods related to the treatment of cancer, particularly central nervous system cancer, and their uses.

Summary of the Invention

[0003] In one aspect, the present technology provides a compound of Formula I, or a pharmaceutically acceptable salt and / or solvate thereof,

Chemical Formula

[0004] In one aspect, a composition is provided that includes a compound, a pharmaceutically acceptable carrier, or one or more excipients, fillers, or agents (hereinafter collectively referred to as "pharmaceutically acceptable carrier" unless otherwise indicated and / or specified) of any of the embodiments disclosed herein.

[0005] In related aspects, there is provided an agent for treating cancer in a subject, comprising a compound of any of the embodiments disclosed herein and optionally a pharmaceutically acceptable carrier.

[0006] In related aspects, there is provided a pharmaceutical composition comprising (i) an effective amount of a compound of any of the embodiments disclosed herein effective for treating cancer and (ii) a pharmaceutically acceptable carrier.

[0007] In related aspects, there is provided a pharmaceutical composition comprising (i) an effective amount of a compound of any of the embodiments disclosed herein present in an amount effective for treating cancer when combined with a second cancer therapy and (ii) a pharmaceutically acceptable carrier.

[0008] In further related aspects, the technology provides a method comprising a compound of any of the aspects or embodiments disclosed herein and / or a composition of any of the embodiments disclosed herein and / or an agent of any of the embodiments disclosed herein. Such methods include methods of treating a subject afflicted with cancer, comprising administering to the subject an effective amount of a compound of any of the embodiments disclosed herein and an effective amount of a second cancer therapy.

BEST MODE FOR CARRYING OUT THE INVENTION

[0009] The following terms are used throughout and are defined as follows.

[0010] As used in this specification and the appended claims, singular articles such as "a," "an," and "the," and similar referents in the context of describing elements (particularly in the context of the following claims) shall be construed to include both the singular and plural forms unless the specification indicates otherwise or is clearly inconsistent with the context. The recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value within the range, and each separate value is incorporated into the specification as if it were individually recited herein, unless the specification indicates otherwise. All methods described herein can be performed in any suitable order unless the specification indicates otherwise or is clearly inconsistent with the context. The use of any examples, or exemplary language (e.g., "such as") provided herein is for the purpose of better understanding the embodiments only and does not limit the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0011] As used herein, "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. When there is a use of a term that is not obvious to those skilled in the art considering the context in which it is used, "about" means plus or minus 10% of the particular term. For example, "about 10 wt%" is understood to mean "9 wt% to 11 wt%." It should be understood that when "about" is in front of a term, that term is construed to disclose not only the term "about" but also the term as modified by "about" and not modified by "about." For example, "about 10 wt%" discloses not only "10 wt%" but also "9 wt% to 11 wt%."

[0012] The phrase "and / or" as used in this disclosure shall be understood to mean any one of the recited members individually or any combination of two or more of them. For example, "A, B, and / or C" means "A, B, C, A and B, A and C, B and C, or the combination of A, B, and C."

[0013] Generally, reference to a particular element such as hydrogen or H means all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it includes deuterium and tritium. Thus, compounds containing radioactive isotopes such as tritium, C 14 , P 32 and S 35 are within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0014] Generally, "substituted" refers to an organic group (e.g., an alkyl group) as defined below in which one or more bonds to hydrogen atoms contained therein are replaced by bonds to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to carbon atom(s) or hydrogen atom(s) are replaced by one or more bonds including double or triple bonds to heteroatoms. Thus, unless otherwise specified, a substituted group is substituted with one or more substituents. In some embodiments, the substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include halogen (i.e., F, Cl, Br, and I), hydroxyl, alkoxy, alkenyloxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups, carbonyl (oxo), carboxylate, ester, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, thiol, sulfide, sulfoxide, sulfone, sulfonyl, pentafluorosulfanyl (i.e., SF5), sulfonamide, amine, N-oxide, hydrazine, hydrazide, hydrazone, azide, amide, urea, amidine, guanidine, enamine, imide, isocyanate, isothiocyanate, cyanate, thiocyanate, imine, nitro group, and nitrile (i.e., CN).

[0015] Substituted cyclic groups such as substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced by a bond to a carbon atom. Thus, substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups may be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0016] Alkyl groups include straight-chain and branched-chain alkyl groups having from 1 to 12 carbon atoms, typically from 1 to 10 carbon atoms, or in some embodiments from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups can be substituted or unsubstituted. Examples of straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above and include, but are not limited to, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

[0017] A cycloalkyl group includes a monocyclic, bicyclic, or tricyclic alkyl group having 3 to 12 carbon atoms within the ring(s), or in some embodiments 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. The cycloalkyl group can be substituted or unsubstituted. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Bicyclic and tricyclic ring systems include, but are not limited to, both bridged cycloalkyl groups and fused rings such as bicyclo[2.1.1]hexane, adamantyl, decalinyl, etc. The substituted cycloalkyl group may be substituted one or more times with the non-hydrogen and non-carbon groups defined above. However, the substituted cycloalkyl group also includes rings substituted with a straight-chain or branched-chain alkyl group as defined above. Representative substituted cycloalkyl groups may be monosubstituted or substituted two or more times and may be substituted with substituents such as those listed above, including, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups.

[0018] A cycloalkylalkyl group is an alkyl group as defined above in which a hydrogen bond or a carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above. The cycloalkylalkyl group can be substituted or unsubstituted. In some embodiments, the cycloalkylalkyl group has 4 to 16 carbon atoms, 4 to 12 carbon atoms, typically 4 to 10 carbon atoms. The substituted cycloalkylalkyl group may be substituted in the alkyl portion of the group, the cycloalkyl portion, or both the alkyl portion and the cycloalkyl portion. Representative substituted cycloalkylalkyl groups may be monosubstituted or substituted two or more times and, without limitation, may be monosubstituted, disubstituted, or trisubstituted with substituents such as those listed above.

[0019] An alkenyl group includes the linear and branched alkyl groups defined above, except that there is at least one double bond between two carbon atoms. The alkenyl group can be substituted or unsubstituted. The alkenyl group has 2 to 12 carbon atoms, typically 2 to 10 carbon atoms, or in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2. Representative substituted alkenyl groups may be mono-substituted or substituted more than twice, and may be mono-substituted, di-substituted, or tri-substituted with substituents such as those listed above.

[0020] A cycloalkenyl group includes the cycloalkyl groups defined above having at least one double bond between two carbon atoms. The cycloalkenyl group can be substituted or unsubstituted. In some embodiments, the cycloalkenyl group may have one, two, or three double bonds, but does not include aromatic compounds. The cycloalkenyl group has 4 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.

[0021] A cycloalkenylalkyl group is an alkyl group as defined above, wherein a hydrogen bond or a carbon bond of the alkyl group is replaced by a bond to a cycloalkenyl group as defined above. The cycloalkenylalkyl group can be substituted or unsubstituted. A substituted cycloalkenylalkyl group may be substituted in the alkyl part, the cycloalkenyl part, or both the alkyl part and the cycloalkenyl part of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0022] An alkynyl group includes the straight-chain and branched-chain alkyl groups defined above, except that there is at least one triple bond between two carbon atoms. An alkynyl group can be substituted or unsubstituted. An alkynyl group has 2 to 12 carbon atoms, typically 2 to 10 carbon atoms, or in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, an alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to, -C≡CH, -C≡CCH3, -CH2C≡CCH3, and -C≡CCH2CH(CH2CH3)2. Representative substituted alkynyl groups may be mono-substituted or substituted more than twice, and may be mono-substituted, di-substituted, or tri-substituted with substituents such as those listed above.

[0023] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. The aryl groups herein include monocyclic, bicyclic, and tricyclic ring systems. An aryl group can be substituted or unsubstituted. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, an aryl group contains 6 to 14 carbon atoms in the ring portion of the group, in other embodiments, 6 to 12, or even 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. The term "aryl group" includes groups containing condensed rings such as condensed aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Representative substituted aryl groups may be mono-substituted (e.g., tolyl) or substituted more than twice. For example, mono-substituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups that can be substituted with substituents such as those listed above.

[0024] An aralkyl group is an alkyl group as defined above, wherein a hydrogen bond or a carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above. The aralkyl group can be substituted or unsubstituted. In some embodiments, the aralkyl group contains 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. A substituted aralkyl group may be substituted in the alkyl portion, the aryl portion, or both the alkyl portion and the aryl portion of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and fused (cycloalkylaryl) alkyl groups such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.

[0025] A heterocyclyl group includes aromatic (also called heteroaryl) and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms such as N, O, and S, but are not limited thereto. The heterocyclyl group can be substituted or unsubstituted. In some embodiments, the heterocyclyl group contains one, two, three, or four heteroatoms. In some embodiments, the heterocyclyl group includes monocyclic, bicyclic, and tricyclic rings having 3 to 16 ring members, although other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. The heterocyclyl group includes aromatic, partially unsaturated, and saturated ring systems such as, for example, imidazolyl, imidazolinyl, and imidazolidinyl groups. The phrase "heterocyclyl group" includes fused ring species including fused aromatic groups and non-aromatic groups such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benz[1,3]dioxolyl. This phrase also includes bridged polycyclic ring systems containing heteroatoms such as, but not limited to, quinuclidyl. This phrase includes heterocyclyl groups having other groups such as alkyl, oxo, or halo groups attached to one of the ring members, called "substituted heterocyclyl groups".Heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidinyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guanylinyl, quinolinyl, isoquinolinyl, quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Exemplary substituted heterocyclic groups may be monosubstituted or may be substituted two or more times, for example, 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above, and include, but are not limited to, pyridyl groups or morpholinyl groups.

[0026] A heteroaryl group is an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, and S. The heteroaryl group may be substituted or unsubstituted. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings, such as indolyl groups, are aromatic, and also include fused ring compounds in which only one ring, such as 2,3-dihydroindolyl groups, is aromatic. Exemplary substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.

[0027] A heterocyclic alkyl group is an alkyl group as defined above, where a hydrogen bond or a carbon bond of the alkyl group is replaced by a bond to a heterocyclic group as defined above. The heterocyclic alkyl group can be substituted or unsubstituted. A substituted heterocyclic alkyl group may be substituted in the alkyl portion, the heterocyclic portion, or both the alkyl portion and the heterocyclic portion of the group. Representative heterocyclic alkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclic alkyl groups may be substituted one or more times with substituents such as those listed above.

[0028] A heteroarylalkyl group is an alkyl group as defined above, where a hydrogen bond or a carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above. The heteroarylalkyl group can be substituted or unsubstituted. A substituted heteroarylalkyl group may be substituted in the alkyl portion, the heteroaryl portion, or both the alkyl portion and the heteroaryl portion of the group. Representative substituted heteroarylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0029] Groups described herein that have two or more attachment points (i.e., divalent, trivalent, or polyvalent) within the compounds of the present technology are designated using the suffix “ylene”. For example, a divalent alkyl group is an alkylene group, a divalent aryl group is an arylene group, a divalent heteroaryl group is a divalent heteroarylene group, and so on. Substituents having a single attachment point to the compounds of the present technology are not referred to using the “ylene” designation. Thus, for example, chloroethyl is not referred to as chloroethylene herein.

[0030] An alkoxy group is a hydroxyl group (-OH) in which the bond to a hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. The alkoxy group can be substituted or unsubstituted. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, etc. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.

[0031] As used herein, the terms "alkanoyl" and "alkanoyloxy" refer to -C(O)-alkyl groups and -O-C(O)-alkyl groups containing 2 to 5 carbon atoms, respectively. Similarly, "aroyl" and "aroyloxy" refer to -C(O)-aryl groups and -O-C(O)-aryl groups.

[0032] The terms "aryloxy" and "arylalkoxy" refer to a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to an oxygen atom in an alkyl, respectively. Examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy groups and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.

[0033] As used herein, the term "carboxylate" refers to a -COOH group.

[0034] As used herein, the term "ester" refers to -COOR 70 and -C(O)O-G groups. R 70is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. G is a carboxylate protecting group. Carboxylate protecting groups are well known to those skilled in the art. A comprehensive list of protecting groups for the carboxylate group functionality can be found in Protective Groups in Organic Synthesis, Greene, T.W, Wuts, P.G.M., John Wiley & Sons, New York, NY, (3rd Edition, 1999), and can be added or removed using the procedures described therein, and the entirety thereof is hereby incorporated by reference herein for all purposes as if fully set forth herein.

[0035] The term "amide" (or "amido") refers to C- and N-amide groups, i.e., -C(O)NR 71 R 72 and -NR 71 C(O)R 72 groups. R 71 and R 72 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Thus, amide groups include, but are not limited to, carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). In some embodiments, the amide is -NR 71 C(O)-(C 1-5 alkyl), and this group is referred to as "carbonylamino", and in other embodiments, the amide is -NHC(O)-alkyl, and this group is referred to as "alkanoylamino".

[0036] The term "nitrile" or "cyano" as used herein refers to a -CN group.

[0037] Urethane groups include N- and O-urethane groups, i.e., -NR 73 C(O)OR74 and -OC(O)NR 73 R 74 groups. R 73 and R 74 are, independently, a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R 73 may be H.

[0038] As used herein, the term "amine" (or "amino") refers to an -NR 75 R 76 group, where R 75 and R 76 are, independently, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is an alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0039] The term "sulfonamide" refers to S- and N-sulfonamide groups, i.e., -SO2NR 78 R 79 and -NR 78 SO2R 79 groups. R 78 and R 79 are, independently, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Thus, sulfonamide groups include, but are not limited to, sulfamoyl groups (-SO2NH2). In some embodiments herein, the sulfonamide is -NHSO2-alkyl and is referred to as an "alkylsulfonylamino" group.

[0040] The term "thiol" refers to an -SH group, while "sulfide" contains an -SR 80 group, "sulfoxide" contains an -S(O)R 81 group, "sulfone" contains an -SO2R 82 group, and "sulfonyl" contains an -SO2OR 83 group. R 80 , R 81 , R 82 , and R 83 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl, or heterocyclylalkyl group as defined herein. In some embodiments, the sulfide is an alkylthio group, -S-alkyl.

[0041] The term "urea" refers to an -NR 84 -C(O)-NR 85 R 86 group. R 84 , R 85 , and R 86 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0042] The term "amidine" refers to -C(NR 87 )NR 88 R 89 and -NR 87 C(NR 88 )R 89 , where R 87 , R 88 , and R 89 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0043] The term "guanidine" refers to -NR 90 C(NR 91 )NR 92 R93 refers to, where R 90 , R 91 , R 92 and R 93 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0044] The term "enamine" refers to -C(R 94 )=C(R 95 )NR 96 R 97 and -NR 94 C(R 95 )=C(R 96 )R 97 refers to, where R 94 , R 95 , R 96 and R 97 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0045] As used herein, the term "halogen" or "halo" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

[0046] As used herein, the term "hydroxyl" refers to -OH or its ionized form, -O-. A "hydroxyalkyl" group is a hydroxyl-substituted alkyl group such as HO-CH2-.

[0047] The term "imide" refers to -C(O)NR 98 C(O)R 99 refers to, where R 98 and R 99is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0048] The term "imine" refers to -CR 100 (NR 101 ) and -N(CR 100 R 101 ) groups, wherein R 100 and R 101 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined herein, provided that both R 100 and R 101 are not hydrogen simultaneously.

[0049] As used herein, the term "nitro" refers to the -NO2 group.

[0050] As used herein, the term "trifluoromethyl" refers to -CF3.

[0051] As used herein, the term "trifluoromethoxy" refers to -OCF3.

[0052] The term "azide" refers to -N3.

[0053] The term "trialkylammonium" refers to the -N(alkyl)3 group. Since the trialkylammonium group is positively charged, it usually has a related anion such as a halogen anion.

[0054] The term "isocyano" refers to -NC.

[0055] The term "isothiocyano" refers to -NCS.

[0056] The term "pentafluorosulfanyl" refers to -SF5.

[0057] As will be understood by those skilled in the art, for any and all purposes, particularly from the perspective of providing a written description, all ranges disclosed herein also include any and all possible sub-ranges and combinations of those sub-ranges. It can be readily recognized that any of the recited ranges are sufficiently described and enabled such that the same range can be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily divided into lower thirds, middle thirds, and upper thirds, etc. As will be understood by those skilled in the art, all words such as "maximum", "at least", "greater than", "less than", etc. include the recited numbers and then refer to ranges that can be divided into sub-ranges as described above. Finally, as will be understood by those skilled in the art, ranges include each individual member. Thus, for example, a group having 1 to 3 atoms refers to a group having 1, 2, or 3 atoms. Similarly, a group having 1 to 5 atoms refers to a group having 1, 2, 3, 4, or 5 atoms, and so on.

[0058] As will be understood by those skilled in the art, "molecular weight" (also known as "relative molar mass") is a dimensionless quantity, but is converted to molar mass by multiplying by 1 gram / mol or 1 Da. For example, a compound with a weight average molecular weight of 5,000 has a weight average molar mass of 5,000 g / mol and a weight average molar mass of 5,000 Da.

[0059] Pharmaceutically acceptable salts of the compounds described herein are within the scope of the present technology, retain the desired pharmacological activity, and are not biologically undesirable (e.g., the salts are not overly toxic, allergic, or irritating and are bioavailable), and include addition salts of acids or bases. When the compounds of the present technology have a basic group such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, boric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid), or acidic amino acids (such as aspartic acid and glutamic acid). When the compounds of the present technology have an acidic group such as, for example, a carboxylic acid group, salts can be formed with metals such as alkali metals and alkaline earth metals (e.g., Na + 、Li + 、K + 、Ca 2+ 、Mg 2+ 、Zn 2+ ), ammonia, or organic amines (such as dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine), or basic amino acids (such as arginine, lysine, ornithine). Such salts can be prepared in situ during the isolation and purification of the compound, or by separately reacting the purified compound in the form of the free base or free acid with the appropriate acid or base and isolating the salt thus formed.

[0060] Those skilled in the art will understand that the compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or stereoisomerism. Since the formula diagrams within this specification and the claims can represent only one of the possible tautomeric, conformational, stereochemical, or geometric isomeric forms, it should be understood that the present technology encompasses the tautomers, conformational isomers, stereochemical isomers, and / or geometric isomeric forms of the compounds having one or more utilities described herein, as well as mixtures of these various different forms.

[0061] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The presence and concentration of the isomers depend on the environment in which the compound exists and may vary, for example, depending on whether the compound is in the solid state, an organic solution, or an aqueous solution. For example, in an aqueous solution, quinazolinone may exhibit the following isomers, which are called tautomers of each other:

Chem.

Chem.

[0062] Stereoisomers of a compound (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of the structure unless a specific stereochemistry is explicitly indicated. Thus, the compounds used in the present technology include enantiomers enriched or separated at any or all of the asymmetric atoms, as is apparent from the depiction. Both racemic mixtures and mixtures of diastereomers, as well as individual optical isomers, can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and all such stereoisomers are within the scope of the present technology.

[0063] The compounds of the present technology may exist as solvates, particularly hydrates. Hydrates may be formed during the manufacture of the compound or a composition containing the compound, or may form over time due to the hygroscopicity of the compound. The compounds of the present technology may also exist as organic solvates, including, inter alia, DMF, ether, and alcohol solvates. The identification and preparation of any particular solvate is within the skill of those in the art of synthetic organic or medicinal chemistry.

[0064] Throughout this disclosure, various publications, patents, and published patent specifications are referenced by identifying citation. Also included within this disclosure are Arabic numerals that refer to the cited references, and the complete bibliographic details thereof are provided after the Examples section. The disclosures of these publications, patents, and published patent specifications are hereby incorporated by reference into this disclosure to more fully describe the present technology.

[0065] The present technology Poly(ADP-ribose) polymerase 1 (PARP1) is a member of a family of proteins involved in numerous cellular processes such as DNA repair, genomic stability, and programmed cell death. PARP1 is an ADP-ribosyltransferase that uses NAD+ as a substrate, modifies -proteins- including itself by PARylation, detects single-strand DNA breaks, and plays an important role in homologous recombination and DNA repair by signaling the enzymatic processes involved in the repair of single-strand DNA breaks.

[0066] Several PARP1 inhibitors have been approved for the treatment of breast and ovarian cancers that are defective in other DNA repair mechanisms. Furthermore, PARP inhibitors are currently being clinically tested for the treatment of ovarian cancer, pancreatic and biliary malignancies, glioblastoma, lung cancer, and prostate cancer. BRCA1 / 2-deficient cancers are highly sensitive to PARP1 inhibition, and PARP inhibition is lethal in cells with loss-of-function mutations in BRCA1 and BRCA2. Reduced homologous recombination (HR) capacity by other mechanisms also sensitizes cells to PARP inhibitors. Cells without DNA repair defects are usually 1000-fold less sensitive to PARP inhibitors than such defective cells. PARP inhibitors reduce PARylation, trap PARP1 on DNA, and cause replication fork collapse and cell death.

[0067] However, current PARP1 inhibitors such as talazoparib, olaparib, rucaparib, and niraparib have low penetration into the central nervous system (CNS), and veliparib has no effect in most tumors. See, for example, Gupta, Shiv K., et al. "PARP inhibitors for sensitization of alkylation chemotherapy in glioblastoma: impact of blood-brain barrier and molecular heterogeneity" Frontiers in oncology 8 (2019): 670; Kizilbash, S.H. et al. "Restricted delivery of talazoparib across the blood-brain barrier limits the sensitizing effects of PARP inhibition on Temozolomide therapy in glioblastoma" Mol. Cancer Ther, 16 (2017): 2735-2746.

[0068] Therefore, there is a need for PARP inhibitors with improved penetration into the central nervous system for the treatment of brain tumors such as glioblastoma, neuroblastoma, and medulloblastoma.

[0069] This technology not only meets these needs but also provides further advantages. According to the company's in-house prediction model, the compounds of this technology are predicted to exhibit desirable blood-brain barrier (BBB) permeability. These unique prediction models were further verified by in vitro assays that are well-established for predicting BBB permeability in vivo and also by in vivo experiments. Accordingly, this technology provides compounds with favorably improved penetration into the central nervous system, as well as compositions and methods particularly suitable for the treatment of central nervous system cancers.

[0070] Accordingly, in one aspect, this technology provides a compound of formula I, or a pharmaceutically acceptable salt and / or solvate thereof,

Chemical formula

[0071] In any embodiment of this specification, the compound of formula I is a compound of formula IA,

Chemical formula

[0072] In any embodiment of this specification, the compound of formula I is a compound of formula IB,

Chemical formula

[0073] In any embodiment of this specification, R 1 may be aryl, heteroaryl, or non-aromatic heterocyclyl, and R 2 may be H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or non-aromatic heterocyclyl. In any embodiment of this specification, R 1 may be aryl, heteroaryl, or non-aromatic heterocyclyl, and R 2 may be H, alkyl, cycloalkyl, or non-aromatic heterocyclyl. In any embodiment of this specification, X 1 may be F. In any embodiment of this specification, X 2 may be NH.

[0074] In one aspect, there is provided a composition comprising a compound of any of the embodiments disclosed herein, a pharmaceutically acceptable carrier, or one or more excipients, fillers or agents (hereinafter collectively referred to as "pharmaceutically acceptable carrier" unless otherwise indicated and / or specified). In a related aspect, there is provided an agent for treating cancer in a subject, comprising a compound of any of the embodiments disclosed herein and optionally a pharmaceutically acceptable carrier. The agent of any embodiment herein may comprise an effective amount of the compound for treating cancer when combined with a second cancer therapy such as radiotherapy, monoclonal antibody, and / or chemotherapy. In any embodiment herein, the cancer can be breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer (such as brain cancer). The CNS cancer may be glioblastoma, neuroblastoma, and / or medulloblastoma. In a related aspect, there is provided a pharmaceutical composition comprising (i) an effective amount of a compound of any of the embodiments disclosed herein effective for treating cancer and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, the cancer can be breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer (such as brain cancer). In any embodiment herein, the cancer can be breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer (such as brain cancer). In a related aspect, there is provided a pharmaceutical composition comprising (i) an effective amount of a compound of any of the embodiments disclosed herein present in an amount effective for treating cancer when combined with a second cancer therapy (such as radiotherapy, monoclonal antibody, and / or chemotherapy) and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, the cancer can be breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer (such as brain cancer). In a further related aspect, the technology provides a method comprising a compound of any aspect or embodiment disclosed herein and / or a composition of any of the embodiments disclosed herein and / or an agent of any of the embodiments disclosed herein.

[0075] "Effective amount" refers to the amount of a compound or composition necessary to produce a desired effect. An example of an effective amount includes an amount or dosage that results in acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use, including but not limited to a decrease in tumor mass. In any aspect or embodiment disclosed herein of the compositions, pharmaceutical compositions, and methods of the present technology (collectively referred to herein as "any embodiment herein", "any embodiment disclosed herein", etc.), the effective amount can be an amount effective for the treatment of cancer (such as breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer), the treatment of tumors, and / or the reduction of tumors. By way of example, the effective amount of any embodiment herein containing a compound of the present technology can be from about 0.01 μg to about 200 mg of the compound (for example, from about 0.1 μg to about 50 mg of the compound, or from about 10 μg to about 20 mg of the compound). The methods and uses according to the present technology can include an effective amount of a compound of any embodiment disclosed herein. In any aspect or embodiment disclosed herein, the effective amount may be determined in relation to the subject. As used herein, "subject" or "patient" is a mammal such as a cat, dog, rodent, primate, etc. Usually, the subject is a human, preferably a human suffering from pain or suspected of suffering from pain. The terms "subject" and "patient" can be used interchangeably.

[0076] Accordingly, the present technology provides pharmaceutical compositions and agents comprising a compound of any of the embodiments disclosed herein (or a composition of any of the embodiments disclosed herein) and a pharmaceutically acceptable carrier. The compositions can be used in the methods and treatments described herein. The pharmaceutical compositions may be packaged in unit dosage forms. The unit dosage forms can be effective for the treatment of cancers (such as breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer, etc.). The unit dosage forms can be effective for the treatment of tumors by reducing the tumor volume when administered to a subject in need thereof. Generally, the unit dosage of the compounds of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, gender, degree of disease, contraindications, combination therapies, etc. Exemplary unit dosages based on these considerations can also be adjusted or modified by those skilled in the art. For example, the unit dosage for a patient comprising a compound of the present technology can range from 1×10 -4 g / kg to 1 g / kg, preferably from 1×10 -3 g / kg to 1.0 g / kg. The dosage of the compounds of the present technology can also vary from 0.01 mg / kg to 100 mg / kg, or preferably from 0.1 mg / kg to 10 mg / kg. Suitable unit dosage forms include, but are not limited to, parenteral solutions, oral solutions, powders, tablets, pills, gel caps, capsules, troches, suppositories, patches, nasal drops, injections, implantable sustained release formulations, mucoadhesive films, topical varnishes, lipid complexes, liquids, etc.

[0077] Pharmaceutical compositions and drugs can be prepared by mixing one or more compounds and / or compositions of the present technology with pharmaceutically acceptable carriers, excipients, binders, diluents, etc. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The compositions of the present invention can be formulated for various routes of administration, such as oral, parenteral, topical, rectal, nasal, intravaginal administration, or via an implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections. The following dosage forms are presented by way of example and should not be construed as limiting the present technology.

[0078] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets can be acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the present technology, or a pharmaceutically acceptable salt or tautomer thereof, with at least one additive such as starch or other additives. Suitable additives are sucrose, lactose, cellulosesugars, mannitol, maltitol, dextran, starch, agar, alginates, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can include an inert diluent, or a lubricant such as magnesium stearate, or a preservative such as parabens or sorbic acid, or an antioxidant such as ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents or fragrances, or other components that assist administration. Tablets and pills may be further treated with suitable coating materials known in the art.

[0079] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, and may contain an inert diluent such as water. Pharmaceutical formulations and agents may be prepared as liquid suspensions or solutions using sterile liquids such as, but not limited to, oils, water, alcohols, and combinations thereof. For oral or parenteral administration, pharmaceutically suitable surfactants, suspending agents, and emulsifying agents may be added.

[0080] As described above, suspensions may contain oil. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suspension formulations may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations may contain alcohols such as ethanol, isopropyl alcohol, cetyl alcohol, glycerol, and propylene glycol, but are not limited thereto. Ethers such as, but not limited to, poly(ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in suspension formulations.

[0081] Injectable dosage forms generally include aqueous suspensions or oily suspensions that can be prepared using suitable dispersing or wetting agents and suspending agents. Injectable forms may be in the solution phase or in the form of a suspension prepared using a solvent or diluent. Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic saline. Alternatively, sterile oil can also be used as a solvent or suspending agent. Usually, the oil or fatty acid is non-volatile and includes natural oils or synthetic oils, fatty acids, monoglycerides, diglycerides, or triglycerides.

[0082] In the case of injection, the pharmaceutical formulation and / or agent may be a powder suitable for reconstitution in a suitable solution as described above. These examples include, but are not limited to, freeze-dried, rotary-dried, or spray-dried powders, amorphous powders, granules, precipitates, or microparticles. In the case of injection, the formulation may optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof.

[0083] The compounds of the present technology can be administered to the lungs by inhalation through the nose or mouth. Pharmaceutical formulations suitable for inhalation include solutions, sprays, dry powders, or aerosols containing any suitable solvent and optionally, but not limited to, other compounds such as stabilizers, antibacterial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary depending on the requirements of the particular compound, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), serum albumin, harmless proteins such as sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, and / or sugar alcohols. Aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols are typically used for the delivery of the compounds of the present technology by inhalation.

[0084] Dosage forms for topical (including buccal and sublingual) or transdermal administration of the compounds of the present technology include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active ingredient can be mixed, under aseptic conditions, with a pharmaceutically acceptable carrier or excipient and any preservatives or buffers that may be required. Powders and sprays can be prepared using excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Ointments, pastes, creams, and gels can contain, in addition to the therapeutic agent, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof. Absorption promoters can also increase the flow of the compounds of the present technology across the skin. The rate of such flow can be controlled either by providing a membrane that controls the rate (e.g., as part of a transdermal patch) or by dispersing the compound in a polymeric matrix or gel.

[0085] In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the technology of the present invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is hereby incorporated by reference.

[0086] The formulations of the present technology can be designed to be short-acting, immediate-release, long-acting, and sustained-release, as described below. Thus, pharmaceutical formulations can also be formulated for controlled or sustained release.

[0087] The compositions of the present invention may also include, for example, micelles or liposomes, or any other encapsulated form, or may be administered in a sustained-release form to provide long-term storage and / or delivery effects. Thus, pharmaceutical formulations and agents can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as implants such as depot injections or stents. Such implants can use known inert materials such as silicone and biodegradable polymers.

[0088] The specific dosage can be adjusted according to the disease state, age, weight, general health, sex and diet of the subject, dosing interval, route of administration, excretion rate, and combination of drugs. Any of the dosage forms containing an effective amount are well within the scope of routine experimentation and are thus well within the scope of the technology of the present invention.

[0089] One skilled in the art can readily determine the effective amount, for example, by increasing the dose of the compound of the present technology administered to a patient until the mass of the target tumor decreases. The compounds of the present technology can be administered to patients at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal adult weighing about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is sufficient. However, the specific dosage used can be varied or adjusted as deemed appropriate by one skilled in the art. For example, the dosage may depend on many factors including the requirements of the patient, the severity of the B-cell malignancy associated with the tumor (e.g., non-Hodgkin lymphoma or chronic lymphocytic leukemia), and the pharmacological activity of the compound used. The determination of the optimal dosage for a particular patient is well known to those skilled in the art.

[0090] A variety of assays and model systems can be readily used to determine the therapeutic efficacy of the treatment according to the present technology. The effectiveness of the compositions (and determination of effective amounts) and methods of the present technology can also be demonstrated by the reduction in tumor mass and / or the delay in tumor growth and / or the increase in the therapeutic responsiveness of the cancer to a second cancer therapy (such as radiation therapy, monoclonal antibodies, and / or chemotherapy).

[0091] For each indication described herein, the subject shows a 10%, 20%, 30%, 50% or more reduction, up to 75 - 90%, or 95% or more reduction in one or more symptoms (s) caused by or associated with the subject's disorder, compared to a placebo-treated control or other appropriate control subject.

[0092] The compounds of the present technology can also be administered to a patient together with other conventional therapeutic agents that may be useful for the treatment or vaccination of tumors. Administration may include oral administration, parenteral administration, or nasal administration. In any of these embodiments, administration may include intratumoral injection, subcutaneous injection, intravenous injection, intraperitoneal injection, or intramuscular injection. In any of these embodiments, administration may include oral administration. The methods of the present technology can also include administering a conventional therapeutic agent in an amount that can potentially or synergistically be effective for the treatment of cancer (e.g., breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer) sequentially or in combination with one or more compounds of the present technology.

[0093] In one aspect, the compounds of the present technology are administered to a patient in an amount or dosage suitable for therapeutic use. Generally, the unit dosage containing the compounds of the present technology will vary depending on the considerations of the patient. Such considerations include, for example, age, protocol, condition, gender, degree of disease, contraindications, combination therapy, etc. Exemplary unit dosages based on these considerations can also be adjusted or changed by a physician skilled in the art. For example, the unit dosage for a patient containing the compounds of the present technology can vary from 1×10 -4 g / kg to 1 g / kg, preferably from 1×10 -3 g / kg to 1.0 g / kg. The dosage of the compounds of the present technology can also vary from 0.01 mg / kg to 100 mg / kg, or preferably from 0.1 mg / kg to 10 mg / kg.

[0094] The compounds of the present technology can also improve pharmacokinetic properties, toxicity, or bioavailability (e.g., prolongation of in vivo half-life) by modification, for example, by covalent bonding of an organic moiety or conjugate. The conjugate can be a linear or branched hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. The polymer group can include a molecular weight that can be adjusted by those skilled in the art to improve, for example, pharmacokinetic properties, toxicity, or bioavailability. Exemplary conjugates can include polyalkylene glycols (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymers, amino acid polymers, or polyvinylpyrrolidone, and fatty acids or fatty acid ester groups, which can independently include from about 8 to about 70 carbon atoms. The conjugate for use with the compounds of the present technology can also function, for example, as a linker to any suitable substituent or group, a radiolabel (marker or tag), a halogen, a protein, an enzyme, a polypeptide, another therapeutic agent (e.g., a pharmaceutical or drug), a nucleoside, a dye, an oligonucleotide, a lipid, a phospholipid, and / or a liposome. In one aspect, the conjugate can include polyethyleneamine (PEI), polyglycine, a hybrid of PEI and polyglycine, polyethylene glycol (PEG), or methoxypolyethylene glycol (mPEG). The complex can also constitute a probe of the present technology by binding the compound of the present technology to, for example, a label (fluorescent or luminescent) or a marker (radionuclide, radioisotope, and / or isotope). The conjugate for use with the compounds of the present technology can, in one aspect, improve the in vivo half-life. Other exemplary conjugates for use with the compounds of the present technology, as well as their uses and related techniques, include those generally described in U.S. Patent No. 5,672,662, which is incorporated herein by reference.

[0095] In another aspect, the present technology provides a method for identifying a target of interest, which includes contacting the target of interest with a detectable amount or an imaging-effective amount of a labeled compound of the present technology. The detectable amount or the imaging-effective amount is the amount of the labeled compound of the present technology necessary to be detected by a selected detection method. For example, the detectable amount can be a dosage sufficient to detect the binding of the labeled compound to the target of interest. Suitable labels are known to those skilled in the art and can include, for example, radioisotopes, radionuclides, isotopes, fluorescent groups, biotin (in combination with streptavidin complexation), and chemiluminescent groups. When the labeled compound binds to the target of interest, the target can be further characterized, such as by being isolated, purified, and determining its amino acid sequence.

[0096] The terms "associate" and / or "bind" may, for example, mean a chemical or physical interaction between a compound of the present technology and a target of interest. Examples of association or interaction include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions, and complexes. Association can be used to describe various chemical or physical interactions and thus may generally refer to "binding" or "affinity". Measuring binding or affinity is also routine for those skilled in the art. For example, a compound of the present technology can bind to or interact with a target of interest or its precursor, moiety, fragment, and peptide, and / or their deposits.

[0097] As described above in the present disclosure, in one aspect, a method for treating a subject suffering from cancer is provided, the method including administering to the subject an effective amount of a compound of any of the embodiments disclosed herein, or an effective amount of a composition of any of the embodiments disclosed herein, and optionally administering an effective amount of a second cancer therapy. In any of the embodiments herein, the cancer can be breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer (such as brain cancer).

[0098] In any embodiment of the present specification, administration may further include administration of radiotherapy, monoclonal antibodies, and / or chemotherapeutic agents (such as alkylating agent nitrosourea, antimetabolites, anthracyclines, topoisomerase II inhibitors, mitotic inhibitors, anti-estrogens, progestins, aromatase inhibitors, anti-androgens, LHRH agonists, corticosteroid hormones, DNA alkylating agents, taxanes, vinca alkaloids, microtubule poisons, or any combination of two or more thereof). In any embodiment of the present specification, administration may further include administration of chemotherapeutic agents such as busulfan, cisplatin, carboplatin, oxaliplatin, octahedral platinum(IV) compounds, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), mechlorethamine (nitrogen mustard), melphalan, temozolomide, carmustine (BCNU), lomustine (CCNU), 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine, pemetrexed, daunorubicin, doxorubicin (adriamycin), epirubicin, idarubicin, mitoxantrone, topotecan, irinotecan, etoposide (VP-16), teniposide, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, L-asparaginase, dactinomycin, thalidomide, tretinoin, imatinib (Gleevec), gefitinib (Iressa), erlotinib (Tarceva), rituximab (Rituxan), bevacizumab (Avastin), ipilimumab, nivolumab (Opdivo), pembrolizumab (Keytruda), tamoxifen, fulvestrant, anastrozole, exemestane, letrozole, megestrol acetate, bicalutamide, flutamide, leuprolide, goserelin, or any combination of two or more thereof.

[0099] In any embodiment of the present specification, administration may include oral, rectal, nasal, vaginal, parenteral, transdermal, intravenous, intramuscular, or inhalation administration. In any embodiment of the present specification, administration may include topical administration of a compound to a site of a subject including cancer, or topical administration of a composition to a site of a subject including cancer.

[0100] The examples herein are provided to illustrate the advantages of the present technology and to further assist those skilled in the art regarding the preparation or use of the compounds and compositions of the present technology. The examples herein are also presented to more fully illustrate the preferred embodiments of the present technology. The examples should in no way be construed as limiting the scope of the present technology as defined by the appended claims. The examples can include or incorporate any of the variations, aspects, or embodiments of the present technology described above. The variations, aspects, or embodiments described above can also further include or incorporate variations of any one or all of the other variations, aspects, or embodiments of the present technology.

Examples

[0101] All solvents and reagents were used as received from commercial suppliers unless otherwise noted. 1The 1H spectra were recorded on a Bruker AM or Varian 400 spectrometer (operating at 400 MHz respectively) in CDCl3 containing 0.03% TMS as an internal standard. The reported chemical shifts (δ) are shown in parts per million (ppm), and the coupling constants (J) are shown in Hertz (Hz). Spin multiplicities are reported as s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dt = triplet of doublets, td = doublet of triplets, and m = multiplet. LCMS analysis was performed on a chromatograph equipped with a photodiode array UV detector and a TOF mass spectrometer. The mass spectrometer utilized a multi-mode source that simultaneously acquired ESI+ / APCI+, a reference mass solution, and a makeup solvent introduced into the LC flow in front of the source to facilitate ionization. As shown in the following examples, a single stereoisomer was isolated and obtained in high purity, but for a particular set of stereoisomers, the final unambiguous assignment of absolute stereochemistry may be pending.

[0102] Synthesis of Comparative Compounds 0092A and 0092B:

Chemical Structure

[0103] Step 2: HCl (4 N in MeOH, 10 mL) was added to a solution of 2-fluoro-4-{[(1Z)-5-fluoro-7-nitro-3-oxo-2-benzofuran-1-ylidene]methyl}benzonitrile (300 mg, 0.91 mmol) in MeOH (10 mL). The solution was stirred at 25 °C for 12 h. The solvent was removed in vacuo. The crude product (300 mg, 87%) was used directly in the next step without further purification. MS (ESI): C 17 H 10 Calculated mass for C 17 H 10 F2N2O5 is 360.0, found m / z 361.0 [M+H]+

[0104] Step 3: TiCl3 (20% in HCl, 2548 mg, 3.33 mmol) was added to a solution of methyl 2-[2-(4-cyano-3-fluorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (200 mg, 0.56 mmol) and 2,4,6-trifluorobenzaldehyde (166 mg, 1.04 mmol) in THF (30 mL) and MeOH (5 mL). The solution was stirred at 40 °C for 12 h. The mixture was quenched with H2O (50 mL), extracted with EA (50 mL × 3), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC (PE:EA = 3:1) to give the desired product (230 mg, 84%) as a white solid. MS (ESI): C 24 H 13 Calculated mass for C 24 H 13 F2N2O3 is 472.0, found m / z 473.0 [M+H]+

[0105] Step 4: Hydrazine hydrate (37 mg, 0.74 mmol) was added to a solution of methyl 3-(4-cyano-3-fluorophenyl)-7-fluoro-4-oxo-2-(2,4,6-trifluorophenyl)-2,3-dihydro-1H-quinoline-5-carboxylate (100 mg, 0.21 mmol) in MeOH (10 mL). The solution was stirred at 25 °C for 2 h. The solution was quenched with H2O (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL). Then, it was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by flash (CH3CN:H2O = 1:3) to obtain the target product (50 mg, 51%) as a white solid. MS(ESI): C 23 H 11 Calculated mass for C19H10F5N4O 454.0, found m / z 455.0 [M+H]+

[0106] Step 5: 2-Fluoro-4-(5-fluoro-3-oxo-8-(2,4,6-trifluorophenyl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-9-yl)benzonitrile was separated by preparative SFC (equipment: SFC80, column: Daicel Chiralcel OD, 250 mm × 30 mm I.D, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 50 / 50, flow rate: 70 g / min, wavelength: UV214 nm, temperature: 35 °C) to obtain 2-fluoro-4-((8S,9R)-5-fluoro-3-oxo-8-(2,4,6-trifluorophenyl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-9-yl)benzonitrile (13.1 mg, 51%) as a white solid, and 2-fluoro-4-((8R,9S)-5-fluoro-3-oxo-8-(2,4,6-trifluorophenyl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-9-yl)benzonitrile (12.6 mg, 51%) as a white solid. MS(ESI): C 23 H 11Calculated mass value for F5N4O is 454.0, measured m / z value is 455.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 7.89 (s, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 12.0 Hz, 1H), 7.31 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.18 (t, J = 8.0 Hz, 2H), 7.09 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 6.85 (dd, J = 10.8 Hz, 2.4 Hz, 1H), 5.28 (d, J = 12.0 Hz, 1H), 4.71 (d, J = 12.0 Hz, 1H).

[0107] Synthesis of 0110A and 0110B [Chemical formula] Step 1: To a solution of 6-fluoro-4-nitro-3H-2-benzofuran-1-one (5 g, 25.4 mmol) in THF (80 mL) were added trimethylamine (5.14 g, 50.8 mmol), Ac2O (15 mL) and 3,4-difluorobenzaldehyde (7.22 g, 50.80 mmol) under N2. After the reaction mixture was stirred at 25 °C for 5 minutes, it was warmed to 80 °C and stirred for 3 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated to give a residue. The residue was stirred with EtOAc (30 mL), filtered, the filter cake was collected and concentrated to give (Z)-3-(2,4-difluorobenzylidene)-6-fluoro-4-nitroisobenzofuran-1(3H)-one (2.2 g, 24%) as a yellow solid.

[0108] Step 2: (Z)-3-(2,4-Difluorobenzylidene)-6-fluoro-4-nitroisobenzofuran-1(3H)-one (1.0 g, 3.00 mmol) was added to 4 M HCl in MeOH (30 mL). The reaction mixture was stirred at 70 °C for 48 h. The reaction mixture was concentrated to give methyl 2-(2-(2,4-difluorophenyl)acetyl)-5-fluoro-3-nitrobenzoate (1.1 g, 90%) as a yellow solid. MS (ESI): C 16 H 10 Calculated mass for C 16 H 10 F3NO5 is 353.05, found m / z 354.1 [M+H]+.

[0109] Step 3: To a solution of 2-(2-(2,4-difluorophenyl)acetyl)-5-fluoro-3-nitrobenzoic acid (270 mg, 0.76 mmol) and 1-methylpiperidine-4-carbaldehyde (194 mg, 1.50 mmol) in THF (18 mL) and MeOH (3 mL) at 0 °C under N2 was added TiCl3 in HCl (5.25 g, 6.82 mmol). The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by preparative TLC (MeOH / DCM = 1 / 10, rf = 0.4) and the fractions having the MS signal of the desired product were collected and concentrated to give methyl 3-(2,4-difluorophenyl)-7-fluoro-2-(1-methylpiperidin-4-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (60 mg, 18%) as a yellow solid. MS (ESI): C 23 H 23 Calculated mass for C 23 H 23 F3N2O3 is 432.17, found m / z 433.1 [M+H]+.

[0110] Step 4: Methyl 3-(2,4-difluorophenyl)-7-fluoro-2-(1-methylpiperidin-4-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (60 mg, 0.18 mmol) was dissolved in MeOH (8 mL), stirred at 25 °C for 20 minutes, and N2H4·H2O (436 mg, 6.96 mmol) was added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u-C18, 150×19 mm, 5um, mobile phase: ACN-H2O (0.1% formic acid), B (acetonitrile), flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give 9-(2,4-difluorophenyl)-5-fluoro-8-(1-methylpiperidin-4-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one as a yellow solid. MS(ESI): C 22 H 21 Calculated mass for C22H22F3N4O is 414.17, measured m / z 415.1 [M+H]+.

[0111] Step 5: 9-(2,4-Difluorophenyl)-5-fluoro-8-(1-methylpiperidin-4-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (40 mg, 0.09 mmol) was separated by preparative SFC (Daicel Chiralpak IB, 30×250 mm, 10um, mobile phase A / B: CO2 / MeOH (0.1% EDA)) = 60 / 40, flow rate: 1.5 mL / min, column temperature: 34 °C) to give (8R,9R)-9-(2,4-difluorophenyl)-5-fluoro-8-(1-methylpiperidin-4-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one as a white solid (6.7 mg, 17%) and (8R,9S)-9-(2,4-difluorophenyl)-5-fluoro-8-(1-methylpiperidin-4-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one as a white solid (8.2 mg, 20%).

[0112] 0110A: MS(ESI): C 22 H 21 Calculated mass for F3N4O: 414.17, measured m / z: 415.1 [M+H]+. 1 H NMR (400 MHz, MeOD) δ = 7.15 (dd, J = 10.0 Hz, 4.0 Hz, 1H), 7.03 - 6.98 (m, 1H), 6.85 - 6.78 (m, 2H), 6.75 - 6.69 (m, 1H), 4.55 (d, J = 3.6 Hz, 1H), 3.37 - 3.31 (m, 1H), 2.99 - 2.90 (m, 2H), 2.33 (s, 3H), 2.14 - 2.03 (m, 2H), 1.81 (d, J = 12.0 Hz, 1H), 1.63 - 1.39 (m, 4H).

[0113] 0110B: MS(ESI): C 22 H 21 Calculated mass for F3N4O: 414.17, measured m / z: 415.1 [M+H]+. 1 H NMR (400 MHz, MeOD) δ = 7.14 (dd, J = 10.0 Hz, 4.0, 1H), 7.02 - 6.97 (m, 1H), 6.85 - 6.78 (m, 2H), 6.75 - 6.69 (m, 1H), 4.55 (d, J = 3.6 Hz, 1H), 3.36 - 3.35 (m, 1H), 2.99 - 2.90 (m, 2H), 2.27 (s, 3H), 2.06 - 1.95 (m, 2H), 1.78 (d, J = 12.0 Hz, 1H), 1.53 - 1.41 (m, 4H).

[0114] Synthesis of 0111-6, 0111, 0111B, 0111C, and 0111D:

Chemical Structure

[0115] Step 2: 1-Bromo-2-methoxyethane (327 mg, 2.35 mmol) and K2CO3 (974 mg, 7.05 mmol) were added to a solution of methyl 3-(2,4-difluorophenyl)-7-fluoro-4-oxo-2-(pyrrolidin-3-yl)-2,3-dihydro-1H-quinoline-5-carboxylate (950 mg, 2.35 mmol) in ACN (10 mL). The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was quenched with H2O (15 mL) and extracted with EA (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on a silica gel column (PE:EA = 3:1) to give methyl 3-(2,4-difluorophenyl)-7-fluoro-2-[1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (600 mg, 50%) as a yellow oil. MS (ESI): C 24 H 25Calculated mass value for F3N2O4 is 462.18, measured m / z value is 463.1 [M+H]+.

[0116] Step 3: N2H4H2O (650 mg, 12.97 mmol) was added to a solution of methyl 3-(2,4-difluorophenyl)-7-fluoro-2-[1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (600 mg, 1.30 mmol) in MeOH (10 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H2O (15 mL) and extracted with EA (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (equipment: Waters preparative HPLC, column: Xbridge preparative c18, 5um, OBD19×150mm / WELCH Xtimate C18 21.2×250mm, 10um, A water (0.1% formic acid), B acetonitrile, flow 10 - 20% B for 8 min, hold at 100% B for 2 min, return to 5% B in 0.5 min, stop at 13 min, flow rate: 20 ml / min, wavelength: 214 / 254 nm) to give 12-(2,4-difluorophenyl)-7-fluoro-11-[1-(2-methoxyethyl)pyrrolidin-3-yl]-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5(13),6,8-tetraen-4-one (“0111-6”, 300 mg, 50%) as a yellow solid. MS(ESI): C 23 H 23 Calculated mass value for F3N4O2 is 444.18, measured m / z value is 445.1 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.24 - 7.15 (m, 1H), 7.08 - 6.96 (m, 1H), 6.91 - 6.62 (m, 3H), 4.47 - 4.27 (m, 1H), 3.71 - 3.57 (m, 4H), 3.45 - 3.39 (m, 3H), 3.39 - 3.33 (m, 3H), 3.29 - 3.23 (m, 1H), 2.75 - 2.59 (m, 1H), 2.39 - 1.96 (m, 3H).

[0117] Step 4: 0111-6 (300 mg, 0.68 mmol) was separated by preparative SFC (apparatus: SFC80 column: Daicel Chiralpak OX_3, 3×150 mm, 3 um, mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 65 / 35, flow rate: 70 g / min, wavelength: UV214 nm, temperature: 35 °C) and (apparatus: SFC80 column: Daicel Chiralpak IE_3, 3.0×150 mm, 3 um, mobile phase: A / B: CO2 / MeOH (0.1% DEA) = 65 / 35, flow rate: 70 g / min, wavelength: UV214 nm, temperature: 35 °C) to obtain 0111 (27.2 mg, 9%) as a yellow solid, 0111B (20.7 mg, 7%) as a white solid, 0111C (48 mg, 16%) as a white solid, and 0111D (54.9 mg, 18%) as a yellow solid.

[0118] 0111A: 1 H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.32 - 7.27 (m, 1H), 7.00 - 6.82 (m, 3H), 6.75 - 6.69 (m, 1H), 6.34 (s, 1H), 4.22 (d, J = 8.0 Hz, 1H), 3.60 - 3.48 (m, 3H), 3.37 (s, 3H), 3.04 (d, J = 8.0 Hz, 2H), 2.82 - 2.72 (m, 1H), 2.70 - 2.60 (m, 1H), 2.43 - 2.30 (m, 2H), 2.29 - 2.20 (m, 1H), 2.11 - 2.01 (m, 1H), 1.82 - 1.70 (m, 1H).

[0119] 0111B: 1 H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.31 - 7.27 (m, 1H), 7.01 - 6.92 (m, 1H), 6.91 - 6.83 (m, 2H), 6.77 - 6.69 (m, 1H), 6.37 (s, 1H), 4.21 (d, J = 9.1 Hz, 1H), 3.61 - 3.49 (m, 3H), 3.37 (s, 3H), 3.14 - 3.00 (m, 2H), 2.84 - 2.73 (m, 1H), 2.73 - 2.63 (m, 1H), 2.42 - 2.31 (m, 2H), 2.30 - 2.20 (m, 1H), 2.12 - 2.02 (m, 1H), 1.83 - 1.74 (m, 1H).

[0120] 0111C: 1 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 7.26 - 7.22 (m, 2H), 7.16 - 7.08 (m, 1H), 6.97 - 6.84 (m, 2H), 6.73 - 6.63 (m, 1H), 4.13 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 12.0 Hz, 1H), 3.60 - 3.52 (m, 2H), 3.43 (s, 3H), 3.27 - 3.14 (m, 1H), 3.04 - 2.90 (m, 1H), 2.84 - 2.74 (m, 1H), 2.69 - 2.56 (m, 1H), 2.44 - 2.30 (m, 1H), 2.28 - 2.17 (m, 1H), 2.10 - 2.02 (m, 1H), 1.92 - 1.75 (m, 2H).

[0121] 0111D: 1 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.26 - 7.21 (m, 2H), 7.17 - 7.07 (m, 1H), 7.00 - 6.77 (m, 2H), 6.65 (d, J = 12.0 Hz, 1H), 4.13 (d, J = 12.0 Hz, 1H), 3.77 (d, J = 12.0 Hz, 1H), 3.60 - 3.49 (m, 2H), 3.44 (s, 3H), 3.26 - 3.11 (m, 1H), 3.02 - 2.88 (m, 1H), 2.85 - 2.69 (m, 1H), 2.69 - 2.53 (m, 1H), 2.45 - 2.27 (m, 1H), 2.25 - 1.98 (m, 3H), 1.90 - 1.77 (m, 1H).

[0122] Synthesis of 0114A and 0114B

Chemical Structure

[0123] Step 2: To a solution of methyl 3-(2,4-difluorophenyl)-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (150 mg, 0.45 mmol) in MeOH (8 mL) was added N2H4·H2O (8 mL) under N2, and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated directly to give a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u-C18, 150 × 19 mm, 5 um, mobile phase A: ACN-H2O (0.1% formic acid), B (acetonitrile), flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give 9-(2,4-difluorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one as a white solid (60 mg, 42%). MS (ESI): C 16 H 10 Calculated mass for C15H10F3N3O 317.08, found m / z 318.1 [M + H]+ + .

[0124] Step 3: 9-(2,4-Difluorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (60 mg, 0.19 mmol) was separated by preparative SFC (Daicel Chiralpak AD_3, 3×150 mm, 3 μm, mobile phase A / B: CO2 / MeOH (0.1% EDA) = 65 / 35, flow rate: 2.0 mL / min, column temperature: 37 °C) to obtain white solid (R)-9-(2,4-difluorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (24.0 mg, 40%) and white solid (S)-9-(2,4-difluorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (25.6 mg, 43%). MS (ESI): C 16 H 10 Calculated mass for C16H11F3N3O 317.08, found m / z 318.1 [M+H] + 。

[0125] 0114A: 1 H NMR (400 MHz, CD3OD) δ 7.18 (dd, J = 9.2, 2.4 Hz, 1H), 7.10 - 6.94 (m, 2H), 6.94 - 6.75 (m, 2H), 4.52 - 4.47 (m, 1H), 3.71 - 3.57 (m, 2H).

[0126] 0114B: 1 H NMR (400 MHz, CD3OD) δ 7.18 (dd, J = 9.2, 2.4 Hz, 1H), 7.10 - 6.95 (m, 2H), 6.93 - 6.78 (m, 2H), 4.53 - 4.47 (m, 1H), 3.71 - 3.56 (m, 2H).

[0127] Synthesis of 0115A, 0115B, 0115C, and 0115D:

Chemical formula

[0128] Step 2: To a solution of methyl (2R,3R)-3-(2,4-difluorophenyl)-7-fluoro-4-oxo-2-(oxolan-3-yl)-2,3-dihydro-1H-quinoline-5-carboxylate (200 mg, 0.49 mmol) in MeOH (5 mL) was added NH2NH2·H2O (1.56 g, 24.67 mmol). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with H2O (15 mL) and extracted with EA (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give the product (110 mg). Then, it was separated by preparative SFC apparatus: SFC80, column: Daicel Chiralcel OJ, 250 mm × 30 mm I.D., 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 80 / 20, flow rate: 70 g / min, wavelength: UV214 nm, temperature: 35 °C) to afford 25.3 mg of the product (0115) as a white solid and 24.0 mg of the product (0115B) as a white solid.

[0129] 0115A: MS(ESI): C 20 H 16 Calculated mass for F3N3O2: 387.12, measured m / z: 388.1 [M+H] + 。 1 H NMR(400 MHz, MeOD) δ 7.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.90 - 6.72 (m, 3H), 4.27 (d, J = 4.0 Hz, 1H), 3.98 - 3.83 (m, 2H), 3.75 - 3.62 (m, 2H), 3.56 - 3.50 (m, 1H), 2.50 - 2.39 (m, 1H), 2.05 - 1.82 (m, 2H).

[0130] 0115B: MS(ESI): C 20 H 16 Calculated mass for F3N3O2: 387.12, measured m / z: 388.1 [M+H] + 。 1 H NMR(400 MHz, MeOD) δ 7.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.02 - 6.96 (m, 1H), 6.90 - 6.72 (m, 3H), 4.27 (d, J = 4.0 Hz, 1H), 3.96 - 3.84 (m, 2H), 3.75 - 3.62 (m, 2H), 3.56 - 3.50 (m, 1H), 2.50 - 2.39 (m, 1H), 2.05 - 1.82 (m, 2H).

[0131] Step 2: NH2NH2·H2O (1.56 g, 24.67 mmol) was added to a solution of methyl (2S,3S)-3-(2,4-difluorophenyl)-7-fluoro-4-oxo-2-(oxolan-3-yl)-2,3-dihydro-1H-quinoline-5-carboxylate (200 mg, 0.49 mmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with H2O (15 mL) and extracted with EA (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give the product (120 mg). Subsequently, it was separated by a preparative SFC apparatus: SFC80, column: Daicel Chiralcel IC, 250 mm × 30 mm I.D., 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 65 / 35, flow rate: 70 g / min, wavelength: UV214 nm, temperature: 35 °C), to give 35.4 mg of the product as a white solid (0115C) and 30.6 mg of the product as a white solid (0115D).

[0132] 0115C: MS(ESI): C 20 H 16 Calculated mass for C + H 1 F3N3O2 is 387.12, measured m / z 388.1 [M+H]

[0133] 0115D: MS(ESI): C 20 H 16 Calculated mass for C + H 11H NMR (400 MHz, MeOD) δ 7.16 (dd, J = 9.2, 2.4 Hz, 1H), 7.05 - 6.96 (m, 1H), 6.85 - 6.75 (m, 2H), 6.70 - 6.62 (m, 1H), 4.45 (d, J = 3.2 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.80 - 3.66 (m, 3H), 3.50 - 3.44 (m, 1H), 2.54 - 2.40 (m, 1H), 2.20 - 2.09 (m, 1H), 1.90 - 1.78 (m, 1H).

[0134] Synthesis of 0116A and 0116B

Chemical Structure

[0135] Step 2: (3Z)-3-[(2-Chlorophenyl)methylene]-6-fluoro-4-nitro-2-benzofuran-1-one (1.1 g, 3.40 mmol) was added to 4 M HCl in MeOH (30 mL). The reaction mixture was stirred at 70 °C for 48 h. The reaction mixture was concentrated to give methyl 2-(2-(2-chlorophenyl)acetyl)-5-fluoro-3-nitrobenzoic acid (920 mg, 76%) as a yellow solid. MS (ESI): C 16 H 11 Calculated mass for C 16 H 11 ClFNO5 is 351.03, found m / z 352.0 [M+H] + .

[0136] Step 3: To a solution of methyl 2-[2-(2-chlorophenyl)acetyl]-5-fluoro-3-nitrobenzoic acid (400 mg, 1.14 mmol) and 1-methylpiperidine-4-carbaldehyde (289 mg, 2.27 mmol) in THF (18 mL) and MeOH (3 mL) was added TiCl3·HCl (5.25 g, 6.82 mmol) at 0 °C under N2. The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give a residue. The residue was purified by preparative TLC (MeOH / DCM = 1 / 10, rf = 0.4) and the fractions containing the MS signal of the desired product were collected and concentrated to give methyl 3-(2-chlorophenyl)-7-fluoro-2-(1-methylpiperidin-4-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg, 24%) as a yellow oil. MS (ESI): C 23 H 24 Calculated mass for C 23 H 24 ClFN2O3 is 430.15, found m / z 431.1 [M+H]+.

[0137] Step 4: Methyl 3-(2-chlorophenyl)-7-fluoro-2-(1-methylpiperidin-4-yl)-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (100 mg, 0.23 mmol) was dissolved in MeOH (8 mL), stirred at 25 °C for 20 minutes, N2H4·H2O (436 mg, 6.96 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u-C18, 150x19 mm, 5 um, mobile phase: ACN-H2O (0.1% formic acid), B (acetonitrile), flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give 9-(2-chlorophenyl)-5-fluoro-8-(1-methylpiperidin-4-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (50 mg, 52%) as a white solid. MS(ESI): C 22 H 22 Calculated mass for ClFN4O 412.15, measured m / z 413.1 [M+Na]+.

[0138] Step 5: 9-(2-chlorophenyl)-5-fluoro-8-(1-methylpiperidin-4-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (50 mg, 0.12 mmol) was separated by preparative SFC (Daicel Chiralpak IB 30×250 mm, 10 um, mobile phase A / B: CO2 / MeOH (0.1% EDA)) = 60 / 40, flow rate: 1.5 mL / min, column temperature: 34 °C) to give (8R,9R)-9-(2-chlorophenyl)-5-fluoro-8-(1-methylpiperidin-4-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (15.0 mg, 30%) as a white solid, and (8S,9S)-9-(2-chlorophenyl)-5-fluoro-8-(1-methylpiperidin-4-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (8.5 mg, 17%) as a white solid.

[0139] 0116A: MS(ESI): C22 H 22 Calculated mass for ClFN4O: 412.15, measured m / z: 413.1 [M+Na] + 。 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.50 (dd, J = 8.0, 1.2 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.26 (td, J = 7.6, 1.6 Hz, 1H), 7.18 (td, J = 7.6, 1.2 Hz, 1H), 7.01 (dd, J = 9.2, 2.4 Hz, 1H), 6.90 (dd, J = 11.2, 2.4 Hz, 1H), 6.66 (dd, J = 7.6, 1.2 Hz, 1H), 4.56 (d, J = 3.6 Hz, 1H), 3.36 - 3.30 (m, 1H), 2.95 - 2.80 (m, 2H), 2.20 (s, 3H), 1.96 (t, J = 10.4 Hz, 1H), 1.91 - 1.75 (m, 2H), 1.72 - 1.50 (m, 2H), 1.45 - 1.33 (m, 2H).

[0140] 0116B: MS (ESI): C 22 H 22 Calculated mass for ClFN4O: 412.15, measured m / z: 413.1 [M+Na] + 。H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.49 (dd, J = 8.0, 1.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.26 (td, J = 7.6, 1.6 Hz, 1H), 7.23 - 7.11 (m, 1H), 7.00 (dd, J = 8.8, 2.4 Hz, 1H), 6.95 - 6.87 (m, 1H), 6.70 - 6.66 (m, 1H), 4.55 (d, J = 3.6 Hz, 1H), 3.34 - 3.32 (m, 1H), 2.84 - 2.68 (m, 2H), 2.08 (s, 3H), 1.72 (t, J = 10.4 Hz, 2H), 1.67 - 1.58 (m, 2H), 1.57 - 1.46 (m, 1H), 1.40 - 1.26 (m, 2H).

[0141] Synthesis of 0117-8, 0117A, 0117B, 0117C, and 0117D:

Chemical Structure

[0142] Step 2: 1-Bromo-2-methoxyethane (207 mg, 1.49 mmol) and K2CO3 (618 mg, 4.47 mmol) were added to a solution of methyl 3-(2-chlorophenyl)-7-fluoro-4-oxo-2-(pyrrolidin-3-yl)-2,3-dihydro-1H-quinoline-5-carboxylate (600 mg, 1.49 mmol) in ACN (10 mL). The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was quenched with H2O (15 mL) and extracted with EA (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on a silica gel column (EA) to obtain methyl 3-(2-chlorophenyl)-7-fluoro-2-[1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (400 mg, 55%) as a yellow oil. MS (ESI): C 24 H 26Calculated mass for ClFN2O4: 460.16, measured m / z: 461.1 [M+H]+.

[0143] Step 3: To a solution of methyl 3-(2-chlorophenyl)-7-fluoro-2-[1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (400 mg, 0.87 mmol) in MeOH (5 mL) was added N2H4H2O (217 mg, 4.34 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H2O (15 mL) and extracted with EA (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (instrument: Waters preparative HPLC, column: Xbridge preparative c18, 5um, OBD, 19 × 150 mm, A water (0.1% formic acid), B acetonitrile, 10 - 20% B in 8 min, hold at 100% B for 2 min, return to 5% B in 0.5 min, stop at 13 min, flow rate: 20 ml / min, wavelength: 214 / 254 nm) to give 12-(2-chlorophenyl)-7-fluoro-11-[1-(2-methoxyethyl)pyrrolidin-3-yl]-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5(13),6,8-tetraen-4-one (「0117-8」, 260 mg, 65%) as a yellow solid. MS (ESI): C 23 H 24 Calculated mass for ClFN4O2: 442.16, measured m / z: 443.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 9.91 (d, J = 80.0 Hz, 1H), 8.56 (s, 0H), 7.48 - 7.40 (m, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.08 (m, 2H), 6.92 - 6.79 (m, 1H), 6.73 - 6.62 (m, 1H), 4.57 - 4.43 (m, 1H), 3.88 - 3.53 (m, 3H), 3.43 - 3.35 (m, 3H), 3.29 - 2.97 (m, 2H), 2.96 - 2.49 (m, 3H), 2.45 - 1.85 (m, 4H).

[0144] Step 4: 0117-8 (300 mg, 0.68 mmol) was separated by preparative SFC (apparatus: SFC80 column: Daicel Chiralpak OX_3, 3×150 mm, 3 um, mobile phase: A / B: CO2 / MeOH(0.1% DEA)=65 / 35, flow rate: 70 g / min, wavelength: UV214 nm, temperature: 35 °C) and (apparatus: SFC80 column: Daicel Chiralpak IE_3, 3.0×150 mm, 3 um, mobile phase: A / B: CO2 / MeOH(0.1% DEA)=50 / 50, flow rate: 70 g / min, wavelength: UV214 nm, temperature: 35 °C), and 0117 (13.6 mg, 18%) as a white solid, 0117B (16.5 mg, 22%) as a white solid, 0117C (26.0 mg, 35%) as a white solid, and 0117D (28 mg, 37%) as a yellow solid were obtained. MS(ESI): C 23 H 24 Calculated mass for C + H

[0145] 0117A: 1 H NMR(400 MHz, CD3OD) δ 7.45 - 7.36 (m, 1H), 7.22 - 7.02 (m, 3H), 6.82 - 6.71 (m, 1H), 6.52 (d, J = 7.6 Hz, 1H), 4.57 (d, J = 2.4 Hz, 1H), 3.55 - 3.42 (m, 3H), 3.33 - 3.28 (m, 3H), 2.95 - 2.61 (m, 6H), 2.54 - 2.38 (m, 1H), 2.19 - 1.91 (m, 2H).

[0146] 0117B: 1 H NMR(400 MHz, CD3OD) δ 7.50 - 7.40 (m, 1H), 7.29 - 7.17 (m, 2H), 7.14 - 7.03 (m, 1H), 6.91 - 6.78 (m, 1H), 6.58 - 6.48 (m, 1H), 4.64 - 4.59 (m, 1H), 3.68 - 3.54 (m, 3H), 3.42 - 3.31 (m, 4H), 3.29 - 3.06 (m, 5H), 2.73 - 2.59 (m, 1H), 2.35 - 2.23 (m, 1H), 2.22 - 2.09 (m, 1H).

[0147] 0117C:1 1H NMR (400 MHz, CD3OD) δ 7.49 - 7.37 (m, 1H), 7.26 - 7.06 (m, 3H), 6.85 - 6.75 (m, 1H), 6.70 - 7.58 (m, 1H), 4.51 - 4.47 (m, 1H), 3.60 - 3.48 (m, 3H), 3.34 (s, 3H), 2.99 - 2.58 (m, 6H), 2.49 - 2.28 (m, 1H), 1.95 - 1.76 (m, 2H).

[0148] 0117D: 1 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.54 - 7.40 (m, 1H), 7.32 - 7.28 (m, 2H), 7.26 (d, J = 2.4 Hz, 1H), 7.13 - 7.01 (m, 1H), 6.96 - 6.90 (m, 1H), 4.48 (d, J = 10.8 Hz, 1H), 3.91 (d, J = 10.4 Hz, 1H), 3.69 - 3.63 (m, 2H), 3.60 - 3.49 (m, 2H), 3.43 - 3.35 (m, 3H), 3.06 - 3.00 (m, 1H), 2.96 - 2.90 (m, 1H), 2.84 - 2.76 (m, 1H), 2.64 - 2.54 (m, 1H), 2.40 - 2.24 (m, 2H), 2.12 - 2.00 (m, 1H).

[0149] Synthesis of 0120A and 0120B

Chemical Structure

[0150] Step 2: A mixture of methyl 3-(2-chlorophenyl)-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (140 mg, 0.42 mmol) and N2H4·H2O / MeOH = 1 / 1 (8 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u-C18 150×19 mm, 5 um, mobile phase A: ACN-H2O (0.1% formic acid), B (acetonitrile), flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give 9-(2-chlorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one as a white solid (50 mg, 38%). MS (ESI): C 16 H 11 Calculated mass for C15H10ClFN3O 315.06, found m / z 316.0, 318.0 [M + H] + .

[0151] Step 3: 9-(2-Chlorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (50 mg, 0.16 mmol) was separated by preparative SFC (Daicel Chiralpak IB 30×250 mm, 10 μm, mobile phase A / B: CO2 / MeOH (0.1% EDA) = 50 / 50, flow rate: 1.5 mL / min, column temperature: 37 °C), and (R)-9-(2-chlorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one, a white solid (14.6 mg, 29%), and (S)-9-(2-chlorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one, a white solid (13.2 mg, 26%) were obtained.

[0152] 0120A: MS (ESI): C 16 H 11 Calculated mass for C + H 1 ClFN3O is 315.06, measured m / z 316.0, 318.0 [M+H]

[0153] 0120B: MS (ESI): C 16 H 11 Calculated mass for C + H 1 ClFN3O is 315.06, measured m / z 316.0, 318.0 [M+H]

[0154] Synthesis of 0121-4, 0121A, 0121B, 0121C, and 0121D:

Chemical formula

[0155] Step 2: NH2NH2·H2O (1.56 g, 24.76 mmol) was added to a solution of methyl 3-(2-chlorophenyl)-7-fluoro-4-oxo-2-(oxolan-3-yl)-2,3-dihydro-1H-quinoline-5-carboxylate (250 mg, 0.6191 mmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with H2O (15 mL) and extracted with EA (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give the product (170 mg). Next, 20 mg of the product was taken and purified by Pre-HPLC (instrument: Waters MS-triggered preparative LC equipped with a QDA detector, column: Xbridge 5u C18, 150 × 19 mm, A water (0.1% formic acid), B acetonitrile, hold at 25 - 55% B for 8 min, hold at 100% B for 2 min, return to 25% B in 0.5 min, stop at 13 min, flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give the target compound as a white solid (“0121-4”, 2.5 mg, 12%).

[0156] 0121-4: MS(ESI): C 20 H 17 Calculated mass for C + . 1 H NMR (400 MHz, MeOD) δ 7.48 - 7.42 (m, 1H), 7.26 - 7.05 (m, 3H), 6.90 - 6.75 (m, 1H), 6.64 - 6.50 (m, 1H), 4.70 - 4.45 (m, 1H), 4.01 - 3.81 (m, 2H), 3.78 - 3.64 (m, 2H), 3.57 - 3.46 (m, 1H), 2.58 - 2.43 (m, 1H), 2.25 - 1.83 (m, 2H).

[0157] Step 3: The product was separated by preparative SFC (equipment: SFC80, column: Daicel Chiralcel IC, 250 mm × 30 mm I.D., 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 60 / 40, flow rate: 70 g / min, wavelength: UV214 nm, temperature: 35 °C), and white solids of 35.8 mg (0121), 31.5 mg (0121B), 19.9 mg (0121C), and 26.3 mg (0121D) were obtained.

[0158] 0121A: MS (ESI): C 20 H 17 Calculated mass for ClFN3O2: 385.10, measured m / z: 386.0 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ 7.37 - 7.33 (m, 1H), 7.15 - 6.98 (m, 3H), 6.78 - 6.71 (m, 1H), 6.54 - 6.48 (m, 1H), 4.38 (d, J = 3.2 Hz, 1H), 3.87 - 3.72 (m, 3H), 3.61 - 3.53 (m, 1H), 3.46 - 3.40 (m, 1H), 2.46 - 2.33 (m, 1H), 1.93 - 1.83 (m, 1H), 1.82 - 1.70 (m, 1H).

[0159] 0121B: MS (ESI): C 20 H 17 Calculated mass for ClFN3O2: 385.10, measured m / z: 386.0 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ 7.38 - 7.33 (m, 1H), 7.15 - 6.98 (m, 3H), 6.78 - 6.71 (m, 1H), 6.54 - 6.48 (m, 1H), 4.38 (d, J = 3.2 Hz, 1H), 3.87 - 3.72 (m, 3H), 3.61 - 3.53 (m, 1H), 3.46 - 3.40 (m, 1H), 2.46 - 2.33 (m, 1H), 1.94 - 1.83 (m, 1H), 1.82 - 1.71 (m, 1H).

[0160] 0121C: MS (ESI): C 20 H 17Calculated mass for ClFN3O2: 385.10, measured m / z: 386.0 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 7.42 - 7.30 (m, 1H), 7.16 - 6.94 (m, 3H), 6.74 - 6.66 (m, 1H), 6.49 - 6.39 (m, 1H), 4.57 (d, J = 2.0 Hz, 1H), 3.92 - 3.82 (m, 1H), 3.71 - 3.54 (m, 3H), 3.46 - 3.36 (m, 1H), 2.47 - 2.32 (m, 1H), 2.15 - 2.01 (m, 1H), 2.00 - 1.86 (m, 1H).

[0161] 0121D: MS (ESI): C 20 H 17 Calculated mass for ClFN3O2: 385.10, measured m / z: 386.0 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 7.39 - 7.33 (m, 1H), 7.16 - 6.95 (m, 3H), 6.75 - 6.65 (m, 1H), 6.49 - 6.39 (m, 1H), 4.57 (d, J = 2.0 Hz, 1H), 3.92 - 3.82 (m, 1H), 3.71 - 3.54 (m, 3H), 3.46 - 3.36 (m, 1H), 2.47 - 2.32 (m, 1H), 2.15 - 2.01 (m, 1H), 2.00 - 1.86 (m, 1H).

[0162] Synthesis of 0171:

Chemical Structure

[0163] Synthesis of 0172A and 0172B:

Chemical Structure

[0164] Step 2: Methyl 3-(2-chlorophenyl)-7-fluoro-2-methyl-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (100 mg, 0.29 mmol) was dissolved in MeOH (8 mL) and stirred at 25 °C for 20 min. N2H4·H2O (540 mg, 8.63 mmol) was added and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated directly to give a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u-C18 150×19 mm, 5um, mobile phase A: ACN-H2O (0.1% formic acid), B (acetonitrile), flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give 9-(2-chlorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (50 mg, 38%) as a white solid. MS(ESI): C 17 H 13Calculated mass value for ClFN3O: 329.07, measured m / z values: 330.1, 332.1 [M+H] + .

[0165] Step 3: 9-(2-Chlorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (90 mg, 0.27 mmol) was separated by preparative SFC (Daicel Chiralpak IB 30×250 mm, 10 μm, mobile phase A / B: CO2 / MeOH (0.1% EDA) = 65 / 35, flow rate: 2.0 mL / min, column temperature: 37 °C) to obtain (8R,9R)-9-(2-chlorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one as a white solid (27.4 mg, 30%) and (8S,9S)-9-(2-chlorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one as a white solid (60.4 mg, 67%).

[0166] 0172A and 0172B: MS(ESI): C 17 H 13 Calculated mass value for ClFN3O: 329.07, measured m / z values: 330.0, 332.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ9.74(s,1H),7.47-7.45(m,1H),7.38-7.35(m,1H),7.26-7.22(m,2H),7.01-6.99(m,1H),6.70-6.67(m,1H),4.47-4.45(m,1H),3.92-3.86(m,1H),1.26(d,J=6.4,3H). 1 H NMR(400MHz,CDCl3)δ9.74(s,1H),7.47-7.45(m,1H),7.37-7.33(m,1H),7.26-7.22(m,2H),7.01-6.99(m,1H),6.70-6.67(m,1H),4.47-4.45(m,1H),3.92-3.86(m,1H),1.26(d,J=6.4,3H).

[0167] Synthesis of 0173:

Chem.

[0168] Synthesis of 0174A and 0174B:

Chem.

[0169] Step 2: To a mixture of methyl 3-(2,4-difluorophenyl)-7-fluoro-2-methyl-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (90 mg, 0.26 mmol) in MeOH (4 mL), N2H4·H2O (4 mL) was added. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u-C18, 150×19 mm, 5 um, mobile phase A: ACN-H2O (0.1% formic acid), B (acetonitrile), flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give 9-(2,4-difluorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (45 mg, 53%) as a white solid. MS(ESI): C 17 H 12 Calculated mass for C16H11F3N3O is 331.19, found m / z 332.1 [M + H] + .

[0170] Step 3: 9-(2,4-Difluorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (45 mg, 0.14 mmol) was separated by preparative SFC (Daicel Chiralpak AD_3, 3 × 150 mm, 3 um, mobile phase A / B: CO2 / MeOH (0.1% EDA) = 75 / 25, flow rate: 2.0 mL / min, column temperature: 37 °C) to obtain the white solid (8R,9R)-9-(2,4-difluorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (0174A, 7.9 mg, 18%), and the white solid (8S,9S)-9-(2,4-difluorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (0174B, 7.8 mg, 17%). MS(ESI): C 17 H 12 Calculated mass for C15H12F3N3O is 331.19, measured m / z 332.1 [M+H]+.

[0171] 0174A: 1 H NMR(400 MHz, CDOD) δ 7.24 - 7.09 (m, 2H), 7.02 - 6.89 (m, 2H), 6.84 - 6.79 (m, 1H), 4.09 - 4.05 (m, 1H), 3.81 - 3.71 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H).

[0172] 0174B: 1 H NMR(400 MHz, CDOD) δ 7.24 - 7.09 (m, 2H), 7.01 - 6.91 (m, 2H), 6.83 - 6.78 (m, 1H), 4.09 - 4.04 (m, 1H), 3.81 - 3.71 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H).

[0173] Synthesis of 0186A and 0186B:

Chemical Structure

[0174] Step 2: To a solution of 2-fluoro-4-{[(1Z)-5-fluoro-7-nitro-3-oxo-2-benzofuran-1-ylidene]methyl}benzonitrile (2.5 g, 7.6 mmol) in DCM (50 mL) and THF (50 mL) was added HCl / MeOH (4 M, 19 mL, 76.0 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the product (2.5 g, 82%) as a yellow solid. MS (ESI): C 17 H 10 Calculated mass for C12H5F2N2O5 360.06, found m / z 361.0 [M + H] + 。

[0175] Step 3: To a solution of methyl 2-[2-(4-cyano-3-fluorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (950 mg, 2.64 mmol) in THF (20 mL) and MeOH (4 mL), HCHO (720 mg, 7.91 mmol) and TiCl3 (12.5 g, 15.82 mmol) were added. The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EA (50 ml × 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE:EA (4:1) to give the product (300 mg, 32%) as a yellow solid. MS(ESI): C 18 H 12 Calculated mass for C F2N2O3: 342.08, measured m / z: 343.0 [M+H] + 。

[0176] Step 4: To a solution of 3-(4-cyano-3-fluorophenyl)-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylic acid (300 mg, 0.88 mmol) in MeOH (5 mL), 85% hydrazinium hydroxide solution (1.1 g, 17.53 mmol) was added. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash column with PE:EA (4:1) to give the product (150 mg, 52%). The product was separated by apparatus: SFC80, column: Daicel Chiralcel IE, 250 mm, 30 mm, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7M solution in MeOH)] = 80 / 20, flow rate: 2.0 g / min, wavelength: UV214 nm, temperature: 35 °C) to give 45.3 mg (0186) of the product as a white solid and 22.2 mg (0186B) of the product as a white solid.

[0177] 0186A: MS(ESI): C 17 H 10 Calculated mass for C F2N4O: 324.08, measured m / z: 325.0 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.90 - 7.83 (m, 1H), 7.49 (dd, J = 10.8, 1.2 Hz, 1H), 7.41 (s, 1H), 7.26 (dd, J = 8.0, 1.2 Hz, 1H), 7.02 (dd, J = 9.2, 2.4 Hz, 1H), 6.84 (dd, J = 11.2, 2.4 Hz, 1H), 4.37 (t, J = 6.4 Hz, 1H), 3.68 - 3.60 (m, 2H).

[0178] 0186B: MS (ESI): C 17 H 10 Calculated mass for C18H12F2N4O: 324.08, Measured m / z: 325.0 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.91 - 7.83 (m, 1H), 7.49 (dd, J = 10.8, 1.2 Hz, 1H), 7.41 (s, 1H), 7.26 (dd, J = 8.0, 1.2 Hz, 1H), 7.02 (dd, J = 9.2, 2.4 Hz, 1H), 6.84 (dd, J = 11.2, 2.4 Hz, 1H), 4.36 (d, J = 6.0 Hz, 1H), 3.67 - 3.59 (m, 2H).

[0179] Synthesis of 0187A and 0187B:

Chemical Structure

[0180] Step 2: HCl / MeOH (4 M, 91.5 mL, 366.0 mmol) was added to a solution of 3-fluoro-4-{[(1Z)-5-fluoro-7-nitro-3-oxo-2-benzofuran-1-ylidene]methyl}benzonitrile (6.0 g, 18.3 mmol) in DCM (20 mL) and THF (50 mL). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced vacuum to give the product (4.5 g, 61%) as a yellow solid.

[0181] Step 3: HCHO (250 mg, 8.33 mmol) and TiCl3 (13.2 g, 16.65 mmol) were added to a solution of methyl 2-[2-(4-cyano-2-fluorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (1000 mg, 2.78 mmol) in THF (20 mL) and MeOH (4 mL). The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EA (20 mL × 2). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE:EA (4:1) to give the product (300 mg, 31%) as a yellow solid.

[0182] Step 4: To a solution of methyl 3-(4-cyano-2-fluorophenyl)-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (230 mg, 0.672 mmol) in MeOH (5 mL) was added 85% hydrazinium hydroxide solution (791.0 mg, 13.44 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure in vacuo to give a residue, which was purified by flash column with PE:EA (4:1) to give the product (200 mg, 91%). The product was separated by apparatus: SFC80, column: Daicel Chiralcel OD, 250 mm, 30 mm, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 80 / 20, flow rate: 2.0 g / min, wavelength: UV214 nm, temperature: 35 °C), to give 75.2 mg (0187) of the product as a white solid and 87.3 mg (0187B) of the product as a white solid.

[0183] 0187A: MS(ESI): C 17 H 10 Calculated mass for C H F2N4O 324.08, measured m / z 325.0 [M+H] + 。 1 H NMR(400 MHz, DMSO-d6) δ 12.35(s, 1H), 7.90(dd, J = 10.4, 1.6 Hz, 1H), 7.65(dd, J = 8.0, 1.6 Hz, 1H), 7.44(s, 1H), 7.38(t, J = 7.6 Hz, 1H), 7.03(dd, J = 9.2, 2.4 Hz, 1H), 6.86(dd, J = 11.6, 2.4 Hz, 1H), 4.51(dd, J = 8.8, 4.8 Hz, 1H), 3.71 - 3.53(m, 2H).

[0184] 0187B: MS(ESI): C 17 H 10 Calculated mass for C H F2N4O 324.08, measured m / z 325.0 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.89 (dd, J = 10.4, 1.2 Hz, 1H), 7.65 (dd, J = 8.0, 1.2 Hz, 1H), 7.44 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.03 (dd, J = 9.2, 2.4 Hz, 1H), 6.86 (dd, J = 11.2, 2.4 Hz, 1H), 4.51 (dd, J = 8.8, 4.8 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.61 - 3.53 (m, 1H).

[0185] Synthesis of 0188-5, 0188A, and 0188B:

Chemical formula

[0186] Step 2: To a solution of methyl 3-(4-chloro-3-fluorophenyl)-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (420 mg, 1.19 mmol) in MeOH (15 mL) was added N2H4·H2O (598 mg, 11.94 mmol) under N2. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated directly to give a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u-C18, 150×19 mm, 5um, mobile phase A: ACN-H2O, B (acetonitrile), flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give 9-(4-chloro-3-fluorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (「0188-5」, 200 mg, 50%) as a yellow solid. MS(ESI): C 16 H 10 Calculated mass for ClF2N3O 333.05, measured m / z 334.0 [M+H] + 。 1 H NMR(400MHz,MeOD)δ7.37(t,J=8.0Hz,1H),7.37(td,J=8.0,4.0Hz,1H),7.03-6.98(m,1H),6.80(dd,J=10.4,2.4Hz,1H),4.30-4.15(m,1H),3.72-3.60(m,2H)。

[0187] Step 3: 9-(4-Chloro-3-fluorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (“0188-5”, 300 mg, 0.72 mmol) was separated by preparative SFC (Daicel Chiralpak AD_3, 3 × 150 mm, 3 um, mobile phase A / B: CO2 / MeOH (0.1% EDA) = 70 / 30, flow rate: 2.0 mL / min, column temperature: 37 °C) to obtain white solid (R)-9-(4-chloro-3-fluorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (0188A, 87.8 mg, 29%), and white solid (S)-9-(4-chloro-3-fluorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (0188B, 87.78 mg, 26%).

[0188] 0188A: MS(ESI): C 16 H 10 Calculated mass for C + . 1 H NMR (400 MHz, MeOD) δ 7.37 (t, J = 8.0 Hz, 1H), 7.18 - 7.09 (m, 2H), 7.03 - 6.97 (m, 1H), 6.83 - 6.74 (m, 1H), 4.28 - 4.18 (m, 1H), 3.73 - 3.58 (m, 2H).

[0189] 0188B: MS(ESI): C 16 H 10 Calculated mass for C + . 1 H NMR (400 MHz, MeOD) δ 7.37 (t, J = 8.0 Hz, 1H), 7.20 - 7.06 (m, 2H), 7.03 - 6.97 (m, 1H), 6.92 - 6.78 (m, 1H), 4.30 - 4.16 (m, 1H), 3.72 - 3.59 (m, 2H).

[0190] Synthesis of 0189A and 0189B: [Chemical formula] Step 1: To a solution of 6-fluoro-4-nitro-3H-2-benzofuran-1-one (10.0 g, 50.7 mmol) in THF (100 mL) were added 4-chloro-2-fluorobenzaldehyde (9.7 g, 60.8 mmol), TEA (30.8 g, 30.4 mmol), and Ac2O (62.1 g, 60.8 mmol). The reaction mixture was stirred at 80 °C for 3 hours. During this time, the reaction mixture was quenched with H2O (500 mL). After filtration, the solid was collected and washed with EtOH (2 × 40 mL) and EA (2 × 40 mL). The solid was dried under vacuum to give the product (9.0 g) as a yellow solid. MS (ESI): C 15 Calculated mass for C + .

[0191] Step 2: To a solution of (3Z)-3-[(4-chloro-2-fluorophenyl)methylene]-6-fluoro-4-nitro-2-benzofuran-1-one (9.0 g, 26.7 mmol) in THF (150 mL) was added HCl / MeOH (67 mL, 268.0 mmol). The reaction mixture was stirred at 70 °C for 16 hours. After concentrating the reaction mixture, it was diluted with EA (150 mL) and H2O (200 mL) and extracted with EA (2 × 150 mL). The organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give the product (6.0 g) as a yellow solid. MS (ESI): C 16 H 10 Calculated mass for C + .

[0192] Step 3: To a solution of methyl 2-[2-(4-chloro-2-fluorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (370 mg, 1.00 mmol) in THF (10 mL) and MeOH (2 mL), aqueous formaldehyde solution (300 mg, 3.00 mmol) and TiCl3 (4.7 g, 6.0 mmol) were added. The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EA (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the product (180 mg) as a yellow solid. MS(ESI): C 17 H 12 Calculated for C14H8ClF2NO3 351.05, found m / z 352.0 [M+H] + .

[0193] Step 4: To a solution of methyl 3-(4-chloro-2-fluorophenyl)-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (180 mg, 0.51 mmol) in MeOH (5 mL), NH2NH2·H2O (647 mg, 10.24 mmol) was added. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EA (2 × 20 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the crude product (90 mg). The crude product was separated by apparatus: SFC150, column: Daicel Chiralcel OJ, 250 mm, 30 mm I.D., 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 80 / 20, flow rate: 2.0 g / min, wavelength: UV214 nm, temperature: 35 °C) to give 17.6 mg of product 0189A as a white solid and 25.0 mg of product 0189B as a white solid.

[0194] 0189A: MS(ESI): C 16 H 10Calculated mass for ClF2N3 O, 333.05, measured m / z 334.0 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 7.32 - 7.06 (m, 3H), 7.02 - 6.92 (1H), 6.82 (dd, J = 10.8, 2.4 Hz, 1H), 4.54 - 4.44 (m, 1H), 3.72 - 3.54 (m, 2H).

[0195] 0189B: MS (ESI): C 16 H 10 Calculated mass for ClF2N3 O, 333.05, measured m / z 334.0 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 7.27 - 7.07 (m, 3H), 7.03 - 6.95 (m, 1H), 6.82 (dd, J = 10.8, 2.4 Hz, 1H), 4.54 - 4.43 (m, 1H), 3.71 - 3.54 (m, 2H).

[0196] Synthesis of 0193A and 0193B:

Chemical formula

[0197] Step 2: HCl / MeOH (4 M, 19 mL, 76.0 mmol) was added to a solution of 2-fluoro-4-{[(1Z)-5-fluoro-7-nitro-3-oxo-2-benzofuran-1-ylidene]methyl}benzonitrile (2.5 g, 7.6 mmol) in DCM (50 mL) and THF (50 mL). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure in vacuo to give the product as a yellow solid (2.5 g, 82%). MS (ESI): C 17 H 10 Calculated mass for C F2N2O5: 360.06, found m / z: 361.0 [M+H] + 。

[0198] Step 3: CH3CHO (294 mg, 6.66 mmol) and TiCl3 (10.6 g, 13.32 mmol) were added to a solution of methyl 2-[2-(4-cyano-3-fluorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (800 mg, 2.22 mmol) in THF (20 mL) and MeOH (4 mL). The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EA (50 ml × 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE:EA (4:1) to give the product as a yellow solid (320 mg, 38%). MS (ESI): C 19 H 14 Calculated mass for C F2N2O3: 356.10, found m / z: 357.0 [M+H] + 。

[0199] Step 4: To a solution of methyl 3-(4-cyano-3-fluorophenyl)-7-fluoro-2-methyl-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (320 mg, 0.90 mmol) in MeOH (10 mL) was added 85% hydrazinium hydroxide solution (1.1 g, 17.96 mmol). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash column with PE:EA (4:1) to give the product (150 mg, 58%). Then, it was separated by apparatus: SFC80, column: Daicel Chiralcel IE, 250 mm, 30 mm, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 80 / 20, flow rate: 2.0 g / min, wavelength: UV214 nm, temperature: 35 °C), and 52.5 mg (0193) of the product as a white solid and 56.6 mg (0193B) of the product as a white solid were obtained.

[0200] 0193A: MS(ESI): C 18 H 12 Calculated mass for C H F2N4O 338.10, measured m / z 339.0 [M+H] + 。 1 H NMR(400MHz,DMSO-d6)δ12.29(s,1H),7.90(t,J=7.2Hz,1H),7.54(d,J=10.8Hz,1H),7.42(s,1H),7.34(d,J=8.0Hz,1H),7.00(dd,J=9.2,2.4Hz,1H),6.83(dd,J=11.2,2.4Hz,1H),4.03(d,J=10.0Hz,1H),3.86 - 3.77(m,1H),1.07(d,J=6.0Hz,3H).

[0201] 0193B: MS(ESI): C 18 H 12 Calculated mass for C H F2N4O 338.10, measured m / z 339.0 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 7.90 (t, J = 7.2 Hz, 1H), 7.54 (d, J = 10.4 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 9.2, 2.4 Hz, 1H), 6.83 (dd, J = 11.2, 2.4 Hz, 1H), 4.03 (d, J = 9.6 Hz, 1H), 3.86 - 3.77 (m, 1H), 1.07 (d, J = 6.0 Hz, 3H).

[0202] Synthesis of 0194A and 0194B:

Chemical formula

[0203] Step 2: To a solution of 3-fluoro-4-{[(1Z)-5-fluoro-7-nitro-3-oxo-2-benzofuran-1-ylidene]methyl}benzonitrile (6.0 g, 18.3 mmol) in DCM (20 mL) and THF (50 mL) was added HCl / MeOH (91.5 mL, 366.0 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure in vacuo to give the product (4.5 g, 61%) as a yellow solid.

[0204] Step 3: To a solution of methyl 2-[2-(4-cyano-2-fluorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (1000 mg, 2.78 mmol) in THF (20 mL) and MeOH (4 mL), CH3CHO (367 mg, 8.33 mmol) and TiCl3 (13.2 g, 16.65 mmol) were added. The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EA (20 mL × 2). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE:EA (5:1) to give the product as a yellow solid (600 mg, 60%).

[0205] Step 4: To a solution of methyl 3-(4-cyano-2-fluorophenyl)-7-fluoro-2-methyl-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (400 mg, 1.23 mmol) in MeOH (5 mL), 85% hydrazinium hydroxide solution (199 mg, 3.37 mmol) was added. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure in vacuo to give a residue, which was purified by flash column with PE:EA (4:1) to give the product (200 mg, 91%). The product was separated by apparatus: SFC80, column: Daicel Chiralcel OD, 250 mm, 30 mm, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 80 / 20, flow rate: 2.0 g / min, wavelength: UV214 nm, temperature: 35 °C) to give 42.0 mg of the product as a white solid (0194A) and 38.9 mg of the product as a white solid (0194B).

[0206] 0194A: MS(ESI): C 18 H 12 Calculated mass for C16H12F2N4O 338.10, found m / z 339.0 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 7.89 (dd, J = 10.0, 1.2 Hz, 1H), 7.71 (dd, J = 8.0, 1.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.02 (dd, J = 9.2, 2.4 Hz, 1H), 6.84 (dd, J = 11.2, 2.4 Hz, 1H), 4.17 (d, J = 10.8 Hz, 1H), 3.87 - 3.77 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H).

[0207] 0194B: MS (ESI): C 18 H 12 Calculated mass for F2N4O: 338.10, measured m / z: 339.0 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 7.89 (dd, J = 10.4, 1.2 Hz, 1H), 7.71 (dd, =J 8.0, 1.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.02 (dd, J = 9.2, 2.4 Hz, 1H), 6.84 (dd, J = 11.2, 2.4 Hz, 1H), 4.17 (d, J = 10.8 Hz, 1H), 3.86 - 3.78 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H).

[0208] Synthesis of 0195-5, 0195A, 0195B:

Chemical Structure

[0209] Step 2: To a solution of methyl 3-(4-chloro-3-fluorophenyl)-7-fluoro-2-methyl-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (300 mg, 0.82 mmol) in MeOH (15 mL) was added N2H4·H2O (411 mg, 8.2 mmol) under N2. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC (chromatography column: Xbridge 5u-C18m, 150×19 mm, 5um, mobile phase A: ACN-H2O, B (acetonitrile), flow rate: 20 mL / min, wavelength: 214 / 254 nm) to give 9-(2-chlorophenyl)-5-fluoro-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one ("0195-5", 200 mg, 72%) as a white solid. MS(ESI): C 17 H 12Calculated mass for ClF2N3O: 347.06, measured m / z: 348.1 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 7.43 (t, J = 8.0 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.08 - 7.02 (m, 1H), 6.82 (dd, J = 11.2, 2.4 Hz, 1H), 3.89 - 3.85 (m, 1H), 3.78 - 3.72 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H).

[0210] Step 3: 9-(4-Chloro-3-fluorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (“0195-5”, 250 mg, 0.72 mmol) was separated by preparative SFC (Daicel Chiralpak AD_33×150 mm, 3 μm, mobile phase A / B: CO2 / MeOH (0.1% EDA) = 70 / 30, flow rate: 2.0 mL / min, column temperature: 37 °C) to obtain an off-white solid (8R,9R)-9-(4-chloro-3-fluorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (0195, 100.7 mg, 40%), and an off-white solid (8S,9S)-9-(4-chloro-3-fluorophenyl)-5-fluoro-8-methyl-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (0195B, 85.7 mg, 34%).

[0211] 0195A: MS (ESI): C 17 H 12 Calculated mass for ClF2N3O: 347.06, measured m / z: 348.1 [M+H] + 。 1 1H NMR (400 MHz, MeOD) δ 7.41 (t, J = 8.0 Hz, 1H), 7.16 - 7.07 (m, 2H), 7.03 (dd, J = 8.4, 1.6 Hz, 1H), 6.79 (dd, J = 11.2, 2.4 Hz, 1H), 3.87 - 3.83 (m, 1H), 3.79 - 3.70 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H).

[0212] 0195B: MS(ESI): C 17 H 12 Calculated mass for ClF2N3O: 347.06, measured m / z: 348.1 [M + H] + 。 1 H NMR (400 MHz, MeOD) δ 7.41 (t, J = 8.0 Hz, 1H), 7.21 - 7.07 (m, 2H), 7.03 (dd, J = 8.4, 1.6 Hz, 1H), 6.79 (dd, J = 11.2, 2.4 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.80 - 3.70 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H).

[0213] Synthesis of 0196A and 0196B:

Chemical Structure

[0214] Step 2: HCl / MeOH (67 mL, 268.0 mmol) was added to a solution of (3Z)-3-[(4-chloro-2-fluorophenyl)methylene]-6-fluoro-4-nitro-2-benzofuran-1-one (9.0 g, 26.7 mmol) in THF (150 mL). The reaction mixture was stirred at 70 °C for 16 h. After concentration of the reaction mixture, it was diluted with EA (150 mL) and H2O (200 mL), and extracted with EA (2 × 150 mL). The organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give the product (6.0 g) as a yellow solid. MS (ESI): C 16 H 10 Calculated mass for C15H7ClF2NO5 369.02, found m / z 392.0 [M+Na] + .

[0215] Step 3: Acetaldehyde (72 mg, 1.62 mmol) and TiCl3 (6.4 g, 8.11 mmol) were added to a solution of methyl 2-[2-(4-chloro-2-fluorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (500 mg, 1.35 mmol) in THF (10 mL) and MeOH (2 mL). The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EA (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the product (300 mg) as a yellow solid. MS (ESI): C 18 H 14 Calculated mass for C15H9ClF2NO3 365.06, found m / z 366.0 [M+H] + .

[0216] Step 4: NH2NH2·H2O (1.1 g, 17.06 mmol) was added to a solution of methyl 3-(4-chloro-2-fluorophenyl)-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (300 mg, 0.85 mmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with H2O (20 mL) and extracted with EA (2 × 30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the crude product (150 mg). The crude product was separated by SFC (equipment: SFC150, column: Daicel Chiralcel OJ, 250 mm × 30 mm I.D., 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 70 / 30, flow rate: 2.0 g / min, wavelength: UV214 nm, temperature: 35 °C) to give 45.9 mg of product 0196A as a white solid and 49.5 mg of product 0196B as a white solid.

[0217] 0196A: MS (ESI): C 17 H 12 Calculated mass for C H ClF2N3O, 347.06, m / z found 348.0 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ 7.32 - 7.10 (m, 4H), 6.83 (dd, J = 10.8, 2.4 Hz, 1H), 4.10 (d, J = 9.6 Hz, 1H), 3.85 - 3.73 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H).

[0218] 0196BA: MS (ESI): C 17 H 12 Calculated mass for C H ClF2N3O, 347.06, m / z found 348.0 [M+H] + 。 1 H NMR (400 MHz, MeOD) δ 7.30 - 7.02 (m, 4H), 6.81 (dd, J = 10.8, 2.4 Hz, 1H), 4.08 (d, J = 9.6 Hz, 1H), 3.86 - 3.71 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H).

[0219] Synthesis of 0206A and 0206B: [Chemical formula] Step 1: To a mixture of 6-fluoro-4-nitro-3H-2-benzofuran-1-one (10.0 g, 50.73 mmol) and 2-chlorobenzaldehyde (14.3 g, 101.46 mmol) in THF (500 mL) were added TEA (15.4 g, 152.19 mmol) and Ac2O (31.1 g, 304.38 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered. The filter cake was washed with water (200 mL × 2) and dried under reduced pressure to obtain (3Z)-3-[(2-chlorophenyl)methylene]-6-fluoro-4-nitro-2-benzofuran-1-one (10.0 g, 56%) as a yellow solid. MS (ESI): C 15 Calculated mass for C + .

[0220] Step 2: A mixture of (3Z)-3-[(2-chlorophenyl)methylene]-6-fluoro-4-nitro-2-benzofuran-1-one (10.0 g, 31.28 mmol) in HCl / EA (500 mL, 4 m in EA) was stirred at 75 °C for 16 hours. The reaction mixture was filtered. The filter cake was washed with methanol (100 mL × 2) and dried under reduced pressure to obtain methyl 2-[2-(2-chlorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (10.0 g, 82%) as a yellow solid. MS (ESI): C 16 H 11 Calculated mass for C + .

[0221] Step 3: To a solution of methyl 2-[2-(2-chlorophenyl)acetyl]-5-fluoro-3-nitrobenzoate (2.0 g, 5.69 mmol) in MeOH (10 mL) and THF (50 mL) were added TiCl3 (20.3 g, 34.12 mmol) and propanal (991 mg, 17.06 mmol). The reaction mixture was stirred at 40 °C for 6 h. The mixture was diluted with water (50 mL) and extracted with EA (100 mL × 3). The organic layer was concentrated and the residue was purified by flash chromatography on silica gel (PE:EA = 3:1) to give methyl 3-(2-chlorophenyl)-2-ethyl-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (1.0 g, 44%) as a yellow oil. MS(ESI): C 19 H 17 Calculated mass for ClFNO3 361.1, found m / z 362.1 [M+H] + 。

[0222] Step 4: To a mixture of methyl 3-(2-chlorophenyl)-2-ethyl-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (750 mg, 2.07 mmol) in MeOH (20 mL) was added N2H4·H2O (199 mg, 6.22 mmol). The reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by reverse-phase column (40% A in B, A: CH3CN, B: 0.1% FA in water) to give 12-(2-chlorophenyl)-11-ethyl-7-fluoro-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one (300 mg, 40%) as a yellow solid. MS(ESI): C 18 H 15 Calculated mass for ClFN3O 343.1, found m / z 344.1 [M+H] + 。

[0223] Step 5: 12-(2-Chlorophenyl)-11-ethyl-7-fluoro-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5(13),6,8-tetraen-4-one (300 mg, 0.87 mmol) was separated by preparative SFC (apparatus: SFC150 column: Daicel Chiralcel IE, 250 mm x 30 mm I.D. mobile phase: CO2 / MeOH [0.2% NH3 (7M solution in MeOH)] = 65 / 35, flow rate: 80 g / min, wavelength: UV214 nm, temperature: 35 °C) to give the white solid (11S,12S)-12-(2-chlorophenyl)-11-ethyl-7-fluoro-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5(13),6,8-tetraen-4-one (57.4 mg, 19%) and the white solid (11R,12R)-12-(2-chlorophenyl)-11-ethyl-7-fluoro-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5(13),6,8-tetraen-4-one (32.4 mg, 11%).

[0224] 0206A: MS(ESI): C 18 H 15 Calculated mass for ClFN3O 343.1, measured m / z 344.1 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 12.34 (s, 1H), 7.52 - 7.48 (m, 1H), 7.41 - 7.20 (m, 3H), 7.10 - 6.85 (m, 3H), 4.38 (d, J = 7.2 Hz, 1H), 3.71 - 3.60 (m, 1H), 1.63 - 1.35 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H).

[0225] 0206B: MS(ESI): C 18 H 15 Calculated mass for ClFN3O 343.1, measured m / z 344.1 [M+H] + 。 11H NMR (400 MHz, DMSO) δ 12.34 (s, 1H), 7.53 - 7.47 (m, 1H), 7.35 - 7.21 (m, 3H), 7.04 - 6.86 (m, 3H), 4.38 (d, J = 7.2 Hz, 1H), 3.70 - 3.61 (m, 1H), 1.64 - 1.35 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H).

[0226] Synthesis of 0207A and 0207B:

Chemical formula

[0227] Step 2: Hydrazine hydrate (193 mg, 6.02 mmol) was added to a mixture of methyl 3-(2-chlorophenyl)-2-cyclopropyl-7-fluoro-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (750 mg, 2.01 mmol) in MeOH (20 mL). The reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by reverse-phase column (40% A in B, A: CH3CN, B: 0.1% FA in water) to afford 12-(2-chlorophenyl)-11-cyclopropyl-7-fluoro-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one (300 mg, 29%) as a yellow solid. MS (ESI): C 20 H 17 Calculated mass for C18H13ClFNO3 373.1, found m / z 374.0 [M+H] + .

[0228] Step 3: 12-(2-Chlorophenyl)-11-cyclopropyl-7-fluoro-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one (300 mg, 0.84 mmol) was separated by preparative SFC (equipment: SFC150 column: Daicel Chiralcel IE, 250 mm × 30 mm I.D. mobile phase: CO2 / MeOH [0.2% NH3 (7 M solution in MeOH)] = 65 / 35, flow rate: 80 g / min, wavelength: UV214 nm, temperature: 35 °C) to afford (11S,12S)-12-(2-chlorophenyl)-11-cyclopropyl-7-fluoro-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one (0207, 10.9 mg, 4%) as a white solid, and (11R,12R)-12-(2-chlorophenyl)-11-cyclopropyl-7-fluoro-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one (0207B, 41.4 mg, 14%) as a white solid.

[0229] 0207A: MS(ESI): C 18 H 15 Calculated mass for ClFN3O: 343.1, measured m / z: 344.1 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 7.50 - 7.45 (m, 1H), 7.42 - 7.22 (m, 3H), 7.06 - 6.88 (m, 3H), 4.55 (d, J = 6.8 Hz, 1H), 2.91 - 2.83 (m, 1H), 1.10 - 0.94 (m, 1H), 0.55 - 0.22 (m, 3H), 0.06 - -0.10 (m, 1H).

[0230] 0207B: MS(ESI): C 18 H 15 Calculated mass for ClFN3O: 343.1, measured m / z: 344.1 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 12.37 (s, 1H), 7.52 - 7.45 (m, 1H), 7.36 (s, 1H), 7.31 - 7.16 (m, 2H), 7.09 - 6.78 (m, 3H), 4.55 (d, J = 6.8 Hz, 1H), 2.95 - 2.82 (m, 1H), 1.11 - 0.90 (m, 1H), 0.53 - 0.26 (m, 3H), 0.04 - -0.07 (m, 1H).

[0231] Synthesis of 0210A and 0210B:

Chemical Structure

[0232] Step 2: To a mixture of methyl 3-(2-chlorophenyl)-7-fluoro-2-(oxan-4-yl)-4-oxo-2,3-dihydro-1H-quinoline-5-carboxylate (750 mg, 1.79 mmol) in MeOH (10 mL), N2H4·H2O (173 mg, 5.38 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by reverse-phase column (40% A in B, A: CH3CN, B: 0.1% FA in water) to give 12-(2-chlorophenyl)-7-fluoro-11-(oxan-4-yl)-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraene-4-one (300 mg, 40%) as a yellow solid. MS(ESI): C 21 H 19 Calculated mass for C17H13ClFN3O2 399.1, found m / z 400.1 [M+H] + 。

[0233] Step 3: 12-(2-Chlorophenyl)-7-fluoro-11-(oxan-4-yl)-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5(13),6,8-tetraen-4-one (140 mg, 0.35 mmol) was separated by preparative SFC (apparatus: SFC150, column: Daicel Chiralpak IA, 4.6×250 mm, 5 μm, mobile phase: CO2 / MeOH[0.2% NH3 (7 M solution in MeOH)] = 60 / 40, flow rate: 80 g / min, wavelength: UV214 nm, temperature: 35 °C) to give a white solid, (11S,12S)-12-(2-chlorophenyl)-7-fluoro-11-(oxan-4-yl)-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5(13),6,8-tetraen-4-one (0210A, 17.5 mg, 13%), and a white solid, (11R,12R)-12-(2-chlorophenyl)-7-fluoro-11-(oxan-4-yl)-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5(13),6,8-tetraen-4-one (0210B, 7 mg, 5%).

[0234] 0210A: MS(ESI): C 21 H 19 Calculated mass for C + H 1 ClFN3O2: 399.1, measured m / z 400.1 [M+H]

[0235] 0210B: MS(ESI): C 21 H 19Calculated mass value for ClFN3O2: 399.1, measured m / z value: 400.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.22 - 7.15 (m, 1H), 7.01 (dd, J = 9.2, 2.4 Hz, 1H), 6.90 (dd, J = 11.2, 2.4 Hz, 1H), 6.69 - 6.63 (m, 1H), 4.57 (d, J = 3.2 Hz, 1H), 3.92 - 3.78 (m, 2H), 3.26 - 3.06 (m, 2H), 1.75 - 1.47 (m, 4H), 1.44 - 1.17 (m, 1H).

[0236] Additional exemplary compounds of the present technology The additional compounds of the present technology are synthesized and isolated according to the same methods and procedures as above, and such additional compounds include, but are not limited to, the following.

Chemical formula

[0237] PARP mass spectrometry assay protocol Materials and Reagents: The PARP1 enzyme was purchased from BPS Bioscience (Catalog No. 80501). Tris-HCl at pH 8.0 was purchased from Corning (Catalog No. 46-031-CM). Magnesium chloride was purchased from Thermo Fisher Scientific (formerly Honeywell Fluka, Catalog No. 63020-1L). All other assay components, activated DNA (Catalog No. D4522), core histones (Catalog No. SRP6590), β-nicotinamide adenine dinucleotide (β-NAD - Catalog No. N8285), 3ABA PARP1 small molecule inhibitor (from PARP1 enzyme activity assay kit, Catalog No. 17-10149), sodium chloride (NaCl, Catalog No. S6546-1L), Triton X-100 (Catalog No. 93443), dithiothreitol (DTT, Catalog No. 43816-250ML) were all purchased from Millipore Sigma.

[0238] Assay Buffer: The assay buffer contains the reagents 50 mM Tris-HCl at pH 8.0, 50 mM NaCl, 10 mM MgCl2, 0.01% Triton X-100 and 1 mM DTT.

[0239] Procedure: The PARP1 enzyme assay was performed in a 384-well plate with 20 μL of assay buffer in total. For the concentration-response curve, the compound was serially diluted 3-fold from a maximum concentration of 2 mM to 0.1013 mM to create a 10-point curve, and 125 nL was transferred to the assay plate using an Echo acoustic dispenser, and 10 μL of the reactant was added to give a final concentration range of 26.6 μM to 1.35 μM. A mixture of 10 nM PARP1 enzyme and 100 nM core histone (2x) was added to the assay plate at 5 microliters and pre-incubated at room temperature (RT) for 30 minutes. The reaction was initiated by adding 5 μL of a mixture of 10 μM β-NAD and 0.02 mg / mL activated DNA (2X). The reactants were incubated at room temperature for 60 minutes. The final concentrations of PARP1 enzyme and substrate were 5 nM and 5 μM, respectively. The positive control (high signal) and negative control (low signal) wells contained 125 nL of DMSO instead of the compound. After incubation was complete, 10 μL of 10 μM 3ABA PARP1 inhibitor was added to stop the reaction, incubated at room temperature for 5 minutes, and placed in an -80 °C freezer for shipment to the Valo Health site in Branford, Connecticut, where the amount of nicotinamide (NAM) was directly detected using mass spectrometry.

[0240] The inhibition rate of enzyme activity was calculated according to the following formula: [Number] S in the formula サンプル , S 高 , and S 低 values refer to the NAM concentrations detected in the assay well, high control well, and low control well, respectively. To determine the IC 50 value of the inhibitor, the inhibition rate (concentration-response curve) of CRC was fitted to a standard single-site four-parameter logistic equation.

[0241] Typical results of exemplary compounds of the present technology Table 1 shows representative initial results for exemplary compounds of the present technology.

Table 1-1

Table 1-2

Table 1-3

[0242] PARylation Immunofluorescence Assay Protocol

Number

Number

[0243] Details of cell culture: HCT116 is a human colorectal epithelial cell line that adheres and grows in tissue culture flasks. Cells grow in T175-sized flasks. According to the standard adherent cell subculture protocol, split at a ratio of 1:5 to 1:10 twice a week at 70 - 80% confluence. The medium is stored refrigerated until the day of cell-based activities and needs to be warmed to at least room temperature before use. Cell culture medium: McCoy's 5A containing 10% FBS, 2 mM L-glutamine, and 20 mM HEPES. Plating medium: McCoy's 5A containing 10% FBS, 2 mM L-glutamine, 20 mM HEPES, and 1% antibiotic-antifungal agent solution.

[0244] Procedure: Day 1: Cell Culture and Cell Plating: The cell culture and cell plating method includes the following steps: Warm the medium before cell culture, take out the flask containing cells from the incubator, treat the cells in a T175 flask with 0.25% trypsin, return the flask to the incubator for about 5 minutes so that the cells fall from the bottom of the flask, add 10 μL of medium to wash away the bottom of the flask, add the cells and medium to a 50 mL conical tube, centrifuge the cells at 1000 rpm for 5 minutes, aspirate and remove the medium, resuspend the pellet in 10 mL of fresh medium, use a hemocytometer cell counter to calculate the number of viable cells, use the number of viable cells and the number of plates required to calculate the amount of resuspended cell pellet medium that needs to be added to fresh plating medium to dispense 5 μL / well at a density of 6000 cells / well into a 384W plate, plate the cells onto a 384W plate, add 5 μL of medium to each well across the plate at 6000 cells / well, after plating, gently shake the plate at 100 rpm for 20 minutes, and incubate the plate overnight at 37 °C and 5% CO2 before treatment.

[0245] Day 2: Treatment, Fixation, and Primary Staining of Compounds and DNA Damage: This method includes the following steps: Using a Labcyte Echo 555, treat a 384W cell seeding plate such that the highest dose of each compound is 10 uM. Stamp 40 nL of a 10 mM highest dose compound plate onto 40 μL of cells in the seeding plate. The Labcyte compound source plate is DMSO-based and contains a 10-point 3-fold dilution series of compounds starting at 10 mM. The transfer volume using the Echo is 40 nL. Incubate at 37°C, 5% CO2 for 5 hours, and add the DNA damaging agent MMS to columns 1 - 23 of the 384W plate seeded with each cell by delivering 40 nl of 19.2% MMS in DMSO using the Echo in DMSO delivery mode. The MMS stock concentration is 99% and needs to be diluted 1:5 with DMSO before delivery to the cell plate. Incubate the cell plate at 37°C, 5% CO2 for 30 minutes, aspirate the medium, add 75 ul of cold methanol using a Bluewasher. The Bluewasher MagBeadSpeed settings for all aspirates are as follows: Rotate the plate clockwise at 800 RPM (35 g) for 5 seconds, keep the dispense line and methanol cooled throughout the fixation process, use the stacker setting to divide the dispense into multiple passes to minimize cell disruption, incubate the fixed plate on ice for 20 minutes, wash the entire plate once with an equal volume of cold DPBS, aspirate using the Bluewasher at MagBeadSpeed, add 20 ul of DPBS 0.1% Triton X-100 to the entire plate, incubate at room temperature for 15 minutes, aspirate using the Bluewasher at MagBeadSpeed, add 20 ul of Roche block to the entire plate, incubate at room temperature for 60 minutes, aspirate using the Bluewasher at MagBeadSpeed, add 20 ul of PAR antibody (1:4,000) to the Roche block, seal the plate, and incubate overnight at 4°C.

[0246] Day 3: Secondary Antibody Staining and Imaging: The method includes the following steps: Use a Bluewasher to aspirate and wash the plate with 25 - 30 ul of 0.05% Tween20 DPBS (3 times), add 20 ul of anti-mouse AF488 secondary antibody (1:1,600) and Hoechst (1:10,000), incubate at room temperature for 60 minutes, aspirate using MagBeadSpeed, wash 3 - 4 times with 25 - 30 ul of 0.05% Tween20 DPBS, add 30 ul of DPBS to seal the plate, and image with a CX7-circle (nucleus) average intensity in channel 1 (360) and channel 2 (488) using the protocol "PAR_HCT116_MeOH_10X_2ChR". Main acquisition settings: Expose the 488 channel at 70 - 80% and in 1 - 2 fields.

[0247] Data Analysis: The raw data files are exported from the CX7 software and paired with the barcoded compound plates to track compound IDs, dose responses, and Echo transfer records. This enables the import and QC analysis of dose-response curves and the determination of IC50 values. Images of each plate and well for both image channels can also be exported. The inhibition rate of PARylation activity was calculated according to the following formula:

Number

[0248] Assay principle: The cellular level of PARylation of PARP1 / 2 substrate proteins (PARP1 and histone) is measured with an anti-PAR antibody using an immunofluorescence assay for DNA damage based on https: / / f1000research.com / articles / 5-736 / v2. PARP inhibitors reduce the level of PARylation when co-treated with the DNA damaging agent MMS.

[0249] Cell-based proliferation assay protocol: 5-day CTG, CTF, CyQuant, or OnePot Live-Dead HCS assay for DLD1 parental vs BRCA2 null

Number

Number

[0250] Procedure Day 1: Cell culture and cell plating: This method includes the following steps: Count the cells (using a Nexcelom cell counter and record the cell number), spin the cells at 1000 rpm for 5 minutes, resuspend the pellet in fresh medium, and plate the cells at a specific cell / well density based on density optimization tests (or historically 100 cells / well for DLD1 parental, 125 cells / well for DLD1 BRCA2 + / - vs - / - null, and μL of cells / well in columns 1 - 47 of a 1536 well plate) in a 1536 well plate, gently shake the plate at room temperature for 30 minutes (100 rpm), then transfer it to an incubator (37°C, 5% CO2) and incubate the plate (37°C, 5% CO2) for 24 hours before treatment.

[0251] Day 2: Compound treatment: For 1536-well plates, compound stamping was performed with 25 nl of source plate compound at a maximum concentration of 10 mM, resulting in a maximum dose concentration of 50 μM for cell-based proliferation assays. The positive control SAHA was stamped at a final concentration of 10 μM.

[0252] Days 3 - 7: Plate incubation: After compound addition, the plates are incubated at 37°C, 5% CO2 for a total of 120 hours / 5 days.

[0253] Days 3 - 7: Addition of readout reagent and plate reading: After incubation, the plates are removed from the incubator and the specified readout reagent is added to the cell plates. For details based on specific readouts, refer to the following. · CTG readout: Remove CTG2.0 reagent from the refrigerator and allow it to return to room temperature before use. Add 4 μL / well of CTG to all wells of each cell plate. For 1536-well plates, incubate the plate at 37°C, 5% CO2 for 30 minutes, and read the plate using the protocol specific to luminescence on the designated plate reader. There are CTG-specific protocols for BMG or Envisions. · CyQUANT Readout: Remove the Cyquant Direct Cell Proliferation Assay Kit from the refrigerator and allow it to return to room temperature before use. If the reagent needs to be thawed by heating in a dry bath, calculate the total amount required based on the well-dispensed volume to ensure sufficient detection reagent. Prepare the detection reagent by combining the assay recipe of 11.7 mL of PBS, 48 μL of CyQuant® Direct nucleic acid stain, and 240 μL of CyQuant® Direct background suppressor. Add 2 μL / well of the Cyquant reagent mixture to all wells, incubate the plate at 37 °C, 5% CO2 for 60 minutes, and read the plate using the CyQuant-specific protocol with a specified plate reader BMG or EnVisions for a specific 1536-well protocol (CyQUANT Direct - 508 / 527 nm, CyQUANT Direct Red - 622 / 645 nm). · CTF Readout: Remove the CTF reagent from the refrigerator and allow it to return to room temperature before use. Prepare 1X reagent and vortex until dissolved (the reagent is stable at room temperature for 24 hours or at 4 °C for 7 days). Add 4 μL / well of CTF to all wells, incubate the plate at 37 °C, 5% CO2 for 180 minutes (3 hours), and read the plate using the fluorescence-specific protocol with a specified plate reader (BMG or Envisions has a CTF-specific protocol (Ex380 - 400, Em505)). · One-pot Live-Dead HCS Readout: After incubation, remove the plate from the incubator. For a 1536-well plate, prepare 4 mL of 1X PBS, add 8 drops of propidium iodide reagent + 4 μL of Hoechst 333242, mix, and use a multi-drop comb to dispense 1 μL / well at medium speed. For a 384-well plate, prepare 6 mL of 1X PBS, add 12 drops of propidium iodide reagent + 6 μL of Hoechst 333242, mix, and use a multi-drop comb to dispense 8 μL / well at medium speed. Incubate at 37 °C and 5% CO2 for 30 minutes, seal the plate with an aluminum seal, spin it in a spin-bucket centrifuge at 1000 RPM for 2 minutes, place the plate on the CX7, and acquire data.

[0254] The analyzed data is exported as a Spotfire file and then processed in ABASE.

[0255] Data analysis of CTG, CyQUANT, and CTF readouts: The raw data files are exported from the BMG, Envision, and CX7 readers and paired with the barcoded compound plates to track compound IDs, dose responses, and Echo transfer records. This enables the import and QC analysis of dose-response curves and the determination of IC 50 values. The data and images of each plate and well on both image channels can also be exported. The inhibition rate of proliferation activity was calculated according to the following formula.

Equation

[0256] Assay principle: Cell viability is measured in an assay that detects a live cell readout of intracellular ATP (CTG), DNA (CyQUANT), and peptidase activity by the cell-permeable substrate Gly-Phe-AFC (CTF) using a luminescence or fluorescence assay during cell proliferation in the presence of a PARP inhibitor compound.

[0257] MDCK-MDR1 permeability assay results for exemplary compounds of the present technology In a bidirectional assay involving a Madin-Darby canine kidney (MDCK) cell line transfected with the human MDR1 gene (P-glycoprotein, P-gp) designed to overexpress the MDR1 efflux transporter, which is the major efflux transporter of the blood-brain barrier (BBB), an established method is used to measure the efflux rate of a compound across a polarized cell monolayer. As is well known in the art, data generated from the MDCK-MDR1 permeability assay can be used to predict in vivo absorption of a drug. The bidirectional MDCK-MDR1 permeability assay can identify and quantify the level of active efflux. Screening the compound in both the apical-to-basolateral direction (A→B) and the basolateral-to-apical direction (B→A) across the entire cell monolayer yields a B→A / A→B ratio (efflux ratio, "ER"). Unlike the Caco-2 assay, the MDCK-MDR1 assay is not affected by potential efflux interference by breast cancer resistance protein (BCRP). If the ER of a compound exceeds 2, it suggests that the compound may be affected by active efflux. This data can be further used to predict blood-brain barrier (BBB) permeability by calculating from data of logarithm (product of permeability and surface area) ("logPS"), as it is well understood that it can predict in vivo logarithm ([brain concentration] / [plasma concentration]).

[0258] Table 2 below provides the initial bidirectional MDCK-MDR1 permeability results for exemplary compounds of the present technology. [Table 2]

[0259] In vivo CNS Penetration of Exemplary Compounds of the Present Technology The compounds of the present technology are predicted to exhibit BBB permeability according to the company's proprietary prediction models. These prediction models were further verified by in vivo experiments. In particular, after continuous intravenous infusion into Sprague-Dawley rats for 24 hours, the unbound brain-to-plasma ratio (Kpuu) in vivo at steady state was measured by comparing the free drug concentrations (protein binding corrected) in the brain and plasma. When Kpuu exceeds 0.3, it indicates good brain exposure of the compound.

[0260] Table 3 below provides the Kpuu results for exemplary compounds of the present technology. As shown in Table 3, the compounds of the present technology exhibit in vivo Kpuu values that are generally recognized as predictive of clinical brain penetration. [Table 3]

[0261] Although specific embodiments have been illustrated and described, those skilled in the art, after reading the foregoing specification, may make changes, substitutions of equivalents, and other types of modifications to the compounds of the present technology or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures described herein. Each of the aspects and embodiments described above may also include or incorporate into the specification variations or aspects as disclosed with respect to any or all of the other aspects and embodiments.

[0262] Also, the present technology is not limited from the perspective of the specific embodiments described herein, and these are intended as single examples of the individual embodiments of the present technology. As will be apparent to those skilled in the art, many changes and modifications of the present technology can be made without departing from its spirit and scope. Functionally equivalent methods within the scope of the present technology will be apparent to those skilled in the art from the foregoing description in addition to those listed in the specification. Such changes and modifications are intended to fall within the scope of the appended claims. The present technology is not limited to a particular method, reagent, compound, composition, labeled compound or biological system, and it should of course be understood that these can also be modified. It is also understood that the terms used herein are for the purpose of describing particular embodiments and are not intended to be limiting. Accordingly, the present specification is intended to be regarded as exemplary only, with the breadth, scope, and spirit of the present technology being indicated only by the appended claims, the definitions therein, and their equivalents.

[0263] The embodiments illustratively described in this specification can be preferably implemented even in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising", "including", "containing", etc. shall be understood broadly without limitation. Further, the terms and expressions used herein are used as terms of explanation rather than limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or parts thereof, but it is recognized that various changes are possible within the scope of the claimed technology. In addition, the phrase "consisting essentially of" will be understood to include the specifically recited elements and additional elements that do not substantially affect the basic and novel features of the claimed technology. The phrase "consisting of" excludes any element not specified.

[0264] In addition, when a feature or aspect of the present disclosure is described from the perspective of a Markush group, one of ordinary skill in the art will recognize that the present disclosure is also described from the perspective of any individual member or subgroup of members of the Markush group. Each group of the narrower species and subgenera that fall within the general disclosure also forms part of the present invention. This includes a comprehensive specification of the invention with a proviso or negative limitation removing any subject matter from that genus, whether or not the removed material is specifically recited herein.

[0265] As will be understood by one of ordinary skill in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also include any and all possible subranges and combinations of those subranges. It can be readily recognized that any of the recited ranges can be adequately described and made possible by dividing the same range into at least equal halves, thirds, quarters, fifths, tenths, etc. By way of non-limiting example, each range discussed herein can be readily divided into lower thirds, middle thirds, and upper thirds, etc. As will be understood by one of ordinary skill in the art, all words such as "greatest", "at least", "greater than", "less than", etc. include the recited numbers and then refer to ranges that can be divided into subranges as described above. Finally, as will be understood by one of ordinary skill in the art, ranges include each individual member.

[0266] All publications, patent applications, issued patents, and other documents (e.g., magazines, articles, and / or textbooks) referred to herein are incorporated herein by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the incorporated text are excluded to the extent they are inconsistent with the definitions in the present disclosure.

[0267] The present technology may include, but is not limited to, the features and combinations of features described in the following paragraphs in writing. It is understood that the following paragraphs are not to be construed as limiting the scope of the claims appended hereto, nor as prescribing that all such features must necessarily be included in such scope of the claims.

[0268] A. A compound of formula I, or a pharmaceutically acceptable salt and / or solvate thereof, wherein

Chem.

[0269] B. The compound of paragraph A is a compound of formula IA, or a pharmaceutically acceptable salt and / or solvate thereof:

Chem.

[0270] C. The compound of paragraph A is a compound of formula IB, or a pharmaceutically acceptable salt and / or solvate thereof:

Chem.

[0271] D. R 1 is aryl, heteroaryl, or non-aromatic heterocyclyl, and R 2 is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or non-aromatic heterocyclyl, a compound of any one of paragraphs A - C.

[0272] E. R 1 is aryl, heteroaryl, or non-aromatic heterocyclyl, and R 2 is H, alkyl, cycloalkyl, or non-aromatic heterocyclyl, a compound of any one of paragraphs A - D.

[0273] F.X 1 is F, a compound of any one of paragraphs A - E.

[0274] G.X 2 is NH, a compound of any one of paragraphs A - F.

[0275] H. The compound is

Chemical Structure

[0276] I. A composition comprising a compound according to any one of paragraphs A - H and a pharmaceutically acceptable carrier.

[0277] J. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of paragraphs A - H, wherein the effective amount of the compound is effective for the treatment of cancer.

[0278] K. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of paragraphs A - H, wherein the compound is present in an amount effective to treat cancer when combined with a second cancer therapy.

[0279] L. A method of treating a subject suffering from a B - cell malignancy, the method comprising administering to the subject an effective amount of a compound according to any one of paragraphs A - H and an effective amount of a second cancer therapy.

[0280] M. An agent for treating cancer in a subject, the agent comprising a compound according to any one of paragraphs A - H.

[0281] N. The agent according to paragraph M, wherein the agent further comprises a pharmaceutically acceptable carrier.

[0282] O. The agent according to paragraph M or paragraph N, wherein the agent comprises an effective amount of the compound for treating cancer when combined with a second cancer therapy.

[0283] Other embodiments are set forth in the following claims, together with the full scope of equivalents to which the claims are entitled.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt and / or solvate thereof, wherein 【Chemical 1】 In the formula,[[]]END]] X １ is H, F, or Cl, X ２ is NH or N—R ３ wherein R １ and R ２ One of them is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl, and R １ and R ２ The remaining one is aryl, heteroaryl, or non-aromatic heterocyclyl, R ３ is a compound that is alkyl, cycloalkyl, alkenylenyl, and non-aromatic heterocyclyl, or a pharmaceutically acceptable salt and / or solvate thereof.

2. R １ is aryl, heteroaryl, or non-aromatic heterocyclyl, R ２ The compound according to claim 1, wherein R is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or non-aromatic heterocyclyl.

3. R １ is aryl, heteroaryl, or non-aromatic heterocyclyl, R ２ The compound according to claim 1, wherein R is H, alkyl, cycloalkyl, or non-aromatic heterocyclyl.

4. X １ The compound according to claim 1, wherein X is F.

5. X ２ The compound according to claim 1, wherein X is NH.

6. The compound is a compound of formula IA, [Chemical 2] Or a pharmaceutically acceptable salt and / or solvate thereof, the compound according to claim 1.

7. R １ is aryl, heteroaryl, or non-aromatic heterocyclyl, R ２ The compound according to claim 6, wherein R is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or non-aromatic heterocyclyl.

8. R １ is aryl, heteroaryl, or non-aromatic heterocyclyl, R ２ The compound according to claim 7, wherein R is H, alkyl, cycloalkyl, or non-aromatic heterocyclyl.

9. X １ The compound according to claim 8, wherein X is F.

10. X ２ The compound according to claim 9, wherein X is NH.

11. The compound is a compound of formula IB, [Chemical 3] Or a pharmaceutically acceptable salt and / or solvate thereof, the compound according to claim 1.

12. R １ is aryl, heteroaryl, or non-aromatic heterocyclyl, R ２ The compound according to claim 11, wherein R is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or non-aromatic heterocyclyl.

13. R １ is aryl, heteroaryl, or non-aromatic heterocyclyl, R ２ The compound according to claim 12, wherein R is H, alkyl, cycloalkyl, or non-aromatic heterocyclyl.

14. X １ The compound according to claim 13, wherein X is F.

15. X ２ The compound according to claim 14, wherein X is NH.

16. A composition comprising the compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound according to any one of claims 1 to 15, wherein the effective amount of the compound is effective for the treatment of cancer.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 15, wherein the compound is present in an amount effective to treat the cancer when combined with a second cancer therapy.

19. A method of treating a subject suffering from a B-cell malignancy, comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 15 and an effective amount of a second cancer therapy.

20. An agent for treating cancer in a subject, comprising the compound according to any one of claims 1 to 15.

21. The agent according to claim 20, further comprising a pharmaceutically acceptable carrier.

22. The agent according to claim 20, comprising an effective amount of the compound for treating the cancer when combined with a second cancer therapy.

23. The agent according to claim 21, comprising an effective amount of the compound for treating the cancer when combined with a second cancer therapy.

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