Benzimidazole diazepinone parp inhibitors and methods of use

Abstract

The present disclosure relates to compounds according to Formula I or a pharmaceutically acceptable salt and / or solvate thereof, wherein X 1 is H, F, or CI; R 1 is H, alkyl, or cycloalkyl; R 2 is H, alkyl, or cycloalkyl; R 3 is H, halo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, or N(R 4 )(R 5 ); and one of R 4 and R 5 is H, alkyl, cycloalkyl, heterocyclyl, or heteroaryl, and the remaining one of R 1 and R 2 is H or alkyl, or R 4 and R 5 together with the nitrogen atom to which they are bound are heterocyclyl or heteroaryl. Furthermore, the present disclosure demonstrates that the compounds of the present disclosure penetrate the central nervous system, thereby allowing for the treatment of central nervous system cancers.

Description

Technical Field

[0001] This technology relates to compounds, compositions, and methods for the treatment of cancer, particularly central nervous system cancers, and their uses. Summary of the Invention

[0002] In one aspect, this technology provides compounds according to Formula I.

[0003]

[0004] Or its pharmaceutically acceptable salts and / or solvates, wherein X 1 It is H, F, or Cl; R 1 It is H, alkyl, or cycloalkyl; R 2 It is H, alkyl, or cycloalkyl; R 3 It is H, halogenated, alkyl, cycloalkyl, heterocyclic, heteroaryl, or N(R) 4 (R) 5 ); and R 4 and R 5 One of them is H, alkyl, cycloalkyl, heterocyclic, or heteroaryl, and R 1 and R 2 The remaining one is H or alkyl, or R 4 and R 5 Together with the nitrogen atom they are bonded to, they are heterocyclic or heteroaryl groups.

[0005] In one aspect, compositions are provided that comprise a compound of any of the embodiments disclosed herein, a pharmaceutically acceptable carrier, or one or more excipients, fillers, or reagents (collectively, “pharmaceutically acceptable carriers”, unless otherwise stated and / or specified).

[0006] In a related respect, medicaments for treating cancer in subjects are provided, comprising compounds of any of the embodiments disclosed herein and optionally pharmaceutically acceptable carriers.

[0007] In related aspects, pharmaceutical compositions are provided comprising (i) an effective amount of a compound of any of the embodiments disclosed herein, wherein such effective amount of the compound is effective for treating cancer; and (ii) a pharmaceutically acceptable carrier.

[0008] In a related respect, pharmaceutical compositions are provided comprising (i) an effective amount of a compound of any of the embodiments disclosed herein, wherein the compound is present in an amount effective for treating cancer when combined with a second cancer therapy; and (ii) a pharmaceutically acceptable carrier.

[0009] In another related aspect, this technology provides methods for including compounds and / or compositions and / or medicaments comprising any aspect or embodiment disclosed herein and / or embodiments disclosed herein. Such methods include methods for treating a subject with a disease, wherein the method includes administering to the subject an effective amount of a compound of any embodiment disclosed herein and an effective amount of a second cancer therapy. Detailed Implementation

[0010] As defined below, the following terms are used throughout.

[0011] As used herein and in the appended claims, unless otherwise specified herein or obviously contradicted by the context, singular articles such as “a / an” and “the,” and similar pronouns, in the context of describing elements (especially in the context of the following claims), shall be construed as covering both the singular and plural. Unless otherwise specified herein, descriptions of value ranges herein are intended only as a way of individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if individually described herein. Unless otherwise indicated herein or obviously contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise stated, the use of any and all instances or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of the claims. No language in this specification should be construed as indicating that any non-claimed element is necessary.

[0012] As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is a use of a term that is not readily apparent to those skilled in the art, “about” will, taking into account the context in which the term is used, mean at most 10% positive or negative for the particular term; for example, “about 10% by weight” will be understood to mean “9% to 11% by weight”. It should be understood that when “about” precedes a term, the term should be interpreted as disclosing “about” as well as terms not modified by “about”, for example, “about 10% by weight” discloses “9% to 11% by weight” and discloses “10% by weight”.

[0013] The phrase “and / or” as used in this disclosure should be understood to mean individually any one of the listed members or a combination of any two or more of them. For example, “A, B and / or C” would mean “A, B, C, A and B, A and C, B and C, or a combination of A, B and C”.

[0014] Generally speaking, mentioning an element (such as hydrogen or H) means including all isotopes of that element. For example, if the R group is defined as including hydrogen or H, it also includes deuterium and tritium. Therefore, it includes radioactive isotopes (such as tritium, carbon, and nitrogen). 14 P 32 and S 35 Compounds of this technology are within the scope of this technology. Based on the disclosure herein, the procedure for inserting such markings into compounds of this technology will be apparent to those skilled in the art.

[0015] Generally, "substituted" means an organic group (e.g., an alkyl group) as defined below, wherein one or more bonds to a hydrogen atom contained therein are replaced by bonds to non-hydrogen or non-carbon atoms. A substituted group also includes a group in which one or more bonds to a carbon or hydrogen atom are replaced by one or more bonds to a heteroatom (including double or triple bonds). Therefore, unless otherwise specified, a substituted group is substituted by one or more substituents. In some embodiments, the substituted group is substituted by one, two, three, four, five, or six substituents. Examples of substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyl groups; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, and heterocyclic alkoxy groups; carbonyl (oxo); carboxylic acid esters; esters; urethanes; oximes; hydroxylamines; alkoxyamines; arylalkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyl groups; pentafluorothioalkyl (i.e., SF5); sulfonamides; amines; N-oxides; hydrazines; acyl hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imides; nitro groups; and nitriles (i.e., CN).

[0016] Substituted cyclic groups, such as substituted cycloalkyl, aryl, heterocyclic, and heteroaryl groups, also include rings and ring systems in which the bonds to hydrogen atoms are replaced by bonds to carbon atoms. Therefore, substituted cycloalkyl, aryl, heterocyclic, and heteroaryl groups can also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0017] Alkyl groups include straight-chain and branched alkyl groups having 1 to 12 carbon atoms, typically 1 to 10 carbon atoms, or in some embodiments 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 groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched 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 once or multiple 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, carboxylalkyl, etc.

[0018] Cycloalkyl groups comprise monocycloalkyl, bicycloalkyl, or tricycloalkyl groups having 3 to 12 carbon atoms in the ring (or, in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms). The cycloalkyl group may be substituted or unsubstituted. Exemplary monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl group may have 3 to 8 ring members, or the number of ring carbon atoms may range from 3 to 5, 3 to 6, or 3 to 7. Bicycloalkyl and tricycloalkyl systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decahydronaphthyl, etc. Substituted cycloalkyl groups may be substituted once or multiple times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also comprise rings substituted with straight-chain or branched alkyl groups as defined above. Representative substituted cycloalkyl groups can be monosubstituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5- or 2,6-disubstituted cyclohexyl groups, which can be substituted by substituents such as those listed above.

[0019] A cycloalkyl group is an alkyl group as defined above, wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to the cycloalkyl group as defined above. The cycloalkyl group may be substituted or unsubstituted. In some embodiments, the cycloalkyl group has 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. A substituted cycloalkyl group may be substituted at the alkyl, cycloalkyl, or both alkyl and cycloalkyl moieties of the group. Representative substituted cycloalkyl groups may be monosubstituted or substituted more than once, such as monosubstituted, disubstituted, or trisubstituted by substituents such as those listed above.

[0020] In addition to at least one double bond between two carbon atoms, the alkenyl group comprises straight-chain and branched alkyl groups as defined above. 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, etc. Representative substituted alkenyl groups can be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted groups (such as those listed above).

[0021] A cycloalkenyl group includes a cycloalkyl group as defined above, having at least one double bond between two carbon atoms. The cycloalkenyl group may 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.

[0022] A cycloalkenylalkyl group is an alkyl group as defined above, wherein the hydrogen or 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 can be substituted at the alkyl moiety, at the cycloalkenyl moiety, or at both the alkyl and cycloalkenyl moiety. Representative substituted cycloalkenylalkyl groups can be substituted once or multiple times by substituents (such as those listed above).

[0023] The alkynyl group includes straight-chain and branched alkyl groups as defined above, differing in that there is at least one triple bond between two carbon atoms. The alkynyl group can be substituted or unsubstituted. The 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, the 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 can be monosubstituted or substituted more than once, such as, but not limited to, monosubstituted, disubstituted, or trisubstituted by substituents (such as those listed above).

[0024] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. The aryl groups described herein include monocyclic, bicyclic, and tricyclic ring systems. Aryl groups can be substituted or unsubstituted. Therefore, aryl groups include, but are not limited to, phenyl, azulel, heptenyl, biphenyl, fluorenyl, phenanthryl, anthracel, indene, indanyl, cyclopentadienyl, and naphthyl groups. In some embodiments, the aryl group contains 6 to 14 carbons in the ring portion of the group, and in other embodiments, it contains 6 to 12 or even 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. The phrase "aryl group" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indene, tetrahydronaphthyl, etc.). Representative substituted aryl groups can be monosubstituted (e.g., tolyl) or substituted more than once. For example, a monosubstituted aryl group includes, but is not limited to, phenyl or naphthyl groups substituted with 2, 3, 4, 5, or 6, which can be substituted by those substituents listed above.

[0025] An aralkyl group is an alkyl group as defined above, wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above. The aralkyl group may 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 at the alkyl, aryl, or both alkyl and aryl moieties of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, as well as fused (cycloalkylaryl) alkyl groups such as 4-indenylethyl. A representative substituted aralkyl group may be substituted once or multiple times with substituents (such as those listed above).

[0026] Heterocyclic groups include aromatic (also called heteroaryl) and non-aromatic cyclic compounds containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Heterocyclic groups may be substituted or unsubstituted. In some embodiments, a heterocyclic group contains 1, 2, 3, or 4 heteroatoms. In some embodiments, a heterocyclic group includes monocyclic, bicyclic, and tricyclic groups having 3 to 16 ring members, while other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclic groups include aromatic, partially unsaturated, and saturated ring systems, such as, for example, imidazolyl, imidazolinyl, and imidazoalkyl groups. The phrase “heterocyclic group” includes fused ring classes, including those containing fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxadienyl, and benzo[1,3]dioxadienyl. This phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinine cyclic groups. This phrase includes heterocyclic groups having other groups (such as alkyl, oxo, or halogenated groups) bonded to one of the ring members, referred to as "substituted heterocyclic groups." Heterocyclic groups include, but are not limited to, acridinel, acridinel, pyrrolidine, imidazolyl, pyrazolidine, thiazolyl, tetrahydrothiophene, tetrahydrofuranyl, dioxacyclopentenyl, furanyl, thiophene, pyrrolyl, pyrrololinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinel, etc. Morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiaranyl, oxothiacyclohexane, dioxacyclohexyl, dithiaranyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydropyridinyl, dihydrodithiaranyl, dihydrodithionyl, homopiperazinyl, quininecycloyl, indoleyl, indolinyl, isoindoleyl, azaindoleyl (pyrrolopyridinyl), indazoleyl, inazinyl, benzotriazolyl, benzimidazolyl Benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiophenyl, benzoxathiophenyl, benzothiazolyl, benzoxazolyl, benzothiazolyl, benzothiazolyl, benzo[1,3]dioxacyclopentenyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purine, xanthine, adenine, guanine, quinolinyl Isoquinolinyl, quinazinyl, quinoxalinyl, quinazolinyl, cyclophosphinyl, phthalazinyl, naphridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxanedienyl, tetrahydroindolyl, tetrahydroindazoleyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl.Representative substituted heterocyclic groups can be monosubstituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups substituted or disubstituted at the 2-, 3-, 4-, 5-, or 6- positions by various substituents (such as those listed above).

[0027] 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 can be substituted or unsubstituted. The heteroaryl group includes, but is not limited to, groups such as pyrroloyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), inzolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxolinyl, and quinazolinyl. Heteroaryl groups include fused-ring compounds in which all rings are aromatic, such as those with an indole group, and fused-ring compounds in which only one ring is aromatic, such as those with a 2,3-dihydroindole group. Representative substituted heteroaryl groups can be replaced once or multiple times by various substituents, such as those listed above.

[0028] A heterocyclic alkyl group is an alkyl group as defined above, wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to the heterocyclic group as defined above. The heterocyclic alkyl group can be substituted or unsubstituted. A substituted heterocyclic alkyl group can be substituted at the alkyl moiety, at the heterocyclic moiety, or at both the alkyl and heterocyclic moieties. Representative heterocyclic alkyl groups include, but are not limited to, morpholino-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. A representative substituted heterocyclic alkyl group can be substituted once or multiple times with substituents (such as those listed above).

[0029] A heteroarylalkyl group is an alkyl group as defined above, wherein the hydrogen or 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 can be substituted at the alkyl moiety, at the heteroaryl moiety, or at both the alkyl and heteroaryl moieties. Representative substituted heteroarylalkyl groups can be substituted once or multiple times by substituents (such as those listed above).

[0030] Groups having two or more connection points (i.e., divalent, trivalent, or polyvalent) in compounds described herein are named using the suffix "ene." 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. Substituted groups having a single connection point in compounds of this technology are not referred to using the name "ene." Thus, for example, chloroethyl is not referred to as vinyl chloride herein.

[0031] 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. Alkoxy groups can be substituted or unsubstituted. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, etc. Examples of branched-chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, etc. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc. Representative substituted alkoxy groups can be substituted once or multiple times by substituents such as those listed above.

[0032] As used herein, the terms "alkanoyl" and "alkanoyloxy" can refer to -C(O)-alkyl groups and -OC(O)-alkyl groups, respectively, containing 2 to 5 carbon atoms. Similarly, "aromaticyl" and "aromaticoxy" refer to -C(O)-aryl groups and -OC(O)-aryl groups.

[0033] 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 at an alkyl group, respectively. Examples include, but are not limited to, phenoxy, naphthoxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted once or multiple times by substituents such as those listed above.

[0034] As used in this article, the term "carboxylate group" refers to the -COOH group.

[0035] As used in this article, the term "ester" refers to –COOR 70 And –C(O)OG group. R 70It is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclic alkyl, or heterocyclic group as defined herein. G is a carboxylic acid ester protecting group. Carboxylic acid ester protecting groups are well known to those skilled in the art. A comprehensive list of protecting groups for functional groups of carboxylic acid esters can be found in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY, (3rd edition, 1999), which may be added or removed using the procedures described herein, and is incorporated herein by reference in its entirety and for any and all purposes, as fully set forth herein.

[0036] The term "amide" (or "amide group") includes C- and N-amide groups, namely -C(O)NR, respectively. 71 R 72 and –NR 71 C(O)R 72 Group. R 71 and R 72 Independently, it is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic alkyl, or heterocyclic group as defined herein. Therefore, the amide group includes, but is 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 the group is referred to as "carbonylamino", and in other embodiments, the amide is -NHC(O)-alkyl, and the group is referred to as "alkanoylamino".

[0037] As used herein, the terms “nitrile” or “cyano” refer to the -CN group.

[0038] Uroalkyl groups include N- and O-uralkyl groups, i.e., -NR, respectively. 73 C(O)OR 74 and -OC(O)NR 73 R 74 Group. R 73 and R 74 Independently, it refers to substituted or unsubstituted alkyl, alkenyl, ynyl, cycloalkyl, aryl, aralkyl, heterocyclic alkyl, or heterocyclic groups as defined herein. 73 It can also be H.

[0039] As used in this article, the term "amine" (or "amino group") refers to –NR 75 R 76Group, wherein R 75 and R 76 Independently, it is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic alkyl, or heterocyclic group as defined herein. The amine can be alkylamino, dialkylamino, arylamino, alkylarylamino, NH₂, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0040] The term "sulfonamide group" includes S-sulfonamide and N-sulfonamide groups, namely, -SO2NR, respectively. 78 R 79 and –NR 78 SO2R 79 Group. R 78 and R 79 Independently, it is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic alkyl, or heterocyclic group as defined herein. Therefore, the sulfonamide group includes, but is not limited to, an aminosulfonyl group (-SO2NH2). In some embodiments herein, the sulfonamide group is –NHSO2-alkyl and is referred to as an “alkylsulfonylamino” group.

[0041] The term "thiol" refers to the -SH group, while "sulfide" includes -SR. 80 Groups, "sulfoxide" include –S(O)R 81 Groups, sulfones include -SO2R 82 Groups, and "sulfonyl" includes –SO2OR 83 R 80 R 81 R 82 and R 83 Each is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclic, or heterocyclic alkyl group as defined herein. In some embodiments, the sulfide is an alkylthio group or an -S-alkyl group.

[0042] The term "urea" refers to –NR 84 -C(O)-NR 85 R 86 Group. R 84 R 85 and R 86 The group is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic or heterocyclic alkyl group as defined herein.

[0043] The term "ammonia" refers to –C(NR) 87 )NR 88 R 89and –NR 87 C(NR 88 )R 89 , where R 87 R 88 and R 89 Each is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclic or heterocyclic alkyl group as defined herein.

[0044] The term "guanidine" refers to –NR 90 C(NR 91 )NR 92 R 93 , where R 90 R 91 R 92 and R 93 Each is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclic or heterocyclic alkyl group as defined herein.

[0045] 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 , where R 94 R 95 R 96 and R 97 Each is independently hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclic or heterocyclic alkyl groups as defined herein.

[0046] As used herein, the term "halogen" or "halogenated" refers to bromine, chlorine, fluorine, or iodine. Preferably, the halogen is fluorine, but it can also be chlorine or bromine.

[0047] As used in this article, the term "hydroxyl group" can refer to -OH or its ionized form –O. – A "hydroxyalkyl" group is an alkyl group that has been substituted with a hydroxyl group, such as HO-CH2-.

[0048] The term "imide" refers to –C(O)NR 98 C(O)R 99 , where R 98 and R 99 Each is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclic or heterocyclic alkyl group as defined herein.

[0049] The term "imine" refers to –CR 100 (NR 101 ) and –N(CR 100 R 101 ) group, wherein R 100 and R 101 Each is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, ynyl, arylaralkyl, heterocyclic, or heterocyclic alkyl group as defined herein, provided that R 100 and R 101 Both are not hydrogen at the same time.

[0050] As used in this article, the term "nitro" refers to the –NO2 group.

[0051] As used in this article, the term "trifluoromethyl" refers to –CF3.

[0052] As used in this article, the term "trifluoromethoxy" refers to –OCF3.

[0053] The term "azido group" refers to -N3.

[0054] The term "trialkylammonium" refers to the -N(alkyl)3 group. Trialkylammonium groups are positively charged and therefore typically have associated anions, such as halide anions.

[0055] The term "isocyanate" refers to -NC.

[0056] The term "isothiocyanate" refers to -NCS.

[0057] The term "pentafluorosulfuryl" refers to -SF5.

[0058] As those skilled in the art will understand, for any and all purposes, particularly for the purpose of providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily considered sufficiently descriptive and such that the same scope can be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily divided into a lower third, a middle third, and an upper third, etc. As those skilled in the art will also understand, all language, such as “up to,” “at least,” “greater than,” “less than,” etc., includes the listed numbers and refers to a scope that can subsequently be decomposed into subscopes as described above. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1 to 3 atoms means a group having 1, 2, or 3 atoms. Similarly, a group having 1 to 5 atoms means a group having 1, 2, 3, 4, or 5 atoms, etc.

[0059] As will be understood by those skilled in the art, “molecular weight” (also known as “relative molar mass”) is a dimensionless quantity, but can be converted to molar mass by multiplying by 1 g / mol or by 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.

[0060] Pharmaceutically acceptable salts of the compounds described herein are within the scope of this technology and include acid addition salts or base addition salts that retain the desired pharmacological activity and are not biologically undesirable (e.g., the salt does not have undue toxicity, allergenicity, or irritation, and is bioavailable). When the compounds of this technology have a basic group (such as, for example, an amino group), the pharmaceutically acceptable salt can be formed from inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (such as 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 this technology have an acidic group (such as, for example, a carboxylic acid group), it can react with metals such as alkali metals and alkaline earth metals (e.g., Na₂O₃). + Li + K + Ca 2+ Mg 2+ Zn 2+ Salts can be formed from ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine, and ornithine). These salts can be prepared on-site during the separation and purification of the compound, or by reacting the purified compound, in its free base or free acid form, with a suitable acid or base and separating the resulting salt.

[0061] Those skilled in the art will understand that the compounds of this technology can exhibit tautomerism, conformational isomerism, geometrical isomerism, and / or stereoisomerism. Since the chemical formula drawings within the specification and claims can only represent one possible tautomerism, conformational isomerism, stereochemical or geometrical isomerism, it should be understood that this technology covers any tautomerism, conformational isomerism, stereochemical and / or geometrical isomerism of compounds having one or more of the utilities described herein, as well as mixtures of these various forms.

[0062] "Tautomers" refer to the isomers of compounds that are in equilibrium with each other. The presence and concentration of isomers will depend on the environment in which the compound is present and can vary depending on, for example, whether the compound is a solid or in an organic solution or an aqueous solution. For example, in aqueous solution, quinolones can exhibit the following isomers (which are also referred to as tautomers of each other):

[0063]

[0064] As another example, guanidine can exhibit the following isomers (also known as tautomers) in protonated organic solutions:

[0065]

[0066] Since the representation of compounds is limited by structural formulas, it should be understood that all chemical formulas of the compounds described herein represent all tautomer forms of the compounds and are within the scope of this technique.

[0067] Unless otherwise specified in the stereochemistry, stereoisomers (also referred to as optical isomers) of a compound encompass all chiral, diastereomeric, and racemic forms of the structure. Therefore, compounds used in this technique include enriched or resolved optical isomers at any or all asymmetric atoms, as is evident from the description. Both racemic mixtures and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized to be substantially free of their enantiomeric or diastereomeric complexes, and these stereoisomers are all within the scope of this technique.

[0068] The compounds of this technique can exist as solvates (especially hydrates). Hydrates can form during the manufacture of the compound or a composition containing the compound, or they can form over time due to the hygroscopic nature of the compound. The compounds of this technique can also exist as organic solvates (including DMF, ether, and alcohol solvates, etc.). The identification and preparation of any particular solvate are within the skill of a person skilled in synthetic organic chemistry or medicinal chemistry.

[0069] Throughout this disclosure, various publications, patents, and published patent specifications are referenced by way of identification citations. Arabic numerals referring to the references are also included within this disclosure, and a complete bibliographical detail is provided after the Examples section. The disclosures of these publications, patents, and published patent specifications are hereby incorporated by reference to this disclosure for a more complete description of the art.

[0070] This technology

[0071] Poly(ADP-ribosyl) polymerase 1 (PARP1) is a member of a family of proteins involved in numerous cellular processes, such as DNA repair, genome stability, and programmed cell death. PARP1 is an ADP-ribosyltransferase that uses NAD+ as a substrate to modify proteins—including itself—through PARylation and to detect single-strand DNA breaks. It plays a crucial role in homologous recombination and DNA repair by signaling the enzymatic processes involved in repairing single-strand DNA breaks.

[0072] Several PARP1 inhibitors have been approved for the treatment of breast and ovarian cancers lacking other DNA repair mechanisms, and additional PARP inhibitors are currently undergoing clinical trials for the treatment of ovarian cancer, pancreatic and biliary malignancies, glioblastoma, lung cancer, and prostate cancer. BRCA1 / 2 deficient cancers are extremely sensitive to PARP1 inhibition, with PARP inhibition being lethal to cells with loss-of-function mutations in both BRCA1 and BRCA2. Reduced homologous recombination (HR) capacity through other mechanisms also sensitizes cells to PARP inhibitors. Cells lacking DNA repair deficiencies are typically 1000 times less susceptible to PARP inhibitors than cells with such deficiencies. PARP inhibitors reduce PAR alkylation and trap PARP1 on DNA, leading to replication fork collapse and cell death.

[0073] However, current PARP1 inhibitors such as talazoparib, olaparib, rucaparib, and niraparib do not have good central nervous system (CNS) penetration, and veliparib is ineffective against most tumors. See, for example, Gupta, Shiv K. et al., "PARP inhibitors for sensitization of alkylation chemotherapy in inglioblastoma: impact of blood-brain barrier and molecular heterogeneity," Frontiers in Oncology 8 (2019): 670; Kizilbash, SH 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.

[0074] Therefore, there is a need for PARP inhibitors with improved central nervous system penetration to treat brain cancers such as glioblastoma, neuroblastoma, and medulloblastoma.

[0075] This technology responds to these needs and provides additional advantages. Based on proprietary internal predictive models, the compounds of this technology are expected to exhibit desirable blood-brain barrier (BBB) ​​permeability. These proprietary predictive models have been validated by in vitro assays, which have been well-established to predict BBB permeability in living subjects, and have also been validated by in vivo experiments. Therefore, this technology provides compounds with advantageously improved central nervous system permeability, and compositions and methods particularly suitable for the treatment of central nervous system cancers.

[0076] Therefore, in one aspect, this technology provides a compound according to Formula I.

[0077]

[0078] Or its pharmaceutically acceptable salts and / or solvates, wherein X 1 It is H, F, or Cl; R 1 It is H, alkyl, or cycloalkyl; R 2 It is H, alkyl, or cycloalkyl; R 3 It is H, halogenated, alkyl, cycloalkyl, heterocyclic, heteroaryl, or N(R) 4 (R) 5 ); and R 4 and R 5 One of them is H, alkyl, cycloalkyl, heterocyclic, or heteroaryl, and R 1 and R 2 The remaining one is H or alkyl, or R 4 and R 5 Together with the nitrogen atom to which they are bonded, they are heterocyclic or heteroaryl groups. For ease of reference, compounds included in any aspect or example herein may be referred to as "a compound of the present technology" or "compounds of the present technology" anywhere in this disclosure. Similarly, for ease of reference, compositions, pharmaceuticals, and pharmaceutical compositions of the present technology may be collectively referred to herein as "compositions," "compositions of the present technology," etc.

[0079] In any embodiment herein, a compound of formula I may have formula IA.

[0080] (IA) or its pharmaceutically acceptable salts and / or solvates.

[0081] In any embodiment herein, a compound of formula I may have formula IB.

[0082] (IB) or its pharmaceutically acceptable salts and / or solvates.

[0083] In any embodiment of this document, the following may be the case: R 1 It is H and R 2 It is H, C1-C6 alkyl or C3-C6 cycloalkyl, or R 1 It is H, C1-C6 alkyl or C3-C6 cycloalkyl and R 2 It is H. In any embodiment herein, X 1 It can be F.

[0084] In any embodiment of this document, R 3 It can be

[0085] , where n is 0 or 1; R 6 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 7 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; X 2 It is CH, C-alkyl, or N; X 3 It is N-R 8 C(R) 9 (R) 10 ) or O; R 8 It is H, alkyl, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 9 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; and R 10 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0086] In any of the embodiments herein, the compound may be any of the following or a pharmaceutically acceptable salt and / or solvation thereof:

[0087]

[0088] In one aspect, compositions are provided comprising a compound of any embodiment disclosed herein, a pharmaceutically acceptable carrier, or one or more excipients, fillers, or reagents (collectively, “pharmaceutically acceptable carriers”, unless otherwise stated and / or specified). In a related aspect, medicaments are provided for treating a subject with cancer, comprising a compound of any embodiment disclosed herein and optionally a pharmaceutically acceptable carrier. A medicament 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 antibodies, and / or chemotherapeutic agents. In any embodiment herein, the cancer may be breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer (such as brain cancer). CNS cancer may be glioblastoma, neuroblastoma, and / or medulloblastoma. In a related aspect, pharmaceutical compositions are provided comprising (i) an effective amount of a compound of any embodiment disclosed herein, wherein such effective amount of the compound is effective for treating cancer; and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, the cancer may 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 may 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, pharmaceutical compositions are provided comprising (i) an effective amount of a compound of any embodiment disclosed herein, wherein the compound is present in an amount effective in treating the cancer when combined with a second cancer therapy (such as radiotherapy, monoclonal antibodies, and / or chemotherapeutic agents); and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, the cancer may be breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer (such as brain cancer). In another related aspect, the technology provides methods comprising compounds and / or compositions and / or medicaments of any embodiment disclosed herein.

[0089] "Effective amount" refers to the amount of a compound or composition required to produce the desired effect. An example of an effective amount includes an amount or dose that produces acceptable levels of toxicity and bioavailability for therapeutic (pharmaceutical) use, including but not limited to reducing tumor masses. In any aspect or embodiment of the compositions, pharmaceutical compositions, and methods disclosed herein that include compounds of the present technology (collectively referred to herein as "any embodiment herein," "any embodiment disclosed herein," etc.), an effective amount may be an amount effective for treating cancers such as breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancers), treating tumors, and / or shrinking tumors. For example, an effective amount of any embodiment of the present invention that includes compounds of the present technology may be about 0.01 µg to about 200 mg of the compound (such as about 0.1 µg to about 50 mg of the compound or about 10 µg to about 20 mg of the compound). Methods and uses according to the present technology may include effective amounts of compounds of any embodiment disclosed herein. In any aspect or embodiment disclosed herein, an effective amount may be determined relative to a subject. As used herein, a "subject" or "patient" is a mammal, such as a cat, dog, rodent, or primate. Typically, subjects are humans, and preferably humans who suffer from or are suspected of suffering from pain. The terms "subject" and "patient" are used interchangeably.

[0090] Therefore, the present technology provides pharmaceutical compositions and medicines comprising compounds (or compositions of any of the embodiments disclosed herein) and pharmaceutically acceptable carriers. The compositions can be used in the methods and treatments described herein. Pharmaceutical compositions can be packaged in unit dosage forms. Unit dosage forms are effective in treating cancers such as breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancers. When administered to a subject in need, the unit dosage form is effective in treating the tumor by reducing tumor volume. Generally, the unit dose of a compound comprising the present technology will vary depending on patient considerations. These considerations include, for example, age, regimen, condition, sex, disease severity, contraindications, concomitant therapies, etc. Exemplary unit doses based on these considerations can also be adjusted or modified by a physician skilled in the art. For example, the unit dose for a patient containing a compound comprising the present technology may be 1 × 10⁻⁶. -4 The value varies between g / kg and 1 g / kg, preferably between 1 × 10⁻⁶ g / kg. –3The dosage of the compound in this technology can also vary between 0.01 mg / kg and 100 mg / kg, or preferably between 0.1 mg / kg and 10 mg / kg. Suitable unit dosage forms include, but are not limited to, parenteral solutions, oral solutions, powders, tablets, pills, soft capsules, capsules, lozenges, suppositories, patches, nasal sprays, injections, implantable sustained-release formulations, mucosal adhesive films, topical protective varnishes, lipid complexes, liquids, etc.

[0091] Pharmaceutical compositions and drugs can be prepared by mixing one or more compounds and / or compositions of the present invention 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, vaginal, or via implantable receptacles. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injection. The following dosage forms are given by way of example and should not be construed as limiting the present technology.

[0092] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules, and capsules as solid dosage forms are acceptable. These can be prepared, for example, by mixing one or more existing compounds of the present technology or their pharmaceutically acceptable salts or tautomers with at least one additive, such as starch or other additives. Suitable additives are sucrose, lactose, cellulose sugars, mannitol, maltitol, dextran, starch, agar, alginate, chitin, deacetylated chitosan, pectin, astragalus gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. Optionally, oral dosage forms may contain other ingredients to aid administration, such as inactive diluents, or lubricants (such as magnesium stearate), or preservatives (such as parabens or sorbic acid), or antioxidants (such as ascorbic acid, tocopherol, or cysteine), disintegrants, binders, thickeners, buffers, sweeteners, flavorings, or aromatizers. Tablets and pills can be further processed with suitable coating materials known in the art.

[0093] Liquid dosage forms for oral administration can be pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, and may contain inert diluents (such as water). Pharmaceutical formulations and drugs can 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 emulsifiers may be added.

[0094] As documented above, suspensions may contain oils. 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 include alcohols, such as, but not limited to, ethanol, isopropanol, cetyl alcohol, glycerol, and propylene glycol. 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.

[0095] Injectable dosage forms typically include aqueous or oil-based suspensions, which can be prepared using suitable dispersants or wetting agents and suspending agents. Injectable forms can be in solution or suspension form (prepared using solvents or diluents). Acceptable solvents or media include sterile water, Ringer's solution, or isotonic saline solutions. Alternatively, sterile oils can be used as solvents or suspending agents. Typically, the oils or fatty acids are non-volatile and include natural or synthetic oils, fatty acids, monoglycerides, diglycerides, or triglycerides.

[0096] For injection, the pharmaceutical formulation and / or the drug may be a powder suitable for reconstitution with the appropriate solution as described above. Examples of these include, but are not limited to, powders, amorphous powders, granules, precipitates, or particles that have been freeze-dried, rotary-dried, or spray-dried. For injection, the formulation may optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof.

[0097] The compounds of this technology can be administered to the lungs via inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any suitable solvent and optional other compounds, such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary depending on the specific compound requirements but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, 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 commonly used for the delivery of compounds of this technology via inhalation.

[0098] Dosage forms for topical (including buccal and sublingual) or transdermal application of the compounds used in this 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 necessary. Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Ointments, pastes, creams, and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, astragalus gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, and zinc oxide, or mixtures thereof. Absorption enhancers may also be used to increase the flux of the compounds of this technology across the skin. The rate of such flux can be controlled by providing a rate-controlled membrane (e.g., as part of a transdermal patch) or by dispersing the compound in a polymer matrix or gel.

[0099] In addition to the representative dosage forms described above, suitable pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the prior art. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub.Co., New Jersey (1991), which is incorporated herein by reference.

[0100] Formulations based on this technology can be designed to be short-acting, rapidly releasing, long-acting, and sustained-release, as described below. Therefore, pharmaceutical formulations can also be formulated for controlled-release or sustained-release applications.

[0101] The compositions of the present invention may also contain, for example, micelles or liposomes, or some other encapsulation form, or may be administered in a sustained-release form to provide prolonged storage and / or delivery effects. Thus, pharmaceutical formulations and drugs may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as reservoir injections or as implants (such as stents). Such implants may be made of known inert materials, such as silicone and biodegradable polymers.

[0102] The specific dosage can be adjusted based on the subject's disease condition, age, weight, general health status, sex, diet, dosing interval, route of administration, excretion rate, and drug combination. Any of the above dosage forms containing an effective amount is entirely within the scope of routine testing and therefore entirely within the scope of the existing technology.

[0103] Those skilled in the art can readily determine the effective dose by simply administering the compound of the present technology to a patient in incremental amounts until, for example, the tumor mass of the subject is reduced. The compound of the present technology can be administered to a patient at dose levels ranging from about 0.1 mg to about 1,000 mg per day. For a normal adult weighing about 70 kg, a dose ranging from about 0.01 mg to about 100 mg per kg of body weight per day is sufficient. However, the specific dose used may vary or may be adjusted at the discretion of those skilled in the art. For example, the dose may depend on many factors, including the patient's needs, the severity of the tumor-associated B-cell malignancy (e.g., non-Hodgkin lymphoma or chronic lymphocytic leukemia), and the pharmacological activity of the compound used. The determination of the optimal dose for a particular patient is well known to those skilled in the art.

[0104] The therapeutic effects of treatments based on this technique can be readily determined using various assay and modeling systems. The effectiveness of the composition (and determination of effective amounts) and method of this technique can also be demonstrated by: a reduction in tumor mass and / or a slowing of tumor growth and / or an increase in the responsiveness of cancer to secondary cancer therapies (such as radiotherapy, monoclonal antibodies, and / or chemotherapeutic agents).

[0105] For each specified condition described herein, compared with placebo-treated or other suitable control subjects, test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction in one or more symptoms caused by or associated with the subject's condition, up to 75% to 90% or 95% or greater reduction.

[0106] The compounds of this technology can also be administered to a patient in combination with other conventional therapeutic agents that can be used to treat tumors or for vaccination. Administration may include oral, parenteral, 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 method of this technology may also include sequentially or in combination administering conventional therapeutic agents with one or more compounds of this technology in amounts that can potentially or synergistically and effectively treat cancers (e.g., breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancers).

[0107] In one aspect, compounds of this technology are administered to patients in amounts or doses suitable for therapeutic use. Generally, the unit dose of a compound containing this technology will vary depending on patient considerations. These considerations include, for example, age, regimen, condition, sex, disease severity, contraindications, concomitant therapies, etc. Exemplary unit doses based on these considerations can also be adjusted or modified by those skilled in the art. For example, a unit dose of a compound containing this technology for a patient may be 1 × 10⁻⁶. -4 The variation is between g / kg and 1 g / kg, preferably between 1 × 10 g / kg. -3 The dosage of the compound can also vary between 0.01 mg / kg and 100 mg / kg, or preferably between 0.1 mg / kg and 10 mg / kg.

[0108] The compounds of this technology can also be modified, for example, by covalently linking organic moieties or conjugates to improve pharmacokinetic properties, toxicity, or bioavailability (e.g., increasing in vivo half-life). Conjugates can be linear or branched hydrophilic polymer groups, fatty acid groups, or fatty acid ester groups. Polymer groups may include molecular weights that can be adjusted by those skilled in the art to improve, for example, pharmacokinetic properties, toxicity, or bioavailability. Exemplary conjugates may include polyalkylene glycols (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymers, amino acid polymers, or polyvinylpyrrolidone and fatty acid or fatty acid ester groups, each group may independently contain about eight to about seventy carbon atoms. Conjugates used with the compounds of this technology can also serve as linkers to, for example, any suitable substituents or groups, radiolabels (markers or tags), halogens, proteins, enzymes, peptides, other therapeutic agents (e.g., pharmaceuticals or drugs), nucleosides, dyes, oligonucleotides, lipids, phospholipids, and / or liposomes. In one aspect, the conjugate may include polyethyleneimine (PEI), polyglycine, a hybrid of PEI and polyglycine, polyethylene glycol (PEG), or methoxy polyethylene glycol (mPEG). The conjugate may also link the compounds of the present technology to, for example, a label (fluorescent or luminescent label) or a marker (radionucleoside, radioisotope, and / or isotope) to form a probe of the present technology. Conjugates used with the compounds of the present technology may, in one aspect, improve in vivo half-life. Other exemplary conjugates used with the compounds of the present technology, their applications, and related technologies include those outlined in U.S. Patent No. 5,672,662, which is hereby incorporated by reference.

[0109] In another aspect, this technology provides a method for identifying a target, comprising contacting the target with a detectable or imaging-effective amount of a labeled compound of this technology. A detectable or imaging-effective amount is the amount of the labeled compound of this technology necessary for detection by a selected detection method. For example, a detectable amount may be an application amount sufficient to detect the binding of the labeled compound to the target. Suitable labels are known to those skilled in the art and may include, for example, radioisotopes, radionuclides, isotopes, fluorescent groups, biotin (which binds to streptavidin complexes), and chemiluminescent groups. After the labeled compound binds to the target, the target can be isolated, purified, and further characterized (e.g., by determining the amino acid sequence).

[0110] The terms “association” and / or “binding” can refer to, for example, a chemical or physical interaction between a compound of this technology and a target. Examples of associations or interactions include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions, and complexes. Association can also generally refer to “binding” or “affinity,” as each can be used to describe a variety of chemical or physical interactions. Measuring binding or affinity is also routine for those skilled in the art. For example, compounds of this technology can bind to or interact with a target or its precursors, portions, fragments, and peptides and / or deposits thereof.

[0111] As previously noted in this disclosure, in one aspect, a method of treating a subject suffering from cancer is provided, wherein the method comprises administering to the subject an effective amount of a compound of any embodiment disclosed herein or an effective amount of a composition of any embodiment disclosed herein, and optionally an effective amount of a second cancer therapy. In any embodiment herein, the cancer may be breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancers (such as brain cancer).

[0112] In any embodiment of this document, administration may further include administration of radiotherapy, monoclonal antibodies, and / or chemotherapeutic agents (such as alkylating agents; nitrosoureas; antimetabolites; anthracyclines; topoisomerase II inhibitors; mitotic inhibitors; antiestrogens; progesterone; aromatase inhibitors; antiandrogens; LHRH agonists; corticosteroids; DNA alkylating agents; taxanes; vinca alkaloids; microtubule toxins, or combinations of any two or more thereof). In any embodiment of this document, administration may also include administration of chemotherapeutic agents such as busulfan, cisplatin, carboplatin, oxaliplatin, octahedral platinum (IV) compounds, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), dichloromethyldiethylamine (nitrogen mustard), melphalan, temozolomide, carmustine (BCNU), lomustine (CCNU), 5-fluorouracil, capecitabine, etc. 6-Mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine, pemetrexed, daunorubicin, doxorubicin (doxorubicin), epirubicin, idarubicin, mitoxantrone, topotecan, irinotecan, etoposide (VP-16), teniposide, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, L-asparaginase, actinomycin, thalidomide Amines, retinoic acid, imatinib (Gleevec), gefitinib (Iressa), erlotinib (Tarceva), rituximab (Rituxan), bevacizumab (Avastin), ipilimumab, nivolumab (Opdivo), pembrolizumab (Keytruda), tamoxifen, fulvestrant, anastrozole, exemestane, letrozole, megestrol acetate, bicalutamide, flutamide, leuprorelin, goserelin, or any combination of two or more thereof.

[0113] In any embodiment herein, administration may include oral, rectal, nasal, vaginal, parenteral, transdermal, intravenous, intramuscular, or inhalation administration. In any embodiment herein, administration may include topical application of the compound to a subject, including a site of cancer, or topical application of the composition to a subject, including a site of cancer.

[0114] Examples provided herein are intended to demonstrate the advantages of the present technology and further assist those skilled in the art in preparing or using compounds and compositions based on the present technology. Examples are also presented herein to illustrate preferred aspects of the present technology more fully. These examples should in no way be construed as limiting the scope of the present technology as defined by the appended claims. Examples may include or incorporate any variations, aspects, or embodiments of the present technology described above. The variations, aspects, or embodiments described above may further include or incorporate any and all other variations, aspects, or embodiments of the present technology.

[0115] Example

[0116] Unless otherwise specified, all solvents and reagents shall be used exactly as received from the commercial supplier. 1 H-s spectra were recorded in CDCl3 with 0.03% TMS as internal standard on a Bruker AM or Varian 400 spectrometer (running at 400 MHz, respectively). Chemical shifts (δ) are reported in parts per million (ppm), and coupling constants (J) are reported in Hertz (Hz). Spin multiplicity is reported as s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet of doublet, dt = doublet of doublet, td = doublet of doublet, and m = multiplicity. LC-MS analysis was performed on a chromatograph with a photodiode array UV detector and a TOF mass spectrometer. The mass spectrometer utilized a multimode source simultaneously acquiring ESI+ / APCI+; a reference mass solution; and a supplementary solvent introduced before the source to assist ionization. Although single stereoisomers were isolated and obtained with high purity in the following examples, the definitive assignment of absolute stereochemistry may not yet be determined for some groups of stereoisomers.

[0117] Exemplary synthesis of certain compounds of this technology:

[0118] Synthesis of Compounds 2303 and 2535

[0119]

[0120] At 0°C, 2-bromo-5-fluoro-3-nitrobenzoic acid (25... Thionyl chloride (30 mL) was added to a solution of 0.095 g (0.095 mol) in MeOH (300 mL). The reaction was then allowed to reach room temperature and subsequently refluxed for 12 h. The reaction mixture was then cooled to room temperature and the solvent was evaporated under vacuum. The residue was washed with saturated NaHCO3 (200 × 3 mL) and extracted with EA (200 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE:EA = 10:1) to give methyl 2-bromo-5-fluoro-3-nitrobenzene (25 g, 95%) as a yellow solid. MS (ESI): C8H5BrFNO4, calculated value, 276.9, m / z, determined value, 277.9 [M+H] + .

[0121] Ethylenediamine (8.1 g, 134.8 mmol) was added to a solution of methyl 2-bromo-5-fluoro-3-nitrobenzene (25 g, 89.9 mmol) and Na₂CO₃ (19 g, 179.8 mmol) in 1-butanol (300 mL). The reaction mixture was stirred at 80 °C for 12 minutes. h, the mixture was concentrated. The residue was purified by silica gel rapid chromatography (DCM:MeOH=10:1) to give 7-fluoro-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazepine-5-one (12 g, 60%) as an orange solid. MS (ESI): calculated value of C9H8FN3O3, 225.1, measured m / z 226.1 [M+H] + .

[0122] A mixture of 7-fluoro-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaza-5-one (12 g, 0.053 mol) and Pd / C (2 g) in EA / AcOH (4:1, 200 mL) was stirred at room temperature for 12 h under H2 at 2 atm. When the reaction was complete, the solid was filtered off. The filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting with DCM / MeOH (10:1)) to give 9-amino-7-fluoro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaza-5-one (6 g, 58%) as a yellow solid. MS (ESI): C9H 10 The calculated mass of FN3O is 195.1, and the measured m / z value is 196.1 [M+H]. + .

[0123] Cyanogen bromide (80 mg, 0.76 mmol) was added to a solution of 9-amino-7-fluoro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazepine-5-one (100 mg, 0.51 mmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 16 h. After completion, the mixture was cooled and the solvent was evaporated under reduced pressure. The crude product was purified by RP-C18 column elution with H2O (0.5% FA) / CH3CN (100:0→50:50) to give 1-amino-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 2303; 80 mg, 71 percent) as a white solid. MS (ESI): C 10 The calculated mass of H9FN4O ​​is 220.1, and the measured m / z value is 221.1 [M+H]. + .

[0124] Cs₂CO₃ (352 mg, 1.08 mmol) and tetrahydro-2H-pyran-4-ylmethanesulfonate (130 mg, 0.72 mmol) were added to a solution of 1-amino-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (80 mg, 0.36 mmol) in DMF (2 mL). The reaction mixture was stirred at 100 °C for 16 h. After completion, the mixture was cooled and the solvent was evaporated under reduced pressure. The crude product was purified by RP-C18 column elution with H2O (0.5% FA) / CH3CN (100:0→50:50) to give 4-fluoro-1-((tetrahydro-2H-pyran-4-yl)amino)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 2535; 10 mg, 10 percent) as a white solid. MS (ESI): C 15 H 17 The calculated mass of FN4O2 is 304.1, and the measured m / z value is 305.1 [M+H]. + . 1 H NMR (400 MHz, CD3OD-d4) δ 7.61 – 7.58 (m,1H), 7.40 – 7.38 (m, 1H), 4.15 – 4.03 (m, 4H), 3.86 – 3.81 (m 1H), 3.75 –3.73 (m, 2H), 3.57 – 3.51 (m, 2H), 2.06 – 2.02 (m, 2H), 1.83 – 1.73 (m, 2H).

[0125] Synthesis of Compound 3801

[0126]

[0127] 1-Methylpiperidin-4-amine (402 mg, 3.5 mmol) was added to a solution of 1-bromo-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (100 mg, 0.35 mmol) in EtOH (5 mL). The mixture was heated at 100 °C for 3 h under microwave irradiation. After completion, the mixture was concentrated under reduced pressure. The residue was purified by RP-C18 column elution with H2O (0.1% TFA) / CH3CN (100:0→50:50) to give 4-fluoro-1-((1-methylpiperidin-4-yl)amino)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (20 mg, 18%) as a yellow oil. MS (ESI): C 16 H 20 The calculated mass of FN5O is 317.1, and the measured m / z value is 318.1 [M+H]. + . 1 H NMR (400 MHz, MeOD-d4) δ 7.63 (d, J = 10.0 Hz, 1H), 7.48 (d, J = 6.4 Hz, 1H), 4.19 - 4.03 (m,3H), 3.76 - 3.64 (m, 4H), 3.47 (s, 1H), 3.24 - 3.12 (m, 2H), 2.95 (s, 3H), 2.41 - 2.27 (m, 3H), 2.07 - 1.95 (m, 2H).

[0128] Synthesis of Compound 3802

[0129]

[0130] Add Cs₂CO₃ (86 mg, 0.26 mmol) and CsF₂ to a solution of 1-bromo-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (50 mg, 0.17 mmol) in DMSO (2 mL). (40 mg, 0.26 mmol) and 5-oxaspiro[3.5]nonane-8-amine (75 mg, 0.53 mmol). The reaction mixture was stirred at 100 °C for 16 h. After completion, the solid was filtered off. The filtrate was purified by passing it through an RP-C18 column (eluted with H2O (0.1% FA) / CH3CN (100:0→50:50)) to give 1-((5-oxaspiro[3.5]nonane-8-yl)amino)-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (12.6 mg, 21%) as a white solid. MS (ESI): C 18 H 21 The calculated mass of FN4O2 is 344.1, and the measured m / z value is 345.1 [M+H]. + . 1 H NMR (400 MHz, MeOD-d4) δ 7.35 - 7.32 (m, 1H), 7.21 -7.18 (m, 1H), 4.08 - 4.00 (m, 3H), 3.83 - 3.79 (m, 1H), 3.71 - 3.60 (m, 3H),2.35 - 2.29 (m, 2H), 2.18 - 1.94 (m, 4H), 1.89 - 1.70 (m, 2H), 1.58 - 1.48 (m, 2H).

[0131] Synthesis of Compound 3819

[0132]

[0133] Add Cs₂CO₃ (172 mg, 0.53 mmol) and CsF₂ to a solution of 1-bromo-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (100 mg, 0.35 mmol) in DMSO (2 mL). (80 mg, 0.53 mmol) and 7-oxabicyclo[2.2.1]heptane-2-amine (40 mg, 0.35 mmol). The reaction mixture was stirred at 100 °C for 16 h. After completion, the solid was filtered off. The filtrate was purified by passing it through an RP-C18 column (eluted with H2O (0.1% FA) / CH3CN (100:0→50:50)) to give 1-((7-oxabicyclo[2.2.1]heptane-2-yl)amino)-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (32.7 mg, 29%) as a white solid. MS (ESI): C 16 H17 The calculated mass of FN4O2 is 316.1, and the measured m / z value is 317.1 [M+H]. + . 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (t, J = 5.6 Hz,1H), 7.27 – 7.24 (m, 1H), 7.18 – 7.15 (m, 1H), 6.84 (d, J = 6.4 Hz, 1H), 4.58(t, J = 4.8 Hz, 1H), 4.45 (d, J = 5.2 Hz, 1H), 4.01 (s, 2H), 3.91 – 3.88 (m,1H), 3.82 – 3.64 (m, 2H), 1.99 – 1.93 (m, 1H), 1.71 – 1.68 (m, 1H), 1.60 –1.39 (m, 4H).

[0134] Synthesis of Compound 3650

[0135]

[0136] At 0°C, 2-bromo-5-fluoro-3-nitrobenzoic acid (25... Thionyl chloride (30 mL) was added to a solution of 0.095 g (0.095 mol) in MeOH (300 mL). The reaction mixture was refluxed and stirred for 12 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under vacuum. The residue was diluted with saturated NaHCO3 (200 × 3 mL) and extracted with EA (200 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE:EA = 10:1) to give methyl 2-bromo-5-fluoro-3-nitrobenzene (25 g, 95%) as a yellow solid. MS (ESI): C8H5BrFNO4, calculated value, 276.9, m / z, determined value, 277.9 [M+H] + .

[0137] Ethylenediamine (8.1 g, 134.8 mmol) was added to a solution of methyl 2-bromo-5-fluoro-3-nitrobenzene (25 g, 89.9 mmol) and Na₂CO₃ (19 g, 179.8 mmol) in 1-butanol (300 mL). The reaction mixture was stirred at 80 °C for 12 minutes. h, the mixture was concentrated. The residue was purified by silica gel rapid chromatography (DCM:MeOH=10:1) to give 7-fluoro-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazepine-5-one (12 g, 60%) as an orange solid. MS (ESI): calculated value of C9H8FN3O3, 225.1, measured m / z 226.1 [M+H] + .

[0138] A mixture of 7-fluoro-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaza-5-one (12 g, 0.053 mol) and Pd / C (2 g) in EA / AcOH (4:1, 200 mL) was stirred at room temperature for 12 h under H2 at 2 atm. When the reaction was complete, the solid was filtered off. The filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting with DCM / MeOH (10:1)) to give 9-amino-7-fluoro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaza-5-one (6 g, 58%) as a yellow solid. MS (ESI): C9H 10 The calculated mass of FN3O is 195.1, and the measured m / z value is 196.1 [M+H]. + .

[0139] BrCN (80 mg, 0.76 mmol) was added to a solution of 9-amino-7-fluoro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazo-5-one (100 mg, 0.51 mmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 16 h. After completion, the mixture was cooled and the solvent was evaporated under reduced pressure. The crude product was purified by RP-C18 column elution with H2O (0.5% FA) / CH3CN (100:0→50:50) to give 1-amino-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (80 mg, 71%) as a white solid. MS (ESI): C 10 The calculated mass of H9FN4O ​​is 220.1, and the measured m / z value is 221.1 [M+H]. + .

[0140] Cs₂CO₃ (221.98 mg, 0.6813 mmol), tetrahydro-2H-pyran-4-ylmethanesulfonate (130 mg, 0.72 mmol), and Pd-PEPPSI-IPent (9.54 mg, 0.0113 mmol) were added to a solution of 2-amino-6-fluoro-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-9-one (50 mg, 0.2271 mmol) in DMF (2.5 mL). The reaction mixture was stirred at 100 °C under N₂ for 16 h. After completion, the mixture was cooled, and the solvent was evaporated under reduced pressure. The crude product was purified by rapid chromatography (CH2Cl2 / MeOH (100:0→30:1)) to give 6-fluoro-2-(isopropylamino)-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-9-one (11 mg, 19%) as a white solid. MS (ESI): C 13 H 15 The calculated mass of FN4O is 262.29, and the measured m / z value is 263.0 [M+H]. + . 1 H NMR (400 MHz, MeOD) δ 7.20 – 7.17 (m, 1H), 7.07 – 7.04 (m, 1H), 4.02 – 3.95 (m, 3H), 3.57 – 3.55 (m, 2H), 1.21 (d, J = 6.4 Hz, 6H).

[0141] Synthesis of Compound 3654 and Compound epi-3654

[0142]

[0143] Add 1-(4-fluorophenyl)ethane-1,2-diamine (1.11 g, 7.2 mmol) to a solution of methyl 2-bromo-5-fluoro-3-nitrobenzene (2 g, 7.2 mmol) and Na₂CO₃ (3.05 g, 28.8 mmol) in 1-butanol (20 mL). Stir the reaction mixture at 85 °C for 12 minutes. h, the mixture was concentrated. The residue was purified by silica gel rapid chromatography (PE:EA=1:1) to give 7-fluoro-2-(4-fluorophenyl)-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazon-5-one (0.9 g, 39%) as an orange solid. MS (ESI): C 15 H 11The calculated mass of F2N3O3 is 319.0, and the measured m / z value is 320.0 [M+H]. + .

[0144] Fe (441 mg, 7.89 mmol) was added to a solution of 7-fluoro-2-(4-fluorophenyl)-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaza-5-one (420 mg, 1.32 mmol) in AcOH (10 mL). The reaction mixture was stirred at 25 °C for 16 minutes. h. When the reaction is complete, the solid is filtered off. The filtrate is concentrated to obtain a crude product, which is purified by silica gel column chromatography (eluting with MeOH / DCM (10:1)) to give 9-amino-7-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaza-5-one (200 mg, 52%) as a yellow solid. MS (ESI): C 15 H 13 The calculated mass of F2N3O is 289.1, and the measured m / z value is 290.1 ​​[M+H]. + .

[0145] To a solution of 9-amino-7-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazepine-5-one (100 mg, 0.35 mmol) in EtOH (2 mL), Na₂S₂O₅ (78 mg, 0.41 mmol) and (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (83 mg, 0.41 mmol) were added. The mixture was stirred at 80 °C for 16 hours. The residue was concentrated under vacuum and extracted with EA (10 mL × 2). The organic phase was washed with brine (10 mL × 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (MeOH: DCM = 10:1) to give (2R)-2-(4-fluoro-9-(4-fluorophenyl)-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azon-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 49%) as a yellow solid. MS (ESI): C 25 H 26 The calculated mass of F₂N₄O₃ is 468.2, and the measured m / z value is 469.2 [M+H]. + .

[0146] A solution of 4 NHCl in ethyl acetate (0.5 mL) was added to a solution of (2R)-2-(4-fluoro-9-(4-fluorophenyl)-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 0.17 mmol) in EA (0.5 mL). The mixture was stirred at 25 °C for 4 hours. After completion, the mixture was concentrated under reduced pressure to give a yellow solid of 4-fluoro-9-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azin-6(7H)-one (30 mg, 47%). MS (ESI): C 20 H 18 The calculated mass of F2N4O is 368.1, and the measured m / z value is 369.1 [M+H]. + .

[0147] 4-Fluoro-9-(4-fluorophenyl)-1-((R)-pyrrolidone-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azon-6(7H)-one (30 mg) was prepared by SFC splitting to obtain (S)-4-fluoro-9-(4-fluorophenyl)-1-((R)-pyrrolidone-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azon-6(7H)-one (compound 3654; 12 mg, 40%) and (R)-4-fluoro-9-(4-fluorophenyl)-1-((R)-pyrrolidone-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azon-6(7H)-one (compound epi-3654; 8 mg, ... mg, 27 percent).

[0148] Compound 3654: MS (ESI): C 20 H 18 The calculated mass of F2N4O is 368.1, and the measured m / z value is 369.1 [M+H]. + . 1 H NMR (400 MHz, CD3OD-d4) δ 7.77 – 7.74 (m, 1H), 7.50 – 7.04 (m, 5H), 5.15 (s, 1H), 4.66 – 4.63 (m, 1H), 4.49 – 4.45 (m, 1H), 3.14 – 2.94 (m, 2H), 2.22– 1.29 (m, 4H), 1.29 (m, 1H), 1.20 – 0.79 (m, 1H).

[0149] Compound epi-3654: MS (ESI): C 20 H 18 The calculated mass of F2N4O is 368.1, and the measured m / z value is 369.1 [M+H]. + . 1 H NMR (400 MHz, CD3OD-d4) δ 7.74 – 7.71 (m, 1H), 7.49 – 7.03 (m, 5H), 5.13 (s, 1H), 4.65 – 4.62 (m, 1H), 4.47 (t, J = 7.2 Hz, 1H), 3.08 (s, 1H),2.99 – 2.93 (m, 1H), 2.25 – 2.12 (m, 2H), 1.97 – 1.88 (m, 2H), 1.28 (s, 1H),1.16 – 0.87 (m, 1H).

[0150] Synthesis of Compounds 3806 and 3807

[0151]

[0152] To a solution of methyl 2-bromo-5-fluoro-3-nitrobenzoate (2.78 g, 0.01 mol) in 1-butanol (80 mL), 1-cyclopropylethane-1,2-diamine (1 g, 0.01 mol) and Na₂CO₃ (4.24 g, 0.04 mol) were added. The reaction mixture was stirred at 85 °C under N₂ for 16 h. The mixture was concentrated. The residue was purified by silica gel rapid chromatography (PE:EA = 1:1) to give 2-cyclopropyl-7-fluoro-9-nitro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (550 mg, 21%) as an orange solid. MS (ESI): C 12 H 12 The calculated mass of FN3O3 is 265.2, and the measured m / z value is 266.0 [M+H]. + .

[0153] A mixture of 2-cyclopropyl-7-fluoro-9-nitro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (550 mg, 2.0736 mmol) and Pd / C (50 mg) in MeOH (10 mL) was stirred at room temperature for 16 h at 2 atm in H₂. When the reaction was complete, the solid was filtered off. The filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting with DCM / MeOH (10:1)) to give 9-amino-2-cyclopropyl-7-fluoro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (436 g, 90%) as an orange solid. MS (ESI): C 12 H 14 The calculated mass of FN3O is 235.1, and the measured m / z value is 236.1 [M+H]. + .

[0154] To a solution of 9-amino-2-cyclopropyl-7-fluoro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (436 mg, 1.8533 mmol) in EtOH / H₂O (8 mL), tert-butyl (2-formylpyrrolidone-1-yl)carboxylate (556 mg, 2.7799 mmol) and NaHSO₃ (771 mg, 7.4132 mmol) were added. The reaction mixture was stirred at 60 °C under air for 4 h. The reaction mixture was quenched with saturated NaHCO₃ (20 mL × 3) and extracted with EA (20 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (DCM:MeOH = 10:1) to give (2R)-2-(9-cyclopropyl-4-fluoro-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (677 mg, 87%) as a white solid. MS (ESI): C 22 H 27 The calculated mass of FN4O3 is 414.2, and the measured m / z value is 415.1 [M+H]. + .

[0155] A mixture of (2R)-2-(9-cyclopropyl-4-fluoro-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.7238 mmol) in HCl / EA (4 ml, 4 N) was stirred at 25 °C for 0.5 h. When the reaction was complete, the solid was filtered off. The filter cake was concentrated to give 9-cyclopropyl-4-fluoro-1-((R)-pyrrolidine-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azin-6(7H)-one (200 mg, 87%) as a white solid. MS (ESI): C 17 H 19 The calculated mass of FN4O is 314.1, and the measured m / z value is 315.1 [M+H]. + .

[0156] 9-Cyclopropyl-4-fluoro-1-((R)-pyrrolidine-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (200 mg) was prepared by SFC splitting to obtain (S)-9-cyclopropyl-4-fluoro-1-((R)-pyrrolidine-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 3806, 100 mg, 50%) and (R)-9-cyclopropyl-4-fluoro-1-((R)-pyrrolidine-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 3807, 20 mg, 10%) as yellow solids.

[0157] Compound 3806: MS (ESI): C 17 H 19 The calculated mass of FN4O is 314.2, and the measured m / z value is 315.2 [M+H]. + . 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.66 – 7.64 (m, 1H), 7.59 (d, J =10.6 Hz, 1H), 4.53 – 4.41 (m, 3H), 3.02 – 2.90 (m, 2H), 2.88 – 2.82 (m, 1H), 2.17 – 2.12 (m, 2H), 1.89 – 1.70 (m, 2H), 0.79 (s, 1H), 0.58 – 0.28 (m, 4H).

[0158] Compound 3807: MS (ESI): C 17 H19 The calculated mass of FN4O is 314.2, and the measured m / z value is 315.2 [M+H]. + . 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.70 (s, 1H), 7.79 – 7.76 (m, 1H), 7.68 (d, J = 9.5 Hz, 1H), 5.10 (t, J = 7.5 Hz, 1H), 4.49 (s, 2H), 3.02 (d, J= 5.1 Hz, 1H), 2.43 – 2.40 (m, 3H), 2.33 (s, 1H), 2.11 – 2.00 (m, 2H), 0.85 (s, 1H), 0.48 – 0.37 (m, 4H).

[0159] Synthesis of Compound 4859

[0160]

[0161] HATU (4.7 g, 0.0123 mol) was added to a mixture of 2-bromo-5-fluoro-3-nitrobenzoic acid (3.26 g, 0.0123 mol) in DMF (50 mL). After stirring at 25 °C for 30 min, [(2R)-1-aminopropane-2-yl]aminotert-butylcarboxylate (1.8 g, 0.0103 mol) and DIEA (6.66 g, 0.0515 mol) were added to the reaction mixture. The reaction mixture was stirred at 25 °C for an additional 6 h. When the reaction was complete, the mixture was poured into water. The solid was filtered off to give [(2R)-1-[(2-bromo-5-fluoro-3-nitrophenyl)carbamate]propane-2-yl]aminotert-butylcarboxylate (3.5 g, 80%) as a yellow solid. MS (ESI): C 15 H 19 The calculated mass of BrFN3O5 is 419.0, and the measured m / z value is 442.0. [M+Na] + .

[0162] A mixture of [(2R)-1-[(2-bromo-5-fluoro-3-nitrophenyl)carbamate]propane-2-yl]amino tert-butylcarbamate (3.5 g, 8.3 mmol) in HCl / EA (40 ml) was stirred at 0 °C for 4 h. When the reaction was complete, the solid was filtered off. The filter cake was concentrated to give methyl N-[(2R)-2-aminopropyl]-2-bromo-5-fluoro-3-nitrobenzamide (2 g, 75%) as a yellow solid. MS (ESI): C 10 H 11 The calculated mass of BrFN3O3 is 319.0, and the measured m / z value is 320.0 [M+H]. + .

[0163] CsF (0.38 g, 0.0024 mol) and TEA (1.57 g, 0.0155 mol) were added to a solution of N-[(2R)-2-aminopropyl]-2-bromo-5-fluoro-3-nitrobenzamide (2 g, 0.0062 mol) in DMSO (30 mL) for 12 h. After completion, the residue was quenched with water (100 mL), extracted with EA (200 mL × 3), and washed with saturated H2O (200 × 3 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE:EA = 1:1) to give (2R)-7-fluoro-2-methyl-9-nitro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (0.36 g, 28%) as an orange solid. MS (ESI): C 10 H 10 The calculated mass of FN3O3 is 239.1, and the measured m / z value is 240.1 [M+H]. + .

[0164] Under N2, Pd / C (80 mg, 0.7525 mmol) was added to a solution of (2R)-7-fluoro-2-methyl-9-nitro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (360 mg, 1.505 mmol) in EA / AcOH (5 mL). The mixture was stirred at 25 °C for 12 h under balloon pressure of H2. When the reaction was complete, the solid was filtered off. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (eluting with DCM / MeOH (10:1)) to give (2R)-9-amino-7-fluoro-2-methyl-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (250 mg, 79%) as a gray solid. MS (ESI): C 10 H 12The calculated mass of FN3O is 209.1, and the measured m / z value is 210.1 [M+H]. + .

[0165] BrCN (189 mg, 1.7923 mmol) was added to a solution of (2R)-9-amino-7-fluoro-2-methyl-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (250 mg, 1.1949 mmol) in MeOH (5 mL). The reaction mixture was stirred at 50 °C for 12 h. After completion, the mixture was evaporated under reduced pressure to give (12R)-2-amino-6-fluoro-12-methyl-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetane-2,4,6,8(13)-tetraen-9-one (250 mg, 89%) as an orange solid. MS (ESI): C 11 H 11 The calculated mass of FN4O is 234.1, and the measured m / z value is 235.1 [M+H]. + .

[0166] Add tert-butyl nitrite (220 mg, 2.1346 mmol) to a solution of ^{4,13}]tetadecan-2,4,6,8(13)-tetraen-9-one (250 mg, 1.0673 mmol) and CuBr2 (476 mg, 2.1346 mmol) in MeCN (5 mL). Stir the reaction mixture at 65 °C for 6 h. When the reaction is complete, filter off the solid. Quench the residue with water (100 mL) and extract with EA (100 mL × 3). Dry the organic layer with Na2SO4, filter and concentrate. The residue was purified by silica gel rapid chromatography (MeOH:DCM=10:1) to give (12R)-2-bromo-6-fluoro-12-methyl-1,3,10-triazatricyclo[6.4.1.0^{4,13}]deca-2,4,6,8(13)-tetraen-9-one (230 mg, 72%) as a yellow solid. MS (ESI): C 11 The calculated mass of H9BrFN3O is 297.0, and the measured m / z value is 298.0 [M+H]. + .

[0167] Morpholine (29 mg, 0.3354 mmol), CsF (38 mg, 0.2515 mmol), and Cs₂CO₃ (82 mg, 0.2515 mmol) were added to a solution of (12R)-2-bromo-6-fluoro-12-methyl-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetrate-2,4,6,8(13)-tetraen-9-one (50 mg, 0.1677 mmol) in DMSO (1 mL) at 100 °C under air for 16 h. After completion, the solid was filtered off at room temperature. The filtrate was purified by passing it through an RP-C18 column (eluting with H2O (0.5% FA) / CH3CN (100:0→50:50)) to give (12R)-6-fluoro-12-methyl-2-(morpholin-4-yl)-1,3,10-triazatricyclic[6.4.1.0^{4,13}]decadec-2,4,6,8(13)-tetraen-9-one (20 mg, 39%) as a yellow solid. MS (ESI): C 15 H 17 The calculated mass of FN4O2 is 304.2, and the measured m / z value is 305.2 [M+H]. + . 1 H NMR (400 MHz, DMSO)δ 8.38 – 8.35 (m, 1H), 7.55 – 7.52 (m, 1H), 7.48 – 7.45 (m, 1H), 4.80 – 4.74(m, 1H), 3.83 – 3.74 (m, 4H), 3.55 – 3.51 (m, 1H), 3.47 – 3.40 (m, 1H), 3.27 – 3.21 (m, 4H), 1.31 (d, J = 8.0 Hz, 3H).

[0168] Synthesis of Compound 4950

[0169]

[0170] To a solution of (12R)-2-bromo-6-fluoro-12-methyl-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-9-one (50 mg, 0.1677 mmol) in DMSO (1 mL), 4,4-difluoropiperidine (40 mg, 0.3354 mmol), CsF (38 mg, 0.2515 mmol), and Cs₂CO₃ (82 mg, 0.2515 mmol) were added. The mixture was stirred at 100 °C under air for 16 h. After completion, the solid was filtered off. The filtrate was purified by passing it through an RP-C18 column (eluting with H2O (0.5% FA) / CH3CN (100:0→50:50)) to give (12R)-2-(4,4-difluoropiperidin-1-yl)-6-fluoro-12-methyl-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-9-one (14 mg, 26%) as a yellow solid. MS (ESI): C 16 H 17 The calculated mass of F3N4O is 338.1, and the measured m / z value is 339.1 [M+H]. + . 1 HNMR (400 MHz, DMSO) δ 8.39 – 8.36 (m, 1H), 7.56 – 7.53 (m, 1H), 7.50 – 7.46(m, 1H), 4.79 – 4.73 (m, 1H), 3.58 –3.53 (m, 1H), 3.47 – 3.43 (m, 1H), 3.37 (t, J = 8.0 Hz, 4H), 2.26 – 2.21 (m, 4H), 1.31 (d, J = 4.0 Hz, 3H).

[0171] Synthesis of Compound 4969

[0172]

[0173] HATU (24.09 g, 0.0633 mol) was added to a mixture of 2-bromo-5-fluoro-3-nitrobenzoic acid (13.94 g, 0.0528 mol) in DMF (250 mL). After stirring at 25 °C for 30 min, tert-butyl (1-aminobutan-2-yl)carbamate (10 g, 0.0528 mol) and DIEA (34.12 g, 0.264 mol) were added to the reaction mixture. The reaction mixture was stirred at 25 °C for 12 h. When the reaction was complete, the mixture was poured into water. The solid was filtered off to give tert-butyl (1-(2-bromo-5-fluoro-3-nitrobenzoamide)butan-2-yl)carbamate (12 g, 52%) as a yellow solid. MS (ESI): C 16 H 21 The calculated mass of BrFN3O5 is 433.0, and the measured m / z value is 456.0. [M+Na] + .

[0174] A mixture of {1-[(2-bromo-5-fluoro-3-nitrophenyl)carbamate]butan-2-yl}amino tert-butylcarbamate (12 g, 0.0276 mol) in HCl / EA (150 ml) was stirred at 0 °C for 4 h. When the reaction was complete, the solid was filtered off. The filter cake was concentrated to give N-(2-aminobutyl)-2-bromo-5-fluoro-3-nitrobenzamide (8 g, 86%) as a yellow solid. MS (ESI): C 11 H 13 The calculated mass of BrFN3O3 is 334.0, and the measured m / z value is 335.0 [M+H]. + .

[0175] CsF (0.73 g, 4.7 mol) and TEA (7.28 g, 18.6 mmol) were added to a solution of N-(2-aminobutyl)-2-bromo-5-fluoro-3-nitrobenzamide (8.0 g, 6.2 mmol) in DMSO (250 mL) for 24 h at 100 °C. Afterward, the mixture was quenched with ice water (200 mL) and extracted with EA (3 × 200 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE:EA = 1:1) to give 1.7 g (28%) of 2-ethyl-7-fluoro-9-nitro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one as an orange solid. MS (ESI): C 11 H 12 The calculated mass of FN3O3 is 253.1, and the measured m / z value is 254.1 [M+H].+ .

[0176] Pd / C (1 g) was added to a solution of 2-ethyl-7-fluoro-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazaza-5-one (1.7 g, 6.7 mmol) in MeOH (50 mL). The mixture was stirred at 25 °C for 6 h under balloon pressure of H2. When the reaction was complete, the solid was filtered off. The filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting with DCM / MeOH (10:1)) to give 9-amino-2-ethyl-7-fluoro-1,2,3,4-tetrahydro-1,4-benzodiaza-5-one (1.3 g, 86%) as a gray solid. MS (ESI): C 11 H 14 The calculated mass of FN3O is 223.1, and the measured m / z value is 224.1 [M+H]. + .

[0177] BrCN (0.92 g, 8.7 mmol) was added to a solution of 9-amino-2-ethyl-7-fluoro-1,2,3,4-tetrahydro-1,4-benzodiazazepine-5-one (1.3 g, 5.8 mmol) in MeOH (15 mL). The reaction mixture was stirred at 25 °C for 16 h. After completion, the mixture was evaporated under reduced pressure to give 1-amino-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (1 g, 69%) as an orange solid. MS (ESI): C 12 H 13 The calculated mass of FN4O is 248.1, and the measured m / z value is 249.1 [M+H]. + .

[0178] To a solution of 9-amino-2-ethyl-7-fluoro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazo-5-one (1 g, 4 mmol) and CuBr2 (1.34 g, 6 mmol) in MeCN (15 mL), tert-butyl nitrite (0.88 g, 8 mmol) was added. The reaction mixture was stirred at 65 °C for 6 h. When the reaction was complete, the solid was filtered off. The residue was quenched with water (100 mL) and extracted with EA (100 mL × 3). The residue was purified by silica gel rapid chromatography (MeOH:DCM = 10:1) to give 1-bromo-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (700 mg, 55%) as a yellow solid. MS (ESI): C 12 H11 The calculated mass of BrFN3O is 311.0, and the measured m / z value is 312.0 [M+H]. + .

[0179] To a solution of 1-bromo-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (100 mg, 0.3204 mmol) in DMSO (2 mL), piperidine (33 mg, 0.3844 mmol), CsF (73 mg, 0.4806 mmol), and Cs₂CO₃ (156 mg, 0.4806 mmol) were added. The reaction mixture was stirred at 100 °C for 16 h. After completion, the solids were filtered off. The filtrate was purified by passing it through an RP-C18 column (eluting with H2O (0.5% FA) / CH3CN (100:0→50:50)) to give 9-ethyl-4-fluoro-1-(piperidin-1-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (70 mg, 69%) as a yellow solid. MS (ESI): C 17 H 21 The calculated mass of FN4O is 316.2, and the measured m / z value is 317.2 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.36 – 8.34 (m, 1H), 7.52 – 7.46 (m, 2H), 4.43 (s,1H), 3.60 – 3.58 (m, 2H), 3.23 – 3.19 (m, 2H), 3.11 – 3.06 (m, 2H), 1.72 –1.55 (m, 8H), 0.90 (t, J = 7.6 Hz, 3H).

[0180] Synthesis of Compounds 4975 and 4976

[0181]

[0182] To a solution of 2-bromo-12-ethyl-6-fluoro-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-9-one (100 mg, 0.3204 mmol) in DMSO (3 mL), 4,4-difluoropiperidine (78 mg, 0.6408 mmol), CsF (73 mg, 0.4806 mmol), and Cs₂CO₃ (156 mg, 0.4806 mmol) were added. The reaction mixture was stirred at 100 °C for 12 h. After completion, the solids were filtered off. The filtrate was purified by passing it through an RP-C18 column (eluting with H2O (0.5% FA) / CH3CN (100:0→50:50)) to give 2-(4,4-difluoropiperidin-1-yl)-12-ethyl-6-fluoro-1,3,10-triazatricyclo[6.4.1.0^{4,13}]decacarbon-2,4,6,8(13)-tetraen-9-one (20 mg, 17%) as a white solid. MS (ESI): C 17 H 19 The calculated mass of F3N4O is 352.3, and the measured m / z value is 353.3 [M+H]. + . 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 12 Hz, 1H), 7.52 (d, J = 4 Hz, 1H), 6.87 (s, 1H), 4.41(s, 1H), 3.75 (s, 2H), 3.44 (s, 4H), 2.23 (s, 4H), 1.96 (d, J = 8 Hz, 1H), 1.76 (s, 1H), 1.01 (s, 3H).

[0183] 2-(4,4-difluoropiperidin-1-yl)-12-ethyl-6-fluoro-1,3,10-triazatricyclo[6.4.1.0^{4,13}]decacarbon-2,4,6,8(13)-tetraen-9-one (20 mg) was prepared by SFC splitting to obtain rel-(R)-1-(4,4-difluoropiperidin-1-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 4975; 4.9) as a white solid. (mg, 25%) and rel-(S)-1-(4,4-difluoropiperidin-1-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 4976; 6.2 mg, 31%), which are white solids.

[0184] Compound 4975: MS (ESI): C 17 H 19 The calculated mass of F3N4O is 352.3, and the measured m / z value is 353.3 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.56 – 7.50 (m, 2H), 4.51 (s, 1H), 3.59 (s, 2H), 3.37 (d, J = 8.0 Hz, 2H), 3.28 (d, J = 8.0 Hz, 2H), 2.24 – 2.14(m, 4H), 1.75 – 1.47 (m, 2H), 0.91 (t, J = 8.0 Hz, 3H).

[0185] Compound 4976: MS (ESI): C 17 H 19 The calculated mass of F3N4O is 352.3, and the measured m / z value is 353.3 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.38 – 8.36 (m,1H), 7.57 – 7.50 (m, 2H), 4.51 (s,1H), 3.59 (d, J = 4.0 Hz, 2H), 3.43 – 3.35 (m, 2H), 3.31 – 3.23 (m, 2H), 2.29– 2.08 (m, 4H), 1.64 (m, 2H), 0.91 (t, J = 8.0 Hz, 3H).

[0186] Synthesis of Compounds 4977 and 4978

[0187]

[0188] Morpholine (112 mg, 1.2814 mmol), CsF (146 mg, 0.9611 mmol), and Cs₂CO₃ (314 mg, 0.9611 mmol) were added to a solution of 2-bromo-12-ethyl-6-fluoro-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-9-one (200 mg, 0.6407 mmol) in DMSO (10 mL). The reaction mixture was stirred at 100 °C for 12 h. After completion, the solids were filtered off. The filtrate was purified by passing it through an RP-C18 column (eluting with H2O (0.5% FA) / CH3CN (100:0→50:50)) to give 12-ethyl-6-fluoro-2-(morpholin-4-yl)-1,3,10-triazatricyclo[6.4.1.0^{4,13}]decadec-2,4,6,8(13)-tetraen-9-one (80 mg, 39%) as a yellow solid. MS (ESI): C 16 H 19 The calculated mass of FN4O2 is 318.1, and the measured m / z value is 319.1 [M+H]. + . 1 H NMR (400 MHz, CDCl3) δ7.78 (d, J = 8 Hz, 1H), 7.53 (d, J = 8 Hz, 1H), 6.88 (s, 1H), 4.44 (s, 1H), 3.91 (s, 4H), 3.73 (s, 2H), 3.30 (s, 4H), 2.10 – 1.90 (m, 1H), 1.82 – 1.72(m, 1H), 1.02 (t, J = 8 Hz, 3H).

[0189] 12-Ethyl-6-fluoro-2-(morpholin-4-yl)-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetane-2,4,6,8(13)-tetraen-9-one (80 mg) was prepared by SFC splitting to obtain rel-(R)-9-ethyl-4-fluoro-1-morpholino-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 4977: 16.4 mg, 21%) and rel-(S)-9-ethyl-4-fluoro-1-morpholino-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 4978: 15.8 mg, 20%) as yellow solids.

[0190] Compound 4977: MS (ESI): C 16 H19 The calculated mass of FN4O2 is 318.1, and the measured m / z value is 319.1 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.36 (t, J = 12 Hz, 1H), 7.56 – 7.48 (m, 2H), 4.54 – 4.54 (m, 1H), 3.83 – 3.71 (m, 4H), 3.61 – 3.53 (m, 2H), 3.31 – 3.23 (m,2H), 3.15 – 3.05 (m, 2H), 1.78 – 1.50 (m, 2H), 0.92 (t, J = 8 Hz, 3H).

[0191] Compound 4978: MS (ESI): C 16 H 19 The calculated mass of FN4O2 is 318.1, and the measured m / z value is 319.1 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.37 (t, J = 12 Hz, 1H), 7.56 – 7.48 (m, 2H), 4.54– 4.50 (m, 1H), 3.77 (s, 4H), 3.63 – 3.50 (m, 2H), 3.31 – 3.23 (m, 2H), 3.15– 3.05 (m, 2H), 1.71 – 1.57 (m, 2H), 0.92 (t, J = 8 Hz, 3H).

[0192] Synthesis of Compounds 4916 and 4917

[0193]

[0194] To a solution of 2-bromo-6-fluoro-11-methyl-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-9-one (150 mg, 0.5032 mmol) in DMSO (4 mL), 4,4-difluoropiperidine (162 mg, 1.3418 mmol), CsF (114 mg, 0.7548 mmol), and Cs₂CO₃ (245 mg, 0.7548 mmol) were added. The mixture was stirred at 100 °C under air for 16 h. After completion, the solid was filtered off. The filtrate was purified by passing it through an RP-C18 column (eluting with H2O (0.5% FA) / CH3CN (100:0→50:50)) to give 2-(4,4-difluoropiperidin-1-yl)-6-fluoro-11-methyl-1,3,10-triazatricyclo[6.4.1.0^{4,13}]decacarbon-2,4,6,8(13)-tetraen-9-one (100 mg, 44%) as a yellow solid. MS (ESI): C 16 H 17 The calculated mass of F3N4O is 338.1, and the measured m / z value is 339.1 [M+H]. +

[0195] 2-(4,4-difluoropiperidin-1-yl)-6-fluoro-11-methyl-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-9-one (100 mg) was prepared by SFC cleavage to obtain rel-(R)-1-(4,4-difluoropiperidin-1-yl)-4-fluoro-8-methyl-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 4916; 20) as a white solid. (mg, 20%) and rel-(R)-1-(4,4-difluoropiperidin-1-yl)-4-fluoro-8-methyl-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 4917; 30 mg, 30 percent) as white solid.

[0196] Compound 4916: MS (ESI): C 16 H 17 The calculated mass of F3N4O is 338.1, and the measured m / z value is 339.1 [M+H]. + . 1H NMR (400 MHz, DMSO) δ 8.38 (d, J = 4.0 Hz, 1H), 7.45 – 7.42 (m, 1H), 7.30 – 7.27 (m, 1H), 4.07 – 3.98 (m, 2H), 3.81 – 3.77 (m, 1H), 3.39 – 3.33(m, 2H), 3.21 – 3.17 (m, 2H), 2.56 – 2.50 (m, 2H), 2.45 – 2.41 (m, 2H), 2.24(s, 3H), 1.26 (d, J = 8.0 Hz, 3H).

[0197] Compound 4917: MS (ESI): C 16 H 17 The calculated mass of F3N4O is 338.1, and the measured m / z value is 339.1 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.40 (d, J = 4.0 Hz, 1H), 7.48 – 7.45 (m, 1H), 7.33 – 7.30 (m, 1H), 4.08 – 4.06 (m, 2H), 3.83 – 3.78 (m, 1H), 3.52 – 3.46(m, 2H), 3.41 – 3.38 (m, 2H), 2.33 – 2.25 (m, 2H), 2.13 – 2.05 (m, 2H), 1.27(d, J = 4.0 Hz, 3H).

[0198] Synthesis of Compounds 4981 and 4982

[0199]

[0200] To a solution of 9-amino-2-ethyl-7-fluoro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazon-5-one (200 mg, 0.8959 mmol) in EtOH (4 mL), tert-butyl (4-formylpiperidin-1-yl)carboxylate (192 mg, 0.8959 mmol) and Na₂S₂O₅ (170 mg, 0.8959 mmol) were added. The reaction mixture was stirred at 80 °C for an additional 12 h. After completion, the residue was concentrated and purified by silica gel rapid chromatography (PE:EA = 5:1) to give tert-butyl 4-(9-ethyl-4-fluoro-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azin-1-yl)piperidin-1-carboxylate (300 mg, 80%) as a white solid. MS (ESI): C 22 H 29 The calculated mass of FN4O3 is 416.2, and the measured m / z value is 417.2. [M+H] + .

[0201] A mixture of tert-butyl 4-(9-ethyl-4-fluoro-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azin-1-yl)piperidin-1-carboxylate (300 mg, 0.7186 mmol) in HCl / EA (4 mL) was stirred at 25 °C for 4 h. When the reaction was complete, the solid was filtered off. The filter cake was concentrated to give 200 mg, 88%, 9-ethyl-4-fluoro-1-(piperidin-4-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azin-6(7H)-one as a white solid. MS (ESI): C 17 H 21 The calculated mass of FN4O is 316.2, and the measured m / z value is 317.2 [M+H]. + .

[0202] In DMF (3 mL), 4,4-difluorocyclohexane-1-one (85 mg, 0.6322 mmol) and AcOH (0.5 mL) were added to a solution of 9-ethyl-4-fluoro-1-(piperidin-4-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (200 mg, 0.6322 mmol). After stirring at 25 °C for 30 min, sodium triacetoxyborohydride (536 mg, 2.5288 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for an additional 12 h. After completion, the residue was extracted with EA (50 mL × 3) and washed with saturated NaHCO3 (50 × 3 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel rapid chromatography (PE:EA = 1:1) to give 1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (80 mg, 29%) as a white solid. MS (ESI): C 23 H 29 The calculated mass of F3N4O is 434.2, and the measured m / z value is 435.2 [M+H]. + .

[0203] 1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (80 mg) was prepared by SFC cleavage to obtain rel-(R)-1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 4981, 25.2) as a white solid. (mg, 31%) and rel-(R)-1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (compound 4982, 28.5 mg, 35%), which are white solids.

[0204] Compound 4981: MS (ESI): C 23 H 29 The calculated mass of F3N4O is 434.2, and the measured m / z value is 435.2 [M+H]. + . 1H NMR (400 MHz, DMSO) δ 8.44 (t, J = 5.6 Hz, 1H), 7.64 (dd, J = 9.2, 2.4Hz, 1H), 7.56 (dd, J = 10.8, 2.4 Hz, 1H), 4.67 – 4.63 (m, 1H), 3.59 – 3.58(m, 2H), 2.98 – 2.88 (m, 3H), 2.35 – 2.30 (m, 2H), 2.06 – 1.53 (m, 15H), 0.97(t, J = 7.6 Hz, 3H).

[0205] Compound 4982: MS (ESI): C 23 H 29 The calculated mass of F3N4O is 434.2, and the measured m / z value is 435.2 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.44 (t, J = 5.6 Hz, 1H), 7.64 (dd, J = 9.2, 2.4Hz, 1H), 7.56 (dd, J = 10.8, 2.4 Hz, 1H), 4.67 – 4.65 (m, 1H), 3.59 – 3.58(m, 2H), 2.98 – 2.90 (m, 3H), 2.35 – 2.30 (m, 2H), 2.05 – 1.53 (m, 15H), 0.97(t, J = 7.6 Hz, 3H).

[0206] Synthesis of Compound 5927

[0207]

[0208] HATU (848 mg, 2.2293 mmol) was added to a mixture of 2-bromo-5-fluoro-3-nitrobenzoic acid (491 mg, 1.8578 mmol) in DMF (20 mL). After stirring at 25 °C for 30 min, (1-amino-3-cyclopropylpropane-2-yl)aminotert-butylcarboxylate (400 mg, 1.8578 mol) and DIEA (961 mg, 7.4312 mmol) were added to the reaction mixture. The pH was adjusted to approximately 9 by gradually adding DIEA. The reaction mixture was stirred at 25 °C for an additional 16 h. The mixture was quenched with ice water (40 mL) and extracted with EA (3 × 20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting with PE / EA (5:1)) to give a yellow solid {1-[(2-bromo-5-fluoro-3-nitrophenyl)carbamate]-3-cyclopropylpropane-2-yl}amino tert-butylcarbamate (600 mg, 63%). MS (ESI): C 18 H 23 The calculated mass of BrFN3O5 is 460.3, and the measured m / z value is 461.3 [M+H]. + .

[0209] A mixture of {1-[(2-bromo-5-fluoro-3-nitrophenyl)carbamate]-3-cyclopropylpropane-2-yl}amino tert-butylcarbamate (600 mg, 2.0118 mmol) in HCl / EA (10 ml) was stirred at 25 °C for 2 h. When the reaction was complete, the solid was filtered off. The filter cake was concentrated to give N-(2-amino-3-cyclopropylpropyl)-2-bromo-5-fluoro-3-nitrobenzamide (340 mg, 69%) as a white solid. MS (ESI): C 13 H 15 The calculated mass of BrFN3O5 is 360.2, and the measured m / z value is 361.2 [M+H]. + .

[0210] TEA (337 mg, 3.3318 mmol) and CsF (34 mg, 0.2221 mmol) were added to a mixture of N-(2-amino-3-cyclopropylpropyl)-2-bromo-5-fluoro-3-nitrobenzamide (400 mg, 1.1106 mmol) in DMSO (10 mL). The reaction mixture was stirred at 100 °C for 16 h. The mixture was quenched with ice water (40 mL) and extracted with EA (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluting with PE / EA (5:1)) to give 2-(cyclopropylmethyl)-7-fluoro-9-nitro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (100 mg, 29%) as a yellow solid. MS (ESI): C 13 H 14 The calculated mass of BrFN3O3 is 279.3, and the measured m / z value is 280.3 [M+H]. + .

[0211] Pd / C was added to a solution of 2-cyclopropyl-7-fluoro-9-nitro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (100 mg, 0.3581 mmol) in MeOH (5 mL) under N2. The mixture was stirred at 25 °C for 6 h under balloon pressure of H2. After the reaction was complete, the catalyst was filtered. The solvent was evaporated under reduced pressure to give 9-amino-2-(cyclopropylmethyl)-7-fluoro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (80 mg, 90%) as a yellow solid. MS (ESI): C 13 H 16 The calculated mass of FN3O is 249.3, and the measured m / z value is 250.3 [M+H]. + .

[0212] To a mixture of 9-amino-2-(cyclopropylmethyl)-7-fluoro-1,2,3,4-tetrahydro-1,4-benzodiazepine-5-one (100 mg, 0.4011 mmol) in EtOH (5 mL), tert-butyl (4-formylpiperidin-1-yl)carboxylate (86 mg, 0.4011 mmol) and Na₂S₂O₅ (76 mg, 0.4011 mmol) were added, and the reaction mixture was stirred at 80 °C for 12 h. The mixture was quenched with ice water (40 mL) and extracted with EA (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting with PE / EA (3:1)) to obtain a yellow solid, tert-butyl 4-[12-(cyclopropylmethyl)-6-fluoro-9-oxo-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-2-yl]piperidin-1-yl}carboxylate (80 mg, 41%). MS (ESI): C 24 H 31 The calculated mass of FN4O3 is 442.3, and the measured m / z value is 443.3 [M+H]. + .

[0213] A mixture of {4-[12-(cyclopropylmethyl)-6-fluoro-9-oxo-1,3,10-triazatricyclo[6.4.1.0^{4,13}]tetadeca-2,4,6,8(13)-tetraen-2-yl]piperidin-1-yl}carbamate (80 mg, 0.2732 mmol) in HCl / EA (2 ml) was stirred at 25 °C for 4 h. The solvent was evaporated under reduced pressure to give 9-(cyclopropylmethyl)-4-fluoro-1-(piperidin-4-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (50 mg, 81%) as a white solid. MS(ESI): C 19 H 23 The calculated mass of FN4O is 342.1, and the measured m / z value is 343.1 [M+H]. + .

[0214] In DMF (1 mL), 4,4-difluorocyclohexane-1-one (8 mg, 0.0584 mmol) and AcOH (0.1 mL) were added to a solution of 9-(cyclopropylmethyl)-4-fluoro-1-(piperidin-4-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (20 mg, 0.0584 mmol). After stirring at 25 °C for 30 min, sodium triacetoxyborohydride (37 mg, 0.1752 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for an additional 12 h. After completion, the crude product was purified by RP-C18 column elution with H2O (0.5% FA) / CH3CN (100:0→50:50) to give 9-(cyclopropylmethyl)-1-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (8 mg, 30%) as a white solid. MS (ESI): C 25 H 31 The calculated mass of F3N4O is 460.2, and the measured m / z value is 461.2 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.43 (t, J = 5.6 Hz, 1H), 7.65 (dd, J =9.2, 2.4 Hz, 1H), 7.56 (dd, J = 10.8, 2.4 Hz, 1H), 4.81 – 4.78 (m, 1H), 3.64(d, J = 2.8 Hz, 4H), 3.00 – 2.92 (m, 3H), 2.33 – 2.25 (m, 2H), 2.09 – 2.01(m, 3H), 1.95 – 1.76 (m, 6H), 1.69 – 1.52 (m, 3H), 1.36 – 1.29 (m, 1H), 0.80– 0.74 (m, 1H), 0.43 – 0.41 (m, 2H), 0.20 – 0.18 (m, 1H), 0.15 – 0.17 (m, 1H).

[0215] Synthesis of Compound 5337

[0216]

[0217] HATU (68.08 g, 179.06 mmol) was added to a solution of 2-bromo-5-fluoro-3-nitrobenzoic acid (36 g, 137.74 mmol) in DMF (300 mL). The mixture was stirred at room temperature for 0.5 h, followed by the addition of (S)-(1-aminopropane-2-yl)carbamate tert-butyl ester (20 g, 114.78 mmol) and DIEA (44.42 g, 344.34 mmol). The resulting mixture was stirred at room temperature for another 16 h. The mixture was diluted with EA (1000 mL) and washed with brine (300 mL × 5). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography on a silica gel column (using PE:EA (4:1)) to give (S)-(1-(2-bromo-5-fluoro-3-nitrobenzamido)propane-2-yl)carbamate (40 g, 83%) as a white solid. MS (ESI): C 15 H 19 The calculated mass of BrFN3O5 is 419.05, and the measured m / z value is 442.0 [M+Na]. + .

[0218] (S)-(1-(2-bromo-5-fluoro-3-nitrobenzamido)propane-2-yl)carbamate tert-butyl ester (40 g, 95.18 mmol) was dissolved in a solution of HCl in EA (4 M, 240 mL). The mixture was stirred at room temperature for 4 hours. The resulting mixture was filtered, and the filter cake was dried under vacuum to give (S)-N-(2-aminopropyl)-2-bromo-5-fluoro-3-nitrobenzamido hydrochloride (28 g, 82%) as a white solid. MS (ESI): C 10 H 12 The calculated mass of BrClFN3O3 is 319.00, and the measured m / z value is 320.1 [M+H]. + .

[0219] Under nitrogen atmosphere, TEA (235.56 g, 235.56 mmol) and CsF (2.39 g, 15.70 mmol) were added to a solution of (S)-N-(2-aminopropyl)-2-bromo-5-fluoro-3-nitrobenzamide hydrochloride (28 g, 78.52 mmol) in DMSO (1100 mL). The reaction mixture was stirred at 100 °C for 8 h. The solution was diluted with EA (1000 mL) and washed with brine (1000 mL × 5). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography on a silica gel column (using PE:EA (4:1)) to give (S)-7-fluoro-2-methyl-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazon-5-one (3.12 g, 16%) as a white solid. MS (ESI): C 10 H 10 The calculated mass of FN3O3 is 239.07, and the measured m / z value is 240.1 [M+H]. + .

[0220] Pd / C (312 mg) was added to a solution of (S)-7-fluoro-2-methyl-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazon-5-one (3.12 g, 13.04 mmol) in EA (60 mL). The mixture was stirred at room temperature under H2 conditions for 6 h. The resulting mixture was filtered and the filtrate was dried under vacuum to give (S)-9-amino-7-fluoro-2-methyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazon-5-one (2.52 g, 92%) as a white solid. MS (ESI): C 10 H 12 The calculated mass of FN3O is 209.10, and the measured m / z value is 210.1 [M+H]. + .

[0221] BrCN (1.91 g, 18.06 mmol) was added to a solution of (S)-9-amino-7-fluoro-2-methyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazon-5-one (2.52 g, 12.04 mmol) in MeOH (50 mL). The mixture was stirred at 50 °C for 16 minutes. h. The resulting mixture was concentrated to give a product as a yellow solid (3 g, crude product), which was used directly in the next step without further purification. MS (ESI): C 11 H 11The calculated mass of FN4O is 234.09, and the measured m / z value is 235.1 [M+H]. + .

[0222] Under N2 conditions, copper chloride (2.97 g, 22.12 mmol) and tert-butyl nitrite (2.28 g, 22.12 mmol) were added to a solution of (S)-1-amino-4-fluoro-9-methyl-8,9-dihydro-2,7,9a-triazabenzo[cd]azine-6(7H)-one (3 g, crude product) in CH3CN (50 mL). The mixture was stirred at 65 °C for 6 hours. h. Quench the mixture with water (100 mL) and extract with EA (50 mL × 3). Dry the organic layer with Na2SO4, filter, and concentrate under vacuum. Purify the residue by passing it through a C18 column (using CH3CN: H2O) to obtain compound 5337 (1.88 g, 67%) as a white solid. MS (ESI): C 11 The calculated mass of H9ClFN3O is 253.04, and the measured m / z value is 254.1 [M+H]. + . 1 H NMR (400 MHz, DMSO) δ 8.55-8.52 (m, 1H), 7.77 (dd, J = 8.8, 2.4 Hz, 1H), 7.66 (dd, J =10.8, 2.4 Hz, 1H), 4.85 – 4.79 (m, 1H), 3.75-3.71 (m, 1H), 3.53-3.46 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H).

[0223] Synthesis of Compound 3654 and Compound epi-3654

[0224]

[0225] Add 1-(4-fluorophenyl)ethane-1,2-diamine (1.11 g, 7.2 mmol) to a solution of methyl 2-bromo-5-fluoro-3-nitrobenzene (2 g, 7.2 mmol) and Na₂CO₃ (3.05 g, 28.8 mmol) in 1-butanol (20 mL). Stir the reaction mixture at 85 °C for 12 minutes. h, the mixture was concentrated. The residue was purified by silica gel rapid chromatography (PE:EA=1:1) to give 7-fluoro-2-(4-fluorophenyl)-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazon-5-one (0.9 g, 39%) as an orange solid. MS (ESI): C15 H 11 The calculated mass of F2N3O3 is 319.0, and the measured m / z value is 320.0 [M+H]. + .

[0226] Fe (441 mg, 7.89 mmol) was added to a solution of 7-fluoro-2-(4-fluorophenyl)-9-nitro-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaza-5-one (420 mg, 1.32 mmol) in AcOH (10 mL). The reaction mixture was stirred at 25 °C for 16 minutes. h. When the reaction is complete, the solid is filtered off. The filtrate is concentrated to obtain a crude product, which is purified by silica gel column chromatography (eluting with MeOH / DCM (10:1)) to give 9-amino-7-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diaza-5-one (200 mg, 52%) as a yellow solid. MS (ESI): C 15 H 13 The calculated mass of F2N3O is 289.1, and the measured m / z value is 290.1 ​​[M+H]. + .

[0227] To a solution of 9-amino-7-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazazepine-5-one (100 mg, 0.35 mmol) in EtOH (2 mL), Na₂S₂O₅ (78 mg, 0.41 mmol) and (R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (83 mg, 0.41 mmol) were added. The mixture was stirred at 80 °C for 16 hours. The residue was concentrated under vacuum and extracted with EA (10 mL × 2). The organic phase was washed with brine (10 mL × 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (MeOH: DCM = 10:1) to give (2R)-2-(4-fluoro-9-(4-fluorophenyl)-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azon-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 49%) as a yellow solid. MS (ESI): C 25 H 26 The calculated mass of F₂N₄O₃ is 468.2, and the measured m / z value is 469.2 [M+H]. + .

[0228] A solution of 4 NHCl in ethyl acetate (0.5 mL) was added to a solution of (2R)-2-(4-fluoro-9-(4-fluorophenyl)-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 0.17 mmol) in EA (0.5 mL). The mixture was stirred at 25 °C for 4 hours. After completion, the mixture was concentrated under reduced pressure to give a yellow solid of 4-fluoro-9-(4-fluorophenyl)-1-((R)-pyrrolidine-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azin-6(7H)-one (30 mg, 47%). MS (ESI): C 20 H 18 The calculated mass of F2N4O is 368.1, and the measured m / z value is 369.1 [M+H]. + .

[0229] 4-Fluoro-9-(4-fluorophenyl)-1-((R)-pyrrolid-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azon-6(7H)-one (30 mg) was prepared by SFC splitting to obtain (S)-4-fluoro-9-(4-fluorophenyl)-1-((R)-pyrrolid-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azon-6(7H)-one (compound 3654, 12 mg, 40%) and (R)-4-fluoro-9-(4-fluorophenyl)-1-((R)-pyrrolid-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azon-6(7H)-one (compound epi-3654, 8 mg) as white solids. mg, 27%).

[0230] Compound 3654: MS (ESI): C 20 H 18 The calculated mass of F2N4O is 368.1, and the measured m / z value is 369.1 [M+H]. + . 1 H NMR (400 MHz, CD3OD-d4) δ 7.77 – 7.74 (m, 1H), 7.50 – 7.04 (m, 5H), 5.15 (s, 1H), 4.66 – 4.63 (m, 1H), 4.49 – 4.45 (m, 1H), 3.14 – 2.94 (m, 2H), 2.22– 1.29 (m, 4H), 1.29 (m, 1H), 1.20 – 0.79 (m, 1H).

[0231] Compound epi-3654: MS (ESI): C 20 H 18 The calculated mass of F2N4O is 368.1, and the measured m / z value is 369.1 [M+H]. + . 1 H NMR (400 MHz, CD3OD-d4) δ 7.74 – 7.71 (m, 1H), 7.49 – 7.03 (m, 5H), 5.13 (s, 1H), 4.65 – 4.62 (m, 1H), 4.47 (t, J = 7.2 Hz, 1H), 3.08 (s, 1H),2.99 – 2.93 (m, 1H), 2.25 – 2.12 (m, 2H), 1.97 – 1.88 (m, 2H), 1.28 (s, 1H),1.16 – 0.87 (m, 1H).

[0232] PARP mass spectrometry protocol

[0233] Materials and reagents: PARP1 enzyme was purchased from BPS Bioscience (catalog number 80501). Tris-HCl (pH 8.0) was purchased from Corning (catalog number 46-031-CM). Magnesium chloride was purchased from Thermo Fisher Scientific (formerly Honeywell Fluka, catalog number 63020-1L). All other assay components, activated DNA (catalog number D4522), core histone (catalog number SRP6590), β-nicotinamide adenine dinucleotide (β-NAD – catalog number N8285), 3ABA PARP1 small molecule inhibitor (from PARP1 enzyme activity assay kit, catalog number 17-10149), sodium chloride (NaCl, catalog number S6546-1L), Triton X-100 (catalog number 93443), and dithiothreitol (DTT, catalog number 43816-250ML) were purchased from Millipore Sigma.

[0234] Assay buffer: The assay buffer contains the following reagents: 50 mM Tris-HCl pH 8.0, 50 mM NaCl, 10 mM MgCl2, 0.01% Triton X-100 and 1 mM DTT.

[0235] program:

[0236] The PARP1 enzyme assay was performed in 384-well plates with a total volume of 20 µL in assay buffer. For concentration response curves, the compound was serially diluted 3-fold (from a maximum concentration of 2 mM to 0.1013 mM) to generate a 10-point curve, and 125 nL was transferred to the assay plate using an Echo dispenser, resulting in a final concentration range of 26.6 µM to 1.35 µM per 10 µL of reactant. Five μL of 10 nM PARP1 enzyme mixed with 100 nM core histone (2x) was added to the assay plate and pre-incubated at room temperature (RT) for 30 min. The reaction was initiated by adding 5 µL of a mixture of 10 uM β-NAD and 0.02 mg / mL activated DNA (2X). The reaction was incubated at RT for 60 min. The final concentrations of PARP1 enzyme and substrate were 5 nM and 5 uM, respectively. Positive control (high signal) wells and negative control (low signal) wells were replaced with 125 nL of DMSO instead of the compound. After incubation, the reaction was terminated by adding 10 μL of 10 μM 3ABA PARP1 inhibitor, incubated at RT for 5 min, and placed in a -80°C freezer before being transported to the Valo Health site in Branford, Connecticut, where mass spectrometry will be used to directly detect the nicotinamide (NAM) content.

[0237] Calculate the percentage of enzyme activity inhibition using the following equation:

[0238]

[0239] S in the equation 样品 S 高 and S 低 The values ​​refer to the NAM concentrations detected in the assay wells, high control wells, and low control wells, respectively. To determine the inhibitor IC50... 50 The value is used to fit the inhibition % of the CRC (concentration response curve) to a standard unit point four-parameter logic equation.

[0240] Representative results of exemplary compounds of this technology

[0241] Table 1 provides representative initial results for exemplary compounds of this technology.

[0242] Table 1.

[0243] PAR-based immunofluorescence assay protocol

[0244] Material:

[0245]

[0246] equipment:

[0247]

[0248] Cell culture details: HCT116 is a human colonic epithelial cell line that grows adherently in tissue culture flasks. Cells are grown in T175 flasks. They are divided twice weekly at a confluence of 70%-80% at a ratio of 1:5 to 1:10, following standard adherent cell passage protocols. The medium is kept refrigerated until the day of cell activity and must be warmed to at least RT before use. Cell culture medium: McCoy5A containing 10% FBS, 2 mM L-glutamine, and 20 mM HEPES. Plating medium: McCoy5A containing 10% FBS, 2 mM L-glutamine, 20 mM HEPES, and 1% antibiotic antifungal solution.

[0249] program:

[0250] Day 1: Cell Culture and Cell Plating: The cell culture and plating method includes the following steps: Heating the culture medium before cell culture; removing the cell flask from the incubator and tryingpticizing the cells in the T175 flask with 0.25% trypsin; returning the flask to the incubator and holding for approximately 5 minutes to allow cells to fall from the bottom; adding 10 μL of culture medium to rinse the bottom of the flask, and adding the cells and culture medium to a 50 mL conical tube; rotating the cells at 1000 rpm for 5 minutes, aspirating the culture medium, and resuspending the pellet in 10 mL of fresh culture medium; using C... Use an ellometer cell counter to count viable cells; using the viable cell count and the required number of plates, calculate the amount of resuspending medium needed to add to fresh plating medium and distribute it into 384W plates at a density of 6000 cells / well at 5 μL / well; plate the cells in the 384W plates, using 5 μL of medium per well for the entire plate at a density of 6000 cells / well; gently shake the plates (100 rpm) after plating for 20 min; and incubate the plates at 37°C and 5% humidity before further treatment. Incubate overnight under CO2.

[0251] Day 2: Compound and DNA damage treatment, fixation and primary staining: The method includes the following steps: A 384W cell seeding plate is treated with a Labcyte Echo 555 to achieve a maximum dose of 10 μM for each compound. 40 nL of the 10 mM maximum dose compound is imprinted onto 40 μL of cells in the seeding plate. The Labcyte compound source plate is based on DMSO, and the compounds are initially diluted 10 mM using a 10-point 3-fold dose dilution. The transfer volume using the Echo is 40 nL; at 37°C, 5%... Incubate at CO2 for 5 hours; add 40 nmol of 19.2% MMS in DMSO solution to columns 1-23 of each seeded 384W plate using Echo delivery mode, where the stock concentration of MMS is 99% and must be diluted 1:5 in DMSO before delivery to the cell plate; incubate the cell plates at 37°C with 5% CO2. Incubate at CO2 for 30 minutes; evacuate the medium using BlueWasher and add 75 μL of cold methanol, with the Bluewasher MagBeadSpeed ​​setting for all evacuated plates set to: rotate the plate clockwise for 5 seconds at 800 RPM (35 g); keep the dispensing line and methanol cool throughout the fixation process and use the intermittent setting to divide the dispensing into multiple sprays to minimize cell damage; incubate the fixed plate on ice for 20 minutes; wash the entire plate 1x with an equal volume of cold DPBS and evacuate using Bluewasher with MagBeadSpeed; add 20 μL of 0.1% Triton X-100 DPBS to the entire plate and incubate at room temperature for 15 minutes, evacuating using Bluewasher with MagBeadSpeed; add 20 μL of Roche blocking reagent to the entire plate and incubate at room temperature for 60 minutes, evacuating using Bluewasher with MagBeadSpeed; add 20 μL of PAR antibody (1:4,000) to the Roche blocking reagent, seal the plate, and incubate overnight at 4°C.

[0252] Day 3: Secondary antibody staining and imaging: The method comprises the following steps: vacuuming the plate (3X) with Bluewasher and washing it with 25–30 μL of 0.05% Tween 20 DPBS; adding 20 μL of anti-mouse AF488 secondary antibody (1:1,600) and Hoechst (1:10,000) and incubating at room temperature for 60 min; vacuuming the plate with MagBeadSpeed ​​and washing it with 25–30 μL of 0.05% Tween 20 DPBS from 3X to 4X; adding 30 μL of DPBS and sealing the plate; and imaging using protocol “PAR_HCT116_MeOH_10X_2ChR” with CX7 – circular (nuclear) medium-average intensity channels 1 (360) and 2 (488). Key acquisition settings: exposing all 488 channels to 70%–80% and 1–2 fields.

[0253] Data Analysis:The raw data file was exported from the CX7 software and paired with the barcode compound plate to track compound IDs, dose-response data, and Echo transfer records. This allows for the import of dose-response curves and QC analysis, as well as IC50 value determination. Images of each plate and well from both imaging channels can also be exported. The percentage of inhibition of PAR-based activity was calculated according to the following equation:

[0254]

[0255] S in the equation 样品 S 高 and S 低 The values ​​represent the PAR-based alkylation levels detected in the assay wells, high control wells, and low control wells, respectively. To determine the inhibitor IC50... 50 The value is used to fit the inhibition % of the CRC (concentration response curve) to a standard unit point four-parameter logic equation.

[0256] Measurement principle: The cellular levels of PAR-synthesized PARP1 / 2 substrate proteins (PARP1 and histones) were measured using an anti-PAR antibody in a DNA damage immunofluorescence assay based on https: / / f1000research.com / articles / 5-736 / v2. PAR-synthesization levels were reduced when treated with a PARP inhibitor in conjunction with the DNA damage agent MMS.

[0257] Cell proliferation assay protocol: DLD1 parent and BRCA2 ineffective for 5 days, CTG, CTF, CyQuant or one-pot assay. (One Pot) Live and Dead HCS Assay

[0258] Reagents and consumables:

[0259]

[0260] equipment:

[0261]

[0262] program

[0263] Day 1: Cell Culture and Cell PlatingThe method includes the following steps: cell counting (using a Nexcelom cell counter and recording cell counts); rotating cells at 1000 rpm for 5 min and resuspending the pellet in fresh culture medium; and seeding cells into 1536-well plates at a specific cell / well density based on a density optimization test (or 100 cells / well for DLD1 parent (historically); 125 cells / well for DLD1 BRCA2+ / - and - / - ineffective; μL of cells / well in columns 1 to 47 for 1536w plates); gently shaking the plate (100 rpm) at room temperature for 30 min, then transferring to an incubator (37°C, 5%). CO2); and before treatment, the plate (37℃, 5%) was placed in the solution; Incubate with CO2 for 24 hours.

[0264] Day 2: Compound treatment: For 1536w, the highest concentration of the source plate compound was imprinted to 25 μL / 10 mM, resulting in a maximum dose concentration of 50 μM for cell-based proliferation assays. The positive control SAHA was imprinted to a final concentration of 10 μM.

[0265] Days 3-7: Plate incubation: After adding the compound, the plate was subjected to a temperature of 37°C and 5% concentration. The incubation period under CO2 was 120 hours for a total of 5 days.

[0266] Days 3-7: Read the reagent additions and plate readings: After incubation, remove the plate from the incubator and add the specified readout reagent to the cell plate. See below for details on specific readouts.

[0267] ●CTG reading: Remove CTG 2.0 reagent from the refrigerator and allow it to reach room temperature before use; add 4 μL / well of CTG to all wells of each cell culture plate; for 1536w plates, at 37°C and 5%... Incubate the plate under CO2 for 30 minutes; and read the plate using a specific luminescence scheme on a designated plate reader; BMG or Envision has a CTG specific scheme.

[0268] ●CyQUANT Reading: Remove the Cyquant Direct Cell Proliferation Assay Kit from the freezer and allow it to reach room temperature before use. Reagents may require thawing in a dry bath; calculate the required total volume based on the dispensing to ensure sufficient reagent is needed. Prepare the assay kit using the following formulation: PBS: 11.7 mL; CyQuant® Direct Nucleic Acid Staining Agent: 48 µL; and CyQuant® Direct Background Inhibitor: 240 µL; add 2 µL / well of the Cyquant reagent mixture to all wells; incubate the plate at 37°C, 5%... Incubate under CO2 for 60 minutes; read the plate using the CyQuant specific scheme and the specific 1536w scheme (CyQUANTDirect—508 / 527nm; CyQUANTDirect Red—622 / 645 nm) on the designated plate reader BMG or EnVisions.

[0269] ●CTF Reading: Before use, remove the CTF reagent from the refrigerator and allow it to return to room temperature. Prepare the 1X reagent and vortex dissolve it (the reagent is stable for 24 hours at RT or 7 days at 4°C). Add 4 μL / well of CTF to all wells and incubate at 37°C with 5% concentration. Incubate the plate under CO2 for 180 minutes (3 h); and read the plate using a fluorescence-specific protocol on a designated plate reader (BMG or Envisions with CTF-specific protocols (Ex 380-400; Em 505)).

[0270] ● One-pot live / dead HCS reading: After incubation, remove the plate from the incubator; for 1536-well plates, prepare 4 mL of 1X PBS and add 8 drops of propidium iodide reagent + 4 μL of Hoechst 333242; mix, and then dispense at a medium speed of 1 μL / well using Multidrop Combi; for 384-well plates: prepare 6 mL of 1X PBS and add 12 drops of propidium iodide reagent + 6 μL of Hoechst 333242, mix, and then dispense at a medium speed of 8 μL / well using Multidrop Combi; incubate at 37°C, 5% Incubate under CO2 for 30 minutes; seal the plate with an aluminum seal; rotate in a rotary centrifuge at 1000 RPM for 2 minutes; load the plate onto a CX7; and acquire data.

[0271] The analyzed data is then exported as an ignition file and processed in ABASE.

[0272] Data analysis of CTG, CyQUANT, and CTF readings: Raw data files were exported from BMG, Envision, and CX7 readers and paired with barcode compound plates to track compound IDs, dose-response data, and Echo transfer records. This allows for the import of dose-response profiles and QC analysis, as well as IC50 value determination. Data and images of each plate and well from both imaging channels can also be exported. The percentage of growth activity inhibition was calculated using the following equation:

[0273]

[0274] S in the equation 样品 S 高 and S 低The values ​​refer to the measurement signals detected in the wells, high control wells, and low control wells, respectively. To determine the inhibitor IC50... 50 The value is used to fit the inhibition % of the CRC (concentration response curve) to a standard unit point four-parameter logic equation.

[0275] Measurement principle: Cell viability was measured using assays that detect the following live cell readings: intracellular ATP (CTG), DNA (CyQUANT), and peptidase activity (CTF) in the presence of the cell permeabilizing substrate Gly-Phe-AFC, obtained by luminescence or fluorescence assays after cell proliferation in the presence of PARP inhibitor compounds.

[0276] Permeability test results of MDCK-MDR1, an exemplary compound of this technology

[0277] The bidirectional assay (containing Mandin Darby canine kidney (MDCK) cell line transfected with the human MDR1 gene (P-glycoprotein; P-gp), which was engineered to overexpress the MDR1 efflux transporter, a major efflux transporter at the blood-brain barrier (BBB)) uses an established method to measure the rate at which a compound passes through a polarized cell monolayer. As is well known in the art, data from the MDCK-MDR1 permeability assay can be used to predict drug absorption in vivo. The bidirectional MDCK-MDR1 permeability assay can identify and quantify the level of active efflux. Compounds that cross the cell monolayer simultaneously in the apical-to-basal-lateral direction (A→B) and the basal-lateral-to-apical direction (B→A) are screened, providing the B→A / A→B ratio (efflux ratio; "ER"). Unlike the Caco-2 assay, the MDCK-MDR1 assay is not affected by the potential efflux of breast cancer resistance protein (BCRP). When a compound has an ER greater than 2, it indicates that the compound is likely to undergo active efflux. This data can be further used to predict blood-brain barrier (BBB) ​​permeability by calculation from log(permeability-surface area product) (“logPS”), which is known to predict log([brain concentration] / [plasma concentration]) in vivo.

[0278] Compounds of this technique will be run in a bidirectional MDCK-MDR1 assay. It is expected that compounds of this technique will exhibit significant efflux and / or have an ER value of approximately 2 or less in the apex-to-substrate direction (A→B).

[0279] In vivo CNS permeation of exemplary compounds of this technology

[0280] Based on proprietary internal predictive models, compounds of this technology are predicted to exhibit BBB channels. These predictive models have been further validated by in vivo experiments with other compounds. In particular, the in vivo unbound brain to plasma ratio (Kpuu) for compounds of this technology will be measured at steady state by comparing the free drug concentrations (corrected for protein binding) in the brain and plasma after 24 hours of continuous intravenous infusion in Sprague Dawley rats, where Kpuu > 0.3 indicates good brain exposure to the compound. Compounds of this technology are expected to exhibit in vivo Kpuu values ​​that are broadly acceptable for predicting clinical brain penetrance.

[0281] Although certain embodiments have been described and illustrated, those skilled in the art, upon reading the foregoing specification, can make changes, equivalent substitutions, and other types of modifications to the compounds of the present technology or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures as set forth herein. Each of the foregoing aspects and embodiments may also be included or incorporated herein by any variations or aspects disclosed with respect to any or all other aspects and embodiments.

[0282] This technology is not limited to the specific aspects described herein, which are intended as a single illustration of individual aspects of this technology. Many modifications and variations can be made to the technology of this invention without departing from the spirit and scope of the invention, as will be apparent to those skilled in the art. In addition to the methods listed herein, those skilled in the art will also find functionally equivalent methods within the scope of this invention from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that the technology of this invention is not limited to specific methods, reagents, compounds, compositions, labeled compounds, or biological systems, which can of course vary. It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting. Therefore, this specification is intended to be illustrative only, wherein the breadth, scope, and spirit of this technology are indicated solely by the appended claims, their definitions, and any equivalents thereof.

[0283] The embodiments described illustratively herein may be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be read broadly without limitation. Furthermore, the terminology and expressions used herein have been adopted as terminology in the specification and are not intended to limit, and the use of such terminology and expressions is not intended to exclude any equivalents or portions thereof of the features shown and described, but it should be understood that various modifications may be made within the scope of the claimed technology. Additionally, the phrase “consistently composed of” will be understood to include those elements specifically described and additional elements that do not materially affect the basic and novel features of the claimed technology. The phrase “consisting of” excludes any unspecified elements.

[0284] Furthermore, in the case of the description of features or aspects of this disclosure in accordance with the Markush Group, those skilled in the art will recognize that this disclosure is also described in accordance with any individual member or subgroup of the Markush Group. Each of the narrower types and subgenus groups falling into the general disclosure also forms part of this invention. This includes a general description of the invention with incidental conditions or negative limitations that remove any subject matter from that genus, regardless of whether the removed material is specifically described herein.

[0285] As those skilled in the art will understand, for any and all purposes, particularly for the purpose of providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily considered sufficiently descriptive and such that the same scope can be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily divided into a lower third, a middle third, and an upper third, etc. As those skilled in the art will also understand, all language such as “up to,” “at least,” “greater than,” “less than,” etc., includes the listed numbers and refers to a scope that can subsequently be decomposed into subscopes as described above. Finally, as those skilled in the art will understand, a scope includes each individual member.

[0286] All publications, patent applications, granted patents, and other documents (e.g., journals, articles, and / or textbooks) referenced in this specification are incorporated herein by reference as if each individual publication, patent application, granted patent, or other document were specifically and individually indicated to be incorporated herein by reference in its entirety. Where a definition contained in the text incorporated by reference contradicts a definition in this disclosure, the definition contained in the text incorporated by reference shall be excluded. Claims (as amended under Article 19 of the Treaty) 1. A compound of formula I in X 1 It is H, F, or Cl; R 1 It is H, alkyl, or cycloalkyl; R 2 It is H, alkyl, or cycloalkyl; R 3 It is H, halogenated, alkyl, cycloalkyl, heterocyclic, heteroaryl, or N(R) 4 (R) 5 );and R 4 and R 5 One of them is H, alkyl, cycloalkyl, heterocyclic, or heteroaryl, and R 4 and R 5 The remaining one is H or alkyl, or R 4 and R 5 Together with the nitrogen atom they are bonded to, they are heterocyclic or heteroaryl groups. 2. The compound according to claim 1, wherein the compound has the formula IA. 3. The compound according to claim 1, wherein the compound has the formula IB 4. The compound according to any one of claims 1 to 3, wherein R 1 It is H; and R 2 It is H, C1-C6 alkyl or C3-C6 cycloalkyl. 5. The compound according to claim 4, wherein... R 2 It is a C1-C6 alkyl or a C3-C6 cycloalkyl. 6. The compound according to any one of claims 1 to 5, wherein X 1 It is F. 7. The compound according to any one of claims 1 to 6, wherein R 3 yes ,in n It is 0 or 1; R 6 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 7 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; X 2 It is CH, C-alkyl, or N; X 3 It is N-R 8 C(R) 9 (R) 10 ) or O; R 8 It is H, alkyl, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 9 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; and R 10 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl. 8. A pharmaceutically acceptable salt and / or solvate of the compound according to any one of claims 1 to 7. 9. A composition comprising a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8, and a pharmaceutically acceptable carrier. 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8, wherein the effective amount is effective for treating cancer. 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, when combined with a second cancer therapy, an amount of a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8 that is effective in treating cancer. 12. A method of treating a subject suffering from B-cell malignancy, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8, and an effective amount of a second cancer therapy. 13. A medicament for treating cancer in a subject, said medicament comprising a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8. 14. The medicament of claim 13, wherein the medicament further comprises a pharmaceutically acceptable carrier. 15. The medicament of claim 13 or claim 14, wherein the medicament comprises an effective amount of the compound and / or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate of claim 8 for use in treating the cancer when combined with a second cancer therapy.

Claims

1. A compound of formula I in X 1 It is H, F, or Cl; R 1 It is H, alkyl, or cycloalkyl; R 2 It is H, alkyl, or cycloalkyl; R 3 It is H, halogenated, alkyl, cycloalkyl, heterocyclic, heteroaryl, or N(R) 4 (R) 5 );and R 4 and R 5 One of them is H, alkyl, cycloalkyl, heterocyclic, or heteroaryl, and R 1 and R 2 The remaining one is H or alkyl, or R 4 and R 5 Together with the nitrogen atom they are bonded to, they are heterocyclic or heteroaryl groups.

2. The compound according to claim 1, wherein the compound has the formula IA.

3. The compound according to claim 1, wherein the compound has the formula IB 4. The compound according to any one of claims 1 to 3, wherein R 1 It is H; and R 2 It is H, C1-C6 alkyl or C3-C6 cycloalkyl.

5. The compound according to claim 4, wherein... R 2 It is a C1-C6 alkyl or a C3-C6 cycloalkyl.

6. The compound according to any one of claims 1 to 5, wherein X 1 It is F.

7. The compound according to any one of claims 1 to 6, wherein R 3 yes ,in n It is 0 or 1; R 6 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 7 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; X 2 It is CH, C-alkyl, or N; X 3 It is N-R 8 C(R) 9 (R) 10 ) or O; R 8 It is H, alkyl, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; R 9 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl; and R 10 It is H, halogenated, hydroxyl, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

8. A pharmaceutically acceptable salt and / or solvate of the compound according to any one of claims 1 to 7.

9. A composition comprising a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8, and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8, wherein the effective amount is effective for treating cancer.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, when combined with a second cancer therapy, an amount of a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate according to claim 8 that is effective in treating cancer.

12. A method of treating a subject suffering from B-cell malignancy, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8, and an effective amount of a second cancer therapy.

13. A medicament for treating cancer in a subject, said medicament comprising a compound according to any one of claims 1 to 7 and / or a pharmaceutically acceptable salt according to claim 8 and / or a pharmaceutically acceptable solvate according to claim 8.

14. The medicament of claim 13, wherein the medicament further comprises a pharmaceutically acceptable carrier.

15. The medicament of claim 13 or claim 14, wherein the medicament comprises an effective amount of the compound and / or a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate of claim 8 for use in treating the cancer when combined with a second cancer therapy.

Images