Isoindolinone-containing PARP inhibitor and method of use

Abstract

This disclosure relates to the compound described in formula (I), [Formula 1] TIFF2026526057000060.tif52170 Or, with respect to pharmaceutically acceptable salts and / or solvates thereof, in the formula, X 1 is H, F, or Cl, and R 1 is H, a substituted aryl, a substituted non-aromatic heterocyclyl, or a heteroaryl, and R 2 This is H or C(O)NH2. In particular, this disclosure demonstrates that the compounds of this disclosure can penetrate the central nervous system and enable the treatment of central nervous system cancers.

Description

[Technical Field]

[0001] This technology relates to compounds, compositions, and methods related to the treatment of cancer, particularly central nervous system cancers, as well as their use. [Overview of the project] [Means for solving the problem]

[0002] In one embodiment, the present technology relates to the compound described in Formula I, [ka] or provides a pharmaceutically acceptable salt and / or solvate thereof, in which X 1 is H, F, or Cl, and R 1 R is a substituted aryl, a substituted non-aromatic heterocyclyl, or a heteroaryl. 2 It is either H or C(O)NH2.

[0003] In one embodiment, a composition is provided comprising a compound of any embodiment disclosed herein, a pharmaceutically acceptable carrier, or one or more excipients, fillers, or agents (collectively referred to as “pharmaceutically acceptable carriers” unless otherwise indicated and / or specified).

[0004] In related embodiments, a pharmaceutical product for treating cancer in a subject is provided, comprising a compound of any embodiment disclosed herein and an optionally pharmaceutically acceptable carrier.

[0005] In a related embodiment, a pharmaceutical composition is provided comprising (i) an effective amount of a compound of any embodiment disclosed herein, wherein the effective amount of the compound is effective in treating cancer, and (ii) a pharmaceutically acceptable carrier.

[0006] In a related embodiment, a pharmaceutical composition is provided comprising (i) an effective amount of a compound of any embodiment disclosed herein, such that the compound is present in an amount effective for treating cancer in combination with a second cancer therapy, and (ii) a pharmaceutically acceptable carrier.

[0007] In further relevant embodiments, the Technology provides a method comprising a compound of any embodiment or example disclosed herein, and / or a composition of any embodiment disclosed herein, and / or a pharmaceutical of any embodiment disclosed herein. Such a method includes a method for treating a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound of any embodiment disclosed herein and an effective amount of a second cancer therapy. [Modes for carrying out the invention]

[0008] The following terms will be used throughout, as defined below.

[0009] Where used herein and in the appended claims, singular articles and similar reference terms such as “a,” “an,” and “the” in the context describing an element (particularly in the context of the following claims) shall be interpreted to encompass both singular and plural unless otherwise indicated herein or the context clearly contradicts this interpretation. The enumeration of ranges of values ​​herein is intended, unless otherwise indicated herein, simply as a concise way of referring individually to each individual value included within the range, and each individual value is incorporated herein as if it were individually described herein. All methods described herein may be carried out in any preferred order unless otherwise indicated herein or the context clearly contradicts this interpretation. Any use of any examples or illustrative language provided herein (e.g., “etc.”) is solely for the purpose of better understanding the embodiments and, unless otherwise stated, does not limit the claims. Nothing in the specification should be interpreted as indicating that an element not claimed is essential.

[0010] Where used herein, “about” is to be understood by those skilled in the art and to some extent depending on the context in which it is used. Where there is a use of the term that is not obvious to those skilled in the art considering the context in which the term is used, “about” is to mean up to plus or minus 10% of a particular term, for example, “about 10% by weight” is to be understood to mean “9% to 11% by weight.” Where “about” precedes a term, that term is to be understood to disclose the “about” term as well as the term not modified by “about,” for example, “about 10% by weight” discloses “9% to 11% by weight” as well as “10% by weight.”

[0011] As used in this disclosure, the phrase "and / or" is understood to mean any one of the members described individually or any combination of two or more of them, for example, "A, B, and / or C" means "A, B, C, A and B, A and C, B and C, or any combination of A, B and C."

[0012] Generally, a reference to a particular element, such as hydrogen or H, implies the inclusion of all isotopes of that element. For example, if the R group is defined as containing hydrogen or H, it also includes deuterium and tritium. Thus, tritium, C 14 , P 32 and S 35 Compounds containing radioactive isotopes such as those mentioned above fall within the scope of this technology. Procedures for inserting such labels into compounds of this technology will be readily apparent to those skilled in the art based on the disclosures herein.

[0013] Generally, "substitution" refers to the replacement of one or more bonds with hydrogen atoms in an organic group (e.g., an alkyl group) with bonds to non-hydrogen or non-carbon atoms, as defined below. A substituted group also includes a group in which one or more bonds with carbon atoms or hydrogen atoms are replaced by one or more bonds, including double or triple bonds with heteroatoms. Therefore, unless otherwise specified, a substituted group is replaced by one or more substituents. In some embodiments, a substituted group is replaced by one, two, three, four, five, or six substituents. Examples of substituents include halogens (i.e., F, Cl, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyl (oxo); carboxylate; ester; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; thiol; sulfide; sulfoxide; sulfone; sulfonyl; pentafluorosulfanil (i.e., SF5), sulfonamide; amine; N-oxide; hydrazine; hydrazide; hydrazone; azide; amide; urea; amidine; guanidine; enamine; imide; isocyanate; isothiocyanate; cyanate; thiocyanate; imine; nitro group; and nitriles (i.e., CN).

[0014] Substituted ring groups, such as substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups, also include rings and ring systems in which the bonds with hydrogen atoms are replaced by bonds with carbon atoms. Thus, substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0015] Alkyl groups include linear and branched alkyl groups having 1 to 12 carbon atoms, and typically 1 to 10 carbon atoms, or in some embodiments, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups may be substituted or unsubstituted. Examples of linear alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Typical substituted alkyl groups may be substituted one or more times with substituents as listed above, and include, but are not limited to, haloalkyls (e.g., trifluoromethyl), hydroxyalkyls, thioalkyls, aminoalkyls, alkylaminoalkyls, dialkylaminoalkyls, alkoxyalkyls, and carboxyalkyls.

[0016] Cycloalkyl groups include monocyclic, bicyclic, or tricyclic alkyl groups having 3 to 12 carbon atoms in the ring(s), or in some embodiments, having 3 to 10, 3 to 8, 3 to 4, 5, or 6 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cycloalkyl groups may have 3 to 8 ring members, or the number of ring carbon atoms may be in the range of 3 to 5, 3 to 6, or 3 to 7. Bicyclic and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but are not limited to, bicyclo[2.1.1]hexane, adamantyl, and dekalinyl. Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined above. Typical substituted cycloalkyl groups are, but are not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups, which may be monosubstituted or multiple times, for example, with substituents listed above.

[0017] A cycloalkylalkyl group is an alkyl group as defined above, wherein the hydrogen or carbon bonds of the alkyl group are substituted with bonds to the cycloalkyl group as defined above. Cycloalkylalkyl groups may be substituted or unsubstituted. In some embodiments, cycloalkylalkyl groups have 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. A substituted cycloalkylalkyl group may be substituted with the alkyl moiety, the cycloalkyl moiety, or both the alkyl and cycloalkyl moieties of the group. Typical substituted cycloalkylalkyl groups may be monosubstituted or multiple times, for example, monosubstituted, disubstituted, or trisubstituted with substituents listed above, but are not limited to these.

[0018] Alkenyl groups include linear and branched alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Alkenyl groups may be substituted or unsubstituted. Alkenyl groups have 2 to 12 carbon atoms, and 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, alkenyl groups have 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), and -C(CH2CH3)=CH2. Typical substituted alkenyl groups may be monosubstituted or multiple times, for example, monosubstituted, disubstituted, or trisubstituted with substituents listed above, but are not limited to these.

[0019] The cycloalkenyl group includes the cycloalkyl group 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 may not contain 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.

[0020] A cycloalkenylalkyl group is an alkyl group as defined above, in which a hydrogen or carbon bond of the alkyl group is substituted with a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. A substituted cycloalkenylalkyl group may be substituted with the alkyl moiety, the cycloalkenyl moiety, or both the alkyl and cycloalkenyl moieties of the group. Typical substituted cycloalkenylalkyl groups may be substituted one or more times with substituents as listed above.

[0021] Alkynyl groups include linear and branched alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Alkynyl groups may be substituted or unsubstituted. Alkynyl groups have 2 to 12 carbon atoms, and 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, alkynyl groups have one, two, or three carbon-carbon triple bonds. Examples include, in particular, -C≡CH, -C≡CCH3, -CH2C≡CCH3, and -C≡CCH2CH(CH2CH3)2. Typical substituted alkynyl groups may be monosubstituted or multiple times, for example, monosubstituted, disubstituted, or trisubstituted with substituents listed above, but are not limited to these.

[0022] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups as used herein include monocyclic, bicyclic, and tricyclic ring systems. Aryl groups may be substituted or unsubstituted. Therefore, aryl groups include, but are not limited to, phenyl, azlenyl, heptarenyl, biphenyl, fluorenyl, phenantrenyl, anthracenyl, indenyl, indanyl, pentarenyl, and naphthyl groups. In some embodiments, aryl groups contain 6 to 14 carbon atoms, and in other embodiments, the ring portion of the group contains 6 to 12 or even 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. The term "aryl group" includes groups containing fused rings, e.g., fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Typical substituted aryl groups may be monosubstituted (e.g., tolyl) or multiple substituted. For example, a monosubstituted aryl group includes, but is not limited to, a 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl group which may be substituted with substituents as listed above.

[0023] An aralkyl group is an alkyl group as defined above, in which a hydrogen or carbon bond of the alkyl group is substituted with 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. The substituted aralkyl group may be substituted with the alkyl moiety, the aryl moiety, or both the alkyl and aryl moieties. Typical aralkyl groups include, but are not limited to, the benzyl and phenethyl groups, and condensed (cycloalkylaryl) alkyl groups such as 4-indanylethyl. Typical substituted aralkyl groups may be substituted one or more times with substituents as listed above.

[0024] Heterocyclyl groups include aromatic (also called heteroaryl) and non-aromatic ring compounds containing three or more ring members, where one or more of the three or more ring members are heteroatoms, such as N, O, and S, but not limited to these. Heterocyclyl groups may be substituted or unsubstituted. In some embodiments, heterocyclyl groups contain one, two, three, or four heteroatoms. In some embodiments, heterocyclyl groups include monocyclic, dicyclic, 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. Heterocyclyl groups include aromatic, partially unsaturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl groups. The term "heterocyclyl group" includes condensed ring species containing condensed aromatic and non-aromatic groups, such as benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxynyl, and benzo[1,3]dioxolyl. The term also includes bridging polycyclic ring systems containing heteroatoms, such as quinuclidyl, but not limited to these. The term also includes heterocyclyl groups, referred to as "substituted heterocyclyl groups," which have other groups, such as alkyl, oxo, or halo groups, bonded to one of the ring members.The heterocyclyl group includes azilidinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, furanil, thiophenyl, pyrrolyl, pyrrolinil, imidazolyl, imidazolinil, pyrazolyl, pyrazolinil, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinil, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, and morpholinil. , thiomorpholinyl, tetrahydropyranil, tetrahydrothiopyranil, oxatian, dioxyl, dithianil, pyranil, pyridyl, pyrimidinil, pyridazinil, pyrazinil, triazinil, dihydropyridyl, dihydrodithinyl, dihydrodithionyl, homopiperazinil, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolidinil, benzotriazolyl, benzimidazolyl, benzofuranil, benzothiophenyl, Benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithinyl, benzoxathinyl, benzothiadinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, This includes, but is not limited to, phthalazinyl, naphthilidinyl, pteridinyl, thianaphthyl, dihydrobenzothiadinyl, dihydrobenzofuranyl, dihydroindyl, dihydrobenzodioxynyl, tetrahydroindyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Typical substituted heterocyclyl groups include, but are not limited to, pyridyl or morpholinyl groups that are monosubstituted or multiple times, for example, 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents as listed above.

[0025] A heteroaryl group is an aromatic ring compound containing five or more ring members, where one or more of the five or more ring members are heteroatoms, such as N, O, and S, but not limited to these. Heteroaryl groups may be substituted or unsubstituted. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianafthyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings are aromatic, such as an indolyl group, and further fused ring compounds in which only one of the rings is aromatic, such as a 2,3-dihydroindolyl group. Typical substituted heteroaryl groups may be substituted one or more times with various substituents as listed above.

[0026] A heterocyclylalkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is substituted with a bond to the heterocyclyl group as defined above. A heterocyclylalkyl group may be substituted or unsubstituted. A substituted heterocyclylalkyl group may be substituted with the alkyl moiety, the heterocyclyl moiety, or both the alkyl and heterocyclyl moieties of the group. Typical heterocyclylalkyl groups include, but are not limited to, morpholine-4-ylethyl, furan-2-ylmethyl, imidazole-4-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl. Typical substituted heterocyclylalkyl groups may be substituted one or more times with substituents as listed above.

[0027] A heteroaralkyl group is an alkyl group as defined above, in which a hydrogen or carbon bond of the alkyl group is substituted with a bond to a heteroaryl group as defined above. A heteroaralkyl group may be substituted or unsubstituted. A substituted heteroaralkyl group may be substituted with the alkyl moiety, the heteroaryl moiety, or both the alkyl and heteroaryl moieties. Typical substituted heteroaralkyl groups may be substituted one or more times with substituents as listed above.

[0028] Groups described herein that have two or more bonding sites (i.e., divalent, trivalent, or polyvalent) within the compounds of the Art are designated by the use of 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. Substituents having a single bonding site with the compounds of the Art are not referred to using the "ene" designation. Therefore, for example, chloroethyl is not referred to as chloroethylene in this specification.

[0029] An alkoxy group is a hydroxyl group (-OH) in which the bond to a hydrogen atom is substituted with a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Alkoxy groups may be substituted or unsubstituted. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Typical substituted alkoxy groups may be substituted one or more times with substituents as listed above.

[0030] As used herein, the terms "alkyloyl" and "alkyloyloxy" may refer to -C(O)-alkyl groups and -OC(O)-alkyl groups, respectively. Similarly, "aryloyl" and "aryloyloxy" may refer to -C(O)-aryl groups and -OC(O)-aryl groups.

[0031] 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 via an alkyl moiety, respectively. Examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy. Typical substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents as listed above.

[0032] As used herein, the term "carboxylate" refers to the -COOH group.

[0033] The term "ester" as used herein refers to -COOR 70 And refers to the -C(O)OG group. 70is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. G is a carboxylate protecting group. Carboxylate protecting groups are well known to those skilled in the art. A comprehensive list of protecting groups for carboxylate group functionality can be found in Protective Groups in Organic Synthesis, Greene, T.W., Wuts, P.G.M., John Wiley & Sons, New York, NY, (3rd Edition, 1999), which can be added or removed using the procedures described therein and is hereby incorporated by reference in its entirety for any and all purposes as if fully set forth herein.

[0034] The term "amide" (or "amido") refers to C- and N-amide groups, namely, -C(O)NR 71 R 72 and -NR 71 C(O)R 72 groups. R 71 and R 72 are independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Thus, amide groups include, but are not limited to, carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). In some embodiments, the amide is -NR 71 C(O)-(C 1-5 alkyl), which group is referred to as "carbonylamino", and alternatively, the amide is -NHC(O)-alkyl, which group is referred to as "alkanoylamino".

[0035] As used herein, the term "nitrile" or "cyano" refers to a -CN group.

[0036] The urethane group consists of N- and O-urethane groups, i.e., -NR groups, respectively. 73 C(O)OR 74 and -OC(O)NR 73 R 74 Includes the group R 73 and R 74 R is independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. 73 It may also be H.

[0037] As used herein, the term "amine" (or "amino") is defined as -NR 75 R 76 It refers to the base, and in the formula, R 75 and R 76 This is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. The amine may be an alkylamino, dialkylamino, arylamino, alkylarylamino, NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0038] The term "sulfonamide" refers to the S- and N-sulfonamide groups, i.e., -SO2NR, respectively. 78 R 79 and -NR 78 SO2R 79 Includes the group R 78 and R 79This group is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Thus, the sulfonamide group includes, but is not limited to, a sulfamoyl group (-SO2NH2). In some embodiments herein, the sulfonamide is -NHSO2-alkyl and is referred to as an "alkylsulfonylamino" group.

[0039] The term "thiol" refers to the -SH group, while "sulfide" refers to the -SR group. 80 The group is included, and "sulfoxide" is -S(O)R 81 The group is included, and "sulfone" is -SO2R 82 The group is included, and "sulfonyl" is -SO2OR 83 Includes R 80 , R 81 , R 82 , and R 83 Each of these is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group, as defined herein. In some embodiments, the sulfide is an alkylthio group, an -S-alkyl group.

[0040] The term "urea" is -NR 84 -C(O)-NR 85 R 86 It refers to the base. R 84 , R 85 , and R 86 The group is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0041] The term "amidine" is -C(NR 87 )NR 88 R 89 and -NR 87 C(NR 88 )R 89It refers to, and in the formula, R 87 , R 88 , and R 89 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0042] The term "guanidine" is -NR 90 C(NR 91 )NR 92 R 93 It refers to, and in the formula, R 90 , R 91 , R 92 , and R 93 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0043] The term "enamin" is -C(R 94 )=C(R 95 )NR 96 R 97 and -NR 94 C(R 95 )=C(R 96 )R 97 It refers to, and in the formula, R 94 , R 95 , R 96 , and R 97 Each of these is independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0044] As used herein, the terms "halogen" or "halo" refer to bromine, chlorine, fluorine, or iodine. Preferably, the halogen is fluorine, but the halogen may also be chlorine or bromine.

[0045] As used herein, the term "hydroxyl" refers to -OH, or its ionized form, -O - This can refer to the following. The "hydroxyalkyl" group is a hydroxyl-substituted alkyl group such as HO-CH2-.

[0046] The term "imide" is -C(O)NR 98 C(O)R 99 It refers to, and in the formula, R 98 and R 99 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0047] The term "imin" is -CR 100 (NR 101 ) and -N(CR 100 R 101 ) refers to the base, and in the formula, R 100 and R 101 Under the condition that both are not hydrogen at the same time, R 100 and R 101 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0048] As used herein, the term "nitro" refers to the -NO2 group.

[0049] As used herein, the term "trifluoromethyl" refers to -CF3.

[0050] As used herein, the term "trifluoromethoxy" refers to -OCF3.

[0051] The term "Azid" refers to -N3.

[0052] The term "trialkylammonium" refers to a -N(alkyl)3 group. The trialkylammonium group is positively charged and therefore typically has associated anions, such as halogen anions.

[0053] The term "isocyano" refers to -NC.

[0054] The term "isothiocyan" refers to -NCS.

[0055] The term "pentafluorosulfanil" refers to -SF5.

[0056] As will be understood by those skilled in the art, for any or all purposes, particularly in terms of providing written explanations, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any enumerated scope can be readily recognized as sufficiently describing and enabling the same scope to be divided into at least equal 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, etc. As a non-limiting example, each scope discussed herein can easily be divided into a lower 1 / 3, a middle 1 / 3, an upper 1 / 3, etc. As will also be understood by those skilled in the art, all language such as “maximum,” “at least,” “greater than,” and “less than” includes the stated number and refers to a scope that can subsequently be divided into subscopes as discussed above. Finally, as will be understood by those skilled in the art, a scope includes each individual member. Thus, for example, a group having 1 to 3 atoms refers to a group having 1, 2, or 3 atoms. Similarly, groups with 1 to 5 atoms refer to groups with 1, 2, 3, 4, or 5 atoms, and so on.

[0057] As will be understood by those skilled in the art, "molecular weight" (also known as "relative molar mass") is a dimensionless quantity, but is converted to molar mass by multiplying by 1 gram / mole or by multiplying by 1 Da. For example, a compound having 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.

[0058] The pharmaceutically acceptable salts of the compounds described herein are within the scope of the present technology, retain the desired pharmacological activity, and include acid or base addition salts that are not biologically undesirable (e.g., the salts are not overly toxic, allergic, or irritating and are biologically available). When the compounds of the present technology have a basic group such as, for example, an amino group, the pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid), or acidic amino acids (such as aspartic acid and glutamic acid). When the compounds of the present technology have an acidic group such as, for example, a carboxylic acid group, the compound can form salts with metals such as alkali and alkaline earth metals (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine), or basic amino acids (such as arginine, lysine, and ornithine). Such salts can be prepared in situ by reacting the purified compound in its free base or free acid form separately with a suitable acid or base during the isolation and purification of the compound and isolating the salt so formed.

[0059] Those skilled in the art will understand that the compounds of this art may exhibit phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or stereoisomerism. Since the formula diagrams in the specification and claims can only represent one of the possible tautomeristic, conformational, stereochemical, or geometric isomeristic forms, it should be understood that this art encompasses any tautomeristic, conformational, stereochemical, and / or geometric isomeristic forms of any compound having one or more of the usefulness described herein, as well as mixtures of various different forms thereof.

[0060] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The presence and concentration of isomers depend on the environment in which the compound exists, and may differ depending on whether the compound is a solid or in an organic or aqueous solution. For example, in an aqueous solution, quinazolinone may exhibit the following isomers called tautomers of each other. [ka] As another example, guanidine can exhibit the following isomers, also known as tautomers, in protic organic solutions. [ka] Due to the limitations of representing compounds by structural formulas, it should be understood that all chemical formulas of the compounds described herein represent all tautomerized forms of the compounds, and that these are within the scope of this technology.

[0061] The stereoisomers (also known as optical isomers) of a compound include all chiral, diastereomer, and racemic forms of the structure unless the specific stereochemistry is explicitly stated. Therefore, the compounds used in this technique, as is evident from the illustrations, include optical isomers concentrated or divided at any or all chiral atoms. Both racemic and diastereomer mixtures, as well as individual optical isomers, can be isolated or synthesized so as to be substantially free of their enantiomer or diastereomer partners, and all of these stereoisomers are within the scope of this technique.

[0062] The compounds of this technology may exist as solvates, particularly hydrates. Hydrates may be formed during the preparation of the compound or a composition containing the compound, or they may be formed over time due to the hygroscopic nature of the compound. The compounds of this technology may also exist as organic solvent hydrates, including, in particular, DMF, ethers, and alcohol solvates. Identifying and preparing any particular solvate is within the scope of the art of those skilled in the field of synthetic organic or medicinal chemistry.

[0063] Throughout this disclosure, various publications, patents, and published patent specifications are referenced by identifying citations. This disclosure also includes Arabic numerals indicating the referenced documents, the complete bibliographic details of which are provided after the Examples section. These publications, patents, and published patent specifications are incorporated into this disclosure by reference to provide a more complete explanation of the Art.

[0064] This technology Poly-ADP-ribose polymerase 1 (PARP1) is a member of a family of proteins involved in countless cellular processes, including DNA repair, genome stability, and programmed cell death. PARP1 is an ADP-ribosyltransferase that uses NAD+ as a substrate to modify proteins (including itself) by PARization and detect single-strand DNA breaks. It plays a crucial role in homologous recombination and DNA repair by signaling the enzymatic processes involved in single-strand DNA break repair.

[0065] Several PARP1 inhibitors have been approved for the treatment of breast and ovarian cancers lacking other mechanisms of DNA repair, and further PARP inhibitors are currently in clinical trials for the treatment of ovarian cancer, pancreatic and biliary tract malignancies, glioblastoma, lung cancer, and prostate cancer. BRCA1 / 2-deficient cancers are highly sensitive to PARP1 inhibition, and PARP inhibition is lethal in cells with loss-of-function mutations in BRCA1 and BRCA2. Reduced homologous recombination (HR) capacity due to other mechanisms also makes cells sensitive to PARP inhibitors. Cells without DNA repair defects are typically 1000 times less sensitive to PARP inhibitors than cells with such defects. PARP inhibitors reduce PARization, trapping PARP1 on DNA and causing replication fork disruption and cell death.

[0066] However, current PARP1 inhibitors such as talazoparib, olaparib, lucaparib, and niraparib do not have good central nervous system (CNS) penetration, and veliparib is ineffective in most tumors. See, for example, Gupta, Shiv K., et al. "PARP inhibitors for sensitization of alkylation chemotherapy in glioblastoma: impact of blood-brain barrier and molecular heterogeneity" Frontiers in oncology 8(2019):670 and 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.

[0067] Therefore, there is a need for PARP inhibitors with improved central nervous system penetration for treating brain cancers such as glioblastoma, neuroblastoma, and medulloblastoma.

[0068] The present technology responds to these needs and provides additional advantages. According to the company's proprietary prediction model, the compounds of the present technology are predicted to exhibit desirable blood-brain barrier (BBB) permeability. These proprietary prediction models were validated by in vitro assays and in vivo experiments that are well-established for predicting BBB permeability in living subjects. Thus, the present technology advantageously provides compounds with improved central nervous system penetration, as well as compositions and methods particularly suitable for the treatment of central nervous system cancers.

[0069] Thus, in one aspect, the present technology provides a compound according to Formula I,

Chemical formula

[0070] In any embodiment herein, R 1 may be a substituted phenyl, substituted non-aromatic heterocyclyl, or bicyclic heteroaryl. In any embodiment herein, R 1 is

Chemical formula

[0071] In any embodiment of this specification, X 1 It may also be F.

[0072] In any embodiment of this specification, the compound may be any one of the following, or a pharmaceutically acceptable salt and / or solvate thereof. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 TIFF2026526057000031.tif74170 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 TIFF2026526057000038.tif75170 Table 1-30 Table 1-31

[0073] In one embodiment, a composition is provided comprising a compound of any embodiment disclosed herein, a pharmaceutically acceptable carrier, or one or more excipients, fillers, or agents (collectively referred to as “pharmaceutically acceptable carriers” unless otherwise indicated and / or specified). In related embodiments, a pharmaceutical product for treating cancer in a subject is provided, comprising a compound of any embodiment disclosed herein and an optionally pharmaceutically acceptable carrier. The pharmaceutical product of any embodiment herein may contain 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). The CNS cancer may be glioblastoma, neuroblastoma, and / or medulloblastoma. In a relevant embodiment, a pharmaceutical composition is provided comprising (i) an effective amount of a compound of any embodiment disclosed herein, wherein the effective amount of the compound is effective in treating cancer, and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, 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 relevant embodiment, a pharmaceutical composition is 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 cancer in combination with a second cancer therapy (such as radiotherapy, monoclonal antibodies, and / or chemotherapeutic agents), and (ii) a pharmaceutically acceptable carrier. In any embodiment of this specification, 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 further relevant embodiments, the Technology provides a method comprising a compound of any embodiment or aspect disclosed herein, and / or a composition of any embodiment disclosed herein, and / or a pharmaceutical of any embodiment disclosed herein.

[0074] "Effective dose" refers to the amount of compound or composition required to achieve the desired effect. An example of an effective dose is an amount or dosage that results in an acceptable level of toxicity and bioavailability for therapeutic (pharmaceutical) use, including but not limited to tumor mass reduction. In any embodiment or part of the compositions, pharmaceutical compositions, and methods disclosed herein (collectively referred to herein as "any embodiment of this specification," "any embodiment disclosed herein," etc.), the effective dose may be an amount effective to treat cancer (such as breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancer), treat a tumor, and / or reduce a tumor. For example, the effective dose of any embodiment of this specification containing the compound of this 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). The methods and uses according to this technology may include an effective dose of the compound of any embodiment disclosed herein. In any aspect or embodiment disclosed herein, the effective amount may be determined in relation to the subject. As used herein, “subject” or “patient” is a mammal such as a cat, dog, rodent, or primate. Typically, the subject is a human, preferably a human who is suffering from or suspected of suffering from pain. The terms “subject” and “patient” can be used interchangeably.

[0075] Accordingly, the present technology provides pharmaceutical compositions and medicinal products comprising a compound (or a composition of any embodiment disclosed herein) and a pharmaceutically acceptable carrier. The composition may be used in the methods and treatments described herein. The pharmaceutical composition may be packaged in unit dosage forms. The unit dosage forms may be effective in treating cancers (such as breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancers). The unit dosage forms may be effective in treating tumors by reducing tumor volume when administered to a target that requires it. In general, the unit doses containing the compounds of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, disease severity, contraindications, and combination therapies. Exemplary unit doses based on these considerations may also be adjusted or modified by a physician skilled in the art. For example, a unit dose for a patient containing the compounds of the present technology may be 1 × 10⁻⁶ -4 g / kg to 1g / kg, preferably 1 × 10 -3 The dosage may vary from g / kg to 1.0 g / kg. The dosage of the compound in this technology may also vary from 0.01 mg / kg to 100 mg / kg, or preferably from 0.1 mg / kg to 10 mg / kg. Suitable unit dosage forms include, but are not limited to, parenteral solutions, oral solutions, powders, tablets, pills, gel caps, capsules, lozenges, suppositories, patches, nasal sprays, injections, implantable sustained-release formulations, mucosal adhesive films, topical varnishes, lipid complexes, and liquids.

[0076] Pharmaceutical compositions and medicinal products may be prepared by mixing one or more compounds and / or compositions of the Technology with pharmaceutically acceptable carriers, excipients, binders, diluents, etc. Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, or solutions. The compositions may be formulated for various routes of administration, e.g., oral, parenteral, topical, rectal, nasal, vaginal, or via implanted reservoirs. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections. The following dosage forms are given as examples and should not be construed as limiting the Technology.

[0077] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel caps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as starch or other additives. Suitable additives include sucrose, lactose, cellulose sugars, mannitol, maltitol, dextran, starch, agar, alginates, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. Optionally, oral dosage forms may contain other components that aid administration, such as inert diluents, or lubricants, such as magnesium stearate, or preservatives, such as parabens or sorbic acid, or antioxidants, disintegrants, binders, thickeners, buffers, sweeteners, flavorings, or fragrances, such as ascorbic acid, tocopherol, or cysteine. Tablets and pills may be further treated with suitable coating materials known in the art.

[0078] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain inert diluents such as water. Pharmaceutical preparations and medicinal products may be prepared as liquid suspensions or solutions using sterile liquids, including but not limited to oils, water, alcohols, and combinations thereof. Pharmaceutically appropriate surfactants, suspending agents, and emulsifiers may be added for oral or parenteral administration.

[0079] As described above, the suspension may contain oil. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. The suspension formulation may also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. The suspension formulation may also contain alcohol, such as, but are not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol. Ethers (such as, but are not limited to, poly(ethylene glycol)), petroleum hydrocarbons such as mineral oil and petrolatum, and water may also be used in the suspension formulation.

[0080] Injectable dosage forms generally include aqueous or oily suspensions, which may be prepared using appropriate dispersants or wetting agents and suspending agents. Injectable dosage forms may also be in the form of a solution phase or suspension, and are prepared with a solvent or diluent. Acceptable solvents or bases include sterile water, Ringer's solution, or isotonic aqueous saline solution. Alternatively, sterile oil may be used as a solvent or suspending agent. Typically, oils or fatty acids are non-volatile and include natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides.

[0081] For injection, pharmaceutical formulations and / or medicinal products may be powders suitable for reconstitution with the appropriate solutions described above. Examples of these include, but are not limited to, lyophilized, tumble-dried, or spray-dried powders, amorphous powders, granules, precipitates, or particles. For injection, formulations may optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof.

[0082] The compounds of this technology may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any suitable solvent, and optionally 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 requirements of the specific compound, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, and lecithin, amino acids such as glycine, buffers, salts, sugars, and / or sugar alcohols. Aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols are typically used for the delivery of the compounds of this technology by inhalation.

[0083] Dosage forms for topical (including buccal and sublingual) or transdermal administration of the compounds of this technology include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active ingredients may be mixed under sterile conditions with pharmaceutically acceptable carriers or excipients and any preservatives or buffers as required. Powders and sprays can be prepared with excipients such as lactose, talc, silicic acid, 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, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof. Absorption enhancers may also be used to increase the flux of the compounds of this technology through the skin. The rate of such flux can be controlled either by providing a rate-controlling membrane (e.g., as part of a transdermal patch) or by dispersing the compounds in a polymer matrix or gel.

[0084] In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in this 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.

[0085] Formulations of this technology may be designed to be short-acting, rapid-release, long-acting, and sustained-release, as described below. Accordingly, pharmaceutical formulations may also be formulated for controlled-release or sustained-release.

[0086] The composition may also include, for example, micelles or liposomes, or several other encapsulation forms, or may be administered in a sustained-release form to provide long-term storage and / or delivery effects. Thus, pharmaceutical formulations and drugs may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may use known inert materials such as silicone and biodegradable polymers.

[0087] The specific dosage may be adjusted depending on the condition of the disease, age, weight, overall health, sex, and diet, administration interval, route of administration, excretion rate, and drug combination. Any of the above dosage forms containing an effective dose are well within the range of normal experimentation and therefore well within the scope of this technology.

[0088] Those skilled in the art can easily determine the effective dose by administering the compound of this technology to a patient, for example, by increasing the dose until the mass of the tumor in the subject decreases. The compound of this technology can be administered to a patient at a dose level ranging from approximately 0.1 to approximately 1,000 mg per day. For a normal human adult weighing approximately 70 kg, a dose ranging from approximately 0.01 to approximately 100 mg per kg of body weight per day is sufficient. However, the specific dose used may vary or be adjusted as deemed appropriate by those skilled in the art. For example, the dose may depend on several factors, including the patient's requirements, the severity of the B-cell malignancy associated with the tumor (e.g., non-Hodgkin lymphoma or chronic lymphocytic leukemia), and the pharmacological activity of the compound used. Determining the optimal dose for a particular patient is well known to those skilled in the art.

[0089] Various assays and model systems can be readily used to determine the therapeutic efficacy of treatment using this technology. The efficacy of the composition (and determination of effective doses) and method of this technology may also be demonstrated by its effect on reducing tumor mass and / or slowing tumor growth and / or increasing the therapeutic response of cancer to a second cancer therapy (such as radiotherapy, monoclonal antibodies, and / or chemotherapeutic agents).

[0090] For each of the conditions described herein, the test subject will show a reduction of 10%, 20%, 30%, 50%, or more in one or more symptoms caused by or associated with the disorder in the subject, compared to placebo treatment or other appropriate control subjects, up to a maximum reduction of 75–90% or 95%, or more.

[0091] The compounds of this technology can also be administered to a patient together with other conventional therapeutic agents that may be useful in the treatment of tumors or in vaccination. Administration may include oral, parenteral, or nasal administration. In any of these embodiments, administration may include intratumoral, subcutaneous, intravenous, intraperitoneal, or intramuscular injection. In any of these embodiments, administration may include oral administration. The methods of this technology may also include administering conventional therapeutic agents sequentially or in combination with one or more compounds of this technology in amounts that may be potentially or synergistically effective in treating cancers (e.g., breast cancer, ovarian cancer, pancreatic cancer, biliary tract cancer, lung cancer, prostate cancer, and / or CNS cancers).

[0092] In one embodiment, the compounds of the present technology are administered to a patient in an amount or dosage suitable for therapeutic use. Generally, the unit dose containing the compounds of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, severity of disease, contraindications, and concomitant therapies. Exemplary unit doses based on these considerations may also be adjusted or modified by a physician skilled in the art. For example, a unit dose containing the compounds of the present technology for a patient might be 1 × 10⁻⁶. -4 g / kg to 1g / kg, preferably 1 × 10 -3 The dosage can vary from g / kg to 1.0 g / kg. The dosage of the compound in this technology can also vary from 0.01 mg / kg to 100 mg / kg, or preferably from 0.1 mg / kg to 10 mg / kg.

[0093] The compounds of this technology can also be modified, for example, by covalent bonding of an organic moiety or conjugate, to improve pharmacokinetic properties, toxicity, or bioavailability (e.g., increased in vivo half-life). The conjugate can be a linear or branched hydrophilic polymer group, a fatty acid group, or a fatty acid ester group. The polymer group may include a molecular weight that can be adjusted by those skilled in the art, for example, to improve pharmacokinetic properties, toxicity, or bioavailability. Exemplary conjugates may include polyalkane 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 independently containing about 8 to about 70 carbon atoms. Conjugates for use with the compounds of this technology can also serve, for example, as linkers to any suitable substituent or group, radiolabels (markers or tags), halogens, proteins, enzymes, polypeptides, other therapeutic agents (e.g., pharmaceuticals or drugs), nucleosides, dyes, oligonucleotides, lipids, phospholipids, and / or liposomes. In one embodiment, the conjugate may include polyethyleneamine (PEI), polyglycine, a hybrid of PEI and polyglycine, polyethylene glycol (PEG), or methoxypolyethylene glycol (mPEG). The conjugate may also include a probe for the technology by linking the compound of the technology to, for example, a label (fluorescent or luminescent) or a marker (radionuclide, radioisotope, and / or isotope). In one embodiment, a conjugate for use with the compound of the technology can improve the in vivo half-life. Other exemplary conjugates for use with the compound of the technology, as well as their applications and related technologies, include those generally described in U.S. Patent No. 5,672,662, which is incorporated herein by reference.

[0094] In another embodiment, the Art provides a method for identifying a target, comprising contacting the target with a detectable or imageable amount of the Art's labeled compound. The detectable or imageable amount is the amount of the Art's labeled compound required to be detected by a selected detection method. For example, the detectable amount may be a dose sufficient to enable detection of 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 (in combination with streptavidin complexing), and chemiluminescent groups. Once the labeled compound has bound to the target, the target may be isolated, purified, and further characterized, such as by determining its amino acid sequence.

[0095] The terms “association” and / or “binding” can refer, for example, to a chemical or physical interaction between the compound of this technology and the target of interest. Examples of associations or interactions include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions, and complexes. Association can also be used to describe various chemical or physical interactions, and therefore can generally refer to “binding” or “affinity.” Measuring binding or affinity is also commonplace for those skilled in the art. For example, the compound of this technology can bind to or interact with the target of interest or its precursors, parts, fragments and peptides, and / or their precipitates.

[0096] As previously shown in this disclosure, one embodiment provides a method for treating a subject having cancer, the method comprising 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 cancer (such as brain cancer).

[0097] In any embodiment of this specification, the administration may further include radiotherapy, monoclonal antibodies, and / or chemotherapeutic agents (such as alkylating agents; nitrosourea; antimetabolites; anthracyclines; topoisomerase II inhibitors; mitotic inhibitors; antiestrogens; progestins; aromatase inhibitors; antiandrogens; LHRH agonists; corticosteroid hormones; DNA alkylating agents; taxanes; vinca alkaloids; microtubule toxins, or any two or more of these in combination). In any embodiment of this specification, the administration may include busulfan, cisplatin, carboplatin, oxaliplatin, octahedral platinum(IV) compounds, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), mechloretamine (nitrogen mustard), melphalan, temozolomide, carmustine (BCNU), lomustine (CCNU), 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine, pemetrexed, daunorubicin, doxorubicin (adriamycin), epirubicin, idarubicin, mitoxantrone, topotecan, irinotecan, etoposide (VP-16), and teniposide. This may further include the administration of chemotherapeutic agents such as paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, L-asparaginase, dactinomycin, thalidomide, tretinoin, imatinib (Gleevec), gefitinib (Iressa), erlotinib (Tarceva), rituximab (Rituxan), bevacizumab (Avastin), ipilimumab, nivolumab (Opdivo), pembrolizumab (Keytruda), tamoxifen, fulvestrant, anastrozole, exemestane, letrozole, megestrol acetate, bicalutamide, flutamide, leuprolide, goserelin, or any two or more of these in combination.

[0098] In any embodiment of this specification, administration may include oral, rectal, nasal, vaginal, parenteral, transdermal, intravenous, intramuscular, or inhalation administration. In any embodiment of this specification, administration may include topical administration of the compound to a site of target including cancer, or topical administration of the composition to a site of target including cancer.

[0099] The examples provided herein are provided to illustrate the advantages of the Art and to further assist those skilled in the art with regard to the preparation or use of the compounds and compositions of the Art. The examples provided herein are also presented to more fully illustrate preferred embodiments of the Art. The examples should not be construed as limiting the scope of the Art as defined by the appended claims. The examples may include or incorporate any of the above-described variations, aspects, or embodiments of the Art. Each of the above-described variations, aspects, or embodiments may further include or incorporate any other variations, aspects, or embodiments of any or all of the Art. [Examples]

[0100] All solvents and reagents were used as they were obtained from commercial suppliers, unless otherwise specified. 1H spectra were recorded in CDCl3 with 0.03% TMS as an internal standard using a Bruker AM or Varian 400 spectrometer (both operating at 400 MHz). Reported chemical shifts (δ) are expressed in parts per million (ppm), and coupling constants (J) are expressed in Hertz (Hz). Spin multiplicity is reported as s=singular, d=double, t=tripular, q=quadular, dd=double-double, ddd=double-double-double, dt=double-tripular, td=triple-double, and m=multiplex. LC-MS analysis was performed chromatograph with photodiode array UV detection and TOF mass spectrometer. The mass spectrometer utilized a multimode source for simultaneous acquisition of ESI+ / APCI+, a reference mass solution, and a makeup solvent introduced into the LC flow before the source to aid ionization. As shown in the following example, a single stereoisomer may be isolated and obtained in high purity, but the final, definitive determination of absolute stereochemistry may remain uncertain for a particular set of stereoisomers.

[0101] Exemplary synthesis of a specific compound using this technology: Synthesis of compound 0313 [ka] To a mixture of 4-bromo-2,3-dihydroisoindole-1-one (1.4 g, 6.6 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.95 g, 6.6 mmol), and Cs2CO3 (6.45 g, 19.7 mmol) in dioxane / H2O (5 / 1, v / v, 20 mL), Pd(dppf)Cl2·DCM (0.54 g, 0.66 mmol) was added at room temperature. The mixture was stirred at 90°C for 6 hours. The mixture was filtered, and the filtrate was extracted with DCM / MeOH (10 / 1, 50 mL x 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (DCM:MeOH=20:1) on a silica gel column to obtain tert-butyl 3-(1-oxoisoindorin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.6 g, 94%) as a white solid. MS(ESI):C 17 H 20 Calculated mass value for N2O3: 301.1, measured m / z value: 301.1 [M+H] + .

[0102] A mixture of tert-butyl 3-(1-oxoisoindolin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.5 g, 5.0 mmol) and Pd / C (160 mg, 1.5 mmol) in MeOH (20 mL) was stirred at room temperature under an H2 balloon for 12 hours. The mixture was filtered through a Celite pad, and the filtrate was evaporated under vacuum. The residue was purified by recrystallization from PE / EA (3 / 1, v / v, 60 mL) to obtain tert-butyl 3-(1-oxoisoindolin-4-yl)pyrrolidine-1-carboxylate (1.5 g, 99%) as a white solid. MS(ESI):C 17 H 22 Calculated mass value for N2O3: 303.1, measured m / z value: 303.2 [M+H] + .

[0103] A solution of tert-butyl 3-(1-oxoisoindorin-4-yl)pyrrolidine-1-carboxylate (1.5 g, 4.9 mmol) in HCl / EA (20 mL) was stirred at room temperature for 2 hours. The solid was collected, washed with EA (100 mL x 2), and dried under vacuum to obtain 4-(pyrrolidine-3-yl)isoindorin-1-one (1 g, 98%) as a white solid. MS(ESI):C 12 H 14 Calculated mass value for N2O: 203.1, measured m / z value: 203.2 [M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ 9.69-9.30(m,2H),8.64(s,1H),7.65(d,J=8.0 Hz,1H),7.59(d,J=8.0 Hz,1H),7.52-7.49(m,1H),4.44(s,2H),3.67-3.60(m,1H),3.58-3.51(m,1H) ,3.48-3.37(m,1H),3.22-3.12(m,2H),2.41-2.33(m,1H),2.06-1.96(m,1H).

[0104] Synthesis of compound 0312 [ka] 4-Bromoisoindorin-1-one (3 g, 14 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.69 g, 18 mmol), PdCl2 (dppf) (1.03 g, 14 mmol), and potassium carbonate (9.74 g, 70 mmol) were added to a three-necked flask. Next, 1,4-dioxane (50 mL) and H2O (10 mL) were added. The reaction mixture was stirred at 80°C for 5 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH=20:1) on a silica gel column to obtain tert-butyl 4-(1-oxoisoindorin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.5 g, 79%) as a yellow solid. MS(ESI):C 18 H 22 Calculated mass value for N2O3: 314.39, measured m / z value: 315.3 [M+H] + .

[0105] A mixture of tert-butyl 4-(1-oxoisoindorin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.5 g, 11 mmol) and Pd / C (2 g, 10.0%) in MeOH (30 mL) was stirred at room temperature for 4 hours. Upon completion, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(1-oxoisoindorin-4-yl)piperidine-1-carboxylate (2.31 g, 66%) as a white solid. MS(ESI):C 18 H 24 Calculated mass value for N2O3: 316.40, measured m / z value: 317.3 [M+H] + .

[0106] To a solution of tert-butyl 4-(1-oxoisoindorin-4-yl)piperidine-1-carboxylate (2.31 g, 7 mmol) in MeOH (80 mL), concentrated HCl (30 mL) was slowly added. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain 4-(piperidine-4-yl)isoindorin-1-one (2.07 g, 98%) as a white solid. MS(ESI):C 13 H 16 Calculated mass value for N2O: 216.28, measured m / z value: 217.2 [M+H] + .

[0107] Synthesis of compounds 5350, 5547, and 5548 [ka] The reaction mixture was prepared by dissolving tert-butyl 4-[(piperidine-3-yl)carbonyl]piperazine-1-carboxylate (100 mg, 0.3363 mmol), Ac2O (35 mg, 0.3363 mmol), and TEA (69 mg, 0.6726 mmol) in DCM (2 mL). The reaction mixture was irradiated in a microwave reactor at 0°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography eluted with PE / EA (5:1) to obtain tert-butyl 4-[(1-acetylpiperidine-3-yl)carbonyl]piperazine-1-carboxylate (50 mg, 59%) as a yellow solid. MS(ESI):C 17 H 29 Calculated mass value for N3O4: 339.2, measured m / z value: 340.2 [M+H] + .

[0108] A mixture of tert-butyl 4-[(1-acetylpiperidine-3-yl)carbonyl]piperazine-1-carboxylate (2 g, 0.0059 mol) in HCl / EA (50 mL) was stirred at 25°C for 5 hours. Upon completion, the solvent was evaporated under reduced pressure to obtain 1-{3-[(piperazine-1-yl)carbonyl]piperidine-1-yl}ethanone (1.3 g, 83%) as a yellow solid. MS(ESI):C 12 H 21 Calculated mass value for N3O3: 239.3, measured m / z value: 240.3 [M+H] + .

[0109] To a mixture of 7-bromo-1-benzofuran-2-carboxylic acid (1.3 g, 0.0054 mol) in DMF (20 mL), HATU (2.46 g, 0.00648 mol) was added. After stirring at 25°C for 30 minutes, 1-{3-[(piperazin-1-yl)carbonyl]piperidine-1-yl}ethenone (1.3 g, 0.0054 mol) and DIEA (2.79 g, 0.0216 mmol) were added to the reaction mixture. The reaction mixture was stirred at 25°C for a further 2 hours. The reaction mixture was quenched with water (100 mL) and extracted with EA (50 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica (PE:EA=3:1) to obtain 1-[3-({4-[(7-bromo-1-benzofuran-2-yl)carbonyl]piperazine-1-yl}carbonyl)piperidine-1-yl]ethanone (1.8g, 90%) as a yellow solid. MS(ESI):C 21 H 24 Calculated mass value for BrN3O4: 462.3, measured m / z value: 463.3 [M+H] + .

[0110] To a solution of 1-[3-({4-[(7-bromo-1-benzofuran-2-yl)carbonyl]piperazine-1-yl}carbonyl)piperidine-1-yl]etanone (200 mg, 0.4326 mmol) in dioxane (10 mL) and H2O (1 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroisoindole-1-one (112 mg, 0.4326 mmol), K2CO3 (179 mg, 1.2978 mmol), and Pd(dppf)Cl2DCM (36 mg, 0.04326 mmol) were added. The reaction mixture was stirred under N2 at 100°C for 8 hours. The mixture was quenched with water (10 mL) and extracted with EA (3 × 10 mL). The organic layer was removed to obtain the crude product. The crude product was purified using an RP-C18 column eluted with H2O (0.5% FA) / CH3CN (100:0 → 50:50) to obtain 4-[2-({4-[(1-acetylpiperidine-3-yl)carbonyl]piperazine-1-yl}carbonyl)-1-benzofuran-7-yl]-2,3-dihydroisoindole-1-one (compound 5350, 200 mg, 81%) as a yellow solid. MS(ESI):C 29 H 30 Calculated mass value for N4O5: 514.3, measured m / z value: 515.3 [M+H] + . 1 H NMR(400 MHz,DMSO)δ 8.67(s,1H),7.87(d,J=8.0 Hz,1H),7.83(d,J=8.0 Hz,1H),7.78(d,J=8.0 Hz,1H),7.71-7.64(m,2H),7.53(s,1H),7.47(t,J=8.0 Hz,1H),4.46(s,2H),4.36-4.27(m,1H),3.92-3.41(m,10H),3.22-2.91(m,1H),2.60(d,J=8.0 Hz, 1H), 2.00 (s, 3H), 1.83 (s, 1H), 1.71-1.61 (m, 1H), 1.56-1.35 (m, 2H).

[0111] 4-[2-({4-[(1-acetylpiperidine-3-yl)carbonyl]piperazine-1-yl}carbonyl)-1-benzofuran-7-yl]-2,3-dihydroisoindole-1-one (200 mg) was divided by preparative fractionation by SFC to obtain (R)-4-(2-(4-(1-acetylpiperidine-3-carbonyl)piperazine-1-carbonyl)benzofuran-7-yl)isoindorin-1-one (48 mg, 24%) as a white solid, and (S)-4-(2-(4-(1-acetylpiperidine-3-carbonyl)piperazine-1-carbonyl)benzofuran-7-yl)isoindorin-1-one (50.5 mg, 25%) as a white solid.

[0112] Compound 5547:MS(ESI):C 29 H 30 Calculated mass value for N4O5: 514.3, measured m / z value: 515.3 [M+H] + . 1 H NMR(400 MHz,DMSO)δ 8.67(s,1H),7.87(d,J=8.0 Hz,1H),7.83(d,J=8.0 Hz,1H),7.78(d,J=8.0 Hz,1H),7.71-7.64(m,2H),7.53(s,1H),7.47(t,J=8.0 Hz,1H),4.46(s,2H),4.36-4.27(m,1H),3.92-3.41(m,10H),3.22-2.91(m,1H),2.60(d,J=8.0 Hz, 1H), 2.00 (s, 3H), 1.83 (s, 1H), 1.71-1.61 (m, 1H), 1.56-1.35 (m, 2H).

[0113] Compound 5548:MS(ESI):C 29 H 30 Calculated mass value for N4O5: 514.3, measured m / z value: 515.3 [M+H] + . 1H NMR(400 MHz,DMSO)δ 8.67(s,1H),7.87(d,J=8.0 Hz,1H),7.83(d,J=8.0 Hz,1H),7.78(d,J=8.0 Hz,1H),7.71-7.64(m,2H),7.53(s,1H),7.47(t,J=8.0 Hz,1H),4.46(s,2H),4.36-4.27(m,1H),3.92-3.41(m,10H),3.22-2.91(m,1H),2.60(d,J=8.0 Hz, 1H), 2.00 (s, 3H), 1.83 (s, 1H), 1.71-1.61 (m, 1H), 1.56-1.35 (m, 2H).

[0114] Synthesis of compound 5335 [ka] To a solution of 7-bromobenzofuran-2-carboxylic acid (200 mg, 0.8297 mmol) in DMF (5 mL), HATU (473 mg, 1.2445 mmol) and DIEA (536 mg, 4.1485 mmol) were added. After stirring for 10 minutes, tert-butylpiperazine-1-carboxylate (155 mg, 0.8297 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography eluted with PE / EA (5:1) to obtain tert-butyl 4-(7-bromobenzofuran-2-carbonyl)piperazine-1-carboxylate (300 mg, 80%) as a yellow solid. MS(ESI):C 18 H 21 Calculated mass value for BrN2O4: 408.0, measured m / z value: 431.0 [M+Na] + .

[0115] A mixture of tert-butyl(S)-3-methyl-8-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (300 mg, 0.7312 mmol) in HCl / EA (4 M, 5 mL) was stirred at 25°C for 4 hours. Upon completion, the solvent was evaporated under reduced pressure to obtain (7-bromobenzofuran-2-yl)(piperazine-1-yl)methanone (200 mg, 88%) as a white solid. MS(ESI):C 13 H 13 Calculated mass value for BrN2O2: 308.0; measured m / z value: 309.0 [M+H] + .

[0116] To a stirred solution of (7-bromobenzofuran-2-yl)(piperazin-1-yl)methanone (180 mg, 0.5822 mmol) in DMF (5 mL), TEA (295 mg, 2.9110 mmol) and 2-bromo-N-methylacetamide (442.44 mg, 2.9110 mmol) were added. The resulting mixture was stirred at 25°C for 4 hours. The mixture was quenched with ice water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography eluted with PE / EA (2:1) to obtain 2-(4-(7-bromobenzofuran-2-carbonyl)piperazin-1-yl)-N-methylacetamide (150 mg, 85%) as a white solid. MS(ESI):C 16 H 18 Calculated mass value for BrN3O3: 379.0, measured m / z value: 380.0 [M+H] + .

[0117] To a solution of 2-(4-(7-bromobenzofuran-2-carbonyl)piperazin-1-yl)-N-methylacetamide (256 mg, 0.6733 mmol) in 1,4-dioxane / H2O (6 mL, 10:1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-1-one (192 mg, 0.7406 mmol), K2CO3 (279 mg, 2.0199 mmol), and Pd(dppf)Cl2 (49 mg, 0.0673 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. The mixture was quenched with ice water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography eluted with PE / EA (2:1) to obtain N-methyl-2-(4-(7-(1-oxoisoindorin-4-yl)benzofuran-2-carbonyl)piperazine-1-yl)acetamide (100 mg, 36%) as a white solid. MS(ESI):C 24 H 24 Calculated mass value for N4O4: 432.2, measured m / z value: 433.2 [M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ 8.68(s,1H),7.87-7.77(m,4H),7.68-7.64(m,2H),7.49(s,1H),7.46(t,J=7.6 Hz,1H),4.45(s,2H),3.71(s,4H),2.94(s,2H),2.62(d,J=4.8 Hz,3H),2.49-2.46(m,4H).

[0118] Synthesis of compound 5336 [ka] To a mixture of 7-bromo-1-benzofuran-2-carboxylic acid (189 mg, 0.7841 mmol) in DMF (5 mL), HATU (358 mg, 0.9409 mmol) was added. After stirring at 25°C for 30 minutes, (2S,4R)-4-fluoro-N-methylpyrrolidine-2-carboxamide (115 mg, 0.7841 mmol) and DIEA (304 mg, 2.3523 mmol) were added to the reaction mixture. The reaction mixture was stirred at 25°C for a further 6 hours. The mixture was quenched with water (20 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography eluted with PE / EA (5:1) to obtain (2S,4R)-1-[(7-bromo-1-benzofuran-2-yl)carbonyl]-4-fluoro-N-methylpyrrolidine-2-carboxamide (200 mg, 62%) as a yellow solid. MS(ESI):C 15 H 14 Calculated mass for BrFN2O3: 369.2; measured m / z value: 370.2 [M+H] + .

[0119] To a solution of (2S,4R)-1-[(7-bromo-1-benzofuran-2-yl)carbonyl]-4-fluoro-N-methylpyrrolidine-2-carboxamide (300 mg, 0.8126 mmol) in dioxane (4 mL) and H2O (1 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroisoindole-1-one (211 mg, 0.8126 mmol), K2CO3 (337 mg, 2.4378 mmol), and Pd(dppf)Cl2·DCM (67 mg, 0.08126 mmol) were added. The reaction mixture was stirred under N2 at 100°C for 8 hours. The mixture was quenched with ice water (10 mL) and extracted with EA (3 × 10 mL). The solvent was removed to obtain the crude product. The crude product was purified by elution with H2O (0.5% FA) / CH3CN (100:0 → 50:50) using an RP-C18 column to obtain (2S,4R)-4-fluoro-N-methyl-1-{[7-(1-oxo-2,3-dihydroisoindole-4-yl)-1-benzofuran-2-yl]carbonyl}pyrrolidine-2-carboxamide (300 mg, 79%) as a yellow solid. MS(ESI):C 23 H 20 Calculated mass of FN3O5: 421.4, measured m / z value: 422.4 [M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ 8.67(s,1H),8.06(d,J=4.0 Hz,1H),7.91(d,J=8.0 Hz,1H),7.86(d,J=8.0 Hz,1H),7.83-7.64(m,5H),7.48(t,J=8.0 Hz,1H),5.42(d,J=52.0 Hz,1H),4.61-4.49(m,2H),4.38(d,J=20.0 Hz,1H),4.28-4.19(m,1H),4.07-4.35(m,1H),2.59(d,J=4.0 Hz,3H),2.14-1.94(m,1H).

[0120] PARP Mass Spectrometry Assay Protocol 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 the 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 all purchased from Millipore Sigma.

[0121] 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.

[0122] procedure: The PARP1 enzyme assay was performed in a 384-well plate with a total volume of 20 μL of assay buffer. For the concentration-response curve, a 10-point curve was generated by serially diluting the compound three-fold from a peak concentration of 0.1013 mM (2 mM). 125 nL was transferred to the assay plate using an Echo acoustic dispenser, and the final concentration range in 10 μL of reactant was set to 26.6 μM to 1.35 μM. 5 microliters of a mixture of 10 nM PARP1 enzyme and 100 nM core histone (2×) was added to the assay plate and pre-incubated at room temperature (RT) for 30 minutes. The reaction was initiated by adding 5 μL of a mixture of 10 μM β-NAD plus 0.02 mg / mL of activated DNA (2×). The reactant was incubated at RT for 60 minutes. The final concentrations of PARP1 enzyme and substrate were 5 nM and 5 μM, respectively. Positive control (high signal) and negative control (low signal) wells contained 125 nL of DMSO instead of the compound. After incubation was complete, the reaction was stopped by adding 10 μL of 10 μM 3ABA PARP1 inhibitor, incubated at RT for 5 minutes, and placed in a -80°C freezer for transport to the Valo Health site in Branford, Connecticut, where the amount of nicotinamide (NAM) was directly detected using mass spectrometry.

[0123] The inhibition rate (%) of enzyme activity was calculated according to the following formula.

number

[0124] Representative results of exemplary compounds using this technology Table 1 provides representative initial results for exemplary compounds of this technology, along with comparative compound A (structure shown below prior to Table 1). [ka] [Table 1-32] [Table 1-33]

[0125] PARylation immunofluorescence assay protocol material: [Table 2]

[0126] device: [Table 3]

[0127] Cell Culture Details: HCT116 is a human colon epithelial cell line that adheres and grows in tissue culture flasks. Cells are grown in T175-size flasks. Cells are divided twice weekly at 70-80% confluence in a division ratio of 1:5-1:10, following a standard adherent cell subculturing protocol. The medium should be refrigerated until the cell-based activity day and warmed to at least RT before use. The cell culture medium is McCoy's 5A with 10% FBS, 2 mM L-glutamine, and 20 mM HEPES. The plating medium is McCoy's 5A with 10% FBS, 2 mM L-glutamine, 20 mM HEPES, and 1% antibiotic-antifungal solution.

[0128] procedure: Day 1: Cell Culture and Cell Plating: The cell culture and cell plating method involves the steps of warming the culture medium before cell culture, removing the cell flask from the incubator and trypsinizing the cells in a T175 flask using 0.25% trypsin, returning the flask to the incubator for about 5 minutes to allow the cells to detach from the bottom of the flask, adding 10 μL of medium to rinse the bottom of the flask, adding the cells and medium to a 50 mL conical tube, centrifuging the cells at 1000 rpm for 5 minutes, aspirating and removing the medium, and resuspending the pellet in 10 mL of fresh medium. The method includes the steps of: calculating the number of viable cells using a cell counter; using the number of viable cells and the required number of plates, calculating the amount of resuspended cell pellet medium that needs to be added to fresh plating medium to dispense 5 μL / well at a density of 6000 cells / well into 384W plates; plating the cells into 384W plates and adding 5 μL of medium to each well so that there are 6000 cells / well in total for the plate; gently shaking the plates for 20 minutes (100 rpm) after plating; and incubating the plates overnight at 37°C, 5% CO2 before processing.

[0129] Day 2: Compound and DNA damage treatment, fixation and primary staining: This method uses Labcyte Echo The steps are: to process 384W cell seeding plates using 555 to reach a maximum dose of 10 μM for each compound, stamping 40 nL of 10 mM maximum dose compound plates onto 40 μL of cells in the seeding plates, the Labcyte compound source plates being DMSO-based with 10 points, 3-fold dose dilutions of compounds starting from 10 mM, and the transfer volume using Echo being 40 nL; incubating at 37°C, 5% CO2 for 5 hours; adding DNA damaging agent MMS to columns 1-23 of each cell seeding 384W plate by supplying 40 nL of 19.2% MMS in DMSO using Echo in DMSO supply mode, the MMS stock concentration being 99% and must be diluted 1:5 with DMSO before supplying to the cell plates; incubating the cell plates at 37°C, 5% CO2 for 30 minutes; draining the medium using BlueWasher and adding 75 μL of cold methanol. The process includes the steps of: rotating the plate clockwise at 800 RPM (35 g) for 5 seconds using the MagBeadSpeed ​​setting; keeping the dispensing line and methanol cool throughout the entire fixation process and using the staccato setting to divide the dispensing into multiple jets to minimize cell disruption; incubating the fixed plate on ice for 20 minutes; washing the full plate once with an equal volume of cold DPBS and draining with the Bluewasher using MagBeadSpeed; adding 20 μl of DPBS 0.1% Triton X-100 to the full plate, incubating at room temperature for 15 minutes, and draining with the Bluewasher using MagBeadSpeed; adding 20 μl of Roche block to the full plate, incubating at room temperature for 60 minutes, and draining with the Bluewasher using MagBeadSpeed; and adding 20 μl of PAR antibody (1:4,000) in the Roche block, sealing the plate, and incubating overnight at 4°C.

[0130] Day 3: Secondary Antibody Staining and Imaging: This method includes the steps of discharging and washing the plate (3 times) with 25 - 30 μl of DPBS 0.05% Tween 20 using a Bluewasher, adding 20 μl of anti - mouse AF488 secondary antibody (1:1,600) plus Hoechst (1:10,000), incubating for 60 minutes at room temperature, discharging using MagBeadSpeed, washing 3 - 4 times with 25 - 30 μl of DPBS 0.05% Tween 20, adding 30 μl of DPBS, sealing the plate, and imaging in channels 1 (360) and 2 (488) of the CX7 - circle (nucleus) average intensity using the protocol "PAR_HCT116_MeOH_10X_2ChR". The main acquisition settings are 70 - 80% and 488 - channel exposure to 1 - 2 fields of view.

[0131] Data Analysis: Raw data files are exported from the CX7 software and paired with the barcoded compound plates to track compound IDs, dose - responses, and Echo transfer records. This enables the import and QC analysis of dose - response curves and the determination of IC50 values. Images of each plate and well on both imaging channels can also be exported. The inhibition rate of PARylation activity was calculated according to the following formula.

Number

[0132] Assay principle: Cellular levels of PARylation of PARP1 / 2 substrate proteins (PARP1 and histones) are measured by anti-PAR antibodies using an immunofluorescence assay at the time of DNA damage, based on https: / / f1000research.com / articles / 5-736 / v2. PARP inhibitors reduce levels of PARylation when co-treated with the DNA damaging agent MMS.

[0133] Cell-based proliferation assay protocols: DLD1 parent strain vs. BRCA2 null 5-day CTG, CTF, CyQuant, or one-pot live-death HCS assay Reagents and consumables: [Table 4]

[0134] device: [Table 5]

[0135] procedure Day 1: Cell Culture and Cell Plating: This method includes the steps of counting the cells (using a Nexcelom serometer and recording the number of cells), centrifuging the cells at 1000 rpm for 5 minutes and resuspending the pellet in fresh medium, plating the cells into a 1536-well plate at a specific cell / well density based on density optimization tests (or 100 cells / well for DLD1 parent strain (based on past results), 125 cells / well for DLD1 BRCA2+ / - vs - / - null, in the volume of cells per well (μL) in columns 1-47 of a 1536w plate), gently shaking the plate at room temperature for 30 minutes (100 rpm) before transferring it to an incubator (37°C, 5% CO2), and incubating the plate for 24 hours (37°C, 5% CO2) before processing.

[0136] Day 2: Compound treatment: For 1536w, compound stamping was performed at a maximum concentration of 10 mM of the source plate compound, resulting in a maximum dose concentration of 50 μM used in cell-based proliferation assays. Positive control SAHA was stamped to a final concentration of 10 μM.

[0137] Days 3-7: Plate incubation: After compound addition, the plates were incubated at 37°C and 5% CO2 for a total of 120 hours / 5 days.

[0138] Days 3-7: Adding Readout Reagents and Plate Reading: After incubation, remove the plate from the incubator and add the specified readout reagents to the cell plate. See below for details based on specific readouts. • CTG Readout: Before use, remove the CTG2.0 reagent from the refrigerator and allow it to come to room temperature. Add 4 μL / well of CTG to all wells of each cell plate. For 1536w plates, incubate the plate at 37°C and 5% CO2 for 30 minutes. Read the plate using the luminescence-specific protocol specified by the plate reader. BMG or Envisions have their own CTG-specific protocols. • CyQUANT Readout: Before use, remove the CyQuant Direct cell proliferation assay kit from the refrigerator and allow it to reach room temperature. Reagents may need to be heated in a dry bath to thaw. Calculate the total amount required based on the dispensed wells to ensure sufficient detection reagent is available. Prepare the detection reagent by combining the assay recipe of PBS: 11.7 mL, CyQuant® Direct nucleic acid stain: 48 μL, and CyQuant® Direct background suppressor: 240 μL. Add 2 μl / well of the CyQuant reagent mixture to all wells, incubate the plate at 37°C, 5% CO2 for 60 minutes, and read the plate using the CyQuant-specific protocol on a designated plate reader BMG or EnVisions with a specific 1536w protocol (CyQUANTDirect-508 / 527 nm, CyQUANTDirect Red-622 / 645 nm). • CTF Readout: Remove the CTF reagent from the freezer, allow it to come to room temperature before use, prepare a 1x reagent, vortex to dissolve (the reagent is stable at RT for 24 hours or at 4°C for 7 days), add 4 μl / well of CTF to each well, incubate the plate at 37°C and 5% CO2 for 180 minutes (3 hours), and read the plate using the fluorescence-specific protocol on the designated plate reader (BMG or Envision have CTF-specific protocols (Ex 380-400, Em 505)). • One-pot live-dead HCS reading: After incubation, remove the plate from the incubator. For a 1536-well plate, prepare 4 mL of 1x PBS, add 8 drops of propidium iodide reagent + 4 μL of Hoechst 333242, mix, then dispense 1 μL / well at medium speed using a Multidrop Combi. For a 384-well plate, prepare 6 mL of 1x PBS, add 12 drops of propidium iodide reagent + 6 μL of Hoechst 333242, mix, then dispense 8 μL / well at medium speed using a Multidrop Combi. Incubate at 37°C, 5% CO2 for 30 minutes, seal the plate with an aluminum seal, centrifuge at 1000 RPM for 2 minutes in a spin bucket centrifuge, place the plate on a CX7, and obtain the data. Next, the analyzed data is exported as a Spotfire file and then processed in ABASE.

[0139] Data analysis of CTG, CyQUANT, and CTF readings: Raw data files are exported from BMG, Envision, and CX7 readers and paired with barcoded compound plates to track compound ID, dose-response, and echo transfer records. This enables the import and QC analysis of dose-response curves, as well as IC50 value determination. Data and images of each plate and well on both imaging channels can also be exported. The inhibition rate of proliferative activity was calculated according to the following formula.

number

[0140] Assay principle: Cell viability is measured using a luminescence or fluorescence assay during cell proliferation in the presence of a PARP inhibitor compound, detecting live cell reads such as peptidase activity mediated by intracellular ATP (CTG), DNA (CyQUANT), and the cell-permeable substrate Gly-Phe-AFC (CTF).

[0141] Results of MDCK-MDR1 permeability assays for exemplary compounds using this technology A bidirectional assay involving Mandin Darby canine kidney (MDCK) cell lines transfected with the human MDR1 gene (P-glycoprotein, P-gp), designed to overexpress the MDR1 efflux transporter, the major efflux transporter at the blood-brain barrier (BBB), uses an established method to measure the flux rate of compounds passing through a polarized cell monolayer. As is well understood in the art, data generated from the MDCK-MDR1 permeability assay may be used to predict in vivo absorption of drugs. The bidirectional MDCK-MDR1 permeability assay can identify and quantify the level of active efflux. Screening compounds passing through the cell monolayer in both the apical-to-basement membrane direction (A→B) and the basement membrane direction (B→A) provides the B→A / A→B ratio (efflux ratio, "ER"). Unlike the Caco-2 assay, the MDCK-MDR1 assay is not subject to potential efflux interference by breast cancer resistance protein (BCRP). If a compound has an ER greater than 2, it suggests that the compound may be subject to active efflux. The data may be further used to predict blood-brain barrier (BBB) ​​permeability by calculation based on the data of Log(permeability - surface area product) ("LogPS"), which is well understood to predict Log([brain concentration] / [plasma concentration]) in vivo.

[0142] The compounds of the present technology will be carried out in a bidirectional MDCK-MDR1 assay. The compounds of the present technology are expected to show significant efflux in the direction from the apical membrane side to the basolateral membrane side (A→B) and / or have an ER of about 2 or less.

[0143] In vivo CNS Penetration of Exemplary Compounds of the Present Technology According to the company's proprietary prediction model, the compounds of the present technology are predicted to show BBB passage. These prediction models have been further verified by in vivo experiments on other compounds. In particular, the in vivo unbound brain-to-plasma ratio (Kpuu) is measured at steady state by comparing the free drug concentrations (corrected for protein binding) in the brain and plasma after 24-hour continuous intravenous infusion into Sprague Dawley rats, and a Kpuu exceeding 0.3 represents good brain exposure of the compound. The compounds of the present technology are expected to show in vivo Kpuu values that are generally accepted as predicting clinical brain permeability.

[0144] Certain embodiments have been illustrated and described, but those skilled in the art, after reading the foregoing specification, can make changes, substitutions of equivalents, and other types of modifications to the compounds of the present technology or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures described herein. Each of the aspects and embodiments described above can also include or incorporate into the specification variations or aspects as disclosed with respect to any or all of the other aspects and embodiments.

[0145] This technology is not limited in terms of any particular embodiment described herein, which are intended as single examples of individual embodiments of this technology. Many modifications and variations of this technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of this technology will be apparent to those skilled in the art from the foregoing description, in addition to those enumerated in the specification. Such modifications and variations are intended to fall within the scope of the appended claims. This technology is not limited to any particular method, reagent, compound, composition, labeled compound, or biological system, which may, of course, vary. It should also be understood that the terms used herein are for describing particular embodiments and are not intended to limit them. Accordingly, this specification is intended to be illustrative in terms of the breadth, scope, and spirit of this technology as indicated only by the appended claims, the definitions therein, and their equivalents.

[0146] Embodiments described herein exemplary may also be suitably implemented without any elements, limitations, or restrictions not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be understood broadly, without limitation. Furthermore, the terms and expressions used herein are for illustrative purposes only, not limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the shown and described features or any part thereof, and it should be recognized that various modifications are possible within the scope of the claimed art. In addition, the phrase “essentially consisting of” should be understood to include the specifically enumerated elements and any additional elements that do not substantially affect the fundamental and novel features of the claimed art. The phrase “consisting of” excludes any elements not specified.

[0147] In addition, where any feature or aspect of this disclosure is described in terms of the Markush group, a person skilled in the art will recognize that this disclosure is also described in terms of any individual member or subgroup of any member of the Markush group. Each of the narrowly defined species and subgenera groups that fall under the general disclosure also constitutes part of the invention. This includes the comprehensive specification of the invention with any proviso or negative limitation that removes any subject matter from its genus, regardless of whether the removed material is specifically described herein.

[0148] As will be understood by those skilled in the art, for any or all purposes, particularly in terms of providing written explanations, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any enumerated scope can be readily recognized as sufficiently describing and enabling the same scope to be divided into at least equal 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 10, etc. As a non-limiting example, each scope discussed herein can easily be divided into a lower 1 / 3, a middle 1 / 3, an upper 1 / 3, etc. As will also be understood by those skilled in the art, all language such as “maximum,” “at least,” “greater than,” and “less than” includes the stated number and refers to a scope that can subsequently be divided into subscopes as discussed above. Finally, as will be understood by those skilled in the art, a scope includes each individual member.

[0149] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) referenced herein are incorporated by reference in the same manner as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in whole. Definitions contained in the documents incorporated by reference are excluded to the extent that they conflict with the definitions in this disclosure.

Claims

1. Compound of formula I: 【Chemistry 1】 During the ceremony, X １ is H, F, or Cl, R １ is H, a substituted aryl, a substituted non-aromatic heterocyclyl, or a heteroaryl. R ２ is H or C(O)NH ２ That is the case.

2. R １ The compound according to claim 1, wherein is a substituted phenyl, a substituted non-aromatic heterocyclyl, or a bicyclic heteroaryl.

3. R １ teeth, 【Chemistry 2】 And, R ３ The compound according to claim 1 or 2, wherein is -C(O)-(substituted alkyl) or -C(O)-heterocyclyl.

4. R ３ The compound according to claim 3, wherein is -C(O)- (substituted non-aromatic heterocyclyl) or -C(O)- (amide-substituted alkyl).

5. R １ is 【Transformation 3】 And, R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and R １１ The compound according to any one of claims 1 to 4, wherein each is independently H, halo, alkyl, cycloalkyl, amide, hydroxyl, aryl, heterocyclyl, or heteroaryl.

6. R １ teeth, 【Chemistry 4】 And, R １２ is H, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkyloyl, or aryloyl, R １３ The compound according to any one of claims 1 to 4, wherein is H, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkyloyl, or aryloyl.

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

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 in treating cancer.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount effective for treating cancer when combined with a second cancer therapy, 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.

12. A method for treating a subject suffering from a B-cell malignancy, the method comprising administering to the subject an effective amount of a compound according to any one of 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 pharmaceutical product for treating cancer in a subject, wherein the pharmaceutical product comprises 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 pharmaceutical product according to claim 13, further comprising a pharmaceutically acceptable carrier.

15. The pharmaceutical product according to claim 13 or claim 14, wherein the pharmaceutical product comprises an effective amount of the compound and / or the pharmaceutically acceptable salt and / or the pharmaceutically acceptable solvate for treating the cancer in combination with a second cancer therapy.

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