Benzamidazole diazapinone parp inhibitors and methods of use

Abstract

The present disclosure relates to compounds according to Formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1 is H, F, or Cl; R1 is H, alkyl or cycloalkyl; R2 is H, alkyl, or cycloalkyl; R3 is H, halo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, or N(R4)(R5); and one of R4 and R5 is H, alkyl, cycloalkyl, heterocyclyl, or heteroaryl and the remaining one of R1 and R2 is H or alkyl, or R4 and R5 together with the nitrogen atom to which they are bound are heterocyclyl or heteroaryl. Among other things, the present disclosure evidences compounds of the present disclosure penetrate the central nervous system allowing for treatment of central nervous system cancers.

Description

BENZAMID AZOLE DIAZAPINONE PARP INHIBITORS AND METHODS OF USE FIELD

[0001] The present technology is directed to compounds, compositions, and methods related to treatment of cancer, especially central nervous system cancers, and uses thereof.SUMMARY

[0002] In an aspect, the present technology provides a compound according to Formula Ior a pharmaceutically acceptable salt and / or solvate thereof, wherein X1is H, F, or Cl; R1is H, alkyl, or cycloalkyl; R2is H, alkyl, or cycloalkyl; R3is H, halo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, or N(R4)(R5); and one of R4and R5is H, alkyl, cycloalkyl, heterocyclyl, or heteroaryl and the remaining one of R1and R2is H or alkyl, or R4and R5together with the nitrogen atom to which they are bound are heterocyclyl or heteroaryl.

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

[0004] In a related aspect, a medicament for treating a cancer in a subject is provided that includes a compound of any embodiment disclosed herein and optionally a pharmaceutically acceptable carrier.

[0005] In a related aspect, a pharmaceutical composition is provided that includes (i) an effective amount of a compound of any embodiment disclosed herein, wherein the effective amount of the compound is effective to treat the cancer; and (ii) a pharmaceutically acceptable carrier.

[0006] In a related aspect, a pharmaceutical composition is provided that includes (i) an effective amount of a compound of any embodiment disclosed herein, where the compound is present in an amount effective to treat a cancer when combined with a second cancer therapy; and (ii) a pharmaceutically acceptable carrier.

[0007] In further related aspects, the present technology provides methods including a compound of any aspect or embodiment disclosed herein and / or a composition of any embodiment disclosed herein and / or a medicament of any embodiment disclosed herein. Such methods include a method of treating a subject suffering from a, where the method includes administering to the subject an effective amount of a compound of any embodiment disclosed herein and an effective amount of a second cancer therapy.DETAILED DESCRIPTION

[0008] The following terms are used throughout as defined below.

[0009] As used herein and in the appended claims, singular articles such as “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0010] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term - for example, “about 10 wt.%” would be understood to mean “9 wt.% to 11 wt.%.” It is to be understood that when “about” precedes a term, the term is to be construed as disclosing “about” the term as well as theterm without modification by “about” - for example, “about 10 wt.%” discloses “9 wt.% to 11 wt.%” as well as disclosing “10 wt.%.”

[0011] The phrase “and / or” as used in the present disclosure will be understood to mean any one of the recited members individually or a combination of any two or more thereof - for example, “A, B, and / or C” would mean “A, B, C, A and B, A and C, B and C, or the combination of A, B, and C.”

[0012] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, C14, P32and S35are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0013] In general, “substituted” refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group is substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (z.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (i.e., SFs), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; 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 a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, 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 straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups may be substituted or unsubstituted. Examples of straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

[0016] Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in the ring(s), or, in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted. Exemplary monocyclic cycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. The cycloalkyl group may have 3 to 8 ring members, or the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Bi- and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1 ]hexane, adamantyl, decalinyl, and the like. 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 that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.

[0017] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above. Cycloalkylalkyl groups may be substituted or unsubstituted. In some embodiments, cycloalkylalkyl groups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group. Representative substitutedcycloalkylalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.

[0018] Alkenyl groups include straight and branched chain 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 from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, among others.Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.

[0019] Cycloalkenyl groups include cycloalkyl groups as defined above, having at least one double bond between two carbon atoms. Cycloalkenyl groups may be substituted or unsubstituted. In some embodiments the cycloalkenyl group may have one, two or three double bonds but does not include aromatic compounds. Cycloalkenyl groups have from 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] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0021] Alkynyl groups include straight and branched chain 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 from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to -C=CH, -C=CCH3, -CH2C=CCH3,and -C=CCH2CH(CH2CH3)2, among others. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or trisubstituted with substituents such as those listed above.

[0022] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems. Aryl groups may be substituted or unsubstituted. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups. In some embodiments, the aryl groups are phenyl or naphthyl. The phrase “aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Representative substituted aryl groups may be mono-substituted (e.g., tolyl) or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.

[0023] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Aralkyl groups may be substituted or unsubstituted. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.

[0024] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and nonaromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Heterocyclyl groups may be substituted or unsubstituted. In some embodiments, the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms. In some embodiments, heterocyclyl groups include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups encompass aromatic, partially unsaturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase “heterocyclylgroup” includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. The phrase includes heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members, referred to as “substituted heterocyclyl groups”. Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl,azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.

[0025] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. 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, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl,benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3 -dihydro indolyl groups. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.

[0026] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group. Representative heterocyclyl alkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl -methyl, pyridin-3-yl -methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0027] Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Heteroaralkyl groups may be substituted or unsubstituted. Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group. Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above.

[0028] Groups described herein having two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the compound of the present technology are designated by use of the suffix, “ene.” For example, divalent alkyl groups are alkylene groups, divalent aryl groups are arylene groups, divalent heteroaryl groups are divalent heteroarylene groups, and so forth. Substituted groups having a single point of attachment to the compound of the present technology are not referred to using the “ene” designation. Thus, e.g., chloroethyl is not referred to herein as chloroethylene.

[0029] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by 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, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, secbutoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.

[0030] The terms “alkanoyl” and “alkanoyloxy” as used herein can refer, respectively, to -C(O)-alkyl groups and -O-C(O)-alkyl groups, each containing 2-5 carbon atoms. Similarly, “aryloyl” and “aryloyloxy” refer to -C(O)-aryl groups and -O-C(O)-aryl groups.

[0031] The terms "aryloxy" and “arylalkoxy” refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.

[0032] The term “carboxylate” as used herein refers to a -COOH group.

[0033] The term “ester” as used herein refers to -COOR70and -C(O)O-G groups. R70is 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 one of ordinary skill in the art. An extensive list of protecting groups for the carboxylate group functionality may 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 set forth therein and which is hereby incorporated by reference in its entirety and for any and all purposes as if fully set forth herein.

[0034] The term “amide” (or “amido”) includes C- and N-amide groups, i.e., -C(O)NR71R72, and -NR71C(O)R72groups, respectively. R71and R72are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include butare not limited to carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). In some embodiments, the amide is -NR71C(O)-(CI-5 alkyl) and the group is termed "carbonylamino," and in others the amide is -NHC(O)-alkyl and the group is termed "alkanoylamino."

[0035] The term “nitrile” or “cyano” as used herein refers to the -CN group.

[0036] Urethane groups include N- and O-urethane groups, i.e., -NR73C(O)OR74and -OC(O)NR73R74groups, respectively. R73and R74are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R73may also be H.

[0037] The term “amine” (or “amino”) as used herein refers to -NR75R76groups, wherein R75and R76are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. The amine may be alkylamino, dialkylamino, arylamino, alkylarylamino, NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0038] The term “sulfonamide” includes S- and N-sulfonamide groups, i.e., -SO2NR78R79and -NR78SO2R79groups, respectively. R78and R79are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO2NH2). In some embodiments herein, the sulfonamide is -NHSCh-alkyl and is referred to as the "alkylsulfonylamino" group.

[0039] The term “thiol” refers to -SH groups, while “sulfides” include -SR80groups, “sulfoxides” include -S(O)R81groups, “sulfones” include -SO2R82groups, and “sulfonyls” include -SO2OR83. R80, R81, R82, and R83are each 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, -S-alkyl.

[0040] The term “urea” refers to -NR84-C(O)-NR85R86groups. R84, R85, and R86groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0041] The term “amidine” refers to -C(NR87)NR88R89and -NR87C(NR88)R89, wherein R87, R88, and R89are each independently hydrogen, or a substituted or unsubstituted alkyl,cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0042] The term “guanidine” refers to -NR90C(NR91)NR92R93, wherein R90, R91, R92and R93are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0043] The term “enamine” refers to -C(R94)=C(R95)NR96R97and -NR94C(R95)=C(R96)R97, wherein R94, R95, R96and R97are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0044] The term “halogen” or “halo” as used herein refers to bromine, chlorine, fluorine, or iodine. Preferably, the halogen is fluorine, but the halogen may also be chlorine or bromine.

[0045] The term “hydroxyl” as used herein can refer to -OH or its ionized form, -O . A “hydroxyalkyl” group is a hydroxyl-substituted alkyl group, such as HO-CH2-.

[0046] The term “imide” refers to -C(O)NR98C(O)R99, wherein R98and R99are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0047] The term “imine” refers to -CR100(NR101) and -N(CR100R101) groups, wherein R100and R101are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R100and R101are not both simultaneously hydrogen.

[0048] The term “nitro” as used herein refers to an -NO2 group.

[0049] The term “trifluoromethyl” as used herein refers to -CF3.

[0050] The term “trifluoromethoxy” as used herein refers to -OCF3.

[0051] The term “azido” refers to -N3.

[0052] The term “trialkyl ammonium” refers to a -N(alkyl)3 group. A trialkylammonium group is positively charged and thus typically has an associated anion, such as halogen anion.

[0053] The term “isocyano” refers to -NC.

[0054] The term “isothiocyano” refers to -NCS.

[0055] The term “pentafluorosulfanyl” refers to -SF5.

[0056] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein alsoencompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

[0057] As understood by one of ordinary skill 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 with a weight-average molecular weight of 5,000 has a weight-average molar mass of 5,000 g / mol and a weight-average molar mass of 5,000 Da.

[0058] Pharmaceutically acceptable salts of compounds described herein are within the scope of the present technology and include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable). When the compound of the present technology has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, 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, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the present technology has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na+, Li+, K+, Ca2+, Mg2+, Zn2+), ammonia or organic amines (e.g., di cyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine). Such salts can be prepared in situ during isolation andpurification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed.

[0059] Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or stereoisomerism. As the formula drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, stereochemical or geometric isomeric forms, it should be understood that the present technology encompasses any tautomeric, conformational isomeric, stereochemical and / or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms.

[0060] ‘Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, quinazolinones may exhibit the following isomeric forms, which are referred to as tautomers of each other:As another example, guanidines may exhibit the following isomeric forms in protic organic solution, also referred to as tautomers of each other:Because of the limits of representing compounds by structural formulas, it is to be understood that all chemical formulas of the compounds described herein represent all tautomeric forms of compounds and are within the scope of the present technology.

[0061] Stereoisomers of compounds (also known as optical isomers) include all chiral, diaster eomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diaster eomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[0062] The compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.

[0063] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. Also within this disclosure are Arabic numerals referring to referenced citations, the full bibliographic details of which are provided subsequent to the Examples section. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the present technology.

[0064] The Present Technology

[0065] Poly ADP ribose polymerase 1 (PARP1) is a member of a family of proteins involved in myriad cellular processes such as DNA repair, genomic stability, and programmed cell death. PARP1 is an ADP-ribosyltransferase that uses NAD+ as a substrate to modify proteins — including itself — by PARylation and detects single-strand DNA breaks, playing a significant role in homologous recombination and DNA repair by signaling the enzymatic processes involved in repairing single-strand DNA breaks.

[0066] Several PARP1 inhibitors have been approved for the treatment of breast and ovarian cancers deficient in other mechanisms of DNA repair, and further P ARP inhibitors are currently in clinical trials for the treatment of ovarian cancer, pancreatic and biliary tract malignancies, glioblastoma, lung cancers, and prostatic cancers. BRCAl / 2-deficient cancers areexquisitely sensitive to PARP1 inhibition, where PARP inhibition is lethal in cells with loss-of- function mutations in BRCA1 and BRCA2. Reduced homologous recombination (HR) capacity through other mechanisms also sensitizes cells to PARP inhibitors. Cells lacking defects in DNA repair are typically 1 OOO-fold less susceptible to PARP inhibitors than those with such defects. PARP inhibitors reduce PARylation and trap PARP1 on DNA causing replication fork collapse and cell death.

[0067] Yet current PARP1 inhibitors such as talazoparib, olaparib, rucaparib, and niraparib do not have good central nervous system (CNS) penetration, and veliparib is not efficacious in most tumors. See, e.g., Gupta, Shiv K., etal. "PARP inhibitors for sensitization of alkylation chemotherapy in glioblastoma: impact of blood-brain barrier and molecular heterogeneity" Frontiers in oncology 8 (2019): 670; Kizilbash, S.H. et al. “Restricted delivery of talazoparib across the blood-brain barrier limits the sensitizing effects of PARP inhibition on Temozolomide therapy in glioblastoma” AfoZ. Cancer Ther, 16 (2017): 2735-2746.

[0068] Accordingly, there is a need for PARP inhibitors with improved central nervous system penetration in order to treat brain cancers such as a glioblastoma, a neuroblastoma, and a medulloblastoma.

[0069] The present technology responds to these needs as well as provides additional advantages. According to internal proprietary predictive models, compounds of the present technology were predicted to exhibit desirable blood brain barrier (BBB) permeability. These proprietary predictive models have been verified by in vitro assays well-established to be predictive of BBB permeability in living subject and by in vivo experiments. Accordingly, the present technology provides compounds with advantageously improved central nervous system penetration, as well as compositions and methods especially suited to treatment of central nervous system cancers.

[0070] Thus, in an aspect, the present technology provides a compound according toFormula Ior a pharmaceutically acceptable salt and / or solvate thereof, wherein X1is H, F, or Cl; R1is H, alkyl, or cycloalkyl; R2is H, alkyl, or cycloalkyl; R3is H, halo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, or N(R4)(R5); and one of R4and R5is H, alkyl, cycloalkyl, heterocyclyl, or heteroaryl and the remaining one of R1and R2is H or alkyl, or R4and R5together with the nitrogen atom to which they are bound are heterocyclyl or heteroaryl. For ease of reference, the compounds included in any aspect or embodiment herein may be referred to anywhere in this disclosure as “a compound of the present technology,” “compounds of the present technology,” or the like. Similarly for ease of reference, the compositions, medicaments, and pharmaceutical compositions of the present technology may collectively be referred to herein as “compositions,” “compositions of the present technology,” or the like.

[0071] In any embodiment herein, the compound of Formula I may be of Formula IA

[0072] In any embodiment herein, the compound of Formula I may be of Formula IBpharmaceutically acceptable salt and / or solvate thereof.

[0073] In any embodiment herein, it may be that R1is H and R2is H, Ci-Ce alkyl, or C3- Ce cycloalkyl, or that R1is H, Ci-Ce alkyl, or C3-C6 cycloalkyl and R2is H. In any embodiment herein, X1may be F.

[0074] In any embodiment herein, R3may behalo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R7is H, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; X2is CH, C — alkyl, or N; X3is N — R8, C(R9)(R10), or O; R8is H, alkyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R9is H, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and R10is H, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0075] In any embodiment herein, the compound may be any one of the following or a pharmaceutically acceptable salt and / or solvate thereof:

[0076] In an aspect, a composition is provided that includes a compound of any embodiment disclosed herein, a pharmaceutically acceptable carrier or one or more excipients,fillers or agents (collectively referred to hereafter as “pharmaceutically acceptable carrier” unless otherwise indicated and / or specified). In a related aspect, a medicament for treating a cancer in a subject is provided that includes a compound of any embodiment disclosed herein and optionally a pharmaceutically acceptable carrier. The medicament of any embodiment herein may include an effective amount of the compound for treating the cancer when combined with a second cancer therapy, such as radiation therapy, a monoclonal antibody, and / or a chemotherapeutic. In any embodiment herein, the cancer may be a breast cancer, an ovarian cancer, a pancreatic cancer, a biliary tract cancer, a lung cancer, a prostatic cancer, and / or a CNS cancer (such as a brain cancer). The CNS cancer may be a glioblastoma, a neuroblastoma, and / or a medulloblastoma. In a related aspect, a pharmaceutical composition is provided that includes (i) an effective amount of a compound of any embodiment disclosed herein, wherein the effective amount of the compound is effective to treat a cancer; and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, the cancer may be a breast cancer, an ovarian cancer, a pancreatic cancer, a biliary tract cancer, a lung cancer, a prostatic cancer, and / or a CNS cancer (such as a brain cancer). In any embodiment herein, the cancer may be a breast cancer, an ovarian cancer, a pancreatic cancer, a biliary tract cancer, a lung cancer, a prostatic cancer, and / or a CNS cancer (such as a brain cancer). In a related aspect, a pharmaceutical composition is provided that includes (i) an effective amount of a compound of any embodiment disclosed herein, where the compound is present in an amount effective to treat a cancer when combined with second cancer therapy (such as radiation therapy, a monoclonal antibody, and / or a chemotherapeutic); and (ii) a pharmaceutically acceptable carrier. In any embodiment herein, the cancer may be a breast cancer, an ovarian cancer, a pancreatic cancer, a biliary tract cancer, a lung cancer, a prostatic cancer, and / or a CNS cancer (such as a brain cancer). In further related aspects, the present technology provides methods including a compound of any aspect or embodiment disclosed herein and / or a composition of any embodiment disclosed herein and / or a medicament of any embodiment disclosed herein.

[0077] ‘Effective amount” refers to the amount of a compound or composition required to produce a desired effect. One example of an effective amount includes amounts or dosages that yield acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use including, but not limited to, reduction of a tumor mass. In any aspect or embodiment disclosed herein (collectively referred to herein as “any embodiment herein,” “any embodiment disclosedherein,” or the like) of the compositions, pharmaceutical compositions, and methods including compounds of the present technology, the effective amount may be an amount effective in treating a cancer (such as a breast cancer, an ovarian cancer, a pancreatic cancer, a biliary tract cancer, a lung cancer, a prostatic cancer, and / or a CNS cancer), treating a tumor, and / or shrinking a tumor. By way of example, the effective amount of any embodiment herein including a compound of the present technology may be from about 0.01 pg to about 200 mg of the compound (such as from about 0.1 pg to about 50 mg of the compound or about 10 pg to about 20 mg of the compound). The methods and uses according to the present technology may include an effective amount of a compound of any embodiment disclosed herein. In any aspect or embodiment disclosed herein, the effective amount may be determined in relation to a subject. As used herein, a “subject” or “patient” is a mammal, such as a cat, dog, rodent or primate. Typically the subject is a human, and, preferably, a human suffering from or suspected of suffering from pain. The term “subject” and “patient” can be used interchangeably.

[0078] Thus, the instant present technology provides pharmaceutical compositions and medicaments including a compound of any embodiment disclosed herein (or a composition of any embodiment disclosed herein) and a pharmaceutically acceptable carrier. The compositions may be used in the methods and treatments described herein. The pharmaceutical composition may be packaged in unit dosage form. The unit dosage form may be effective in treating a cancer (such as a breast cancer, an ovarian cancer, a pancreatic cancer, a biliary tract cancer, a lung cancer, a prostatic cancer, and / or a CNS cancer). The unit dosage form may be effective in treating a tumor by reducing a tumor volume when administered to a subject in need thereof. Generally, a unit dosage including a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies and the like. An exemplary unit dosage based on these considerations may also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound of the present technology may vary from 1 x 104g / kg to 1 g / kg, preferably, 1 x ICT3g / kg to 1.0 g / kg. Dosage of a compound of the present 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, gelcaps, capsules, lozenges,suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, mucoadherent films, topical varnishes, lipid complexes, liquids, etc.

[0079] The pharmaceutical compositions and medicaments may be prepared by mixing one or more compounds and / or compositions of the present technology with pharmaceutically acceptable carriers, excipients, binders, diluents or the like. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular, injections. The following dosage forms are given by way of example and should not be construed as limiting the instant present technology.

[0080] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or antioxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.

[0081] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.

[0082] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.

[0083] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[0084] For injection, the pharmaceutical formulation and / or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.

[0085] Compounds of the present 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 appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars and / or sugar alcohols. Aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols are typically used for delivery of compounds of the present technology by inhalation.

[0086] Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds of the present technology include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required. Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Absorption enhancers can also be used to increase the flux of the compounds of the present technology across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane (e.g., as part of a transdermal patch) or dispersing the compound in a polymer matrix or gel.

[0087] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant present technology. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0088] The formulations of the present technology may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.

[0089] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and / or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.

[0090] Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant present technology.

[0091] Those skilled in the art are readily able to determine an effective amount by simply administering a compound of the present technology to a patient in increasing amounts until, for example, there is a reduction in the mass of a tumor in a subject. The compounds of the present technology can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is sufficient. The specific dosage used, however, can vary or may be adjusted as considered appropriate by those of ordinary skill in the art. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the B-cell malignancy (e.g., nonHodgkin lymphoma or chronic lymphocytic leukemia) associated with the tumor, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

[0092] Various assays and model systems can be readily employed to determine the therapeutic effectiveness of the treatment according to the present technology. Effectiveness of the compositions (as well as determination of effective amounts) and methods of the present technology may also be demonstrated by a decrease in the mass of a tumor and / or slowing the growth of a tumor and / or affecting an increase in the therapeutic responsiveness of a cancer to a second cancer therapy (such as a radiation therapy, a monoclonal antibody, and / or a chemotherapeutic).

[0093] For each of the indicated conditions described herein, test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%, or 95% or greater, reduction, in one or more symptom(s) caused by, or associated with, the disorder in the subject, compared to placebo-treated or other suitable control subjects.

[0094] The compounds of the present technology can also be administered to a patient along with other conventional therapeutic agents that may be useful in the treatment of tumors or in vaccination. The administration may include oral administration, parenteral administration, or nasal administration. In any of these embodiments, the administration may include intratumoral injections, subcutaneous injections, intravenous injections, intraperitoneal injections, or intramuscular injections. In any of these embodiments, the administration may include oraladministration. The methods of the present technology can also include administering, either sequentially or in combination with one or more compounds of the present technology, a conventional therapeutic agent in an amount that can potentially or synergistically be effective for the treatment a cancer (e.g., a breast cancer, an ovarian cancer, a pancreatic cancer, a biliary tract cancer, a lung cancer, a prostatic cancer, and / or a CNS cancer).

[0095] In one aspect, a compound of the present technology is administered to a patient in an amount or dosage suitable for therapeutic use. Generally, a unit dosage comprising a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapies and the like. An exemplary unit dosage based on these considerations can also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound of the present technology can vary from 1 x 104g / kg to 1 g / kg, preferably, 1 x 10 g / kg to 1.0 g / kg. Dosage of a compound of the present technology can also vary from 0.01 mg / kg to 100 mg / kg or, preferably, from 0.1 mg / kg to 10 mg / kg.

[0096] A compound of the present technology can also be modified, for example, by the covalent attachment 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 polymeric group, fatty acid group or fatty acid ester group. A polymeric group can comprise a molecular weight that can be adjusted by one of ordinary skill in the art to improve, for example, pharmacokinetic properties, toxicity or bioavailability. Exemplary conjugates can include a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymer, amino acid polymer or polyvinyl pyrrolidone and a fatty acid or fatty acid ester group, each of which can independently comprise from about eight to about seventy carbon atoms. Conjugates for use with a compound of the present technology can also serve as linkers to, for example, any suitable substituents or groups, radiolabels (marker or tags), halogens, proteins, enzymes, polypeptides, other therapeutic agents (for example, a pharmaceutical or drug), nucleosides, dyes, oligonucleotides, lipids, phospholipids and / or liposomes. In one aspect, conjugates can include polyethylene amine (PEI), polyglycine, hybrids of PEI and polyglycine, polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG). A conjugate can also link a compound of the present technology to, for example, a label(fluorescent or luminescent) or marker (radionuclide, radioisotope and / or isotope) to comprise a probe of the present technology. Conjugates for use with a compound of the present technology can, in one aspect, improve in vivo half-life. Other exemplary conjugates for use with a compound of the present technology as well as applications thereof and related techniques include those generally described by U.S. Patent No. 5,672,662, which is hereby incorporated by reference herein.

[0097] In another aspect, the present technology provides methods of identifying a target of interest including contacting the target of interest with a detectable or imaging effective quantity of a labeled compound of the present technology. A detectable or imaging effective quantity is a quantity of a labeled compound of the present technology necessary to be detected by the detection method chosen. For example, a detectable quantity can be an administered amount sufficient to enable detection of binding of the labeled compound to a target of interest. Suitable labels are known by those skilled in the art and can include, for example, radioisotopes, radionuclides, isotopes, fluorescent groups, biotin (in conjunction with streptavidin complexation), and chemiluminescent groups. Upon binding of the labeled compound to the target of interest, the target may be isolated, purified and further characterized such as by determining the amino acid sequence.

[0098] The terms “associated” and / or “binding” can mean a chemical or physical interaction, for example, between a compound of the present technology and a target of interest. Examples of associations or interactions include covalent bonds, ionic bonds, hydrophilic- hydrophilic interactions, hydrophobic-hydrophobic interactions and complexes. Associated can also refer generally to “binding” or “affinity” as each can be used to describe various chemical or physical interactions. Measuring binding or affinity is also routine to those skilled in the art. For example, compounds of the present technology can bind to or interact with a target of interest or precursors, portions, fragments and peptides thereof and / or their deposits.

[0099] As indicated previously in this disclosure, in an aspect a method of treating a subject suffering from a cancer is provided, where the method includes administering to the subject an effective amount of a compound of any embodiment disclosed herein or administering an effective amount of a composition of any embodiment disclosed herein, and optionally an effective amount of second cancer therapy. In any embodiment herein, the cancer may be abreast cancer, an ovarian cancer, a pancreatic cancer, a biliary tract cancer, a lung cancer, a prostatic cancer, and / or a CNS cancer (such as a brain cancer).

[0100] In any embodiment herein, the administering may further include administration of a radiation therapy, a monoclonal antibody, and / or a chemotherapeutic (such as an alkylating agent; a nitrosourea; an antimetabolite; an anthracycline; a topoisomerase II inhibitor; a mitotic inhibitor; an anti-estrogen; a progestin; an aromatase inhibitor; an anti-androgen; an LHRH agonist; a corticosteroid hormone; a DNA alkylating agent; a taxane; a vinca alkaloid; a microtubule poison, or a combination of any two or more thereof. In any embodiment herein, the administering may further include administration of a chemotherapeutic agent such as busulfan, cisplatin, carboplatin, oxaliplatin, an octahedral platinum (IV) compound, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), mechlorethamine (nitrogen mustard), melphalan, temozolomide, carmustine (BCNU), lomustine (CCNU), 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine, pemetrexed, daunorubicin, doxorubicin (Adriamycin), epirubicin, idarubicin, mitoxantrone, topotecan, irinotecan, etoposide (VP- 16), teniposide, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, prednisone, dexamethasone, L-asparaginase, dactinomycin, thalidomide, tretinoin, imatinib (Gleevec), gefitinib (Iressa), erlotinib (Tarceva), rituximab (Rituxan), bevacizumab (Avastin), ipilimumab, nivolumab (Opdivo), pembrolizumab (Ketruda), tamoxifen, fulvestrant, anastrozole, exemestane, letrozole, megestrol acetate, bicalutamide, flutamide, leuprolide, goserelin, or a combination of any two or more thereof).

[0101] In any embodiment herein, the administering may include oral, rectal, nasal, vaginal, parenteral, transdermal, intravenous, intramuscular, or inhalation administration. In any embodiment herein, the administering may include local administration of the compound to a site in the subject including the cancer or local administration of the composition to a site in the subject including the cancer.

[0102] The examples herein are provided to illustrate advantages of the present technology and to further assist a person of ordinary skill in the art with preparing or using the compounds and compositions of the present technology. The examples herein are also presented in order to more fully illustrate the preferred aspects of the present technology. The examples should in no way be construed as limiting the scope of the present technology, as defined by the appended claims. The examples can include or incorporate any of the variations, aspects, orembodiments of the present technology described above. The variations, aspects, or embodiments described above may also further each include or incorporate the variations of any or all other variations, aspects, or embodiments of the present technology.EXAMPLES

[0103] All solvents and reagents were used as received from commercial suppliers, unless noted otherwise.JH spectra were recorded on a Bruker AM or Varian 400 spectrometer (operating at 400 MHz respectively) in CDCh with 0.03% TMS as an internal standard. The chemical shifts (8) reported are given in parts per million (ppm) and the coupling constants (J) are in Hertz (Hz). The spin multiplicities are reported as s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, and m = multiplet. The LCMS analysis was performed on a chromatograph with photodiode array UV detection and a TOF mass spectrometer. The mass spectrometer utilized a multimode source which simultaneously acquires ESI+ / APCI+; a reference mass solution; and a make-up solvent which was introduced to the LC flow prior to the source to assist ionization. While single stereoisomers were isolated and obtained in high purity where indicated in the below examples, a final unambiguous assignment of absolute stereochemistry may be pending for certain sets of stereoisomers.

[0104] Exemplary Synthesis of Certain Compounds of the Present Technology:

[0105] Synthesis of Compound 2303 and Compound 25352303 2535

[0106] To a solution of 2-bromo-5-fluoro-3 -nitrobenzoic acid (25 g, 0.095 mol) in MeOH (300 mL) was added thionyl chloride (30 mL) at 0 °C. The reaction was then brought to room temperature, followed by refluxing for 12 h. The reaction mixture was then cooled to room temperature, and the solvent was evaporated under vacuum. The residue was washed with saturated NaHCO, (200 x 3 mL) and extracted with EA (200 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatographyon silica (PE: EA=10: l) to afford methyl 2-bromo-5-fluoro-3 -nitrobenzoate (25 g, 95%) as a yellow solid. MS (ESI): mass calcd. for CsHsBrFNC , 276.9, m / z found TH.9 [M+H]+.

[0107] To a solution of methyl 2-bromo-5-fluoro-3 -nitrobenzoate (25 g, 89.9 mmol) and Na2CO3(19 g, 179.8 mmol) in 1-Butanol (300 mL) was added ethylenediamine (8.1 g, 134.8 mmol). The reaction mixture was stirred at 80 °C for 12 h. The mixture was concentrated. The residue was purified by flash chromatography on silica (DCM: MeOH=10: 1) to afford 7-fluoro- 9-nitro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5-one (12 g, 60%) as an orange solid. MS (ESI): mass calcd. for C9H8FN3O3, 225.1, m / z found 226.1 [M+H]+.

[0108] A mixture of 7-fluoro-9-nitro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5- one (12 g, 0.053 mol) and Pd / C (2 g) in EA / AcOH (4: 1, 200 mL) was stirred under 2 atm of H2 at room temperature for 12 h. When the reaction was completed, the solids were filtered out. The filtrate was concentrated to afford crude which was purified by silica gel column chromatography eluted with DCM / MeOH (10: 1) to afford 9-amino-7-fluoro-l,2,3,4-tetrahydro- 5H-benzo[e] [1,4] diazepin-5-one (6 g, 58%) as a yellow solid. MS (ESI): mass calcd. for C9HIOFN30, 195.1, m / z found 196.1 [M+H]+.

[0109] To a solution of 9-amino-7-fluoro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin- 5-one (100 mg, 0.51 mmol) in MeOH (5 mL) was added cyanogen bromide (80 mg, 0.76 mmol). The reaction mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was cooled, and the solvent was evaporated under reduced pressure. The crude product was purified by RP- C18 column eluted with H2O (0.5% FA) / CH3CN (100:0— >50:50) to afford l-amino-4-fluoro-8,9- dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Compound 2303; 80 mg, 71%) as a white solid. MS (ESI): mass calcd. for C10H9FN4O, 220.1, m / z found 221.1 [M+H]+.

[0110] To a solution of l-amino-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen- 6(7H)-one (80 mg, 0.36 mmol) in DMF (2 mL) were added Cs2CO3(352 mg, 1.08 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (130 mg, 0.72 mmol). The reaction mixture was stirred at 100 °C for 16 h. Upon completion, the mixture was cooled, and the solvent was evaporated under reduced pressure. The crude product was purified by RP-C18 column eluted with H2O (0.5% FA) / CH3CN ( 100:0^50:50) to afford 4-fluoro-l-((tetrahydro-2H-pyran-4- yl)amino)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Compound 2535; 10 mg, 10%) as a white solid. MS (ESI): mass calcd. for C15H17FN4O2, 304.1, m / z found 305.1 [M+H]+. 'H NMR (400 MHz, CD3OD-r / 4) 87.61 - 7.58 (m, 1H), 7.40 - 7.38 (m, 1H), 4.15 - 4.03 (m, 4H),3.86 - 3.81 (m 1H), 3.75 - 3.73 (m, 2H), 3.57 - 3.51 (m, 2H), 2.06 - 2.02 (m, 2H), 1.83 - 1.73 (m, 2H).

[0111] Synthesis of Compound 3801

[0113] To a solution of l-bromo-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (100 mg, 0.35 mmol) in EtOH (5 mL) was added 1 -methylpiperidin-4-amine (402 mg, 3.5 mmol). The mixture was heated under microwave irradiation at 100 °C for 3 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by RP-C18 column eluted with H2O (0.1% TFA) / CH3CN (100:0— >50:50) to afford 4-fluoro-l-((l- methylpiperidin-4-yl) amino)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (20 mg, 18%) as a yellow oil. MS (ESI): mass calcd. for C16H20FN5O, 317.1, m / z found 318.1 [M+H]+.JH NMR (400 MHz, MeOD-4) 8 7.63 (d, J= 10.0 Hz, 1H), 7.48 (d, J= 6.4 Hz, 1H), 4.19 - 4.03 (m, 3H), 3.76 - 3.64 (m, 4H), 3.47 (s, 1H), 3.24 - 3.12 (m, 2H), 2.95 (s, 3H), 2.41 - 2.27 (m, 3H), 2.07 - 1.95 (m, 2H).

[0114] Synthesis of Compound 3802

[0115] To a solution of l-bromo-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen- 6(7H)-one (50 mg, 0.17 mmol) in DMSO (2 mL) were added CS2CO3 (86 mg, 0.26 mmol), CsF (40 mg, 0.26 mmol), and 5-oxaspiro [3.5] nonan-8-amine (75 mg, 0.53 mmol). The reaction mixture was stirred at 100 °C for 16 h. Upon completion, the solids were filtered out. The filtrate was purified by RP-C18 column eluted with H2O (0.1% FA) / CH3CN (100:0— >50:50) to afford 1- ((5-oxaspiro [3.5] nonan-8-yl) amino)-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)- one (12.6 mg, 21%) as a white solid. MS (ESI): mass calcd. for C18H21FN4O2, 344.1, m / z found 345.1 [M+H]+.XH NMR (400 MHz, MeOD-r / 4) 8 7.35 - 7.32 (m, 1H), 7.21 - 7.18 (m, 1H), 4.08- 4.00 (m, 3H), 3.83 - 3.79 (m, 1H), 3.71 - 3.60 (m, 3H), 2.35 - 2.29 (m, 2H), 2.18 - 1.94 (m, 4H),1.89 - 1.70 (m, 2H), 1.58 - 1.48 (m, 2H).

[0116] Synthesis of Compound 3819

[0117] To a solution of l-bromo-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen- 6(7H)-one (100 mg, 0.35 mmol) in DMSO (2 mL) were added CS2CO3 (172 mg, 0.53 mmol), CsF (80 mg, 0.53 mmol) and 7-oxabicyclo [2.2.1] heptan-2 -amine (40 mg, 0.35 mmol). The reaction mixture was stirred at 100 °C for 16 h. Upon completion, the solids were filtered out. The filtrate was purified by RP-C18 column eluted with H2O (0.1% FA) / CH3CN (100:0— >50:50) to afford 1 -((7-oxabicyclo [2.2.1] heptan-2-yl) amino)-4-fluoro-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (32.7 mg, 29%) as a white solid. MS (ESI): mass calcd. for C16H17FN4O2, 316.1, m / z found 317.1 [M+H]+. 'H NMR (400 MHz, DMSO- e) 8 8.35 (t, J = 5.6 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.18 - 7.15 (m, 1H), 6.84 (d, J= 6.4 Hz, 1H), 4.58 (t, J = 4.8 Hz, 1H), 4.45 (d, J= 5.2 Hz, 1H), 4.01 (s, 2H), 3.91 - 3.88 (m, 1H), 3.82 - 3.64 (m, 2H), 1.99 - 1.93 (m, 1H), 1.71 - 1.68 (m, 1H), 1.60 - 1.39 (m, 4H).

[0118] Synthesis of Compound 3650

[0119] To a solution of 2-bromo-5-fluoro-3 -nitrobenzoic acid (25 g, 0.095 mol) in MeOH (300 mL) was added Thionyl chloride (30 mL) at 0 °C. The reaction was stirred at reflux for 12 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was diluted with saturated NaHCO, (200 x 3 mL) and extracted with EA (200 mL x 3). The organic layer was dried over Na2SC>4, filtered and concentrated. The residue was purified by flash chromatography on silica (PE: EA=10: 1) to afford methyl 2- bromo-5-fluoro-3 -nitrobenzoate (25 g, 95%) as a yellow solid. MS (ESI): mass calcd. for C8H5BrFNO4, 276.9, m / z found 277.9 [M+H]+.

[0120] To a solution of methyl 2-bromo-5-fluoro-3 -nitrobenzoate (25 g, 89.9 mmol) and Na2CCh (19 g, 179.8 mmol) in 1 -Butanol (300 mb) was added Ethylenediamine (8.1 g, 134.8 mmol). The reaction mixture was stirred at 80 °C for 12 h. The mixture was concentrated. The residue was purified by flash chromatography on silica (DCM: MeOH=10: 1) to afford 7-fluoro- 9-nitro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5-one (12 g, 60%) as an orange solid. MS (ESI): mass calcd. for C9H8FN3O3, 225.1, m / z found 226.1 [M+H]+.

[0121] A mixture of 7-fluoro-9-nitro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5- one (12 g, 0.053 mol) and Pd / C (2 g) in EA / AcOH (4: 1, 200 mL) was stirred under 2 atm of H2 at room temperature for 12 h. When the reaction was completed, the solids were filtered out. The filtrate was concentrated to afford crude which was purified by silica gel column chromatography eluted with DCM / MeOH (10: 1) to afford 9-amino-7-fluoro-l,2,3,4-tetrahydro- 5H-benzo[e] [1,4] diazepin-5-one (6 g, 58%) as a yellow solid. MS (ESI): mass calcd. for C9H10FN3O, 195.1, m / z found 196.1 [M+H]+.

[0122] To a solution of 9-amino-7-fluoro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin- 5-one (100 mg, 0.51 mmol) in MeOH (5 mL) was added BrCN (80 mg, 0.76 mmol). The reaction mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was cooled, and the solvent was evaporated under reduced pressure. The crude product was purified by RP-C18 column eluted with H2O (0.5% FA) / CH3CN (100:0— >-50:50) to afford l-amino-4-fluoro-8,9- dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (80 mg, 71%) as a white solid. MS (ESI): mass calcd. for C10H9FN4O, 220.1, m / z found 221.1 [M+H]+.

[0123] To a solution of 2-amino-6-fluoro-l,3,10-triazatricyclo[6.4.1.0A{4,13}]trideca- 2,4,6,8(13)-tetraen-9-one (50 mg, 0.2271 mmol) in DMF (2.5 mL) were added CS2CO3 (221.98 mg, 0.6813 mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (130 mg, 0.72 mmol) and Pd- PEPPSI-IPent (9.54 mg, 0.0113 mmol). The reaction mixture was stirred under N2 at 100 °C for 16 h. Upon completion, the mixture was cooled, and the solvent was evaporated under reduced pressure. The crude product was purified by Flash Chromatography with OUCb / MeOH ( 100:0— >30: 1 ) to afford 6-fhroro-2-(isopropylamino)-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (11 mg, 19%) as a white solid. MS (ESI): mass calcd. for C13H15FN4O, 262.29, m / z found 263.0 [M+H]+. 'H NMR (400 MHz, MeOD) 8 7.20 - 7.17 (m, 1H), 7.07 - 7.04 (m, 1H), 4.02 - 3.95 (m, 3H), 3.57 - 3.55 (m, 2H), 1.21 (d, J= 6.4 Hz, 6H).

[0124] Synthesis of Compound 3654 and Compound epz-36543654 epz-3654

[0125] To a solution of methyl 2-bromo-5-fluoro-3 -nitrobenzoate (2 g, 7.2 mmol) and Na2CCh (3.05 g, 28.8 mmol) in 1 -Butanol (20 mL) was added 1 -(4-fluorophenyl) ethane-1,2- diamine (1.11 g, 7.2 mmol). The reaction mixture was stirred at 85 °C for 12 h. The mixture was concentrated. The residue was purified by flash chromatography on silica (PE: EA=1: 1) to afford 7-fluoro-2-(4-fluorophenyl)-9-nitro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5-one (0.9 g, 39%) as an orange solid. MS (ESI): mass calcd. for C15H11F2N3O3, 319.0, m / z found 320.0 [M+H]+.

[0126] To a solution of 7-fhioro-2-(4-fluorophenyl)-9-nitro-l,2,3,4-tetrahydro-5H- benzo[e] [1,4] diazepin-5-one (420 mg, 1.32 mmol) in AcOH (10 mL) was added Fe (441 mg, 7.89 mmol). The reaction mixture was stirred at 25 °C for 16 h. When the reaction was completed, the solids were filtered out. The filtrate was concentrated to afford crude, which was purified by silica gel column chromatography eluted with MeOH / DCM (10:1) to afford 9-amino- 7-fhioro-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5-one (200 mg, 52%) as a yellow solid. MS (ESI): mass calcd. for C15H13F2N3O, 289.1, m / z found 290.1 [M+H]+.

[0127] To a solution of 9-amino-7-fluoro-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-5H- benzo[e] [1,4] diazepin-5-one (100 mg, 0.35 mmol) in EtOH (2 mL) were added Na2S20s (78 mg, 0.41 mmol) and tert-butyl (R)-2-formylpyrrolidine-l -carboxylate (83 mg, 0.41 mmol). The mixture was stirred at 80 °C for 16 hours. The residue was concentrated in vacuo and extracted with EA (10 mLx2). The organic phase was washed with brine (10 mLx3), dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica (MeOH: DCM=10:l) to afford tert-butyl (2R)-2-(4-fluoro-9-(4- fluorophenyl)-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azulen-l-yl) pyrrolidine- 1- carboxylate (80 mg, 49%) as a yellow solid. MS (ESI): mass calcd. for C25H26F2N4O3, 468.2, m / z found 469.2 [M+H]+.

[0128] To a solution of tert-butyl (2R)-2-(4-fluoro-9-(4-fluorophenyl)-6-oxo-6, 7,8,9- tetrahydro-2,7,9a-triazabenzo[cd]azulen-l-yl) pyrrolidine- 1 -carboxylate (80 mg, 0.17 mmol) in EA (0.5 mL) was added 4 N HC1 in ethyl acetate (0.5 m ). The mixture was stirred at 25 °C for 4 hours. Upon completion, the mixture was concentrated under reduced pressure to afford 4- fluoro-9-(4-fluorophenyl)-l-((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen- 6(7H)-one (30 mg, 47%) as a yellow solid. MS (ESI): mass calcd. for C20H18F2N4O, 368.1, m / z found 369.1 [M+H]+.

[0129] 4-fluoro-9-(4-fluorophenyl)- 1 -((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (30 mg) was split by prep-SFC to give (S)-4-fluoro-9-(4- fluorophenyl)-l-((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Compound 3654; 12 mg, 40%) and (R)-4-fluoro-9-(4-fluorophenyl)-l-((R)-pyrrolidin-2-yl)-8,9- dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Compound epz-3654; 8 mg, 27%) as a white solid.

[0130] Compound 3654: MS (ESI): mass calcd. for C20H18F2N4O, 368.1, m / z found 369.1 [M+H]+. 'H NMR (400 MHz, CD3OD-74) 8 7.77 - 7.74 (m, 1H), 7.50 - 7.04 (m, 5H), 5.15 (s, 1H), 4.66 - 4.63 (m, 1H), 4.49 - 4.45 (m, 1H), 3.14 - 2.94 (m, 2H), 2.22 - 1.29 (m, 4H), 1.29 (m, 1H), 1.20 - 0.79 (m, 1H).

[0131] Compound epz-3654: MS (ESI): mass calcd. for C20H18F2N4O, 368.1, m / z found 369.1 [M+H]+.1H NMR (400 MHz, CD3OD-74) 87.74 - 7.71 (m, 1H), 7.49 - 7.03 (m, 5H), 5.13 (s, 1H), 4.65 - 4.62 (m, 1H), 4.47 (t, 7 = 7.2 Hz, 1H), 3.08 (s, 1H), 2.99 - 2.93 (m, 1H), 2.25 - 2.12 (m, 2H), 1.97 - 1.88 (m, 2H), 1.28 (s, 1H), 1.16 - 0.87 (m, 1H).

[0132] Synthesis of Compound 3806 and Compound 38073806 3807

[0133] To a solution of methyl 2-bromo-5-fluoro-3 -nitrobenzoate (2.78 g, 0.01 mol) in 1- tutanol (80 mL) was added l-cyclopropylethane-l,2-diamine (1 g, 0.01 mol) and Na2CO3(4.24 g, 0.04 mol). The reaction mixture was stirred at 85 °C under N2 for 16 h. The mixture wasconcentrated. The residue was purified by flash chromatography on silica (PE: EA=1: 1) to afford 2-cyclopropyl-7-fluoro-9-nitro-l,2,3,4-tetrahydro-l,4-benzodiazepin-5-one (550 mg, 21%) as an orange solid. MS (ESI): mass calcd. for C12H12FN3O3, 265.2, m / z found 266.0 [M+H]+.

[0134] A mixture of 2-cyclopropyl-7-fluoro-9-nitro-l, 2, 3, 4- tetrahydro-1, 4- benzodiazepin-5-one (550 mg, 2.0736 mmol) and Pd / C (50 mg) in MeOH (10 mL) was stirred under 2 atm of H2 at room temperature for 16 h. When the reaction was completed, the solids were filtered out. The filtrate was concentrated to afford crude product which was purified by silica gel column chromatography eluted with DCM / MeOH (10: 1) to afford 9-amino-2- cyclopropyl-7-fluoro-l,2,3,4-tetrahydro-l,4-benzodiazepin-5-one (436 g, 90%) as an orange solid. MS (ESI): mass calcd. for C12H14FN3O, 235.1, m / z found 236.1 [M+H]+.

[0135] To a solution of 9-amino-2-cyclopropyl-7-fluoro-l,2,3,4-tetrahydro-l,4- benzodiazepin-5-one (436 mg, 1.8533 mmol) in EtOH / H2O (8 mL) was added tert-butyl (2- formylpyrrolidin-l-yl) formate (556 mg, 2.7799 mmol) and NaHSCh (771 mg, 7.4132 mmol). The reaction mixture was stirred at 60 °C under air for 4 h. The reaction mixture was quenched with saturated NaHCCb (20 mL x 3) and extracted with EA (20 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica (DCM: MeOH=10:l) to afford tert-butyl (2R)-2-(9-cyclopropyl-4-fluoro-6-oxo-6, 7,8,9- tetrahydro-2,7,9a-triazabenzo[cd]azulen-l-yl)pyrrolidine-l-carboxylate (677 mg, 87%) as a white solid. MS (ESI): mass calcd. for C22H27FN4O3, 414.2, m / z found 415.1 [M+H]+.

[0136] The mixture of tert-butyl (2R)-2-(9-cyclopropyl-4-fluoro-6-oxo-6, 7,8,9- tetrahydro-2,7,9a-triazabenzo[cd]azulen-l-yl)pyrrolidine-l-carboxylate (300 mg, 0.7238 mmol) in HC1 / EA (4 ml, 4 N) was stirred at 25 °C for 0.5 h. When the reaction was completed, the solids were filtered out. The filtrate cake was concentrated to afford 9-cyclopropyl-4-fluoro-l- ((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (200 mg, 87%) as a white solid. MS (ESI): mass calcd. for C17H19FN4O, 314.1, m / z found 315.1 [M+H]+.

[0137] 9-cyclopropyl-4-fluoro-l-((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (200 mg) was split by prep-SFC to give (S)-9-cyclopropyl-4- fhioro-l-((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Compound 3806, 100 mg, 50%) and (R)-9-cyclopropyl-4-fluoro-l-((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (Compound 3807, 20 mg, 10%) as a yellow solid.

[0138] Compound 3806: MS (ESI): mass calcd. for C17H19FN4O, 314.2, m / z found 315.2 [M+H]+. 'H NMR (400 MHz, DMSO- G) 8 8.61 (s, 1H), 7.66 - 7.64 (m, 1H), 7.59 (d, J = 10.6 Hz, 1H), 4.53 - 4.41 (m, 3H), 3.02 - 2.90 (m, 2H), 2.88 - 2.82 (m, 1H), 2.17 - 2.12 (m, 2H), 1.89 - 1.70 (m, 2H), 0.79 (s, 1H), 0.58 - 0.28 (m, 4H).

[0139] Compound 3807: MS (ESI): mass calcd. for C17H19FN4O, 314.2, m / z found 315.2 [M+H]+. 'H NMR (400 MHz, DMSO- G) 89.68 (s, 1H), 8.70 (s, 1H), 7.79 - 7.76 (m, 1H), 7.68 (d, J= 9.5 Hz, 1H), 5.10 (t, J= 7.5 Hz, 1H), 4.49 (s, 2H), 3.02 (d, J= 5.1 Hz, 1H), 2.43 - 2.40 (m, 3H), 2.33 (s, 1H), 2.11 - 2.00 (m, 2H), 0.85 (s, 1H), 0.48 - 0.37 (m, 4H).

[0140] Synthesis of Compound 4859

[0141] To the mixture of 2-bromo-5-fluoro-3 -nitrobenzoic acid (3.26 g, 0.0123 mol) in DMF (50 mL) was added HATU (4.7 g, 0.0123 mol). After stirring for 30 minutes at 25 °C, to the reaction mixture was added [(2R)-l-aminopropan-2-yl] amino tert-butyl formate (1.8 g, 0.0103 mol) and DIEA (6.66 g, 0.0515 mol). The reaction mixture was stirred at 25 °C for additional 6 h. When the reaction was completed, the mixture was poured into water. The solids were filtered out to afford [(2R)-l-[(2-bromo-5-fluoro-3-nitrophenyl)formamido]propan-2- yl]amino tert-butyl formate (3.5 g, 80%) as a yellow solid. MS (ESI): mass calcd. for Ci5Hi9BrFN3O5419.0, m / z found 442.0 [M+Na]+.

[0142] The mixture of [(2R)-l-[(2-bromo-5-fluoro-3-nitrophenyl)formamido]propan-2- yl] amino tert- butyl formate (3.5 g, 8.3 mmol) in HC1 / EA (40 ml) was stirred at 0 °C for 4 h. When the reaction was completed, the solids were filtered out. The filtrate cake was concentrated to afford methyl N-[(2R)-2-aminopropyl]-2-bromo-5-fluoro-3-nitrobenzamide (2 g, 75%) as a yellow solid. MS (ESI): mass calcd. for CioHnBrFNsCh, 319.0, m / z found 320.0 [M+H]+.

[0143] To the solution of N-[(2R)-2-aminopropyl]-2-bromo-5-fluoro-3-nitrobenzamide (2 g, 0.0062 mol) in DMSO (30 mL) was added CsF (0.38 g, 0.0024 mol) and TEA (1.57 g, 0.0155 mol) at 100°C for 12 h. Upon completion, the residue was quenched with water (100 mL) and extracted with EA (200 mL x 3) and washed with saturated H2O (200 x 3 mL). The organic layer was dried over Na2SC>4, filtered and concentrated. The residue was purified by flashchromatography on silica (PE: EA=1:1) to afford (2R)-7-fhroro-2-methyl-9-nitro-l, 2,3,4- tetrahydro-l,4-benzodiazepin-5-one (0.36 g, 28%) as an orange solid. MS (ESI): mass calcd. for C10H10FN3O3, 239.1, m / z found 240.1 [M+H]+.

[0144] To a solution of (2R)-7-fluoro-2-methyl-9-nitro-l,2,3,4-tetrahydro-l,4- benzodiazepin-5-one (360 mg, 1.505 mmol) in EA / AcOH (5 mL) was added Pd / C (80 mg, 0.7525 mmol) under N2. The mixture was stirred under balloon pressure of H2 at 25 °C for 12 h. When the reaction was completed, the solids were filtered out. The filtrate was concentrated to afford the residue which was purified by silica gel column chromatography eluted with DCM / MeOH (10: 1) to afford (2R)-9-amino-7-fluoro-2-methyl-l,2,3,4-tetrahydro-l,4- benzodiazepin-5-one (250 mg, 79%) as a grey solid. MS (ESI): mass calcd. for C10H12FN3O, 209.1, m / z found 210.1 [M+H]+.

[0145] To a solution of (2R)-9-amino-7-fluoro-2-methyl- 1,2,3, 4-tetrahydro- 1,4- benzodiazepin-5-one (250 mg, 1.1949mmol) in MeOH (5 mL) was added BrCN (189 mg, 1.7923 mmol). The reaction mixture was stirred at 50 °C for 12 h. Upon completion, the mixture was evaporated under reduced pressure to afford (12R)-2-amino-6-fluoro-12-methyl-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (250 mg, 89%) as an orange solid. MS (ESI): mass calcd. for C11H11FN4O, 234.1, m / z found 235.1 [M+H]+.

[0146] To a solution ofA{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (250 mg, 1.0673 mmol) and CuBn (476 mg, 2.1346 mmol) in MeCN (5 mL) was added tert-Butyl nitrite (220 mg, 2.1346 mmol). The reaction mixture was stirred at 65 °C for 6 h. When the reaction was completed, the solids were filtered out. The residue was quenched with water (100 mL) and extracted with EA (100 mL x 3). The organic layer was dried over Na2SC>4, filtered and concentrated. The residue was purified by flash chromatography on silica (MeOH: DCM = 10:1) to ( 12R)-2-bromo-6-fluoro- 12-methy 1- 1,3,10-triazatricy clo[6.4.1.0A{4, 13 } ]trideca-2,4, 6, 8( 13)- tetraen-9-one (230 mg, 72%) as a yellow solid. MS (ESI): mass calcd. for CuHrBrFlShO, 297.0, m / z found 298.0 [M+H]+.

[0147] To the solution of (12R)-2-bromo-6-fhroro-12-methyl-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one(50 mg, 0.1677mmol) in DMSO (ImL) was added Morpholine (29 mg, 0.3354mmol), CsF (38 mg, 0.2515 mmol) and CS2CO3 (82 mg, 0.2515 mmol) at 100°C under air for 16 h. Upon completion, the solid was filtered out at room temperature. The filtrate was purified by RP-C18 column eluted with H2O (0.5%FA) / CH3CN (100:0— >50:50) to afford (12R)-6-fluoro-12-methyl-2-(morpholin-4-yl)-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (20 mg, 39%) as a yellow solid. MS (ESI): mass calcd. for C15H17FN4O2, 304.2, m / z found 305.2 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.38 - 8.35 (m, 1H), 7.55 - 7.52 (m, 1H), 7.48 - 7.45 (m, 1H), 4.80 - 4.74 (m, 1H), 3.83 - 3.74 (m, 4H), 3.55 - 3.51 (m, 1H), 3.47 - 3.40 (m, 1H), 3.27 - 3.21 (m, 4H), 1.31 (d, J = 8.0 Hz, 3H).

[0148] Synthesis of Compound 4950

[0149] To the solution of (12R)-2-bromo-6-fhroro-12-methyl-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (50 mg, 0.1677mmol) in DMSO (ImL) was added 4,4-difluoropiperidine (40 mg, 0.3354mmol), CsF (38 mg, 0.2515 mmol) and CS2CO3 (82 mg, 0.2515 mmol). The mixture was stirred at 100°C under air for 16 h. Upon completion, the solids were filtered out. The filtrate was purified by RP-C18 column eluted with H2O (0.5% FA) / CH3CN (100:0— >50:50) to afford (12R)-2-(4,4-difhroropiperidin-l-yl)-6-fhioro- 12-methyl-l,3,10-triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (14 mg, 26%) as a yellow solid. MS (ESI): mass calcd. for C16H17F3N4O, 338.1 m / z found 339.1 [M+H]+.1H NMR (400 MHz, DMSO) 8 8.39 - 8.36 (m, 1H), 7.56 - 7.53 (m, 1H), 7.50 - 7.46 (m, 1H), 4.79 - 4.73 (m, 1H), 3.58 -3.53 (m, 1H), 3.47 - 3.43 (m, 1H), 3.37 (t, J= 8.0 Hz, 4H), 2.26 - 2.21(m, 4H), 1.31 (d, J = 4.0 Hz, 3H).

[0150] Synthesis of Compound 4969

[0151] To the mixture of 2-bromo-5-fluoro-3 -nitrobenzoic acid (13.94 g, 0.0528 mol) in DMF (250 mL) was added HATU (24.09 g, 0.0633 mol). After stirring for 30 minutes at 25 °C, to the reaction mixture was added tert-butyl (l-aminobutan-2-yl) carbamate (10 g, 0.0528 mol) and DIEA (34.12 g, 0.264 mol). The reaction mixture was stirred at 25 °C for 12 h. When thereaction was completed, the mixture was poured into water. The solids were filtered out to afford tert-butyl (l-(2-bromo-5-fluoro-3-nitrobenzamido) butan-2-yl) carbamate (12 g, 52%) as a yellow solid. MS (ESI): mass calcd. for CietEiBrFNsCb 433.0 m / z found 456.0 [M+Na]+.

[0152] The mixture of {l-[(2-bromo-5-fluoro-3-nitrophenyl)formamido]butan-2- yl}amino tert-butyl formate (12 g, 0.0276 mol) in HC1 / EA (150 ml) was stirred at 0 °C for 4 h. When the reaction was completed, the solids were filtered out. The filtrate cake was concentrated to afford N-(2-aminobutyl)-2-bromo-5-fluoro-3-nitrobenzamide (8 g, 86%) as a yellow solid.MS (ESI): mass calcd. for CiiHi3BrFN3O3, 334.0, m / z found 335.0 [M+H]+.

[0153] To the solution of N-(2-aminobutyl)-2-bromo-5-fluoro-3 -nitrobenzamide (8.0 g, 6.2 mmol) in DMSO (250 mL) was added CsF (0.73 g, 4.7 mol) and TEA (7.28 g, 18.6 mmol) at 100 °C for 24 h. Upon completion, the mixture was quenched with ice water (200 mL) and extracted with EA (3x200 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica (PE: EA=1: 1) to afford 2-ethyl-7-fluoro-9-nitro-l,2,3,4-tetrahydro-l,4-benzodiazepin-5-one (1.7 g, 28%) as an orange solid. MS (ESI): mass calcd. for CnHi2FN3O3, 253.1, m / z found 254.1 [M+H]+.

[0154] To a solution of 2-ethyl-7-fluoro-9-nitro-l,2,3,4-tetrahydro-5H- benzo[e][l,4]diazepin-5-one (1.7 g, 6.7 mmol) in MeOH (50 mL) was added Pd / C (1 g). The mixture was stirred under balloon pressure of H2 at 25 °C for 6 h. When the reaction was completed, the solids were filtered out. The filtrate was concentrated to afford crude which was purified by silica gel column chromatography eluted with DCM / MeOH (10: 1) to afford 9-amino- 2-ethyl-7-fluoro-l,2,3,4-tetrahydro-l,4-benzodiazepin-5-one (1.3 g, 86%) as a grey solid. MS (ESI): mass calcd. for CnHi4FN3O, 223.1, m / z found 224 .1 [M+H]+.

[0155] To a solution of 9-amino-2-ethy 1-7-fluoro- 1,2,3, 4-tetrahydro-l, 4-benzodiazepin- 5-one (1.3 g, 5.8 mmol) in MeOH (15 mL) was added BrCN (0.92 g, 8.7 mmol). The reaction mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was evaporated under reduced pressure to afford l-amino-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen- 6(7H)-one (1 g, 69%) as an orange solid. MS (ESI): mass calcd. for C12HBFN4O, 248.1, m / z found 249.1 [M+H]+.

[0156] To a solution of 9-amino-2-ethyl-7-fluoro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5-one (1 g, 4 mmol) and CuBn (1.34 g, 6 mmol) in MeCN (15 mL) was added tert- Butyl nitrite (0.88 g, 8 mmol). The reaction mixture was stirred at 65 °C for 6 h. When thereaction was completed, the solids were filtered out. The residue was quenched with water (100 mL) and extracted with EA (100 mL x 3). The residue was purified by flash chromatography on silica (MeOH: DCM = 10:1) to l-bromo-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (700 mg, 55%) as a yellow solid. MS (ESI): mass calcd. for Ci2HiiBrFN3O, 311.0, m / z found 312.0 [M+H]+.

[0157] To a solution of l-bromo-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (100 mg, 0.3204 mmol) in DMSO (2 mL) was added piperidine (33 mg, 0.3844 mmol), CsF (73 mg, 0.4806 mmol) and CS2CO3 (156 mg, 0.4806 mmol). The reaction mixture was stirred at 100 °C for 16 h. Upon completion, the solids were filtered out. The filtrate was purified by RP-C18 column eluted with H2O (0.5% FA) / CH3CN (100:0— >-50:50) to afford 9-ethyl-4-fhioro-l-(piperidin-l-yl)-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (70 mg, 69%) as a yellow solid. MS (ESI): mass calcd. for C17H21FN4O, 316.2, m / z found 317.2 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.36 - 8.34 (m, 1H), 7.52 - 7.46 (m, 2H), 4.43 (s, 1H), 3.60 - 3.58 (m, 2H), 3.23 - 3.19 (m, 2H), 3.11 - 3.06 (m, 2H), 1.72 - 1.55 (m, 8H), 0.90 (t, J= 7.6 Hz, 3H).

[0158] Synthesis of Compound 4975 and Compound 49764975 4976

[0159] To the solution of 2-bromo-12-ethyl-6-fluoro-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (100 mg, 0.3204 mmol) in DMSO (3 mL) were added 4,4-difluoropiperidine (78 mg, 0.6408 mmol), CsF (73 mg, 0.4806 mmol) and Cs2CO3(156 mg, 0.4806 mmol). The reaction mixture was stirred at 100 °C for 12 h. Upon completion, the solids were filtered out. The filtrate was purified by RP-C18 column eluted with H2O (0.5% FA) / CH3CN ( 100:0— >50:50) to afford 2-(4,4-difhroropiperidin-l-yl)-12-ethyl-6- fluoro-l,3,10-triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (20 mg, 17%) as a white solid. MS (ESI): mass calcd. for Ci?Hi9F3N4O, 352.3, m / z found 353.3 [M+H]+. 'H NMR (400 MHz, CDC13) 8 7.79 (d, J= 12 Hz, 1H), 7.52 (d, J= 4 Hz, 1H), 6.87 (s, 1H), 4.41 (s, 1H), 3.75 (s, 2H), 3.44 (s, 4H), 2.23 (s, 4H), 1.96 (d, J= 8 Hz, 1H), 1.76 (s, 1H), 1.01 (s, 3H).

[0160] 2-(4,4-difluoropiperidin-l-yl)-12-ethyl-6-fluoro-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (20 mg) was split by prep-SFC to give rel-(R)-l-(4,4-difluoropiperidin-l-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (Compound 4975; 4.9 mg, 25%) as a white solid and rel-(S)-l- (4,4-difluoropiperidin-l-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)- one (Compound 4976; 6.2 mg, 31%) as a white solid.

[0161] Compound 4975: MS (ESI): mass calcd. for C17H19F3N4O, 352.3, m / z found 353.3 [M+H]+.XH NMR (400 MHz, DMSO) 8 8.37 (s, 1H), 7.56 - 7.50 (m, 2H), 4.51 (s, 1H), 3.59 (s, 2H), 3.37 (d, J = 8.0 Hz, 2H), 3.28 (d, J = 8.0 Hz, 2H), 2.24 - 2.14 (m, 4H), 1.75 - 1.47 (m, 2H), 0.91 (t, J = 8.0 Hz, 3H).

[0162] Compound 4976: MS (ESI): mass calcd. for C17H19F3N4O, 352.3, m / z found353.3 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.38 - 8.36 (m,lH), 7.57 - 7.50 (m, 2H), 4.51 (s, 1H), 3.59 (d, J = 4.0 Hz, 2H), 3.43 - 3.35 (m, 2H), 3.31 - 3.23 (m, 2H), 2.29 - 2.08 (m, 4H), 1.64 (m, 2H), 0.91 (t, J = 8.0 Hz, 3H).

[0163] Synthesis of Compound 4977 and Compound 4978

[0164] To the solution of 2-bromo-12-ethyl-6-fluoro-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (200 mg, 0.6407 mmol) in DMSO (10 mL) was added morpholine (112 mg, 1.2814 mmol), CsF (146 mg, 0.9611 mmol) and CS2CO3 (314 mg, 0.9611 mmol). The reaction mixture was stirred at 100 °C for 12 h. Upon completion, the solids were filtered out. The filtrate was purified by RP-C18 column eluted with H2O (0.5% FA) / CH3CN (100:0— >50:50) to afford 12-ethyl-6-fluoro-2-(morpholin-4-yl)-l,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (80 mg, 39%) as a yellow solid. MS (ESI): mass calcd. for C16H19FN4O2, 318.1, m / z found 319.1 [M+H]+.XH NMR (400 MHz, CDCI3) 8 7.78 (d, J= 8 Hz, 1H), 7.53 (d, J= 8 Hz, 1H), 6.88 (s, 1H), 4.44 (s, 1H), 3.91 (s, 4H), 3.73 (s, 2H), 3.30 (s, 4H), 2.10 - 1.90 (m, 1H), 1.82 - 1.72 (m, 1H), 1.02 (t, J= 8 Hz, 3H).

[0165] 12-ethyl-6-fluoro-2-(morpholin-4-yl)- 1 ,3 , 10-triazatricyclo[6.4.1.0A{4, 13 } ]trideca-2,4,6,8(13)-tetraen-9-one (80 mg) was split by prep-SFC to give rel-(R)-9-ethyl-4-fluoro-l- morpholino-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Compound 4977: 16.4 mg, 21%) as a yellow solid and rel-(S)-9-ethyl-4-fluoro-l-morpholino-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (Compound 4978; 15.8 mg, 20%) as a yellow solid.

[0166] Compound 4977: MS (ESI): mass calcd. for C16H19FN4O2, 318.1, m / z found319.1 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.36 (t, J = 12 Hz, 1H), 7.56 - 7.48 (m, 2H), 4.54 - 4.54 (m, 1H), 3.83 - 3.71 (m, 4H), 3.61 - 3.53 (m, 2H), 3.31 - 3.23 (m, 2H), 3.15 - 3.05 (m, 2H), 1.78 - 1.50 (m, 2H), 0.92 (t, J = 8 Hz, 3H).

[0167] Compound 4978: MS (ESI): mass calcd. for C16H19FN4O2, 318.1, m / z found319.1 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.37 (t, J = 12 Hz, 1H), 7.56 - 7.48 (m, 2H), 4.54 - 4.50 (m, 1H), 3.77 (s, 4H), 3.63 - 3.50 (m, 2H), 3.31 - 3.23 (m, 2H), 3.15 - 3.05 (m, 2H), 1.71 - 1.57 (m, 2H), 0.92 (t, J = 8 Hz, 3H).

[0168] Synthesis of Compound 4916 and Compound 49174916 4917

[0169] To the solution of 2-bromo-6-fhroro-l l-methyl-1,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (150 mg, 0.5032 mmol) in DMSO (4 mL) was added 4,4-difluoropiperidine (162 mg, 1.3418 mmol), CsF (114 mg, 0.7548 mmol) and CS2CO3 (245 mg, 0.7548 mmol). The mixture was stirred at 100°C under air for 16 h. Upon completion, the solids were filtered out. The filtrate was purified by RP-C18 column eluted with H2O (0.5% FA) / CH3CN (100:0— >50:50) to afford 2-(4,4-difhroropiperidin-l-yl)-6-fhioro-l l- methyl-l,3,10-triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (100 mg, 44%) as a yellow solid. MS (ESI): mass calcd. for C16H17F3N4O, 338.1 m / z found 339.1 [M+H]+

[0170] 2-(4,4-difluoropiperidin- 1 -yl)-6-fluoro- 11 -methyl- 1,3,10- triazatricyclo[6.4.1.0A{4,13}]trideca-2,4,6,8(13)-tetraen-9-one (100 mg) was split by prep-SFC to giverel-(R)-l-(4,4-difluoropiperidin-l-yl)-4-fluoro-8-methyl-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (Compound 4916; 20 mg, 20%) as a white solid and rel-(R)-l-(4,4-difluoropiperidin-l-yl)-4-fluoro-8-methyl-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)- one (Compound 4917; 30 mg, 30%) as a white solid.

[0171] Compound 4916: MS (ESI): mass calcd. for C16H17F3N4O, 338.1 m / z found339.1 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.38 (d, J= 4.0 Hz, 1H), 7.45 - 7.42 (m, 1H), 7.30 - 7.27 (m, 1H), 4.07 - 3.98 (m, 2H), 3.81 - 3.77 (m, 1H), 3.39 - 3.33 (m, 2H), 3.21 - 3.17 (m, 2H), 2.56 - 2.50 (m, 2H), 2.45 - 2.41 (m, 2H), 2.24 (s, 3H), 1.26 (d, J= 8.0 Hz, 3H).

[0172] Compound 4917: MS (ESI): mass calcd. for C16H17F3N4O, 338.1 m / z found339.1 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.40 (d, J= 4.0 Hz, 1H), 7.48 - 7.45 (m, 1H), 7.33 - 7.30 (m, 1H), 4.08 - 4.06 (m, 2H), 3.83 - 3.78 (m, 1H), 3.52 - 3.46 (m, 2H), 3.41 - 3.38 (m, 2H), 2.33 - 2.25 (m, 2H), 2.13 - 2.05 (m, 2H), 1.27 (d, J= 4.0 Hz, 3H).

[0173] Synthesis of Compound 4981 and Compound 4982

[0174] To the solution of 9-amino-2-ethyl-7-fluoro-l,2,3,4-tetrahydro-5H- benzo[e][l,4]diazepin-5-one (200 mg, 0.8959 mmol) in EtOH (4 mL) was added tert-butyl (4- formylpiperidin-l-yl) formate (192 mg, 0.8959 mmol) and Na2S20s (170 mg, 0.8959 mmol). The reaction mixture was stirred at 80 °C for additional 12 h. Upon completion, the residue was concentrated and purified by flash chromatography on silica (PE: EA=5:1) to afford tert-butyl 4- (9-ethyl-4-fluoro-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azulen-l-yl) piperidine-1- carboxylate (300 mg, 80%) as a white solid. MS (ESI): mass calcd. for C22H29FN4O3 416.2 m / z found 417.2 [M+H]+.

[0175] The mixture of tert-butyl 4-(9-ethyl-4-fluoro-6-oxo-6,7,8,9-tetrahydro-2,7,9a- triazabenzo[cd]azulen-l-yl) piperidine- 1 -carboxylate (300 mg, 0.7186 mmol) in HC1 / EA (4 mL) was stirred at 25 °C for 4 h. When the reaction was completed, the solids were filtered out. The filtrate cake was concentrated to afford 9-ethyl-4-fluoro-l-(piperidin-4-yl)-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (200 mg, 88%) as a white solid. MS (ESI): mass calcd. for C17H21FN4O 316.2, m / z found 317.2 [M+H]+.

[0176] The solution of 9-ethyl-4-fluoro-l-(piperidin-4-yl)-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (200 mg, 0.6322 mmol) was added 4,4-difluorocyclohexan-l- one (85 mg, 0.6322mmol) and AcOH (0.5 mL) inDMF (3mL). After stirring for 30 minutes at 25 °C, to the reaction mixture was added sodium triacetoxyborohydride (536 mg, 2.5288 mmol). The reaction mixture was stirred at 25 °C for additional 12 h. Upon completion, the residue was extracted with EA (50 mL x 3) and washed with saturated NaHCO, (50 x 3 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica (PE: EA=1:1) to afford l-(l-(4,4-difluorocyclohexyl) piperidin-4-yl)- 9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (80 mg, 29%) as a white solid. MS (ESI): mass calcd. for C23H29F3N4O 434.2, m / z found 435.2 [M+H]+.

[0177] l-(l-(4,4-difluorocyclohexyl) piperidin-4-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a- triazabenzo [cd] azulen-6(7H)-one (80 mg) was split by prep-SFC to give rel-(R)-l-(l-(4,4- difluorocyclohexyl) piperidin-4-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen- 6(7H)-one (Compound 4981, 25.2 mg, 31%) as a white solid and rel-(R)-l-(l-(4,4- difluorocyclohexyl) piperidin-4-yl)-9-ethyl-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo [cd] azulen- 6(7H)-one (Compound 4982, 28.5 mg, 35%) as a white solid.

[0178] Compound 4981 : MS (ESI): mass calcd. for C23H29F3N4O 434.2, m / z found 435.2 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.44 (t, J= 5.6 Hz, 1H), 7.64 (dd, J= 9.2, 2.4 Hz, 1H), 7.56 (dd, J= 10.8, 2.4 Hz, 1H), 4.67 - 4.63 (m, 1H), 3.59 - 3.58 (m, 2H), 2.98 - 2.88 (m, 3H), 2.35 - 2.30 (m, 2H), 2.06 - 1.53 (m, 15H), 0.97 (t, J= 7.6 Hz, 3H).

[0179] Compound 4982: MS (ESI): mass calcd. for C23H29F3N4O 434.2, m / z found 435.2 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.44 (t, J= 5.6 Hz, 1H), 7.64 (dd, J= 9.2, 2.4 Hz, 1H), 7.56 (dd, J= 10.8, 2.4 Hz, 1H), 4.67 - 4.65 (m, 1H), 3.59 - 3.58 (m, 2H), 2.98 - 2.90 (m, 3H), 2.35 - 2.30 (m, 2H), 2.05 - 1.53 (m, 15H), 0.97 (t, J= 7.6 Hz, 3H).

[0180] Synthesis of Compound 5927

[0181] To a mixture of 2-bromo-5-fluoro-3-nitrobenzoic acid (491 mg, 1.8578 mmol) in DMF (20 mL) was added HATU (848 mg, 2.2293 mmol). After stirring for 30 minutes at 25 °C,to the reaction mixture was added (l-amino-3-cyclopropylpropan-2-yl) amino tert-butyl formate (400 mg, 1.8578 mol) and DIEA (961 mg, 7.4312 mmol). The pH was adjusted to around 9 by progressively adding DIEA. The reaction mixture was stirred at 25 °C for additional 16 h. The mixture was quenched with ice water (40 mL) and extracted with EA (3 20 mL). The combine organic layer was dried over Na2SC>4 and concentrated under reduced pressure to afford crude which was purified by silica gel column chromatography eluted with PE / EA (5: 1) to afford {1- [(2-bromo-5-fluoro-3-nitrophenyl) formamido]-3-cyclopropylpropan-2-yl} amino tert-butyl formate (600 mg, 63%) as a yellow solid. MS (ESI): mass calcd. for Ci^sBrFNsOs, 460.3, m / z found 461.3 [M+H]+.

[0182] The mixture of {l-[(2-bromo-5-fluoro-3-nitrophenyl) formamido]-3- cyclopropylpropan-2-yl} amino tert-butyl formate (600 mg, 2.0118 mmol) in HC1 / EA (10 ml) was stirred at 25 °C for 2 h. When the reaction was completed, the solids were filtered out. The filtrate cake was concentrated to afford N-(2-amino-3-cyclopropylpropyl)-2-bromo-5-fluoro-3- nitrobenzamide (340 mg, 69%) as a white solid. MS (ESI): mass calcd. for CnHisBrFNsOs, 360.2, m / z found 361.2 [M+H]+.

[0183] To the mixture of N-(2-amino-3-cyclopropylpropyl)-2-bromo-5-fluoro-3- nitrobenzamide (400 mg, 1.1106 mmol) in DMSO (10 mL) was added TEA (337 mg, 3.3318 mmol) and CsF (34 mg, 0.2221 mmol). The reaction mixture was stirred at 100 °C for 16 h. The mixture was quenched with ice water (40 mL) and extracted with EA (3 20 mL). The combine organic layer was dried over Na2SC>4 and concentrated under reduced pressure to afford crude which was purified by silica gel column chromatography eluted with PE / EA (5: 1) to afford 2- (cyclopropylmethyl)-7-fluoro-9-nitro-l,2,3,4-tetrahydro-l,4-benzodiazepin-5-on (100 mg, 29%) as a yellow solid. MS (ESI): mass calcd. for CnHuBrFNsCh, 279.3, m / z found 280.3 [M+H]+.

[0184] To a solution of 2-cyclopropyl-7-fluoro-9-nitro-l,2,3,4-tetrahydro-l,4- benzodiazepin-5-one (100 mg, 0.3581 mmol) in MeOH (5 mL) was added Pd / C under N2. The mixture was stirred under balloon pressure of H2 at 25 °C for 6 h. After completion of the reaction, the catalyst was filtrated. The solvent was evaporated under reduced pressure to afford 9-amino-2-(cyclopropylmethyl)-7-fluoro-l,2,3,4-tetrahydro-l,4-benzodiazepin-5-one (80 mg, 90 %) as a yellow solid. MS (ESI): mass calcd. for C13H16FN3O, 249.3, m / z found 250.3 [M+H]+.

[0185] To the mixture of 9-amino-2-(cyclopropylmethyl)-7-fluoro- 1,2,3, 4-tetrahydro- l,4-benzodiazepin-5-one (100 mg, 0.4011 mmol) in EtOH (5 mL) was added tert-butyl (4-formylpiperidin-l-yl) formate 86 mg, 0.4011 mmol) and Na2S20s (76 mg, 0.4011 mmol), the reaction mixture was stirred at 80 °C for 12 h. The mixture was quenched with ice water (40 mL) and extracted with EA (3x20 mL). The combine organic layer was dried over Na2SC>4 and concentrated under reduced pressure to afford crude which was purified by silica gel column chromatography eluted with PE / EA (3: 1) to afford tert-butyl {4-[12-(cyclopropylmethyl)-6- fluoro-9-oxo- 1,3,10-triazatricyclo[6.4.1.0A{4, 13 } ]trideca-2,4,6,8( 13)-tetraen-2-yl]piperidin- 1 -yl} formate (80 mg, 41%) as a yellow solid. MS (ESI): mass calcd. for C24H31FN4O3, 442.3, m / z found 443.3 [M+H]+.

[0186] The mixture of {4-[12-(cyclopropylmethyl)-6-fluoro-9-oxo-l,3,10-triazatricyclo [6.4.1.0A{4,13}] trideca-2,4,6,8(13)-tetraen-2-yl] piperidin-l-yl} formate (80 mg, 0.2732 mmol) in HC1 / EA (2 ml) was stirred at 25 °C for 4 h. The solvent was evaporated under reduced pressure to afford 9-(cyclopropylmethyl)-4-fluoro-l-(piperidin-4-yl)-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (50 mg, 81%) as a white solid. MS (ESI): mass calcd. for C19H23FN4O, 342.1, m / z found 343.1 [M+H]+.

[0187] To the solution of 9-(cyclopropylmethyl)-4-fluoro-l-(piperidin-4-yl)-8,9-dihydro- 2,7,9a-triazabenzo[cd]azulen-6(7H)-one (20 mg, 0.0584 mmol) was added 4,4- difluorocyclohexan-l-one (8 mg, 0.0584 mmol) and AcOH (0.1 mL) in DMF (1 mL). After stirring for 30 minutes at 25 °C, to the reaction mixture was added sodium triacetoxyborohydride (37 mg, 0.1752 mmol). The reaction mixture was stirred at 25°C for additional 12 h. Upon completion, the crude product was purified by RP-C18 column eluted with H2O (0.5% FA) / CH3CN (100:0— >50:50) to afford 9-(cyclopropylmethyl)-l-(l-(4,4-difluorocyclohexyl) piperidin-4-yl)-4-fluoro-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (8 mg, 30%) as a white solid. MS (ESI): mass calcd. for C25H31F3N4O, 460.2, m / z found 461.2 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.43 (t, J= 5.6 Hz, 1H), 7.65 (dd, J= 9.2, 2.4 Hz, 1H), 7.56 (dd, J = 10.8, 2.4 Hz, 1H), 4.81 - 4.78 (m, 1H), 3.64 (d, J= 2.8 Hz, 4H), 3.00 - 2.92 (m, 3H), 2.33 - 2.25 (m, 2H), 2.09 - 2.01 (m, 3H), 1.95 - 1.76 (m, 6H), 1.69 - 1.52 (m, 3H), 1.36 - 1.29 (m, 1H), 0.80 - 0.74 (m, 1H), 0.43 - 0.41 (m, 2H), 0.20 - 0.18 (m, 1H), 0.15 - 0.17 (m, 1H).

[0188] Synthesis of Compound 5337

[0189] To a solution of 2-bromo-5-fluoro-3 -nitrobenzoic acid (36 g, 137.74 mmol) in DMF (300 mb) was added HATU (68.08 g, 179.06 mmol). The mixture was stirred at room temperature for 0.5 hour followed by addition of tert-butyl (S)-(l-aminopropan-2-yl)carbamate (20 g, 114.78 mmol) and DIEA (44.42 g, 344.34 mmol). The resulting mixture was stirred at room temperature for another 16 hours. The mixture was diluted with EA (1000 mL), washed with brine (300 mL x 5). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatograph on silica gel column using PE: EA (4: 1) to afford tert-butyl (S)-(l-(2-bromo-5-fluoro-3-nitrobenzamido) propan-2 -yl) carbamate (40 g, 83%) as a white solid. MS (ESI): mass calcd. for CisH^BrENsOs, 419.05, m / z found 442.0 [M+Na]+.

[0190] Tert-butyl (S)-(l-(2-bromo-5-fluoro-3-nitrobenzamido)propan-2-yl)carbamate (40 g, 95.18 mmol) was dissolved in HC1 in EA (4M, 240 mL). The mixture was stirred at room temperature for 4 hours. The resulting mixture was filtered and the filter cake was dried in vacuo to afford (S)-N-(2-aminopropyl)-2-bromo-5-fluoro-3 -nitrobenzamide hydrochloride (28 g, 82%) as a white solid. MS (ESI): mass calcd. for CioHnBrCIFNsCh, 319.00, m / z found 320.1 [M+H]+.

[0191] To a solution of (S)-N-(2-aminopropyl)-2-bromo-5-fluoro-3 -nitrobenzamide hydrochloride (28 g, 78.52 mmol) in DMSO (1100 mL) was added TEA (235.56 g, 235.56 mmol) and CsF (2.39 g, 15.70 mmol) under nitrogen condition. The reaction mixture was stirred at 100 °C for 8 h. The solution was diluted with EA (1000 mL), washed with brine (1000 mL x 5). The organic layer was dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by flash chromatograph on silica gel column using PE: EA (4: 1) to afford (S)-7-fluoro- 2-methyl-9-nitro-l,2,3,4-tetrahydro-5H-benzo[e][l,4]diazepin-5-one (3.12 g, 16%) as a white solid. MS (ESI): mass calcd. for C10H10FN3O3, 239.07, m / z found 240.1 [M+H]+.

[0192] To a solution of (S)-7-fluoro-2-methyl-9-nitro-l,2,3,4-tetrahydro-5H- benzo[e][l,4]diazepin-5-one (3.12 g, 13.04 mmol) in EA (60 mL) was added Pd / C (312 mg). The mixture was stirred at room temperature for 6 h under H2 condition. The resulting mixture was filtered and filtration was dried in vacuo to afford (S)-9-amino-7-fluoro-2-methyl-l,2,3,4-tetrahydro-5H-benzo[e][l,4]diazepin-5-one (2.52 g, 92%) as a white solid. MS (ESI): mass calcd. for C10H12FN3O, 209.10, m / z found 210.1 [M+H]+.

[0193] To a solution of (S)-9-amino-7-fluoro-2-methyl-l,2,3,4-tetrahydro-5H- benzo[e][l,4]diazepin-5-one (2.52 g, 12.04 mmol) in MeOH (50 mL) was added BrCN (1.91 g, 18.06 mmol). The mixture was stirred at 50 °C for 16 h. The resulting mixture was concentrated to afford the product (3 g, crude) as a yellow solid, which was used for next step directly without further purification. MS (ESI): mass calcd. for C11H11FN4O, 234.09, m / z found 235.1 [M+H]+.

[0194] To a solution of (S)-l-amino-4-fluoro-9-methyl-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (3 g, crude) in CH3CN (50 mL) were added Copper chloride (2.97 g, 22.12 mmol) and tert-Butyl nitrite (2.28 g, 22.12 mmol) under N2 condition. The mixture was stirred at 65 °C for 6 h. The 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 in vacuo. The residue was purified by C18-column using CH3CN: H2O to obtain Compound 5337 (1.88 g, 67%) as a white solid. MS (ESI): mass calcd. for C11H9CIFN3O, 253.04, m / z found 254.1 [M+H]+. 'H NMR (400 MHz, DMSO) 8 8.55-8.52 (m, 1H), 7.77 (dd, J= 8.8, 2.4 Hz, 1H), 7.66 (dd, J= 10.8, 2.4 Hz, 1H), 4.85 - 4.79 (m, 1H), 3.75-3.71 (m, 1H), 3.53-3.46 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H).

[0195] Synthesis of Compound 3654 and Compound epz-3654

[0196] To a solution of methyl 2-bromo-5-fluoro-3 -nitrobenzoate (2 g, 7.2 mmol) and Na2CC>3 (3.05 g, 28.8 mmol) in 1 -butanol (20 mL) was added 1 -(4-fluorophenyl) ethane- 1,2- diamine (1.11 g, 7.2 mmol). The reaction mixture was stirred at 85 °C for 12 h. The mixture was concentrated. The residue was purified by flash chromatography on silica (PE: EA=1: 1) to afford 7-fluoro-2-(4-fluorophenyl)-9-nitro-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5-one (0.9 g, 39%) as an orange solid. MS (ESI): mass calcd. for C15H11F2N3O3, 319.0, m / z found 320.0 [M+H]+.

[0197] To a solution of 7-fluoro-2-(4-fluorophenyl)-9-nitro-l,2,3,4-tetrahydro-5H- benzo[e] [1,4] diazepin-5-one (420 mg, 1.32 mmol) in AcOH (10 mL) was added Fe (441 mg, 7.89 mmol). The reaction mixture was stirred at 25 °C for 16 h. When the reaction was completed, the solids were filtered out. The filtrate was concentrated to afford crude, which was purified by silica gel column chromatography eluted with MeOH / DCM (10:1) to afford 9-amino- 7-fluoro-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-5H-benzo[e] [1,4] diazepin-5-one (200 mg, 52%) as a yellow solid. MS (ESI): mass calcd. for C15H13F2N3O, 289.1, m / z found 290.1 [M+H]+.

[0198] To a solution of 9-amino-7-fluoro-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-5H- benzo[e] [1,4] diazepin-5-one (100 mg, 0.35 mmol) in EtOH (2 mL) were added Na2S20s (78 mg, 0.41 mmol) and tert-butyl (R)-2-formylpyrrolidine-l -carboxylate (83 mg, 0.41 mmol). The mixture was stirred at 80 °C for 16 hours. The residue was concentrated in vacuo and extracted with EA (10 mLx2). The organic phase was washed with brine (10 mLx3), dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica (MeOH: DCM=10:l) to afford tert-butyl (2R)-2-(4-fluoro-9-(4- fluorophenyl)-6-oxo-6,7,8,9-tetrahydro-2,7,9a-triazabenzo[cd]azulen-l-yl) pyrrolidine- 1- carboxylate (80 mg, 49%) as a yellow solid. MS (ESI): mass calcd. for C25H26F2N4O3, 468.2, m / z found 469.2 [M+H]+.

[0199] To a solution of tert-butyl (2R)-2-(4-fluoro-9-(4-fluorophenyl)-6-oxo-6, 7,8,9- tetrahydro-2,7,9a-triazabenzo[cd]azulen-l-yl) pyrrolidine- 1 -carboxylate (80 mg, 0.17 mmol) in EA (0.5 mL) was added 4 N HC1 in ethyl acetate (0.5 mL). The mixture was stirred at 25 °C for 4 hours. Upon completion, the mixture was concentrated under reduced pressure to afford 4- fluoro-9-(4-fluorophenyl)-l-((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen- 6(7H)-one (30 mg, 47%) as a yellow solid. MS (ESI): mass calcd. for C20H18F2N4O, 368.1, m / z found 369.1 [M+H]+.

[0200] 4-fhioro-9-(4-fluorophenyl)- 1 -((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a- triazabenzo[cd]azulen-6(7H)-one (30 mg) was split by prep-SFC to give (S)-4-fluoro-9-(4- fluorophenyl)-l-((R)-pyrrolidin-2-yl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Compound 3654, 12 mg, 40%) and (R)-4-fluoro-9-(4-fluorophenyl)-l-((R)-pyrrolidin-2-yl)-8,9- dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one (Compound epz-3654, 8 mg, 27%) as a white solid.

[0201] Compound 3654: MS (ESI): mass calcd. for C20H18F2N4O, 368.1, m / z found 369.1 [M+H]+. 'H NMR (400 MHz, CD3OD-74) 8 7.77 - 7.74 (m, 1H), 7.50 - 7.04 (m, 5H), 5.15 (s, 1H), 4.66 - 4.63 (m, 1H), 4.49 - 4.45 (m, 1H), 3.14 - 2.94 (m, 2H), 2.22 - 1.29 (m, 4H), 1.29 (m, 1H), 1.20 - 0.79 (m, 1H).

[0202] Compound epz-3654: MS (ESI): mass calcd. for C20H18F2N4O, 368.1, m / z found 369.1 [M+H]+.1H NMR (400 MHz, CD3OD-74) 8 7.74 - 7.71 (m, 1H), 7.49 - 7.03 (m, 5H), 5.13 (s, 1H), 4.65 - 4.62 (m, 1H), 4.47 (t, 7 = 7.2 Hz, 1H), 3.08 (s, 1H), 2.99 - 2.93 (m, 1H), 2.25 - 2.12 (m, 2H), 1.97 - 1.88 (m, 2H), 1.28 (s, 1H), 1.16 - 0.87 (m, 1H).

[0203] PARP Mass Spectroscopy Assay Protocol

[0204] Materials and Reagents: The PARP1 enzyme was purchased from BPS Bioscience (cat# 80501). Tris-HCl, pH 8.0 was purchased from Corning (cat# 46-031 -CM). Magnesium chloride was purchased from Thermo Fisher Scientific (previously Honeywell Fluka, cat# 63020-1L). All other assay components, activated DNA (cat# D4522), core histones (cat# SRP6590), P-Nicotinamide adenine dinucleotide (P-NAD - cat# N8285), 3ABA PARP1 small molecule inhibitor (from the PARP1 Enzyme Activity Assay kit, cat# 17-10149), Sodium Chloride (NaCl, cat #S6546-1L), Triton X-100 (cat# 93443), Dithiothreitol (DTT, cat#43816- 250ML) were all purchased from Millipore Sigma.

[0205] Assay Buffer: The assay buffer includes the following reagents: 50 mM Tris-HCl pH 8.0, 50mM NaCl, lOmM, MgC12, 0.01% Triton X-100, and ImM DTT.

[0206] Procedure:

[0207] PARP1 enzymatic assays were performed in 384- well plates in a total volume of 20 pL in the assay buffer. For concentration response curves, compounds were serially diluted 3- fold from 2 mM highest concentration 0.1013 mM to generate a 10-point curve, and 125 nL was transferred to the assay plate using the Echo acoustic dispenser for a final concentration range of 26.6 pM to 1.35 pM in 10 pL reaction. Five microliters of 10 nM PARPl enzyme and lOOnM core histones (2x) mix were added to the assay plates and pre- incubated for 30 mins at room temperature (RT). The reaction was initiated by the addition of a 5 pL of 10 uM P-NAD plus 0.02 mg / mL activated DNA (2X) mix. The reaction is incubated for 60 min at RT. The final concentration of the PARP1 enzyme and substrate concentrations were 5 nM and 5 uM, respectively. The positive control (high signal) and negative control (low signal) wells had 125 nL of DMSO in place of compounds. After the incubation is complete, the reaction is stopped bythe addition of 10 uL of 10 uM of the 3 AB A PARP1 inhibitor, incubated for 5 min at RT, and placed in the -80C freezer for shipment to the Vaio Health site in Branford Connecticut where mass spectrometry will be used to directly detect quantities of nicotinamide (NAM).

[0208] The percent inhibition of enzyme activity was calculated according to the following equation:The values of S sample, Shigh, and Siowin the equation refer to the NAM concentration detected in the assay wells, high control wells, and low control wells, respectively. To determine inhibitor IC50 values, % inhibition of the CRCs (concentration response curves) was fitted to the standard single-site four-parameter logistic equation.

[0209] Representative Results for Exemplary Compounds Of the Present Technology

[0210] Table 1 provides representative initial results for exemplary compounds of the present technology.Table 1.

[0211] PARylation Immunofluorescence Assay Protocol

[0212] Materials:

[0213] Equipment:

[0214] Cell Culture Details: HCT116 is a human colon epithelial cell line, which grows adherently in tissue culture flasks. Cells are grown in T175-sized flasks. Split two times a week, at 70-80% confluence, varying from 1:5 - 1: 10 splits, following standard adherent cell subculturing protocols. Media is kept refrigerated until day of cell-based activities and needs to be warmed to at least RT prior to usage. Cell Culture Media: McCoy’s 5A with 10%FBS, 2mM L-Glutamine, 20mM HEPES. Plating Media: McCoy’s 5A with 10%FBS, 2mM L-Glutamine, 20mM HEPES, 1% Antibiotic- Antimycotic solution.

[0215] Procedure:

[0216] Day 1 : Cell Culture and Cell Plating: The cell culture and cell plating methods include the following steps: Warm media prior to cell culture; remove flask of cells from incubator and trypsinize cells in T175 flask using 0.25% Trypsin; return the flask to the incubator for ~5 minutes to allow the cells to fall away from the bottom of the flask; add 1 OuL of media to rinse bottom of the flask and add cells and media to a 50mL conical tube; spin cells at lOOOrpm for 5min, aspirate out media, and resuspend pellet with lOmL fresh media; using the Cellometer Cell Counter, calculate the live cell count; using the live cell count, and the number of plates needed, calculate the amount of resuspended cell pellet media needed to add to fresh plating media to dispense 5uL / well at the density of 6000cell / well into the 384W plates; plate cells in 384W plates, 5uL of media in each well at 6000cells / well for the entire plate; gently shake plates (lOOrpm) for 20min after plating; and incubate plates at 37°C, 5% CO2 overnight prior to treatment.

[0217] Day 2: Compound and DNA damage treatment, fixation and primary staining: The methods include the following steps: Using the Labcyte Echo 555, treat the 384W cell seeded plates to achieve a top dose of 1 OuM for each compound. 40nL of 1 OmM top dose compound plates are stamped into the 40uL of cells in the seeded plates. The Labcyte compound source plates are DMSO-based with ten-point, threefold dose dilutions of compounds, starting at lOmM. The transfer volume using the Echo was 40nL; incubate for 5 hours at 37°C, 5% CO2;add DNA damaging agent MMS to columns 1-23 of each cell seeded 384W plate by delivering 40nl of 19.2% MMS in DMSO using Echo in DMSO delivery mode, wherein the MMS stock concentration is 99% and must be diluted 1:5 in DMSO prior to delivery to cell plates; incubate cell plates at 37°C, 5% CO2 for 30 minutes; evacuate media and add 75ul of cold methanol using BlueWasher, wherein the Bluewasher MagBeadSpeed setting for all evacuations is: Spins plate 5 sec clock-wise at 800RPM (35g); keep the dispense line and the methanol, chilled throughout fixation process, and use the staccato setting to break dispense into multiple squirts to minimize cell disruption; incubate fixed plates for 20 mins, on ice; wash full plate lx with equal volume of cold DPBS and evacuate with Bluewasher at MagBeadSpeed; add 20ul of DPBS 0.1% Triton X- 100 to full plate and incubate 15 min at room temp and evacuate with Bluewasher at MagBeadSpeed; add 20ul of Roche block to the full plate and incubate for 60 minutes at room temperature and evacuate with Bluewasher at MagBeadSpeed; and add 20ul of PAR antibody (1:4,000) in Roche block, seal plate and incubate overnight at 4C.

[0218] Day 3 : Secondary Antibody Staining and Imaging: The methods include the following steps: Evacuate and wash plates (3X) with 25-30ul of DPBS 0.05% Tween 20 using the Bluewasher; add 20ul of anti-mouse AF488 secondary antibody (1:1,600) plus Hoechst (1 : 10,000) and incubate for 60min at room temperature; evacuate using MagBeadSpeed and wash 3-4X with 25-30ul of DPBS 0.05% Tween 20; add 30ul DPBS and seal plates; and image with CX7 - Circle (Nuclear) Mean Average Intensity Channel 1 (360) and Channel 2 (488) using Protocol ‘PAR HCT116_MeOH_l 0X_2ChR’ . Key acquisition settings: exposure of 488 channels to 70-80% and 1-2 fields.

[0219] Data analysis: Raw data files are exported from the CX7 software, paired with barcoded compound plates to track compound ID, dose responses and Echo transfer records. This allows for import and QC analysis of dose response curves, and IC50 values determination. Images of each plate and well on both imaged channels can be exported as well. The percent inhibition of PARylation activity was calculated according to the following equation:The values of S sample, Shigh, and Siowin the equation refer to the PARylation levels detected in the assay wells, high control wells, and low control wells, respectively. To determine inhibitor IC50values, % inhibition of the CRCs (concentration response curves) was fitted to the standard single-site four-parameter logistic equation.

[0220] Assay Principle: Cellular levels of PARylation of PARP1 / 2 substrate proteins (PARP1 and histones) are measured with an anti-PAR antibody using an immunofluorescence assay upon DNA damage based on https: / / fl000research.com / articles / 5-736 / v2. PARP inhibitors, when co-treated with the DNA damaging agent MMS, reduce the levels of PARylation.

[0221] Cell-based Proliferation Assay Protocol: DLD1 parental vs BRCA2 null 5Day CTG, CTF, CyQuant, or One Pot Live-Dead HCS Assays

[0222] Reagents and consumables:

[0223] Equipment:

[0224] Procedure

[0225] Dav 1 : Cell Culture and Cell Plating: The method includes the following steps: count cells (using Nexcelom cellometer and record cell count); spin cells at lOOOrpm for 5min and re-suspend pellet with fresh media; and plate cells in 1536 well plate at specific cells / well density based on density optimization testing (or DLDl parental (historically) 100 cell / well; for DLD1 BRCA2+ / - vs. -I- null is 125 cell / well; uL of cells / well in columns 1-47 for 1536w plates); gently shake plates (lOOrpm) for 30min at room temperature before transfer to incubator (37°C, 5% CO2); and incubate plates (37°C, 5% CO2) for 24h prior to treatment.

[0226] Day 2: Compound Treatment: For 1536w, compound stamping was 25nl of lOmM on the top concentration of the source plate compounds, resulting in 50uM top dose concentration used for cell-based proliferation assay. Positive control SAHA is stamped to 1 OuM final concentration

[0227] Days 3-7: Plate Incubation: Plates are left to incubate at 37°C, 5% CO2 for a total of 120h / 5 days after compound addition.

[0228] Days 3-7: Readout Reagent Addition and Plate Reading: After incubation, plates are removed from the incubator, and the designated read out reagent is added to the cell plates. See below for details based on the specific readout.• CTG Readout: Remove CTG 2.0 reagent from the fridge and bring to room temperature prior to use; add 4uL / well CTG to all wells of each cell plate; incubate plates at 37°C, 5% CO2, 30 minutes for 1536w plates; and read plates using luminescence-specific protocol on designated plate readers; BMGs or Envisions have CTG-specific protocols.• CyQUANT Readout: Remove Cyquant Direct Cell Proliferation Assay Kit from the fridge and bring to room temperature prior to use. The reagents may need to be heated up in a drybath to thaw; calculate the total volume required based on well dispensed to ensureenough detection reagent is needed. Make up the detection reagent by combining the following assay recipe: PBS: 11.7 mL; CyQuant® Direct nucleic acid stain: 48 pL; and CyQuant® Direct background suppressor: 240 pL; add 2ul / well Cy quant reagent mix to all wells; incubate plates at 37°C, 5% CO2, for 60 minutes; read plates using CyQuant- specific protocol on designated plate readers BMGs or EnVisions with specific 1536w protocol (CyQUANTDirect 508 / 527nm; CyQUANTDirect Red 622 / 645 nm).• CTF Readout: Remove CTF reagent from the freezer and bring to room temperature prior to use, prepare IX reagent and vortex to dissolve (reagent stable at RT for 24h or at 4C for 7 days); add 4ul / well CTF to all wells and incubate plates at 37°C, 5% CO2, 180 minutes (3h); and read plates using fluorescence-specific protocol on designated plate readers (BMGs or Envisions have CTF-specific protocols (Ex 380-400; Em 505)).• One Pot Live-Dead HCS Readout: After incubation, plates are removed from the incubator; for 1536 well plates, make 4mL IX PBS and add 8 drops of Propidium Iodide reagent + 4uL of Hoechst 333242; mix and then using a Multidrop Combi dispense luL / well with medium speed; for 384 well plates: make 6mL IX PBS and add 12 drops of Propidium Iodide reagent + 6uL of Hoechst 333242, mix and then using a Multidrop Combi dispense 8uL / well with medium speed; incubate for 30 minutes at 37°C, 5% CO2; seal the plates with an aluminum seal; spin for 2 minutes at 1000 RPM in a spin bucket centrifuge; load plate onto CX7; and acquire data.Analyzed data is then exported as spot fire file and then processed in ABASE.

[0229] Data analysis for CTG. CyQUANT and CTF readouts: Raw data files are exported from the BMG, Envision and CX7 readers, paired with barcoded compound plates to track compound ID, dose responses and Echo transfer records. This allows for import and QC analysis of dose response curves, and IC50 values determination. Data and images of each plate and well on both imaged channels can be exported as well. The percent inhibition of growth activity was calculated according to the following equation:The values of Ssampie, Shigh, and Siowin the equation refer to the assay signals detected in the wells, high control wells, and low control wells, respectively. To determine inhibitor IC50 values,% inhibition of the CRCs (concentration response curves) was fitted to the standard single-site four-parameter logistic equation.

[0230] Assay Principle: Cell viability is measured with assays that detect live-cell readouts: intracellular ATP (CTG), DNA (CyQUANT) and peptidase activity with cell permeant substrate Gly-Phe-AFC (CTF) using luminescence or fluorescence assays upon cell proliferation in the presence of P ARP inhibitor compounds

[0231] MDCK-MDR1 Permeability Assay Results for Exemplary Compounds of the Present Technology

[0232] The bi-directional assay containing a Mandin Darby canine kidney (MDCK) cell line transfected with human MDR1 gene (P -glycoprotein; P-gp) designed to overexpress the MDR1 efflux transporter, a major efflux transporter at the blood brain barrier (BBB), uses an established method that measures the rate of flux of a compound across polarized cell monolayers. As well appreciated in the art, the data generated from the MDCK-MDR1 permeability assay may be used to predict in vivo absorption of drugs. The bi-directional MDCK-MDR1 permeability assay can identify and quantify levels of active efflux. Screening compounds in both the apical to basolateral direction (A— >B) and basolateral to apical direction (B— A) across the cell monolayer provides a ratio of B— >A / A— >B (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). When a compound has an ER of greater than 2, it suggests that the compound may be subject to active efflux. The data may further be used to predict blood brain barrier (BBB) permeability via calculation from the data of log(permeability- surface area product) (“logPS”), well-understood to be predictive of the in vivo log([brain concentration] / [plasma concentration]).

[0233] Compounds of the present technology will be run in the bi-directional MDCK-MDR1 assay. It is expected that compounds of the present technology will exhibit significant efflux in the apical to basolateral direction (A— >B) and / or have an ER of about 2 or less.

[0234] In vivo CNS Penetration of Exemplary Compounds of the Present Technology

[0235] Compounds of the present technology are predicted to show BBB passage according to internal proprietary predictive models. These predictive models have been furtherverified by in vivo experiments for other compounds. In particular, in vivo unbound brain to plasma ratio (Kpuu) will be measured at steady state for compounds of the present technology by comparison of free drug concentrations (protein binding corrected) in brain and plasma after continuous intravenous infusion in Sprague Dawley rats over 24 hours, where a Kpuu of >0.3 represents good brain exposure of the compound. It is expected that compounds of the present technology will exhibit in vivo Kpuu values generally accepted to be predictive of clinical brain penetrance.

[0236] While certain embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[0237] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present 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 the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0238] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0239] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0240] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0241] All publications, patent applications, issued patents, and other documents (for example, journals, articles and / or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Claims

CLAIMS1. A compound of Formula IwhereinX1is H, F, or Cl;R1is H, alkyl or cycloalkyl;R2is H, alkyl, or cycloalkyl;R3is H, halo, alkyl, cycloalkyl, heterocyclyl, heteroaryl, or N(R4)(R5); and one of R4and R5is H, alkyl, cycloalkyl, heterocyclyl, or heteroaryl and the remaining one of R1and R2is H or alkyl, or R4and R5together with the nitrogen atom to which they are bound are heterocyclyl or heteroaryl.

2. The compound of Claim 1, wherein the compound is of Formula IA3. The compound of Claim 1, wherein the compound is of Formula IB4. The compound of any one of Claims 1-3, whereinR1is H; andR2is H, Ci-C6alkyl, or C3-C6 cycloalkyl.

5. The compound of Claim 4, whereinR2is Ci-Ce alkyl, or C3-C6 cycloalkyl.

6. The compound of any one of Claims 1-5, wherein X1is F.

7. The compound of any one of Claims 1 -6, wherein R3is, where n is 0 or 1 ;R6is H, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;R7is H, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;X2is CH, C — alkyl, or N;X3is N— R8, C(R9)(R10), or O;R8is H, alkyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;R9is H, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and R10is H, halo, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

8. A pharmaceutically acceptable salt and / or solvate of the compound of any one of Claims 1-7.

9. A composition comprising the compound of any one of Claims 1-7 and / or the pharmaceutically acceptable salt of Claim 8 and / or the pharmaceutically acceptable solvate of Claim 8 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound of any one of Claims 1-7 and / or the pharmaceutically acceptable salt of Claim 8 and / or the pharmaceutically acceptable solvate of Claim 8, wherein the effective amount is effective to treat a cancer.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of any one of Claims 1-7 and / or the pharmaceutically acceptable salt of Claim 8 and / or the pharmaceutically acceptable solvate of Claim 8 in an amount effective to treat a cancer when combined with a second cancer therapy.

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

13. A medicament for treating a cancer in a subject, the medicament comprising the compound of any one of Claims 1-7 and / or the pharmaceutically acceptable salt of Claim 8 and / or the pharmaceutically acceptable solvate of Claim 8.

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

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

Images