Fused polycyclic compounds and their use as PARP1 inhibitors

Abstract

Provided herein are certain fused polycyclic compounds having a polycyclic linker, such as compounds of Formula (I), as PARP1 inhibitors, pharmaceutical compositions comprising the compounds, and methods of using the compounds or pharmaceutical compositions in the treatment of diseases or disorders. [Formula 1] JPEG2025541981000347.jpg30128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to International Patent Application No. PCT / CN2022 / 130788, filed November 9, 2022, and International Patent Application No. PCT / CN2023 / 076158, filed February 15, 2023, each of which is incorporated by reference in its entirety.

[0002] Provided herein are certain fused polycyclic compounds with polycyclic linkers as PARP1 inhibitors, pharmaceutical compositions containing the compounds, and methods of using the compounds or pharmaceutical compositions in the treatment of diseases or disorders. [Background technology]

[0003] Poly(ADP-ribose) polymerase enzymes (PARPs) catalyze poly(ADP-ribosylation) with nicotinamide adenine dinucleotide (NAD) as a substrate. DNA damage-induced PARylation is primarily mediated by PARP1 (also known as ARTD1), which is primarily activated by DNA single- and double-strand breaks and accounts for >90% of DNA damage-induced PARylation (Nucleic Acids Research 44, 10386-10405).

[0004] Auto-PARylation, driven by the catalytic activity of PARP, releases PARP from DNA, allowing access to additional repair proteins and resolution of DNA breaks and stalled replication forks (Sci. Transl. Med. 8(362)(2016)362ps17). Inhibition of PARP family enzymes has been explored as a strategy for selectively killing cancer cells by inactivating complementary DNA repair pathways. PARP inhibitors (PARPi) currently in clinical use inhibit PARylation through competitive binding to the NAD+ binding sites of PARP1 and PARP2, which has improved clinical benefit against BRCA-mutated tumors. In addition to catalytic inhibition, "PARP trapping" is another important mechanism involving PARPi. PAPRi has been reported to be more cytotoxic than PARP depletion due to its ability to trap PARP enzymes on damaged DNA, which prevents DNA replication (Cancer Res. 2012;72:5588-5599).

[0005] BRCA1 and BRCA2 play important roles in DNA replication and double-strand break (DSB) repair. Both factors promote homologous recombination repair (HR), a DNA repair pathway active during the S / G2 phase of the cell cycle, which also provides a pathway for restarting stalled replication forks. Several studies have shown that BRCA-deficient cells, and more broadly, cells with HR deficiency (HRD), appear to be highly sensitive to PARP inhibition (Nat Rev Cancer 2004;4:814-9).

[0006] Hematological toxicity is a common adverse event associated with PARPi therapy. PARP2 has been shown to be required for the survival of hematopoietic stem / progenitor cells (HSPCs) under steady-state conditions and in response to stress (Blood. 2013 July 4;122(1):44-54). PARP inhibitors with improved selectivity for PARP1 may have improved efficacy and reduced toxicity compared with other clinical PARP1 / 2 inhibitors. Selective and potent inhibition of PARP1 is thought to result in the trapping of PARP1 on DNA, leading to DNA double-strand breaks (DSBs) via replication fork collapse in S phase. PARP1-DNA trapping may also be an effective mechanism for selectively killing tumor cells with HRD.

[0007] Thus, there is an unmet medical need for effective and safe PARP inhibitors, particularly PARP inhibitors that have selectivity for PARP1. Summary of the Invention

[0008] In one embodiment, provided herein are fused polycyclic compounds with polycyclic linkers as PARP1 inhibitors.

[0009] In one embodiment, the compound of formula (I)

[0010] [ka] or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, is provided herein, wherein

[0011] [ka] X 1 , X 2 , X 3 , X 4 , R a5 , Ring A, Y 1 , Y2 and R is as defined herein or elsewhere.

[0012] Also provided herein are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.

[0013] Also provided herein are methods for inhibiting PARP1 protein, comprising contacting the PARP1 protein with a compound provided herein or a pharmaceutical composition provided herein.

[0014] Also provided herein are methods for treating a PARP1-mediated disease or cancer, comprising administering to a subject having the disease or cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, those in this section prevail unless stated otherwise.

[0016] As used herein, and in the specification and appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents unless the context clearly dictates otherwise.

[0017] As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of a referenced feature or component, but do not exclude the presence or addition of one or more features, components, or groups thereof. Furthermore, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of." Thus, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments.

[0018] As used herein, the term "or" should be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B, or C" means any of the following: B; C; A and B; A and C; B and C; B and C; Exceptions to this definition occur only when combinations of elements, features, steps, or operations are in some way inherently mutually exclusive.

[0019] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both A and B; A or B; A alone; and B alone. Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0020] Note that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure is given more weight.

[0021] As used herein, unless otherwise specified, the term "alkyl" refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms. In one embodiment, an alkyl group is an alkyl group having, for example, 1 to 24 carbon atoms (C1 to C6). 24 alkyl), 4 to 20 carbon atoms (C4 to C 20 alkyl), 6 to 16 carbon atoms (C6 to C 16 alkyl), 6 to 9 carbon atoms (C6 to C9 alkyl), 1 to 15 carbon atoms (C1 to C 15 alkyl), 1 to 12 carbon atoms (C1 to C 12 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), or 1 to 6 carbon atoms (1-C6 alkyl), and are attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specified, alkyl groups are optionally substituted.

[0022] As used herein, unless otherwise specified, the term "alkenyl" refers to a straight or branched hydrocarbon chain radical, composed solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds. The term "alkenyl" also embraces radicals having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations, as understood by those of ordinary skill in the art. In one embodiment, an alkenyl group is an alkyl group having, for example, 2 to 24 carbon atoms (C2 to C6). 24 Alkenyl, 4 to 20 carbon atoms (C4 to C 20 Alkenyl, 6 to 16 carbon atoms (C6 to C 16 alkenyl), 6 to 9 carbon atoms (C6 to C9 alkenyl), 2 to 15 carbon atoms (C2 to C 15 Alkenyl), 2 to 12 carbon atoms (C2 to C 12Alkenyl groups have 2 to 8 carbon atoms (C2-C8 alkenyl), or 2 to 6 carbon atoms (C2-C6 alkenyl), and are attached to the rest of the molecule by a single bond. Examples of alkenyl groups include, but are not limited to, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless otherwise specified, alkenyl groups are optionally substituted.

[0023] As used herein, unless otherwise specified, the term "alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms containing one or more carbon-carbon triple bonds. In one embodiment, an alkynyl group is an alkynyl group of 2 to 24 carbon atoms (C2-C6). 24 Alkynyl group, 4 to 20 carbon atoms (C4 to C 20 Alkynyl group, 6 to 16 carbon atoms (C6 to C 16 Alkynyl groups), 6 to 9 carbon atoms (C6 to C9 alkynyl groups), 2 to 15 carbon atoms (C2 to C 15 Alkynyl group, 2 to 12 carbon atoms (C2 to C 12 Alkynyl groups have 2 to 8 carbon atoms (C2-C8 alkynyl groups), or 2 to 6 carbon atoms (C2-C6 alkynyl groups) and are attached to the rest of the molecule by a single bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specified, alkynyl groups are optionally substituted.

[0024] As used herein, unless otherwise specified, the term "cycloalkyl" refers to a saturated non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms. Cycloalkyl groups can include fused, bridged, or spiro ring systems. In one embodiment, cycloalkyl includes, for example, those having 3 to 15 ring carbon atoms (C3 to C6). 15 cycloalkyl), those having 3 to 10 ring carbon atoms (C3 to C 10Cycloalkyls are those having from 1 to 8 ring carbon atoms (C3-C8 cycloalkyl). Cycloalkyls are attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specified, cycloalkyl groups are optionally substituted.

[0025] As used herein, unless otherwise specified, the term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms and containing one or more carbon-carbon double bonds. Cycloalkenyls can include fused, bridged, or spiro ring systems. In one embodiment, cycloalkenyls include those having, for example, 3 to 15 ring carbon atoms (C3 to C6). 15 cycloalkenyl), those having 3 to 10 ring carbon atoms (C3 to C 10

[0023] Cycloalkenyls are those having from 1 to 8 ring carbon atoms (C3-C8 cycloalkenyl). A cycloalkenyl is attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Unless otherwise specified, cycloalkenyl groups are optionally substituted. Similarly, as used herein, unless otherwise specified, the term "cycloalkynyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms and containing one or more carbon-carbon triple bonds.

[0026] As used herein, unless otherwise specified, the term "heteroalkyl" refers to an alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, and phosphorus, or combinations thereof. Numerical ranges can be provided to refer to the total chain length. For example, the -CHOCHCH radical is referred to as a "C" heteroalkyl. The bond to the parent molecular structure can be through either a heteroatom or a carbon in the heteroalkyl chain. One or more heteroatoms in a heteroalkyl group can be optionally oxidized. One or more nitrogen atoms, if present, can be optionally quaternized. Unless otherwise specified, a heteroalkyl group is optionally substituted.

[0027] As used herein, unless otherwise specified, the term "aryl" refers to a monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic hydrocarbon ring. In certain embodiments, an aryl has 6 to 18 ring carbon atoms (C6 to C8). 18 aryl), having 6 to 14 ring carbon atoms (C6 to C 14 aryl), or having 6 to 10 ring carbon atoms (C6 to C 10 Aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The term "aryl" also refers to bicyclic, tricyclic, or other polycyclic hydrocarbon rings, where at least one ring is aromatic and the others may be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). Unless otherwise specified, aryl groups are optionally substituted.

[0028] As used herein, unless otherwise specified, the term "heteroaryl" refers to a monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., 1, 1 or 2, 1 to 3, or 1 to 4) heteroatoms independently selected from O, S, and N. A heteroaryl may be attached to the main structure at any heteroatom or carbon atom. In certain embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. The term "heteroaryl" also refers to bicyclic, tricyclic, or other polycyclic rings, wherein at least one of the rings is aromatic and the others may be saturated, partially unsaturated, or aromatic, and wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, and xanthenyl. Unless otherwise specified, heteroaryl groups are optionally substituted.

[0029] As used herein, unless otherwise specified, the term "heterocyclyl" refers to a monocyclic and / or polycyclic non-aromatic group containing one or more (e.g., 1, 1 or 2, 1 to 3, or 1 to 4) heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocyclyl may be attached to the main structure at any heteroatom or carbon atom. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other polycyclic ring system, where the polycyclic ring system may be a fused, bridged, or spiro ring system. A heterocyclyl polycyclic ring system can contain one or more heteroatoms in one or more rings. A heterocyclyl group can be saturated or partially unsaturated. A saturated heterocyclyl group can be referred to as a "heterocycloalkyl." Partially unsaturated heterocyclyl groups can be referred to as "heterocycloalkenyl" if the heterocyclyl contains at least one double bond or "heterocycloalkynyl" if the heterocyclyl contains at least one triple bond. In one embodiment, the heterocyclyl has, for example, 3 to 18 ring atoms (3- to 18-membered heterocyclyl), 4 to 18 ring atoms (4- to 18-membered heterocyclyl), 5 to 18 ring atoms (5- to 18-membered heterocyclyl), 4 to 8 ring atoms (4- to 8-membered heterocyclyl), or 5 to 8 ring atoms (5- to 8-membered heterocyclyl). Examples of heterocyclyl groups include, but are not limited to, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and piperidinyl. Unless otherwise specified, a heterocyclyl group is optionally substituted.

[0030] Whenever described herein, a numerical range such as "3 to 18" refers to each integer within the given range. For example, a heterocyclyl having "3 to 18 ring atoms" means that the heterocyclyl group can consist of up to 18 ring atoms, such as 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc. Similarly, a C1-C6 alkyl means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.

[0031] As used herein, unless otherwise stated, a "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups can be substituted on the alkyl, cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, and the like.

[0032] As used herein, unless otherwise specified, an "aralkyl" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups may be substituted on 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 aralkyl groups in which the aryl group is fused to a cycloalkyl group (e.g., indan-4-ylethyl).

[0033] As used herein, unless otherwise specified, other similar compound terms reflect the above descriptions for "cycloalkylalkyl" and "aralkyl." For example, a "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. A "heteroarylalkyl" group is a radical of the formula: -alkyl-heteroaryl, where alkyl and heteroaryl are defined above. A "heterocycloalkylalkyl" group is a radical of the formula: -alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above.

[0034] As used herein, unless otherwise stated, the terms "halogen," "halide," or "halo" refer to fluorine, chlorine, bromine, and / or iodine. As used herein, unless otherwise stated, the terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" refer to alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof.

[0035] As used herein, unless otherwise specified, the term "alkoxy" refers to -O(alkyl), where alkyl is defined above. As used herein, unless otherwise specified, the term "aryloxy" refers to -O-(aryl), where aryl is defined above.

[0036] As used herein, unless otherwise stated, the term "alkylsulfonyl" refers to -SO2-alkyl, where alkyl is defined above.

[0037] As used herein, unless otherwise specified, the terms "carboxyl" and "carboxy" refer to --COOH.

[0038] As used herein, unless otherwise stated, the term "alkoxycarbonyl" refers to -C(=O)O-(alkyl), where alkyl is defined above. As used herein, unless otherwise stated, the term "arylalkyloxy" refers to -O-(alkyl)-(aryl), where alkyl and aryl are defined above. As used herein, unless otherwise stated, the term "cycloalkyloxy" refers to -O-(cycloalkyl), where cycloalkyl is defined above. As used herein, unless otherwise stated, the term "cycloalkylalkyloxy" refers to -O-(alkyl)-(cycloalkyl), where cycloalkyl and alkyl are defined above.

[0039] As used herein, unless otherwise specified, the term "acyl" refers to a group consisting of -C(O)-R a refers to R a may be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. a may be unsubstituted or substituted with one or more substituents.

[0040] As used herein, unless otherwise specified, the term "acyloxy" refers to -OC(O)-R a refers to R a may be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. a may be unsubstituted or substituted with one or more substituents.

[0041] As used herein, unless otherwise specified, the term "amino" refers to -N(R # )(R # ) and each R #may independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. # )(R # ) groups are two R other than hydrogen # , they can be attached to the nitrogen atom to form a ring. In one embodiment, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In one embodiment, one or more ring atoms is a heteroatom independently selected from O, S, or N. The term "amino" also refers to an N-oxide (-N + (R # )(R # )O - In certain embodiments, each R # or -N(R # )(R # ) can independently be unsubstituted or substituted with one or more substituents.

[0042] As used herein, unless otherwise specified, the term "amide" refers to -C(O)N(R # )2 or -NR # C(O)R # (In the formula, each R # may independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. aC(O)N(R # )2 groups are two R other than hydrogen. # In certain embodiments, each R may be bonded to the nitrogen atom to form a ring. In one embodiment, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In one embodiment, one or more ring atoms is a heteroatom independently selected from O, S, or N. In certain embodiments, each R # or -N(R # )(R # ) may independently be unsubstituted or substituted with one or more substituents.

[0043] As used herein, unless otherwise stated, the term "aminoalkyl" refers to -(alkyl)-(amino), where alkyl and amino are defined above. As used herein, unless otherwise stated, the term "aminoalkoxy" refers to -O-(alkyl)-(amino), where alkyl and amino are defined above.

[0044] As used herein, unless otherwise stated, the term "alkylamino" refers to -NH(alkyl) or -N(alkyl)(alkyl), where alkyl is defined above. Examples of such alkylamino groups include, but are not limited to, NHCH, -NHCHCH, -NH(CH)CH, -NH(CH)CH, -NH(CH)CH, -NH(CH)CH, -NH(CH)CH, -N(CH), -N(CHCH), -N((CH)CH), -N(CH)(CHCH), and the like.

[0045] As used herein, unless otherwise specified, the term "arylamino" refers to -NH(aryl) or -N(aryl)(aryl), where aryl is defined above. As used herein, unless otherwise specified, similar compound terms such as "arylalkylamino" and "cycloalkylamino" reflect the above descriptions for "alkylamino" and "arylamino."

[0046] As used herein, unless otherwise specified, the terms "sulfanyl," "sulfido," or "thio" refer to -SR a refers to R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.

[0047] As used herein, unless otherwise specified, the term "sulfoxide" refers to -S(O)-R a refers to R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.

[0048] As used herein, unless otherwise specified, the term "sulfonyl" or "sulfone" refers to -S(O)-R a refers to R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.

[0049] As used herein, unless otherwise specified, the term "sulfonamide" or "sulfonamido" refers to -S(=O)2-N(R # )2 or -N(R # -S(=O)2-R # (wherein each R # may independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. # ) Two groups other than hydrogen R # When R 1 has a nitrogen atom, they can be attached to the nitrogen atom to form a ring. In one embodiment, the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In one embodiment, one or more ring atoms is a heteroatom independently selected from O, S, or N. In certain embodiments, each R # or -N(R # )(R #) may independently be unsubstituted or substituted with one or more substituents.

[0050] "Azide" refers to the -N3 radical.

[0051] "Cyano" refers to the -CN radical.

[0052] "Nitro" refers to the -NO2 radical.

[0053] "Oxa" refers to the -O- radical.

[0054] "Oxo" refers to the =O radical.

[0055] As used herein, unless otherwise specified, the term "optional" or "optionally" (e.g., optionally substituted) means that the subsequently described circumstance event may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may be substituted or unsubstituted, and that the description includes both substituted and unsubstituted alkyl groups.

[0056] When groups described herein are said to be "substituted," they may be substituted with any suitable substituent(s). Illustrative examples of substituents include, but are not limited to, those found in the exemplary compounds and embodiments provided herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxo(=O); B(OH), O(alkoxy ... cycloalkyl, which may be a single ring or multiple fused or non-fused rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl, which may be a single ring or multiple fused or non-fused rings (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused multiple rings; aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0057] As used herein, unless otherwise specified, the term "isomer" refers to different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Atropisomers" are stereoisomers resulting from restricted rotation about a single bond. "Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion may be known as a "racemic" mixture. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light within the wavelength of the sodium D line. However, the sign of optical rotation, i.e., (+) and (-), is independent of the absolute configuration of the molecule, i.e., R and S. Certain compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomers that may be defined as (R)- or S-, with respect to the absolute stereochemistry at each asymmetric atom. The chemical compounds, pharmaceutical compositions, and methods of the present invention are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0058] "Stereoisomer" can also include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds described herein are isolated as either the E or Z isomer. In other embodiments, the compounds described herein are a mixture of E and Z isomers.

[0059] "Tautomer" refers to isomers of a compound that are in equilibrium with each other. The concentration of isomers depends on the environment in which the compound is found, and can vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomers, called tautomers of each other:

[0060] [ka]

[0061] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salts" includes both acid and base addition salts.

[0062] Examples of pharmaceutically acceptable acid addition salts include those with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-hydroxyethanesulfonic ... oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0063] Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts prepared from the addition of an inorganic base or an organic base to a free acid compound. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In one embodiment, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins (e.g., ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like). In one embodiment, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0064] As used herein, unless otherwise specified, the term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., with reference to a mammalian subject, such as a human subject. In one embodiment, the subject is a human. In one embodiment, the subject is a human.

[0065] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" refer to the eradication or amelioration of a disease or disorder, or one or more symptoms associated with a disease or disorder. Generally, treatment is performed after the onset of a disease or disorder. In certain embodiments, the term refers to minimizing the spread or worsening of a disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with a disease or disorder.

[0066] As used herein, unless otherwise specified, the terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of a disease or disorder, or one or more symptoms thereof. Generally, prevention occurs before the onset of a disease or disorder.

[0067] As used herein, unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease or disorder, or one or more symptoms thereof. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disease or disorder.

[0068] As used herein, unless otherwise specified, the term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to that amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or clinician.

[0069] As used herein, unless otherwise specified, "IC 50 The term "maximal inhibition" refers to the amount, concentration, or dose of a compound required for 50% inhibition of a maximal response in an assay that measures such response.

[0070] As used herein, unless otherwise specified, the terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. ,Remington:The Science and Practice of Pharmacy,21st Edition,Lippincott Williams &Wilkins:Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients,5th Edition,Rowe et al.,Eds.,The Pharmaceutical Press and the American Pharmaceutical Association:2005;and Handbook of Pharmaceutical Additives,3rd Edition,Ash and Ash Eds.,Gower Publishing Company:2007;Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.

[0071] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that can be incorporated into the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O.17 O. 31 P, 32 P, 35 S, 18 F, and 36 For example, substitution or enrichment of hydrogen with deuterium or tritium at one or more atoms in a molecule, or 13 C or 14 Provided herein are compounds having the structures of the present invention except for the replacement or enrichment of a carbon with C. In one embodiment, provided herein are isotopically labeled compounds in which one or more hydrogen atoms have been replaced or enriched with deuterium. In one embodiment, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced or enriched with tritium. In one embodiment, provided herein are isotopically labeled compounds in which one or more carbon atoms have been replaced or enriched with tritium. 13 In one embodiment, provided herein are isotopically labeled compounds substituted or enriched with C. 14 isotopically labeled compounds having one or more carbon atoms substituted or enriched with C.

[0072] As used herein, unless otherwise specified, the term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0073] compound In one embodiment, provided herein are fused polycyclic compounds with polycyclic linkers as PARP1 inhibitors. In one embodiment, provided herein are bicyclic or tricyclic compounds with an octahydropyrrolo[3,4-c]pyrrole (in one particular embodiment, a particular stereoisomer of octahydropyrrolo[3,4-c]pyrrole) linker as PARP1 inhibitors.

[0074] In one embodiment, provided herein are compounds of formula (I):

[0075] [ka] or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein

[0076] [ka] is a single or double bond, X 1 is CR a1 , C(R a1 )2, or NR a1 and X 2 is CR a2 , C(R a2 )2, N, NR a2 , or O, Each R a1 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; Each R a2 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; R a1 and R a2 form a 3- to 6-membered ring B together with the atoms to which they are attached; X 3 is CR a3 or N and R a3is hydrogen, C1-C6 alkyl, or halogen, X 4 is CR a4 or N and R a4 is hydrogen, C1-C6 alkyl, or halogen, R a5 is hydrogen, C1-C6 alkyl, or halogen, Ring A is a fused, bridged, or spiroheterocyclyl; Y 1 is CR 2 or N, Y 2 is CR 2 or N, Each R 2 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl; R is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)-R 3 , -C(=O)-OR 3 , -C(=O)-NHR 3 , -S(O)2-R 3 , -NH-C(=O)-R 3 or nitro, R 3 is hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)-(C1-C6 alkyl), C3-C8 cycloalkyl, or 4-10 membered heterocyclyl, and alkyl, cycloalkyl, alkoxy, heterocyclyl, Ring A, and Ring B are optionally substituted; however,

[0077] [ka] but

[0078] [ka] When (i) ring A is a fused or spiro heterocyclyl, or (ii) R is —C(═O)—NHR 3 is.

[0079] In one embodiment, provided herein are compounds of formula (I):

[0080] [ka] or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein

[0081] [ka] is a single or double bond, X 1 is CR a1 , C(R a1 )2, or NR a1 and X 2 is CR a2 , C(R a2 )2, N, NR a2 , or O, Each R a1 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; Each R a2 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; R a1 and R a2 form a 3- to 6-membered ring B together with the atoms to which they are attached; X 3 is CR a3 or N and R a3 is hydrogen, C1-C6 alkyl, or halogen, X 4 is CR a4 or N and R a4 is hydrogen, C1-C6 alkyl, or halogen, R a5 is hydrogen, C1-C6 alkyl, or halogen, Ring A is a fused, bridged, or spiroheterocyclyl; Y 1 is CR 2 or N, Y 2 is CR 2 or N, Each R 2 are independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl; R is halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)-R 3 , -C(=O)-OR 3 , -C(=O)-NHR 3 , -S(O)2-R 3 , -NH-C(=O)-R 3 or nitro, R 3 is hydrogen, C1-C6 alkyl, (C1-C6 alkoxy)-(C1-C6 alkyl), or C3-C8 cycloalkyl, and alkyl, cycloalkyl, alkoxy, Ring A, and Ring B are optionally substituted; however,

[0082] [ka] but

[0083] [ka] When (i) ring A is a fused or spiro heterocyclyl, or (ii) R is —C(═O)—NHR 3 is.

[0084] In one embodiment, X 1 is CR a1 In one embodiment, X 1is C-(C1-C6 alkyl). In one embodiment, X 1 is C-C-C cycloalkyl). 1 is C-(C1-C6 alkoxy). 1 is C-(n-propyl) or C-(iso-propyl). 1 is C-(n-butyl), C-(iso-butyl), or C-(tert-butyl). 1 is C-(C alkyl). In one embodiment, X 1 is C-(C alkyl). In one embodiment, X 1 is C-(cyclopropyl). In one embodiment, X 1 is C-(cyclobutyl). In one embodiment, X 1 is C-(cyclopentyl). In one embodiment, X 1 is C-(cyclohexyl). In one embodiment, X 1 is C-(cycloheptyl). In one embodiment, X 1 is C-(cyclooctyl). In one embodiment, X 1 is C-methoxyl. In one embodiment, X 1 is C-ethoxyl. In one embodiment, X 1 is C-(Calkoxy). In one embodiment, X 1 is C-(C4 alkoxy). In one embodiment, X 1 is C-(C5 alkoxy). In one embodiment, X 1 is C-(C6 alkoxy).

[0085] In one embodiment, X 1 is C(R a1 )2. In one embodiment, X 1 is C-(C1-C6 alkyl). In one embodiment, X 1 is C-(C-C cycloalkyl). In one embodiment, X 1 is C-(C1-C6 alkoxy)2.

[0086] In one embodiment, X 1 is NR a1 In one embodiment, X 1 is N—(C1-C6 alkyl). In one embodiment, X 1 is N-(C-C cycloalkyl). In one embodiment, X 1 is N-(C1-C6 alkoxy).

[0087] In one embodiment, X 1 is CH. In one embodiment, X 1 is C—CH3. In one embodiment, X 1 is C-C2H5. In one embodiment, X 1 is C—OCH3. In one embodiment, X 1 is NH. In one embodiment, X 1 is CH-CH3. In one embodiment, X 1 is CH-C2H5.

[0088] In one embodiment, X 2 is CR a2 In one embodiment, X 2 is C-(C1-C6 alkyl). In one embodiment, X 2 is C-C-C cycloalkyl). 2 is C-(C1-C6 alkoxy). 2 is C-(n-propyl) or C-(iso-propyl). 2 is C-(n-butyl), C-(iso-butyl), or C-(tert-butyl). 2 is C-(C alkyl). In one embodiment, X 2 is C-(C alkyl). In one embodiment, X 2 is C-(cyclopropyl). In one embodiment, X 2 is C-(cyclobutyl). In one embodiment, X 2is C-(cyclopentyl). In one embodiment, X 2 is C-(cyclohexyl). In one embodiment, X 2 is C-(cycloheptyl). In one embodiment, X 2 is C-(cyclooctyl). In one embodiment, X 2 is C-methoxyl. In one embodiment, X 2 is C-ethoxyl. In one embodiment, X 2 is C-(Calkoxy). In one embodiment, X 2 is C-(C4 alkoxy). In one embodiment, X 2 is C-(C5 alkoxy). In one embodiment, X 2 is C-(C6 alkoxy).

[0089] In one embodiment, X 2 is C(R a2 )2. In one embodiment, X 2 is C-(C1-C6 alkyl). In one embodiment, X 2 is C-(C-C cycloalkyl). In one embodiment, X 2 is C-(C1-C6 alkoxy)2.

[0090] In one embodiment, X 2 is NR a2 In one embodiment, X 2 is N—(C1-C6 alkyl). In one embodiment, X 2 is N-(C-C cycloalkyl). In one embodiment, X 2 is N-(C1-C6 alkoxy).

[0091] In one embodiment, X 2 is CH. In one embodiment, X 2 is N. In one embodiment, X 2 is O.

[0092] In one embodiment, X 1 is CR a1and X 2 is CH. In one embodiment, X 1 is CR a1 and X 2 is N. In one embodiment, X 1 is CHR a1 and X 2 is O.

[0093] In one embodiment, X 1 is C-CH3, and X 2 is CH. In one embodiment, X 1 is C-C2H5, and X 2 is CH. In one embodiment, X 1 is C-CH3, and X 2 is N. In one embodiment, X 1 is C-C2H5, and X 2 is N. In one embodiment, X 1 is CH-CH3, and X 2 is O. In one embodiment, X 1 is CH-C2H5, and X 2 is O.

[0094] In one embodiment, Y 1 is CR 2 In one embodiment, Y 1 is a C-halogen. 1 is C-(C1-C6 alkyl). In one embodiment, Y 1 is C-(C1-C6 alkoxy). 1 is CH. In one embodiment, Y 1 is CF. In one embodiment, Y 1 is N.

[0095] In one embodiment, Y 2 is CR 2 In one embodiment, Y 2 is a C-halogen. 2 is C-(C1-C6 alkyl). In one embodiment, Y2 is C-(C1-C6 alkoxy). 2 is CH. In one embodiment, Y 2 is CF. In one embodiment, Y 2 is N.

[0096] In one embodiment, Y 1 is CR 2 and Y 2 is N. In one embodiment, Y 1 is N and Y 2 is CR 2 In one embodiment, Y 1 is CR 2 and Y 2 is CR 2 In one embodiment, Y 1 is N and Y 2 is N.

[0097] In one embodiment, Y 1 is CH and Y 2 In one embodiment, Y 1 is CF and Y 2 In one embodiment, Y 1 N and Y 2 is CH. In one embodiment, Y 1 is N and Y 2 is CF.

[0098] In one embodiment, R is halogen. In one embodiment, R is C1-C6 alkyl. In one embodiment, R is C1-C6 alkoxy. In one embodiment, R is -C(=O)-R 3 In one embodiment, R is -C(=O)-OR 3 In one embodiment, R is -S(O)-R 3 In one embodiment, R is —NH—C(═O)—R 3 In one embodiment, R is nitro. In one embodiment, R is -CN. In one embodiment, R is -C(=O)-NHR 3In one embodiment, R is -C(=O)-NHR 3 and R 3 is a C3-C8 cycloalkyl or a 4-10 membered heterocyclyl.

[0099] In one embodiment, R is -C(=O)-NH-(C1-C6 alkyl). In one embodiment, R is -C(=O)-NH-(C3-C8 cycloalkyl). In one embodiment, R is -C(=O)-NH-(C3-C6 cycloalkyl). In one embodiment, R is -C(=O)-NH-(4- to 10-membered heterocyclyl). In one embodiment, R is -C(=O)-NH-(4- to 6-membered heterocyclyl). In one embodiment, R is -C(=O)-NH-(4- to 6-membered oxygen-containing heterocyclyl). In one embodiment, R is -C(=O)-(C1-C6 alkyl). In one embodiment, R is -C(=O)-(C3-C8 cycloalkyl). In one embodiment, R is -C(=O)-O-(C1-C6 alkyl). In one embodiment, R is -C(=O)-O-(C3-C8 cycloalkyl). In one embodiment, R is -NH-C(=O)-(C1-C6 alkyl). In one embodiment, R is -NH-C(=O)-(C3-C8 cycloalkyl). In one embodiment, R is -NH-C(=O)-(4- to 10-membered heterocyclyl). In one embodiment, R is -NH-C(=O)-(4- to 6-membered heterocyclyl). In one embodiment, R is -S(O)2-(C1-C6 alkyl). In one embodiment, R is -S(O)2-(C3-C8 cycloalkyl). In one embodiment, R is C(=O)-NH2. In one embodiment, R is C(=O)-NH-CH3. In one embodiment, R is C(=O)-NH-CH2CH2OCH3. In one embodiment, R is C(=O)-NH-cyclopropyl. In one embodiment, R is C(=O)-NH-cyclobutyl.

[0100] In one embodiment, R is selected from the group consisting of:

[0101] [ka] In one embodiment, provided herein is a compound of formula (IA):

[0102] [ka]

[0103] or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0104] In one embodiment,

[0105] [ka] is a double bond.

[0106] In one embodiment,

[0107] [ka] is a double bond, and X 1 is CR a1 In one embodiment,

[0108] [ka] is a double bond, and X 1 is CH. In one embodiment,

[0109] [ka] is a double bond, and X 1 is C—CH3. In one embodiment,

[0110] [ka] is a double bond, and X 1 is C—CH2CH3. In one embodiment,

[0111] [ka] is a double bond, and X 1 is C-OCH3.

[0112] In one embodiment,

[0113] [ka] is a double bond, and X 2 is CR a2 In one embodiment,

[0114] [ka] is a double bond, and X 2 is CH. In one embodiment,

[0115] [ka] is a double bond, and X 2 is C—CH3. In one embodiment,

[0116] [ka] is a double bond, and X 2 is C—CH2CH3. In one embodiment,

[0117] [ka] is a double bond, and X 2 is N.

[0118] In one embodiment,

[0119] [ka] is a double bond, and X 1 is CR a1 and X 2 is N. In one embodiment,

[0120] [ka] is a double bond, and X 1 is CR a1 and X 2 is CR a2 In one embodiment,

[0121] [ka] is a double bond, and X 1 is N and X 2 is CR a2 is.

[0122] In one embodiment,

[0123] [ka] is a double bond, and X 1 is C-CH3, and X 2 is CH. In one embodiment,

[0124] [ka] is a double bond, and X 1 is C-C2H5, and X2 is CH. In one embodiment,

[0125] [ka] is a double bond, and X 1 is C-CH3, and X 2 is N. In one embodiment,

[0126] [ka] is a double bond, and X 1 is C-OCH3, and X 2 is CH.

[0127] In one embodiment,

[0128] [ka] is a single bond.

[0129] In one embodiment,

[0130] [ka] is a single bond, and X 1 is C(R a1 )2. In one embodiment,

[0131] [ka] is a single bond, and X 1 is CHR a1 In one embodiment,

[0132] [ka] is a single bond, and X 1 is CH-CH3. In one embodiment,

[0133] [ka] is a single bond, and X 1 is CH-CH2CH3.

[0134] In one embodiment,

[0135] [ka] is a single bond, and X 1 is NR a1 is.

[0136] In one embodiment,

[0137] [ka] is a single bond, and X 2 is O. In one embodiment,

[0138] [ka] is a single bond, and X 2 is NR a2 is.

[0139] In one embodiment,

[0140] [ka] is a single bond, and X 1 is CH(R a1 ) and X 2 is O. In one embodiment,

[0141] [ka] is a single bond, and X 1 is CH(R a1 ) and X 2 is NR a2 In one embodiment,

[0142] [ka] is a single bond, and X 1 is N(R a1 ) and X 2 is CR a2 is.

[0143] In one embodiment,

[0144] [ka] is a single bond, and X 1 is CH-C2H3, and X 2 is O. In one embodiment,

[0145] [ka] is a single bond, and X 1 is CH-CH3, and X 2 is O.

[0146] In one embodiment,

[0147] [ka] is a single bond, and X 1 , X 2 is R a1 and R a2 together to form a 3- to 6-membered ring B. In one embodiment,

[0148] [ka] is a single bond, and X 1 , X 2 is R a1 and R a2 together with

[0149] [ka] is a single bond, and X 1 , X 2 is R a1 and R a2 together with and form a 3- to 6-membered heterocyclyl.

[0150] [ka] is a single bond, and X 1 , X 2 is R a1 and R a2 together with

[0151] [ka] is a single bond, and X 1 , X 2 is R a1 and R a2 together with form a 5-membered heterocyclyl.

[0152] In one embodiment, R a1 is hydrogen. In one embodiment, R a1 is C1-C6 alkyl. In one embodiment, R a1 is C3-C8 cycloalkyl. In one embodiment, R a1 is C1-C6 alkoxy.

[0153] In one embodiment, R a1 is C1-C4 alkyl. In one embodiment, R a1 is C1-C4 fluoroalkyl. a1 is methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl, or methoxy. a1 is methyl. In one embodiment, R a1 is ethyl. In one embodiment, R a1 is cyclopropyl. In one embodiment, R a1 is methoxy.

[0154] In one embodiment, R a2 is hydrogen. In one embodiment, R a2 is C1-C6 alkyl. In one embodiment, R a2 is C3-C8 cycloalkyl. In one embodiment, R a2 is cyclopropyl. In one embodiment, R a2 is C1-C6 alkoxy. In one embodiment, R a2 is methoxy. In one embodiment, R a1 is methyl and R a2 is hydrogen. In one embodiment, R a1 is ethyl, and R a2 is hydrogen.

[0155] In one embodiment, R a1 and R a2 together with the atoms to which they are attached form a 3- to 6-membered ring B.

[0156] In one embodiment, the compound is of formula (IB), (IC), or (ID).

[0157] [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0158] In one embodiment, the compound is of formula (IB-1), (IC-1), or (ID-1).

[0159] [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof; During the ceremony m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; Z is O or C(R 4 )2; and Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0160] In one embodiment, Ring B is phenyl. In one embodiment, Ring B is 5- to 6-membered heteroaryl. In one embodiment, Ring B is 3- to 6-membered cycloalkyl. In one embodiment, Ring B is 3- to 6-membered heterocyclyl. In one embodiment, Ring B is 4- to 6-membered heterocyclyl. In one embodiment, Ring B is 4- to 5-membered heterocyclyl. In one embodiment, Ring B is 4- to 6-membered oxygen-containing heterocyclyl.

[0161] In one embodiment, ring B is a 3-membered heterocyclyl. In one embodiment, ring B is a 4-membered heterocyclyl. In one embodiment, ring B is a 5-membered heterocyclyl. In one embodiment, ring B is a 6-membered heterocyclyl. In one embodiment, ring B is a 4-5-membered heterocyclyl containing at least one ring nitrogen atom. In one embodiment, ring B contains at least one ring oxygen atom. In one embodiment, ring B contains only one ring oxygen atom. In one embodiment, ring B is a 5-membered heterocyclyl containing one ring oxygen atom. In one embodiment, ring B is a 6-membered heterocyclyl containing one ring oxygen atom.

[0162] In one embodiment, Ring B is a 5-membered heteroaryl. In one embodiment, Ring B is a 5-membered heteroaryl containing at least one ring nitrogen atom. In one embodiment, Ring B is a 5-membered heteroaryl containing at least one ring oxygen atom.

[0163] In one embodiment, Ring B is a 4- to 6-membered cycloalkyl. In one embodiment, Ring B is a 4- to 5-membered cycloalkyl. In one embodiment, Ring B is a 4-membered cycloalkyl. In one embodiment, Ring B is a 5-membered cycloalkyl. In one embodiment, Ring B is a 6-membered cycloalkyl.

[0164] In one embodiment, Ring B is a 4- to 6-membered cycloalkenyl. In one embodiment, Ring B is a 4- or 5-membered cycloalkenyl. In one embodiment, Ring B is a 4-membered cycloalkenyl. In one embodiment, Ring B is a 5-membered cycloalkenyl. In one embodiment, Ring B is a 6-membered cycloalkenyl.

[0165] In one embodiment, ring B is a pyrrole ring. In one embodiment, ring B is a pyrrolidine ring. In one embodiment, ring B is an imidazole ring. In one embodiment, ring B is a cyclopentane ring. In one embodiment, ring B is a cyclopentene ring. In one embodiment, ring B is a cyclohexane ring. In one embodiment, ring B is a cyclohexene ring. In one embodiment, ring B is a tetrahydrofuran ring. In one embodiment, ring B is an adihydrofuran ring. In one embodiment, ring B is a tetrahydropyran ring. In one embodiment, ring B is a dihydropyran ring.

[0166] In one embodiment, Ring B is substituted. In one embodiment, Ring B is substituted with one or more halogen, —CN, C1-C6 alkyl, C1-C6 alkoxy, or nitro. In one embodiment, Ring B is substituted with fluoro. In one embodiment, Ring B is substituted with chloro. In one embodiment, Ring B is substituted with bromo. In one embodiment, Ring B is substituted with cyano. In one embodiment, Ring B is substituted with nitro. In one embodiment, Ring B is substituted with methyl. In one embodiment, Ring B is substituted with ethyl. In one embodiment, Ring B is substituted with methoxy. In one embodiment, Ring B is substituted with ethoxy.

[0167] In one embodiment, Ring B is unsubstituted.

[0168] In one embodiment, X 3 is CR a3 In one embodiment, X 3 is C-(C1-C6 alkyl). In one embodiment, X 3 is a C-halogen. In one embodiment, X 3 is CH. In one embodiment, X 3 is N.

[0169] In one embodiment, X 4 is CR a4In one embodiment, X 4 is C-(C1-C6 alkyl). In one embodiment, X 4 is a C-halogen. In one embodiment, X 4 is CH. In one embodiment, X 4 is N.

[0170] In one embodiment, X 3 is N and X 4 is CR a4 In one embodiment, X 3 is CR a3 and X 4 is CR a4 In one embodiment, X 3 is CR a3 and X 4 is N.

[0171] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 3 is N. In one embodiment, X 1 is CR a1 and X 2 is N and X 3 is CR a3 In one embodiment, X 1 is CHR a1 and X 2 is O and X 3 is CR a3 In one embodiment, X 1 is CHR a1 and X 2 is N and X 3 is CR a3 In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 3 is CR a3 In one embodiment, X 1 is NR a1 and X 2 is CRa2 and X 3 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and X 3 is CR a3 is.

[0172] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 4 is N. In one embodiment, X 1 is CR a1 and X 2 is N and X 4 is CR a4 In one embodiment, X 1 is CHR a1 and X 2 is O and X 4 is CR a4 In one embodiment, X 1 is CHR a1 and X 2 is N and X 4 is CR a4 In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 4 is CR a4 In one embodiment, X 1 is NR a1 and X 2 is CR a2 and X 4 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and X 4 is CR a4 is.

[0173] In one embodiment, X 1 is CR a1 and X 2 is CRa2 and X 3 is N and X 4 is CR a4 In one embodiment, X 1 is CR a1 and X 2 is N and X 3 is CR a3 and X 4 is CR a4 In one embodiment, X 1 is CR a1 and X 2 is N and X 3 is N and X 4 is CR a4 In one embodiment, X 1 is CHR a1 and X 2 is O and X 3 is N and X 4 is CR a4 In one embodiment, X 1 is CHR a1 and X 2 is O and X 3 is CR a3 and X 4 is CR a4 In one embodiment, X 1 is CHR a1 and X 2 N and X 3 is CR a3 and X 4 is N. In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 3 is CR a3 and X 4 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and X 3 N and X 4 is CR a4 In one embodiment, X 1 is NR a1 and X2 is CR a2 and X 3 is CR a3 and X 4 is CR a4 is.

[0174] In one embodiment, the compound has formulas (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), ( II-I), (II-J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P), (II-Q), (II-R), (I I-S), (II-T), (II-U), (II-V), (II-W), (II-X), (II-Y), (II-Z), (II-AA), (II-AB), (II-AC), (II-AD), (II-AE), (II-AF), (II-AG), (II-AH), (II-AI), or (II-AJ).

[0175] [ka]

[0176] [ka]

[0177] [ka]

[0178] [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0179] In one embodiment, the compound is of formula (II-V-1), (II-AA-1), (II-AB-1), or (II-AI-1).

[0180] [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof; During the ceremony m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; Z is O or C(R 4 )2; and Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0181] In one embodiment of formula (II-D) (or a subformula thereof), ring A is

[0182] [ka] where: * is ring A and X 4 In one embodiment of formula (II-D) (or a subformula thereof), ring A is

[0183] [ka] where: * is the ring A and X 4 The methylene group connecting the ring containing the formula (I) is directed toward the methylene group connecting the ring containing the formula (I).

[0184] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and Y 1 is CR 2 In one embodiment, X 1 is CR a1 and X 2 is N and Y 1 is CR 2 In one embodiment, X 1 is CHRa1 and X 2 is O and Y 1 is CR 2 In one embodiment, X 1 is CHR a1 and X 2 is N and Y 1 is CR 2 In one embodiment, X 1 is CR a1 and X 2 is CR a2 and Y 1 is CR 2 In one embodiment, X 1 is NR a1 and X 2 is CR a2 and Y 1 is CR 2 In one embodiment, X 1 is NR a1 and X 2 is CR a2 and Y 1 is CR 2 is.

[0185] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CR a1 and X 2 N and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CHR a1 and X 2 is O and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CHR a1 and X 2 is N and Y 1 is CR2 and Y 2 is N. In one embodiment, X 1 is CR a1 and X 2 is CR a2 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and Y 1 is CR 2 and Y 2 is N.

[0186] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 4 is N and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CR a1 and X 2 is N and X 4 is CR a4 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CHR a1 and X 2 is O and X 4 is CR a4 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CHR a1 and X 2 is N and X4 is CR a4 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 4 is CR a4 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and X 4 is N and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and X 4 is CR a4 and Y 1 is CR 2 and Y 2 is N.

[0187] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 3 is N and X 4 is CR a4 and Y 1 is CR 2 and Y 2 In one embodiment, X 1 is CR a1 and X 2 is N and X 3 is CR a3 and X 4 is CR a4 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1is CR a1 and X 2 is N and X 3 is N and X 4 is CR a4 and Y 1 is CR 2 and Y 2 In one embodiment, X 1 is CHR a1 and X 2 is O and X 3 is N and X 4 is CR a4 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CHR a1 and X 2 is O and X 3 is CR a3 and X 4 is CR a4 and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CHR a1 and X 2 is N and X 3 is CR a3 and X 4 is N and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 3 is CR a3 and X 4 is N and Y 1 is CR 2 and Y 2 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and X 3 is N and X 4 is CR a4 and Y1 is CR 2 and Y 2 is N. In one embodiment, X 1 is NR a1 and X 2 is CR a2 and X 3 is CR a3 and X 4 is CR a4 and Y 1 is CR 2 and Y 2 is N.

[0188] In one embodiment, R a5 is C1-C6 alkyl. In one embodiment, R a5 is methyl. In one embodiment, R a5 is ethyl. In one embodiment, R a5 is n-propyl or isopropyl. In one embodiment, R a5 is n-butyl, iso-butyl or tert-butyl. a5 is C5 alkyl. In one embodiment, R a5 is C alkyl. In one embodiment, R a5 is halogen. In one embodiment, R a5 is fluoro. In one embodiment, R a5 is chloro. In one embodiment, R a5 is bromo. In one embodiment, R a5 is hydrogen.

[0189] In one embodiment, ring A is a fused heterocyclyl. In one embodiment, ring A is a 6- to 12-membered fused heterocyclyl. In one embodiment, ring A is a 6-membered fused heterocyclyl. In one embodiment, ring A is a 7-membered fused heterocyclyl. In one embodiment, ring A is an 8-membered fused heterocyclyl. In one embodiment, ring A is a 9-membered fused heterocyclyl. In one embodiment, ring A is a 10-membered fused heterocyclyl. In one embodiment, ring A is an 11-membered fused heterocyclyl. In one embodiment, ring A is a 12-membered fused heterocyclyl. In one embodiment, ring A is a fused bicyclic heterocyclyl.

[0190] In one embodiment, ring A is a bridged heterocyclyl. In one embodiment, ring A is a 6- to 12-membered bridged heterocyclyl. In one embodiment, ring A is a 6-membered bridged heterocyclyl. In one embodiment, ring A is a 7-membered bridged heterocyclyl. In one embodiment, ring A is an 8-membered bridged heterocyclyl. In one embodiment, ring A is a 9-membered bridged heterocyclyl. In one embodiment, ring A is a 10-membered bridged heterocyclyl. In one embodiment, ring A is an 11-membered bridged heterocyclyl. In one embodiment, ring A is a 12-membered bridged heterocyclyl. In one embodiment, ring A is a bridged bicyclic heterocyclyl.

[0191] In one embodiment, ring A is a spiroheterocyclyl. In one embodiment, ring A is a 6- to 12-membered spiroheterocyclyl. In one embodiment, ring A is a 6-membered spiroheterocyclyl. In one embodiment, ring A is a 7-membered spiroheterocyclyl. In one embodiment, ring A is an 8-membered spiroheterocyclyl. In one embodiment, ring A is a 9-membered spiroheterocyclyl. In one embodiment, ring A is a 10-membered spiroheterocyclyl. In one embodiment, ring A is an 11-membered spiroheterocyclyl. In one embodiment, ring A is a 12-membered spiroheterocyclyl. In one embodiment, ring A is a spiro bicyclic heterocyclyl.

[0192] In one embodiment, ring A contains at least two heteroatoms. In one embodiment, ring A contains at least two heteroatoms that are both nitrogen. In one embodiment, ring A contains only two heteroatoms that are both nitrogen.

[0193] In one embodiment, ring A is

[0194] [ka]

[0195] [ka] where: * is the ring A and X 4 The methylene group connecting the ring containing the formula (I) is directed toward the methylene group connecting the ring containing the formula (I).

[0196] In one embodiment, ring A is

[0197] [ka] In one embodiment, ring A is

[0198] [ka] In one embodiment, ring A is

[0199] [ka] In one embodiment, ring A is

[0200] [ka] In one embodiment, ring A is

[0201] [ka] In one embodiment, ring A is

[0202] [ka] In one embodiment, ring A is

[0203] [ka] is.

[0204] In one embodiment, Ring A is octahydropyrrolo[3,4-c]pyrrole. In one embodiment, Ring A is 2,6-diazaspiro[3.3]heptane. In one embodiment, Ring A is 2,5-diazabicyclo[4.1.0]heptane. In one embodiment, Ring A is 2,5-diazabicyclo[2.2.1]heptane. In one embodiment, Ring A is 4,7-diazaspiro[2.5]octane.

[0205] In one embodiment, ring A is (3ar,6ar)-octahydropyrrolo[3,4-c]pyrrole. In one embodiment, ring A is (3as,6as)-octahydropyrrolo[3,4-c]pyrrole.

[0206] In one embodiment, X 2 is N and ring A is

[0207] [ka] In one embodiment, X 3 is N and ring A is

[0208] [ka] In one embodiment, X 4 is N and ring A is

[0209] [ka] In one embodiment, X 2 is N and X 3 is N and ring A is

[0210] [ka] In one embodiment, X 2 is N and X 4 is N and ring A is

[0211] [ka] In one embodiment, X 2 is O and X 3 is N and ring A is

[0212] [ka] In one embodiment, X 2 is O and X 4 is N and ring A is

[0213] [ka] In one embodiment, X 2 is O and ring A is

[0214] [ka] In one embodiment, X 2 is N and X 3 is N and ring A is

[0215] [ka] In one embodiment, ring A is

[0216] [ka] Ring B is heteroaryl; * is the ring A and X 4 The ring is oriented in the direction of the methylene group connecting the ring containing

[0217] In one embodiment, Ring A is substituted. In one embodiment, Ring A is substituted with one or more groups selected from the group consisting of halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, and nitro.

[0218] In one embodiment, ring A is unsubstituted.

[0219] In one embodiment, the compound is of Formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (III-J), (III-K), (III-L), (III-M), (III-N), (III-O), (III-P), (III-Q), (III-R), (III-S), (III-T), (III-U), (III-V), (III-W), (III-X), (III-Y), (III-Z), (III-AA), (III-AB), (III-AC), (III-AD), (III-AE), (III-AF), (III-AG), (III-AH), (III-AI), or (III-AJ).

[0220] [ka]

[0221] [ka]

[0222] [ka]

[0223] [ka]

[0224] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0225] In one embodiment of formula (III-D) (or a subformula thereof), ring A is

[0226] [ka] where: * is the ring A and X 4 In one embodiment of formula (III-D) (or a subformula thereof), ring A is

[0227] [ka] where: * is the ring A and X 4 The methylene group connecting the ring containing the formula (I) is directed toward the methylene group connecting the ring containing the formula (I).

[0228] In one embodiment, ring A is

[0229] [ka] is.

[0230] In one embodiment, ring A is

[0231] [ka] In one embodiment, ring A is

[0232] [ka] In one embodiment, ring A is

[0233] [ka] In one embodiment, without being bound by any particular theory, ring A is

[0234] [ka] (or stereoisomers, e.g.

[0235] [ka] ) as ring A.

[0236] [ka] In one embodiment, without being bound by any particular theory, one of the stereoisomers exhibits better potency and / or efficacy than the corresponding compound having

[0237] In one embodiment, ring A is

[0238] [ka] In one embodiment, ring A is

[0239] [ka] In one embodiment, ring A is

[0240] [ka] In one embodiment, ring A is

[0241] [ka] In one embodiment, ring A is

[0242] [ka] In one embodiment, ring A is

[0243] [ka] is.

[0244] In one embodiment, X 3 is N and ring A is

[0245] [ka] In one embodiment, X 3 is N and ring A is

[0246] [ka] In one embodiment, X3 is N and ring A is

[0247] [ka] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 3 is N and X 4 is CR a4 and ring A is

[0248] [ka] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 3 is N and X 4 is CR a4 and ring A is

[0249] [ka] In one embodiment, X 1 is CR a1 and X 2 is CR a2 and X 3 is N and X 4 is CR a4 and ring A is

[0250] [ka] is.

[0251] In one embodiment, X 2 is N and ring A is

[0252] [ka] In one embodiment, X 3 is N and ring A is

[0253] [ka] In one embodiment, X 4 is N and ring A is

[0254] [ka] In one embodiment, X 2 is N and X 3 is N and ring A is

[0255] [ka] In one embodiment, X 2 is N and X 4 is N and ring A is

[0256] [ka] In one embodiment, X 2 is O and X 3 is N and ring A is

[0257] [ka] In one embodiment, X 2 is O and X 4 is N and ring A is

[0258] [ka] In one embodiment, X2 is O and ring A is

[0259] [ka] In one embodiment, X 2 is N and X 3 is N and ring A is

[0260] [ka] In one embodiment, ring A is

[0261] [ka] Ring B is heteroaryl.

[0262] In one embodiment, the compound has the formula (IV-A1), (IV-B1), (IV-C1), (IV-D1), (IV-E1), (IV-F1), (IV-G1), (IV-H1), (IV-I1), (IV-J1), (IV-K1), (IV-L1), (IV-M1), (IV-N1), (IV-O1), (IV-P1), (IV-Q1), (IV-R1), The compound is (IV-S1), (IV-T1), (IV-U1), (IV-V1), (IV-W1), (IV-X1), (IV-Y1), (IV-Z1), (IV-AA1), (IV-AB1), (IV-AC1), (IV-AD1), (IV-AE1), (IV-AF1), (IV-AG1), (IV-AH1), (IV-AI1) or (IV-AJ1).

[0263] [ka]

[0264] [ka]

[0265] [ka]

[0266] [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0267] In one embodiment, the compound is of formula (IV-V1-1), (IV-AA1-1), (IV-AB1-1), or (IV-AI1-1).

[0268] [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; Z is O or C(R 4 )2; and Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0269] In one embodiment, the compound has formula (IV-A2), (IV-B2), (IV-C2), (IV-D2), (IV-E2), (IV-F2), (IV-G2), (IV-H2), (IV-I2), (IV-J2), (IV-K2), (IV-L2), (IV-M2), (IV-N2), (IV-O2), (IV-P2), (IV-Q2), (IV-R ... The compound is selected from the group consisting of (IV-S2), (IV-T2), (IV-U2), (IV-V2), (IV-W2), (IV-X2), (IV-Y2), (IV-Z2), (IV-AA2), (IV-AB2), (IV-AC2), (IV-AD2), (IV-AE2), (IV-AF2), (IV-AG2), (IV-AH2), (IV-AI2) and (IV-AJ2).

[0270] [ka]

[0271] [ka]

[0272] [ka]

[0273] [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0274] In one embodiment, the compound is of formula (IV-V2-1), (IV-AA2-1), (IV-AB2-1), or (IV-AI2-1).

[0275] [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof; During the ceremony m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; Z is O or C(R 4 )2; and Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0276] In one embodiment, R 2 is hydrogen.

[0277] In one embodiment, R 2 is halogen. In one embodiment, R 2 is fluoro. In one embodiment, R 2 is chloro. In one embodiment, R 2 is bromo.

[0278] In one embodiment, R 2 is C1-C6 alkyl. In one embodiment, R 2 is C1-C4 alkyl. In one embodiment, R 2 is C1-C6 haloalkyl. In one embodiment, R 2 is C1-C4 fluoroalkyl. In one embodiment, R 2 is methyl. In one embodiment, R 2 is ethyl. In one embodiment, R 2 is propyl or isopropyl. In one embodiment, R 2 is n-butyl, iso-butyl or tert-butyl. 2 is fluoromethyl. In one embodiment, R 2 is bromomethyl. In one embodiment, R 2 is chloromethyl. In one embodiment, R 2 is difluoromethyl. In one embodiment, R 2 is trifluoromethyl.

[0279] In one embodiment, R2 is C1-C6 alkoxy. In one embodiment, R 2 is methoxy. In one embodiment, R 2 is ethoxy.

[0280] In one embodiment, R 2 is C3-C8 cycloalkyl. In one embodiment, R 2 is C3-C6 cycloalkyl. In one embodiment, R 2 is cyclopropyl. In one embodiment, R 2 is cyclobutyl. In one embodiment, R 2 is cyclopentyl. In one embodiment, R 2 is cyclohexyl. In one embodiment, cycloalkyl is optionally substituted.

[0281] In one embodiment, R 2 is hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C6 cycloalkyl. 2 is hydrogen, chloro, fluoro, methyl, difluoromethyl, trifluoromethyl, or cyclopropyl.

[0282] In one embodiment, R 3 is hydrogen.

[0283] In one embodiment, R 3 is C1-C6 alkyl. In one embodiment, R 3 is C1-C4 alkyl. In one embodiment, R 3 is methyl. In one embodiment, R 3 is ethyl. In one embodiment, R 3 is n-propyl or isopropyl. In one embodiment, R 3 is n-butyl, iso-butyl or tert-butyl. 3 is C5 alkyl. In one embodiment, R 3 is C alkyl. In one embodiment, R 3is C3-C8 cycloalkyl. In one embodiment, R 3 is C3-C6 cycloalkyl. In one embodiment, R 3 is cyclopropyl. In one embodiment, R 3 is cyclobutyl. In one embodiment, R 3 is cyclopentyl. In one embodiment, R 3 is cyclohexyl.

[0284] In one embodiment, R 3 is a 4- to 10-membered heterocyclyl. 3 is a 4- to 8-membered heterocyclyl. 3 is a 4- to 6-membered heterocyclyl. 3 is a 4-membered heterocyclyl. In one embodiment, R 3 is a 5-membered heterocyclyl. 3 is a 6-membered heterocyclyl. In one embodiment, R 3 is a 4-8 membered oxygen-containing heterocyclyl. 3 is a 4-6 membered oxygen-containing heterocyclyl. 3 is a 4-8 membered nitrogen-containing heterocyclyl. 3 is a 4-membered oxygen-containing heterocyclyl. 3 is a 5-membered oxygen-containing heterocyclyl. 3 is a 6-membered oxygen-containing heterocyclyl. In one embodiment, R 3 is oxetan-3-yl. In one embodiment, R 3 is tetrahydrofuran-3-yl. In one embodiment, R 3 is (R)-tetrahydrofuran-3-yl. In one embodiment, R 3 is (S)-tetrahydrofuran-3-yl. In one embodiment, R 3 is tetrahydro-2H-pyran-4-yl.

[0285] In one embodiment, R 3 teeth

[0286] [ka] In one embodiment, R 3 teeth

[0287] [ka] (for example,

[0288] [ka] In one embodiment, R 3 teeth

[0289] [ka] (for example

[0290] [ka] ) and R 4 is C1-C3 alkoxy (for example, methoxy).

[0291] In one embodiment, when Ring B does not contain an oxygen ring atom (e.g., when Ring B is a carbocyclic ring, e.g., Formula (II-V-1), Formula (II-AI-1), Formula (IV-V1-1), Formula (IV-AI1-1), Formula (IV-V2-1), Formula (IV-AI2-1)), R 3 teeth

[0292] [ka] (for example,

[0293] [ka] ).

[0294] In one embodiment, when Ring B contains an oxygen ring atom (e.g., when Ring B is an oxygen-containing heterocyclyl, e.g., Formula (II-AA-1), Formula (II-AB-1), Formula (IV-AA1-1), Formula (IV-AB1-1), Formula (IV-AA2-1), Formula (IV-AB2-1)), R 3 teeth

[0295] [ka] (for example

[0296] [ka] ) and R 4 is C1-C3 alkoxy (e.g., methoxy). 4 is hydrogen or C1-C3 alkyl (instead of C1-C3 alkoxy).

[0297] In one embodiment, m+n=1. In one embodiment, m+n=2. In one embodiment, m+n=3. In one embodiment, m+n=4. In one embodiment, m is 0 and n is 1. In one embodiment, m is 0 and n is 2. In one embodiment, m is 0 and n is 3. In one embodiment, m is 0 and n is 4. In one embodiment, m is 1 and n is 1. In one embodiment, m is 1 and n is 2. In one embodiment, m is 1 and n is 3. In one embodiment, m is 2 and n is 2.

[0298] In one embodiment, Z is O. In one embodiment, Z is C(R 4 )2. In one embodiment, Z is CHR 4In one embodiment, Z is CH2.

[0299] In one embodiment, R 4 is hydrogen. In one embodiment, R 4 is C1-C6 alkyl. In one embodiment, R 4 is C1-C3 alkyl. In one embodiment, R 4 is methyl. In one embodiment, R 4 is ethyl. In one embodiment, R 4 is n-propyl or isopropyl. In one embodiment, R 4 is C4 alkyl. In one embodiment, R 4 is C5 alkyl. In one embodiment, R 4 is C alkyl. In one embodiment, R 4 is C1-C6 alkoxy. In one embodiment, R 4 is C1-C3 alkoxy. In one embodiment, R 4 is methoxy. In one embodiment, R 4 is ethoxy.

[0300] In one embodiment, R 3 is non-substituted.

[0301] In one embodiment, R 3 is C1-C6 alkyl substituted with alkoxy. In one embodiment, R 3 is C1-C6 alkyl substituted with C1-C6 alkoxy. 3 is (C1-C6 alkoxy)-(C1-C6 alkyl). In one embodiment, R 3 is (C1-C4 alkoxy)-(C1-C4 alkyl). In one embodiment, R 3 is C1-C6 alkyl substituted with methoxy. 3 is C1-C6 alkyl substituted with ethoxy. 3 is 2-methoxymethyl. In one embodiment, R 3is 2-methoxyethyl. In one embodiment, R 3 is 2-ethoxymethyl. In one embodiment, R 3 is 2-ethoxyethyl. In one embodiment, R 3 is C1-C6 alkyl substituted with halogen.

[0302] In one embodiment, R 3 is a C-C cycloalkyl substituted with alkoxy. 3 is a C3-C8 cycloalkyl substituted with a C1-C6 alkoxy. 3 is (C1-C6 alkoxy)-(C3-C8 cycloalkyl). In one embodiment, R 3 is (C1-C4 alkoxy)-(C3-C6 cycloalkyl). In one embodiment, R 3 is (C1-C6 alkoxy)-(cyclopropyl). In one embodiment, R 3 is (C1-C6 alkoxy)-(cyclobutyl). In one embodiment, R 3 is a C-C cycloalkyl substituted with methoxy. 3 is a C3-C8 cycloalkyl substituted with ethoxy. 3 is a C3-C8 cycloalkyl substituted with halogen. 3 is 3-methoxycyclobutyl. In one embodiment, R 3 is (1S,3S)-3-methoxycyclobutyl. In one embodiment, R 3 is (1R,3R)-3-methoxycyclobutyl.

[0303] In one embodiment, R 3 is a 4-10 membered heterocyclyl substituted with alkoxy. 3 is a 4-8 membered heterocyclyl substituted with C1-C6 alkoxy. 3 is (C1-C4 alkoxy)-(4- to 6-membered heterocyclyl).

[0304] In one embodiment, R 3 When R has a chiral center, R has the S configuration. 3 If has a chiral center, it has the R configuration.

[0305] In one embodiment, X 1 If the carbon at X is a chiral center, it has the S configuration. 1 If the carbon at position 1 is a chiral center, it has the R configuration.

[0306] In one embodiment, the compounds provided herein are single enantiomers. In one embodiment, the compounds provided herein are single diastereoisomers. In one embodiment, the compounds provided herein are mixtures of enantiomers. In one embodiment, the compounds provided herein are mixtures of diastereoisomers. In one embodiment, the compounds provided herein are racemic.

[0307] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0308] [Table 1-1]

[0309] [Table 1-2]

[0310] [Table 1-3]

[0311] [Table 1-4]

[0312] [Table 1-5]

[0313] In one embodiment, without being bound by theory, the compounds provided herein are poly(ADP-ribose) polymerase 1 (PARP1) inhibitors that exhibit strong DNA capture ability. In one embodiment, the compounds provided herein have an IC of less than 100 nM as measured by a DNA capture assay. 50 In one embodiment, the IC 50 In one embodiment, the IC 50 is less than 10 nM.

[0314] In one embodiment, without being bound by any particular theory, the compounds provided herein are PARP1 inhibitors that exhibit good tumor penetration and retention (e.g., long residence time in tumor tissue). In one embodiment, without being bound by any particular theory, the compounds can achieve higher concentrations in tumors than in plasma (e.g., higher tumor / plasma concentration ratios). In one embodiment, without being bound by any particular theory, lower plasma concentrations may result in fewer side effects.

[0315] In one embodiment, the compounds provided herein are poly(ADP-ribose) polymerase 1 (PARP1) inhibitors that reduce the level of PARP1 protein and / or inhibit or reduce at least one biological activity of PARP1 protein. In one embodiment, the expression level of PARP1 protein is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. In one embodiment, the biological activity of PARP1 protein is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.

[0316] In one embodiment, the compounds provided herein can penetrate the blood-brain barrier (BBB). In one embodiment, the ratio of the compound that penetrates the BBB is >0.05, with 1 being complete BBB penetration and 0 being no penetration. In one embodiment, the ratio of the compound that penetrates the BBB is greater than 0.1. In one embodiment, the ratio of the compound that penetrates the BBB is >0.2. In one embodiment, the ratio of the compound that penetrates the BBB is >0.3. In one embodiment, the ratio of the compound that penetrates the BBB is >0.3.

[0317] In one embodiment, the compounds provided herein bind to PARP1 protein with an affinity ranging from about 1 pM to about 100 μM, from about 1 pM to about 1 μM, from about 1 pM to about 500 nM, or from about 1 pM to about 100 nM. In some embodiments, the compounds provided herein bind to PARP1 protein with an affinity of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. In some embodiments, the compounds provided herein are administered at a concentration of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 μM, about 300 nM to about 400 nM, about 300 nM to about 500 nM, about 100 nM to about 600 nM, about 100 nM to about 700 nM, about 100 nM to about 800 nM, about 100 nM to about 900 nM, about 100 nM to about 1000 nM, about 100 nM to about 200 nM, about 200 nM to about 1 μM, about 300 nM to about 400 nM, about 300 nM to about 5 ...500 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 μM, about 300 nM to about 40 The antibody binds to PARP1 protein with an affinity of about 100 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM.In some embodiments, the compounds provided herein may be administered at concentrations of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, The compounds bind to PARP1 protein with an affinity of 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM. In some embodiments, the compounds provided herein bind to PARP1 protein with an affinity of less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In one embodiment, the compounds provided herein bind to PARP1 protein with an affinity of less than 1 nM.

[0318] In one embodiment, the compounds provided herein have an IC of about 1 pM to about 100 μM, or about 1 pM to about 1 μM, or about 1 pM to about 500 nM, or about 1 pM to about 100 nM. 50 In one embodiment, the compounds provided herein have an IC50 of about 1 pM to about 100 μM, about 1 nM to about 100 μM, about 1 μM to about 100 μM, about 1 μM to about 50 μM, about 1 μM to about 40 μM, about 1 μM to about 30 μM, about 1 μM to about 20 μM, or about 1 μM to about 10 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. 50In some embodiments, the compounds provided herein inhibit PARP1 activity at concentrations of about 100 nM to about 1 μM, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 500 nM, about 100 nM to about 600 nM, about 100 nM to about 700 nM, about 100 nM to about 800 nM, about 100 nM to about 900 nM, about 100 nM to about 1000 nM, about 100 nM to about 200 nM, about 200 nM to about 300 nM, about 100 nM to about 300 nM, about 100 nM to about 400 nM, about 100 nM to about 500 nM, about 100 nM to about 600 nM, about 100 nM to about 700 nM, about 100 nM to about 800 nM, about 100 nM to about 900 nM, about 100 nM to about 1000 nM, about 100 nM to about 200 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 100 nM to about 300 nM, about 100 nM to about 300 nM, about 100 nM to about 400 nM IC50 of about 1 μM, about 300 nM to about 1 μM, about 400 nM to about 1 μM, about 500 nM to about 1 μM, about 600 nM to about 1 μM, about 700 nM to about 1 μM, about 800 nM to about 1 μM, about 900 nM to about 1 μM, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, or about 900 nM 50 In some embodiments, the compounds provided herein inhibit PARP1 activity at concentrations of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM, IC50 of about 100 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM 50 In one embodiment, the compounds provided herein inhibit PARP1 activity at ICs of less than 1 μM, less than 500 nM, less than 100 nM, less than 10 nM, or less than 1 nM. 50 In one embodiment, the compounds provided herein inhibit PARP1 activity at an IC of less than 1 nM. 50 inhibits PARP1 activity.

[0319] How to use In one embodiment, provided herein is a method for treating a disease or condition by inhibiting PARP1 protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.

[0320] In one embodiment, provided herein is a method of treating cancer, comprising administering to a subject with cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.

[0321] In one embodiment, the cancer is deficient in the homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway.

[0322] In one embodiment, the cancer comprises one or more cancer cells that have a reduced or abrogated ability to repair DNA DSBs by HR compared to normal cells.

[0323] In one embodiment, the cancer is one comprising cancer cells that are heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway. Without being bound by any particular theory, a cancer that is deficient in HR-dependent DNA DSB repair may comprise one or more cancer cells that have a reduced or abrogated ability to repair DNA DSBs via that pathway compared to normal cells.

[0324] In one embodiment, provided herein is a method for treating cancers that are deficient in homologous recombination (HR)-dependent DNA DSB repair activity. Without being bound by any particular theory, the HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via a homologous mechanism to reform a continuous DNA helix (KK Khanna and SP Jackson, Nat. Genet. 27(3):247-254(2001)). HR-dependent DNA Components of the DSB repair pathway include ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), and RA These include, but are not limited to, D52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11A (NM_005590) and NBS1 (NM_002485).

[0325] In one embodiment, the cancer cells have a breast cancer type 1 (BRCA1) or breast cancer type 2 (BRCA2) deficient phenotype.

[0326] In one embodiment, the cancer cells are deficient in BRCA1. In one embodiment, the cancer cells are deficient in BRCA2. In one embodiment, the cancer cells are deficient in both BRCA1 and BRCA2.

[0327] In one embodiment, the cancer is one comprising cancer cells that are heterozygous for a mutation in BRCA1 and / or BRCA2.

[0328] In one embodiment, a compound provided herein is used to treat cancer, wherein the cancer is a BRCA1 mutant cancer. In one embodiment, a compound provided herein is used to treat cancer, wherein the cancer is a BRCA2 mutant cancer. In one embodiment, a compound provided herein is used to treat cancer, wherein the cancer is a BRCA1 mutant cancer and a BRCA2 mutant cancer. In one embodiment, the cancer is not a BRCA1 mutant cancer or a BRCA2 mutant cancer. In one embodiment, the cancer is a BRCA1 deficient cancer. In one embodiment, the cancer is a BRCA2 deficient cancer. In one embodiment, the cancer is a BRCA1 deficient cancer and a BRCA2 deficient cancer.

[0329] In one embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, lung cancer, or brain cancer. In one embodiment, the brain cancer is a glioma or glioblastoma. In one embodiment, the brain cancer is a metastatic cancer arising from a tumor elsewhere in the body, such as breast, ovarian, pancreatic, prostate, hematological, gastrointestinal, e.g., gastric and colorectal, or lung cancer, e.g., small cell or non-small cell lung cancer.

[0330] In one embodiment, provided herein is a method of inhibiting PARP1 protein, comprising contacting the PARP1 protein with an effective amount of a compound provided herein or a pharmaceutical composition provided herein. In one embodiment, the inhibition occurs in a subject suffering from a PARP1-mediated disease or condition.

[0331] In one embodiment, the PARP1-mediated disease or condition is cancer.

[0332] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is a blood cancer. In one embodiment, the cancer is gastrointestinal cancer. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is brain cancer.

[0333] In some embodiments, such methods include (a) identifying a cancer in a subject as a PARP1 inhibitor-sensitive cancer, and then (b) administering to the subject a therapeutically effective amount of a compound provided herein.

[0334] In some embodiments, the compounds provided herein are provided for use as a medicament or for use in the preparation of a medicament, e.g., for the treatment of cancer. In some embodiments, the compounds provided herein are provided for use in a method of treating cancer.

[0335] In one embodiment, the compounds provided herein are provided for use in a method of treating a disease or condition by inhibiting the PARP1 protein.

[0336] Pharmaceutical Composition Also provided herein are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.

[0337] The pharmaceutical compositions provided herein can be administered to mammals, including rodents and humans, by a variety of routes. In one embodiment, administration is intranasal, intravenous, intraperitoneal, intramuscular, intraarticular, intralesional, intratracheal, subcutaneous, or intradermal. In one embodiment, administration is intravenous. In one embodiment, administration is intramuscular.

[0338] In one embodiment, the pharmaceutical compositions provided herein may be orally administered in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions.

[0339] In one embodiment, the compounds provided herein are administered to a mammal in the form of a raw chemical, free of other components. In one embodiment, the compounds provided herein are administered to a mammal as part of a pharmaceutical composition containing the compound in combination with a suitable pharmaceutically acceptable carrier (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Non-limiting examples of pharmaceutically suitable carriers include solids and / or liquids such as water, alcohol, and glycerol. The amount of carrier in a therapeutic composition can range from about 5 to about 99% by weight, based on the total weight of the therapeutic composition or therapeutic combination. Pharmaceutically acceptable excipients and diluents include, but are not limited to, buffers, preservatives, binders, fillers, disintegrants, lubricants, wetting agents, antioxidants, flavoring agents, thickening agents, coloring agents, emulsifying agents, suspending agents, etc. Non-limiting examples of excipients and diluents also include sucrose, lactose, dextrose, sorbitol, mannitol, erythritol, maltitol, starch, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0340] In one embodiment, the pharmaceutical compositions provided herein may be prepared as a liquid suspension or solution using a liquid such as an oil, water, an alcohol, and combinations thereof.

[0341] In one embodiment, the pharmaceutical compositions provided herein can be prepared as sterile injections, which can be aqueous or oily suspensions.Suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting agents (e.g., polysorbates).Sterile injection preparations can also be sterile injection solutions or suspensions in diluents or solvents.In addition, sterile fixed oils are conventionally used as solvents or suspending media.Pharmaceutically acceptable natural oils or fatty acids can also be used to prepare injectable preparations.

[0342] In one embodiment, the pharmaceutical compositions provided herein may be administered in the form of suppositories for rectal administration.

[0343] In one embodiment, the pharmaceutical compositions provided herein can also be administered topically, especially when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract.Topical application for the lower intestinal tract can be achieved with a rectal suppository formulation or a suitable enema formulation.Topical transdermal patches can also be used.For topical application, the pharmaceutical composition can be formulated into a suitable ointment, lotion, or cream containing the active ingredient suspended or dissolved in one or more carriers.

[0344] In one embodiment, the pharmaceutical compositions provided herein are also administered ophthalmically and may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. In one embodiment, for ophthalmic use, the pharmaceutical composition may be formulated into an ointment such as petrolatum.

[0345] In one embodiment, the pharmaceutical compositions provided herein may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0346] In one embodiment, pharmaceutical compositions to be used for in vivo administration can be sterile, which in one embodiment is accomplished by, for example, filtration through sterile filtration membranes.

[0347] In one embodiment, the pharmaceutical compositions provided herein include any composition in which a compound provided herein is combined with one or more pharmaceutically acceptable carriers. In one embodiment, the compound provided herein is present in the composition in an amount effective to achieve its intended therapeutic purpose.

[0348] In one embodiment, the pharmaceutical compositions provided herein can be administered to any patient who may experience the beneficial effects of the compounds provided herein. In one embodiment, the patient is a mammal, such as a human or companion animal. In one embodiment, the subject is a human.

[0349] In one embodiment, also provided herein are kits comprising a compound provided herein (or a composition comprising a compound provided herein) packaged in a manner that facilitates their use to practice a method provided herein. In one embodiment, the kit comprises a compound provided herein (or a composition comprising a compound provided herein) packaged in a container, such as a sealed vial, with a label affixed to the container or included in the kit that describes the use of the compound or composition to practice a method provided herein. In one embodiment, the compound or composition is packaged in a unit dosage form. In one embodiment, the kit further comprises a device suitable for administering the compound or composition according to the intended route of administration. In one embodiment, the kit comprises a compound provided herein and instructions for administering the compound to a patient with cancer. [Example]

[0350] Example 1: Preparation process In one embodiment, provided herein is a process (Method 1) for the preparation of a compound provided herein, comprising the steps of:

[0351] [ka] where X is a halogen such as Br and Cl.

[0352] Step 1: In a suitable solvent such as THF, in the presence of a suitable inorganic base such as sodium hydride, at a suitable temperature such as about -78 to 25°C.

[0353] Step 2: At a suitable temperature, for example 25-80° C., in the presence of a suitable hydrogenation catalyst, for example palladium on carbon, in the presence of hydrogen, at a suitable pressure, for example 15-100 psi, in a suitable solvent, for example EtOAc or EtOH.

[0354] Step 3: In a suitable solvent such as THF or dioxane, in the presence of a suitable oxidizing agent such as DDQ or MnO2, at a suitable temperature such as room temperature to about 120°C.

[0355] Step 4: In a suitable solvent such as THF, in the presence of a suitable reducing agent such as LiAlH4, at a suitable temperature such as 0-25°C.

[0356] Step 5: In a suitable solvent such as DCM or AcOH, in the presence of a suitable halogenating reagent such as SOCl2 or HBr, at a suitable temperature such as 25-80 °C.

[0357] Step 6: At a suitable temperature, for example 25-80° C., in the presence of a suitable base, for example DIEA or TEA, in the presence of an additive, for example potassium iodide, in a suitable solvent, for example MeCN.

[0358] In one embodiment, provided herein is a process (Method 2) for the preparation of a compound provided herein, comprising the steps of:

[0359] [ka] where X is a halogen such as Br and Cl.

[0360] Step 1: In a suitable solvent such as THF or MeCN, in the presence of a suitable base such as DIEA or TEA, at a suitable temperature such as about -78 to 25°C.

[0361] Step 2: At a suitable temperature, for example 25-80° C., in the presence of a suitable hydrogenation catalyst, for example palladium on carbon, in the presence of hydrogen, at a suitable pressure, for example 15-100 psi, in a suitable solvent, for example EtOAc or EtOH.

[0362] Step 3: In a suitable solvent such as THF or dioxane, in the presence of a suitable oxidizing agent such as DDQ or MnO2, at a suitable temperature such as room temperature to about 120°C.

[0363] Step 4: In a suitable solvent such as THF, in the presence of a suitable reducing agent such as LiAlH4, at a suitable temperature such as 0-25°C.

[0364] Step 5: In a suitable solvent such as DCM or AcOH, in the presence of a suitable halogenating reagent such as SOCl2 or HBr, at a suitable temperature such as 25-80 °C.

[0365] Step 6: At a suitable temperature, for example 25-80° C., in the presence of a suitable base, for example DIEA or TEA, in the presence of an additive, for example potassium iodide, in a suitable solvent, for example MeCN.

[0366] In one embodiment, provided herein is a process (Method 3) for the preparation of a compound provided herein, comprising the steps of:

[0367] [ka] where X is a halogen such as Br and Cl.

[0368] Step 1: In a suitable solvent (eg, THF or MeCN) in the presence of a suitable base (eg, DIEA or sodium hydride) at a suitable temperature (eg, about −78 to 25° C.).

[0369] Step 2: At a suitable temperature, for example 25-80° C., in the presence of a suitable hydrogenation catalyst, for example palladium on carbon, in the presence of hydrogen, at a suitable pressure, for example 15-100 psi, in a suitable solvent, for example EtOAc or EtOH.

[0370] Step 3: In a suitable solvent such as THF or dioxane, in the presence of a suitable oxidizing agent such as DDQ or MnO2, at a suitable temperature such as room temperature to about 120°C.

[0371] Step 4: In a suitable solvent such as THF, in the presence of a suitable reducing agent such as LiAlH4, at a suitable temperature such as 0-25°C.

[0372] Step 5: In a suitable solvent such as DCM or AcOH, in the presence of a suitable halogenating reagent such as SOCl2 or HBr, at a suitable temperature such as 25-80 °C.

[0373] Step 6: At a suitable temperature, for example 25-80° C., in the presence of a suitable base, for example DIEA or TEA, in the presence of an additive, for example potassium iodide, in a suitable solvent, for example MeCN.

[0374] In one embodiment, provided herein is a process (Method 4) for the preparation of a compound provided herein, comprising the steps of:

[0375] [ka] X is a halogen such as Br, Cl, etc. In the formula, Alk is methyl or ethyl.

[0376] Step 1: In the presence of a suitable base such as DIEA, sodium hydride or 2,6-di-tert-butyl-4-methylpyridine, in the presence of a suitable triflating reagent such as trifluoromethanesulfonic anhydride, in a suitable solvent such as DCM, at a suitable temperature such as -78°C to room temperature.

[0377] Step 2: In a suitable solvent such as dioxane, in the presence of a suitable base such as KOAc, in the presence of a suitable palladium catalyst such as Pd(dppf)Cl 2 at a suitable temperature such as room temperature to 120° C.

[0378] Step 3: In the presence of a suitable inorganic base such as K2CO3 or Cs2CO3, in the presence of a suitable palladium catalyst such as Pd(dppf)Cl2 or Pd(PPh3)4, at a suitable temperature such as 60-120 °C, in a suitable solvent or mixture of solvents such as dioxane or dioxane / H2O.

[0379] Step 4: In the presence of a suitable inorganic additive such as NH4Cl, in the presence of a suitable metal reducing agent such as Fe, in a suitable solvent mixture such as THF / MeOH / H2O at a suitable temperature such as room temperature to 120°C.

[0380] Step 5: In a suitable solvent such as THF, in the presence of a suitable reducing agent such as LiAlH4, at a suitable temperature such as 0-25°C.

[0381] Step 6: In a suitable solvent such as DCM or AcOH, in the presence of a suitable halogenating reagent such as SOCl2 or HBr, at a suitable temperature such as 25-80 °C.

[0382] Step 7: At a suitable temperature, for example 25-80° C., in the presence of a suitable base, for example DIEA or TEA, in the presence of an additive, for example potassium iodide, in a suitable solvent, for example MeCN.

[0383] In one embodiment, provided herein is a process (Method 5) for the preparation of a compound provided herein, comprising the steps of:

[0384] [ka] wherein Alk is methyl or ethyl.

[0385] Step 1: In the presence of a suitable base such as DIEA, sodium hydride, etc., at a suitable temperature such as -78°C to room temperature, or in the presence of 2,6-di-tert-butyl-4-methylpyridine and a suitable triflating reagent such as trifluoromethanesulfonic anhydride, in a suitable solvent such as DCM.

[0386] Step 2: In a suitable solvent such as dioxane, in the presence of a suitable base such as KOAc, in the presence of a suitable palladium catalyst such as Pd(dppf)Cl 2 at a suitable temperature such as room temperature to 120° C.

[0387] Step 3: In the presence of a suitable inorganic base such as K2CO3, in the presence of a suitable palladium catalyst such as Pd(dppf)Cl2, at a suitable temperature such as 60-120 °C, in a suitable solvent or mixture of solvents such as dioxane or dioxane / H2O.

[0388] Step 4: In the presence of a suitable inorganic base such as K2CO3, in the presence of a suitable palladium catalyst such as Pd(dppf)Cl2, in a suitable solvent mixture such as dioxane / H2O at a suitable temperature such as 60-120 °C.

[0389] Step 5: At a suitable temperature, for example room temperature to 60° C., in the presence of a suitable oxidizing reagent combination, for example K 2 OsO 4 / NaIO 4 , in the presence of a suitable base, for example 2,6-lutidine, in a suitable solvent mixture, for example THF / H 2 O.

[0390] Step 6: In the presence of a suitable reducing agent such as NaBH3CN or NaBH(OAc)3, in the presence of a suitable acidic additive such as AcOH, in a suitable solvent such as DCM or MeOH, at a suitable temperature such as room temperature to 60°C.

[0391] Several methods for preparing the compounds provided herein are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or could be synthesized by one of ordinary skill in the art using well-known methods.

[0392] [Table 2-1]

[0393] [Table 2-2]

[0394] Example 2: Preparation of intermediates For intermediates that were used in the next reaction step as crude or partially purified intermediates, in some cases no molar amount is stated for such intermediate in the next reaction step, or alternatively, an estimated or theoretical molar amount for such intermediate in the next reaction step is shown in the reaction protocols set forth below.

[0395] Preparation of Intermediate 1

[0396] [ka]

[0397] To a solution of ethyl 6-methyl-5-nitronicotinate (10 g, 47.58 mmol) in dioxane (200 mL) was added SeO (7.92 g, 71.38 mmol). The mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, and the Celite was washed with ethyl acetate. The combined filtrate was concentrated, and the residue was purified by silica gel chromatography to give Intermediate 1 (9.3 g, yield: 87%) as a yellow oil.

[0398] Preparation of intermediate 2

[0399] [ka]

[0400] To a stirred solution of NaH (6.6 g, 165.10 mmol) in anhydrous THF (100 mL) was added ethyl 2-(diethoxyphosphoryl)butanoate (41.64 g, 165.10 mmol) in anhydrous THF (100 mL) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature over 10 minutes and stirred at 40° C. for 5 minutes. The reaction mixture was then cooled to −78° C., and a solution of Intermediate 1 (15.478 g, 68.79 mmol) in anhydrous THF (150 mL) was slowly added. The mixture was stirred at −78° C. for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride in THF (20 mL) and extracted with ethyl acetate (200×2 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated, and the resulting residue was purified by silica gel chromatography to give Intermediate 2 (E / Z isomer mixture = 1:1) (13.7 g, yield: 62%) as a yellow oil.

[0401] The following intermediates were synthesized by methods similar to those described above for intermediate 2.

[0402] [Table 3]

[0403] Preparation of intermediate 3

[0404] [ka]

[0405] To a mixture of intermediate 2 (13.7 g, 42.51 mmol) (E / Z isomer mixture = 1:1) in EtOH (200 mL) was added 10 wt% Pd / C (7 g), and the mixture was stirred overnight at room temperature under an H atmosphere. The mixture was filtered through a Celite bed, and the Celite bed was washed with ethanol. After concentration, 4 M HCl in dioxane (100 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtO, and the precipitate was filtered and washed twice with diethyl ether to give intermediate 3 (6.7 g, yield: 63.6%) as a white solid.

[0406] The following intermediates were synthesized by methods similar to those described above for intermediate 3.

[0407] [Table 4]

[0408] [ka] Preparation of

[0409] To a solution of intermediate 3 (6.7 g, 26.99 mmol) in 1,4-dioxane (120 mL) was added DDQ (6.738 g, 29.68 mmol). The mixture was stirred under reflux for 3 hours. The solvent was removed under reduced pressure, and then saturated aqueous sodium bicarbonate solution was added to the residue. The resulting mixture was stirred at room temperature for 1 hour. The precipitate was filtered to give intermediate 4 (4 g, yield: 60%) as a gray solid.

[0410] The following intermediates were synthesized by methods similar to those described above for intermediate 4.

[0411] [Table 5]

[0412] Preparation of Intermediate 5

[0413] [ka]

[0414] To a solution of intermediate 4 (4 g, 16.26 mmol) in THF (20 mL) was added LiAlH (32.52 mL, 32.52 mmol, 1 M in THF) dropwise over 45 min under nitrogen at 0 °C. The resulting mixture was stirred at 0 °C for 1.5 h. The reaction mixture was quenched with 1 M HCl (aq) (15 mL). The reaction mixture was concentrated, and the solid was diluted with water (ca. 70 mL) and 15 mL of 1 M HCl solution to give a yellow suspension. The solid was collected by filtration, washed with water, diethyl ether, and dried to give the crude product as a yellow solid (contaminated with some inorganic salts). The solid was suspended in a mixture of methanol and DCM (2:1) (100 mL) and heated to reflux for 1 h. The solid was filtered off. The solid was resuspended in a methanol / DCM mixture, and this procedure was repeated five times to extract most of the product from the solid mixture. The combined filtrate was then concentrated to about 40 mL, and the solid was collected by filtration, washed with ether, and dried under vacuum to give Intermediate 5 (2.67 g, yield: 80.39%) as a yellow solid.

[0415] The following intermediates were synthesized by methods similar to those described above for intermediate 5.

[0416] [Table 6]

[0417] Preparation of Intermediate 6

[0418] [ka]

[0419] To a suspension of intermediate 6 (204 mg, 1.00 mmol) in DCM (4 mL) was added SOCl (714 mg, 6.00 mmol) and 1 drop of DMF at 0 °C. The resulting mixture was stirred at room temperature for 6 h. The mixture was concentrated to give crude intermediate 6 (222 mg, yield: 100%), which was used directly in the next step.

[0420] The following intermediates were synthesized by methods similar to those described above for intermediate 6.

[0421] [Table 7-1]

[0422] [Table 7-2]

[0423] Preparation of intermediate 7

[0424] [ka]

[0425] To a solution of 1,3-difluoro-2-nitrobenzene (23.28 mL, 220 mmol) and methyl 2-aminopropanoate (27.22 g, 264 mmol) in DMF (120 mL) and DIPEA (85.30 g, 660 mmol) was added dropwise. The mixture was heated to 60 °C and stirred for 2 h. The solution was quenched with HO and then extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, concentrated, and chromatographed on silica gel (PE / EA 20:1 to 10:1 to 8:1) to give Intermediate 7 (38.7 g, yield: 72.6%) as a yellow solid.

[0426] The following intermediates were synthesized by methods similar to those described above for intermediate 7.

[0427] [Table 8]

[0428] Preparation of Intermediate 8

[0429] [ka]

[0430] To a solution of Intermediate 7 (4.4 g, 18.1 mmol) in DMF (50 mL) was added NBS (3.23 g, 18.1 mmol). The mixture was stirred at room temperature under an air atmosphere for 18 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was used in the next step without further purification.

[0431] Preparation of Intermediate 9

[0432] [ka]

[0433] A mixture of intermediate 8 (9.7 g crude, 30.2 mmol), Zn (11.8 g, 181 mmol), and NH4Cl (16.2 g, 53.5 mmol) in THF (50 mL) / MeOH (50 mL) / HO (25 mL) was heated to 80 °C and stirred for 3 h. The mixture was filtered, and the filtrate was concentrated to give the crude product, which was chromatographed on silica gel (PE / EA 20:1 to 10:1 to 5:1) to give intermediate 9 (7.1 g, 90.7% yield).

[0434] Preparation of Intermediate 10

[0435] [ka]

[0436] To a solution of intermediate 9 (620 mg, 2.39 mmol) in DCM (10 mL) was added a solution of DDQ (651 mg, 2.87 mmol) in DCM dropwise. The mixture was stirred at room temperature for 2 h and concentrated to give the crude product, which was chromatographed on silica gel (PE / EA 10:1 to 7:1 to 5:1) to give intermediate 10 (500 mg, 81.2% yield) as a white solid.

[0437] Preparation of intermediate 11

[0438] [ka]

[0439] To a solution of intermediate 10 (1 g, 3.8 mmol) in dioxane (40 mL) were added (tributylstannyl)methanol (1.50 g, 4.6 mmol) and Xphos Pd G2 (0.15 g, 0.195 mmol). The mixture was stirred at 80 °C under a N2 atmosphere for 18 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with DCM / MeOH (1 / 0 to 10 / 1) to give intermediate 11 (600 mg, yield: 74%).

[0440] The following intermediates were synthesized by methods similar to those described above for intermediate 11.

[0441] [Table 9]

[0442] Preparation of Intermediate 12

[0443] [ka]

[0444] To a solution of intermediate 11 (200 mg, 0.961 mmol) in AcOH (8 mL) and HO (4 mL) was added HBr (9.3 g, 115.2 mmol). The mixture was stirred at 80 °C for 3 h. The resulting mixture was poured into saturated NaHCO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with PE / EA (5 / 1 to 1 / 1) and concentrated under reduced pressure to give intermediate 12 (105 mg, yield: 40%).

[0445] The following intermediates were synthesized by methods similar to those described above for intermediate 12.

[0446] [Table 10]

[0447] Preparation of intermediate 13

[0448] [ka]

[0449] To a solution of methyl 6-chloro-5-nitropyridine-3-carboxylate (1.5 g, 6.92 mmol) in DMF (5 mL) was added methyl 1H-pyrrole-2-carboxylate (1.04 g, 8.31 mmol) and CsCO (6.77 g, 20.7 mmol), and the reaction was stirred at 60 °C for 30 min. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1:1) to give intermediate 13 (900 mg, yield: 40.4%) as a yellow oil.

[0450] Preparation of intermediate 14

[0451] [ka]

[0452] To a solution of intermediate 13 (700 mg, 2.29 mmol) in AcOH (5 mL), HO (5 mL), and THF (5 mL) was added Zn (1.8 g, 27.5 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered and washed with DCM / MeOH (1 / 1). The filtrate was concentrated under reduced pressure to give the crude product, which was used in the next step without further purification (500 mg, yield: 89.6%).

[0453] Preparation of intermediate 17

[0454] [ka]

[0455] To methyl 6-chloro-5-nitropyridine-3-carboxylate (1 g, 4.6 mmol) and methyl 2-hydroxybutanoate (0.65 g, 5.5 mmol) in anhydrous tetrahydrofuran (15 mL) at 0 °C under nitrogen, DBU (1.03 mL, 6.92 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min and then at ambient temperature for 1 h. A solid precipitated from the solution. The reaction mixture was then diluted with ethyl acetate (15 mL), the solid was removed by filtration, and the filtrate was concentrated over silica to give the crude product, which was purified by column chromatography eluting with a gradient of 10 to 50% ethyl acetate in hexane to give Intermediate 17 (1.2 g, 87.1% yield) as a white solid.

[0456] Preparation of intermediate 18

[0457] [ka]

[0458] To a solution of intermediate 17 (1.2 g, 4.02 mmol) in glacial acetic acid (10 mL) was added iron powder (1.12 g, 20.1 mmol). The resulting suspension was heated to 80° C. for 2 hours. The resulting reaction mixture was then cooled to room temperature, filtered through Celite, and washed with ethyl acetate. The filtrate was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give intermediate 18 (0.8 g, yield: 84.2%) as a crude product, which was used directly in the next step without further purification.

[0459] The following intermediates were synthesized by methods similar to those described above for intermediate 18.

[0460] [Table 11]

[0461] Preparation of intermediate 19

[0462] [ka]

[0463] To a solution of intermediate 18 (500 mg, 2.1 mmol) in dry THF (10 mL) at 0 °C, DIBAL-H (4.2 mL, 1 M in toluene) was added over 1 h. After the addition, the reaction mixture was warmed to room temperature. After the reaction was complete as indicated by TLC analysis, the reaction was quenched with saturated NH4Cl solution (20 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (DCM:MeOH = 20:1 to 10:1) to give intermediate 19 (150 mg, yield: 34.1%).

[0464] Preparation of intermediate 21

[0465] [ka]

[0466] To a solution of 5-bromo-2-chloro-3-nitropyridine (8 g, 33.69 mmol) in DMF (100 mL) was added methyl (2R)-pyrrolidine-2-carboxylate hydrochloride (6.14 g, 37.0 mmol) and DIEA (16.7 mL, 101.0 mmol). The resulting reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give Intermediate 21 (10 g, yield: 80.9%) as a yellow oil.

[0467] Preparation of intermediate 22

[0468] [ka]

[0469] To a solution of intermediate 21 (10.0 g, 27.2 mmol) in MeOH (100 mL) and HO (20 mL) was added Fe (7.6 g, 136.3 mmol) and NHCl (14.6 g, 272.6 mmol). The resulting reaction mixture was stirred at 85 °C for 1 h. The reaction was filtered, and the filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give intermediate 22 (2 g, yield: 24.6%) as a yellow solid.

[0470] Preparation of Intermediate 25

[0471] [ka]

[0472] A mixture of methyl 6-chloro-5-nitropyridine-3-carboxylate (2 g, 9.23 mmol), {1-[(tert-butoxy)carbonyl]-1H-pyrrol-2-yl}boronic acid (2.34 g, 11.0 mmol), Pd(dppf)Cl (0.68 g, 0.92 mmol), and NaCO (2.94 g, 27.7 mmol) in 1,4-dioxane (60 mL) and HO (15 mL) was stirred at 100 °C for 1 h and overnight under a N atmosphere. The reaction was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (5:1) to give intermediate 25 (1.1 g, 30.8% yield) as a red oil.

[0473] Preparation of Intermediate 26

[0474] [ka]

[0475] To a solution of intermediate 25 (1 g, 2.59 mmol) in THF (15 mL) and HO (15 mL) was added Zn (1.65 g, 25.9 mmol) and NHCl (2.8 g, 51.8 mmol). The reaction was stirred at 80 °C for 6 h. The reaction was diluted with EtOAc and brine. The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with methanol in DCM to give intermediate 26 (300 mg, yield: 45.2%) as a white solid.

[0476] Preparation of intermediate 29

[0477] [ka]

[0478] To a solution of tert-butyl 2-bromo-1H-imidazole-1-carboxylate (1.27 g, 5.12 mmol) and [4-(methoxycarbonyl)-2-nitrophenyl]boronic acid (900 mg, 4.0 mmol) in dioxane (20 mL) and water (10 mL) was added Pd(dppf)Cl (0.38 g, 0.51 mmol) and CsCO (3.34 g, 10.2 mmol). The mixture was stirred at 100 °C for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with PE / EA (1 / 0 to 1 / 2) to give intermediate 29 (170 mg, yield: 13.6%).

[0479] Preparation of intermediate 32

[0480] [ka]

[0481] To a solution of 1,3-difluoro-2-nitrobenzene (5.00 g, 31.4 mmol) in HSO (15 mL) was added NBS (5.60 g, 31.4 mmol). The mixture was stirred at 80 °C for 18 hours. The reaction mixture was poured into ice water (600 mL) and extracted with EtOAc (200 mL). The organic layer was washed with saturated NaHCO (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel to give Intermediate 32 (6.9 g, yield: 92.6%) as a brown oil.

[0482] Preparation of intermediate 33

[0483] [ka]

[0484] To a solution of intermediate 32 (4.75 g, 19.9 mmol) and methyl 2-hydroxypropanoate (2.7 g, 25.9 mmol) in DMF (50 mL) was added CsCO (13 g, 39.9 mmol). The mixture was stirred at room temperature for 18 hours. The reaction was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with brine (100 mL × 3). The organic layer was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel to give intermediate 33 (500 mg, yield: 7.78%) as a brown solid.

[0485] Preparation of Intermediate 35

[0486] [ka]

[0487] To a solution of intermediate 34 (180 mg, 0.66 mmol) in MeOH (4 mL), THF (2 mL), and HO (2 mL) was added Zn (259 mg, 3.9 mmol) and NHCl (352 mg, 6.60 mmol). The mixture was stirred at 80 °C for 3 h. The reaction was filtered, and the filtrate was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to give intermediate 35 (50 mg, yield: 35.9%) as a yellow oil.

[0488] Preparation of intermediate 42

[0489] [ka]

[0490] A mixture of 5-bromo-2-methyl-3-nitropyridine (1 g, 4.60 mmol) and SeO (0.77 g, 6.9 mmol) in dioxane (5 mL) was stirred at 110 °C for 48 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was washed with ethyl acetate. The combined filtrate was concentrated, and the resulting residue was purified by flash silica gel chromatography (elution gradient 0–70% ethyl acetate / hexane) to afford Intermediate 42 (600 mg, 56.3% yield) as a brown oil.

[0491] Preparation of intermediate 43

[0492] [ka]

[0493] To a solution of intermediate 42 (5.1 g, 22.0 mmol) in THF (45 mL) was added Fe (6.17 g, 110.3 mmol) and AcOH (5 mL). The reaction mixture was stirred at 25 °C for 1 h, filtered through Celite, and washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel using 0-5% EtOAc in hexanes to give intermediate 43 (4 g, yield: 90.1%) as a yellow solid.

[0494] Preparation of intermediate 44

[0495] [ka]

[0496] At -78°C, ethyl 2-methoxyacetate (1.763 mL, 14.9 mmol) was added to a solution of Li-HMDS (14.9 mL, 14.9 mmol) in THF. After 20 minutes, a solution of Intermediate 43 (3 g, 14.9 mmol) in THF (20 mL) was added dropwise via syringe. The resulting mixture was allowed to warm slowly to room temperature. After 18 hours, the reaction was quenched with 6N HCl (1.1 mL, 6.6 mmol), resulting in a precipitate. The mixture was heated to reflux for 2 hours. The reaction was then concentrated in vacuo, and the residue was triturated with dichloromethane and methanol. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The combined filtrate was concentrated and the resulting residue was purified by flash silica chromatography (eluent, 100% dichloromethane to 100:10:1 dichloromethane:methanol; triethylamine) to afford Intermediate 44 (2.5 g, 61.34% yield) as a white solid.

[0497] Preparation of intermediate 45

[0498] [ka]

[0499] A mixture of intermediate 44 (2.5 g, 9.15 mmol), CDI (4.45 g, 27.4 mmol) in MeCN (30 mL) was degassed and stirred at 50 °C overnight. The mixture was filtered through Celite, and the Celite was washed with EtOAc and EtOH. The mixture was diluted with ether, and the solid was filtered off, washed with diethyl ether, and dried under vacuum to give intermediate 45 (1.5 g, 64.2% yield) as a white solid.

[0500] Preparation of Intermediate 100

[0501] [ka]

[0502] To a solution of 5-bromo-2-chloro-3-nitropyridine (10 g, 42.1 mmol) in DMF (100 mL) was added methyl 2-aminobutanoate hydrochloride (7.76 g, 50.5 mmol) and DIEA (20.8 mL, 126.3 mmol). The mixture was stirred at 80 °C for 3 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with brine (100 mL × 3). The organic layer was dried over Na SO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with PE / EA (10 / 1) to give Intermediate 100 (11.2 g, 84% yield).

[0503] Preparation of Intermediate 101

[0504] [ka]

[0505] To a solution of intermediate 100 (3 g, 9.430 mmol) and (tributylstannyl)methanol (3.63 g, 11.3 mmol) in dioxane (60 mL) was added Xphos Pd G2 (24.64 mg, 0.031 mmol). The mixture was stirred at 80 °C under a N2 atmosphere for 18 h. The reaction was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with PE / EA (10 / 1 to 3 / 1) to give intermediate 101 (2.3 g, 90% yield).

[0506] Preparation of Intermediate 102

[0507] [ka]

[0508] To a solution of intermediate 101 (1.2 g, 4.4 mmol) in MeOH (20 mL) was added Pd / C 10% (0.47 g). The mixture was stirred at room temperature under an H atmosphere for 18 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give intermediate 102 as a crude product, which was used in the next step without further purification.

[0509] Preparation of Intermediate 103

[0510] [ka]

[0511] To a solution of intermediate 102 (1.0 g, 4.1 mmol) in DMF (20 mL) was added KCO (1.16 g, 8.3 mmol). The mixture was stirred at 80 °C for 18 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was triturated with EtOAc (50 mL) and filtered. The filter pellet was dried under reduced pressure to give intermediate 103 as a crude product, which was used in the next step without further purification.

[0512] Preparation of Intermediate 104

[0513] [ka]

[0514] To a suspension of intermediate 103 (200 mg, 0.96 mmol) in DCM (8 mL) was added SOCl (0.070 mL, 0.96 mmol). The mixture was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure to give a residue which was triturated with EtOAc (30 mL) and filtered. The filtrate was dried under reduced pressure to give intermediate 104 (100 mg, 46% yield) as a crude product, which was used in the next step without further purification.

[0515] Preparation of Intermediate 105

[0516] [ka]

[0517] To a solution of intermediate 104 (100 mg, crude) in CHCN (6 mL) was added intermediate 67 (100 mg, 0.33 mmol), DIEA (128.5 mg, 0.99 mmol), and potassium iodide (5.5 mg, 0.03 mmol). The reaction mixture was stirred at 80° C. for 2 hours. It was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with DCM / MeOH (10 / 1) to give intermediate 105 (43 mg, yield: 28.5%) as a brown solid.

[0518] Preparation of Intermediate 106

[0519] [ka]

[0520] To a solution of methyl butanoate (10.9 mL, 95.8 mmol) in THF (50 mL) was added LDA (2N, 49.4 mL, 98.9 mmol) at −75° C. After stirring at −78° C. for 1 h, 4-amino-6-chloropyridine-3-carbaldehyde (5 g, 31.935 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=20:1) to give Intermediate 106 (3.7 g, 56.4% yield) as a white solid.

[0521] The following intermediates were synthesized by methods similar to those described above for intermediate 106.

[0522] [Table 12]

[0523] Preparation of Intermediate 107

[0524] [ka]

[0525] Pd(dppf)Cl (245.4 mg, 0.33 mmol) was added to a stirred mixture of Intermediate 106 (700 mg, 3.3 mmol), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.68 mL, 4.0 mmol), and KCO (1.39 g, 10.0 mmol) in 1,4-dioxane (5 mL) / water (1 mL), and the resulting mixture was stirred at 90 °C under N overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give the crude product. The residue was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. The product fractions were concentrated to dryness under reduced pressure to give Intermediate 107 (600 mg, 89.3% yield) as a yellow solid.

[0526] The following intermediates were synthesized by methods similar to those described above for intermediate 107.

[0527] [Table 13]

[0528] Preparation of Intermediate 108

[0529] [ka]

[0530] A mixture of potassium osmate(VI) (184 mg, 0.49 mmol) in HO (3 mL) was added to a solution of Intermediate 107 (500 mg, 2.49 mmol), 2,6-lutidine (0.58 mL, 4.9 mmol), and NaIO (2136 mg, 9.9 mmol) in THF (6 mL), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated to dryness. The resulting residue was purified by flash silica chromatography, elution gradient 0 to 15% MeOH in DCM. The product fractions were concentrated under reduced pressure to give Intermediate 108 (250 mg, 49.5% yield) as a dark yellow foam.

[0531] The following intermediates were synthesized by methods similar to those described above for intermediate 108.

[0532] [Table 14]

[0533] Preparation of Intermediate 112

[0534] [ka]

[0535] To a solution of methyl 2-oxocyclopentane-1-carboxylate (2 g, 14.07 mmol) in DCM (40 mL) was added NaH (0.68 g, 16.88 mmol) at 0 °C. The reaction mixture was stirred for 0.5 h, and trifluoromethanesulfonic anhydride (4.76 g, 16.88 mmol) was added. The reaction mixture was warmed and stirred at room temperature for 18 h. The reaction was quenched with saturated NH4Cl (100 mL) and extracted with DCM (50 mL × 2). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with PE / EA (10 / 1) to give intermediate 112 (750 mg, yield: 19.44%) as a yellow oil.

[0536] Preparation of Intermediate 113

[0537] [ka]

[0538] To a solution of Intermediate 112 (750 mg, 2.73 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (792.9 mg, 3.12 mmol) in dioxane (10 mL) was added KOAc (510.7 mg, 5.2 mmol) and Pd(dppf)Cl (190.3 mg, 0.26 mmol). The reaction mixture was stirred at 80 °C under a N atmosphere for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with PE / EA (10 / 1) to give intermediate 113 (600 mg, yield: 86.64%) as a white solid.

[0539] The following intermediates were synthesized by methods similar to those described above for intermediate 113.

[0540] [Table 15]

[0541] Preparation of Intermediate 114

[0542] [ka]

[0543] To a solution of intermediate 113 (600 mg, 2.25 mmol) and methyl 6-chloro-5-nitropyridine-3-carboxylate (400 mg, 1.84 mmol) in 10 mL of dioxane and 2 mL of HO was added Pd(dppf)Cl (135.14 mg, 0.185 mmol) and KCO (510.52 mg, 3.694 mmol). The reaction mixture was stirred at 100 °C under a N atmosphere for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with PE / EA (10 / 1) to give intermediate 114 (400 mg, yield: 67.62%) as a yellow solid.

[0544] The following intermediates were synthesized by methods similar to those described above for intermediate 114.

[0545] [Table 16]

[0546] Preparation of Intermediate 115

[0547] [ka]

[0548] To a solution of intermediate 114 (400 mg, 1.24 mmol) in MeOH (6 mL), THF (3 mL), and HO (3 mL) was added NHCl (668 mg, 12.4 mmol) and Fe (350 mg, 6.2 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with DCM / MeOH (10 / 1, 100 mL × 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with DCM / MeOH (3.6% MeOH) to give intermediate 115 (80 mg, yield: 26.23%) as a yellow solid.

[0549] The following intermediates were synthesized by methods similar to those described above for intermediate 115.

[0550] [Table 17]

[0551] Preparation of Intermediate 116

[0552] [ka]

[0553] To a solution of intermediate 115 (80 mg, 0.32 mmol) in THF (6 mL) was added LiAlH (0.98 mL, 1N in THF, 0.98 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with MeOH and concentrated under reduced pressure to give intermediate 116 (70 mg, yield: 98.83%) as a white solid, which was used directly in the next step without further purification.

[0554] The following intermediates were synthesized by methods similar to those described above for intermediate 116.

[0555] [Table 18-1]

[0556] [Table 18-2]

[0557] Preparation of Intermediate 117

[0558] [ka]

[0559] To a solution of intermediate 116 (65 mg, 0.30 mmol) in DCM (10 mL) was added SOCl (107.2 mg, 0.90 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with DCM / MeOH (10 / 1) to give intermediate 117 (70 mg, yield: 99.22%) as a white solid.

[0560] The following intermediates were synthesized by methods similar to those described above for intermediate 117.

[0561] [Table 19-1]

[0562] [Table 19-2]

[0563] Preparation of Intermediate 118

[0564] [ka]

[0565] To a mixture of 5-bromo-2-chloropyridin-4-amine (2.34 g, 11.2 mmol) in dioxane (30 mL) and water (5 mL) was added Intermediate 113 (3.0 g, 11.27 mmol), Pd(dppf)Cl (826 mg, 1.13 mmol), and KCO (4.67 g, 33.82 mmol). The resulting mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the reaction was diluted with water (20 mL) and extracted with DCM (100 mL × 3). The combined organics were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH:DCM = 1:10) to give Intermediate 118 (1.8 g, yield: 72.37%) as a white solid.

[0566] The following intermediates were synthesized by methods similar to those described above for intermediate 118.

[0567] [Table 20]

[0568] Preparation of Intermediate 121

[0569] [ka]

[0570] To a solution of methyl 4-oxotetrahydrofuran-3-carboxylate (2 g, 13.8 mmol) in DCM (5 mL) was added DIEA (3.59 g, 27.7 mmol) in DCM (30 mL) at −78° C. under a nitrogen atmosphere, followed by the dropwise addition of trifluoromethanesulfonic anhydride (3.5 mL, 20.82 mmol) in DCM (5 mL) at −70° C. for 15 minutes. The reaction mixture was stirred at 0° C. for 3 hours and quenched with cold water (30 mL). The mixture was extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to give intermediate 121 (3.2 g, yield: 83.50%) as a yellow oil.

[0571] The following intermediates were synthesized by methods similar to those described above for intermediate 121.

[0572] [Table 21]

[0573] Preparation of Intermediate 122

[0574] [ka]

[0575] To a solution of methyl intermediate 121 (1.8 g, 6.52 mmol) in dioxane (20 mL) was added (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid (1.47 g, 6.52 mmol), Pd(PPh) (0.75 g, 0.65 mmol), and CsCO (4.25 g, 13.04 mmol). The resulting reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give intermediate 122 (1.6 g, yield: 79.90%) as a white solid.

[0576] Preparation of Intermediate 123

[0577] [ka]

[0578] To a solution of intermediate 122 (1 g, 3.26 mmol) in EtOH (20 mL) / water (10 mL) was added Fe (0.91 g, 16.28 mmol) and NH4Cl (0.87 g, 16.28 mmol). The resulting reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. After the mixture was cooled to room temperature, it was filtered through Celite, and the filtrate was concentrated to give intermediate 13 (crude, 600 mg, 75.18%) as a yellow solid, which was used directly in the next step without further purification.

[0579] Preparation of Intermediate 126

[0580] [ka]

[0581] To a stirred solution of methyl 4-oxoxane-3-carboxylate (2 g, 12.65 mmol) in DCM (8 mL) was added a solution of 2,6-di-tert-butyl-4-methylpyridine (2.60 mL, 12.65 mmol) in DCM (2 mL) at 0° C. under a nitrogen atmosphere, followed by the dropwise addition of trifluoromethanesulfonic anhydride (2.10 mL, 12.65 mmol) under nitrogen at 0° C. The resulting reaction mixture was stirred at room temperature for 16 hours. The solids were filtered off through a pad of Celite, and the filtrate was evaporated under reduced pressure to give crude intermediate 126 (3 g, 10.34 mmol) as a yellow oil, which was used directly in the next step without further purification.

[0582] The following intermediates were synthesized by methods similar to those described above for intermediate 126.

[0583] [Table 22]

[0584] Preparation of Intermediate 127

[0585] [ka]

[0586] To a mixture of [2-amino-4-(methoxycarbonyl)phenyl]boronic acid (2.02 g, 10.34 mmol) and Intermediate 126 (3 g, 10.34 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added PdCl(dppf) (0.75 g, 1.03 mmol) and KCO (4.29 g, 31.01 mmol). The resulting mixture was stirred at 100 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with DCM (100 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH:DCM = 1:10) to give Intermediate 127 (1.5 g, yield: 55.97%) as a white solid.

[0587] The following intermediates were synthesized by methods similar to those described above for intermediate 127.

[0588] [Table 23]

[0589] Preparation of Intermediate 132

[0590] [ka]

[0591] To a solution of methyl 5-amino-6-chloronicotinate (280 mg, 1.50 mmol) and intermediate 131 (482.79 mg, 1.80 mmol) in dioxane / water (4 / 1 ratio, 6 mL) was added KCO (414.78 mg, 3.00 mmol) and Pd(dppf)Cl (109.79 mg, 0.15 mmol). The resulting reaction mixture was stirred at 100 °C under a N atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with DCM / MeOH (25 / 1) to give intermediate 132 (150 mg, yield: 38.41%) as a brown solid.

[0592] The following intermediates were synthesized by methods similar to those described above for intermediate 132.

[0593] [Table 24]

[0594] Preparation of Intermediate 135

[0595] [ka]

[0596] To a solution of 5-bromo-2-chloropyridin-4-amine (1 g, 4.82 mmol) and intermediate 130 (1.55 g, 5.78 mmol) in dioxane and water (4 / 1, 22 mL) was added KCO (1.33 g, 9.64 mmol) and Pd(dppf)Cl (0.35 g, 0.48 mmol). The resulting reaction mixture was stirred at 100 °C under a N atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with DCM / MeOH (25 / 1) to give intermediate 135 (680 mg, yield: 59.61%) as a yellow solid.

[0597] Preparation of intermediate 53

[0598] [ka]

[0599] A solution of methyl 5-bromopicolinate (300 mg, 1.39 mmol), (3aRS,6aRS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (295 mg, 1.39 mmol), Cs2CO3 (893 mg, 2.74 mmol), and RuPhosPd3 (117 mg, 0.14 mmol) in dioxane (20 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. The solvent was removed, and the residue was diluted with 30 mL of water and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The residue was purified using a C18 column (acetonitrile:water (0.1% ammonium bicarbonate) = 5% to 60%) to give intermediate 53 (350 mg, yield: 72.56%) as a yellow solid.

[0600] The following intermediates were synthesized by methods similar to those described above for intermediate 53.

[0601] [Table 25]

[0602] Preparation of intermediate 54

[0603] [ka]

[0604] To a solution of intermediate 53 (350 mg, 1.01 mmol) in THF / MeOH (10 mL / 2 mL) was added a solution of lithium hydroxide in water (3 mL, 1.0 mmol). The mixture was stirred at 20 °C for 3 h. The mixture was concentrated, diluted with water, acidified to pH = 5 with 1 M HCl (aq), and extracted with ethyl acetate. The organic layer was dried over Na SO , filtered, and concentrated to give intermediate 54 (280 mg, crude) as a yellow oil, which was used directly in the next step.

[0605] The following intermediates were synthesized by methods similar to those described above for intermediate 54.

[0606] [Table 26]

[0607] Preparation of intermediate 55

[0608] [ka]

[0609] To a solution of intermediate 54 (260 mg, crude) in N,N-dimethylformamide (5 mL) at 25 °C, DIEA (202 mg, 1.56 mmol), HATU (445 mg, 1.17 mmol), and methanamine hydrochloride (79 mg, 1.17 mmol) were added. The resulting mixture was stirred at room temperature for 5 hours. The solvent was removed, and the residue was diluted with 10 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate = 1:1) to give intermediate 55 (180 mg, yield: 66.91%) as a yellow solid.

[0610] The following intermediates were synthesized by methods similar to those described above for intermediate 55.

[0611] [Table 27-1]

[0612] [Table 27-2]

[0613] [Table 27-3]

[0614] Preparation of intermediate 56

[0615] [ka]

[0616] A mixture of intermediate 55 (180 mg, 0.52 mmol) in TFA (1 mL) and DCM (5 mL) was stirred at room temperature for 1 h. The solvent was removed, and the residue was diluted with EtOAc, basified with 1 M NaOH (aq), and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give intermediate 56 (90 mg, crude) as a yellow oil, which was used directly in the next step.

[0617] The following intermediates were synthesized by methods similar to those described above for intermediate 56.

[0618] [Table 28-1]

[0619] [Table 28-2]

[0620] [Table 28-3]

[0621] Preparation of intermediate 57

[0622] [ka]

[0623] A solution of benzyl 2,5-dioxopyrrolidine-1-carboxylate (3.63 g, 15.55 mmol) in DCM (20 mL) was slowly added to a solution of (3aRS,6aRS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate oxalate (3 g, 14.13 mmol) and TEA (1.43 g, 14.13 mmol) in DCM (50 mL) at room temperature under N2. The mixture was stirred at 20 °C for 12 h. The mixture was diluted with 20 mL of water and extracted with DCM (20 mL × 2). The organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 57 (4.3 g, yield: 83.4%) as a white solid.

[0624] Preparation of Intermediates 58 and 59

[0625] [ka]

[0626] Intermediate 57 (4.3 g, 11.79 mmol) was separated by chiral HPLC (Separation conditions: Column: IH-3.0 cm; Mobile phase: Hex:EtOH = 95:5, 25 mL / min; Temperature: 40 °C; Wavelength: 214 nm). The first fraction was collected as Intermediate 58 (1.7 g, RT = 10.72 min, 100% ee) as a white solid, and the second fraction was collected as Intermediate 59 (1.7 g, RT = 12.43 min, 97.65% ee) as a white solid.

[0627] Preparation of Intermediate 60

[0628] [ka]

[0629] To a solution of intermediate 59 (280 mg, 0.81 mmol) in MeOH (10 mL) was added Pd / C 10% (280 mg, 2.63 mmol). The mixture was stirred at room temperature under an H atmosphere for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 60 (crude) as a white solid, which was used in the next step without further purification.

[0630] The following intermediates were synthesized by methods similar to those described above for intermediate 60.

[0631] [Table 29]

[0632] Preparation of Intermediate 62

[0633] [ka]

[0634] A solution of methyl 5-bromopicolinate (200 mg, 0.91 mmol), Intermediate 60 (193 mg, 0.91 mmol), CsCO (591 mg, 1.82 mmol), and RuPhos Pd (76 mg, 0.091 mmol) in dioxane (10 mL) was stirred at 100 °C for 5 h under a nitrogen atmosphere. The solvent was removed, and the residue was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified using a C18 column (acetonitrile:water (0.1% ammonium bicarbonate) = 5% to 60%) to give Intermediate 62 (220 mg, yield: 62.8%) as a yellow solid.

[0635] The following intermediates were synthesized by methods similar to those described above for intermediate 62.

[0636] [Table 30]

[0637] Preparation of intermediate 63

[0638] [ka]

[0639] A solution of intermediate 62 (220 mg, 0.63 mmol) in 33% methylamine in ethanol (2 mL) was stirred for 12 hours at 60° C. The mixture was concentrated to give intermediate 63 (200 mg, yield: 82.1%) as a yellow oil, which was used in the next step without further purification.

[0640] The following intermediates were synthesized by methods similar to those described above for intermediate 63.

[0641] [Table 31]

[0642] Preparation of intermediate 64

[0643] [ka]

[0644] To a solution of intermediate 63 (200 mg, 0.58 mmol) in DCM (5 mL) was added TFA (0.4 mL, 5.77 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The solvent was removed, and the residue was diluted with EtOAc, basified with 1 M NaOH (aq), and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give crude intermediate 64 (120 mg, yield: 84.4%) as a yellow oil, which was used directly in the next step.

[0645] The following intermediates were synthesized by methods similar to those described above for intermediate 64.

[0646] [Table 32]

[0647] Preparation of intermediate 65

[0648] [ka]

[0649] To a solution of intermediate 60 (120 mg, 0.57 mmol) and methyl 5-bromo-6-fluoropyridine-2-carboxylate (145 mg, 0.62 mmol) in dioxane (10 mL) was added CsCO (368 mg, 1.13 mmol) and RuPhos PdG (12 mg, 0.014 mmol). The mixture was stirred at 80 °C under a N atmosphere for 3 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel to give intermediate 65 (80 mg, yield: 38.73%) as a white solid.

[0650] The following intermediates were synthesized by methods similar to those described above for intermediate 65.

[0651] [Table 33]

[0652] Preparation of Intermediate 66

[0653] [ka]

[0654] To a solution of intermediate 66 (80 mg, 0.22 mmol) in EtOH (8 mL) was added a solution of methanamine in EtOH (0.009 mL, 0.018 mmol). The resulting reaction mixture was stirred at 60° C. for 18 hours. The reaction was concentrated under reduced pressure to give intermediate 66 (crude) as a white solid, which was used in the next step without further purification.

[0655] The following intermediates were synthesized by methods similar to those described above for intermediate 66.

[0656] [Table 34]

[0657] Preparation of intermediate 67

[0658] [ka]

[0659] To a solution of intermediate 66 (79 mg, 0.22 mmol) in DCM was added HCl (6 mL, 4N) in EtOAc. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give intermediate 67 (crude), which was used in the next step without further purification.

[0660] The following intermediates were synthesized by methods similar to those described above for intermediate 67.

[0661] [Table 35]

[0662] Preparation of intermediate 99

[0663] [ka]

[0664] To a mixture of intermediate 5 (220 mg, 1.08 mmol) in DCM (20 mL) was added MnO (938 mg, 10.80 mmol) at 0 °C. The mixture was stirred under a nitrogen atmosphere at 30 °C for 12 h. The mixture was filtered off, washed with DCM, and the filtrate was concentrated under reduced pressure to give intermediate 99 (180 mg, crude) as a white solid, which was used directly in the next step.

[0665] Preparation of Intermediate 182

[0666] [ka]

[0667] To a solution of ethyl 2-diazoacetate (5.96 g, 52.27 mmol) and oxolan-2-one (3.00 g, 34.85 mmol) in THF (180 mL) was added Li-HMDS (52.3 mL, 52.3 mmol) at −78° C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction mixture was poured into saturated NaHCO (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine. The organic layer was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with PE / EtOAc (2 / 1) to give intermediate 182 (3.6 g, yield: 40.14%) as a yellow solid.

[0668] Preparation of intermediate 183

[0669] [ka]

[0670] To a solution of intermediate 182 (3.6 g, 17.98 mmol) in toluene (360 mL) was added Rh(OAc) (0.08 g, 0.18 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with PE / EtOAc (3 / 1) to give intermediate 183 (1.23 g, yield: 39.72%) as a yellow oil.

[0671] Preparation of Intermediate 184

[0672] [ka]

[0673] To a solution of intermediate 183 (1.23 g, 7.14 mmol) in DCM (35 mL) was added 2,6-di-tert-butyl-4-methylpyridine (1.5 mL, 7.14 mmol) in DCM (35 mL) at 0 °C under a nitrogen atmosphere. To the mixture was added TfO (2.014 g, 7.14 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with PE / EtOAc (5 / 1) to give intermediate 184 (900 mg, yield: 41.41%) as a yellow oil.

[0674] The following intermediates were synthesized by methods similar to those described above for intermediate 184.

[0675] [Table 36]

[0676] Preparation of Intermediate 185

[0677] [ka]

[0678] To a solution of intermediate 184 (900 mg, 2.96 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (901 mg, 3.55 mmol) in dioxane (15 mL) was added KOAc (580 mg, 5.92 mmol) and Pd(dppf)Cl (216 mg, 0.30 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with PE / EtOAc (5 / 1) to give intermediate 185 (800 mg, yield: 95.85%) as a colorless oil.

[0679] The following intermediates were synthesized by methods similar to those described above for intermediate 185.

[0680] [Table 37]

[0681] Preparation of Intermediate 186

[0682] [ka]

[0683] To a solution of intermediate 185 (400 mg, 1.42 mmol) and methyl 5-amino-6-chloropyridine-3-carboxylate (241 mg, 1.29 mmol) in dioxane / water (5 / 1, 6 mL) was added Pd(dppf)Cl (94 mg, 0.13 mmol) and KCO (356 mg, 2.58 mmol). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The reaction mixture was diluted with water (30 mL). The reaction mixture was extracted with DCM, and the combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (MeOH in DCM = 0-10%) to give intermediate 186 (75 mg, yield: 22.36%) as a white solid.

[0684] The following intermediates were synthesized by methods similar to those described above for intermediate 186.

[0685] [Table 38]

[0686] Preparation of Intermediate 194

[0687] [ka]

[0688] To a solution of 6-chloro-5-fluoropyridine-2-carboxylic acid (800 mg, 4.56 mmol) in t-BuOH (5 mL) was added (Boc)O (1.988 g, 9.11 mmol) and DMAP (612 mg, 5.01 mmol). The reaction mixture was stirred at 50° C. under a N atmosphere for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc (10 / 1) to give intermediate 194 (300 mg, yield: 28.42%) as a white solid.

[0689] Preparation of Intermediate 195

[0690] [ka]

[0691] To a solution of benzyl (3aS,6aS)-3a,6a-dihydrogenio-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (212 mg, 0.86 mmol) in DMF (5 mL) was added intermediate 194 (200 mg, 0.86 mmol) and DIEA (558 mg, 4.32 mmol). The reaction mixture was stirred at 100 °C under a N atmosphere for 16 h. The reaction mixture was poured into water, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc (1 / 1) to give intermediate 195 (350 mg, yield: 88.52%) as a white solid.

[0692] Preparation of Intermediate 196

[0693] [ka]

[0694] To a solution of intermediate 195 (350 mg, 0.76 mmol) in DCM (2 mL) was added TFA (2 mL, 26.93 mmol) at room temperature. The reaction mixture was stirred at 40° C. for 4 hours. TFA was removed in vacuo, the residue was diluted with water, and the mixture was adjusted to pH 2 with aqueous hydrochloric acid (1 M). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 196 (300 mg, yield: 97.68%) as a yellow solid.

[0695] Preparation of Intermediate 197

[0696] [ka]

[0697] To a solution of intermediate 196 (300 mg, 0.75 mmol) in DMF (5 mL) was added oxetan-3-amine (545 mg, 7.46 mmol), HATU (852 mg, 2.24 mmol), and DIEA (482 mg, 3.73 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with PE / EA (1 / 2) to give intermediate 197 (300 mg, yield: 87.95%) as a yellow solid.

[0698] Preparation of Intermediate 198

[0699] [ka]

[0700] To a solution of intermediate 197 (300 mg, 0.66 mmol) in EtOH (5 mL) was added PdCl (11 mg, 0.066 mmol). The reaction mixture was stirred at room temperature under an H atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 198 (110 mg, yield: 51.90%) as a yellow solid.

[0701] Preparation of Intermediate 199

[0702] [ka]

[0703] To a solution of methyl 4-bromo-3-nitrobenzoate (2.0 g, 7.69 mmol) in MeOH (20 mL) and HO (7 mL) was added Fe (2.2 g, 38 mmol) and NHCl (4.1 g, 77 mmol). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give intermediate 199 (1.7 g, yield: 96.1%) as a yellow oil.

[0704] Preparation of Intermediate 200

[0705] [ka]

[0706] To a solution of intermediate 199 (270 mg, 1.17 mmol) and intermediate 185 (397 mg, 1.41 mmol) in dioxane / water (6 mL, v / v=10:1) was added KCO (324 mg, 2.35 mmol) and Pd(dppf)Cl (86 mg, 0.12 mmol). The reaction mixture was stirred at 80 °C under a N atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluted with DCM / MeOH (25:1) to give intermediate 200 (131 mg, yield: 43.0%) as a yellow solid.

[0707] Preparation of Intermediate 203

[0708] [ka]

[0709] To a solution of methyl 3-amino-2-fluorobenzoate (6000 mg, 35.47 mmol) in HOAc (30 mL) was added dropwise Br2 (1.8 mL, 35.47 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (30 mL). The reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with NaOH solution (1 M) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (0-10% EtOAc in PE to 5-95% ACN / HO) to give intermediate 203 (550 mg, yield: 6.25%) as a yellow solid.

[0710] Preparation of Intermediate 204

[0711] [ka]

[0712] To a solution of intermediate 203 (630 mg, 2.54 mmol) and intermediate 113 (676 mg, 2.54 mmol) in dioxane-water (5 / 1, 20 mL) was added Pd(dppf)Cl (186 mg, 0.25 mmol) and KCO (1053 mg, 7.62 mmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (30 mL). The reaction mixture was extracted with DCM (30 mL × 3), and the combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography (0-50% EtOAc in PE) to give intermediate 204 (300 mg, yield: 45.21%) as a yellow solid.

[0713] Example 3: Preparation of compounds Preparation of Compound 2

[0714] [ka]

[0715] To a mixture of compound intermediate 56 (50 mg, 0.24 mmol) and intermediate 99 (60 mg, 0.24 mmol) in DCE (10 mL) was added sodium triacetoxyborohydride (102 mg, 0.48 mmol) and AcOH (0.01 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and purified by preparative HPLC (column: Xbridge C18 (5 μm)). * Purification by HPLC (150 mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, GT: 10 min, gradient: 5–50% (% B)) gave compound 2 (28 mg, yield: 27.01%) as a white solid.

[0716] The following compounds were synthesized by methods similar to those described above for compound 2.

[0717] [Table 39]

[0718] Preparation of Compound 3

[0719] [ka]

[0720] To a solution of intermediate 73 (90 mg, 0.299 mmol) in acetonitrile (10 mL) was added intermediate 12 (81.12 mg, 0.299 mmol) and DIEA (0.049 mL, 0.299 mmol). The mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The mixture was concentrated, and the residue was dissolved in DMF (1 mL). This was purified by preparative HPLC to give compound 3 (20 mg, 14% yield) as a white solid.

[0721] The following compounds were synthesized by methods similar to those described above for compound 3.

[0722] [Table 40-1]

[0723] [Table 40-2]

[0724] [Table 40-3]

[0725] Preparation of Compound 9

[0726] [ka]

[0727] To a solution of intermediate 76 (109 mg, 0.39 mmol) in MeCN (10 mL) was added intermediate 6 (100 mg, 0.39 mmol), DIEA (1 mL, 6.05 mmol), and potassium iodide (13 mg, 0.077 mmol). The reaction mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (Xbridge C18 (5 μm 19 * 150mm), mobile phase A: water ( 0.1%NH4 HCl), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, temperature: room temperature, gradient: 10-40% (% B)) to give compound 9 (28.8 mg, yield: 17.3%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)11.82(s,1H),8.41(d,J=1.6Hz,1H),8.29-8.28(m,1H),7.85(d,J=2 .4Hz,1H),7.79(d,J=8.8Hz,1H),7.74(s,1H),7.62(s,1H),6.93(dd,J=8.8,2.8Hz,1H),4.0 3-3.94(m,2H),3.53-3.49(m,2H),3.08(t,J=9.2Hz,2H),2.92-2.89(m,2H),2.77(d,J=4.8 Hz,3H), 2.66(t,J=8.8Hz,2H),2.57-2.51(m,2H),2.40-2.39(m,2H),1.18(t,J=7.2Hz,3H).

[0728] The following compounds were synthesized by methods similar to those described above for compound 9.

[0729] [Table 41]

[0730] Preparation of Compound 15

[0731] [ka]

[0732] To a solution of intermediate 64 (150 mg, 0.61 mmol), DIEA (393 mg, 3.04 mmol), and potassium iodide (10 mg, 0.061 mmol) in acetonitrile (20 mL) was added intermediate 6 (51 mg, 0.19 mmol). The resulting reaction mixture was stirred at 80° C. for 2 hours. The mixture was concentrated to give the crude compound, which was purified by preparative HPLC (column: RP-PREP-5Xbridge C18 (5 μm 19 * Purification using a 150 mm column (mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, GT: 10 min, temperature: room temperature, gradient: 10-55% (% B)) afforded compound 15 (130 mg, yield: 49%) as a white solid.

[0733] 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.40(d,J=1.6Hz,1H),8.30-8.26(m,1H),7.85(d,J=2 .8Hz,1H),7.79(d,J=8.8Hz,1H),7.74(s,1H),7.62(s,1H),6.92(dd,J=8.8,2.8Hz,1H),4.0 3-3.92(m,2H),3.53-3.49(m,2H),3.08(t,J=9.6Hz,2H),2.92-2.89(m,2H),2.76(d,J=4.8H z,2H),2.66(t,J=10.0Hz,2H),2.59-2.53(m,2H),2.42-2.36(m,2H),1.18(t,J=7.2Hz,3H).

[0734] The following compounds were synthesized by methods similar to those described above for compound 15.

[0735] [Table 42]

[0736] Preparation of Compound 27

[0737] [ka]

[0738] To a solution of intermediate 67 (33 mg, 0.13 mmol) in acetonitrile (6 mL) was added intermediate 6 (33 mg, 0.15 mmol), DIEA (0.062 mL, 0.38 mmol), and potassium iodide (2 mg, 0.013 mmol). The mixture was stirred at 80° C. for 3 h. The reaction was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (Xbridge C18 (5 μm 19 * Purification using a 150 mm column, mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, temperature: room temperature, gradient: 45-80% (% B)) afforded compound 27 (22.6 mg, yield: 38.80%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.82(s,1H),8.40(d,J=1.6Hz,1H),8.18(d,J=4.8Hz,1H ),7.74-7.72(m,2H),7.62(s,1H),7.13-7.08(m,1H),4.02-3.93(m,2H),3.55(d, J=2.8Hz,2H),3.25(d,J=8.8Hz,2H),2.90-2.87(m,2H),2.75(d,J=4.8Hz,3H),2. 66-2.62(m,2H),2.57-2.53(m,2H),2.35(t,J=4.8Hz,2H),1.18(t,J=7.2Hz,3H).

[0739] The following compounds were synthesized by methods similar to those described above for compound 27.

[0740] [Table 43]

[0741] Preparation of Compound 28

[0742] [ka]

[0743] To a solution of intermediate 72 (80 mg, 0.27 mmol) in MeCN (10 mL) was added intermediate 6 (70 mg, 0.31 mmol), DIEA (0.6 mL, 3.87 mmol), and potassium iodide (10 mg, 0.060 mmol). The mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (SunFire C18 (5 μm 19 * Purification using a 150 mm column, mobile phase A: water (0.2% HCOOH), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, temperature: room temperature, gradient: 5-25% (% B)) afforded compound 28 (10 mg, yield: 8.3%) as a white solid. 1 HNMR(400MHz,DMSO-d6)11.83(s,1H),8.41(d,J=0.8Hz,1H),8.26(s,0.5H),8.18(d ,J=4.8Hz,1H),7.74-7.73(m,2H),7.62(s,1H),7.13-7.08(m,1H),4.02-3.93(m,2H) ,3.55-3.54(m,2H),3.26(t,J=8.8Hz,2H),2.91-2.87(m,2H),2.75(d,J=4.4Hz,3H) ,2.64(t,J=9.2Hz,2H),2.57-2.51(m,2H),2.36-2.35(m,2H),1.18(t,J=7.6Hz,3H).

[0744] Preparation of Compound 37

[0745] [ka]

[0746] To a solution of intermediate 105 (43 mg, 0.095 mmol) in DCM (16 mL) and MeOH (1.6 mL) was added MnO (164.5 mg, 1.89 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 16 hours. After filtration through a pad of Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluted with DCM / MeOH (10 / 1) to give compound 37 (11.5 mg, yield: 23.34%) as a yellow solid.

[0747] Preparation of Compound 40

[0748] [ka]

[0749] To a solution of intermediate 108 (80 mg, 0.396 mmol) in DCM (8 mL) and MeOH (2 mL) was added intermediate 67 (104.6 mg, 0.40 mmol), NaBHCN (93.2 mg, 1.48 mmol), and one drop of AcOH. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the crude product. The crude product was purified by preparative HPLC (column: Xbridge C18 (5 μm 19 * Further purification was performed using a 150 mm column (mobile phase A: water (0.2% HCOOH), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient conditions: 5% B to 25% B) to obtain compound 40 (40 mg, yield: 22.44%) as a white solid. 1 H NMR(400MHz,DMSO-d6)8.71(s,1H),8.18(d,J=4.4Hz,1H),7.79-7.72(m,2H),7.29(s,1H),710(dd,J=8.4Hz,10.8Hz,1H),4.08-3.98(m,2H) ),3.76-3.70(m,2H),3.29-3.25(m,2H),2.97-2.94(m,2H),2.78-2.68(m,5H),2.53-2.50(m,2H),2.39-2.36(m,2H),1.17(t,J=7.2Hz,3H).

[0750] The following compounds were synthesized by methods similar to those described above for compound 40.

[0751] [Table 44]

[0752] Preparation of Compound 46

[0753] [ka]

[0754] To a solution of intermediate 161 (31.1 mg, 0.11 mmol) and intermediate 16 (25 mg, 0.11 mmol) in CH3CN (4 mL) was added DIEA (0.053 mL, 0.321 mmol) and KI (17.0 mg, 0.11 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with DCM / MeOH (10 / 1) to give the crude compound. The crude product was purified by preparative HPLC (column: Xbridge C18 (5 μm 19 * Further purification was performed using a 150 mm column (mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient conditions: 10% B to 60% B) to obtain compound 46 (11.6 mg, yield: 22.01%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.34(s,1H),8.23(d,J=5.2Hz,1H),8.16(d,J=2.4Hz,1H),8.12-8.11( m,1H),7.87(d,J=2.8Hz,1H),7.79(d,J=8.8Hz,1H),7.65(d,J=1.6Hz,1H),7.10-7.09(m,1H),6 .95-6.93(m,1H),6.73-6.71(m,1H),4.00-3.92(m,2H),3.54-3.50(m,2H),3.46-3.40(m,4H),3 .26(s,3H),3.08(t,J=9.6Hz,2H),2.94-2.90(m,2H),2.67(t,J=9.6Hz,2H),2.43-2.36(m,2H).

[0755] The following compounds were synthesized by methods similar to those described above for compound 46.

[0756] [Table 45]

[0757] Preparation of compound 48

[0758] [ka]

[0759] To a solution of intermediate 67 (50 mg, 0.19 mmol) in CHCN (8 mL) was added intermediate 117 (44.40 mg, 0.19 mmol), DIEA (0.031 mL, 0.19 mmol), and KI (9.0 mg, 0.02 mmol). The reaction mixture was stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with DCM / MeOH (10 / 1) to give the crude product, which was further purified by preparative HPLC (Xbridge C185 μm*150 mm, 10-50% B); mobile phase: B (ACN), mobile phase: A (HO (0.1% NHHCO)) to give compound 48 (12.3 mg, 0.026 mmol, 13.62%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.66(s,1H),8.41(d,J=2.0Hz,1H),8.20-8.17(m,1H),7.74-7. 72(m,1H),7.65(d,J=1.6Hz,1H),7.13-7.08(m,1H),4.02-3.93(m,2H),3.55(t,J=5.6H z,2H),3.26(t,J=7.2Hz,2H),3.16(t,J=7.6Hz,2H),2.90-2.86(m,2H),2.80(t,J=7.2H z,2H),2.74(d,J=4.8Hz,3H),2.67-2.61(m,2H),2.50-2.32(m,2H),2.15-2.07(m,2H).

[0760] The following compounds were synthesized by methods similar to those described above for compound 48.

[0761] [Table 46]

[0762] Preparation of Compound 52

[0763] [ka]

[0764] To a solution of intermediate 168 (60 mg, 0.20 mmol) in MeCN (5 mL) was added intermediate 117 (43.2 mg, 0.20 mmol), DIEA (0.162 mL, 0.979 mmol), and KI (3.3 mg, 0.020 mmol). The resulting reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Xbridge C18 (5 μm 19 * Purification using a 150 mm column, mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 45–80% (% B)) afforded compound 52 (30 mg, yield: 30.36%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.65(s,1H),8.86(d,J=6.8Hz,1H),8.41(d,J=1.6Hz,1H),7.73(dd,J= 8.4Hz,1.6Hz,1H),7.65(d,J=1.6Hz,1H),7.11(dd,J=10.8Hz,8.4Hz,1H),5.02-4.93(m,1H),4 .70-4.63(m,4H),3.43-3.93(m,2H),3.57-3.56(m,2H),3.31-3.25(m,2H),3.18-3.14(m,2H), 2.90-2.87(m,2H),2.82-2.79(m,2H),2.67-2.62(m,2H),2.40-2.31(m,2H),2.15-2.07(m,2H).

[0765] The following compounds were synthesized by methods similar to those described above for compound 48.

[0766] [Table 47]

[0767] Preparation of Compound 54

[0768] [ka]

[0769] To a solution of intermediate 67 (185 mg, 0.70 mmol) in MeOH (5 mL) was added intermediate 120 (150 mg, 0.70 mmol). After the reaction mixture was stirred at room temperature for 1 h, NaBHCN (132.00 mg, 0.21 mmol) and 1 drop of HOAc were added, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC (Xbridge C18 (5 μm 19 * Purification using a 150 mm column (mobile phase A: water (0.2% TFA), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 45–80% (% B)) afforded compound 54 (30 mg, yield: 9.29%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.81(s,1H),8.68(s,1H),8.18(d,J=5.2Hz,1H),7.74(dd,J=8.0Hz,1.6Hz,1H),7.34(s,1H),7.11(dd,J=10.4Hz,8.4Hz,1H),4 .17-4.08(m,2H),3.58-3.56(m,2H),3.31-3.27(m,2H),3.17-3.13(m,2H), 3.06-3.02(m,2H),2.82-2.74(m,7H),2.40-2.41(m,2H),2.16-2.08(m,2H).

[0770] The following compounds were synthesized by methods similar to those described above for compound 54.

[0771] [Table 48-1]

[0772] [Table 48-2]

[0773] Preparation of Compound 60

[0774] [ka]

[0775] To a solution of intermediate 125 in CH3CN (10 mL) was added intermediate 67 (112 mg, 0.43 mmol), DIEA (166 mg, 1.29 mmol), and potassium iodide (7 mg, 0.04 mmol). The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (C18 (5 μm 19 * Purification using a 150 mm column, mobile phase A: water (0.2% HCOOH), mobile phase B: acetonitrile, UV: 214 nm, flow rate: 15 mL / min, temperature: room temperature, gradient: 10–25% (% B)) afforded compound 60 (16 mg, yield: 8.14%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.78(s,1H),8.18-8.14(m,1.5H),7.72(dd,J=8.4Hz,J=2. 0Hz,1H),7.44-7.41(m,2H),7.21-7.18(m,1H),7.13-7.08(m,1H),5.29(t,J=3.6Hz ,2H),4.96(t,J=3.6Hz,2H),4.05-3.92(m,2H),3.56-3.53(m,2H),3.28-3.23(m,2 H),2.91-2.88(m,2H),2.74(d,J=4.8Hz,3H),2.68-2.64(m,2H),2.38-2.33(m,2H).

[0776] The following compounds were synthesized by methods similar to those described above for compound 60.

[0777] [Table 49]

[0778] Preparation of Compound 66

[0779] [ka]

[0780] To a solution of Intermediate 67 (42.34 mg, 0.16 mmol) in MeCN (5 mL) was added DIEA (0.13 mL, 0.80 mmol), potassium iodide (2.6 mg, 0.016 mmol), and Intermediate 129 (40 mg, 0.16 mmol). The resulting solution was stirred at 80° C. for 2 h. The reaction mixture was evaporated in vacuo. The crude material was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by preparative HPLC (Xbridge C18 (5 μm 19 * Purification using a 150 mm column (mobile phase A: water (0.2% FA), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 45–80% (% B)) afforded compound 66 (30 mg, yield: 37.50%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.70(s,1H),8.17(d,J=5.2Hz,1H),8.14(s,0.85H),7.73(dd,J= 8.0Hz,2.0Hz,1H),7.62(d,J=8.0Hz,1H),7.32(s,1H),7.20(dd,J=8.4Hz,0.8Hz,1H),7.1 0(dd,J=10.8Hz,8.4Hz,1H),4.45(s,2H),3.97-3.91(m,4H),3.57-3.53(m,2H),3.29-3.2 4(m,2H),2.91-2.86(m,4H),2.74(d,J=4.8Hz,3H),2.68-2.63(m,2H),2.39-2.30(m,2H).

[0781] The following compounds were synthesized by methods similar to those described above for compound 66.

[0782] [Table 50]

[0783] Preparation of Compound 69

[0784] [ka]

[0785] To a solution of intermediate 129 in MeCN (5 mL) was added intermediate 168 (60 mg, 0.20 mmol), DIEA (0.08 mL, 0.60 mmol), and potassium iodide (3.2 mg, 0.02 mmol). The resulting solution was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (Xbridge C18 (5 μm)). * Purification using a 150 mm column (mobile phase A: water (0.2% FA), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 5–30% (% B)) afforded compound 69 (10 mg, yield: 9.9%) as a white solid. 1 H NMR(400MHz,DMSO-d6)12.70(s,1H),8.86(d,J=6.8Hz,1H),8.15(s,0.71H),7.74-7.7 2(m,1H),7.62(d,J=8.4Hz,1H),7.32(s,1H),7.20(d,J=8.0Hz,1H),7.13-7.08(m,1H), 5.00-4.95(m,1H),4.70-4.64(m,4H),4.45(s,2H),4.01-3.91(m,4H),3.57-3.48(m,2 H),3.27(t,J=8.8Hz,2H),2.91-2.86(m,4H),2.63(t,J=8.8Hz,2H),2.39-2.33(m,2H).

[0786] Preparation of Compound 71

[0787] [ka]

[0788] To a solution of intermediate 134 (50 mg, 0.189 mmol) in CHCN (8 mL) was added intermediate 67 (47.43 mg, 0.189 mmol), DIEA (73.28 mg, 0.57 mmol), and KI (8.98 mg, 0.02 mmol). The resulting reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the crude product, which was purified by preparative HPLC (Xbridge C185um19 * Further purification by 150 mm 5-25% B; mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH)) gave compound 71 (13.9 mg, 15.3% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.83(s,1H),8.45(d,J=1.6Hz,1H),8.20-8.15(m,1.7H),7.72(d d,J=8.0Hz,J=1.6Hz,1H),7.65(d,J=1.2Hz,1H),7.13-7.08(m,1H),4.47(s,2H),4.05-3. 95(m,2H),3.92(t,J=5.6Hz,2H),3.59-3.52(m,2H),3.26(t,J=8.8Hz,2H),3.00-2.94(m, 2H),2.91-2.87(m,2H),2.74(d,J=4.8Hz,3H),2.65(t,J=10.4Hz,2H),2.38-2.32(m,2H).

[0789] The following compounds were synthesized by methods similar to those described above for compound 71.

[0790] [Table 51]

[0791] Preparation of Compound 73

[0792] [ka]

[0793] To a solution of intermediate 134 (100 mg, 0.40 mmol) and intermediate 172 (133.4 mg, 0.40 mmol) in CH3CN (8 mL) was added DIEA (154.7 mg, 1.20 mmol) and KI (6.4 mg, 0.04 mmol). The resulting reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with DCM / MeOH (10 / 1) to give the crude product. The crude product was further purified by preparative HPLC (column: SunFire C185um19 * Purification at 150 mm; mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH), UV: 254 nm, flow rate: 15 mL / min, gradient: 10–25% B) afforded compound 73 (18.5 mg, yield: 8.40%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.84(s,1H),8.45(d,J=1.6Hz,1H),8.33(d,J=8.4Hz,1H),8. 18(s,0.47H),7.73-7.70(m,1H),7.65(d,J=1.2Hz,1H),7.12-7.08(m,1H),4.47(s,2H) ),4.04-3.91(m,5H),3.59-3.54(m,3H),3.27(t,J=8.8Hz,4H),3.13(s,3H),2.99-2.9 6(m,2H),2.97-2.87(m,2H),2.67-2.62(m,2H),2.39-2.33(m,2H),2.05-1.98(m,2H).

[0794] Preparation of Compound 77

[0795] [ka]

[0796] To a solution of intermediate 67 (50 mg, 0.19 mmol) in DCM (8 mL) and MeOH (2 mL) was added intermediate 137 (52.26 mg, 0.23 mmol), HOAc (35.3 mg, 0.19 mmol), and NaBH(OAc) (198.64 mg, 0.95 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with DCM / MeOH (10 / 1) to give the crude product. The crude product was purified by preparative HPLC (Xbridge C185um19 * Further purification with 150 mm5-25% B; mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH)) gave compound 77 (25.5 mg, yield: 27.96%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.93(s,1H),8.79(s,1H),8.19-8.15(m,1.88H),7.75-7.72(m,1H),7.32(s,1H),7.13-7.09(m,1H),4.45(s,2H),4 .10-4.00(m,2H),3.93(t,J=5.6Hz,2H),3.61-3.52(m,2H),3.28(t,J=8.8Hz,2H),3.01-2.91(m,4H),2.75-2.67(m,5H),2.44-2.33(m,2H).

[0797] Preparation of Compound 81

[0798] [ka]

[0799] To a solution of intermediate 188 (55 mg, 0.22 mmol) in MeCN (10 mL) was added intermediate 67 (58 mg, 0.22 mmol), KI (36 mg, 0.22 mmol) and DIEA (28 mg, 0.22 mmol). The reaction mixture was heated to 80° C. and stirred for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (SunFire C185 μm; *150 mm; 10-25% B); mobile phase: B (ACN), mobile phase A (HO (0.2% HCOOH)) to afford compound 81 (3.9 mg, yield: 3.60%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.83(s,1H),8.38(d,J=1.6Hz,1H),8.34(s,1.43H),8.19-8. 16(m,1H),7.74-7.71(m,1H),7.57(d,J=1.2Hz,1H),7.13-7.08(m,1H),4.22(t,J=4. 0Hz,2H),3.99-3.90(m,2H),3.60-3.51(m,2H),3.26(t,J=8.4Hz,2H),2.91-2.86(m, 4H), 2.74(d,J=4.8Hz,3H),2.67-2.60(m,2H),2.38-2.31(m,2H),2.01-1.98(m,2H).

[0800] Preparation of Compound 82

[0801] [ka]

[0802] To a solution of intermediate 193 (105 mg, 0.42 mmol) and intermediate 67 (93 mg, 0.35 mmol) in MeCN (10 mL) was added DIEA (137 mg, 1.06 mol) and KI (6 mg, 0.04 mmol). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with DCM / MeOH (10 / 1) to give the crude product, which was further purified by preparative HPLC (column: SunFire C185 μm). * Purification with 150 mm; mobile phase: B (ACN), mobile phase A (HO (0.2% HCOOH), UV: 254 nm, flow rate: 15 mL / min, gradient: 5–35% B) afforded compound 82 (9 mg, yield: 5.32%) as a white solid. 1H NMR(400MHz,DMSO-d6)11.66(s,1H),8.41(d,J=1.6Hz,1H),8.17(d,J=4.8 Hz,1H),7.74-7.72(m,1H),7.60(s,1H),7.11-7.10(m,1H),3.98-3.96(m, 2H),3.55-3.54(m,2H),3.26-3.21(m,4H),2.95(s,2H),2.90-2.87(m,2H) ,2.74(d,J=4.8Hz,3H),2.67-2.61(m,2H),2.37-2.33(m,2H),1.76(s,4H).

[0803] The following compounds were synthesized by methods similar to those described above for compound 82.

[0804] [Table 52]

[0805] Preparation of Compound 87

[0806] [ka]

[0807] To a solution of intermediate 168 (65.3 mg, 0.21 mmol) in MeCN (5 mL) was added DIEA (0.18 mL, 1.07 mmol), KI (3.55 mg, 0.02 mmol) and intermediate 181 (50 mg, 0.21 mmol). The resulting solution was stirred at 80° C. for 2 h. The reaction mixture was evaporated in vacuo. The crude material was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative HPLC (Xbridge C18 (5 μm 19 * Purification using a 150 mm column, mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile, UV: 254 nm, flow rate: 15 mL / min, gradient: 45-80% (% B)) afforded compound 87 (50 mg, yield: 46.43%) as a white solid. 1H NMR(400MHz,DMSO-d6)11.50(s,1H),8.86(d,J=6.8Hz,1H),7.73(dd,J=8.0Hz,1.6Hz,1H),7 .47(d,J=8.0Hz,1H),7.33(s,1H),7.17-7.08(m,2H),5.00-4.93(m,1H),4.70-4.63(m,4H), 3.93(dd,J=26.8Hz,14.0Hz,2H),3.57-3.55(m,2H),3.31-3.25(m,2H),3.09-3.06(m,2H),2 .89-2.86(m,2H)2.77-2.74(m,2H),2.66-2.61(m,2H),2.36-2.33(m,2H),2.13-2.06(m,2H).

[0808] The following compounds were synthesized by methods similar to those described above for compound 87.

[0809] [Table 53]

[0810] Preparation of Compound 88

[0811] [ka]

[0812] To a solution of intermediate 67 (50 mg, 0.19 mmol) and intermediate 202 (40 mg, 0.16 mmol) in MeCN (10 mL) was added DIEA (72 mg, 0.56 mmol) and KI (3.1 mg, 0.019 mmol). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with DCM / MeOH (10 / 1) to give the crude product, which was purified by preparative HPLC (column: SunFire C18 5 μm 19 *Further purification with 150 mm; mobile phase: B (ACN), mobile phase: A (HO (0.2% HCOOH), UV: 254 nm, flow rate: 15 mL / min, gradient: 5–35% B) afforded compound 88 (38.5 mg, yield: 42.6%) as a white solid. 1 H NMR(400MHz,DMSO-d6)11.66(s,1H),8.23(s,1H),7.74-7.71(m,1H),7.48(d ,J=8.4Hz,1H),7.25(s,1H),7.16-7.08(m,2H),4.15(t,J=4.8Hz,2H),3.95- 3.85(m,2H),3.55-3.54(m,3H),3.25(t,J=8.8Hz,2H),2.88-2.85(m,2H),2. 80-2.74(m,4H),2.62(t,J=10Hz,2H),2.37-2.33(m,2H),2.04-2.00(m,2H).

[0813] The following compounds were synthesized by methods similar to those described above for compound 82.

[0814] [Table 54]

[0815] Example 4: General Protocol for LCMS (Liquid Chromatography / Mass Spectrometry) High-performance liquid chromatography (HPLC) measurements were performed using the LC pump, diode array (DAD) or UV detector, and column specified for each method. The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of one skilled in the art to set tuning parameters (e.g., scan range, residence time, etc.) to obtain ions that allow identification of the nominal monoisotopic molecular weight (MW) of the compound. Data acquisition was performed using appropriate software.

[0816] Compounds are described by their experimental retention time (Rt) and ion. Unless specified differently in the data tables, the reported molecular ion is [M+H] +protonated molecule) and / or [MH] - (corresponding to the deprotonated molecule). All results were obtained with experimental uncertainties generally associated with the methods used.

[0817] Method 1: Instrument: Agilent Technologies 1200 Series, G1329A; Column: Xbridge C18, 5 μm 4.6 * 50 mm; Mobile phase: A: 0.05% TFA; B: CH3CN; Gradient: 95% A for 0.01 min, to 40% A at 4.49 min, then to 5% A at 0.30 min, hold for 1.00 min, return to 95% A at 0.20 min, hold for 0.50 min. Flow rate and column temperature: 1.5 mL / min, 40 °C; Run time: 6.5 min.

[0818] Method 2: Instrument: Agilent Technologies 1200 Series, G1329A; Column: Xbridge C18, 5 μm 4.6 * 50 mm; Mobile phase: A: 0.05% TFA; B: CH3CN; Gradient: 95% A for 0.01 min, to 5% A at 4.49 min, hold for 1.30 min, return to 95% A at 0.20 min, hold for 0.50 min. Flow rate and column temperature: 1.5 mL / min, 40 °C; Run time: 6.5 min.

[0819] Method 3: Instrument: SHIMA DZU SIL-20A; Column: Xbridge C18, 5 μm 4.6 * 50 mm; Mobile phase: A: 0.02% NHOAc; B: CHCN; Gradient: 95% A for 0.01 min, to 40% A at 4.49 min, then to 5% A at 0.30 min, hold for 1.00 min, return to 95% A at 0.20 min, hold for 0.50 min. Flow rate and column temperature: 1.5 mL / min, 40 °C; Run time: 6.5 min.

[0820] Method 4: Instrument: SHIMA DZU SIL-20A; Column: Proshell-EC-C18, 5 μm 4.6 *50 mm; Mobile phase: A: 0.05% TFA; B: CH3CN; Gradient: 95% A for 0.01 min, to 60% A at 4.49 min, then to 5% A at 0.30 min, hold for 1.00 min, return to 95% A at 0.20 min, hold for 0.50 min. Flow rate and column temperature: 1.0 mL / min, 40 °C; Run time: 6.5 min.

[0821] Method 5: Instrument: Agilent Technologies 1200 Series, G6130A; Column: Xbridge C18, 3.5 μm 4.6 * 50 mm; Mobile phase: A: 0.05% TFA; B: CH3CN; Gradient: 95% A for 0.50 min, to 5% A at 3.50 min, hold for 1.50 min, return to 95% A at 0.10 min, hold for 0.40 min. Flow rate and column temperature: 1.5 mL / min, 40 °C; Run time: 6.0 min.

[0822] Example 5: Analytical Data The analytical information for the compounds listed above or in the table below.

[0823] [Table 55-1]

[0824] [Table 55-2]

[0825] [Table 55-3]

[0826] Example 6: PARP1-DNA enzyme capture assay The enzyme capture assay measures the dissociation process of PARP1 from fluorescein-labeled DNA during enzymatic activity. The assay was performed in a total reaction volume of 10 μL containing 10 nM PARP1 and 5 nM DNA probe in binding buffer (50 mM Tris-HCl pH 8.0, 50 mM NaCl, 1 mM MgCl, 0.1 mM EDTA, and 0.01% IGEPAL) and initiated by adding NAD+ substrate to a final concentration of 2 mM.

[0827] PARP1 poly(ADP-ribosylation) (PARylation) inhibition assays were performed using compounds dissolved in DMSO at a starting concentration of 5 μM. The dissolved compounds were added to a 384-well microplate and premixed with the PARP1 enzyme and DNA probe by incubation for 20 minutes. The enzyme reaction was initiated by adding NAD+ to the mixture, and each well was read at 30 minutes using a microplate reader (VICTORNivo®, PerkinElmer) to detect fluorescence polarization signals at 480 nm excitation / 530 nm dual emission.

[0828] Measured IC 50 All values ​​were calculated using a four-parameter dose-response inhibition model in GraphPad Prism 8.0.2 (La Jolla, California, USA, www.graphpad.com).

[0829] Example 7: PARP2-FL displacement assay A potent PARP inhibitor conjugated to the BDY FL fluorophore (PARPi-FL, Cat. No. 6461, Tocris Bioscience) was employed to characterize PARP2 activity by measuring the displacement of PARPi-FL binding to PARP2. Test compounds were prepared at concentrations ranging from 1 to 10 mM and serially diluted 3-fold with 100% DMSO in polypropylene plates (Bio-One small volume microplates, black, Cat. No. 784076, Greiner). 100 nL of test compound was dispensed into a 384-well polypropylene microplate, followed by the addition of 10 μL of premixed reaction solution containing 20 nM PARP2 and 3 nM PARPi-FL. After 4 h of incubation at room temperature, the fluorescence polarization signal was measured using a VICTORNivo® multimode plate reader (PerkinElmer) at 480 / 30 nm excitation and 530 / 30 nm dual emission. The measured IC 50 All values ​​were calculated using a four-parameter dose-response inhibition model in GraphPad Prism 8.0.2 (LaJolla, California, USA, www.graphpad.com).

[0830] Example 8: Cell proliferation assay For PARP1 sensitivity, exponentially growing MDA-MB-436 cells and DLD1 BRCA2 - / - Cells were seeded at very low density (typically 0.3 to 1.2 k cells / well) in 96- or 384-well plates with the goal of not dividing for at least 7 days. Cells were seeded on day 1 and treated with DMSO or increasing concentrations of PARP1 inhibitors on day 0. At the end of the experiment, cell viability was estimated using Cell-TiterGlo (Promega).

[0831] The results of Examples 6 to 8 are shown in the table below.

[0832] [Table 56-1]

[0833] [Table 56-2]

[0834] [Table 56-3]

[0835] Example 9: Efficacy study of tumor / plasma ratio in mice 1×10 7 MDA-MB-436 cells were subcutaneously implanted into the flanks of female NOD-SCID mice (6-8 weeks old, weighing approximately 18-22 g). Tumors grew to approximately 150-180 mm. 3Upon reaching the target concentration, mice were randomly assigned to treatment groups. Mice were administered the compound for 28 consecutive days. On day 29, blood (50 μL) and tumor tissue samples were collected 24 hours after the last dose. The collected blood samples were then centrifuged at 4600 rpm for 5 minutes at 4°C to obtain plasma. To determine the compound levels in the plasma samples, each plasma sample was prepared using the appropriate dilution factor and compared to an 11-point standard calibration curve (1-5,000 ng / mL) prepared in DMSO and spiked into blank plasma. Acetonitrile (200 μL) along with the internal standard was added to 20 μL of the plasma sample, followed by centrifugation at 5,500 rpm for 10 minutes. The supernatant (150 μL) was then diluted with water (150 μL) and analyzed by LC-MS / MS. Tumor tissue samples were weighed and then homogenized with 80% methanol at a ratio of 1:5 or 1:10 (tumor weight in grams to methanol volume in milliliters). Acetonitrile (300 μL) was added to 30 μL of tumor homogenate sample along with the internal standard. The sample was vortexed for 30 seconds and then centrifuged at 5,500 rpm for 10 minutes at 4°C. The supernatant (150 μL) was transferred to a 96-well plate, diluted with water (150 μL), and analyzed by LC-MS / MS. If the sample concentration in the initial assay did not fall within the range of the predetermined standard curve, appropriate dilution and concentration procedures were used in replicate tests. Exemplary substitutions are shown in the table below. Compared to the reference compound (AZD5305), the compounds described herein exhibited significantly higher tumor / plasma ratios, indicating better tumor penetration and retention.

[0836] [Table 57]

[0837] The above-described embodiments are intended to be merely illustrative; those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of this invention and are covered by the appended claims.

Claims

1. A compound of formula (I) 【Chemistry 1】 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein 【Chemistry 2】 is a single or double bond, X １ is CR ａ１ , C(R ａ１ ) ２ , or NR ａ１ and X ２ is CR ａ２ , C(R ａ２ ) ２ , N, N.R. ａ２ , or O, Each R ａ１ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ８ cycloalkyl, or C １ ~C ６ is an alkoxy; Each R ａ２ are independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ８ cycloalkyl, or C １ ~C ６ is an alkoxy; R ａ１ and R ａ２ together with the atoms to which they are attached form a 3- to 6-membered ring B; X ３ is CR ａ３ or N, and R ａ３ is hydrogen, C １ ~C ６ alkyl, or halogen; X ４ is CR ａ４ or N, and R ａ４ is hydrogen, C １ ~C ６ alkyl, or halogen; R ａ５ is hydrogen, C １ ~C ６ alkyl, or halogen; Ring A is a fused, bridged, or spiroheterocyclyl; Y １ is CR ２ or N, Y ２ is CR ２ or N, Each R ２ are independently hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, or C ３ ~C ８ is cycloalkyl, R is halogen, —CN, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, —C(═O)—R ３ , -C(=O)-OR ３ , -C(=O)-NHR ３ , -S(O) ２ -R ３ , -NH-C(=O)-R ３ or nitro, R ３ is hydrogen, C １ ~C ６ Alkyl, (C １ ~C ６ alkoxy)-(C １ ~C ６ alkyl), C ３ ~C ８ cycloalkyl, or 4- to 10-membered heterocyclyl, and alkyl, cycloalkyl, alkoxy, heterocyclyl, Ring A, and Ring B are optionally substituted; however, 【Transformation 3】 but 【Chemistry 4】 (i) ring A is a fused or spiro heterocyclyl, or (ii) R is —C(═O)—NHR ３ A compound.

2. Y １ is CR ２ and Y ２ The compound of claim 1 , wherein is N.

3. Y １ is N and Y ２ is CR ２ 2. The compound of claim 1, wherein:

4. Y １ is CR ２ and Y ２ is CR ２ 2. The compound of claim 1, wherein:

5. R is —C(═O)—NHR ３ The compound according to any one of claims 1 to 4,

6. The compound of any one of claims 1 to 4, wherein R is -CN.

7. a compound of formula (IA) 【Transformation 5】 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 8】 【Transformation 6】 The compound according to any one of claims 1 to 7, wherein is a double bond.

9. X １ is CR ａ１ and X ２ The compound of claim 8 wherein is N. 【Request Item 10】 【Chemistry 7】 The compound according to any one of claims 1 to 7, wherein is a single bond.

11. X １ is CH(R ａ１ ) and X ２ The compound of claim 10, wherein is O.

12. X １ is CH(R ａ１ ) and X ２ NR ａ２ 11. The compound of claim 10, wherein:

13. R ａ１ But C １ ~C ４ Alkyl or C １ ~C ４ The compound of any one of claims 1 to 12, which is fluoroalkyl.

14. R ａ１ The compound of claim 13, wherein is methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl, or methoxy.

15. R ａ１ 15. The compound of claim 14, wherein is methyl or ethyl.

16. R ａ１ and R ａ２ The compound according to any one of claims 1 to 7, wherein, together with the atoms to which they are attached, form a 3- to 6-membered ring B.

17. a compound of formula (IB), (IC), or (ID), 【Transformation 8】 or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

18. 17. The compound of claim 16, wherein Ring B is a 4- to 6-membered heterocyclyl.

19. 19. The compound of claim 18, wherein the heterocyclyl is an oxygen-containing heterocyclyl.

20. 17. The compound of claim 16, wherein Ring B is a 5-membered heteroaryl.

21. 17. The compound of claim 16, wherein Ring B is a 5- or 6-membered cycloalkenyl.

22. The compound of any one of claims 1 to 21, wherein Ring B is unsubstituted.

23. X ３ is CR ａ３ The compound according to any one of claims 1 to 22,

24. X ３ The compound of any one of claims 1 to 22, wherein is N.

25. X ４ is CR ａ４ The compound according to any one of claims 1 to 24,

26. X ４ The compound of any one of claims 1 to 24, wherein is N.

27. Formulas (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II- J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P), (II-Q), (II-R), (II-S), (I IT), (II-U), (II-V), (II-W), (II-X), (II-Y), (II-Z), (II-AA), (II-AB), (II-A C), (II-AD), (II-AE), (II-AF), (II-AG), (II-AH), (II-AI) or (II-AJ); 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

28. R ａ５ The compound of any one of claims 1 to 27, wherein is hydrogen.

29. R ａ５ The compound of any one of claims 1 to 27, wherein is fluoro.

30. The compound of any one of claims 1 to 29, wherein Ring A is a fused bicyclic heterocyclyl.

31. The compound of any one of claims 1 to 29, wherein Ring A is a spiro bicyclic heterocyclyl.

32. The compound of any one of claims 1 to 29, wherein Ring A is a bridged bicyclic heterocyclyl.

33. 33. The compound of any one of claims 1 to 32, wherein ring A contains only two heteroatoms, both of which are nitrogen.

34. Ring A is 【Chemistry 13】 【Chemistry 14】 and During the ceremony, ＊ is ring A and X ４ and a ring comprising:

35. The compound of any one of claims 1 to 34, wherein ring A is unsubstituted.

36. Formulas (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I), (III -J), (III-K), (III-L), (III-M), (III-N), (III-O), (III-P), (III-Q), (III-R), (III-S), ( III-T), (III-U), (III-V), (III-W), (III-X), (III-Y), (III-Z), (III-AA), (III-AB), (III -AC), (III-AD), (III-AE), (III-AF), (III-AG), (III-AH), (III-AI) or (III-AJ); 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

37. Ring A is 【Chemistry 19】 The compound according to any one of claims 1 to 36.

38. Ring A is 【Chemistry 20】 The compound according to any one of claims 1 to 36, wherein

39. Ring A is 【Chemistry 21】 39. The compound of claim 38, wherein:

40. Ring A is 【Chemistry 22】 39. The compound of claim 38, wherein:

41. Formulas (IV-A1), (IV-B1), (IV-C1), (IV-D1), (IV-E1), (IV-F1), (IV-G1), (IV-H1), (IV-I1), (IV- J1), (IV-K1), (IV-L1), (IV-M1), (IV-N1), (IV-O1), (IV-P1), (IV-Q1), (IV-R1), (IV-S1), ( IV-T1), (IV-U1), (IV-V1), (IV-W1), (IV-X1), (IV-Y1), (IV-Z1), (IV-AA1), (IV-AB1), (IV-AC1), (IV-AD1), (IV-AE1), (IV-AF1), (IV-AG1), (IV-AH1), (IV-AI1) or (IV-AJ1), 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

42. Formulas (IV-A2), (IV-B2), (IV-C2), (IV-D2), (IV-E2), (IV-F2), (IV-G2), (IV-H2), (IV-I2), (IV- J2), (IV-K2), (IV-L2), (IV-M2), (IV-N2), (IV-O2), (IV-P2), (IV-Q2), (IV-R2), (IV-S2), ( (IV-T2), (IV-U2), (IV-V2), (IV-W2), (IV-X2), (IV-Y2), (IV-Z2), (IV-AA2), (IV-AB2), (IV-AC2), (IV-AD2), (IV-AE2), (IV-AF2), (IV-AG2), (IV-AH2), (IV-AI2), or (IV-AJ2); 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

43. a compound of formula (IV-V2-1), (IV-AA2-1), (IV-AB2-1), or (IV-AI2-1); 【Chemistry 31】 or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; Z is O or C(R ４ ) ２ and Each R ４ are independently hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ 43. The compound of claim 42, which is alkoxy.

44. 44. The compound of claim 43, wherein Z is O.

45. Z is CHR ４ and R ４ is C １ ~C ３ 44. The compound of claim 43, which is alkoxy.

46. R ２ But hydrogen, halogen, C １ ~C ４ Alkyl, C １ ~C ４ Fluoroalkyl, or C ３ ~C ６ The compound of any one of claims 1 to 45, which is cycloalkyl.

47. R ２ 47. The compound of claim 46, wherein is hydrogen, chloro, fluoro, methyl, difluoromethyl, trifluoromethyl, or cyclopropyl.

48. R ３ But hydrogen, C １ ~C ４ Alkyl, (C １ ~C ４ alkoxy)-(C １ ~C ４ alkyl), C ３ ~C ６ 48. The compound of any one of claims 1 to 47, which is cycloalkyl or 4- to 8-membered heterocyclyl.

49. R ３ 49. The compound of claim 48, wherein is a 4- to 6-membered heterocyclyl.

50. 50. The compound of claim 49, wherein said heterocyclyl is an oxygen-containing heterocyclyl.

51. R ３ 49. The compound of claim 48, wherein is methyl, 2-methoxyethyl, cyclopropyl, cyclobutyl, 3-methoxycyclobutyl, oxetan-3-yl, tetrahydrofuran-3-yl, or tetrahydro-2H-pyran-4-yl.

52. R ３ But halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 52. The compound of any one of claims 1 to 51, which is substituted with alkoxy.

53. X １ 53. The compound of any one of claims 1 to 52, wherein the carbon at position 1 has the S configuration when it is a chiral center.

54. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound according to any one of claims 1 to 54 and a pharmaceutically acceptable excipient.

56. A method for treating cancer, comprising administering to a subject having cancer a therapeutically effective amount of a compound according to any one of claims 1 to 54 or a pharmaceutical composition according to claim 55.

57. 57. The method of claim 56, wherein the cancer is deficient in the HR-dependent DNA DSB repair pathway.

58. 57. The method of claim 56, wherein the cancer comprises one or more cancer cells that have a reduced or abrogated ability to repair DNA DSBs by HR compared to normal cells.

59. 59. The method of claim 58, wherein the cancer cells have a BRCA1 or BRCA2 deficient phenotype.

60. 60. The method of claim 59, wherein the cancer cells are BRCA1 or BRCA2 deficient.

61. 61. The method of any one of claims 56 to 60, wherein said subject is heterozygous for a mutation in a gene encoding a component of said HR dependent DNA DSB repair pathway.

62. 62. The method of claim 61, wherein the subject is heterozygous for a mutation in BRCA1 or BRCA2.

63. 63. The method of any one of claims 56 to 62, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, lung cancer, or brain cancer.

64. 56. A method of inhibiting PARP1 protein, comprising contacting said PARP1 protein with an effective amount of a compound according to any one of claims 1 to 54 or a pharmaceutical composition according to claim 55.

65. 65. The method of claim 64, wherein the inhibition occurs in a subject suffering from a PARP1-mediated disease or condition.

66. 66. The method of claim 65, wherein the disease or condition is cancer.

67. 67. The method of claim 66, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, lung cancer, or brain cancer.

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