PARP1 inhibitor compounds

Abstract

PARP1 inhibitor compounds have the structure of formula (i). Dashed lines represent single or double bonds, and y is 0, 1, or 2. Each X D Selected from C, O, and N. No more than one X. D It is O. When X D When it is O or N, the ring D is non-aromatic. Each R 1 It does not exist; it is an H or organic group. Each R... 4 It does not exist; it is H; halogen; C(R9)0-3; OR 9 ; or S(R) 9 )1-5. Each R 9 It is an H or an organic group. R 2 and R 3 Each is either an H or an organic group. L is formula (ii). Each X 1 X 3 X 4 and X 5 It is C or N. Each X 2 It is C, N, O, or S. n+m and r+s are 2 to 5. p and q are each 1 to 3. p+q is 2 to 5. Each R 5A R 5B R 5C and R 6 It does not exist; it is H or an organic group. Q 1 and Q 2 Each is an independent bond or linking group. (i)(ii)

Description

Technical Field

[0001] This invention relates to PARP1 inhibitor compounds, and more particularly to PARP1 inhibitor compounds for use in medicine. The inhibitors of this invention can be used in pharmaceutical compositions, and especially in pharmaceutical compositions for treating cancer. This invention also relates to methods for preparing such inhibitors, and methods for using such inhibitors.

[0002] background

[0003] The poly(ADP-ribose) polymerase (PARP) family consists of 17 PARP proteins that catalyze the transfer of ADP-ribose to target proteins, a post-translational process known as PARP alkylation. PARP alkylation of target proteins causes significant functional changes, and therefore PARPs play crucial roles in many cellular processes such as chromatin remodeling, transcription, replication, recombination, cell cycle progression, and DNA damage repair (Kamaletdinova, T. et al.). Cell . 2019; 8: 1625).

[0004] PARP1 and 2 are the most extensively studied PARP enzymes, primarily because of their roles in DNA damage repair, particularly in base excision repair (BER) of single-strand breaks in DNA (Ngoi, YL. et al.). Cancer J (2021; 27:521-528). PARP1 is activated by DNA damage breaks, and subsequent PARylation of target proteins leads to the recruitment of additional factors that initiate DNA damage repair. PARP's own PARylation triggers the release of bound PARP from DNA, allowing other DNA repair proteins to access and complete the repair. This highlights the crucial role PARP plays in enabling cancer cells to repair DNA damage caused by exogenous factors such as radiation therapy and chemotherapy agents.

[0005] Inhibition of PARP enzymes has been used as a strategy to selectively kill cancer cells carrying genetic defects in complementary DNA damage repair pathways (Farmer, H. et al.). Nature. 2005; 434: 917-921). This synthetic lethal regimen has been successfully demonstrated in tumors with epigenetic modifications or harmful mutations in BRCA1 and BRCA2, two functionally redundant tumor suppressor proteins involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) (Lord, CJ. and Ashworth, A.). Science(2017;355:1152-1158). Such HR-deficient (HRD) tumors rely on PARP function for survival—after PARP inhibition in these tumors, DSB breaks will be handled by alternative error-prone repair pathways, leading to genomic instability and cancer cell death.

[0006] Inhibition of PARP can trap inactivated PARP at sites of DNA damage. This causes replication fork arrest, and subsequently, when the replication fork reaches the site of the trapped PARP, it breaks down in S phase, leading to the generation of genotoxic DNA double-strand breaks. This PARP1-DNA trapping is believed to cause selective death in cancer cells carrying HRD (Farmer, H. et al.). Nature 2005;434: 917-921).

[0007] This strategy has led to the successful approval of several PARP inhibitors for the treatment of cancers with HRD, such as breast, ovarian and prostate cancer with BRCA1 / 2- mutations, as well as ovarian and prostate cancers carrying the genomic consequences of HRD and ovarian cancer in a maintenance scenario where platinum sensitivity acts as a substitute for HRD (Fong, PC. et al.). N . Engl . J . Med 2009;361: 123-134).

[0008] Recent studies have shown that genomic instability in the form of unrepaired DNA double-strand breaks or micronucleus disruptions can trigger innate immune system activation via the cytosol DNA sensor circular GMP-AMP synthase (cGAS), leading to the generation of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and the induction of dimerization of interferon gene-stimulating factor (STING). STING then translocates from the endoplasmic reticulum to the Golgi apparatus, where it recruits and activates TANK-binding kinase 1 (TBK1). TBK1 phosphorylates interferon-regulated transcription factor 3 (IRF3), which drives the production of type I interferons and supports the induction of adaptive immune responses (Zhu, Y. et al.). Mol . Cancer . 2019, 18:152).

[0009] For example, PARP inhibitor-induced STING pathway activation and anti-tumor immune responses have been demonstrated in various tumor models, providing a theoretical basis for using the combination of PARP inhibitors and immunotherapy to improve therapeutic efficacy (Sen, T. et al.). Cancer Discov2019;9:646-661). For example, the combination of the PARP inhibitor olaparib with a synthetic cyclic dinucleotide sTING agonist has recently been shown to induce synthetic lethal effects in DNA damage repair-deficient cancer cells and BRCA-deficient breast cancer models (Pantelidou, C. et al.). 2021: bioRxiv 2021.01.26.428337v1).

[0010] Overall, modulation of the nucleic acid sensing pathway through multiple mechanisms has been shown to enhance antitumor efficacy in various cell and animal models, demonstrating therapeutic potential for enhancing immunotherapy efficacy and overcoming resistance to immune checkpoint blockade by using PARP inhibitors. Numerous ongoing clinical trials combining PARP inhibitors with immunotherapy exist (see review in Chabanon, RM, et al.). Nat . Rev . Cancer 2021;21: 701-717).

[0011] In recent years, PARP1 has also been shown to bind to the Epstein-Barr virus (EBV) genome, and PARP1 inhibition can alter EBV chromatin structure and potential gene expression (Morgan, SM. et al.). Nat . Commun 2022;13:187). Therefore, PARP1 inhibitors may play a role in cancers where EBV plays a contributing role, such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal and gastrointestinal cancers. Interestingly, EBV has also been shown to be a pathogenic factor in multiple sclerosis (MS), thereby EBV infection significantly increases the risk of subsequent MS (Bjornevik, K. et al.). Science (2021); 375:296-301).

[0012] First-generation PARP inhibitors typically exhibit non-selective activity at PARP1 and 2. Hematologic toxicities such as anemia, neutropenia, and thrombocytopenia are associated with the clinical use of these molecules, which limits their use in combination with cytotoxic chemotherapy and other targeted agents due to dose-limiting hematologic cytopenia (LaFargue, CJ, et al.). Lancet Oncol. 2019, 20, e15-e28). Evidence from preclinical mouse studies strongly suggests that PARP2 inhibition is a major driver of these hematologic toxicities, with PARP2 being particularly associated with erythropoiesis in mice (Farrés, J. et al.). Blood.2013; 122: 44-54). Furthermore, PARP2 function has been shown to be non-essential for antitumor activity in HRD mouse cancer models (Ronson, G E. et al.). Nat . Commun (2018, 9: 746). In summary, these data indicate an unmet medical need to develop inhibitors that offer improved selectivity against PARP1 relative to PARP2 and other PARPs, thereby providing (1) expanded therapeutic utility as a single agent and (2) in combination with other anticancer agents.

[0013] To date, two PARP1 selective inhibitors, AZD5305 and AZD9574, have entered clinical development. AZD5305 is described as a potent PARP1 inhibitor and trapper with 500-fold selectivity relative to PARP2 and lower off-target activity against minor pharmacological targets than first-generation PARP inhibitors (Johannes, JW. et al.). J . Med . Chem .2021;64: 14498-14512). Importantly, the hematologic toxicity of AZD5305 observed in rodent models was significantly lower than that of first-generation PARP inhibitors, confirming the reported pathogenic role of PARP2 in hematologic toxicity (Illuzzi, G. et al.). Clin . Cancer Res 2022; CCR-22-0301).

[0014] In view of the foregoing, an object of the present invention is to provide a PARP1 inhibitor, and particularly a PARP1 inhibitor for medical use. A further object is to provide pharmaceutical compositions comprising such inhibitors, and particularly to provide compounds and pharmaceutical compositions for treating cancer. A further object is to provide a method for synthesizing said compounds.

[0015] Overview

[0016] In one aspect, the present invention provides PARP1 inhibitor compounds having the following structure:

[0017]

[0018] in:

[0019] Dashed lines represent bonds selected from single and double bonds;

[0020] y is 0, 1, or 2;

[0021] Ring D is either an aromatic or non-aromatic genus;

[0022] Each X D Independently selected from C, O, and N; the prerequisite is:

[0023] No more than one X D It is O; and

[0024] When X D When it is O or N, ring D is non-aromatic;

[0025] Each R 1 It either does not exist independently, or it exists and is selected from H and substituted or unsubstituted organic groups;

[0026] Each R 4 It does not exist independently or is selected from:

[0027] H;

[0028] halogen;

[0029] C(R 9 ) i , where i is an integer in the range of 1 to 3;

[0030] OR 9 ;and

[0031] S(R 9 ) j , where j is an integer in the range of 1 to 5;

[0032] Each R 9 Independently selected from H and substituted or unsubstituted organic groups;

[0033] R 2 and R 3 Each is independently selected from H and substituted or unsubstituted organic groups; and

[0034] L is a group having the following structure:

[0035]

[0036] in:

[0037] X 1 X 3 X 4 and X 5 Each is independently selected from C and N;

[0038] Each X 2 Independently selected from C, N, O, and S;

[0039] n is 0, 1, 2, 3, 4 or 5;

[0040] m can be 0, 1, 2, 3, 4 or 5, provided that n + m is within the range of 1 to 5 (any 2 to 5);

[0041] p is 1, 2, or 3;

[0042] q is 1, 2, or 3, provided that p + q is in the range of 2 to 5;

[0043] r is 0, 1, 2, 3, 4 or 5;

[0044] s can be 0, 1, 2, 3, 4 or 5, provided that r + s is in the range of 2 to 5;

[0045] Each R 5A R 5B and R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups;

[0046] R 6 It does not contain or is selected from H and substituted or unsubstituted organic groups; and

[0047] Q 1 and Q 2 Each is independently a bond or a linking group having a structure selected from the following:

[0048]

[0049]

[0050] in:

[0051] t is 0, 1, 2, 3, 4, or 5;

[0052] u can be 0, 1, 2, 3, 4, or 5, provided that t + u is within the range of 0 to 6; and

[0053] Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0054] Optional, Q 1 The key is m + n, and m + n is in the range 2 to 5.

[0055] The PARP1 inhibitor compound can be used in medicine. For example, the PARP1 inhibitor compound can be used to treat cancer.

[0056] Another aspect of the invention provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein.

[0057] Another aspect of the invention provides a pharmaceutical kit for treating cancer. The pharmaceutical kit comprises a PARP1 inhibitor compound as defined herein and additional agents for treating cancer. The PARP1 inhibitor compound and the additional agents are suitable for simultaneous, sequential, or separate administration.

[0058] Another aspect of the invention provides a method for treating diseases and / or conditions and / or disorders, the method comprising administering to a patient a PARP1 inhibitor compound, composition, or kit product as defined herein.

[0059] Another aspect of the present invention provides a method for synthesizing PARP1 inhibitor compounds as defined herein. The method comprises carrying out a reaction between a first reactant and a second reactant:

[0060] i) A first reactant comprising rings D and E and a first moiety bearing the group L, and

[0061] ii) A second reactant, which contains the remainder of the group L.

[0062] To form the PARP1 inhibitor compound.

[0063] This overview is provided to introduce the selection of concepts in a simplified form, which are further described in detail below. This overview is not intended to identify key or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter. The claimed subject matter is also not limited to embodiments that address any or all of the shortcomings pointed out herein.

[0064] Detailed Explanation

[0065] General definition

[0066] The verb "to comprise" is used in this text as a shorthand for "to include" or "to consist of." In other words, while the verb "to comprise" is intended as an open term, it is explicitly considered that the closed term "to consist of" should be used instead, especially when used with chemical compositions.

[0067] It should be understood that some of the compounds disclosed herein may be ionizable, meaning that some compounds may be weak acids, weak bases, or amphoteric electrolytes. The presentation of the free form of ionizable compounds is intended to encompass the corresponding ionized forms. Ionizable compounds may be in their free form or in the form of pharmaceutically acceptable salts.

[0068] A compound is considered a PARP1 inhibitor if its presence prevents or reduces the ability of immobilized PARP1 to undergo self-poly-ADP-ribosylation (self-PARylation) after incubation with biotinylated NAD+ (compared to the same process in the absence of the compound). Generally, a compound is considered a PARP1 inhibitor if it has an IC50 < 10 μM in a suitable assay. A suitable assay can be performed using 2 nM PARP1, 2 μM biotin-NAD+ assay solution in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v) assay buffer. PARylation can be performed at room temperature for 2 h and can be detected using dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) readout. Particularly suitable assays are described in the examples below. Preferably, the compound has an IC50 of < 1 μM in a PARP1 inhibitor assay, more preferably < 100 nM and most preferably < 10 nM.

[0069] A compound is considered a selective PARP1 inhibitor if its presence displaces or reduces the ability of a high-affinity Cy5 fluorescent dye-labeled chemical probe to bind to PARP1, while simultaneously displacing the same chemical probe at PARP2 with at least a 10-fold weaker activity. Generally, a compound is considered a selective PARP1 inhibitor if it has an IC50 < 10 μM at PARP1 in the assay and at least a 10-fold selective preference relative to PARP2. A suitable assay can be performed at room temperature for 1 h using 10 nM PARP1 or PARP2, a Tb-caecin antibody, and PARP1 / 2 binding probes in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v) assay buffer. Homogeneous time-resolved fluorescent detection probe binding displacement can be used. Particularly suitable assays are described in the examples below. Preferably, the selective preference of PARP1 relative to PARP2 is at least 50-fold, more preferably at least 100-fold.

[0070] A compound is also considered a selective PARP1 inhibitor if it has an IC50 < 10 μM at PARP1 and a selectivity preference of at least 10-fold relative to PARP2 in a NanoBRET assay demonstrating cellular target involvement. These assays are based on bioluminescent resonance energy transfer (BRET) between a nano-luc-tagged protein (e.g., PARP1 or PARP2) and a fluorescent group on a high-affinity NAD+ competitively binding probe. Such cellular probe substitution assays can be used to measure the ratio of inhibitor affinity and selectivity at PARP1 and 2. Particularly suitable assays are described in the examples below. Preferably, the selectivity preference of PARP1 relative to PARP2 is at least 50-fold, more preferably at least 100-fold.

[0071] The term "substituted or unsubstituted organic group" is used herein as a synonym for "substituent". Examples of organic groups are discussed in more detail below.

[0072] When it is said that an organic group is "replaced", it means that the H in the organic group is replaced by another organic group.

[0073] In the structural formula, the dashed lines represent any suitable non-zero-order covalent bonds, most commonly single or double bonds. It will be understood that systems containing multiple double bonds can be conjugated or aromatic.

[0074] Unless the configuration of a specific bond is explicitly stated, all formulas herein are presented in non-stereoisomeric form and are intended to represent all possible stereoisomers of a particular structure, including all possible separate enantiomers corresponding to that formula, all possible mixtures of the corresponding enantiomers, all possible mixtures of the corresponding diastereomers, all possible mixtures of the corresponding epimers, and all possible racemic mixtures corresponding to that formula. Furthermore, all formulas herein are intended to represent all tautomeric forms equivalent to their corresponding formulas.

[0075] In describing stereochemistry, the stereochemistry shown is relative stereochemistry, not absolute stereochemistry.

[0076] The term "aliphatic ring" is used in this document in the broad sense of non-aromatic rings. Aliphatic rings can be carbocyclic or heterocyclic, and can be substituted or unsubstituted.

[0077] Compound numbering

[0078] Many of the compounds presented in this article are enantiomers or diastereomers. When a suffix is ​​applied to a compound number, the suffix indicates the stereochemistry. Compound numbers without a suffix indicate compounds with an indicated structural formula, but without defining the stereochemistry.

[0079] The suffix "rac" in a compound designation indicates a racemic mixture.

[0080] The suffixes “cis” and “trans” indicate compounds with cis and trans ring configurations, respectively, as explained in the “Stereochemistry” section below. For diastereomers, the cis and trans suffixes can refer to diastereomer pairs having the indicated ring configuration. Nuclear Overhausen effect nuclear magnetic resonance spectroscopy (“NOE NMR”) can be used to determine the stereochemistry of compounds as described herein.

[0081] The suffix "a" in the compound designation indicates the enantiomer eluted as the first fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography ("SFC") using a chiral column.

[0082] The suffix "b" in the compound designation indicates the enantiomer eluted as a second fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography ("SFC") using a chiral column.

[0083] discuss

[0084] This article provides PARP1 inhibitor compounds with the following structures:

[0085]

[0086] in:

[0087] Dashed lines represent bonds selected from single and double bonds;

[0088] y is 0, 1, or 2;

[0089] Ring D is either an aromatic or non-aromatic genus;

[0090] Each X D Independently selected from C, O, and N; the prerequisite is:

[0091] No more than one X D It is O; and

[0092] When X D When it is O or N, ring D is non-aromatic;

[0093] Each R 1 It either does not exist independently, or it exists and is selected from H and substituted or unsubstituted organic groups;

[0094] Each R 4 It does not exist independently or is selected from:

[0095] H;

[0096] halogen;

[0097] C(R 9 ) i , where i is an integer in the range of 1 to 3;

[0098] OR 9 ;and

[0099] S(R 9 ) j , where j is an integer in the range of 1 to 5;

[0100] Each R 9 Independently selected from H and substituted or unsubstituted organic groups;

[0101] R 2 and R 3 Each is independently selected from H and substituted or unsubstituted organic groups; and

[0102] X 1 X 3 X 4 and X 5 Each is independently selected from C and N;

[0103] Each X 2 Independently selected from C, N, O, and S;

[0104] n is 0, 1, 2, 3, 4 or 5;

[0105] m can be 0, 1, 2, 3, 4 or 5, provided that n + m is in the range of 1 to 5;

[0106] p is 1, 2, or 3;

[0107] q is 1, 2, or 3, provided that p + q is in the range of 2 to 5;

[0108] r is 0, 1, 2, 3, 4 or 5;

[0109] s can be 0, 1, 2, 3, 4 or 5, provided that r + s is in the range of 2 to 5;

[0110] Each R 5A R 5B and R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups;

[0111] R6 It does not contain or is selected from H and substituted or unsubstituted organic groups; and

[0112] Q 1 and Q 2 Each is independently a bond or a linking group having a structure selected from the following:

[0113]

[0114]

[0115] in:

[0116] t is 0, 1, 2, 3, 4, or 5;

[0117] u can be 0, 1, 2, 3, 4, or 5, provided that t + u is within the range of 0 to 6; and

[0118] Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0119] Optional, Q 1 The key is m+n, and m+n is in the range of 2 to 5.

[0120] The PARP1 inhibitor compounds presented in this article are selective for PARP1 relative to PARP2.

[0121] The various aspects of the above general structure will now be discussed in more detail.

[0122] Stereochemistry

[0123] Some of the PARP1 inhibitor compounds described herein include one or more chiral centers. Such compounds may be provided as: isolated enantiomers; mixtures of two or more enantiomers; mixtures of two or more diastereomers or epimers; or racemic mixtures.

[0124] Some PARP1 inhibitor compounds may be capable of tautomerism. Such compounds can be provided in any possible tautomer form.

[0125] When ring A of the PARP1 inhibitor compound is a cycloalkane, the compound can exhibit cis-trans isomerism. In the context of this disclosure, unless otherwise explicitly stated, "cis" compounds have a cis configuration in ring A:

[0126]

[0127] Furthermore, the "trans" compound has a trans configuration in ring A:

[0128]

[0129] Substituents – General

[0130] The expression "R" 5 "Group" usually refers to group R 5A R 5B and R 5C “R” 5A "The group is R attached to ring A" 5 Groups, and so on. Some formulas shown in this article use R... 5 A more specific identifier for the group. For example, "R" 5A1 "Identified as R" 5A A subset of groups.

[0131] The expression "atom X" usually refers to any variable ring atom (X... D X 1 X 2 X 3 X 4 X 5 ).

[0132] In the compounds provided in this article, R 6 With R 1 R 4 and R 5 Multiple groups may be absent. The dashed lines in the structural formulas shown in this article represent any non-zero order covalent bonds.

[0133] It will be understood that the number of ring bonds and substituents is chosen to maintain stable valences of the atoms in the ring. Maintaining stable valences means ensuring that the atoms in the organic compound have their normal (most common) valences (i.e., oxygen is 2; sulfur is 2 or 6; nitrogen is 3 or 4; and carbon is 4).

[0134] When the X atom is N, the atom most preferably has a valence of 3. Compounds containing tetravalent N atoms are also considered. Preferably, the PARP1 inhibitor compound comprises at most one tetravalent N atom, and more preferably does not include a tetravalent N atom.

[0135] The PARP1 inhibitor compounds typically do not contain OO bonds. When the X atom is O, its two directly adjacent ring atoms are not O.

[0136] When the X atom is S, its corresponding R group can be either absent or selected from =O and =NR. 10 , where R 10It is H or a substituted or unsubstituted organic group, preferably a C1 to C3 alkyl group.

[0137] Each R 1 R 4 and R 5 Groups may exist or not exist independently, and they may be the same or different.

[0138] Substituents (i.e., R groups; R) 1 R 2 R 4 R 5 R 6 R 7 and R 8 There are no particular restrictions, provided that they do not prevent the PARP1 inhibition function from occurring. Substituents are selected from H and substituted or unsubstituted organic groups. Therefore, in the foregoing and hereinafter, the terms “substituent” and “organic group” are not particularly limited and can be any functional group or any atom, especially any functional group or atom common in organic chemistry.

[0139] Any R 5 Or R 6 The group can be associated with any other R on adjacent and / or nearest neighbor atoms. 5 Or R 6 Groups forming a ring, although this is not preferred in most embodiments unless explicitly specified. Therefore, the following substituents can form a ring together: R 5A With another R 5A ;R 5B With another R 5B ;R 5C With another R 5C Or R 5C With R 6 In the context of this invention, adjacent and / or near-neighbor atoms can refer to another atom directly bonded to the atom (adjacent), or two atoms with only a single atom between them (near-neighbor), or two atoms spatially close enough to form a ring (near-neighbor). Preferably, R connected to the same atom 5 / R 6 Groups will not form a ring together, although this is not excluded.

[0140] A single R on an atom 1 R 4 R 5 Or R 6 Groups, or two R atoms on the same atom 1 / R 4 / R 5A group can form a group that is linked to a double bond of that atom. Therefore, an R 1 R 4 R 5 Or R 6 Groups, or two R atoms attached to the same atom 1 / R 4 / R 5 The groups can together form a =O group or a =C(R')2 group (where each R' group may be the same or different, and is H or an organic group, preferably H or a straight-chain or branched C1-C6 alkyl group). This is more commonly the case where the R group is attached to a C atom, causing them to together form a C=O group or a C=C(R')2 group. Thus, in some cases, X as C 2 The group can contain an =O group.

[0141] For example, a pair of R atoms connected to the same atom 5A Groups can be used together to represent carbonyl groups. Similarly, a pair of R4 groups attached to the same atom can be used together to represent carbonyl groups.

[0142] "Substituent" and "organic group" can have any of the following meanings.

[0143] The organic group may contain any one or more atoms from any of Groups IIIA, IVA, VA, VIA or VIIA of the periodic table, such as B, Si, N, P, O or S atoms (e.g. OH, OR, NH2, NHR, NR2, SH, SR, SO2R, SO3H, PO4H2) or halogen atoms (e.g. F, Cl, Br or I), wherein R is a straight-chain or branched lower hydrocarbon (1-6 C atoms) or a straight-chain or branched higher hydrocarbon (7 C atoms or more, e.g. 7-40 C atoms).

[0144] The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may comprise a straight-chain, branched, or cyclic group. Independently, the hydrocarbon group may comprise an aliphatic or aromatic group. Also independently, the hydrocarbon group may comprise a saturated or unsaturated group.

[0145] When the hydrocarbon contains unsaturated groups, it may contain one or more olefinic functional groups and / or one or more alkyne functional groups. When the hydrocarbon contains straight-chain or branched groups, it may contain one or more primary, secondary, and / or tertiary alkyl groups.

[0146] When the hydrocarbon contains a cyclic group, it may contain aromatic rings, non-aromatic rings, aliphatic rings, heterocyclic groups, and / or fused-ring derivatives of these groups. The ring may be fully saturated, partially saturated, or completely unsaturated. Therefore, the cyclic group may contain benzene, naphthalene, anthracene, phenanthrene, phenanthene, biphenylene, cyclopentadiene, indene, asymmetric indene, symmetric indene, acenaphthene, fluorene, fluoranthene, phenanthrene acetate, azulene, hepta-benzone, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetraazole, pyrrolidine, furan, oxacyclobutane, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole, isoxazole. Furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiacyclopentane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran, tetrahydropyran, 2-azapyran, 3-azapyran, 4-azapyran, 2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, thiaran, 2-azathiaran, 3-azathiaran, 4- Azathioran, thiacyclohexane, indole, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaisoindole, 5-azaisoindole, 6-azaisoindole, 7-azaisoindole, indazine, 1-azaindazine, 2-azaindazine, 3-azaindazine, 5-azaindazine, 6-azaindazine, 7-azaindazine, 8-azaindazine, 9-azaindazine Azides, purines, carbazoles, carboline, benzofurans, isobenzofurans, benzothiophenes, isobenzothiophenes, quinoline, cycloline, quinazoline, quinoxaline, 5-azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7-azaisoquinoline, pteridine, chromene, isochromene, acridine, phenanthridine, chloridine, phenanthroline, phenoxazine, xanthone, phenoxthia and / or thiaanthracene, and regioisomers of the above groups. These groups can generally be attached at any point within the group, and can also be attached at heteroatoms or carbon atoms. In some cases, specific attachment points are preferred, such as at 1-yl, 2-yl, etc., and these are explicitly specified where appropriate. All tautomeric ring forms are included in these definitions. For example, pyrrole is intended to include 1-yl... H -pyrrole, 2 H -pyrrole and 3 H -pyrrole.

[0147] The number of carbon atoms in the hydrocarbon group is not particularly limited, but preferably the hydrocarbon group contains 1 to 40 C atoms. Therefore, the hydrocarbon group can be a lower hydrocarbon (1-6 C atoms) or a higher hydrocarbon (7 C atoms or more, for example, 7-40 C atoms). The lower hydrocarbon group can be a methyl, ethyl, propyl, butyl, pentyl, or hexyl group or a regioisomer of these groups, such as isopropyl, isobutyl, tert-butyl, etc. The number of atoms in the ring of the cyclic group is not particularly limited, but preferably the ring of the cyclic group contains 3 to 10 atoms, such as 3, 4, 5, 6, 7, 8, 9, or 10 atoms.

[0148] The aforementioned heteroatom-containing groups, as well as any other groups defined above, may contain one or more heteroatoms from any of Groups IIIA, IVA, VA, VIA, or VIIA of the periodic table, such as B, Si, N, P, O, or S atoms, or halogen atoms (e.g., F, Cl, Br, or I). Therefore, the substituents may contain one or more of any common functional groups in organic chemistry, such as hydroxyl groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulfate ester groups, sulfonic acid groups, sulfonyl groups, and phosphate ester groups. The substituents may also contain derivatives of these groups, such as carboxylic anhydrides and carboxylic acid halides.

[0149] Furthermore, any substituent may contain a combination of two or more substituents and / or functional groups as defined herein.

[0150] When we say substituent (R) 1 R 2 R 3 R 4 R 5A (e.g. R) 5A1 R 5A2 R 5A3 ), R 5B R 5C (For example, R) 5C1 ), R 6 R 7 R 8 R 51 and / or R 52 When ) is a substituted or unsubstituted organic group, said or each substituted or unsubstituted organic group may be specifically and independently selected from:

[0151] deuterium;

[0152] Halogens (such as -F, -Cl, -Br and -I);

[0153] Nitrile group;

[0154] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups

[0155] (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl);

[0156] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups

[0157] (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph);

[0158] Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups

[0159] (such as -CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3, -CBr3, -CCI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3 and -CH2CH2CCI3);

[0160] NH2 or substituted or unsubstituted straight-chain or branched primary, secondary or tertiary C1-C6 amine groups

[0161] (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, -NBuH, -NBuMe, -NBuEt, -CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, -CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe and -CH2-NPrEt);

[0162] Substituted or unsubstituted amino-aryl groups

[0163] (such as -NH-Ph, -NH-(2, 3, or 4)F-Ph, -NH-(2, 3, or 4)Cl-Ph, -NH-(2, 3, or 4)Br-Ph, -NH-(2, 3, or 4)I-Ph, -NH-(2, 3, or 4)Me-Ph, -NH-(2, 3, or 4)Et-Ph, -NH-(2, 3, or 4)Pr-Ph, -NH-(2, 3, or 4)Bu-Ph, NH-(2, 3, or 4)OMe-Ph, -NH-(2, 3, or 4)OEt-Ph, -NH-(2, 3, or 4)OPr-Ph) h, -NH-(2, 3 or 4)OBu-Ph, -NH-2,(3, 4, 5 or 6)F2-Ph, -NH-2,(3, 4, 5 or 6)Cl2-Ph, -NH-2,(3, 4, 5 or 6)Br2-Ph, -NH-2,(3, 4, 5 or 6)I2-Ph, -NH-2,(3, 4, 5 or 6)Me2-Ph, -NH-2,(3, 4, 5 or 6)Et2-Ph, -NH-2,(3, 4, 5 or 6)Pr2-Ph, -NH-2,(3, 4, 5 or 6)Bu2-Ph),

[0164] Substituted or unsubstituted cyclic amine or amide groups

[0165] (such as pyrrolid-1-yl, pyrrolid-2-yl, pyrrolid-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolyl, 3-keto-pyrrolyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl);

[0166] Substituted or unsubstituted cyclic C3-C8 alkyl groups

[0167] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl);

[0168] -OH group;

[0169] Substituted or unsubstituted straight-chain or branched C1-C6 alcohol groups

[0170] (Such as -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH and -CH2CH2CH2CH2CH2CH2OH);

[0171] Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid groups

[0172] (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH);

[0173] Substituted or unsubstituted straight-chain or branched carbonyl groups

[0174] (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl; -(CO)NH2, - (CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholino-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe and -(CO)NHCH2CH2NMe2);

[0175] Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups

[0176] (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe);

[0177] Substituted or unsubstituted straight-chain or branched C1-C6 amide groups

[0178] (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt);

[0179] Substituted or unsubstituted straight-chain or branched C1-C7 amino carbonyl groups

[0180] (such as -NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, -NMe-CO-Ph);

[0181] Substituted or unsubstituted straight-chain or branched C1-C7 alkoxy or aryloxy groups

[0182] (such as -OMe, -OEt, -OPr, -Oi-Pr, -On-Bu, -Oi-Bu, -Ot-Bu, -O-pentyl, -O-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -O-Ph, -O-CH2-Ph, -O-CH2-(2, 3 or 4)-F-Ph, -O-CH2-(2, 3 or 4)-Cl-Ph, -CH2OMe, -CH2OEt, -CH2OPr, -CH2OBu, -CH2CH2OMe, -CH2CH2CH2OMe, -CH2CH2CH2CH2OMe and -CH2CH2CH2CH2CH2OMe);

[0183] Substituted or unsubstituted straight-chain or branched aminoalkoxy groups

[0184] (such as -OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt and -OCH2CH2NEt2);

[0185] Substituted or unsubstituted sulfonyl groups

[0186] (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholino-N-yl, -SO2NHCH2OMe and -SO2NHCH2CH2OMe);

[0187] Substituted or unsubstituted aminosulfonyl groups

[0188] (such as -NHSO2Me, -NHSO2Et, -NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2, 3 or 4)-F-Ph, -NHSO2-cyclopropyl, -NHSO2CH2CH2OCH3);

[0189] Substituted or unsubstituted aromatic groups

[0190] (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2-Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)- Pr2-Ph-、2,(3,4,5 or 6)-Bu2-Ph-、2,(3,4,5 or 6)-(CN)2-Ph-、2,(3,4,5 or 6)-(NO2)2-Ph-、2,(3,4,5 or 6)-(NH2)2-Ph-、2,(3,4,5 or 6)-(MeO)2-Ph-、2,(3,4,5 or 6)-(CF3)2-Ph-、3,(4 or 5)-F2-Ph-、3,(4 or 5)-Cl2-Ph-、3,(4 or 5)-Br2-Ph-、3,(4 or 5)-I2-Ph-、3,(4 or 5)-Me2-Ph-、3,(4 or 5)-Et2-Ph-、3, (4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN) -Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-);

[0191] Saturated or unsaturated, substituted or unsubstituted heterocyclic groups, optionally aromatic or non-aromatic heterocyclic groups.

[0192] (such as pyrrolo-1-yl, pyrrolo-2-yl, pyrrolo-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-) Triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl Piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-1-yl, 2-azapiperidin-3-yl, 2-azapiperidin-4-yl, 3-azapiperidin-1-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazine-1-yl, piperazine-2-yl, furan-2 -yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran -6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxacyclobutane-2-yl, oxacyclobutane-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl Morpholin-2-yl, Morpholin-3-yl, Morpholin-4-yl, Thiophene-2-yl, Thiophene-3-yl, Isothiazol-3-yl, Isothiazol-4-yl, Isothiazol-5-yl, Thiazol-2-yl, Thiazol-4-yl, Thiazol-5-yl, Thian-2-yl, Thian-3-yl, Thian-4-yl, 2-azathiaran-2-yl, 2-azathiaran-3-yl2-azathiaran-4-yl, 2-azathiaran-5-yl, 2-azathiaran-6-yl, 3-azathiaran-2-yl, 3-azathiaran-4-yl, 3-azathiaran-5-yl, 3-azathiaran-6-yl, 4-azathiaran-2-yl, 4-azathiaran-3-yl, 4-azathiaran-4-yl, 4-azathiaran-5-yl, 4-azathiaran-6-yl, thiacyclopentan-2-yl, thiacyclopentan-3-yl, thiacyclohexane-2-yl Thiazole-3-yl, thiacyclohexane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazon-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl).

[0193] Besides R 4 In addition, substituent groups with matching identifiers can form a ring together.

[0194] For example, a pair of substituent groups attached to different atoms in the same ring can connect to form a ring. A pair of R groups attached to different atoms 5A Groups can form a ring together with atom A of the ring. A pair of R atoms attached to different atoms 5B Groups can form a ring together with the B atom of the ring. A pair of R atoms attached to different atoms 5C Groups can form rings together with ring carbon atoms.

[0195] Also consider R connected to different atoms 5C Groups and R 6 Groups can form rings together with ring carbon atoms.

[0196] Preferably, each R 5 Group (R) 5A R 5B R 5C It does not exist independently or is selected from:

[0197] H,

[0198] deuterium,

[0199] Halogens (such as -F, -Cl, -Br and -I; preferably F or Cl),

[0200] Nitrile group,

[0201] C1-C6 alkyl groups,

[0202] C1-C6 haloalkyl groups (preferably CF3 or CHF2),

[0203] Cyclopropyl group,

[0204] -OH group,

[0205] C1-C6 alcohol groups,

[0206] C1-C7 amino carbonyl groups (such as -NH-CO-Me),

[0207] -NH2 group,

[0208] C1-C6 amino groups and

[0209] C1-C6 alkoxy groups.

[0210] When a pair of R 5 When the group forms a ring, this pair of R 5 The groups can be selected together from -CH2-, -CH2CH2-, -CH=CH-CH=CH- or -NH-CO-NH-.

[0211] Specifically, consider two Rs. 5A The groups can together represent the alkyl groups of bridging ring A.

[0212] Multiple substituent groups can be bonded to a nitrogen atom. For example, when Q... 1 Or Q 2 yes:

[0213] hour

[0214] R 8 Bonded to nitrogen. In some cases, R 1 R 4 Or R 5A Or R 5B The group can be attached to a ring atom that is N; and R 3 Connected to N. The preferred substituents for the N atom are:

[0215] H;

[0216] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups

[0217] (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl);

[0218] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups

[0219] (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph);

[0220] Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups

[0221] (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3);

[0222] Substituted or unsubstituted cyclic amine or amide groups

[0223] (such as pyrrolidine-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolyl, 3-keto-pyrrolyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl);

[0224] Substituted or unsubstituted cyclic C3-C8 alkyl groups

[0225] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl);

[0226] Substituted or unsubstituted straight-chain or branched C2-C6 alcohol groups

[0227] (Such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH (CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH and -CH2CH2CH2CH2CH2CH2OH);

[0228] Substituted or unsubstituted straight-chain or branched C2-C6 carboxylic acid groups

[0229] (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH);

[0230] Substituted or unsubstituted straight-chain or branched carbonyl groups

[0231] (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl, -(CO)N H2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholino-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe and -(CO)NHCH2CH2NMe2);

[0232] Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups

[0233] (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe);

[0234] Substituted or unsubstituted straight-chain or branched C1-C6 amide groups

[0235] (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt);

[0236] Substituted or unsubstituted sulfonyl groups

[0237] (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholino-N-yl, -SO2NHCH2OMe and -SO2NHCH2CH2OMe);

[0238] Substituted or unsubstituted aromatic groups

[0239] (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2-Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)- Pr2-Ph-、2,(3,4,5 or 6)-Bu2-Ph-、2,(3,4,5 or 6)-(CN)2-Ph-、2,(3,4,5 or 6)-(NO2)2-Ph-、2,(3,4,5 or 6)-(NH2)2-Ph-、2,(3,4,5 or 6)-(MeO)2-Ph-、2,(3,4,5 or 6)-(CF3)2-Ph-、3,(4 or 5)-F2-Ph-、3,(4 or 5)-Cl2-Ph-、3,(4 or 5)-Br2-Ph-、3,(4 or 5)-I2-Ph-、3,(4 or 5)-Me2-Ph-、3,(4 or 5)-Et2-Ph-、3, (4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN) -Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, and

[0240] Substituted or unsubstituted heterocyclic groups

[0241] (such as pyrrolo-2-yl, pyrrolo-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-Triazol-5-yl, Pyridin-2-yl, Pyridin-3-yl, Pyridin-4-yl, Pyridazin-3-yl, Pyridazin-4-yl, Pyriminin-2-yl, Pyriminin-4-yl, Pyriminin-5-yl, Pyriminin-6-yl, Pyrazin-2-yl, Pyrrolidine-2-yl, Pyrrolidine-3-yl, Piperidin-2-yl, Piperidin-3-yl, Piperidin-4-yl, 2-azapiperidin-3-yl -yl, 2-azapiperidin-4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran Azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran- 3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxacyclobutane-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, thiophen-2-yl, thiophen-3-yl Isothiazol-3-yl, Isothiazol-4-yl, Isothiazol-5-yl, Thiazol-2-yl, Thiazol-4-yl, Thiazol-5-yl, Thian-2-yl, Thian-3-yl, Thian-4-yl, 2-azathiaran-3-yl, 2-azathiaran-4-yl, 2-azathiaran-5-yl, 2-azathiaran-6-yl, 3-azathiaran-2-yl, 3- Azathiaran-4-yl, 3-azathiaran-5-yl, 3-azathiaran-6-yl, 4-azathiaran-2-yl, 4-azathiaran-3-yl, 4-azathiaran-5-yl, 4-azathiaran-6-yl, thiacyclopentan-2-yl, thiacyclopentan-3-yl, thiacyclohexane-2-yl, thiacyclohexane-3-yl, thiacyclohexane-4-yl Oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazon-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-5-yl.

[0242] Optional, R 8 Or any R connected to cyclic nitrogen 1 R 4 、or R 5A Or R 5B It can preferably be selected from H, substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups and substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups.

[0243] R connected to N 1 Or R 4 Preferably selected from H, C1 to C3 alkyl groups and C1 to C3 fluoroalkyl groups, such as CH2CF3.

[0244] Head base - general

[0245] The head group of the PARP1 inhibitor compound comprises rings D and E, as shown in the following general formula:

[0246]

[0247] Dashed lines represent bonds selected from single and double bonds. Ring D can be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring.

[0248] y is 0, 1, or 2. In other words, ring D can be a 5-membered, 6-membered, or 7-membered ring. In particular, ring D can be a 5-membered ring (y=0) or a 6-membered ring (y=1). Compounds having a 6-membered D-ring (y=1) are particularly preferred.

[0249] Each individual X D Selected from C, O, and N. No more than one X. D It is O. When X D When it is O or N, ring D is non-aromatic. Optionally, each X... D It's C.

[0250] Each R 1 It does not exist independently, and is either H or a substituted or unsubstituted organic group.

[0251] Each R 4 It does not exist independently or is selected from:

[0252] H;

[0253] halogen;

[0254] C(R 9 ) i , where i is an integer in the range of 1 to 3;

[0255] OR 9 ;and

[0256] S(R 9 ) j , where j is an integer in the range of 1 to 5.

[0257] Each R 9 It is independently selected from H and substituted or unsubstituted organic groups.

[0258] When R 4 It is C(R) 9 ) i And when i is 1, R 9 It can be nitrile nitrogen, .

[0259] Each R 1 and each R 4 It can specifically not exist or be selected from:

[0260] H;

[0261] halogen;

[0262] Nitrile group;

[0263] C1 to C6 alkyl groups, such as C3 to C6 cycloalkyl groups;

[0264] C1 to C6 alkoxy groups;

[0265] C1 to C6 haloalkoxy groups, such as -OCF3 or OCHF2;

[0266] Halogenated alkyl groups; and

[0267] ,

[0268] R 22 Selected from H, halogens, C1 to C6 alkyl groups, C3 to C6 cycloalkyl groups, C1 to C6 alkoxy groups, and C1 to C6 haloalkyl groups, and

[0269] Each R 23 Independently selected from H, halogens, C1 to C6 straight-chain or branched alkyl groups, C1 to C6 straight-chain or branched aminoalkyl groups, C1 to C6 alkoxy groups, C1 to C6 haloalkoxy groups, such as -OCF3 or OCHF2; and C1 to C6 haloalkyl groups.

[0270] Optionally, each R 1 and each R 4The following are not present independently or are selected from H; halogens, optionally Cl or F; C1 to C3 alkyl groups, optionally methyl groups; C1 to C3 haloalkyl groups, optionally halomethyl groups such as -CH2F, -CHF2 or -CF3; haloethyl groups, such as -CH2CF3; and nitrile groups.

[0271] Further, optionally, each R 1 and each R 4 It is either absent independently or selected from: H; Cl; F; halomethyl groups, such as CF3; and nitrile groups.

[0272] Preferably, each R 1 and each R 4 It does not exist independently or is selected from H and F. Optionally, exactly one R 1 Or exactly one R 4 It is F. For example, each R 4 It can be H, and exactly one R. 1 It can be F.

[0273] R 2 and R 3 Each is independently selected from H and substituted or unsubstituted organic groups.

[0274] R 2 It may be specifically selected from H; halogen, optionally F or Cl; C1 to C3 alkyl group, optionally isopropyl or cyclopropyl; C1 to C3 haloalkyl group, optionally -CH2F, -CHF2, -CF3, -CH2CF3 or -CH2CH2F; C1 to C3 alcohol group, optionally -CH2CH2OH; C1 to C3 alkoxy group, optionally methoxy, methoxymethyl or methoxyethyl; and C1 to C3 aminoalkyl group. Most preferably, R 2 It is H.

[0275] R 3 Typically selected from H, C1 to C3 alkyl groups, and C1 to C3 haloalkyl groups. Most preferably, R 3 It is H.

[0276] Head-based Aroma Examples

[0277] When each X D When the atom is C and y is 1, ring D can be an aromatic ring. In such an example, the PARP1 inhibitor compound has the following structure:

[0278]

[0279] The PARP1 inhibitor compound optionally has the following structure:

[0280] .

[0281] In such instances, each R 1 Preferably selected from H and F. More preferably, the PARP1 inhibitor compound may have a structure selected from the following:

[0282] or .

[0283] The most preferred structure with an aromatic D-ring is:

[0284] and .

[0285] Further examples of PARP1 inhibitor compounds having an aromatic D-ring include those having the following structures:

[0286]

[0287] Head base - non-aromatic examples

[0288] Alternatively, ring D can be non-aromatic. In such compounds, ring D can be a carbocyclic or heterocyclic ring.

[0289] The PARP1 inhibitor compound may, for example, have a structure selected from the following:

[0290]

[0291] Each R 1 and each R 4 exist.

[0292] In particular, the compound may have the following structure:

[0293] .

[0294] Optionally, an X D The atom can be O. In such an example, the PARP1 inhibitor compound can have a structure selected from the following:

[0295]

[0296] Each R 1 and each R 4 exist.

[0297] Among these, the following structures are preferred:

[0298] or .

[0299] According to another possibility, the PARP1 inhibitor compound may have the following structure:

[0300]

[0301] The PARP1 inhibitor compound may specifically have the following structure:

[0302] or .

[0303] Optionally, an X D The atom can be N. In such an example, the PARP1 inhibitor compound can have a structure selected from the following:

[0304]

[0305] Among these, the following structures are preferred:

[0306] .

[0307] According to another possibility, the PARP1 inhibitor compound may have a structure selected from the following:

[0308]

[0309] Other examples of PARP1 inhibitor compounds include:

[0310]

[0311] The most preferred general structure of a PARP1 inhibitor compound having a non-aromatic head group is:

[0312]

[0313] L group -generally

[0314] The PARP1 inhibitor compounds provided in this article have a group L with a structure according to the following general formula:

[0315]

[0316] in:

[0317] X 1 X 3 X 4 and X 5 Each is independently selected from C and N;

[0318] Each X 2 Independently selected from C, N, O, and S;

[0319] n is 0, 1, 2, 3, 4 or 5;

[0320] m can be 0, 1, 2, 3, 4 or 5, provided that n + m is in the range of 1 to 5 (usually 2 to 5);

[0321] p is 1, 2, or 3;

[0322] q is 1, 2, or 3, provided that p + q is in the range of 2 to 5;

[0323] r is 0, 1, 2, 3, 4 or 5;

[0324] s can be 0, 1, 2, 3, 4 or 5, provided that r + s is in the range of 2 to 5;

[0325] Each R 5A R 5B and R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups;

[0326] R 6 It does not contain or is selected from H and substituted or unsubstituted organic groups; and

[0327] Q 1 and Q 2 Each is independently a bond or a linking group having a structure selected from the following:

[0328]

[0329]

[0330] in:

[0331] t is 0, 1, 2, 3, 4, or 5;

[0332] u can be 0, 1, 2, 3, 4, or 5, provided that t + u is within the range of 0 to 6; and

[0333] Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0334] Optional, Q 1 It is a bond and the group L has the following structure:

[0335]

[0336] One or more of the following conditions, and all of the optimal options, may apply:

[0337] i) At least one X atom in each ring is C. When ring A or ring B is quaternary, the ring typically includes at most one heteroatom. When ring A or ring B is quinary or septate, the ring typically includes at most three heteroatoms, optionally at most two heteroatoms.

[0338] ii) Each of rings A, B and C may individually contain up to three heteroatoms.

[0339] iii) The compound is not a quaternary ammonium compound.

[0340] iv) The compound does not contain OO, SS and SO bonds.

[0341] Each part of group L will be discussed in more detail below.

[0342] Ring A

[0343] The ring A of the PARP1 inhibitor compound has the following general structure:

[0344]

[0345] n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, 4, or 5, provided that n + m is within the range of 1 to 5, typically 2 to 5, and arbitrarily 2 to 4. In other words, ring A can be a 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered ring. Ring A is typically a 4-membered, 5-membered, 6-membered, or 7-membered ring, arbitrarily 4-membered, 5-membered, or 6-membered ring. Preferably, ring A is a 5-membered ring (n + m = 3) or a 6-membered ring (n + m = 4). Most preferably, ring A is a 5-membered ring (n + m = 3).

[0346] Preferably, both n and m are at least 1. In other words, the atoms that connect ring A to rings E and B are preferably not adjacent.

[0347] X 1 Bonded to ring E, and selected from C and N. When X 1 When it is N, R 5A1 It does not exist. When X 1 When it is C, R 5A1 It may or may not exist, but it is preferred to exist.

[0348] Each X 2 Independently selected from C, N, O, and S. Optionally, each X2 can be selected from C, N, and O. Further optionally, each X... 2 Independently selected from C and N. Most preferably, each X 2 It's C.

[0349] Each R 5AGroup (i.e., R) 5A1 R 5A2 R 5A3 It exists independently or is selected from H and substituted or unsubstituted organic groups. R can be selected. 5A The number of groups allows ring A to be saturated, unsaturated, non-aromatic, or aromatic. Typically, ring A is non-aromatic. Preferably, ring A is saturated.

[0350] In most implementations, no more than two R 5A The group is an organic group that is either substituted or unsubstituted. Most typically, it consists of no more than one R group. 5A A group is an organic group that has been substituted or not substituted.

[0351] Typically, when R 5A When the group is present, the R 5A The group is preferably H.

[0352] Ring A can be a double ring, where the two R's are... 5A The groups are fused together. The bicyclic rings can be bridging bicyclic rings.

[0353] R 5A3 The most common is H.

[0354] Preferably, when present, each R 5A Independently selected from H; halogen, optionally F; hydroxyl group; carbonyl group; and C1 to C3 alkyl group, optionally one pair of which is R 5A The group forms a ring, and optionally the ring bridges ring A.

[0355] Particularly preferred:

[0356] i) A pair of R 5A The group forms a bridging ring A with a -CH2- group, and each other R 5A It is H; or

[0357] ii) Each R 5A It is H.

[0358] Ring A can be a 7-membered ring. For example, ring A can be a cycloheptane having a structure selected from the following:

[0359] and

[0360] Each R 5A exist.

[0361] Alternatively, ring A can be a 6-membered non-aromatic ring, such as cyclohexane, cyclohexene, or tetrahydropyran. Ring A can, for example, have a structure selected from the following:

[0362]

[0363] Each R 5A exist.

[0364] Alternatively, ring A can be a 5-membered non-aromatic ring, such as cyclopentane, cyclopentene, or tetrahydrofuran. Ring A can, for example, have a structure selected from the following:

[0365]

[0366] Each R 5A exist.

[0367] In other instances, ring A can be a 4-membered ring with the following structure:

[0368] ;

[0369] Each R 5A and R 5A3 exist.

[0370] Alternatively, ring A could be a bridge ring. Examples of suitable bridge ring structures include:

[0371]

[0372] Each R 5A Yes, it exists. Ring A typically includes no more than one bridging group. In the three examples just mentioned above, there is no R. 5A The groups fuse to form additional rings, and each R 5A The group is preferably H.

[0373] Other examples of suitable bridge ring structures include:

[0374]

[0375] In the six examples just mentioned above, there is no R. 5A The groups fuse to form additional rings, and each R 5A The group is preferably H.

[0376] Examples of suitable structures for ring A include:

[0377]

[0378]

[0379] Other examples of suitable structures for ring A include:

[0380]

[0381] Ring A can have the following structure:

[0382]

[0383] in:

[0384] n is 1, 2, or 3;

[0385] m is 0, 1, or 2;

[0386] X 1 It is C or N;

[0387] Each X 2 Independently selected from C and O; and

[0388] Each R 5A1 R 5A2 and R 5A3 It does not exist independently or is selected from H and substituted or unsubstituted organic groups;

[0389] The prerequisite is:

[0390] When X 1 When it is N, R 5A1 Does not exist; and

[0391] When the corresponding X 2 When it is O, R 5A2 It does not exist.

[0392] In one instance, an X 2 The atom is O and ring A is tetrahydrofuran or tetrahydropyran.

[0393] According to another possibility, ring A can have the following structure:

[0394]

[0395] in:

[0396] m is 1 or 2;

[0397] n is 1 or 2;

[0398] Each R 5A2 and R 5A3 Independently absent or selected from H and substituted or unsubstituted organic groups, preferably wherein R 5A3 It is H;

[0399] And among them:

[0400] i) X1 is C and R 5A1 Selected from H and substituted or unsubstituted organic groups; or

[0401] ii) X1 is N and R 5A1It does not exist.

[0402] Each R 5A1 R 5A2 and R 5A3 It may be absent independently or selected from H; halogen, optionally F; hydroxyl group; carbonyl group (in other words, oxo group = O); and C1 to C3 alkyl groups, optionally one pair of which R 5A The group forms a C1 to C3 alkyl group (optionally -CH2- or -CH2-CH2-) bridging ring A. Preferably, each R 5A1 R 5A2 and R 5A3 It either does not exist or it is H.

[0403] According to another possibility, R 5A1 Does not exist, is H, or is with R 5A2 Group or R 5A3 Together they form -CH2- or -CH2CH2- groups; each R 5A2 It does not exist independently, is H, an oxo group (carbonyl group; =O), or is associated with R. 5A1 R 5A3 Or another R 5A2 Together they form -CH2- or -CH2CH2- groups; and R 5A3 Is it H or R? 5A1 Or R 5A2 The groups together form -CH2- or -CH2CH2- groups.

[0404] According to another possibility, exactly two are selected from R 5A1 R 5A2 and R 5A3 The groups together represent a phenyl group fused with ring A; and R 5A1 R 5A2 and R 5A3 Each of the other groups in the group is independent of the others, and is either an H or an oxo group.

[0405] Preferred A-ring structures include:

[0406]

[0407] Other preferred A-ring structures include:

[0408]

[0409] Most preferably, ring A has the following structure:

[0410] .

[0411] Ring B

[0412] The ring B of group L has the following general structure:

[0413]

[0414] Each X 2 Independently selected from C, N, O, and S. X 3 Choose from C and N, and optionally X 3 It is N.

[0415] p is 1, 2, or 3; and q is 1, 2, or 3, provided that p + q is within the range of 2 to 5. In other words, ring B can be a 4-membered, 5-membered, 6-membered, or 7-membered ring. Preferably, ring B is a 6-membered ring, and most preferably, both p and q are equal to 2.

[0416] Each R 5B Independently absent or selected from H and substituted or unsubstituted organic groups. Preferably, each R 5B It either does not exist independently or it is H.

[0417] Depending on the existence of R 5B The number of groups, and whether ring B is saturated or unsaturated. Preferably, ring B is a saturated ring.

[0418] Preferably, each X 2 It is C, and ring B has the following structure:

[0419] .

[0420] X 3 Preferably, it is N. In such an example, ring B can have the following structure:

[0421] .

[0422] Available location, X 3 It can be C. In such an example, ring B can be an azircyclic heptane, optionally having the following structure:

[0423]

[0424] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H.

[0425] According to another possibility, ring B can be piperidine, optionally having the following structure:

[0426]

[0427] Each R 5BIndependently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H.

[0428] Alternatively, ring B may be pyrrolidine, optionally having the following structure:

[0429]

[0430] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H.

[0431] According to another possibility, ring B can have the following structure:

[0432]

[0433] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H.

[0434] Ring B can have a general structure selected from the following:

[0435]

[0436] More specific examples of suitable ring B structures include:

[0437]

[0438] When ring B has the following structure:

[0439]

[0440] Q 2 Optionally -O-.

[0441] Most preferably, ring B has the following structure:

[0442] .

[0443] Linking group - group Q 1 and Q 2

[0444] Ring A via the first connecting base Q 1 Coupled to ring B, and ring B via a second connection base Q. 2 Coupled to ring C:

[0445]

[0446] Optional, Q1 It is a key that allows ring A to be directly connected to ring B:

[0447]

[0448] Specifically, when ring A is a 4-element, 5-element, 6-element, or 7-element ring, Q 1 It can be a key. For example, Q. 1 It can be a key, and the ring A can be selected from A1, A3, A4, A5, A6, A12, A13 and A14 as defined above.

[0449] When ring A is a 3-element or 4-element ring, Q 1 It can be a linking group. For example, when ring A is:

[0450] hour

[0451] Q 1 It can be -CH2-.

[0452] Q 2 It can be a bond. In other words, atom X 3 It can be directly connected to ring C.

[0453] Q 1 and Q 2 Each is independently selected from bond and linking groups, wherein the linking group is selected from:

[0454]

[0455] in:

[0456] t is a number selected from 0, 1, 2, 3, 4, and 5; and u is independently a number selected from 0, 1, 2, 3, 4, and 5; provided that t + u is a number selected from 0, 1, 2, 3, 4, 5, and 6; and

[0457] Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0458] Optionally, t+u is at least 1.

[0459] Preferably, each R 7 Independently selected from H; halogen, optionally F; C1 to C6 alkyl group; and C1 to C6 haloalkyl group.

[0460] Typically, rings are not connected via N / N bonds. For this purpose, when Q 1 yes When u is usually at least 1; and when the X of ring B is... 3 It is N and Q 2 yes In this case, t is usually at least 1.

[0461] When Q 1 Or Q 2 yes:

[0462] hour

[0463] R 8 You can choose from:

[0464] H;

[0465] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups

[0466] (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl);

[0467] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups

[0468] (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph);

[0469] Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups

[0470] (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3);

[0471] Substituted or unsubstituted cyclic amine or amide groups

[0472] (such as pyrrolidine-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolyl, 3-keto-pyrrolyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl);

[0473] Substituted or unsubstituted cyclic C3-C8 alkyl groups

[0474] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl);

[0475] Substituted or unsubstituted straight-chain or branched C2-C6 alcohol groups

[0476] (Such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH (CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH and -CH2CH2CH2CH2CH2CH2OH);

[0477] Substituted or unsubstituted straight-chain or branched C2-C6 carboxylic acid groups

[0478] (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH);

[0479] Substituted or unsubstituted straight-chain or branched carbonyl groups

[0480] (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl; -(CO)N H2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholino-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe and -(CO)NHCH2CH2NMe2);

[0481] Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups

[0482] (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe);

[0483] Substituted or unsubstituted straight-chain or branched C1-C6 amide groups

[0484] (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt);

[0485] Substituted or unsubstituted sulfonyl groups

[0486] (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholino-N-yl, -SO2NHCH2OMe and -SO2NHCH2CH2OMe);

[0487] Substituted or unsubstituted aromatic groups

[0488] (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2-Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)- Pr2-Ph-、2,(3,4,5 or 6)-Bu2-Ph-、2,(3,4,5 or 6)-(CN)2-Ph-、2,(3,4,5 or 6)-(NO2)2-Ph-、2,(3,4,5 or 6)-(NH2)2-Ph-、2,(3,4,5 or 6)-(MeO)2-Ph-、2,(3,4,5 or 6)-(CF3)2-Ph-、3,(4 or 5)-F2-Ph-、3,(4 or 5)-Cl2-Ph-、3,(4 or 5)-Br2-Ph-、3,(4 or 5)-I2-Ph-、3,(4 or 5)-Me2-Ph-、3,(4 or 5)-Et2-Ph-、3, (4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN) -Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, and

[0489] Substituted or unsubstituted heterocyclic groups

[0490] (such as pyrrolo-2-yl, pyrrolo-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-Triazol-5-yl, Pyridin-2-yl, Pyridin-3-yl, Pyridin-4-yl, Pyridazin-3-yl, Pyridazin-4-yl, Pyriminin-2-yl, Pyriminin-4-yl, Pyriminin-5-yl, Pyriminin-6-yl, Pyrazin-2-yl, Pyrrolidine-2-yl, Pyrrolidine-3-yl, Piperidin-2-yl, Piperidin-3-yl, Piperidin-4-yl, 2-azapiperidin-3-yl -yl, 2-azapiperidin-4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran Azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran- 3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxacyclobutane-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, thiophen-2-yl, thiophen-3-yl Isothiazol-3-yl, Isothiazol-4-yl, Isothiazol-5-yl, Thiazol-2-yl, Thiazol-4-yl, Thiazol-5-yl, Thian-2-yl, Thian-3-yl, Thian-4-yl, 2-azathiaran-3-yl, 2-azathiaran-4-yl, 2-azathiaran-5-yl, 2-azathiaran-6-yl, 3-azathiaran-2-yl, 3- Azathiaran-4-yl, 3-azathiaran-5-yl, 3-azathiaran-6-yl, 4-azathiaran-2-yl, 4-azathiaran-3-yl, 4-azathiaran-5-yl, 4-azathiaran-6-yl, thiacyclopentan-2-yl, thiacyclopentan-3-yl, thiacyclohexane-2-yl, thiacyclohexane-3-yl, thiacyclohexane-4-yl Oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazon-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-5-yl.

[0491] In particular, R 8 It can be selected from H, substituted or unsubstituted C1-C6 alkyl groups, or substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups.

[0492] Preferably, Q 2 It is a bond or -CH2-. Most preferably, Q 2 It is a key.

[0493] When ring B is a 4-element ring, Q 2 It can be -O-.

[0494] Ring C

[0495] The ring C of the PARP1 inhibitor compound has the following structure:

[0496]

[0497] X 4 and X 5 Each is independently selected from C and N. Preferably, X 4 It is C and X 5 It's C.

[0498] Rings B and C are not connected by an N-N bond.

[0499] When Q 2 yes:

[0500] And when u=0, X 4 It's C.

[0501] When atom X of ring B 3 When N is the key and Q is the key, X 4 It's C. According to another possibility, X... 3 It is C and X 4 It's C.

[0502] Each X 2 Independently selected from C, N, O, and S, with C and N being preferred. Choose X. 2 Atoms, such that the ring C contains no OO, OS, or SS bonds. Optionally, at least one X 2 The atom is C.

[0503] Ring C is preferably a heterocyclic ring. Optionally, an X 2 The atom is N, and each of the other X atoms is N. 2 The atom is C.

[0504] Optionally, each X 2 The atom is C.

[0505] Each R 5C Independently absent or selected from H and substituted or unsubstituted organic groups. Two Rs 5C Group, or R 5C Groups and R 6 Fusing can make ring C a bridged ring system.

[0506] Each R 5C It may be independently absent, or be an H or organic group selected from halogens, preferably F; C1 to C3 alkyl groups, optionally cyclopropyl groups; C1 to C3 haloalkyl groups, optionally fluoromethyl groups such as CF2H or CF3; C1 to C3 alkoxy groups; and nitrile groups. Optionally, each R 5C It may be absent independently, or be an H or an organic group selected from halogens, preferably F; C1 to C3 alkyl groups; C1 to C3 haloalkyl groups, optionally fluoromethyl groups such as CF2H or CF3; and nitrile groups.

[0507] When R 5C When the group is present, the R 5C The group can be specifically selected from H and halogens. The preferred halogen is F.

[0508] Optionally, exactly one R 5C It is an organic group. The most preferred organic group is F.

[0509] r is 0, 1, 2, 3, 4, or 5, and s is 0, 1, 2, 3, 4, or 5, provided that r + s is in the range of 2 to 5. In other words, ring C can be a 4-membered, 5-membered, 6-membered, or 7-membered ring. Typically, r is at least 1 and s is at least 1. Optionally, ring C is a 5-membered ring (r + s = 3) or a 6-membered ring (r + s = 4), with a 6-membered ring being preferred.

[0510] Depending on the chosen R 5C The number of groups, ring C can be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring. Preferably, ring C is an aromatic ring. Most preferably, ring C is a 6-membered aromatic ring.

[0511] Ring C can be a 6-membered saturated ring, optionally having the following structure:

[0512]

[0513] Each R 5C and R 5C1 Independently selected from H and substituted or unsubstituted organic groups, preferably wherein R 5C1 It is H, more preferably R. 5C1 and each R 5C It is H.

[0514] According to another possibility, ring C can be a 6-membered saturated ring with the following structure:

[0515]

[0516] Each R 5C and R 5C1 Independently selected from H and substituted or unsubstituted organic groups, preferably wherein R 5C1 It is H, more preferably R. 5C1 and each R 5C It is H.

[0517] Alternatively, ring C can be a 6-membered aromatic ring.

[0518] For example, the ring C can be an optionally substituted phenyl group, optionally having the following structure:

[0519] or

[0520] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0521] According to another possibility, the ring C can be a pyridine group, optionally having a structure selected from the following:

[0522] , , , and ,

[0523] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0524] Alternatively, the ring C may be a diazine group, optionally having a structure selected from:

[0525] , , , , , and ,

[0526] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0527] Compounds in which ring C is a 5-membered aromatic ring are also considered.

[0528] For example, the ring C can be an imidazole group, optionally having an imidazole group with a structure selected from the following:

[0529] and ,

[0530] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0531] Alternatively, the ring C may be a thiophene group, optionally having a structure selected from:

[0532] , ,and ,

[0533] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0534] According to another possibility, the ring C can be a thiazole group, optionally having a structure selected from the following:

[0535] , , and ,

[0536] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0537] In other embodiments, ring C may be a triazole, optionally having the following structure:

[0538] or ,

[0539] R 5C Selected from H and substituted or unsubstituted organic groups, optionally wherein R 5C It is H.

[0540] Suitable examples of C-ring structures include:

[0541]

[0542]

[0543] Other examples of suitable C-ring structures include:

[0544]

[0545] Ring C may optionally have a structure selected from C3, C8, C10, C11, C13, C14, C15, C18, C19, C21, C25, C28, C36, C37 and C38 as defined above.

[0546] According to another possibility, ring C can have the following structure:

[0547]

[0548] in:

[0549] Each X C The atoms are selected from C and N, provided that there are at least two X atoms. C The atom is C;

[0550] When X C When it is N, the corresponding R 5C It does not exist;

[0551] When X C When it is C, the corresponding R 5C It is H or a substituent selected from the following: halogens, such as F or Cl; -CN; methyl groups; and halomethyl groups, such as -CHF2;

[0552] Optionally, no more than one of R 5C It is a substituent.

[0553] For example, ring C can have the following structure:

[0554]

[0555] in:

[0556] X Co and X Cm Each is selected from C and N, preferably X. Co and X Cm One of them is N;

[0557] When X Co When it is C, R Co It can be H or halogen, or F;

[0558] When X Co When it is N, R Co It does not exist;

[0559] When X Cm When it is C, R Cm It is either H or halogen, or F; and

[0560] When X Cm When it is N, R Cm It does not exist.

[0561] When it exists, R Co Preferably H or F. When present, R Cm H is preferred.

[0562] Most preferably, ring C has a structure selected from the following:

[0563] , and .

[0564] Ring C can have a structure selected from the following:

[0565]

[0566]

[0567] terminal substituent R 6

[0568] Ring C with substituent R 6 It is selected from H and substituted or unsubstituted organic groups.

[0569] R 6 It can be specifically selected from H, -F, -Cl, -Br, -I, -CN, -CONR 51 R 51 -NR 51 COR 52 -SO2NR 51 R 51 -NR 51 SO2R 52 -O-CR 52 R 52 R 52 -CR 52 R 52 NR 51 R 51 and any of the following structures:

[0570]

[0571] R 51 and R 52 Each is independently selected from H and substituted or unsubstituted organic groups. Optionally, R 51 and R 52 Each is independently selected from H, halogen, optionally deuterated C1 to C3 alkyl and C1 to C3 haloalkyl.

[0572] Optional, R6 Selected from -F, -Cl, -CN, -CONH2, -CONHMe (optionally -CONHCD3), -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, -CONH-CH2-CHF2, -OCHF2, -NHCOMe, -NHSO2Me, -SO2NHMe, -CONHSO2Me, , , , , , , , and .

[0573] According to another possibility, R 6 It can have the following structure:

[0574]

[0575] Where R 51 Selected from:

[0576] C1 to C6 alkyl groups, optionally C3 to C6 cycloalkyl groups, C1 to C3 alkyl groups or C1 to C3 deuterated alkyl groups;

[0577] C1 to C3 haloalkyl groups, optionally C1 to C3 fluoroalkyl groups; and

[0578] A 4-, 5-, 6-, or 7-membered saturated heterocyclic group, optionally a 4-, 5-, or 6-membered cyclic ether group.

[0579] R 6 Can be selected from:

[0580]

[0581] Among these, -CONHMe, -C(O)NHEt, , -C(O)NHCH2CF3, C(O)NHCH2CH2F and It is the preferred option.

[0582] Particularly preferred, R 6 Selected from:

[0583] i) CONHMe;

[0584] ia) CONHCD3;

[0585] ii) Cl; and

[0586] iii) CN.

[0587] Using R selected from i) to iii) just defined above 6 In the case of a compound being described by a group, explicitly consider replacing R with any other group from i) to iii). 6 Group.

[0588] In some instances, R 6 It is F.

[0589] According to yet another possibility, R 6 It can have the following structure:

[0590]

[0591] in:

[0592] Each X 6 Independently selected from C, N, and O;

[0593] R 61 It either does not exist or is H;

[0594] Each R 62 Independently absent or selected from H; halogenated groups, such as F; oxo groups; C1 to C3 alkyl groups; C1 to C3 haloalkyl groups, optionally C1 to C3 fluoroalkyl groups; and -NHR 63 , where R 63 It is an H or C1 to C3 alkyl group.

[0595] R in this class 6 Examples of functional groups include:

[0596]

[0597] Example L group

[0598] The group L of the PARP1 inhibitor compound may, for example, have a structure selected from the following:

[0599]

[0600]

[0601] Where R 6 As defined above.

[0602] The L group in the PARP1 inhibitor compound can be specifically selected from:

[0603]

[0604] Other examples of L-group structures include:

[0605]

[0606]

[0607] The rings E and B of the PARP1 inhibitor compound can be in a cis configuration relative to ring A. In such a compound, the group L can be selected from:

[0608]

[0609] Other examples of groups with a cis configuration and an L-structure include:

[0610]

[0611]

[0612] Alternatively, rings E and B can be in a trans configuration relative to ring A. In such compounds, group L can be selected from:

[0613]

[0614] Other examples of L-shaped groups with a trans configuration include:

[0615]

[0616]

[0617] Example compounds

[0618] This article provides PARP1 inhibitor compounds with the following structures:

[0619]

[0620] in:

[0621] Each Z independently represents -CH2- or is selected from -O- and -N(R). D ()- fragments containing heteroatoms, provided that no more than one Z is a fragment containing heteroatoms;

[0622] Where R D It is an H or C1 to C3 alkyl group;

[0623] X C1 and X C2 Each is independently selected from C and N;

[0624] When X C1When it is N, R 5C1 It does not exist;

[0625] When X C1 When it is C, R 5C1 Selected from H and halogens, with F being preferred;

[0626] When X C2 When it is N, R 5C2 It does not exist;

[0627] When X C2 When it is C, R5 C2 Selected from H and halogens, with F being preferred;

[0628] R 6 Selected from -CONHMe, -Cl, and -CN.

[0629] When it exists, R D Preferably, it is a methyl group.

[0630] When it exists, R 5C1 Preferably, it is H or F.

[0631] When it exists, R 5C2 Preferably, it is H or F.

[0632] X C2 Preferably, it is N. More preferably, it is X. C1 It is C and X C2 It is N.

[0633] R 6 Preferably, it is -CONHMe, for example -CONHCD3.

[0634] The compound may have a cis configuration:

[0635]

[0636] Or trans configuration:

[0637]

[0638] Examples of compounds in this class include the following:

[0639]

[0640]

[0641] This article also provides PARP1 inhibitor compounds based on the following general formula:

[0642]

[0643] in:

[0644] R D1 and R D2 Each is independently selected from H and F;

[0645] Two Rs 5A The groups together represent the -CH2- group of bridging ring A, and each other R 5A The group is H; or

[0646] Each R 5A It is H;

[0647] Each X C The atoms are selected from C and N, provided that there are at least two X atoms. C The atom is C;

[0648] When X C When it is N, the corresponding R 5C It does not exist;

[0649] When X C When it is C, the corresponding R 5C It is H or a substituent selected from the following: halogens, such as F or Cl; -CN; methyl groups; and halomethyl groups, such as -CHF2;

[0650] R 6 Selected from halogens, -CN and

[0651] Where R 51 It is selected from C1 to C3 alkyl groups; C1 to C3 deuterated alkyl groups; C1 to C3 fluoroalkyl groups; tetrahydrofuranyl groups; and tetrahydropyranyl groups.

[0652] For example, the PARP1 inhibitor compound may have the following structure:

[0653]

[0654] in:

[0655] R D1 and R D2 Each is independently selected from H and F;

[0656] X C1 and X C2 Each is independently selected from C and N;

[0657] When X C1 When it is N, R 5C1 It does not exist;

[0658] When X C1 When it is C, R 5C1 Selected from H and halogens, with F being preferred;

[0659] When X C2 When it is N, R C2 It does not exist;

[0660] When X C2 When it is C, R5 C2 Selected from H and halogens, with F being preferred;

[0661] R 6 Selected from -CONHMe, -Cl, and -CN.

[0662] Preferably, R D1 and R D2 One of them is F.

[0663] Preferably, X C1 and X C2 One of them is N. For example, X C1 It can be C and X C2 It can be N. Alternatively, X C2 It can be C and X C1 It can be N; in such instances, R 5C2 H is preferred.

[0664] The compound may have a cis configuration:

[0665]

[0666] Or trans configuration:

[0667]

[0668] Examples of PARP1 inhibitor compounds in this class include:

[0669]

[0670]

[0671]

[0672] This article provides the following PARP1 inhibitor compounds:

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691] Medical Use

[0692] The compounds described herein can be used in medicine. In the context of this invention, pharmaceutical use is not particularly limited, provided that it is a use facilitated by the PARP1 inhibitory effect of the compounds. Therefore, the compounds of this invention can be used in any disease, condition, or disorder that can be prevented, improved, or treated using PARP1 inhibitors.

[0693] The PARP1 inhibitor compounds presented herein are selective for PARP1 relative to PARP2. Therefore, these PARP1 inhibitor compounds may exhibit reduced toxicity. PARP2 inhibition is considered a major driver of hematological toxicities such as anemia, neutropenia, and thrombocytopenia.

[0694] The PARP1 inhibitor compounds can be used to treat cancer. There are no particular limitations on the nature of the cancer, provided that it is a cancer that can be treated, prevented, or improved by using a PARP1 inhibitor. Cancers can include solid tumors or liquid tumors.

[0695] For example, cancer can be selected from: eye cancer, brain cancer (such as glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, and astrocytoma), spinal cord cancer, kidney cancer, oral cancer, lip cancer, laryngeal cancer, oral cavity cancer, nasal cavity cancer, small intestine cancer, colon cancer, parathyroid cancer, gallbladder cancer, head and neck cancer, breast cancer, bone cancer, bile duct cancer, cervical cancer, heart cancer, subpharyngeal gland cancer, lung cancer, bronchial cancer, liver cancer, skin cancer, ureteral cancer, urethral cancer, testicular cancer, vaginal cancer, and anal cancer. Laryngeal gland cancer, ovarian cancer, thyroid cancer, esophageal cancer, nasopharyngeal gland cancer, pituitary cancer, salivary gland cancer, prostate cancer, pancreatic cancer, adrenal cancer; endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, hemangioma, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilms' tumor, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN hamartoma-tumor syndrome (PHTS). (Such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukemia, and lymphoma (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary exudative lymphoma, AIDS-related lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer. For example, cancer can be brain cancer or spinal cord cancer.

[0696] Furthermore, the compounds described herein can be used in cancers in which Epstein-Barr virus (EBV) plays a contributing role, such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer.

[0697] The compounds described herein may be provided for the treatment of cancers deficient in one or more DNA damage response repair pathways, particularly in homologous recombination (“HR”)-dependent DNA double-strand break (“DSB”) DNA repair activity. Components of the HR-dependent DNA DSB repair pathway and other DNA damage response pathways include, but are not limited to, the following proteins: ATM, ATR, ERCC1, XRCC1, XRCC2, XRCC3, RAD51, RAD51L1, RAD51C, RAD51D, RAD51L3, DMC1, RAD52, RAD54L, RAD54B, RAD50, MRE11A, NBS1, BRCA1, BRCA2, FANCP (SLX4), FEN1, PALB2, PBRM1, SMARCA4, ARID1A, ARID1B, FANCD2, and BLM. Other components involved in HR-dependent DNA DSB repair include regulatory factors such as ESMY (Hughes-Davies, L. et al.). Cell (2003;115: 523-535). Cancers with defective HR-dependent DNA DSB repair often become dependent on alternative DSB pathway repair mechanisms. Such cancers include, but are not limited to, ovarian cancer, prostate cancer, breast cancer, lung cancer, gastrointestinal cancer, leukemia, and pancreatic cancer.

[0698] Cancer cells can exhibit BRCA1 and / or BRCA2 deficiency phenotypes, meaning that cancer cells may have defects in the function of BRCA1 and / or BRCA2. These defects can be caused by mutations, polymorphisms, or epigenetic silencing of nucleic acids, or by mutations, polymorphisms, or amplifications of genes encoding regulatory factors (e.g., the ESMY gene encoding a BRCA2 regulatory factor) (Hughes-Davies, L. et al.). Cell (2003; 115: 523-535). Amplification of the ESMY gene is associated with breast and ovarian cancer. Carriers of mutations in the tumor suppressor genes BRCA1 and / or BRCA2 are known to have an increased risk of developing certain cancers, including ovarian, prostate, and breast cancer. Wild-type alleles of BRCA1 and / or BRCA2 are frequently lost in the tumors of heterozygous carriers (Jasin, M. et al.). Oncogene. 2002; 21: 8981-93), and their detection as a method of patient selection is well known in the art (Radice, PJ. et al.). Exp . Clin . Cancer . Res . 2002;21:9-12;Chappnis, PO and Foulkes WO. Cancer Treat Res . 2002;107: 29-59).

[0699] The compounds described herein may be administered to patients undergoing radiation therapy and / or chemotherapy using other agents used to treat cancer.

[0700] For example, the PARP1 inhibitor compound can be administered in combination with other agents used to treat cancer.

[0701] Other agents used to treat cancer may be selected from: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, apoptosis-promoting agents, radioligand therapy, cell cycle signaling inhibitors, and anti-angiogenic agents.

[0702] In particular, other agents may include immunotherapeutic agents selected from the following: anti-tumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy (CAR-T); small molecule immunomodulators; and tumor microenvironment modulators.

[0703] Pharmaceutical Composition

[0704] On the other hand, pharmaceutical compositions are provided that contain PARP1 inhibitor compounds as defined herein.

[0705] Typically, the composition contains pharmaceutically acceptable additives and / or excipients.

[0706] In the pharmaceutical composition, the PARP1 inhibitor compound as defined above may be present in the above-described form, but may optionally be in a form suitable for improving bioavailability, solubility, and / or activity, and / or in a form suitable for improving the formulation. Therefore, the compound may be in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other suitable alternative form.

[0707] Typically, the composition is intended for use in medicine, for example, to treat diseases, conditions, or disorders as defined above.

[0708] For example, the pharmaceutical composition can be used to treat cancer. The composition may also contain additional agents for treating cancer. There are no particular limitations on the additional agents for treating cancer, provided they provide some efficacy in cancer treatment.

[0709] Other agents used to treat cancer may include one or more chemotherapeutic agents such as antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell scavengers, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, apoptosis-promoting agents, radioligand therapy, anti-angiogenic agents, and cell cycle signaling inhibitors.

[0710] In particular, other agents for treating cancer may include immunotherapeutic agents selected from the following: antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy (CAR-T); small molecule immunomodulators; and tumor microenvironment modulators.

[0711] Package products

[0712] On the other hand, drug kits for treating cancer are provided. These drug kits contain a PARP1 inhibitor compound as defined herein and additional agents for treating cancer. The compound and the additional agents are suitable for simultaneous, sequential, or separate administration.

[0713] The additional agent for treating cancer may be any additional agent for treating cancer identified in the discussion of pharmaceutical compositions above.

[0714] In particular, other agents used to treat cancer may include one or more chemotherapeutic agents selected from the following: antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell scavengers, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone deprivation therapy, radioligand therapy, anti-angiogenic agents, and immunotherapeutic agents (such as those selected from antitumor vaccines, lysozyme inhibitors, etc.). Tumor viruses, immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3 and anti-GITR, pattern recognition receptor agonists such as STING, TLR-9 or RIG-I helicase agonists, IDO or TDO inhibitors, novel adjuvants, peptides, cytokines, chimeric antigen receptor T-cell therapy (CAR-T), small molecule immunomodulators, tumor microenvironment modulators, apoptosis-promoting agents and cell cycle signaling inhibitors.

[0715] Treatment

[0716] Another aspect of the invention provides a method for treating diseases and / or conditions and / or disorders, the method comprising administering to a patient (or subject) a PARP1 inhibitor compound or composition or kit product as defined herein. The method is generally used for treating any disease, condition, or disorder mentioned herein. In a typical embodiment, the method is used for treating cancer.

[0717] The patient can be any animal, preferably a mammal. For example, the patient can be a human, dog, horse, or cat; and preferably a human.

[0718] The method may include administering to a patient (or subject) a compound or composition as defined above and an additional agent as defined above for treating cancer. Depending on the agent involved, the patient, and the disease to be treated (e.g., the type of cancer to be treated), the compound or composition and the additional agent may be administered simultaneously, sequentially, or separately.

[0719] The patient may be undergoing treatment using ionizing radiation.

[0720] Methods for synthesizing PARP1 inhibitor compounds

[0721] Methods for synthesizing PARP1 inhibitor compounds as defined herein are also provided. Generally, the methods comprise a reaction between: i) a first reactant comprising a first portion containing rings D and E and carrying a group L, and ii) a second reactant comprising the remaining portion of the group L, to form a PARP1 inhibitor compound. Those skilled in the art can select reaction conditions based on suitable starting materials and with reference to known synthetic techniques. The methods may include one or more additional steps. Exemplary synthetic methods are shown in the examples below.

[0722] In one example method, the first reactant comprises rings D, E, and A, and the second reactant comprises a cyclic B precursor with a reactive group, the method comprising attaching ring A to the cyclic B precursor. In this method, the reactive group of the cyclic B precursor may comprise a carbonyl group, an alkyl halide, or a sulfonic acid alkyl ester. The reaction may include alkylation, reductive amination, or amide formation to form group L.

[0723] In another example method, the first reactant comprises rings D, E, A, and B, and the second reactant comprises a ring C derivative with a leaving group (such as a halide or sulfonate). In this method, the reaction may include a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, to form a group L.

[0724] The PARP1 inhibitor compound can be obtained as a mixture of two or more structural isomers. The method may also include separating the structural isomers. For example, the method may further include separating the structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography (“SFC”) and / or chiral high-performance liquid chromatography (“HPLC”).

[0725] When the PARP1 inhibitor compound is a diastereomer, separation can be performed in two stages. In the first stage, the two pairs of stereoisomers can be separated by HPLC. In the second stage, a single stereoisomer can be separated from the stereoisomer pair by SFC.

[0726] Example

[0727] Example 1: Synthesis of compounds 5ci-a, 5ci-b, 5trans-a, and 5trans-b

[0728]

[0729] Option 1

[0730] 8-Fluoro-2-(4-methoxybenzyl)-3-(3-oxocyclopent-1-en-1-yl)isoquinoline-1(2H)-one (1003) preparation

[0731] A suspension of 3-chloro-8-fluoro-2-(4-methoxybenzyl)isoquinoline-1(2H)-one 1001 (1800 mg, 5.6650 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)cyclopent-2-en-1-one 1002 (1178 mg, 5.6650 mmol), Na₂CO₃ (1201 mg, 11.3300 mmol), and Pd(dppf)Cl₂ (462 mg, 0.5665 mmol) in dioxane (100 mL) was heated at 100 °C for 8 h under N₂. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (using EtOAc / PE, elution from 0 to 15%) to produce 8-fluoro-2-(4-methoxybenzyl)-3-(3-oxocyclopent-1-en-1-yl)isoquinoline-1(2H)-one 1003 (800 mg, 80% purity, 31% yield) as a yellow oil.

[0732] C 22 H 18 LCMS (ESI) calculation value of FNO3 [M + H] + m / z 364.13, measured value 364.00.

[0733] 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopent-2-ene- Preparation of 1-yl)piperazine-1-yl)-N-methylpyridine amide (1005)

[0734] N-methyl-5-(piperazin-1-yl)pyridineamide 1004 (218 mg, 0.9907 mmol), NaBH(OAc)3 (875 mg, 4.1280 mmol), and NaBH3CN (259 mg, 4.1280 mmol) were sequentially added to a solution of 8-fluoro-2-(4-methoxybenzyl)-3-(3-oxocyclopent-1-en-1-yl)isoquinoline-1(2H)-one 1003 (300 mg, 0.8256 mmol) in MeOH (6 mL). The reaction mixture was stirred at 60 °C for 48 h. The reaction mixture was quenched with water and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to provide 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyridineamide 1005 (220 mg, 90% purity, 42% yield) as a colorless oil.

[0735] C33 H 34 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 568.26, measured value 568.30.

[0736] 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperyl Preparation of 1-azine-1-yl)-N-methylpyridine amide (1006)

[0737] A solution of 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyridineamide 1005 (200 mg, 0.3523 mmol) and Pd(OH)2 / C (99 mg, 0.7046 mmol) in MeOH (5 mL) was stirred at 50 °C for 48 h under H2 atmosphere. The resulting solution was filtered through diatomaceous earth and the filter cake was washed with DCM (10 mL). The filtrate was concentrated under reduced pressure to produce 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1006 (180 mg, 85% purity, 76% yield) as a colorless oil.

[0738] C 33 H 36 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 570.28, measured value 570.35.

[0739] 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridine Preparation of amides (5 cis-a, 5 cis-b, 5 trans-a, and 5 trans-b)

[0740] A solution of 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1006 (180 mg, 0.3160 ​​mmol) in TFA (3 mL) and TfOH (0.3 mL) was stirred at 100 °C for 10 min. The reaction solution was cooled to room temperature and adjusted to pH 8 with NaHCO3 aqueous solution, and then extracted with EtOAc (100 mL × 2). The combined organic layers were concentrated under reduced pressure and purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); gradient: 25-70) to give 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridinamide 5 cis-a / 5 cis-b racemic mixture (27.6 mg, 95% purity, 18% yield) and 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridinamide 5 trans-a / 5 trans-b racemic mixture (7.5 mg, 98% purity, 5% yield) as white solid.

[0741] 5cis-a / 5cis-b racemic mixture

[0742] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.63 (s, 1 H), 8.44-8.36 (m, 1 H), 8.29 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.8 Hz, 1 H), 7.64-7.57 (m, 1 H), 7.42(dd, J =8.8, 2.8 Hz, 1 H), 7.36 (d, J =7.6 Hz, 1 H), 7.11-7.04 (m, 1 H), 6.45 (s, 1 H), 3.52-3.35 (m, 4 H), 3.12-2.99 (m, 1 H), 2.79 (d, J =4.8 Hz, 3 H), 2.72-2.61 (m, 5 H), 2.2-2.05 (m, 2 H), 1.89-1.63 (m, 4 H).

[0743] NOE experiments demonstrate the cis stereochemistry of this pair of enantiomers.

[0744] C 25 H 28 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 450.22, measured value 450.40.

[0745] 5-trans-a / 5-trans-b racemic mixture

[0746] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.17 (s, 1 H), 8.43-8.34 (m, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.65-7.57 (m, 1 H), 7.43-7.34 (m, 2 H), 7.13-7.05 (m, 1 H), 6.42 (s, 1 H), 3.36-3.32 (m, 4 H), 3.10-2.96 (m, 1 H), 2.90-2.81 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.65-2.54 (m, 4H), 2.13-1.94 (m, 3 H), 1.92-1.80 (m, 1 H), 1.77-1.64 (m, 1 H), 1.61-1.48 (m, 1 H).

[0747] NOE experiments demonstrate the trans stereochemistry of this pair of enantiomers.

[0748] C 25 H 28 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 450.22, measured value 450.25.

[0749] Example 2: Synthesis of 2cis-a, 2cis-b, 2trans-a, and 2trans-b

[0750]

[0751] Option 2

[0752] Preparation of 3-chloro-7-fluoro-1-methoxyisoquinoline (1102)

[0753] MeONa (251 mg, 4.65 mmol) was added to a solution of 1,3-dichloro-7-fluoroisoquinoline 1101 (1.0 g, 4.65 mmol) in MeOH (15 mL) under N2. The reaction mixture was stirred at 60 °C for 16 h. The reaction solution was cooled to room temperature, quenched with water, and extracted with EtOAc (100 mL × 4). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to give 3-chloro-7-fluoro-1-methoxyisoquinoline 1102 (900 mg, 80% purity, 73% yield) as a white solid.

[0754] C 10 LCMS (ESI) values ​​of H7ClFNO [M + H] + m / z 212.02, measured value 212.10.

[0755] Preparation of 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclopent-2-en-1-one (1103)

[0756] Na₂CO₃ (901 mg, 8.50 mmol) was added to a solution of 3-chloro-7-fluoro-1-methoxyisoquinoline 110⁻²⁻ (900 mg, 4.25 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)cyclopent-2-en-1-one 100⁻²⁻ (15 mL) in dioxane / H₂O under N₂ conditions. The reaction mixture was stirred at 90 °C for 2 h. The reaction solution was cooled to room temperature, quenched with water, and extracted with EtOAc (100 mL × 4). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to produce 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclopent-2-en-1-one 1103 (800 mg, 90% purity, 66% yield) as a white solid.

[0757] C 15 H 12 LCMS (ESI) calculation value of FNO2 [M + H] + m / z 258.09, measured value 258.10.

[0758] 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyrazine Preparation of pyridine amide (1104)

[0759] To a solution of 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclopent-2-en-1-one 1103 (460 mg, 1.79 mmol) in MeOH (20 mL), N-methyl-5-(piperazin-1-yl)pyridineamide hydrochloride 1004 (1.37 g, 5.40 mmol) and 2 drops of AcOH were added, followed by the addition of NaBH3CN (1.12 g, 17.9 mmol). The reaction mixture was stirred at 60 °C for 48 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to produce 5-(4-(3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyridineamide 1104 (530 mg, 70% purity, 44% yield) as a white solid.

[0760] C 26 H 28 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 462.22, measured value 462.20.

[0761] 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide Preparation of (1105)

[0762] Pd(OH)₂ / C (160 mg) was added to a solution of 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyridine amide 1104 (530 mg, 1.14 mmol) in MeOH (20 mL) under H₂. The reaction mixture was stirred at 50 °C for 4 h. The resulting solution was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure to yield 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridine amide 1105 (320 mg, 70% purity, 42% yield) as a white solid.

[0763] C 26 H 30 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 464.24, measured value 464.30.

[0764] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridine Preparation of amides (2 cis-a, 2 cis-b, 2 trans-a, 2 trans-b)

[0765] TMSI (414 mg, 2.07 mmol) was added to a solution of 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1105 (320 mg, 0.69 mmol) in ACN (20 mL). The reaction mixture was stirred at 50 °C for 3 h. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5 μm C18 150×21.2 mm, mobile phase: ACN-H2O (0.05% NH3), gradient: 30-65) to produce a racemic mixture of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridinamide 2 cis-a, 2 cis-b (cis, 38 mg, 95% purity, 10% yield) and a racemic mixture of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridinamide 2 trans-a, 2 trans-b (trans, 68 mg, 98% purity, 21% yield) as a white solid.

[0766] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridine Preparation of amides (2 cis-a and 2 cis-b)

[0767] A racemic mixture of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 2cis-a and 2cis-b (38 mg, 0.08 mmol) was separated by SFC (column: DAICEL IH 20 mm I.D. ×250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to provide a first fraction as 2cis-a (8.6 mg, 95.49% purity, ee%: 100, white solid) and a second fraction as 2cis-b (10.7 mg, 97.15% purity, ee%: 100, white solid).

[0768] 2 cis-a

[0769] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.80 (s, 1 H), 8.44-8.35 (m, 1 H), 8.29 (d, J =2.4 Hz, 1 H), 7.85 (d, J=8.8 Hz, 1 H), 7.75 (dd, J =9.2, 2.4 Hz, 1H), 7.71-7.63 (m, 1 H), 7.59-7.51 (m, 1 H), 7.42 (dd, J =8.8, 2.8 Hz, 1 H), 6.50 (s, 1 H), 3.53-3.35 (m, 4 H), 3.14-3.01 (m, 1 H), 2.79 (d, J =4.8 Hz, 3H), 2.75-2.69 (m, 1 H), 2.69-2.60 (m, 4 H), 2.23-2.06 (m, 2 H), 1.93-1.83 (m, 1 H), 1.82-1.72 (m, 2 H), 1.71-1.59 (m, 1 H).

[0770] NOE experiments revealed the cis stereochemistry of this compound.

[0771] C 25 H 28 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 450.22, measured value 450.40.

[0772] 2 cis-b

[0773] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.80 (s, 1 H), 8.48-8.35 (m, 1 H), 8.29 (d, J =2.4 Hz, 1 H), 7.85 (d, J =8.8 Hz, 1 H), 7.75 (dd, J =9.2, 2.4 Hz, 1H), 7.70-7.63 (m, 1 H), 7.59-7.50 (m, 1 H), 7.42 (dd, J =8.8, 2.8 Hz, 1 H), 6.50 (s, 1 H), 3.52-3.35 (m, 4 H), 3.14-3.00 (m, 1 H), 2.79 (d, J=4.8 Hz, 3H), 2.75-2.69 (m, 1 H), 2.69-2.61 (m, 4 H), 2.23-2.05 (m, 2 H), 1.94-1.82 (m, 1 H), 1.81-1.72 (m, 2 H), 1.71-1.58 (m, 1 H).

[0774] NOE experiments revealed the cis stereochemistry of this compound.

[0775] C 25 H 28 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 450.22, measured value 450.40.

[0776] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridine Preparation of amides (2-trans-a and 2-trans-b)

[0777] A racemic mixture of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 2-trans-a and 2-trans-b (68 mg, 0.15 mmol) was separated by SFC (column: DAICEL IH 20 mm ID × 250 mmL, 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to provide a first fraction as 2-trans-a (18.0 mg, 98.04% purity, ee%: 100, white solid) and a second fraction as 2-trans-b (16.0 mg, 97.86% purity, ee%: 100, white solid).

[0778] 2 trans-a

[0779] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.32 (s, 1 H), 8.43-8.33 (m, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.86-7.80 (m, 1 H), 7.77 (dd, J =9.6, 2.8 Hz, 1 H),7.72-7.65 (m, 1 H), 7.59-7.50 (m, 1 H), 7.39 (dd, J=8.8, 2.8 Hz, 1 H), 6.47(s, 1 H), 3.35-3.32 (m, 4 H), 3.11-2.99 (m, 1 H), 2.90-2.80 (m, 1 H), 2.78(d, J =4.8 Hz, 3 H), 2.61-2.55 (m, 4 H), 2.12-1.95 (m, 3 H), 1.91-1.80 (m, 1H), 1.76-1.64 (m, 1 H), 1.62-1.48 (m, 1 H).

[0780] NOE experiments revealed the trans stereochemistry of this compound.

[0781] C 25 H 28 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 450.22, measured value 450.40.

[0782] 2 trans-b

[0783] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.32 (s, 1 H), 8.42-8.33 (m, 1 H), 8.27 (d, J =2.4 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.77 (dd, J =9.2, 2.4 Hz, 1H), 7.73-7.64 (m, 1 H), 7.60-7.51 (m, 1 H), 7.39 (dd, J =8.8, 2.8 Hz, 1 H),6.47 (s, 1 H), 3.35-3.32 (m, 4 H), 3.12-3.00 (m, 1 H), 2.89-2.81 (m, 1 H),2.78 (d, J =4.8 Hz, 3 H), 2.61-2.55 (m, 4 H), 2.12-1.93 (m, 3 H), 1.90-1.80 (m, 1 H), 1.76-1.64 (m, 1 H), 1.60-1.48 (m, 1 H).

[0784] NOE experiments revealed the trans stereochemistry of this compound.

[0785] C 25 H 28 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 450.22, measured value 450.40.

[0786] Example 3: Synthesis of 1 cis-a, 1 cis-b, 1 trans-a, and 1 trans-b

[0787]

[0788] Option 3

[0789] Preparation of 3-chloro-1-methoxyisoquinoline (1202)

[0790] MeONa (4.1 g, 75.6 mmol) was added to a solution of 1,3-dichloroisoquinoline 1201 (5.0 g, 25.2 mmol) in MeOH (100 mL). The mixture was heated at 80 °C for 16 hours. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 30% to 60%) to produce 3-chloro-1-methoxyisoquinoline 1202 (5.0 g, 90% purity, 92% yield) as a white solid.

[0791] C 10 LCMS (ESI) calculated value of H8ClNO [M + H] + m / z 194.03, measured value 193.90.

[0792] Preparation of 3-(1-methoxyisoquinolin-3-yl)cyclopent-2-en-1-one (1203)

[0793] A mixture of 3-chloro-1-methoxyisoquinoline 1202 (1.00 g, 5.20 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)cyclopent-2-en-1-one 1002 (1.62 g, 7.80 mmol), RuPhos Pd G3 (CAS No. 1445085-77-7, 0.44 g, 0.52 mmol), RuPhos (CAS No. 787618-22-8, 0.73 g, 1.56 mmol), and Na2CO3 (1.65 g, 15.60 mmol) in dioxane (30 mL) and H2O (3 mL) was heated at 100 °C for 2 hours under a nitrogen atmosphere. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by rapid chromatography (eluting with EtOAc / PE, 30% to 60%) to give 3-(1-methoxyisoquinolin-3-yl)cyclopent-2-en-1-one 1203 (1 g, 90% purity, 73% yield) as a white solid.

[0794] C 15 H 13 LCMS (ESI) calculation value of NO2 [M + H] + m / z 240.10, measured value 239.90.

[0795] Preparation of 4-(3-(1-methoxyisoquinolin-3-yl)cyclopent-2-en-1-yl)piperazine-1-carboxylic acid benzyl ester (1205)

[0796] To a solution of 3-(1-methoxyisoquinolin-3-yl)cyclopent-2-en-1-one 1203 (1.0 g, 4.2 mmol) in MeOH (30 mL) at room temperature, benzyl piperazine-1-carboxylate 1204 (1.4 g, 6.3 mmol), AcOH (0.5 g, 8.4 mmol), and NaBH3CN (2.64 g, 41.9 mmol) were added. The reaction mixture was stirred at 60 °C for 24 h. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by rapid chromatography (using EtOAc / PE, elution 50% to 70%) to produce a mixture of 4-(3-(1-methoxyisoquinoline-3-yl)cyclopent-2-en-1-yl)piperazine-1-carboxylate 1205 and 4-(3-(1-methoxyisoquinoline-3-yl)cyclopentyl)piperazine-1-carboxylate 1205a as a white solid (1.2 g, 90% purity, ~57% yield).

[0797] The calculated LCMS (ESI) value of C27H29N3O3 is [M + H] + m / z 444.22, and the measured value is 444.05.

[0798] Preparation of 1-methoxy-3-(3-(piperazin-1-yl)cyclopentyl)-5,6,7,8-tetrahydroisoquinoline (1206)

[0799] PtO2 (0.6 g, 2.7 mmol) was added to a solution of a mixture of 4-(3-(1-methoxyisoquinoline-3-yl)cyclopent-2-en-1-yl)piperazin-1-carboxylate 1205 and 4-(3-(1-methoxyisoquinoline-3-yl)cyclopentyl)piperazin-1-carboxylate 1205a (1.2 g, ~2.7 mmol) in TFA (20 mL). The mixture was evacuated and backfilled with hydrogen three times, and then purged with hydrogen. The resulting mixture was stirred at room temperature for 16 hours under a H2 atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to produce crude 1-methoxy-3-(3-(piperazin-1-yl)cyclopentyl)-5,6,7,8-tetrahydroisoquinoline 1206 (1.2 g, 60% purity, 85% yield) as a yellow oil, which was used directly in the next step without further purification.

[0800] C 19 H 29 LCMS (ESI) calculation value of N3O [M + H] + m / z 316.23, measured value 316.20.

[0801] 5-(4-(3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)pyridinecarboxylic acid Preparation of ester (1208)

[0802] Methyl 5-fluoropyridinecarboxylate 1207 (0.8 g, 5.2 mmol) and DIPEA (2.3 g, 17.5 mmol) were added to a solution of 1-methoxy-3-(3-(piperazin-1-yl)cyclopentyl)-5,6,7,8-tetrahydroisoquinoline 1206 (1.1 g, 3.5 mmol) in DMSO (30 mL). The mixture was heated at 100 °C for 1 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 50% to 80%) to produce methyl 5-(4-(3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)pyridinecarboxylate 1208 (500 mg, 90% purity, 28% yield) as a white solid.

[0803] C 26 H 34LCMS (ESI) values ​​of N4O3 [M + H] + m / z 451.27, measured value 451.20.

[0804] 5-(4-(3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyrazine Preparation of pyridine amide (1209)

[0805] A solution of methyl 5-(4-(3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)pyridinecarboxylate 1208 (500 mg, 1.1 mmol) in MeNH2·MeOH (10 mL, 30% by weight) was heated at 80 °C for 2 hours. The resulting mixture was concentrated to produce 5-(4-(3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1209 (500 mg, 90% purity, 90% yield) as a yellow solid.

[0806] C 26 H 35 LCMS (ESI) values ​​of N5O2 [M + H] + m / z 450.28, measured value 450.30.

[0807] N-Methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl) Preparation of pyridine amide (1 cis-a / 1 cis-b / 1 trans-a / 1 trans-b)

[0808] TMSI (667 mg, 3.34 mmol) was added to a solution of 5-(4-(3-(1-methoxy-5,6,7,8-tetrahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1209 (500 mg, 1.11 mmol) in ACN (20 mL). The mixture was heated at 50 °C for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with MeOH / DCM, 5% to 10%). The obtained solids were separated by SFC (column: Torus 2-PIC OBD 20 mm ID × 250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 25 / 75) to provide a first fraction as a racemic mixture of N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)pyridineamide 1 cis-a / 1 cis-b (cis, 20 mg, 90% purity, 3% yield, white solid) and a second fraction as a racemic mixture of N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl)pyridineamide 1 trans-a / 1 trans-b (trans, 20 mg, 20 μm, 5 ... (mg, 90% purity, 3% yield, white solid).

[0809] N-Methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl) Preparation of pyridine amides (1-cis-a and 1-cis-b)

[0810] The racemic mixture of 1 cis-a / 1 cis-b was separated by SFC (column: Daicel Chiralpak-IH 20 mm I.D. × 250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 70 / 30) and concentrated under reduced pressure to provide a first fraction as 1 cis-a (4.0 mg, 99.00% purity, 100% ee, white solid) and a second fraction as 1 cis-b (4.0 mg, 95.74% purity, 100% ee, white solid).

[0811] 1 cis-a

[0812] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.50 (s, 1 H), 8.45-8.33 (m, 1 H), 8.28 (s, 1 H), 7.84 (d,J =8.8 Hz, 1 H), 7.47-7.34 (m, 1 H), 5.81 (s, 1 H), 3.48-3.35 (m, 4 H), 3.02-2.89 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.69-2.60(m, 5 H), 2.45-2.40 (m, 2 H), 2.28-2.21 (m, 2 H), 2.13-1.96 (m, 2 H), 1.86-1.72 (m, 2 H), 1.68-1.53 ​​(m, 6 H).

[0813] NOE experiments revealed the cis stereochemistry of this compound.

[0814] C 25 H 33 LCMS (ESI) values ​​of N5O2 [M + H] + m / z 436.27, measured value 436.20.

[0815] 1 cis-b

[0816] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.50 (s, 1 H), 8.40 (q, J =4.6 Hz, 1H), 8.27 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.8 Hz, 1 H), 7.40 (dd, J =8.8, 2.8Hz, 1 H), 5.81 (s, 1 H), 3.50-3.40 (m, 4 H), 3.01-2.88 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.67-2.58 (m, 5 H), 2.45-2.41 (m, 2 H), 2.29-2.22 (m, 2 H), 2.12-1.98 (m, 2 H), 1.85-1.71 (m, 2 H), 1.67-1.53 ​​(m, 6 H).

[0817] NOE experiments revealed the cis stereochemistry of this compound.

[0818] C 25 H33 LCMS (ESI) values ​​of N5O2 [M + H] + m / z 436.27, measured value 436.25.

[0819] N-Methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinoline-3-yl)cyclopentyl)piperazin-1-yl) Preparation of pyridine amides (1-trans-a and 1-trans-b)

[0820] The racemic mixture of 1-trans-a / trans-b was separated by SFC (column: Daicel Chiralpak-IH 20 mm I.D. × 250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)]=70 / 30) and concentrated under reduced pressure to provide a first fraction as 1-trans-a (5.2 mg, 99.16% purity, 100% ee, white solid) and a second fraction as 1-trans-b (5.2 mg, 99.39% purity, 100% ee, white solid).

[0821] 1. Trans-a

[0822] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.11 (s, 1 H), 8.48-8.35 (m, 1 H), 8.26 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.39 (dd, J =8.8, 2.8 Hz, 1H), 5.77 (s, 1 H), 3.31-3.28 (m, 4 H), 2.99-2.87 (m, 1 H), 2.85-2.74 (m, 4H), 2.57-2.53 (m, 4 H), 2.46-2.41 (m, 2 H), 2.29-2.23 (m, 2 H), 2.03-1.88 (m, 3 H), 1.82-1.68 (m, 1 H), 1.67-1.44 (m, 6 H).

[0823] NOE experiments revealed the trans stereochemistry of this compound.

[0824] C 25 H 33 LCMS (ESI) values ​​of N5O2 [M + H] + m / z 436.27, measured value 436.25.

[0825] 1 trans-b

[0826] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: δ 11.12 (s, 1 H), 8.49-8.32 (m, 1H), 8.26 (s, 1 H), 7.83 (d, J =8.4 Hz, 1 H), 7.48-7.26 (m, 1 H), 5.77 (s, 1H), 3.31-3.29 (m, 4 H), 2.96-2.88 (m, 1 H), 2.81-2.72 (m, 4 H), 2.57-2.53 (m, 4 H), 2.46-2.42 (m, 2 H), 2.30-2.23 (m, 2 H), 2.00-1.91 (m, 3 H), 1.79-1.71 (m, 1 H), 1.64-1.46 (m, 6 H).

[0827] NOE experiments revealed the trans stereochemistry of this compound.

[0828] C 25 H 33 The calculated LCMS (ESI) value of N5O2 [M + H] + m / z is 436.27, and the measured value is 436.25.

[0829] Example 4: Synthesis of 16cis-a, 16cis-b, 16trans-a, and 16trans-b

[0830]

[0831] Option 4

[0832] Preparation of 3-chloro-7-fluoro-1-methoxyisoquinoline (1302)

[0833] CH3ONa (4.99 g, 0.092 mol) was added to a solution of 1,3-dichloro-7-fluoroisoquinoline 1301 (5 g, 0.023 mol) in MeOH (100 mL). The mixture was stirred at 65 °C for 4 h. The reaction solution was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to produce 3-chloro-7-fluoro-1-methoxyisoquinoline 1302 (4.5 g, 90% purity, 83% yield) as a white solid.

[0834] C 10 LCMS (ESI) values ​​of H7ClFNO [M + H] +m / z 212.02, measured value 211.85.

[0835] Preparation of 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohex-2-en-1-one (1304)

[0836] Na₂CO₃ (4508 mg, 42.53 mmol) was added to a solution of 3-chloro-7-fluoro-1-methoxyisoquinoline 1302 (3000 mg, 14.18 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)cyclohex-2-en-1-one 1303 (4093 mg, 18.43 mmol), and RuPhos Pd G3 (CAS No. 1445085-77-7) (1187 mg, 1.42 mmol) in dioxane / H₂O = 10:1 (60 mL) under N₂. The reaction mixture was stirred at 100 °C for 3 h. The reaction solution was cooled to room temperature, quenched with water, and extracted with EtOAc (200 mL × 4). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to produce 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohex-2-en-1-one 1304 (3200 mg, 80% purity, 67% yield) as a yellow solid.

[0837] C 16 H 14 LCMS (ESI) calculation value of FNO2 [M + H] + m / z 272.10, measured value 271.90.

[0838] 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclohex-2-en-1-yl)piperazin-1-yl)-N-methylpyrazine Preparation of pyridine amide (1305)

[0839] To a solution of 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohex-2-en-1-one 1304 (1500 mg, 5.53 mmol) in EtOH (40 mL), N-methyl-5-(piperazin-1-yl)pyridineamide 1004 (1462 mg, 6.64 mmol) and 10 drops of HOAc were added, followed by the addition of NaBH(OAc)3 (2344 mg, 11.06 mmol). The reaction mixture was stirred for 10 min, then NaBH3CN (347 mg, 5.53 mmol) was added and the mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to yield a mixture of 1305 and 1306 as a yellow solid (1100 mg, 80% purity, 33% yield).

[0840] C 27 H 30 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 476.24, measured value 476.20.

[0841] 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridineamide Preparation of (1306)

[0842] Pd(OH)₂ / C (500 mg) was added to a mixture of 1305 and 1306 (1000 mg) in MeOH (20 mL). The reaction mixture was degassed with H₂ and stirred at 50 °C for 16 h under H₂. The resulting solution was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to produce 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridineamide 1306 (1000 mg, 60% purity, 60% yield) as a yellow solid.

[0843] C 27 H 32 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 478.25, measured value 478.35.

[0844] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridine Preparation of amides (16-cis-rac and 16-trans-rac)

[0845] TMSI (1676 mg, 8.38 mmol) was added to a solution of 5-(4-(3-(7-fluoro-1-methoxyisoquinoline-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridinamide 1306 (1000 mg, 2.09 mmol) in ACN (20 mL). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to produce 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridinamide 16cis-rac (80 mg, 95% purity, 8% yield) and 16trans-rac (40 mg, 95% purity, 4% yield) as a white solid.

[0846] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridine Preparation of amides (16cis-a and 16cis-b)

[0847] 16cis-rac was separated by an SFC (column: DAICEL AS-H 20 mm ID × 250 mmL 5 μm; mobile phase: CO2 / MEOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to provide a first fraction as 16cis-a (cis, 33.7 mg, 99% purity, ee%: 100, 3% yield, white solid) and a second fraction as 16cis-b (cis, 30.6 mg, 99% purity, ee%: 100, 3% yield, white solid).

[0848] 16 cis-a

[0849] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.33 (s, 1 H), 8.47-8.35 (m, 1 H), 8.26 (d, J =2.8 Hz, 1 H), 7.82 (d, J =8.8 Hz, 1 H), 7.77 (dd, J =9.6, 2.8 Hz, 1H), 7.72-7.65 (m, 1 H), 7.60-7.52 (m, 1 H), 7.39 (dd, J =9.0, 3.0 Hz, 1 H), 6.44 (s, 1 H), 3.31-3.27 (m, 4 H), 2.78 (d, J=4.8 Hz, 3 H), 2.73-2.65 (m, 4H), 2.55-2.51 (m, 2 H), 2.10-2.03 (m, 1 H), 1.92-1.80 (m, 3 H), 1.55-1.43 (m,1 H), 1.40-1.19 (m, 3 H).

[0850] Based on NOE experimental designation of cis-stereochemistry.

[0851] C 26 H 30 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 464.24, measured value 464.10.

[0852] 16 cis-b

[0853] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.33 (s, 1 H), 8.44-8.33 (m, 1 H), 8.28-8.22 (m, 1 H), 7.85-7.79 (m, 1 H), 7.79-7.75 (m, 1 H), 7.72-7.64 (m, 1H), 7.60-7.51 (m, 1 H), 7.42-7.34 (m, 1 H), 6.44 (s, 1 H), 3.31-3.24 (m, 4H), 2.78 (d, J =4.8 Hz, 3 H), 2.73-2.63 (m, 4 H), 2.56-2.51 (m, 2 H), 2.11-2.01 (m, 1 H), 1.92-1.80 (m, 3 H), 1.56-1.43 (m, 1 H), 1.41-1.21 (m, 3 H).

[0854] Based on NOE experimental designation of cis-stereochemistry.

[0855] C 26 H 30 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 464.24, measured value 464.05.

[0856] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridine Preparation of amides (16-trans-a and 16-trans-b)

[0857] 16-trans-rac was separated by an SFC (column: DAICEL AS-H 20 mm ID × 250 mmL 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to provide a first fraction as 16-trans-a (trans, 11.8 mg, 99% purity, ee%: 100, 3% yield, white solid) and a second fraction as 16-trans-b (trans-, 12.7 mg, 99% purity, ee%: 100, 1% yield, white solid).

[0858] 16 trans-a

[0859] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.34 (s, 1 H), 8.47-8.34 (m, 1 H), 8.28 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.8 Hz, 1 H), 7.77 (dd, J =9.4, 2.6 Hz, 1H), 7.73-7.65 (m, 1 H), 7.60-7.52 (m, 1 H), 7.41 (dd, J =8.8, 2.8 Hz, 1 H), 6.45 (s, 1 H), 3.46-3.33 (m, 4 H), 2.97-2.86 (m, 1 H), 2.78 (d, J =4.8 Hz, 3H), 2.70-2.55 (m, 4 H), 2.39-2.35 (m, 1 H), 2.16-2.07 (m, 1 H), 2.02-1.85 (m, 2 H), 1.81-1.66 (m, 2 H), 1.64-1.38 (m, 3 H).

[0860] Based on NOE experimental designation of trans stereochemistry.

[0861] C 26 H 30 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 464.24, measured value 464.10.

[0862] 16 trans-b

[0863] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.34 (s, 1 H), 8.46-8.36 (m, 1 H), 8.28 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.4 Hz, 1 H), 7.77 (dd, J =9.4, 2.6 Hz, 1H), 7.73-7.66 (m, 1 H), 7.60-7.53 (m, 1 H), 7.41 (dd, J =8.8, 2.8 Hz, 1 H), 6.45 (s, 1 H), 3.46-3.33 (m, 4 H), 2.99-2.86 (m, 1 H), 2.78 (d, J =4.8 Hz, 3H), 2.70-2.55 (m, 4 H), 2.39-2.35 (m, 1 H), 2.16-2.07 (m, 1 H), 2.02-1.85 (m, 2 H), 1.80-1.66 (m, 2 H), 1.64-1.39 (m, 3 H).

[0864] Based on NOE experimental designation of trans stereochemistry.

[0865] C 26 H 30 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 464.24, measured value 464.10.

[0866] Example 5: Synthesis of 26 cis and 26 trans

[0867]

[0868] Option 5

[0869] Preparation of N-methoxy-N-methyl-3-oxocyclobutane-1-carboxamide (1402)

[0870] DIEA (10 g, 77.52 mmol) and T4P (50% by weight, 40 g, 55.56 mmol in EtOAc) were successively added to a solution of 3-oxocyclobutane-1-carboxylic acid 1401 (5 g, 43.86 mmol) and N,O-dimethylhydroxylamine hydrochloride (15 g, 154.64 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 99:1) to provide N-methoxy-N-methyl-3-oxocyclobutane-1-carboxamide 1402 (5 g, 72% yield) as a colorless oil.

[0871] C7H 11 LCMS (ESI) calculation value of NO3 [M + H] + m / z 158.07, measured value 158.00.

[0872] Preparation of 4-(3-(methoxy(methyl)carbamoyl)cyclobutyl)piperazine-1-carboxylic acid benzyl ester (1403)

[0873] Ten drops of acetic acid were added to a solution of N-methoxy-N-methyl-3-oxocyclobutane-1-carboxamide 1402 (5 g, 31.85 mmol) and benzyl piperazine-1-carboxylate (10 g, 63.69 mmol) in MeOH (60 mL), followed by the addition of NaBH3CN (3 g, 48.39 mmol) after 10 minutes. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 97:3) to provide 4-(3-(methoxy(methyl)carbamoyl)cyclobutyl)piperazine-1-carboxylate 1403 (5 g, 43% yield) as a yellow oil.

[0874] C 17 H 27 LCMS (ESI) values ​​of N3O4 [M + H] + m / z 362.20, measured value 362.10.

[0875] Preparation of 4-(3-formylcyclobutyl)piperazine-1-carboxylic acid benzyl ester (1404)

[0876] DIBAL-H (1M hexane solution, 20 mL, 20 mmol) was added to a solution of 4-(3-(methoxy(methyl)carbamoyl)cyclobutyl)piperazine-1-carboxylate 1403 (5 g, 13.85 mmol) in THF (80 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water and then extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 96:4) to provide 4-(3-formylcyclobutyl)piperazine-1-carboxylate 1404 (2.8 g, 66% yield) as a yellow oil.

[0877] C 11 H 17 LCMS (ESI) calculation value of NO3 [M + H] + m / z 303.16, measured value 303.10.

[0878] Preparation of 4-(3-ethynylcyclobutyl)piperazine-1-carboxylic acid benzyl ester (1406)

[0879] To a solution of 4-(3-formylcyclobutyl)piperazine-1-carboxylate 1404 (1.4 g, 4.64 mmol) in MeOH (30 mL), dimethyl 1-diazo-2-oxopropyl)phosphonate 1405 (2.8 g, 14.58 mmol) and K₂CO₃ (2.0 g, 14.49 mol) were successively added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 96:4) to provide 4-(3-ethynylcyclobutyl)piperazine-1-carboxylate 1406 (800 mg, 57% yield) as a yellow oil.

[0880] C 18 H 22 LCMS (ESI) values ​​of N₂O₂ [M + H] + m / z 299.17, measured value 299.10.

[0881] 4-(3-(8-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazine-1-carboxylic acid benzyl ester Preparation of (1408)

[0882] 4-ethynyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid benzyl ester 1406 (800 mg, 2.68 mol), AcOCs (1 g, 5.21 mol), and [Rh(Cp] were successively added to a solution of 4-(3-ethynylcyclobutyl)piperazine-1-carboxylic acid benzyl ester 1406 (800 mg, 2.68 mol) in MeOH (35 mL). [Cl2]2 (150 mg, 0.24 mol). The reaction mixture was stirred at 45 °C for 18 h. The reaction solution was concentrated under reduced pressure and the residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 96:4) to provide 4-(3-(8-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazine-1-carboxylic acid benzyl ester 1408 (200 mg, 15% yield) as a yellow solid.

[0883] C 25 H 25 LCMS (ESI) calculated values ​​of FClN3O3 [M + H] + m / z 470.16, measured value 470.15.

[0884] Preparation of 7-fluoro-3-(3-(piperazin-1-yl)cyclobutyl)isoquinoline-1(2H)-one (1409)

[0885] Pd / C (50 mg, 0.47 mmol) was added to a solution of 4-(3-(8-chloro-7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazine-1-carboxylate 1408 (200 mg, 0.43 mol) in IPA (30 mL). The reaction mixture was stirred at 70 °C for 18 h under H2. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to provide 7-fluoro-3-(3-(piperazine-1-yl)cyclobutyl)isoquinoline-1(2H)-one 1409 (100 mg, 77% yield) as a yellow solid.

[0886] C 17 H 20 LCMS (ESI) values ​​of FN3O [M + H] + m / z 302.16, measured value 302.10.

[0887] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazin-1-yl)pyridinecarboxylic acid Preparation of ester (1411)

[0888] Methyl 5-fluoropyridinecarboxylate 1410 (100 g, 0.64 mmol) and DIEA (2.5 mL) were added sequentially to a solution of 7-fluoro-3-(3-(piperazin-1-yl)cyclobutyl)isoquinoline-1(2H)-one 1409 (100 mg, 0.33 mol) in DMSO (10 mL). The reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 94:6) to provide methyl 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazin-1-yl)pyridinecarboxylate 1411 (70 mg, 48% yield) as a yellow solid.

[0889] C 24 H 25 LCMS (ESI) values ​​of FN4O3 [M + H] + m / z 437.19, measured value 437.10.

[0890] 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazin-1-yl)-N-methylpyridine Preparation of amides (26 cis / trans mixture)

[0891] Methyl 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazin-1-yl)pyridinecarboxylate 1411 (70 mg, 0.16 mmol) was added partically to a MeOH solution of MeNH2 (30-33% by weight, 10 mL). The reaction mixture was stirred in a sealed test tube at 100 °C for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); gradient: 30-85) to produce a mixture of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazin-1-yl)-N-methylpyridineamide 26 cis / trans (25 mg, 35% yield) as a white solid.

[0892] C 24 H 26 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 436.21, measured value 436.15.

[0893] 5-(4-((1s,3s)-3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazin-1-yl)-N- Methylpyridineamide (26 cis) and 5-(4-((1r,3r)-3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutane Preparation of (26-trans)piperazine-1-yl)-N-methylpyridine amide

[0894] A mixture of 26 cis / trans 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)cyclobutyl)piperazin-1-yl)-N-methylpyridineamide 26 (25 mg, 0.05 mmol) was passed through an SFC column (DAICEL OJ-H 4.6 mm column). 250 mmL 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M MeOH solution)] = 65 / 35) separated and concentrated under reduced pressure to provide 26 cis (12 mg, 99% purity, white solid) as the first fraction and 26 trans (0.9 mg, 97% purity, white solid) as the second fraction.

[0895] 26-way sequence

[0896] 1 H NMR (400 MHz, DMSO) δ 11.50 (s, 1 H), 8.39 (q, J =4.4 Hz, 1 H), 8.31-8.25 (m, 1 H), 7.88-7.80 (m, 1 H), 7.79-7.67 (m, 2 H), 7.60-7.50 (m, 1H), 7.45-7.37 (m, 1 H), 6.47 (s, 1 H), 3.38-3.32 (m, 4 H), 3.11-3.00 (m, 1H), 2.83-2.72 (m, 4 H), 2.48-2.44 (m, 6 H), 2.00-1.88 (m, 2 H).

[0897] Based on NOE experimental designation of cis-stereochemistry.

[0898] C 24 H 26 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 436.21, measured value 436.15.

[0899] 26 trans

[0900] 1 H NMR (400 MHz, DMSO) δ 11.64 (s, 1 H), 8.40 (q, J =4.8 Hz, 1 H),8.31-8.25 (s, 1 H), 7.96 (d, J=8.0 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.59-7.49 (m, 1 H), 7.46-7.38 (m, 2 H), 6.38 (s, 1 H), 3.38-3.34 (m, 4 H), 3.15-3.07 (m, 1 H), 2.83-2.74 (m, 4 H), 2.56-2.54 (m, 2 H), 2.49-2.47 (m, 4 H), 2.02-1.93 (m, 2 H).

[0901] Based on NOE experimental designation of trans stereochemistry.

[0902] C 24 H 26 LCMS (ESI) values ​​of FN5O2 [M + H] + m / z 436.21, measured value 436.15.

[0903] Example 6: Synthesis of 31cis-a, 31cis-b, 31trans-a, and 31trans-b

[0904]

[0905] Option 6

[0906] Preparation of 3-chloro-7-fluoro-1-methoxyisoquinoline (1502)

[0907] MeONa (5.5 g, 101.86 mmol) was added to a solution of 1,3-dichloro-7-fluoroisoquinoline 1501 (20 g, 92.60 mmol) in MeOH (300 mL). The mixture was stirred at 60 °C for 4 h. The mixture was quenched with water and extracted with EtOAc (300 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (PE / EtOAc = 100:0 to 90:10) to provide 3-chloro-7-fluoro-1-methoxyisoquinoline 1502 (14 g, 90% purity, 64% yield) as a white solid.

[0908] C 10 LCMS (ESI) values ​​of H7ClFNO [M + H] + m / z 212.02, measured value 211.90.

[0909] Preparation of 7-fluoro-1-methoxy-3-vinylisoquinoline (1504)

[0910] Tributyl(vinyl)stanane 1503 (31.5 g, 99.30 mmol) and Pd(amphos)Cl2 (4.7 g, 6.62 mmol) were added to a solution of 3-chloro-7-fluoro-1-methoxyisoquinoline 1502 (14 g, 66.20 mmol) in ACN (200 mL). The reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 70:30) to provide 7-fluoro-1-methoxy-3-vinylisoquinoline 1504 (9 g, 90% purity, 60% yield) as a white solid.

[0911] C 12 H 10 LCMS (ESI) calculation value of FNO [M + H] + m / z 204.07, measured value 204.00.

[0912] Preparation of 7-fluoro-1-methoxyisoquinoline-3-carboxaldehyde (1505)

[0913] To a solution of 7-fluoro-1-methoxy-3-vinylisoquinoline 1504 (9 g, 44.30 mmol) in dioxane / H2O (200 mL, 2:1), K2OsO4·2H2O (820 mg, 2.22 mmol) and NaIO4 (38 g, 177.20 mmol) were added. The reaction mixture was stirred at room temperature for 6 h. The mixture was filtered through a diatomaceous earth mat and the filtrate was diluted with water. The aqueous layer was extracted with EtOAc (300 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to provide 7-fluoro-1-methoxyisoquinoline-3-carboxaldehyde 1505 (3.5 g, 90% purity, 34% yield) as a white solid.

[0914] C 11 The calculated LCMS (ESI) value of H8FNO2 is [M + H] + m / z 206.05, and the measured value is 206.00.

[0915] 1 - (7 -fluorine- 1 -Methoxyisoquinoline- 3 -base ) Man- 3 -ene- 1 -alcohol Preparation of (1507)

[0916] Under a nitrogen atmosphere at 0 °C, allyl magnesium bromide 1506 (34.2 mL, 34.2 mmol, 1 M THF solution) was added to a solution of 7-fluoro-1-methoxyisoquinoline-3-carboxaldehyde 1505 (3.5 g, 17.10 mmol) in THF (80 mL). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with aqueous NH4Cl solution and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 40:60) to provide 1-(7-fluoro-1-methoxyisoquinoline-3-yl)but-3-en-1-ol 1507 (2.4 g, 90% purity, 50% yield) as a white solid.

[0917] C 14 H 14 LCMS (ESI) calculation value of FNO2 [M + H] + m / z 248.10, measured value 248.00.

[0918] Preparation of 4-(7-fluoro-1-methoxyisoquinoline-3-yl)butane-1,2,4-triol (1508)

[0919] NMO (11.4 g, 97.0 mmol) and K₂O₅sO₄·2H₂O (180 mg, 0.49 mmol) were added to a solution of 1-(7-fluoro-1-methoxyisoquinoline-3-yl)but-3-en-1-ol 1507 (2.4 g, 9.70 mmol) in THF / H₂O (50 mL, 5:1). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with H₂O and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to provide 4-(7-fluoro-1-methoxyisoquinoline-3-yl)butane-1,2,4-triol 1508 (1.3 g, 90% purity, 43% yield) as a colorless oil.

[0920] C 14 H 16 LCMS (ESI) calculation value of FNO4 [M + H] + m / z 282.11, measured value 282.05.

[0921] Preparation of 5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydrofuran-3-ol (1509)

[0922] CMBP (2.2 g, 9.20 mmol) was added to a solution of 4-(7-fluoro-1-methoxyisoquinoline-3-yl)butane-1,2,4-triol 1508 (1.3 g, 4.60 mmol) in toluene (15 mL). The reaction mixture was stirred in a sealed tube at 100 °C for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 20:80) to provide 5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydrofuran-3-ol 1509 (750 mg, 90% purity, 56% yield) as a yellow solid.

[0923] C 14 H 14 LCMS (ESI) calculation value of FNO3 [M + H] + m / z 264.10, measured value 264.10.

[0924] Preparation of 5-(7-fluoro-1-methoxyisoquinolin-3-yl)dihydrofuran-3(2H)-one (1510)

[0925] Add Desmond-Martin periodide (3.6 g, 8.55 mmol) to a solution of 5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydrofuran-3-ol 1509 (750 mg, 2.85 mmol) in DCM (25 mL) at room temperature. Stir the reaction mixture at room temperature for 6 h. Quench the reaction mixture with aqueous NaHCO3 solution and extract the aqueous layer with DCM (50 mL × 3). Concentrate the combined organic layers under reduced pressure. Purify the residue by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to provide 5-(7-fluoro-1-methoxyisoquinoline-3-yl)dihydrofuran-3(2H)-one 1510 (520 mg, 90% purity, 62% yield) as a yellow solid.

[0926] C 14 H 12 LCMS (ESI) calculation value of FNO3 [M + H] + m / z 262.08, measured value 262.05.

[0927] 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N-methylpyridine Preparation of amide (1511)

[0928] To a solution of 5-(7-fluoro-1-methoxyisoquinolin-3-yl)dihydrofuran-3(2H)-one 1510 (520 mg, 1.99 mmol) in MeOH (10 mL), N-methyl-5-(piperazin-1-yl)pyridineamide 1004 (658 mg, 2.99 mmol), AcOH (2 drops), and NaBH3CN (250 mg, 3.98 mmol) were added. The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with EtOAc (30 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to provide 5-(4-(5-(7-fluoro-1-methoxyisoquinolin-3-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N-methylpyridineamide 1511 (480 mg, 90% purity, 46% yield) as a white solid.

[0929] C 25 H 28 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 466.22, measured value 466.11.

[0930] 5-(4-(5-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N- Preparation of methylpyridine amide (compound 31)

[0931] TMSI (619 mg, 3.09 mmol) was added to a solution of 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N-methylpyridineamide 1511 (480 mg, 1.03 mmol) in ACN (15 mL). The reaction mixture was stirred at 50 °C for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to yield compound 31 (a mixture of cis- and trans-isomers). The mixture was separated by preparative HPLC (column: YMC-Actus Triar - C18 150×21.2 mm, 5 μm; mobile phase: ACN - H2O (0.05% NH3); gradient: 30 - 70) to produce 31-trans-rac as a white solid (first fraction, 5.01 mg, 99% purity) and 31-cis-rac as a white solid (second fraction, 38 mg, 95% purity).

[0932] 31-cis-rac was then separated by an SFC (column: Chiralpak-OD-H SFC 30 mm ID × 250 mmL, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M MeOH solution)] = 70 / 30) and concentrated under reduced pressure to provide a first fraction as 31-cis-a (9.2 mg, 99% purity, ee%: 100, white solid) and a second fraction as 31-cis-b (10.6 mg, 95% purity, ee%: 100, white solid).

[0933] 31 trans-rac

[0934] 1 H NMR (400 MHz, DMSO- d 6 ,, ppm) δ: 11.35 (s, 1H), 8.45-8.33 (m, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.81-7.72 (m, 2 H), 7.64-7.51 (m, 1 H), 7.40 (dd, J =8.8, 2.8 Hz, 1 H), 6.58 (s, 1 H), 4.86 (t, J =7.0Hz, 1 H), 4.26-4.15 (m, 1 H), 3.81-3.71 (m, 1 H), 3.37-3.32 (m, 4 H), 3.15-3.02 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.66-2.51 (m, 4 H), 2.37-2.29 (m, 1H), 2.09-1.99 (m, 1 H).

[0935] Based on NOE experimental designation of trans stereochemistry.

[0936] C 24 H 26 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 452.20, measured value 452.35.

[0937] 31 cis-a

[0938] 1H NMR (400 MHz, DMSO- d 6 ,, ppm) δ: 12.12 (s, 1 H), 8.46-8.36 (m, 1 H), 8.31 (d, J =2.8 Hz, 1 H), 7.86 (d, J =8.8 Hz, 1 H), 7.79-7.68 (m, 2 H), 7.67-7.51 (m, 1 H), 7.43 (dd, J =8.8, 2.8 Hz, 1 H), 6.64 (s, 1 H), 4.86-4.79 (m, 1H), 4.27-4.17 (m, 1 H), 3.79-3.71 (m, 1 H), 3.57-3.37 (m, 4 H), 3.07-2.94 (m,1 H), 2.79 (d, J =4.8 Hz, 3 H), 2.76-2.65 (m, 4 H), 2.47-2.44 (m, 1 H), 2.18-2.09 (m, 1 H).

[0939] Based on NOE experimental designation of cis-stereochemistry.

[0940] C 24 H 26 The calculated LCMS (ESI) value of FN5O3 [M + H] + m / z is 452.20, and the measured value is 452.35.

[0941] 31 cis-b

[0942] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 12.13 (s, 1 H), 8.47-8.38 (m, 1 H), 8.31 (d, J =2.8 Hz, 1 H), 7.86 (d, J =8.8 Hz, 1 H), 7.80-7.70 (m, 2 H), 7.62-7.55 (m, 1 H), 7.44 (dd, J=8.8, 2.8 Hz, 1 H), 6.64 (s, 1 H), 4.89-4.77 (m, 1H), 4.29-4.13 (m, 1 H), 3.82-3.69 (m, 1 H), 3.57-3.39 (m, 4 H), 3.06-2.97 (m,1 H), 2.79 (d, J =4.8 Hz, 3 H), 2.76-2.66 (m, 4 H), 2.48-2.46 (m, 1 H), 2.20-2.07 (m, 1 H).

[0943] Based on NOE experimental designation of cis-stereochemistry.

[0944] C 24 H 26 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 452.20, measured value 452.35.

[0945] Example 7: Synthesis of 48cis-a, 48cis-b, 48trans-a, and 48trans-b

[0946]

[0947] Option 7

[0948] Preparation of 5-(7-fluoro-1-methoxyisoquinolin-3-yl)-2H-pyran-3(6H)-one (1603)

[0949] To a solution of 3-chloro-7-fluoro-1-methoxyisoquinoline 1602 (4.7 g, 22.30 mmol) in dioxane / H2O (50 mL, 10:1), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2H-pyran-3(6H)-one 1601 (5 g, 22.30 mmol), RuPhos Pd G3 (1.9 g, 2.23 mmol), and Na2CO3 (7.1 g, 66.90 mmol) were added. The reaction mixture was stirred at 80 °C for 6 h under a N2 atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to provide 5-(7-fluoro-1-methoxyisoquinolin-3-yl)-2H-pyran-3(6H)-one 1603 (580 mg, 90% purity, 8% yield) as a white solid.

[0950] C 15 H 12 LCMS (ESI) calculation value of FNO3 [M + H] +m / z 274.08, measured value 274.00.

[0951] 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)-3,6-dihydro-2H-pyran-3-yl)piperazin-1-yl)- Preparation of N-methylpyridine amide (1604)

[0952] N-methyl-5-(piperazin-1-yl)pyridineamide 1004 (701 mg, 3.18 mmol), NaBH(OAc)3 (900 mg, 4.25 mmol), and NaBH3CN (133 mg, 2.12 mmol) were sequentially added to a solution of 5-(7-fluoro-1-methoxyisoquinolin-3-yl)-2H-pyran-3(6H)-one 1603 (580 mg, 2.12 mmol) in EtOH (25 mL) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and quenched with water, and then concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to provide a mixture of 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)-3,6-dihydro-2H-pyran-3-yl)piperazin-1-yl)-N-methylpyridineamide 1604 (750 mg, 90% purity, 66% yield) and 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydro-2H-pyran-3-yl)piperazin-1-yl)-N-methylpyridineamide 1605 as a white solid.

[0953] C 26 H 28 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 478.22, measured value 478.40.

[0954] 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydro-2H-pyran-3-yl)piperazin-1-yl)-N-methyl Preparation of pyridine amide (1605)

[0955] 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)-3,6-dihydro-2H-pyran-3-yl)piperazin-1-yl)-N-methylpyridinamide 1604 (750 mg, 1.57 mmol) and Pd(OH)2 / C (110 mg, 0.79 mmol) in MeOH (25 mL) were stirred at 50 °C for 16 h under H2 balloon pressure. The mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated to produce 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydro-2H-pyran-3-yl)piperazin-1-yl)-N-methylpyridinamide 1605 (700 mg, 80% purity, 74% yield) as a colorless oil.

[0956] C26 H 30 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 480.23, measured value 480.40.

[0957] 5-(4-(5-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-3-yl)tetrahydro-2H-pyran-3-yl)piperazine-1- Preparation of 48-N-methylpyridine amide (compound 48)

[0958] TMSI (876 mg, 4.38 mmol) was added to a solution of 5-(4-(5-(7-fluoro-1-methoxyisoquinoline-3-yl)tetrahydro-2H-pyran-3-yl)piperazin-1-yl)-N-methylpyridineamide 1605 (700 mg, 1.46 mmol) in ACN (25 mL). The reaction mixture was stirred at 50 °C for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 60:40) and preparative HPLC (column: Gemini - C18150 × 21.2 mm, 5 μm; mobile phase: ACN - H2O (0.1% FA); gradient: 5 - 50) to yield 5-(4-(5-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)tetrahydro-2H-pyran-3-yl)piperazin-1-yl)-N-methylpyridineamide compound 48 (a mixture of cis- and trans-isomers). The mixture was separated by an SFC (column: DAICEL OJ-H SFC 30mm ID × 250 mm, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M MeOH solution)] = 60 / 40) and concentrated under reduced pressure to provide the first fraction as 48-trans-a (17.6 mg, 96% purity, ee%: 100, white solid), the second fraction as 48-cis-a (35.4 mg, 99% purity, ee%: 100, white solid), the third fraction as 48-cis-b (40.7 mg, 99% purity, ee%: 100, white solid) and the fourth fraction as 48-trans-b (16.4 mg, 99% purity, ee%: 100, white solid).

[0959] 48 trans-a

[0960] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.37 (s, 1 H), 8.43-8.36 (m, 1 H), 8.27 (d, J=2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.78 (dd, J =9.6, 2.8 Hz, 1H), 7.75-7.69 (m, 1 H), 7.63-7.53 (m, 1 H), 7.40 (dd, J =8.8, 3.2 Hz, 1 H), 6.55 (s, 1 H), 3.95-3.78 (m, 2 H), 3.75-3.60 (m, 2 H), 3.37-3.32 (m, 4 H), 3.17-3.04 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.73-2.63 (m, 4 H), 2.43-2.35 (m, 1 H), 2.21-2.11 (m, 1 H), 2.09-1.96 (m, 1 H).

[0961] Based on NOE experimental designation of trans stereochemistry.

[0962] C 25 H 28 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 466.22, measured value 466.35.

[0963] 48 trans-b

[0964] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.38 (s, 1 H), 8.46-8.36 (m, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.78 (dd, J =9.6, 2.8 Hz, 1H), 7.75-7.67 (m, 1 H), 7.61-7.53 (m, 1 H), 7.40 (dd, J=8.8, 2.8 Hz, 1 H), 6.55 (s, 1 H), 3.94-3.78 (m, 2 H), 3.75-3.62 (m, 2 H), 3.36-3.33 (m, 4 H), 3.15-3.05 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.74-2.62 (m, 4 H), 2.42-2.34 (m, 1H), 2.22-2.08 (m, 1 H), 2.08-1.95 (m, 1 H).

[0965] Based on NOE experimental designation of trans stereochemistry.

[0966] C 25 H 28 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 466.22, measured value 466.30.

[0967] 48 cis-a

[0968] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.47 (s, 1 H), 8.43-8.34 (m, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.78 (dd, J =9.6, 2.8 Hz, 1H), 7.73-7.65 (m, 1 H), 7.63-7.53 (m, 1 H), 7.40 (dd, J =8.8, 2.8 Hz, 1 H),6.52 (s, 1 H), 4.06-3.94 (m, 2 H), 3.32-3.25 (m, 6 H), 2.87-2.80 (m, 1 H),2.78 (d, J =4.8 Hz, 3 H), 2.76-2.66 (m, 4 H), 2.63-2.54 (m, 1 H), 2.29-2.16 (m, 1 H), 1.86-1.70 (m, 1 H).

[0969] Based on NOE experimental designation of cis-stereochemistry.

[0970] C 25 H 28 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 466.22, measured value 466.35.

[0971] 48 cis-b

[0972] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.48 (s, 1 H), 8.44-8.35 (m, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.78 (dd, J =9.2, 2.8 Hz, 1H), 7.73-7.66 (m, 1 H), 7.63-7.51 (m, 1 H), 7.40 (dd, J =8.8, 2.8 Hz, 1 H),6.52 (s, 1 H), 4.06-3.94 (m, 2 H), 3.33-3.24 (m, 6 H), 2.87-2.80 (m, 1 H),2.78 (d, J =4.8 Hz, 3 H), 2.76-2.65 (m, 4 H), 2.62-2.54 (m, 1 H), 2.29-2.18 (m, 1 H), 1.85-1.71 (m, 1 H).

[0973] Based on NOE experimental designation of cis-stereochemistry.

[0974] C 25 H 28 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 466.22, measured value 466.35.

[0975] Example 8: Measurement

[0976] Exemplary compounds of the present invention were prepared and tested to determine their efficacy as inhibitors of PARP1 and PARP2. Typical assays are described below.

[0977] Example 8A. PARP1 biodissociation-enhanced fluorescence immunoassay of lanthanides (DELFIA assay)

[0978] Optiplate HB 384-well plates were coated overnight at 4°C with anti-FLAG antibody (supplying as a 4 mg / ml solution) using Na2CO3 / HCO3 coating buffer at pH 9.6 to achieve final immobilization of 0.3 μg per well. The wells were then washed 3 x 5 min in coating wash buffer (PBS / 0.05% Tween (v / v)) and blocked overnight at 4°C with 2% BSA (w / v) in coating wash buffer. Before assay, the wells were washed 3 x 5 min in coating wash buffer. For the assay, 20 μl of 2.5 nM recombinant full-length human N-terminal FLAG-labeled PARP1 was added to each well of the 384-well plate and incubated at room temperature for 30 min, followed by the addition of 50 nL of the compound solution in DMSO using the pintool technique. After incubation at room temperature for 30 min, 5 μl of 10 μM biotin-NAD was added. + 10 nM activated DNA (sequence shown below) was added to a solution in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v) assay buffer. Self-PARation was performed at room temperature for 2 h, followed by the addition of 5 μl of 12 mM NAD. + Quenching solution. After 30 min at room temperature, remove the assay solution and wash five times for 3 min each, then add 100 μl of a 1:1000 dilution of DELFIA Eu-N1 streptavidin reagent. Incubate the plate at room temperature for 30 min. Remove the reaction mixture and wash the plate five times for 3 min each, then add 25 μl of DELFIA enhancement solution. After 30 min at room temperature, measure fluorescence on a Pherastar FS (Ex 337 nm, Em 620 nm; integration start 60 μs; integration time 400 μs).

[0979] Typically, compounds are tested starting at 20 μM with 3-fold dilution intervals in a 12-point concentration-response curve to determine the IC50. 50 Values. Data were analyzed using ActivityBase software, and the average values ​​of replicates for low (enzyme-free, 0.2% DMSO) and high (0.2% DMSO)% controls were taken. Data obtained from the test compounds were expressed as a percentage of 100% using the following formula:

[0980] % value = 100 - (100) ((High control - Unknown) / (High control - Low control))

[0981] The percentage data were fitted to a nonlinear regression equation (log inhibitor relative to the slope of the response variable, 4 parameters) to obtain the IC. 50 value.

[0982] IC50 of various test compounds 50 The values ​​are shown in Table 1.

[0983] Activated DNA sequence:

[0984]

[0985] Example 8B. Homogeneous Time-Resolved Fluorescence Assay (HTRF) with PARP1 Probe Replacement

[0986] A 10 nM full-length N-terminal FLAG-labeled PARP1 was bound to a 2 nM anti-FLAG Tb-caecilin antibody and a PARP1 / 2Cy5 fluorescent dye-labeled binding probe (10-fold probe K). d The Cy5-labeled binding probe (270 nM) was incubated together with 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v) assay buffer at room temperature for 40 min. The Cy5-labeled binding probe is shown below and described in Papeo, G. et al. J . Biomol . Screen . 2014; 19:1212-1219. Six μl of the reaction mixture was then transferred to each well of a black, unbound surface 384-well plate, and 35 nl of the compound solution in DMSO was added using a pintool technique. After incubation at room temperature for 1 h, fluorescence was measured using an HTRF module on a Pherastar FS (Ex 337 nm, Em 620 nm, em 665 nm; integration start 60 μs; integration time 400 μs).

[0987] Typically, compounds are tested at 58.5 μM with 3-fold dilution intervals in a 12-point concentration-response curve to determine the IC50. 50 Values. Data were analyzed using ActivityBase software, and the average values ​​of replicates for low (enzyme-free but containing probe and Tb-caecin antibody, 0.6% DMSO) and high (0.6% DMSO)% controls were averaged. Data obtained from the test compound were expressed as a 100% percentage using the following formula:

[0988] %activity=100 (Value - Low Control) / (High Control - Low Control)

[0989] The % activity data were fitted to a nonlinear regression equation to obtain the IC50 value.

[0990] Calculate K using the Cheng-Prussoff formula. d value:

[0991] IC 50 =(1+ ([probe concentration] / [Km)) 探针 ])) K d

[0992] Therefore, K d =IC 50 / (1+[[probe concentration] / [Km]) 探针 Using 10 x K m The probe, which is equivalent to K d =IC 50 / 11

[0993] Example 8C. Homogeneous Time-Resolved Fluorescence Assay (HTRF) with PARP2 Probe Replacement

[0994] The assay was performed under the same conditions as PARP1, except that N-terminal FLAG-labeled PARP2 (amino acids 1-583) was used instead of PARP1, and the probe K was 10-fold stronger. d =540 nM using PARP1 / 2 binding probes. Data analysis was performed in the same manner as with PARP1.

[0995] Cy5 probe structure:

[0996]

[0997] NanoBRET Cell Target Occupation Assay

[0998] NanoBRET assays were used to demonstrate cellular target engagement and selectivity at PARP1 and PARP2. These assays are based on the interaction of nano-luc-tagged proteins (e.g., PARP1 or PARP2) with high-affinity NAD+. + Bioluminescent resonance energy transfer (BRET) between fluorescent groups on competitively binding probes. Such cell probe displacement assays can be used to measure the ratio of inhibitor affinity and selectivity at PARP1 and 2.

[0999] Frozen HEK293 cells transiently transfected with the PARP1-NanoLuc® fusion or the PARP2-NanoLuc® fusion construct (Promega) were thawed and separately distributed as suspensions in 384-well microplates at a density of 1750 cells per well. NanoBRET was then added. TMTE PARP Tracer-01 was used to determine final concentrations of 11 and 2 nM for PARP1 and PARP2, respectively. Compounds were added in 3-fold dilution intervals starting at 25 μM in a 12-point concentration-response curve, and the plate was incubated at 37°C for 2 hours. NanoBRET was then added according to the manufacturer's instructions. TM Following Nano-Glo® substrate and extracellular NanoLuc® inhibitor, the BRET ratio was measured using a NanoBRET module (LUM 610-LP 450-80) and a Pherastar FS or FSX reader. The Kd value was calculated using the Cheng-Prussoff formula:

[1000] IC50 = (1 + ([tracer concentration] / [Km])) 示踪剂 ])) Kd

[1001] Table 1 shows the binned power, affinity, and selectivity data for various test compounds, using DELFIA and probe-alternative HTRF assays. Table 1 also shows the binned power, affinity, and selectivity data for subsets of test compounds, using NanoBRET assays.

[1002] Table 1

[1003] Results of Parp 1 / 2 assays for selected compounds (DELFIA and probe-replaced HTRF)

[1004]

[1005]

[1006]

[1007]

[1008]

[1009] Table 2

[1010] Results of Parp 1 / 2 determination for selected compounds (NanoBRET)

[1011]

[1012] Symbol explanation:

[1013] Classification of DELFIA, probe-replacement HTRF, and NanoBRET assays:

[1014] - Indicates ICs with a value higher than 10 μM 50 or K d value

[1015] + Indicates ICs with values ​​from 1 μM up to 10 μM. 50 or K d value

[1016] ++ indicates ICs with a range from 100 nM to 1 μM. 50 or K d value

[1017] +++ indicates ICs with speeds up to 10 nM up to 100 nM. 50 or K d value

[1018] ++++Indicates ICs of 10 nM or lower 50 or K d value

[1019] Selective classification:

[1020] - Indicates a value less than 10

[1021] + Indicates a value from 10 to less than 50.

[1022] ++ indicates a value from 50 to less than 100.

[1023] +++ indicates a value of at least 100.

[1024] NT: Not tested

[1025] The selectivity values ​​are related to the selectivity preference of PARP1 relative to PARP2. They are determined by the K-suppression of PARP1 and PARP2. d Value ratio K d (PARP2) / K d (PARP1) calculation.

[1026] It should be understood that the above implementation plan is described only by way of example.

[1027] Once the disclosure herein is given, other variations or applications of the disclosed technology will become apparent to those skilled in the art. The scope of this disclosure is not limited to the described embodiments, but only to the appended claims.

Claims

1. A PARP1 inhibitor compound having the following structure: in: Dashed lines represent bonds selected from single and double bonds; y is 0, 1, or 2; Ring D is either an aromatic or non-aromatic genus; Each X D Independently selected from C, O, and N; the prerequisite is: No more than one X D It is O; and When X D When it is O or N, ring D is non-aromatic; Each R 1 It either does not exist independently, or it exists and is selected from H and substituted or unsubstituted organic groups; Each R 4 It does not exist independently or is selected from: H； halogen; C(R 9 ) i , where i is an integer in the range of 1 to 3; OR 9 ; and S(R 9 ) j , where j is an integer in the range of 1 to 5; Each R 9 Independently selected from H and substituted or unsubstituted organic groups; R 2 and R 3 Each is independently selected from H and substituted or unsubstituted organic groups; and L is a group having the following structure: in: X 1 X 3 X 4 and X 5 Each is independently selected from C and N; Each X 2 Independently selected from C, N, O, and S; n is 0, 1, 2, 3, 4 or 5; m can be 0, 1, 2, 3, 4 or 5, provided that n + m is in the range of 1 to 5; p is 1, 2, or 3; q is 1, 2, or 3, provided that p + q is in the range of 2 to 5; r is 0, 1, 2, 3, 4 or 5; s can be 0, 1, 2, 3, 4 or 5, provided that r + s is in the range of 2 to 5; Each R 5A R 5B and R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups; R 6 It does not contain or is selected from H and substituted or unsubstituted organic groups; and Q 1 and Q 2 Each is independently a bond or a linking group having a structure selected from the following: in: t is 0, 1, 2, 3, 4, or 5; u can be 0, 1, 2, 3, 4, or 5, provided that t + u is within the range of 0 to 6; and Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

2. The PARP1 inhibitor compound according to claim 1, wherein each R 1 and each R 4 It does not exist independently or is selected from: H； halogen; Nitrile group; C1 to C6 alkyl groups, such as C3 to C6 cycloalkyl groups; C1 to C6 alkoxy groups; C1 to C6 haloalkoxy groups, such as -OCF3 or OCHF2; Halogenated alkyl groups; and ， R 22 Selected from H, halogens, C1 to C6 alkyl groups, C3 to C6 cycloalkyl groups, C1 to C6 alkoxy groups, and C1 to C6 haloalkyl groups, and Each R 23 Independently selected from H, halogens, C1 to C6 straight-chain or branched alkyl groups, C1 to C6 straight-chain or branched aminoalkyl groups, C1 to C6 alkoxy groups, C1 to C6 haloalkoxy groups, such as -OCF3 or OCHF2; and C1 to C6 haloalkyl groups.

3. The PARP1 inhibitor compound according to claim 2, wherein each R 1 and each R 4 The following are not present independently or are selected from H; halogens, optionally Cl or F; C1 to C3 alkyl groups, optionally methyl groups; C1 to C3 haloalkyl groups, optionally halomethyl groups such as -CH2F, -CHF2 or -CF3; haloethyl groups, such as -CH2CF3; and nitrile groups.

4. The PARP1 inhibitor compound according to claim 3, wherein each R 1 and each R 4 It is either absent independently or selected from: H; Cl; F; halomethyl groups, such as CF3; and nitrile groups.

5. The PARP1 inhibitor compound according to claim 4, wherein each R 1 and each R 4 It does not exist independently or is selected from H and F; Optionally, each of R 4 It's H.

6. The PARP1 inhibitor compound according to claim 5, wherein exactly one R 1 Or exactly one R 4 It is F.

7. The PARP1 inhibitor compound according to any of the preceding claims, wherein y is 1.

8. The PARP1 inhibitor compound according to any of the preceding claims, wherein each X D It's C.

9. The PARP1 inhibitor compound according to claim 8, having the following structure: Choose any .

10. The PARP1 inhibitor compound according to claim 9, having the following structure: or .

11. The PARP1 inhibitor compound according to claim 9, having a structure selected from the following:

12. The PARP1 inhibitor compound according to any one of claims 1 to 8, wherein ring D is non-aromatic.

13. The PARP1 inhibitor compound according to claim 12, having a structure selected from the following: Each R 1 and each R 4 exist; Optionally, the compound described herein has the following structure: 。 14. The PARP1 inhibitor compound according to claim 12, having a structure selected from the following: And preferably has the following structure: or .

15. The PARP1 inhibitor compound according to claim 14, having the following structure: or .

16. The PARP1 inhibitor compound according to claim 12, having a structure selected from the following: And preferably has the following structure: 。 17. The PARP1 inhibitor compound according to claim 16, having a structure selected from the following:

18. The PARP1 inhibitor compound according to any of the preceding claims, wherein R 2 Selected from H; halogen, optionally F or Cl; C1 to C3 alkyl group, optionally isopropyl or cyclopropyl; C1 to C3 haloalkyl group, optionally -CH2F, -CHF2, -CF3, -CH2CF3 or -CH2CH2F; C1 to C3 alcohol group, optionally -CH2CH2OH; C1 to C3 alkoxy group, optionally methoxy, methoxymethyl or methoxyethyl; and C1 to C3 aminoalkyl group.

19. The PARP1 inhibitor compound according to claim 18, wherein R 2 It's H.

20. The PARP1 inhibitor compound according to any of the preceding claims, wherein R 3 It is selected from H, C1 to C3 alkyl groups and C1 to C3 haloalkyl groups.

21. The PARP1 inhibitor compound of claim 20, wherein R 3 It's H.

22. The PARP1 inhibitor compound according to any of the preceding claims, having a structure selected from:

23. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein ring A is a non-aromatic ring.

24. The PARP1 inhibitor compound according to claim 23, wherein ring A is a saturated ring.

25. The PARP1 inhibitor compound according to any of the preceding claims, wherein, when present, each R 5A Independently selected from H; halogen, optionally F; hydroxyl group; carbonyl group; and C1 to C3 alkyl group, optionally one of a pair of R 5A The group forms a ring, and optionally the ring bridges ring A; Preferably, each R 5A It's H.

26. The PARP1 inhibitor compound according to any of the preceding claims, wherein n + m is in the range of 2 to 5, optionally 2 to 4; and / or wherein both n and m are at least 1.

27. The PARP1 inhibitor compound according to claim 26, wherein: i) Ring A is a 7-membered ring, optionally having a cycloheptane structure selected from the following: and Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The most preferred option is H; or ii) Ring A is a 6-membered non-aromatic ring, optionally cyclohexane, cyclohexene, or tetrahydropyran, and further optionally has a structure selected from the following: Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The most preferred option is H; or iii) Ring A is a 5-membered non-aromatic ring, optionally cyclopentane, cyclopentene, or tetrahydrofuran, and further optionally has a structure selected from the following: Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The most preferred option is H; or iv) Ring A is a 4-membered ring with the following structure: ； Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The most preferred option is H; or v) Ring A is a bridge ring, optionally having a structure selected from the following: Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The preferred option is H.

28. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein ring A has the following structure: in: n is 1, 2, or 3; m is 0, 1, or 2; X 1 It is C or N; Each X 2 Independently selected from C and O; and Each R 5A1 R 5A2 and R 5A3 It does not exist independently or is selected from H and substituted or unsubstituted organic groups; The prerequisite is: When X 1 When it is N, R 5A1 It does not exist; and When the corresponding X 2 When it is O, R 5A2 It does not exist.

29. The PARP1 inhibitor compound according to claim 28, wherein ring A has the following structure: in: m is 1 or 2; n is 1 or 2; and Preferably, R 5A3 It's H.

30. The PARP1 inhibitor compound according to claim 28 or claim 29, wherein: R 5A1 Does not exist, is H, or is with R 5A2 Group or R 5A3 Together they form -CH2- or -CH2CH2- groups; Each R 5A2 It does not exist independently, is an H, an oxo group, or is associated with R. 5A1 R 5A3 Or another R 5A2 Together they form -CH2- or -CH2CH2- groups; R 5A3 Is it H or R? 5A1 or R 5A2 The groups together form -CH2- or -CH2CH2- groups.

31. The PARP1 inhibitor compound according to claim 28 or claim 29, wherein: Exactly two were selected from R 5A1 R 5A2 and R 5A3 The groups together represent a phenyl group fused with ring A; and R 5A1 R 5A2 and R 5A3 Each of the other groups in the group is independent of the others, and is either an H or an oxo group.

32. The PARP1 inhibitor compound according to claim 28 or claim 29, wherein each R 5A2 It does not exist independently, or it is H.

33. The PARP1 inhibitor compound according to claim 28, wherein ring A is tetrahydrofuran or tetrahydropyran.

34. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring A has a structure selected from: Optionally, ring A has a structure selected from the following: A1, A3 to A8 and A15 to A42.

35. The PARP1 inhibitor compound according to claim 34, wherein ring A has a structure selected from:

36. The PARP1 inhibitor compound according to claim 35, wherein: Q 1 The bond A is a ring A having a structure selected from the following: A1, A3, A4, A5, A6, A12, A13, and A14; or Ring A is selected from A1, A2, A3, A5, A7, A8, A10, A11, A15, and A16.

37. The PARP1 inhibitor compound according to claim 36, wherein ring A has the following structure: 。 38. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring A is a 3- or 4-membered ring, and wherein Q... 1 It is -CH2-; Where ring A is chosen by choice: 。 39. The PARP1 inhibitor compound according to any one of claims 1 to 36, wherein Q 1 It is a key.

40. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein ring B is a saturated heterocycle.

41. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring B has the following structure: Choose any .

42. The PARP1 inhibitor compound according to any of the preceding claims, wherein X 3 It is N.

43. The PARP1 inhibitor compound according to claim 41 or claim 42, wherein ring B has a structure selected from:

44. The PARP1 inhibitor compound according to any of the preceding claims, wherein each R 5B It does not exist independently, or it is H.

45. The PARP1 inhibitor compound according to claim 43, wherein ring B has a structure selected from:

46. ​​The PARP1 inhibitor compound according to claim 45, wherein ring B has the following structure: 。 47. The PARP1 inhibitor compound according to claim 45, wherein ring B has the following structure: And Q 2 Yes -O-.

48. The PARP1 inhibitor compound for the said use according to claim 41, wherein: i) Ring B is an azacyclic heptane, optionally having the following structure: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H; or ii) Ring B is piperidine, optionally having the following structure: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H; or iii) Cycle B is a pyrrolidine, optionally having the following structure: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It's H.

49. The PARP1 inhibitor compound according to claim 41, wherein ring B has the following structure: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It's H.

50. The PARP1 inhibitor compound according to any of the preceding claims, wherein Q 1 and Q 2 At least one of them is a linking group selected from the following: Where t + u is at least 1; and Where R 7 Selected from H; halogens, such as -F, -Cl, -Br and -I, and preferably -F; -OH groups; C1 to C6 alkyl groups; C1 to C6 haloalkyl groups, preferably CF3; -NH2 groups; C1 to C6 amino groups; C1 to C6 alcohol groups; and C1 to C6 alkoxy groups.

51. The PARP1 inhibitor compound according to claim 50, wherein R 7 Selected from: H; halogen, optionally F; C1 to C6 alkyl group; and C1 to C6 haloalkyl group.

52. The PARP1 inhibitor compound according to any of the preceding claims, wherein Q 1 and Q 2 At least one of them has the following structure: And R 8 Selected from: H； Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl); Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph); Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); Substituted or unsubstituted cyclic amine or amide groups (such as pyrrolidine-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolyl, 3-keto-pyrrolyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl); Substituted or unsubstituted cyclic C3-C8 alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); Substituted or unsubstituted straight-chain or branched C2-C6 alcohol groups (Such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH (CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH and -CH2CH2CH2CH2CH2CH2OH); Substituted or unsubstituted straight-chain or branched C2-C6 carboxylic acid groups (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH); Substituted or unsubstituted straight-chain or branched carbonyl groups (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl; -(CO)N H2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholino-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe and -(CO)NHCH2CH2NMe2); Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe and -CH2CH2CH2CH2COOMe); Substituted or unsubstituted straight-chain or branched C1-C6 amide groups (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt); Substituted or unsubstituted sulfonyl groups (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholino-N-yl, -SO2NHCH2OMe and -SO2NHCH2CH2OMe); Substituted or unsubstituted aromatic groups (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2-Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)- Pr2-Ph-、2,(3,4,5 or 6)-Bu2-Ph-、2,(3,4,5 or 6)-(CN)2-Ph-、2,(3,4,5 or 6)-(NO2)2-Ph-、2,(3,4,5 or 6)-(NH2)2-Ph-、2,(3,4,5 or 6)-(MeO)2-Ph-、2,(3,4,5 or 6)-(CF3)2-Ph-、3,(4 or 5)-F2-Ph-、3,(4 or 5)-Cl2-Ph-、3,(4 or 5)-Br2-Ph-、3,(4 or 5)-I2-Ph-、3,(4 or 5)-Me2-Ph-、3,(4 or 5)-Et2-Ph-、3, (4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN) -Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, and Substituted or unsubstituted heterocyclic groups (such as pyrrolo-2-yl, pyrrolo-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-Triazol-5-yl, Pyridin-2-yl, Pyridin-3-yl, Pyridin-4-yl, Pyridazin-3-yl, Pyridazin-4-yl, Pyriminin-2-yl, Pyriminin-4-yl, Pyriminin-5-yl, Pyriminin-6-yl, Pyrazin-2-yl, Pyrrolidine-2-yl, Pyrrolidine-3-yl, Piperidin-2-yl, Piperidin-3-yl, Piperidin-4-yl, 2-azapiperidin-3-yl -yl, 2-azapiperidin-4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran Azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran- 3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxacyclobutane-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, thiophen-2-yl, thiophen-3-yl Isothiazol-3-yl, Isothiazol-4-yl, Isothiazol-5-yl, Thiazol-2-yl, Thiazol-4-yl, Thiazol-5-yl, Thian-2-yl, Thian-3-yl, Thian-4-yl, 2-azathiaran-3-yl, 2-azathiaran-4-yl, 2-azathiaran-5-yl, 2-azathiaran-6-yl, 3-azathiaran-2-yl, 3- Azathiaran-4-yl, 3-azathiaran-5-yl, 3-azathiaran-6-yl, 4-azathiaran-2-yl, 4-azathiaran-3-yl, 4-azathiaran-5-yl, 4-azathiaran-6-yl, thiacyclopentan-2-yl, thiacyclopentan-3-yl, thiacyclohexane-2-yl, thiacyclohexane-3-yl, thiacyclohexane-4-yl Oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazon-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-5-yl.

53. The PARP1 inhibitor compound according to claim 52, wherein R 8 It is selected from H, substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups and substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups.

54. The PARP1 inhibitor compound according to any of the preceding claims, wherein Q 2 It is a bond or -CH2-. Preferably, where Q 2 It is a key.

55. The PARP1 inhibitor compound according to any of the preceding claims, wherein X 3 It is C and X 4 It's C.

56. The PARP1 inhibitor compound according to any of the preceding claims, wherein both r and s are at least 1. Optionally, the sum of r and s is 3 or 4.

57. The PARP1 inhibitor compound according to claim 56, wherein: i) Ring C is a 6-membered aliphatic ring, and any 6-membered aliphatic ring with the following structure can be selected: or Each R 5C and R 5C1 Independently selected from H and substituted or unsubstituted organic groups, preferably wherein R 5C1 It is H, more preferably R. 5C1 and each R 5C It is H; or ii) Ring C is a 6-membered aromatic ring, arbitrarily selected from: iia)phenyl group, optionally having the following structure: or Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; iib)pyridine group, optionally having a structure selected from the following: , , , and , Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; (iic) diazine group, optionally having a structure selected from the following: , , , , , and , Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; or iii) Ring C is a 5-membered aromatic ring, arbitrarily selected from: iiia) An imidazole group, optionally having an imidazole group having a structure selected from the following: and , Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; iiib) A thiophene group, optionally having a structure selected from the following: , and , Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; (iiic)thiazole group, optionally having a structure selected from the following: , , and , Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; iiid) Triazoles, optionally triazoles having the following structures: or , R 5C Selected from H and substituted or unsubstituted organic groups, optionally wherein R 5C It is H.

58. The PARP1 inhibitor compound according to any of the preceding claims, wherein, when present, each R 5C It is an H or an organic group, said organic group being selected from halogens, preferably F; a C1 to C3 alkyl group, optionally a cyclopropyl group; a C1 to C3 haloalkyl group, optionally a fluoromethyl group such as CF2H or CF3; a C1 to C3 alkoxy group; and a nitrile group; Optionally, where each R, when present, 5C It is an H or an organic group, the organic group being selected from halogens, preferably F; C1 to C3 alkyl groups; C1 to C3 haloalkyl groups, optionally fluoromethyl groups such as CF2H or CF3; and nitrile groups.

59. The PARP1 inhibitor compound of claim 58, wherein exactly one R 5C It is an organic group.

60. The PARP1 inhibitor compound according to claim 59, wherein the organic group is F.

61. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring C has the following structure: in: Each X C The atoms are selected from C and N, provided that there are at least two X atoms. C The atom is C; When X C When it is N, the corresponding R 5C It does not exist; When X C When it is C, the corresponding R 5C It is H or a substituent selected from the following: halogens, such as F or Cl; -CN; methyl groups; and halomethyl groups, such as -CHF2; Optionally, no more than one of R 5C It is a substituent.

62. The PARP1 inhibitor compound according to claim 61, wherein ring C has the following structure: in: X Co and X Cm Each is selected from C and N; When X Co When it is C, R Co It is H or a halogen, with F being the preferred halogen; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or a halogen, with F being the preferred halogen; and When X Cm When it is N, R Cm It does not exist; Choose any one of X Co and X Cm At least one of them is N.

63. The PARP1 inhibitor compound according to claim 62, wherein X Co and X Cm One of them is N.

64. The PARP1 inhibitor compound according to any of the preceding claims, wherein the ring C has a structure selected from:

65. The PARP1 inhibitor compound according to claim 64, wherein: Ring C has a structure selected from C1 to C36; or Ring C has a structure selected from C3, C8, C10, C11, C13, C14, C15, C18, C19, C21, C25, C28, C36, C37 and C38.

66. The PARP1 inhibitor compound according to claim 64 or claim 65, wherein ring C has a structure selected from:

67. The PARP1 inhibitor compound according to any of the preceding claims, wherein R 6 Selected from H, -F, -Cl, -Br, -I, -CN, -CONR 51 R 51 -NR 51 COR 52 -SO2NR 51 R 51 -NR 51 SO2R 52 -O-CR 52 R 52 R 52 -CR 52 R 52 NR 51 R 51 and any of the following structures: Where R 51 and R 52 Each is independently selected from H and substituted or unsubstituted organic groups, optionally wherein R 51 and R 52 Each is independently selected from H, halogen, optionally deuterated C1 to C3 alkyl and C1 to C3 haloalkyl.

68. The PARP1 inhibitor compound according to claim 67, wherein R 6 Selected from -F, -Cl, -CN, -CONH2, -CONHMe (optionally -CONHCD3), -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, -CONH-CH2-CHF2, -OCHF2, -NHCOMe, -NHSO2Me, -SO2NHMe, -CONHSO2Me, , , , , , , , and .

69. The PARP1 inhibitor compound according to claim 68, wherein R 6 It is F.

70. The PARP1 inhibitor compound according to claim 68, wherein R 6 It is Cl.

71. The PARP1 inhibitor compound according to claim 68, wherein R 6 It's CN.

72. The PARP1 inhibitor compound according to claim 67, wherein R 6 It has the following structure: Where R 51 Selected from: C1 to C6 alkyl groups, optionally C3 to C6 cycloalkyl groups, C1 to C3 alkyl groups or C1 to C3 deuterated alkyl groups; C1 to C3 haloalkyl groups, optionally C1 to C3 fluoroalkyl groups; and A 4-, 5-, 6-, or 7-membered saturated heterocyclic group, optionally a 4-, 5-, or 6-membered cyclic ether group.

73. The PARP1 inhibitor compound according to claim 72, wherein R 6 Selected from:

74. The PARP1 inhibitor compound according to claim 73, wherein R 6 Yes -CONHMe.

75. The PARP1 inhibitor compound according to claim 73, wherein R 6 yes .

76. The PARP1 inhibitor compound according to claim 73, wherein R6 is -C(O)NHEt.

77. The PARP1 inhibitor compound according to claim 73, wherein R 6 yes .

78. The PARP1 inhibitor compound according to claim 73, wherein R 6 yes .

79. The PARP1 inhibitor compound according to claim 73, wherein R 6 It is -C(O)NHCH2CF3.

80. The PARP1 inhibitor compound according to claim 73, wherein R 6 It is C(O)NHCH2CH2F.

81. The PARP1 inhibitor compound according to claim 73, wherein R 51 It is a tetrahydropyranyl group, wherein R is optionally a tetrahydropyranyl group. 6 yes: 。 82. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 66, wherein R 6 It has the following structure: in: Each X 6 Independently selected from C, N, and O; R 61 It does not exist or is H; Each R 62 Independently absent or selected from H; halogenated groups, such as F; oxo groups; C1 to C3 alkyl groups; C1 to C3 haloalkyl groups, optionally C1 to C3 fluoroalkyl groups; and -NHR 63 , where R 63 It is an H or C1 to C3 alkyl group.

83. The PARP1 inhibitor compound for the said use according to claim 82, wherein R 6 Selected from:

84. The PARP1 inhibitor compound according to any of the preceding claims, wherein L has a structure selected from:

85. The PARP1 inhibitor compound according to claim 84, wherein L has a structure selected from:

86. The PARP1 inhibitor compound according to any of the preceding claims, wherein rings D and B are in a cis configuration relative to ring A, optionally wherein group L is selected from:

87. The PARP1 inhibitor compound according to any one of claims 1 to 85, wherein rings D and B are in a trans configuration relative to ring A, optionally wherein group L is selected from:

88. The PARP1 inhibitor compound according to claim 1, having the following structure: in: Each Z independently represents -CH2- or is selected from -O- and -N(R). D ()- fragments containing heteroatoms, provided that no more than one Z is a fragment containing heteroatoms; Where R D It is an H or C1 to C3 alkyl group, preferably a methyl group; X C1 and X C2 Each is independently selected from C and N; When X C1 When it is N, R 5C1 It does not exist; When X C1 When it is C, R 5C1 Selected from H and halogens; When X C2 When it is N, R C2 It does not exist; When X C2 When it is C, R5 C2 Selected from H and halogens; R 6 Selected from -CONHMe, -Cl, and -CN.

89. The PARP1 inhibitor compound according to claim 88, wherein: When X C1 When it is C, R 5C1 Selected from H and F; and When X C2 When it is C, R5 C2 Selected from H and F.

90. The PARP1 inhibitor compound according to claim 88 or claim 89, wherein X C1 and X C2 One of them is N, and preferably X is X. C1 It is C and X C2 It is N.

91. The PARP1 inhibitor compound according to any one of claims 88 to 90, wherein R 6 It is CONHMe, choose -CONHCD3.

92. The PARP1 inhibitor compound according to claim 1, having the following structure: in: R D1 and R D2 Each is independently selected from H and F; Two Rs 5A The groups together represent the -CH2- group of bridging ring A, and each other R 5A The group is H; or Each R 5A It is H; Each X C The atoms are selected from C and N, provided that there are at least two X atoms. C The atom is C; When X C When it is N, the corresponding R 5C It does not exist; When X C When it is C, the corresponding R 5C It is H or a substituent selected from the following: halogens, such as F or Cl; -CN; methyl groups; and halomethyl groups, such as -CHF2; R 6 Selected from halogens, -CN and Where R 51 It is selected from C1 to C3 alkyl groups; C1 to C3 deuterated alkyl groups; C1 to C3 fluoroalkyl groups; tetrahydrofuranyl groups; and tetrahydropyranyl groups.

93. The PARP1 inhibitor compound according to claim 92, having the following structure: in: R D1 and R D2 Each is independently selected from H and F; X C1 and X C2 Each is independently selected from C and N; When X C1 When it is N, R 5C1 It does not exist; When X C1 When it is C, R 5C1 Selected from H and halogens, with F being preferred; When X C2 When it is N, R C2 It does not exist; When X C2 When it is C, R5 C2 Selected from H and halogens, with F being preferred; R 6 Selected from -CONHMe, -Cl, and -CN.

94. The PARP1 inhibitor compound according to claim 92 or claim 93, wherein X C1 and X C2 One of them is N.

95. The PARP1 inhibitor compound according to claim 94, wherein X C2 It is C and X C1 It is N, and arbitrarily where R is 5C2 It's H.

96. The PARP1 inhibitor compound according to claim 94, wherein X C1 It is C and X C2 It is N.

97. The PARP1 inhibitor compound according to any one of claims 92 to 96, wherein R D1 and R D2 One of them is F.

98. The PARP1 inhibitor compound according to claim 1, wherein the compound is selected from:

99. The PARP1 inhibitor compound according to any one of claims 1 to 87, wherein when R 1 R 2 R 3 R 5A (e.g. R) 5A1 R 5A2 R 5A3 ), R 5B R 5C (e.g. R) 5C1 ), R 6 R 7 R 9 R 51 and R 52 When one or more of the organic groups are substituted or unsubstituted, said or each substituted or unsubstituted organic group is independently selected from: deuterium; Halogens (such as -F, -Cl, -Br and -I); Nitrile group; Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl); Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph); Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (such as -CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3, -CBr3, -CCI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3 and -CH2CH2CCI3); NH2 or substituted or unsubstituted straight-chain or branched primary, secondary or tertiary C1-C6 amine groups (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, -NBuH, -NBuMe, -NBuEt, -CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, -CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe and -CH2-NPrEt); Substituted or unsubstituted amino-aryl groups (such as -NH-Ph, -NH-(2, 3, or 4)F-Ph, -NH-(2, 3, or 4)Cl-Ph, -NH-(2, 3, or 4)Br-Ph, -NH-(2, 3, or 4)I-Ph, -NH-(2, 3, or 4)Me-Ph, -NH-(2, 3, or 4)Et-Ph, -NH-(2, 3, or 4)Pr-Ph, -NH-(2, 3, or 4)Bu-Ph, NH-(2, 3, or 4)OMe-Ph, -NH-(2, 3, or 4)OEt-Ph, -NH-(2, 3, or 4)OPr-Ph) h, -NH-(2, 3 or 4)OBu-Ph, -NH-2,(3, 4, 5 or 6)F2-Ph, -NH-2,(3, 4, 5 or 6)Cl2-Ph, -NH-2,(3, 4, 5 or 6)Br2-Ph, -NH-2,(3, 4, 5 or 6)I2-Ph, -NH-2,(3, 4, 5 or 6)Me2-Ph, -NH-2,(3, 4, 5 or 6)Et2-Ph, -NH-2,(3, 4, 5 or 6)Pr2-Ph, -NH-2,(3, 4, 5 or 6)Bu2-Ph), Substituted or unsubstituted cyclic amine or amide groups (such as pyrrolid-1-yl, pyrrolid-2-yl, pyrrolid-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolyl, 3-keto-pyrrolyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); Substituted or unsubstituted cyclic C3-C8 alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); -OH group; Substituted or unsubstituted straight-chain or branched C1-C6 alcohol groups (Such as -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH and -CH2CH2CH2CH2CH2CH2OH); Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid groups (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH); Substituted or unsubstituted straight-chain or branched carbonyl groups (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl, -(CO)NH2, - (CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholino-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe and -(CO)NHCH2CH2NMe2); Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe and -CH2CH2CH2CH2COOMe); Substituted or unsubstituted straight-chain or branched C1-C6 amide groups (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt); Substituted or unsubstituted straight-chain or branched C1-C7 amino carbonyl groups (such as -NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, -NMe-CO-Ph); Substituted or unsubstituted straight-chain or branched C1-C7 alkoxy or aryloxy groups (such as -OMe, -OEt, -OPr, -Oi-Pr, -On-Bu, -Oi-Bu, -Ot-Bu, -O-pentyl, -O-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -O-Ph, -O-CH2-Ph, -O-CH2-(2, 3 or 4)-F-Ph, -O-CH2-(2, 3 or 4)-Cl-Ph, -CH2OMe, -CH2OEt, -CH2OPr, -CH2OBu, -CH2CH2OMe, -CH2CH2CH2OMe, -CH2CH2CH2CH2OMe and -CH2CH2CH2CH2CH2OMe); Substituted or unsubstituted straight-chain or branched aminoalkoxy groups (such as -OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt and -OCH2CH2NEt2); Substituted or unsubstituted sulfonyl groups (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholino-N-yl, -SO2NHCH2OMe and -SO2NHCH2CH2OMe); Substituted or unsubstituted aminosulfonyl groups (such as -NHSO2Me, -NHSO2Et, -NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2, 3 or 4)-F-Ph, -NHSO2-cyclopropyl, -NHSO2CH2CH2OCH3); Substituted or unsubstituted aromatic groups (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2-Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)- Pr2-Ph-、2,(3,4,5 or 6)-Bu2-Ph-、2,(3,4,5 or 6)-(CN)2-Ph-、2,(3,4,5 or 6)-(NO2)2-Ph-、2,(3,4,5 or 6)-(NH2)2-Ph-、2,(3,4,5 or 6)-(MeO)2-Ph-、2,(3,4,5 or 6)-(CF3)2-Ph-、3,(4 or 5)-F2-Ph-、3,(4 or 5)-Cl2-Ph-、3,(4 or 5)-Br2-Ph-、3,(4 or 5)-I2-Ph-、3,(4 or 5)-Me2-Ph-、3,(4 or 5)-Et2-Ph-、3, (4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN) -Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); Saturated or unsaturated, substituted or unsubstituted heterocyclic groups, optionally aromatic or non-aromatic heterocyclic groups. (such as pyrrolo-1-yl, pyrrolo-2-yl, pyrrolo-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-) Triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl Piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-1-yl, 2-azapiperidin-3-yl, 2-azapiperidin-4-yl, 3-azapiperidin-1-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazine-1-yl, piperazine-2-yl, furan-2 -yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran -6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxacyclobutane-2-yl, oxacyclobutane-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl Morpholin-2-yl, Morpholin-3-yl, Morpholin-4-yl, Thiophene-2-yl, Thiophene-3-yl, Isothiazol-3-yl, Isothiazol-4-yl, Isothiazol-5-yl, Thiazol-2-yl, Thiazol-4-yl, Thiazol-5-yl, Thian-2-yl, Thian-3-yl, Thian-4-yl, 2-azathiaran-2-yl, 2-azathiaran-3-yl2-azathiaran-4-yl, 2-azathiaran-5-yl, 2-azathiaran-6-yl, 3-azathiaran-2-yl, 3-azathiaran-4-yl, 3-azathiaran-5-yl, 3-azathiaran-6-yl, 4-azathiaran-2-yl, 4-azathiaran-3-yl, 4-azathiaran-4-yl, 4-azathiaran-5-yl, 4-azathiaran-6-yl, thiacyclopentan-2-yl, thiacyclopentan-3-yl, thiacyclohexane-2-yl Thiazole-3-yl, thiacyclohexane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl); in: A pair of R atoms connected to different atoms 5A The group can form a ring together with the A atom of the ring; and / or A pair of R atoms connected to different atoms 5B The group can form a ring together with the B atom of the ring, and / or A pair of R atoms connected to different atoms 5C Groups can form a ring together with the carbon atoms of the ring; and / or R connected to different atoms 5C Groups and R 6 Groups can form rings together with ring carbon atoms.

100. The PARP1 inhibitor compound according to claim 99, wherein R 5A (For example, R) 5A1 R 5A2 R 5A3 ), R 5B and R 5C (For example, R) 5C1 Each of the following is either independent or selected from: H， deuterium, Halogens, such as -F, -Cl, -Br and -I; preferably F or Cl; Nitrile group; C1-C6 alkyl groups; C1-C6 haloalkyl groups, preferably CF3 or CHF2; Cyclopropyl group; -OH group; C1-C6 alcohol groups; C1-C7 amino carbonyl groups, such as -NH-CO-Me; -NH2 group; C1-C6 amino groups; and C1-C6 alkoxy groups; in, When a pair of R atoms are attached to different atoms 5A The group together forms a ring with the ring A atom and / or a pair of R atoms attached to different atoms. 5B The group together forms a ring with the ring B atom and / or a pair of R atoms attached to different atoms. 5C When the group forms a ring together with the ring C atom, the R 5A R 5B or R 5C Each of the group pairs independently contains -CH2- or -CH2CH2-, or the group pairs together contain -CH=CH-CH=CH- or -NH-CO-NH-.

101. The PARP1 inhibitor compound according to any of the preceding claims, wherein it is in the following form: Separate enantiomers, or A mixture of two or more enantiomers, or A mixture of two or more diastereomers and / or epimers, or racemic mixture, or The tautomers of the compound.

102. The PARP1 inhibitor compound according to any of the preceding claims, which is selective for PARP1 relative to PARP2.

103. Any PARP1 inhibitor compound as claimed in the preceding claims, for use in medicine.

104. The PARP1 inhibitor compound of claim 103 for the stated purpose, used for the treatment of cancer.

105. The PARP1 inhibitor compound for the purpose according to claim 104, wherein the cancer is selected from: eye cancer; brain cancer, such as glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, and astrocytoma; spinal cord cancer; kidney cancer; oral cancer; lip cancer; laryngeal cancer; oral cavity cancer; nasal cavity cancer; small intestine cancer; colon cancer; parathyroid cancer; gallbladder cancer; head and neck cancer; breast cancer; bone cancer; bile duct cancer; cervical cancer; heart cancer; subpharyngeal gland cancer; lung cancer; bronchial cancer; liver cancer; skin cancer; ureteral cancer; urethral cancer; testicular cancer; vaginal cancer; anal cancer; laryngeal gland cancer; ovarian cancer; thyroid cancer; esophageal cancer; nasopharyngeal gland cancer; pituitary cancer; salivary gland cancer; prostate cancer; pancreatic cancer; adrenal cancer; endometrial cancer; oral cancer; melanoma; neuroblastoma; gastric cancer; hemangioma; hemangioblastoma; pheochromocytoma; pancreatic cyst Swelling; Renal cell carcinoma; Wilms' tumor; Squamous cell carcinoma; Sarcoma; Osteosarcoma; Kaposi's sarcoma; Rhabdomyosarcoma; Hepatocellular carcinoma; PTEN hamartoma-tumor syndromes, such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome; Leukemia and lymphoma, such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia, large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary exudative lymphoma, AIDS-related lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer; Optionally, the cancer mentioned above is brain cancer or spinal cord cancer.

106. The PARP1 inhibitor compound for the said use according to claim 104 or claim 105, wherein the cancer is deficient in DNA damage response repair pathways, such as homologous recombination-dependent DNA double-strand break DNA repair activity.

107. A PARP1 inhibitor compound for the said use according to any one of claims 104 to 106, wherein said cancer is defective in BRCA1 and / or BRCA2 function.

108. The PARP1 inhibitor compound for the stated use according to any one of claims 104 to 107, administered in combination with another agent for treating cancer; optionally, said other agent for treating cancer is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell scavengers, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, apoptosis-promoting agents, radioligand therapy, cell cycle signaling inhibitors, and anti-angiogenic agents.

109. The PARP1 inhibitor compound for the stated use according to claim 108, wherein the additional agent is selected from the group consisting of: antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy; small molecule immunomodulators; and tumor microenvironment modulators.

110. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any one of claims 1 to 102.

111. The pharmaceutical composition of claim 110, further comprising pharmaceutically acceptable additives and / or excipients, and / or wherein the compound is in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative form of the compound.

112. The pharmaceutical composition of claim 110 or claim 111, further comprising an additional agent for treating cancer; optionally, wherein the additional agent for treating cancer is selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell scavengers, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, apoptosis-promoting agents, radioligand therapy, anti-angiogenic agents, and cell cycle signaling inhibitors.

113. The pharmaceutical composition of claim 112, wherein the additional agent comprises an immunotherapeutic agent selected from: antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy; small molecule immunomodulators; and tumor microenvironment modulators.

114. The pharmaceutical composition according to any one of claims 110 to 113, for the treatment of cancer.

115. A drug kit for treating cancer, said drug kit comprising: a) A PARP1 inhibitor compound as defined in any one of claims 1 to 102; and b) Other medications used to treat cancer; The PARP1 inhibitor compound and the other agents are suitable for simultaneous, sequential, or separate administration; and Optionally, the additional agents used to treat cancer described herein are selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell scavengers, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone deprivation therapy, immunotherapeutic agents (such as those selected from antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3 and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9 or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy; small molecule immunomodulators; tumor microenvironment modulators), apoptosis-promoting agents, radioligand therapy, anti-angiogenic agents and cell cycle signaling inhibitors.

116. A method of treating a disease and / or condition and / or disorder, the method comprising administering to a patient a PARP1 inhibitor compound, composition, or kit product as defined in any of the preceding claims.

117. The method of claim 116, wherein the patient is an animal, preferably a mammal, optionally a human, dog, horse or cat; and preferably a human.

118. A method for synthesizing a PARP1 inhibitor compound as defined in any one of claims 1 to 102, the method comprising carrying out a reaction between the following reactants: i) A first reactant comprising rings D and E and a first moiety bearing the group L, and ii) A second reactant, which contains the remainder of the group L. To form the PARP1 inhibitor compound.

119. The method of claim 118, wherein the first reactant comprises rings D, E and A, and the second reactant comprises a ring B precursor with a reactive group, the method comprising attaching ring A to the ring B precursor.

120. The method of claim 119, wherein the reactive precursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate ester.

121. The method according to any one of claims 118 to 120, wherein the reaction comprises alkylation, reductive amination or amide formation to form a group L.

122. The method of claim 118, wherein the first reactant comprises ring D, ring E, ring A and ring B, and the second reactant comprises a ring C derivative having a leaving group such as a halogen or sulfonate.

123. The method of claim 122, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, thereby forming a group L.

124. The method according to any one of claims 118 to 123, further comprising separating the structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography and / or chiral high-performance liquid chromatography.

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