PARP1 inhibitor compounds

Abstract

The PARP1 inhibitor compound has the structure of (I). Each R1 and R2 are independently absent and are H or an organic group. And R3 is H or an organic group. Z1, Z2u, Z2l and each Z3 are independently C or N. In the formula, Z1, Z2u, Z2l and each Z3 are And at least one of Z2u and Z2l is N. L is (II), b is absent or (III). Each R5A, R5B, R5C and R6 is independently absent, is H or an organic group. Each X1 is C or N. Each X2 is C, N, O, or S. N, m, p, q, r, and s are each an integer in the range of 0 to 6. M + n, p + q, and r + s each range from 2 to 6. QAE, QAB and QBC are independently absent or an alkyl, alkenyl, ester, amine or ketone linker. The compounds are useful, for example, in the treatment of cancer. Also provided are compositions and kits comprising the compounds, as well as methods of synthesizing the compounds. (I) (II) (III)

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] This document provides a PARP1 inhibitor compound for medical use. The PARP1 inhibitor compound has the following structure:

[0017]

[0018] in:

[0019] Each R 1 It does not exist independently or is selected from H and substituted or unsubstituted organic groups;

[0020] R 2It is absent or selected from H and substituted or unsubstituted organic groups;

[0021] R 3 Selected from H and substituted or unsubstituted organic groups;

[0022] Z 1 It is C or N;

[0023] Z 2u and Z 2l Each is selected from C and N, provided that Z 2u and Z 2l At least one of them is N;

[0024] Each Z 3 Independently selected from C and N; and

[0025] L has the following structure:

[0026]

[0027] Optional

[0028] in:

[0029] Dashed lines indicate single or double bonds;

[0030] Each R 5A and each R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups;

[0031] R 6 It is absent or selected from H and substituted or unsubstituted organic groups;

[0032] Each X 1 Independently selected from C and N;

[0033] Each X 2 Independently selected from C, N, O, and S;

[0034] n is a number selected from 0, 1, 2, 3, 4, 5, and 6; and m is a number selected from 0, 1, 2, 3, 4, 5, and 6; provided that m + n is a number selected from 2, 3, 4, 5, and 6.

[0035] r is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; and s is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; provided that r + s is a number selected from 2, 3, 4, 5, and 6.

[0036] b is a ring that either does not exist or has the following structure:

[0037] ;

[0038] in:

[0039] p is a number selected from 0, 1, 2, 3, 4, 5, and 6; and q is a number selected from 0, 1, 2, 3, 4, 5, and 6; provided that p + q is a number selected from 2, 3, 4, 5, and 6; and

[0040] Each R 5B It independently does not exist or is selected from H and substituted or unsubstituted organic groups; and

[0041] Q AE Q AB and Q BC Each exists independently or is selected from:

[0042] , , ,

[0043] ,and ;

[0044] in:

[0045] 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

[0046] Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0047] On the other hand, pharmaceutical compositions are provided that contain PARP1 inhibitor compounds as defined herein.

[0048] Another aspect provides pharmaceutical kits for treating cancer. These 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.

[0049] On the other hand, methods for treating diseases and / or conditions and / or disorders are provided, including administering to a patient a compound, composition, or kit product as provided herein.

[0050] On the other hand, compounds with the following structures are provided:

[0051] or

[0052]

[0053] in:

[0054] Z 1 It is C or N;

[0055] Z 2u and Z 2l One is C, and Z 2u and Z 2l The other one is N;

[0056] Each Z 3 Independently selected from C and N,

[0057] Each R 1 It is either absent independently or selected from H, halogens (e.g., F), methyl, halomethyl (e.g., CF3) and CN;

[0058] R 5C2o It is an H, a methyl group, or a halogen;

[0059] X 2CM It is N and R 5C2M Does not exist or X 2CM It is C and R 5C2M It is H; and

[0060] R 6 yes (optional) )or .

[0061] Typically, in these compounds, when Z 3 When it is N, the corresponding R 1 It does not exist; and when Z 3 When it is C, the corresponding R 1 It does not exist.

[0062] Optional, R 5C2o It is H or halogens such as F.

[0063] On the other hand, a method for synthesizing PARP1 inhibitor compounds as provided herein is provided. The method includes performing a reaction between a first reactant and a second reactant to form a PARP1 inhibitor compound, the first reactant comprising a ring E with a first portion bearing a group L, and the second reactant comprising the remaining portion of the group L.

[0064] Some more specific aspects of the invention are set forth in the dependent claims.

[0065] 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.

[0066] Detailed Explanation

[0067] General definition

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] Compound numbering

[0079] 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.

[0080] The suffix "rac" in a compound designation indicates a racemic mixture.

[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] And it is usually:

[0087] ,

[0088] Ring B is optional. The various aspects of this general structure are discussed in detail below.

[0089] Substituents

[0090] The expression "R" 5"Group" usually represents 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.

[0091] In the compounds provided in this article, R 1 R 2 and R 5 Multiple groups may be absent. The dashed lines in the structural formulas shown in this paper represent any non-zero order covalent bonds. It will be understood that the number of ring bonds and substituents are chosen such that Z... 1 Z 2 Z 3 X 1 and X 2 Atoms maintain stable valences. Maintaining stable valences means ensuring that atoms in organic compounds 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).

[0092] When X 1 X 2 Z 1 Z 2u Z 2l or Z 3 When the atom is N, it is optimal for the atom to have a valence of 3. The value of X is also considered. 1 X 2 Z 1 Z 2u Z 2l or Z 3 The atom is a compound with tetravalent nitrogen. Tetravalent nitrogen carries a positive charge, and such compounds can have counterions.

[0093] Preferably, the PARP1 inhibitor compound contains at most one tetravalent N, and more preferably does not contain a tetravalent N.

[0094] Each R 5 Groups may or may not be present, and they may be the same or different. To avoid confusion, in R... 5 When the number of groups can vary depending on the choice of the corresponding X group, the following conditions generally apply:

[0095] i) When X 1 When it is N, its corresponding R 5 It does not exist.

[0096] ii) When X1 When it is C and forms a double bond with an adjacent ring atom, its corresponding R 5 It does not exist.

[0097] iii) When X 1 When it is C and does not form a double bond with an adjacent ring atom, its corresponding R 5 exist.

[0098] iv) When X 2 When it is 0, its corresponding R 5 / R 6 Neither of the functional groups exists.

[0099] v) When X 2 When it is S, its corresponding R 5 / R 6 Neither of the groups is present, or both are selected from =O and =NR. 10 , where R 10 It is H or a substituted or unsubstituted organic group, preferably a C1 to C3 alkyl group.

[0100] vi) When X 2 When N is N and forms a double bond with an adjacent ring atom, the or each corresponding R 5 / R 6 It does not exist.

[0101] vii) When X 2 When N is an atom and does not form a double bond with an adjacent ring atom, there exists exactly one corresponding R. 5 / R 6 .

[0102] viii) When X 2 When a carbon atom forms a double bond with an adjacent ring atom, there exists exactly one corresponding R atom. 5 / R 6 .

[0103] ix) When X 2 When it is C and does not form a double bond with an adjacent ring atom, the two corresponding R 5 Group or two corresponding R 5 and R 6 All functional groups are present.

[0104] Substituents (i.e., R groups; R) 1 R 2 R 3 R 5 R 6 R 7 and R 8There 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.

[0105] 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.

[0106] A single R on an atom 5 Or R 6 Groups, or two R atoms on the same atom 5 / R 6 A group can form a group that is linked to a double bond of that atom. Therefore, an R 5 Or R 6 Groups, or two R atoms attached to the same atom 5 / R 6 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.

[0107] "Substituent" and "organic group" can have any of the following meanings.

[0108] 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).

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] Furthermore, any substituent may contain a combination of two or more substituents and / or functional groups as defined herein.

[0115] Typically, when R 1 R 2 R 3 R 5A (For example, R) 5A1 R 5A2 R 5A3 ), R 5B (For example, R) 5B1 R 5B2 R 5B3 ), R 5C (For example, R) 5C1 ), R 6 R 7 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:

[0116] deuterium;

[0117] Halogens (such as -F, -Cl, -Br and -I);

[0118] Nitrile group;

[0119] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups

[0120] (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl);

[0121] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups

[0122] (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);

[0123] Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups

[0124] (such as -CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3, -CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3 and -CH2CCI3);

[0125] NH2 or substituted or unsubstituted straight-chain or branched primary, secondary or tertiary C1-C6 amine groups

[0126] (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);

[0127] Substituted or unsubstituted amino-aryl groups

[0128] (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),

[0129] Substituted or unsubstituted cyclic amine or amide groups

[0130] (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);

[0131] Substituted or unsubstituted cyclic C3-C8 alkyl groups

[0132] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl);

[0133] -OH group;

[0134] Substituted or unsubstituted straight-chain or branched C1-C6 alcohol groups

[0135] (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);

[0136] Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid groups

[0137] (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH);

[0138] Substituted or unsubstituted straight-chain or branched carbonyl groups

[0139] (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);

[0140] Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups

[0141] (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe and -CH2CH2CH2CH2COOMe);

[0142] Substituted or unsubstituted straight-chain or branched C1-C6 amide groups

[0143] (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt);

[0144] Substituted or unsubstituted straight-chain or branched C1-C7 amino carbonyl groups

[0145] (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);

[0146] Substituted or unsubstituted straight-chain or branched C1-C7 alkoxy or aryloxy groups

[0147] (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);

[0148] Substituted or unsubstituted straight-chain or branched aminoalkoxy groups

[0149] (such as -OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt and -OCH2CH2NEt2);

[0150] Substituted or unsubstituted sulfonyl groups

[0151] (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);

[0152] Substituted or unsubstituted aminosulfonyl groups

[0153] (such as -NHSO2Me, -NHSO2Et, -NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2, 3 or 4)-F-Ph, -NHSO2-cyclopropyl, -NHSO2CH2CH2OCH3);

[0154] Substituted or unsubstituted aromatic groups

[0155] (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-);

[0156] Saturated or unsaturated, substituted or unsubstituted heterocyclic groups, optionally aromatic or non-aromatic heterocyclic groups.

[0157] (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).

[0158] A pair of R atoms connected to different atoms 5A The group can form a ring together with the A atom of the ring.

[0159] A pair of R atoms connected to different atoms 5B The group can form a ring together with the B atom of the ring.

[0160] A pair of R atoms connected to different atoms 5C Groups can form rings together with ring carbon atoms.

[0161] R connected to different atoms 5C Groups and R 6 Groups can form rings together with ring carbon atoms.

[0162] R 5 Group (R) 5A Such as R 5A1 R 5A2 R 5A3 ;R 5B ; or R 5C Such as R 5C1 It can specifically not exist or be selected from:

[0163] H,

[0164] deuterium,

[0165] Halogens (such as -F, -Cl, -Br and -I; preferably F or Cl),

[0166] Nitrile group,

[0167] Substituted or unsubstituted C1-C6 alkyl groups,

[0168] Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (preferably CF3 or CHF2),

[0169] Cyclopropyl group,

[0170] -OH group,

[0171] Substituted or unsubstituted straight-chain or branched C1-C6 alcohol groups,

[0172] Substituted or unsubstituted straight-chain or branched C1-C7 amino carbonyl groups (such as -NH-CO-Me),

[0173] -NH2 group,

[0174] Substituted or unsubstituted C1-C6 amino groups, and

[0175] Substituted or unsubstituted C1-C6 alkoxy groups.

[0176] 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-.

[0177] Rings D and E

[0178] The compounds presented in this article have the following structures for rings D and E (also collectively referred to as "head groups"):

[0179]

[0180] in:

[0181] Each R 1 It does not exist independently or is selected from H and substituted or unsubstituted organic groups;

[0182] R 2 It is absent or selected from H and substituted or unsubstituted organic groups;

[0183] R 3 Selected from H and substituted or unsubstituted organic groups;

[0184] Z 1 It is C or N;

[0185] Z 2u and Z 2l Each is selected from C and N, provided that Z 2u and Z 2l At least one of them is N; and

[0186] Each Z 3 Selected independently from C and N.

[0187] When Z 3 When it is C, the relevant R 1 Existence. When Z 3 When it is N, the relevant R 1 The optimal choice does not exist.

[0188] In containing more than one R 1 In compounds containing groups, each R is independently selected. 1 .

[0189] Suitable R 1 Examples of functional groups include:

[0190] H;

[0191] C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl groups;

[0192] C3 to C6 cycloalkyl groups;

[0193] Halogen groups;

[0194] Nitrile group;

[0195] and

[0196]

[0197] Where R 22 Selected from H, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl and halogen (optionally F), and each R 23 Independently selected from H and substituted or unsubstituted organic groups,

[0198] Optionally, each of R 23 Independently selected from H, C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl groups and halogen groups, and further optionally at least one of them R 23 It is H.

[0199] Preferably, each R 1Independently absent or selected from H; halogen, optionally Cl or F; C1 to C3 alkyl group, optionally methyl group; C1 to C3 haloalkyl group, optionally halomethyl group (-CH2F, -CHF2 or -CF3) or haloethyl group (e.g., -CH2CF3); and nitrile group.

[0200] More preferably, each R 1 It is either absent independently or selected from: H, Cl, F, methyl groups, CF3, and nitrile groups. Typically, at least one R... 1 It is H.

[0201] Optional, not exceeding one R 1 It is a substituted or unsubstituted organic group, while each other R 1 It is H or it does not exist.

[0202] Z 1 It can be C. When Z 1 When it is C, R 2 It may be present and selected from H; halogen, optionally F or Cl; C1 to C3 alkyl, optionally isopropyl or cyclopropyl; C1 to C3 haloalkyl, optionally -CH2F, -CHF2, -CF3, -CH2CF3 or -CH2CH2F; C1 to C3 alcohol, optionally -CH2CH2OH; C1 to C3 alkoxy, optionally methoxy, methoxymethyl or methoxyethyl; or C1 to C3 aminoalkyl. In particular, R 2 It can be H.

[0203] Available location, Z 1 It can be N. In such compounds, R 2 It does not exist.

[0204] R 3 It can be selected from H, C1 to C3 alkyl and C1 to C3 haloalkyl, with H being the most preferred.

[0205] Each Z 3 The atoms are independently selected from C and N. Optionally, at least two Z atoms are also selected. 3 The atom is C.

[0206] Typically, Z 2u and Z 2l One of them is C.

[0207] Z 2u It can be C and Z 2l It can be N, such that the PARP1 inhibitor compound has the following structure:

[0208] .

[0209] Choose any location, not exceeding one Z 3 The atom is N. For example, the PARP1 inhibitor compound may have a structure selected from the following:

[0210] , , and .

[0211] More specifically, the PARP1 inhibitor compound may have a structure selected from the following:

[0212]

[0213] According to another possibility, the PARP1 inhibitor compound may have the following structure:

[0214] or .

[0215] Available location, Z 2u It can be N and Z 2l It can be C, such that the PARP1 inhibitor compound has the following structure:

[0216] .

[0217] In such instances, arbitrarily no more than one Z 3 The atom is N. The PARP1 inhibitor compound may have a structure selected from the following:

[0218] , , and .

[0219] More specific examples of PARP1 inhibitor compounds have structures selected from the following:

[0220] , , , and .

[0221] Rings A, B, and C – General

[0222] The group L of the PARP1 inhibitor compound has the following structure:

[0223] And it is usually: .

[0224] The optional group b is preferably present. In such an example, group L has the following structure:

[0225] And it is usually: .

[0226] The variable atoms that form part of the framework of rings A, B, and C are usually called "X" atoms. Each X 1 The atoms are independently selected from C and N. Each X 2 The atoms are independently selected from C, N, O and S; among which C and N are particularly preferred.

[0227] Select each X independently 1 and X 2 Atoms. One or more of the following conditions, and all of the optimal options, may apply:

[0228] Typically, each ring has at least one C-group. When rings A, B, or C are quaternary, the ring typically contains at most one heteroatom. When rings A, B, or C are quinary or septate, the ring typically contains at most three heteroatoms, optionally at most two heteroatoms.

[0229] Each of rings A, B, and C can individually contain up to three heteroatoms.

[0230] The compound is typically not a quaternary ammonium compound. X as N 1 Atoms typically do not contain R 5 Group. X as N 2 Atoms typically carry at most one R 5 Group.

[0231] The compound in X 2 There are no OO, SS, or SO bonds between the atoms. When X... 2 When the atom is O or S, its adjacent ring atom is C or N. More generally, the compound may not contain OO and SS bonds.

[0232] Each part of group L will be discussed in more detail below.

[0233] Ring A

[0234] Ring A of PARP1 inhibitor compounds has a general structure:

[0235]

[0236] X 1AE Through the connection base Q AE X of connecting ring E 1 Atom. X 2A X represents X as part of ring A 2 atom.

[0237] Each R5A It exists independently or is selected from H and substituted or unsubstituted organic groups. R 5A1 Indicates with X 1AE Combined R 5A R 5A2 Indicates with X 2A Atomic bond R 5A .

[0238] X 1AE It can be C or N, but C is preferred.

[0239] When Q AE yes And when u=0, X 1AE It's C.

[0240] When X 1AE When it is N, R 5A1 It usually does not exist.

[0241] Rings A and B are most typically not connected by an N-N bond. For this purpose, when Q AB yes When t is at least 1.

[0242] Each X 2A The atoms are independently selected from C, N, O, and S; among which C and N are particularly preferred. Choose X. 2A Atoms, such that ring A contains no OO, OS, or SS bonds. Optionally, at least one X 2A The atom is C. Particularly preferably, all X 2A The atom is C.

[0243] Ring A is a 4, 5, 6, 7, or 8-membered ring. For this purpose, n is 0 or an integer in the range of 1 to 6; m is 0 or an integer in the range of 1 to 6, and the sum of n and m is an integer in the range of 2 to 6.

[0244] Specifically, ring A can be a 4-, 5-, or 6-membered ring, preferably a 5- or 6-membered ring. In other words, the sum of n+m can be an integer in the range of 2 to 4.

[0245] Preferably, both n and m are at least 1.

[0246] Ring A can be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring, depending on the presence of R. 5A The number of functional groups. Saturated and unsaturated non-aromatic rings are preferred.

[0247] In particular, ring A can be a 5-element (n+m=3) saturated ring.

[0248] In most implementations, no more than two R 5AThe group is an organic group that has been substituted or not substituted. Most typically, it contains no more than one R group. 5A A group is an organic group that has been substituted or not substituted.

[0249] Typically, when R 5A When the group is present, the R 5A The preferred radical is H.

[0250] 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.

[0251] For example, ring A can be a bridging ring with the following structure:

[0252]

[0253] in:

[0254] x is 0 or an integer in the range of 1 to 6 and y is 0 or an integer in the range of 1 to 6, provided that the sum of x and y is (n-1).

[0255] i is 0 or an integer in the range of 1 to 6 and j is 0 or an integer in the range of 1 to 6, provided that the sum of i and j is (m-1);

[0256] h is an integer in the range of 1 to 3; and

[0257] n is an integer in the range of 1 to 6 and m is an integer in the range of 1 to 6, provided that the sum of n and m is an integer in the range of 2 to 6.

[0258] Alternatively, ring A can be a bridging ring with the following structure:

[0259]

[0260] in:

[0261] i is 0 or an integer in the range of 1 to 6 and j is 0 or an integer in the range of 1 to 6, provided that the sum of i and j is (n-1);

[0262] h is an integer in the range of 1 to 3; and

[0263] n is an integer in the range of 1 to 6 and m is 0 or an integer in the range of 1 to 6, provided that the sum of n and m is an integer in the range of 2 to 6.

[0264] The value of h can be appropriately chosen based on the values ​​of i and m. h is usually 1 or 2.

[0265] For example, ring A can be a bridging 5-element ring, where h is 1, i is 1, j is 0, and m is 1.

[0266] The preferred type is the bridging ring A with the following structure:

[0267] .

[0268] The preferred bridging ring A has the following structure:

[0269] .

[0270] Ring A may comprise a substituted or unsubstituted 7-membered ring, optionally a homopiperidine. For example, ring A may be a homopiperidine having a structure selected from:

[0271] and .

[0272] Alternatively, ring A may be a substituted or unsubstituted six-membered aliphatic (i.e., saturated or unsaturated non-aromatic) heterocycle. For example, ring A may have a structure selected from:

[0273] , , , , , , , , , and .

[0274] In yet another instance, ring A can be a substituted or unsubstituted 5-membered aliphatic heterocycle. Examples of 5-membered aliphatic heterocycles include:

[0275] , , , , and .

[0276] In other examples, ring A is a 5-membered aromatic ring, optionally pyrrole or pyrazole. Examples of suitable 5-membered aromatic rings include:

[0277] , and .

[0278] According to another possibility, ring A can be a substituted or unsubstituted azacyclic butane, such as azacyclic butane having the following structure:

[0279] .

[0280] More specific examples of suitable ring A structures include:

[0281]

[0282] In particular, ring A can have a structure selected from the following:

[0283] , , and .

[0284] The preferred ring A structure is:

[0285] and .

[0286] Specifically, ring A can be:

[0287] .

[0288] Ring B

[0289] The PARP1 inhibitor compound optionally comprises ring B. Although compounds without ring B are considered, ring B is commonly present. When present, ring B has the following structure:

[0290] .

[0291] X 1BA Through the connection base Q AB X connected to ring A 1 Atom. X 1BC Through the connection base Q BC X connected to ring C 1 Atom. X 1BA and X 1BC Each is independently selected from C and N.

[0292] X 2B X represents X as part of ring B 2 Atoms. Each X 2B The atoms are independently selected from C, N, O, and S; among which C and N are preferred. X is selected. 2B The atoms ensure that ring B is free of OO, OS, and SS bonds. Optionally, at least one X 2B The atom is C. Preferably, all X 2B The atom is C.

[0293] Each R 5B It exists independently or is selected from H and substituted or unsubstituted organic groups. R 5B1 Indicates with X 1BACombined R 5B R 5B2 Indicates with X 2B Atomic bond R 5B R 5B3 Indicates with X 1BC Combined R 5B .

[0294] When X 1BA When it is N, R 5B1 It does not exist.

[0295] When X 1BC When it is N, R 5B3 It does not exist.

[0296] Rings A and B are typically not connected by an N / N bond. When X 1BA It is N and Q AB yes When t is at least 1 and u is at least 1.

[0297] Rings B and C are typically not connected by an N-N bond. When X 1BC It is N and Q BC yes When t is at least 1.

[0298] When X 1BC X is N and is a C-ring as determined below. 1CB When it is N, Q BC It does not exist.

[0299] Preferably, X 1BA It's C. X 1BA It can be C and X 1BC It can be N, such that ring B has the following structure:

[0300] .

[0301] Group L can have the following structures:

[0302] .

[0303] Ring B is a 4, 5, 6, 7, or 8-membered ring. For this purpose, p is 0 or an integer in the range of 1 to 6; q is 0 or an integer in the range of 1 to 6, and the sum of p and q is an integer in the range of 2 to 6.

[0304] Preferably, p and q are each at least 1.

[0305] Typically, it is preferred that ring B is a 5-membered or 6-membered ring. In other words, the sum of p and q can be 3 or 4. More preferably, ring B is a 6-membered ring, where p=2 and q=2.

[0306] Ring B can be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring, depending on the presence of R. 5B The number of functional groups. Saturated and unsaturated non-aromatic rings are preferred.

[0307] When R 5B When it exists, this R 5B H is preferred. In most instances, no more than one R. 5B It is an organic group that has been substituted or not substituted.

[0308] Two Rs 5B The groups can fused together such that ring B is a bridged bicycle, similar to what was described with respect to ring A. Most commonly, ring B is not a bridged bicycle.

[0309] Ring B can be a 7-membered saturated heterocycle, which optionally has the following structure:

[0310]

[0311] in:

[0312] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H;

[0313] X 1BA It is C and R 5B1 Selected from H and substituted or unsubstituted organic groups, and optionally H; or X 1BA It is N and R 5B1 It does not exist; and

[0314] X 1BC It is C and R 5B3 Selected from H and substituted or unsubstituted organic groups or X 1BC It is N and R 5B3 It does not exist.

[0315] Alternatively, ring B can be a 6-membered saturated heterocycle, which optionally has the following structure:

[0316]

[0317] in:

[0318] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H;

[0319] X 1BA It is C and R 5B1 Selected from H and substituted or unsubstituted organic groups, and optionally H; or X 1BAIt is N and R 5B1 It does not exist; and

[0320] X 1BC It is C and R 5B3 Selected from H and substituted or unsubstituted organic groups or X 1BC It is N and R 5B3 It does not exist.

[0321] In other examples, ring B is a 5-membered saturated heterocycle, which optionally has the following structure:

[0322]

[0323] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H;

[0324] X 1BA It is C and R 5B1 Selected from H and substituted or unsubstituted organic groups, and optionally H; or X 1BA It is N and R 5B1 It does not exist; and

[0325] X 1BC It is C and R 5B3 Selected from H and substituted or unsubstituted organic groups or X 1BC It is N and R 5B3 It does not exist.

[0326] In the above examples of 5-element, 6-element, and 7-element B-rings, X 1BA It can be C and R 5B1 It can be selected from H and substituted or unsubstituted organic groups; and R 5B1 H is optional. X is optional or alternative. 1BC It can be N and R 5B3 It can be non-existent.

[0327] The optimal B-ring structure is:

[0328] .

[0329] Ring C

[0330] The ring C of the PARP1 inhibitor compound has the following structure:

[0331] .

[0332] X 1CB Through the connection base Q BC X connected to ring B 1 atom.

[0333] X 1CB It is selected from N and C, and preferably C. When X 1CB When it is N, R 5C1 It does not exist.

[0334] Rings B and C are not connected by an N-N bond. For this purpose, when Q... BC yes And when u=0, X 1CB It is C. When atom X of ring B... 1BC It is N and Q BC When X does not exist, 1CB It's C.

[0335] X 2C X represents X as part of ring C 2 Atom. X 2CT It contains R 6 X 2C Atoms. Each X 2C The atoms are independently selected from C, N, O, and S; among which C and N are preferred. X is selected. 2C The atoms ensure that the ring C contains no OO, OS, or SS bonds. Optionally, at least one X 2C The atom is C. All X 2C The atom can be carbon (C). Preferably, exactly one X atom... 2C The atom is N, and each of the other X atoms is N. 2C The atom is C.

[0336] Each R 5C It exists independently or is selected from H and substituted or unsubstituted organic groups. R 5C1 Indicates with X 1CB Combined R 5C R 5C2 Indicates with X 2C Atomic bond R 5C R 5C3 Indicates with X 2CT Combined R 5 .

[0337] Two Rs 5C Group, or R 5C Groups and R 6 It can fused together to make ring C a bridged ring system.

[0338] 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.

[0339] In most instances, there is no more than one R. 5CIt is an organic group that has been substituted or not substituted.

[0340] Optionally, each R that is not non-existent 5C Selected from H and halogens. In such instances, no more than one R can be applied. 5C It is a condition for halogens.

[0341] The ring C can be a 4-, 5-, 6-, 7-, or 8-membered ring. For this purpose, r is 0 or an integer in the range of 1 to 6; s is 0 or an integer in the range of 1 to 6, and the sum of r and s is an integer in the range of 2 to 6.

[0342] Preferably, each of r and s is at least 1.

[0343] Ring C is preferably a 5-membered or 6-membered ring, and particularly preferably a 6-membered ring. In other words, the sum of r and s can be 3 or 4, preferably 4.

[0344] Depending on the chosen R 5C The number of groups, the ring C can be a saturated ring, an unsaturated non-aromatic ring or an aromatic ring.

[0345] Ring C can be a 6-membered aliphatic ring, optionally having the following structure:

[0346]

[0347] 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.

[0348] Alternatively, ring C can be a 6-membered aromatic ring.

[0349] For example, the ring C can be an optionally substituted phenyl group, which optionally has the following structure:

[0350] or

[0351] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0352] According to another possibility, the ring C can be a pyridine group, which optionally has a structure selected from the following:

[0353] , , , and ,

[0354] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0355] The ring C may optionally be a diazine group, which optionally has a structure selected from the following:

[0356] , , , , , and ,

[0357] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0358] Compounds in which ring C is a 5-membered aromatic ring are also considered.

[0359] For example, the ring C can be an imidazole group, optionally having an imidazole group selected from the following structures:

[0360] and ,

[0361] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0362] The ring C can be a thiophene group, which optionally has a structure selected from the following:

[0363] , and ,

[0364] Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0365] The ring C can be a thiazole group, which optionally has a structure selected from the following:

[0366] , , and

[0367] Each R 5CIndependently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H.

[0368] The ring C can be a triazole, optionally having the following structure:

[0369] or ,

[0370] R 5C Selected from H and substituted or unsubstituted organic groups, optionally wherein R 5C It is H.

[0371] Examples of C-ring structures include:

[0372]

[0373]

[0374] Particularly preferably, ring C has the following structure:

[0375]

[0376] in:

[0377] R 5C2o Selected from H, methyl groups, and halogens; and

[0378] i) X 2CM It is C and R 5C2M It is H; or

[0379] ii) X 2CM It is N and R5 C2M It does not exist.

[0380] Optional, R 5C2o Selected from H and halogens. Specifically, R 5C2o It can be a halogen, with F being the most preferred halogen.

[0381] Among the PARP1 inhibitor compounds provided in this article, R 6 It is absent or selected from H and substituted or unsubstituted organic groups. Preferably, 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 R52 R 52 -CR 52 R 52 NR 51 R 51 and any of the following structures:

[0382] , , ,

[0383] , , ,

[0384] and

[0385] Where 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, C1 to C3 optionally deuterated alkyl and C1 to C3 haloalkyl.

[0386] More preferably, 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 .

[0387] According to another possibility, R 6 It can have the following structure:

[0388]

[0389] Where R 51 Selected from:

[0390] C1 to C6 alkyl groups, optionally C3 to C6 cycloalkyl groups, C1 to C3 alkyl groups, or C1 to C3 deuterated alkyl groups;

[0391] C1 to C3 haloalkyl groups, optionally C1 to C3 fluoroalkyl groups; and

[0392] A 4-, 5-, 6-, or 7-membered saturated heterocyclic group, optionally a 4-, 5-, or 6-membered cyclic ether group.

[0393] For example, R 6 You can choose from:

[0394]

[0395] Optional, R 6 You can choose from:

[0396]

[0397] The optimal R 6 The group is CONHMe (i.e. )and .

[0398] When R 6 When the group is a CONHMe group, the CONHMe group is optionally deuterated: Deuteration of the CONHMe group can beneficially reduce the rate of compound metabolism.

[0399] When describing compounds, L groups, or C-ring structures as having R... 6 In the case of =CONHMe or CONHCD3, consider using Replace R 6 Group.

[0400] When describing compounds, L groups, or C-ring structures as having R... 6 = In this case, consider replacing R with CONHMe (optionally CONHCD3). 6 Group.

[0401] Available location, R 6 It can have the following structure:

[0402]

[0403] in:

[0404] Each X 6 Independently selected from C, N, and O;

[0405] R 61 It either does not exist or is H;

[0406] Each R 62Independently absent or selected from H; halogen 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.

[0407] Such R 6 Examples of functional groups include:

[0408]

[0409] The optimal C-ring is:

[0410] (optional) ), ,

[0411] (optional) )and

[0412]

[0413] According to another possibility, ring C can be selected from:

[0414] (optional) )or

[0415] .

[0416] According to another possibility, ring C can be selected from:

[0417]

[0418] Among the variants of the PARP1 inhibitor compounds provided in this article, R 6 And an R 5C The groups together form a ring. In other words, R 6 and R 5C One of the groups can fuse to form a ring system.

[0419] For example, ring C can have the following structure:

[0420]

[0421] in:

[0422] Each X F Independently selected from C, N, O, and S, with C and N optional;

[0423] Each R 5F It independently does not exist or is selected from H and substituted or unsubstituted organic groups; and

[0424] w is 1 or 2.

[0425] Usually, X is chosen. F The atoms ensure that the ring F does not contain OO, OS, and SS bonds.

[0426] Each R 5F Preferably, it is absent or selected from H and carbonyl groups.

[0427] X 2CT and X 2CF Each represents the X of the bridging rings C and F. 2 Atom. X 2CT and X 2CF Preferably, each is C.

[0428] The following are examples of fused ring systems that can be used as ring C:

[0429]

[0430] In such instances, each R 5F It is H or an organic group selected from substituted or unsubstituted groups. Preferably, each R 5F It is an H or C1 to C3 alkyl group.

[0431] As a more specific example, ring C can have the following structure:

[0432] .

[0433] In other examples of fused ring systems, ring F is an optionally substituted benzene ring:

[0434]

[0435] In such instances, each R 5F It is H or an organic group selected from substituted or unsubstituted groups. Preferably, each R 5F It is H.

[0436] More specific cyclic C groups in the above categories are:

[0437] .

[0438] Linking group (Q group)

[0439] As shown in the following formula, rings E, A, optional rings B and C are connected via a base Q. AE Q AB and Q BC connect:

[0440] .

[0441] The linker group may be referred to as the "Q group" in this paper. AE Q AB Q BC The rings A through C can be collectively referred to as group L.

[0442] Each linker may optionally be absent. When we say a linker "is absent," portions on either side of the linker are directly bonded by covalent bonds. For example, the expression "Q" AE "Does not exist" and "Q" AE "is key" is equivalent. When Q AB Ring B and Q BC When neither exists, there are covalent bonds between ring A and ring C.

[0443] Each linker is either independent (i.e., a bond) or selected from:

[0444] ,

[0445] and

[0446] in:

[0447] 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

[0448] Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0449] When Q group is In this case, t and u are chosen such that the Q group is attached to the ring via a CN bond instead of an NN bond. Typically, t is at least 1 and u is at least 1.

[0450] For example, Q AE Q AB and Q BC At least one of them can be:

[0451] , ,

[0452] or

[0453] Where t + u is at least one; and

[0454] Where R 7 The group is selected from H, halogens (such as -F, -Cl, -Br and -I, preferably -F), substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (preferably CF3), -NH2 groups or substituted or unsubstituted C1-C6 amino groups, -OH groups or substituted or unsubstituted straight-chain or branched C1-C6 alcohol groups and substituted or unsubstituted C1-C6 alkoxy groups.

[0455] In particular, R 7 It can be selected from H, halogen (preferably F), substituted or unsubstituted C1-C6 alkyl groups or substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups.

[0456] When Q AE Q AB and Q BC When at least one of them has the following structure:

[0457]

[0458] R 8 You can choose from:

[0459] H;

[0460] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups

[0461] (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl);

[0462] Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups

[0463] (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);

[0464] Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups

[0465] (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3);

[0466] Substituted or unsubstituted cyclic amine or amide groups

[0467] (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);

[0468] Substituted or unsubstituted cyclic C3-C8 alkyl groups

[0469] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl);

[0470] Substituted or unsubstituted straight-chain or branched C2-C6 alcohol groups

[0471] (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);

[0472] Substituted or unsubstituted straight-chain or branched C2-C6 carboxylic acid groups

[0473] (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH);

[0474] Substituted or unsubstituted straight-chain or branched carbonyl groups

[0475] (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);

[0476] Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups

[0477] (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe and -CH2CH2CH2CH2COOMe);

[0478] Substituted or unsubstituted straight-chain or branched C1-C6 amide groups

[0479] (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt);

[0480] Substituted or unsubstituted sulfonyl groups

[0481] (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);

[0482] Substituted or unsubstituted aromatic groups

[0483] (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

[0484] Substituted or unsubstituted heterocyclic groups

[0485] (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.

[0486] 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.

[0487] Preferably, Q AE It does not exist or is -CH2-. More preferably, Q AE It does not exist.

[0488] Preferably, Q AB It does not exist or is -CH2-. More preferably, Q AB It does not exist. When Q AB When absent, group L can have the following structure:

[0489] .

[0490] Preferably, Q BC It does not exist or is -CH2-. More preferably, Q BC It does not exist.

[0491] Q AB and Q BC Neither of these two can be present. In such an instance, group L can have the following structure:

[0492] .

[0493] Ideally, ring b exists, and all Q... AE Q AB and Q BC No. In such an instance, the PARP1 inhibitor compound may have the following structure:

[0494]

[0495] Example L group

[0496] In particular, the group L can have a structure selected from the following:

[0497] , ,

[0498] , , , , and .

[0499] Particularly preferably, L may have the following structure:

[0500] or .

[0501] R 5A R 5B R 5C and R 6 As defined above.

[0502] The particularly preferred L group is an L group that, in which:

[0503] Each R 5A (For example, R) 5A1 ) is H;

[0504] Each R 5B It is H;

[0505] Each R 5C The components are independently selected from H, methyl groups, and halogens (preferably F), provided that no more than one R is present. 5C It is a methyl group or a halogen; and

[0506] R 6 yes (optional) )or .

[0507] Optionally, each R 5C The components are independently selected from H and halogens (preferably F), provided that no more than one R is selected. 5C It is halogen.

[0508] The group L can specifically have a structure selected from the following:

[0509] , , and .

[0510] According to another possibility, L could be:

[0511]

[0512] Example compounds

[0513] Specifically, PARP1 inhibitor compounds having the following structures are provided:

[0514] or

[0515]

[0516] in:

[0517] Z 1 It is C or N;

[0518] Z 2u and Z 2l One is C, and Z 2u and Z 2l The other one is N;

[0519] Each Z 3 Independently selected from C and N;

[0520] R 1 It is absent or selected from H, halogens (e.g., F), methyl, halomethyl (e.g., CF3) and CN;

[0521] R 5C2o It is an H, a methyl group, or a halogen (e.g., F);

[0522] X 2CM It is N and R 5C2M Does not exist or X 2CM It is C and R 5C2M It is H; and

[0523] R 6 yes (optional) )or .

[0524] Optional, R 5C2o It is H or a halogen, such as F.

[0525] R 1 It can be selected from H, halogen (e.g., F), methyl, halomethyl (e.g., CF3) and CN.

[0526] Specific PARP1 inhibitor compounds include:

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533] Some of the PARP1 inhibitor compounds described herein contain 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.

[0534] Some PARP1 inhibitor compounds may be capable of tautomerism. Such compounds can be provided in any possible tautomer form.

[0535] Medical Use

[0536] 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.

[0537] Specifically, 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 type of cancer that can be treated, prevented, or improved using a PARP1 inhibitor. Cancers can include solid tumors or liquid tumors.

[0538] For example, cancers include: 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).

[0539] 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.

[0540] The compounds described herein may be provided for the treatment of cancers deficient in DNA damage response repair pathways, particularly 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.

[0541] 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).

[0542] The compounds described herein may be administered to patients undergoing radiation therapy and / or chemotherapy using other agents used to treat cancer.

[0543] For example, the PARP1 inhibitor compound can be administered in combination with other agents used to treat cancer.

[0544] 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, anti-angiogenic agents, and cell cycle signaling inhibitors.

[0545] 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.

[0546] Pharmaceutical Composition

[0547] On the other hand, a pharmaceutical composition is provided that comprises a PARP1 inhibitor compound as defined above.

[0548] Typically, the composition contains pharmaceutically acceptable additives and / or excipients.

[0549] 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.

[0550] Typically, the composition is intended for use in medicine, for example, to treat diseases, conditions, or disorders as defined above.

[0551] 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.

[0552] 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.

[0553] 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.

[0554] Package products

[0555] 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.

[0556] The additional agent for treating cancer may be any additional agent for treating cancer identified in the discussion of pharmaceutical compositions above.

[0557] 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.

[0558] Treatment

[0559] 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.

[0560] 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.

[0561] 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.

[0562] The patient may be undergoing treatment using ionizing radiation.

[0563] Methods for synthesizing PARP1 inhibitor compounds

[0564] Methods for synthesizing PARP1 inhibitor compounds as defined herein are also provided. Generally, the methods involve a reaction between the following reactants:

[0565] i) A first reactant comprising rings D and E and a first moiety having a group L.

[0566] ii) A second reactant, which contains the remainder of the group L.

[0567] To form a PARP1 inhibitor compound. Those skilled in the art can select reaction conditions based on suitable starting materials and known synthetic techniques. The method may include one or more additional steps. Exemplary synthetic methods are shown in the examples below.

[0568] In one example method, the first reactant comprises rings D, E, and A, and the second reactant comprises Q with a reactive group. AB The precursor, and the method includes connecting ring A to Q. AB Precursor. In this method, Q AB The reactive group of the precursor may include a carbonyl group, an alkyl halide, or an alkyl sulfonate ester. The reaction may include alkylation, reductive amination, or amide formation to form the group L.

[0569] In some embodiments of this example method, the first reactant has the following structure:

[0570] .

[0571] The first reactant can be prepared by deprotecting an intermediate product having the following structure:

[0572] ,

[0573] Where R PG It is a protecting group.

[0574] It should be understood that R 1 R 2 R 5 The X and Z groups are as defined above for PARP1 inhibitor compounds.

[0575] The first reactant can be prepared by providing a precursor having the following structure:

[0576]

[0577] And by using NHR 3 The precursor may be treated with its conjugate acid to carry out a ring-closing reaction to form the first reactant. R 3 As described above regarding compounds.

[0578] R 9 It is a C1 to C6 alkyl group, optionally an ethyl group.

[0579] R PG It can be a Boc.

[0580] R 3 It can be H.

[0581] Z 2l It can be N and Z 2u It could be C.

[0582] In some implementations, Z 1 It is C and the precursor may have the following structure:

[0583] .

[0584] In the alternative implementation, Z 1 It is N and the precursor has the following structure:

[0585] .

[0586] The above precursors can be obtained through the following methods:

[0587] a) In the presence of a base (such as sodium hydride), make a compound having the following structure:

[0588]

[0589] Reaction with phenylhydroxylamine having the following structure:

[0590]

[0591] Where EWG represents one or more electron-withdrawing groups;

[0592] To obtain an intermediate product having the following structure:

[0593] ;and

[0594] b) React the intermediate with a carboxylic acid having the following structure:

[0595]

[0596] The precursor was obtained.

[0597] In this method, the substituted phenylhydroxylamine can be O-(2,4-dinitrophenyl)hydroxylamine:

[0598] .

[0599] Alternative methods for preparing a first reactant having the following structure include:

[0600]

[0601] a) Provide a first precursor having the following structure:

[0602]

[0603] Where R 10 It is a C1 to C6 alkyl group, optionally a tert-butyl group;

[0604] b) Provide a second precursor having the following structure:

[0605]

[0606] Where R PG It is a protecting group, optionally Boc; and

[0607] c) Using a catalyst, optionally [Cp] The RhCl2]2 catalyst couples the first precursor and the second precursor to form the first reactant.

[0608] The second reactant may have the following structure:

[0609] .

[0610] The second reactant can be prepared as follows:

[0611] i) Provide the first precursor of the following formula:

[0612]

[0613] in:

[0614] a) X 2CM It is C and R 5C2M It is H; or

[0615] b) X 2CM It is N and R5 C2M It does not exist.

[0616] ii) Provide a second precursor for the following formula:

[0617]

[0618] iii) Using a base, optionally a cesium base such as Cs₂CO₃, to couple the first and second precursors to obtain an intermediate of the following formula:

[0619] ;and

[0620] iv) Treat the intermediate with acid to obtain the second reactant, wherein the second reactant has the following structure:

[0621] .

[0622] The second precursor is 1,4-dioxa-8-azaspiro[4.5]decane:

[0623] .

[0624] The reaction may include coupling a first reagent and a second reagent with a reducing agent in the presence of an acid.

[0625] In another example method, the first reactant comprises rings A, B, D and E, Q. AE and Q AB The second reactant comprises a cyclic C derivative with a leaving group (such as a halogen 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.

[0626] A mixture of PARP1 inhibitor compounds as structural isomers can be obtained. In such embodiments, the method may further include separating the structural isomers using chiral supercritical fluid chromatography and / or chiral high-performance liquid chromatography.

[0627] Example

[0628] Example 1: Synthesis of 1a / 1b

[0629]

[0630] Option 1

[0631] Preparation of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1003)

[0632] To a solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid 1001 (5.0 g, 0.0231 mol) in DCM (200 mL), N,O-dimethylhydroxylamine hydrochloride 1002 (4.5 g, 0.0462 mol), DIPEA (14.9 g, 0.115 mol), and HATU (17.6 g, 0.0462 mol) were added. The mixture was stirred at room temperature for 2 h, diluted with water (1.6 L), and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylic acid 1003 (6.0 g, 80% purity, 80% yield) as a colorless oil.

[0633] C 12 H 22 LCMS (ESI) calculated value of N₂O₄ [M - 56 + H] +m / z 203.10, measured value 202.95.

[0634] Preparation of tert-butyl 3-acetylpyrrolidine-1-carboxylate (1004)

[0635] MeMgBr (38.5 mL, 0.1155 mol, 3 MTF solution) was added to a solution of tert-butyl 3-acetylpyrrolidine-1-carboxylate 1003 (6.0 g, 0.0231 mol) in THF (300 mL) at -78 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 1 h, quenched with saturated NH4Cl solution, and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give tert-butyl 3-acetylpyrrolidine-1-carboxylate 1004 (3.5 g, 90% purity, 63% yield) as a colorless oil.

[0636] C 11 H 19 LCMS (ESI) calculation value of NO3 [M - 56 + H] + m / z 158.08, measured value 158.00.

[0637] Preparation of tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate (1005)

[0638] TBABr3 (5.4 g, 11.2 mol) was added to a solution of tert-butyl 3-acetylpyrrolidine-1-carboxylate 1004 (1.2 g, 5.6 mmol) in DCM / MeOH (2:1, 30 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (eluting with 30% to 40% EtOAc / PE) to yield tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 1005 (300 mg, 50% purity, 8% yield) as a colorless oil.

[0639] C 11 H 18 LCMS (ESI) values ​​of BrNO3 [M - 56 + H] + m / z 235.99, measured value 235.85.

[0640] 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-5-methyl-1H-pyrrole-2-carboxylic acid Preparation of ethyl acetate (1007)

[0641] Add tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 1005 (300 mg, 1.02 mmol) to a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate 1006 (157 mg, 1.02 mmol) and Cs₂CO₃ (667 mg, 2.05 mmol) in DMF (10 mL). Heat the mixture at 50 °C for 1 h. Quench the reaction mixture with water and extract with EtOAc (50 mL × 3). Wash the combined organic layers with brine, dry to Na₂SO₄, and concentrate under reduced pressure. The residue was purified by rapid chromatography (eluting with 30% to 50% EtOAc / PE) to produce ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-5-methyl-1H-pyrrole-2-carboxylate 1007 (130 mg, 50% purity, 17% yield) as a yellow oil.

[0642] C 19 H 28 LCMS (ESI) calculated value of N2O5 [M + H] + m / z 365.20, measured value 365.03.

[0643] 3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester Preparation of (1008)

[0644] A solution of 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-5-methyl-1H-pyrrolo-2-carboxylate ethyl 1007 (130 mg, 0.35 mmol) in NH3-MeOH (7 M, 20 mL) was stirred in a sealed test tube at 110 °C for 16 h. The resulting mixture was concentrated and purified by silica gel column chromatography (eluting with 50% to 70% EtOAc / PE) to yield 3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylate tert-butyl 1008 (60 mg, 90% purity, 47% yield) as a white solid.

[0645] C 17 H 23 LCMS (ESI) values ​​of N3O3 [M + H] + m / z 318.18, measured value 318.15.

[0646] Preparation of 6-methyl-3-(pyrrolidine-3-yl)pyrrolo[1,2-a]pyrazine-1(2H)-one hydrochloride (1009)

[0647] A solution of tert-butyl 3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylate 1008 (60 mg, 0.19 mmol) in HCl-dioxane solution (4 M, 5 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and ground in DCM. The precipitate was collected and dried under vacuum to provide 6-methyl-3-(pyrrolo-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one hydrochloride 1009 (50 mg, 80% purity, 83% yield) as a white solid.

[0648] C 12 H 15 LCMS (ESI) values ​​of N3O [M + H] + m / z 218.12, measured value 218.15.

[0649] Racemic N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl) Preparation of pyrrolidine-1-yl)piperidin-1-yl)pyridineamide (1rac)

[0650] To a solution of 6-methyl-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one hydrochloride 1009 (50 mg, 0.20 mmol) in MeOH (5 mL), N-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-carboxamide INT-1 (80 mg, 0.34 mmol), 2 drops of AcOH, NaBH3CN (14 mg, 0.23 mmol), and NaBH(OAc)3 (146 mg, 0.69 mmol) were added. The reaction mixture was stirred at room temperature for 1 h, quenched with 2 drops of water, and concentrated under reduced pressure. The residue was analyzed by preparative HPLC (Gemini 5 μm C). 18 150 × 21.2 mm, purified with 40% to 80% ACN / H2O containing 0.05% NH3·H2O to produce a racemic mixture of N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide 1rac, 1a and 1b as a white solid (20 mg, 95% purity, 22% yield).

[0651] Chiral separation of racemic N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyridine (1rac) azinon-3-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide (1rac) to obtain 1a and 1b

[0652] A racemic mixture of N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide was separated by SFC (column: Daicel Chiralpak IH 20 mm ID × 250 mm, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 70 / 30) and concentrated under reduced pressure to provide a first fraction as 1a (4.7 mg, 94% purity, 100% ee, white solid) and a second fraction as 1b (3.8 mg, 96% purity, 100% ee, white solid).

[0653] 1a

[0654] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 10.18 (s, 1 H), 8.46-8.31 (m, 1 H), 8.28 (d, J =2.8 Hz, 1 H), 7.82 (d, J =8.8 Hz, 1 H), 7.40 (dd, J =8.8, 2.8 Hz, 1H), 6.99 (s, 1H), 6.75 (d, J =3.6 Hz, 1 H), 6.28 (d, J =4.0 Hz, 1 H), 3.93-3.71 (m, 2 H), 3.18-3.07 (m, 1 H), 2.99 (t, J =11.6 Hz, 2 H), 2.90-2.75 (m, 5H), 2.73-2.64 (m, 2 H), 2.33 (s, 3 H), 2.20-2.13 (m, 1 H), 2.00-1.91 (m, 2H), 1.89-1.80 (m, 1 H), 1.62-1.50 (m, 2H).

[0655] C 24 H 30 LCMS (ESI) values ​​of N6O2 [M + H] + m / z 435.25, measured value 435.09.

[0656] 1b

[0657] 1H NMR (400 MHz, DMSO- d 6, ppm) δ: 10.17 (s, 1 H), 8.38 (q, J =4.7 Hz, 1H), 8.28 (d, J =2.8 Hz, 1 H), 7.82 (d, J =8.8 Hz, 1 H), 7.40 (dd, J =8.8, 2.8Hz, 1H), 6.99 (s, 1H), 6.75 (d, J =3.6 Hz, 1 H), 6.28 (d, J =3.6 Hz, 1 H),3.85-3.74 (m, 2 H), 3.15-3.05 (m, 1 H), 2.99 (t, J =11.6 Hz, 2 H), 2.90-2.81(m, 2 H), 2.78 (d, J =4.8 Hz, 3 H), 2.73-2.62 (m, 2 H), 2.33 (s, 3 H), 2.22-2.10 (m, 1 H), 2.01-1.90 (m, 2 H), 1.89-1.77 (m, 1 H), 1.61-1.45 (m, 2 H).

[0658] C 24 H 30 LCMS (ESI) values ​​of N6O2 [M + H] + m / z 435.25, measured value 435.12.

[0659] Example 2: Synthesis of 2rac

[0660]

[0661] Option 2

[0662] 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-5-carboxylic acid Preparation of ethyl ester (1102)

[0663] To a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate 1101 (110 mg, 0.71 mmol) in DMF (5 mL) at room temperature, tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 1005 (230 mg, 0.78 mmol) and Cs₂CO₃ (465 mg, 1.43 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction solution was quenched with ice water and extracted with EtOAc (30 mL x 3). The organic phase was concentrated under reduced pressure and the residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 70:30) to produce ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-5-carboxylate 1102 (40 mg, 80% purity, 12% yield) as a yellow oil.

[0664] C 18 H 27 LCMS (ESI) calculated value of N3O5 [M + H] + m / z 366.20, measured value 366.35.

[0665] 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl)pyrrolidine-1-carboxylic acid tert-butyl ester Preparation of (1103)

[0666] NH4OAc (170 mg, 2.20 mmol) was added to a solution of 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-5-carboxylate 1102 (40 mg, 0.11 mmol) in EtOH (3 mL) at room temperature. The reaction mixture was stirred in a sealed test tube at 110 °C for 8 h. The reaction solution was concentrated under reduced pressure and the residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 30:70) to give 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl)pyrrolidine-1-carboxylate tert-butyl ester 1103 (23 mg, 80% purity, 42% yield) as a yellow oil.

[0667] C 16 H 22 LCMS (ESI) calculation of N4O3 [M - t-Bu + H] + m / z 263.17, measured value 263.20.

[0668] Preparation of 2-methyl-6-(pyrrolidone-3-yl)pyrazolo[1,5-a]pyrazine-4(5H)-one hydrochloride (1104)

[0669] To a solution of 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 1103 (23 mg, 0.072 mmol) in DCM (2 mL), 4 M HCl / dioxane (5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to give 2-methyl-6-(pyrrolidine-3-yl)pyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride 1104 (20 mg, 80% purity, 87% yield) as a yellow solid.

[0670] C 11 H 14 LCMS (ESI) values ​​of N4O [M + H] + m / z 219.12, measured value 219.10.

[0671] Racemic N-methyl-5-(4-(3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl) Preparation of pyrrolidone-1-yl)piperidin-1-yl)pyridine amide (2rac)

[0672] TEA (1 mL) was added to a solution of 2-methyl-6-(pyrrolidone-3-yl)pyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride 1104 (20 mg, 0.092 mmol) in MeOH (1 mL) at room temperature and stirred for 5 min. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (5 mL) and AcOH (0.1 mL) at room temperature. N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide INT-1 (26 mg, 0.11 mmol) and NaBH3CN (12 mg, 0.19 mmol) were added at room temperature. The reaction mixture was then stirred at 50 °C for 1 h. The resulting reaction solution was concentrated under reduced pressure and the residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) and preparative HPLC (Gemini 5 μm C18 150 × 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 40 - 95) to produce 2rac (6.9 mg, 98% purity, 17% yield) of racemic N-methyl-5-(4-(3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide as a white solid.

[0673] 1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.03 (s, 1 H), 8.42-8.34 (m, 1 H), 8.28 (d, J=2.8 Hz, 1 H), 8.14 (s, 0.9 H), 7.82 (d, J=8.8 Hz, 1 H), 7.49 (s, 1H), 7.40 (dd, J=8.8, 2.8 Hz, 1 H), 6.70 (s, 1 H), 3.88-3.79 (m, 2 H), 3.20-3.13 (m, 1 H), 3.00-2.92 (m, 3 H), 2.88-2.82 (m, 1 H), 2.78 (d, J=4.8 Hz, 3H), 2.76-2.69 (m, 2 H), 2.44-2.40 (m, 1 H), 2.31 (s, 3 H), 2.22-2.13 (m, 1 H), 2.00-1.92 (m, 2 H), 1.90-1.81 (m, 1 H), 1.60-1.47 (m, 2 H).

[0674] C 23 H 29 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 436.24, measured value 436.25.

[0675] Example 3: Synthesis of 6rac

[0676]

[0677] Option 3

[0678] Preparation of 1H-pyrrole-1-carboxylic acid (1202)

[0679] 1H-pyrrole 1201 (2.3 g, 34.3 mmol) was slowly added to an ice-cold solution of t-BuOK (4.23 g, 37.7 mmol) in 120 mL of Et₂O / THF (1:1). The reaction mixture was warmed to room temperature and stirred for 30 min. After this time, excess solid CO₂ was slowly added through the top of the flask, resulting in vigorous bubbling and a drop in reaction temperature. The reaction vessel was placed in a room temperature water bath and allowed to stand until no solid CO₂ remained at the bottom of the flask. 300 mL of H₂O was added, and the contents were transferred to a separatory funnel. The aqueous layer was collected, and the organic phase was washed with 300 mL of H₂O. The combined aqueous extracts were acidified to pH < 1 with 1.0 M HCl aqueous solution. Then 40 mL of Et₂O was added to this aqueous solution, and the contents were transferred to a separatory funnel again. The organic phase was collected, and the aqueous phase was extracted with 2 x 40 mL of Et₂O. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 1H-pyrrole-1-carboxylic acid 12O2 as a white solid (1.6 g, 90% purity, 37% yield).

[0680] LCMS (ESI) values ​​of C5H5NO2 [M + H] + m / z 112.04, no MS signal.

[0681] Preparation of N-(neovaleroxy)-1H-pyrrole-1-carboxamide (1204)

[0682] DMF (0.070 g, 0.90 mmol) was added to a stirred solution of (COCl)₂ (1.26 g, 9.90 mmol) in THF (25 mL) at 0 °C. The reaction mixture was stirred for 10 min and then added in two portions at 0 °C to 1H-pyrrole-1-carboxylic acid 1202 (1.0 g, 9.00 mmol). The reaction mixture was stirred at 0 °C for 15 min, the cooling bath was removed, and the reaction mixture was then stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to give crude acyl chloride. O-neopentylhydroxylamine trifluoromethanesulfonate 1203 (2.4 g, 9.00 mmol) was added to a stirred solution of Na₂CO₃ (1.91 g, 18.00 mmol) in EtOAc (40 mL) and water (20 mL) at 0 °C, followed by the addition of acyl chloride in EtOAc (5 mL). The reaction mixture was stirred at 0 °C for 2 h, and the reaction progress was monitored by TLC. EtOAc (60 mL) was added to the mixture. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 20% to 40% EtOAc / PE) to give N-(neovaleroxy)-1H-pyrrole-1-carboxamide 1204 (0.60 g, 90% purity, 28% yield) as a white solid.

[0683] C 10 H 14 LCMS (ESI) values ​​of N₂O₃ [M - H] - m / z 209.09, measured value 209.10.

[0684] 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1206) and Preparation of tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-4-yl)pyrrolidine-1-carboxylate (1206a)

[0685] Add AcOCs (0.55 g, 2.85 mmol) and [Rh(Cp) to a stirred solution of N-(neopentyloxy)-1H-pyrrole-1-carboxamide 1204 (0.6 g, 2.85 mmol) in MeOH (20 mL) [Cl2]2 (0.17 g, 2.85 mmol) and tert-butyl 3-ethynylpyrrolidine-1-carboxylate 1205 (0.56 g, 2.85 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated and purified by rapid chromatography (eluting with 30% to 60% EtOAc / PE) to give tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3-yl)pyrrolidine-1-carboxylate 1206 (300 mg, 90% purity, 31% yield) and tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-4-yl)pyrrolidine-1-carboxylate 1206a (200 mg, 90% purity, 21% yield) as yellow solids.

[0686] 1206: C 16 H 21 LCMS (ESI) values ​​of N3O3 [M + H] + m / z 304.16, measured value 303.97.

[0687] 1206a: C 16 H 21 LCMS (ESI) values ​​of N3O3 [M + H] + m / z 304.16, measured value 303.95.

[0688] Preparation of 3-(pyrrolidine-3-yl)pyrrolo[1,2-c]pyrimidine-1(2H)-one hydrochloride (1207)

[0689] A solution of tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3-yl)pyrrolidine-1-carboxylate 1206 (100 mg, 0.32 mmol) in HCl dioxane solution (4 M, 10 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to provide 3-(pyrrolidin-3-yl)pyrrolo[1,2-c]pyrimidin-1(2H)-one hydrochloride 1207 (80 mg, 90% purity, 94% yield) as a brown solid.

[0690] C 11 H 13 LCMS (ESI) values ​​of N3O [M + H] + m / z 204.11, measured value 204.10.

[0691] Racemic N-methyl-5-(4-(3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3-yl)pyrrolidine- Preparation of 1-yl)piperidin-1-yl)pyridine amide (6rac)

[0692] To a solution of 3-(pyrrolidine-3-yl)pyrrolo[1,2-c]pyrimidin-1(2H)-one hydrochloride 1207 (80 mg, 0.34 mmol) in MeOH (10 mL) at room temperature, N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-1 (120 mg, 0.52 mmol), 2 drops of acetic acid, NaBH3CN (22 mg, 0.34 mmol), and NaBH(OAc)3 (146 mg, 0.69 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, eluted with 15% to 45% ACN / H2O containing 0.05% NH3) to produce N-methyl-5-(4-(3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide 6rac racemic mixture (5.1 mg) as a white solid.

[0693] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 10.70 (s, 1 H), 8.41-8.35 (m, 1 H), 8.31-8.28 (m, 1.4 H), 8.28-8.25 (m, 1 H), 7.82 (d, J =8.8 Hz, 1 H), 7.44-7.35(m, 2 H), 6.57 (t, J =3.2 Hz, 1 H), 6.35 (s, 1 H), 6.22-6.17 (m, 1 H), 3.84-3.79 (m, 2 H), 3.13-3.08 (m, 1 H), 2.99-2.90 (m, 3 H), 2.81-2.74 (m, 4 H),2.70-2.64 (m, 2 H), 2.37-2.32 (m, 1 H), 2.24-2.11 (m, 1 H), 1.99-1.91 (m, 2H), 1.84-1.76 (m, 1 H), 1.60-1.48 (m, 2 H).

[0694] C 23 H 28 LCMS (ESI) values ​​of N6O2 [M + H] + m / z 421.23, measured value 421.35.

[0695] Example 4: Synthesis of 8rac

[0696]

[0697] Option 4

[0698] Preparation of 6-bromo-8-methoxyimidazo[1,2-a]pyrazine (1302)

[0699] Sodium hydride (60% dispersion in mineral oil, 173 mg, 4.333 mmol) was added fractionally to a mixture of 6,8-dibromoimidazolo[1,2-a]pyrazine 1301 (1000 mg, 3.611 mmol) in MeOH (30 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and most of the MeOH was removed by evaporation. The residue was extracted three times with EtOAc. The combined organic layers were washed with water and brine, concentrated under vacuum, and purified by rapid silica gel chromatography (eluting with 0 to 8% MeOH / DCM) to 6-bromo-8-methoxyimidazolo[1,2-a]pyrazine 1302 (680 mg, 90% purity, 74% yield) as a yellow solid.

[0700] LCMS (ESI) values ​​of C7H6BrN3O [M + H] + m / z 227.97, measured value 227.85.

[0701] 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester Preparation of (1304)

[0702] A suspension of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 1303 (324 mg, 1.096 mmol), 6-bromo-8-methoxyimidazo[1,2-a]pyrazine 1302 (250 mg, 1.096 mmol), Na₂CO₃ (228 mg, 2.192 mmol), and Pd(dppf)Cl₂ (80 mg, 0.109 mmol) in dioxane / H₂O (4 / 1, 10 mL) was heated at 90 °C for 2 h under N₂. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with EtOAc (50 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 (eluting with 0 to 85% EtOAc / PE) to produce tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 1304 (220 mg, 90% purity, 56% yield) as a white solid.

[0703] C 16 H 20 LCMS (ESI) values ​​of N4O3 [M + H] + m / z 317.15, measured value 317.15.

[0704] Preparation of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)pyrrolidine-1-carboxylate (1305)

[0705] A solution of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)-2,5-dihydro-1H-pyrrolo-1-carboxylate 1304 (220 mg, 0.693 mmol) and Pd / C (10%, 147 mg) in MeOH (10 mL) was stirred at room temperature for 2 h under H2 atmosphere. The resulting solution was filtered and concentrated under reduced pressure to provide tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)pyrrolo-1-carboxylate 1305 (180 mg, 90% purity, 73% yield) as a white solid.

[0706] C 16 H 22 LCMS (ESI) values ​​of N4O3 [M + H] + m / z 319.17, measured value 319.25.

[0707] Preparation of 6-(pyrrolidone-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one (1306)

[0708] A solution of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)pyrrolidine-1-carboxylate 1305 (180 mg, 0.563 mmol) in HBr in H2O (48 wt%, 5 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated. The residue was diluted with MeOH (5 mL), TEA (1 mL) was added and stirred for 5 min, and then concentrated to dryness to give 6-(pyrrolidine-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one 1306 (100 mg, 90% purity, 78% yield) as a yellow oil.

[0709] C 10 H 12 LCMS (ESI) values ​​of N4O [M + H] + m / z 205.10, measured value 205.00.

[0710] Racemic N-methyl-5-(4-(3-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-6-yl)pyrrolidine- Preparation of 1-yl)piperidin-1-yl)pyridine amide (8rac)

[0711] N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-1 (68 mg, 0.293 mmol) and NaBH3CN (37 mg, 0.587 mmol) were added to a solution of 6-(pyrrolidone-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one 1306 (60 mg, 0.293 mmol) in MeOH (10 mL) and AcOH (0.01 mL) at room temperature. The reaction mixture was stirred at 50 °C for 1 h. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (Gemini 5 μm C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 30-60) and SFC (Daicel ChiralpakOJ-H 250 mm×20 mm ID, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3)=70 / 30) to produce N-methyl-5-(4-(3-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-6-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide 8rac racemic as a white solid (30.2 mg, 99% purity, 24% yield).

[0712] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.01 (s, 1 H), 8.41-8.34 (m, 1 H), 8.27 (d, J =2.4 Hz, 1 H), 7.82 (d, J =8.8 Hz, 1 H), 7.73 (s, 1 H), 7.45-7.37(m, 3 H), 3.87-3.78 (m, 2 H), 3.16-3.10 (m, 1 H), 3.00-2.88 (m, 3 H), 2.81-2.74 (m, 4 H), 2.71-2.63 (m, 2 H), 2.36-2.29 (m, 1 H), 2.24-2.14 (m, 1 H), 1.97-1.89 (m, 2 H), 1.84-1.75 (m, 1 H), 1.58-1.45 (m, 2 H).

[0713] C 22 H 27 LCMS (ESI) values ​​of N7O2 [M + H] +m / z 422.22, measured value 422.15.

[0714] Example 5: Synthesis of 10a / 10b

[0715]

[0716] Option 5A

[0717]

[0718] Option 5B

[0719]

[0720] Solution 5C

[0721] 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-fluoro-1H-pyrrole-2-carboxylic acid Preparation of ester (1403)

[0722] A solution of ethyl 3-fluoro-1H-pyrrole-2-carboxylate 1401 (600 mg, 3.825 mmol), Cs₂CO₃ (2506 mg, 7.619 mmol), and tert-butyl 3-(2-bromoacetyl)pyrrole-1-carboxylate 1005 (740 mg, 2.543 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (eluting with DCM / MeOH at a ratio of 100:0 to 90:10) to produce ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-fluoro-1H-pyrrole-2-carboxylate 1403 (1000 mg, 90% purity, 63% yield) as a yellow oil.

[0723] C 18 H 25 LCMS (ESI) calculation of FN2O5 [M - t-Bu + H] + m / z 313.17, measured value 313.10.

[0724] 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester Preparation of (1404)

[0725] NH4OAc (20900 mg, 27.17 mmol) was added to a solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-fluoro-1H-pyrrole-2-carboxylate 1403 (1000 mg, 2.717 mmol) in EtOH (15 mL). The mixture was stirred in a steel reactor at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (eluting with DCM / MeOH at a ratio of 100:0 to 90:10) to yield a racemic mixture of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylate 1404 (600 mg, 95% purity, 65% yield) as a yellow oil.

[0726] C 16 H 20 LCMS (ESI) values ​​of FN3O3 [M + H] + m / z 321.15, measured value 321.70.

[0727] 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester Preparation of (1404-P1 and 1404-P2)

[0728] The racemic mixture of 1404 (300 mg, 0.934 mmol) was separated by SFC (column: Daicel Chiralpak IH 20 mm ID×250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)]=60 / 40) and concentrated under reduced pressure to provide the first fraction as 1404-P1 (120 mg, 95% purity, white solid) and the second fraction as 1404-P2 (90 mg, 95% purity, white solid).

[0729] Preparation of 8-fluoro-3-(pyrrolidine-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one (1405-P1)

[0730] A solution of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylate 1404-P1 (120 mg, 0.374 mmol) in HCl-dioxane (4 M, 2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was diluted with MeOH (5 mL) and TEA (1 mL). After stirring at room temperature for 5 min, the solution was concentrated to dryness to give 8-fluoro-3-(pyrrolo-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one 1405-P1 (100 mg, 70% purity, 84% yield) as a white solid.

[0731] C11 H 12 LCMS (ESI) values ​​of FN3O [M + H] + m / z 222.10, measured value 222.30.

[0732] 6-Fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidin-1-yl) Preparation of piperidine-1-yl)-N-methylpyridine amide (10a)

[0733] To a solution of 8-fluoro-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one 1405-P1 (35 mg, 0.157 mmol) in MeOH (10 mL), 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-2 (47 mg, 0.188 mmol), 2 drops of HOAc, and NaBH(OAc)3 (33 mg, 0.157 mmol) were added. The mixture was stirred at 50 °C for 30 min, and NaBH3CN (10 mg, 0.158 mmol) was added and stirred at 50 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (Gemini 5 μm C). 18 150 × 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 5 - 90) Purification to produce 6-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-yl)piperidin-1-yl)-N-methylpyridineamide 10a (37.2 mg, 98% purity, 100% ee, 52% yield) as a white solid.

[0734] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 10.22 (s, 1 H), 8.47-8.31 (m, 1 H), 7.83 (d, J =8.0 Hz, 1 H), 7.58 (dd, J =10.4, 8.0 Hz, 1 H), 7.26-7.17 (m, 1 H),7.13 (s, 1 H), 6.36 (d, J=2.8 Hz, 1 H), 3.57-3.45 (m, 2 H), 3.10-2.96 (m, 1H), 2.93-2.81 (m, 3 H), 2.81-2.70 (m, 4 H), 2.69-2.57 (m, 2 H), 2.31-2.21 (m,1 H), 2.22-2.08 (m, 1 H), 2.04-1.89 (m, 2 H), 1.84-1.68 (m, 1 H), 1.67-1.49 (m, 2 H).

[0735] C 23 H 26 LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 457.21, measured value 457.30.

[0736] Preparation of 8-fluoro-3-(pyrrolidine-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one (1405-P2)

[0737] A solution of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylate 1404-P2 (90 mg, 0.281 mmol) in HCl-dioxane (4 M, 2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was diluted with MeOH (5 mL) and TEA (1 mL). After stirring at room temperature for 5 min, the solution was concentrated to dryness to give 8-fluoro-3-(pyrroloidine-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one 1405-P2 (70 mg, 70% purity, 78% yield) as a white solid.

[0738] C 11 H 12 LCMS (ESI) values ​​of FN3O [M + H] + m / z 222.10, measured value 222.25.

[0739] 6-Fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidin-1-yl) Preparation of piperidine-1-yl)-N-methylpyridine amide (10b)

[0740] To a solution of 8-fluoro-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one 1405-P2 (35 mg, 0.157 mmol) in MeOH (10 mL), 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-2 (47 mg, 0.188 mmol), 2 drops of HOAc, and NaBH(OAc)3 (33 mg, 0.157 mmol) were added. The mixture was stirred at 50 °C for 30 min, and NaBH3CN (10 mg, 0.158 mmol) was added and stirred at 50 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to preparative HPLC (Gemini 5 μm C). 18 150 × 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 5 - 90) purification to produce 6-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-yl)piperidin-1-yl)-N-methylpyridineamide as a white solid 10b (36.3 mg, 98% purity, 100% ee, 50% yield).

[0741] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 10.22 (s, 1 H), 8.47-8.30 (m, 1 H), 7.84 (d, J =8.0 Hz, 1 H), 7.58 (dd, J =10.4, 8.0 Hz, 1 H), 7.23-7.18 (m, 1 H),7.13 (s, 1 H), 6.36 (d, J =2.8 Hz, 1 H), 3.55-3.48 (m, 2 H), 3.09-2.97 (m, 1H), 2.93-2.81 (m, 3 H), 2.81-2.74 (m, 4 H), 2.71-2.58 (m, 2 H), 2.35-2.22 (m,1 H), 2.22-2.08 (m, 1 H), 2.04-1.90 (m, 2 H), 1.85-1.68 (m, 1 H), 1.66-1.49 (m, 2 H).

[0742] C 23 H 26LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 457.21, measured value 457.30.

[0743] Example 6: Synthesis of 12a / 12b

[0744]

[0745] Option 6

[0746] Preparation of ethyl 2-methyl-1H-imidazolium-5-carboxylate (1502)

[0747] Ethyl 2-chloro-4,4,4-trifluoro-3-oxobutyrate 1501 (2.5 g, 0.0114 mol) was combined with formamidin (5.1 g, 0.114 mol) and water (5 mL). The mixture was heated and kept at 130 °C for 2 h in a sealed test tube. The mixture was then cooled to room temperature and 100 mL of ice water was added. The solid formed was collected, washed with water, and then dried under vacuum to produce ethyl 4-(trifluoromethyl)-1H-imidazolium-5-carboxylate 1502 (0.8 g, 90% purity, 30% yield) as a brown solid.

[0748] LCMS (ESI) values ​​of C7H7F3N2O2 [M + H] + m / z 209.05, measured value 209.15.

[0749] 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-4-(trifluoromethyl)-1H-imidazol- Preparation of ethyl 5-formate (1503)

[0750] Under N2, tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 1005 (528 mg, 1.8 mmol) and Cs2CO3 (782 mg, 2.4 mmol) were slowly added to a solution of ethyl 4-(trifluoromethyl)-1H-imidazolium-5-carboxylate 1502 (250 mg, 1.2 mmol) in NMP (5 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (50 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 3% to 10% MeOH / DCM) to produce ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-4-(trifluoromethyl)-1H-imidazolium-5-carboxylate 1503 (200 mg, 90% purity, 35% yield) as a yellow solid.

[0751] C 18 H 24LCMS (ESI) calculated value of F3N3O5 [M + H] + m / z 420.17, measured value 419.98.

[0752] 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazin-6-yl)pyrrolidine-1-carboxylic acid tert- Preparation of Butyl Acetate (1504)

[0753] A solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-4-(trifluoromethyl)-1H-imidazolium-5-carboxylate 1503 (200 mg, 0.49 mmol) in NH3-MeOH (7 M, 20 mL) was heated in a steel reactor at 130 °C for 16 h. The resulting mixture was concentrated and purified by silica gel column chromatography (eluting with 3% to 10% MeOH / DCM) to yield tert-butyl 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazin-6-yl)pyrrolidine-1-carboxylate 1504 (120 mg, 90% purity, 58% yield) as a white solid.

[0754] C 16 H 19 LCMS (ESI) values ​​of F3N4O3 [M + H] + m / z 373.14, measured value 373.10.

[0755] 6-(pyrrolidone-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazine-8(7H)-one hydrochloride (1505) preparation

[0756] A solution of tert-butyl 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazin-6-yl)pyrrolidine-1-carboxylate 1504 (120 mg, 0.32 mmol) in HCl dioxane solution (4 M, 5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to provide 6-(pyrrolidine-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazin-8(7H)-one hydrochloride 1505 (80 mg, 90% purity, 72% yield) as a white solid.

[0757] C 11 H 11 LCMS (ESI) values ​​of F3N4O [M + H] + m / z 273.09, measured value 273.15.

[0758] Racemic N-methyl-5-(4-(3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyridine Preparation of 12rac (1-azin-6-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide

[0759] To a solution of 6-(pyrrolidin-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazin-8(7H)-one hydrochloride 1505 (80 mg, 0.26 mmol) in MeOH (5 mL), N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-1 (90 mg, 0.39 mmol), 2 drops of acetic acid, NaBH3CN (16 mg, 0.26 mmol), and NaBH(OAc)3 (109 mg, 0.52 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini-C18 150 x 21.2 mm, eluted with 10% to 40% ACN / H2O containing 0.1% FA) to produce a racemic mixture of N-methyl-5-(4-(3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazin-6-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide 12rac, 12a and 12b as a white solid (30 mg, 95% purity, 22% yield).

[0760] Chiral separation of N-methyl-5-(4-(3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyridine (azin-6-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide to obtain 12a and 12b

[0761] The 12rac racemic mixture was separated by SFC (column: Regis (R,R)-Whelk-O1 20 mm × 250 mm ID, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 60 / 40) and concentrated under reduced pressure to provide a first fraction as 12a (12.4 mg, 99% purity, 100% ee, white solid) and a second fraction as 12b (7.2 mg, 99% purity, 100% ee, white solid).

[0762] 12a

[0763] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.00 (s, 1 H), 8.43-8.34 (m, 1 H),8.32 (s, 1 H), 8.28 (d, J =2.8 Hz, 1 H), 7.82 (d, J=8.8 Hz, 1 H), 7.47 (s, 1H), 7.41-7.33 (m, 1 H), 3.88-3.78 (m, 2 H), 3.15-3.11 (m, 1 H), 2.99-2.86 (m, 3 H), 2.80-2.75 (m, 4 H), 2.66-2.62 (m, 2 H), 2.21-2.17 (m, 1 H), 1.97-1.91 (m, 2 H), 1.83-1.77 (m, 1 H), 1.58-1.45 (m, 2 H).

[0764] C 23 H 26 LCMS (ESI) values ​​of F3N7O2 [M + H] + m / z 490.21, measured value 490.15.

[0765] 12b

[0766] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.04 (s, 1 H), 8.41-8.35 (m, 1 H),8.33 (s, 1 H), 8.28 (d, J =2.8 Hz, 1 H), 7.82 (d, J =8.8 Hz, 1 H), 7.48 (s, 1H), 7.43-7.35 (m, 1 H), 3.87-3.80 (m, 2 H), 3.15-3.09 (m, 1 H), 3.00-2.85 (m, 3 H), 2.81-2.70 (m, 4 H), 2.70-2.61 (m, 2 H), 2.26-2.10 (m, 1 H), 1.98-1.88 (m, 2 H), 1.83-1.74 (m, 1 H), 1.58-1.44 (m, 2 H).

[0767] C 23 H 26 LCMS (ESI) values ​​of F3N7O2 [M + H] + m / z 490.21, measured value 490.15.

[0768] Example 7: Synthesis of 15a / 15b

[0769]

[0770] Option 7

[0771] Preparation of ethyl 1-amino-5-methyl-1H-pyrrole-2-carboxylate (1603)

[0772] NaH (849 mg, 21.217 mmol, 60 wt% in mineral oil) was added to a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate 1601 (2500 mg, 16.321 mmol) in DMF (50 mL) at 0 °C. After stirring at 0 °C for 30 min, a solution of O-(2,4-dinitrophenyl)hydroxylamine 1602 (3900 mg, 19.585 mmol) in DMF (5 mL) was added. The mixture was then stirred at room temperature for 2 h. The resulting reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give ethyl 1-amino-5-methyl-1H-pyrrole-2-carboxylate 1603 (3.2 g, 80% purity, 95% yield) as a white solid.

[0773] C8H 12 LCMS (ESI) values ​​of N₂O₂ [M + H] + m / z 169.09, measured value 169.00

[0774] 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (1605) Preparation

[0775] To a solution of ethyl 1-amino-5-methyl-1H-pyrrole-2-carboxylate 1603 (3.0 g, 17.837 mmol) in DCM (120 mL), 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid 1604 (4.2 g, 19.620 mmol), DIPEA (6.9 g, 53.510 mmol), and T4P (15.4 g, 21.404 mmol, 50 wt% in EtOAc) were added. The mixture was stirred at room temperature for 3 h, concentrated, and purified by rapid silica gel chromatography (eluting with 0 to 50% EtOAc / PE) to give ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H-pyrrole-2-carboxylate 1605 (5.1 g, 93% purity, 72% yield) as an off-white solid.

[0776] C 18 H 27 LCMS (ESI) calculated value of N3O5 [M + H] + m / z 366.20, measured value 366.15.

[0777] Preparation of 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H-pyrrole-2-carboxylic acid (1606) Preparation

[0778] To a solution of ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H-pyrrole-2-carboxylic acid 1605 (4.9 g, 0.013 mol) in MeOH / H₂O (3:1, 120 mL), NaOH (1.6 g, 0.040 mol) was added. The mixture was heated at 90 °C for 2 h, acidified with 1 M HCl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by rapid silica gel chromatography (eluting with 0 to 8% MeOH / DCM) to give 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H-pyrrole-2-carboxylic acid 1606 (1.4 g, 80% purity, 24% yield) as a white solid.

[0779] C 16 H 23 LCMS (ESI) calculation value of N3O5 [M - Boc + H] + m / z 238.16, measured value 238.15.

[0780] 3-((2-carbamoyl-5-methyl-1H-pyrrolo-1-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1607) Preparation

[0781] To a solution of 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H-pyrrolo-2-carboxylic acid 1606 (1350 mg, 3.990 mmol) in THF (50 mL), (NH4)2CO3 (1533 mg, 15.958 mmol), EDCI (1147 mg, 5.984 mmol), and HOBT (269 mg, 1.995 mmol) were added. The mixture was stirred at room temperature for 2 h, washed with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by rapid silica gel chromatography (eluting with 0 to 80% EtOAc / PE) to give tert-butyl 3-((2-carbamoyl-5-methyl-1H-pyrrolo-1-yl)carbamoyl)pyrrolidine-1-carboxylate 1607 (535 mg, 80% purity, 31% yield) as a yellow solid.

[0782] C 16 H 24 LCMS (ESI) calculated value of N4O4 [M + H] + m / z 337.18, measured value 337.00.

[0783] 3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-2-yl)pyrrolidine-1-carboxylic acid Preparation of tert-butyl ester (1608)

[0784] A solution of tert-butyl 3-((2-carbamoyl-5-methyl-1H-pyrrolo-1-yl)carbamoyl)pyrrolidine-1-carboxylate 1607 (500 mg, 1.482 mmol) in NH3·H2O (12 mL, 25 wt%) was heated in a sealed test tube at 90 °C for 18 h. The resulting mixture was concentrated and purified by rapid silica gel chromatography (eluting with 0 to 60% EtOAc / PE) to give tert-butyl 3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-1-carboxylate 1608 (355 mg, 70% purity, 52% yield) as a yellow solid.

[0785] C 16 H 22 LCMS (ESI) calculation of N4O3 [M - t-Bu + H] + m / z 263.17, measured value 263.10.

[0786] 7-Methyl-2-(pyrrolidine-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (1609) preparation

[0787] A solution of tert-butyl 3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-1-carboxylate 1608 (350 mg, 1.096 mmol) in HCl-dioxane (5 mL, 4 M) was stirred at room temperature for 30 min and then concentrated to give 7-methyl-2-(pyrrolo-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one hydrochloride 1609 (290 mg, 80% purity, 83% yield) as a white solid.

[0788] C 11 H 14 LCMS (ESI) values ​​of N4O [M + H] + m / z 219.12, measured value 219.10.

[0789] N-Methyl-5-(4-(3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl) Preparation of pyrrolidone-1-yl)piperidin-1-yl)pyridine amide (15rac)

[0790] TEA (2 mL) was added to a solution of 7-methyl-2-(pyrrolidone-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride 1609 (100 mg, 0.393 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 30 min and concentrated. The residue was diluted with MeOH (5 mL) and N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-1 (101 mg, 0.432 mmol) and NaBH3CN (37 mg, 0.589 mmol) were added. The mixture was stirred at room temperature for 2 h, concentrated, and purified by rapid silica gel chromatography (eluting with 0 to 10% MeOH / DCM) to give 15 rac (50 mg, 95% purity, 27% yield) of racemic N-methyl-5-(4-(3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide as a white solid.

[0791] N-Methyl-5-(4-(3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl) Chiral resolution of pyrrolidine-1-yl)piperidin-1-yl)pyridineamide (15rac)

[0792] The racemic mixture 15rac was separated by SFC (column: Daicel OJ-H 250 mm × 20 mm ID, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 60 / 40) and concentrated under reduced pressure to provide the first fraction as 15a (15.1 mg, 98% purity, 100% ee, white solid) and the second fraction as 15b (13.5 mg, 98% purity, 100% ee, white solid).

[0793] 15a

[0794] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.32 (s, 1 H), 8.42-8.32 (m, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.81 (d, J =8.4 Hz, 1 H), 7.39 (dd, J =8.8, 2.8 Hz, 1H), 6.77 (d, J =4.0 Hz, 1 H), 6.32 (d, J=4.0 Hz, 1 H), 3.87-3.76 (m, 2 H), 3.25-3.21 (m, 1 H), 3.03-2.91 (m, 3 H), 2.87-2.80 (m, 1 H), 2.78 (d, J =4.8Hz, 3 H), 2.74-2.66 (m, 2 H), 2.39-2.32 (m, 4 H), 2.20-2.07 (m, 2 H), 1.98-1.89 (m, 2 H), 1.59-1.45 (m, 2 H).

[0795] C 23 H 29 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 436.24, measured value 436.25.

[0796] 15b

[0797] 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 =2.8 Hz, 1 H), 7.81 (d, J =8.8 Hz, 1 H), 7.39 (dd, J =8.8, 2.8 Hz, 1H), 6.77 (d, J =4.4 Hz, 1 H), 6.32 (d, J =4.4 Hz, 1 H), 3.87-3.75 (m, 2 H), 3.23-3.18 (m, 1 H), 3.04-2.90 (m, 3 H), 2.86-2.80 (m, 1 H), 2.78 (d, J =4.8Hz, 3 H), 2.74-2.66 (m, 2 H), 2.39-2.30 (m, 4 H), 2.19-2.06 (m, 2 H), 1.99-1.88 (m, 2 H), 1.58-1.45 (m, 2 H).

[0798] C 23 H 29 LCMS (ESI) values ​​of N7O2 [M + H] +m / z 436.24, measured value 436.25.

[0799] Example 8: Synthesis of INT-1 (Refer to Example)

[0800] The method for synthesizing INT-1 will now be described with reference to embodiment 8, where INT-1 is an intermediate product that can be used in some embodiments of the synthesis method of the present invention:

[0801]

[0802] Option 8

[0803] Preparation of 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide (2003)

[0804] 1,4-dioxa-8-azaspiro[4.5]decane 2002 (1.40 g, 9.75 mmol) was added to a solution of 5-fluoro-N-methylpyridin-2-carboxamide 2001 (1.00 g, 6.50 mmol) in DMF (15 mL) at room temperature, followed by the addition of Cs₂CO₃ (2.12 g, 6.50 mmol). The reaction mixture was stirred in a microwave at 150 °C for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 97:3) to yield 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridin-2-carboxamide 2003 (1.50 g, 76% yield) as a white solid.

[0805] C 14 H 19 LCMS (ESI) values ​​of N3O3 [M + H] + m / z 278.14, measured value 278.14.

[0806] Preparation of N-methyl-5-(4-oxopiperidin-1-yl)pyridine amide (INT-1)

[0807] A solution of 1,4-dioxane in HCl (4 M, 20 mL) was added to a solution of 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridin-2-carboxamide 2003 (1.50 g, 5.40 mmol) in H2O (10 mL) at room temperature. The reaction mixture was stirred at 50 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH > 7 using NaHCO3 solution, then extracted with EtOAc (50 mL x 3), and the organic phase was dried over Na2SO4 and concentrated to yield N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-1 (1.50 g, 76% yield) as a yellow solid.

[0808] C 12 H 15 LCMS (ESI) values ​​of N3O2 [M + H] + m / z 234.12, measured value 234.18.

[0809] Example 9: Synthesis of INT-2 (Refer to Example)

[0810] The method for synthesizing INT-2 will now be described with reference to Scheme 9, where INT-2 is an intermediate product that can be used in some implementations of the synthesis method of the present invention:

[0811]

[0812] Option 9

[0813] Preparation of 6-chloro-5-fluoro-N-methylpyridine amide (2102)

[0814] Methylamine (420 mg, 13.68 mmol), DIEA (4.42 g, 34.20 mmol), and HATU (6.50 g, 17.10 mmol) were sequentially added to a solution of 6-chloro-5-fluoropyridinecarboxylic acid 2101 (2.00 g, 11.40 mmol) in DMF (50 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 70:30) to provide 6-chloro-5-fluoro-N-methylpyridine amide 2102 (2.00 g, 88% yield) as a white solid.

[0815] LCMS (ESI) calculated value of C7H6ClFN2O [M + H] +m / z 189.02, measured value 188.90.

[0816] Preparation of 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine amide (2104)

[0817] Cs₂CO₃ (6.91 g, 21.20 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane 2002 (3.04 g, 21.20 mmol) were added to a solution of 6-chloro-5-fluoro-N-methylpyridineamide 2102 (2.00 g, 10.60 mmol) in DMF (20 mL). The mixture was stirred at 120 °C for 4 h in a sealed tube. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAC = 100:0 to 50:50) to provide 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridineamide 2104 (1.60 g, 42% yield) as a white solid.

[0818] C 14 H 18 LCMS (ESI) calculated value of ClN3O3 [M + H] + m / z 312.10, measured value 311.95.

[0819] Preparation of 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine amide (2105)

[0820] CsF (293 mg, 1.93 mmol) was added to a solution of 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine amide 2104 (300 mg, 0.96 mmol) in DMF (20 mL). The mixture was stirred in a microwave at 150 °C for 20 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAC = 100:0 to 30:70) to 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine amide 2105 (200 mg, 69% yield) as a yellow solid.

[0821] C 14 H 18 LCMS (ESI) values ​​of FN3O3 [M + H] + m / z 296.13, measured value 295.95.

[0822] Preparation of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridine amide (INT-2)

[0823] Formic acid (2 mL) was added to a solution of 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine amide 2105 (200 mg, 0.68 mmol) in H2O (3 mL), and the mixture was stirred at 50 °C for 1 h. The aqueous solution was adjusted to pH 7-8 with NaHCO3 aqueous solution. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, and concentrated to produce crude 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridine amide INT-2 as a yellow solid (100 mg, 47% yield).

[0824] C 12 H 14 LCMS (ESI) values ​​of FN3O2 [M + H] + m / z 252.11, measured value 251.90.

[0825] Example 10: Synthesis of 21

[0826]

[0827] Option 10

[0828] Preparation of methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1703)

[0829] NaH (186 mg, 4.66 mmol, 60 wt% in mineral oil) was slowly added to a solution of methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1701 (900 mg, 4.66 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, O-(2,4-dinitrophenyl)hydroxylamine 1702 (1392 mg, 6.99 mmol) was added. The mixture was stirred at room temperature for 5 h. The mixture was slowly quenched with water and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, and concentrated to provide methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1703 (730 mg, 85% purity, 63% yield) as a yellow solid.

[0830] LCMS (ESI) values ​​of C7H7F3N2O2 [M + H] + m / z 209.05, measured value 209.15.

[0831] 4-((2-(methoxycarbonyl)-3-(trifluoromethyl)-1H-pyrrolo-1-yl)carbamoyl)-2-azabicyclo [2.1.1] Preparation of tert-butyl hexane-2-carboxylate (1705)

[0832] T4P (5345 mg, 7.42 mmol, 50 wt% in EtOAc) was added to a solution of methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1703 (730 mg, 3.51 mmol) in pyridine (9 mL), followed by 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 1704 (640 mg, 2.80 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated and purified by rapid silica gel chromatography (DCM / MeOH = 100:0 to 93:7) to provide 4-((2-(methoxycarbonyl)-3-(trifluoromethyl)-1H-pyrrolo-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 1705 (1180 mg, 85% purity, 80% yield) as a yellow solid.

[0833] C 18 H 22 LCMS (ESI) calculated value of F3N3O5 [M + Na] + m / z 440.15, measured value 440.10.

[0834] 1-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carbamate)-3-(trifluoromethyl)- Preparation of 1H-pyrrole-2-carboxylic acid (1706)

[0835] Sn(CH3)3OH (0.94 g, 0.0052 mol) was added to a solution of tert-butyl hexane-2-carboxylate 1705 (1.1 g, 0.0026 mol) in DME (15 mL). The resulting mixture was stirred at 80 °C for 2 h. The mixture was then concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 93:7) to give 1-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamido)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid 1706 (900 mg, 90% purity, 76% yield) as a yellow solid.

[0836] C 17 H 20 LCMS (ESI) values ​​of F3N3O5 [M - H] - m / z 402.14, measured value 402.05.

[0837] 4-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrolo-1-yl)carbamoyl)-2-azabicyclo[2.1.1] Preparation of tert-butyl hexane-2-carboxylate (1707)

[0838] To a solution of 1-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamido)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid 1706 (900 mg, 2.23 mmol) in THF (20 mL), (NH4)2CO3 (950 mg, 9.89 mmol), EDCI (711 mg, 3.70 mmol), and HOBT (167 mg, 1.23 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. The mixture was then concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 96:4) to give 4-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrolo-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 1707 (915 mg, 90% purity, 91% yield) as a yellow solid.

[0839] C 17 H 21 LCMS (ESI) values ​​of F3N4O4 [M - H] - m / z 401.15, measured value 401.10.

[0840] 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-2-yl)-2-aza Preparation of bicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (1708)

[0841] A solution of 4-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrolo-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester 1707 (500 mg, 1.23 mmol) in NH3·H2O (10 mL, ~25 wt%) was stirred in a steel reactor at 90 °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 give 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester 1708 (230 mg, 80% purity, 38% yield) as a yellow solid.

[0842] C 17 H 19 LCMS (ESI) values ​​of F3N4O3 [M - H] - m / z 383.14, measured value 383.35.

[0843] 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4 Preparation of (3H)-ketone (1709)

[0844] A solution of 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 1708 (220 mg, 0.57 mmol) in HCl-dioxane (4 M, 6 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with MeOH (4 mL), TEA (0.5 mL) was added, and the mixture was stirred at room temperature for 10 min. The mixture was then concentrated under reduced pressure to give 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 1709 (200 mg, 70% purity, 86% yield) as a yellow solid.

[0845] C 12 H 11 LCMS (ESI) values ​​of F3N4O [M + H] + m / z 285.09, measured value 285.15.

[0846] N-Methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine- Preparation of 2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidin-1-yl)pyridine amide (21)

[0847] AcOH (0.3 mL) and N-methyl-5-(4-oxopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one 1709 (45 mg, 0.15 mmol) were added to a stirred solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one 1709 in MeOH (10 mL) and stirred for 20 min at room temperature. Then NaBH3CN (9 mg, 0.15 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 15% to 65% MeCN / H2O containing 0.1% FA) to give N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)pyridineamide 21 (0.22 FA salt, 20.3 mg, 97.13% purity, 24% yield) as a white solid.

[0848] 1H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.10 (s, 1 H), 8.45-8.33 (m, 1 H), 8.29 (d, J =2.8 Hz, 1 H), 8.14 (s, 0.22 H), 7.82 (d, J =8.8 Hz, 1 H), 7.69 (d, J =2.8 Hz, 1 H), 7.42 (dd, J =9.0, 2.6 Hz, 1 H), 6.90 (d, J =2.8 Hz, 1 H), 3.95-3.83 (m, 2 H), 3.81-3.72 (m, 1 H), 3.13-3.02 (m, 2 H), 3.00-2.86 (m, 2 H), 2.78 (d, J =4.8 Hz, 3 H), 2.65-2.56 (m, 1 H), 2.20-2.07 (m, 2 H), 2.04-1.83 (m, 4 H), 1.57-1.39 (m, 2 H).

[0849] C 24 H 26 LCMS (ESI) values ​​of F3N7O2 [M + H] + m / z 502.21, measured value 502.15.

[0850] Example 11: Synthesis of 22

[0851]

[0852] Option 11

[0853] 6-Fluoro-N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]) Preparation of triazine-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidin-1-yl)pyridine amide (22)

[0854] AcOH (0.3 mL) and 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one 1709 (45 mg, 0.15 mmol) were added to a stirred solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one 1709 in MeOH (10 mL) and 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-2 (59 mg, 0.23 mmol) were added, and the reaction mixture was stirred at room temperature for 20 min. Then NaBH3CN (9 mg, 0.15 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 15% to 65% MeCN / H2O containing 0.1% FA) to give 6-fluoro-N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidin-1-yl)pyridineamide 22 (0.63 FA salt, 19.3 mg, 96% purity, 21% yield) as a grayish-white solid.

[0855] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.23 (s, 1 H), 8.44-8.34 (m, 1 H), 8.16 (s, 0.63 H), 7.84 (d, J =8.0 Hz, 1 H), 7.69 (d, J =2.8 Hz, 1 H), 7.59 (dd, J =10.6, 8.2 Hz, 1 H), 6.90 (d, J =3.2 Hz, 1 H), 3.76-3.68 (m, 1 H), 3.59-3.51(m, 2 H), 3.08-2.99 (m, 2 H), 2.90-2.81 (m, 2 H), 2.77 (d, J =4.8 Hz, 3 H), 2.57-2.53 (m, 1 H), 2.15-2.06 (m, 2 H), 2.03-1.92 (m, 2 H), 1.91-1.82 (m, 2H), 1.59-1.45 (m, 2 H).

[0856] C 24 H25 LCMS (ESI) values ​​of F4N7O2 [M + H] + m / z 520.20, measured value 520.15.

[0857] Example 12: Synthesis of 26a / 26b

[0858]

[0859] Option 12

[0860] Preparation of 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine (1802)

[0861] A solution of 5,7-dichloroimidazolo[1,2-c]pyrimidine 1801 (1 g, 0.0053 mol) and MeONa (570 mg, 0.0106 mol) in MeOH (20 mL) was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to provide 7-chloro-5-methoxyimidazolo[1,2-c]pyrimidine 1802 (790 mg, 90% purity, 73% yield) as a white solid.

[0862] LCMS (ESI) calculated value of C7H6ClN3O [M + H] + m / z 184.02, measured value 183.95.

[0863] 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester Preparation of (1804)

[0864] To a solution of 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine 1802 (790 mg, 4.3029 mmol) in dioxane / H₂O (15 mL, 10:1), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid 1803 (1.4 g, 4.7331 mmol), RuPhos Pd G3 (360 mg, 0.4302 mmol), and K₂CO₃ (1.78 g, 12.9087 mmol) were successively added. The reaction mixture was stirred at 80 °C for 2 h under a nitrogen 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 tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 1804 (900 mg, 90% purity, 59% yield) as a yellow solid.

[0865] C 16 H 20 LCMS (ESI) values ​​of N4O3 [M + H] + m / z 317.15, measured value 317.25.

[0866] Preparation of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-carboxylate (1805)

[0867] A solution of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)-2,5-dihydro-1H-pyrrolo-1-carboxylate 1804 (900 mg, 2.8359 mmol) and Pd / C (302 mg, 10 wt%) in MeOH (15 mL) was stirred at room temperature for 2 h under H2 balloon pressure. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated to produce tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolo-1-carboxylate 1805 (850 mg, 90% purity, 84% yield) as a colorless oil.

[0868] C 16 H 22 LCMS (ESI) values ​​of N4O3 [M + H] + m / z 319.17, measured value 319.20.

[0869] Preparation of tert-butyl 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-carboxylate (1806) Preparation

[0870] NIS (599 mg, 2.6614 mmol) was added to a solution of 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-carboxylate tert-butyl ester 1805 (850 mg, 2.6614 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure and purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to provide 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-carboxylate tert-butyl ester 1806 (1.04 g, 90% purity, 78% yield) as a white solid.

[0871] C 16 H 21 LCMS (ESI) values ​​of IN4O3 [M + H] + m / z 445.07, measured value 445.05.

[0872] 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester Preparation of (1808)

[0873] Nano-Cu (143 mg, 2.2458 mmol) and 5-(trifluoromethyl)-4a,10a-dihydro-5H-thiaanthracene-5-onium 1807 (648 mg, 2.2458 mmol) were sequentially added to a solution of 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-carboxylate 1806 (500 mg, 1.1229 mmol) in DMF (15 mL). The reaction mixture was stirred at 100 °C for 6 h under N2. The reaction mixture was poured into water and then extracted with EtOAc (50 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 PE / EtOAc = 100:0 to 50:50) to provide tert-butyl 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-carboxylate 1808 (150 mg, 90% purity, 30% yield) as a white solid.

[0874] C 17 H 21 LCMS (ESI) values ​​of F3N4O3 [M + H] + m / z 387.16, measured value 387.10.

[0875] Preparation of 7-(pyrrolidone-3-yl)-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5(6H)-one (1809)

[0876] A solution of tert-butyl 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-carboxylate 1808 (150 mg, 0.3862 mmol) in HBr (3 mL, 48% H2O solution) was stirred at 80 °C for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with MeOH (3 mL) and TEA (0.5 mL) and then stirred at room temperature for 5 min. The mixture was concentrated under reduced pressure to give 7-(pyrrolidine-3-yl)-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5(6H)-one 1809 (115 mg, 90% purity, 98% yield) as a white solid.

[0877] C 11 H 11 LCMS (ESI) values ​​of F3N4O [M + H] + m / z 273.09, measured value 273.05.

[0878] N-Methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-c]pyrimidin-7-yl)pyridine Preparation of pyrrolidine-1-yl)piperidin-1-yl)pyridine amide (26a / 26b racemic mixture)

[0879] N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide INT-1 (118 mg, 0.5050 mmol), AcOH (1 drop), and NaBH3CN (53 mg, 0.8418 mmol) were sequentially added to a solution of 7-(pyrrolidone-3-yl)-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5(6H)-one 1809 (115 mg, 0.4209 mmol) in MeOH (5 mL). The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched with water (2 mL) and 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: 30-95) to produce a racemic mixture of N-methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1-yl)piperidin-1-yl)pyridineamide 26a / 26b as a white solid (70 mg, 95% purity, 32% yield).

[0880] N-Methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-c]pyrimidin-7-yl)pyridine Chiral resolution of pyrrolidine-1-yl)piperidin-1-yl)pyridineamide (26a / 26b racemic mixture)

[0881] The racemic mixture of 26a / 26b was separated by an SFC (column: Daicel Chiralpak IH SFC; 20 mm ID × 250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 70 / 30) and concentrated under reduced pressure to provide the first fraction as compound 26a (27.8 mg, 96.88% purity, 100% ee, white solid) and the second fraction as compound 26b (29.3 mg, 98.66% purity, 100% ee, white solid).

[0882] Compound 26a

[0883] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 8.41-8.35 (m, 1 H), 8.28 (d, J =2.4Hz, 1H), 7.89 (s, 1H), 7.82 (d, J =8.8 Hz, 1 H), 7.40 (dd, J=8.8, 2.8 Hz, 1H), 6.59 (s, 1 H), 3.87-3.78 (m, 2 H), 3.29-3.15 (m, 1 H), 3.04-2.88 (m, 3H), 2.86-2.72 (m, 5 H), 2.72-2.60 (m, 1 H), 2.40-2.29 (m, 1 H), 2.26-2.14 (m, 1 H), 2.00-1.83 (m, 3 H), 1.60-1.46 (m, 2 H).

[0884] C 23 H 26 LCMS (ESI) values ​​of F3N7O2 [M + H] + m / z 490.21, measured value 490.10.

[0885] Compound 26b

[0886] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 8.43-8.33 (m, 1 H), 8.27 (d, J =2.8Hz, 1 H), 7.85-7.78 (m, 2 H), 7.40 (dd, J =8.8, 3.0 Hz, 1 H), 6.51 (s, 1 H), 3.86-3.79 (m, 2 H), 3.26-3.13 (m, 1 H), 3.02-2.85 (m, 3 H), 2.78 (d, J =4.8Hz, 3 H), 2.76-2.65 (m, 3 H), 2.37-2.31 (m, 1 H), 2.24-2.10 (m, 1 H), 2.01-1.87 (m, 3 H), 1.61-1.44 (m, 2 H).

[0887] C 23 H 26 LCMS (ESI) values ​​of F3N7O2 [M + H] + m / z 490.21, measured value 490.10.

[0888] Example 13: Measurement

[0889] 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.

[0890] Example 13A. PARP1 biodissociation-enhanced fluorescence immunoassay of lanthanides (DELFIA assay)

[0891] 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 minutes at room temperature, remove the assay solution and wash five times for 3 minutes each, then add 100 μl of a 1:1000 dilution of DELFIA Eu-N1 streptavidin reagent. Incubate the plate at room temperature for 30 minutes. Remove the reaction mixture and wash the plate five times for 3 minutes each, then add 25 μl of DELFIA enhancement solution. After 30 minutes at room temperature, measure fluorescence on a Pherastar FS (Ex 337 nm, Em 620 nm; integration start 60 μs; integration time 400 μs).

[0892] 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:

[0893] % value = 100 - (100) ((High control - Unknown) / (High control - Low control))

[0894] 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.

[0895] IC50 of various test compounds 50 The values ​​are shown in Table 1.

[0896] Activated DNA sequence:

[0897]

[0898] Example 13B. Homogeneous Time-Resolved Fluorescence Assay (HTRF) with PARP1 Probe Replacement

[0899] 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).

[0900] 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:

[0901] %activity=100 (Value - Low Control) / (High Control - Low Control)

[0902] The % activity data were fitted to a nonlinear regression equation to obtain the IC50 value.

[0903] Calculate K using the Cheng-Prussoff formula. d value:

[0904] IC 50 =(1+ ([probe concentration] / [Km)) 探针 ])) K d

[0905] 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

[0906] Example 13C. Homogeneous Time-Resolved Fluorescence Assay (HTRF) with PARP2 Probe Replacement

[0907] 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.

[0908] Cy5 probe structure:

[0909]

[0910] NanoBRET Cell Target Occupation Assay

[0911] 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.

[0912] 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. TM TE 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:

[0913] IC50 = (1 + ([tracer concentration] / [Km])) 示踪剂 ])) Kd

[0914] 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.

[0915] Table 1

[0916] Results of Parp 1 / 2 assays for selected compounds (DELFIA and probe-replaced HTRF)

[0917]

[0918]

[0919] Table 2

[0920] Results of Parp 1 / 2 determination for selected compounds (NanoBRET)

[0921]

[0922] Symbol explanation:

[0923] Classification of DELFIA, probe-replacement HTRF, and NanoBRET assays:

[0924] - Indicates ICs with a value higher than 10 μM 50 or K d value

[0925] + Indicates ICs with values ​​from 1 μM up to 10 μM. 50 or K d value

[0926] ++ indicates ICs with a range from 100 nM to 1 μM. 50 or K d value

[0927] +++ indicates ICs with speeds up to 10 nM up to 100 nM. 50 or K d value

[0928] ++++Indicates ICs of 10 nM or lower 50 or K d value

[0929] Selective classification:

[0930] - Indicates a value less than 10

[0931] + Indicates a value from 10 to less than 50.

[0932] ++ indicates a value from 50 to less than 100.

[0933] +++ indicates a value of at least 100.

[0934] 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.

[0935] It should be understood that the above implementation plan is described only by way of example.

[0936] 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 for use in medicine, said PARP1 inhibitor compound having the following structure: in: Each R 1 It does not exist independently or is selected from H and substituted or unsubstituted organic groups; R 2 It is absent or selected from H and substituted or unsubstituted organic groups; R 3 Selected from H and substituted or unsubstituted organic groups; Z 1 It is C or N; Z 2u and Z 2l Each is selected from C and N, provided that Z 2u and Z 2l At least one of them is N; Each Z 3 Independently selected from C and N; and L has the following structure: in: Dashed lines indicate single or double bonds; Each R 5A and each R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups; R 6 It is absent or selected from H and substituted or unsubstituted organic groups; Each X 1 Independently selected from C and N; Each X 2 Independently selected from C, N, O, and S; n is a number selected from 0, 1, 2, 3, 4, 5, and 6; and m is a number selected from 0, 1, 2, 3, 4, 5, and 6; provided that m + n is a number selected from 2, 3, 4, 5, and 6. r is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; and s is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; provided that r + s is a number selected from 2, 3, 4, 5, and 6. b is a ring that either does not exist or has the following structure: ； in: p is a number selected from 0, 1, 2, 3, 4, 5, and 6; and q is a number selected from 0, 1, 2, 3, 4, 5, and 6; provided that p + q is a number selected from 2, 3, 4, 5, and 6; and Each R 5B It independently does not exist or is selected from H and substituted or unsubstituted organic groups; and Q AE Q AB and Q BC Each exists independently or is selected from: 、 、 、 and ; in: 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 Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

2. The PARP1 inhibitor compound for the said use according to claim 1, wherein L has the following structure: 。 3. The PARP1 inhibitor compound for the said use according to claim 1 or claim 2, wherein each R 1 It does not exist independently or is selected from: H； C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl groups; C3 to C6 cycloalkyl groups; Halogen groups; Nitrile group; and Where R 22 Selected from H, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl and halogen (optionally F), and each R 23 Independently selected from H and substituted or unsubstituted organic groups, Optionally, each of R 23 Independently selected from H, C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl groups and halogen groups, and further optionally at least one of them R 23 It is H.

4. The PARP1 inhibitor compound for the said use according to claim 3, wherein each R 1 Independently absent or selected from H; halogen, optionally Cl or F; C1 to C3 alkyl group, optionally methyl group; C1 to C3 haloalkyl group, optionally halomethyl group (-CH2F, -CHF2 or -CF3) or haloethyl group (e.g., -CH2CF3); and nitrile group.

5. The PARP1 inhibitor compound for the said use according to claim 4, wherein each R 1 It does not exist independently or is selected from: H, Cl, F, methyl group, CF3 and nitrile group.

6. The PARP1 inhibitor compound for the said use according to claim 4, wherein: Exactly one R 1 Selected from Cl, F, methyl groups, CF3, and nitrile groups; and Each other R 1 It is H or it does not exist.

7. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein at least one R 1 It is H.

8. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein Z 1 It's C.

9. The PARP1 inhibitor compound for the said use according to claim 8, wherein R 2 Selected from H; halogen, optionally F or Cl; C1 to C3 alkyl, optionally isopropyl or cyclopropyl; C1 to C3 haloalkyl, optionally -CH2F, -CHF2, -CF3, -CH2CF3 or -CH2CH2F; C1 to C3 alcohol, optionally -CH2CH2OH; C1 to C3 alkoxy, optionally methoxy, methoxymethyl or methoxyethyl; or C1 to C3 aminoalkyl.

10. The PARP1 inhibitor compound for the said use according to claim 9, wherein R 2 It is H.

11. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 7, wherein Z 1 It is N and R 2 It does not exist.

12. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein R 3 Selected from H, C1 to C3 alkyl groups and C1 to C3 haloalkyl groups; Preferably, R 3 It is H.

13. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein at least two Z's are present. 3 The atom is C.

14. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein Z 2u and Z 2l One of them is C.

15. The PARP1 inhibitor compound for the said use according to claim 13, having the following structure: 。 16. The PARP1 inhibitor compound for the said use according to claim 15, having a structure selected from the following: , , and .

17. The PARP1 inhibitor compound for the said use according to claim 15, having a structure selected from the following:

18. The PARP1 inhibitor compound for the said use according to claim 16, having the following structure: or .

19. The PARP1 inhibitor compound for the said use according to claim 14, having the following structure: 。 20. The PARP1 inhibitor compound for the said use according to claim 19, having a structure selected from the following: , , and .

21. The PARP1 inhibitor compound for the said use according to claim 20, having a structure selected from the following: , , , and .

22. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein Q AE It does not exist or is -CH2-. Choose any one of Q AE It does not exist.

23. The PARP1 inhibitor compound according to any of the preceding claims, wherein both n and m are at least 1.

24. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring A has the following structure: in: i is a number selected from 0, 1, 2, 3, 4, 5, 6; and j is a number selected from 0, 1, 2, 3, 4, 5, 6, provided that the sum of i and j is (n-1). h is a number selected from 1, 2, and 3; and n is at least 1.

25. The PARP1 inhibitor compound according to claim 24, wherein ring A has the following structure: 。 26. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 23, wherein: i) Ring A is a substituted or unsubstituted perpiperidine, and optionally has a perpiperidine structure selected from: and in: Each R 5A Independently selected from H and substituted or unsubstituted organic groups; or ii) Ring A is a substituted or unsubstituted 6-membered aliphatic heterocycle, optionally having a structure selected from the following: , , , , , , , , , and , in: Each R 5A Independently selected from H and substituted or unsubstituted organic groups; or iii) Ring A is a substituted or unsubstituted 5-membered aliphatic heterocycle, optionally having a structure selected from the following: , , , , and in: Each R 5A Independently selected from H and substituted or unsubstituted organic groups; or iv) Ring A is a 5-membered aromatic ring, optionally pyrrole or pyrazole, and further optionally has a structure selected from the following: , and , Each R 5A Independently selected from H and substituted or unsubstituted organic groups; or v) Ring A is a substituted or unsubstituted azacyclic butane, which optionally has the following structure: ； in: Each R 5A It is independently selected from H and substituted or unsubstituted organic groups.

27. The PARP1 inhibitor compound for the said use according to claim 26, wherein ring A has a structure selected from:

28. The PARP1 inhibitor compound for the said use according to claim 27, wherein ring A has a number selected from... and The structure, Preferably, ring A has The structure.

29. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein Q AB It does not exist or is -CH2-. Choose any one of Q AB It does not exist.

30. The PARP1 inhibitor compound for the said use according to claim 29, wherein L has the following structure: 。 31. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein both p and q are at least 1; Optionally, the sum of p and q is 3 or 4, and further optionally, p is 2 and q is 2.

32. The PARP1 inhibitor compound for the said use according to claim 31, wherein: i) Ring B is a 7-membered saturated heterocycle, which optionally has the following structure: in: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H; X 1BA It is C and R 5B1 Selected from H and substituted or unsubstituted organic groups, and optionally H; or X 1BA It is N and R 5B1 It does not exist; and X 1BC It is C and R 5B3 Selected from H and substituted or unsubstituted organic groups, or X 1BC It is N and R 5B3 It does not exist; or ii) Ring B is a 6-membered saturated heterocycle, which optionally has the following structure: in: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H; X 1BA It is C and R 5B1 Selected from H and substituted or unsubstituted organic groups, and optionally H; or X 1BA It is N and R 5B1 It does not exist; and X 1BC It is C and R 5B3 Selected from H and substituted or unsubstituted organic groups, or X 1BC It is N and R 5B3 It does not exist; or iii) Ring B is a 5-membered saturated heterocycle, which optionally has the following structure: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H; X 1BA It is C and R 5B1 Selected from H and substituted or unsubstituted organic groups, and optionally H; or X 1BA It is N and R 5B1 It does not exist; and X 1BC It is C and R 5B3 Selected from H and substituted or unsubstituted organic groups, or X 1BC It is N and R 5B3 It does not exist.

33. The PARP1 inhibitor compound for the said use according to claim 32, wherein X 1BA It is C and R 5B1 Selected from H and substituted or unsubstituted organic groups; Optionally, R 5B1 It is H.

34. The PARP1 inhibitor compound for the said use according to claim 32 or claim 33, wherein X 1BC It is N and R 5B3 It does not exist.

35. The PARP1 inhibitor compound for the said use according to claim 34, wherein ring B has the following structure: 。 36. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein Q BC It does not exist or is -CH2-. Choose any one of Q BC It does not exist.

37. The PARP1 inhibitor compound for the said use according to claim 36, wherein L has the following structure: 。 38. A PARP1 inhibitor compound for the said use 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.

39. The PARP1 inhibitor compound for said use according to claim 38, wherein: i) Ring C is a 6-membered aliphatic ring, optionally having the following structure: 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, which optionally has 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, which optionally has 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, which optionally has 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 selected from the following structures: 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, which optionally has 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, which optionally has a structure selected from the following: 、 、 、 Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; iiid) Triazoles, optionally having the following structures: or R 5C Selected from H and substituted or unsubstituted organic groups, optionally wherein R 5C It is H.

40. The PARP1 inhibitor compound for the said use according to claim 39, wherein ring C has a structure selected from:

41. The PARP1 inhibitor compound for the said use according to claim 39, wherein the ring C has the following structure: in: R 5C2o Selected from H, methyl groups, and halogens; and i) X 2CM It is C and R 5C2M It is H; or ii) X 2CM It is N and R5 C2M It does not exist.

42. The PARP1 inhibitor compound for the said use according to claim 41, wherein R 5C2o Selected from H and halogens.

43. The PARP1 inhibitor compound for the said use according to claim 42, wherein R 5C2o It is halogen, wherein R is optional 5C2o It is F.

44. The PARP1 inhibitor compound for the said use according to any one of claims 41 to 43, wherein ring C has a structure selected from: (optional) ), , (optional) )and 。 45. The PARP1 inhibitor compound for the said use according to claim 41, wherein ring C has the following structure: (optional) )or 。 46. ​​The PARP1 inhibitor compound for the said use according to any one of claims 41 to 45, wherein ring C has a structure selected from:

47. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 43, 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: 、 、 、 、 、 、 and 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.

48. The PARP1 inhibitor compound for the said use according to claim 47, 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.

49. The PARP1 inhibitor compound for the said use according to claim 48, wherein R 6 Selected from:

50. The PARP1 inhibitor compound for the said use according to claim 47, 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 .

51. The PARP1 inhibitor compound for the said use according to claim 50, wherein R 6 It is CONHMe.

52. The PARP1 inhibitor compound according to claim 51, wherein R 6 yes .

53. The PARP1 inhibitor compound for the said use according to claim 50, wherein R 6 yes .

54. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 40, wherein R 6 It has the following structure: in: Each X 6 Independently selected from C, N, and O; R 61 It either does not exist or is H; Each R 62 Independently absent or selected from H; halogen 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.

55. The PARP1 inhibitor compound for the said use according to claim 54, wherein R 6 It has a structure selected from the following:

56. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 39, wherein R 6 And an R 5C The groups together form a ring.

57. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein each R 5A (For example, R) 5A1 R 5A2 R 5A3 ) is H.

58. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein each R 5B (For example, R) 5B1 R 5B3 ) is H.

59. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein each R 5C (For example, R) 5C1 The components are selected from H and halogens, provided that no more than one R is present. 5C It's halogen. Optionally, the halogen mentioned therein is F.

60. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein Q AE Q AB and Q BC At least one of them is: 、 、 or Where t + u is at least 1; and Where R 7 The group is selected from H, halogens (such as -F, -Cl, -Br and -I, preferably -F), substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (preferably CF3), -NH2 groups or substituted or unsubstituted C1-C6 amino groups, -OH groups or substituted or unsubstituted straight-chain or branched C1-C6 alcohol groups and substituted or unsubstituted C1-C6 alkoxy groups.

61. The PARP1 inhibitor compound for the said use according to claim 60, wherein R 7 Selected from: H; halogen, optionally F; substituted or unsubstituted C1-C6 alkyl group; or substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl group.

62. A PARP1 inhibitor compound for the said use according to any of the preceding claims, wherein Q AE Q AB and Q BC 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)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 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.

63. The PARP1 inhibitor compound for the said use according to claim 62, 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.

64. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 59, wherein L has a structure selected from: 、 、 、 、 、 、 and ； in: Each R 5A R 5A1 R 5B R 5B1 R 5C and R 6 It is independently selected from H and substituted or unsubstituted organic groups.

65. The PARP1 inhibitor compound for the said use according to claim 64, wherein L has the following structure: or 。 66. The PARP1 inhibitor compound according to any one of claims 1 to 59, having the following structure: or in: Z 1 It is C or N; Z 2u and Z 2l One is C, and Z 2u and Z 2l The other one is N; Each Z 3 Independently selected from C and N, Each R 1 It is either absent independently or selected from H, halogens (e.g., F or Cl), methyl, halomethyl (e.g., CF3) and CN; R 5C2o It is an H, a methyl group, or a halogen; X 2CM It is N and R 5C2M Does not exist, or X 2CM It is C and R 5C2M It is H; and R 6 yes (optional) )or .

67. The PARP1 inhibitor compound for the said use according to claim 66, wherein R 5C2o It is H or halogen, or optionally F.

68. The PARP1 inhibitor compound for the said use according to claim 67, wherein L has a structure selected from:

69. The PARP1 inhibitor compound for the said use according to claim 66, wherein L has the following structure: 。 70. A PARP1 inhibitor compound for the said use according to any one of claims 66 to 69, wherein said compound has a structure selected from:

71. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 65, wherein when R 1 R 2 R 3 R 5A (For example, R) 5A1 R 5A2 ), R 5B (For example, R) 5B1 R 5B3 ), R 5C (For example, R) 5C1 ), R 6 R 7 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, -CI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3 and -CH2CCI3); 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.

72. The PARP1 inhibitor compound for the said use according to claim 71, wherein R 5A (For example, R) 5A1 R 5A2 R 5A3 ), R 5B (For example, R) 5B1 R 5B3 ) 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, Substituted or unsubstituted C1-C6 alkyl groups, Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (preferably CF3 or CHF2), Cyclopropyl group, -OH group, Substituted or unsubstituted straight-chain or branched C1-C6 alcohol groups, Substituted or unsubstituted straight-chain or branched C1-C7 amino carbonyl groups (such as -NH-CO-Me), -NH2 group, Substituted or unsubstituted C1-C6 amino groups, and Substituted or unsubstituted 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-.

73. A PARP1 inhibitor compound for the said use according to any of the preceding claims, said compound comprising: 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.

74. A PARP1 inhibitor compound for the stated use according to any of the preceding claims, which is selective for PARP1 relative to PARP2.

75. A PARP1 inhibitor compound for the stated use according to any of the preceding claims, used for the treatment of cancer.

76. The PARP1 inhibitor compound for the stated use according to claim 75, 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, renal cell carcinoma, vitrectomyces, urethral cancer, etc. Hermosis, 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; Optionally, the cancer mentioned above is brain cancer or spinal cord cancer.

77. The PARP1 inhibitor compound for the said use according to claim 75 or claim 76, wherein the cancer is deficient in DNA damage response repair pathways, such as homologous recombination-dependent DNA double-strand break DNA repair activity.

78. The PARP1 inhibitor compound for the said use according to any one of claims 75 to 77, wherein said cancer is defective in BRCA1 and / or BRCA2 function.

79. The PARP1 inhibitor compound for the stated use according to any one of claims 75 to 78, administered in combination with a further agent for treating cancer; optionally, said further 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.

80. The PARP1 inhibitor compound for the stated use according to claim 79, 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 (CAR-T); small molecule immunomodulators; and tumor microenvironment modulators.

81. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any one of claims 1 to 74.

82. The pharmaceutical composition of claim 81, further comprising pharmaceutically acceptable additives and / or excipients, and / or wherein said compound is in the form of a pharmaceutically acceptable salt, hydrate, acid, ester or other alternative form of said compound.

83. The pharmaceutical composition according to claim 81 or claim 82, 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.

84. The pharmaceutical composition of claim 83, 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 (CAR-T); small molecule immunomodulators; and tumor microenvironment modulators.

85. The pharmaceutical composition according to any one of claims 81 to 84, for the treatment of cancer.

86. A drug kit for treating cancer, the drug kit comprising: a) A PARP1 inhibitor compound as defined in any one of claims 1 to 74; and b) Other medications used to treat cancer; The compounds and the additional agents described herein 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 (CAR-T); small molecule immunomodulators; tumor microenvironment modulators), apoptosis-promoting agents, radioligand therapy, anti-angiogenic agents and cell cycle signaling inhibitors.

87. A compound having the following structure: or in: Z 1 It is C or N; Z 2u and Z 2l One is C, and Z 2u and Z 2l The other one is N; Each Z 3 Independently selected from C and N, Each R 1 It is either absent independently or selected from H, halogens (e.g., F or Cl), methyl, halomethyl (e.g., CF3) and CN; R 5C2o It is an H, a methyl group, or a halogen; X 2CM It is N and R 5C2M Does not exist, or X 2CM It is C and R 5C2M It is H; and R 6 yes (optional) )or .

88. The compound according to claim 87, wherein R 5C2o It is H or halogen, or optionally F.

89. The compound according to claim 87 or claim 88, wherein the compound has a structure selected from:

90. The compound according to any one of claims 87 to 89, wherein the compound comprises: 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.

91. 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.

92. The method of claim 91, wherein the patient is an animal, preferably a mammal, optionally a human, dog, horse or cat; and preferably a human.

93. A method for synthesizing a PARP1 inhibitor compound as defined in any one of claims 1 to 74, 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.

94. The method of claim 93, wherein the first reactant comprises rings D, E, and A, and the second reactant comprises Q with a reactive group. AB The precursor, the method includes connecting ring A to Q. AB Precursor.

95. The method of claim 94, wherein the Q AB The reactive groups of the precursor include carbonyl groups, alkyl halides, or alkyl sulfonates.

96. The method according to any one of claims 93 to 95, wherein the reaction comprises alkylation, reductive amination or amide formation to form a group L.

97. The method according to any one of claims 93 to 96, further comprising preparing the first reactant by: a) Provide a precursor having the following structure: in: R 9 It is a C1 to C6 alkyl group; and R PG It is a protecting group; b) By using NHR 3 The precursor may be treated with its conjugate acid to perform a ring-closing reaction to form an intermediate having the following structure: ;and c) Deprotecting the intermediate to obtain the first reactant, the first reactant having the following structure: 。 98. The method of claim 97, wherein Z 2l It is N and Z 2u It's C.

99. The method of claim 98, wherein the precursor has the following structure: 。 100. The method of claim 98, wherein the precursor has the following structure: 。 101. The method of claim 100, wherein providing the precursor comprises: a) In the presence of a base such as sodium hydride, a compound having the following structure is formed: Reaction with phenylhydroxylamine having the following structure: Where EWG represents one or more electron-withdrawing groups; To obtain an intermediate product having the following structure: ;and b) React the intermediate with a carboxylic acid having the following structure: The precursor was obtained.

102. The method of claim 101, wherein the substituted phenylhydroxylamine is O-(2,4-dinitrophenyl)hydroxylamine: 。 103. The method according to any one of claims 97 to 102, wherein R 9 It is an ethyl group.

104. The method according to any one of claims 97 to 103, wherein R PG It is Boc.

105. The method according to any one of claims 97 to 104, wherein R 3 It is H.

106. The method according to any one of claims 93 to 96, further comprising preparing the first reactant by: a) Provide a first precursor having the following structure: Where R 10 It is a C1 to C6 alkyl group, optionally a tert-butyl group; b) Provide a second precursor having the following structure: Where R PG It is a protecting group, optionally Boc; and c) Using a catalyst, optionally [Cp] The RhCl2]2 catalyst, coupled with the first precursor and the second precursor, forms the first reactant, which has the following structure: 。 107. The method according to any one of claims 93 to 106, wherein the second reactant has the following structure: 。 108. The method of claim 107, further comprising preparing the second reactant by: i) Provide the first precursor of the following formula: in: a) X 2CM It is C and R 5C2M It is H; or b) X 2CM It is N and R5 C2M It does not exist; ii) Provide a second precursor for the following formula: iii) Using a base, optionally a cesium base such as Cs₂CO₃, to couple the first and second precursors to obtain an intermediate of the following formula: ;and iv) Treat the intermediate with acid to obtain the second reactant, wherein the second reactant has the following structure: 。 109. The method according to claim 108, wherein the second precursor is 1,4-dioxa-8-azaspiro[4.5]decane: 。 110. The method according to any one of claims 93 to 109, wherein carrying out the reaction comprises coupling the first reagent and the second reagent with a reducing agent in the presence of an acid.

111. The method of claim 93, wherein the first reactant comprises rings A, B, D and E, Q. AE and Q AB Furthermore, the second reactant comprises a cyclic C derivative with a leaving group such as a halogen or a sulfonate.

112. The method according to any one of claims 93 to 111, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, thereby forming a group L.

113. The method according to any one of claims 93 to 112, further comprising separating the structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography and / or chiral high-performance liquid chromatography.

Images