Parp1 inhibitor compounds

Abstract

PARP1 inhibitor compounds have structure (I). y is 0, 1, or 2. Each X D Selected from C, N, O, or S. X ET and X EB Selected from C and N. Each R 1 and each R 4 Independently, it is absent, H, or an organic group. R 4 The groups do not fuse to form a ring. R 3 It is an H or organic group. L is (II). The ring C is aromatic. X A1 and X B3 Selected from C and N. Each X A2 X B2 and X C Selected from C, N, O, and S. The C ring is a heterocyclic ring. Each R... 5A R 5B and R 5C It is absent, H, or an organic group. R 6 It is an H or organic group. n, m, p, q, r, and s are integers, where n+m is 1 to 5, p+q is 2 to 6, and r+s is 3 or 4. Q 1 and Q 2 Each is an independent bond or linking group. (I)(II)

Description

Technical Field

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

[0002] background

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

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

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

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

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

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

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

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

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

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

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

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

[0015] Overview

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

[0017] in: Dashed lines represent bonds selected from single and double bonds; y is 0, 1, or 2; Each X D Independently selected from C, N, O, and S; X ET and X EB Each is independently selected from C and N; Each R 1 It does not exist independently or is selected from H and substituted or unsubstituted organic groups; Each R 4 Independently absent or selected from H and substituted or unsubstituted organic groups, provided that the R 4 The groups do not fuse to form a ring; R 3 It is H or a substituted or unsubstituted organic group; L is a group having the following structure:

[0018] in: Ring C is an aromatic ring; X A1 It is C or N; Each X A2 Independently selected from C, N, O, and S; Each X B2 Independently selected from C, N, O, and S; X B3 Selected from C and N; Each X C The ring is independently selected from C, N, O, and S, provided that the ring C is a heterocyclic ring. Each R 5A and R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups; Each R 5B Independently, it is absent, H, substituted or unsubstituted organic groups, or related to another R. 5B Together they represent the key of bridging ring B; R 6 Selected from H and substituted or unsubstituted organic groups; n is 0, 1, 2, 3, 4 or 5; m can be 0, 1, 2, 3, 4 or 5, provided that n + m is in the range of 1 to 5; p is 1, 2, or 3; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; and s can be 0, 1, 2, 3 or 4, provided that r + s is 3 or 4; Q 1 and Q 2 Each is independently a bond or a linking group having a structure selected from the following:

[0019] in: t is 0, 1, 2, 3, 4, or 5; u can be 0, 1, 2, 3, 4, or 5, provided that t + u is within the range of 0 to 6; and Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0020] Optional, Q 1 It is a key; each R 5B It is independent of or selected from H and substituted or unsubstituted organic groups; n + m is in the range of 2 to 5; and p + q is in the range of 2 to 5.

[0021] The PARP1 inhibitor compound can be used in medicine. For example, the PARP1 inhibitor compound can be used to treat cancer.

[0022] Another aspect of the invention provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein.

[0023] Another aspect of the invention provides a pharmaceutical kit for treating cancer. The pharmaceutical kit comprises a PARP1 inhibitor compound as defined herein and additional agents for treating cancer. The PARP1 inhibitor compound and the additional agents are suitable for simultaneous, sequential, or separate administration.

[0024] Another aspect of the invention provides a method for treating diseases and / or conditions and / or disorders, the method comprising administering to a patient a PARP1 inhibitor compound, composition, or kit product as defined herein.

[0025] Another aspect of the present invention provides a method for synthesizing PARP1 inhibitor compounds as defined herein. The method comprises carrying out a reaction between 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.

[0026] 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.

[0027] Detailed Explanation

[0028] General definition

[0029] 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.

[0030] 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.

[0031] 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 in 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] The term "aliphatic ring" is used in this document in the broad sense of a non-aromatic ring. Aliphatic rings can be carbocyclic or heterocyclic, saturated or partially unsaturated, and substituted or unsubstituted.

[0039] In the general formula, in the form (X) i In the case of describing elements, where X is a variable element and i is a number, parentheses are expanded before assigning each X. For example, if the variable X can be C or N, then (X)2 covers CC, CN, and NN.

[0040] In describing stereochemistry, the stereochemistry shown is relative stereochemistry, not absolute stereochemistry.

[0041] Compound numbering

[0042] 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.

[0043] The suffix "rac" in a compound designation indicates a racemic mixture.

[0044] The suffixes “cis” and “trans” indicate compounds with cis and trans ring configurations, respectively, as explained in the “Stereochemistry” section below. For diastereomers, the cis and trans suffixes can refer to diastereomer pairs having the indicated ring configuration. Nuclear Overhausen effect nuclear magnetic resonance spectroscopy (“NOE NMR”) can be used to determine the stereochemistry of compounds as described herein.

[0045] 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.

[0046] 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.

[0047] discuss

[0048] This article provides PARP1 inhibitor compounds with the following structures:

[0049] in: Dashed lines represent bonds selected from single and double bonds; y is 0, 1, or 2; Each X D Independently selected from C, N, O, and S; X ET and X EB Each is independently selected from C and N; Each R 1 It does not exist independently or is selected from H and substituted or unsubstituted organic groups; Each R 4 Independently absent or selected from H and substituted or unsubstituted organic groups, provided that the R 4 The groups do not fuse to form a ring; R 3 It is H or a substituted or unsubstituted organic group; Ring C is an aromatic ring; X A1 It is C or N; Each X A2 Independently selected from C, N, O, and S; Each X B2 Independently selected from C, N, O, and S; X B3 Selected from C and N; Each X C The ring is independently selected from C, N, O, and S, provided that the ring C is a heterocyclic ring. Each R 5A and R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups; Each R 5B Independently, it is absent, H, substituted or unsubstituted organic groups, or related to another R. 5B Together they represent the key of bridging ring B; R 6 Selected from H and substituted or unsubstituted organic groups; n is 0, 1, 2, 3, 4 or 5; m can be 0, 1, 2, 3, 4 or 5, provided that n + m is in the range of 1 to 5; p is 1, 2, or 3; q is 1, 2, or 3; r is 0, 1, 2, 3 or 4; s can be 0, 1, 2, 3, or 4, provided that r + s is 3 or 4; and Q 1 and Q 2 Each is independently a bond or linking group, and the linking group has a structure selected from the following:

[0050] in: t is 0, 1, 2, 3, 4, or 5; u can be 0, 1, 2, 3, 4, or 5, provided that t + u is within the range of 0 to 6; and Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0051] Optional, Q 1 It is a key; each R 5B It is either absent independently or selected from H and substituted or unsubstituted organic groups; n + m is in the range of 2 to 5; and p + q is in the range of 2 to 5.

[0052] The various aspects of the above general structure will now be discussed in more detail.

[0053] Stereochemistry

[0054] Some of the PARP1 inhibitor compounds described herein include one or more chiral centers. Such compounds may be provided as: isolated enantiomers; mixtures of two or more enantiomers; mixtures of two or more diastereomers or epimers; or racemic mixtures.

[0055] Some PARP1 inhibitor compounds may be capable of tautomerism. Such compounds can be provided in any possible tautomer form.

[0056] When ring A of the PARP1 inhibitor compound is a cycloalkane, the compound can exhibit cis-trans isomerism. In the context of this disclosure, unless otherwise explicitly stated, "cis" compounds have a cis configuration on ring A:

[0057] Furthermore, the "trans" compound has a trans configuration on ring A:

[0058] Substituents – General

[0059] The expression "R" 5 "Group" usually refers to group R 5A R 5B and R 5C “R” 5A "The group is R attached to ring A" 5 Groups, and so on. Some formulas shown in this article use R... 5 A more specific identifier for the group. For example, "R" 5A1 "Identified as R" 5A A subset of groups.

[0060] The expression "atom X" usually refers to any variable ring atom (X... D X ET X EB X A1 X A2 X B2 X B3 X C ).

[0061] In the compounds provided in this article, R 1 R 4 and R 5 Multiple groups may be absent. The dashed lines in the structural formulas shown in this article represent any non-zero order covalent bonds.

[0062] It will be understood that the number of ring bonds and substituents is chosen to maintain stable valences of the atoms in the ring. Maintaining stable valences means ensuring that the atoms in the organic compound have their normal (most common) valences (i.e., oxygen is 2; sulfur is 2 or 6; nitrogen is 3 or 4; and carbon is 4).

[0063] When the X atom is N, the atom most preferably has a valence of 3. Compounds containing tetravalent N atoms are also considered. Preferably, the PARP1 inhibitor compound comprises at most one tetravalent N atom, and more preferably does not include a tetravalent N atom.

[0064] Each R 1 R 4 and R 5Groups may be absent or present independently, and may be the same or different. To avoid confusion, when the number of R groups attached to an atom can vary depending on the choice of the corresponding X group, the following conditions generally apply: i) When the X atom is O, neither of its corresponding R groups exists.

[0065] ii) When the X atom is S, its corresponding R group either does not exist 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.

[0066] iii) When X is N and is connected to an adjacent ring atom by a double bond, its corresponding R group does not exist.

[0067] iv) When X is N and not connected to an adjacent ring atom by a double bond, exactly one corresponding R group exists.

[0068] v) When X is C and is connected to an adjacent ring atom by a double bond, exactly one corresponding R group exists.

[0069] vi) When X is C and not connected to an adjacent ring atom by a double bond, the two corresponding R 5 Group or two corresponding R 5 and R 6 All functional groups are present.

[0070] Atom X of ring A A1 It's a special case because this atom connects ring E and ring A. Only when X... A1 When X is C and does not form double bonds with other ring atoms, A1 Only those with R 5 Substituents.

[0071] Substituents (i.e., R groups; R) 1 R 3 R 4 R 5 R 6 R 7 and R 8 There are no particular restrictions, provided that they do not prevent the PARP1 inhibition function from occurring. Substituents are selected from H and substituted or unsubstituted organic groups. Therefore, in the foregoing and hereinafter, the terms “substituent” and “organic group” are not particularly limited and can be any functional group or any atom, especially any functional group or atom common in organic chemistry.

[0072] Any R 5 Or R 6 The group can be associated with any other R on adjacent and / or nearest neighbor atoms. 5Or 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.

[0073] A single R on an atom 1 R 4 R 5 Or R 6 Groups, or two R atoms on the same atom 1 / R 4 / R 5 A group can form a group that is linked to a double bond of that atom. Therefore, an R 1 R 4 R 5 Or R 6 Group, or two R atoms attached to the same atom 1 / R 4 / R 5 The groups can together form a =O group or a =C(R')2 group (where each R' group may be the same or different, and is H or an organic group, preferably H or a straight-chain or branched C1-C6 alkyl group). This is more commonly the case where the R group is attached to a C atom, causing them to together form a C=O group or a C=C(R')2 group. Thus, in some cases, X as C D X A2 or X B2 Atoms can have =O groups.

[0074] "Substituent" and "organic group" can have any of the following meanings.

[0075] 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).

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] Furthermore, any substituent may contain a combination of two or more substituents and / or functional groups as defined herein.

[0082] When we say substituent (R) 1 R 3 R 4 R 5A (e.g. R) 5A1 R 5A2 R 5A3 ), R 5B R 5C R 6 R 7 R 8 R 51 and / or R 52 When ) is a substituted or unsubstituted organic group, said or each substituted or unsubstituted organic group may be specifically and independently selected from: deuterium; Halogens (such as -F, -Cl, -Br and -I); Nitrile group; Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl); Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph); Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (such as -CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3, -CBr3, -CCI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3 and -CH2CH2CI3); 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, 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).

[0083] Besides R 4 In addition, substituent groups with matching identifiers can together form a single group.

[0084] For example, a pair of R atoms connected to the same atom 5A Groups can be used together to represent carbonyl groups.

[0085] Optionally or additionally, a pair of substituent groups attached to different atoms in the same ring can be linked to form a ring. A pair of R groups attached to different atoms 5A Groups can form a ring together with atom A of the ring. A pair of R atoms attached to different atoms 5B Groups can form a ring together with the B atom of the ring. A pair of R atoms attached to different atoms 5C Groups can form rings together with ring carbon atoms.

[0086] Also consider R connected to different atoms 5C Groups and R 6 Groups can form rings together with ring carbon atoms.

[0087] R 4 The groups do not fuse to form a ring. Specifically, R 4 The group does not fuse into the spiropropyl group.

[0088] Preferably, each R 5 Group (R) 5A R 5B R 5C It does not exist independently or is selected from: H, deuterium, Halogens (such as -F, -Cl, -Br and -I; preferably F or Cl), Nitrile group, C1-C6 alkyl groups, C1-C6 haloalkyl groups (preferably CF3, CHF2 or CH2CF3), Cyclopropyl group, -OH group, C1-C6 alcohol groups, C1-C7 amino carbonyl groups (such as -NH-CO-Me), -NH2 group, C1-C6 amino groups and C1-C6 alkoxy groups.

[0089] When a pair of R 5 When the group forms a ring, this pair of R 5 The groups can be represented together by groups selected from -CH2-, -CH2CH2-, -CH=CH-CH=CH- or -NH-CO-NH-.

[0090] Specifically, consider two Rs. 5A The groups can together represent the alkyl groups of bridging ring A.

[0091] Multiple substituent groups can be bonded to a nitrogen atom. For example, when Q... 1 Or Q 2 yes: hour R 8 Bonded to nitrogen. In some cases, R 1 R 4 Or R 5A Or R 5B The group can be attached to a ring atom of N. Preferred substituents for the N atom are: H; Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl); Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph); Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); Substituted or unsubstituted cyclic amine or amide groups (such as pyrrolidine-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolyl, 3-keto-pyrrolyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl); Substituted or unsubstituted cyclic C3-C8 alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); Substituted or unsubstituted straight-chain or branched C2-C6 alcohol groups (Such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH (CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH and -CH2CH2CH2CH2CH2CH2OH); Substituted or unsubstituted straight-chain or branched C2-C6 carboxylic acid groups (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH); Substituted or unsubstituted straight-chain or branched carbonyl groups (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl, -(CO)N H2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholino-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe and -(CO)NHCH2CH2NMe2); Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); Substituted or unsubstituted straight-chain or branched C1-C6 amide groups (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt); Substituted or unsubstituted sulfonyl groups (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholino-N-yl, -SO2NHCH2OMe and -SO2NHCH2CH2OMe); Substituted or unsubstituted aromatic groups (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2-Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)- Pr2-Ph-、2,(3,4,5 or 6)-Bu2-Ph-、2,(3,4,5 or 6)-(CN)2-Ph-、2,(3,4,5 or 6)-(NO2)2-Ph-、2,(3,4,5 or 6)-(NH2)2-Ph-、2,(3,4,5 or 6)-(MeO)2-Ph-、2,(3,4,5 or 6)-(CF3)2-Ph-、3,(4 or 5)-F2-Ph-、3,(4 or 5)-Cl2-Ph-、3,(4 or 5)-Br2-Ph-、3,(4 or 5)-I2-Ph-、3,(4 or 5)-Me2-Ph-、3,(4 or 5)-Et2-Ph-、3, (4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN) -Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, and Substituted or unsubstituted heterocyclic groups (such as pyrrolo-2-yl, pyrrolo-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-Triazol-5-yl, Pyridin-2-yl, Pyridin-3-yl, Pyridin-4-yl, Pyridazin-3-yl, Pyridazin-4-yl, Pyriminin-2-yl, Pyriminin-4-yl, Pyriminin-5-yl, Pyriminin-6-yl, Pyrazin-2-yl, Pyrrolidine-2-yl, Pyrrolidine-3-yl, Piperidin-2-yl, Piperidin-3-yl, Piperidin-4-yl, 2-azapiperidin-3-yl -yl, 2-azapiperidin-4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran Azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran- 3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxacyclobutane-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, thiophen-2-yl, thiophen-3-yl Isothiazol-3-yl, Isothiazol-4-yl, Isothiazol-5-yl, Thiazol-2-yl, Thiazol-4-yl, Thiazol-5-yl, Thian-2-yl, Thian-3-yl, Thian-4-yl, 2-azathiaran-3-yl, 2-azathiaran-4-yl, 2-azathiaran-5-yl, 2-azathiaran-6-yl, 3-azathiaran-2-yl, 3- Azathiaran-4-yl, 3-azathiaran-5-yl, 3-azathiaran-6-yl, 4-azathiaran-2-yl, 4-azathiaran-3-yl, 4-azathiaran-5-yl, 4-azathiaran-6-yl, thiacyclopentan-2-yl, thiacyclopentan-3-yl, thiacyclohexane-2-yl, thiacyclohexane-3-yl, thiacyclohexane-4-yl Oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazon-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-5-yl.

[0092] Optional, R 8 Or any R connected to cyclic nitrogen 1 R 4 、or R 5A Or R 5B It can preferably be selected from H, substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups and substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups.

[0093] R connected to N 1 Or R 4 Preferably selected from H, C1 to C3 alkyl groups and C1 to C3 fluoroalkyl groups, such as -CH2CF3.

[0094] Head base - general

[0095] The head group of the PARP1 inhibitor compound comprises rings D and E, as shown in the following general formula:

[0096] Dashed lines represent bonds selected from single and double bonds. Ring D can be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring.

[0097] y is 0, 1, or 2. In other words, ring D can be a 5-membered, 6-membered, or 7-membered ring. In particular, ring D can be a 5-membered ring (y=0) or a 6-membered ring (y=1). Compounds having a 6-membered D-ring are particularly preferred.

[0098] Each X D This indicates atoms independently selected from C, N, O, and S. X is usually chosen. D The atoms ensure that ring D contains no O-type bonds. Typically, at least one X atom... D It's C.

[0099] Optionally, each X D Independently selected from C and N. Further, optionally, each X D It's C.

[0100] Rings D and E are connected via atom X ET and X EB Connections. These atoms can be referred to as "bridgehead atoms" in this paper. X ET and X EB Each is individually selected from C and N. Typically, X... ET and X EB At least one of them is C. Preferably, X ET It is C and X EB It is C or N, and most preferably X. ET and X EBEach is C.

[0101] Ring D may have optional substituent R. 1 and R 4 In the above general formula, each R 1 Independently absent or selected from H and substituted or unsubstituted organic groups; and each R 4 Independently absent or selected from H and substituted or unsubstituted organic groups, provided that the R 4 The groups do not fuse to form a ring.

[0102] For any given ring D atom X D Substituent (R) 1 Or R 4 The number of groups and the nature of the bonds with adjacent atoms of ring D are determined according to X. D The identity of an atom is appropriately selected to satisfy its normal valence.

[0103] When X D When the atom is O: The atom lacks any substituents (R). 1 Or R 4 ); The atoms are bonded to adjacent ring atoms via single bonds; and Neither of the adjacent ring atoms is O.

[0104] When X D When the atom is N: The atom carries at most one substituent (R) 1 Or R 4 ); If the atom carries a substituent, then the atom is bonded to an adjacent ring atom via a single bond; or If the atom does not have substituents, then the atom forms a double bond with one adjacent ring atom and a single bond with another adjacent ring atom.

[0105] When X D When the atom is C: The atom carries one or two substituents (R). 1 Or R 4 ); If the atom carries two substituents, then the atom is bonded to an adjacent ring atom via a single bond; or If the atom carries a substituent, then the atom forms a double bond with one adjacent ring atom and a single bond with another adjacent ring atom.

[0106] Each R 1 and each R 4It may be absent independently or selected from H and substituted or unsubstituted organic groups. The organic groups may be selected from any of the various groups already discussed, provided that R... 4 The groups do not fuse to form a ring. Specifically, R 4 The group does not represent a spirocyclopropyl group.

[0107] For example, each R 1 and each R 4 It can exist independently or be selected from: H; halogen; Nitrile group; C1 to C6 acyclic alkyl groups; C1 to C6 have no cycloalkoxy groups; C1 to C6 acyclic haloalkyl groups; C1 to C6 acyclic halogenated alkoxy groups, such as -OCF3 or OCHF2; C1 to C6 acyclic aminoalkyl groups; and , R 22 Selected from H, halogens, C1 to C6 alkyl groups, C3 to C6 cycloalkyl groups, C1 to C6 alkoxy groups, and C1 to C6 haloalkyl groups, and Each R 23 Independently selected from H; halogen; C1 to C6 alkyl group; C1 to C6 aminoalkyl group; C1 to C6 alkoxy group; C1 to C6 haloalkoxy group; such as -OCF3 or OCHF2; and C1 to C6 haloalkyl group.

[0108] Optionally, each R 1 and each R 4 The following are not present independently or are selected from H; halogens, optionally Cl or F; C1 to C3 acyclic alkyl groups, optionally methyl groups; C1 to C3 haloalkyl groups, optionally halomethyl groups such as -CH2F, -CHF2 or -CF3; haloethyl groups, such as -CH2CF3; and nitrile groups.

[0109] Preferably, each R 1 and each R 4 It is either absent independently or selected from: H; Cl; F; halomethyl groups, such as CF3; and nitrile groups.

[0110] Most preferably, each R 1 and each R 4 It does not exist independently or is selected from H and F.

[0111] For example, exactly one R 1It can be F, or exactly one R. 4 It can be F.

[0112] Or, each R 1 and each R 4 It either does not exist or it is H.

[0113] Typically, ring D carries a total of no more than two organic groups, and all other R... 1 and R 4 The group is absent or is H.

[0114] As shown in the general formula, ring E carries a substituent R. 3 It can be H or a substituted or unsubstituted organic group.

[0115] R 3 Preferably selected from H, C1 to C3 alkyl groups, and C1 to C3 haloalkyl groups. Most preferably, R 3 It is H.

[0116] Instance header base-N-bridge variant

[0117] When X EB When N is present, the PARP1 inhibitor compound may have a structure selected from the following:

[0118] Where R 1 R 4 and R 3 Each is defined as above.

[0119] The preferred head base in this class is:

[0120] General structural formula of head-base-C-bridge variant

[0121] In which X EB and X ET In instances where each compound is a C, the PARP1 inhibitor compound may have a structure selected from the following:

[0122] Where R 1 R 3 and R 4 Each as discussed previously.

[0123] According to another possibility, the PARP1 inhibitor compound may have a structure selected from the following:

[0124] Where R 1 R 3 and R 4 Each as discussed previously.

[0125] Head-based Aroma Examples

[0126] The ring D of the PARP1 inhibitor compound can be an aromatic ring.

[0127] For example, ring D can be a 6-membered carbon ring: .

[0128] R 4 and each R 1 exist.

[0129] In such an example, the head group of the PARP1 inhibitor compound may have the following substitution pattern: , And can be chosen from: or .

[0130] Preferred PARP1 inhibitor compounds in this class include:

[0131] Other preferred examples of PARP1 inhibitor compounds having an aromatic D-ring include:

[0132] R 4 and each R 1 exist.

[0133] The most preferred PARP1 inhibitors in this class can be selected from:

[0134] Further examples of PARP1 inhibitor compounds having an aromatic D-ring include those having a structure selected from the following:

[0135] R 4 and each R 1 exist.

[0136] Preferred structures of PARP1 inhibitor compounds having an aromatic D-ring include:

[0137] Another preferred structure for PARP1 inhibitor compounds having an aromatic D-ring is:

[0138] Other examples of PARP1 inhibitor compounds include those having a structure selected from the following:

[0139] Head base - non-aromatic examples

[0140] Alternatively, ring D can be a non-aromatic ring.

[0141] Ring D can be a non-aromatic carbide ring. For example, the PARP1 inhibitor compound can have a structure selected from the following:

[0142] It will be understood that in these instances, each R 1 and each R 4 exist.

[0143] Preferred PARP1 inhibitor compounds in the above categories have the following structures: .

[0144] Ring D may optionally be a cyclic ether having a structure selected from the following:

[0145] Each R 1 and each R 4 exist.

[0146] Another example of a compound in which ring D is a cyclic ether is:

[0147] Each R 1 and each R 4 exist.

[0148] According to another possibility, ring D can be a cyclic amine. Examples of such PARP1 inhibitor compounds include:

[0149] Each R 1 and each R 4 exist.

[0150] Other examples of PARP1 inhibitor compounds in which ring D is a cyclic amine are:

[0151] Each R 1and each R 4 exist.

[0152] bonded to N R 1 Or R 4 Preferably selected from H, C1 to C3 alkyl groups and C1 to C3 fluoroalkyl groups.

[0153] Preferred structures of PARP1 inhibitor compounds having a non-aromatic D-ring include:

[0154] Other examples of the structure of PARP1 inhibitor compounds include:

[0155] L group – generally

[0156] The PARP1 inhibitor compounds provided in this article have a group L with a structure according to the following general formula:

[0157] in: Ring C is an aromatic ring; X A1 It is C or N; Each X A2 Independently selected from C, N, O, and S; Each X B2 Independently selected from C, N, O, and S; X B3 Selected from C and N; Each X C The ring is independently selected from C, N, O, and S, provided that the ring C is a heterocyclic ring. Each R 5A and R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups; Each R 5B Independently, it is absent, H, substituted or unsubstituted organic groups, or related to another R. 5B Together they represent the key of bridging ring B; R 6 Selected from H and substituted or unsubstituted organic groups; n is 0, 1, 2, 3, 4 or 5; m can be 0, 1, 2, 3, 4 or 5, provided that n + m is in the range of 1 to 5; p is 1, 2, or 3; q is 1, 2, or 3, provided that p + q is in the range of 2 to 5; r is 0, 1, 2, 3, or 4; and s can be 0, 1, 2, 3, or 4, provided that r + s is 3 or 4; and Q 1 and Q 2 Each is independently a bond or a linking group having a structure selected from the following:

[0158] in: t is 0, 1, 2, 3, 4, or 5; u can be 0, 1, 2, 3, 4, or 5, provided that t + u is within the range of 0 to 6; and Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

[0159] Each X A2 Each X B2 and each X C Independently selected from C, N, O, and S, provided that at least one X C It is O, N, or S (preferably N), such that ring C is a heterocyclic ring.

[0160] Optional, Q 1 It is a key.

[0161] Optionally, n + m is in the range of 2 to 5.

[0162] Optionally, p + q is in the range of 2 to 5.

[0163] Optionally, each R B It is either absent independently or selected from H and substituted or unsubstituted organic groups.

[0164] Typically, Q 1 It is a key; n + m is in the range 2 to 5; p + q is in the range 2 to 5; and each R B It is either absent independently or selected from H and substituted or unsubstituted organic groups.

[0165] One or more of the following conditions, and all of the optimal options, may apply: i) At least one X atom in each ring is C. When ring A is a 3-membered ring, ring A is typically a carbon ring. When ring A or ring B is 4-membered, the ring typically includes at most one heteroatom. When ring A or ring B is 5- or 6-membered, the ring typically includes at most three heteroatoms, optionally at most two heteroatoms.

[0166] ii) Each of rings A, B and C may individually contain up to three heteroatoms.

[0167] iii) The compound is not a quaternary ammonium compound.

[0168] iv) The compound does not contain OO, SS and SO bonds.

[0169] Each part of group L will be discussed in more detail below.

[0170] Ring A

[0171] Ring A of the PARP1 inhibitor compound has a general structure:

[0172] n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, 4, or 5, provided that n + m is in the range 1 to 5. In other words, ring A can be a 3-, 4-, 5-, 6-, or 7-membered ring. Optionally, n + m is in the range 2 to 5, such that ring A is a 4-, 5-, 6-, or 7-membered ring. Preferably, ring A is a 5- or 6-membered ring (n + m = 3 or 4), with a 5-membered ring (n + m = 3) being particularly preferred.

[0173] Preferably, both n and m are at least 1. In other words, the atoms that connect ring A to rings E and B are preferably not adjacent.

[0174] X A1 Bonded to ring E, and selected from C and N. When X A1 When it is N, R 5A1 It does not exist. When X A1 When it is C, R 5A1 It may or may not exist, but it is preferred to exist.

[0175] Each X A2 Independently selected from C, N, O, and S. Preferably, each X A2 Independently selected from C and N. Most preferably, each X A2 It's C.

[0176] Each R 5A Group (i.e., R) 5A1 R 5A2 R 5A3 It exists independently or is selected from H and substituted or unsubstituted organic groups. R can be selected. 5A The number of groups allows ring A to be saturated, unsaturated, non-aromatic, or aromatic. Preferably, ring A is saturated.

[0177] In most implementations, no more than two R5A The 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.

[0178] Typically, when R 5A When the group is present, the R 5A The preferred radical is H.

[0179] 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.

[0180] R 5A3 The most common is H.

[0181] Preferably, when present, each R 5A Independently selected from H; halogen, optionally F; hydroxyl group; oxo group (in other words, carbonyl group:=O); and C1 to C3 alkyl group, optionally one pair of which is R 5A The group forms a ring, and optionally, said ring bridges ring A. According to another possibility, two R groups on adjacent atoms... 5A The groups can together represent the ring fused with ring A, optionally a phenyl group fused with ring A.

[0182] Particularly preferred: i) A pair of R 5A The group forms a bridging ring A with a -CH2- group, and each other R 5A It is H; or ii) Each R 5A It is H.

[0183] Ring A can be a 7-membered ring. For example, ring A can be a cycloheptane having a structure selected from the following:

[0184] Each R 5A exist.

[0185] Alternatively, ring A can be a 6-membered non-aromatic ring, such as cyclohexane, cyclohexene, or tetrahydropyran. Ring A can, for example, have a structure selected from the following:

[0186] Each R 5A exist.

[0187] Alternatively, ring A can be a 5-membered non-aromatic ring, such as cyclopentane, cyclopentene, or tetrahydrofuran. Ring A can, for example, have a structure selected from the following:

[0188] Each R 5A exist.

[0189] According to another possibility, ring A can be a 5-membered aromatic ring, optionally oxazole or isoxazole, optionally having a structure selected from the following:

[0190] Each R 5A It is independently selected from H and substituted or unsubstituted organic groups.

[0191] In other instances, ring A can be a 4-membered ring with the following structure: ; Each R 5A and R 5A3 exist.

[0192] Alternatively, ring A can be a 3-membered ring with the following structure:

[0193] Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The optimal choice is H.

[0194] Alternatively, ring A could be a bridge ring. Examples of suitable bridge ring structures include:

[0195] Each R 5A exist.

[0196] Other examples of bridge ring A structures include:

[0197] Ring A typically includes no more than one bridging group. In the example bridged rings shown above, there is no R. 5A The groups fuse to form another ring, and each R 5A The group is preferably H.

[0198] Examples of suitable structures for ring A include:

[0199] Other examples of suitable structures for ring A include:

[0200] Ring A can have the following structure:

[0201] in: m is 1 or 2; n is 1 or 2; Each R 5A2 and R 5A3 Independently absent or selected from H and substituted or unsubstituted organic groups, preferably wherein R 5A3 It is H; And among them: i) X A1 It is C and R 5A1 Selected from H and substituted or unsubstituted organic groups; or ii) X A1 It is N and R 5A1 It does not exist.

[0202] Each R 5A1 R 5A2 and R 5A3 It may be absent independently or selected from H; halogen, optionally F; hydroxyl group; oxo group (also called carbonyl group; =O); and C1 to C3 alkyl group, optionally one pair of which R 5A The group forms a bridging ring A with a C1 to C3 alkyl group. Preferably, each R 5A1 R 5A2 and R 5A3 It either does not exist or it is H.

[0203] Preferred A-ring structures include:

[0204] The particularly preferred A-ring structures include:

[0205] Other particularly preferred ring A structures are:

[0206] The optimal ring A structure is:

[0207] Q 1 Typically, it's a bond. When ring A is a 3- or 4-membered ring, Q... 1 Optionally, a linking group such as -CH2- or -CH(CH3)- is used. In particular, when ring A is: or hour, Q 1 It can be a linking group selected from -CH2- or -CH(CH3)-.

[0208] Ring B

[0209] The ring B of group L has the following general structure:

[0210] Each X B2 Independently selected from C, N, O, and S. X B3 Selected from C and N.

[0211] p is 1, 2, or 3; and q is 1, 2, or 3. Typically, p + q is in the range of 2 to 5. In other words, ring B is typically a 4-membered, 5-membered, 6-membered, or 7-membered ring. Preferably, ring B is a 6-membered ring, and most preferably, both p and q are equal to 2.

[0212] Typically, each R 5B Independently absent or selected from H and substituted or unsubstituted organic groups. Preferably, each R 5B It either does not exist independently or it is H.

[0213] In some instances, especially those where p + q is 6, the two R... 5B Groups can together represent the bonds bridging ring B. In other words, ring B can be a fused ring system containing two rings.

[0214] Depending on the existence of R 5B The number of groups, and whether ring B is saturated or unsaturated. Preferably, ring B is a saturated ring.

[0215] Preferably, each X B2 It is C, and ring B has the following structure: .

[0216] X B3 Preferably, it is N. In such an embodiment, ring B may have the following structure: .

[0217] Ring B can have a general structure selected from the following:

[0218] X B3 It can be C. For example, ring B can be an azircyclic heptane, optionally having the following structure:

[0219] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H.

[0220] According to another possibility, ring B can be piperidine, optionally having the following structure:

[0221] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H.

[0222] Alternatively, ring B may be pyrrolidine, optionally having the following structure:

[0223] Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H.

[0224] More specific examples of suitable ring B structures include:

[0225] Most preferably, ring B has the following structure: or .

[0226] According to another possibility, ring B can have the following structure: .

[0227] Q 2 Typically, it's a bond. When ring B is a 4-membered ring, such as the azahexacyclic butane just explained above, Q... 2 It can be a linking group, such as -O-.

[0228] According to another possibility, p + q can be 6 and ring B can contain two fused rings. For example, ring B can have the following structure:

[0229] Optionally, each of R 5B It either does not exist or it is H.

[0230] Optionally, ring B can have the following structure: .

[0231] Alternatively, ring B can have the following structure:

[0232] or .

[0233] More specific examples of B-ring structures containing fused rings include: and .

[0234] Connector base - Q 1 and Q 2 Group

[0235] Ring A via connecting base Q 1 Coupled to ring B, and ring B is connected to connection base Q. 2 Coupled to ring C:

[0236] Typically, Q 1 It is a key that allows rings A and B to be directly connected to each other:

[0237] Q 2 It can be a bond. In other words, atom X B3 It can be directly connected to ring C.

[0238] Available location, Q 1 and / or Q 2 It can be a group selected from the following:

[0239] 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.

[0240] R 7 It may be selected from H; halogen; such as -F, -Cl, -Br or -I, and preferably -F; -OH group; C1 to C6 alkyl group; C1 to C6 haloalkyl group, preferably -CF3; -NH2 group; C1 to C6 amino group; C1 to C6 alcohol group; and C1 to C6 alkoxy group.

[0241] Preferably, each R 7 Independently selected from H; halogen, optionally F; C1 to C6 alkyl group; and C1 to C6 haloalkyl group.

[0242] When the X of ring B B3 It is N, and Q2 yes In this case, t is usually at least 1.

[0243] When Q 1 and / or Q 2 yes: hour R 8 You can choose from: H; Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl); Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph); Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); Substituted or unsubstituted cyclic amine or amide groups (such as pyrrolidine-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolyl, 3-keto-pyrrolyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl); Substituted or unsubstituted cyclic C3-C8 alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); Substituted or unsubstituted straight-chain or branched C2-C6 alcohol groups (Such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH (CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH and -CH2CH2CH2CH2CH2CH2OH); Substituted or unsubstituted straight-chain or branched C2-C6 carboxylic acid groups (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH and -CH2CH2CH2CH2CH2COOH); Substituted or unsubstituted straight-chain or branched carbonyl groups (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl; -(CO)N H2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholino-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe and -(CO)NHCH2CH2NMe2); Substituted or unsubstituted straight-chain or branched C1-C6 carboxylic acid ester groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); Substituted or unsubstituted straight-chain or branched C1-C6 amide groups (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe and -CO-NPrEt); Substituted or unsubstituted sulfonyl groups (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2, 3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholino-N-yl, -SO2NHCH2OMe and -SO2NHCH2CH2OMe); Substituted or unsubstituted aromatic groups (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5, or 6)-F2-Ph-, 2,(3,4,5, or 6)-Cl2-Ph-, 2,(3,4,5, or 6)-Br2-Ph-, 2,(3,4,5, or 6)-I2-Ph-, 2,(3,4,5, or 6)-Me2-Ph-, 2,(3,4,5, or 6)-Et2-Ph-, 2,(3,4,5, or 6)- Pr2-Ph-、2,(3,4,5 or 6)-Bu2-Ph-、2,(3,4,5 or 6)-(CN)2-Ph-、2,(3,4,5 or 6)-(NO2)2-Ph-、2,(3,4,5 or 6)-(NH2)2-Ph-、2,(3,4,5 or 6)-(MeO)2-Ph-、2,(3,4,5 or 6)-(CF3)2-Ph-、3,(4 or 5)-F2-Ph-、3,(4 or 5)-Cl2-Ph-、3,(4 or 5)-Br2-Ph-、3,(4 or 5)-I2-Ph-、3,(4 or 5)-Me2-Ph-、3,(4 or 5)-Et2-Ph-、3, (4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN) -Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, and Substituted or unsubstituted heterocyclic groups (such as pyrrolo-2-yl, pyrrolo-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-Triazol-5-yl, Pyridin-2-yl, Pyridin-3-yl, Pyridin-4-yl, Pyridazin-3-yl, Pyridazin-4-yl, Pyriminin-2-yl, Pyriminin-4-yl, Pyriminin-5-yl, Pyriminin-6-yl, Pyrazin-2-yl, Pyrrolidine-2-yl, Pyrrolidine-3-yl, Piperidin-2-yl, Piperidin-3-yl, Piperidin-4-yl, 2-azapiperidin-3-yl -yl, 2-azapiperidin-4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran Azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran- 3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxacyclobutane-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, thiophen-2-yl, thiophen-3-yl Isothiazol-3-yl, Isothiazol-4-yl, Isothiazol-5-yl, Thiazol-2-yl, Thiazol-4-yl, Thiazol-5-yl, Thian-2-yl, Thian-3-yl, Thian-4-yl, 2-azathiaran-3-yl, 2-azathiaran-4-yl, 2-azathiaran-5-yl, 2-azathiaran-6-yl, 3-azathiaran-2-yl, 3- Azathiaran-4-yl, 3-azathiaran-5-yl, 3-azathiaran-6-yl, 4-azathiaran-2-yl, 4-azathiaran-3-yl, 4-azathiaran-5-yl, 4-azathiaran-6-yl, thiacyclopentan-2-yl, thiacyclopentan-3-yl, thiacyclohexane-2-yl, thiacyclohexane-3-yl, thiacyclohexane-4-yl Oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazon-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-5-yl.

[0244] 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.

[0245] Preferably, Q 2 It is a key, -O-, or -CH2-; optional key or -CH2-. Most preferably, Q 2 It is a key.

[0246] Ring C

[0247] The ring C of the PARP1 inhibitor compound is a heteroaromatic ring having the following general structure:

[0248] r can be 0, 1, 2, 3, or 4; and s can be 0, 1, 2, 3, or 4, provided that r + s is 3 or 4. In other words, ring C can be a 5-membered ring or a 6-membered ring.

[0249] Each R 5C It is either absent independently or selected from H and substituted or unsubstituted organic groups.

[0250] Each R 5C It may be independent of the absence of H or an organic group, said organic group being selected from halogens, preferably F; C1 to C3 alkyl groups, optionally cyclopropyl groups; C1 to C3 haloalkyl groups, optionally fluoromethyl groups such as CF2H or CF3; C1 to C3 alkoxy groups; and nitrile groups.

[0251] Preferably, each R 5C The organic group is absent, H, or an organic group selected from halogens, preferably F; C1 to C3 alkyl groups; C1 to C3 haloalkyl groups, optionally fluoromethyl groups such as CF2H or CF3; and nitrile groups. Optionally, the organic group may be selected from F, Cl, nitrile groups, methyl groups, and fluoromethyl groups such as -CF2H. F is a preferred organic group.

[0252] Optionally, exactly one R 5C It is an organic group. Further, optionally, exactly one R 5C It is F, and every other R 5C It either does not exist or it is H.

[0253] Optionally, each R 5C It can be non-existent or H.

[0254] At least one X C It is a heteroatom.

[0255] When ring C is a 5-element ring, each X C Independently selected from C, N, O, and S, wherein at least one X C It is C, N, or O. Optionally, each X C Independently selected from C and N. Further, optionally, exactly one X C The atom is N or exactly two X atoms. C The atom is N.

[0256] When ring C is a 6-element ring, each X C Independently selected from C and N, wherein at least one X C It is N.

[0257] Preferably, with connection base Q 2 The linked carbon atom and the terminal substituent R 6 The carbon atoms are not adjacent. In other words, preferably, r is at least 1 and s is at least 1.

[0258] Ring C can be a 6-membered ring (r + s = 4). Preferably, in such an embodiment, Q 2 It is the terminal substituent R 6 The alignment (r=2, s=2).

[0259] Ring C preferably has the following general structure:

[0260] in: X Co and X Cm Each is selected from C and N, provided that X Co and X Cm At least one of them is N; When X Co When it is C, R Co It is H or a halogen, with F being the preferred halogen; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or a halogen, with F being the preferred halogen; When X Cm When it is N, R Cm It does not exist.

[0261] Optional, X Co and X Cm One of them is N.

[0262] The ring C can be a pyridine group, optionally having a structure selected from the following:

[0263] Preferably, the ring C is a pyridine group having the following structure: ; More preferably, ring C has the following structure: .

[0264] Most preferably, ring C has the following structure: or .

[0265] Alternatively, the ring C may be a diazine group, optionally having a structure selected from: , , , , , and .

[0266] In particular, ring C can have a structure selected from the following: , and .

[0267] According to another possibility, ring C could be a 5-membered ring (r+s=3).

[0268] For example, the ring C can be an imidazole group, optional. or .

[0269] Alternatively, the ring C may be a thiophene group, optionally having a structure selected from: , and .

[0270] Alternatively, the ring C can be a thiazole group. For example, the ring C can have a structure selected from the following: , , and .

[0271] The preferred thiazole structure of ring C is: Optional of R 5C It is H.

[0272] Alternatively, the ring C may be a triazole, optionally having a structure selected from the following: and .

[0273] More specific examples of suitable C-ring structures include:

[0274] According to another possibility, ring C can have the following structure:

[0275] C29.

[0276] Specific examples of the C-ring structure include:

[0277] terminal substituent R 6

[0278] Cycle C with substituent R 6 It is selected from H and substituted or unsubstituted organic groups.

[0279] R 6 It can be specifically selected from H, -F, -Cl, -Br, -I, -CN, -CONR 51 R 51 -NR 51 COR 52 -SO2NR 51 R 51 -NR 51 SO2R 52 -O-CR 52 R 52 R 52 -CR 52 R 52 NR 51 R 51 and any of the following structures:

[0280] R 51 and R 52 Each is independently selected from H and substituted or unsubstituted organic groups. Optionally, R 51 and R 52 Each is independently selected from H, halogen, optionally deuterated C1 to C3 alkyl and C1 to C3 haloalkyl.

[0281] Optional, R 6Selected 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 .

[0282] R 6 The option available is H.

[0283] Particularly preferred, R 6 Selected from: i) CONHMe; ia) CONHCD3; ii) ; iii) F; iv) Cl; and v) CN.

[0284] Using R selected from i) to v) just defined above 6 When describing a compound by a group, explicitly consider replacing R with any other group from group i) to v). 6 Group.

[0285] According to another possibility, R 6 It can have the following structure:

[0286] 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.

[0287] According to the above general formula R 6 Examples of functional groups include:

[0288] R 6 You can choose from the following list: -CONHMe; ; -C(O)NHEt; ; ; -C(O)NHCH2CH2F; -C(O)NHCH2CHF2; and .

[0289] Available location, R 6 It can have the following structure:

[0290] 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; halogenated groups, such as F; oxo groups; C1 to C3 alkyl groups; C1 to C3 haloalkyl groups, optionally C1 to C3 fluoroalkyl groups; and -NHR 63 , where R 63 It is an H or C1 to C3 alkyl group.

[0291] According to the above formula, the annular R 6 Examples of functional groups include:

[0292] Preferred circular R 6 The functional group is: .

[0293] Example L group

[0294] The L group in the PARP1 inhibitor compound can be specifically selected from:

[0295] Alternatively, the group L may be selected from:

[0296] Group L can have a cis configuration relative to ring A. For example, group L can have a structure selected from the following:

[0297] Another example of an L-group having a cis configuration is:

[0298] Alternatively, group L may have a trans configuration relative to ring A. For example, group L may have a structure selected from the following:

[0299] Another example of an L group having a trans configuration is:

[0300] Example compounds

[0301] PARP1 inhibitor compounds with the following structures are provided:

[0302] in: X D Selected from C and N; When X D When it is N: R D1 Selected from H, C1 to C3 alkyl groups and C1 to C3 haloalkyl groups; preferably methyl groups; and R D2 It does not exist; When X D When it is C: R D1 and R D2 Each is H; n is 1 or 2; R A1 and R A3 Each is H or R A1 and R A3 Together, they represent the -CH2- group of bridging ring A, provided that when n is 1, R A1 and R A3 Each is H; X Co and X Cm Each is selected from C and N, provided that X Co and X Cm At least one of them is N; When XCo When it is C, R Co It is H or halogen, preferably F; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or halogen, preferably F; When X Cm When it is N, R Cm It does not exist; R 6 Selected from -C(O)NHMe; -CN; and halogens, optionally F or Cl.

[0303] X D C is preferred.

[0304] n is preferably 2.

[0305] R A1 and R A3 H is preferred for each.

[0306] X Cm Preferably, it is N, and R Co Preferably, it is H or F.

[0307] R 6 Preferably, it is -C(O)NHMe, for example, C(O)NHCD3.

[0308] When R A1 and R A3 When each of the two atoms is H, the compound can have a cis configuration on ring A:

[0309] Or it may have a trans configuration on ring A: .

[0310] Specific examples of compounds in this class are:

[0311] PARP1 inhibitor compounds with the following general structures are also provided:

[0312] in: X D It is C or N; When X D When it is C, R D4 Selected from H and halogens, with H being the preferred choice; When X D When it is N, R D4 It does not exist; R D1 and R D2 Each is independently selected from H and halogens; n is 1 or 2; X A It is C or N; When X A When it is C: R A1 and R A3 Each is H or R A1 and R A3 Together, they represent the -CH2- group of bridging ring A, provided that when n is 1, R A1 and R A3 Each is H; When X A When it is N: R A1 It does not exist, and R A3 It is H; X Co and X Cm Each is selected from C and N, provided that X Co and X Cm At least one of them is N; When X Co When it is C, R Co It is H or halogen, preferably H or F; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or halogen, preferably H or F; When X Cm When it is N, R Cm It does not exist; R 6 Selected from -C(O)NHMe; -CN; and halogens, optionally F or Cl.

[0313] Preferably, X D It is C and R D4 It is H.

[0314] R D1 and R D2 Preferably selected from H and F. In such an example, R D1 and R D2 One of them can be F.

[0315] n is preferably 2.

[0316] When R6 When it is C(O)NHMe, X Cm N is preferred.

[0317] When X A It is C and R A1 and R A3 When each of the two atoms is H, the compound can have a cis configuration on ring A:

[0318] Or it may have a trans configuration on ring A: .

[0319] Examples of compounds in this class include:

[0320] Further, PARP1 inhibitor compounds with the following general structures are provided:

[0321] in: Dashed lines indicate single or double bonds; X EB It is C or N; X D1 and X D2 Each is independently selected from C and N, provided that when X EB When it is N, X D1 It is C; R D1 and R D2 Each of them is either absent or present and selected from H, halogens, methyl groups and halomethyl groups, such as CF3; R D3 Selected from H, halogens, methyl groups and halomethyl groups, such as CF3; n is 1 or 2; R A1 and R A3 Each is H or R A1 and R A3 Together, they represent the -CH2- group of bridging ring A, provided that when n is 1, R A1 and R A3 Each is H; X Coand X Cm Each is selected from C and N, provided that X Co and X Cm At least one of them is N; When X Co When it is C, R Co It is H or a halogen, and optionally H or F; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or a halogen, and optionally H or F; When X Cm When it is N, R Cm It does not exist; R 6 Selected from -C(O)NHMe; -CN; and halogens, optionally F or Cl.

[0322] Specifically: a) X EB It could be C or X D1 It can be N, and X D2 It can be C, and R at the same time D1 and R D2 Each exists independently; or b) X EB It could be C or X D1 It can be N, and X D2 It can be N, and R D1 Existence and R D2 Does not exist; or c) X EB It can be N, and X D1 and X D2 Each can be C, and R can be R. D1 and R D2 Each exists R D3 CF3 is preferred.

[0323] n is preferably 2.

[0324] R A1 and R A3 H is preferred for each.

[0325] R 6 Preferably, it is C(O)NHMe (e.g., C(O)NHCD3).

[0326] X Cm Preferably, it is N. R Co H is preferred.

[0327] Examples of compounds in this class include:

[0328] Other example compounds provided in this article are:

[0329] Medical Use

[0330] 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.

[0331] The PARP1 inhibitor compounds presented herein are selective for PARP1 relative to PARP2. Therefore, these PARP1 inhibitor compounds may exhibit reduced toxicity. PARP2 inhibition is considered a major driver of hematological toxicities such as anemia, neutropenia, and thrombocytopenia.

[0332] The PARP1 inhibitor compounds can be used to treat cancer. There are no particular limitations on the nature of the cancer, provided that it is a cancer that can be treated, prevented, or improved by using a PARP1 inhibitor. Cancers can include solid tumors or liquid tumors.

[0333] For example, cancer can be selected from: eye cancer, brain cancer (such as glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, and astrocytoma), spinal cord cancer, kidney cancer, oral cancer, lip cancer, laryngeal cancer, oral cavity cancer, nasal cavity cancer, small intestine cancer, colon cancer, parathyroid cancer, gallbladder cancer, head and neck cancer, breast cancer, bone cancer, bile duct cancer, cervical cancer, heart cancer, subpharyngeal gland cancer, lung cancer, bronchial cancer, liver cancer, skin cancer, ureteral cancer, urethral cancer, testicular cancer, vaginal cancer, and anal cancer. Laryngeal gland cancer, ovarian cancer, thyroid cancer, esophageal cancer, nasopharyngeal gland cancer, pituitary cancer, salivary gland cancer, prostate cancer, pancreatic cancer, adrenal cancer; endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, hemangioma, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilms' tumor, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN hamartoma-tumor syndrome (PHTS). (Such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukemia, and lymphoma (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary exudative lymphoma, AIDS-related lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer. For example, cancer can be brain cancer or spinal cord cancer.

[0334] 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.

[0335] The compounds described herein may be provided for the treatment of cancers deficient in one or more DNA damage response repair pathways, particularly in homologous recombination (“HR”)-dependent DNA double-strand break (“DSB”) DNA repair activity. Components of the HR-dependent DNA DSB repair pathway and other DNA damage response pathways include, but are not limited to, the following proteins: ATM, ATR, ERCC1, XRCC1, XRCC2, XRCC3, RAD51, RAD51L1, RAD51C, RAD51D, RAD51L3, DMC1, RAD52, RAD54L, RAD54B, RAD50, MRE11A, NBS1, BRCA1, BRCA2, FANCP (SLX4), FEN1, PALB2, PBRM1, SMARCA4, ARID1A, ARID1B, FANCD2, and BLM. Other components involved in HR-dependent DNA DSB repair include regulatory factors such as ESMY (Hughes-Davies, L. et al.). Cell (2003;115: 523-535). Cancers with defective HR-dependent DNA DSB repair often become dependent on alternative DSB pathway repair mechanisms. Such cancers include, but are not limited to, ovarian cancer, prostate cancer, breast cancer, lung cancer, gastrointestinal cancer, leukemia, and pancreatic cancer.

[0336] 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).

[0337] The compounds described herein may be administered to patients undergoing radiation therapy and / or chemotherapy using other agents used to treat cancer.

[0338] For example, the PARP1 inhibitor compound can be administered in combination with other agents used to treat cancer.

[0339] Other agents used to treat cancer may be selected from: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, apoptosis-promoting agents, radioligand therapy, cell cycle signaling inhibitors, and anti-angiogenic agents.

[0340] 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.

[0341] Pharmaceutical Composition

[0342] On the other hand, pharmaceutical compositions are provided that contain PARP1 inhibitor compounds as defined herein.

[0343] Typically, the composition contains pharmaceutically acceptable additives and / or excipients.

[0344] 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.

[0345] Typically, the composition is intended for use in medicine, for example, to treat diseases, conditions, or disorders as defined above.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] Package products

[0350] 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.

[0351] The additional agent for treating cancer may be any additional agent for treating cancer identified in the discussion of pharmaceutical compositions above.

[0352] 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.

[0353] Treatment

[0354] 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.

[0355] 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.

[0356] 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.

[0357] The patient may be undergoing treatment using ionizing radiation.

[0358] Methods for synthesizing PARP1 inhibitor compounds

[0359] Methods for synthesizing PARP1 inhibitor compounds as defined herein are also provided. Generally, the methods involve reacting: i) a first reactant comprising a ring E with a first portion bearing a group L, and ii) a second reactant comprising the remaining portion of the group L, to form a PARP1 inhibitor compound. Those skilled in the art can select reaction conditions based on suitable starting materials and with reference to known synthetic techniques. The methods may include one or more additional steps. Exemplary synthetic methods are shown in the examples below.

[0360] In one example method, the first reactant comprises rings D, E, and A, and the second reactant comprises a cyclic B precursor with a reactive group, the method comprising attaching ring A to the cyclic B precursor. In this method, the reactive group of the cyclic B precursor may comprise a carbonyl group, an alkyl halide, or a sulfonic acid alkyl ester. The reaction may include alkylation, reductive amination, or amide formation to form group L.

[0361] In another example method, the first reactant comprises rings D, E, A, and Q. 1 The second reactant comprises a ring B and a ring C derivative having a leaving group (such as a halide or sulfonate). In this method, the reaction may include a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, to form a group L.

[0362] The PARP1 inhibitor compound can be obtained as a mixture of two or more structural isomers. The method may also include separating the structural isomers. For example, the method may further include separating the structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography (“SFC”) and / or chiral high-performance liquid chromatography (“HPLC”).

[0363] When the PARP1 inhibitor compound is a diastereomer, separation can be performed in two stages. In the first stage, the two pairs of stereoisomers can be separated by HPLC. In the second stage, a single stereoisomer can be separated from the stereoisomer pair by SFC.

[0364] Example

[0365] Example 1: Synthesis of 4a and 4b

[0366] Option 1

[0367] 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1003) preparation

[0368] N-methyl-5-(piperazin-1-yl)pyridineamide 1002 (202 mg, 0.92 mmol) was added to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate 1001 (170 mg, 0.92 mmol) in MeOH (5 mL). Acetic acid (2 drops) and NaBH3CN (115 mg, 1.84 mmol) were then added. The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 93:7) to yield tert-butyl 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)pyrrolidine-1-carboxylate 1003 (195 mg, 49% yield) as a white solid.

[0369] C 20 H 31 LCMS (ESI) values ​​of N5O3 [M + H] + m / z 390.24, measured value 390.10.

[0370] Preparation of N-methyl-5-(4-(pyrrolidone-3-yl)piperazin-1-yl)pyridineamide (1004)

[0371] 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 1003 (195 mg, 0.50 mmol) was added to a solution of HCl in dioxane (4 M, 10 mL), stirred at room temperature for 1 h, and concentrated to produce N-methyl-5-(4-(pyrrolidine-3-yl)piperazin-1-yl)pyridineamide 1004 (160 mg, 99% yield) as a yellow solid.

[0372] C 15 H 17 LCMS (ESI) calculation value of N3O [M + H] + m / z 290.19, measured value 290.20.

[0373] 5-(4-(1-(4-methoxyquinazoline-2-yl)pyrrolidine-3-yl)piperazin-1-yl)-N-methylpyridineamide Preparation of (1006)

[0374] DIEA (143 mg, 1.1 mmol) was added to a solution of N-methyl-5-(4-(pyrrolidone-3-yl)piperazin-1-yl)pyridineamide 1004 (160 mg, 0.56 mmol) and 2-chloro-4-methoxyquinazoline 1005 (215 mg, 1.11 mmol) in dioxane (10 mL). The reaction mixture was irradiated in a microwave reactor at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to yield 5-(4-(1-(4-methoxyquinazoline-2-yl)pyrrolidone-3-yl)piperazin-1-yl)-N-methylpyridineamide 1006 (120 mg, 44% yield) as a white solid.

[0375] C 24 H 29 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 448.24, measured value 448.15.

[0376] tert-Butyl N-methyl-5-(4-(1-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-3-yl)piperazine-1- Preparation of pyridine amides (4a and 4b)

[0377] 5-(4-(1-(4-methoxyquinazoline-2-yl)pyrrolidine-3-yl)piperazin-1-yl)-N-methylpyridineamide 1006 (120 mg, 0.27 mmol) was added to pyridine hydrochloride (62 mg, 0.54 mmol), heated to 130 °C, stirred for 1 h, and then cooled to room temperature. The solution was then diluted with EtOAc (30 mL). 3) Separate from brine, concentrate the organic phase and purify it by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to produce a crude product, which is then separated by SFC (column: Daicel Chiralpak OJ-H 250 mm × 20 mm ID, 5 μmm; mobile phase: CO2 / MeOH [0.1%(NH3)] = 65 / 35) and concentrated under reduced pressure to provide the first fraction as 4a (28.05 mg, 100% purity, ee%: 100, white solid) and the second fraction as 4b (37.9 mg, 100% purity, ee%: 100, white solid).

[0378] 4a

[0379] 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.40 (dd, J=4.0 Hz, 1H), 8.29(d, J =2.4 Hz, 1H), 7.93-7.81 (m, 2H), 7.60-7.51 (m, 1H), 7.44-7.39 (m, 1H),7.24 (d, J =8.4 Hz, 1H), 7.14-6.98 (m, 1H), 3.90-3.83 (m, 1H), 3.78-3.71 (m,1H), 3.49-3.43 (m, 1H), 3.39-3.34 (m, 4H), 3.28 (s, 1H), 3.00-2.89 (m, 1H),2.78 (d, J =4.8 Hz, 3H), 2.69-2.56 (m, 4H), 2.24-2.15 (m, 1H), 1.90-1.77 (m, 1H).

[0380] C 23 H 27 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 434.22, measured value 434.40.

[0381] 4b

[0382] 1 H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.40 (q, J =4.4 Hz, 1H), 8.29(d, J =2.8 Hz, 1H), 7.91-7.81 (m, 2H), 7.59-7.51 (m, 1H), 7.41 (dd, J =8.8, 2.8Hz, 1H), 7.30-7.16 (m, 1H), 7.15-7.00 (m, 1H), 3.91-3.82 (m, 1H), 3.79-3.70(m, 1H), 3.49-3.42 (m, 1H), 3.38-3.34 (m, 4H), 3.28 (s, 1H), 3.01-2.89 (m,1H), 2.78 (d, J =4.8 Hz, 3H), 2.71-2.63 (m, 2H), 2.61-2.55 (m, 2H), 2.25-2.15(m, 1H), 1.90-1.77 (m, 1H).

[0383] C 23 H 27 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 434.22, measured value 434.35.

[0384] Example 2: Synthesis of 5 cis and 5 trans

[0385] Option 2

[0386] Preparation of methyl 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutane-1-carboxylate (1102) Preparation

[0387] N-methyl-5-(piperazin-1-yl)pyridineamide 1002 (395 mg, 1.80 mmol) was added to a solution of methyl 3-oxocyclobutane-1-carboxylate 1101 (230 mg, 1.80 mmol) in MeOH (50 mL), followed by the addition of two drops of acetic acid and NaBH(OAc)3 (950 mg, 4.49 mmol) at room temperature. After 1 h, NaBH3CN (135 mg, 2.15 mmol) was added. The reaction mixture was stirred at 50 °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 90:10) to yield 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutane-1-carboxylate 1102 (600 mg, 90% yield) as a white solid.

[0388] C 17 H 24 LCMS (ESI) values ​​of N4O3 [M + H] + m / z 333.18, measured value 333.00.

[0389] Preparation of 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutane-1-carboxylic acid (1103)

[0390] LiOH (43 mg, 1.80 mmol) was added to a solution of methyl 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutane-1-carboxylic acid 1102 (400 mg, 1.20 mmol) in MeOH:H2O = 1:1 (20 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to produce 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutane-1-carboxylic acid 1103 (260 mg, 61% yield) as a white solid.

[0391] C 16 H 22 LCMS (ESI) values ​​of N4O3 [M + H] + m / z 319.17, measured value 319.00.

[0392] 5-(4-(3-((2-carbamoylphenyl)carbamoyl)cyclobutyl)piperazin-1-yl)-N-methylpyridineamide Preparation of (1105)

[0393] To a solution of 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclobutane-1-carboxylic acid 1103 (260 mg, 0.86 mmol) in DMF (10 mL), 2-aminobenzamide 1104 (222 mg, 1.63 mmol), HATU (621 mg, 1.63 mmol), and DIEA (528 mg, 4.08 mmol) were added, and the mixture was stirred at room temperature for 1 h. 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-(4-(3-((2-carbamoylphenyl)carbamoyl)cyclobutyl)piperazin-1-yl)-N-methylpyridinamide 1105 (150 mg, 53% yield) as a white solid.

[0394] C 23 H 28 LCMS (ESI) values ​​of N6O3 [M + H] + m / z 437.22, measured value 437.10.

[0395] N-Methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)cyclobutyl)piperazin-1-yl)pyridineamide (5) Preparation

[0396] To a solution of 5-(4-(3-((2-carbamoylphenyl)carbamoyl)cyclobutyl)piperazin-1-yl)-N-methylpyridineamide 1105 (150 mg, 0.34 mmol) in DME (15 mL), KOH (81 mg, 1.03 mmol) was added. The reaction mixture was stirred at 60 °C for 2 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 95:5) to give N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazoline-2-yl)cyclobutyl)piperazin-1-yl)pyridineamide 5 (30 mg, 19% yield) as a white solid.

[0397] C 23 H 26 LCMS (ESI) values ​​of N6O2 [M + H]+ m / z 419.21, measured value 419.00.

[0398] N-Methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)cyclobutyl)piperazin-1-yl)pyridineamide Preparation of (5 cis and 5 trans)

[0399] The cis / trans mixture of N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)cyclobutyl)piperazin-1-yl)pyridine amide was subjected to preparative HPLC (Column Gemini 5µm C18 150) 21.2 mm; Mobile phase: ACN--H2O (0.1% FA) Separation and concentration under reduced pressure to provide a first fraction as 5 cis (14 mg, 97% purity, white solid) and a second fraction as 5 trans (1.8 mg, 97% purity, white solid).

[0400] 5-way

[0401] 1 H NMR (400 MHz, DMSO) δ 12.21 (s, 1 H), 8.41 (d, J =4.8 Hz, 1 H),8.27 (s, 1 H), 8.07 (d, J =8.0 Hz, 1 H), 7.87-7.74 (m, 2 H), 7.65 (d, J =8.0Hz, 1 H), 7.50-7.36 (m, 2 H), 3.20-3.13 (m, 1 H), 2.78 (d, J =4.8 Hz, 4 H),2.50-2.49 (m, 4 H), 2.44 (s, 6 H), 2.23 (d, J =9.6 Hz, 2 H).

[0402] NOE experiments suggest that this compound has cis stereochemistry.

[0403] C 23 H 26 LCMS (ESI) values ​​of N6O2 [M + H] + m / z 419.21, measured value 419.00.

[0404] 5 trans

[0405] 1H NMR (400 MHz, DMSO) δ 12.11 (s, 1 H), 8.41 (d, J =4.8 Hz, 1 H),8.28 (s, 1 H), 8.08 (d, J =7.6 Hz, 1 H), 7.89-7.73 (m, 2 H), 7.66 (d, J =8.0Hz, 1 H), 7.43 (dd, J =23.3, 8.0 Hz, 2 H), 3.04-2.89 (m, 2 H), 2.78 (d, J =3.6Hz, 3 H), 2.49-2.48 (m, 3 H), 2.45 (s, 7 H), 2.28 (d, J =7.6 Hz, 2 H).

[0406] NOE experiments suggest that this compound has trans stereochemistry.

[0407] C 23 H 26 LCMS (ESI) values ​​of N6O2 [M + H] + m / z 419.21, measured value 419.00.

[0408] Example 3: Synthesis of 6

[0409] Option 3

[0410] (4-((2-carbamoylphenyl)carbamoyl)bicyclo[2.1.1]hexane-1-yl)tert-butyl carbamate Preparation of (1202)

[0411] EDCI (305 mg, 1.59 mmol) was added to a solution of 4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic acid 1201 (350 mg, 1.45 mmol) and 2-aminobenzamide 1104 (217 mg, 1.59 mmol) in pyridine (20 mL). The mixture was then stirred at room temperature for 12 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na2SO4, and concentrated under reduced pressure to produce a product (500 mg, 86% yield) of (4-((2-carbamoylphenyl)carbamoyl)bicyclo[2.1.1]hexane-1-yl)carbamate tert-butyl ester 1202 as a white solid.

[0412] C19 H 25 LCMS (ESI) values ​​of N3O4 [M + H] + m / z 360.18, measured value 360.10.

[0413] (4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)tert-butyl carbamate Preparation of (1203)

[0414] KOH (234 mg, 4.17 mmol) was added to a solution of (4-((2-carbamoylphenyl)carbamoyl)bicyclo[2.1.1]hexane-1-yl)carbamate tert-butyl ester 1202 (500 mg, 1.39 mmol) in DME (50 mL), and the mixture was stirred at 60 °C for 2 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 90:10) to yield (4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)carbamate tert-butyl ester 1203 (400 mg, 76% yield) as a white solid.

[0415] C 19 H 23 LCMS (ESI) values ​​of N3O3 [M + H] + m / z 342.17, measured value 342.15.

[0416] Preparation of 2-(4-aminobicyclo[2.1.1]hexane-1-yl)quinazolin-4(3H)-one (1204)

[0417] A solution of HCl in dioxane (4M, 10 mL) was added to a solution of (4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexan-1-yl)carbamate tert-butyl ester 1203 (400 mg, 1.17 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to produce a product (250 mg, 80% yield) of 2-(4-aminobicyclo[2.1.1]hexan-1-yl)quinazolin-4(3H)-one 1204 as a white solid.

[0418] C 14 H 15 LCMS (ESI) calculation value of N3O [M + H] + m / z 242.12, measured value 242.10.

[0419] Preparation of 2-(4-(4-benzylpiperazin-1-yl)bicyclo[2.1.1]hexane-1-yl)quinazolin-4(3H)-one (1206) Preparation

[0420] N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine 1205 (483 mg, 2.07 mmol) was added to a solution of 2-(4-aminobicyclo[2.1.1]hexan-1-yl)quinazolin-4(3H)-one 1204 (250 mg, 1.04 mmol) in DIPEA (40 mL). The reaction mixture was stirred at 120 °C for 5 h and concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to yield N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine 1206 (150 mg, 29% yield) as a brown solid.

[0421] C 25 H 28 LCMS (ESI) values ​​of N4O [M + H] + m / z 401.23, measured value 401.15.

[0422] Preparation of 2-(4-(piperazin-1-yl)bicyclo[2.1.1]hexane-1-yl)quinazolin-4(3H)-one (1207)

[0423] Pd / C (39 mg) was added to a solution of N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine 1206 (150 mg, 0.37 mmol) in IPA (30 mL). The mixture was evacuated and backfilled with hydrogen three times and then purged with hydrogen. The resulting mixture was stirred at 70 °C for 5 h. The mixture was then filtered through diatomaceous earth and concentrated under vacuum to produce 2-(4-(piperazin-1-yl)bicyclo[2.1.1]hexan-1-yl)quinazolin-4(3H)-one 1207 (90 mg, 62% yield) as a white solid.

[0424] C 18 H 22 LCMS (ESI) values ​​of N4O [M + H] + m / z 311.18, measured value 311.10.

[0425] N-Methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)piperazine- Preparation of 1-yl)pyridine amide (6)

[0426] Cs₂CO₃ (63 mg, 0.19 mmol) and 5-fluoro-N-methylpyridine amide 1208 (22 mg, 0.14 mmol) were added to a solution of 2-(4-(piperazin-1-yl)bicyclo[2.1.1]hexan-1-yl)quinazolin-4(3H)-one 1207 (30 mg, 0.09 mmol) in DMF (5 mL). The mixture was stirred in a microwave at 150 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 92:8) to produce crude N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexan-1-yl)piperazin-1-yl)pyridine amide (10 mg, 70% purity) as a yellow solid. The crude product was subjected to preparative HPLC (Gemini 5 μm C). 18 150 × 21.2 mm, mobile phase: ACN - H2O (0.1% TFA), gradient: 20 - 80) to purify to produce N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-1-yl)piperazin-1-yl)pyridineamide 6 (1.8 mg, 91% purity, 4% yield) as a yellow solid.

[0427] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 12.28 (s, 1 H), 11.79-11.33 (m, 1H), 8.46 (d, J =4.6 Hz, 1 H), 8.37-8.44 (m, 1 H), 8.11 (dd, J =6.8 Hz, 1.6 Hz,1 H), 7.91 (d, J =8.8 Hz, 1 H), 7.83-7.79 (m, 1 H), 7.63 (d, J =8.0 Hz, 1 H),7.56-7.49 (m, 2 H), 4.16-4.13 (m, 2 H), 3.92 (s, 2 H), 3.27 (s, 4 H), 2.80(d, J =4.8 Hz, 3 H), 2.43 (s, 2 H), 2.13-2.12 (m, 4 H), 2.04 (s, 2 H).

[0428] C 25H 28 LCMS (ESI) values ​​of N6O2 [M + H] + m / z 445.23, measured value 445.20.

[0429] Example 4:3 sequence - a. 3-way sequence - b, 3-inverse - a. 3-fold reverse - b Synthesis

[0430] Option 4

[0431] Preparation of 2-fluoro-6-(3-oxocyclopentane-1-carbamoyl)benzamide (1303)

[0432] 2-Amino-6-fluorobenzamide 1301 (2.5 g, 16.2 mmol) and EDCI (6.2 g, 32.4 mmol) were sequentially added to a solution of 3-oxocyclopentane-1-carboxylic acid 1302 (2.08 g, 16.2 mmol) in pyridine (30 mL) at room temperature. The mixture was stirred at room temperature for 2 h. 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 (with MeOH / DCM, elution 2% to 5%) to produce 2-fluoro-6-(3-oxocyclopentane-1-carboxamido)benzamide 1303 (3 g, 90% purity, 62% yield) as a yellow solid.

[0433] C 13 H 13 LCMS (ESI) calculated values ​​of FN2O3 [M + H] + m / z 265.09, measured value 265.05.

[0434] Preparation of 5-fluoro-2-(3-oxocyclopentyl)quinazolin-4(3H)-one (1304)

[0435] KOH (1.92 g, 34.2 mmol) was added to a solution of 2-fluoro-6-(3-oxocyclopentan-1-carbamate)benzamide 1303 (3 g, 11.4 mmol) in DME (200 mL). The mixture was heated at 50 °C for 2 hours. The final mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to yield 5-fluoro-2-(3-oxocyclopentanyl)quinazolin-4(3H)-one 1304 (2 g, 90% purity, 64% yield) as a yellow solid.

[0436] C13 H 11 LCMS (ESI) values ​​of FN2O2 [M + H] + m / z 247.08, measured value 247.05.

[0437] 6-Fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclopentyl)piperazin-1-yl)-N-methyl Preparation of pyridine amides (a mixture of 3 cis-a / 3 cis-b racemic compounds and a mixture of 3 trans-a / 3 trans-b racemic compounds)

[0438] To a solution of 5-fluoro-2-(3-oxocyclopentyl)quinazolin-4(3H)-one 1304 (300 mg, 1.22 mmol) in MeOH (30 mL) at room temperature, 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide 1305 (435 mg, 1.83 mmol), NaBH3CN (77 mg, 1.22 mmol), and NaBH(OAc)3 (516 mg, 2.44 mmol) were added. The reaction mixture was stirred at 50 °C for 1 h. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to provide a first fraction as a white solid as a racemic mixture of 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridinamide 3 cis-a / 3 cis-b (50 mg, 90% purity, 8% yield, racemic mixture of cis enantiomers) and a second fraction as a racemic mixture of 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridinamide 3 trans-a / 3 trans-b (25 mg, 90% purity, 4% yield, racemic mixture of trans enantiomers).

[0439] 6-Fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclopentyl)piperazin-1-yl)-N-methyl Preparation of pyridine amides (3 cis-a and 3 cis-b)

[0440] The racemic mixture of 3ci-a / 3ci-b was separated by SFC (column: Daicel Chiralpak-AD-H 20 mm I.D. × 250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 60 / 40) and concentrated under reduced pressure to provide a first fraction as 3ci-a (13.6 mg, 99.94% purity, 100% ee, white solid) and a second fraction as 3ci-b (16.6 mg, 99.37% purity, 100% ee, white solid).

[0441] 3-way - a

[0442] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.49 (s, 1 H), 8.44-8.37 (m, 1.4H), 7.86 (d, J =8.0 Hz, 1 H), 7.78-7.68 (m, 1 H), 7.60-7.51 (m, 1 H), 7.42 (d, J =8.0 Hz, 1 H), 7.26-7.10 (m, 1 H), 3.24-3.19 (m, 4 H), 3.15-3.08 (m, 1 H), 2.78-2.70 (m, 4 H), 2.68-2.63 (m, 4 H), 2.23-2.16 (m, 1 H), 2.09-2.00 (m, 1H), 1.98-1.86 (m, 2 H), 1.86-1.72 (m, 2 H).

[0443] NOE experiments suggest cis stereochemistry.

[0444] C 24 H 26 LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 469.21, measured value 469.25.

[0445] 3-way - b

[0446] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.50 (s, 1 H), 8.45-8.34 (m, 1.5H), 7.86 (d, J =8.0 Hz, 1 H), 7.79-7.68 (m, 1 H), 7.62-7.53 (m, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 7.24-7.13 (m, 1 H), 3.24-3.18 (m, 4 H), 3.15-3.09 (m, 1 H), 2.80-2.70 (m, 4 H), 2.69-2.63 (m, 4 H), 2.27-2.16 (m, 1 H), 2.12-2.01 (m, 1H), 1.97-1.87 (m, 2 H), 1.85-1.65 (m, 2 H).

[0447] NOE experiments suggest cis stereochemistry.

[0448] C 24 H 26 LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 469.21, measured value 469.20.

[0449] 6-Fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclopentyl)piperazin-1-yl)-N-methyl Preparation of pyridine amides (3-trans-a and 3-trans-b)

[0450] The racemic mixture of 3-trans-a / 3-trans-b was separated by SFC (column: Daicel IJ 20 mm I.D. × 250 mm L, 5 μmm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 75 / 25) and concentrated under reduced pressure to provide the first fraction as 3-trans-a (9.3 mg, 99.54% purity, 100% ee, white solid) and the second fraction as 3-trans-b (7.0 mg, 99.79% purity, 100% ee, white solid).

[0451] 3 trans - a

[0452] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.56-11.47 (m, 1 H), 8.42-8.35 (m, 2 H), 7.90-7.82 (m, 1 H), 7.76-7.69 (m, 1 H), 7.61-7.51 (m, 1 H), 7.42 (d, J =8.4 Hz, 1 H), 7.25-7.13 (m, 1 H), 3.19-3.14 (m, 5 H), 2.86-2.80 (m, 1 H), 2.77 (d, J=4.8 Hz, 3 H), 2.62-2.56 (m, 4 H), 2.22-2.06 (m, 2 H), 2.01-1.88 (m, 3 H), 1.57-1.47 (m, 1 H).

[0453] NOE experiments suggest trans stereochemistry.

[0454] C 24 H 26 LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 469.21, measured value 469.10.

[0455] 3 trans - b

[0456] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.17 (s, 1 H), 8.43-8.36 (m, 1.6H), 7.85 (d, J =8.0 Hz, 1 H), 7.76-7.66 (m, 1 H), 7.61-7.51 (m, 1 H), 7.41 (d, J =8.4 Hz, 1 H), 7.22-7.14 (m, 1 H), 3.20-3.11 (m, 5 H), 2.87-2.80 (m, 1 H), 2.77 (d, J =4.8 Hz, 3 H), 2.64-2.56 (m, 4 H), 2.21-2.02 (m, 2 H), 2.03-1.85 (m, 3 H), 1.59-1.47 (m, 1 H).

[0457] NOE experiments suggest trans stereochemistry.

[0458] C 24 H 26 LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 469.21, measured value 469.10.

[0459] Example 5: Synthesis of 14 cis-a, 14 cis-b, and 14 trans-rac

[0460] Option 5

[0461] 3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopent-2-ene- Preparation of 1-one (1403)

[0462] To a solution of 6-chloro-4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidine 1401 (1.10 g, 4.14 mmol) in dioxane:H₂O = 5:1 (24 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)cyclopent-2-en-1-one 1402 (2 g, 9.61 mmol), RuPhos-Pd-G3 (110 mg, 0.13 mmol), and Na₂CO₃ (1.50 g, 14.15 mmol) were added. The reaction mixture was stirred at 100 °C for 5 h under N₂. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 75:25) to produce 3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopent-2-en-1-one 1403 (210 mg, 16% yield) as a white solid.

[0463] C 13 H 11 LCMS (ESI) calculated value of F3N4O2 [M + H] + m / z 313.08, measured value 313.00.

[0464] 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentan- Preparation of 2-en-1-yl)piperazin-1-yl)-N-methylpyridine amide (1404)

[0465] To a solution of 3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopent-2-en-1-one 1403 (210 mg, 0.67 mmol) in EtOH (10 mL), N-methyl-5-(piperazin-1-yl)pyridineamide 1002 (210 mg, 0.95 mmol) and 3 drops of HOAc were added. After 10 minutes, NaBH3CN (400 mg, 6.45 mmol) was added. The reaction mixture was stirred at 90 °C for 15 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 93:7) to produce 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyridineamide 1404 as a yellow solid (250 mg, a mixture containing compound 1405, 72% yield).

[0466] C 24 H 27 LCMS (ESI) calculated value of F3N8O2 [M + H] + m / z 517.22, measured value 517.10.

[0467] 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentanol Preparation of (1405)piperazine-1-yl)-N-methylpyridine amide

[0468] Pd / C (100 mg, 0.94 mmol) was added to a solution of 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyridineamide 1404 (250 mg (a mixture containing compound 1405), 0.48 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature under H2 for 3 h. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to yield 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1405 (160 mg, 64% yield) as a yellow solid.

[0469] C 24 H 29 LCMS (ESI) calculated value of F3N8O2 [M + H] + m / z 519.24, measured value 519.2.

[0470] N-Methyl-5-(4-(3-(1-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]) Preparation of pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)pyridine amide (a mixture of 14,4 isomers)

[0471] TMSI (200 mg, 1.00 mmol) was added to a solution of 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1405 (160 mg, 0.31 mmol) in ACN (10 mL). The reaction mixture was stirred at 50 °C for 2 h. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 10 - 25) to produce N-methyl-5-(4-(3-(1-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)pyridineamide 14 as a white solid, as a mixture of four isomers (50 mg, 93% purity, 32% yield).

[0472] C 23 H 27 LCMS (ESI) calculated value of F3N8O2 [M + H] + m / z 505.22, measured value 505.19.

[0473] N-Methyl-5-(4-(3-(1-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]) Preparation of pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)pyridine amide (14-trans-rac / 14-cis-a / 14-cis-b)

[0474] A mixture of four isomers of N-methyl-5-(4-(3-(1-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)pyridine amide compound 14 (50 mg, 0.10 mmol) was subjected to SFC (column: (R,R)-Whelk-O1 4.6 mm) 250 mmL 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) Separate and concentrate under reduced pressure to provide the first fraction as 14-trans-rac (10 mg, 97% purity, ee%: 100, white solid), the second fraction as 14-cis-a (5 mg, 99% purity, ee%: 100, white solid) and the third fraction as 14-cis-b (0.8 mg, 98% purity, ee%: 100, white solid).

[0475] 14 trans - rac

[0476] 1H NMR (400 MHz, DMSO) δ 12.39 (s, 1 H), 8.39 (q, J =5.2 Hz, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.39 (dd, J =8.8, 2.8 Hz, 1H), 3.95 (s, 3 H), 3.38-3.32 (m, 4 H), 3.28-3.22 (m, 1 H), 2.93-2.80 (m, 1H), 2.78 (d, J =4.8 Hz, 3 H), 2.62-2.55 (m, 4 H), 2.19-2.05 (m, 2 H), 2.05-1.85 (m, 3 H), 1.63-1.47 (m, 1 H).

[0477] Based on NOE experimental designation of trans stereochemistry.

[0478] C 23 H 27 LCMS (ESI) calculated value of F3N8O2 [M + H] + m / z 505.22, measured value 505.20.

[0479] 14-way sequence - a

[0480] 1 H NMR (400 MHz, DMSO) δ 12.79 (s, 1 H), 8.40 (q, J =5.2 Hz, 1 H), 8.28 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.8 Hz, 1 H), 7.41 (dd, J =8.8, 2.8 Hz, 1H), 3.95 (s, 3 H), 3.48-3.35 (m, 4 H), 3.27-3.17 (m, 1 H), 2.78 (d, J=4.8 Hz,3 H), 2.76-2.69 (m, 1 H), 2.68-2.61 (m, 4 H), 2.25-2.16 (m, 1 H), 2.14-2.03(m, 1 H), 2.00-1.90 (m, 2 H), 1.87-1.75 (m, 2 H).

[0481] Based on NOE experimental designation of cis-stereochemistry.

[0482] C 23 H 27 LCMS (ESI) calculated value of F3N8O2 [M + H] + m / z 505.22, measured value 505.25.

[0483] 14-way sequence - b

[0484] 1 H NMR (400 MHz, MeOD) δ 8.30 (d, J =2.8 Hz, 1 H), 7.91 (d, J =8.8 Hz, 1 H), 7.39 (dd, J =8.8, 2.9 Hz, 1 H), 4.00 (s, 3 H), 3.59-3.43 (m, 5 H), 2.93 (s, 3 H), 2.88-2.78 (m, 5 H), 2.37-2.28 (m, 1 H), 2.26-2.18 (m, 1 H), 2.17-2.04 (m, 2 H), 2.03-1.96 (m, 2 H).

[0485] Based on NOE experimental designation of cis-stereochemistry.

[0486] C 23 H 27 LCMS (ESI) calculated value of F3N8O2 [M + H] + m / z 505.22, measured value 505.15.

[0487] Example 6: Synthesis of 16cis-a, 16cis-b, 16trans-a and 16trans-b

[0488] Option 6

[0489] Preparation of 2-chloro-4-methoxypyrido[2,3-d]pyrimidine (1502)

[0490] MeONa (0.88 g, 0.0162 mol) was added to a solution of 2,4-dichloropyrido[2,3-d]pyrimidine 1501 (2.5 g, 0.0125 mol) in MeOH (50 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and the residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to provide 2-chloro-4-methoxypyrido[2,3-d]pyrimidine 1502 (2.1 g, 90% purity, 77% yield) as a white solid.

[0491] LCMS (ESI) calculated value of C8H6ClN3O [M + H] + m / z 196.02, measured value 196.10.

[0492] Preparation of 2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (1503)

[0493] A solution of 2-chloro-4-methoxypyrido[2,3-d]pyrimidine 1502 (2.1 g, 0.0107 mol) and PtO2 (2.4 g, 0.0107 mol) in THF / H2O (50 mL, 5:1) was stirred at room temperature for 6 h under H2 balloon pressure. The mixture was filtered through a diatomaceous earth mat, and the filtrate was washed with EtOAc (50 mL × 2). The combined organic layers were concentrated to yield 2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 1503 (2.1 g, 90% purity, 88% yield) as a white solid.

[0494] C8H 10 LCMS (ESI) values ​​of ClN3O [M + H] + m / z 200.05, measured value 200.15.

[0495] Preparation of 2-chloro-4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (1504)

[0496] NaH (633 mg, 0.0157 mol, 60 wt%) was added to a solution of 2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 1503 (2.1 g, 0.0105 mol) in DMF (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. MeI (2.2 g, 0.0157 mol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL × 3) and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to provide 2-chloro-4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 1504 (1.6 g, 95% purity, 67% yield) as a white solid.

[0497] C9H 12 LCMS (ESI) values ​​of ClN3O [M + H] + m / z 214.07, measured value 213.89.

[0498] 3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopent-2-en-1-one Preparation of (1505)

[0499] To a solution of 2-chloro-4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 1504 (400 mg, 1.8721 mmol) in dioxane / H₂O (25 mL, 5:1), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)cyclopent-2-en-1-one 1402 (506 mg, 2.4337 mmol), Pd(dppf)Cl₂ (137 mg, 0.1872 mmol), and Na₂CO₃ (584 mg, 5.6163 mmol) were successively added. The reaction mixture was stirred at 80 °C for 4 h under a N₂ atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to provide 3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopent-2-en-1-one 1505 (400 mg, 90% purity, 74% yield) as a white solid.

[0500] C 14 H 17 LCMS (ESI) values ​​of N3O2 [M + H]+ m / z 260.13, measured value 260.20.

[0501] 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopentan-2- Preparation of en-1-yl)piperazin-1-yl)-N-methylpyridine amide (1506)

[0502] N-methyl-5-(piperazin-1-yl)pyridinosylamide 1002 (510 mg, 2.3139 mmol), NaBH(OAc)3 (981 mg, 4.6278 mmol), and NaBH3CN (97 mg, 1.5426 mmol) were sequentially added to a solution of 3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopent-2-en-1-one 1505 (400 mg, 1.5426 mmol) in EtOH (15 mL) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. The reaction solution was cooled to room temperature, quenched with water (10 mL), and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 93:7) to provide 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyridino[2,3-d]pyrimidin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyridineamide 1506 (gave as a mixture containing compound 1507, 420 mg, 90% purity, 52% yield).

[0503] C 25 H 33 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 464.27, measured value 464.20.

[0504] 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopentyl)piperyl Preparation of 1-azine-1-yl)-N-methylpyridine amide (1507)

[0505] A solution of 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpyridine amide 1506 (400 mg, 0.8629 mmol, a mixture containing compound 1507) and Pd(OH)2 / C (121 mg) in MeOH (15 mL) was stirred at room temperature for 16 h under H2 balloon pressure. The mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated to produce 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridine amide 1507 (400 mg, 80% yield, 79% yield) as a colorless oil.

[0506] C 25 H 35 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 466.29, measured value 466.14.

[0507] N-Methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl) Preparation of cyclopentyl)piperazin-1-yl)pyridine amide (16)

[0508] A solution of 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1507 (400 mg, 0.8591 mmol) in HBr (10 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 purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) and preparative HPLC (column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% TFA); gradient: 15-45) to give N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyridino[2,3-d]pyrimidin-2-yl)cyclopentyl)piperazin-1-yl)pyridineamide 16 as a mixture of four isomers.

[0509] The mixture of isomers was separated by SFC (column: IH, SFC 30 mm ID × 250 mmL, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) to provide 16 cis-rac and 16 trans-rac.

[0510] 16ci-rac was separated by SFC (column: Chiralpak IB N-5, SFC 30 mm ID × 250 mmL, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) to provide a first fraction as 16ci-a (9.8 mg, 93% purity, ee%: 100, white solid) and a second fraction as 16ci-b (9.6 mg, 97% purity, ee%: 100, white solid).

[0511] 16-trans-rac was separated by SFC (column: Chiralpak-IB N-5, SFC 30 mm ID × 250 mmL, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) to provide a first fraction as 16-trans-a (16.1 mg, 97% purity, ee%: 100, white solid) and a second fraction as 16-trans-b (15.9 mg, 99% purity, ee%: 100, white solid).

[0512] 16-way - a

[0513] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.57 (s, 1 H), 8.50-8.32 (m, 1 H), 8.26 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.39 (dd, J =8.8, 2.8 Hz, 1H), 3.40-3.34 (m, 2 H), 3.32-3.27 (m, 2 H), 3.25-3.19 (m, 2 H), 3.04 (s, 3H), 2.98-2.85 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.71-2.63 (m, 1 H), 2.62-2.54 (m, 4 H), 2.35-2.29 (m, 2 H), 2.18-2.08 (m, 1 H), 1.97-1.84 (m, 2 H),1.83-1.65 (m, 5 H)

[0514] Based on NOE experimental designation of cis-stereochemistry.

[0515] C 24 H 33 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 452.27, measured value 452.45.

[0516] 16-way - b

[0517] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.57 (s, 1 H), 8.46-8.37 (m, 1 H), 8.26 (d, J =2.4 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.39 (dd, J =8.8, 2.8 Hz, 1H), 3.39-3.34 (m, 2 H), 3.33-3.29 (m, 2 H), 3.26-3.18 (m, 2 H), 3.04 (s, 3H), 2.98-2.86 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.71-2.62 (m, 1 H), 2.61-2.56 (m, 4 H), 2.35-2.28 (m, 2 H), 2.18-2.05 (m, 1 H), 1.94-1.64 (m, 7 H).

[0518] Based on NOE experimental designation of cis-stereochemistry.

[0519] C 24 H 33 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 452.27, measured value 452.45.

[0520] 16 trans - a

[0521] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 11.39 (s, 1 H), 8.44-8.34 (m, 1 H), 8.26 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.8 Hz, 1 H), 7.38 (dd, J =8.8, 2.8 Hz, 1H), 3.31-3.28 (m, 4 H), 3.25-3.19 (m, 2 H), 3.04 (s, 3 H), 3.01-2.94 (m, 1H), 2.84-2.73 (m, 4 H), 2.60-2.53 (m, 4 H), 2.35-2.29 (m, 2 H), 2.09-1.90 (m, 3 H), 1.86-1.67 (m, 4 H), 1.57-1.39 (m, 1H).

[0522] Based on NOE experimental designation of trans stereochemistry.

[0523] C 24 H 33 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 452.27, measured value 452.45.

[0524] 16 trans - b

[0525] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 11.40 (s, 1 H), 8.45-8.35 (m, 1 H), 8.26 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.38 (dd, J =8.8, 2.4 Hz, 1H), 3.32-3.26 (m, 4 H), 3.25-3.18 (m, 2 H), 3.04 (s, 3 H), 3.03-2.94 (m, 1H), 2.84-2.73 (m, 4 H), 2.61-2.53 (m, 4 H), 2.36-2.28 (m, 2 H), 2.11-1.89 (m, 3 H), 1.87-1.70 (m, 4 H), 1.56-1.39 (m, 1 H).

[0526] Based on NOE experimental designation of trans stereochemistry.

[0527] C 24 H 33 LCMS (ESI) values ​​of N7O2 [M + H] + m / z 452.27, measured value 452.45.

[0528] Example 7: Synthesis of 17ci-a, 17ci-b and 17trans-rac

[0529] Option 7A

[0530] Option 7B

[0531] Preparation of methyl 3-bromo-1-(benzenesulfonyl)-1H-pyrrole-2-carboxylate (1603)

[0532] NaH (2.94 g, 0.073 mol, 60 wt%) was added to a solution of methyl 3-bromo-1H-pyrrole-2-carboxylate 1601 (10 g, 0.049 mol) in DMF (100 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, benzenesulfonyl chloride 1602 (9.52 g, 0.054 mol) was added and the mixture was stirred at room temperature for 2 h. The mixture was slowly quenched with water and then extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, and concentrated to give methyl 3-bromo-1-(benzenesulfonyl)-1H-pyrrole-2-carboxylate 1603 (12.9 g, 85% purity, 65% yield) as a yellow gel.

[0533] C 12 H 10 LCMS (ESI) values ​​of BrNO4S [M + H] + m / z 343.95, measured value 343.95.

[0534] Preparation of methyl 1-(benzenesulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1605)

[0535] A mixture of methyl 3-bromo-1-(benzenesulfonyl)-1H-pyrrole-2-carboxylate 1603 (12.9 g, 0.037 mol), CuI (7.14 g, 0.037 mol), and HMPA (33.60 g, 0.19 mol) in NMP (100 mL) was heated to 130 °C under N2, and then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 1604 (36.02 g, 0.19 mol) was added dropwise. The mixture was stirred at 130 °C for 2 h under N2 atmosphere. The mixture was cooled, slowly quenched with water, and then extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, concentrated, and purified by rapid silica gel chromatography (eluting with EtOAc / PE, 0 to 13%) to give methyl 1-(benzenesulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1605 (6.2 g, 90% purity, 44% yield) as a yellow solid.

[0536] C 13 H 10 LCMS (ESI) calculation value of F3NO4S [M + H] + m / z 334.03, measured value 333.55.

[0537] Preparation of methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1606)

[0538] MeONa (5.00 g, 0.093 mol) was added to a solution of methyl 1-(benzenesulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1605 (6.2 g, 0.019 mol) in MeOH (60 mL), and the reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, concentrated, and purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to give methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1606 (4.2 g, 80% purity, 93% yield) as a yellow solid.

[0539] LCMS (ESI) values ​​of C7H6F3NO2 [M + H] + m / z 194.04, no MS signal.

[0540] 1 H NMR (400 MHz, DMSO- d6, ppm) δ: 9.87-9.33 (m, 1 H), 6.92 (t, J =2.8Hz, 1 H), 6.55 (t, J =2.8 Hz, 1 H), 3.92 (s, 3 H).

[0541] 19 F NMR (376.69 MHz, DMSO- d 6, ppm) δ: 62.21.

[0542] Preparation of methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1608)

[0543] NaH (0.16 g, 0.0041 mol, 60 wt%) was added to a solution of methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1606 (800 mg, 0.0041 mol) in DMF (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 40 min. Then, O-(2,4-dinitrophenyl)hydroxylamine 1607 (0.98 g, 0.0049 mol) was added at 0 °C, and the mixture was stirred at room temperature for 4 h. The mixture was slowly quenched with water and then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, and concentrated to give methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1608 (810 mg, 80% purity, 75% yield) as a brown oil.

[0544] LCMS (ESI) values ​​of C7H7F3N2O2 [M + H] + m / z 209.05, measured value 208.95.

[0545] Preparation of 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentane-1-carboxylic acid (1610)

[0546] N-methyl-5-(piperazin-1-yl)pyridineamide 1002 (1.37 g, 0.0062 mol) was added to a solution of 3-oxocyclopentane-1-carboxylic acid 1609 (1 g, 0.0078 mol) in MeOH (10 mL) and AcOH (0.05 mL), and the mixture was stirred at 50 °C for 30 min. Then, NaBH3CN (0.49 g, 0.0078 mol) was added, and the reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated and purified by rapid silica gel chromatography (DCM / MeOH = 100:0 to 90:10) to give 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentane-1-carboxylic acid 1610 (800 mg, 85% purity, 26% yield) as a yellow gel.

[0547] C 17 H 24 LCMS (ESI) values ​​of N4O3 [M + H] + m / z 333.18, measured value 333.00.

[0548] 1-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentane-1-carbamate)-3-(tri-) Preparation of methyl fluoromethyl 1H-pyrrole-2-carboxylate (1611)

[0549] Methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1608 (677 mg, 3.25 mmol) and EDCI (833 mg, 4.34 mmol) were added to a solution of 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentane-1-carboxylic acid 1610 (720 mg, 2.17 mmol) in pyridine (7 mL). The mixture was stirred at room temperature for 18 h. The mixture was then slowly quenched with water and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, concentrated, and purified by rapid silica gel chromatography (DCM / MeOH = 100:0 to 85:15) to give methyl 1-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentan-1-carboxamido)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1611 (181 mg, 80% purity, 12% yield) as a yellow solid.

[0550] C 24 H 29 LCMS (ESI) calculated value of F3N6O4 [M + Na] + m / z 545.22, measured value 545.25.

[0551] 1-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentane-1-carbamate)-3-(tri-) Preparation of fluoromethyl)-1H-pyrrole-2-carboxylic acid (1612)

[0552] Sn(CH3)3OH (188 mg, 1.04 mmol) was added to a solution of methyl 1-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentan-1-carbamate)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid 1611 (181 mg, 0.35 mmol) in DME (8 mL). The resulting mixture was stirred at 80 °C for 48 h. The mixture was concentrated and purified by rapid silica gel chromatography (DCM / MeOH = 100:0 to 40:60) to give 1-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentan-1-carbamate)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid 1612 (135 mg, 80% purity, 61% yield) as a yellow gel.

[0553] C 23 H 27 LCMS (ESI) values ​​of F3N6O4 [M + H] + m / z 509.20, measured value 509.05.

[0554] 5-(4-(3-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrolo-1-yl)carbamoyl)cyclopentyl)piperazine- Preparation of 1-yl)-N-methylpyridine amide (1613)

[0555] To a solution of 1-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentan-1-carboxamido)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid 1612 (135 mg, 0.27 mmol) in THF (8 mL), (NH4)2CO3 (102 mg, 1.06 mmol), EDCI (76 mg, 0.40 mmol), and HOBT (18 mg, 0.13 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated and purified by rapid silica gel chromatography (DCM / MeOH = 100:0 to 90:10) to give 5-(4-(3-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrolo-1-yl)carbamoyl)cyclopentyl)piperazin-1-yl)-N-methylpyridinamide 1613 (90 mg, 85% purity, 56% yield) as a yellow gel.

[0556] C 23 H 28 LCMS (ESI) values ​​of F3N7O3 [M + H] + m / z 508.22, measured value 508.45.

[0557] N-Methyl-5-(4-(3-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine- Preparation of 2-yl)cyclopentyl)piperazin-1-yl)pyridine amide (17)

[0558] MeONa (19 mg, 0.35 mmol) was added to a solution of 5-(4-(3-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrolo-1-yl)carbamoyl)cyclopentyl)piperazin-1-yl)-N-methylpyridineamide 1613 (90 mg, 0.18 mmol) in MeOH (6 mL). The reaction mixture was stirred at 60 °C for 8 h. The mixture was then concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) and preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluting with 0 to 35% MeCN / H2O containing 0.1% NH3) to give N-methyl-5-(4-(3-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopentyl)piperazin-1-yl)pyridineamide 17 (30 mg, 95% purity, 32% yield, mixture of 4 isomers) as a yellow solid.

[0559] N-Methyl-5-(4-(3-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine- Chiral resolution of 2-yl)cyclopentyl)piperazin-1-yl)pyridineamide (17)

[0560] Compound 17 (a mixture of four isomers) was separated by SFC (column: DAICEL OJ-H 20 mm ID × 250 mmL 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 65 / 35) and concentrated under reduced pressure to provide the first fraction as 17cis-a (8.0 mg, 99% purity, 100% ee, white solid), the second fraction as 17cis-b (7.2 mg, 98% purity, 95% ee, white solid) and the third fraction as 17trans-rac (12.0 mg, 98% purity, white solid).

[0561] 17-way - a

[0562] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.68 (s, 1 H), 8.46-8.37 (m, 1 H), 8.29 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.8 Hz, 1 H), 7.66 (d,J =2.8 Hz, 1 H), 7.42 (dd, J =8.8, 2.8 Hz, 1 H), 6.88 (d, J =2.8 Hz, 1 H), 3.48-3.36 (m, 4 H), 3.16-3.07 (m, 1 H), 2.78 (d, J =5.2 Hz, 3 H), 2.75-2.61 (m, 5 H), 2.22-2.05 (m, 2 H), 2.03-1.94 (m, 1 H), 1.91-1.75 (m, 3 H).

[0563] Based on NOE experimental designation of cis-stereochemistry.

[0564] C 23 H 26 LCMS (ESI) values ​​of F3N7O2 [M + H] + m / z 490.21, measured value 490.10.

[0565] 17-way - b

[0566] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.67 (s, 1 H), 8.44-8.37 (m, 1 H), 8.29 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.8 Hz, 1 H), 7.66 (d, J =2.8 Hz, 1 H), 7.42 (dd, J =8.8, 2.8 Hz, 1 H), 6.88 (d, J =2.8 Hz, 1 H), 3.48-3.36 (m, 4 H), 3.17-3.07 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.75-2.63 (m, 5 H), 2.23-2.05 (m, 2 H), 2.03-1.94 (m, 1 H), 1.91-1.74 (m, 3 H).

[0567] Based on NOE experimental designation of cis-stereochemistry.

[0568] C23 H 26 LCMS (ESI) values ​​of F3N7O2 [M + H] + m / z 490.21, measured value 490.10.

[0569] 17 trans - rac

[0570] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.06 (s, 1 H), 8.45-8.37 (m, 1 H), 8.27 (d, J =2.8 Hz, 1 H), 7.83 (d, J =8.8 Hz, 1 H), 7.67 (d, J =2.8 Hz, 1 H), 7.41 (dd, J =8.8, 2.8 Hz, 1 H), 6.88 (d, J =2.8 Hz, 1 H), 3.33-3.28 (m, 4 H), 3.19-3.08 (m, 1 H), 2.85-2.72 (m, 4 H), 2.62-2.54 (m, 4 H), 2.16-2.04 (m, 2H), 2.03-1.92 (m, 2 H), 1.91-1.80 (m, 1 H), 1.59-1.46 (m, 1 H).

[0571] Based on NOE experimental designation of trans stereochemistry.

[0572] C 23 H 26 LCMS (ESI) values ​​of F3N7O2 [M + H] + m / z 490.21, measured value 490.10.

[0573] Example 8: Synthesis of 18cis-a, 18cis-b, 18trans-a and 18trans-b

[0574] Option 8

[0575] Preparation of ethyl 2-(3-oxocyclopentan-1-carbamate)cyclohex-1-ene-1-carboxylate (1702)

[0576] 3-oxocyclopentan-1-carboxylic acid 1609 (1.5 g, 0.0118 mol) and POCl3 (2.7 g, 0.0177 mol) were successively added to a solution of 2-aminocyclohexane-1-ene-1-carboxylic acid 1701 (2.0 g, 0.0118 mol) in pyridine (20 mL). The reaction mixture was stirred at room temperature for 6 h. The reaction solution was concentrated under reduced pressure and the residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to provide 2-(3-oxocyclopentan-1-carboxamido)cyclohexane-1-ene-1-carboxylic acid 1702 (1.55 g, 90% purity, 42% yield) as a colorless oil.

[0577] C 15 H 21 LCMS (ESI) calculation value of NO4 [M + H] + m / z 280.15, measured value 280.10.

[0578] 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentane-1-carboxamido) Preparation of ethyl cyclohexyl-1-en-1-carboxylate (1703)

[0579] To a solution of ethyl 2-(3-oxocyclopentan-1-carbamate)cyclohexyl-1-en-1-carboxylate 1702 (410 mg, 1.4678 mmol) in MeOH (15 mL), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide 1305 (420 mg, 1.7613 mmol), AcOH (3 drops), and NaBH3CN (185 mg, 2.9356 mmol) were added sequentially. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to provide ethyl 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentan-1-carboxamido)cyclohex-1-ene-1-carboxylate 1703 (305 mg, 85% purity, 38% yield) as a colorless oil.

[0580] C 26 H 36 LCMS (ESI) values ​​of FN5O4 [M + H] + m / z 502.28, measured value 502.25.

[0581] 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentane-1-carboxamido) Preparation of cyclohexyl-1-en-1-carboxylic acid (1704)

[0582] LiOH (29 mg, 1.2162 mmol) was added to a solution of ethyl 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentan-1-carbamate (10 mL, 3:1). The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure to produce 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentan-1-carbamate (250 mg, 90% purity, 78% yield) as a white solid.

[0583] C 24 H 32 LCMS (ESI) values ​​of FN5O4 [M + H] + m / z 474.24, measured value 474.16.

[0584] 6-Fluoro-N-methyl-5-(4-(3-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)cyclopentyl)piperazine- Preparation of 1-yl)pyridine amide (compound 18)

[0585] NMI (130 mg, 1.5837 mmol) and TCFH (296 mg, 1.0558 mmol) were successively added to a solution of 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)cyclopentan-1-carboxamido)cyclohex-1-en-1-carboxylic acid 1704 (250 mg, 0.5279 mmol) in ACN (5 mL) at room temperature. The reaction mixture was heated to 50 °C and NH3-MeOH (15 mL, 7 M) was added at 50 °C. The reaction solution was stirred at 50 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) and preparative HPLC (column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); gradient: 35-75) to produce 6-fluoro-N-methyl-5-(4-(3-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)cyclopentyl)piperazin-1-yl)pyridineamide 18cis-rac (35 mg, 95% purity, 13% yield) and 18trans-rac (30 mg, 95% purity, 11% yield) as white solids.

[0586] 6-Fluoro-N-methyl-5-(4-(3-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)cyclopentyl)piperazine- Chiral resolution of 1-yl)pyridine amide (18cis-rac)

[0587] Compound 18cis-rac was separated by an SFC (column: Daicel Chiralpak IH SFC; 20 mm ID × 250 mmL, 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to provide a first fraction as 18cis-a (7.3 mg, 97.27% purity, 100% ee, white solid) and a second fraction as 18cis-b (9.6 mg, 95.19% purity, 100% ee, white solid).

[0588] 18-way - a

[0589] 1 H NMR (400 MHz, DMSO- d6 , ppm) δ: 12.33 (s, 1 H), 8.47-8.35 (m, 1 H), 7.88-7.81 (m, 1 H), 7.63-7.51 (m, 1 H), 3.25-3.14 (m, 4 H), 3.05-2.94 (m, 1H), 2.76 (d, J =4.8 Hz, 3 H), 2.70-2.66 (m, 1 H), 2.64-2.57 (m, 4 H), 2.47-2.44 (m, 2 H), 2.32-2.24 (m, 2 H), 2.17-2.06 (m, 1 H), 2.03-1.91 (m, 1 H),1.85-1.75 (m, 3 H), 1.72-1.59 (m, 5 H).

[0590] Based on NOE experimental designation of cis-stereochemistry.

[0591] C 24 H 31 LCMS (ESI) values ​​of FN6O2 [M + H] + m / z 455.25, measured value 455.40.

[0592] 18-way - b

[0593] 1 H NMR (400 MHz, DMSO- d6, ppm) δ: 12.33 (s, 1 H), 8.47-8.32 (m, 1 H), 7.95-7.77 (m, 1 H), 7.65-7.49 (m, 1 H), 3.26-3.12 (m, 4 H), 3.06-2.93 (m, 1H), 2.76 (d, J =4.8 Hz, 3 H), 2.69-2.65 (m, 1 H), 2.65-2.57 (m, 4 H), 2.48-2.44 (m, 2 H), 2.32-2.24 (m, 2 H), 2.18-2.06 (m, 1 H), 2.04-1.91 (m, 1 H),1.87-1.75 (m, 3 H), 1.75-1.58 (m, 5 H).

[0594] Based on NOE experimental designation of cis-stereochemistry.

[0595] C 24 H 31 LCMS (ESI) values ​​of FN6O2 [M + H] + m / z 455.25, measured value 455.45.

[0596] 6-Fluoro-N-methyl-5-(4-(3-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)cyclopentyl)piperazine- Chiral resolution of 1-yl)pyridine amide (18-trans-rac)

[0597] Compound 18-trans-rac was separated by an SFC (column: Daicel Chiralpak IH SFC; 20 mm ID × 250 mmL, 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to provide a first fraction as 18-trans-a (4.3 mg, 98.29% purity, 100% ee, white solid) and a second fraction as 18-trans-b (5.5 mg, 99.96% purity, 100% ee, white solid).

[0598] 18 trans - a

[0599] 1 H NMR (400 MHz, DMSO- d6, ppm) δ: 12.07 (s, 1 H), 8.49-8.32 (m, 1 H), 7.94-7.77 (m, 1 H), 7.61-7.49 (m, 1 H), 3.20-3.11 (m, 4 H), 3.09-2.98 (m, 1H), 2.83-2.72 (m, 4 H), 2.61-2.54 (m, 4 H), 2.47-2.43 (m, 2 H), 2.31-2.25 (m, 2 H), 2.07-1.91 (m, 3 H), 1.89-1.73 (m, 2 H), 1.72-1.59 (m, 4 H), 1.53-1.41 (m, 1 H).

[0600] Based on NOE experimental designation of trans stereochemistry.

[0601] C 24 H 31 LCMS (ESI) values ​​of FN6O2 [M + H] + m / z 455.25, measured value 455.40.

[0602] 18 trans - b

[0603] 1 H NMR (400 MHz, DMSO- d6 , ppm) δ: 12.07 (s, 1 H), 8.47-8.36 (m, 1 H), 7.90-7.80 (m, 1 H), 7.62-7.48 (m, 1 H), 3.19-3.10 (m, 4 H), 3.09-2.99 (m, 1H), 2.82-2.73 (m, 4 H), 2.61-2.55 (m, 4 H), 2.47-2.45 (m, 2 H), 2.32-2.25 (m, 2 H), 2.07-1.92 (m, 3 H), 1.89-1.73 (m, 2 H), 1.73-1.59 (m, 4 H), 1.53-1.42 (m, 1 H).

[0604] Based on NOE experimental designation of trans stereochemistry.

[0605] C 24 H 31 LCMS (ESI) values ​​of FN6O2 [M + H] +m / z 455.25, measured value 455.40.

[0606] Example 9 ： 21-way - a. 21 sequential - b. 21 Reverse - a. 21-fold reverse - b Synthesis

[0607] Option 9

[0608] Preparation of methyl 5-((1-(tert-butoxycarbonyl)azacyclobutane-3-yl)oxy)pyridinecarboxylate (1803)

[0609] Methyl 5-hydroxypyridinecarboxylate 1802 (0.87 g, 5 mmol), PPh3 (2.99 g, 11 mmol), and DIAD (2.31 g, 11 mmol) were added to a solution of tert-butyl 3-hydroxyazacyclobutane-1-carboxylate 1801 (1 g, 5 mmol) in THF (30 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was then removed under reduced pressure. The residue was purified by rapid column chromatography (PE / EtOAc = 100:0 to 46:54) to provide methyl 5-((1-(tert-butoxycarbonyl)azacyclobutane-3-yl)oxy)pyridinecarboxylate 1803 (1.5 g, 90% purity, 77% yield) as a yellow oil.

[0610] C 15 H 20 The calculated LCMS (ESI) value of N2O5 is [M + H] + m / z 309.14, and the measured value is 309.15.

[0611] Preparation of 5-((1-(tert-butoxycarbonyl)azacyclobutane-3-yl)oxy)pyridinecarboxylic acid (1804)

[0612] Sodium hydroxide (0.38 g, 9 mmol) was added to a solution of methyl 5-((1-(tert-butoxycarbonyl)azacyclobutane-3-yl)oxy)pyridinecarboxylic acid 1803 (1.5 g, 4 mmol) in THF (10 mL) and H2O (10 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The organic solvent was then removed under reduced pressure. The reaction mixture was diluted with water (15 mL) and adjusted to pH 6 with 1 M HCl aqueous solution, and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated to provide 5-((1-(tert-butoxycarbonyl)azacyclobutane-3-yl)oxy)pyridinecarboxylic acid 1804 (1.4 g, 90% purity, 89% yield) as a yellow oil.

[0613] C 14 H 18 LCMS (ESI) calculated value of N2O5 [M + H] + m / z 295.12, measured value 295.15.

[0614] Preparation of tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azacyclobutane-1-carboxylate (1805) Preparation

[0615] DIPEA (1.82 g, 14 mmol) and T4P (50% in EtOAc, 3.39 g, 9 mmol) were added to a solution of 5-((1-(tert-butoxycarbonyl)azacyclobutan-3-yl)oxy)pyridinecarboxylic acid 1804 (1.4 g, 4 mmol) and MeNH2·HCl (0.95 g, 14 mmol) in DCM (20 mL) at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated, and purified by column chromatography on silica gel (eluting with EtOAc / PE, 0 to 20%) to provide tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azacyclobutane-1-carboxylate 1805 (1.2 g, 90% purity, 74% yield) as a yellow oil.

[0616] C 15 H 21 LCMS (ESI) values ​​of N3O4 [M + H] + m / z 308.15, measured value 308.15.

[0617] Preparation of 5-(azacyclobutane-3-yloxy)-N-methylpyridine amide 2,2,2-trifluoroacetate (1806)

[0618] TFA (5 mL) was added to a solution of tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azacyclobutane-1-carboxylate 1805 (500 mg, 1.6 mmol) in DCM (5 mL) at room temperature. The solution was then stirred at room temperature for 1 h. The reaction mixture was concentrated to provide 5-(azacyclobutane-3-yloxy)-N-methylpyridinamide 2,2,2-trifluoroacetate 1806 (350 mg, 90% purity, 93% yield) as a yellow oil.

[0619] C 10 H 13 LCMS (ESI) values ​​of N3O2 [M + H] + m / z 208.10, measured value 208.15.

[0620] 5-((1-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclopentyl)azacyclobutane-3-yl)oxy Preparation of 21-N-methylpyridine amide

[0621] To a solution of 5-(azacyclobutan-3-yloxy)-N-methylpyridinamide 2,2,2-trifluoroacetate 1806 (200 mg, 0.9 mmol) in MeOH (30 mL), 6-fluoro-2-(3-oxocyclopentyl)quinazolin-4(3H)-one 1807 (237 mg, 0.9 mmol, prepared in a similar manner to compound 1304) was added, followed by the addition of two drops of acetic acid and NaBH3CN (60 mg, 0.9 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was analyzed by rapid chromatography (eluting with DCM / MeOH = 100:0 to 92:8) and C2... 18 Column (Gemini 5 μm C) 18 150 × 21.2 mm, mobile phase: ACN - H2O (0.05% NH3·H2O), gradient: 25 - 60) purified to provide 5-((1-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclopentyl)azacyclobutane-3-yl)oxy)-N-methylpyridineamide 21-trans-rac (60 mg, 95% purity) and 21-cis-rac (90 mg, 95% purity).

[0622] 21-trans-rac was then separated by an SFC (column: DAICEL IH SFC 30 mm ID × 250 mmL, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 70 / 30) and concentrated under reduced pressure to provide a first fraction as 21-trans-a (14.4 mg, 99% purity, ee%: 100, white solid) and a second fraction as 21-trans-b (20.9 mg, 99% purity, ee%: 100, white solid).

[0623] 21-cis-rac was then separated by an SFC (column: DAICEL OJ-H SFC 30 mm ID × 250 mmL, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 65 / 35) and concentrated under reduced pressure to provide a first fraction as 21-cis-a (38.2 mg, 99% purity, ee%: 100, white solid) and a second fraction as 21-cis-b (37.4 mg, 99% purity, ee%: 100, white solid).

[0624] 21 trans - a

[0625] C 23 H 24 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 438.19, measured value 438.15.

[0626] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.26 (s, 1 H), 8.60-8.54 (m, 1 H), 8.23 ​​(d, J =2.8 Hz, 1 H), 7.96 (d, J =8.4 Hz, 1 H), 7.77-7.71 (m, 1 H), 7.65(d, 2 H), 7.42 (dd, J =8.8, 2.8 Hz, 1 H), 5.00-4.90 (m, 1 H), 3.77-3.68 (m, 2H), 3.28-3.19 (m, 1 H), 3.07-2.99 (m, 2 H), 2.99-2.92 (m, 1 H), 2.79 (d, J =4.8 Hz, 3 H), 2.13-2.01 (m, 1 H), 1.96-1.84 (m, 3 H), 1.83-1.73 (m, 1 H), 1.50-1.41 (m, 1 H).

[0627] Based on NOE experimental designation of trans stereochemistry.

[0628] 21 trans - b

[0629] C 23 H 24 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 438.19, measured value 438.20.

[0630] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.27 (s, 1 H), 8.61-8.55 (m, 1 H), 8.24 (d, J=2.8 Hz, 1 H), 7.96 (d, J =8.8Hz, 1 H), 7.77-7.72 (m, 1 H), 7.68-7.63 (m, 2 H), 7.42 (dd, J =8.8, 2.8 Hz, 1 H), 4.99-4.92 (m, 1 H), 3.76-3.69(m, 2 H), 3.27-3.19 (m, 1 H), 3.07-2.99 (m, 2 H), 2.99-2.92 (m, 1 H), 2.79(d, J =4.8 Hz, 3 H), 2.12-2.03 (m, 1 H), 1.94-1.83 (m, 3 H), 1.83-1.75 (m, 1H), 1.50-1.41 (m, 1 H).

[0631] Based on NOE experimental designation of trans stereochemistry.

[0632] 21-way - a

[0633] C 23 H 24 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 438.19, measured value 438.10.

[0634] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.86 (s, 1 H), 8.63-8.55 (m, 1 H), 8.26 (d, J =2.8 Hz, 1 H), 7.97 (d, J =8.4 Hz, 1 H), 7.78-7.71 (m, 1 H), 7.70-7.63 (m, 2 H), 7.42 (dd, J =8.6, 2.6 Hz, 1 H), 5.02-4.94 (m, 1 H), 3.86-3.76(m, 2 H), 3.22-3.12 (m, 3 H), 3.03-2.96 (m, 1 H), 2.79 (d, J=4.8 Hz, 3 H), 2.14-1.99 (m, 2 H), 1.94-1.84 (m, 1 H), 1.82-1.74 (m, 1 H), 1.71-1.60 (m, 2H).

[0635] Based on NOE experimental designation of cis-stereochemistry.

[0636] 21-way - b

[0637] C 23 H 24 LCMS (ESI) values ​​of FN5O3 [M + H] + m / z 438.19, measured value 438.10.

[0638] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.86 (s, 1 H), 8.61-8.54 (m, 1 H), 8.25 (d, J =2.8 Hz, 1 H), 7.97 (d, J =8.8 Hz, 1 H), 7.77-7.71 (m, 1 H), 7.69-7.63 (m, 2 H), 7.42 (dd, J =8.6, 3.0 Hz, 1 H), 5.05-4.94 (m, 1 H), 3.86-3.76(m, 2 H), 3.22-3.12 (m, 3 H), 3.03-2.95 (m, 1 H), 2.79 (d, J =4.8 Hz, 3 H), 2.12-1.99 (m, 2 H), 1.94-1.83 (m, 1 H), 1.81-1.74 (m, 1 H), 1.69-1.61 (m, 2H).

[0639] Based on NOE experimental designation of cis-stereochemistry.

[0640] Example 10: Synthesis of 2,3-cis-rac and 2,3-trans-rac

[0641] Option 10

[0642] Preparation of 5-fluoro-2-(3-oxocyclohexane-1-carbamoyl)benzamide (1903)

[0643] To a solution of 2-amino-5-fluorobenzamide 1901 (1.5 g, 0.0097 mol) in pyridine (10 mL), 3-oxocyclohexane-1-carboxylic acid 1902 (1.52 g, 0.011 mol) and EDCI (0.91 g, 0.014 mol) were added, and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 97:3) to give 5-fluoro-2-(3-oxocyclohexane-1-carboxamido)benzamide 1903 (2.1 g, 85% purity, 65% yield) as a yellow solid.

[0644] C 14 H 15 LCMS (ESI) calculated values ​​of FN2O3 [M + H] + m / z 279.11, measured value 279.10.

[0645] Preparation of 6-fluoro-2-(3-oxocyclohexyl)quinazolin-4(3H)-one (1904)

[0646] MeONa (0.81 g, 0.015 mol) was added to a solution of 5-fluoro-2-(3-oxocyclohexane-1-carbamate)benzamide 1903 (2.1 g, 0.0075 mol) in MeOH (20 mL). The reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 97:3) to give 6-fluoro-2-(3-oxocyclohexyl)quinazolin-4(3H)-one 1904 (1.5 g, 90% purity, 69% yield) as a brown gel.

[0647] C 14 H 13 LCMS (ESI) values ​​of FN2O2 [M + H] + m / z 261.10, measured value 261.10.

[0648] 5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridine Preparation of amide (23)

[0649] To a solution of 6-fluoro-2-(3-oxocyclohexyl)quinazolin-4(3H)-one 1904 (600 mg, 2.30 mmol) in DMF (10 mL), N-methyl-5-(piperazin-1-yl)pyridineamide 1002 (406 mg, 1.84 mmol) and two drops of AcOH were added. After stirring at 50 °C for 30 min, NaBH3CN (145 mg, 2.30 mmol) was added, and the reaction mixture was stirred at 50 °C for another 2 h. The mixture was then concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 97:3) and preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluting with 20% to 65% MeCN / H2O containing 0.05% NH3) to give 5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridineamide 23 (a mixture of four isomers) (30 mg, 98% purity, 2% yield) as a white solid.

[0650] 5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclohexyl)piperazin-1-yl)-N-methylpyridine Chiral resolution of amide (compound 23)

[0651] Compound 23 (a mixture of four isomers) was separated by SFC (column: IB N-5 30 mm × 250 mmL, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 60 / 40) and concentrated under reduced pressure to provide the first fraction as 23cis-rac (13.0 mg, 99% purity, racemic, white solid) and the second fraction as 23trans-rac (8.9 mg, 99% purity, racemic, white solid).

[0652] 23 sequence - rac

[0653] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.24 (s, 1 H), 8.70-8.65 (m, 1 H), 8.19 (dd, J=8.8, 2.4 Hz, 1 H), 7.76-7.71 (m, 1 H), 7.69-7.61 (m, 2 H), 7.08-7.02 (m, 1 H), 5.28-5.10 (m, 1 H), 3.72-3.62 (m, 2 H), 3.28-3.18 (m, 1 H), 3.07-2.99 (m, 2 H), 2.97-2.91 (m, 1 H), 2.12-2.01 (m, 1 H), 1.93-1.74 (m, 4H), 1.48-1.39 (m, 1 H).

[0654] Based on NOE experimental designation of cis-stereochemistry.

[0655] C 25 H 29 LCMS (ESI) values ​​of FN6O2 [M + H] + m / z 465.23, measured value 465.15.

[0656] 23 trans - rac

[0657] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.21 (s, 1 H), 8.44-8.36 (m, 1 H), 8.28 (d, J =2.8 Hz, 1 H), 7.84 (d, J =8.8 Hz, 1 H), 7.74 (dd, J =8.4, 2.4 Hz, 1H), 7.71-7.62 (m, 2 H), 7.41 (dd, J =8.8, 2.8 Hz, 1 H), 3.41-3.33 (m, 4 H), 3.12-3.01 (m, 1 H), 2.78 (d, J =4.8 Hz, 3 H), 2.70-2.56 (m, 4 H), 2.48-2.47 (m, 1 H), 2.15-2.05 (m, 1 H), 1.93-1.64 (m, 5 H), 1.59-1.41 (m, 2 H).

[0658] Based on NOE experimental designation of trans stereochemistry.

[0659] C 25 H29 LCMS (ESI) values ​​of FN6O2 [M + H] + m / z 465.23, measured value 465.10.

[0660] Example 11: Synthesis of 38 cis-rac and 38 trans-rac

[0661] Option 11

[0662] Preparation of tert-butyl 4-(6-cyanopyridin-3-yl)piperazine-1-carboxylate (2003)

[0663] To a solution of 5-fluoropyridinium 2001 (2 g, 0.016 mol) in NMP (25 mL), piperazine-1-carboxylic acid tert-butyl ester 2002 (4.61 g, 0.025 mol) and K2CO3 (5.66 g, 0.041 mol) were added. The reaction mixture was stirred at 100 °C for 3 h. The mixture was cooled to room temperature, 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, concentrated, and purified by rapid silica gel chromatography (PE / EtOAc = 100:0 to 70:30) to give 4-(6-cyanopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 2003 (3.2 g, 85% purity, 57% yield) as a yellow solid.

[0664] C 15 H 20 LCMS (ESI) values ​​of N4O2 [M + H] + m / z 289.16, measured value 288.85.

[0665] Preparation of tert-butyl 4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine-1-carboxylate (2005) Preparation

[0666] To a solution of tert-butyl piperazine-1-carboxylate 2003 (2 g, 0.0069 mol) in MeOH (20 mL), propane hydrazide 2004 (3.04 g, 0.034 mol) and MeONa (0.75 g, 0.014 mol) were added. The reaction mixture was stirred at 70 °C for 4 h. Then AcOH (1.66 g, 0.028 mol) was added and the mixture was stirred at 70 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 92:10) to give tert-butyl piperazine-1-carboxylate 2005 (1 g, 85% purity, 34% yield) as a yellow gel.

[0667] C 18 H 26 LCMS (ESI) values ​​of N6O2 [M + H] + m / z 359.21, measured value 359.20.

[0668] Preparation of 1-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine hydrochloride (2006)

[0669] A solution of tert-butyl 4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine-1-carboxylate 2005 (1 g, 0.0028 mol) in a dioxane solution (4.0 M, 10 mL) of HCl was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give 1-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine hydrochloride 2006 (800 mg, 85% purity, 92% yield) as a yellow solid.

[0670] C 13 H 18 LCMS (ESI) calculation value of N6 [M + H] + m / z 259.16, measured value 259.20.

[0671] 2-(3-(4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-1-yl)cyclopentyl)-6- Preparation of fluoroquinazoline-4(3H)-one (38)

[0672] To a solution of 1-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine hydrochloride 2006 (220 mg, 0.85 mmol) in MeOH (8 mL), 6-fluoro-2-(3-oxocyclopentyl)quinazolin-4(3H)-one 1807 (315 mg, 1.28 mmol) and two drops of AcOH were added, and the mixture was stirred at 50 °C for 30 min. Then, NaBH3CN (107 mg, 1.70 mmol) was added, and the reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 97:3) and preparative TLC (MeOH / DCM, 1 / 30) to give 2-(3-(4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-1-yl)cyclopentyl)-6-fluoroquinazolin-4(3H)-one 38 (40 mg, 98% purity, 9% yield) as a white solid.

[0673] 2-(3-(4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-1-yl)cyclopentyl)-6- Chiral resolution of fluoroquinazoline-4(3H)-one (38)

[0674] Compound 38 (a mixture of four isomers) was separated by SFC (column: DAICEL IH 20 mm ID × 250 mmL 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 80 / 20) and concentrated under reduced pressure to provide the first fraction as 38 cis-rac (18.6 mg, 93% purity, yellow solid) and the second fraction as 38 trans-rac (8.9 mg, 94% purity, yellow solid).

[0675] 38-way - rac

[0676] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 13.94 (s, 1 H), 12.64 (s, 1 H), 8.40-8.30 (m, 1 H), 8.21 (s, 0.50 H), 7.86 (d, J=8.8 Hz, 1 H), 7.77-7.62 (m,3 H), 7.49-7.37 (m, 1 H), 3.32-3.26 (m, 4 H), 3.19-3.13 (m, 1 H), 2.77-2.56(m, 7 H), 2.27-2.16 (m, 1 H), 2.12-2.03 (m, 1 H), 2.01-1.90 (m, 2 H), 1.88-1.72 (m, 2 H), 1.25 (t, J =7.4 Hz, 3 H).

[0677] Based on NOE experimental designation of cis-stereochemistry.

[0678] C 26 H 29 LCMS (ESI) calculation value of FN8O [M + H] + m / z 489.24, measured value 489.15.

[0679] 38 trans - rac

[0680] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 13.95 (s, 1 H), 12.28 (s, 1 H), 8.39-8.31 (m, 1 H), 8.15 (s, 0.70 H), 7.85 (d, J =8.8 Hz, 1 H), 7.75 (dd, J =8.4, 2.4 Hz, 1 H), 7.72-7.63 (m, 2 H), 7.48-7.36 (m, 1 H), 3.31-3.24 (m, 4H), 3.23-3.17 (m, 1 H), 2.87-2.78 (m, 1 H), 2.73-2.57 (m, 6 H), 2.24-2.06 (m,2 H), 2.05-1.87 (m, 3 H), 1.61-1.47 (m, 1 H), 1.25 (t, J =7.6 Hz, 3 H).

[0681] Based on NOE experimental designation of trans stereochemistry.

[0682] C 26 H 29LCMS (ESI) calculation value of FN8O [M + H] + m / z 489.24, measured value 489.25.

[0683] Example 12: Synthesis of 40a and 40b

[0684] Option 12

[0685] Preparation of N-(2-carbamoyl-4-fluorophenyl)-3-oxobicyclo[2.1.1]hexane-1-carboxamide (2103)

[0686] 3-oxobicyclo[2.1.1]hexane-1-carboxylic acid 2102 (136 mg, 0.9 mmol) and EDCI (373 mg, 1.9 mmol) were added to a solution of 2-amino-5-fluorobenzamide 2101 (150 mg, 0.9 mmol) in pyridine (10 mL) at room temperature. The mixture was stirred at 50 °C for 1 h. The mixture was concentrated and purified by column chromatography on silica gel (eluting with DCM / MeOH, 0 to 10%) to provide N-(2-carbamoyl-4-fluorophenyl)-3-oxobicyclo[2.1.1]hexane-1-carboxamide 2103 (150 mg, 90% purity, 50% yield) as a yellow solid.

[0687] C 14 H 13 LCMS (ESI) calculated values ​​of FN2O3 [M + H] + m / z 277.09, measured value 277.05.

[0688] Preparation of 6-fluoro-2-(3-oxobicyclo[2.1.1]hexane-1-yl)quinazolin-4(3H)-one (2104)

[0689] MeONa (117 mg, 2.1 mmol) was added to a solution of N-(2-carbamoyl-4-fluorophenyl)-3-oxobicyclo[2.1.1]hexane-1-carboxamide 2103 (150 mg, 0.5 mmol) in MeOH (30 mL) at room temperature. The mixture was stirred at 50 °C for 4 h. The mixture was concentrated and purified by column chromatography on silica gel (with DCM / MeOH, elution from 0 to 10%) to provide 6-fluoro-2-(3-oxobicyclo[2.1.1]hexane-1-yl)quinazolin-4(3H)-one 2104 (150 mg, 90% purity, 96% yield) as a yellow oil.

[0690] C 14 H 11 LCMS (ESI) values ​​of FN2O2 [M + H] + m / z 259.08, measured value 259.10.

[0691] 6-Fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-2-yl)piperyl Preparation of azinon-1-yl)-N-methylpyridine amide (40)

[0692] Add 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide 1305 (69 mg, 0.2 mmol) to a solution of 6-fluoro-2-(3-oxobicyclo[2.1.1]hexan-1-yl)quinazolin-4(3H)-one 2104 (75 mg, 0.2 mmol) in MeOH (10 mL), followed by two drops of acetic acid at room temperature. Stir the reaction mixture at 50 °C for 1 h. Then add NaBH3CN (1 mg, 0.01 mmol) and NaBH(OAc)3 (85 mg, 0.4 mmol). Stir the reaction mixture at 50 °C for 4 h. After cooling to room temperature, concentrate the reaction mixture to dryness under reduced pressure. Analyze the residue using rapid silica gel chromatography (eluting with MeOH / DCM, 0 to 10%) and C. 18 Column (Gemini 5 μm C) 18 150 × 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 10 - 50) purified to provide 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexane-2-yl)piperazin-1-yl)-N-methylpyridineamide 40rac (80 mg, 95% purity, 40% yield) as a white solid.

[0693] Product 40rac was then separated by an SFC (column: IB N-5 SFC 30 mm ID × 250 mmL, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to provide the first fraction as 40a (38.7 mg, 98% purity, ee%: 100, white solid) and the second fraction as 40b (24.2 mg, 99% purity, ee%: 100, white solid).

[0694] 40a

[0695] C 25 H 26 LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 481.21, measured value 481.10.

[0696] 1 H NMR (400 MHz, DMSO- d6, ppm) δ: 12.19 (s, 1 H), 8.46 - 8.39 (m, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.79 - 7.73 (m, 1 H), 7.72 - 7.64 (m, 2 H), 7.58 (dd, J = 10.4, 8.2 Hz, 1 H), 3.18 (s, 4 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.71 - 2.67 (m, 1 H), 2.65 - 2.57 (m, 5 H), 2.19 - 2.12 (m, 1 H), 2.11 - 2.05 (m, 1 H), 1.99 - 1.90 (m, 2 H), 1.87 - 1.80 (m, 1 H), 1.58 - 1.52 (m, 1 H).

[0697] 40b

[0698] C 25 H 26 LCMS (ESI) calculated value of F2N6O2 [M + H] + m / z 481.21, found 481.15.

[0699] 1 1H NMR (400 MHz, DMSO - d 6, ppm) δ: 12.19 (s, 1 H), 8.46 - 8.39 (m, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.76 (dd, J = 8.0, 2.0 Hz, 1 H), 7.71 - 7.64 (m, 2 H), 7.58 (dd, J = 10.4, 8.4 Hz, 1 H), 3.18 (s, 4 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.71 - 2.67 (m, 1 H), 2.65 - 2.57 (m, 5 H), 2.19 - 2.13 (m, 1 H), 2.10 - 2.05 (m, 1 H), 1.99 - 1.90 (m, 2 H), 1.88 - 1.81 (m, 1 H), 1.58 - 1.51 (m, 1 H).

[0700] Example 13: Synthesis of 54

[0701] Option 13

[0702] Preparation of 2-chloro-6-fluoro-4-methoxyquinazoline (2202)

[0703] MeONa (9.00 g, 0.167 mol) was added to a solution of 2,4-dichloro-6-fluoroquinazoline 2201 (30.0 g, 0.139 mol) in MeOH (100 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to provide 2-chloro-6-fluoro-4-methoxyquinazoline 2202 (25.9 g, 88% yield) as a white solid.

[0704] LCMS (ESI) calculated value of C9H6ClFN2O [M + H] + m / z 213.02, measured value 213.10.

[0705] Preparation of 6-fluoro-4-methoxy-2-vinylquinazoline (2204)

[0706] Tributyl(vinyl)stanane 2203 (116 g, 0.366 mol) and Pd(amphos)Cl2 (2.59 g, 3.65 mmol) were added to a solution of 2-chloro-6-fluoro-4-methoxyquinazoline 2202 (25.9 g, 0.122 mol) in ACN (500 mL) at room temperature. The resulting mixture was stirred at 100 °C for 6 h under N2. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to give 6-fluoro-4-methoxy-2-vinylquinazoline 2204 (8.10 g, 33% yield) as a white solid.

[0707] C 11 LCMS (ESI) values ​​of H9FN2O [M + H] + m / z 205.07, measured value 205.15.

[0708] Preparation of 6-fluoro-4-methoxyquinazoline-2-carboxaldehyde (2205)

[0709] K₂O₄·2H₂O (730 mg, 1.98 mmol) and NaIO₄ (16.98 g, 79.3 mmol) were added to a solution of 6-fluoro-4-methoxy-2-vinylquinazoline 2204 (8.10 g, 39.2 mmol) in 1,4-dioxane / H₂O (2:1, 150 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 40:60) to produce 6-fluoro-4-methoxyquinazoline-2-carboxaldehyde 2205 (6.10 g, 75% yield) as a white solid.

[0710] C 10 LCMS (ESI) values ​​of H7FN2O2 [M + H] + m / z 207.05, measured value 207.15.

[0711] Preparation of 1-(6-fluoro-4-methoxyquinazoline-2-yl)but-3-en-1-ol (2206)

[0712] Allyl magnesium bromide (1M, 33 mL) was slowly added to a solution of 6-fluoro-4-methoxyquinazoline-2-carboxaldehyde 2205 (6.10 g, 30 mmol) in THF (120 mL) at room temperature. The reaction mixture was stirred at 0 °C under N2 for 2 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL × 2), dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was purified by rapid column chromatography (PE / EtOAc = 100:0 to 20:80) to provide 1-(6-fluoro-4-methoxyquinazoline-2-yl)but-3-en-1-ol 2206 (900 mg, 12% yield) as a yellow oil.

[0713] C 13 H 13 LCMS (ESI) values ​​of FN2O2 [M + H] + m / z 249.10, measured value 249.15.

[0714] Preparation of 4-(6-fluoro-4-methoxyquinazolin-2-yl)butane-1,2,4-triol (2207)

[0715] K₂O₄·2H₂O (67 mg, 0.182 mmol) and NMO (4.24 g, 36.24 mmol) were added to a solution of 1-(6-fluoro-4-methoxyquinazoline-2-yl)but-3-en-1-ol 2206 (900 mg, 3.63 mmol) in THF / H₂O (5:1, 50 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to yield 4-(6-fluoro-4-methoxyquinazoline-2-yl)butane-1,2,4-triol 2207 (1.0 g, 98% yield) as a yellow oil.

[0716] C 13 H 15 LCMS (ESI) values ​​of FN₂O₄ [M + H] + m / z 283.10, measured value 283.20.

[0717] Preparation of 5-(6-fluoro-4-methoxyquinazolin-2-yl)tetrahydrofuran-3-ol (2208)

[0718] CMBP (10 mL) was added to a solution of 4-(6-fluoro-4-methoxyquinazoline-2-yl)butane-1,2,4-triol 2207 (1 g, 3.54 mmol) in toluene (25 mL). The reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (eluting with PE / EtOAc = 100:0 to 0:100) to yield 5-(6-fluoro-4-methoxyquinazoline-2-yl)oxepane-3-ol 2208 (700 mg, 75% yield) as a yellow oil.

[0719] C 13 H 15 LCMS (ESI) values ​​of FN₂O₄ [M + H] + m / z 265.09, measured value 265.15.

[0720] Preparation of 5-(6-fluoro-4-methoxyquinazolin-2-yl)dihydrofuran-3(2H)-one (2209)

[0721] Add Dys-Martin reagent (2.25 g, 5.30 mmol) to a solution of 5-(6-fluoro-4-methoxyquinazoline-2-yl)oxepane-3-ol 2208 (700 mg, 2.65 mmol) in DCM (3 mL). Stir the reaction mixture at 25 °C for 2 h. Quench the reaction mixture with water and extract with DCM (50 mL × 3). Wash the combined organic layers with brine, dry to Na2SO4, and concentrate under reduced pressure. Purify the residue by rapid chromatography (eluting with PE / EtOAc = 100:0 to 0:100) to yield 5-(6-fluoro-4-methoxyquinazoline-2-yl)dihydrofuran-3(2H)-one 2209 (170 mg, 24% yield) as a yellow oil.

[0722] C 13 H 11 LCMS (ESI) calculated values ​​of FN2O3 [M + H] + m / z 263.08, measured value 263.15.

[0723] 5-(4-(5-(6-fluoro-4-methoxyquinazoline-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N-methylpyridine Preparation of amide (2210)

[0724] To a solution of 5-(6-fluoro-4-methoxyquinazoline-2-yl)dihydrofuran-3(2H)-one 2209 (170 mg, 0.648 mmol) and N-methyl-5-(piperazin-1-yl)pyridineamide 1002 (214 mg, 0.971 mmol) in EtOH (3 mL), NaBH(OAc)3 (206 mg, 0.972 mmol) and two drops of HOAc were added, and the mixture was stirred at 90 °C for 10 min. Then NaBH3CN (122 mg, 1.941 mmol) was added. The reaction mixture was stirred at 90 °C for 3 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 90:10) to produce 5-(4-(5-(6-fluoro-4-methoxyquinazoline-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N-methylpyridineamide 2210 (200 mg, 66% yield) as a yellow oil.

[0725] C 24 H 27 LCMS (ESI) values ​​of FN6O3 [M + H] + m / z 467.21, measured value 467.10.

[0726] 5-(4-(5-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N- Preparation of methylpyridine amide (54)

[0727] TMSI (300 mg, 2.14 mmol) was added to a solution of 5-(4-(5-(6-fluoro-4-methoxyquinazolin-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N-methylpyridineamide 2210 (500 mg, 1.07 mmol) in ACN (5 mL). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was subjected to preparative HPLC (Gemini 5µm C18 150) 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 30% - 95%) purified to provide 5-(4-(5-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)-N-methylpyridine amide 54 fraction 1 (8.8 mg, 97% purity) and 54 fraction 2 (2.2 mg, 89% purity) as white solids.

[0728] One of fractions 1 and 2 is a racemic mixture of cis isomers, and the other of fractions 1 and 2 is a racemic mixture of trans isomers.

[0729] 54th grade, 1st grade

[0730] 1 H NMR (400 MHz, MeOD- d 4, ppm) δ: 8.29 (d, J =2.4 Hz, 1H), 7.91 (d, J =8.8 Hz, 1H), 7.79 (dd, J =8.4, 2.8 Hz, 1H), 7.75-7.71 (m, 1H), 7.62-7.57 (m,1H), 7.38 (dd, J =8.8, 2.8 Hz, 1H), 4.95-4.90 (m, 1H), 4.36 (dd, J =9.6, 2.4Hz, 1H), 3.95-3.89 (m, 1H), 3.51-3.45 (m, 4H), 3.13-3.10 (m, 1H), 2.93 (s,3H), 2.81 (t, J =4.8 Hz, 4H), 2.65-2.57 (m, 1H), 2.48-2.41 (m, 1H).

[0731] C 23 H25 LCMS (ESI) values ​​of FN6O3 [M + H] + m / z 453.20, measured value 453.30.

[0732] 54th grade, 2nd grade

[0733] 1H NMR (400 MHz, MeOD-d4, ppm) δ: 8.29 (d, J =2.8 Hz, 1H), 7.91 (d, J =8.8 Hz, 1H), 7.83 (dd, J =8.4, 2.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.64-7.57 (m,1H), 7.37 (dd, J =8.8, 2.8 Hz, 1H), 5.08-5.00 (m, 1H), 4.32-4.26 (m, 1H), 3.93-3.89 (m, 1H), 3.40 (t, J =4.8 Hz, 4H), 3.21-3.19 (m, 1H), 2.93 (s, 3H), 2.80-2.74 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.46 (m, 2H).

[0734] C 23 H 25 LCMS (ESI) values ​​of FN6O3 [M + H] + m / z 453.20, measured value 453.30.

[0735] Example 14: Synthesis of 59

[0736] Option 14

[0737] 3 - ( Methoxymethylene ) Cyclobutane- 1 methyl formate Preparation of (2303)

[0738] Add (5.35 g, 0.015 mol) of (methoxymethyl)triphenylphosphonium chloride 2302 in 20 mL of THF to a solution at 0 °C under N2 conditions. tBuOK (1.75 g, 0.016 mol). The mixture was stirred at room temperature for 30 min. Then, methyl 3-oxocyclobutane-1-carboxylate 2301 (1 g, 0.0078 mol) was added to the mixture. The mixture was heated at 70 °C for 2 h. The resulting mixture was diluted with water (50 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 (using EtOAc / PE, elution from 0 to 50%) to produce methyl 3-(methoxymethylene)cyclobutane-1-carboxylate 2303 (200 mg, 90% purity, 15% yield) as a white solid.

[0739] C8H 12 LCMS (ESI) calculation value of O3 [M + H] + m / z 157.08, no MS signal detected.

[0740] Preparation of methyl 3-formylcyclobutane-1-carboxylate (2304)

[0741] TFA (292 mg, 2.56 mol) was added to a solution of methyl 3-(methoxymethylene)cyclobutane-1-carboxylate 2303 (200 mg, 1.28 mmol) in DCM / H2O = 10:1 (11 mL). The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield methyl 3-formylcyclobutane-1-carboxylate 2304 (100 mg, 90% purity, 49% yield) as a white solid.

[0742] C7H 10 LCMS (ESI) calculation value of O3 [M + H] + m / z 143.06, no MS signal detected.

[0743] 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)cyclobutane-1-carboxylic acid Preparation of ester (2305)

[0744] AcOH (0.1 mL) was added to a solution of methyl 3-formylcyclobutane-1-carboxylate 2304 (100 mg, 0.70 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide 1305 (168 mg, 0.70 mmol) in MeOH (10 mL). The mixture was heated at 50 °C for 10 min. Then NaBH3CN (89 mg, 1.4 mmol) was added to the mixture. The mixture was stirred at 50 °C for 1 h. The resulting mixture was quenched with water (1 mL) and concentrated under reduced pressure, then purified by silica gel column chromatography (with MeOH / DCM, elution from 0 to 10%) to produce methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)cyclobutane-1-carboxylate 2305 (120 mg, 90% purity, 42% yield) as a white solid.

[0745] C 18 H 25 LCMS (ESI) values ​​of FN4O3 [M + H] + m / z 365.19, measured value 365.15

[0746] 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)cyclobutane-1-carboxylic acid Preparation of (2306)

[0747] LiOH (14 mg, 0.55 mmol) was added to a solution of methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)cyclobutane-1-carboxylate 2305 (100 mg, 0.27 mmol) in THF / H₂O (3 / 1, 10 mL). The mixture was stirred at room temperature for 1 h. The organic solvent was then removed under reduced pressure. The aqueous solution was adjusted to pH 2–3 with 1 M HCl. The resulting solution was purified by preparative HPLC (Gemini 5 μm C18 150 × 21.2 mm, eluted with 5% to 40% MeCN / H2O containing 0.1% HCOOH) to provide crude 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)cyclobutane-1-carboxylic acid 2306 (60 mg, 90% purity, 56% yield) as an orange solid.

[0748] C 17 H 23 LCMS (ESI) values ​​of FN4O3 [M + H] + m / z 351.18, measured value 351.10.

[0749] 5-(4-((3-((2-carbamoyl-4-fluorophenyl)carbamoyl)cyclobutyl)methyl)piperazin-1-yl)-6-fluoro- Preparation of N-methylpyridine amide (2308)

[0750] Add 2-amino-5-fluorobenzamide 2307 (40 mg, 0.26 mmol) and EDCI (66 mg, 0.34 mmol) to a solution of 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)cyclobutane-1-carboxylic acid 2306 (60 mg, 0.17 mmol) in pyridine (5 mL). Stir the mixture at room temperature for 2 hours. Dilute the resulting mixture with water (50 mL) and extract with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (using MeOH / DCM, elution 0 to 10%) to produce 5-(4-((3-((2-carbamoyl-4-fluorophenyl)carbamoyl)cyclobutyl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide 2308 (50 mg, 90% purity, 54% yield) as a white solid.

[0751] C 24 H 28 LCMS (ESI) values ​​of F2N6O3 [M + H] + m / z 487.22, measured value 487.15.

[0752] 6-Fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclobutyl)methyl)piperazine-1- Preparation of α-N-methylpyridine amide (59)

[0753] To a solution of 5-(4-((3-((2-carbamoyl-4-fluorophenyl)carbamoyl)cyclobutyl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridinamide 2308 (50 mg, 0.10 mmol) in DME (10 mL), KOH (17 mg, 0.21 mmol) was added. The mixture was heated at 50 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (with MeOH / DCM, elution from 0 to 10%) to give 6-fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)cyclobutyl)methyl)piperazin-1-yl)-N-methylpyridinamide 59 (40 mg, 99% purity, 74% yield, cis / trans mixture) as a white solid.

[0754] 6-Fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclobutyl)methyl)piperazine-1- Isolation of isomers of α-N-methylpyridine amide (59)

[0755] Compound 59 (cis / trans mixture) was separated by an SFC (column: Daicel Chiralpak IH SFC, 20 mm I.D. × 250 mmL, 20 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to provide the first fraction as 59a (2.0 mg, 99.8% purity, ee%: 100, white solid) and the second fraction as 59b (1.2 mg, 97.0% purity, ee%: 95, white solid). NOE experiments were unsuccessful in determining the cis or trans stereochemistry of either sample.

[0756] 59a

[0757] 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ: 12.23 (s, 1 H), 8.44-8.39 (m, 1 H), 7.86-7.83 (m, 1 H), 7.76-7.64 (m, 3 H), 7.59-7.52 (m, 1 H), 3.41-3.36 (m, 1H), 3.17-3.12 (m, 4 H), 2.76 (d, J =4.8 Hz, 3 H), 2.55-2.51 (m, 5 H), 2.45-2.36 (m, 4 H), 2.12-2.00 (m, 2 H).

[0758] C 24 H 26 LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 469.21, measured value 469.15.

[0759] 59b

[0760] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.19 (s, 1 H), 8.44-8.38 (m, 1 H), 7.87-7.82 (m, 1 H), 7.78-7.71 (m, 2 H), 7.70-7.64 (m, 1 H), 7.60-7.53 (m, 1H), 3.54-3.46 (m, 1 H), 3.20-3.11 (m, 4 H), 2.76 (d, J =4.8 Hz, 3 H), 2.57-2.51 (m, 9 H), 2.10-2.02 (m, 2 H).

[0761] C 24 H 26 LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 469.21, measured value 469.15.

[0762] Example 15: Synthesis of 62

[0763] Option 15

[0764] Preparation of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (2402)

[0765] PCC (8.28 g, 38 mmol) was added to a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate 2401 (3 g, 19 mmol) in DCM (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by rapid column chromatography (eluting with PE / EtOAc = 100:0 to 0:100) to provide methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate 2402 (2.5 g, 90% purity, 76% yield) as a yellow oil.

[0766] No MS signal.

[0767] 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane- Preparation of methyl 1-formate (2403)

[0768] Two drops of AcOH were added to a solution of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate 2402 (600 mg, 3.8 mmol), 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridineamide 1305 (927 mg, 3.8 mmol), and NaBH(OAc)3 (1649 mg, 7.7 mmol) in MeOH (30 mL) at room temperature, and the mixture was stirred for 10 min. Then NaBH3CN (244 mg, 3.8 mmol) was added. 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 purified by rapid column chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to provide methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate 2403 (600 mg, 90% purity, 36% yield) as a yellow oil.

[0769] C 19 H 25 LCMS (ESI) values ​​of FN4O3 [M + H] + m / z 377.19, measured value 377.15.

[0770] 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane- Preparation of 1-formic acid (2404)

[0771] LiOH (153 mg, 6.3 mmol) was added to a solution of methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylate 2403 (600 mg, 1.5 mmol) in THF / H2O = 1 / 1 (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 6 with 1 M HCl aqueous solution. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum to obtain 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid 2404 (500 mg, 90% purity, 77% yield) as a yellow oil.

[0772] C 18 H 23 LCMS (ESI) values ​​of FN4O3 [M + H] +m / z 363.18, measured value 363.10.

[0773] 5-(4-((3-((2-carbamoyl-4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperyl Preparation of (1-azinyl)-6-fluoro-N-methylpyridine amide (2406)

[0774] EDCI (528 mg, 2.7 mmol) was added to a solution of 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid 2404 (500 mg, 1.3 mmol) and 2-amino-5-fluorobenzamide 2405 (425 mg, 2.7 mmol) in pyridine (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to obtain a crude product, which was purified by rapid column chromatography (DCM / MeOH = 100:0 to 90:10) to provide 5-(4-((3-((2-carbamoyl-4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridine amide 2406 (500 mg, 90% purity, 65% yield) as a yellow oil.

[0775] C 25 H 28 LCMS (ESI) values ​​of F2N6O3 [M + H] + m / z 499.22, measured value 499.10.

[0776] 6-Fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pentane-1-yl) Preparation of (62)-methylpiperazine-1-yl)-N-methylpyridine amide

[0777] Sodium ethoxide (68 mg, 1.0 mmol) was added to a solution of 5-(4-((3-((2-carbamoyl-4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpyridineamide 2406 (250 mg, 0.5 mmol) in EtOH (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under vacuum to give a crude product, which was purified by rapid column chromatography (DCM / MeOH = 100:0 to 90:10) to provide 6-fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pentan-1-yl)methyl)piperazin-1-yl)-N-methylpyridineamide 62 (117.5 mg, 96% purity, 43% yield) as a white solid.

[0778] C 25 H 26LCMS (ESI) values ​​of F2N6O2 [M + H] + m / z 481.21, measured value 481.10.

[0779] 1 H NMR (400 MHz, DMSO- d 6, ppm) δ: 12.29 (s, 1 H), 8.43-8.37 (m, 1 H), 7.89-7.82 (m, 1 H), 7.79-7.73 (m, 1 H), 7.72-7.64 (m, 2 H), 7.60-7.52 (m, 1H), 3.22-3.13 (m, 4 H), 2.77 (d, J =4.8 Hz, 3 H), 2.65-2.58 (m, 4 H), 2.53-2.51 (m, 2 H), 2.14 (s, 6 H).

[0780] Example 16: Measurement

[0781] 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.

[0782] Example 16A. PARP1 biodissociation-enhanced fluorescence immunoassay of lanthanides (DELFIA assay)

[0783] Optiplate HB 384-well plates were coated overnight at 4°C with anti-FLAG antibody (supplying as a 4 mg / ml solution) using Na2CO3 / HCO3 coating buffer at pH 9.6 to achieve final immobilization of 0.3 μg per well. The wells were then washed 3 x 5 min in coating wash buffer (PBS / 0.05% Tween (v / v)) and blocked overnight at 4°C with 2% BSA (w / v) in coating wash buffer. Before assay, the wells were washed 3 x 5 min in coating wash buffer. For the assay, 20 μl of 2.5 nM recombinant full-length human N-terminal FLAG-labeled PARP1 was added to each well of the 384-well plate and incubated at room temperature for 30 min, followed by the addition of 50 nL of the compound solution in DMSO using the pintool technique. After incubation at room temperature for 30 min, 5 μl of 10 μM biotin-NAD was added. +10 nM activated DNA (sequence shown below) was added to a solution in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v) assay buffer. Self-PARation was performed at room temperature for 2 h, followed by the addition of 5 μl of 12 mM NAD. + Quenching solution. After 30 min at room temperature, remove the assay solution and wash five times for 3 min each, then add 100 μl of a 1:1000 dilution of DELFIA Eu-N1 streptavidin reagent. Incubate the plate at room temperature for 30 min. Remove the reaction mixture and wash the plate five times for 3 min each, then add 25 μl of DELFIA enhancement solution. After 30 min at room temperature, measure fluorescence on a Pherastar FS (Ex 337 nm, Em 620 nm; integration start 60 μs; integration time 400 μs).

[0784] 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: % value = 100 - (100) ((High control - Unknown) / (High control - Low control)) 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.

[0785] IC50 of various test compounds 50 The values ​​are shown in Table 1.

[0786] Activated DNA sequence:

[0787] Example 16B. PARP1 probe replacement homogeneous time-resolved fluorescence assay (HTRF assay)

[0788] 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). dThe 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).

[0789] 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: %activity=100 (Value - Low Control) / (High Control - Low Control) The % activity data were fitted to a nonlinear regression equation to obtain the IC50 value. Calculate K using the Cheng-Prussoff formula. d value: IC 50 =(1+ ([probe concentration] / [Km)) 探针 ])) K d

[0790] 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

[0791] Example 16C. Homogeneous Time-Resolved Fluorescence Assay (HTRF) with PARP2 Probe Replacement

[0792] 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 a 10-fold probe K was used. d =540 nM using PARP1 / 2 binding probes. Data analysis was performed in the same manner as with PARP1.

[0793] Cy5 probe structure:

[0794] NanoBRET Cell Target Occupation Assay

[0795] 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.

[0796] 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: IC50 = (1 + ([tracer concentration] / [Km])) 示踪剂 ])) Kd 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.

[0797] Table 1

[0798] Results of Parp 1 / 2 assays for selected compounds (DELFIA and probe-replaced HTRF) The stereochemistry of this compound has not yet been definitively determined. One of fractions 1 and 2 is a cis isomer, and the other of fractions 1 and 2 is a trans isomer.

[0799] Table 2

[0800] Results of Parp 1 / 2 determination for selected compounds (NanoBRET)

[0801] Symbol explanation: Classification of DELFIA, probe-replacement HTRF, and NanoBRET assays: - Indicates ICs with a value higher than 10 μM 50 or K d value + Indicates ICs with values ​​from 1 μM up to 10 μM. 50 or K d value ++ indicates ICs with a range from 100 nM to 1 μM. 50 or K d value +++ indicates ICs with speeds up to 10 nM up to 100 nM. 50 or K d value ++++Indicates ICs of 10 nM or lower 50 or K d value NT: Not tested Selective classification: - Indicates a value less than 10 + Indicates a value from 10 to less than 50. ++ indicates a value from 50 to less than 100. +++ indicates a value of at least 100. 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.

[0802] It should be understood that the above implementation plan is described only by way of example.

[0803] Once the disclosure herein is given, other variations or applications of the disclosed technology will become apparent to those skilled in the art. The scope of this disclosure is not limited to the described embodiments, but only to the appended claims.

Claims

1. A PARP1 inhibitor compound having the following structure: in: Dashed lines represent bonds selected from single and double bonds; y is 0, 1, or 2; Each X D Independently selected from C, N, O, and S; X ET and X EB Each is independently selected from C and N; Each R 1 It does not exist independently or is selected from H and substituted or unsubstituted organic groups; Each R 4 Independently absent or selected from H and substituted or unsubstituted organic groups, provided that the R 4 The groups do not fuse to form a ring; R 3 It is H or a substituted or unsubstituted organic group; L is a group having the following structure: in: Ring C is an aromatic ring; X A1 It is C or N; Each X A2 Independently selected from C, N, O, and S; Each X B2 Independently selected from C, N, O, and S; X B3 Selected from C and N; Each X C The ring is independently selected from C, N, O, and S, provided that the ring C is a heterocyclic ring. Each R 5A and R 5C It does not exist independently or is selected from H and substituted or unsubstituted organic groups; Each R 5B Independently, it is absent, H, substituted or unsubstituted organic groups, or related to another R. 5B Together they represent the key of bridging ring B; R 6 Selected from H and substituted or unsubstituted organic groups; n is 0, 1, 2, 3, 4 or 5; m can be 0, 1, 2, 3, 4 or 5, provided that n + m is in the range of 1 to 5; p is 1, 2, or 3; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; and s can be 0, 1, 2, 3 or 4, provided that r + s is 3 or 4; Q 1 and Q 2 Each is independently a bond or a linking group having a structure selected from the following: in: t is 0, 1, 2, 3, 4, or 5; u can be 0, 1, 2, 3, 4, or 5, provided that t + u is within the range of 0 to 6; and Each R 7 and R 8 It is independently selected from H and substituted or unsubstituted organic groups.

2. The PARP1 inhibitor compound according to any of the preceding claims, wherein each R 1 and each R 4 It does not exist independently or is selected from: H； halogen; Nitrile group; C1 to C6 acyclic alkyl groups; C1 to C6 have no cycloalkoxy groups; C1 to C6 acyclic haloalkyl groups; C1 to C6 acyclic halogenated alkoxy groups, such as -OCF3 or OCHF2; C1 to C6 acyclic aminoalkyl groups; and ， R 22 Selected from H, halogens, C1 to C6 alkyl groups, C3 to C6 cycloalkyl groups, C1 to C6 alkoxy groups, and C1 to C6 haloalkyl groups, and Each R 23 Independently selected from H; halogen; C1 to C6 alkyl group; C1 to C6 aminoalkyl group; C1 to C6 alkoxy group; C1 to C6 haloalkoxy group; such as -OCF3 or OCHF2; and C1 to C6 haloalkyl group.

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

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

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

6. The PARP1 inhibitor compound according to claim 5, wherein exactly one R 1 Or exactly one R 4 It is F; Or each of R 1 and each R 4 It either does not exist or it is H.

7. The PARP1 inhibitor compound according to any of the preceding claims, wherein X ET and X EB At least one of them is C.

8. The PARP1 inhibitor compound according to claim 7, wherein X EB It is N.

9. The PARP1 inhibitor compound according to claim 8, having a structure selected from the following:

10. The PARP1 inhibitor compound according to claim 7, wherein X ET It is C and X EB It's C.

11. The PARP1 inhibitor compound according to claim 10, having a structure selected from the following:

12. The PARP1 inhibitor compound according to any of the preceding claims, wherein each X D Selected independently from C and N.

13. The PARP1 inhibitor compound of claim 12, wherein each X D It's C.

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

15. The PARP1 inhibitor compound according to any one of claims 1 to 13, wherein y is 0.

16. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring D is an aromatic ring.

17. The PARP1 inhibitor compound according to claim 16, having the following structure: Optional , Further optional or .

18. The PARP1 inhibitor compound according to claim 17, having a structure selected from the following:

19. The PARP1 inhibitor compound according to claim 16, having a structure selected from the following:

20. The PARP1 inhibitor compound according to claim 19, having a structure selected from the following:

21. The PARP1 inhibitor compound according to claim 19, having a structure selected from the following:

22. The PARP1 inhibitor compound according to any one of claims 1 to 15, wherein ring D is a non-aromatic ring.

23. The PARP1 inhibitor compound according to claim 22, having a structure selected from the following:

24. The PARP1 inhibitor compound according to claim 23, having the following structure: 。 25. The PARP1 inhibitor compound according to claim 22, having a structure selected from the following:

26. The PARP1 inhibitor compound according to claim 22, having a structure selected from the following:

27. The PARP1 inhibitor compound according to claim 22, having a structure selected from the following:

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

29. The PARP1 inhibitor compound according to claim 28, wherein R 3 It is H.

30. The PARP1 inhibitor compound according to claim 1, having a structure selected from the following:

31. The PARP1 inhibitor compound according to any of the preceding claims, wherein n + m is in the range of 2 to 5.

32. The PARP1 inhibitor compound of claim 31, wherein both n and m are at least 1.

33. The PARP1 inhibitor compound according to any of the preceding claims, wherein X A1 It's C.

34. The PARP1 inhibitor compound according to claim 33, wherein: i) Ring A is a 7-membered ring, optionally having a cycloheptane with a structure selected from the following: and Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The optimal choice is H; or ii) Ring A is a 6-membered non-aromatic ring, optionally cyclohexane, cyclohexene, or tetrahydropyran, and further optionally has a structure selected from the following: Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The optimal choice is H; or iii) Ring A is a 5-membered non-aromatic ring, optionally cyclopentane, cyclopentene, or tetrahydrofuran, and further optionally has a structure selected from the following: Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The optimal choice is H; or iv) Ring A is a 5-membered aromatic ring, optionally oxazole or isoxazole, optionally having a structure selected from the following: Each R 5A Independently selected from H and substituted or unsubstituted organic groups, v) Ring A is a 4-membered ring with the following structure: ； Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The optimal choice is H; or vi) Ring A is a 3-membered ring with the following structure: Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The optimal choice is H; vii) Ring A is a bridge ring, optionally having a structure selected from the following: Each R 5A and R 5A3 Independently selected from H and substituted or unsubstituted organic groups, wherein R 5A3 The optimal choice is H.

35. The PARP1 inhibitor compound according to any of the preceding claims, wherein, when present, each R 5A Independently selected from H; halogen, optionally F; hydroxyl group; oxo group; and C1 to C3 alkyl group, optionally one pair of which is R 5A The group forms a ring, further optionally wherein said ring bridges ring A; or two R on adjacent atoms. 5A The groups can be used together to represent phenyl groups fused with ring A; Preferably, each R 5A It is H.

36. The PARP1 inhibitor compound of claim 35, wherein a pair of R 5A The group forms a ring fused with ring A; optionally, the ring fused with ring A is a phenyl group.

37. The PARP1 inhibitor compound according to claim 34, wherein ring A has a structure selected from: Optionally, ring A has a structure selected from A1 to A37.

38. The PARP1 inhibitor compound according to claim 32, wherein ring A has the following structure: in: m is 1 or 2; n is 1 or 2; Each R 5A2 and R 5A3 Independently absent or selected from H and substituted or unsubstituted organic groups, preferably wherein R 5A3 It is H; And among them: i) X A1 It is C and R 5A1 It is absent or selected from H and substituted or unsubstituted organic groups; or ii) X A1 It is N and R 5A1 It does not exist.

39. The PARP1 inhibitor compound of claim 38, wherein each R 5A1 R 5A2 and R 5A3 Independently absent or selected from H; halogen, optionally F; hydroxyl group; oxo group; and C1 to C3 alkyl group, optionally one of a pair of R 5A The group forms a C1 to C3 alkyl group bridging ring A; Preferably, each R 5A1 R 5A2 and R 5A3 It either does not exist or it is H.

40. The PARP1 inhibitor compound according to claim 38 or claim 39, wherein ring A has a structure selected from:

41. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring A has a structure selected from: And optionally, ring A has the following structure: 。 42. The PARP1 inhibitor compound according to any of the preceding claims, wherein ring A is a 5-membered ring.

43. The PARP1 inhibitor compound according to any one of claims 1 to 41, wherein ring A is a 3- or 4-membered ring, and wherein Q 1 It is -CH2- or -CH(CH3)-; Where ring A is chosen arbitrarily. or .

44. The PARP1 inhibitor compound according to any of the preceding claims, wherein p + q is in the range of 2 to 5.

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

46. ​​The PARP1 inhibitor compound according to any of the preceding claims, wherein X B3 It is N.

47. The PARP1 inhibitor compound according to claim 45 or claim 46, wherein ring B has a structure selected from:

48. The PARP1 inhibitor compound according to claim 45, wherein: i) Ring B is an azacyclic heptane, optionally having the following structure: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H; or ii) Ring B is piperidine, optionally having the following structure: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H; or iii) Cycle B is a pyrrolidine, optionally having the following structure: Each R 5B Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5B It is H.

49. The PARP1 inhibitor compound according to any of the preceding claims, wherein each R 5B Independently, it is an organic group that is absent, H, substituted, or unsubstituted.

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

51. The PARP1 inhibitor compound according to claim 47, wherein ring B has a structure selected from:

52. The PARP1 inhibitor compound according to claim 51, wherein ring B has the following structure: 。 53. The PARP1 inhibitor compound according to claim 51, wherein ring B has the following structure: 。 54. The PARP1 inhibitor compound according to claim 51, wherein ring B has the following structure: Choose any one of Q 2 It is O.

55. The PARP1 inhibitor compound according to any one of claims 1 to 43, wherein p + q is 6, and wherein ring B comprises two fused rings.

56. The PARP1 inhibitor compound according to claim 55, wherein ring B has the following structure: ； Optionally, each of R 5B It either does not exist or it is H.

57. The PARP1 inhibitor compound according to claim 56, wherein ring B has the following structure: 。 58. The PARP1 inhibitor compound according to claim 57, wherein ring B has the following structure: or 。 59. The PARP1 inhibitor compound according to claim 58, wherein ring B has the following structure: or .

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

61. The PARP1 inhibitor compound according to claim 60, wherein R 7 Selected from: H; halogen, optionally F; C1 to C6 alkyl group; and C1 to C6 haloalkyl group.

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

63. The PARP1 inhibitor compound 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 according to any of the preceding claims, wherein Q 1 It is a key.

65. The PARP1 inhibitor compound according to any of the preceding claims, wherein Q 2 It is a bond, -O- or -CH2-; Optional key or -CH2-.

66. The PARP1 inhibitor of claim 65, wherein Q 2 It is a key.

67. The PARP1 inhibitor compound according to any of the preceding claims, wherein r is at least 1 and s is at least 1.

68. The PARP1 inhibitor compound according to any of the preceding claims, wherein each X C Selected independently from C and N.

69. The PARP1 inhibitor compound according to claim 68, wherein r+s is 4; Arbitrarily, where r is 2 and s is 2.

70. The PARP1 inhibitor compound of claim 69, wherein exactly one X C The atom is N, or exactly two of them are X. C The atom is N.

71. The PARP1 inhibitor compound according to claim 69 or claim 70, wherein the ring C has the following structure: in: X Co and X Cm Each is selected from C and N, provided that X Co and X Cm At least one of them is N; When X Co When it is C, R Co It is H or a halogen, with F being the preferred halogen; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or a halogen, with F being the preferred halogen; and When X Cm When it is N, R Cm It does not exist; Choose any one of X Co and X Cm One of them is N.

72. The PARP1 inhibitor compound according to claim 71, wherein the ring C is a pyridine group, optionally having a structure selected from: , , , and , Each R 5C It is independently selected from H and substituted or unsubstituted organic groups.

73. The PARP1 inhibitor compound according to claim 72, wherein the ring C is a pyridine group having the following structure: Preferred , And more preferably or .

74. The PARP1 inhibitor compound according to claim 70, wherein the ring C is a diazine group, optionally having a structure selected from: , , , , , and Each R 5C It is independently selected from H and substituted or unsubstituted organic groups.

75. The PARP1 inhibitor compound according to claim 74, wherein ring C has a structure selected from: , and .

76. The PARP1 inhibitor compound according to any one of claims 1 to 68, wherein r+s is 3 and each X C It is independently selected from C, N, O and S.

77. The PARP1 inhibitor compound according to claim 76, wherein ring C is selected from: i) An imidazole group, optionally having an imidazole group having a structure selected from the following: and , Each R 5C Independently selected from H and substituted or unsubstituted organic groups; ii) A thiophene group, optionally having a structure selected from the following: , and , Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; iii) A thiazole group, optionally having a structure selected from the following: , , and , Each R 5C Independently selected from H and substituted or unsubstituted organic groups, optionally wherein each R 5C It is H; iv) Triazoles, optionally triazoles having the following structures: or , R 5C Selected from H and substituted or unsubstituted organic groups, optionally wherein R 5C It is H.

78. The PARP1 inhibitor compound according to claim 77, wherein ring C has the following structure: Optionally, among which R 5C It is H.

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

80. The PARP1 inhibitor compound according to claim 79, wherein the organic group is selected from F, Cl, nitrile group, methyl group and fluoromethyl group, optionally CF2H.

81. The PARP1 inhibitor compound according to claim 79 or claim 80, wherein exactly one R 5C It is an organic group.

82. The PARP1 inhibitor compound according to claim 81, wherein exactly one R 5C It is F.

83. The PARP1 inhibitor compound of claim 79, wherein, when present, each R 5C It is H.

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

85. The PARP1 inhibitor compound according to claim 84, wherein ring C has a structure selected from:

86. The PARP1 inhibitor compound according to any one of claims 1 to 84, wherein R 6 Selected from H, -F, -Cl, -Br, -I, -CN, -CONR 51 R 51 -NR 51 COR 52 -SO2NR 51 R 51 -NR 51 SO2R 52 -O-CR 52 R 52 R 52 -CR 52 R 52 NR 51 R 51 and any of the following structures: Where R 51 and R 52 Each is independently selected from H and substituted or unsubstituted organic groups, optionally wherein R 51 and R 52 Each is independently selected from H, halogen, optionally deuterated C1 to C3 alkyl and C1 to C3 haloalkyl.

87. The PARP1 inhibitor compound according to claim 86, wherein R 6 It is H.

88. The PARP1 inhibitor compound according to claim 86, 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 .

89. The PARP1 inhibitor compound according to claim 88, wherein R 6 It is F.

90. The PARP1 inhibitor compound according to claim 88, wherein R 6 It is Cl.

91. The PARP1 inhibitor compound according to claim 88, wherein R 6 It's CN.

92. The PARP1 inhibitor compound according to claim 86, 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, with any 4-, 5-, or 6-membered cyclic ether group.

93. The PARP1 inhibitor compound according to claim 92, wherein R 6 Selected from:

94. The PARP1 inhibitor compound according to claim 93, wherein R 6 Yes -CONHMe.

95. The PARP1 inhibitor compound according to claim 93, wherein R 6 yes .

96. The PARP1 inhibitor compound according to claim 93, wherein R 6 It is -C(O)NHEt.

97. The PARP1 inhibitor compound according to claim 93, wherein R 6 yes .

98. The PARP1 inhibitor compound according to claim 93, wherein R 6 yes .

99. The PARP1 inhibitor compound according to claim 93, wherein R 6 It is C(O)NHCH2CH2F.

100. The PARP1 inhibitor compound according to claim 93, wherein R 6 It is C(O)NHCH2CHF2.

101. The PARP1 inhibitor compound according to claim 93, wherein R 6 It is -C(O)NHCH2CF3.

102. The PARP1 inhibitor compound according to claim 93, wherein R 51 It is a tetrahydropyranyl group, wherein R is optionally a tetrahydropyranyl group. 6 yes: 。 103. The PARP1 inhibitor compound for the said use according to any one of claims 1 to 84, 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; halogenated groups, such as F; oxo groups; C1 to C3 alkyl groups; C1 to C3 haloalkyl groups, optionally C1 to C3 fluoroalkyl groups; and -NHR 63 , where R 63 It is an H or C1 to C3 alkyl group.

104. The PARP1 inhibitor compound for the said use according to claim 103, wherein R 6 Selected from: Optionally, R6 is: 。 105. The PARP1 inhibitor compound according to any of the preceding claims, wherein L has a structure selected from:

106. The PARP1 inhibitor compound according to any of the preceding claims, wherein rings E and B are in a cis configuration relative to ring A, optionally wherein group L is selected from:

107. The PARP1 inhibitor compound according to any one of claims 1 to 105, wherein rings E and B are in a trans configuration relative to ring A, and optionally wherein group L is selected from:

108. The PARP1 inhibitor compound according to any of the preceding claims, having the following structure: in: X D Selected from C and N; When X D When it is N: R D1 Selected from H, C1 to C3 alkyl groups and C1 to C3 haloalkyl groups; preferably methyl groups; and R D2 It does not exist; When X D When it is C: R D1 and R D2 Each is H; n is 1 or 2; R A1 and R A3 Each is H or R A1 and R A3 Together, they represent the -CH2- group of bridging ring A, provided that when n is 1, R A1 and R A3 Each is H; X Co and X Cm Each is selected from C and N, provided that X Co and X Cm At least one of them is N; When X Co When it is C, R Co It is H or a halogen, and optionally H or F; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or a halogen, and optionally H or F; When X Cm When it is N, R Cm It does not exist; R 6 Selected from -C(O)NHMe; -CN; and halogens, optionally F or Cl.

109. The PARP1 inhibitor compound according to any one of claims 1 to 107, having the following structure: in: X D It is C or N; When X D When it is C, R D4 Selected from H and halogens, with H being preferred; When X D When it is N, R D4 It does not exist; R D1 and R D2 Each is independently selected from H and halogens; n is 1 or 2; X A It is C or N; When X A When it is C: R A1 and R A3 Each is H or R A1 and R A3 Together, they represent the -CH2- group of bridging ring A, provided that when n is 1, R A1 and R A3 Each is H; When X A When it is N: R A1 It does not exist, and R A3 It is H; X Co and X Cm Each is selected from C and N, provided that X Co and X Cm At least one of them is N; When X Co When it is C, R Co It is H or a halogen, and optionally H or F; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or a halogen, and optionally H or F; When X Cm When it is N, R Cm It does not exist; R 6 Selected from -C(O)NHMe; -CN; and halogens, optionally F or Cl.

110. The PARP1 inhibitor compound according to any one of claims 1 to 107, having the following structure: in: Dashed lines indicate single or double bonds; X EB It is C or N; X D1 and X D2 Each is independently selected from C and N, provided that when X EB When it is N, X D1 It is C; R D1 and R D2 Each of them either does not exist independently or exists and is selected from H, halogens, methyl groups and halomethyl groups, such as CF3; R D3 Selected from H, halogens, methyl groups and halomethyl groups, such as CF3; n is 1 or 2; R A1 and R A3 Each is H or R A1 and R A3 Together, they represent the -CH2- group of bridging ring A, provided that when n is 1, R A1 and R A3 Each is H; X Co and X Cm Each is selected from C and N, provided that X Co and X Cm At least one of them is N; When X Co When it is C, R Co It is H or a halogen, and optionally H or F; When X Co When it is N, R Co It does not exist; When X Cm When it is C, R Cm It is H or a halogen, and optionally H or F; When X Cm When it is N, R Cm It does not exist; R 6 Selected from -C(O)NHMe; -CN; and halogens, optionally F or Cl.

111. The PARP1 inhibitor compound according to claim 1, having a structure selected from the following:

112. The PARP1 inhibitor compound according to any one of claims 1 to 107, wherein when R 1 R 3 R 4 R 5A (e.g. R) 5A1 R 5A2 R 5A3 ), R 5B R 5C R 6 R 7 R 8 R 51 and R 52 When one or more of the organic groups are substituted or unsubstituted, said or each substituted or unsubstituted organic group is independently selected from: deuterium; Halogens (such as -F, -Cl, -Br and -I); Nitrile group; Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl, and hexyl); Substituted or unsubstituted straight-chain or branched C1-C6 alkyl-aryl groups (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph ​​and -CH2CH2CH2CH2CH2CH2Ph); Substituted or unsubstituted straight-chain or branched C1-C6 haloalkyl groups (such as -CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3, -CBr3, -CCI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3 and -CH2CH2CI3); 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.

113. The PARP1 inhibitor compound for the said use according to claim 112, wherein R 5A (For example, R) 5A1 R 5A2 R 5A3 ), R 5B and R 5C Each of the following is either independent or selected from: H， deuterium, Halogens (such as -F, -Cl, -Br and -I; preferably F or Cl), Nitrile group, C1-C6 alkyl groups, C1-C6 haloalkyl groups (preferably CF3 or CHF2), Cyclopropyl group, -OH group, C1-C6 alcohol groups, C1-C7 amino carbonyl groups (such as -NH-CO-Me), -NH2 group, C1-C6 amino groups, and C1-C6 alkoxy groups; in, When a pair of R atoms are attached to different atoms 5A The group together forms a ring with the ring A atom and / or a pair of R atoms attached to different atoms. 5B The group together forms a ring with the ring B atom and / or a pair of R atoms attached to different atoms. 5C When the group forms a ring together with the ring C atom, the R 5A R 5B Or R 5C Group pairs represent alkyl groups such as -CH2- or -CH2CH2-; or -CH=CH-CH=CH-; or -NH-CO-NH-.

114. The PARP1 inhibitor compound according to any of the preceding claims, wherein it is in the following form: Separate enantiomers, or A mixture of two or more enantiomers, or A mixture of two or more diastereomers and / or epimers, or racemic mixture, or The tautomers of the compound.

115. The PARP1 inhibitor compound according to any of the preceding claims, which is selective for PARP1 relative to PARP2.

116. The PARP1 inhibitor compound according to any of the preceding claims, for use in medicine.

117. The PARP1 inhibitor compound of claim 116 for the stated purpose, for the treatment of cancer.

118. The PARP1 inhibitor compound for the stated use according to claim 117, wherein the cancer is selected from: eye cancer; brain cancer, such as glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, and astrocytoma; spinal cord cancer; kidney cancer; oral cancer; lip cancer; laryngeal cancer; oral cavity cancer; nasal cavity cancer; small intestine cancer; colon cancer; parathyroid cancer; gallbladder cancer; head and neck cancer; breast cancer; bone cancer; bile duct cancer; cervical cancer; heart cancer; subpharyngeal gland cancer; lung cancer; bronchial cancer; liver cancer; skin cancer; ureteral cancer; urethral cancer; testicular cancer; vaginal cancer; anal cancer; laryngeal gland cancer; ovarian cancer; thyroid cancer; esophageal cancer; nasopharyngeal gland cancer; pituitary cancer; salivary gland cancer; prostate cancer; pancreatic cancer; adrenal cancer; endometrial cancer; oral cancer; melanoma; neuroblastoma; gastric cancer; hemangioma; hemangioblastoma; pheochromocytoma; pancreatic cyst Swelling; Renal cell carcinoma; Wilms' tumor; Squamous cell carcinoma; Sarcoma; Osteosarcoma; Kaposi's sarcoma; Rhabdomyosarcoma; Hepatocellular carcinoma; PTEN hamartoma-tumor syndromes, such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome; Leukemia and lymphoma, such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia, large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary exudative lymphoma, AIDS-related lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer; Optionally, the cancer mentioned above is brain cancer or spinal cord cancer.

119. The PARP1 inhibitor compound for the said use according to claim 117 or claim 118, wherein the cancer is deficient in DNA damage response repair pathways, such as homologous recombination-dependent DNA double-strand break DNA repair activity.

120. A PARP1 inhibitor compound for the said use according to any one of claims 117 to 119, wherein said cancer is defective in BRCA1 and / or BRCA2 function.

121. The PARP1 inhibitor compound for the stated use according to any one of claims 117 to 120, administered in combination with a further agent for treating cancer; optionally, wherein the 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.

122. The PARP1 inhibitor compound for the stated use according to claim 121, wherein the additional agent is selected from the group consisting of: antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy; small molecule immunomodulators; and tumor microenvironment modulators.

123. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any one of claims 1 to 115.

124. The pharmaceutical composition of claim 123, further comprising pharmaceutically acceptable additives and / or excipients, and / or wherein the compound is in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative form of the compound.

125. The pharmaceutical composition of claim 123 or claim 124, 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.

126. The pharmaceutical composition of claim 125, wherein the additional agent comprises an immunotherapeutic agent selected from: antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9, or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy; small molecule immunomodulators; and tumor microenvironment modulators.

127. The pharmaceutical composition according to any one of claims 123 to 126, for treating cancer.

128. A pharmaceutical kit for treating cancer, the pharmaceutical kit comprising: a) A PARP1 inhibitor compound as defined in any one of claims 1 to 115; and b) Other medications used to treat cancer; The PARP1 inhibitor compound and the other agents are suitable for simultaneous, sequential, or separate administration; and Optionally, the additional agents used to treat cancer described herein are selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell scavengers, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone deprivation therapy, immunotherapeutic agents (such as those selected from antitumor vaccines; oncolytic viruses; immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3 and anti-GITR; pattern recognition receptor agonists such as STING, TLR-9 or RIG-I helicase agonists; IDO or TDO inhibitors; novel adjuvants; peptides; cytokines; chimeric antigen receptor T-cell therapy; small molecule immunomodulators; tumor microenvironment modulators), apoptosis-promoting agents, radioligand therapy, anti-angiogenic agents and cell cycle signaling inhibitors.

129. 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.

130. The method of claim 129, wherein the patient is an animal, preferably a mammal, optionally a human, dog, horse or cat; and preferably a human.

131. A method for synthesizing a PARP1 inhibitor compound as defined in any one of claims 1 to 115, 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.

132. The method of claim 131, wherein the first reactant comprises rings D, E and A, and the second reactant comprises a ring B precursor with a reactive group, the method comprising attaching ring A to the ring B precursor.

133. The method of claim 121, wherein the reactive precursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate ester.

134. The method according to any one of claims 131 to 133, wherein the reaction comprises alkylation, reductive amination or amide formation to form a group L.

135. The method of claim 131, wherein the first reactant comprises rings D, E, A, and Q. 1 And ring B, and the second reactant comprises a ring C derivative with a leaving group such as a halogen or sulfonate.

136. The method of claim 135, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, thereby forming a group L.

137. The method according to any one of claims 131 to 136, further comprising separating the structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography and / or chiral high-performance liquid chromatography.

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