PARP1 inhibitor compounds
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- DUKE STREET BIO LTD
- Filing Date
- 2024-07-17
- Publication Date
- 2026-08-06
Smart Images
Figure 2026526236000001_ABST
Abstract
Description
[Technical Field]
[0001] The present invention relates to PARP1 inhibitor compounds, and more particularly to PARP1 inhibitor compounds for use in pharmaceuticals. The inhibitors according to the present invention can be used in pharmaceutical compositions, in particular pharmaceutical compositions for treating cancer. The present invention also relates to methods for producing such inhibitors and therapeutic methods using such inhibitors. [Background technology]
[0002] The poly(ADP-ribose) polymerase (PARP) family consists of 17 PARP proteins that catalyze a post-translational process called polyADP-ribosylation, which involves the transfer of ADP-ribose to target proteins. Modification of target proteins by polyADP-ribosylation causes significant changes in their function. Therefore, PARPs play crucial roles in many cellular processes, including chromatin remodeling, transcription, replication, recombination, cell cycle progression, and DNA damage repair (Non-Patent Literature 1).
[0003] PARP1 and 2 are the most widely studied PARP enzymes, primarily for their role in DNA damage repair, particularly in the base excision repair (BER) process of single-strand breaks (SSBs) (Non-Patent Literature 2). PARP1 is activated by DNA damage breaks, and subsequent poly-ADP ribosylation of target proteins leads to the recruitment of additional factors to initiate DNA damage repair. Self-poly-ADP ribosylation of PARP triggers the dissociation of bound PARP from DNA, thereby allowing other DNA repair proteins to access and complete the repair of the damage. This highlights the important role that PARP plays in enabling cancer cells to repair DNA damage caused by exogenous agents such as radiation therapy and chemotherapy.
[0004] Inhibition of the PARP enzyme has been used as a strategy to selectively kill cancer cells with genetic defects in the complementary DNA damage repair pathway (Non-Patent Literature 3). This synthetic lethal approach has been successfully demonstrated in tumors with epigenetic modifications or harmful mutations in BRCA1 and BRCA2, two tumor suppressor proteins with functional redundancy involved in the repair of double-strand breaks (DSBs) by homologous recombination (HR) (Non-Patent Literature 4). Such tumors with homologous recombination repair deficiency (HRD) depend on PARP function for their survival. When PARP is inhibited in such tumors, DSB breaks are processed by error-prone alternative repair pathways, leading to genomic instability and cancer cell death.
[0005] By inhibiting PARP, inactivated PARP can be trapped at DNA damage sites. This causes replication forks to stall and subsequently disintegrate when they reach the trapped PARP site during the S phase, resulting in genotoxic DNA double-strand breaks. This PARP1-DNA trapping is thought to lead to the selective death of cancer cells with HRD (Non-Patent Literature 3).
[0006] This strategy has led to the approval of several PARP inhibitors for the treatment of cancers with HRD, including breast, ovarian, and prostate cancers with BRCA1 / 2 mutations, ovarian and prostate cancers with genomic effects due to HRD, and maintenance therapy for ovarian cancer in which platinum sensitivity acts as a surrogate for HRD (Non-Patent Literature 5).
[0007] In recent years, genomic instability, in the form of unrepaired DNA double-strand breaks or micronuclear collapse, has been shown to trigger activation of the innate immune system via cyclic GMP-AMP synthase (cGAS), a cytoplasmic DNA sensor, leading to the production of cyclic guanosine-phosphate-adenosine-phosphate (cGAMP) and the dimerization of interferon-stimulating factor (STING). STING then moves from the endoplasmic reticulum to the Golgi apparatus, where it recruits and activates tank-binding kinase 1 (TBK1). TBK1 phosphorylates interferon-regulating transcription factor 3 (IRF3), which induces the production of type I interferons and supports the induction of an adaptive immune response (Non-Patent Literature 6).
[0008] For example, activation of the STING pathway and antitumor immune response induced by PARP inhibitors have been demonstrated in multiple tumor models, providing a basis for using a combination of PARP inhibitors and immunotherapy to improve therapeutic efficacy (Non-Patent Literature 7). For instance, the PARP inhibitor olaparib has recently been shown to induce synthetic lethal effects in combination with synthetic cyclic dinucleotide STING agonists in DNA damage repair-deficient cancer cells and BRCA-deficient breast cancer models (Non-Patent Literature 8).
[0009] Overall, in various cell and animal models, the regulation of nucleic acid recognition pathways through multiple mechanisms has been shown to enhance antitumor effects, suggesting the potential of using PARP inhibitors to enhance the effects of immunotherapy and overcome resistance to immune checkpoint inhibitors. Numerous clinical trials combining PARP inhibitors with immunotherapy are underway (reviewed in Non-Patent Document 9).
[0010] In recent years, it has been shown that PARP1 binds to the Epstein-Barr virus (EBV) genome, and that PARP1 inhibitors alter EBV chromatin structure and latent gene expression (Non-Patent Literature 10). Therefore, PARP1 inhibitors may play a role in EBV-related cancers such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal cancer, and gastrointestinal cancers. Interestingly, EBV has also been shown to be a causative factor in multiple sclerosis (MS), where EBV infection significantly increases the risk of subsequent MS (Non-Patent Literature 11).
[0011] First-generation PARP inhibitors generally exhibit non-selective activity against PARP1 and PARP2. Clinical use of these molecules is associated with hematological toxicities such as anemia, neutropenia, and thrombocytopenia, and dose-limiting cytopenia restricts their use in combination with cytotoxic chemotherapy and other targeted agents (Non-Patent Literature 12). Evidence from preclinical mouse studies strongly suggests that PARP2 inhibition is a major factor in these hematological toxicities and that PARP2 is particularly involved in mouse erythropogenesis (Non-Patent Literature 13). Furthermore, PARP2 function has been shown to be non-essential for antitumor activity in HRD mouse cancer models (Non-Patent Literature 14). In summary, these data suggest an unmet medical need for the development of inhibitors that offer improved selectivity for PARP1 compared to PARP2 and other PARPs, thereby providing expanded therapeutic utility (1) as monotherapy and (2) in combination with other anticancer agents.
[0012] To date, two PARP1 selective inhibitors, AZD5305 and AZD9574, are in clinical development. AZD5305 is a potent PARP1 inhibitor and trapper with 500-fold selectivity over PARP2, and is reported to have lower off-target activity against secondary pharmacological targets than first-generation PARP inhibitors (Non-Patent Literature 15). Importantly, in rodent models, AZD5305 showed significantly lower hematological toxicity than first-generation PARP inhibitors, confirming the pathogenic role of PARP2 in reported hematological toxicity (Non-Patent Literature 16). [Prior art documents] [Non-patent literature]
[0013] [Non-Patent Document 1] Kamaletdinova, T. et al. Cell. 2019;8:1625. [Non-Patent Document 2] Ngoi, YL. et al. Cancer J. 2021;27:521-528. [Non-Patent Document 3] Farmer, H. et al. Nature. 2005;434:917-921. [Non-Patent Document 4] Lord, C.J. and Ashworth, A. Science. 2017;355:1152-1158. [Non-Patent Document 5] Fong, PC. et al. N. Engl. J. Med. 2009;361:123-134. [Non-Patent Document 6] Zhu,Y. et al. Mol. Cancer. 2019,18:152. [Non-Patent Document 7] Sen, T. et al. Cancer Discov. 2019;9:646-661. [Non-Patent Document 8] Pantelidou, C. et al. 2021: bioRxiv 2021.01.26.428337v1.
Non-licensed literature 9
Non-licensed literature 10
Non-licensed Document 11
Non-licensed Document 12
Non-licensed Document 13
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Non-licensed Document 15
Non-licensed Document 16
Non-licensed Document 17
Non-licensed Document 18
Non-licensed Document 19
Non-Patent Document 20
Summary of the Invention
Problems to be Solved by the Invention
[0014] In view of the above, one object of the present invention is to provide a PARP1 inhibitor, particularly a PARP1 inhibitor for use in medicine. A further object is to provide a pharmaceutical composition comprising such an inhibitor, particularly a compound and a pharmaceutical composition for treating cancer. It is also an object to provide a method for synthesizing the said compound.
[0015] [Summary] The present disclosure provides a PARP1 inhibitor compound for use in medicine. The PARP1 inhibitor compound has the following structure:
Chemical Formula
[0016] According to another aspect, there is provided a pharmaceutical composition comprising a PARP1 inhibitor compound as defined in the present disclosure.
[0017] According to a further aspect, there is provided a pharmaceutical kit for treating cancer. The pharmaceutical kit comprises a PARP inhibitor compound as defined in the present disclosure; and a further agent for treating cancer. The compound and the further agent are suitable for being administered simultaneously, sequentially, or separately.
[0018] According to another aspect, there is provided a method for treating a disease and / or condition and / or disorder, the method comprising administering to a patient a compound, composition, or kit as defined in the present disclosure.
[0019] According to yet another aspect, there is provided a compound having the following structure:
Chemical formula
Chemical formula
[0020] Typically, in these compounds, Z 3 If N, then the corresponding R 1 It does not exist; Z 3 If C, then the corresponding R 1 It exists.
[0021] Optionally, R 5C2о This is a halogen such as H or, for example, F.
[0022] In another aspect, a method for synthesizing a PARP1 inhibitor compound provided in this disclosure is provided. The method comprises a reaction between a first reactant comprising a ring E having a first portion of group L and a second reactant comprising the remaining portion of group L, thereby forming the PARP1 inhibitor compound.
[0023] Specific and more concrete aspects of the present invention are defined in the dependent claims.
[0024] This summary is provided to introduce, in simplified form, some concepts that will be further described in the detailed description below. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. Further, the claimed subject matter is not limited to embodiments that solve some or all of the disadvantages described herein.
[0025] [Detailed Description] general definition In the present disclosure, the verb "comprising" is used as an abbreviation meaning "including, or consisting of". In other words, although the verb "comprising" is intended to be an open-ended term, its replacement with the closed-ended term "consisting of" is explicitly contemplated, particularly when used in relation to chemical compositions.
[0026] It will be understood that some of the compounds disclosed in the present disclosure may be ionizable, i.e., some compounds may be weak acids, weak bases, or ampholytes. The representation of the non-ionized form of an ionizable compound is intended to encompass the corresponding ionized form. An ionizable compound may be in its non-ionized form or in the form of a pharmaceutically acceptable salt.
[0027] A compound is considered a PARP1 inhibitor if, compared to the same process in its absence, its presence prevents or reduces the ability of immobilized PARP1 to undergo auto-poly-ADP-ribosylation (autoPARylation) after incubation with biotinylated-NAD+. Typically, a compound is considered a PARP1 inhibitor if its IC50 < 10 μM in a suitable assay. A suitable assay may be performed using an assay solution containing 2 nM PARP1 and 2 μM biotin-NAD+ in an assay buffer of 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v). Poly-ADP-ribosylation (PARylation) may be performed at room temperature for 2 hours and may be detected using a readout from a dissociation-enhanced lantanide fluorescence immunoassay (DELFIA). Particularly suitable assays are described in the following examples. In the PARP1 inhibitor assay, the compound preferably has an IC50 < 1 μM, more preferably < 100 nM, and most preferably < 10 nM.
[0028] A compound is considered a selective PARP1 inhibitor if its presence can displace or reduce the ability of a high-affinity Cy5 fluorescent dye-labeled chemical probe to bind to PARP1, while displacing the ability of the same chemical probe to bind to PARP2 by at least a tenfold decrease in activity. Typically, a compound is considered a selective PARP1 inhibitor if it exhibits an IC50 < 10 μM for PARP1 in this assay and has at least a tenfold selectivity for PARP2. Such a suitable assay may be performed at room temperature for 1 hour using 10 nM PARP1 or PARP2, a Tb-cryptate antibody, and a PARP1 / 2-binding probe in assay buffer consisting of 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), and 0.02% Tween (v / v). Probe binding displacement may be detected using homogeneous time-resolved fluorescence (HTRF). Particularly suitable assays are described in the following examples. The selectivity for PARP1 over PARP2 is preferably at least 50 times, and more preferably at least 100 times.
[0029] A compound is considered a selective PARP1 inhibitor if, in a NanoBRET assay demonstrating engagement with a cellular target, it exhibits an IC50 < 10 μM for PARP1 and at least 10-fold selectivity for PARP2. These assays are based on bioluminescence resonance energy transfer (BRET) between a nano-luc labeled protein (e.g., PARP1 or PARP2) and a fluorescent group on a high-affinity NAD+ competitively binding probe. Such cell probe substitution assays can be used to measure the affinity and selectivity of inhibitors for PARP1 and PARP2. Particularly suitable assays are described in the examples below. The selectivity for PARP1 over PARP2 is preferably at least 50-fold, and more preferably at least 100-fold.
[0030] In this disclosure, the expression “substituted or unsubstituted organic group” is used as a synonym for “substituent.” Examples of organic groups are described in more detail below in this disclosure.
[0031] When an organic group is said to be "substituted," it means that the hydrogen atom of that organic group has been replaced by another organic group.
[0032] In structural formulas, dotted lines represent covalent bonds of a non-zero degree, most typically single or double bonds. As is understood, systems with multiple double bonds may be conjugated or aromatic systems.
[0033] Unless the stereochemistry of a particular bond is explicitly stated, all formulas in this disclosure are expressed in nonstereoisomer form and are intended to represent all possible stereoisomers of a particular structure. This includes all possible isolated enantiomers corresponding to the formula, all possible mixtures of enantiomers corresponding to the formula, all possible mixtures of diastereomers corresponding to the formula, all possible mixtures of epimers corresponding to the formula, and all possible racemic mixtures corresponding to the formula. Furthermore, all formulas in this disclosure are intended to represent all equivalent tautomers of the corresponding formula.
[0034] In this disclosure, the term "aliphatic ring" is used in a broad sense to mean a non-aromatic ring. The aliphatic ring may be a carbocyclic or heterocyclic ring, and may be substituted or unsubstituted.
[0035] Numbering of compounds Some of the compounds provided in this disclosure are enantiomers or diastereomers. If a compound number is followed by a suffix, the suffix indicates stereochemistry. A compound number without a suffix refers to a compound having the given structural formula without specifying its stereochemistry.
[0036] The suffix "rac" in compound numbers indicates a racemic mixture.
[0037] The suffix "a" in the compound number indicates the enantiomer that elutes as the first fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography (SFC) using a chiral column.
[0038] The "b" suffix in compound numbers indicates the enantiomer that elutes as the second fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography (SFC) using a chiral column.
[0039] According to this disclosure, the following structure: [ka] Typically, it has the following structure: [ka] A PARP1 inhibitor compound having the following is provided, where ring B is optional. Various aspects of this general structure are described in detail below.
[0040] substituent "R 5 The expression "base" is generally used in R 5A , R 5B , and R 5C It means base. 5A The group is R bonded to ring A. 5 It is a base, and the same applies hereafter. In some of the formulas shown in this disclosure, R 5 A more specific identification code is used for the base. For example, "R 5A1 The identification code for " is R 5A This identifies a subset of the original.
[0041] In the compounds provided in this disclosure, R 1 , R 2 , and R 5Some of the groups may be absent. In the structural formulas shown herein, the dotted lines represent covalent bonds of any non-zero bond order. As is understood, the number of ring bonds and substituents is Z 1 , Z 2 , Z 3 , X 1 , and, X 2 Atoms are selected to maintain a stable valency. Maintaining a stable valency means that an atom has its normal (typically most common) valency in an organic compound (i.e., 2 for oxygen, 2 or 6 for sulfur, 3 or 4 for nitrogen, and 4 for carbon).
[0042] X 1 , X 2 , Z 1 , Z 2u , Z 2l or Z 3 If the atom is N, it most preferably has a valency of 3. 1 , X 2 , Z 1 , Z 2u , Z 2l , or Z 3 Compounds in which the atom is tetravalent nitrogen are also conceivable. Tetravalent nitrogen carries a positive charge, and such compounds may have counterions.
[0043] Preferably, the PARP1 inhibitor compound contains at most one tetravalent nitrogen atom, and more preferably, does not contain any tetravalent nitrogen.
[0044] Each R 5 The base may or may not exist. Also, each R 5 The bases may be the same or different. To avoid ambiguity, R 5 If the number of units can vary depending on the selection of the corresponding X units, the following conditions typically apply: i)X 1 If N, then the corresponding R 5 It does not exist. ii)X 1 If is C and is double-bonded to an adjacent ring atom, then the corresponding R5 does not exist. iii) X 1 is C and is not double-bonded to an adjacent ring atom, the corresponding R 5 exists. iv) X 2 is O, the corresponding R 5 / R 6 groups do not both exist. v) X 2 is S, the corresponding R 5 / R 6 groups do not both exist, or both are selected from =O and =NR 10 . Here, R 10 is H or a substituted or unsubstituted organic group, preferably a C1-C3 alkyl group. vi) X 2 is N and is double-bonded to an adjacent ring atom, the corresponding R 5 / R 6 does not exist. vii) X 2 is N and is not double-bonded to an adjacent ring atom, the corresponding R 5 / R 6 group exists exactly one. viii) X 2 is C and is double-bonded to an adjacent ring atom, the corresponding R 5 / R 6 group exists exactly one. ix) X 2 is C and is not double-bonded to an adjacent ring atom, both of the corresponding R 5 groups, or both of the corresponding R 5 group and R 6 group both exist.
[0045] Substituents (i.e., R groups; R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8The substituents are not particularly limited, as long as they do not interfere with the expression of the PARP1 inhibitory function. The substituents are selected from H and organic groups. Therefore, in both the foregoing and following descriptions, the terms “substituents” and “organic groups” are not particularly limited and may be any functional group or any atom, in particular any functional group or atom common in organic chemistry.
[0046] Unless explicitly stated otherwise, this is undesirable in most embodiments, but any R 5 Base or R 6 The group is any other R on adjacent and / or nearby atoms. 5 Base or R 6 The group may form a ring. Therefore, the following substituents may together form a ring: a R 5A and other R 5A , a certain R 5B and other R 5B , a certain R 5C and other R 5C , or a certain R 5C and R 6 In the context of this disclosure, adjacent and / or nearby atoms may mean other atoms directly bonded to an atom (adjacent), two atoms with only one atom between them (proximal), or two atoms that are sterically close enough to form a ring (proximal). 5 / R 6 It is preferable that the groups do not come together to form a ring, but this is not excluded.
[0047] One R on a certain atom 5 or R 6 A group, or two R groups on the same atom 5 / R 6 The group may form a double bond with that atom. Therefore, one R 5 Base or R 6 A group, or two R groups bonded to the same atom 5 / R 6The groups may combine to form a C=O group or a C=C(R')² group (where each R' group is either identical or distinct, and is either H or an organic group, preferably H or a linear or branched C1-C6 alkyl group). This is more typical when multiple R groups are bonded to a single C atom so as to combine to form a C=O group or a C=C(R')² group. Thus, in some cases, X is C. 2 The group may also have an O group.
[0048] The terms "substituent" and "organic group" may have any of the following meanings:
[0049] The organic group may comprise one or more atoms from any of groups IIIA, IVA, VA, VIA, or VIIA of the periodic table, for example, 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), where R is a linear or branched lower hydrocarbon (containing 1 to 6 carbon atoms) or a linear or branched higher hydrocarbon (containing 7 or more carbon atoms, for example, 7 to 40 carbon atoms).
[0050] The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may be linear, branched, or cyclic. Independently, the hydrocarbon group may comprise an aliphatic group or an aromatic group. Also independently, the hydrocarbon group may comprise a saturated group or an unsaturated group.
[0051] If the hydrocarbon has an unsaturated group, it may have one or more alkene functionalities and / or one or more alkyne functionalities. If the hydrocarbon has a linear or branched group, it may have one or more primary, secondary, and / or tertiary alkyl groups.
[0052] If the hydrocarbon comprises a cyclic group, it may also comprise an aromatic ring, an aromatic ring, an aliphatic ring, a heterocycle, and / or fused cyclic derivatives of these groups. The ring may be fully saturated, partially saturated, or completely unsaturated.Therefore, the cyclic groups are benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, fluorantene, acephenanthrylene, azulene, heptalene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, oxetane, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole Isooxazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiolan, 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, thiopyran, 2-azathiopyran, 3-azathiopyran, 4-azathiopyran N, Chian, Indole, Indazole, Benzimidazole, 4-Azaindole, 5-Azaindole, 6-Azaindole, 7-Azaindole, Isoindole, 4-Azaisoindole, 5-Azaisoindole, 6-Azaisoindole, 7-Azaisoindole, Indoridine, 1-Azaindinidine, 2-Azaindinidine, 3-Azaindinidine, 5-Azaindinidine, 6-Azaindinidine, 7-Azaindinidine, 8-Azaindinidine, 9-Azaindinidine, Purine, Carbazole, Cal The compounds may include borin, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, cinnoline, quinazoline, quinoxaline, 5-azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7-azaisoquinoline, pteridine, chromene, isochromene, acridine, phenanthridine, perimidine, phenanthroline, phenoxazine, xanthene, phenoxanthiine, and / or thianthlene, as well as positional isomers of the above groups. These groups may generally be bonded at any point on the group, and may be bonded to a heteroatom or a carbon atom.In some examples, specific binding sites are preferred, such as 1-yl and 2-yl, and these are explicitly specified where appropriate. These definitions include all tautomer ring forms. For example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole, and 3H-pyrrole.
[0053] The number of carbon atoms in a hydrocarbon group is not particularly limited, but it is preferable that the hydrocarbon group has 1 to 40 carbon atoms. Therefore, the hydrocarbon group may be a lower hydrocarbon (1 to 6 carbon atoms) or a higher hydrocarbon (7 or more carbon atoms, for example, 7 to 40 carbon atoms). The lower hydrocarbon group may be a methyl group, ethyl group, propyl group, butyl group, pentyl group, or hexyl group, or positional isomers of these groups, for example, isopropyl group, isobutyl group, tert-butyl group, etc. The number of atoms in the ring of a cyclic group is not particularly limited, but it is preferable that the ring of a cyclic group has 3 to 10 atoms, for example, 3, 4, 5, 6, 7, 8, 9, or 10 atoms.
[0054] The group comprising the heteroatoms described above may, like the other groups defined above, comprise one or more heteroatoms from any of the groups IIIA, IVA, VA, VIA, or VIIA of the periodic table, such as B, Si, N, P, O, S atoms, or halogen atoms (e.g., F, Cl, Br, or I). Therefore, the substituent may comprise one or more of the 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 groups, sulfonic acid groups, sulfonyl groups, and phosphate groups. The substituent may also comprise derivatives of these groups, such as carboxylic acid anhydrides and carboxylic acid halides.
[0055] Furthermore, any substituent may comprise two or more combinations of substituents and / or functional groups as defined above.
[0056] Typically, R 1 , R 2 , R3 , R 5A (For example, R 5A1 , R 5A2 , R 5A3 ), R 5B (For example, R 5B1 , R 5B2 , R 5B3 ), R 5C (For example, R 5C1 ), R 6 , R 7 , R 51 , and R 52 If one or more of the organic groups are substituted or unsubstituted, then the substituted or unsubstituted organic groups are independently selected from the following: -deuterium; - Halogens (e.g., -F, -Cl, -Br, and -I); - Nitrile group; - Substituted or unsubstituted linear or branched C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, and hexyl groups); - Substituted or unsubstituted linear or branched C1-C6 alkyl-aryl groups (e.g., -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, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph, etc.); - Substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (e.g., -CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3, -CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3, and -CH2CCI3, etc.); --NH2, or substituted or unsubstituted linear or branched primary, secondary, or tertiary C1-C6 amine groups (e.g., -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, etc.); - Substituted or unsubstituted amino-aryl groups (e.g., -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, -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, and -NH-2,(3,4,5 or 6)Bu2-Ph, etc.); - Substituted or unsubstituted cyclic amine or amide groups (e.g., pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl, etc.); - Substituted or unsubstituted cyclic C3-C8 alkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); --OH group; - Substituted or unsubstituted linear or branched C1-C6 alcohol groups (e.g., -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, etc.); - Substituted or unsubstituted linear or branched C1-C6 carboxylic acid groups (e.g., -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH, etc.); - Substituted or unsubstituted linear or branched carbonyl groups (e.g., -(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)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methylpiperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2, etc.); - Substituted or unsubstituted linear or branched C1-C6 carboxylic acid ester groups (e.g., -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe, etc.); - Substituted or unsubstituted linear or branched C1-C6 amide groups (e.g., -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt, etc.); - Substituted or unsubstituted linear or branched C1-C7 aminocarbonyl groups (e.g., -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, and -NMe-CO-Ph, etc.); - Substituted or unsubstituted linear or branched C1-C7 alkoxy or aryloxy groups (e.g., -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, etc.); - Substituted or unsubstituted linear or branched aminoalkoxy groups (e.g., -OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt, and -OCH2CH2NEt2, etc.); - Substituted or unsubstituted sulfonyl groups (e.g., -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-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe, etc.); - Substituted or unsubstituted aminosulfonyl groups (e.g., -NHSO2Me, -NHSO2Et, -NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2,3 or 4)-F-Ph, -NHSO2-cyclopropyl, and -NHSO2CH2CH2OCH3, etc.); - Substituted or unsubstituted aromatic groups (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)-E t2-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 (e.g., pyrrole-1-yl, pyrrole-2-yl, pyrrole-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-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl) 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrimidine-6-yl, pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl, 2-azapiperidine-3-yl 2-Azapiperidine-4-yl, 3-Azapiperidine-1-yl, 3-Azapiperidine-2-yl, 3-Azapiperidine-4-yl, 3-Azapiperidine-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 -Azapiran-6-yl, 4-Azapiran-2-yl, 4-Azapiran-3-yl, 4-Azapiran-4-yl, 4-Azapiran-5-yl, 4-Azapiran-6-yl, Oxetane-2-yl, Oxetane-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, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophene-2-yl, thiophene-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2 -Azathiopyran-3-yl, 2-Azathiopyran-4-yl, 2-Azathiopyran-5-yl, 2-Azathiopyran-6-yl, 3-Azathiopyran-2-yl, 3-Azathiopyran-4-yl, 3-Azathiopyran-5-yl, 3-Azathiopyran-6-yl, 4-Azathiopyran-2-yl, 4-Azathiopyran-3-yl, 4-Azathiopyran-4-yl, 4-Azathiopyran-5-yl, 4-Azathiopyran-6-yl, Thioran-2-yl, Thioran-3-yl, Chian-2-yl, Chian-3-yl (e.g., thian-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-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 tetrazole-1-yl, tetrazole-2-yl, and tetrazole-5-yl).
[0057] A pair of R atoms bonded to different atoms 5AThe groups may come together to form a ring with the atoms that make up ring A.
[0058] A pair of R atoms bonded to different atoms 5B The groups may come together to form a ring with the atoms that make up ring B.
[0059] A pair of R atoms bonded to different atoms 5C The groups may come together to form a ring with the atoms that make up the ring C.
[0060] R bonded to different atoms 5C Base and R 6 The groups may come together to form a ring with the atoms that make up the ring C.
[0061] R 5 Group(R 5A1 , R 5A2 , and R 5A3 R such as 5A ;R 5B ; or, R 5C1 R such as 5C ) may be absent or selected from the following: -hydrogen; -deuterium; -Halogens (e.g., -F, -Cl, -Br, and -I; preferably F or Cl); - Nitrile group; - Substituted or unsubstituted C1-C6 alkyl groups; - Substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (preferably CF3 or CHF2); -Cyclopropyl group; --OH group; - Substituted or unsubstituted linear or branched C1-C6 alcohol groups; - Substituted or unsubstituted linear or branched C1-C7 aminocarbonyl groups (e.g., -NH-CO-Me); --NH2 group; - Substituted or unsubstituted C1-C6 amino groups; - A substituted or unsubstituted C1-C6 alkoxy group.
[0062] A pair of R atoms bonded to different atoms 5A When the groups come together to form a ring with the atoms that make up ring A; and / or when a pair of R groups bonded to different atoms 5B When the groups come together to form a ring with the atoms that make up ring B; and / or when a pair of R groups bonded to different atoms 5C When the groups come together and form a ring with the atoms that make up the ring C, the pair of R 5A Group, R 5B Base, or R 5C Each of the groups independently comprises -CH2- or -CH2CH2-, or the pair of groups together comprises -CH=CH-CH=CH- or -NH-CO-NH-.
[0063] Rings D and E The rings D and E of the compound provided in this disclosure (sometimes collectively referred to as the "head group") have the following structures: [ka] (In the formula, Each R 1 These are independently either absent or selected from H and substituted or unsubstituted organic groups; R 2 It is either absent or selected from H and substituted or unsubstituted organic groups; R 3 This is selected from H and substituted or unsubstituted organic groups; Z 1 is C or N; Z 2u and Z 2l These are selected from C and N, respectively; however, Z 2u and Z 2l Provided that at least one of them is N; each Z 3 (These are independently selected from C and N.)
[0064] Z 3 If C, then the corresponding R 1 It exists. Z3 If N, then the corresponding R 1 It is preferable that it does not exist.
[0065] Two or more R 1 In compounds containing the group, each R 1 These are selected independently.
[0066] Preferred R 1 Examples of the basis include: -hydrogen; -C1-C6 alkyl, aminoalkyl, alkoxy, or haloalkyl groups; -C3~C6 cycloalkyl groups; -halogen group; - Nitrile group; and, -below: [ka] (In the formula, R 22 R is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and halogen (optionally F); each R 23 R is independently selected from H and substituted or unsubstituted organic groups; here, optionally, each R 23 The group is independently selected from H, C1-C6 alkyl, aminoalkyl, alkoxy, or haloalkyl groups, and halogen groups; further optionally, at least one R 23 (is H.)
[0067] Preferably, each R 1 Independently, the following are present, or selected from H; halogen, optionally Cl or F; C1-C3 alkyl group, optionally methyl group; C1-C3 haloalkyl group, optionally halomethyl group (-CH2F, -CHF2, or -CF3), or haloethyl group (e.g., -CH2CF3); and nitrile group.
[0068] Comfortable, each R 1These are independently absent or selected from H, Cl, F, methyl group, CF3, and nitrile group. Typically, at least one R 1 H is H.
[0069] Optionally, R is a substituted or unsubstituted organic group. 1 There is one or fewer other R 1 Each of them is either H or does not exist.
[0070] Z 1 It could also be C. 1 If C, then R 2 The following may be selected: H; halogen, optionally F or Cl; C1-C3 alkyl, optionally isopropyl or cyclopropyl; C1-C3 haloalkyl, optionally -CH2F, -CHF2, -CF3, -CH2CF3, or -CH2CH2F; C1-C3 alcohol, optionally -CH2CH2OH; C1-C3 alkoxy, optionally methoxy, methoxymethyl, or methoxyethyl; or C1-C3 aminoalkyl. In particular, R 2 H may also be used.
[0071] Alternatively, Z 1 R may be N. In such compounds, 2 It does not exist.
[0072] R 3 The group may be selected from H, C1-C3 alkyl groups, and C1-C3 haloalkyl groups, but H is most preferred.
[0073] each Z 3 The atoms are independently selected from C and N. Optionally, at least two Z atoms are selected. 3 The atom is C.
[0074] Typically, Z 2u and Z 2l Exactly one of them is C.
[0075] Z 2u may be C, and Z2l may be N, and as a result, the PARP1 inhibitor compound may have the following structure. [ka]
[0076] Optionally, Z is N. 3 The number of atoms is one or less. For example, the PARP1 inhibitor compound may have a structure selected from the following: [ka]
[0077] More preferably, the PARP1 inhibitor compound may have a structure selected from the following: [ka]
[0078] According to other possibilities, the PARP1 inhibitor compound may have the following structure. [ka]
[0079] Alternatively, Z 2u may be N, and Z 2l is also C, and as a result, the PARP1 inhibitor compound may have the following structure. [ka]
[0080] In such an example, arbitrarily, Z is N. 3 The atom is one or less. The PARP1 inhibitor compound may have a structure selected from the following. [ka]
[0081] More specific examples of PARP1 inhibitor compounds include those having structures selected from the following: [ka]
[0082] Rings A, B, and C - General Matters - The group L of the PARP1 inhibitor compound has the following structure: [ka] Typically, it has the following structure: [ka] It has.
[0083] An optional group b is most preferably present. In such an example, group L has the following structure: [ka] Typically, it has the following structure: [ka] It has.
[0084] The variable atoms that are part of the framework of rings A, B, and C are collectively referred to as "X" atoms. 1 The atoms are independently selected from C and N. 2 The atoms are independently selected from C, N, O, and S, with C and N being particularly preferred.
[0085] X 1 and X 2 Each atom is selected independently. One or more, most preferably all, of the following conditions may apply: Typically, each ring has at least one X group that is carbon. If rings A, B, or C are four-membered rings, they typically contain at most one heteroatom. If rings A, B, or C are five-membered or six-membered rings, they typically contain at most three heteroatoms, and optionally at most two. Each of rings A, B, and C may individually contain up to three heteroatoms. -The aforementioned compounds are typically not quaternary ammonium compounds. X is N. 1 Atoms are typically R 5 It has no base. X is N. 2 Atoms typically have at most one R 5 It has a base. -The aforementioned compound is X 2 It does not have OO bonds, SS bonds, or SO bonds between atoms. 2 If is O or S, the adjacent ring atom is C or N. More generally, the compound may not have OO bonds or SS bonds.
[0086] The following provides a more detailed explanation of each part of the L group.
[0087] Ring A The ring A of the PARP1 inhibitor compound has the following general structure. [ka]
[0088] X 1AE Linker Q AE X is bonded to ring E via 1 It is an atom. X 2A X is part of ring A. 2 It refers to an atom.
[0089] Each R 5A R is independently selected from those that are absent or from H and substituted or unsubstituted organic groups. 5A1 X 1AE R is linked to5A This refers to R. 5A2 X 2A R that binds to atoms 5A It refers to.
[0090] X 1AE This can be C or N, and is preferably C.
[0091] Q AE The following: [ka] And if u=0, then X 1AE C is C.
[0092] X 1AE If R is N, 5A1 They typically do not exist.
[0093] Rings A and B are not typically linked via NN bonds. Therefore, Q AB The following: [ka] If this is the case, then t is 1 or greater.
[0094] each X 2A The atoms are independently selected from C, N, O, and S, but C and N are particularly preferred. 2A The atoms are selected such that ring A does not contain OO bonds, OS bonds, and SS bonds. Optionally, at least one X 2A The atom is C. Particularly preferably, all X 2A The atom is C.
[0095] Ring A is a 4, 5, 6, 7, or 8-membered ring. Therefore, n is an integer between 0 and 6; m is an integer between 0 and 6; and the sum of n and m is an integer between 2 and 6.
[0096] In particular, ring A may be a 4, 5, or 6-membered ring, and preferably a 5 or 6-membered ring. In other words, n+m may be an integer in the range of 2 to 4.
[0097] Preferably, both n and m are 1 or greater.
[0098] Ring A is such that R exists 5A Depending on the number of groups, it may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring, but a saturated or unsaturated non-aromatic ring is preferred.
[0099] In particular, ring A may be a saturated 5-membered ring (n+m=3).
[0100] In most embodiments, there are two or fewer R 5A The group is an organic group, either substituted or unsubstituted. Most typically, it has one or fewer R groups. 5A The group is an organic group that is either substituted or unsubstituted.
[0101] Generally, R 5A If a base exists, its R 5A The base is preferably H.
[0102] Ring A may be a biring ring, and in such a biring ring there are two R 5A The groups are condensed with each other. The biring ring may also be a bridged biring ring.
[0103] For example, ring A may be a bridged biring ring having the following structure: [ka] (In the formula, x is an integer between 0 and 1 to 6, and y is an integer between 0 and 1 to 6; provided that the sum of x and y is (n-1); i is an integer between 0 and 1 to 6, and j is an integer between 0 and 1 to 6; provided that the sum of i and j is (m-1); h is an integer between 1 and 3; n is an integer between 1 and 6, and m is an integer between 1 and 6; provided that the sum of n and m is an integer between 2 and 6.
[0104] Alternatively, ring A may be a bridging bicyclic ring having the following structure: [ka] (In the formula, i is an integer between 0 and 1 through 6, and j is an integer between 0 and 1 through 6; provided that the sum of i and j is (n-1); h is an integer between 1 and 3; n is an integer between 1 and 6, and m is 0 or an integer between 1 and 6; provided that the sum of n and m is an integer between 2 and 6.
[0105] The value of h may be appropriately selected based on the values of i and m. Typically, h is 1 or 2.
[0106] For example, ring A may be a bridging five-membered ring where h is 1, i is 1, j is 0, and m is 1.
[0107] Preferably, it is a bridging bicyclic ring A having the following structure: [ka]
[0108] The most preferred bridging bicyclic ring A has the following structure: [ka]
[0109] Ring A may comprise a substituted or unsubstituted seven-membered ring, and may optionally comprise a homopiperidine. For example, ring A may be a homopiperidine having a structure selected from the following: [ka]
[0110] Alternatively, ring A may be a substituted or unsubstituted six-membered aliphatic (i.e., substituted or unsubstituted non-aromatic) heterocycle. For example, ring A may have a structure selected from the following: [ka] [ka]
[0111] In further examples, ring A may be a substituted or unsubstituted five-membered aliphatic heteroring. Examples of five-membered aliphatic heterorings include: [ka]
[0112] In other examples, ring A is a five-membered aromatic ring, optionally pyrrole or pyrazole. Examples of preferred five-membered aromatic rings include: [ka]
[0113] According to other possibilities, ring A may be a substituted or unsubstituted azetidine, for example, an azetidine having the following structure: [ka]
[0114] More specific examples of preferred ring A structures include: [ka]
[0115] In particular, ring A may have a structure selected from the following: [ka]
[0116] The preferred structure of ring A is as follows: [ka]
[0117] In particular, ring A may be as follows: [ka]
[0118] Ring B The PARP1 inhibitor compound optionally contains ring B. Although compounds without ring B are conceivable, ring B is usually present. When ring B is present, it has the following structure: [ka]
[0119] X 1BA Linker Q AB X is bonded to ring A via 1 It is an atom. X 1BC Linker Q BC X is bonded to ring C via 1 It is an atom. X 1BA and X 1BC Each of these is independently selected from C and N.
[0120] X 2B X is part of ring B. 2 Refers to atoms. Each X 2B The atoms are independently selected from C, N, O, and S, but C and N are particularly preferred. 2B The atoms are selected such that ring B does not contain OO, OS, or SS bonds. Optionally, at least one X 2B The atom is C. Particularly preferably, all X 2BThe atom is C.
[0121] Each R 5B R is independently selected from those that are absent or from H and substituted or unsubstituted organic groups. 5B1 X 1BA R is linked to 5B This refers to R. 5B2 X 2B R that binds to atoms 5B This refers to R. 5B3 X 1BC R is linked to 5B It refers to.
[0122] X 1BA If R is N, 5B1 It does not exist.
[0123] X 1BC If R is N, 5B3 It does not exist.
[0124] Rings A and B are typically not linked via NN bonds. 1BA If N and Q AB The following: [ka] If this is the case, then t is 1 or greater, and u is 1 or greater.
[0125] Rings B and C are typically not linked via NN bonds. 1BC If N and Q BC The following: [ka] If this is the case, then t is 1 or greater.
[0126] X 1BC X is N and is part of the ring C defined below. 1CB If Q is N, BC It exists.
[0127] X 1BAIt is preferable that X is C. 1BA It may be C, X 1BC may be N, and as a result, ring B may have the following structure: [ka]
[0128] Base L may have the following structure: [ka]
[0129] Ring B is a 4, 5, 6, 7, or 8-membered ring. Therefore, p is 0 or an integer between 1 and 6; q is 0 or an integer between 1 and 6; and the sum of p and q is an integer between 2 and 6.
[0130] Preferably, each of p and q is 1 or greater.
[0131] Generally, ring B is preferably a 5- or 6-membered ring. In other words, the sum of p and q may be 3 or 4. More preferably, ring B is a 6-membered ring, where p=2 and q=2.
[0132] Ring B is such that R exists 5B Depending on the number of groups, it may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring, but a saturated or unsaturated non-aromatic ring is preferred.
[0133] R 5B If it exists, then R 5B is preferably H. In most cases, there is one or fewer R 5B These are substituted or unsubstituted organic groups.
[0134] Similar to what was described for ring A, the two R's 5B The groups may condense, and ring B may be a bridged bicyclic ring. Most typically, ring B is not a bridged bicyclic ring.
[0135] Ring B may be a 7-membered saturated hetero ring and may optionally have the following structure: [ka] (In the formula, Each R 5B Each R is independently selected from H and substituted or unsubstituted organic groups. 5B is H; X 1BA C is R 5B1 is selected from H and substituted or unsubstituted organic groups, and is optionally H; or X 1BA is N, and R 5B1 It does not exist; and, X 1BC C is R 5B3 is selected from H and substituted or unsubstituted organic groups; or X 1BC is N, and R 5B3 It does not exist.
[0136] Alternatively, ring B may be a 6-membered saturated heteroring and may optionally have the following structure: [ka] (In the formula, Each R 5B Each R is independently selected from H and substituted or unsubstituted organic groups. 5B is H; X 1BA C is R 5B1 is selected from H and substituted or unsubstituted organic groups, and is optionally H; or X 1BA is N, and R 5B1 It does not exist; and, X 1BC C is R 5B3 is selected from H and substituted or unsubstituted organic groups; or X 1BC is N, and R 5B3 It does not exist.
[0137] In other examples, ring B is a 5-membered saturated heterocycle and may optionally have the following structure: [ka] (In the formula, Each R 5B Each R is independently selected from H and substituted or unsubstituted organic groups. 5B is H; X 1BA C is R 5B1 is selected from H and substituted or unsubstituted organic groups, and is optionally H; or X 1BA is N, and R 5B1 It does not exist; and, X 1BC C is R 5B3 is selected from H and substituted or unsubstituted organic groups; or X 1BC is N, and R 5B3 It does not exist.
[0138] In the above example of ring B which is a 5, 6, and 7-membered ring, X 1BA It can be C, R 5B1 R may be selected from H and substituted or unsubstituted organic groups. 5B1 is optionally H. Alternatively, or additionally, X 1BC R can be N, 5B3 It does not need to exist.
[0139] The most preferred structure of ring B is as follows: [ka]
[0140] Ring C The ring C of the PARP1 inhibitor compound has the following structure: [ka]
[0141] X 1CB Linker Q BC X is bonded to ring B via 1 It is an atom.
[0142] X 1CB X is selected from N and C, and is preferably C. 1CB If R is N, 5C1 It does not exist.
[0143] Rings B and C are not connected by an NN bond. Therefore, Q BC The following: [ka] And if u=0, then X 1CB is C. X of ring B 1BC If N is Q BC If X does not exist, 1CB C is C.
[0144] X 2C X is part of ring C. 2 Refers to an atom. X 2CT R 6 X that carries 2C Refers to atoms. Each X 2C The atoms are independently selected from C, N, O, and S, but C and N are particularly preferred. 2C The atoms are selected such that the ring C does not contain OO bonds, OS bonds, and SS bonds. Optionally, at least one X 2C The atom is C. All X 2C The atom may be C. Preferably, exactly one X 2C The atom is N, and the other X 2C Each atom is carbon (C).
[0145] Each R 5C R is independently selected from those that are absent or from H and substituted or unsubstituted organic groups. 5C1 X 1CB R is linked to 5C This refers to R. 5C2 X 2C R that binds to atoms 5C This refers to R. 5C3 X 2CT R is linked to 5 It refers to.
[0146] Two R's 5C Base, or R 5C Base and R 6 The rings may condense, and ring C may form a bridged ring.
[0147] R 5C If it exists, then R 5C This may be selected in particular from H and halogens. A preferred halogen is F.
[0148] In most cases, there is one or fewer R 5C These are substituted or unsubstituted organic groups.
[0149] Arbitrarily, there exists an R. 5C Each of these is selected from H and halogens. In such an example, one or fewer R 5C The condition that it is a halogen may apply.
[0150] The ring C may be a 4, 5, 6, 7, or 8-membered ring. Therefore, r is 0 or an integer between 1 and 6; s is 0 or an integer between 1 and 6; and the sum of r and s is an integer between 2 and 6.
[0151] It is preferable that each of r and s is 1 or greater.
[0152] Ring C is preferably a 5- or 6-membered ring, and particularly preferably a 6-membered ring. In other words, the sum of r and s may be 3 or 4, and preferably 4.
[0153] Selected R 5C Depending on the number of groups, ring C may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring.
[0154] Ring C may be a 6-membered aliphatic ring, and may optionally be a 6-membered aliphatic ring having the following structure: [ka] (In the formula, R 5C and R 5C1 Each of these is independently selected from H and a substituted or unsubstituted organic group, where preferably R 5C1 is H, and more preferably R 5C1 and each R 5C (is H.)
[0155] Alternatively, ring C may be a six-membered aromatic ring.
[0156] For example, the ring C may be an optionally substituted phenyl group, and may optionally have the following structure: [ka] (In the formula, Each R 5C R is independently selected from H and substituted or unsubstituted organic groups, and optionally, here each R 5C (is H.)
[0157] According to other possibilities, the ring C may be a pyridine group and may optionally have a structure selected from the following: [ka] (In the formula, Each R 5C R is independently selected from H and substituted or unsubstituted organic groups, and optionally, here each R 5C (is H.)
[0158] The ring C may alternatively be a diazine group and may optionally have a structure selected from the following: [ka] (In the formula, Each R 5C R is independently selected from H and substituted or unsubstituted organic groups, and optionally, here each R 5C (is H.)
[0159] Compounds in which the carbon ring is a five-membered aromatic ring are also conceivable.
[0160] For example, ring C may be an imidazole group, and may be an imidazole group having a structure optionally selected from the following: [ka] (In the formula, Each R 5C R is independently selected from H and substituted or unsubstituted organic groups, and optionally, here each R 5C (is H.)
[0161] The ring C may be a thiophene group and may optionally have a structure selected from the following: [ka] (In the formula, Each R 5C R is independently selected from H and substituted or unsubstituted organic groups, and optionally, here each R 5C (is H.)
[0162] The ring C may be a thiazole group and may optionally have a structure selected from the following: [ka] (In the formula, Each R 5C R is independently selected from H and substituted or unsubstituted organic groups, and optionally, here each R 5C (is H.)
[0163] Ring C may be a triazole group, and optionally may be a triazole group having the following structure: [ka] (In the formula, R 5C is selected from H and substituted or unsubstituted organic groups, and optionally R 5C(is H.)
[0164] Examples of ring C structures include: [ka] [ka]
[0165] Particularly preferably, ring C has the following structure: [ka] (In the formula, R 5C2о is selected from H, methyl group, and halogen; and, i)X 2CM C is R 5C2M is H; or, ii)X 2CM is N, and R 5C2M It does not exist.
[0166] Optionally, R 5C2о is selected from H and halogens. In particular, R 5C2о This can be a halogen, and the most preferred halogen is F.
[0167] In the PARP1 inhibitor compounds provided in this disclosure, R 6 is either absent or selected from H and substituted or unsubstituted organic groups. Preferably, R 6 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 R51 , and one of the following structures: [ka] (In the formula, R 51 and R 52 Each is independently selected from H and a substituted or unsubstituted organic group. Optionally, R 51 and R 52 Each of these is independently selected from H, a halogen, an optionally deuterated alkyl group (C1-C3), and a C1-C3 haloalkyl group.
[0168] Comfortable, R 6 -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 selected from the following: [ka]
[0169] According to another possibility, R 6 The following structure may be present: [ka] (In the formula, R 51 The following can be selected: - C1-C6 alkyl groups, optionally C3-C6 cycloalkyl groups, C1-C3 alkyl groups, or C1-C3 deuterated alkyl groups; -C1-C3 haloalkyl groups, optionally C1-C3 fluoroalkyl groups; and, - A saturated heterocyclic group with 4, 5, 6, or 7 members, or optionally a cyclic ether group with 4, 5, or 6 members.
[0170] For example, R 6 You may choose from the following: [ka]
[0171] Optionally, R 6 You may choose from the following: [ka]
[0172] Most preferred R 6 The base is -CONHMe (i.e., below: [ka] ), and the following: [ka] That is the case.
[0173] R 6 If the CONHMe group is a CONHMe group, the CONHMe group may optionally be deuterated: [ka] By deuterating the CONHMe group, the rate at which the compound is metabolized can be advantageously reduced.
[0174] The compound, L group, or ring C substructure is R 6 If it is depicted as having CONHMe or CONHCD3, then R 6 The basis is as follows: [ka] It is assumed that this will be replaced by [this].
[0175] The structure of the compound, L group, or ring C is R 6 As follows: [ka] If it is depicted as having R 6 It is assumed that the base will be replaced with CONHMe (or optionally, CONHCD3).
[0176] Alternatively, R 6 The following structure may be present: [ka] (In the formula, each X 6 These are independently selected from C, N, and O; R 61 It either does not exist or is H; Each R 62 These are independently absent, or H, a halo group (e.g., F), an oxo group, a C1-C3 alkyl group, a C1-C3 haloalkyl group (optionally a C1-C3 fluoroalkyl group), and -NHR 63 (Here, R 63 (is selected from H or C1-C3 alkyl groups.)
[0177] Such R 6 Examples of the basis include: [ka]
[0178] The most preferred ring C is as follows: [ka]
[0179] According to other possibilities, ring C may be selected from the following: [ka]
[0180] According to other possibilities, ring C may be selected from the following: [ka]
[0181] In the modified PARP1 inhibitor compounds provided in this disclosure, R 6 Base and one R 5C The elements come together to form a ring. In other words, R 6 Base and one R 5C The groups may condense to form a ring.
[0182] For example, ring C may have the following structure: [ka] (In the formula, each X F It is independently selected from C, N, O, and S, and is optionally C and N; Each R 5F independently, is absent, or selected from H and substituted or unsubstituted organic groups; and, w is either 1 or 2.
[0183] X F The atoms are typically selected such that the ring F does not have OO, OS, or SS bonds.
[0184] Each R 5F Preferably, it is absent or selected from H and carbonyl groups.
[0185] X 2CT and X 2CF These are X, which bridges ring C and ring F, respectively. 2 Refers to an atom. X 2CT and X 2CF Preferably, each of these is C.
[0186] An exemplary class of fused ring systems useful as ring C has the following structure: [ka]
[0187] In such an example, each R 5F is either H or selected from substituted or unsubstituted organic groups. Preferably, each R 5F is H or a C1-C3 alkyl group.
[0188] As a more specific example, ring C may have the following structure: [ka]
[0189] In other examples of fused ring systems, ring F is a benzene ring that may be optionally substituted: [ka]
[0190] In such an example, each R 5F is H, or selected from substituted or unsubstituted organic groups. Preferably, each R 5F H is H.
[0191] A more specific ring C in the above class is as follows: [ka]
[0192] Linker (Q base) As shown in the following equation, ring E, ring A, an arbitrary ring B, and ring C are linked by linker Q AE Q AB , and Q BC It is connected by: [ka]
[0193] In this disclosure, linkers may be collectively referred to as "Q bases." AE QAB , and Q BC Furthermore, rings A through C are sometimes collectively referred to as base L.
[0194] Each linker is optional. When a linker "does not exist," the parts on both sides of that linker are directly connected via covalent bonds. For example, "Q AE The expression "does not exist" and "Q AE The expression "is a combination" is equivalent. Q AB , ring B, and Q BC If none of the elements exist, then a covalent bond exists between ring A and ring C.
[0195] Each linker is either independent, nonexistent (i.e., coupled), or selected from the following: [ka] (In the formula, t is a number selected from 0, 1, 2, 3, 4, and 5, and u is a number independently 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 (These are independently selected from H and substituted or unsubstituted organic groups.)
[0196] The Q group is as follows: [ka] In this case, t and u are selected so that the Q group is bonded to the ring via a CN bond rather than an NN bond. Typically, t is 1 or greater, and u is 1 or greater.
[0197] For example, Q AE Q AB and Q BC At least one of the following may be: [ka] (In the formula, t+u is greater than or equal to 1; R 7 This is selected from H, halogens (e.g., -F, -Cl, -Br, and -I, preferably -F), substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (preferably CF3), -NH2 groups or substituted or unsubstituted C1-C6 amino groups, -OH groups or substituted or unsubstituted linear or branched C1-C6 alcohol groups, and substituted or unsubstituted C1-C6 alkoxy groups.
[0198] In particular, R 7 This may be selected from H, halogens (preferably F), substituted or unsubstituted C1-C6 alkyl groups, and substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups.
[0199] Q AE Q AB and Q BC At least one of them has the following structure: [ka] If R is provided, 8 You may choose from the following: -H; - Substituted or unsubstituted linear or branched C1-C6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, and hexyl groups); - Substituted or unsubstituted linear or branched C1-C6 alkyl-aryl groups (e.g., -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, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph, etc.); - Substituted or unsubstituted linear or branched C1-C6 halogenated alkyl groups (e.g., -CH2F, -CF3, -CH2CH2F, and -CH2CF3, etc.); - Substituted or unsubstituted cyclic amine or amide groups (e.g., pyrrolidine-3-yl, piperidine-3-yl, piperidine-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl, etc.); - Substituted or unsubstituted C3-C8 cyclic alkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); - Substituted or unsubstituted linear or branched C2-C6 alcohol groups (e.g., -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, etc.); - Substituted or unsubstituted linear or branched C2-C6 carboxylic acid groups (e.g., -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH, etc.); - Substituted or unsubstituted linear or branched carbonyl groups (e.g., -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl, -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrrolidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methylpiperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2, etc. - Substituted or unsubstituted linear or branched C1-C6 carboxylic acid ester groups (e.g., -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe, etc.); - Substituted or unsubstituted linear or branched C1-C6 amide groups (e.g., -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt, etc.); - Substituted or unsubstituted sulfonyl groups (e.g., -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-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe, etc.); - Substitutable or unsubstituted aromatic groups (e.g., 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-);and; - Substituted or unsubstituted heterocyclic groups (e.g., pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine- 4-yl, pyrimidine-5-yl, pyrimidine-6-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, fran-2-yl, fran-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl , 2-azapiran-5-yl, 2-azapiran-6-yl, 3-azapiran-2-yl, 3-azapiran-4-yl, 3-azapiran-5-yl, 3-azapiran-6-yl, 4-azapiran-2-yl, 4-azapiran-3-yl, 4-azapiran-5-yl, 4-azapiran-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-teto Lahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetane-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, Thiofen-2-yl, Thiofen-3-yl, Isothiazole-3-yl, Isothiazole-4-yl, Isothiazole-5-yl, Thiazol-2-yl, Thiazol-4-yl, Thiazol-5-yl, Thiopyran-2-yl, Thiopyran-3-yl, Thiopyran-4-yl, 2-Azathiopyran-3-yl, 2-Azathiopyran-4-yl, 2-Azathiopyran-5-yl, 2-Azathiopyran-6-yl, 3-Azathiopyran-2-yl, 3-Azathiopyran-4-yl, 3-Azathiopyran-5-yl, 3-Azathiopyran-6-yl, 4-Azathiopyran-2-yl, 4 (e.g., azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolan-2-yl, thiolan-3-yl, thian-2-yl, thian-3-yl, thian-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-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 tetrazole-5-yl).
[0200] In particular, R 8 This may be selected from H, a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group.
[0201] Preferably, Q AE It does not exist, or it is -CH2-. More preferably, Q AE It does not exist.
[0202] Preferably, Q AB It does not exist, or it is -CH2-. More preferably, Q AB It does not exist. Q AB If not present, base L may have the following structure: [ka]
[0203] Preferably, Q BC It does not exist, or it is -CH2-. More preferably, Q BC It does not exist.
[0204] Q AB and Q BC Neither of these may be present. In such an example, the base L may have the following structure: [ka]
[0205] Most preferably, ring b exists and Q AE Q AB , and Q BC None of these are present. In such an example, the PARP1 inhibitor compound may have the following structure: [ka]
[0206] Example of L-base In particular, base L may have a structure selected from the following: [ka] [ka]
[0207] Particularly preferably, L may have the following structure: [ka]
[0208] R 5A , R 5B , R 5C , and R 6This is defined above in this disclosure.
[0209] Particularly preferred L groups are Each R 5A (For example, R 5A1 ) is H; Each R 5B is H; Each R 5C R is independently selected from H, a methyl group, and a halogen (preferably F), provided that R is a methyl group or a halogen. 5C The condition is that there is one or fewer; and, R 6 The following: [ka] Or, the following: [ka] It is, it is the basis.
[0210] Optionally, each R 5C R is independently selected from H and halogens (preferably F). However, R is a halogen. 5C The condition is that there must be one or fewer of them.
[0211] Base L may have a structure selected from the following: [ka]
[0212] According to other possibilities, L may be: [ka]
[0213] Examples of compounds In particular, PARP1 inhibitor compounds having structures selected from the following are provided: [ka] (In the formula, Z 1 is C or N; Z 2u and Z 2l Either of them is C, and Z 2u and Z 2l The other side is N; each Z 3 These are independently selected from C and N; R 1 is either absent or selected from H, halogens (e.g., F), methyl, halomethyl (e.g., CF3), and CN; R 5C2о is H, a methyl group, or a halogen (e.g., F); X 2CM is N, and R 5C2M It does not exist, or X 2CM C is R 5C2M is H; and, R 6 The following: [ka] , or the following: [ka] (That is the case.)
[0214] Optionally, R 5C2о is H, or a halogen (e.g., F);
[0215] R 1 This may be selected from H, halogens (e.g., F), methyl, halomethyl (e.g., CF3), and CN.
[0216] Specific PARP1 inhibitor compounds include the following: [ka] [ka] [ka] [ka] [ka]
[0217] Some of the PARP1 inhibitor compounds provided in this disclosure contain one or more chiral centers. Such compounds may be provided in the form of isolated enantiomers, mixtures of two or more enantiomers, mixtures of two or more diastereomers or epimers, or racemic mixtures.
[0218] Some PARP1 inhibitor compounds may undergo tautomerism. Such compounds may be provided in any possible tautomer form.
[0219] Medical use The compounds described herein may also be compounds for pharmaceutical use. In the context of the present invention, pharmaceutical uses are not particularly limited, as long as they are uses facilitated by the PARP1 inhibitory effect of the compounds. Accordingly, the compounds of the present invention may be used for any disease, condition or disorder that can be prevented, improved or treated with PARP1 inhibitors.
[0220] In particular, PARP1 inhibitor compounds may be used to treat cancer. The nature of the cancer is not particularly limited, insofar as it can be treated, prevented, or improved with a PARP1 inhibitor. Cancer may include solid tumors or humoral tumors.
[0221] For example, cancer may be selected from the following: cancer of the eye, brain (glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma and astrocytoma, etc.), spinal cord, kidney, mouth, lips, pharynx, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gallbladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchi, liver, skin, ureter, urethra, testicle, vagina, anus, laryngeal gland, ovary, thyroid gland, esophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, and adrenal gland; endometrial cancer, oral cancer, malignant 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 Syndromes (PHTS) (Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome, etc.), leukemia and lymphoma (acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prelymphocytic 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-associated lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal cancer, and gastrointestinal cancer).
[0222] In addition, the compounds described herein may be used in cancers associated with Epstein-Barr virus (EBV), such as Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal cancer, and gastrointestinal cancer.
[0223] The compounds described herein may be used to treat cancers lacking DNA damage response repair pathways, particularly cancers lacking homologous recombination (HR)-dependent DNA double-strand break (DSB) repair activity. Components of the homologous recombination-dependent DNA double-strand break (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 homologous recombination (HR)-dependent DNA double-strand breaks (DSBs) include regulatory factors such as ESMY (Non-Patent Literature 17). Cancers lacking the ability to repair homologous recombination (HR)-dependent DNA double-strand breaks (DSBs) typically become dependent on alternative DSB repair pathways. Such cancers include, but are not limited to, ovarian, prostate, breast, lung, gastrointestinal, hematological, and pancreatic cancers.
[0224] Cancer cells may have a phenotype lacking BRCA1 and / or BRCA2, that is, cancer cells may lack the function of BRCA1 and / or BRCA2. Such deficiencies can result from mutations, polymorphisms, or epigenetic silencing of the nucleic acids encoding BRCA1 and / or BRCA2, or from mutations, polymorphisms, or amplifications of genes encoding regulatory factors (e.g., the ESMY gene encoding the BRCA2 regulator; Non-Patent Literature 17). Amplification of the ESMY gene has been associated with breast and ovarian cancer. Carriers of mutations in the tumor suppressor genes BRCA1 and / or BRCA2 are known to be at high risk of developing certain cancers, including ovarian, prostate, and breast cancer. Wild-type alleles of BRCA1 and / or BRCA2 are frequently lost in tumors of heterozygous carriers (Non-Patent Literature 18), and their detection is well known in the art as a means of patient selection (Non-Patent Literature 19; Non-Patent Literature 20).
[0225] The compounds provided in this disclosure may be administered to patients undergoing radiotherapy and / or chemotherapy with further agents for treating cancer.
[0226] For example, PARP1 inhibitor compounds may be administered in combination with other agents used to treat cancer.
[0227] Further agents for treating cancer may be selected from the following: microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapies, hormone deprivation therapies, apoptosis inducers, radioligand therapies, angiogenesis inhibitors, and cell cycle signaling inhibitors.
[0228] In particular, the further agents may comprise 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-cell therapy); small molecule immunomodulators; and tumor microenvironment modifiers.
[0229] Pharmaceutical composition In other respects, a pharmaceutical composition comprising the PARP1 inhibitor compound defined above is provided.
[0230] Typically, the composition contains pharmaceutically acceptable additives and / or excipients.
[0231] In a pharmaceutical composition, the PARP1 inhibitor compound as defined above may exist in the form described above, or alternatively, in a form suitable for improving bioavailability, solubility and / or activity, and / or in a form suitable for improving formulation. Accordingly, the compound may be in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other suitable alternative form.
[0232] Typically, pharmaceutical compositions are used for medical purposes, for example, to treat the diseases, conditions, or disorders defined above.
[0233] For example, a pharmaceutical composition may be used to treat cancer. The pharmaceutical composition may further comprise a further agent for treating cancer. The further agent for treating cancer is not particularly limited, as long as it provides some usefulness in treating cancer.
[0234] Further agents for treating cancer may comprise one or more chemotherapeutic agents such as microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapies, apoptosis inducers, radioligand therapies, angiogenesis inhibitors, and cell cycle signaling inhibitors.
[0235] In particular, the further agents for treating cancer may comprise 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-cell therapy); small molecule immunomodulators and tumor microenvironment modifiers.
[0236] kit In other respects, a medical kit for treating cancer is provided. The medical kit comprises the PARP1 inhibitor compound defined above and further agents for treating cancer. The compound and further agents are suitable for simultaneous, sequential, or separate administration.
[0237] Further agents for treating cancer may be any of the further agents for treating cancer identified in the description of the above pharmaceutical composition.
[0238] In particular, further agents for treating cancer may comprise one or more chemotherapeutic agents selected from the following: microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone deprivation therapies, radioligand therapies, angiogenesis inhibitors, and immunotherapeutic agents (e.g., 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 cell therapy); small molecule immunomodulators, and tumor microenvironment modifiers (selected from these); apoptosis inducers, and cell cycle signaling inhibitors.
[0239] Treatment method Another aspect of the present invention provides a method for treating a disease and / or condition and / or disorder, comprising administering a PARP1 inhibitor compound, composition, or kit as appropriate in this disclosure to a patient (or subject). Such a method is typically for treating any disease, condition, or disorder mentioned in this disclosure. In a typical embodiment, such a method is for treating cancer.
[0240] The patient may be any animal, but preferably a mammal. For example, the patient may be a human, dog, horse, or cat, but preferably a human.
[0241] The treatment method may comprise administering to the patient (or subject) the compound or composition defined above and further agents for treating the cancer defined above. The compound, composition, and further agents may be administered simultaneously, sequentially, or separately, depending on the drugs, the patient, and the disease being treated (e.g., the type of cancer being treated).
[0242] The patient may be one who is receiving treatment using ionizing radiation.
[0243] Method for synthesizing PARP1 inhibitor compounds Furthermore, a method for synthesizing PARP1 inhibitor compounds as defined in this disclosure is provided. Generally, such a method is (i) A first reactant comprising rings D and E and having a first portion of group L, (ii) A second reactant comprising the remaining portion of group L The method comprises a reaction between the two to form the PARP1 inhibitor compound. Those skilled in the art may select reaction conditions by reference to known synthetic techniques, depending on the appropriate starting materials. The method may include one or more additional steps. Exemplary synthetic methods are shown in the examples of this disclosure described later.
[0244] In one exemplary method, the first reactant comprises rings D, E and A, and the second reactant comprises Q having a reactive group. AB The method comprises a precursor, and the ring A is Q AB The method comprises bonding to a precursor. AB The reactive group of the precursor may comprise a carbonyl group, an alkyl halide, or an alkyl sulfonate. The reaction may comprise alkylation, reductive amination, or amidation to form group L.
[0245] In some embodiments of this exemplary method, the first reactant has the following structure: [ka]
[0246] The first reactant may be prepared by deprotecting an intermediate having the following structure: [ka] (In the formula, R PG (This is a protecting group.)
[0247] R 1 , R 2 , R 5 It will be understood that the X and Z groups are as previously defined for PARP1 inhibitor compounds.
[0248] The first reactant has the following structure: [ka] A precursor having said precursor is provided, and said precursor is NHR 3 Alternatively, it may be prepared by treating it with its conjugate acid to carry out a ring-closing reaction and form the first reactant. 3 Regarding this, the aspects related to the compound have been described above.
[0249] R 9 This is a C1-C6 alkyl group, and optionally an ethyl group.
[0250] R PG Boc may also be used.
[0251] R 3 H may also be used.
[0252] Z 2l may be N, and Z 2u It may also be C.
[0253] In some embodiments, Z 1 is C, and the precursor may have the following structure: [ka]
[0254] An alternative embodiment is Z 1 is N, and the precursor has the following structure: [ka]
[0255] The above precursor is a) The following structure: [ka] A compound having the following structure: [ka] Phenylhydroxylamine having (wherein EWG represents one or more electron-withdrawing groups) is reacted with a base, such as sodium hydride, to form the following structure: [ka] To obtain an intermediate having, b) The intermediate has the following structure: [ka] The precursor is obtained by reacting it with a carboxylic acid having the above-mentioned properties. It can be obtained by this method.
[0256] In this method, the substituted phenylhydroxylamine is O-(2,4-dinitrophenyl)hydroxylamine: [ka] That's fine.
[0257] The following structure: [ka] An alternative method for preparing a first reactant having is: a) The following structure: [ka] (In the formula, R 10 To provide a first precursor having a C1-C6 alkyl group, optionally a t-butyl group; b) The following structure: [ka] (In the formula, R PG is a protecting group, optionally Boc. ) To provide a second precursor having ); and, c) The first precursor and the second precursor as a catalyst, optionally [Cp * Coupling is performed using a RhCl2]2 catalyst to form the first reactant; It is equipped with.
[0258] The second reactant may have the following structure: [ka]
[0259] The second reactant is i) The following formula: [ka] (In the formula, a)X 2CM C is R 5C2M is H, or, b)X 2CM is N, and R 5C2M To provide a first precursor represented by (which does not exist); ii) The following formula: [ka] To provide a second precursor represented by iii) Using a base, optionally a cesium base such as Cs2CO3, the first precursor and the second precursor are coupled to form the following equation: [ka] To obtain an intermediate represented by; and, iv) The intermediate can be prepared by treating it with an acid to form the second reactant, where the second reactant has the following structure: [ka]
[0260] The second precursor is 1,4-dioxa-8-azaspiro[4.5]decane: is: [ka]
[0261] The aforementioned reaction may involve coupling the first reagent with the second reagent using a reducing agent in the presence of an acid.
[0262] In other exemplary methods, the first reactant comprises rings A, B, D, and E, Q. AE , and also, Q AB The method comprises the first reactant, and the second reactant comprises a derivative of a ring C having a leaving group, such as a halide or a sulfonic acid ester. In this method, the reaction may include a nucleophilic substitution reaction, such as an aromatic nucleophilic substitution reaction, for forming the group L.
[0263] The PARP1 inhibitor compound may be obtained in the form of a mixture of structural isomers. In such embodiments, the method may further comprise separating the structural isomers using chiral supercritical fluid chromatography (SFC) and / or chiral high-performance liquid chromatography.
[0264] example Example 1: Synthesis of 1a / 1b
[0265] [ka]
[0266] Preparation of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1003) To a solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (1001) (5.0 g, 0.0231 mol) in DCM (200 mL), N,O-dimethylhydroxylamine hydrochloride (1002) (4.5 g, 0.0462 mol), DIPEA (14.9 g, 0.115 mol), and HATU (17.6 g, 0.0462 mol) were added. The resulting mixture was stirred at room temperature for 2 hours, diluted with water (1.6 L), and extracted with ELISA (200 mL x 3). The combined organic layer was washed with saturated brine, dried over Na2SO4, and concentrated to obtain tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1003) (6.0 g, purity 80%, yield 80%) as a colorless oil. LCMS(ESI) C 12 H 22 N2O4[M-56+H] + m / z Calculated value: 203.10, Measured value: 202.95.
[0267] Preparation of tert-butyl 3-acetylpyrrolidine-1-carboxylate (1004) Under a nitrogen atmosphere at -78°C, tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1003) (6.0 g, 0.0231 mol) was added to a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1003) (300 mL) in THF (38.5 mL, 0.1155 mol, 3 M in THF). The resulting mixture was stirred at 0°C for 1 hour, quenched with saturated NH4Cl solution, and extracted with  (100 mL x 3). The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under vacuum to obtain tert-butyl 3-acetylpyrrolidine-1-carboxylate (1004) (3.5 g, purity 90%, yield 63%) as a colorless oil. LCMS(ESI) C 11 H 19 NO3 [M-56+H] + m / z Calculated value: 158.08, Measured value: 158.00.
[0268] Preparation of tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate (1005) At room temperature, tert-butyl 3-acetylpyrrolidine-1-carboxylate (1004) (1.2 g, 5.6 mmol) was dissolved in DCM / MeOH (2:1, 30 mL) and TBABr3 (5.4 g, 11.2 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica column chromatography (Â1 / PE, eluted at 30% to 40%) to obtain tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate (1005) (300 mg, purity 50%, yield 8%) as a colorless oil. LCMS(ESI) C 11 H 18 BrNO3[M-56+H] + m / z Calculated value: 235.99, Measured value: 235.85.
[0269] Preparation of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-5-methyl-1H-pyrrole-2-carboxylate (1007) To a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate (1006) (157 mg, 1.02 mmol) and Cs2CO3 (667 mg, 2.05 mmol) in DMF (10 mL), tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate (1005) (300 mg, 1.02 mmol) was added. The resulting mixture was heated at 50°C for 1 hour. The reaction mixture was quenched with water and extracted with Â(50 mL × 3). The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (Â1 / PE, eluted at 30% to 50%) to obtain ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-5-methyl-1H-pyrrole-2-carboxylate (1007) (130 mg, purity 50%, yield 17%) as a yellow oil. LCMS(ESI) C 19 H 28 N2O5[M+H] + m / z Calculated value: 365.20, Measured value: 365.03.
[0270] Preparation of tert-butyl 3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrroridine-1-carboxylate (1008) A solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-5-methyl-1H-pyrrole-2-carboxylate (1007) (130 mg, 0.35 mmol) in NH3-MeOH (7 M, 20 mL) was stirred in a sealed test tube at 110°C for 16 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (siRNA / PE, elution at 50% to 70%) to obtain tert-butyl 3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-carboxylate (1008) (60 mg, purity 90%, yield 47%) as a white solid. LCMS(ESI) C 17 H 23 N3O3[M+H] + m / z Calculated value: 318.18, Measured value: 318.15.
[0271] Preparation of 6-methyl-3-(pyrroridine-3-yl)pyrrolo[1,2-a]pyrazine-1(2H)-one hydrochloride (1009) A solution of tert-butyl 3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-carboxylate (1008) (60 mg, 0.19 mmol) in HCl-dioxane (4 M, 5 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and triturated in DCM. The precipitate was collected and dried under vacuum to obtain 6-methyl-3-(pyrrolidine-3-yl)pyrrololo[1,2-a]pyrazine-1(2H)-one hydrochloride (1009) (50 mg, purity 80%, yield 83%) as a white solid. LCMS(ESI) C 12 H 15 N3O [M+H] + m / z Calculated value: 218.12, Measured value: 218.15.
[0272] Preparation of a racemic mixture (1rac) of N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrroridine-1-yl)piperidine-1-yl)picolinamide To a solution of 6-methyl-3-(pyrroridine-3-yl)pyrrolo[1,2-a]pyrazine-1(2H)-one hydrochloride (1009) (50 mg, 0.20 mmol) in MeOH (5 mL), N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide (INT-1) (80 mg, 0.34 mmol), 2 drops of AcOH, NaBH3CN (14 mg, 0.23 mmol), and NaBH(OAc)3 (146 mg, 0.69 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, quenched with 2 drops of water, and then concentrated under reduced pressure. The residue was separated by preparative HPLC (Gemini 5 μm C). 18 The mixture was purified using a 150×21.2mm filter (eluted with 40% to 80% ACN / H2O containing 0.05% NH3·H2O) to obtain N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (1rac) (20 mg, purity 95%, yield 22%), a racemic mixture of 1a and 1b, as a white solid.
[0273] Chiral separation of the racemic mixture (1rac) of N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrrolidine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide to obtain 1a and 1b. A racemic mixture (1rac) of N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide was separated by SFC (column: Daicel Chiralpak IH, inner diameter 20 mm × 250 mm, 5 μm; mobile phase: CO2 / MeOH (0.1% NH3) = 70 / 30) and concentrated under reduced pressure. This yielded the first fraction as 1a (4.7 mg, purity 94%, 100% ee, white solid) and the second fraction as 1b (3.8 mg, purity 96%, 100% ee, white solid). 1a 1 H NMR(400MHz,DMSO-d6,ppm) δ:10.18(s,1H),8.46-8.31(m,1H),8.28(d,J=2.8Hz,1H),7.82(d,J=8.8Hz,1H),7.40(dd ,J=8.8,2.8Hz,1H),6.99(s,1H),6.75(d,J=3.6Hz,1H),6.28(d,J=4.0Hz,1H),3.93-3.71 (m,2H),3.18-3.07(m,1H),2.99(t,J=11.6Hz,2H),2.90-2.75(m,5H),2.73-2.64(m,2H), 2.33(s,3H),2.20-2.13(m,1H),2.00-1.91(m,2H),1.89-1.80(m,1H),1.62-1.50(m,2H). LCMS(ESI) C 24 H 30 N6O2[M+H] + m / z Calculated value: 435.25, Measured value: 435.09. 1b 1H NMR(400MHz,DMSO-d6,ppm) δ:10.17(s,1H),8.38(q,J=4.7Hz,1H),8.28(d,J=2.8Hz,1H),7.82(d,J=8.8Hz,1H),7.40(dd,J =8.8,2.8Hz,1H),6.99(s,1H),6.75(d,J=3.6Hz,1H),6.28(d,J=3.6Hz,1H),3.85-3.74(m,2H),3 .15-3.05(m,1H),2.99(t,J=11.6Hz,2H),2.90-2.81(m,2H),2.78(d,J=4.8Hz,3H),2.73-2.62( m,2H),2.33(s,3H),2.22-2.10(m,1H),2.01-1.90(m,2H),1.89-1.77(m,1H),1.61-1.45(m,2H). LCMS(ESI) C 24 H 30 N6O2[M+H] + m / z calculated value: 435.25, measured value: 435.12.
[0274] Example 2: 2rac synthesis
change
[0275] Preparation of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-5-carboxylate (1102) To a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (1101) (110 mg, 0.71 mmol) in DMF (5 mL), tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate (1005) (230 mg, 0.78 mmol) and Cs2CO3 (465 mg, 1.43 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with ice water and extracted with Â(30 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 70:30) to obtain ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-5-carboxylate (1102) (40 mg, purity 80%, yield 12%) as a yellow oil. LCMS(ESI) C 18 H 27 N3O5[M+H] + m / z Calculated value: 366.20, Measured value: 366.35.
[0276] Preparation of tert-butyl 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1103) To a solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-5-carboxylate (1102) (40 mg, 0.11 mmol) in EtOH (3 mL), NH4OAc (170 mg, 2.20 mmol) was added at room temperature. The reaction mixture was stirred in a sealed test tube at 110 °C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (elution at PE / siRNA = 100:0 to 30:70) to obtain tert-butyl 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1103) (23 mg, purity 80%, yield 42%) as a yellow oil. LCMS(ESI) C 16 H 22 N4O3[Mt‐Bu+H] +m / z Calculated value: 263.17, Measured value: 263.20.
[0277] Preparation of 2-methyl-6-(pyrroridine-3-yl)pyrazolo[1,5-a]pyrazine-4(5H)-one hydrochloride (1104) To a solution of tert-butyl 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1103) (23 mg, 0.072 mmol) in DCM (2 mL), 4 M HCl / dioxane (5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. By concentrating the reaction solution under reduced pressure, 2-methyl-6-(pyrrolidine-3-yl)pyrazolo[1,5-a]pyrazine-4(5H)-one hydrochloride (1104) (20 mg, purity 80%, yield 87%) was obtained as a yellow solid. LCMS(ESI) C 11 H 14 N4O [M+H] + m / z Calculated value: 219.12, Measured value: 219.10.
[0278] Preparation of a racemic mixture (2rac) of N-methyl-5-(4-(3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide To a solution of 2-methyl-6-(pyrroridine-3-yl)pyrazolo[1,5-a]pyrazine-4(5H)-one hydrochloride (1104) (20 mg, 0.092 mmol) in MeOH (1 mL), TEA (1 mL) was added at room temperature, and the mixture was stirred for 5 minutes. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (5 mL) and AcOH (0.1 mL) at room temperature. N-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-carboxamide (INT-1) (26 mg, 0.11 mmol) and NaBH3CN (12 mg, 0.19 mmol) were then added at room temperature. The reaction mixture was then stirred at 50°C for 1 hour. The resulting reaction solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (elution at DCM / MeOH = 100:0 to 90:10) and preparative HPLC (Gemii 5μm C18 150×21.2mm, mobile phase: ACN-H2O (0.1% FA), gradient: 40-95) to obtain a racemic mixture (2rac) (6.9 mg, purity 98%, yield 17%) of N-methyl-5-(4-(3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide as a white solid. 1 H NMR(400MHz,DMSO-d6,ppm) δ:11.03(s,1H),8.42-8.34(m,1H),8.28(d,J=2.8Hz,1H),8.14(s,0.9H),7.82(d,J=8.8Hz,1H ),7.49(s,1H),7.40(dd,J=8.8,2.8Hz,1H),6.70(s,1H),3.88-3.79(m,2H),3.20-3.13(m,1H) ,3.00-2.92(m,3H),2.88-2.82(m,1H),2.78(d,J=4.8Hz,3H),2.76-2.69(m,2H),2.44-2.40(m ,1H),2.31(s,3H),2.22-2.13(m,1H),2.00-1.92(m,2H),1.90-1.81(m,1H),1.60-1.47(m,2H). LCMS(ESI) C 23 H 29 N7O2[M+H]+ m / z Calculated value: 436.24, Measured value: 436.25.
[0279] Example 3: Synthesis of 6rac [ka]
[0280] Preparation of 1H-pyrrole-1-carboxylic acid (1202) Under ice cooling, 1H-pyrrole (1201) (2.3g, 34.3 mmol) was gradually added to a solution of t-BuOK (4.23g, 37.7 mmol) in Et2O / THF (1:1, 120 mL). The reaction mixture was heated to room temperature and stirred for 30 minutes. Then, an excess amount of solid CO2 was slowly added from the top of the flask. Vigorous foaming occurred, and the reaction temperature decreased. The reaction vessel was immersed in a water bath at room temperature and left until no solid CO2 remained at the bottom of the flask. H2O (300 mL) was added, and the contents were transferred to a separatory funnel. The aqueous layer was collected, and the organic phase was washed with 300 mL of H2O. The combined aqueous extract was acidified to pH < 1 using a 1.0 M aqueous HCl solution. Then, 40 mL of Et2O was added to this aqueous solution, and the contents were again transferred to a separatory funnel. The organic phase was recovered, and the aqueous phase was extracted with Et2O (2 × 40 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1H-pyrrole-1-carboxylic acid (1202) (1.6 g, purity 90%, yield 37%) as a white solid. LCMS(ESI) C5H5NO2[M+H] + Calculated m / z value: 112.04, Measured value: No MS signal.
[0281] Preparation of N-(pivaloyloxy)-1H-pyrrole-1-carboxamide (1204) At 0°C, DMF (0.070 g, 0.90 mmol) was added to a solution of (COCl)2 (1.26 g, 9.90 mmol) in THF (25 mL) under stirring. The reaction mixture was stirred for 10 minutes, and at 0°C, 1H-pyrrole-1-carboxylic acid (1202) (1.0 g, 9.00 mmol) was added in two batches. After stirring the reaction mixture at 0°C for 15 minutes, the cooling bath was removed, and the reaction mixture was then stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to obtain the crude acid chloride. In a separate round-bottom flask, O-pivaloylhydroxylamine trifluoromethanesulfonate (1203) (2.4 g, 9.00 mmol) was added to a solution of Na2CO3 (1.91 g, 18.00 mmol) in Depositphotos (40 mL) and water (20 mL) at 0°C with stirring, followed by the addition of the acid chloride solution in Depositphotos (5 mL). The reaction mixture was stirred at 0°C for 2 hours, and the progress of the reaction was monitored by TLC. Then, Depositphotos (60 mL) was added. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography ( Depositphotos / PE, eluted at 20% to 40%) to obtain N-(pivaloyloxy)-1H-pyrrole-1-carboxamide (1204) (0.60 g, purity 90%, yield 28%) as a white solid. LCMS(ESI) C 10 H 14 N2O3[MH] - m / z Calculated value: 209.09, Measured value: 209.10.
[0282] Preparation of tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidine-3-yl)pyrrolidine-1-carboxylate (1206) and tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidine-4-yl)pyrrolidine-1-carboxylate (1206a) To a 20 mL solution of MeOH containing N-(pivaloyloxy)-1H-pyrrole-1-carboxyamide (1204) (0.6 g, 2.85 mmol), AcOCs (0.55 g, 2.85 mmol), [Rh(Cp*)Cl2]2 (0.17 g, 2.85 mmol), and tert-butyl 3-ethynylpyrrolidine-1-carboxylate (1205) (0.56 g, 2.85 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated and purified by flash chromatography (siRNA / PE, eluting at 30% to 60%) to obtain tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidine-3-yl)pyrrolidine-1-carboxylate (1206) (300 mg, purity 90%, yield 31%) and tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidine-4-yl)pyrrolidine-1-carboxylate (1206a) (200 mg, purity 90%, yield 21%) as yellow solids. 1206: LCMS(ESI) C 16 H 21 N3O3[M+H] + m / z Calculated value: 304.16, Measured value: 303.97. 1206a: LCMS(ESI) C 16 H 21 N3O3[M+H] + m / z Calculated value: 304.16, Measured value: 303.95.
[0283] Preparation of 3-(pyrrolidine-3-yl)pyrrolo[1,2-c]pyrimidine-1(2H)-one hydrochloride (1207) A solution of tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidine-3-yl)pyrrolidine-1-carboxylate (1206) (100 mg, 0.32 mmol) in HCl-dioxane (4 M, 10 mL) was stirred at room temperature for 2 hours. By concentrating the mixture under reduced pressure, 3-(pyrrolidine-3-yl)pyrrolo[1,2-c]pyrimidine-1(2H)-one hydrochloride (1207) (80 mg, purity 90%, yield 94%) was obtained as a brown solid. LCMS(ESI) C 11 H 13 N3O [M+H] + m / z Calculated value: 204.11, Measured value: 204.10.
[0284] Preparation of a racemic mixture (6rac) of N-methyl-5-(4-(3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide To a 10 mL solution of 3-(pyrroridine-3-yl)pyrrolo[1,2-c]pyrimidine-1(2H)-one hydrochloride (1207) (80 mg, 0.34 mmol) in MeOH (1), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-1) (120 mg, 0.52 mmol), 2 drops of acetic acid, NaBH3CN (22 mg, 0.34 mmol), and NaBH(OAc)3 (146 mg, 0.69 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini-C18 150 × 21.2 mm, eluted with 15% to 45% ACN / H2O containing 0.05% NH3) to obtain a racemic mixture (6 rac) (5.1 mg) of N-methyl-5-(4-(3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide as a white solid. 1 H NMR(400MHz,DMSO-d6,ppm) δ:10.70(s,1H),8.41-8.35(m,1H),8.31-8.28(m,1.4H),8.28-8.25(m,1H),7.82(d,J=8.8 Hz,1H),7.44-7.35(m,2H),6.57(t,J=3.2Hz,1H),6.35(s,1H),6.22-6.17(m,1H),3.84-3. 79(m,2H),3.13-3.08(m,1H),2.99-2.90(m,3H),2.81-2.74(m,4H),2.70-2.64(m,2H),2.3 7-2.32(m,1H),2.24-2.11(m,1H),1.99-1.91(m,2H),1.84-1.76(m,1H),1.60-1.48(m,2H). LCMS(ESI) C 23 H28 N6O2[M+H] + m / z Calculated value: 421.23, Measured value: 421.35.
[0285] Example 4: Synthesis of 8rac [ka]
[0286] Preparation of 6-bromo-8-methoxyimidazo[1,2-a]pyrazine (1302) To a mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (1301) (1000 mg, 3.611 mmol) in MeOH (30 mL), sodium hydride (60% dispersion in mineral oil, 173 mg, 4.333 mmol) was added in small increments, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, and most of the MeOH was removed by evaporation. The residue was extracted three times with ELISA. The combined organic layers were washed with water and saturated brine, concentrated under vacuum, and purified by flash silica chromatography (MeOH / DCM, eluting from 0% to 8%) to obtain 6-bromo-8-methoxyimidazo[1,2-a]pyrazine (1302) (680 mg, purity 90%, yield 74%) as a yellow solid. LCMS(ESI) C7H6BrN3O [M+H] + m / z calculated value: 227.97, measured value: 227.85.
[0287] Preparation of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazine-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1304) A suspension of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1303) (324 mg, 1.096 mmol), 6-bromo-8-methoxyimidazo[1,2-a]pyrazine (1302) (250 mg, 1.096 mmol), Na2CO3 (228 mg, 2.192 mmol), and Pd(dppf)Cl2 (80 mg, 0.109 mmol) in dioxane / H2O (4 / 1,10 mL) was heated at 90°C for 2 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into ice water and then extracted with ELISA (50 mL x 3). The combined organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (Â1 / PE, elution from 0% to 85%) to obtain tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazine-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1304) (220 mg, purity 90%, yield 56%) as a white solid. LCMS(ESI) C 16 H 20 N4O3[M+H] + m / z Calculated value: 317.15, Measured value: 317.15.
[0288] Preparation of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1305) A solution of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazine-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1304) (220 mg, 0.693 mmol) and Pd / C (10%, 147 mg) in MeOH (10 mL) was stirred at room temperature for 2 hours under an H2 atmosphere. The resulting solution was filtered and concentrated under reduced pressure to obtain tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1305) (180 mg, purity 90%, yield 73%) as a white solid. LCMS(ESI) C 16 H 22 N4O3[M+H]+ m / z Calculated value: 319.17, Measured value: 319.25.
[0289] Preparation of 6-(pyrroridine-3-yl)imidazo[1,2-a]pyrazine-8(7H)-one (1306) A solution of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1305) (180 mg, 0.563 mmol) in an aqueous HBr solution (48 wt.%, 5 mL) was stirred at 100°C for 2 hours. The reaction mixture was concentrated. The residue was diluted with MeOH (5 mL), TEA (1 mL) was added, and the mixture was stirred for 5 minutes. Subsequently, by concentration to dryness, 6-(pyrrolidine-3-yl)imidazo[1,2-a]pyrazine-8(7H)-one (1306) (100 mg, purity 90%, yield 78%) was obtained as a yellow oil. LCMS(ESI) C 10 H 12 N4O [M+H] + m / z Calculated value: 205.10, Measured value: 205.00.
[0290] Preparation of a racemic mixture (8rac) of N-methyl-5-(4-(3-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide To a solution of 6-(pyrroridine-3-yl)imidazo[1,2-a]pyrazine-8(7H)-one (1306) (60 mg, 0.293 mmol) in MeOH (10 mL) and AcOH (0.01 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-1) (68 mg, 0.293 mmol) and NaBH3CN (37 mg, 0.587 mmol) were added at room temperature. The reaction mixture was stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Gemini 5μm C18 150×21.2mm, mobile phase: ACN-H2O (0.1% FA), gradient: 30-60) and SFC (column: Daicel Chiralpak OJ-H 250mm×20mm ID, 5μm; mobile phase: CO2 / MeOH (0.1% NH3) = 70 / 30) to obtain a racemic mixture (30.2 mg, purity 99%, yield 24%) of N-methyl-5-(4-(3-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (8rac) as a white solid. 1 1H NMR (400MHz, DMSO-d6, ppm) δ:11.01(s,1H),8.41-8.34(m,1H),8.27(d,J=2.4Hz,1H),7.82(d,J=8.8Hz ,1H),7.73(s,1H),7.45-7.37(m,3H),3.87-3.78(m,2H),3.16-3.10(m,1H), 3.00-2.88(m,3H),2.81-2.74(m,4H),2.71-2.63(m,2H),2.36-2.29(m,1H), 2.24-2.14(m,1H),1.97-1.89(m,2H),1.84-1.75(m,1H),1.58-1.45(m,2H). LCMS(ESI) C 22 H 27 N7O2[M+H] + m / z Calculated value: 422.22, Measured value: 422.15.
[0291] Example 5: Synthesis of 10a / 10b [ka] [ka] [ka]
[0292] Preparation of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-fluoro-1H-pyrrol-2-carboxylate (1403) A solution of ethyl 3-fluoro-1H-pyrrol-2-carboxylate (1401) (600 mg, 3.825 mmol), Cs2CO3 (2506 mg, 7.619 mmol), and tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate (1005) (740 mg, 2.543 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl butyl (50 mL x 3). The combined organic layer was washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel (DCM / MeOH, elution from 100:0 to 90:10) to obtain ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-fluoro-1H-pyrrol-2-carboxylate (1403) (1000 mg, purity 90%, yield 63%) as a yellow oil. LCMS(ESI) C 18 H 25 FN2O5[Mt-Bu+H] + m / z Calculated value: 313.17, Measured value: 313.10.
[0293] Preparation of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-carboxylate (1404) To a solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-3-fluoro-1H-pyrrol-2-carboxylate (1403) (1000 mg, 2.717 mmol) in EtOH (15 mL), NH4OAc (20900 mg, 27.17 mmol) was added. The mixture was stirred in a steel bomb at 100°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel (elution at DCM / MeOH, 100:0 to 90:10) to obtain a racemic mixture of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-carboxylate (1404) (600 mg, purity 95%, yield 65%) as a yellow oil. LCMS(ESI) C 16 H 20 FN3O3[M+H] + m / z Calculated value: 321.15, Measured value: 321.70.
[0294] Preparation of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-carboxylate (1404-P1 and 1404-P2) A racemic mixture of 1404 (300 mg, 0.934 mmol) was separated by SFC (column: Daicel Chiralpak IH 20 mm I.D. × 250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% (NH3)] = 60 / 40) and concentrated under reduced pressure to obtain 1404-P1 (120 mg, 95% purity, white solid) as the first fraction and 1404-P2 (90 mg, 95% purity, white solid) as the second fraction.
[0295] Preparation of 8-fluoro-3-(pyrroridine-3-yl)pyrrolo[1,2-a]pyrazine-1(2H)-one (1405-P1) A solution of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-carboxylate (1404-P1) (120 mg, 0.374 mmol) in HCl-dioxane (4 M, 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was diluted with MeOH (5 mL) and TEA (1 mL). After stirring at room temperature for 5 minutes, the solution was concentrated to dryness to obtain 8-fluoro-3-(pyrrolidine-3-yl)pyrrololo[1,2-a]pyrazine-1(2H)-one (1405-P1) (100 mg, purity 70%, yield 84%) as a white solid. LCMS(ESI) C 11 H 12 FN3O [M+H] + m / z Calculated value: 222.10, Measured value: 222.30.
[0296] Preparation of 6-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrroridine-1-yl)piperidine-1-yl)-N-methylpicolinamide (10a) To a solution of 8-fluoro-3-(pyrroridine-3-yl)pyrrolo[1,2-a]pyrazine-1(2H)-one (1405-P1) (35 mg, 0.157 mmol) in MeOH (10 mL), 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) (47 mg, 0.188 mmol), 2 drops of HOAc, and NaBH(OAc)3 (33 mg, 0.157 mmol) were added. The mixture was stirred at 50°C for 30 minutes, then NaBH3CN (10 mg, 0.158 mmol) was added and the mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC (Gemini 5 μm C). 18 The sample was purified using a 150×21.2mm microscope with mobile phase ACN-H2O (0.1% FA) and a gradient of 5-90 degrees to obtain 6-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (10a) (37.2 mg, purity 98%, 100% ee, yield 52%) as a white solid. 1H NMR(400MHz,DMSO-d6,ppm) δ:10.22(s,1H),8.47-8.31(m,1H),7.83(d,J=8.0Hz,1H),7.58(dd,J=10.4,8.0Hz, 1H),7.26-7.17(m,1H),7.13(s,1H),6.36(d,J=2.8Hz,1H),3.57-3.45(m,2H),3.10 -2.96(m,1H),2.93-2.81(m,3H),2.81-2.70(m,4H),2.69-2.57(m,2H),2.31-2.21( m,1H),2.22-2.08(m,1H),2.04-1.89(m,2H),1.84-1.68(m,1H),1.67-1.49(m,2H). LCMS(ESI) C 23 H 26 F2N6O2[M+H] + m / z Calculated value: 457.21, Measured value: 457.30.
[0297] Preparation of 8-fluoro-3-(pyrroridine-3-yl)pyrrolo[1,2-a]pyrazine-1(2H)-one (1405-P2) A solution of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-carboxylate (1404-P2) (90 mg, 0.281 mmol) in HCl-dioxane (4 M, 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was diluted with MeOH (5 mL) and TEA (1 mL). After stirring at room temperature for 5 minutes, the solution was concentrated to dryness to obtain 8-fluoro-3-(pyrrolidine-3-yl)pyrrololo[1,2-a]pyrazine-1(2H)-one (1405-P2) (70 mg, purity 70%, yield 78%) as a white solid. LCMS(ESI) C 11 H 12 FN3O [M+H] + m / z Calculated value: 222.10, Measured value: 222.25.
[0298] Preparation of 6-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (10b) To a 10 mL solution of 8-fluoro-3-(pyrroridine-3-yl)pyrrolo[1,2-a]pyrazine-1(2H)-one (1405-P2) (35 mg, 0.157 mmol) in MeOH (10 mL), 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) (47 mg, 0.188 mmol), 2 drops of HOAc, and NaBH(OAc)3 (33 mg, 0.157 mmol) were added. The mixture was stirred at 50°C for 30 minutes, then NaBH3CN (10 mg, 0.158 mmol) was added and the mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was separated by preparative HPLC (Gemini 5 μm C). 18 The mixture was purified using a 150×21.2mm mobile phase (ACN-H2O (0.1% FA), gradient: 5-90) to obtain 6-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-3-yl)pyrrolidine-1-yl)piperidine-1-yl)-N-methylpicolinamide (10b) (36.3 mg, purity 98%, 100% ee, yield 50%) as a white solid. 1 H NMR(400MHz,DMSO-d6,ppm) δ:10.22(s,1H),8.47-8.30(m,1H),7.84(d,J=8.0Hz,1H),7.58(dd,J=10.4,8.0Hz, 1H),7.23-7.18(m,1H),7.13(s,1H),6.36(d,J=2.8Hz,1H),3.55-3.48(m,2H),3.09 -2.97(m,1H),2.93-2.81(m,3H),2.81-2.74(m,4H),2.71-2.58(m,2H),2.35-2.22( m,1H),2.22-2.08(m,1H),2.04-1.90(m,2H),1.85-1.68(m,1H),1.66-1.49(m,2H). LCMS(ESI) C 23 H 26 F2N6O2[M+H] + m / z Calculated value: 457.21, Measured value: 457.30.
[0299] Example 6: Synthesis of 12a / 12b [ka]
[0300] Preparation of ethyl 2-methyl-1H-imidazole-5-carboxylate (1502) Ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (1501) (2.5 g, 0.0114 mol) was mixed with formamidine (5.1 g, 0.114 mol) and water (5 mL). The mixture was exothermic and heated in a sealed test tube at 130 °C for 2 hours. The mixture was then cooled to room temperature and 100 mL of ice water was added. The resulting solid was collected, washed with water, and dried under vacuum to obtain ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate (1502) (0.8 g, purity 90%, yield 30%) as a brown solid. LCMS(ESI) C7H7F3N2O2[M+H] + m / z Calculated value: 209.05, Measured value: 209.15.
[0301] Preparation of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-4-(trifluoromethyl)-1H-imidazol-5-carboxylate (1503) To a 5 mL solution of ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate (1502) (250 mg, 1.2 mmol) in NMP (5 mL), tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate (1005) (528 mg, 1.8 mmol) and Cs2CO3 (782 mg, 2.4 mmol) were slowly added under an N2 atmosphere. The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with Â(50 mL × 3). The combined organic phases were washed with saturated saline solution, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH / DCM, eluted at 3% to 10%) to obtain ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-4-(trifluoromethyl)-1H-imidazol-5-carboxylate (1503) (200 mg, purity 90%, yield 35%) as a yellow solid. LCMS(ESI) C 18 H 24 F3N3O5[M+H] + m / z Calculated value: 420.17, Measured value: 419.98.
[0302] Preparation of tert-butyl 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1504) A solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxoethyl)-4-(trifluoromethyl)-1H-imidazo-l-5-carboxylate (1503) (200 mg, 0.49 mmol) in NH3-MeOH (7 M, 20 mL) was heated in a steel bomb at 130 °C for 16 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (MeOH / DCM, elution at 3% to 10%) to obtain tert-butyl 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1504) (120 mg, purity 90%, yield 58%) as a white solid. LCMS(ESI) C 16 H 19 F3N4O3[M+H] + m / z: Calculated value: 373.14, Measured value: 373.10.
[0303] Preparation of 6-(pyrroridine-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazine-8(7H)-one hydrochloride (1505) A solution of tert-butyl 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazine-6-yl)pyrrolidine-1-carboxylate (1504) (120 mg, 0.32 mmol) in HCl-dioxane (4 M, 5 mL) was stirred at room temperature for 2 hours. By concentrating the mixture under reduced pressure, 6-(pyrrolidine-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazine-8(7H)-one hydrochloride (1505) (80 mg, purity 90%, yield 72%) was obtained as a white solid. LCMS(ESI) C 11 H 11 F3N4O [M+H] +m / z Calculated value: 273.09, Measured value: 273.15.
[0304] Preparation of a racemic mixture (12rac) of N-methyl-5-(4-(3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide To a 5 mL solution of 6-(pyrroridine-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazine-8(7H)-one hydrochloride (1505) (80 mg, 0.26 mmol) in MeOH, N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-1) (90 mg, 0.39 mmol), 2 drops of acetic acid, NaBH3CN (16 mg, 0.26 mmol), and NaBH(OAc)3 (109 mg, 0.52 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini-C18 150×21.2 mm, eluted with 10% to 40% ACN / H2O containing 0.1% FA) to obtain N-methyl-5-(4-(3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (12rac) (30 mg, purity 95%, yield 22%), a racemic mixture of 12a and 12b, as a white solid.
[0305] Chiral separation of N-methyl-5-(4-(3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazine-6-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide to obtain 12a and 12b 12rac (racemic mixture) was separated by SFC (column: Regis(R,R)-Whelk-O1 20mm×250mm I.D., 5μm; mobile phase: CO2 / MeOH[0.1%(NH3)]=60 / 40) and concentrated under reduced pressure to obtain fraction 12a (12.4mg, purity 99%, 100% ee, white solid) as the first fraction and fraction 12b (7.2mg, purity 99%, 100% ee, white solid) as the second fraction. 12a 1¹H NMR (400MHz, DMSO-d6, ppm) δ:11.00(s,1H),8.43-8.34(m,1H),8.32(s,1H),8.28(d,J=2.8Hz,1H),7. 82(d,J=8.8Hz,1H),7.47(s,1H),7.41-7.33(m,1H),3.88-3.78(m,2H),3.1 5-3.11(m,1H),2.99-2.86(m,3H),2.80-2.75(m,4H),2.66-2.62(m,2H),2 .21-2.17(m,1H),1.97-1.91(m,2H),1.83-1.77(m,1H),1.58-1.45(m,2H). LCMS(ESI) C 23 H 26 F3N7O2[M+H] + m / z calculated value: 490.21, measured value: 490.15. 12b 1 ¹H NMR (400MHz, DMSO-d6, ppm) δ:11.04(s,1H),8.41-8.35(m,1H),8.33(s,1H),8.28(d,J=2.8Hz,1H),7. 82(d,J=8.8Hz,1H),7.48(s,1H),7.43-7.35(m,1H),3.87-3.80(m,2H),3.1 5-3.09(m,1H),3.00-2.85(m,3H),2.81-2.70(m,4H),2.70-2.61(m,2H),2 .26-2.10(m,1H),1.98-1.88(m,2H),1.83-1.74(m,1H),1.58-1.44(m,2H). LCMS(ESI) C 23 H 26 F3N7O2[M+H] + m / z calculated value: 490.21, measured value: 490.15.
[0306] Example 7: Synthesis of 15a / 15b
change
[0307] Preparation of ethyl 1-amino-5-methyl-1H-pyrrol-2-carboxylate (1603) To a solution of ethyl 5-methyl-1H-pyrrol-2-carboxylate (1601) (2500 mg, 16.321 mmol) in DMF (50 mL), NaH (849 mg, 21.217 mmol, 60 wt% in mineral oil) was added at 0°C. After stirring at 0°C for 30 minutes, a solution of O-(2,4-dinitrophenyl)hydroxylamine (1602) (3900 mg, 19.585 mmol) in DMF (5 mL) was added. The mixture was then stirred at room temperature for 2 hours. The resulting reaction mixture was diluted with water and extracted with Â. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain ethyl 1-amino-5-methyl-1H-pyrrol-2-carboxylate (1603) (3.2 g, purity 80%, yield 95%) as a white solid. LCMS(ESI) C8H 12 N2O2[M+H] + m / z Calculated value: 169.09, Measured value: 169.00.
[0308] Preparation of ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamide)-5-methyl-1H-pyrrol-2-carboxylate (1605) To a solution of ethyl 1-amino-5-methyl-1H-pyrrol-2-carboxylate (1603) (3.0 g, 17.837 mmol) in DCM (120 mL), 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (1604) (4.2 g, 19.620 mmol), DIPEA (6.9 g, 53.510 mmol), and T4P (15.4 g, 21.404 mmol, 50 wt% in ethyl acetate) were added. The mixture was stirred at room temperature for 3 hours, concentrated, and purified by flash silica chromatography (Â1 / PE, elution from 0% to 50%) to obtain ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamide)-5-methyl-1H-pyrrol-2-carboxylate (1605) (5.1 g, purity 93%, yield 72%) as an off-white solid. LCMS(ESI) C 18 H 27 N3O5[M+H] +m / z Calculated value: 366.20, Measured value: 366.15.
[0309] Preparation of 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamide)-5-methyl-1H-pyrrol-2-carboxylic acid (1606) To a solution of ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamide)-5-methyl-1H-pyrrol-2-carboxylate (1605) (4.9 g, 0.013 mol) in MeOH / H2O (3:1, 120 mL), NaOH (1.6 g, 0.040 mol) was added. The mixture was heated at 90°C for 2 hours, acidified with 1 M HCl, and extracted with ELISA. The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by flash silica chromatography (MeOH / DCM, eluted from 0% to 8%) to obtain 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamide)-5-methyl-1H-pyrrol-2-carboxylic acid (1606) (1.4 g, purity 80%, yield 24%) as a white solid. LCMS(ESI) C 16 H 23 N3O5[M-Boc+H] + m / z Calculated value: 238.16, Measured value: 238.15.
[0310] Preparation of tert-butyl 3-((2-carbamoyl-5-methyl-1H-pyrrol-1-yl)carbamoyl)pyrrolidine-1-carboxylate (1607) To a solution of 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamide)-5-methyl-1H-pyrrol-2-carboxylic acid (1606) (1350 mg, 3.990 mmol) in THF (50 mL), (NH4)2CO3 (1533 mg, 15.958 mmol), EDCI (1147 mg, 5.984 mmol), and HOBT (269 mg, 1.995 mmol) were added. The mixture was stirred at room temperature for 2 hours, washed with water, and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by flash silica chromatography (Â / PE, elution from 0% to 80%) to obtain tert-butyl 3-((2-carbamoyl-5-methyl-1H-pyrrol-1-yl)carbamoyl)pyrrolidine-1-carboxylate (1607) (535 mg, purity 80%, yield 31%) as a yellow solid. LCMS(ESI) C 16 H 24 N4O4[M+H] + m / z Calculated value: 337.18, Measured value: 337.00.
[0311] Preparation of tert-butyl 3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-1-carboxylate (1608) In a sealed test tube, a solution of tert-butyl 3-((2-carbamoyl-5-methyl-1H-pyrrol-1-yl)carbamoyl)pyrrolidine-1-carboxylate (1607) (500 mg, 1.482 mmol) in aqueous ammonia (NH3·H2O, 12 mL, 25 wt%) was heated at 90°C for 18 hours. The resulting mixture was concentrated and purified by flash silica chromatography (Â1 / PE, elution from 0% to 60%) to obtain tert-butyl 3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-2-yl)pyrrolidine-1-carboxylate (1608) (355 mg, purity 70%, yield 52%) as a yellow solid. LCMS(ESI) C 16 H 22 N4O3[Mt-Bu+H] + m / z Calculated value: 263.17, Measured value: 263.10.
[0312] Preparation of 7-methyl-2-(pyrroridine-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (1609) A solution of tert-butyl 3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-2-yl)pyrroridine-1-carboxylate (1608) (350 mg, 1.096 mmol) in HCl-dioxane (5 mL, 4 M) was stirred at room temperature for 30 minutes and then concentrated to obtain 7-methyl-2-(pyrroridine-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (1609) (290 mg, purity 80%, yield 83%) as a white solid. LCMS(ESI) C 11 H 14 N4O [M+H] + m / z Calculated value: 219.12, Measured value: 219.10.
[0313] Preparation of N-methyl-5-(4-(3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-2-yl)pyrroridine-1-yl)piperidine-1-yl)picolinamide (15rac) 7-methyl-2-(pyrroridine-3-yl)pyrrolo[2,1-f][1,2,4]triazine-4(3H)-one hydrochloride (1609) (100 mg, 0.393 mmol) was dissolved in MeOH (5 mL) and TEA (2 mL) was added. The mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was diluted with MeOH (5 mL) and N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-1) (101 mg, 0.432 mmol) and NaBH3CN (37 mg, 0.589 mmol) were added. The mixture was stirred at room temperature for 2 hours, concentrated, and purified by flash silica chromatography (MeOH / DCM, elution at 0% to 10%) to obtain a racemic mixture (15 rac) (50 mg, purity 95%, yield 27%) of N-methyl-5-(4-(3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-2-yl)pyrroridine-1-yl)piperidine-1-yl)picolinamide as a white solid.
[0314] Chiral resolution of N-methyl-5-(4-(3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-2-yl)pyrroridine-1-yl)piperidine-1-yl)picolinamide (15rac) to obtain 15a and 15b. 15rac (racemic mixture) was separated by SFC (column: Daicel OJ-H 250mm × 20mm ID, 5μm; mobile phase: CO2 / MeOH (0.1%NH3) = 60 / 40) and concentrated under reduced pressure to obtain fraction 15a (15.1 mg, purity 98%, 100% ee, white solid) as the first fraction and fraction 15b (13.5 mg, purity 98%, 100% ee, white solid) as the second fraction. 15a 1 H NMR(400MHz,DMSO-d6,ppm) δ:11.32(s,1H),8.42-8.32(m,1H),8.27(d,J=2.8Hz,1H),7.81(d,J=8.4Hz,1H),7.39( dd,J=8.8,2.8Hz,1H),6.77(d,J=4.0Hz,1H),6.32(d,J=4.0Hz,1H),3.87-3.76(m,2H), 3.25-3.21(m,1H),3.03-2.91(m,3H),2.87-2.80(m,1H),2.78(d,J=4.8Hz,3H),2.74-2 .66(m,2H),2.39-2.32(m,4H),2.20-2.07(m,2H),1.98-1.89(m,2H),1.59-1.45(m,2H). LCMS(ESI) C 23 H 29 N7O2[M+H] + m / z Calculated value: 436.24, Measured value: 436.25. 15b 1H NMR(400MHz,DMSO-d6,ppm) δ:11.32(s,1H),8.42-8.33(m,1H),8.27(d,J=2.8Hz,1H),7.81(d,J=8.8Hz,1H),7.39( dd,J=8.8,2.8Hz,1H),6.77(d,J=4.4Hz,1H),6.32(d,J=4.4Hz,1H),3.87-3.75(m,2H), 3.23-3.18(m,1H),3.04-2.90(m,3H),2.86-2.80(m,1H),2.78(d,J=4.8Hz,3H),2.74-2 .66(m,2H),2.39-2.30(m,4H),2.19-2.06(m,2H),1.99-1.88(m,2H),1.58-1.45(m,2H). LCMS(ESI) C 23 H 29 N7O2[M+H] + m / z Calculated value: 436.24, Measured value: 436.25.
[0315] Example 8: Synthesis of INT-1 (Reference Example) A method for synthesizing INT-1, a useful intermediate in some embodiments of the synthesis method of the present invention, will be described below with reference to Scheme 8. [ka]
[0316] Preparation of 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide (2003) To a solution of 5-fluoro-N-methylpyridine-2-carboxamide (2001) (1.00 g, 6.50 mmol) in DMF (15 mL), 1,4-dioxa-8-azaspiro[4.5]decane (2002) (1.40 g, 9.75 mmol) was added, followed by the addition of Cs2CO3 (2.12 g, 6.50 mmol) at room temperature. The reaction mixture was stirred at 150 °C for 5 hours using a microwave. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 97:3) to obtain 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide (2003) (1.50 g, yield 76%) as a white solid. LCMS(ESI) C 14 H 19 N3O3[M+H] + m / z Calculated value: 278.14, Measured value: 278.14.
[0317] Preparation of N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-1) To a solution of 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide (2003) (1.50 g, 5.40 mmol) in H2O (10 mL), HCl (4 M, 20 mL) in 1,4-dioxane was added at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH > 7 using NaHCO3 solution and then extracted with ELISA (50 mL x 3). The organic phase was dried over Na2SO4 and concentrated to obtain N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-1) (1.50 g, yield 76%) as a yellow solid. LCMS(ESI) C 12 H 15 N3O2[M+H] + m / z Calculated value: 234.12, Measured value: 234.18.
[0318] Example 9: Synthesis of INT-2 (Reference Example) A method for synthesizing INT-2, a useful intermediate in some embodiments of the synthesis method of the present invention, will be described below with reference to Scheme 9. [ka]
[0319] Preparation of 6-chloro-5-fluoro-N-methylpicolinamide (2102) To a solution of 6-chloro-5-fluoropicolinic acid (2101) (2.00 g, 11.40 mmol) in DMF (50 mL), methanamine (420 mg, 13.68 mmol), DIEA (4.42 g, 34.20 mmol), and HATU (6.50 g, 17.10 mmol) were sequentially added at room temperature. The mixture was stirred continuously at room temperature for 1 hour. The resulting mixture was diluted with water and extracted with siRNA (200 mL x 3). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting PE / siRNA = 100:0 to 70:30) to obtain 6-chloro-5-fluoro-N-methylpicolinamide (2102) (2.00 g, yield 88%) as a white solid. LCMS(ESI) C7H6ClFN2O [M+H] + m / z Calculated value: 189.02, Measured value: 188.90.
[0320] Preparation of 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (2104) To a solution of 6-chloro-5-fluoro-N-methylpicolinamide (2102) (2.00 g, 10.60 mmol) in DMF (20 mL), Cs2CO3 (6.91 g, 21.20 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (2002) (3.04 g, 21.20 mmol) were added. Using a sealed test tube, the reaction mixture was stirred at 120 °C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / siRNA = 100:0 to 50:50) to obtain 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide 2104 (1.60 g, yield 42%) as a white solid. LCMS(ESI) C 14 H 18 ClN3O3[M+H] + m / z Calculated value: 312.10, Measured value: 311.95.
[0321] Preparation of 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (2105) 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (2104) (300 mg, 0.96 mmol) was dissolved in DMF (20 mL) and CsF (293 mg, 1.93 mmol) was added. The mixture was stirred using a microwave at 150 °C for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at PE / Â=100:0 to 30:70) to obtain 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (2105) (200 mg, yield 69%) as a yellow solid. LCMS(ESI) C 14 H 18 FN3O3[M+H] + m / z Calculated value: 296.13, Measured value: 295.95.
[0322] Preparation of 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) 6-Fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (2105) (200 mg, 0.68 mmol) was dissolved in H2O (3 mL), to which formic acid (2 mL) was added and the mixture was stirred at 50°C for 1 hour. The pH of the aqueous solution was adjusted to pH 7-8 with NaHCO3 aqueous solution. The mixture was diluted with water (50 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, and concentrated to obtain the crude product of 6-Fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) (100 mg, yield 47%) as a yellow solid. LCMS(ESI) C 12 H14 FN3O2[M+H]+ m / z Calculated value: 252.11, Measured value: 251.90.
[0323] Example 10:21 synthesis [ka]
[0324] Preparation of methyl 1-amino-3-(trifluoromethyl)-1H-pyrrol-2-carboxylate (1703) To a solution of methyl 3-(trifluoromethyl)-1H-pyrrol-2-carboxylate (1701) (900 mg, 4.66 mmol) in DMF (10 mL), NaH (186 mg, 4.66 mmol, 60 wt% in mineral oil) was gradually added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Then, O-(2,4-dinitrophenyl)hydroxylamine (1702) (1392 mg, 6.99 mmol) was added. The mixture was stirred at room temperature for 5 hours. The mixture was gradually quenched with water and then extracted with Âx (100 mL x 3). The combined organic layers were washed with saturated brine (3 times), dried over Na2SO4, filtered, and concentrated to obtain methyl 1-amino-3-(trifluoromethyl)-1H-pyrrol-2-carboxylate (1703) (730 mg, purity 85%, yield 63%) as a yellow solid. LCMS(ESI) C7H7F3N2O2[M+H] + m / z Calculated value: 209.05, Measured value: 209.15.
[0325] Preparation of tert-butyl 4-((2-(methoxycarbonyl)-3-(trifluoromethyl)-1H-pyrrol-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1705) To a solution of methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1703) (730 mg, 3.51 mmol) in pyridine (9 mL), T4P (5345 mg, 7.42 mmol, 50 wt%) in ethyl ammonium was added, followed by 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (1704) (640 mg, 2.80 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by flash silica chromatography (eluting at DCM / MeOH = 100:0 to 93:7) to obtain tert-butyl 4-((2-(methoxycarbonyl)-3-(trifluoromethyl)-1H-pyrol-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1705) (1180 mg, purity 85%, yield 80%) as a yellow solid. LCMS(ESI) C 18 H 22 F3N3O5[M+Na] + m / z Calculated value: 440.15, Measured value: 440.10.
[0326] Preparation of 1-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (1706) To a solution of tert-butyl 4-((2-(methoxycarbonyl)-3-(trifluoromethyl)-1H-pyrrole-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1705) (1.1 g, 0.0026 mol) in DME (15 mL), Sn(CH3)3OH (0.94 g, 0.0052 mol) was added. The resulting mixture was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (elution at DCM / MeOH = 100:0 to 93:7) to obtain 1-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (1706) (900 mg, purity 90%, yield 76%) as a yellow solid. LCMS(ESI) C 17 H 20F3N3O5[MH] - m / z Calculated value: 402.14, Measured value: 402.05.
[0327] Preparation of tert-butyl 4-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrol-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1707) To a solution of 1-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide)-3-(trifluoromethyl)-1H-pyrrol-2-carboxylic acid (1706) (900 mg, 2.23 mmol) in THF (20 mL), (NH4)2CO3 (950 mg, 9.89 mmol), EDCI (711 mg, 3.70 mmol), and HOBT (167 mg, 1.23 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (elution at DCM / MeOH = 100:0 to 96:4) to obtain tert-butyl 4-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrol-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1707) (915 mg, purity 90%, yield 91%) as a yellow solid. LCMS(ESI) C 17 H 21 F3N4O4[MH] - m / z Calculated value: 401.15, Measured value: 401.10.
[0328] Preparation of tert-butyl 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1708) A solution of tert-butyl 4-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrole-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1707) (500 mg, 1.23 mmol) in NH3·H2O (10 mL, approximately 25 wt%) was stirred in a steel bomb at 90°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting at DCM / MeOH = 100:0 to 90:10) to obtain tert-butyl 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1708) (230 mg, purity 80%, yield 38%) as a yellow solid. LCMS(ESI) C 17 H 19 F3N4O3[MH] - m / z Calculated value: 383.14, Measured value: 383.35.
[0329] Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-(trifluoromethyl)pyrrolo[2.1.1-f][1,2,4]triazine-4(3H)-one (1709) A solution of tert-butyl 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1708) (220 mg, 0.57 mmol) in HCl-dioxane (4 M, 6 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with MeOH (4 mL), TEA (0.5 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was then concentrated under reduced pressure to obtain 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-(trifluoromethyl)pyrrolo[2.1-f][1,2,4]triazine-4(3H)-one (1709) (200 mg, purity 70%, yield 86%) as a yellow solid. LCMS(ESI) C 12 H 11 F3N4O [M+H] + m / z Calculated value: 285.09, Measured value: 285.15.
[0330] Preparation of N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (21) To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-(trifluoromethyl)pyrrolo[2.1.f][1,2,4]triazine-4(3H)-one (1709) (45 mg, 0.15 mmol) in MeOH (10 mL) under stirring, AcOH (0.3 mL) and N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-1) (55 mg, 0.23 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Then, NaBH3CN (9 mg, 0.15 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5μm C18 column, 150×21.2mm, eluted with 15% to 65% MeCN / H2O containing 0.1% FA) to obtain N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (21) (0.22FA salt, 20.3 mg, purity 97.13%, yield 24%) as a white solid. 1 H NMR(400MHz,DMSO-d6,ppm) δ:12.10(s,1H),8.45-8.33(m,1H),8.29(d,J=2.8Hz,1H),8.14(s,0.22H),7.82(d,J= 8.8Hz,1H),7.69(d,J=2.8Hz,1H),7.42(dd,J=9.0,2.6Hz,1H),6.90(d,J=2.8Hz,1H),3 .95-3.83(m,2H),3.81-3.72(m,1H),3.13-3.02(m,2H),3.00-2.86(m,2H),2.78(d,J=4 .8Hz,3H),2.65-2.56(m,1H),2.20-2.07(m,2H),2.04-1.83(m,4H),1.57-1.39(m,2H). LCMS(ESI) C 24 H 26 F3N7O2[M+H] +m / z Calculated value: 502.21, Measured value: 502.15.
[0331] Example 11:22 synthesis [ka]
[0332] Preparation of 6-fluoro-N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2.1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (22) To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-(trifluoromethyl)pyrrolo[2.1-f][1,2,4]triazine-4(3H)-one (1709) (45 mg, 0.15 mmol) in MeOH (10 mL) under stirring, AcOH (0.3 mL) and 6-fluoro-N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-2) (59 mg, 0.23 mmol) were added, and the reaction mixture was stirred at room temperature for 20 minutes. Then, NaBH3CN (9 mg, 0.15 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluted with 15% to 65% MeCN / H2O containing 0.1% FA) to obtain 6-fluoro-N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2.1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-yl)piperidine-1-yl)picolinamide (22) (0.63 FA salt, 19.3 mg, purity 96%, yield 21%) as an off-white solid. 1H NMR(400MHz,DMSO-d6,ppm) δ:12.23(s,1H),8.44-8.34(m,1H),8.16(s,0.63H),7.84(d,J=8.0Hz,1H),7.69(d,J= 2.8Hz,1H),7.59(dd,J=10.6,8.2Hz,1H),6.90(d,J=3.2Hz,1H),3.76-3.68(m,1H),3. 59-3.51(m,2H),3.08-2.99(m,2H),2.90-2.81(m,2H),2.77(d,J=4.8Hz,3H),2.57-2. 53(m,1H),2.15-2.06(m,2H),2.03-1.92(m,2H),1.91-1.82(m,2H),1.59-1.45(m,2H). LCMS(ESI) C 24 H 25 F4N7O2[M+H] + m / z Calculated value: 520.20, Measured value: 520.15.
[0333] Example 12: Synthesis of 26a / 26b [ka]
[0334] Preparation of 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine (1802) A solution of 5,7-dichloroimidazo[1,2-c]pyrimidine (1801) (1 g, 0.0053 mol) and MeONa (570 mg, 0.0106 mol) in MeOH (20 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / SiO = 100:0 to 80:20) to obtain 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine (1802) (790 mg, purity 90%, yield 73%) as a white solid. LCMS(ESI) C7H6ClN3O [M+H] + m / z Calculated value: 184.02, Measured value: 183.95.
[0335] Preparation of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidine-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1804) To a solution of 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine (1802) (790 mg, 4.3029 mmol) in dioxane / H2O (15 mL, 10:1), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1803) (1.4 g, 4.7331 mmol), RuPhos Pd G3 (360 mg, 0.4302 mmol), and K2CO3 (1.78 g, 12.9087 mmol) were sequentially added. The reaction mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / siRNA = 100:0 to 60:40) to obtain tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidine-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1804) (900 mg, purity 90%, yield 59%) as a yellow solid. LCMS(ESI) C 16 H 20 N4O3[M+H]+ m / z Calculated value: 317.15, Measured value: 317.25.
[0336] Preparation of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1805) A solution of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidine-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1804) (900 mg, 2.8359 mmol) and Pd / C (302 mg, 10 wt%) in MeOH (15 mL) was stirred at room temperature for 2 hours under a balloon pressure H2 environment. The mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1805) (850 mg, purity 90%, yield 84%) as a colorless oil. LCMS(ESI) C 16 H 22 N4O3[M+H] + m / z Calculated value: 319.17, Measured value: 319.20.
[0337] Preparation of tert-butyl 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1806) To a solution of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1805) (850 mg, 2.6614 mmol) in DCM (30 mL), NIS (599 mg, 2.6614 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by flash column chromatography (elution at PE / siRNA = 100:0 to 60:40) to obtain tert-butyl 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1806) (1.04 g, purity 90%, yield 78%) as a white solid. LCMS(ESI) C 16 H 21 IN4O3[M+H] + m / z Calculated value: 445.07, Measured value: 445.05.
[0338] Preparation of tert-butyl 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1808) To a 15 mL solution of tert-butyl 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1806) (500 mg, 1.1229 mmol) in DMF (15 mL), nano Cu (143 mg, 2.2458 mmol) and 5-(trifluoromethyl)-4a,10a-dihydro-5H-thianthrene-5-ium (1807) (648 mg, 2.2458 mmol) were sequentially added. The reaction mixture was stirred at 100°C for 6 hours under an N2 atmosphere. The reaction mixture was poured into water and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting at PE / Â = 100:0 to 50:50) to obtain tert-butyl 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1808) (150 mg, purity 90%, yield 30%) as a white solid. LCMS(ESI) C 17 H 21 F3N4O3[M+H] + m / z Calculated value: 387.16, Measured value: 387.10.
[0339] Preparation of 7-(pyrrolidine-3-yl)-3-(trifluoromethyl)imidazo[1,2-c]pyrimidine-5(6H)-one (1809) A solution of tert-butyl 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-carboxylate (1808) (150 mg, 0.3862 mmol) in HBr (3 mL, 48% in H2O) was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with MeOH (3 mL) and TEA (0.5 mL) and stirred at room temperature for 5 minutes. The mixture was concentrated under reduced pressure to obtain 7-(pyrrolidine-3-yl)-3-(trifluoromethyl)imidazo[1,2-c]pyrimidine-5(6H)-one (1809) (115 mg, purity 90%, yield 98%) as a white solid. LCMS(ESI) C 11 H11 F3N4O [M+H] + m / z Calculated value: 273.09, Measured value: 273.05.
[0340] Preparation of N-methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (26a / 26b racemic mixture) To a solution of 7-(pyrroridine-3-yl)-3-(trifluoromethyl)imidazo[1,2-c]pyrimidine-5(6H)-one (1809) (115 mg, 0.4209 mmol) in MeOH (5 mL), N-methyl-5-(4-oxopiperidine-1-yl)picolinamide (INT-1) (118 mg, 0.5050 mmol), AcOH (1 drop), and NaBH3CN (53 mg, 0.8418 mmol) were sequentially added. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: ACN-H2O (0.05% NH3); gradient: 30-95) to obtain N-methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (26a / 26b racemic mixture) (70 mg, purity 95%, yield 32%) as a white solid.
[0341] Chiral separation of N-methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-c]pyrimidine-7-yl)pyrrolidine-1-yl)piperidine-1-yl)picolinamide (26a / 26b racemic mixture) The 26a / 26b racemic mixture was separated by SFC (column: Daicel Chiralpak IH SFC; 20 mm I.D. × 250 mm, 5 μm; mobile phase: CO2 / MeOH [0.1% NH3 (7M MeOH solution)] = 70 / 30), and concentrated under reduced pressure to obtain compound 26a (27.8 mg, purity 96.88%, 100% ee, white solid) as the first fraction and compound 26b (29.3 mg, purity 98.66%, 100% ee, white solid) as the second fraction. Compound 26a 1H NMR(400MHz,DMSO-d6,ppm) δ:8.41-8.35(m,1H),8.28(d,J=2.4Hz,1H),7.89(s,1H),7.82(d,J=8.8H z,1H),7.40(dd,J=8.8,2.8Hz,1H),6.59(s,1H),3.87-3.78(m,2H),3.29- 3.15(m,1H),3.04-2.88(m,3H),2.86-2.72(m,5H),2.72-2.60(m,1H),2. 40-2.29(m,1H),2.26-2.14(m,1H),2.00-1.83(m,3H),1.60-1.46(m,2H). LCMS(ESI) C 23 H 26 F3N7O2[M+H] + m / z Calculated value: 490.21, Measured value: 490.10. Compound 26b 1 H NMR(400MHz,DMSO-d6,ppm) δ:8.43-8.33(m,1H),8.27(d,J=2.8Hz,1H),7.85-7.78(m,2H),7.40(dd,J=8.8,3.0Hz,1H),6.51(s,1H),3.86-3.79(m,2H),3.26-3.13(m,1 H),3.02-2.85(m,3H),2.78(d,J=4.8Hz,3H),2.76-2.65(m,3H),2.37- 2.31(m,1H),2.24-2.10(m,1H),2.01-1.87(m,3H),1.61-1.44(m,2H). LCMS(ESI) C 23 H 26 F3N7O2[M+H] + m / z Calculated value: 490.21, Measured value: 490.10.
[0342] Example 13: Assay Exemplary compounds of the present invention were prepared and tested to determine their effects as PARP1 and PARP2 inhibitors. Typical assays are described below.
[0343] Example 13A: PARP1 biochemical dissociation-enhanced lantanide fluorescence immunoassay (DELFIA assay) Optiplate HB 384-well plates were coated with anti-FLAG antibody. The anti-FLAG antibody was supplied as a 4 mg / ml solution, and coating was performed overnight at 4°C using Na2CO3 / HCO3 coating buffer at pH 9.6, so that 0.3 g per well was ultimately immobilized. Next, the wells were washed three times for 5 minutes with coating wash buffer (PBS / 0.05% Tween (v / v)) and blocked overnight at 4°C with coating wash buffer containing 2% BSA (w / v). Before assay, each well was washed three times for 5 minutes with coating wash buffer. For the assay, 20 μL of 2.5 nM recombinant full-length N-terminal FLAG-tagged human PARP1 was added to each well of the 384-well plate and left at room temperature for 30 minutes, after which 50 nL of DMSO solution of each compound was added using the pin tool technique. After incubation at room temperature for 30 minutes, 5 μL of assay buffer (20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), 0.02% Tween (v / v)) containing 10 μM biotin-NAD+ and 10 nM activated DNA (sequence below) was added. After allowing autoparylation of poly-ADP-ribosylation to proceed at room temperature for 2 hours, 5 μL of 12 mM NAD+ quench solution was added. After 30 minutes at room temperature, the assay solution was removed, the plate was washed 5 times for 3 minutes, and 100 μL of a 1:1000 dilution of DELFIA Eu-N1 streptavidin reagent was added. The plate was then incubated at room temperature for 30 minutes. The reaction mixture was removed, the plate was washed 5 times for 3 minutes, and 25 μL of DELFIA enhancement solution was added. After incubation at room temperature for 30 minutes, fluorescence was measured using Pherastar FS (Ex: 337 nm, Em: 620 nm, integration start: 60 μs, integration time: 400 μs).
[0344] Typically, the compound is tested in a 12-point concentration-response curve at 3-fold dilution intervals starting from 20 μM, and IC50 is measured. 50The values were determined. The data were analyzed using ActivityBase software, and the replicate values for low control (no enzyme, 0.2% DMSO) and high control (0.2% DMSO) were averaged. The data obtained from the test compound were expressed as a percentage of 100% using the following formula: % value = 100 - (100 * ((high control - value) / (high control - low control)) The % data were fitted using a nonlinear regression equation (log inhibitor vs response - variable slope (4 parameters)), and IC 50 The value was calculated. IC of various test compounds 50 The values are shown in Table 1.
[0345] Activated DNA sequence [ka]
[0346] Example 13B: PARP1 probe-substituted homogeneous time-resolved fluorescence assay (HTRF assay) 10 nM full-length N-terminal FLAG-tagged PARP1 was incubated with 2 nM anti-FLAG Tb-cryptate antibody and a PARP1 / 2 Cy5 fluorescent dye-labeled conjugated probe (10x probe Kd = 270 nM) in assay buffer (20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w / v), 0.02% Tween (v / v)) at room temperature for 40 minutes. The Cy5-labeled conjugated probe is shown below and is also described in Papeo, G. et al. J. Biomol.Screen. 2014;19:1212-1219. Next, this reaction mixture (6 μL) was transferred to each well of a black non-binding surface 384-well plate, and DMSO solution (35 nl) of each compound was added using the pin tool technique. After incubation at room temperature for 1 hour, fluorescence was measured using an HTRF module with Pherastar FS (Ex: 337 nm, Em: 620 nm, em: 665 nm, integration start 60 μs, integration time 400 μs).
[0347] Typically, the compound is tested in a 12-point concentration-response curve at 3-fold dilution intervals starting from 58.5 μM, and IC50 is measured. 50 The values were determined. Data were analyzed using ActivityBase software. The replicate values for the low control (no enzyme, with probe and Tb-cryptate antibody, 0.6% DMSO) and high control (0.6% DMSO) were averaged, and the data obtained from the test compound were expressed as % activity relative to 100% using the following formula: % activity = 100 * (value - low control) / (high control - low control) The % activity data was fitted using a nonlinear regression equation, and IC 50 The value was calculated.
[0348] K d The values were calculated using the Cheng-Prussoff formula: I C 50 =(1+([probe concentration] / [K m(probe) ]))*K d Therefore, K d =IC 50 / (1+[[probe concentration] / [K m(probe) ]]) and 10 × K m Using the probe, this equation becomes K d =IC 50 It is equal to / 11.
[0349] Example 13C: PARP2 probe-substituted homogeneous time-resolved fluorescence assay (HTRF assay) This assay uses N-terminal FLAG-tagged PARP2 (amino acids 1-583) instead of PARP1, and uses a PARP1 / 2 binding probe with a 10x probe K d The assay was performed under the same conditions as for PARP1, except that it was performed at a concentration of 540 nM. Data analysis was performed using the same method as for PARP1.
[0350] Structure of the Cy5 probe [ka]
[0351] NanoBRET cell target occupation assay NanoBRET assays were used to demonstrate cell target engagement and selectivity for PARP1 and PARP2. 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 cell probe substitution assays can be used to measure inhibitor affinity and selectivity for PARP1 and 2.
[0352] Frozen HEK293 cells transiently transfected with either the PARP1-NanoLuc(R) fusion construct or the PARP2-NanoLuc(R) fusion construct (Promega) were thawed, and the suspension was dispensed into 384-well microplates at a cell density of 1750 cells per well. Next, NanoBRET was used for the PARP1 and PARP2 assays. TM TE PARP Tracer-01 was added to final concentrations of 11 nM and 2 nM, respectively. The compounds were added at 3-fold dilution intervals starting from 25 μM to create 12 points on the concentration-reaction curve, and the plate was incubated at 37°C for 2 hours. Next, NanoBRET was performed according to the manufacturer's instructions. TM After adding Nano-Glo(R) substrate and extracellular NanoLuc(R) inhibitor, the BRET ratio was measured using a NanoBRET module (LUM 610-LP 450-80) and a PHERAstar FS or FSX reader. d The values were calculated using the Cheng-Prussoff formula: I C 50 =(1+([tracer concentration] / [K m(tracer) ]))*K d
[0353] Table 1 summarizes the efficacy, affinity, and selectivity data for various test compounds obtained using DELFIA and probe-substituted HTRF assays. Table 1 also summarizes the efficacy, affinity, and selectivity data for some test compounds obtained using the NanoBRET assay.
[0354] Table 1: Results of PARP1 / 2 assays for selected compounds (DELFIA and probe-substituted HTRF) [Table 1-1] [Table 1-2]
[0355] Table 2: Results of PARP1 / 2 assay for selected compounds (NanoBRET) [Table 2]
[0356] Legend The results of the DELFIA, probe-substituted HTRF, and NanoBRET assays are categorized as follows: "-" is IC 50 or K d This indicates that the value is greater than 10 μM. "+" is IC 50 or K d This indicates that the value is greater than 1 μM and less than or equal to 10 μM. "++" is IC 50 or K d This indicates that the value is greater than 100 nM and less than or equal to 1 μM. "+++" is IC 50 or K d This indicates that the value is greater than 10 nM and less than or equal to 100 nM. "++++" is IC 50 or K d This indicates that the value is 10 nM or less. Selectivity can be categorized as follows: The "-" indicates that the value is less than 10. The "+" sign indicates that the value is between 10 and 50 (inclusive). "++" indicates that the value is between 50 and 100. "+++" indicates that the value is 100 or greater. The selectivity value represents the selectivity that preferentially inhibits PARP1 over PARP2. These are the K values for inhibiting PARP1 and PARP2. d Based on the ratio of values, K d (PARP2) / K d It is calculated as (PARP1).
[0357] It should be understood that the embodiments described above are merely illustrative examples.
[0358] Other variations or uses of the technology described herein will be apparent to those skilled in the art who have access to this disclosure. The scope of this disclosure is not limited to the embodiments described herein, but is limited only by the appended claims.
Claims
1. A PARP1 inhibitor compound for use in pharmaceuticals, having the following structure: 【Chemistry 1】 (In the formula, Each R １ These are independently selected from H and substituted or unsubstituted organic groups; R ２ is either absent or selected from H and substituted or unsubstituted organic groups; R ３ is selected from H and substituted or unsubstituted organic groups; Z １ is C or N; Z ２ｕ and Z ２ｌ These are selected from C and N, respectively; however, Z ２ｕ and Z ２ｌ Provided that at least one of them is N; Each Z ３ is independently selected from C and N; and L has the following structure: 【Chemistry 2】 (In the formula, Dashed lines represent single or double bonds; Each R ５Ａ and each R ５Ｃ These are independently selected from H and substituted or unsubstituted organic groups; R ６ is either absent or selected from H and substituted or unsubstituted organic groups; each X １ These are independently selected from C and N; each X ２ These are independently selected from C, N, O, and S; n is a number selected from 0, 1, 2, 3, 4, 5, and 6; m is a number selected from 0, 1, 2, 3, 4, 5, and 6; provided that m + n is a number selected from 2, 3, 4, 5, and 6; r is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; s is a number independently selected from 0, 1, 2, 3, 4, 5, and 6; provided that r + s is a number selected from 2, 3, 4, 5, and 6; b does not exist, or has the following structure: 【Transformation 3】 (In the formula, p is a number selected from 0, 1, 2, 3, 4, 5, and 6; q is a number selected from 0, 1, 2, 3, 4, 5, and 6; provided that p + q is a number selected from 2, 3, 4, 5, and 6; Each R ５Ｂ This is a ring having, independently, absent, or selected from H and substituted or unsubstituted organic groups; Q ＡＥ Q ＡＢ , and Q ＢＣ Each of these is independent, does not exist, or is selected from the following: 【Chemistry 4】 (In the formula, t is a number selected from 0, 1, 2, 3, 4, and 5; 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; Each R ７ and R ８ These are independently selected from H and substituted or unsubstituted organic groups.
2. The PARP1 inhibitor compound according to claim 1, wherein L has the following structure. 【Transformation 5】
3. Each R １ It does not exist independently, or -hydrogen; -C １ ~C ６ Alkyl, aminoalkyl, alkoxy, or haloalkyl groups; -C3 to C6 cycloalkyl groups; - Halogen group; - Nitrile group; and, -below: 【Transformation 6】 (In the formula, R ２２ H, C １ ~C ６ alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ alkoxy, C １ ~C ６ Selected from haloalkyls and halogens (optionally F); each R ２３ R is independently selected from H and substituted or unsubstituted organic groups; here, optionally, each R ２３ H and C are independent of each other. １ ~C ６ Selected from alkyl, aminoalkyl, alkoxy, or haloalkyl groups, and halogen groups; further optionally, at least one R ２３ (is H.) A PARP1 inhibitor compound selected from, according to claim 1 or 2.
4. Each R １ Independently, non-existent, or H; halogen, optionally Cl or F; C １ ~C ３ Alkyl group, optionally methyl group; C １ ~C ３ A haloalkyl group, optionally a halomethyl group (-CH ２ F, -CHF ２ , or -CF ３ ), or a haloethyl group (e.g., -CH ２ CF ３ ); and a PARP1 inhibitor compound according to claim 3, selected from a nitrile group.
5. Each R １ These are independently absent, or H, Cl, F, methyl group, CF ３ A PARP1 inhibitor compound according to claim 4, selected from a nitrile group.
6. Exactly one R １ Cl, F, methyl group, CF ３ , and selected from nitrile groups; and, Other R １ Each of them is either H or does not exist. The PARP1 inhibitor compound according to claim 4.
7. at least one R １ A PARP1 inhibitor compound according to any of the preceding claims, wherein is H.
8. Z １ A PARP1 inhibitor compound according to any of the prior claims, wherein C is C.
9. R ２ H; halogen, optionally F or Cl; C １ ~C ３ Alkyl, optionally isopropyl or cyclopropyl; C １ ~C ３ Haloalkyl, optionally -CH ２ F, -CHF ２ , -CF ３ ien-CH ２ CF ３ , or -CH ２ CH ２ F;C １ ~C ３ Alcohol, optionally -CH ２ CH ２ OH; C １ ~C ３ alkoxy, optionally methoxy, methoxymethyl, or methoxyethyl; or C １ ~C ３ A PARP1 inhibitor compound according to claim 8, selected from the aminoalkyl groups.
10. R ２ The PARP1 inhibitor compound according to claim 9, wherein is H.
11. Z １ is N, R ２ A PARP1 inhibitor compound according to any one of claims 1 to 7, which does not exist.
12. R ３ H, C １ ~C ３ Alkyl and C １ ~C ３ A PARP1 inhibitor compound according to any of the preceding claims, selected from the haloalkyl groups.
13. at least two Z ３ A PARP1 inhibitor compound according to any of the preceding claims, wherein the atom is C.
14. Z ２ｕ and Z ２ｌ A PARP1 inhibitor compound according to any of the preceding claims, wherein either of the following is C.
15. A PARP1 inhibitor compound according to claim 13, having the following structure. 【Transformation 7】
16. A PARP1 inhibitor compound according to claim 15, having a structure selected from the following. 【Transformation 8】
17. A PARP1 inhibitor compound according to claim 15, having a structure selected from the following. 【Chemistry 9】
18. A PARP1 inhibitor compound according to claim 16, having any of the following structures. 【Chemistry 10】
19. A PARP1 inhibitor compound according to claim 14, having the following structure. 【Chemistry 11】
20. A PARP1 inhibitor compound according to claim 19, having a structure selected from the following. 【Chemistry 12】
21. A PARP1 inhibitor compound according to claim 20, having a structure selected from the following. 【Chemistry 13】
22. Q ＡＥ It does not exist, or -CH ２ - and optionally Q ＡＥ A PARP1 inhibitor compound according to any of the prior claims does not exist.
23. A PARP1 inhibitor compound according to any of the preceding claims, wherein both n and m are 1 or greater.
24. Ring A has the following structure, the PARP1 inhibitor compound according to any of the preceding claims: 【Chemistry 14】 (In the formula, i is a number selected from 0, 1, 2, 3, 4, 5, and 6; j is a number selected from 0, 1, 2, 3, 4, 5, and 6; provided that the sum of i and j is (n-1); h is a number selected from 1, 2, and 3; n is 1 or greater.
25. The PARP1 inhibitor compound according to claim 24, wherein ring A has the following structure. 【Chemistry 15】
26. i) Ring A is a substituted or unsubstituted homopiperidine, optionally: 【Chemistry 16】 (In the formula, each R ５Ａ is a homopiperidine having a structure selected from H and a substituted or unsubstituted organic group: or ii) Ring A is a substituted or unsubstituted 6-membered aliphatic heteroring, and optionally: 【Chemistry 17-1】 【Chemistry 17-2】 (wherein each R ５Ａ is independently selected from H and a substituted or unsubstituted organic group); or iii) Ring A is a substituted or unsubstituted five-membered aliphatic heteroring, and optionally: [Chemistry 18] (In the formula, each R ５Ａ It has a structure selected from H and substituted or unsubstituted organic groups independently; or, iv) Ring A is a five-membered aromatic ring, optionally pyrrole or pyrazole, and further optionally: 【Chemistry 19】 (In the formula, each R ５Ａ It has a structure that is independently selected from H and substituted or unsubstituted organic groups; or v) Ring A is a substituted or unsubstituted azetidine, optionally: 【Chemistry 20】 (In the formula, each R ５Ａ The structure is independently selected from H and substituted or unsubstituted organic groups. A PARP1 inhibitor compound according to any one of claims 1 to 23.
27. The PARP1 inhibitor compound according to claim 26, wherein ring A has a structure selected from the following. 【Chemistry 21】
28. Ring A is as follows: 【Chemistry 22】 It has a structure selected from the following, preferably ring A is: 【Chemistry 23】 A PARP1 inhibitor compound according to claim 27, having the structure described above.
29. Q ＡＢ It does not exist, or -CH ２ - and optionally Q ＡＢ A PARP1 inhibitor compound according to any of the prior claims does not exist.
30. L is the PARP1 inhibitor compound according to claim 29, having the following structure. 【Chemistry 24】
31. A PARP1 inhibitor compound according to any of the preceding claims, wherein both p and q are 1 or greater, the sum of p and q is optionally 3 or 4, and further optionally p is 2 and q is 2.
32. i) Ring B is a 7-membered saturated heterocycle and can optionally have the following structure: 【Chemistry 25】 (In the formula, Each R ５Ｂ is independently selected from H and a substituted or unsubstituted organic group, and optionally each R ５Ｂ is H; X １ＢＡ C is R ５Ｂ１ is selected from H and substituted or unsubstituted organic groups, and is optionally H; or X １ＢＡ is N, R ５Ｂ１ It does not exist; and, X １ＢＣ C is R ５Ｂ３ is selected from H and substituted or unsubstituted organic groups; or X １ＢＣ is N, R ５Ｂ３ It does not exist.) has; or, ii) Ring B is a 6-membered saturated heterocycle and can optionally have the following structure: 【Chemistry 26】 (In the formula, Each R ５Ｂ Each R is independently selected from H and substituted or unsubstituted organic groups. ５Ｂ is H; X １ＢＡ C is R ５Ｂ１ is selected from H and substituted or unsubstituted organic groups, and is optionally H; or X １ＢＡ is N, R ５Ｂ１ It does not exist; and, X １ＢＣ C is R ５Ｂ３ is selected from H and substituted or unsubstituted organic groups; or X １ＢＣ is N, R ５Ｂ３ It does not exist.) has; or, iii) Ring B is a 5-membered saturated hetero ring and can optionally have the following structure: 【Chemistry 27】 (In the formula, Each R ５Ｂ Each R is independently selected from H and substituted or unsubstituted organic groups. ５Ｂ is H; X １ＢＡ C is R ５Ｂ１ is selected from H and substituted or unsubstituted organic groups, and is optionally H; or X １ＢＡ is N, R ５Ｂ１ It does not exist; and, X １ＢＣ C is R ５Ｂ３ is selected from H and substituted or unsubstituted organic groups; or X １ＢＣ is N, R ５Ｂ３ It does not exist. ) has; The PARP1 inhibitor compound according to claim 31.
33. X １ＢＡ C is R ５Ｂ１ is selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｂ１ The PARP1 inhibitor compound according to claim 32, wherein is H.
34. X １ＢＣ is N, R ５Ｂ３ The PARP1 inhibitor compound according to claim 32 or 33 does not exist.
35. The PARP1 inhibitor compound according to claim 34, wherein ring B has the following structure. 【Chemistry 28】
36. Q ＢＣ It does not exist, or -CH ２ - and optionally Q ＢＣ A PARP1 inhibitor compound according to any of the prior claims does not exist.
37. L is the PARP1 inhibitor compound according to claim 36, having the following structure. 【Chemistry 29】
38. A PARP1 inhibitor compound according to any of the preceding claims, wherein both r and s are 1 or greater, and optionally the sum of r and s is 3 or 4.
39. i) Ring C is a 6-membered aliphatic ring and can optionally have the following structure: 【Transformation 30】 (In the formula, R ５Ｃ and R ５Ｃ１ Each of these is independently selected from H and a substituted or unsubstituted organic group, preferably where R ５Ｃ１ H is H, and more preferably, R ５Ｃ１ and each R ５Ｃ It is a six-membered aliphatic ring having H; or, ii) Ring C is a 6-membered aromatic ring, and optionally, ii) Phenyl group, optionally: 【Chemistry 31】 (In the formula, each R ５Ｃ R is independently selected from H and substituted or unsubstituted organic groups, and optionally, each R ５Ｃ It is H.) It has a structure selected from; or, iib) Pyridine group, optionally: 【Chemistry 32】 (In the formula, each R ５Ｃ R is independently selected from H and substituted or unsubstituted organic groups, and optionally, each R ５Ｃ It has a structure selected from H; ii) Diazine group, optionally the following: 【Transformation 33】 (In the formula, each R ５Ｃ R is independently selected from H and substituted or unsubstituted organic groups, and optionally, each R ５Ｃ It has a structure selected from H; Select from: or, iii) Ring C is a five-membered aromatic ring, and optionally, iii) Imidazole group, optionally the following: 【Transformation 34】 (In the formula, each R ５Ｃ R is independently selected from H and substituted or unsubstituted organic groups, and optionally, each R ５Ｃ an imidazole group having a structure selected from H; iiib) Thiophene group, optionally: 【Chemistry 35】 (In the formula, each R ５Ｃ R is independently selected from H and substituted or unsubstituted organic groups, and optionally, each R ５Ｃ It has a structure selected from H; iii) Thiazole group, optionally the following: 【Transformation 36】 (In the formula, each R ５Ｃ R is independently selected from H and substituted or unsubstituted organic groups, and optionally, each R ５Ｃ It has a structure selected from H; iii) Triazole group, optionally the following: 【Chemistry 37】 (In the formula, R ５Ｃ is selected from H and substituted or unsubstituted organic groups, and optionally R ５Ｃ A triazole group having a structure selected from H; Selected from, The PARP1 inhibitor compound according to claim 38.
40. The PARP1 inhibitor compound according to claim 39, wherein ring C is selected from the following. 【Chemistry 38-1】 【Chemistry 38-2】
41. The PARP1 inhibitor compound according to claim 39, wherein ring C has the following structure: 【Chemistry 39】 (In the formula, R ５Ｃ２о is selected from H, methyl group, and halogen; and, i) X ２ＣＭ C is R ５Ｃ２Ｍ is H; or, ii) X ２ＣＭ is N, R ５Ｃ２Ｍ It does not exist.
42. R ５Ｃ２о The PARP1 inhibitor compound according to claim 41, wherein the compound is selected from H and halogens.
43. R ５Ｃ２о The PARP1 inhibitor compound according to claim 42, wherein is a halogen, and optionally F.
44. The PARP1 inhibitor compound according to any one of claims 41 to 43, wherein ring C has a structure selected from the following. 【Chemistry 40】
45. The PARP1 inhibitor compound according to claim 41, wherein ring C has a structure selected from the following. 【Chemistry 41】
46. The PARP1 inhibitor compound according to any one of claims 41 to 45, wherein ring C has a structure selected from the following. 【Chemistry 42】
47. R ６ H, -F, -Cl, -Br, -I, -CN, -CONR ５１ R ５１ , -NR ５１ COR ５２ , -SO ２ NR ５１ R ５１ , -NR ５１ SO ２ R ５２ , -O-CR ５２ R ５２ R ５２ , -CR ５２ R ５２ NR ５１ R ５１ , and the following structure: 【Chemistry 43】 (In the formula, R ５１ and R ５２ Each is independently selected from H and a substituted or unsubstituted organic group, and optionally R ５１ and R ５２ These are H, halogen, and optionally deuterized C, each independently. １ ~C ３ Alkyl and C １ ~C ３ A PARP1 inhibitor compound according to any one of claims 1 to 43, selected from any of the haloalkyl groups.
48. R ６ The PARP1 inhibitor compound according to claim 47, having the following structure: 【Chemistry 44】 (In the formula, R ５１ The following can be selected: -C １ ~C ６ Alkyl alkyl group, optionally C ３ ~C ６ Cycloalkyl groups, C １ ~C ３ an alkyl group, or C １ ~C ３ Deuterated alkyl groups; -C １ ~C ３ A haloalkyl group, optionally C １ ~C ３ Fluoroalkyl groups; and, - A saturated heterocyclic group with 4, 5, 6, or 7 members, or optionally a cyclic ether group with 4, 5, or 6 members.
49. R ６ The PARP1 inhibitor compound according to claim 48, which is selected from the following. 【Chemistry 45】
50. R ６ -F, -Cl, -CN, -CONH ２ , -CONHMe (optionally -CONHCD) ３ ), -CONHEt, -CONMe ２ , -CONHCMe, -CONHCH ２ -CH ２ OMe, -CONH-CH ２ -CH ２ F, -CONH-CH ２ -CF ３ , -CONH-CH ２ - CHF ２ , -OCHF ２ , -NHCOMe, -NHSO ２ Me, -SO ２ NHMe, -CONHSO ２ Me, and the following: 【Chemistry 46】 A PARP1 inhibitor compound according to claim 47, selected from the above.
51. R ６ The PARP1 inhibitor compound according to claim 50, wherein the compound is CONHMe.
52. R ６ The following: 【Chemistry 47】 The PARP1 inhibitor compound according to claim 51.
53. R ６ The following: 【Chemistry 48】 The PARP1 inhibitor compound according to claim 50.
54. R ６ The PARP1 inhibitor compound according to any one of claims 1 to 40, having the following structure: 【Chemistry 49】 (In the formula, each X ６ These are independently selected from C, N, and O; R ６１ It either does not exist or is H; Each R ６２ These are either not present independently, or they are H, a halo group (e.g., F), an oxo group, or C. １ ~C ３ alkyl group, C １ ~C ３ Haloalkyl group (optionally C １ ~C ３ (of fluoroalkyl groups), and -NHR ６３ (Here, R ６３ is H or C １ ~C ３ It is an alkyl group. (Selected from the following.)
55. R ６ The PARP1 inhibitor compound according to claim 54, wherein the compound has a structure selected from the following. [Transformation 50]
56. R ６ and one R ５Ｃ The groups combine to form a ring, the PARP1 inhibitor compound according to any one of claims 1 to 39.
57. R ５Ａ (For example, R ５Ａ１ , R ５Ａ２ , and R ５Ａ３ A PARP1 inhibitor compound according to any of the prior claims, wherein each of the elements is H.
58. R ５Ｂ (For example, R ５Ｂ１ , and R ５Ｂ３ A PARP1 inhibitor compound according to any of the prior claims, wherein each of the elements is H.
59. R ５Ｃ (For example, R ５Ｃ１ Each of the following is selected from H and halogen, where R is a halogen. ５Ｃ A PARP1 inhibitor compound according to any of the preceding claims, wherein there is one or fewer halogens, and optionally the halogen is F.
60. Q ＡＥ Q ＡＢ , and Q ＢＣ At least one of the PARP1 inhibitor compounds according to any of the preceding claims is selected from the following: 【Chemistry 51】 (In the formula, t+u is greater than or equal to 1; R ７ This includes H, halogens (e.g., -F, -Cl, -Br, and -I, preferably -F), and substituted or unsubstituted C. １ ~C ６ Alkyl alkyl groups, substituted or unsubstituted linear or branched C １ ~C ６ Halogenated alkyl group (preferably CF) ３ ), -NH ２ C as a base, substituted, or unsubstituted group １ ~C ６ amino group, -OH group, or substituted or unsubstituted linear or branched C １ ~C ６ The alcohol group and substituted or unsubstituted C １ ~C ６ Selected from the alkoxy groups.
61. R ７ This includes H, halogen (preferably F), and substituted or unsubstituted C. １ ~C ６ Alkyl groups, and substituted or unsubstituted linear or branched C １ ~C ６ A PARP1 inhibitor compound according to claim 60, selected from the halogenated alkyl groups.
62. Q ＡＥ Q ＡＢ , and Q ＢＣ At least one of the PARP1 inhibitor compounds according to any of the preceding claims has the following structure: 【Chemistry 52】 (In the formula, R ８ The following can be selected: -H; - Substitutable or unsubstituted linear or branched C １ ~C ６ Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, pentyl group, and hexyl group); - Substitutable or unsubstituted linear or branched C １ ~C ６ alkyl-aryl groups (e.g., -CH ２ Ph, -CH ２ (2, 3 or 4) F-Ph, -CH ２ (2, 3 or 4) Cl-Ph, -CH ２ (2, 3 or 4) Br-Ph, -CH ２ (2, 3 or 4) I-Ph, -CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ CH ２ Ph, and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., pH); - Substitutable or unsubstituted linear or branched C １ ~C ６ halogenated alkyl groups (e.g., -CH ２ F, -CF ３ ien-CH ２ CH ２ F, and -CH ２ CF ３ etc.); - Substituted or unsubstituted cyclic amine or amide groups (e.g., pyrrolidine-3-yl, piperidine-3-yl, piperidine-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl, etc.); - Substitutable or non-substitutable C ３ ~C ８ cyclic alkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); - Substitutable or unsubstituted linear or branched C ２ ~C ６ The alcohol group (e.g., -CH ２ CH ２ OH, -CH(CH ３ )CH ２ OH, -C(CH ３ ) ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ OH, -CH(CH ３ )CH ２ CH ２ OH, -CH(CH ３ )CH(CH ３ )OH, -CH(CH ２ CH ３ )CH ２ OH, -C(CH ３ ) ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ CH ２ OH and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., OH); - Substitutable or unsubstituted linear or branched C ２ ~C ６ The carboxylic acid group (e.g., -CH ２ COOH, -CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ CH ２ COOH and -CH ２ CH ２ CH ２ CH ２ CH ２ COOH, etc.; - Substituted or unsubstituted linear or branched carbonyl groups (e.g., -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH ２ Ph, -(CO)CH ２ OH, -(CO)CH ２ OCH ３ ,-(CO)CH ２ NH ２ ,-(CO)CH ２ NHMe, -(CO)CH ２ NMe ２ -(CO)-cyclopropyl,-(CO)-1,3-epoxypropane-2-yl,-(CO)NH ２ , -(CO)NHMe, -(CO)NMe ２ , -(CO)NHEt, -(CO)NET ２ -(CO)-pyrrolidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methylpiperazine-N-yl, -(CO)NHCH ２ CH ２ OH, -(CO)NHCH ２ CH ２ OMe, -(CO)NHCH ２ CH ２ NH ２ , -(CO)NHCH ２ CH ２ NHMe and -(CO)NHCH ２ CH ２ NMe ２ etc.); - Substitutable or unsubstituted linear or branched C １ ~C ６ Carboxylic acid ester groups (e.g., -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH ２ COOMe, -CH ２ CH ２ COOMe, -CH ２ CH ２ CH ２ COOMe, and -CH ２ CH ２ CH ２ CH ２ COOME, etc.; - Substitutable or unsubstituted linear or branched C １ ~C ６ amide group (e.g., -CO-NH) ２ , -CO-NMeH, -CO-NMe ２ , -CO-NEtH, -CO-NEtMe, -CO-NEt ２ (e.g., -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); - Substituted or unsubstituted sulfonyl groups (e.g., -SO ２ Me, -SO ２ Et, -SO ２ Pr, -SO ２ iPr, -SO ２ Ph, -SO ２ -(2, 3 or 4)-F-Ph, -SO ２ -Cyclopropyl, -SO ２ CH ２ CH ２ OCH ３ , -SO ２ NH ２ , -SO ２ NHMe, -SO ２ NMe ２ , -SO ２ NHEt, -SO ２ NET ２ , -SO ２ -pyrrolidine-N-yl, -SO ２ -morpholine-N-yl, -SO ２ NHCH ２ OMe, and -SO ２ NHCH ２ CH ２ (OMe, etc.); - Substitutable or unsubstituted aromatic groups (e.g., 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)-F ２ -Ph-, 2, (3, 4, 5 or 6)-Cl ２ -Ph-, 2, (3, 4, 5 or 6)-Br ２ -Ph-, 2, (3, 4, 5 or 6)-I ２ -Ph-, 2, (3, 4, 5 or 6)-Me ２ -Ph-, 2, (3, 4, 5 or 6)-Et ２ -Ph-, 2, (3, 4, 5 or 6)-Pr ２ -Ph-, 2, (3, 4, 5 or 6)-Bu ２ -Ph-, 2, (3, 4, 5 or 6)-(CN) ２ -Ph-, 2, (3, 4, 5 or 6)- (NO ２ ) ２ -Ph-, 2, (3, 4, 5 or 6)-(NH ２ ) ２ -Ph-, 2, (3, 4, 5 or 6)-(MeO) ２ -Ph-, 2, (3, 4, 5 or 6)-(CF ３ ) ２ -Ph-, 3, (4 or 5)-F ２ -Ph-, 3, (4 or 5)-Cl ２ -Ph-, 3, (4 or 5)-Br ２ -Ph-, 3, (4 or 5)-I ２ -Ph-, 3, (4 or 5)-Me ２ -Ph-, 3, (4 or 5)-Et ２ -Ph-, 3, (4 or 5)-Pr ２ -Ph-, 3, (4 or 5)-Bu ２ -Ph-, 3, (4 or 5)-(CN) ２ -Ph-, 3, (4 or 5)- (NO ２ ) ２ -Ph-, 3, (4 or 5)-(NH ２ ) ２ -Ph-, 3, (4 or 5)-(MeO) ２ -Ph-, 3, (4 or 5)-(CF ３ ) 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-(NO ２ )-Ph-, 3-(NO ２ )-Ph-, 4-(NO ２ )-Ph-, 2-(NH ２ )-Ph-, 3-(NH ２ )-Ph-, 4-(NH ２ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH ２ -CO)-Ph-, 3-(NH ２ -CO)-Ph-, 4-(NH ２ -CO)-Ph-, 2-CF ３ -Ph-, 3-CF ３ -Ph-, 4-CF ３ -Ph-, 2-CF ３ O-Ph-, 3-CF ３ O-Ph-, and 4-CF ３ O-Ph-, etc.); and, - Substituted or unsubstituted heterocyclic groups (e.g., pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine- 4-yl, pyrimidine-5-yl, pyrimidine-6-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, fran-2-yl, fran-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-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-azapyran-tetrahydrofuran-3-yl, 2-azapyran-tetrahydrofuran-4-yl, 2-azapyran-tetrahydrofuran-5-yl, 3-azapyran-tetrahydrofuran-2-yl, 3-azapyran-teto Lahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetan-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, Thiofen-2-yl, Thiofen-3-yl, Isothiazole-3-yl, Isothiazole-4-yl, Isothiazole-5-yl, Thiazole-2-yl, Thiazole-4-yl, Thiazole-5-yl, Thiopyran-2-yl, Thiopyran-3-yl, Thiopyran-4-yl, 2-Azathiopyran-3-yl, 2-Azathiopyran-4-yl, 2-Azathiopyran-5-yl, 2-Azathiopyran-6-yl, 3-Azathiopyran-2-yl, 3-Azathiopyran-4-yl, 3-Azathiopyran-5-yl, 3-Azathiopyran-6-yl, 4-Azathiopyran-2-yl, 4 (e.g., azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolan-2-yl, thiolan-3-yl, thian-2-yl, thian-3-yl, thian-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-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 tetrazole-5-yl)
63. R ８ H, substituted or unsubstituted C １ ~C ６ Alkyl groups, and substituted or unsubstituted linear or branched C １ ~C ６ A PARP1 inhibitor compound according to claim 62, selected from the halogenated alkyl groups.
64. L is a PARP1 inhibitor compound according to any one of claims 1 to 59, having a structure selected from the following: 【Chemistry 53-1】 【Chemistry 53-2】 (In the formula, R ５Ａ , R ５Ａ１ , R ５Ｂ , R ５Ｂ１ , R ５Ｃ , and R ６ Each of these is independently selected from H and a substituted or unsubstituted organic group.
65. The PARP1 inhibitor compound according to claim 64, wherein L has a structure selected from the following. 【Chemistry 54】
66. A PARP1 inhibitor compound according to any one of claims 1 to 59, having a structure selected from the following: 【Transformation 55】 (In the formula, Z １ is C or N; Z ２ｕ and Z ２ｌ Either of them is C, and Z ２ｕ and Z ２ｌ The other side is N; Each Z ３ These are independently selected from C and N; Each R １ These are independently absent, or H, halogens (e.g., F or Cl), methyl, halomethyl (e.g., CF) ３ ), and selected from CN; R ５Ｃ２о is H, a methyl group, or a halogen; X ２ＣＭ is N, and R ５Ｃ２Ｍ It does not exist, or X ２ＣＭ is C, and R ５Ｃ２Ｍ is H; and, R ６ The following: 【Transformation 56】 Alternatively, see below: 【Chemistry 57】 (That is the case.)
67. R ５Ｃ２о The PARP1 inhibitor compound according to claim 66, wherein is H or a halogen, and optionally F.
68. L is a PARP1 inhibitor compound according to claim 67, wherein L has a structure selected from the following. 【Chemistry 58】
69. L is the PARP1 inhibitor compound according to claim 66, having the following structure. 【Chemistry 59】
70. The PARP1 inhibitor compound according to any one of claims 66 to 69, wherein the compound has a structure selected from the following. 【Chemistry 60-1】 【Chemistry 60-2】 【Transformation 60-3】 【Chemistry 60-4】 【Transformation 60-5】
71. R １ , R ２ , R ３ , R ５Ａ (For example, R ５Ａ１ , R ５Ａ２ ), R ５Ｂ (For example, R ５Ｂ１ , R ５Ｂ２ , R ５Ｂ３ ), R ５Ｃ (For example, R ５Ｃ１ ), R ６ , R ７ , R ５１ , and R ５２ If one or more of the organic groups are substituted or unsubstituted, the PARP1 inhibitor compound according to any one of claims 1 to 65, wherein the substituted or unsubstituted organic groups are independently selected from the following: -deuterium; - Halogens (e.g., -F, -Cl, -Br, and -I); - Nitrile group; - Substitutable or unsubstituted linear or branched C １ ~C ６ Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, pentyl group, and hexyl group); - Substitutable or unsubstituted linear or branched C １ ~C ６ alkyl-aryl groups (e.g., -CH ２ Ph, -CH ２ (2, 3 or 4) F-Ph, -CH ２ (2, 3 or 4) Cl-Ph, -CH ２ (2, 3 or 4) Br-Ph, -CH ２ (2, 3 or 4) I-Ph, -CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ Ph, -CH ２ CH ２ CH ２ CH ２ CH ２ Ph, and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., pH); - Substitutable or unsubstituted linear or branched C １ ~C ６ halogenated alkyl groups (e.g., -CH ２ F, -CH ２ Cl, -CH ２ Br, -CH ２ I, -CHF ２ , -CF ３ , -CCl ３ , - CBr ３ , -CI ３ ien-CH ２ CH ２ F, -CH ２ CF ３ ien-CH ２ CCl ３ ien-CH ２ CBr ３ , and, -CH ２ CCI ３ etc.); --NH ２ , or substituted or unsubstituted linear or branched primary, secondary or tertiary C １ ~C ６ Amine groups (e.g., -NMeH, -NMe ２ , -NEtH, -NEtMe, -NEt ２ , -NPrH, -NPrMe, -NPrEt, -NPr ２ , -NBuH, -NBuMe, -NBuEt, -CH ２ -NH ２ ien-CH ２ -NMeH, -CH ２ -NMe ２ ien-CH ２ -NETH, -CH ２ -NEtMe, -CH ２ -NET ２ ien-CH ２ -NPrH, -CH ２ -NPrMe and -CH ２ (e.g., NPrEt); - Substituted or unsubstituted aminoaryl groups (e.g., -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, -NH-(2,3 or 4)OBu-Ph, -NH-2,(3,4,5 or 6)F ２ -Ph, -NH-2, (3, 4, 5 or 6)Cl ２ -Ph, -NH-2, (3, 4, 5 or 6)Br ２ -Ph, -NH-2, (3, 4, 5 or 6)I ２ -Ph, -NH-2, (3, 4, 5 or 6)Me ２ -Ph, -NH-2, (3, 4, 5 or 6)Et ２ -Ph, -NH-2, (3, 4, 5 or 6)Pr ２ -Ph, and -NH-2, (3, 4, 5 or 6)Bu ２ (e.g., Ph); - Substituted or unsubstituted cyclic amine or amide groups (e.g., pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl, etc.); - Substituted or unsubstituted cyclic C ３ ~C ８ Alkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); --OH group; - Substitutable or unsubstituted linear or branched C １ ~C ６ The alcohol group (e.g., -CH ２ OH, -CH ２ CH ２ OH, -CH(CH ３ )CH ２ OH, -C(CH ３ ) ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ OH, -CH(CH ３ )CH ２ CH ２ OH, -CH(CH ３ )CH(CH ３ )OH, -CH(CH ２ CH ３ )CH ２ OH, -C(CH ３ ) ２ CH ２ OH, -CH ２ CH ２ CH ２ CH ２ CH ２ OH and -CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., OH); - Substituted or unsubstituted linear or branched C １ ~C ６ Carboxylic acid groups (e.g., -COOH, -CH) ２ COOH, -CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ COOH, -CH ２ CH ２ CH ２ CH ２ COOH and -CH ２ CH ２ CH ２ CH ２ CH ２ COOH, etc.; - Substituted or unsubstituted linear or branched carbonyl groups (e.g., -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH ２ Ph, -(CO)CH ２ OH, -(CO)CH ２ OCH ３ ,-(CO)CH ２ NH ２ ,-(CO)CH ２ NHMe, -(CO)CH ２ NMe ２ -(CO)-cyclopropyl,-(CO)-1,3-epoxypropane-2-yl,-(CO)NH ２ , -(CO)NHMe, -(CO)NMe ２ , -(CO)NHEt, -(CO)NET ２ -(CO)-pyrrolidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methylpiperazine-N-yl, -(CO)NHCH ２ CH ２ OH, -(CO)NHCH ２ CH ２ OMe, -(CO)NHCH ２ CH ２ NH ２ , -(CO)NHCH ２ CH ２ NHMe and -(CO)NHCH ２ CH ２ NMe ２ etc.); - Substitutable or unsubstituted linear or branched C １ ~C ６ Carboxylic acid ester groups (e.g., -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH ２ COOMe, -CH ２ CH ２ COOMe, -CH ２ CH ２ CH ２ COOMe, and -CH ２ CH ２ CH ２ CH ２ COOME, etc.; - Substitutable or unsubstituted linear or branched C １ ~C ６ amide group (e.g., -CO-NH) ２ , -CO-NMeH, -CO-NMe ２ , -CO-NEtH, -CO-NEtMe, -CO-NEt ２ (e.g., -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); - Substitutable or unsubstituted linear or branched C １ ~C ７ The aminocarbonyl group (e.g., -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, and -NMe-CO-Ph, etc.); - Substitutable or unsubstituted linear or branched C １ ~C ７ Alkoxy or aryloxy groups (e.g., -OMe, -OEt, -OPr, -O-i-Pr, -O-n-Bu, -O-i-Bu, -O-t-Bu, -O-pentyl, -O-hexyl, -OCH) ２ F, -OCHF ２ , -OCF ３ , -OCH ２ Cl, -OHCl ２ -OCCl ３ , -O-Ph, -O-CH ２ -Ph, -O-CH ２ -(2,3 or 4)-F-Ph, -O-CH ２ -(2,3 or 4)-Cl-Ph, -CH ２ OMe, -CH ２ OEt, -CH ２ OPr, -CH ２ OBu, -CH ２ CH ２ OMe, -CH ２ CH ２ CH ２ OMe, -CH ２ CH ２ CH ２ CH ２ OMe, and -CH ２ CH ２ CH ２ CH ２ CH ２ (e.g., OMe); - Substituted or unsubstituted linear or branched aminoalkoxy groups (e.g., -OCH ２ NH ２ , -OCH ２ NHMe, -OCH ２ NMe ２ , -OCH ２ NHEt, -OCH ２ NET ２ , -OCH ２ CH ２ NH ２ , -OCH ２ CH ２ NHMe, -OCH ２ CH ２ NMe ２ , -OCH ２ CH ２ NHEt, and -OCH ２ CH ２ NET ２ etc.); - Substituted or unsubstituted sulfonyl groups (e.g., -SO ２ Me, -SO ２ Et, -SO ２ Pr, -SO ２ iPr, -SO ２ Ph, -SO ２ -(2, 3 or 4)-F-Ph, -SO ２ -Cyclopropyl, -SO ２ CH ２ CH ２ OCH ３ , -SO ２ NH ２ , -SO ２ NHMe, -SO ２ NMe ２ , -SO ２ NHEt, -SO ２ NET ２ , -SO ２ -pyrrolidine-N-yl, -SO ２ -morpholine-N-yl, -SO ２ NHCH ２ OMe, and -SO ２ NHCH ２ CH ２ (e.g., OMe); - Substituted or unsubstituted aminosulfonyl groups (e.g., -NHSO) ２ Me, -NHSO ２ Et, -NHSO ２ Pr, - NHSO ２ iPr, -NHSO ２ Ph, -NHSO ２ -(2, 3 or 4)-F-Ph, -NHSO ２ -Cyclopropyl and -NHSO ２ CH ２ CH ２ OCH ３ etc.); - Substitutable or unsubstituted aromatic groups (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)-F ２ -Ph-, 2, (3, 4, 5 or 6)-Cl ２ -Ph-, 2, (3, 4, 5 or 6)-Br ２ -Ph-, 2, (3, 4, 5 or 6)-I ２ -Ph-, 2, (3, 4, 5 or 6)-Me ２ -Ph-, 2, (3, 4, 5 or 6)-Et ２ -Ph-, 2, (3, 4, 5 or 6)-Pr ２ -Ph-, 2, (3, 4, 5 or 6)-Bu ２ -Ph-, 2, (3, 4, 5 or 6)-(CN) ２ -Ph-, 2, (3, 4, 5 or 6)- (NO ２ ) ２ -Ph-, 2, (3, 4, 5 or 6)-(NH ２ ) ２ -Ph-, 2, (3, 4, 5 or 6)-(MeO) ２ -Ph-, 2, (3, 4, 5 or 6)-(CF ３ ) ２ -Ph-, 3, (4 or 5)-F ２ -Ph-, 3, (4 or 5)-Cl ２ -Ph-, 3, (4 or 5)-Br ２ -Ph-, 3, (4 or 5)-I ２ -Ph-, 3, (4 or 5)-Me ２ -Ph-, 3, (4 or 5)-Et ２ -Ph-, 3, (4 or 5)-Pr ２ -Ph-, 3, (4 or 5)-Bu ２ -Ph-, 3, (4 or 5)-(CN) ２ -Ph-, 3, (4 or 5)- (NO ２ ) ２ -Ph-, 3, (4 or 5)-(NH ２ ) ２ -Ph-, 3, (4 or 5)-(MeO) ２ -Ph-, 3, (4 or 5)-(CF ３ ) 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-(NO ２ )-Ph-, 3-(NO ２ )-Ph-, 4-(NO ２ )-Ph-, 2-(NH ２ )-Ph-, 3-(NH ２ )-Ph-, 4-(NH ２ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH ２ -CO)-Ph-, 3-(NH ２ -CO)-Ph-, 4-(NH ２ -CO)-Ph-, 2-CF ３ -Ph-, 3-CF ３ -Ph-, 4-CF ３ -Ph-, 2-CF ３ O-Ph-, 3-CF ３ O-Ph-, and 4-CF ３ O-Ph-, etc.); -Saturated or unsaturated substituted or unsubstituted heterocyclic groups, optionally aromatic heterocyclic groups or non-aromatic heterocyclic groups (e.g., pyrrole-1-yl, pyrrole-2-yl, pyrrole-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-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1,2, 4-Triazole-3-yl, 1,2,4-Triazole-5-yl, Pyridine-2-yl, Pyridine-3-yl, Pyridine-4-yl, Pyridazine-3-yl, Pyridazine-4-yl, Pyrimidine-2-yl, Pyrimidine-4-yl, Pyrimidine-5-yl, Pyrimidine-6-yl, Pyrazine-2-yl, Pyrrolidine-1-yl, Pyrrolidine-2-yl, Pyrrolidine-3-yl, Piperidine-1-yl, Piperidine-2-yl, Piperidine-3-yl, Piperidine-4-yl, 2-Azapiperidine-1-yl, 2-Azapiperidine-3-yl, 2- Azapiperidine-4-yl, 3-azapiperidine-1-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl, fran-2-yl, fran-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-a Zapiran-6-yl, 4-azapiran-2-yl, 4-azapiran-3-yl, 4-azapiran-4-yl, 4-azapiran-5-yl, 4-azapiran-6-yl, oxetane-2-yl, oxetane-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-te Trahydropyran-4-yl, 3-azatetrahydropyran-5-yl, 3-azatetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophene-2-yl, thiophene-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2- Azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolan-2-yl, thiolan-3-yl, thian-2-yl, thian-3-yl, Thian-4-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-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 tetrazole-1-yl, tetrazole-2-yl, and tetrazole-5-yl, etc.); Here, A pair of R atoms bonded to different atoms ５Ａ The groups may together form a ring with the atoms that make up ring A; and / or, A pair of R atoms bonded to different atoms ５Ｂ The groups may together form a ring with the atoms constituting ring B; and / or, A pair of R atoms bonded to different atoms ５Ｃ The groups may together form a ring with the atoms constituting the ring C; and / or, R bonded to different atoms ５Ｃ Base and R ６ The groups may come together to form a ring with the atoms that make up the ring C.
72. R ５Ａ (For example, R ５Ａ１ , R ５Ａ２ , R ５Ａ３ ), R ５Ｂ (For example, R ５Ｂ１ , R ５Ｂ３ ), and R ５Ｃ (For example, R ５Ｃ１ Each of the above is either absent or selected from the following, the PARP1 inhibitor compound according to claim 71: -hydrogen; -deuterium; -Halogens (e.g., -F, -Cl, -Br, and -I; preferably F or Cl); - Nitrile group; - Substitutable or non-substitutable C １ ~C ６ alkyl group; - Substitutable or unsubstituted linear or branched C １ ~C ６ Halogenated alkyl group (preferably CF) ３ or CHF ２ ); - Cyclopropyl group; --OH group; - Substitutable or unsubstituted linear or branched C １ ~C ６ The alcohol group; - Substitutable or unsubstituted linear or branched C １ ~C ７ The aminocarbonyl group (e.g., -NH-CO-Me); --NH ２ base; - Substitutable or non-substitutable C １ ~C ６ The amino group; - Substitutable or non-substitutable C １ ~C ６ alkoxy group; Here, a pair of R atoms bonded to different atoms ５Ａ When the groups come together to form a ring with the atoms that make up ring A; and / or when a pair of R groups bonded to different atoms ５Ｂ When the groups come together to form a ring with the atoms that make up ring B; and / or when a pair of R groups bonded to different atoms ５Ｃ When the groups come together and form a ring with the atoms that make up the ring C, the pair of R ５Ａ group, R ５Ｂ Base, or R ５Ｃ Each of the elements is independently -CH ２ - or -CH ２ CH ２ - comprises, or the pair of groups together comprises -CH=CH-CH=CH- or -NH-CO-NH-.
73. The aforementioned compound, - Isolated enantiomer, or - A mixture of two or more enantiomers, or - A mixture of two or more diastereomers and / or epimers, - Racemic mixture, or - Tautomers of the above compound A PARP1 inhibitor compound according to any of the prior claims, comprising:
74. A PARP1 inhibitor compound according to any of the prior claims, exhibiting greater selectivity for PARP1 than for PARP2.
75. A PARP1 inhibitor compound according to any of the preceding claims, used for the treatment of cancer.
76. The aforementioned cancers include cancers of the eye, brain (glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma, and astrocytoma, etc.), spinal cord, kidney, mouth, lips, pharynx, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gallbladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchi, liver, skin, ureter, urethra, testicle, vagina, anus, laryngeal gland, ovary, thyroid gland, esophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, and adrenal gland; endometrial cancer, oral cancer, malignant 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, and PTEN hamartoma syndrome (PHT). S) (Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome and Proteus-like syndrome, etc.), leukemia and lymphoma (acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prelymphocytic 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-associated lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal cancer, and gastrointestinal cancer, A PARP1 inhibitor compound according to claim 75, selected from, optionally, the cancer being a cancer of the brain or spinal cord.
77. The PARP1 inhibitor compound according to claim 75 or 76, wherein the cancer is deficient in DNA damage response repair pathways such as homologous recombination-dependent DNA double-strand break DNA repair activity.
78. The PARP1 inhibitor compound according to any one of claims 75 to 77, wherein the cancer is deficient in the function of BRCA1 and / or BRCA2.
79. A PARP1 inhibitor compound according to any one of claims 89 to 92, which is administered in combination with further agents for treating cancer, Optionally, the further agents for treating cancer are PARP1 inhibitor compounds selected from microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapies, apoptosis inducers, radioligand therapies, cell cycle signaling inhibitors, and angiogenesis inhibitors.
80. The further agent for treating cancer is an immunotherapy agent selected from the following PARP1 inhibitor compound according to claim 79: 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-cell therapy); small molecule immunomodulators; and tumor microenvironment modifiers.
81. A pharmaceutical composition comprising a PARP1 inhibitor compound according to any one of claims 1 to 74.
82. The pharmaceutical composition according to claim 81, further comprising a pharmaceutically acceptable additive and / or excipient, and / or the compound being a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative form of the compound.
83. Equipped with further drugs to treat cancer, Optionally, the further agents for treating cancer are selected from microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapies, apoptosis inducers, radioligand therapies, angiogenesis inhibitors, and cell cycle signaling inhibitors. The pharmaceutical composition according to claim 81 or 82.
84. The pharmaceutical composition according to claim 83, wherein the further agent for treating cancer comprises an immunotherapy agent 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-cell therapy); small molecule immunomodulators; and tumor microenvironment modifiers.
85. A pharmaceutical composition according to any one of claims 81 to 84, used for treating cancer.
86. It is a medical kit for treating cancer, a) A PARP1 inhibitor compound according to any one of claims 1 to 74, and b) Further drugs to treat cancer, Equipped with; The aforementioned compounds and the further agents are suitable for simultaneous, sequential, or separate administration; and, Optionally, the further agents for treating cancer include microtubule inhibitors, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senescent cell deconjugates, hormones and hormone analogs, signaling pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone deprivation therapies, immunotherapeutic agents (e.g., antitumor vaccines; oncolytic viruses; anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, Immunostimulatory antibodies such as 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-cell therapy); small molecule immunomodulators, and tumor microenvironment modifiers, etc., are selected from: apoptosis inducers, radioligand therapies, angiogenesis inhibitors, and cell cycle signaling inhibitors. Medical kit.
87. Compounds having any of the following structures: 【Chemistry 61】 (In the formula, Z １ is C or N; Z ２ｕ and Z ２ｌ Either of them is C, and Z ２ｕ and Z ２ｌ The other side is N; Each Z ３ These are independently selected from C and N; Each R １ These are independently absent, or H, halogens (e.g., F or Cl), methyl, halomethyl (e.g., CF) ３ ), and selected from CN; R ５Ｃ２о is H, a methyl group, or a halogen; X ２ＣＭ is N, and R ５Ｃ２Ｍ It does not exist, or X ２ＣＭ is C, and R ５Ｃ２Ｍ is H; and, R ６ The following: 【Transformation 62】 Alternatively, see below: 【Transformation 63】 (That is the case.)
88. R ５Ｃ２о The compound according to claim 87, wherein is H or a halogen, and optionally F.
89. The compound according to claim 87, having a structure selected from the following. 【Chemistry 64-1】 【Chemistry 64-2】 【Chemistry 64-3】 【Chemistry 64-4】 【Chemistry 64-5】
90. The aforementioned compound, - Isolated enantiomer, or - A mixture of two or more enantiomers, or - A mixture of two or more diastereomers and / or epimers, - Racemic mixture, or - Tautomers of the above compound A compound according to any one of claims 87 to 89, comprising:
91. A method for treating a disease and / or condition and / or disorder, comprising administering to a patient a PARP1 inhibitor compound, composition, or kit described in any of the preceding claims.
92. The method according to claim 91, wherein the patient is an animal, preferably a mammal, optionally a human, dog, horse, or cat, preferably a human.
93. A method for synthesizing a PARP1 inhibitor compound according to any one of claims 1 to 74, (i) A first reactant comprising rings D and E and having a first portion of group L, (ii) A second reactant comprising the remaining portion of group L A method comprising carrying out a reaction between and to form the PARP1 inhibitor compound.
94. The first reactant comprises rings D, E, and A. The second reactant is Q having a reactive group. ＡＢ Equipped with a precursor, The above method involves ring A to Q ＡＢ The method according to claim 93, further comprising binding to a precursor.
95. The aforementioned Q ＡＢ The method according to claim 94, wherein the reactive group of the precursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate.
96. The method according to any one of claims 93 to 95, wherein the reaction comprises alkylation, reductive amination, or amidation for forming group L.
97. a) The following structure: 【Transformation 65】 (In the formula, R ９ is C １ ~C ６ It is an alkyl group; R ＰＧ To provide a precursor having a protecting group; b) The precursor is NHR ３ Alternatively, treatment with its conjugate acid can be used to carry out a ring-closing reaction, resulting in the following structure: 【Chemical Formula 66】 To form an intermediate having: and, c) Deprotect the intermediate, and obtain the first reactant having the following structure: 【Transformation 67】 To obtain the first reactant having, The method according to claims 93 to 96, further comprising preparing the first reactant by means of the above.
98. Z ２ｌ is N, Z ２ｕ The method according to claim 97, wherein C is C.
99. The method according to claim 98, wherein the precursor has the following structure. 【Transformation 68】
100. The method according to claim 98, wherein the precursor has the following structure. 【Transformation 69】
101. To provide the aforementioned precursor, a) The following structure: 【Transformation 70】 A compound having the following structure: 【Chemistry 71】 Phenylhydroxylamine having (wherein EWG represents one or more electron-withdrawing groups) is reacted with a base, such as sodium hydride, to form the following structure: 【Chemistry 72】 To obtain an intermediate having, b) The intermediate has the following structure: 【Transformation 73】 The precursor is obtained by reacting it with a carboxylic acid having the above-mentioned properties. The method according to claim 100, comprising:
102. The substituted phenylhydrochylamine is O-(2,4-dinitrophenyl)hydrochylamine: 【Chemistry 74】 The method according to claim 101.
103. R ９ The method according to any one of claims 97 to 102, wherein is an ethyl group.
104. R ＰＧ The method according to any one of claims 97 to 103, wherein is Boc.
105. R ３ The method according to any one of claims 97 to 104, wherein is H.
106. a) The following structure: 【Chemistry 75】 (wherein, R １０ is a C １ - C ６ alkyl group, optionally a t-butyl group). To provide a first precursor having; b) The following structure: 【Transformation 76】 (In the formula, R ＰＧ To provide a second precursor having deprotection, optionally Boc; and, c) Catalyst, optionally [Cp ＊ RhCl ２ ] ２ Using a catalyst, the first precursor and the second precursor are coupled to form the first reactant, which has the following structure: 【Chemical 77】 To form a first reactant having; The method according to any one of claims 93 to 96, further comprising preparing the first reactant by means of the method.
107. The method according to any one of claims 93 to 106, wherein the second reactant has the following structure. 【Transformation 78】
108. i) The following formula: 【Chemistry 79】 (In the formula, a) X ２ＣＭ C is R ５Ｃ２Ｍ is H; or, b) X ２ＣＭ is N and R ５Ｃ２Ｍ does not exist. To provide a first precursor represented by). ii) The following formula: 【Chemistry 80】 To provide a second precursor represented by ; iii) A base, preferably, for example, Cs ２ CO ３ Using cesium bases such as the above, the first precursor and the second precursor are coupled, resulting in the following equation: 【Chemistry 81】 To obtain an intermediate represented by; and, iv) Treating the intermediate with acid to obtain the second reactant having the following structure: 【Chemistry 82】 To obtain the second reactant having, The method according to claim 107, further comprising preparing the second reactant by means of the method.
109. The second precursor is 1,4-dioxa-8-azaspiro[4.5]decane: 【Chemistry 83】 The method according to claim 108.
110. The method according to any one of claims 93 to 109, wherein the reaction is carried out by coupling the first reagent with the second reagent using a reducing agent in the presence of an acid.
111. The first reactant is rings A, B, D, and E, Q. ＡＥ , and also, Q ＡＢ Equipped with, The method according to claim 93, wherein the second reactant comprises a derivative of a ring C having a leaving group, such as a halogen or a sulfonic acid ester.
112. The method according to claims 93 to 111, wherein the reaction comprises a nucleophilic substitution reaction, such as an aromatic nucleophilic substitution reaction, for forming a group L.
113. The method according to any one of claims 93 to 112, further comprising separating structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography and / or chiral high-performance liquid chromatography.
Citation Information
Patent Citations
WO.2002