Compound as a PARP1 inhibitor

Abstract

The present invention relates to compounds that inhibit enzymes of the poly(ADP-ribose) polymerase (PARP) family and pharmaceutically acceptable salts thereof. The present invention also relates to the use of these compounds or pharmaceutically acceptable salts thereof in the treatment of diseases.

Description

Technical Field

[0001] The present invention relates to compounds that inhibit enzymes of the poly(ADP-ribose) polymerase (PARP) family and pharmaceutically acceptable salts thereof. The present invention also relates to the use of these compounds or pharmaceutically acceptable salts thereof in the treatment of diseases.

Background Art

[0002] The family of poly(ADP-ribose) polymerases (PARP) consists of approximately 17 proteins, including PARP-1, PARP-2, PARP-3, PARP-4 (vPARP), PARP-5 (tankyrase-1, tankyrase-2), PARP-7, PARP-10, and others. Although these proteins all show a certain level of homology in the catalytic domain, their cellular functions are different.

[0003] Among the many functions attributed to PARP-1 and PARP-2, their main role is to promote DNA repair by ADP-ribosylation and thus cooperate with several DNA repair proteins. Activation of PARP is induced by DNA single-strand breaks after exposure to radiation, oxygen free radicals, or nitric oxide (NO), etc. DNA damage leads to PARP activation, which repairs DNA single-strand breaks, and thus PARP can contribute to the resistance that can occur in various types in cancer treatment. In particular, PARP inhibitors have been reported to be useful for specifically killing tumors lacking DNA double-strand repair factors such as BRCA-1 and BRCA-2, and thus have been developed as patient-specific anti-cancer agents for various types of cancer, including breast cancer, ovarian cancer, prostate cancer, etc., in which DNA double-strand damage repair factors are abnormal.

[0004] PARP family enzyme inhibition has been explored as a strategy to selectively kill cancer cells by inactivating the complementary DNA repair pathway. Several preclinical and clinical trials have shown that tumor cells carrying deleterious changes in the tumor suppressor protein BRCA1 or BRCA2, which is key in double-strand DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of PARP family DNA repair enzymes. Such tumors have a defective homologous recombination repair (HRR) pathway and are dependent on PARP enzyme function for survival. PARP inhibitor therapy mainly targets BRCA-mutated cancers, but PARP inhibitors are being clinically tested in non-BRCA mutant tumors that exhibit homologous recombination deficiency (HRD). SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0005] PARP inhibitors with improved selectivity for PARP1 are thought to have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. Also, selective and potent inhibition of PARP1 is thought to lead to the trapping of PARP1 on DNA, resulting in DNA double-strand breaks (DSBs) via the collapse of replication forks in the S phase. PARP1-DNA trapping is also thought to be an effective mechanism for selectively killing tumor cells with HRD. Therefore, there is an unmet medical need for effective and safe PARP inhibitors, especially PARP inhibitors with selectivity for PARP1. MEANS FOR SOLVING THE PROBLEMS

[0006] Summary of the Invention The present invention relates to compounds or pharmaceutically acceptable salts having PARP inhibitory activity and thus may be useful in the treatment of diseases and conditions in which PARP function has pharmacological significance. Further, the compounds described herein have high selectivity for PARP1 over PARP2.

[0007] In one aspect, the present invention relates to a compound having PARP inhibitory activity or a pharmaceutically acceptable salt thereof. Preferably, the compounds described herein have high selectivity for PARP1 over other PARP family members such as PARP2.

[0008] In another aspect, the present invention provides a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof. Preferably, the composition further comprises at least one pharmaceutically acceptable diluent, additive or inert carrier.

[0009] In another aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof or a composition thereof for use as a medicament.

[0010] In another aspect, the present invention provides a method of treatment comprising administering a therapeutically effective amount of a compound to a patient in need of treatment. Preferably, the patient in need of treatment has cancer. Preferably, the cancer has a deficiency in the HR-dependent DNA DSB repair pathway. More preferably, the cancer cells have a BRCA1 or BRCA2-deficient phenotype or the cancer cells are deficient in BRCA1 or BRCA2. More preferably, the cancer is selected from any of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.

[0011] In another aspect, the present invention provides a method of treating or preventing a disease or condition in which inhibition of PARP1 is beneficial, comprising administering a therapeutically effective amount of a compound to a patient in need of treatment. Preferably, the patient in need of treatment has cancer. More preferably, the patient is heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway or the patient is heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway.

[0012] In another aspect, the present invention provides the use of a compound in the manufacture of a medicament for the treatment of cancer. More preferably, the cancer has a deficiency in the HR-dependent DNA DSB repair pathway.

DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description of the Invention (I) Compound In one aspect, the present invention provides a compound of formula I having PARP inhibitory activity or a pharmaceutically acceptable salt thereof. Preferably, the compounds described herein have high selectivity for PARP1 over other PARP family members such as PARP2.

[0014] In one embodiment, the compound is of formula I:

Chemical formula

Chemical formula

Chemical formula

[0015] In certain embodiments, the compound of formula I is

Chemical formula

[0016] In one embodiment, A is -O-; B is monosubstituted or unsubstituted

Chemical formula

Chemical formula

[0017] In certain embodiments, formula I is

Chemical formula

Chemical formula

[0018] In certain embodiments, two R3 is a compound of formula I that is not H at the same time.

[0019] In certain embodiments, R 2 is

Chemical formula

[0020] In certain embodiments, formula I is

Chemical formula

Chemical formula

[0021] In certain embodiments, preferably, R 1 is selected from the group consisting of C 1 -C 3 alkyl; each R 3 is independently selected from the group consisting of H or unsubstituted -C 1 -C 3 alkyl; each R 4a is independently selected from the group consisting of H, -CH 3 and F, and is a compound of formula I.

[0022] In certain embodiments, the compound of formula I is selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0023]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

[0024] To minimize the risk of off-target effects, it is desirable for the drug molecule to have selectivity for the specific target. Advantageously, the compound of formula I has selectivity for PARP1 over PARP2. In certain embodiments, compounds of formula I having 10-fold selectivity for PARP1 over PARP2 are provided. In certain embodiments, compounds of formula I having 100-fold selectivity for PARP1 over PARP2 are provided.

[0025] (II) Pharmaceutical Composition In other aspects, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof. The composition further comprises at least one pharmaceutically acceptable diluent, additive or inert carrier. Preferably, the composition is for use in the treatment of cancer.

[0026] In certain variations, the composition is a solid formulation suitable for oral administration. In other specific variations, the composition is a liquid formulation suitable for oral administration. In still other specific variations, the composition is a tablet. In yet other specific variations, the composition is a liquid formulation suitable for parenteral administration.

[0027] The present invention also provides a pharmaceutical composition comprising a compound of any of the above embodiments and variations, wherein the composition is suitable for administration by a route selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transmucosal, intranasal, liposomal, inhalation, vaginal, intraocular, local delivery (e.g., by catheter or stent), subcutaneous, intradermal, intraarticular and intrathecal.

[0028] (III) Method of Treatment In another aspect, the present invention provides a method of treatment comprising administering a therapeutically effective amount of a compound to a patient in need of treatment. Preferably, the patient in need of treatment has cancer. Preferably, the cancer has a defect in the HR-dependent DNA DSB repair pathway. More preferably, the cancer cells have a BRCA1 or BRCA2-deficient phenotype or the cancer cells are deficient in BRCA1 or BRCA2. More preferably, the cancer is selected from any of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.

[0029] In another aspect, the present invention provides a method of treating or preventing a disease or condition in which inhibition of PARP1 is beneficial, comprising administering a therapeutically effective amount of a compound to a patient in need of treatment. Preferably, the patient in need of treatment has cancer. More preferably, the patient is heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway or the patient is heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway.

[0030] (IV) Products In another aspect, the present invention provides the use of a compound in the manufacture of a medicament for use in the treatment of a disease or condition in which inhibition of PARP1 is beneficial. In certain embodiments, the cancer is a gastrointestinal cancer such as breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastric cancer and colorectal cancer or lung cancer. In certain embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer or prostate cancer.

[0031] (V) General Definitions Unless the context requires otherwise, throughout this specification and the claims, the terms "comprising" and variations such as "comprises" and "comprising" are to be construed in an open, inclusive sense, i.e., "including, but not limited to".

[0032] The description of "one embodiment" or "an embodiment" in this specification means that the specific properties, structures or features described in relation to that embodiment are included in at least one embodiment disclosed herein. Therefore, the descriptions of "in one embodiment" or "in an embodiment" in various places in this specification do not necessarily all refer to the same embodiment. Furthermore, the specific properties, structures or features can be combined in any suitable way in one or more embodiments.

[0033] "C u-v " or a prefix such as (C u -C v ) indicates that the subsequent group has u to v carbon atoms. For example, "C 1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0034] "Alkyl" is saturated and has 1 to 12 carbon atoms (C 1-12 alkyl), in certain embodiments, 1 to 8 carbon atoms (C 1-8 alkyl) or 1 to 6 carbon atoms (C 1-6 alkyl) or 1 to 4 carbon atoms (C 1-4 alkyl) or 1 to 3 carbon atoms (C 1-3 alkyl), and is a straight-chain or branched-chain hydrocarbon radical consisting of carbon and hydrogen atoms, which is bonded to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, etc.

[0035] "Condensed" refers to a carbocyclic, heterocyclic, aromatic or heteroaromatic ring structure as described herein, which is bonded to an existing ring structure in the compounds disclosed herein through two adjacent atoms shared by the condensed ring structure and the existing ring structure.

[0036] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[0037] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more of the halogen radicals defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0038] "Alkoxy" means an oxygen moiety having a further alkyl substituent. The alkoxy groups of the present invention may optionally be substituted.

[0039] "Cycloalkyl" means a saturated monocyclic, bicyclic, spirocyclic or bridged carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. In certain embodiments of the present invention, cycloalkyl is selected from cyclopropane, cyclobutane and cyclohexane. In other embodiments, cycloalkyl is cyclopropane, cyclobutane or cyclopentane. In other embodiments, cycloalkyl is cyclopropane or cyclobutane. In other embodiments, cycloalkyl is cyclopropane. In other embodiments, cycloalkyl is cyclobutane. In other embodiments, cycloalkyl is cyclopentane. In other embodiments, cycloalkyl is cyclohexane. In other embodiments, cycloalkyl is cycloheptane.

[0040] "Oxo" refers to the =O substituent.

[0041] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0042] As used herein, unless otherwise indicated, the term "effective amount" means an amount of a compound or composition that is sufficient to effect a marked and favorable modification of the symptoms and / or conditions being treated (e.g., to provide a good clinical response). The effective amount of the active ingredient used in a pharmaceutical composition will vary depending on the particular condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent treatment, the particular active ingredient used, the particular pharmaceutically acceptable additive / carrier used, and similar factors within the knowledge and experience of the treating physician.

[0043] As used herein, unless otherwise indicated, the term "treatment" means, for a disorder or condition to which such term is applicable, or for one or more symptoms of such a disorder or condition, the restoration, alleviation, arrest of the progression, delay in the progression, delay in the onset, or prevention of the disorder or condition. As used herein, unless otherwise indicated, the term "treatment" refers to the act of treatment as defined immediately above. The term "treatment" also includes adjuvant and neoadjuvant treatment of a subject. To avoid doubt, "treatment" as referred to herein includes curative, palliative, and prophylactic treatment and the administration of medicaments for use in such treatment.

[0044] The compounds of Formula I can form stable pharmaceutically acceptable acid or base salts, in which case administration of the compound as a salt may be appropriate.

[0045] Salts can be formed by conventional means, such as by reacting the product in free base form with one or more equivalents of a suitable acid in a solvent or medium in which the salt is insoluble or in a solvent such as water that is removed by evaporation under reduced pressure or by lyophilization, or by exchanging the anions of an existing salt with the anions of another anion of a suitable ion exchange resin.

[0046] The compounds of formula I may have more than one chiral center, and it should be understood that this application encompasses all individual stereoisomers, enantiomers and diastereoisomers and mixtures thereof. Thus, as long as the compounds of formula I can exist as optically active or racemic forms due to one or more asymmetric carbon atoms, it should be understood that this application encompasses any such optically active or racemic forms having the above activity in its definition. This application encompasses all such stereoisomers having the activity defined herein.

[0047] It should also be understood that a compound of formula I and its pharmaceutically acceptable salts can exist in solvated and unsolvated forms, for example, hydrated and anhydrous forms. The compounds herein include all such solvated forms. For the sake of clarity, this includes the free form of the compound in solvated (e.g., hydrated) form and the compound of the salt in solvated (e.g., hydrated) form.

[0048] Formula I as described herein is intended to include all isotopes of its constituent atoms. For example, H (or hydrogen) includes any isotopic form of hydrogen including 1 H, 2 H (D) and 3 H (T); C includes any isotopic form of carbon including 12 C, 13 C and 14 C; O includes any isotopic form of oxygen including 16 O, 17 O and 18 O; N includes any isotopic form of nitrogen including 13 N, 14 N and 15 N. It should be understood that this application encompasses all such isotopic forms.

[0049] The compound of formula I or a pharmaceutically acceptable salt thereof is usually administered via the oral route in the form of a pharmaceutical preparation comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof or a solvate of such a salt in a pharmaceutically acceptable dosage form. Depending on the disorder being treated and the patient, the composition can be administered in various dosages.

[0050] The pharmaceutical preparation of the compound of formula I above can be manufactured for oral administration, in particular in the form of tablets or capsules, and involves in particular techniques aimed at providing colon-specific drug release.

[0051] The pharmaceutical preparation of the compound of formula I above can conveniently be administered in unit dosage form and can be manufactured by any of the methods well known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).

[0052] Pharmaceutical preparations suitable for oral administration can contain one or more physiologically compatible carriers and / or additives and can be in solid or liquid form. Tablets and capsules can be manufactured with binders, fillers, lubricants and / or surfactants, such as sodium lauryl sulfate. Liquid compositions can contain conventional additives such as suspending agents, emulsifying agents and / or preservatives. The liquid composition can be encapsulated, for example in gelatin, to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. Such two-piece hard shell capsules can be manufactured, for example, by filling the compound of formula (I) into a gelatin or hydroxypropyl methylcellulose (HPMC) shell.

[0053] The dry shell formulation typically contains gelatin at a concentration of about 40% - 60 w / w%, a plasticizer (such as glycerin, sorbitol, or propylene glycol) at a concentration of about 20% - 30%, and water at a concentration of about 30% - 40%. Other substances such as preservatives, pigments, opacifiers, and flavoring agents may also be present. The liquid filling contains a solid drug that has been dissolved, solubilized, or dispersed (together with a suspending agent such as beeswax, hydrogenated castor oil, or polyethylene glycol 4000) or a liquid drug in a medium or combination of media such as mineral oil, vegetable oil, triglyceride, glycol, polyol, and surfactant.

[0054] An appropriate daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in the treatment of humans is about 0.0001 - 100 mg / kg body weight.

[0055] Oral formulations, particularly tablets or capsules that can be formulated in a manner known to those skilled in the art to provide a dose of the active compound in the range of 0.1 mg - 1000 mg, are preferred.

Example

[0056] The present invention will be further illustrated and described with reference to the following examples. It should be noted that the following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0057] Example 1: Preparation of 5 - ((1 - ((7 - ethyl - 6 - oxo - 5,6 - dihydro - 1,5 - naphthyridin - 3 - yl)methyl)azetidin - 3 - yl)oxy) - 3 - fluoro - N - methylpicolinamide (Compound 2) Step 1: Methyl 3 - fluoro - 5 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyridine - 2 - carboxylate

Chemical formula

[0058] Step 2: Methyl 3-fluoro-5-hydroxypyridine-2-carboxylate

Chemical formula

[0059] Step 3: Methyl 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}-3-fluoropyridine-2-carboxylate

Chem.

[0060] Step 4: tert-Butyl 3-{[5-fluoro-6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate

Chem.

[0061] Step 5: 5-(Azetidin-3-yloxy)-3-fluoro-N-methylpyridine-2-carboxamide

Chemical formula

[0062] Step 6: 5-((1-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)azetidin-3-yl)oxy)-3-fluoro-N-methylpicolinamide

Chemical formula

[0063] Example 2: Preparation of (R)-5-((1-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-N-methylpicolinamide (Compound 4) and (S)-5-((1-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-N-methylpicolinamide (Compound 5) Process 1: tert-Butyl 3-[(6-cyanopyridin-3-yl)oxy]azetidine-1-carboxylate

Chem.

[0064] Process 2: 5-{[1-(tert-Butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylic acid

Chem.

[0065] Step 3: tert-Butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate [Chemical formula] A solution of 5-{[1-(tert-butoxycarbonyl)azetidin-3-yl]oxy}pyridine-2-carboxylic acid (700 mg, 2.38 mmol, 1.0 equiv) and methylamine hydrochloride (208 mg, 3.09 mmol, 1.3 equiv) in DMF (7.00 mL) was treated with DIPEA (1.36 mL, 7.85 mmol, 3.3 equiv) at -15 °C, and then a solution of T 3 P (1.97 g, 6.18 mmol, 2.6 equiv) in DMF (7.00 mL) was added dropwise at -15 °C. The resulting mixture was stirred at room temperature for 2 h. Saturated sodium carbonate solution was added to the resulting mixture, and the mixture was stirred at room temperature for 15 min. The precipitated solid was collected by filtration and washed with water (2 × 5 mL). The crude product was purified by reverse-phase chromatography (column: XBridge Prep C18 OBD column, 30 * 100 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 35% B - 65% B for 7 min) to obtain tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (500 mg, 68% yield).

[0066] Step 4: 5-(Azetidin-3-yloxy)-N-methylpyridine-2-carboxamide [Chemical formula] A solution of tert-butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (500 mg, 1.63 mmol, 1.0 eq) in a solution of HCl (5 mL, 4.0 M) in 1,4-dioxane was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give 5-(azetidin-3-yloxy)-N-methylpyridine-2-carboxamide, HCl salt (250 mg, 74% yield). The crude product was used directly in the next step without further purification.

[0067] Step 5: 5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-N-methylpicolinamide (Compound 43)

Chemical formula

[0068] Step 6: [Chemical] The enantiomeric mixture (40 mg) was separated by chiral SFC (column: CHIRAL ART Amylose - SA, 2 * 25 cm, 5 μm; mobile phase A: MtBE (10 mM NH 3 -MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 50% B for 40 minutes; wavelength: 220 / 242 nm; RT1 (min): 13.02; RT2 (min): 29.36; sample solvent: MeOH:DCM = 1:1; injection volume: 1 mL; run times: 2) to obtain the following compound: (R)-5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-N-methylpicolinamide (Compound 4) (16.9 mg, 42.3% yield). LC-MS (ES + ) m / z: 408.35 (M + H) + 1 H NMR (400 MHz, DMSO-d 6) δ 11.86 (s, 1H), 8.45 (m, 1H), 8.36 (m, 1H), 8.18 (s, 1H), 8.13 (m, 1H), 7.74 (s, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 5.04 (m, 1H), 3.87 - 3.78 (m, 1H), 3.58 - 3.54 (m, 2H), 3.19 (m, 1H), 3.16 (m, 1H), 2.75 (m, 3H), 2.57 - 2.52 (m, 2H), 1.18 (m, 6H). Chiral analysis SFC conditions for Compound 4: Column: Chiralpak IA - 3, 50×3 mm, 1.6 μm Mobile phase: (MtBE:DCM = 1:1)(0.1% DEA):MeOH = 80:20 Flow rate: 1.67 ml / min RT = 0.92 min; 100% (S)-5-((1-(1-(7 - ethyl - 6 - oxo - 5,6 - dihydro - 1,5 - naphthyridin - 3 - yl)ethyl)azetidin - 3 - yl)oxy)-N - methylpicolinamide (Compound 5) (14.8 mg, 37.0% yield). LC - MS (ES + ) m / z: 408.35 (M + H) + 1 H NMR (400 MHz, DMSO - d 6 ) δ 11.86 (s, 1H), 8.45 (m, 1H), 8.36 (m, 1H), 8.18 (s, 1H), 8.13 (m, 1H), 7.74 (s, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 5.04 (m, 1H), 3.87 - 3.78 (m, 1H), 3.58 - 3.54 (m, 2H), 3.19 (m, 1H), 3.16 (m, 1H), 2.75 (m, 3H), 2.57 - 2.52 (m, 2H), 1.18 (m, 6H). Chiral analysis SFC conditions for Compound 5: Column: Chiralpak IA - 3, 50×3 mm, 1.6 μm Mobile phase: (MtBE:DCM = 1:1)(0.1% DEA):MeOH = 80:20 Flow rate: 1.67 ml / min RT = 1.24 min; 99.8%

[0069] Alternative production method of Compound 5: Step 8: (R)-N-((S)-1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)-2-methylpropan-2-sulfinamide

Chem.

[0070] Step 9: (S)-7-(1-Aminoethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

Chem.

[0071] Step 10: (S)-3-Ethyl-7-(1-(3-hydroxyazetidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one

Chemical formula

[0072] Step 11: (S)-5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)picolinonitrile

Chemical formula

[0073] Step 12: (S)-5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)picolinate

Chemical Structure

[0074] Step 13: (S)-5-((1-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-N-methylpicolinamide (Compound 5)

Chem.

[0075] Example 3: Preparation of 6 - ((1 - ((7 - ethyl - 6 - oxo - 5,6 - dihydro - 1,5 - naphthyridin - 3 - yl)methyl)pyrrolidin - 3 - yl)amino)-N - methylnicotinamide (Compound 10) Step 1: Methyl 5-{[1-(tert - butoxycarbonyl)pyrrolidin - 3 - yl]amino}pyridine - 2 - carboxylate

Chemical Structure

[0076] Step 2: tert-Butyl 3-{[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylate

Chemical formula

[0077] Step 3: N-Methyl-5-(pyrrolidin-3-ylamino)pyridine-2-carboxamide hydrochloride

Chemical formula

[0078] Step 4: 6-((1-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)amino)-N-methylnicotinamide

Chemical Structure

[0079] Example 4: Preparation of (enantiomer 1)-5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N-methylpicolinamide (Compound 16) and (enantiomer 2)-5-((1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pyrrolidin-3-yl)(methyl)amino)-N-methylpicolinamide (Compound 17) Step 1: Methyl 5-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl](methyl)amino}pyridine-2-carboxylate

Chemical formula

[0080] Step 2: tert-Butyl 3-{methyl[6-(methylcarbamoyl)pyridin-3-yl]amino}pyrrolidine-1-carboxylate

Chemical formula

[0081] Step 3: N-Methyl-5-[methyl(pyrrolidin-3-yl)amino]pyridine-2-carboxamide hydrochloride

Chemical formula

[0082] Step 4: 5-({1-[(7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]pyrrolidin-3-yl}(methyl)amino)-N-methylpyridine-2-carboxamide

Chemical formula

[0083] Step 5: (Enantiomer 1)-5 - ((1 - ((7 - ethyl - 6 - oxo - 5,6 - dihydro - 1,5 - naphthyridin - 3 - yl)methyl)pyrrolidin - 3 - yl)(methyl)amino)-N - methylpicolinamide (Compound 16) and (Enantiomer 2)-5 - ((1 - ((7 - ethyl - 6 - oxo - 5,6 - dihydro - 1,5 - naphthyridin - 3 - yl)methyl)pyrrolidin - 3 - yl)(methyl)amino)-N - methylpicolinamide (Compound 17)

Chemical Structure

[0084] Example 5: Preparation of (Enantiomer 1)-5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 45) and (Enantiomer 2)-5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 46) Step 1: tert-Butyl 3-[(6-chloro-2-fluoropyridin-3-yl)oxy]azetidine-1-carboxylate [Chemical formula] While stirring, tert-butyl 3-hydroxyazetidine-1-carboxylate (2.00 g, 11.5 mmol, 1.0 equivalent), 6-chloro-2-fluoropyridin-3-ol (1.70 g, 11.5 mmol, 1.0 equivalent) and PPh 3To a solution of (3.63 g, 13.9 mmol, 1.2 equiv) in THF (20 mL), DIAD (2.72 mL, 13.9 mmol, 1.2 equiv) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 3 mL). The filtrate was concentrated under reduced pressure and then purified by reverse-phase flash chromatography (column, C 18 ; mobile phase, aqueous MeCN solution (10 mmol / L NH 4 HCO 3 ), 10% - 70% gradient for 15 min; detector, UV 254 nm) to obtain tert-butyl 3-[(6-chloro-2-fluoropyridin-3-yl)oxy]azetidine-1-carboxylate (1.00 g, 29% yield) as a pale yellow solid.

[0085] Step 2: tert-butyl 3-[(6-cyano-2-fluoropyridin-3-yl)oxy]azetidine-1-carboxylate

Chemical Structure

[0086] Step 3: tert-butyl 3-((6-carbamoyl-2-fluoropyridin-3-yl)oxy)azetidine-1-carboxylate

Chem.

[0087] Step 4: tert-butyl 3-{[2-fluoro-6-(methylcarbamoyl)pyridin-3-yl]oxy}azetidine-1-carboxylate

Chem.

[0088] Step 5: 5-(Azetidin-3-yloxy)-6-fluoro-N-methylpicolinamide

Chemical formula

[0089] Step 6: 5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 21) [Chemical formula] To a 20 mL vial, 5-(azetidin-3-yloxy)-6-fluoro-N-methylpicolinamide hydrochloride (170 mg, 0.75 mmol, 1.7 eq), 7-(1-chloroethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (105 mg, 0.44 mmol, 1.0 eq), KI (22.1 mg, 0.13 mmol, 0.3 eq) and MeCN (8 mL) were added at room temperature. To the above mixture, DIEA (425 μL, 2.44 mmol, 5.5 eq) was added dropwise at room temperature, and the resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (CH 3 CN / H 2 O 3:1) to give 5-((1-(1-(7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 21) (19.1 mg, 10% yield). LC-MS (ES + ) m / z: 426.2 (M+H) + 1 H NMR (400 MHz, DMSO-d 6) δ 11.85 (s, 1H), 8.48 (q, J = 4.7 Hz, 1H), 8.42 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 7.65 - 7.51 (m, 2H), 5.00 (t, J = 5.5 Hz, 1H), 3.83 (d, J = 7.0 Hz, 1H), 3.59 (td, J = 6.6, 4.1 Hz, 2H), 3.18 (dd, J = 8.1, 5.0 Hz, 1H), 3.08 (dd, J = 8.1, 5.0 Hz, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.58 - 2.53 (m, 2H), 1.24 - 1.16 (m, 6H).

[0090] Step 7: (Enantiomer 1)-5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 45) and (Enantiomer 2)-5-((1-(1-(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 46)

Chem.

[0091] Example 6: Preparation of (Enantiomer 1)-5-((1-(1-(3-Ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 49) and (Enantiomer 2)-5-((1-(1-(3-Ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 50) Step 6: 7-Chloro-3-ethyl-1,6-naphthyridin-2(1H)-one [Chemical formula] A solution of 4-amino-6-chloropyridine-3-carbaldehyde (10.0 g, 64.0 mmol, 1.0 eq), DIEA (55.8 mL, 320 mmol, 5.0 eq), and DMAP (1.56 g, 12.8 mmol, 0.20 eq) in DCM (100 mL) was treated with butyryl chloride (21.9 mL, 211 mmol, 3.30 eq) at 0 °C for 4 h under a nitrogen atmosphere, and then butyryl chloride (19.7 mL, 190 mmol, 3.0 eq) was added dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by the addition of water (100 mL) at room temperature. The precipitated solid was collected by filtration and washed with water (3 × 50 mL). This gave 7-chloro-3-ethyl-1,6-naphthyridin-2(1H)-one (2.40 g, 36% yield) as a white solid. The crude product was used without further purification.

[0092] Step 7: 7-(1-Ethoxyvinyl)-3-ethyl-1,6-naphthyridin-2(1H)-one

Chemical formula

[0093] Step 8: 7-Acetyl-3-ethyl-1,6-naphthyridin-2(1H)-one

Chemical formula

[0094] Step 9: 3-Ethyl-7-(1-hydroxyethyl)-1,6-naphthyridin-2(1H)-one

Chemical formula

[0095] Step 10: 7-(1-Bromoethyl)-3-ethyl-1,6-naphthyridin-2(1H)-one

Chemical formula

[0096] Step 11: 5-((1-(1-(3-Ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide

Chemical formula

[0097] Step 12: (Enantiomer 1)-5-((1-(1-(3-Ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 49) and (Enantiomer 2)-5-((1-(1-(3-Ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 50) [Chemical Structure] The enantiomers (100 mg) of 5-((1-(1-(3-Ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide were separated by SFC (Column: CHIRAL ART Cellulose-SB, 4.6*100 mm, 3.0 μm; Mobile phase: MtBE(0.1% DEA):EtOH = 80:20; Flow rate: 1.67 mL / min) to obtain the following compounds: (Enantiomer 1)-5-((1-(1-(3-Ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 49) (30 mg, 30% yield). LC-MS (ES + ) m / z: 426.0 (M+H) + 11H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H), 8.71 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.78 (s, 1H), 7.56 (dd, J = 10.2, 8.2 Hz, 1H), 7.23 (s, 1H), 5.02 (t, J = 5.4 Hz, 1H), 3.79 (t, J = 6.9 Hz, 1H), 3.68 (t, J = 7.1 Hz, 1H), 3.57 (q, J = 6.4 Hz, 1H), 3.23 (dd, J = 8.1, 4.7 Hz, 1H), 3.11 (dd, J = 8.3, 4.8 Hz, 1H), 2.77 (d, J = 4.7 Hz, 3H), 2.52 (s,1H), 2.50 - 2.44 (m, 1H), 1.26 - 1.12 (m, 6H). SFC RT = 1.993 min; 100% (Enantiomer 2)-5-((1-(1-(3-Ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)ethyl)azetidin-3-yl)oxy)-6-fluoro-N-methylpicolinamide (Compound 50) (34 mg, 34% yield). LC-MS (ES + ) m / z: 426.0 (M+H) + 11H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H), 8.71 (s, 1H), 8.48 (q, J = 4.7 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.78 (s, 1H), 7.56 (dd, J = 10.1, 8.2 Hz, 1H), 7.23 (s, 1H), 5.01 (q, J = 5.4 Hz, 1H), 3.79 (t, J = 7.0 Hz, 1H), 3.68 (t, J = 7.2 Hz, 1H), 3.57 (q, J = 6.5 Hz, 1H), 3.23 (dd, J = 8.2, 4.8 Hz, 1H), 3.11 (dd, J = 8.1, 4.8 Hz, 1H), 2.77 (d, J = 4.7 Hz, 3H), 2.52 (s,1H), 2.50 - 2.44 (m, 1H), 1.26 - 1.12 (m, 6H). SFC RT = 2.353 min; 100% The absolute configuration of the chiral centers of each isolated enantiomer is unknown.

[0098] Example 7 Biological Assay FP assay: The FP experiment was performed at room temperature using non-binding black 384-well microplates. Recombinant full-length PARP1 and PARP2 proteins produced in-house were diluted to 20 nM and 60 nM, respectively, with assay buffer (50 mM Tris pH8, 0.001% Triton X100, 10 mM MgCl 2 and 150 mM NaCl), and incubated for 4 hours with an equal volume of 8 nM fluorescent probe diluted with assay buffer. The fluorescence anisotropy of the probe when bound to the protein was measured in the presence of test compound or solvent control, and the effect on anisotropy was determined. Polarization was read on an Envision plate reader using excitation and emission wavelengths of 590 nm and 630 nm, respectively. All FP values are shown in mP units. The inhibition ratio was calculated using the readout (mP) according to the following formula: Inhibition (%) = 100 × (mP HC - mPサンプル ) / (mP HC -mP LC ), where HC and LC indicate high and low control wells, respectively. % inhibition values for various test compound concentrations were calculated and XLfit was used to fit to a four-parameter logistic plot to determine the IC 50 value. The test results are summarized in Table 2.

[0099] Cell Proliferation Assay in DLD1-BRCA2 - / - Cell Line BRCA2 (- / -) cells cultured in rpmI 1640 + 10% FBS were collected and diluted to 1×10 4 cells / mL and 2×10 4 cells / mL, respectively. Cells (40 μL / well) were seeded into a 384-well cell culture plate. The plate was covered and incubated overnight at 37 °C, 5% CO 2 , and then the test compound or vehicle was added. The plate was then cultured at 37 °C, 5% CO 2 for 7 days. On day 8, the plate was removed from the incubator and equilibrated at room temperature for 15 minutes. CellTiter-Glo (40 μL, 1:1 to culture medium) was added to each well and the plate was left standing at room temperature for 30 minutes. Luminescence was measured using an Envision plate reader. The obtained data were analyzed as follows; here, LC is cell-free culture medium: % vehicle = 100×(Lum test sample - Lum LC) / (Lum HC - Lum LC), where LC and HC are low and high control wells, respectively. % inhibition values for various test compound concentrations were calculated and XLfit was used to fit to a four-parameter logistic plot to determine the IC 50 value. The test results are summarized in Table 2.

[0100] Assay Method for Caco2 (A-B / B-A) Apical-to-basolateral (A-B) and basolateral-to-apical (B-A) transport of 5 μM test compound in HBSS (10 mM HEPES, pH 7.4) was measured across Caco-2 cell monolayers (cells were from American Type Culture Collection, Manassas, Virginia). Incubation in duplicate was carried out at approximately 37 °C for 120 minutes, and the functionality of the test system was confirmed using 5 μM propranolol and digoxin as control compounds. An aliquot (50 μL) from both apical and basolateral wells was transferred to two new 96-well plates and quenched with an acetonitrile solution containing an analytical internal standard. Samples were vortexed, centrifuged, and 100 μL aliquots of the resulting supernatant were mixed with an equal volume of ultrapure water and then analyzed by UPLC-MS / MS. Apparent permeability (Papp) in the A-B and B-A directions was calculated using the concentrations of the test compound and control compounds in the incubation medium in the donor and receiver compartments at the start and end of the incubation. The efflux ratio (ER) was expressed as Papp B-A / Papp A-B . The integrity of the cell monolayer after 2-hour incubation was calculated using the marker reagent lucifer yellow. The test results are summarized in Table 2.

[0101]

Table 2-1

Table 2-2

[0102] Example 8 Solubility Assay Kinetic solubility, PBS, pH 7.4 Kinetic solubility Solubility incubations were performed in duplicate for 2 hours at 25 °C and 1100 rpm in 1.5 mL glass vials on an Eppendorf Thermomixer Comfort plate shaker with PBS pH 7.4 containing 300 μM of the test compound or the control compound progesterone prepared at a concentration of 10 mM in DMSO. After incubation, the samples were filtered and the filtrate was diluted 1000-fold with water:acetonitrile 1:1 (v / v) for analysis by UPLC MS / MS to determine the concentration of the test compound. Solubility values were calculated by quantification against standards of known concentration. The test results are summarized in Table 3.

[0103] Thermodynamic solubility, FaSSiF All incubations were performed in duplicate. The test compound or the control compound diclofenac sodium (1.0 mg) was placed in a 1.5 mL glass vial. FaSSIF (1000 μL) was added to the vial. The sample was transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 25 °C and 1100 rpm for 24 hours. The sample was then filtered. The filtrate was diluted 1000-fold with water:acetonitrile 1:1 (v / v) for analysis by UPLC MS / MS to determine the concentration of the test compound. Solubility values were calculated by quantification against standards of known concentration. The test results are summarized in Table 3.

[0104] [Table 3] * Test results of two different batches # Test results of three different batches

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, X １ , X ２ or X ３ is independently selected from the group consisting of N or CH; X ５ is selected from the group consisting of N, CH, or CF; A is —O—; B is monosubstituted or unsubstituted 【Chemistry 2】 and the substituent at any position of ring B is selected from the group consisting of R ５ and R １ is C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C ３ -C ５ cycloalkyl; R ２ teeth 【Transformation 3】 where one X ４ is N, and one X ４ is CH; Each R ３ is H or unsubstituted or substituted —C １ -C ６ independently selected from the group consisting of alkyl, １ -C ６ Alkyl substituents are H, —O—CH ３ , —CN, —OH, or two R ３ is combined to C ３ -C ５ Forming a cycloalkyl; Each R ４ａ H, CN, halogen, C １ -C ６ Alkyl, —O-alkyl, C １ -C ６ haloalkyl or -C １ -C ６ independently selected from the group consisting of alkoxy; R ５ is H, C １ -C ６ Alkyl, ═O, —(CH ２ ) １－３ OH or halogen. or a pharmaceutically acceptable salt thereof.

2. Formula I 【Chemistry 4】 2. The compound of claim 1, wherein:

3. A is selected from -O-; B is monosubstituted or unsubstituted 【Transformation 5】 and the substituent at any position of ring B is selected from the group consisting of R ５ and R １ is C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C ３ -C ５ cycloalkyl; R ２ but 【Transformation 6】 where one X ４ is N, and one X ４ is CH; Each R ３ is H or unsubstituted or substituted —C １ -C ６ independently selected from the group consisting of alkyl, １ -C ６ The alkyl substituent is H, —O—CH ３ , —CN, —OH, or two R ３ are combined to form C ３ -C ６ Forming a cycloalkyl; R ４ａ H, CN, halogen, C １ -C ３ Alkyl, —O—C １ -C ３ Alkyl, C １ -C ３ haloalkyl or -C １ -C ３ alkoxy; preferably, each R ４ａ is H, -CH ３ , -CN, and F; R ５ Ga-CH ３ , -CH ２ selected from the group consisting of -OH or -F; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. Formula I 【Transformation 7】 and A is selected from -O-; R １ is C １ -C ３ Alkyl, C ３ -C ５ cycloalkyl; R ２ but 【Transformation 8】 where one X ４ is N, and one X ４ is CH; Each R ３ is H or unsubstituted or substituted —C １ -C ６ independently selected from the group consisting of alkyl, １ -C ６ The alkyl substituent is H, —O—CH ３ , —CN, —OH, or two R ３ are combined to form C ３ -C ５ Forming a cycloalkyl; Each R ４ａ is H, -CH ３ , -CN, F; 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

5. Two R's ３ and n is not simultaneously H, or a pharmaceutically acceptable salt thereof.

6. R ２ but 【Chemistry 9】 and each R ４ａ is H, -CH ３ , -CN, and F; Each R ３ is H or -C １ -C ３ alkyl, wherein two R ３ and n is not simultaneously H, or a pharmaceutically acceptable salt thereof.

7. Formula I 【Chemistry 10】 and A is selected from -O-; R １ is C １ -C ３ Alkyl, C ３ -C ５ cycloalkyl; R ２ but 【Chemistry 11】 and Each R ３ is H or unsubstituted or substituted —C １ -C ６ independently selected from the group consisting of alkyl, １ -C ６ The alkyl substituent is H, —O—CH ３ , —CN, —OH, or two R ３ are combined to form C ３ -C ５ Forming a cycloalkyl; Each R ４ａ is H, -CH ３ , -CN, F; 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

8. R １ is C １ -C ３ selected from the group consisting of alkyl; Each R ３ is H or unsubstituted —C １ -C ３ independently selected from the group consisting of alkyl; Each R ４ａ is H, -CH ３ , F; 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof.

9. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8

10. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: Table 9

11. 10. A pharmaceutical composition comprising a compound of claim 1 or 9 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable diluent, excipient or inert carrier.

12. A pharmaceutical composition for treating cancer in an individual, comprising a compound according to claim 1 or 9, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition of claim 12, wherein the cancer has a defect in the HR-dependent DNA DSB repair pathway, or the ability of the cancer cells to repair DNA DSBs by HR is reduced or suppressed compared to normal cells.

14. The pharmaceutical of claim 13, wherein the cancer cells have a BRCA1 or BRCA2 deficient phenotype and / or the cancer cells are deficient in BRCA1 or BRCA2.

15. 15. The pharmaceutical of claim 14, wherein the individual is heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway, and / or the individual is heterozygous for a mutation in BRCA1 and / or BRCA2.

16. The pharmaceutical of claim 12, wherein the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer, and / or PARP1 inhibition is beneficial in the treatment.

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