TWI633107B - Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors - Google Patents

Abstract

The present invention discloses a fused four or five membered ring compound, and salts thereof, pharmaceutical compositions thereof, and methods of use thereof.

Description

Fused tetra- or penta-dihydrodiazepine-oxazolone as a PARP inhibitor

The present invention discloses a fused quaternary or five-membered ring compound which inhibits the activity of poly(ADP-ribose) polymerase (PARP), which comprises at least one compound disclosed in the present invention for treatment. Specific disease.

Poly(ADP-ribose) polymerase (PARP), previously recognized as poly(ADP-ribose) synthase or poly(ADP-ribose) transferase, is a class of proteins containing PARP catalytic regions ( BMC Genomics , October 4, 2005) Day; 6:139). To date, approximately 17 members of the PARP family have been discovered, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), PARP-5a (terminal anchorase-1, Tankyrase-1). , PARP5b (terminal anchorase-2, Tankyrase-2), PARP-6, PARP-7 (tiPARP), PARP-8, PARP-9 (BAL1), PARP-10, PARP-11, PARP-12, PARP -13 (ZAP), PARP-14 (CoaSt6), PARP-15 and PARP-16. The catalytic activity of various PARPs is such that a portion of the ADP-ribose can be transferred from the nicotinamide adenine dinucleotide (NAD ⁺ ) to the glutamate residue of many target proteins, thereby forming a long chain of the ADP-ribose polymer. . However, it has been reported that some members of the PARP family can only catalyze the single ADP-ribosylation of target proteins, and the activity of other PARP family members has not been reported ( Mol. Cell. October 10, 2008; 32(1) :57-69.). Studies have shown that many PARP enzymes have important functional roles in many aspects, such as DNA repair, transcriptional regulation, mitotic progression, maintenance of genomic integrity, telomere stability, cell death, and Wnt signaling pathways.

PARP-1 is probably the largest and most studied family member, and PARP-2 may be the closest member of PARP-1. The damaged DNA fragment can initiate PARP, and once activated, catalyzes the poly ADP ribose unit, which is linked to a variety of nuclear proteins, including histones and PARP itself. Studies have shown that the focus of poly(ADP-ribose) synthesis is to stop transcription and increase repair enzymes where DNA is damaged. Studies have reported that PARP plays a key role in the repair of broken DNA strands. Knocking out PARP-1 makes cells more sensitive to a variety of therapeutic modalities, such as alkylating agents, topoisomerase (topo) I inhibitors, and gamma-irradiation. Studies have shown that PARP inhibitors can enhance the sensitivity of tumors to radiation therapy (including ionizing radiation and other DNA-damaging treatments), as well as increase the sensitivity of anticancer drugs (including platinum drugs, temozolomide and topoisomerase I inhibition). Agent). Studies have also shown that PARP inhibitors also have an effect on radiosensitized (hypoxic) tumor cells and prevent tumor cells from recovering from potentially lethal and sublethal DNA damage after radiotherapy, possibly because of PARP inhibitors. It can inhibit the DNA strand reorganization of rupture and can affect some signal transmission channels of DNA damage.

PARP inhibitors can effectively destroy tumors with BRCA1 or BRCA2 gene defects by synthesizing a lethal concept. At the same time, wild-type BRCA gene tumors are not sensitive to PARP inhibitors. Defects of BRCA1 or BRCA2 Significantly increase the sensitivity of these genes to PARP inhibitors. PARP inhibitors may increase DNA single-strand breaks (SSB), in which single-strand breaks are converted to toxic DNA double-strand breaks (DSB), while double-strand breaks are not possible in BRCA1/2 deficient cells. Repair by homologous recombination. Studies have also shown that PARP inhibitors can lead to synthetic lethality when ATM, ATR, RAD51 deficiency, and other homologous recombination repairs are defective. PARP inhibitors can treat cancers with DNA repair defects.

Activation of PARP may also be used to treat cell death. Ischemia-reperfusion injury and nerve damage during stroke, trauma, and Parkinson's disease may be accompanied by excessive initiation of PARP. Excessive initiation of PARP may also cause rapid depletion of NAD ⁺ to form ADP ribose polymers. Because the biosynthesis of NAD ⁺ consumes ATP, the level of ATP in the cells is subsequently depleted, dying from ischemic cell necrosis. Inhibition of PARP is likely to reduce the possibility of cell necrosis by maintaining the NAD ⁺ and ATP levels of the cells and preventing the initiation of specific inflammatory pathways that cause the cells to be further destroyed by an immune response.

It has been reported that the initiation of PARP plays an important role in NMDA and NO-induced neurotoxicity. This report is based on cortical culture and hippocampal slices, where prevention of toxicity is directly related to the inhibitory activity of PARP. It can be assumed that PARP inhibitors have a potential role in the treatment of neurodegenerative diseases and head trauma.

Studies have shown that PARP inhibitors can be used to treat and prevent autoimmune diseases such as type I diabetes and diabetic complications (Pharmaceutical Research (2005) 52: 60-71).

PARP-3 is a member of the PARP family with new features. Recently research Studies have shown that PARP-3 plays an important role in maintaining genomic integrity and mitosis (PNAS February 15, 2011 | Vol. 108 | No. 7 | 2783-2788). Insufficient PARP-3 causes a decrease in cellular response to DNA double-strand breaks. The lack of PARP-3 deficiency in the use of PARP-1/2 inhibitors results in a decrease in cell viability after x-irradiation. PARP-3 is necessary to maintain the integrity of the mitotic spindle and the stability of the telomeres. Therefore, PARP-3 may also have potential anticancer activity.

Tankyrase-1 (ADP-ribose polymerase 1 associated with TRF1 interacting with ankyrin) was initially considered to be a component of the human telomerase complex. The sequence homology of Tankyrase-2 to tankyrase-1 may be 83% and the sequence similarity may be 90%. Mouse genetic studies have shown that tankyrase-1 and tankyrase-2 have a large number of functions. Tankyrase-1 is capable of positively regulating telomere length and prolonging telomeres. Inhibition of tankyrase can make cells more sensitive to telomerase inhibitors. Tankyrase-1 is necessary for sister telomere breakdown in mitosis. Mitotic arrest can be induced by RNAi inhibition of tankyrase-1. Inhibition of tankyrase may have potential anticancer activity.

Studies have shown that tankyrase is involved in the regulation of Wnt signaling. The Wnt signaling pathway is negatively regulated by the β-catenin degradation complex by hydrolysis of the downstream effector β-catenin, which includes adenomatous polyposis (APC), axin (Axin) and Glycogen synthase kinase 3α/β (GSK3α/β). Studies have shown that inappropriate initiation of the Wnt signaling pathway is found in a variety of cancers. The truncation mutation of the tumor suppressor gene APC is clearly the most common genetic variation in colorectal cancer. APC mutations may produce defective β-links Cyclin-degrading complexes, accumulation of nuclear β-catenin, and/or active transcription of Wnt signaling pathway-responsive genes. It has also been reported that a tankyrase inhibitor can stabilize the β-catenin degradation complex by increasing the level of the axon. Axin, a key component of the β-catenin degradation complex, can be degraded by polyadenylation, ribylation and ubiquitination. Inhibition of tankyrase can reduce axonal degradation and/or increase axon levels. Studies have shown that tankyrase inhibitors inhibit colony formation in colon cancer cells that inhibit APC deficiency. Therefore, tankyrase inhibitors may have potential therapeutic effects on cancers that initiate the Wnt signaling pathway.

The present invention provides a compound and/or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprises at least one of these compounds and a pharmaceutically acceptable salt thereof for inhibiting PARP activity, thereby treating a disease such as cancer. For example, the compounds and compositions described herein can be used to treat cancers that are defective in DNA repair pathways, and/or to enhance the efficacy of chemotherapy and radiation therapy.

It has been reported that certain small molecule compounds can be used as PARP inhibitors. For example, PCT Publication Nos. WO 2000/42040 and 2004/800713, reported tricyclic indole derivatives as PARP inhibitors. PCT Publication Nos. WO 2002/44183 and 2004/105700 report tricyclic diazepine derivatives as PARP inhibitors. PCT Publication No. WO 2011/130661 and GB Patent 2,462,361, reported dihydropyridazinone derivatives as PARP inhibitors. The following inventions report other cyclic compounds as PARP inhibitors, US 7,915,280; US 7,235,557; USRE041150; US 6,887,996 and EP1339402B1.

PCT Publication No. WO 2004/4014294, published on Feb. 19, 2004, discloses 4,7-disubstituted indole derivatives as PARP inhibitors. its His cyclic compound as a PARP inhibitor is also reported in US Pat. No. 6,906,096, issued on May 22, 2009, which discloses a pyrazinozin derivative as a PARP inhibitor. GB Patent No. 2,462,361, published on October 2, 2010, discloses dihydropyridazinone derivatives as PARP inhibitors. US 7,429,578, published on September 30, 2008, discloses tricyclic derivatives as PARP inhibitors. The following invention reports other cyclic compounds as PARP inhibitors: EP1140936B1; US 6,495,541; US 6,799,298. US 6,423,705, published July 23, 2003, discloses a combination therapy using a PARP inhibitor. The following invention reports other combination therapies using PARP inhibitors: US 2009/0312280 A1; WO 2007113647 A1. US 6,967,198, published November 22, 2005, discloses tricyclic compounds as protein kinase inhibitors to enhance the efficacy of anti-tumor drugs and radiation therapy. US 7,462,713, published on December 9, 2008, also discloses tricyclic compounds as protein kinase inhibitors to enhance the efficacy of anti-tumor drugs and radiation therapy. EP Patent No. 1585749, published on August 13, 2008, reports the use of diazepine derivatives to enhance the efficacy of anti-tumor drugs and radiation therapy.

The compounds disclosed in the present invention can be used as inhibitors of poly(ADP-ribosyl)transferases (PARPs), and can be used for the treatment of cancer, stroke, brain trauma, and neurodegenerative diseases. For use in the treatment of cancer, the compounds disclosed herein and their pharmaceutically acceptable salts can be administered with DNA-damaging cytotoxic agents such as cisplatin, topotecan, irinotecan, temozolomide (temozolomide), and / or radiation therapy.

The present invention also provides at least one compound selected from the formula (I) , an isomer thereof, and a pharmaceutically acceptable salt thereof:

Wherein: R _{N is} selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl The aryl or heteroaryl group may be independently substituted with at least one substituent R ¹² ; X is selected from the group consisting of C, N, O and S; m and n may be the same or different and may be respectively Is an integer of 0, 1, 2 or 3; t is an integer of 0, ¹ , 2 or 3; R ¹ is independently selected from halogen, cyano, NO ₂ , OR ⁹ , NR ⁹ R ¹⁰ at each occurrence , NR ⁹ COR ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group may be independently optionally substituted with at least one substituent R ¹² ; R ^{2 is} selected from the group consisting of hydrogen, COR ⁹ , CONR ⁹ R ¹⁰ , CO ₂ R ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring The alkyl group, the heterocyclic group, the aryl group and the heteroaryl group may each independently be taken by at least one Group optionally substituted by R ^{12; R 3, R 4, R} 5, R 6, R 7 and R ^8, may be the same or different, are independently selected from hydrogen, ^{halogen, -NR 9 R 10, -OR 9} , Oxy, -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹¹ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ and -SO ₂ R ⁹ , alkane a base, an alkenyl group, a cycloalkyl group, an aryl group, a heterocyclic group, an alkynyl group and a heteroaryl group; wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heterocyclic group and heteroaryl group may be Independently substituted by at least one substituent R ¹² , or (R ³ and R ⁴ ) and/or (R ⁴ and R ⁵ ) and/or (R ⁵ and R ⁶ ) and/or (R ⁶ and R ⁷ ) and / or (R ⁷ and R ^8), with one or more atoms to which they are attached, together form a saturated 3-8 yuan having 1 or 2 heteroatoms, partially unsaturated or fully unsaturated a ring, the hetero atom may be independently selected from -NR ¹³ -, -O-, -S-, -SO-, and -SO ₂ -, and the ring may be optionally substituted with at least one substituent R ¹² , provided that : when X is O, R ⁵ and R ⁶ are absent, when X is N, R ⁶ is not present when X is S, R ⁵ and R ⁶ do not exist, or R ⁵ and R ⁶ at least one of Group, where R ³ and R ⁴ is a group of one when the other one is absent, when R ⁷ and R ⁸ is a group when one of the other one does not exist, and when X is C, When one of R ⁵ and R ⁶ is an oxy group, the other one is absent; R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and are respectively selected from hydrogen, alkyl, alkenyl, alkynyl, and ring. An alkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may be independently substituted with at least one substituent R ¹² Optionally substituted; R ^{12 is} selected from cyano, halo, haloalkyl, NO ₂ , -NR'R", -OR', oxy, -COR', -CO ₂ R', -CONR'R", - NR'CONR"R"', -NR'CO ₂ R", -NR'SO ₂ R", -SO ₂ R', alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and a heteroaryl group, wherein R', R" and R"' are independently selected from the group consisting of hydrogen, haloalkyl, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and hetero An aryl group, or (R' and R") and/or (R" and R"'), together with several carbon atoms to which they are attached, form 3 to 8 having 0, 1 or 2 additional heteroatoms Saturated Partially unsaturated or fully unsaturated ring, the additional heteroatoms may be independently selected from ^{-NR 13 -, - O -,} - S -, - SO- and -SO ₂ -.

R ^{13 is} selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

The present invention also provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, and at least one compound selected from the group consisting of the compound of the formula (I) and a pharmaceutically acceptable salt thereof.

The present invention provides a method of inhibiting PARP by contacting PARP with an amount of at least one compound selected from the group consisting of structural formula (I) and a pharmaceutically acceptable salt thereof, which is effective for inhibiting the activity of PARP.

The present invention also provides a method of treating at least one disease associated with PARP inhibition, comprising administering to a subject for confirming the need to treat at least one related disease, and the medicament comprising a quantity of at least one of the present invention A compound selected from the group consisting of the general formula (I) and a pharmaceutically acceptable salt thereof are described. The drug can treat at least one of the following diseases, such as cancer (such as leukemia, colon cancer, glioblastoma, lymphoma, melanoma, breast cancer and cervical cancer), cytotoxic cancer, ischemia-reperfusion injury (such as those related) Combined with, but not limited to, heart failure, myocardial infarction, stroke, other nerve damage and organ transplantation, etc., reperfusion injury (such as eyes, kidneys, intestines and bones) Reperfusion of skeletal muscle), inflammatory diseases (such as arthritis, gout, inflammatory bowel disease, central nervous system inflammation, multiple sclerosis, allergic encephalitis, sepsis, septic shock, hemorrhagic shock, lung fiber And uveitis), immune diseases or disorders (such as rheumatoid arthritis and septic shock), degenerative diseases (such as diabetes, Parkinson's disease), hypoglycemia, retroviral infection, acetaminophen Hepatic toxicity induced by phenol excess, doxorubicin and platinum-based anti-tumor drugs, heart and kidney toxicity, secondary damage to skin caused by sulfur mustard.

The present invention provides at least one use of a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as described herein, for the manufacture of a medicament which inhibits the activity of PARP.

The present invention provides at least one use of a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as described herein, for the manufacture of a medicament for the treatment of at least one of the following diseases, such as cancer (eg leukemia, colon) Cancer, glioblastoma, lymphoma, melanoma, breast and cervical cancer), cytotoxic cancer, ischemia-reperfusion injury (such as those associated with, but not limited to, heart failure, myocardial infarction, stroke, other nerves) Injury and organ transplantation, etc., reperfusion injury (such as reperfusion of eyes, kidneys, intestines and skeletal muscle), inflammatory diseases (such as arthritis, gout, inflammatory bowel disease, central nervous system inflammation, multiple sclerosis) , allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis), immune diseases or disorders (such as rheumatoid arthritis and septic shock), degenerative diseases (such as diabetes, Parkinson's disease), hypoglycemia, retroviral infection, hepatotoxicity caused by excessive acetaminophen, doxorubicin and platinum-based anti-tumor drugs Dirty and kidney toxicity, secondary damage to the skin caused by sulfur mustard.

In the present invention, unless otherwise indicated in the context, the meanings of the words, phrases and symbols to be used below are as follows. The following abbreviations and terms have the meaning throughout the text: The term "alkyl" as used herein refers to a hydrocarbyl group selected from saturated straight-chain and branched hydrocarbyl groups, including from 1 to 18, for example from 1 to 12, further For example, 1 to 6 carbon atoms. Examples of alkyl groups may be selected from methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-Butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), And 1,1-dimethylethyl or tert-butyl ("t-Bu"). Examples of other alkyl groups may be selected from the group consisting of 1-pentyl (--CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (--CH(CH ₃ )CH ₂ CH ₂ CH ₃ , 3-pentyl (--CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (--C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2- Butyl (--CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (--CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butene (--CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (--CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (--CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (--CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (--C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (--CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (--CH(CH) ₃ ) CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (--C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-- _{CH (CH 2 CH 3) CH} (CH 3) 2), 2,3- dimethyl-2-butyl _{(--C (CH 3) 2 CH} (CH 3) 2) and 3,3-dimethyl -2-butyl _{(--CH (CH 3) C (} CH 3) 3) and the like.

The term "alkenyl" as used herein refers to a hydrocarbon group selected from linear and branched chains, which includes at least one C=C double bond and 2 to 18, for example 2 to 6 carbon atoms. Examples of alkenyl groups may be selected from ethylene or vinyl (--CH=CH2), 1-propenyl (--CH=CHCH3), 2-propenyl (--CH2CH=CH2), 2-methyl -1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methyl-1,3-butadienyl, 1-positive Butenyl, 2-n-butenyl, 3-n-butenyl, 4-n-butenyl and 1,3-n-hexadienyl groups.

The term "alkynyl" as used herein refers to a hydrocarbon group selected from linear and branched chains comprising at least one C≡C triple bond and 2 to 18, for example 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl (-C≡CH), 1-propynyl (-C≡CCH ₃ ), 2-propynyl (propargyl, -CH ₂ C≡CH), 1-butynyl , 2-butynyl and 3-butynyl groups.

The term "cycloalkyl" as used herein refers to a cyclic hydrocarbon group selected from the group consisting of saturated and partially unsaturated, including cyclocyclic and polycyclic (eg, bicyclic and tricyclic) groups. For example, the cycloalkyl group may include 3 to 12, such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from 3 to 12, for example, a monocyclic group of 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkane groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentan-1-enyl, 1-cyclopentan-2-enyl, 1-cyclopentane-3- Alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, Cyclodecyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of the bicyclic cycloalkyl group include a bicyclic group or a bridged bicyclic group consisting of 7 to 12 ring atoms, and the double ring is selected from [4, 4], [4, 5], [5, 5], [5,6] and [6,6] ring systems, the bridge bicyclic ring is selected from the group consisting of bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] decane. The ring may be saturated or have at least one double bond (eg, partially unsaturated), but is not fully conjugated and is not aromatic, as defined herein.

The term "aromatic group" as used herein means a group selected from the group consisting of a 5-membered and 6-membered carbocyclic aromatic ring, for example, a phenyl group; a bicyclic system such as a 7- to 12-membered bicyclic ring system in which at least one ring is a carbocyclic ring. And an aromatic ring, such as said bicyclic ring system selected from, for example, naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline; and a tricyclic system such as a 10 to 15 membered tricyclic system wherein at least one ring is a carbocyclic ring And aromatic rings, such as 芴.

For example, the aryl group is an aryl group selected from the group consisting of a 5- and 6-membered carbocyclic aromatic ring and a 5- to 7-membered cycloalkyl or heterocyclic ring, the 5- to 7-membered cycloalkyl or heterocyclic ring. Containing at least one hetero atom selected from N, O and S, if the carbon aromatic ring and a heterocyclic ring are attached to the carbon aromatic ring, if the carbon aromatic ring is bonded to the cycloalkyl ring, the point of attachment may be in the carbon aromatic Ring or cycloalkyl. A divalent group formed on a substituted phenyl derivative and having a free valence in a ring atom is referred to as a substituted phenylene radical. The monovalent polycyclic hydrocarbon group is named after a "- group", and a monovalent polycyclic hydrocarbon group is removed from a carbon atom having a free valence to obtain a divalent group, and a "subunit" is added to the name of the corresponding monovalent group. ", such as a naphthyl group having two points of attachment, is called a dihydronaphthyl group. However, in any case, the aryl group does not include or overlap with the heteroaryl group, which will be defined separately below. Thus, if one or more carbon aromatic rings are fused to a heterocyclic aromatic ring, the resulting ring system is a heteroaryl group as defined in the specification, rather than an aryl group.

The term "arylalkyl" as used herein refers to an alkyl group as defined above substituted with an aryl group as defined above.

The term "halogen" or "halo" as used herein refers to F, Cl, Br or I.

The term "heteroaryl" as used herein is selected from the group consisting of: a 5- to 7-membered aromatic monocyclic ring comprising at least one heteroatom, for example, from 1 to 4, and in some embodiments, from 1 to 3 heteroatoms. The heteroatoms are selected from N, O and S, the remaining ring atoms are carbon; the 8- to 12-membered bicyclic ring contains at least one heteroatom, for example, from 1 to 4, and in some embodiments, from 1 to 3 heteroatoms. Or, in other embodiments, 1 or 2 heteroatoms. The hetero atom is selected from N, O and S, the remaining ring atoms are carbon, and at least one of the rings is aromatic and has at least one hetero atom in the aromatic ring; the 11 to 14 membered tricyclic ring contains at least one hetero atom, For example, from 1 to 4, in some embodiments, 1 to 3 heteroatoms, or, in other embodiments, 1 or 2 heteroatoms. The heteroatoms are selected from N, O and S, the remaining ring atoms are carbon and at least one of the rings is aromatic and the aromatic ring has at least one heteroatom.

For example, a heteroaryl group includes a 5 to 7 membered heteroaryl ring and a 5 to 7 membered cycloalkyl ring. For such a bicyclic ring, only one of the rings in the biheteroaromatic ring system contains at least one hetero atom, and the point of attachment may be in a heteroaryl ring or a cycloalkyl ring.

When the total number of S and O atoms on the heteroaryl group exceeds 1, these heteroatoms are not adjacent. In some embodiments, the total number of S and O on the heteroaryl group does not exceed two. In some embodiments, the total number of S and O on the heteroaryl ring does not exceed one.

Examples of heteroaryl groups include, but are not limited to, (encoded from a preferentially specified linkage position) pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), hydrazine Lolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thia Diazole, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolyl, isodecyl, indanyl, pyridazinyl , pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridine-5- , pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazole-6-yl), butterfly Pyridyl, fluorenyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazole, 1-oxa-2,5-oxadiazolyl, 1-oxa- 3,4-diazolyl, 1-thio-2,3-oxadiazolyl, 1-thio-2,4-oxadiazole, 1-thio-2,5-diazolyl, 1-sulfur 3,4-oxadiazolyl, furazanyl, benzofurazyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, Furopyridinyl, benzothiazolyl (such as benzo[d]thiazole-6-yl), fluorenyl (ratio Such as 1H-carbazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

The term "heterocyclic" or "heterocyclic" or "heterocyclyl" as used herein refers to a monocyclic, bicyclic or tricyclic ring selected from 4- to 12-membered rings which are saturated and partially unsubstituted. The saturated ring includes at least one hetero atom selected from N, O and S, for example, from 1 to 4, further, for example, 1 to 3 hetero atoms, or, further, for example, 1 or 2 hetero atoms. Outside the heteroatom, at least one carbon atom. The term "heterocycle" as used herein also refers to a class of 5- to 7-membered heterocyclic rings consisting of at least one hetero atom selected from N, O and S, and 5-, 6- and/or 7-membered a cycloalkyl ring, a carbocyclic aromatic ring or a heteroaryl ring-and-ring, when the heterocyclic ring is ring-bonded to a carbocyclic aromatic ring or a heteroaromatic ring, the point of attachment is on the heterocyclic ring, and when the heterocyclic ring is bonded to the cycloalkyl group The ring-bonding point can be on a cycloalkyl or heterocyclic ring.

The "heterocyclic ring" herein also refers to a class of aliphatic spiro rings including at least one hetero atom selected from N, O and S, to which the point of attachment is. These rings may be saturated or contain at least one double bond (ie, partially unsaturated). The above heterocyclic ring may be substituted by oxygen. The point of attachment may be a carbon atom or a hetero atom on the heterocycle. A heterocyclic ring is not a heteroaryl ring as defined herein.

Examples of heterocycles include, but are not limited to, (encoded from a preferred position of the linkage 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolyl, 1 - piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-pyridazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, epoxy B Alkyl, azacyclopropenyl, cyclohexylethane, azetidinyl, oxetanyl, thioheterobutyl, 1,2-dithiot-butyl, 1,3-di Thiopyletyl, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, oxathiolanyl, pyridazinyl, oxazinyl, homopiperidinyl, azepanyl , oxetanyl, thiaheptanyl, 1,4-oxathiolanyl, 1,4-dioxanyl, 1,4-oxathiaheptyl , 1,4-azacycloheptyl, 1,4-dithiaheptanyl, 1,4-azetidinyl and 1,4-diazepane, 1- 1,4-Dithiaalkyl, 1,4-azetidinyl, oxazepine, diazepine, thiazepine, dihydrothienyl, dihydropyranyl, dihydrofuran Base, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyran , tetrahydrothiopyranyl, 1-pyrroline, 2-pyrolinyl, 3-pyrroline, porphyrin, 2H-pyranyl, 4H-pyranyl, 1,4-dioxe Hexyl, 1,3-dioxocyclopentyl, pyrazolinyl, pyrazolidinyl, dithiaalkyl, dithiacyclopentyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, 1, 1-Dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl. Substituted heterocyclic groups also include one or more oxy group substituted rings Systems such as N-oxypiperidinyl, N-oxymorpholinyl, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

The compounds described herein may contain an asymmetric center and thus may exist as enantiomers. The compounds described herein have two or more asymmetric centers which may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broad class of stereoisomers. All such possible stereoisomers include substantially pure resolved enantiomers, racemic mixtures, and diastereomeric mixtures. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are included. Unless otherwise specifically mentioned, one of the isomers mentioned applies to any reasonable isomer. All possible isomers are included whenever the isomeric component is not indicated.

The term "substantially pure" as used in the present invention means that the other stereoisomers contained in the target stereoisomer have a weight of no more than 35%, such as no more than 30%, further no more than 25%, or even no more than 20%. In some embodiments, the term "substantially pure" means that the other stereoisomers contained in the target stereoisomer have a weight of no more than 10%, such as no more than 5%, such as no more than 1%.

When the compounds described herein contain olefinic double bonds, these double bonds include the E and Z geometric isomers unless otherwise specified.

Some of the compounds described in the present invention may have different hydrogen atom attachment points and are referred to as tautomers. For example, a compound comprising a carbonyl-CH ₂ C(O)- group (keto form) can undergo tautomerization to form a hydroxy-CH=C(OH)- group (enol form). The keto and enol forms, when used, are also included in a single form as well as mixtures.

It is advantageous to separate the reaction products from each other or separately from the starting materials. Each step or series of steps of the target is isolated and/or purified (using separations hereinafter) to achieve the desired uniformity by techniques commonly employed in the art. Representative separation techniques include multiphase extraction, recrystallization, distillation, sublimation, or chromatography with a solvent or mixed solvent. Chromatography can involve a number of methods including, for example, reversed phase and normal phase; molecular sieves; ion exchange; high, medium and low pressure liquid chromatography and equipment; small amount analysis; simulated moving bed ("SMB") and preparation of thin layers Or thick layer chromatography, as with small thin layers and flash chromatography. Those skilled in the art use these techniques to achieve the desired resolution.

Mixtures of diastereomers can be separated into the individual diastereomers by techniques well known in the art using physicochemical differences in mixtures of such diastereomers, such as by chromatography and/or fractionation. Step crystallization. An enantiomer can be converted to a mixture of diastereomers by reaction of a mixture of enantiomers with a suitable optically active compound (for example, a chiral auxiliary such as a chiral alcohol or Mosher chloro), and then The mixture of diastereomers is separated and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. The enantiomers can also be separated by a chiral HPLC column.

Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolution of the racemic mixture, such as by the use of optically active resolving agents to form diastereomers (Eliel, E. And Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113 (3) (1975): pp. 283-302). The racemic mixture of the chiral compound of the present invention can be isolated by any suitable method, including: (1) formation of an ionic, diastereomeric salt with a chiral compound, followed by separation by fractional crystallization or other methods. (2) forming a diastereomeric compound with a chiral derivatizing reagent, separating the diastereomer formed and converting into a pure stereoisomer, and (3) separating substantially pure or under chiral conditions. Enriched stereoisomers. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

"Pharmaceutically acceptable salts" include, but are not limited to, mineral acid salts selected from, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromides, sulfates, sulfites, and nitrates; , selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, a salt of a benzoate, a salicylate, a stearate, an alkanoate such as an acetate, and HOOC-(CH ₂ ) _n -COOH, wherein n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium salts.

Alternatively, if an acid addition salt of one of the compounds described herein is obtained, the free base can be obtained by basifying the solution of the acid salt. Conversely, if the compound is a free base, an addition salt (eg, a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, with a basic compound The conventional procedure for preparing acid addition salts is consistent. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable additions without undue experimentation. salt.

As defined herein, a "pharmaceutically acceptable salt" includes at least one salt selected from the group consisting of compounds of Formulas I, II (including II-1, II-2, or II-3) and III, and at least one selected Salts of the stereoisomers of the formula I, II (including II-1, II-2, or II-3) and III, such as the salts of the enantiomers and/or diastereomers.

"Treatment" or "alleviation" refers to the administration of at least one compound and/or at least one of the stereoisomers thereof, and/or at least one pharmaceutically acceptable salt disclosed herein to a subject that confirms the need for each of the foregoing, for example The subject has cancer and/or inflammatory disease, or has a symptom, such as a cancer and/or an inflammatory disease, or has a tendency, for example, a cancer and/or an inflammatory disease, to heal, heal, Ameliorating, relieving, transforming, remedying, ameliorating, or influencing, for example, cancer and/or inflammatory diseases, symptoms of the subject, for example, cancer and/or inflammatory diseases, or predispositions, for example, cancer and/or Or an inflammatory disease.

The term "effective amount" means that the amount and/or at least one pharmaceutically acceptable salt of at least one compound of the invention is effective to "treat" a disease or condition as described above. In the case of cancer, a subject of any change that may be caused by an effective amount is "treatment" and "alleviation". For example, an effective amount reduces the number of cancer or tumor cells; the tumor shrinks; inhibits or prevents tumor cells from infiltrating surrounding organs including, for example, the spread of tumors to soft tissues and bones; inhibits and prevents tumor metastasis; inhibits and prevents tumor growth; To some extent alleviate one or more cancer-related symptoms, reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount can be an amount sufficient to reduce the symptoms of a disease that responds to PARP inhibition. for The effects of cancer treatment can be, for example, measured by the estimated survival time, time to disease progression (TTP), response rate (RR), response time, and/or quality of life. The effective amount may vary, as recognized in these technical techniques, depending on the route of administration, the use of excipients, and in combination with other drugs.

The term "inhibition" refers to reduced biological activity or baseline activity in the process. By "inhibiting PARP" is meant that the presence and/or at least one pharmaceutically acceptable salt of at least one compound of the invention directly or indirectly reduces PARP activity, at least one compound and/or at least one pharmaceutically acceptable salt may cause PARP activity is reduced. The decrease in activity is not bound by theory, possibly due to the direct or interaction of at least one compound and/or at least one pharmaceutically acceptable salt of the invention with PARP, or due to at least one compound and/or at least one pharmaceutically acceptable Acceptable salt interactions, with one or more other factors, in turn affect PARP activity. For example, the presence of at least one compound and/or at least one pharmaceutically acceptable salt, by direct binding of PARP, may reduce PARP activity, and another factor (directly or indirectly) reduces the amount of PARP in cells or tissues. Reduce the activity of PARP.

The term "at least one is replaced" as disclosed herein, for example from 1 to 4, such as from 1 to 3, further such as from 1 to 2. For example, at least one substituted R ¹² disclosed herein comprises from 1 to 4, such as from 1 to 3, and further such as from 1 to 2, the substituents are selected from the groups listed in R ¹² .

In a first aspect, at least one compound is provided in the invention, the isomer thereof and a pharmaceutically acceptable salt thereof are selected from the formula (I) :

Wherein: R _{N is} selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl And aryl and heteroaryl may be independently substituted by at least one substituent R ¹² ; X is selected from the group consisting of C, N, O and S; m and n may be the same or different and may be respectively Is an integer of 0, 1, 2 or 3; t is an integer of 0, ¹ , 2 or 3; R ¹ is independently selected from halogen, cyano, NO ₂ , OR ⁹ , NR ⁹ R ¹⁰ at each occurrence , NR ⁹ COR ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, Wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group may be independently optionally substituted with at least one substituent R ¹² ; R ^{2 is} selected from hydrogen, COR ⁹ , CONR a group consisting of ⁹ R ¹⁰ , CO ₂ R ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be independently Optionally substituted with at least one substituent R ¹² ; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different and are each independently selected from hydrogen, halogen, -NR ⁹ R ¹⁰ , - OR ⁹ , oxy, -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹¹ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ and -SO ₂ R ^9, an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, a heterocyclic group, an alkynyl group, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl group may independently be substituted with at least one R ¹² group is optionally substituted, or (R ³ and R ⁴⁾ and / or (R ⁴ and R ⁵⁾ and / or (R ⁵ and R ⁶⁾ and / or (R ⁶ And R ⁷ ) and/or (R ⁷ and R ⁸ ), together with one or more of the atoms to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or all of which has 0, 1 or 2 heteroatoms. a saturated ring, the hetero atom may be independently selected from -NR ¹³ -, -O-, -S-, -SO- or -SO ₂ -, and the ring may be optionally substituted with at least one substituent R ¹² , with the proviso that: when X is O, R ⁵ and R ⁶ are absent, when X is N, R ⁶ is not present when X is S, R ⁵ and R ⁶ do not exist, or R ⁵ and R ⁶ are to Is one group, when R ³ and R ⁴ is a group of one when the other one is absent, when R ⁷ and R ⁸ is a group when one of the other one does not exist, and when X Is C and one of R ⁵ and R ⁶ is an oxy group, the other one is absent; R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and are respectively selected from hydrogen, alkyl, alkenyl, alkyne a base, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group may be independently substituted by at least one The group R ^{12 is} optionally substituted; R ^{12 is} selected from the group consisting of cyano, halogen, haloalkyl, NO ₂ , -NR'R", -OR', oxy, -COR', -CO ₂ R', -CONR'R ", -NR'CONR"R"', -NR'CO ₂ R", -NR'SO ₂ R", -SO ₂ R', alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, Aryl and heteroaryl, wherein R', R" and R" are independently selected from the group consisting of hydrogen, haloalkyl, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl And heteroaryl, or (R' and R") and/or (R" and R"'), together with the several atoms to which they are attached, form 3 with 0, 1 or 2 additional heteroatoms To 8 yuan full , Partially unsaturated or fully unsaturated ring, the additional heteroatoms may be independently selected from ^{-NR 13 -, - O -,} - S -, - SO- and -SO ₂ -.

R ^{13 is} selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

In some embodiments, X in formula (I) is C. In some embodiments, X in formula (I) is N.

In some embodiments, m and n in formula (I) are both integers 1. In some embodiments, formula (I) in which n is an integer of 1, formula (I) wherein m is an integer of 2; In some other embodiments of formula (I) wherein n is an integer of 2, of formula (I) m in is an integer 1.

In some embodiments, t in formula (I) is an integer zero. In some embodiments, t in formula (I) is an integer of 1, and R ¹ in formula (I) is selected from the group consisting of halogen, cyano, NO ₂ , OR ⁹ , NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, The alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may each independently be optionally substituted with at least one substituent R ¹² as defined above. In some further embodiments, t in formula (I) is an integer of 1, and R ¹ in formula (I) is halo (eg, F, Cl, and Br, further, for example, F) or alkyl (eg, 1- A 12 carbon alkyl group, further, for example, an alkyl group of 1 to 6 carbons). In some further embodiments, t in formula (I) is an integer of 1, and R ¹ in formula (I) is a halogen (eg, F).

In some embodiments, R _N in formula (I) is hydroxy or alkoxy optionally substituted alkyl. In some further embodiments, R _N in formula (I) is a hydroxy or an alkoxy group of 1 to 12 carbons optionally substituted with an alkyl group of 1 to 12 carbons. In some further embodiments, R _N in formula (I) is hydroxy or an alkoxy group of 1-6 carbons, optionally substituted 1-6 carbon alkyl.

In some embodiments, R ² in formula (I) is hydrogen or alkyl (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be subjected to at least one of the above formulas. The intermediate substituent R ¹² in the definition of (I) is optionally substituted. In some embodiments, R ² in formula (I) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R ¹² Optionally substituted, herein, R ^{12 is} selected from the group consisting of -NR'R", -OR', heterocyclyl and aryl, wherein R' and R''' are independently selected from hydrogen, haloalkyl, alkyl and aralkyl. a radical, or R' and R", together with the atom to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms, said additional The heteroatoms can be independently selected from the group consisting of -NR ¹³ -, -O-, -S-, -SO-, and -SO ₂ -. In some further embodiments, R ² in formula (I) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R ^{12 is} optionally substituted, wherein R ^{12 is} selected from -NR'R", -OR', heterocyclyl and aryl (eg, phenyl), where R' and R" are independently selected from hydrogen, haloalkyl (for example, a haloalkyl group of 1 to 12 carbons, further, for example, a haloalkyl group of 1 to 6 carbons), an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 to 6 carbons) An alkyl group, an aralkyl group (for example, an alkyl group of 1 to 12 carbons of a phenyl group, further, for example, an alkyl group of 1 to 6 carbons of a phenyl group), or R' and R", and an atom to which they are attached, Together, a 3 to 8 membered saturated, partially unsaturated or totally unsaturated ring having 0, 1 or 2 additional heteroatoms may be formed, which may be independently selected from -NR ¹³ -, -O-, -S-, -SO- and -SO ₂ - (for example, there are 0 or 1 additional heteroatoms on a 5 or 6-membered saturated ring, the hetero atom is an oxygen atom, further, for example, a 5-membered saturated ring, a 6-membered saturated ring , or a 6-membered saturated ring with 1 oxygen heteroatom on the ring). Embodiment, formula (I) in R ² is alkyl (e.g., 1 to 12 carbons, further such as 1 to 6 carbons), may be at least one selected from aryl ( For example, a substituent of phenyl), optionally substituted, a 3, 4, 5, 6, 7, 8-membered heterocyclic ring containing a nitrogen atom and/or an oxygen atom, -OR' and -NR'R", Here, R' and R" are independently selected from hydrogen, haloalkyl (for example, haloalkyl of 1 to 12 carbons, further, for example, haloalkyl of 1 to 6 carbons), alkyl (for example, 1 to 12) a carbon alkyl group, further, for example, an alkyl group of 1 to 6 carbons, an aralkyl group (for example, an alkyl group having 1 to 6 carbon atoms). In some further embodiments, in the formula (I) R ² is an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be optionally substituted with at least one substituent selected from an aryl group (for example, a phenyl group). Substituted; 3, 4, 5, 6, 7, 8 yuan heterocyclic ring containing a nitrogen atom and/or an oxygen atom, the heterocyclic ring may be selected from pyrrolidinyl, piperidinyl, morpholinyl and epoxyethyl ;-OR'; and -NR'R", where R' and R" are independently selected from hydrogen, haloalkyl (eg, 1-6 carbons) An alkyl group, an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), and an aralkyl group (for example, an alkyl group having 1 to 6 carbon atoms), further For example, benzyl).

In some embodiments, R ⁵ in formula (I) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR ⁹ and -COOR ⁹ wherein each alkyl, cycloalkyl and aryl group may be independently substituted with at least one substituent group is optionally substituted with R ^12, R ⁹ is an alkyl or cycloalkyl group may be substituted with at least one of R ¹² is optionally substituted, R ^12, see the definition of formula (I). In some embodiments, R ⁵ in formula (I) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR ⁹ and -COOR ⁹ wherein each alkyl, cycloalkyl, or aryl group is may be independently substituted with at least one substituent optionally substituted with R ^12, R ⁹ is an alkyl or cycloalkyl group may be substituted with at least one of R ¹² is optionally substituted, R ¹² is selected from -NR'R ", aryl group, and -NR'CO ₂ R", wherein R' and R" are independently selected from the group consisting of hydrogen, haloalkyl and alkyl. In some further embodiments, R ⁵ in formula (I) is selected from hydrogen; alkyl ( For example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons, may be substituted with at least one substituent selected from the group consisting of -NR'R" and an aryl group (for example, a phenyl group), optionally Substituted; cycloalkyl (eg, 3, 4, 5, 6, 7, 8 carbon cycloalkyl); aryl (eg, phenyl), optionally substituted by -NR'R"; -COR ⁹ Here, R ⁹ is a cycloalkyl group (for example, a cycloalkyl group of 3, 4, 5, 6, 7, 8 carbons), or an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 a -6 carbon alkyl group, each of the cycloalkyl group and the alkyl group, may be at least one selected from the group consisting of -NR'R", an aryl group (for example, a phenyl group) And a substituent of -NR'CO ₂ R" is optionally substituted, wherein R' and R" are independently selected from hydrogen, haloalkyl (for example, haloalkyl of 1 to 6 carbons), alkyl (for example, 1-6 carbon alkyl groups). In some further embodiments, formula (I) in R ⁵ is selected from hydrogen; 1-6 carbon alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, or 3, 3- dimethylbutyl), may be substituted -NR'R "optionally substituted; cyclohexyl; substituted group -NR'R" optionally substituted phenyl; -COR ^9, where, R ⁹ is a cyclic a propyl group, or an alkyl group of 1 to 6 carbons (for example, methyl, ethyl, propyl, isopropyl, or butyl), each of which is a cyclopropyl group and a 1-6 carbon alkyl group may be at least A substituent selected from -NR'R", an aryl group (for example, phenyl) and -NR'CO ₂ R" is optionally substituted, wherein R' and R" are independently selected from hydrogen, and 1 to 6 carbons Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl).

In some embodiments, R ⁴ and R ⁵ in formula (I) , together with several carbon atoms to which they are attached, form 3, 4, 5, 6, 7 or 0, 1 or 2 heteroatoms or An 8-membered saturated, partially unsaturated or fully unsaturated ring, said heteroatoms being independently selected from the group consisting of -NR ¹³ -, -O-, -S-, -SO-, and -SO ₂ -, and the ring may be The substituent R ¹² in the definition of at least one of the above formula (I) is optionally substituted. In some embodiments, R ⁴ and R ⁵ in formula (I) , together with the several carbon atoms to which they are attached, form a 5-membered saturated ring containing a nitrogen heteroatom.

In some embodiments, at least one pair (R ³ and R ⁴ ), (R ⁵ and R ⁶ ), and (R ⁷ and R ⁸ ) of formula (I ) are alkyl groups (eg, 1-12 carbons) An alkyl group, further, for example, an alkyl group of 1 to 6 carbons, further, for example, a methyl group. In some embodiments, R ³ and R ⁴ in formula (I) may be the same or different and are each independently selected from hydrogen, alkyl (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 - 6 carbon alkyl) and hydroxyl.

In a second aspect, at least one of the present invention is selected from the group consisting of a compound of formula (I) , a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, selected from the group consisting of the following formula (II) :

Wherein: R _{N is} selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl And aryl and heteroaryl may be independently substituted by at least one substituent R ¹² ; m and n may be the same or different and may each be an integer of 0, 1, 2 or 3; t is an integer of 0, An integer of ¹ , 2 or 3; R ¹ , independently selected from the group consisting of halogen, cyano, NO ₂ , OR ⁹ , NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , CONR ⁹ at each occurrence R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, The heterocyclic group, the aryl group and the heteroaryl group may each independently be optionally substituted with at least one substituent R ¹² ; R ^{2 is} selected from the group consisting of hydrogen, COR ⁹ , CONR ⁹ R ¹⁰ , CO ₂ R ⁹ , SO ₂ R ⁹ , alkane a base, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Independently substituted with at least one substituent R ¹² ; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, -NR ⁹ R ¹⁰ , -OR ⁹ , oxy, -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹¹ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ and -SO ₂ R ⁹ , alkyl, alkenyl, cycloalkyl, aryl, hetero a cycloalkyl, alkynyl and heteroaryl group, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl group is independently optionally substituted with at least one substituent R ¹² ; or (R ³ and R ⁴⁾ and / or (R ⁴ and R ⁵⁾ and / or (R ⁵ and R ⁶⁾ and / or (R ⁶ and R ⁷⁾ and / or (R ⁷ and R ^8), and The one or more atoms to which they are joined together form a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 heteroatoms, which may be independently selected from -NR ¹³ -, -O-, -S-, -SO- and -SO ₂ -, and the ring may be optionally substituted by at least one substituent R ¹² , provided that: one of R ³ and R ⁴ is an oxy group when the other one does not exist, when the R ⁷ and R ⁸ is one group, the further one is absent, when R ⁵ and R ⁶ is one group, the further Does not exist; R ^9, R ¹⁰ and R ^11, may be the same or different, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may each independently be optionally substituted with at least one substituent R ¹² ; R ^{12 is} selected from cyano, halo, haloalkyl , NO ₂ , -NR'R", OR', oxy, -COR', -CO ₂ R', -CONR'R", -NR'CONR"R"', -NR'CO ₂ R", - NR'SO ₂ R", -SO ₂ R', alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein R', R" and R''' independently Selected from hydrogen, haloalkyl, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or (R' and R") and/or (R" And R"'), together with the atoms to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms, said additional The atoms may be independently selected from -NR ¹³ -, -O-, -S-, -SO- or -SO ₂ -.

R ^{13 is} selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

In some embodiments, m and n in formula (II) are both integers 1. In some embodiments, the formula (II) in which n is 1, the formula (II) wherein m is 2; in other embodiments, the formula (II) wherein n is 2, the formula (II) in m it's 1.

In some embodiments, t in formula (II) is zero. In some embodiments, the formula (II) in t is 1, the formula ^(II), R ¹ is selected from halogen, ^{_{cyano, NO 2, OR 9, NR}} 9 R 10, NR 9 COR 10, NR 9 SO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkyne The base, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may each independently be optionally substituted with at least one substituent R ¹² as defined above; in some further embodiments, t in formula (II) Is 1, R ¹ in the formula (II) is a halogen (for example, F, Cl, and Br, further, for example, F) or an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 to 6 carbons) alkyl). In some further embodiments, of formula (II) in t is 1, the formula ^(II), R ¹ is halogen (e.g., F).

In some embodiments, R _N in formula (II) is at least one substituent selected from the group consisting of a hydroxyl group and an alkoxy group. In some further embodiments, R _N in formula (II) is an optionally substituted alkyl group of 1 to 12 carbons, and the substituent is substituted with at least one alkoxy group selected from the group consisting of a hydroxyl group and 1 to 12 carbons. base. In some further embodiments, R _N in formula (II) is an optionally substituted 1-6 carbon alkyl group, and the substituent is at least one substituent selected from a hydroxyl group or an alkoxy group of 1 to 6 carbons. base.

In some embodiments, R ² in formula (II) is hydrogen or an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be subjected to at least one of the above formulas. The intermediate substituent R ¹² in the definition of (II) is optionally substituted. In some embodiments, R ² in formula (II) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R ¹² Optionally substituted, here, R ^{12 is} selected from -NR'R", -OR', heterocyclyl and aryl, wherein R' and R''' are independently selected from hydrogen, haloalkyl, alkyl and aralkyl a group, or R' and R", together with several carbon atoms to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or totally unsaturated ring having 0, 1 or 2 additional heteroatoms. The additional heteroatoms can be independently selected from the group consisting of -NR ¹³ -, -O-, -S-, -SO-, and -SO ₂ -. In some further embodiments, R ² in formula (II) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R ^{12 is} optionally substituted, wherein R ^{12 is} selected from the group consisting of -NR'R", -OR', heterocyclyl, and aryl (for example, phenyl), wherein R' and R" are independently selected from hydrogen, haloalkane. a group (for example, a haloalkyl group of 1 to 12 carbons, further, for example, a haloalkyl group of 1 to 6 carbons), an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 to 6 carbons) Alkyl), aralkyl (eg, phenyl 1-12 carbon alkyl, further, for example, phenyl 1-6 carbon alkyl), or R' and R", with the atom to which they are attached Forming together a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms, which may be independently selected from -NR ¹³ -, -O- , -S-, -SO-, and -SO ₂ - (for example, there are 0 or 1 additional heteroatoms on a 5 or 6-membered saturated ring, the heteroatoms are oxygen atoms, further, for example, a 5-membered saturated ring, 6-membered saturated Ring, or a 6-membered saturated ring, with 1 oxygen atom on the ring). Step embodiment, of formula (II) in R ² is alkyl (e.g., 1 to 12 carbons, further such as 1 to 6 carbons), may be at least one selected from aryl a substituent (for example, phenyl), optionally substituted, a 3, 4, 5, 6, 7, 8-membered heterocyclic ring containing a nitrogen atom and/or an oxygen atom, -OR' and -NR'R" Wherein R' and R" are independently selected from hydrogen, haloalkyl (for example, haloalkyl of 1 to 12 carbons, further, for example, haloalkyl of 1 to 6 carbons), alkyl (for example, 1- a 12 carbon alkyl group, further, for example, a 1-6 carbon alkyl group, an aralkyl group (eg, a phenyl group of 1 to 6 carbon alkyl groups). In some further embodiments, the formula (II) R ² in the group is an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent selected from an aryl group (for example, a phenyl group). Optionally substituted; 3, 4, 5, 6, 7, 8 of a heterocyclic ring containing a nitrogen atom and/or an oxygen atom, the heterocyclic ring may be selected from pyrrolidinyl, piperidinyl, morpholinyl and epoxy Ethyl; -OR' and -NR'R", where R' and R" are independently selected from hydrogen, haloalkyl (eg, 1-6 Haloalkyl), alkyl (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), and an aralkyl group (for example, an alkyl group of 1 to 6 carbons) Further, for example, benzyl).

In some embodiments, R ⁵ in formula (II) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR ⁹ , and -COOR ⁹ wherein each alkyl, cycloalkyl, and aryl group may be independently substituted with at least one substituent optionally substituted with R ^12, R ⁹ is an alkyl or cycloalkyl group may be substituted with at least one R ¹² group is optionally substituted, R ^12, see the definition of formula (II). In some embodiments, R ⁵ in formula (II) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR ⁹ and -COOR ⁹ wherein each alkyl, cycloalkyl, or aryl group is may be independently substituted with at least one substituent optionally substituted with R ^12, R ⁹ is an alkyl or cycloalkyl group may be substituted with at least one of R ¹² is optionally substituted, R ¹² is selected from -NR'R ", aryl group, and -NR'CO ₂ R", where R' and R" are independently selected from the group consisting of hydrogen, haloalkyl and alkyl. In some further embodiments, R ⁵ in formula (II) is selected from hydrogen; alkyl ( For example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons, may be substituted with at least one substituent selected from the group consisting of -NR'R" and an aryl group (for example, a phenyl group), optionally Substituted; cycloalkyl (eg, 3, 4, 5, 6, 7, 8 carbon cycloalkyl); aryl (eg, phenyl), optionally substituted by -NR'R"; -COR ⁹ Here, R ⁹ is a cycloalkyl group (for example, a cycloalkyl group of 3, 4, 5, 6, 7, 8 carbons), or an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 a -6 carbon alkyl group, wherein each cycloalkyl group and alkyl group may be selected from at least one selected from the group consisting of -NR'R" and an aryl group (for example, Yl) and -NR'CO ₂ R "substituent optionally substituted, where R 'and R" are independently selected from hydrogen, haloalkyl (e.g., 1-6 carbon haloalkyl), alkyl (e.g. , 1-6 carbon alkyl). In some further embodiments, R ⁵ in formula (II) is selected from the group consisting of hydrogen; 1-6 carbon alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, or 3, 3-dimethylbutyl), which may be optionally substituted by a substituent -NR'R";cyclohexyl; phenyl, optionally substituted by a substituent -NR'R"; -COR ⁹ , where R ⁹ is a ring a propyl group, or an alkyl group of 1 to 6 carbons (for example, methyl, ethyl, propyl, isopropyl, or butyl), each of which is a cyclopropyl group or a 1-6 carbon alkyl group A substituent selected from the group consisting of -NR'R", aryl (for example, phenyl) and -NR'CO ₂ R" is optionally substituted, wherein R' and R" are independently selected from hydrogen, and 1-6 carbons Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl).

In some embodiments, R ⁴ and R ⁵ in formula (II) , together with the atom to which they are attached, form a 3, 4, 5, 6, 7, 8 elementary saturation having 0, 1 or 2 heteroatoms. a partially unsaturated or fully unsaturated ring, said heteroatoms being independently selected from the group consisting of -NR ¹³ -, -O-, -S-, -SO-, and -SO ₂ -, and the ring may be at least one of the above The intermediate substituent R ¹² in the definition of formula (II) is optionally substituted. In some further embodiments, R ⁴ and R ⁵ in formula (II) , together with the atoms to which they are attached, form a 5-membered saturated ring having a nitrogen atom.

In some embodiments, the at least one pair of (R ³ and R ⁴⁾ of formula (II) is, (R ⁵ and R ⁶⁾ and (R ⁷ and R ⁸⁾ is alkyl (e.g., 1 to 12 carbons An alkyl group, further, for example, an alkyl group of 1 to 6 carbons, further, for example, a methyl group. In some embodiments, the formula (II), R ³ and R ^4, may be the same or different, are independently selected from hydrogen, alkyl (e.g., 1 to 12 carbons, further such as 1- 6 carbon alkyl) and hydroxyl.

In a third aspect, at least one of the present invention is selected from the group consisting of a compound of formula (I) , a stereoisomer thereof, and a pharmaceutically acceptable salt thereof, selected from the group consisting of the following formula (III) :

Wherein: R _{N is} selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl The aryl and heteroaryl groups may each be independently substituted with at least one substituent R ¹² ; m and n may be the same or different and may each be an integer of 0, 1, 2 or 3; t is an integer of 0, An integer of ¹ , 2 or 3; R ¹ , independently selected from the group consisting of halogen, cyano, NO ₂ , OR ⁹ , NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , CONR ⁹ at each occurrence R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, The heterocyclic group, the aryl group and the heteroaryl group may each independently be optionally substituted with at least one substituent R ¹² ; R ^{2 is} selected from the group consisting of hydrogen, COR ⁹ , CONR ⁹ R ¹⁰ , CO ₂ R ⁹ , SO ₂ R ⁹ , alkane a base, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Independently substituted with at least one substituent R ¹² ; R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, -NR ⁹ R ¹⁰ , -OR ⁹ , oxy, -COR ⁹ , -CO ₂ R ⁹ , -CONR ⁹ R ¹⁰ , -NR ⁹ CONR ¹⁰ R ¹¹ , -NR ⁹ CO ₂ R ¹⁰ , -NR ⁹ SO ₂ R ¹⁰ and -SO ₂ R ⁹ , alkyl, alkenyl, cycloalkyl, aryl, heterocyclic, Alkynyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl group is independently optionally substituted with at least one substituent R ¹² ; or (R ³ and R ⁴ ) and/or (R ⁴ and R ⁵ ) and/or (R ⁵ and R ⁷ ) and/or (R ⁷ and R ⁸ ) together with one or more of the atoms to which they are attached a 3 to 8 membered saturated, partially unsaturated or totally unsaturated ring of 0, 1 or 2 heteroatoms which may be independently selected from the group consisting of -NR ¹³ -, -O-, -S-, -SO- And -SO ₂ -, and the ring may be optionally substituted by at least one substituent R ¹² , when one of R ³ and R ⁴ is an oxy group, the other is absent, when in R ⁷ and R ⁸ When one is an oxy group, the other one is absent, and R ⁹ , R ¹⁰ and R ¹¹ may be the same or different and are respectively selected from hydrogen, an alkyl group, an alkenyl group, An alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may be independently at least one Substituent R ^{12 is} optionally substituted; R ^{12 is} selected from cyano, halo, haloalkyl, NO ₂ , -NR'R", -OR', oxy, -COR', -CO ₂ R', -CONR'R",-NR'CONR"R"',-NR'CO ₂ R", -NR'SO ₂ R", -SO ₂ R', alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic And aryl and heteroaryl, wherein R', R" and R" are independently selected from the group consisting of hydrogen, haloalkyl, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl, or (R' and R") and/or (R" and R"'), together with several atoms to which they are attached, form 0, 1 or 2 additional heteroatoms a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring, said additional heteroatoms being independently selected from -NR ¹³ -, -O-, -S-, -SO- or -SO ₂ -; R ^{13 is} selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

In some embodiments, m and n in formula (III) are both integer 1. In some embodiments, formula (III) in which n is an integer of 1, of formula (III) wherein m is an integer of 2; In other embodiments, the formula (III) wherein n is 2, the formula (III), m is 1.

In some embodiments, t in formula (III) is zero. In some embodiments, formula (III) in t is 1, the formula ^(III), R ¹ is selected from halogen, ^{_{cyano, NO 2, OR 9, NR}} 9 R 10, NR 9 COR 10, NR 9 SO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COOR ⁹ , SO ₂ R ⁹ , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein each alkyl, alkenyl, alkyne The benzyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may each independently be optionally substituted with at least one substituent R ¹² as defined above. In some further embodiments, the formula (III) in t is 1, the formula ^(III), R ¹ is halogen (e.g. F, Cl and Br, further such as, F) or alkyl (e.g., 1-12 A carbon alkyl group, further, for example, an alkyl group of 1 to 6 carbons). In some further embodiments, the formula (III) in t is 1, the formula ^(III), R ¹ is halogen (e.g., F).

In some embodiments, R _N in formula (III) is at least one alkyl substituent selected from the group consisting of a hydroxyl group and an alkoxy group. In some further embodiments, R _N in formula (III) is an optionally substituted alkyl group of 1 to 12 carbons, and the alkyl group is substituted with at least one alkoxy group selected from the group consisting of a hydroxyl group and 1 to 12 carbons. base. In some further embodiments, R _N in formula (III) is an optionally substituted 1-6 carbon alkyl group, and the alkyl group is at least one substituent selected from a hydroxyl group or an alkoxy group of 1 to 6 carbons. base.

In some embodiments, R ² in formula (III) is hydrogen or an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be subjected to at least one of the above formulas. The intermediate substituent R ¹² in the definition of (III) is optionally substituted. In some embodiments, R ² in formula (III) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R ¹² Optionally substituted, herein, R ^{12 is} selected from the group consisting of -NR'R", -OR', heterocyclyl and aryl, wherein R' and R''' are independently selected from hydrogen, haloalkyl, alkyl and aralkyl. a radical, or R' and R", together with the atom to which they are attached, form a 3 to 8 membered saturated, partially unsaturated or fully unsaturated ring having 0, 1 or 2 additional heteroatoms, said additional The heteroatoms can be independently selected from the group consisting of -NR ¹³ -, -O-, -S-, -SO-, and -SO ₂ -. In some further embodiments, R ² in formula (III) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one substituent R ^{12 is} optionally substituted, wherein R ^{12 is} selected from -NR'R", -OR', heterocyclyl and aryl (for example, phenyl), wherein R' and R" are independently selected from hydrogen, haloalkyl (for example, a haloalkyl group of 1 to 12 carbons, further, for example, a haloalkyl group of 1 to 6 carbons), an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1 to 6 carbons) An alkyl group, an aralkyl group (for example, an alkyl group of 1 to 12 carbons of a phenyl group, further, for example, an alkyl group of 1 to 6 carbons of a phenyl group), or R' and R", and an atom to which they are attached, Together, a 3 to 8 membered saturated, partially unsaturated or totally unsaturated ring having 0, 1 or 2 additional heteroatoms may be formed, which may be independently selected from -NR ¹³ -, -O-, -S-, -SO- or -SO ₂ - (for example, there are 0 or 1 additional heteroatoms on a 5 or 6-membered saturated ring, the hetero atom is an oxygen atom, further, for example, a 5-membered saturated ring, a 6-membered saturated ring , or a 6-membered saturated ring with 1 oxygen heteroatom on the ring). In an embodiment of the formula, R ² in formula (III) is an alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), which may be substituted with at least one optional aryl group (eg, a substituent of a phenyl group; a heterocyclic ring containing a nitrogen atom and/or an oxygen atom of the 3, 4, 5, 6, 7 and 8 membered rings, -OR' and -NR'R", where R' and R" is independently selected from hydrogen, haloalkyl (for example, haloalkyl of 1 to 12 carbons, further, for example, haloalkyl of 1 to 6 carbons), alkyl (for example, 1 to 12 carbons of alkane) Further, for example, an alkyl group of 1 to 6 carbons, an aralkyl group (for example, an alkyl group of 1 to 6 carbons). In some further embodiments, R ² in the formula (III) is An alkyl group (eg, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), may be substituted with at least one optional aryl group (eg, phenyl); 3, 4, 5, 6 a 7- and 8-membered ring heterocyclic ring containing a nitrogen atom and/or an oxygen atom, the heterocyclic ring may be selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl and epoxyethyl; -OR'; and -NR 'R', where R' and R" are independently selected from hydrogen, haloalkyl (eg, haloalkyl of 1 to 6 carbons), alkane (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), and an aralkyl group (for example, an alkyl group of a phenyl group of 1 to 6 carbons, further, for example, a benzyl group) .

In some embodiments, R ⁵ in formula (III) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR ⁹ and -COOR ⁹ wherein each alkyl, cycloalkyl and aryl group may be independently substituted with at least one substituent group is optionally substituted with R ^12, R ⁹ is an alkyl or cycloalkyl group may be substituted with at least one of R ¹² is optionally substituted, R ^12, see the definition of the formula (III). In some embodiments, R ⁵ in formula (III) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, -COR ⁹ and -COOR ⁹ wherein each alkyl, cycloalkyl, or aryl group is may be independently substituted with at least one substituent optionally substituted with R ^12, R ⁹ is an alkyl or cycloalkyl group may be substituted with at least one of R ¹² is optionally substituted, R ¹² is selected from -NR'R ", aryl group, and -NR'CO ₂ R", wherein R' and R" are independently selected from the group consisting of hydrogen, haloalkyl, and alkyl. In some further embodiments, R ⁵ in formula (III) is selected from hydrogen; alkyl (for example, an alkyl group of 1 to 12 carbons, further, for example, an alkyl group of 1 to 6 carbons), may be substituted with at least one substituent selected from the group consisting of -NR'R" and an aryl group (for example, a phenyl group) Alternative; cycloalkyl (eg, 3, 4, 5, 6, 7, 8 carbon cycloalkyl); aryl (eg, phenyl), optionally substituted by -NR'R"; -COR ^9. Here, R ⁹ is a cycloalkyl group (for example, a cycloalkyl group of 3, 4, 5, 6, 7, 8 carbons), or an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, a 1-6 carbon alkyl group, wherein each cycloalkyl group and alkyl group may be selected from at least one selected from the group consisting of -NR'R" and an aryl group (for example Substituents of phenyl) and -NR'CO ₂ R" are optionally substituted, wherein R' and R" are independently selected from hydrogen, haloalkyl (eg haloalkyl of 1 to 6 carbons), alkyl (for example, an alkyl group of 1 to 6 carbons). In some further embodiments, R ⁵ in formula (III) is selected from the group consisting of hydrogen; 1-6 carbon alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, or 3, 3-dimethylbutyl), which may be optionally substituted by a substituent -NR'R";cyclohexyl; phenyl, optionally substituted by a substituent -NR'R"; -COR ⁹ , where R ⁹ is a ring a propyl group, or an alkyl group of 1 to 6 carbons (for example, methyl, ethyl, propyl, isopropyl, or butyl), each of which is a cyclopropyl group or a 1-6 carbon alkyl group A substituent selected from the group consisting of -NR'R", aryl (for example, phenyl) and -NR'CO ₂ R" is optionally substituted, wherein R' and R" are independently selected from hydrogen, and 1-6 carbons Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl).

In some embodiments, R ⁴ and R ⁵ in formula (III) , together with several atoms to which R ⁴ and R ⁵ are attached, form 3, 4, 5 having 0, 1 or 2 additional heteroatoms. , 6, 7 or 8-membered saturated, partially unsaturated or fully unsaturated ring, the additional heteroatoms may be independently selected from ^{-NR 13 -, - O -,} - S -, - SO- or -SO ₂ And, the ring may be optionally substituted by at least one of the above-mentioned intermediate substituents R ¹² in the definition of formula (III) . In some further embodiments, R ⁴ and R ⁵ in formula (III) , together with one or more atoms to which R ⁴ and R ⁵ are attached, form a 5-membered saturated ring having a nitrogen atom.

In some embodiments, R ³ and R ⁴ in the formula (III) may be the same or different and are each independently selected from hydrogen, an alkyl group (for example, an alkyl group of 1 to 12 carbons, further, for example, 1-6 a carbon alkyl group) and a hydroxyl group.

The invention also provides at least one compound selected from the group consisting of the following compounds, isomers thereof, and pharmaceutically acceptable salts thereof:

The invention also provides a method of inhibiting PARP activity. The method comprises contacting an effective amount of at least one compound, a stereoisomer of at least one compound, and/or a pharmaceutically acceptable salt of at least one compound with PARP to inhibit PARP activity.

The present invention provides a method of treating at least one PARP-associated disease comprising administering to a subject (e.g., a mammal or a human) who is in need of treatment for at least one related disease, and wherein the drug is an amount of at least one of the present invention The compounds described and their pharmaceutically acceptable salts.

It can treat at least one of the following diseases, for example, ovarian cancer, breast cancer, colon cancer, leukemia, glioblastoma, lymphoma, melanoma, palace Cervical cancer and other cytotoxic cancers.

The at least one compound disclosed in the present invention, the stereoisomer of at least one compound, and/or the pharmaceutically acceptable salt of at least one compound may be used alone or in combination with radiation therapy and chemotherapy, for example, increasing tumor cell apoptosis and limiting tumors. Growth, reduce metastasis, and prolong the survival of tumor-bearing animals.

In certain embodiments, at least one compound disclosed in the present invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt can be used in combination with at least one additional therapeutic agent, such as at least one additional Chemotherapeutic agent.

"Chemotherapy Reagent" is a compound that does not consider the mechanism of action and is used to treat cancer. The chemotherapeutic agent can be a compound used in "targeted therapy" and conventional chemotherapy. Suitable chemotherapeutic agents can be selected, for example, from agents that cause apoptosis; polynucleotides (eg, ribozymes); polypeptides (eg, enzymes); drugs; biomime; alkaloids; alkylating agents; Antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies used in combination with anticancer drugs, toxins, and/or radionuclides; biological response modifiers (interferons such as IFN-a and interleukins such as IL) -2); adoptive immunotherapeutic agents; hematopoietic growth factors; agents that cause tumor cell differentiation (eg, all-trans-retinoic acid); gene therapy agents; antisense therapeutic agents and nucleosides; tumor vaccines; and some angiogenesis inhibitors .

Examples of chemotherapeutic drugs include erlotinib (Terroy®, Genentech/OSI Pharm.); bortezomib (Millennium Pharm.); fulvestrant (FASLODEX®, AstraZeneca); Tini (Soltan®, Pfizer); Letrozole (Fron®, Novartis); Imatinib mesylate (Gleevec®, Novartis); PTK787/ZK 222584 (Nova); oxaliplatin Leshadine®, Sanofi); 5-FU (5-fluorouracil); calcium leucovorin; rapamycin (sirolimus, RAPAMUNE®, Wyeth); lapartini ® (GSK572016, GlaxoSmithKline; Lonafani (SCH 66336); Sorafenib (Nexaco®, Bayer); Irinotecan (CAMPTOSAR®, Pfizer) and Gefitinib (Iressa®, AstraZeneca) AG1478, AG1571 (SU 5271, Sugen); alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, propylene buffalo and valprosone; Aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenimines and methylamelamines such as hexamethylene melamine, triethylenemelamine, triethylenephosphonium, triethylene thiophosphonamide and tris Melamine; lactones (such as bullatacin and bullatacinone); camptothecin (such as synthetic analogs of topotecan); bryostatin; callistatin; CC-1065 and its adoline, card, new, discount New synthetic analogues; cryptophycins (such as cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin and its synthetic analogues such as KW-2189 and CB1-TM1; eleutherobin; pancratistatin; a sarcodictyin; spongistatin; Such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, nitrogen mustard, nitrogen oxide mustard hydrochloride, melphalan, neombibic, phenesterine, splash Nidnane mustard (prednimustine), tricotine cyclophosphamide, uracil mustard; nitrosourea such as carmustine, chlorfluazuron, formoterol, lomustine, nimustine and raminnustine Antibiotics such as enediyne antibiotics (such as calicheamicin gamma1I and calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186)); dynemicin, such as dynemicin A; Bisphosphonates such as clodronate; espermati; and new A chromophore for carcinogens, and related chromophores of chromogenic diacetylene antibiotics, aclacinomysins, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, Carabicin, caminomycin, carzinophilin, chromomycinis, actinomycin D, daunorubicin; detorubicin, 6-diazo-5-oxo-L-norleucine, ^® adriamycin (doxorubicin, doxorubicin), morpholino - doxorubicin, morpholino-cyano - doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin, epirubicin (epirubicin), Essoubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, oleomycin (olivomycins), pilomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptavidin, streptozotocin, tuberculin, uranium Benzis, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouridine Pyrimidine (5-FU); folic acid analogs such as dimethyl phthalate (denopterin), methotrexate, pteroquinone, trimethoate; guanidine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, sulfur Guanine; pyrimidine analogs such as cyclocytidine, azacitidine, 6-azauridine, carmofur, cytarabine, di-deoxyuridine, deoxyfluorouridine, Notitabine, fluorouridine; androgens, such as calpressone, dromostanolone propionate, cyclostrankrol, mepitiostane, testosterone; anti-adrenalin Aminoglutamine, mitoxantrone, and tromethamine; folic acid supplements such as frolinic acid; acetaldehyde lactone; aldoxime; aminolevulinic acid; eniluracil; amidine; bestrabucil; Bisantrene); defofamine; defolamine; demecolcine; diziquone; elformithine; elliptinium acetate; epothilone; etoglucid; Lentinus edodes; lonidainine; maytansinoids, such as maytansine Maytansine) and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentastatin; phenamet; pirarubicin; (losoxantrone);podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; Spirogermanium; tenuazonic acid; triaziquone; tris(2-chloroethyl)amine; trichosporin (eg T-2 toxin, verracurin A, Roridin A and anguidine); urethane; vindesine; nitromethamine; mannitol mustard; mitobronitol; mitolactol; Pipobroman; gacytosine; arabinoside ("Ara-C");cyclophosphamide;thiotepa; taxanes, for example, TAXOL® (Paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (Cremophor-free), albumin engineered paclitaxel nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Ill.) Taxotere ^{® (doxetaxel; Rhone-Poulenc Rorer} , Antony, France); chloranmbucil; GEMZAR ^® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, carboplatin; Vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; noviben® (vinorelbine); novantrone; Nipaside; edatrexate; daunorubicin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; Fluoromethylornithine (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids and any of the above derivatives.

"Chemotherapeutic agents" may also be selected, for example, from (i) anti-hormonal agents that modulate or inhibit the action of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, Moxifene (including NOLVADEX ^® ; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trevoxifen, keoxifene, LY117018, ol's ketone and FARESTON ^® (toremifine citrate); (ii) an aromatase inhibitor capable of inhibiting aromatase, which regulates the production of estrogen in the adrenal gland, for example, 4(5)-imidazole, aminoglutethimide, MEGASE ^® Progesterone acetate), AROMASIN ^® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR ^® (voltazole), FEMARA ^® (letrozole; Novartis) and ARIMIDEX ^® (anastrozole; AstraZeneca) (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and troxacitabine (1,3-dioxine) (iv) protein kinase inhibitor; (v) lipid kinase inhibitor; (vi) antisense oligonucleoside These antisense oligonucleotides can inhibit the expression of genes in signaling pathways that cause proliferation of some variant cells, such as PKC-alpha, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors ( Such as ANGIOZYME ^® ) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines such as ALLOVECTIN ^® , LEUVECTIN ^® , and VAXID ^® ; PROLEUKIN ^® rIL-2; topoisomerase I inhibitors such as LURTOTECAN ^® ; ABARELIX ^® rmRH; (ix) an anti-angiogenic agent such as bevacizumab (AVASTIN ^® , Genentech); and (x) a pharmaceutically acceptable salt, an acid, and the analogs mentioned above.

"Chemotherapeutic agents" may also be selected from, for example, therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN ^® , Genentech); cetuximab (ERBITUX ^® , Imclone); Pani Monoclonal antibody (VECTIBIX ^® , Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG ^® , 2C4, Genentech), trastuzumab (HERCEPTIN ^® , Genentech), Toximozumab (Bexxar, Corixia), and antibody drug conjugate, gemtuzumab MYZOLARG ^® (Wyeth).

The potentially potent humanized monoclonal antibody can be used as a chemotherapeutic agent in combination with at least one compound of the present invention, and an isomer thereof, and/or a pharmaceutically acceptable salt thereof, for example, can be selected from: Rumuzumab, apocilizumab, acezumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab injection, cidfusituzumab, cidtuzumab, daclizumab, Eculizumab, ezetuzumab, epratuzumab, erlizumab (ehelizumab), felvizumab (panvizumab), fontolizumab, gemtuzumab Zommidin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, meboli Monoclonal antibody, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pa Topuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siprilizumab ( Siplizumab), soxemumab, tacatuzumab tetraxetan, tadocizumab, talibizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab Celmoleukin, tucusituzumab, umavizumab, urtoxazumab and visilizumab.

Also provided is a composition comprising at least one compound of the invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt disclosed herein, and at least one pharmaceutically acceptable a.

The composition comprises at least one compound of the invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt disclosed herein, which may be administered in a variety of known manners, such as orally, Overcoat, rectal, parenteral, inhalation spray, or by implantable kit, although in some hypothetical situations the most appropriate route of administration depends on the particular host, and when the active ingredient is administered The natural conditions and the severity of the disease. "Parenteral administration" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and cranial Internal injection or infusion technology. The compositions disclosed herein are conveniently prepared in unit dosage form and by any methods known in the art.

At least one compound of the invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt disclosed herein, can be orally administered in a solid dosage form, such as a capsule, tablet, tablet, dragee Or granules and powders, or oral administration in liquid dosage forms such as elixirs, syrups, emulsions, dispersions and suspensions. At least one compound of the invention, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt disclosed herein may also be administered parenterally, in a sterile liquid dosage form, such as a dispersion, Suspension or solution. The compounds of the present invention and isomers thereof, and pharmaceutically acceptable salts thereof, may also be administered in other dosage forms such as: ointments, creams, drops, topical transdermal patches or powders, to the eye. Ophthalmic administration in the form of a solution or suspension such as eye drops, inhalation or nasal administration in the form of a spray or a powder composition, or rectal or vaginal administration in the form of a cream, ointment, spray, or suppository.

Gelatin capsules comprise at least one compound disclosed herein, a stereoisomer of at least one compound, and/or at least one pharmaceutically acceptable salt and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, Stearic acid and analogs can also be used. A similar diluent can be used for tableting. Both tablets and capsules can be formulated as sustained release products for continued administration over a period of time. Compressed tablets may be coated with sugar or film to mask an unpleasant taste while protecting the tablet from air, or the enteric coating may be selectively dissolved in the gastrointestinal tract.

The liquid dosage form for oral administration further comprises at least one selected from the group consisting of A reagent for colorants and flavors to increase patient acceptance.

In general, water, a suitable oil, a saline solution, an aqueous dextrose solution (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycol may be suitable carriers for parenteral solutions. Solutions for parenteral administration comprise a water-soluble salt of at least one compound of the invention, at least one suitable stabilizer, and, if necessary, at least one buffer. Some antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, can be used as suitable stabilizers. Citric acid and its salts and sodium edetate can also be used as suitable stabilizers. In addition to this, the parenteral administration solution may further comprise at least one preservative selected from, for example, benzalkonium chloride, methyl- and propyl-p-hydroxybenzoate and chlorobutanol.

The pharmaceutically acceptable carrier can be selected, for example, from a carrier which is compatible with the active ingredient in the pharmaceutical combination (in some specific examples, the active ingredient can be stabilized) and which is not deleterious to the subject. For example, some solubilizing cyclodextrins (which are capable of forming a specific, more soluble complex with at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein) can be used as a pharmaceutical excipient to deliver the active ingredient. Other carriers include colloidal cerium oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and some pigments such as D&C Yellow No. 10. Some suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol and can be used as standard text in the art.

The at least one compound, at least one stereoisomer of the compound, and/or at least one pharmaceutically acceptable salt disclosed herein can be used to initially assess the efficacy of inhibiting PARP activity in an in vitro assay. The invention discloses At least one compound, at least one stereoisomer of the compound, and/or at least one pharmaceutically acceptable salt can be further used to test the efficacy of the cancer in an in vivo experiment. For example, at least one compound, at least one stereoisomer of the compound, and/or at least one pharmaceutically acceptable salt disclosed herein can be administered to an animal (eg, a mouse model) having cancer, thereby evaluating the A therapeutic effect of at least one compound, an isomer thereof, and/or at least one pharmaceutically acceptable salt. A positive result in one or more of these tests can effectively enhance the treasure trove of scientific knowledge, thereby effectively demonstrating the utility of these compounds and/or salts. Based on these experimental results, the dosage and route of administration to animals and humans can be determined.

For inhaled mode of administration, at least one compound, stereoisomers thereof and/or at least one pharmaceutically acceptable salt disclosed herein can be conveniently delivered as an aerosol spray from a compressor or nebulizer. The at least one compound, stereoisomers thereof and/or at least one pharmaceutically acceptable salt disclosed herein may also be delivered in the form of a powder of a dosage form or inhalation of a powder composition with the aid of a spray dry powder inhaler device. A metered dose inhalation nebulizer (MDI) is a typical inhalation delivery system that can make at least one compound, a stereoisomer thereof, and/or at least one pharmaceutically acceptable salt disclosed herein at least one propellant, such as A suspension or solution from a fluorocarbon and a hydrocarbon compound.

For ophthalmic administration, ophthalmic preparations may be prepared by formulating a suitable amount by weight of a solution or suspension of at least one compound, a stereoisomer thereof and/or at least one pharmaceutically acceptable salt disclosed herein. An ophthalmic carrier, such as at least one compound disclosed in the present invention, The isomer and/or at least one pharmaceutically acceptable salt remains in contact with the surface of the eye for a sufficient period of time to allow penetration of the compound into the cornea and internal regions of the eye.

Pharmaceutically acceptable dosage forms of at least one compound, stereoisomers thereof and/or at least one pharmaceutically acceptable salt disclosed herein include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions .

The dose is related to a number of factors, such as age, subject's health and weight, degree of disease, type of concurrent treatment, if any, frequency of treatment and desired effect. In general, the daily dosage of the active ingredient can vary, for example, from 0.1 to 2000 mg per day. For example, 10-500 mg once or more times a day may achieve the desired effect.

In some embodiments, a plurality of unit capsules can be prepared in two standard hard gelatin capsules filled with standard, for example, at least one compound, stereoisomers, and/or at least one pharmaceutically acceptable amount disclosed herein in the form of 100 mg of powder. Acceptable salt, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

In some embodiments, the mixture is selected from at least one compound, stereoisomers thereof and/or at least one pharmaceutically acceptable salt and digestible oil, such as soybean oil, cottonseed oil or olive oil, in the present invention. It can be prepared or injected by actively replacing the pumped gelatin to form a soft gelatin capsule containing 100 mg of the active ingredient. The capsules are then washed and dried.

In some embodiments, a plurality of tablets may be prepared by conventional procedures, each dosage unit comprising, for example, 100 mg of a compound selected from the invention, at least one compound, a stereoisomer thereof, and/or at least one pharmaceutically acceptable Acceptable salts, 0.2 mg colloidal cerium oxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg magnesium stearate. A suitable coating can be used to increase palatability or delay absorption.

In some embodiments, a parenteral composition suitable for administration by injection may be stirred by stirring 1.5% by weight of at least one compound disclosed herein, a stereoisomer thereof, and/or at least one pharmaceutically acceptable salt, Prepared in 10% by volume of propylene glycol. The solution is added to the intended volume with water for injection and sterilized.

In some embodiments, a water soluble suspension for oral administration can be prepared. For example, each 5 ml of aqueous suspension contains 100 mg of finely divided at least one compound disclosed herein, a stereoisomer thereof, and/or at least one pharmaceutically acceptable salt, 100 mg of sodium carboxymethylcellulose. , 5 mg sodium benzoate, 1 gram sorbitol solution, USP and 0.025 ml vanillin.

The same dosage form may be used when at least one compound, a stereoisomer thereof, and/or at least one pharmaceutically acceptable salt disclosed herein is administered stepwise or together with at least one other therapeutic agent. When the drug is administered in a physical combination, the choice of dosage form and route of administration will depend on the compatibility of the combination drug. Thus, the simultaneous administration of the term is understood to mean the administration of at least two agents simultaneously or sequentially, or in a fixed dose of a combination of at least two active ingredients.

The at least one compound, stereoisomer thereof, and/or at least one pharmaceutically acceptable salt disclosed herein may be administered as a single active ingredient or in combination with at least one second active ingredient, for example, selected from the well-known Other active ingredients for treating cancer are administered in combination.

General reaction scheme

The compounds disclosed herein, and/or pharmaceutically acceptable salts thereof, can be synthesized from commercially available starting materials and starting materials prepared in accordance with the present invention. The following schemes describe the preparation of some of the disclosed compounds.

In this embodiment, the 3-amino-2-ionol-benzoate (the leaving group such as Br, I, OTf) in the formula 1 is reacted with the cyclic 1,3-dicarbonyl compound in the molecule 2. The enaminone in molecule 3 is obtained, and then cyclized with a catalyst such as palladium to obtain an oxocarbazole formate in the formula 4, and then the ester is cyclized with hydrazine hydrate to obtain the formula (I) , (II ) . ) or (III) in diazepino Long trazodone derivative.

In the first step of the scheme, a Dean-Stark apparatus is used, and the solvent may be toluene or the like, and the reaction is carried out under reflux. Purification by chromatography on a silica gel column, the obtained fraction The enaminone in subformula 3.

In the second step of the scheme, a palladium/phosphorus catalyst is used, and the reaction is carried out by heating with acetonitrile or DMF as a solvent. Heck reaction in this molecule (Bozell, JJ, Hegedus, LSJ Org. Chem. 1981, 46, 2561; Maruyama, J., Yamashida, H., Watanabe, T., Arai, S., Nishida, A. Tetrahedron 2009 , 65, 1327, incorporated herein by reference), generally takes about 5-24 hours. The oxocarbazole formate in Formula 4 is isolated using standard post-treatment conditions and can be purified either by chromatography or by recrystallization.

In the third step of synthesizing the novel compound in the formula (I) , the compound in the formula 4 undergoes an intramolecular cyclization reaction, and the diazapine in the formula (I) , (II) or (III) shown in the scheme 1 is obtained. Oxazolone derivatives. The cyclization reaction can be typically carried out using 1-2 equivalents of hydrazine hydrate, and a suitable alcohol as a solvent. The cyclization reaction can be typically carried out from 50 ° C to an alcohol reflux condition, for example, 0.25 to 4 hours.

Scheme 2 describes the synthesis of some of the compounds of formula (III) . The compound of the formula a is also a compound of the formula (III) , which can also be produced by the method of the scheme 1.

Deprotection of the compound of formula a yields a compound of formula b (also a compound of formula (III) ). The compound of formula b and the electrophile continue to undergo corresponding alkylation, coupling, or reductive alkylation to provide some of the compounds of formula (III) . Electrophiles such as haloalkyl, halogenated arene, carboxylic acid, hydrazine chloride, sulfonium chloride, aldehyde, ketone, and the like.

Reaction example

The following examples are intended to be purely exemplary and should not be construed in any way. While every effort has been made to ensure the accuracy of the data (eg, volume, temperature, etc.), some experimental errors and deviations are inevitable. Unless otherwise stated, the temperature is Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise stated.

Unless otherwise stated, the following reactions are carried out in an anhydrous solvent, under a positive pressure of nitrogen or argon or using a drying tube; the reaction flask is filled with a rubber septum, the substrate and reagents are added via a syringe; the glassware is dried and/or heated. dry.

Unless otherwise indicated, column chromatography purification was performed on a Biotage system with a silica gel column (manufacturer: Dyax), or with a ceria seppak cartridge (Waters), or with a pre-filled silica gel column in a Teledyne Isco combiflash purification system is carried out.

The nuclear magnetic data was run at 400 MHz using a Varian device. The solvent used in the nuclear magnetic data is CDCl ₃ , CD ₂ Cl ₂ , CD ₃ OD, D ₂ O, d ₆ -DMSO, d ₆ -acetone or (CD ₃ ) ₂ CO, based on tetramethyl decane (0.00 ppm). Or based on residual solvent (CDCl ₃ : 7.25 ppm; CD ₃ OD: 3.31 ppm; D ₂ O: 4.79 ppm; d ₆ -DMSO: 2.50 ppm; d ₆ -acetone: 2.05; (CD ₃ ) ₂ CO: 2.05 ). When the peak shape diversity is indicated, the following abbreviations indicate different peak shapes: s (single peak), d (double peak), t (triplet), q (quadruple), qn (five peak), sx (six Heavy peak), m (multiple peak), br (wide peak), dd (two double peaks), dt (two triplets). If a coupling constant is given, it is in Hertz (Hz). Other reagents other than solvent are named after Chemdraw 12.0.

In the following example, the following shorthand is used:

Example 1: Synthesis of Compound 1-19

Compound 1 : 2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6- def ]carbazole-6(1H)-one

Step 1: Methyl 2-bromo-3-((3-oxycyclohexyl-1-en-1-yl)amino)benzoate

Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) and 1,3-dicarbonylcyclohexane (1.12 g, 10.0 mmol) were dissolved in acetic acid (10 mL). The reaction mixture was reacted at 80 ° C for 8 hours. (Reaction mixture spin-drying) The obtained solid was purified by chromatography (eluent: n-hexane and ethyl acetate) to give 2-bromo-3-((3-oxycyclohexyl-1-en-1-yl)amino Methyl benzoate (2.46 g, 76%) as a tan foam. ¹ H NMR (CDCl ₃ -d ₁ ) δ 7.53-7.55 (m, 2H), 7.37 (dd, 1H, J = 7.2, 8.4 Hz), 6.34 (br s, 1H), 5.57 (s, 1H), 3.95 (s, 3H), 2.56-2.59 (m, 2H), 2.40-2.42 (m, 2H), 2.08-2.11 (m, 2H). MS (ESI) m / e [M+1] ⁺ 324.0.

Step 2: Methyl 4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate

Methyl 2-bromo-3-(3-oxocyclohexyl-1-enylamine)benzoate (0.97 g, 3.0 mmol), palladium acetate (0.14 g, 0.6 mmol), tris (o-methylphenyl) A mixture of phosphorus (0.73 g, 2.4 mmol), triethylamine (0.38 g, 3.6 mmol) and acetonitrile (10 mL) was heated to 100 ° C in a sealed tube under nitrogen atmosphere for 20 hours. The reaction mixture was cooled and DCM (3×50 mL) and water (10 mL). The organic phase was separated, washed with water, dried over anhydrous sodium sulfate, concentrated and the residue purified by column chromatography using silica gel: to give the title compound (eluant 0-100% ethyl acetate in ^{n-hexane) (0.61g, 84%) 1} H. NMR (CDCl ₃ -d ₁ ) δ 9.47 (s, 1H), 7.36-7.40 (m, 2H), 7.22 (t, 1H, J = 7.8 Hz), 2.90 - 2.92 (m, 2H), 2.51-2.54 ( m, 2H), 2.14 - 2.16 (m, 2H). MS (ESI) m / e [M+1] ⁺ 244.0.

Step 3: 2,3,5,10-Tetrahydro-[1,2]diazepine [3,4,5,6- def ]carbazole-6(1H)-one

Methyl 4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate (73 mg, 0.3 mmol), dissolved in methanol (4 mL), ethyl acetate (0.15mL, 2.6mmol) and hydrated肼 (0.86 mL, 1.5 mmol) was heated to reflux for 8 h. The solid which was formed by the reaction was filtered, washed with water, ethyl acetate ¹ H NMR (DMSO-d ₆ ) δ 11.70 (s, 1H), 9.79 (s, 1H), 7.36-7.38 (m, 2H), 7.05 (t, 1H, J = 7.8 Hz), 2.77-2.79 (m) , 2H), 2.35-2.37 (m, 2H), 1.92-1.93 (m, 2H). MS (ESI) m / e [ M + 1] + 226.0.

In the following reaction examples, compounds 2 to 19 are prepared in a similar manner to the synthesis of compound 1, using the corresponding substituted or unsubstituted methyl 3-amino-2-bromobenzoate and a 1,3-dicarbonyl cyclic compound. , synthesized by skilled operators in the field.

Example 2: Synthesis of Compound 20-21

Compound 20 : 8-oxo-3,4,8,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]indole-2(1H)-formic acid benzyl ester

Step 1: 3-((2-Bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-formic acid benzyl ester

Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl 3,5-dioxypiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved at 25 ° C under nitrogen. Acetic acid (10 mL). The mixture was stirred at 70 ° C for 8 hours. The obtained solid was purified by chromatography (eluent: n-hexane and ethyl acetate) to give 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6- Hydrogen pyridine-1(2H)-benzyl formate 0.13 g (51%) was a tan foamy material. ¹ H NMR (CDCl ₃ -d ₁ ) δ 7.53-7.58 (m, 3H), 7.42-7.48 (m, 5H), 5.56 (s, 1H), 5.16 (s, 2H), 4.46 (s, 2H), 4.13 (s, 2H), 3.93 (s, 3H). MS (ESI) m / e [M+1] ⁺ 459.0.

Step 2: Methyl 4-oxo-3,4-dihydro-1H-pyrido[3,4-b]indole-2,5(9H)-2-carboxylate-5-carboxylate

3-((2-Bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (0.13 g, 0.28 mmol), a mixture of palladium acetate (0.013 g, 0.06 mmol), tris(o-methylphenyl)phosphine (0.72 g, 0.19 mmol), triethylamine (0.36 g, 0.36 mmol), acetonitrile (2 mL) The tube was heated to 100 ° C and reacted for 9 hours. The reaction mixture was cooled and extracted with EtOAc EtOAc m. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate sulfatessssssssssssssssssss ¹ H NMR (CDCl ₃ -d ₁ ) δ 9.62 (s, 1H), 7.24 - 7.50 (m, 8H), 5.18 (s, 2H), 4.88 (s, 2H), 4.27 (s, 2H), 3.98 ( s, 3H). MS (ESI) m / e [ M + 1] + 379.0.

Step 3: 8-oxo-3,4,8,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]indole-2(1H)-benzyl formate

Methyl 4-oxo-3,4-dihydro-1H-pyrido[3,4-b]indole-2,5(9H)-2-carboxylate-5-carboxylate (70 mg, 0.18 mmol), Dissolved in methanol (4 mL), added acetic acid (0.15 mL, 2.6 mmol), EtOAc (EtOAc: The solid formed by the reaction was filtered, washed with EtOAcjjjjjjjj ¹ H NMR (DMSO-d ₆ ) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.54 (d, 1H, J = 8.4 Hz), 7.48 (d, 1H, J = 7.2 Hz), 7.38 ( m, 4H), 7.32 (m, 1H), 7.18 (dd, 1H, J = 8.4, 7.2 Hz), 5.15 (s, 2H), 4.82 (m, 2H), 4.28 (m, 2H). MS (ESI) m / e [M+1] ⁺ 361.

6 -Fluoro-8-oxo-3,4,8,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-2(1H)-benzyl formate

Compound 21 is prepared from 2-bromo-5-fluoro-3-amino-benzoic acid methyl ester and 3,5-dioxypiperidine-1-carboxylic acid benzyl ester in a similar manner to the synthesis of compound 20 , from the art. Skilled operator synthesis. ¹ H NMR (DMSO-d ₆ ) δ 11.9 (s, 1H), 10.3 (s, 1H), 7.33-7.45 (m, 6H), 7.23 (dd, 1H, J = 10.2, 1.8 Hz), 5.15 (s , 2H), 4.79-4.83 (m, 2H), 4.28-4.30 (m, 2H). MS (ESI) m/e [M+1] ⁺ 379.

Example 3: Synthesis of Compound 22-25

Compound 22: 10-methyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one

Step 1: Methyl 9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate

Methyl 4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate (0.27 g, 1 mmol) was dissolved in THF (5 mL). (0.12 g, 1.05 mmol). After the reaction mixture was stirred for 30 minutes, iodomethane (0.76 g, 5.0 mmol) was added. After 3 hours, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjj Filtered and concentrated to give a solid (0.46 g). The solid was used in the next step without further purification. ¹ H NMR (DMSO-d ₆ ) δ 7.35-7.39 (m, 2H), 7.29 (t, 1H, J = 7.2 Hz), 4.01 (s, 3H), 3.72 (s, 3H), 2.93 - 2.95 (m) , 2H), 2.54-2.56 (m, 2H), 2.23 - 2.26 (m, 2H). MS (ESI) m/e [M+1] ⁺ 258.0.

Step 2: 10-Methyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one

The target compound was synthesized in a similar manner to the third step of the synthesis of Compound 1 . ¹ H NMR (DMSO-d ₆ ) δ 9.88 (s, 1H), 7.55 (d, 1H, J = 7.8 Hz,), 7.45 (d, 1H, J = 7.8 Hz,), 7.15 (t, 1H, J) = 7.8 Hz), 3.70 (s, 3H), 2.77-2.79 (m, 2H), 2.35-2.37 (m, 2H), 1.92-1.93 (m, 2H). MS (ESI) m/e [M+1] ⁺ 240.0.

Compound 23: 2,2,10-trimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]carbazole-6 (1H )-ketone

Compound 23 is prepared from methyl 2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate and methyl iodide in a similar manner to compound 22 . Synthesized by skilled operators in the art. ¹ H NMR (DMSO-d ₆ ) δ 9.86 (s, 1H), 7.42-7.53 (m, 2H), 7.12 (t, 1H, J = 7.8 Hz), 3.66 (s, 3H), 2.67 (s, 2H) ), 2.20 (s, 2H), 1.04 (s, 6H). MS (ESI) m/e [M+1] ⁺ 268.

Compound 24: 10-benzyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one

Compound 24 is prepared from methyl 2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-indazole-5-carboxylate and benzyl chloride in a similar manner to compound 22 . , synthesized by skilled operators in the field. ¹ H NMR (DMSO-d ₆ ) δ 9.96 (s, 1H), 7.56 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.11 - 7.33 (m, 6 H) , 5.45 (s, 2H), 2.82-2.84 (m, 2H), 2.41-2.43 (m, 2H), 1.97-2.00 (m, 2H). MS (ESI) m/e [M+1] ⁺ 316.

Compound 25: 2,2,5,10-tetramethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]carbazole-6 (1H)-ketone

The target compound was synthesized in a similar manner to the first step of Compound 22 . 2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one (0.02 g </RTI></RTI><RTIID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; ¹ H NMR (DMSO-d ₆ ) δ 7.51 - 7.55 (m, 2H), 7.16 (t, 1H, J = 7.8 Hz), 3.69 (s, 3H), 3.42 (s, 3H), 2.72 (s, 2H), 2.27 (s, 2H), 1.09 (s, 6H). MS (ESI) m/e [M+1] ⁺ 282.

Example 4: Synthesis of Compound 26

Compound 26 : 8-fluoro-2,2-dimethyl-2,3-dihydro-[1,2]diazepine [3,4,5,6-def]indazole-1,6 (5H ,10H)-dione

8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H) - one (0.5g, 1.8mmol) was dissolved in anhydrous dioxane (25mL), was added SeO ₂ (0.32g, 2.7mmol). The mixture was refluxed for 40 h, filtered over EtOAc EtOAcEtOAcEtOAc The residue was purified with EtOAcqqq elut elut elut ¹ H NMR (DMSO-d ₆ ) δ 12.70 (s, 1H), 10.90 (s, 1H), 7.41 (dd, 1H, J = 10.2, 1.8 Hz), 7.09 (dd, 1H, J = 9.6, 1.8 Hz) ), 2.87 (s, 2H), 1.23 (s, 6H). MS (ESI) m/e [M+1] ⁺ 286.

Example 5: Synthesis of Compound 27

Compound 27 : 8-fluoro-1-hydroxy-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def] Carbazole-6(1H)-one

8-fluoro-2,2-dimethyl-2,3-dihydro-[1,2]diazepine [3,4,5,6-def]carbazole-1,6(5H,10H) - dione (50mg, 0.18mmol) was dissolved in MeOH (10mL), at 0 ℃ was added NaBH ₄ (0.18mmol), stirred for half an hour. The reaction mixture was poured into EtOAc (EtOAc) (EtOAc m. The filtrate was concentrated and the residue was purifiedjjjjjjlilili ¹ H NMR (DMSO-d ₆ ) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.23 (dd, 1H, J = 9.2, 2.0 Hz), 7.17 (dd, 1H, J = 10.8, 2.4 Hz ), 5.68 (d, 1H, J = 6.0 Hz), 5.49 (d, 1H, J = 6.0 Hz), 2.31 (s, 2H), 1.00 (s, 3H), 0.88 (s, 3H). MS (ESI) m / e [M+1] ⁺ 288.

Example 6: Synthesis of Compound 28-39

Compound 28 : 10-(2-(Dimethylamino)ethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4, 5,6-def]carbazole-6(1H)-one

2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one (94 mg , 0.37mmol) in DMF (10mL) was cooled to 0 ℃, was slowly added _{K 2 CO 3 (205mg, 1.48mmol} ) and N, N- dimethylamino-2-chloroethane (53mg, 0.37mmol). The mixture was stirred at 70 ° C for 4 hours, and after cooling, water (10 mL) was added. The title compound (90 mg, 75%) was obtained as a yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 9.91 (s, 1H), 7.58 (d, 1H, J = 7.8 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 4.23 (m, 2H), 2.74 (s, 2H), 2.51 (m, 2H), 2.25 (s, 2H), 2.18 (s, 6H), 1.07 (s, 6H). MS (ESI) m / e [M + 1] ⁺ 325.

Compounds 29-39 were synthesized in a similar manner to Compound 28 using the corresponding starting materials and synthesized by those skilled in the art.

Example 7: Synthesis of Compound 40

Compound 40 : 10-(2-(Dimethylamino)ethyl)-8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]carbazole-6(1H)-one

Compound 40 is 8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]carbazole-6 (1H)-ketone and N,N-dimethylamino-2-chloroethane were used as starting materials, which were prepared in a similar manner to compound 28 . ¹ H NMR (DMSO-d ₆ ) δ 10.1 (s, 1H), 7.56 (dd, 1H, J = 9.6, 1.8 Hz), 7.21. (dd, 1H, J = 10.2, 1.8 Hz), 4.22 (m, 2H) ), 2.74 (s, 2H), 2.51 (m, 2H), 2.26 (s, 2H), 2.17 (s, 6H), 1.06 (s, 6H). MS (ESI) m/e [M+1] ⁺ 343.

Example 8: Synthesis of Compound 41

Compound 41 : 2,2-dimethyl-10-(oxiranyl-2-yl-methyl)-2,3,5,10-tetrahydro-[1,2]diazepine [3, 4,5,6-def]carbazole-6(1H)-one

Compound 41 is 2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)- The ketone and 2-(chloromethyl)oxirane were used as starting materials and were prepared in a similar manner to compound 28 . ¹ H NMR (DMSO-d ₆ ) δ 9.96 (s, 1H), 7.65 (d, 1H, J = 8.4 Hz), 7.49 (d, 1H, J = 7.8 Hz), 7.18 (dd, 1H, J = 8.4 , 7.8 Hz), 4.60-4.63 (m, 1H), 4.21-4.24 (m, 1H), 3.27-3.29 (m, 1H), 2.76-2.77 (m, 1H), 2.75 (s, 2H), 2.46- 2.48 (m, 1H), 2.26 (s, 2H), 0.92 (s, 6H). MS (ESI) m/e [M+1] ⁺ 310.

Example 9: Synthesis of Compound 42

Compound 42 : 2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 20 (34 mg, 0.1 mmol) was dissolved in methanol (10 mL), and then 10% palladium carbon (10 mg). The mixture was filtered through celite and washed with methanol. The filtrate was concentrated, and the residue was purified by ethylamine. ¹ H NMR (DMSO-d ₆ ) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.40-7.45 (m, 2H), 7.09 (t, 1H, J = 8.0 Hz), 3.94 (s, 2H) ), 3.41 (s, 2H). MS (ESI) m / e [M + 1] ⁺ 227.

Example 10: Synthesis of Compound 43

Compound 43 : 6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 43 was prepared from Compound 21 and 10% palladium on carbon in a similar manner to Compound 42 . ¹ H NMR (DMSO-d ₆ ) δ 11.8 (s, 1H), 10.04 (s, 1H), 7.29 (dd, 1H, J = 10.0, 1.6 Hz), 7.11 (dd, 1H, J = 10.4, 1.6 Hz ), 3.93 (s, 2H), 3.45 (s, 2H). MS (ESI) m / e [M+1] ⁺ 245.

Example 11: Synthesis of Compound 44

Compound 44 : 2-methyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Step 1: Methyl 2-methyl-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate

4-oxo-2,3,4,9-tetrahydro -1H- pyrido [3,4-b] indol-5-carboxylate (0.04g, 0.016mmol), and NaCNBH ₃ (2.4mg, 0.04mmol MeOH (2 mL) was added followed by a 27% aqueous solution of formaldehyde (0.5 mL). The reaction mixture was stirred for 2 h, then added 2N EtOAc (2 mL) The reaction mixture was added to a concentrated aqueous NaOH solution and adjusted to pH = 11. The mixture was extracted with dichloromethane (3×10 mL). The crude product was used directly in the next reaction without further purification.

Step 2: 2-Methyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 44 is prepared from methyl 2-methyl-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate. Synthetic Compound 1 was synthesized in a similar manner. ¹ H NMR (DMSO-d ₆ ) δ 11.7 (s, 1H), 9.87 (s, 1H), 7.43 (d, 1H, J = 8.0 Hz), 7.39 (d, 1H, J = 7.6 Hz), 7.14 ( Dd, 1H, J = 8.0, 7.6 Hz), 3.70 (s, 2H), 3.13 (s, 2H), 2.39 (s, 3H). MS (ESI) m / e [M+1] ⁺ 241.

Example 12: Synthesis of Compound 45

Compound 45 : 2-isopropyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 45 is prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and acetone using a similar procedure to that of compound 44 . synthesis. ¹ H NMR (DMSO-d ₆ ) δ 11.7 (s, 1H), 9.83 (s, 1H), 7.43 (d, 1H, J = 8.4 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.08 ( Dd, 1H, J = 8.4, 7.6 Hz), 3.78 (s, 2H), 3.26 (s, 2H), 2.93 - 2.96 (m, 1H), 1.04 (d, 6H, J = 6.4 Hz). MS (ESI) m/e [M+1] ⁺ 269.

Example 13: Synthesis of Compound 46

Compound 46 : 6-fluoro-2-isopropyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 46 is synthesized from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and acetone. 44 similar steps to synthesize. ¹ H NMR (DMSO-d ₆ ) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.35 (dd, 1H, J = 2.4, 9.6 Hz), 7.18 (dd, 1H, J = 2.4, 10.2 Hz ), 3.82 (s, 2H), 3.32 (s, 2H), 2.98-3.00 (m, 1H), 1.09 (d, 6H, J = 7.2 Hz). MS (ESI) m/e [M+1] ⁺ 287.

Example 14: Synthesis of Compound 47

Compound 47 : 2-(cyclopropylcarbonyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Step 1: Methyl 2-(cyclopropylcarbonyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate

Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (0.21 g, 0.82 mmol) was dissolved in dichloromethane (10 mL). Add cyclopropylmethyl hydrazine chloride (0.074 mL, 0.82 mmol) and N,N-diisopropylethylamine (0.143 mL) at 0 ° C, stir at -5 ° C for 1 hour, and evaporate the solvent to obtain a thin layer chromatography. Target product (170 mg). MS (ESI) m/e [M+1] ⁺ 313.

Step 2: 2-(cyclopropylcarbonyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 47 is prepared from methyl 2-(cyclopropylcarbonyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and hydrazine hydrate. , synthesized in a similar manner to the synthesis of Compound 1 . ¹ H NMR (DMSO-d ₆ ) δ 11.9 (s, 1H), 10.0 (s, 1H), 7.47-7.53 (m, 2H), 7.17 (dd, 1H, J = 7.2, 7.8 Hz), 4.89 (s) , 2H), 4.35 (s, 2H), 2.08-2.11 (m, 1H), 0.78-0.79 (m, 4H). MS (ESI) m/e [M+1] ⁺ 295.

Example 15: Synthesis of Compound 48

Compound 48 : 2-(cyclopropylcarbonyl)-4-(2-(dimethylamino)ethyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacycloheptyl [def]芴-8(1H)-ketone

Compound 48 is 2-(cyclopropanecarbonyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one and N, N-dimethylamino-2-chloroethane was used as a starting material, which was synthesized in a similar manner to the compound of Compound 28 . ¹ H NMR (DMSO-d ₆ ) δ 10.0 (s, 1H), 7.67 (d, 1H, J = 8.4 Hz), 7.51 (d, 1H, J = 7.8 Hz), 7.23 (dd, 1H, J = 8.4 , 7.8 Hz), 5.22 (s, 1H), 4.98 (s, 1H), 4.55 (s, 1H), 4.28-4.35 (m, 3H), 2.58-2.62 (m, 2H), 2.19 (s, 6H) , 2.09-2.13 (m, 1H), 0.79 (s, 4H). MS (ESI) m / e [M+1] ⁺ 366.

Example 16: Synthesis of Compound 49

Compound 49 : 2-(cyclopropylcarbonyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def] 芴-8(1H)- ketone

Compound 49 is prepared from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and cyclopropylformamidine chloride. Synthesized using a similar procedure to the synthesis of Compound 47 . ¹ H NMR (DMSO-d ₆ ) δ 9.64 (s, 1H), 6.80-7.08 (m, 2H), 4.95 (s, 1H), 4.74 (s, 1H), 4.40 (s, 1H), 4.20 (s) , 1H), 2.03-2.07 (m, 1H), 0.75 (s, 4H). MS (ESI) m / e [M+1] ⁺ 313.

Example 17: Synthesis of Compound 50

Compound 50 : 2-(cyclopropylcarbonyl)-4-(2-(dimethylamino)ethyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetrazine Heterocycloheptyl [def] 芴-8(1H)-one

Compound 50 is 2-(cyclopropylcarbonyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)- ketones and N, N- dimethylamino-2-chloroethane as starting material, and the synthetic procedure similar to the synthesis of compound 28. ¹ H NMR (DMSO-d ₆ ) δ 10.0 (s, 1H), 7.66 (dd, 1H, J = 2.4, 9.6 Hz), 7.26 (dd, 1H, J = 2.4, 10.2 Hz), 5.21 (s, 1H) ), 4.96 (s, 1H), 4.55 (s, 1H), 4.27-4.36 (m, 3H), 2.56-2.59 (m, 2H), 2.18 (s, 6H), 2.11-2.13 (m, 1H), 0.79 (s, 4H). MS (ESI) m/e [M+1] ⁺ 384.

Example 18: Synthesis of Compound 51

Compound 51 : 2-trimethylethenyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 51 is prepared by using 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylic acid methyl ester and trimethylacetamidine chloride as raw materials. Compound 47 was synthesized in a similar manner. ¹ H NMR (DMSO-d ₆ ) 9.63 (s, 1H), 7.27-7.47 (m, 2H), 6.96 (s, 1H), 4.89 (s, 2H), 4.33 (s, 2H), 1.24 (s, 9H). MS (ESI) m / e [M + 1] ⁺ 311.

Example 19: Synthesis of Compound 52

Compound 52 : 6-fluoro-2-trimethylethylidene-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]芴-8 (1H) -ketone

Compound 52 is prepared from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and trimethylacetamidine chloride. Synthesized using a similar procedure to the synthesis of Compound 47 . ¹ H NMR (DMSO-d ₆ ) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.45 (dd, 1H, J = 2.4, 9.6 Hz), 7.22 (dd, 1H, J = 2.4, 10.2 Hz ), 4.92 (s, 2H), 4.42 (s, 2H), 1.24 (s, 9H). MS (ESI) m/e [M+1] ⁺ 329.

Example 20: Synthesis of Compound 53

Compound 53 : 2-cyclohexyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 53 is based on 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylic acid methyl ester and cyclohexanone, and is similar to synthetic compound 44. The steps are synthesized. ¹ H NMR (DMSO-d ₆ ) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.47 (d, 1H, J = 7.8 Hz), 7.42 (d, 1H, J = 7.8 Hz), 7.12 ( t,1H,J=7.8Hz), 3.91(s,2H), 3.38(s,2H), 2.50-2.56(m,1H), 1.58-1.84(m,4H),1.11-1.31(m,6H) . MS (ESI) m / e [M + 1] ⁺ 309.

Example 21: Synthesis of Compound 54

Compound 54 : 2-(3,3-dimethylbutyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]芴-8 (1H )-ketone

Compound 54 is 2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]indole-8(1H)-one and 3,3-dimethyl-n-butyraldehyde As a raw material, it was synthesized in a similar manner to the synthesis of Compound 44 . ¹ H NMR (DMSO-d ₆ ) 11.9 (s, 1H), 9.89 (s, 1H), 7.48 (d, 1H, J = 7.8 Hz), 7.43 (d, 1H, J = 7.2 Hz), 7.13 (dd , 1H, J=7.2, 7.8 Hz), 3.81 (br s, 2H), 3.29 (br s, 2H), 2.57-2.58 (m, 2H), 1.43-1.46 (m, 2H), 0.91 (s, 9H) ). MS (ESI) m / e [M + 1] ⁺ 311.

Example 22: Synthesis of Compound 55

Compound 55 : 6-fluoro-2-methyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 55 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound 44 . ¹ H NMR (DMSO-d ₆ ) 11.9 (s, 1H), 10.1 (s, 1H), 7.36 (dd, 1H, J = 1.8, 9.6 Hz), 7.20 (dd, 1H, J = 1.8, 10.2 Hz) , 3.75 (s, 2H), 3.24 (s, 2H), 2.44 (s, 3H). MS (ESI) m/e [M+1] ⁺ 259.

Example 23: Synthesis of Compound 56

Compound 56 : 2-propyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 56 is prepared from methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and n-propanal, using a similar compound as compound 44 . Step synthesis. ¹ H NMR (DMSO-d ₆ ) δ 11.7 (s, 1H), 9.92 (s, 1H), 7.47 (d, 1H, J = 7.8 Hz), 7.43 (d, 1H, J = 7.8 Hz), 7.13 ( t,1H,J=7.8Hz),3.81(s,2H), 3.28(s,2H), 2.50-2.55(m,2H),1.51-1.54(m, 2H),0.89(t,3H,J= 7.8 Hz). MS (ESI) m/e [M+1] ⁺ 269.

Example 24: Synthesis of Compound 57

Compound 57 : 6-fluoro-2-propyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 57 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound 44 . ¹ H NMR (DMSO-d ₆ ) 11.8 (s, 1 H), 10.1 (s, 1 H), 7.36 (dd, 1H, J = 1.8, 9.0 Hz), 7.19 (dd, 1H, J = 1.8, 10.2 Hz) , 3.80 (s, 2H), 3.30 (s, 2H), 2.50-2.54 (m, 2H), 1.50-1.54 (m, 2H), 0.89 (t, 3H, J = 7.8 Hz). MS (ESI) m/e [M+1] ⁺ 287.

Example 25: Synthesis of Compound 58

Compound 58 : 2-ethyl-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 58 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound 44 . ¹ H NMR (DMSO-d ₆ ) 11.8 (s, 1 H), 10.1 (s, 1H), 7.35 (dd, 1H, J = 2.4, 9.6 Hz), 7.19 (dd, 1H, J = 2.4, 10.2 Hz) , 3.80 (s, 2H), 3.30 (s, 2H), 2.60-2.64 (m, 2H), 1.09 (t, 3H, J = 7.2 Hz). MS (ESI) m / e [M+1] ⁺ 273.

Example 26: Synthesis of Compound 59

Compound 59 : 2-n-butyl-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one

Compound 59 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound 44 . ¹ H NMR (DMSO-d ₆ ) 11.8 (s, 1 H), 10.1 (s, 1H), 7.36 (dd, 1H, J = 2.4, 9.6 Hz), 7.19 (dd, 1H, J = 2.4, 10.2 Hz) , 3.80 (s, 2H), 3.30 (s, 2H), 2.54-2.57 (m, 2H), 1.47-1.50 (m, 2H), 1.30-1.34 (m, 2H), 0.91 (t, 3H, J = 7.2 Hz). MS (ESI) m / e [M + 1] ⁺ 301.

Example 27: Synthesis of Compound 60

Compound 60: 2-(2-(Dimethylamino)ethyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]芴-8 (1H )-ketone

Step 1: 2-(2-(Dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylic acid ester

Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (183 mg, 0.75 mol) was dissolved in DMF (20 mL). chloro -N, N- dimethyl-ethanamine hydrochloride (107mg, 0.75mmol) and _{K 2 CO 3 (207mg, 1.5mmol} ). The reaction solution was stirred at 50 ° C until the starting material disappeared. The reaction solution was diluted with dichloromethane (15 ml) and washed with water three times. The organic phase was dried over anhydrous magnesium sulfate, and most of the solvent was evaporated to dryness, the crude product is purified by silica gel column chromatography (eluent _{CH 2 Cl 2 / MeOH / NH} 3 .H 2 O), to give 2- (2- (dimethylamino) ethyl Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (0.09 g). MS (ESI) m/e [M+1] ⁺ 316.

Step 2: 2-(2-(Dimethylamino)ethyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]芴-8 (1H )-ketone

Compound 60 is 2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylic acid The ester and hydrazine hydrate were used as starting materials and synthesized in a similar manner to the synthesis of Compound 1 . ¹ H NMR (DMSO-d ₆ ) δ 9.92 (s, 1H), 7.60 (d, 1H, J = 8.4 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.13 (dd, 1H, J = 8.4 , 7.8 Hz), 4.20-4.22 (m, 2H), 4.03 (s, 2H), 3.41 (s, 2H), 2.51-2.54 (m, 2H), 2.18 (s, 6H). MS (ESI) m/e [M+1] ⁺ 298.

Example 28: Synthesis of Compound 61

Compound 61 : 2-(2-(2-Dimethylamino)ethyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacycloheptyl [def]芴-8(1H)-ketone

Compound 61 was synthesized from methyl 2-bromo-5-fluoro-3-aminophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to the compound compound 60 . ¹ H NMR (DMSO-d ₆ ) δ 10.1 (s, 1H), 7.58 (dd, 1H, J = 1.8, 10.2 Hz), 7.21. (dd, 1H, J = 1.8, 10.2 Hz), 4.20-4.22 (m) , 2H), 4.03 (s, 2H), 3.42 (s, 2H), 2.51-2.54 (m, 2H), 2.19 (s, 6H). MS (ESI) m/e [M+1] ⁺ 316.

Example 29: Synthesis of Compound 62

Compound 62: 2-(2-Amino-2-methylpropenyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacycloheptyl [def]芴-8 (1H)-ketone

Step 1: 2-(2-(((Benzyloxy)carbonyl)amino)-2-methylpropenyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3 ,4-b]indole-5-formic acid methyl ester

Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (36 mg), 2-(((benzyloxy)carbonyl)amino 2-methylpropionic acid (21 mg), dissolved in DMF (8 ml), diisopropylethylamine (58 mg) was added, and then a solution of HATU (86 mg) dissolved in DMF (2 ml). The reaction mixture was stirred at room temperature for 16 hours. DMF was evaporated to dryness to give 2-(2-(((benzyl))carbonyl)amino)-2-methylpropenyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyridine and [ Methyl 3,4-b]indole-5-carboxylate was used in the next step without further purification.

Step 2: (2-Methyl-1-oxo-1-(8-oxo-8,9-dihydro-2,4,9,10-tetraazaheptyl[def]indole-2 (1H, Benzyl 3H,4H)-yl)propyl-2-yl)carbamate

The target product is 2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropenyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyridin[3 , 4-b]indole-5-formic acid methyl ester and hydrazine hydrate were used as starting materials, and synthesized in a similar manner to the synthesis of compound 1. ¹ H NMR (DMSO-d ₆ ) δ 11.8 (s, 1H), 10.2 (s, 1H), 7.18-7.55 (m, 8H), 4.82-4.91 (m, 4H), 4.43-4.55 (m, 2H) , 1.25 (s, 6H). MS (ESI) m / e [M+1] ⁺ 446.

Step 3: 2-(2-Amino-2-methylpropenyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacycloheptyl [def]芴-8 (1H)-ketone

Compound 62 is (2-methyl-1-oxo-1-(8-oxo-8,9-dihydro-2,4,9,10-tetraazacycloheptyl [def] 芴-2 (1H, 3H, 4H) - yl) propyl-2-yl) carbamate and palladium on carbon (10%) as a starting material, was synthesized in a procedure similar to the synthesis of compound 42. ¹ H NMR (DMSO-d ₆ ) δ 11.8 (s, 1H), 9.99 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 7.43 (d, 1H, J = 7.2 Hz), 7.13 ( Dd, 1H, J = 8.0, 7.2 Hz), 5.29 - 5.31 (m, 2H), 4.69 - 4.75 (m, 2H), 1.26 (s, 6H). MS (ESI) m / e [M+1] ⁺ 312.

Example 30: Synthesis of Compound 63

Compound 63 : (S)-tert-butyl (1-oxo-1-(8-oxo-8,9-dihydro-2,4,9,10-tetraazacycloheptyl [def] 芴-2 ( 1H,3H,4H)-yl)-3-phenylpropyl-2-yl)carbamate

Compound 63 is 2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl[def]indole-8(1H)-one and (S)-2-((tert-butyl) The carbonyl)amino)-3-phenylpropionic acid was used as a starting material and synthesized in a similar manner to the compound 62 . ¹ H NMR (DMSO-d ₆ ) δ 11.8 (s, 1H), 10.0 (s, 1H), 7.51 (d, 1H, J = 8.0 Hz), 7.05-7.47 (m, 7H), 4.96-5.02 ( m, 1H), 4.25-4.81 (m, 4H), 2.62-2.88 (m, 2H), 1.27 (s, 6H), 1.16 (s, 3H). MS (ESI) m / e [M+1] ⁺ 474.

Example 31: Synthesis of Compound 64

Compound 64 : (S)-2-(2-Amino-3-phenylpropanyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def]芴-8(1H)-ketone

Compound 64 was synthesized from compound 63 and hydrogen chloride using a procedure similar to that of compound 62 . ¹ H NMR (DMSO-d ₆ ) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.48 (d, 1H, J = 8.0 Hz), 7.48-7.52 (m, 2H), 7.10-7.20 ( m, 6H), 4.93-4.96 (m, 3H), 4.18-4.25 (m, 2H), 4.00-4.03 (m, 2H), 2.78-2.85 (m, 1H), 2.61-2.65 (m, 1H). MS (ESI) m/e [M+1] ⁺ 374.

Example 32: Synthesis of Compound 65

Compound 65 : 2-(2-Amino-2-methylpropenyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazaheptyl [def ]芴-8(1H)-ketone

Compound 65 was synthesized from methyl 2-bromo-5-fluoro-3-nitrophenyl acid and benzyl 3,5-dioxypiperidine-1-carboxylate in a similar manner to that of compound 62 . ¹ H NMR (DMSO-d ₆ ) δ 12.1 (s, 1H), 10.2 (s, 1H), 7.40 (dd, 1H, J = 1.8, 10.2 Hz), 7.20 (dd, 1H, J = 1.8, 10.2 Hz) ), 5.25 (s, 2H), 4.75 (s, 1H), 1.32 (s, 6H). MS (ESI) m/e [M+1] ⁺ 330.

Example 33: Synthesis of Compound 66

Compound 66 : 5,10-bis(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5 ,6-def]carbazole-6(1H)-one

2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one (100 mg , 0.39 mmol) was dissolved in dry DMF (8 mL). The reaction mixture was stirred at 0 ° C for 40 minutes. After adding 2-(2-bromoethoxy)tetrahydro-2H-pyran (194 mg, 1.17 mmol) at 0 ° C, it was stirred at room temperature for 6 hr. Water (100 mL) was added, and the mixture was combined with methylene chloride (50 mL × 3) and ethyl acetate (50 mL × 3). The organic phase was concentrated to give a crude material. The crude product was dissolved in MeOH (15 mL). Water (150 mL) was added, and the mixture was combined with EtOAc EtOAc. /MeOH = 10/1) to give 5,10-bis(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [ 3,4,5,6-def]carbazole-6(1H)-one (40 mg, 30%) as a yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 7.57 (m, 2H), 7.15 (dd, 1H, J = 7.2, 8.4 Hz), 4.88 (t, 1H, J = 5.4 Hz), 4.61 (t, 1H, J) =6.0 Hz), 4.21 (t, 2H, J = 5.4 Hz), 3.94 (t, 2H, J = 6.6 Hz), 3.94 (t, 2H, J = 6.6 Hz), 3.63 - 3.68 (m, 2H), 2.77 (s, 2H), 2.28 (s, 2H), 1.08 (s, 6H). MS (ESI) m / e [ M + 1] + 342.2.

Example 34: Synthesis of Compound 67

Compound 67 : 10-(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6- Def]carbazole-6(1H)-one

2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one (100 mg , 0.39 mmol) dissolved in dry DMF (8 mL), EtOAc (EtOAc (EtOAc) Stir at 1100 hours to 70 °C. Water (100 mL) was added, and the mixture was evaporated. Methanol (15 mL), p-toluenesulfonic acid monohydrate (100 mg, 0.52 mmol). Water (100 mL) was added, and the mixture was evaporated. Concentration, the residue was purified with a silica gel column (mobile phase: n-hexane/ethyl acetate) to afford 80 mg (69% yield) of 10-(2-hydroxyethyl)-2,2-dimethyl-2,3 , 5,10-Tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one as a yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 9.89 (s, 1H), 7.58 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.2 Hz), 7.15 (dd, 1H, J = 7.2 , 8.4 Hz), 4.88 (t, 1H, J = 5.4 Hz), 4.21 (t, 2H, J = 5.4 Hz), 3.65-3.68 (m, 1H), 2.76 (s, 2H), 2.25 (s, 2H) ), 1.07 (s, 6H). MS (ESI) m / e [ M + 1] + 298.1.

Example 35: Synthesis of Compound 68

Compound 68 : (R)-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazaheptyl [def]cyclopentyl[a]芴-4(5H)-ketone

Step 1: (R)-Methyl 2-(1-(benzyloxycarbonyl)-2-methyltetrahydropyrrole-2-yl)-1H-indole-4-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (1.72 g, 1.5 mmol) and CuI (0.29 g, 1.5 mmol), toluene (54 mL) and methyl 3-amino-2-bromo-benzoate (2.3 g, 10 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g, 12 mmol), triethylamine (7 mL, 50 mmol). The mixture was heated to 100 ° C under nitrogen for a period of 18 hours. Cooled and added water (20 mL). Extracted with ethyl acetate (20 mL×3), combined organic layers, brine (20 mL) Washed, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness, and the residue was purified using silica gel column (mobile phase: dichloromethane) to afford (R)-benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2 Methylpyrrolidine-1-carboxylate (2.31 g).

(R)-Benzyl 2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate (1.1 g, 2.8 mmol) and dibromo Ethane (5.21 g, 2.8 mmol) was dissolved in ethanol (20 mL). The reaction mixture was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated The filtrate was concentrated to give a pale brown oil (yield: hexane: ethyl acetate = 5:1) to afford (R)-methyl 2-(1-(benzyloxycarbonyl)-2- Tetrahydropyrrol-2-yl)-1H-indole-4-carboxylate (307 mg, 0.78 mmol). ¹ H NMR (CDCl ₃ -d) δ 10.3 (s, 1H), 7.83 (d, 1H, J = 7.8 Hz), 7.53 (d, 1H, J = 7.8 Hz), 7.29-7.35 (m, 5H), 7.16(t,1H,J=7.8Hz), 6.96(s,1H), 5.15(s,2H),3.95(s,3H),3.56-3.59(m,2H),2.83-2.85(m,1H) , 2.03-2.07 (m, 2H), 1.84-1.93 (m, 4H). MS (ESI) m / e [M+1] ⁺ 393.0.

Step 2: (R)-Methyl 2-(2-methyltetrahydropyrrol-2-yl)-1H-indole-4-carboxylate

(R)-Methyl 2-(1-(benzyloxycarbonyl)-2-methyltetrahydropyrrole-2-yl)-1H-indole-4-carboxylate (307 mg, 0.78 mol), methanol (10 mL And 10% palladium on carbon (50 mg), stirred at room temperature under hydrogen for 2 hours. The reaction mixture was filtered over EtOAc EtOAc (EtOAc)EtOAc. ¹ H NMR (CDCl ₃ -d ₁ ) δ 10.9 (s, 1H), 7.86 (d, 1H, J = 7.8 Hz), 7.63 (d, 1H, J = 7.8 Hz), 7.24 (t, 1H, J = 7.8 Hz), 7.14 (s, 1H), 3.96 (s, 3H), 3.40-3.43 (m, 1H), 3.12-3.15 (m, 1H), 2.78-2.81 (m, 1H), 2.23 - 2.26 (m , 3H), 1.94 (s, 3H). MS (ESI) m/e [M+1] ⁺ 259.0.

Step 3: (R)-Methyl 2-(1-(2-methoxy-2-oxoethyl)-2-methyltetrahydropyrrole-2-yl)-1H-indole-4-A Acid ester

(R)-Methyl 2-(2-methyltetrahydropyrrol-2-yl)-1H-indole-4-carboxylate (190 mg, 0.74 mmol) dissolved in acetonitrile (25 mL) Ethyl ester (250 mg, 1.6 mmol) and N,N-diisopropylethylamine (350 mg, 2.7 mmol). The reaction mixture was stirred at room temperature for 20 hours, then dichloromethane (15 ml) was added and washed three times with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to afford (D)-methyl 2-(1-(2-methoxy-2-oxoethyl)-2-methyltetrahydropyrrol-2-yl)- 1H-indole-4-carboxylate (146 mg). ¹ H NMR (CDCl ₃ -d) δ 7.85 (d, 1H, J = 7.8 Hz), 7.13 - 7.29 (m, 3H), 4.92 (s, 2H), 3.95 (s, 3H), 3.70 (s, 3H) ), 3.56-3.62 (m, 2H), 1.95-2.06 (m, 4H), 1.94 (s, 3H). MS (ESI) m / e [ M + 1] + 331.0.

Step 4: (R)-Methyl 11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-pyridazine [8,7-b]吲哚-7- Formate

(R)-Methyl 2-(1-(2-methoxy-2-oxoethyl)-2-methyltetrahydropyrrole-2-yl)-1H-indole-4-carboxylate ( 146 mg, 0.44 mmol) was placed in a 25 mL reaction flask and anhydrous methanesulfonic acid (10 mL) was added. The reaction was heated to 60 ° C for 1 hour. The reaction mixture was cooled with an ice water bath and diluted with water. Add sodium bicarbonate aqueous solution to adjust to a pH of about 8. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The filtrate was concentrated, and the residue was purified on a silica gel column (mobile phase: 20-60% ethyl acetate in n-hexane) to afford (R)-methyl 11b-methyl-6-oxo-2,3,5,6 , 11,11b-Hexahydro-1H-pyridazine [8,7-b]indole-7-carboxylate (58 mg, 44%). MS (ESI) m / e [ M + 1] + 299.0.

Step 5: (R)-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazaheptyl [def]cyclopentyl[a]芴-4(5H)-ketone

(R)-Methyl 11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-pyridazine [8,7-b]indole-7-formate (58 mg, 0.19 mmol), dissolved in MeOH (10 mL), EtOAc (EtOAc) (EtOAc) The organic layer was combined and washed with brine (10 mL). The filtrate was concentrated and the residue was purified by preparative thin layer chromatography (mobile phase: methylene chloride) to afford (R)-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a, 11-tetraazacycloheptyl [def]cyclopentyl[a]indole-4(5H)-one (40 mg). ¹ H NMR (DMSO-d ₆ ) δ 12.9 (s, 1H), 10.6 (s, 1H), 7.50-7.52 (m, 2H), 7.12 (t, 1H, J = 7.8 Hz), 3.24-3.26 (m) , 1H), 2.91 (d, 1H, J = 18.4 Hz), 2.37-2.38 (m, 1H), 2.30-2.32 (m, 1H), 2.20-2.21 (m, 1H), 1.95-1.96 (m, 1H) ), 1.41-1.43 (m, 1H), 1.34 (s, 3H), 1.18-1.19 (m 1H). MS (ESI) m / e [ M + 1] + 281.0.

Example 36: Synthesis of Compound 69

Compound 69: (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptyl [def]cyclopentyl Base [a]芴-4(5H)-one

Step 1: Methyl 2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate

3-amino-2-bromo-benzoic acid methyl ester (25.0 g, 100 mmol) was dissolved in dichloromethane (250 mL), potassium carbonate (42.0 g, 302 mmol) was added, 5-10 ° C, under nitrogen, 2,2 2-Fluoroacetic anhydride (249.0 g, 1.197 mol). The reaction mixture was stirred at 25 ° C overnight. Diluted with dichloromethane, washed with water (200 mL × 2) and aqueous sodium hydrogen carbonate (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-bromo-5-fluoro-3-(2,2,2 Methyl trifluoroacetamidoamino)benzoate (34.0 g, 98%) as a white solid. ¹ H NMR (CDCl ₃ -d ₁ ) δ 8.87 (s, 1H), 8.36 (d, 1H, J = 6.4 Hz), 7.43 (d, 1H, J = 5.2 Hz), 3.98 (s, 3H).

Step 2: (R)-Benzyl 2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methyl Pyrrolidine-1-carboxylate

Methyl 2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate (27.52 g, 80 mmol) was dissolved in DMF (200 mL) and (PPH ₃ ) ₂ PdCl ₂ (2.8 g, 4 mmol), (R)-benzyl 2-ethynyl-2-methylpyrrolidine-1-carboxylate (19.44 g, 80 mmol), cuprous iodide (764 mg, 4 mmol), tetramethylhydrazine ( 27.6 g, 240 mmol), heated to 80 ° C under nitrogen atmosphere and stirred for 16 hours. The reaction mixture was cooled, EtOAc (EtOAc m. The residue was purified with a silica gel column (mobile phase: 0-30% ethyl acetate in n-hexane) to afford (R)-benzyl 2-((4-fluoro-2-(methoxycarbonyl)-6-(2) , 2,2,3-trifluoroethylamino)phenyl)ethynyl)-2-methylpyrrolidin-1-carboxylate (21 g, 53%) as a white solid. ¹ H NMR (DMSO-d ₁ ) δ 11.01 (s, 1H), 7.64-7.77 (m, 1H), 7.36 (m, 5H), 7.19-7.31 (m, 1H), 5.04-5.12 (m, 2H) , 3.85 (s, 3H), 3.44 - 3.47 (m, 2H), 2.0-2.29 (m, 2H), 1.90-1.97 (m, 2H), 1.69 (s, 3H). MS (ESI) m / e [ M + 1] + 507.0.

Step 3: (R)-Methyl 6-fluoro-2-(2-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-indole-4 -formate

(R)-Benzyl 2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methylpyrrolidine- 1-formate (5.0 g, 10 mmol) was dissolved in toluene, and zinc bromide (11.25 g, 50 mmol) was added at room temperature, and the mixture was heated to 80 ° C under a nitrogen atmosphere and stirred for 15 hours. The solvent was evaporated to dryness <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Mobile phase: 0-50% ethyl acetate in n-hexane) afforded (R)-methyl 6-fluoro-2-(2-methyl-1-(2,2,2-trifluoroethyl) Pyrrolidin-2-yl)-1H-indole-4-carboxylate (1.9 g, 51%) as a yellow solid. ¹ H NMR (CDCl ₃ -d ₁ ) δ 9.97 (s, 1H), 7.62 (d, 1H, J = 10.2 Hz), 7.27 (d, 1H, J = 9.6 Hz), 7.05 (d, 1H, J = 1.2 Hz), 3.98 (s, 3H), 3.86-3.88 (m, 2H), 2.91-2.96 (m, 1H), 2.25-2.28 (m, 1H), 2.12-2.16 (m, 2H), 1.99 (s) , 3H). MS (ESI) m / e [ M + 1] + 507.0.

Step 4: (R)-Methyl 6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate

(R)-methyl 6-fluoro-2-(2-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)-1H-indole-4-carboxylic acid ester (1.0g, 1.9mmol) was dissolved in methanol, at room temperature was added NaBH ₄ (706mg, 11.4mmol). The reaction mixture was heated under reflux for 4 hr. EtOAc (EtOAc m. Compound (R)-Methyl 6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (727 mg, 98%). ¹ H NMR (CD ₃ OD-d ₁ ) δ 7.50 (dd, 1H, J = 10.2, 2.4 Hz), 7.32 (d, 1H, J = 9.0, 2.4 Hz), 6.93 (s, 1H), 3.97 (s) , 3H), 3.03-3.12 (m, 2H), 2.27-2.32 (m, 1H), 1.88-1.98 (m, 3H), 1.60 (s, 3H). MS (ESI) m / e [ M + 1] + 276.0.

Step 5: (R)-Methyl 6-fluoro-2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole- 4-formate

(R)-Methyl 6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (1.0 g, 1.27 mol), dissolved in acetonitrile (50 ml). Methyl bromoacetate (0.58 g, 3.82 mmol), and N,N-diisopropylethylamine (0.82 g, 6.35 mmol). Dichloromethane (15 mL) was added, washed with water three times, dried over anhydrous magnesium sulfate, filtered and evaporated to afford (R)-methyl 6-fluoro-2-(1-(2-methoxy-2-oxoethyl)- 2-Methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (0.85 g). ¹ H NMR (CD ₃ OD-d ₄ ) δ 7.47 (dd, 1H, J = 2.4, 12.0 Hz), 7.27 (dd, 1H, J = 2.4, 9.0 Hz), 6.89 (s, 1H), 3.95 (s) , 3H), 3.66-3.68 (m, 1H), 3.64 (s, 3H), 3.16-3.17 (m, 2H), 2.72-2.75 (m, 1H), 1.88-2.02 (m, 4H), 1.44 (s , 3H). MS (ESI) m / e [ M + 1] + 349.0.

Step 6: (R)-Methyl 9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-pyridazine [8,7-b]吲哚-7-formate

(R)-Methyl 6-fluoro 2-(1-(2-methoxy-2-oxoethyl)-2-methyltetrahydropyrrole-2-yl)-1H-indole-4-A The acid ester (100 mg) was placed in a 25 mL reaction flask and anhydrous methanesulfonic acid (6 mL) was added. The reaction was heated to 60 ° C for 1 hour. The reaction mixture was cooled in an ice water bath and diluted with distilled water (6.0 mL). Add sodium bicarbonate aqueous solution to adjust to a pH of about 8. The mixture was extracted with ethyl acetate (5 mL, EtOAc). The filtrate was concentrated, and the residue was purified using a thin-layer preparation plate to obtain (R)-methyl 9-fluoro 11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-pyridazine [8,7-b]indole-7-formate (30 mg). ¹ H NMR (CDCl ₃ -d) δ 7.14-7.224 (m, 2H), 4.03 (s, 3H), 3.81-3.84 (m, 1H), 3.57-3.59 (m, 1H), 3.22-3.24 (m, 1H), 2.92-2.94 (m, 1H), 2.39-2.40 (m, 1H), 2.16-30 2.17 (m, 1H), 1.93-1.94 (m, 1H), 1.63 (s, 3H), 1.56-1.57 (m, 1H). MS (ESI) m / e [ M + 1] + 317.0.

Step 7: (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptyl [def]cyclopentane Base [a]芴-4(5H)-one

(R)-methyl 9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-pyridazine [8,7-b]吲哚-7 - Formate (90 mg), dissolved in MeOH (30 mL), EtOAc (EtOAc) (EtOAc) (EtOAc) The extract was combined, and the organic layer was combined, washed with brine (10 mL) The filtrate was concentrated, and the residue was purified by EtOAc EtOAc (EtOAc:EtOAc) 6,7a,11-tetraazacycloheptyl[def]cyclopentyl[a]indole-4(5H)-one (80 mg). ¹ H NMR (DMSO-d ₆ ) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.30 (d, 1H, J = 9.6 Hz), 7.20 (d, 1H, J = 10.2 Hz), 3.76 ( d, 1H, J = 16.4 Hz), 3.34 (d, 1H, J = 16.4 Hz), 2.99-3.02 (m, 1H), 2.54-2.58 (m, 1H), 2.35-2.40 (m, 1H), 1.90 -1.94 (m, 1H), 1.73-1.75 (m, 1H), 1.48 (s, 3H), 1.43-1.45 (m, 1H). MS (ESI) m/e [M+1] ⁺ 299.

Biological activity

PARP-1 enzyme activity assay

The method of PARP-1 enzyme activity assay is derived from an improved high-throughput homologous PARP fluorostainment assay kit (Trevigen). In a buffer containing a final concentration of 100 mM Tris-HCl pH 8.0, 100 mM NaCl, 20 mM MgCl2, and 1% DMSO, 8.8 nM of PARP1 was pre-incubated with different concentrations of compound for 30 minutes at room temperature. 500 nM NAD and 20 ng/uL activated DNA (Sigma) were added to initiate a self-poly-ADP ribose polymerization reaction of PARP1 at room temperature for 40 minutes. The loop enzymatic assay reagent was added to the room temperature reaction for 50 minutes to detect the remaining NAD content after the reaction. The loop enzymatic assay reagent contained ethanol at a final concentration of 1%, 0.3 U/ml alcohol dehydrogenase, 25 μM resazurin, and 0.25 U/ml diaphorase. The concentration of NAD is proportional to the fluorescence signal (Ex = 540 nm, Em = 590 nm). Calculated based on the residual activity of the compound (i.e., the rate of decrease NAD) at various concentrations of compound inhibition concentration (IC _50).

PARP-2 and PARP-3 enzyme activity assay

The PARP-2 and PARP-3 enzyme assays were performed using the commercial PARP-2/PARP-3 chemiluminescence assay kit (BPS Biosciences) and its associated assays. Briefly, histones were first coated on high-binding plate, and then PARP-2 or PARP-3 was added and various concentrations of compounds were incubated for 0.5 hours. Biotinylated NAD and activated DNA are then added. The biotinylated poly(ADP-ribose) ribylation product was detected by the addition of streptavidin-labeled horseradish peroxidase and a horseradish peroxidase substrate that can produce chemiluminescence. Finally, the compound is calculated based on the residual enzyme activity at different concentrations of compound inhibition concentration (IC _50).

Tankyrase-2 enzyme activity assay

The Tankyrase-2 enzyme assay uses the commercially available Tankyrase-2 chemiluminescence assay kit (BPS Biosciences) and its associated assay. GST-fused Tankyrase-2 (expressed with a baculovirus insect expression system and purified recombinant protein) was first coated onto a glutathione pre-coated microplate. Incubate with different concentrations of compound for 0.5 hours. Biotinylated NAD is then added. The biotinylated self poly polyadenyl ribose auto-PARylation product was detected by the addition of streptavidin-labeled horseradish peroxidase and a horseradish peroxidase substrate that can produce chemiluminescence. Finally, the compound is calculated based on the residual enzyme activity at different concentrations of compound inhibition concentration (IC _50).

Determination of poly(ADP-ribose) ribylation (PARylation)

Hela cells were inoculated into the black wall at an initial concentration of 5000 cells per well in medium (100 μL MEM containing 10% fetal bovine serum, 0.1 mg/mL chelostine, 2 mM L-glutamine). In a 96-well plate. Incubate for 4 hours in a 37 ° C incubator with 5% carbon dioxide. Then add serial dilution A total of 8 concentration points of the compound were then dosed from 0.01 μM to 10 μM in 0.1% DMSO medium. After continuing to incubate for 18 hours in a 37 ° C incubator with 5% carbon dioxide, 60 μL of an aqueous solution of hydrogen peroxide (final concentration of 200 μM in PBS) was added dropwise to excite DNA damage. Among them, the cells were treated with no hydrogen peroxide as a negative control. After the plate was allowed to stand at 37 ° C for 5 minutes, the medium was gently inverted to remove the medium. Ice-treated methanol (100 μL per well) was added dropwise to the plate to fix the cells, and placed in a refrigerator at -20 ° C for 20 minutes. The liquid was discarded by inverting the plate and washed ten times with PBS (120 μL per well) to remove the fixing agent, and then the test solution (50 μL per well) was added. The test solution contains PBS, 0.1% Tween, 1 mg/mL bovine serum albumin, PAR monoclonal primary antibody (Alexis ALX-804-220, 1:2000), AlexaFluor 488-labeled anti-mouse secondary antibody (Molecular Probes A11029, 1 : 2000), nucleic acid dye DAPI (Molecular Probes D3571, 150 nM). After incubating overnight at 4 ° C in the dark, the test solution was removed, washed 6 times with PBS (120 μL per well), and the plate was read on an ArrayScan VTI instrument (ThermoFisher). The PAR polymer content was monitored by detecting the AlexaFluor 488 signal (XF100_485_20, exposure time 0.05 sec); the number of nuclei was identified by detecting the DAPI signal (XF100_386_23, exposure time 0.01 sec). The average of the individual cell nuclear fluorescence intensities (representing the amount of PAR polymer in the cells) can be obtained by calculating the ratio of the total fluorescence intensity of Alexa Fluor 488 per well to the total number of cells labeled with DAPI. The half effect concentration (EC50) of the compound was calculated based on the remaining enzyme activity at different concentrations of the compound.

The compounds of Examples 1-69 reported in the present invention have been found to have an inhibitory effect on PARP, such as PARP-1, PARP-2, PARP-3, and Tankyrase-2, and the range of IC ₅₀ values. From below nanomolar to 10 micromolar.

Claims (6)

A compound of formula (I) , a stereoisomer thereof or a pharmaceutically acceptable salt: Wherein: R _{N is} selected from the group consisting of hydrogen and alkyl, wherein the alkyl group is optionally substituted with at least one substituent R ¹² , R ^{12 is} selected from -OR', wherein R' is hydrogen; and X is selected from the group consisting of C and N. Groups; m and n , which may be the same or different, each being an integer of 1 or 2; t is an integer of 0 or 1; R ¹ is independently selected from halogen at each occurrence; R ^{2 is} selected from hydrogen and an alkane group, wherein the alkyl group may be substituted with at least one R ¹² group is optionally substituted; R ^3, R ^4, may be the same or different, are independently selected from hydrogen, -OR ^9, and an alkyl group; R ⁵ is selected from From hydrogen, -COR ⁹ , -CO ₂ R ⁹ , alkyl, cyclohexyl and phenyl, wherein the alkyl, cyclohexyl and phenyl are independently optionally substituted by at least one substituent R ¹² ; R ^{6 is} selected from Hydrogen, alkyl and phenyl, wherein the alkyl and phenyl are independently optionally substituted by at least one substituent R ¹² ; R ⁷ and R ⁸ may be the same or different and are independently selected from hydrogen and alkyl, respectively. Or R ⁴ and R ⁵ together with the atom to which they are attached form a 5-membered ring which is saturated, provided that when X is N, R ⁶ is absent, and when one of R ³ and R ⁴ is When oxy, One outer absent; R ⁹ is selected from hydrogen, alkyl, and cyclopropyl, wherein the cyclopropyl group and may be independently substituted with at least one R ¹² group is optionally substituted; R _N in addition, other groups The substituent R ^{12 present is} selected from the group consisting of -NR'R", -OR', -NR'CO ₂ R", alkyl, pyrrolidinyl, piperidinyl, morpholinyl, oxiranyl and phenyl, Wherein R', R" are independently selected from the group consisting of hydrogen, alkyl and phenylalkyl; wherein the alkyl group has from 1 to 6 carbon atoms. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the formula ( II ), a stereoisomer thereof or a pharmaceutically acceptable salt: Wherein: R _{N is} selected from the group consisting of hydrogen and alkyl, wherein the alkyl group is optionally substituted with at least one substituent R ¹² , and R ^{12 is} selected from -OR', wherein R' is hydrogen; m and n may be the same or different Is an integer of 1 or 2; t is an integer of 0 or 1; R ¹ is independently selected from halogen at each occurrence; R ^{2 is} selected from hydrogen and alkyl, wherein the alkyl group may be substituted with at least one substituent R ^{12 is} optionally substituted; R ³ and R ⁴ may be the same or different and are independently selected from hydrogen, -OR ⁹ and an oxy group; and R ⁵ and R ⁶ may be the same or different and are independently selected from hydrogen. And an alkyl group and a phenyl group, wherein the alkyl group and the phenyl group are independently optionally substituted by at least one substituent R ¹² ; R ⁷ and R ⁸ may be the same or different and are each independently selected from hydrogen and an alkyl group; Provided that when one of R ³ and R ⁴ is an oxy group, the other one is absent; R ^{9 is} selected from hydrogen; and in addition to R _N , the substituent R ¹² present in the other group is selected from -NR'R",-OR', pyrrolidinyl, piperidinyl, morpholinyl, oxiranyl and phenyl, wherein R', R" are independently selected from the group consisting of hydrogen, alkyl and phenylalkyl; Alkyl groups have 1 to 6 carbons Child. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the formula ( III ), a stereoisomer thereof or a pharmaceutically acceptable salt: Wherein: R _{N is} selected from hydrogen; m and n are each an integer of 1; t is an integer of 0 or 1; R ¹ is independently selected from halogen at each occurrence; and R ^{2 is} selected from hydrogen and alkyl, wherein The alkyl group may be optionally substituted by at least one substituent R ¹² ; R ³ , R ⁴ may be the same or different and are each independently selected from hydrogen and an alkyl group; R ^{5 is} selected from hydrogen, -COR ⁹ , -CO ₂ R ^And an alkyl group and a cyclohexyl group, wherein the alkyl group and the cyclohexyl group are independently optionally substituted by at least one substituent R ¹² ; R ⁷ and R ⁸ are each independently selected from hydrogen; or R ⁴ and R ⁵ are bonded thereto together with the atom to form a 5-membered ring, the ring is saturated, R ⁹ is selected from alkyl and cyclopropyl, wherein the cyclopropyl group and may be independently substituted with at least one substituent optionally substituted with R ^12; R ¹² selected from the group _{-NR'R ", - NR'CO 2 R"} , alkyl and phenyl, wherein R ', R "are independently selected from hydrogen and alkyl; and wherein the alkyl group has from 1 to 6 carbon atoms. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt, selected from the group consisting of: The compound according to claim 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which has the formula: A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, and a therapeutically effective amount of a compound, a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in claim 1 as an active ingredient.