TW201305181A - Phthalazinone derivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present disclosure relates to phthalazinone derivatives, preparation processes and pharmaceutical compositions containing them. Specifically, the present disclosure relates to novel phthalazinone derivatives presented by formula (I), preparation processes and pharmaceutical compositions containing the same, as well as the uses for treatment especially for Poly (ADP-ribose) polymerase (PARP) inhibitors, in which each substitute group of general formula (I) is as defined in the specification.

Description

Pyridazinone derivatives, preparation method thereof and application thereof in medicine

The present invention relates to a novel pyridazinone derivative represented by the general formula (I), a process for producing the same, a pharmaceutical composition containing the same, and a therapeutic agent as a poly(ADP-ribose) polymerase (PARP) The use of inhibitors.

Chemotherapeutic drugs and ionizing radiation therapy are two common methods of treating cancer. Both treatments induce DNA single-strand and/or double-strand breaks to produce cytotoxic effects, and the target tumor cells die due to chromosome damage. An important consequence of responding to DNA damage signals is that the cell cycle regulatory site signal is activated to protect cells from mitosis in the event of DNA damage and to avoid cell damage. In most cases, tumor cells have a high proliferation rate while exhibiting signal defects at the cell cycle regulatory site. Therefore, it can be inferred that there is a specific DNA repair mechanism in tumor cells, which can quickly respond to and repair chromosomal damage associated with proliferation regulation, thereby freeing itself from the cytotoxic effects of some therapeutic drugs and maintaining continued survival.

In clinical applications, the effective concentration of the chemotherapeutic drug or the therapeutic radiation intensity can counteract these DNA repair mechanisms and ensure the killing effect on the target tumor cells. However, tumor cells can be tolerant to treatment by enhancing their DNA damage repair mechanisms, allowing them to survive deadly DNA damage. In order to overcome the tolerance, it is usually necessary to increase the dose of the therapeutic drug or increase the radiation intensity, which will have an adverse effect on the normal tissue near the lesion, so that the treatment process is accompanied by serious adverse reactions, thereby increasing The risk of treatment. At the same time, increasing tolerance will reduce the therapeutic effect, so it can be inferred that by modulating the DNA damage signal repair mechanism, the cytotoxicity of the DNA damage agent can be improved in a tumor cell-specific manner.

PARPs (Poly(ADP-ribose) polymerases) characterized by polyadenosine diphosphate-ribosylation activity constitute a superfamily of 18 nuclear and cytoplasmic enzymes. This polyadenosine diphosphate-ribosylation regulates the catalytic activity and protein interactions of the protein of interest and regulates many basic biological processes, including DNA repair, cell death, and genomic stability (see also D' Amours et al. Biochem . J , 1999, 342, 249).

PARP-1 activity accounts for approximately 80% of total cellular PARP activity, and together with its closest counterpart, PARP-2, becomes a member of the PARP family with the ability to repair DNA damage. As a sensor and signaling protein for DNA damage, PARP-1 can rapidly detect and directly bind to DNA damage sites, and then induce a variety of proteins required for DNA repair, thereby repairing DNA damage. When PARP-1 is deficient in cells, PARP-2 can replace PARP-1 to repair DNA damage.

Studies have shown that the expression of PARPs in solid tumors is generally enhanced compared to normal cells. In addition, tumors for DNA repair-related gene deletions (such as BRCA-1 or BRCA-2), such as breast tumors and ovarian cancer, show extreme sensitivity to PARP-1 inhibitors, suggesting that PARP inhibitors are used as single agents. The potential use of this treatment, referred to as triple negative breast cancer (see Plummer, ER Curr. Opin. Pharmacol . 2006, 6, 364; Ratnam, et al; Clin. Cancer Res. 2007, 13, 1383). At the same time, because the DNA damage repair mechanism is the main mechanism for tumor cells to respond to chemotherapy drugs and ionizing radiation therapy, PARP-1 is considered to be an effective target for exploring new cancer treatment methods.

The PARP inhibitors developed in the early days were developed using the NAD ⁺ nicotinamide as a PARP catalytic substrate as a model. These inhibitors act as competitive inhibitors of NAD ⁺ and compete with NAD ⁺ for the catalytic site of PARP, thereby preventing the synthesis of poly(ADP-ribose) chains. The absence of poly(ADP-ribosylation) modification of PARP could not be dissociated from the DNA damage site, which would cause other proteins involved in the repair to enter the injury site, and thus could not perform the repair process. Thus, under the action of cytotoxic drugs or radiation, the presence of PARP inhibitors ultimately results in the death of damaged DNA cells.

In addition, NAD ⁺ consumed as a PARP catalytic matrix is an essential factor in the process of cell synthesis of ATP. At high PARP activity levels, intracellular NAD ⁺ levels are significantly reduced, which in turn affects intracellular ATP levels. Due to insufficient intracellular ATP content, cells cannot achieve an ATP-dependent stylized death process and can only turn to the special apoptotic process of necrosis. During necrosis, a large number of inflammatory factors are released, which can cause toxic effects on other organs and tissues (Horvath EM et al. Drug News Perspect , 2007, 20, 171-181). Therefore, PARP inhibitors can also be used to treat a variety of diseases associated with this mechanism, including neurodegenerative diseases (such as Alzheimer's disease, Huntington's disease, Parkinson's disease), diabetes, ischemia or ischemia-reperfusion Concurrent diseases such as myocardial infarction and acute renal failure, circulatory diseases such as septic shock, and inflammatory diseases such as chronic rheumatism (see Tentori L, et al. Pharmacol Res. , 2002, 45, 73-85; Horvath EM et al. Drug News Perspect , 2007, 20, 171.; Faro R, et al. Ann Thorac Surg , 2002, 73, 575.; Kumaran D, et al. Brain Res , 2008, 192, 178.).

A number of patent applications for pyridazinone PARP inhibitors have been disclosed, including WO2002036576, WO2004080976 and WO2006021801.

Although a series of PARP inhibitors for treating tumors have been disclosed, there is still a need to develop new compounds having better pharmacological effects and pharmacological results. With continuous efforts, the present invention has a design represented by the general formula (I). A compound of the structure, and a compound having such a structure is found to exhibit excellent effects and effects.

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a pyridazinone derivatives of the formula (I), and their tautomers, enantiomers, diastereomers, racemates And pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs.

Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituted by a substituent selected from a halogen, a hydroxyl group, an alkyl group or an alkoxy group; R ^{5 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an oxo group, C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl or alkoxy. Substituted ; R ⁶ and R ⁷ are each independently selected from hydrogen atoms, alkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, ^{heteroaryl, -C (O) OR 8,} -OC (O R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ , or R ⁶ and R ⁷ together form an oxo group; ring atoms D or E are each independently selected from C or N atoms; when n is 1, D and E are bonded to each other to form 6 Up to 10 membered ring X, when cyclized, in accordance with the valence bond theory, the 6 to 10 membered ring X is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group aryl or heteroaryl is independently optionally further substituted with one or more substituents selected from alkyl, halo, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzyl, oxo, -OR ^8, - C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O Substituted by a substituent of R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group And the heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkane , Cycloalkyl, heterocyclyl, aryl, heteroaryl, ^{oxo, -C (O) OR 8,} -OC (O) R 8, -O (CH 2) p C (O) OR 8, -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ Substituted by a substituent; when n is 2, D and E are bonded to each other to form a 5- to 10-membered ring X, which conforms to the valence bond theory, and the 5- to 10-membered ring X is selected from a cycloalkyl group and a heterocyclic group. Or a heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ Substituted with a substituent of -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ , wherein Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocycle. Base, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) Substituted with a substituent of _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ ; R ^{8 is} selected from a hydrogen atom, An alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from one or more Substituted with a substituent of an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, An alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from one or more Substituted by a substituent of an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or, R ⁹ and R ¹⁰ are bonded to a nitrogen atom The atom forms a heterocyclic group, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group is optionally further selected from one or more selected from the group consisting of an alkyl group, a halogen, and a hydroxyl group. , alkoxy, cycloalkyl, heterocyclic, aryl, Substituted by a substituent of a heteroaryl, carboxylic acid or carboxylic acid ester; m is 0, 1 or 2; n is 1 or 2; and p is 0, 1 or 2.

A preferred embodiment of the invention, a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (II) or a pharmaceutically acceptable salt thereof:

Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituted by a substituent selected from a halogen, a hydroxyl group, an alkyl group or an alkoxy group; R ^{5 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an oxo group, C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl or alkoxy. Substituted The ring atoms D or E are each independently selected from C or N atoms; D and E are bonded to each other to form a 6 to 10 membered ring X, which conforms to the valence bond theory, and the 6 to 10 membered ring X is selected from cycloalkyl groups. Or a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cycloalkane , heterocyclic, aryl, heteroaryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O) OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR Substituted by a substituent of ⁹ R ¹⁰ wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ is substituted with a substituent; ^{R. 8} is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group Wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocycle Substituted with a substituent of a aryl group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocycle Substituted with a substituent of a aryl group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or, R ⁹ and R ¹⁰ form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatom, and the heterocyclic group is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted by a substituent of an aryl group, a carboxylic acid or a carboxylic acid ester; m is 0, 1 or 2; and p is 0, 1 or 2.

A preferred embodiment of the invention, a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (III) or a pharmaceutically acceptable salt thereof:

Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituents selected from halogen, hydroxy, alkyl or alkoxy are substituted; Y, Z, G and J are each independently selected from N or C atoms; provided that Y, Z, G or J are not simultaneously N atoms, at the same time, any three ring atoms that are arbitrarily connected cannot be N atoms at the same time; when Y, Z, G and J are selected from N atoms, there is no substitution; when Y, Z, G and J are selected from C atoms Wherein, Y, Z, G and J are each independently optionally further selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a benzyl group, an oxo group, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ , wherein alkyl, cycloalkyl, heterocyclyl, aryl, The heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -C. (O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O) Substituted with a substituent of R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ ; R ^{8 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic ring a aryl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy Substituted by a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester R ⁹ or R ¹⁰ are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each Independently optionally further substituted with one or more substituents selected from alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters; Alternatively, R ⁹ and R ¹⁰ form a heterocyclic group with the attached nitrogen atom, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group is optionally further Substituted by one or more substituents selected from alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester; m is selected from 0,1 Or 2; and p is selected from 0, 1 or 2.

A preferred embodiment of the invention, a compound of the formula (II) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (IV) or a pharmaceutically acceptable salt thereof:

Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituted by a substituent selected from a halogen, a hydroxyl group, an alkyl group or an alkoxy group; R ^{5 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an oxo group, C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl or alkoxy. Substituted ; Y, Z, G, and J are each independently selected from O atoms, N (R ¹¹⁾ or ^{C (R 11) (R 12} ); with the proviso that, Y, Z, G or J are not both N (R ¹¹⁾ Meanwhile, the arbitrarily connected three ring atoms cannot be N(R ¹¹ ) at the same time; and, when Y, Z, J or G is selected from N(R ¹¹ ) or C(R ¹¹ )(R ¹² ), any adjacent The two ring atoms may form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; R ^{8 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by a substituent of a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by a substituent of a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or R ⁹ and R ¹⁰ together with the nitrogen atom attached form a heterocyclyl, wherein the heterocyclyl contains within one or more N, O or S (O) _m hetero atoms, and the heterocyclic group optionally further substituted with one or Substituting a plurality of substituents selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ¹¹ and R ¹² are each independently selected From hydrogen atom, alkyl, halogen, hydroxy, cycloalkyl, heterocyclic, aryl, heteroaryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC( O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected by one or more From alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C (O) NR ⁹ R ¹⁰ group substituted with substituent; m is selected from 0, 1 or 2; and p is selected from 0, 1 or 2

A preferred embodiment of the invention is a compound of the formula (IV) or a pharmaceutically acceptable salt thereof, wherein: A and B together with a carbon atom to which they are bonded form a cycloalkyl group, a heterocyclic group, an aryl group or a heterocyclic group. An aryl group, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is, independently, each optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl , aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O Substituting a substituent of R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from Hydrogen atom, halogen, hydroxy, alkyl, cyano, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C (O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further substituted by one or more substituents selected from halogen, hydroxy, alkyl or alkoxy; R ^{5 is} selected from a hydrogen atom , hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , Wherein the alkyl group is optional One step is substituted with one or more substituents selected from halogen, hydroxy, alkyl or alkoxy; Y, Z, G and J are each independently selected from an O atom, N(R ¹¹ ) or C(R ¹¹ ) (R ¹² ); wherein: J is an O atom or N(R ¹¹ ), G is C(R ¹¹ )(R ¹² ), Z is C(R ¹¹ )(R ¹² ), Y is an O atom, N(R ¹¹ ) or C(R ¹¹ )(R ¹² ); J is C(R ¹¹ )(R ¹² ), G is N(R ¹¹ ) or C(R ¹¹ )(R ¹² ), and Z is C(R ¹¹ ) (R ¹² ), Y is C(R ¹¹ )(R ¹² ); J is C(R ¹¹ )(R ¹² ), G is C(R ¹¹ )(R ¹² ), and Z is N(R ¹¹ ) or C (R ¹¹ )(R ¹² ), Y is C(R ¹¹ )(R ¹² ); and, when Y, Z, J or G is selected from N(R ¹¹ ) or C(R ¹¹ )(R ¹² ), any The adjacent two ring atoms may form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; and R ^{8 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is, independently, each optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl , substituted aryl, heteroaryl, carboxylic acid or carboxylic ester substituted; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, An alkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from the group consisting of alkyl groups and halogens. Substituted with a substituent of a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or, R ⁹ and R ¹⁰ form a heterocyclic ring with a nitrogen atom bonded thereto a group wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ¹¹ and R ¹² are each independently selected from a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, a cycloalkyl group , heterocyclic, aryl, heteroaryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ , wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected from one or more selected from alkane Base, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or- Substituted by a substituent of C(O)NR ⁹ R ¹⁰ ; m is selected from 0, 1 or 2; and p is selected from 0, 1 or 2.

A preferred embodiment of the present invention, which is a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which comprises a compound of the formula (V) or a pharmaceutically acceptable salt thereof:

Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, An aryl or heteroaryl group, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituted by a substituent selected from a halogen, a hydroxyl group, an alkyl group or an alkoxy group; R ^{5 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an oxo group, C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl or alkoxy. Substituted D and E are each independently selected from N or C atoms; D and E are bonded to each other to form a 5 to 10 membered ring X, which is valence-bonded in the ring, and the 5 to 10 membered ring X is selected from cycloalkyl, hetero a cycloalkyl or heteroaryl group, wherein the cycloalkyl, heterocyclyl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, cycloalkyl, heterocyclyl, aryl , heteroaryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O) Substituted by a substituent of R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ Wherein alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, cycloalkyl, Heterocyclyl, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R _{^{8, -S (O) m R}} 8, -NHC (O) R 8, -NR 9 R 10, -OC (O) NR 9 R 10 or -C (O) NR ⁹ R ¹⁰ substituted with a substituent; R ⁸ is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, The radical, heterocyclyl, aryl or heteroaryl are each, independently, optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituting a substituent of a carboxylic acid or a carboxylic acid ester; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group or the cycloalkane The radical, heterocyclyl, aryl or heteroaryl are each, independently, optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituting a substituent of a carboxylic acid or a carboxylic acid ester; or, R ⁹ and R ¹⁰ form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid Substituted by an ester substituent; m is selected from 0, 1 or 2; and p is 0, 1 or 2.

A preferred embodiment of the invention is a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein A and B together with the carbon atom to which they are attached form an aryl group, preferably a phenyl group.

A preferred embodiment of the invention is a compound of the formula (I), wherein R ^{1 is} selected from a hydrogen atom or a halogen, preferably a hydrogen atom or a fluorine atom, or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the invention is a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ is halogen, preferably a fluorine atom.

A preferred embodiment of the invention, wherein the compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ or R ⁴ are each independently a hydrogen atom.

A preferred embodiment of the invention, wherein the compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² , R ³ or R ⁴ are each independently a hydrogen atom, and R ¹ is a halogen, preferably a fluorine atom.

A preferred embodiment of the invention is a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom.

A preferred embodiment of the invention is a compound of the formula (I), wherein R ⁶ or R ⁷ are each independently a hydrogen atom, or R ⁶ and R ⁷ together form an oxo group, or a pharmaceutically acceptable salt thereof.

The compounds of the formula (I) may contain asymmetric carbon atoms and may therefore exist in the form of optically pure diastereomers, diastereomeric mixtures, diastereomeric racemates, mixtures of diastereomeric racemates. Or exist as a meso compound. The invention includes all of these forms. Mixtures of diastereomeric mixtures, diastereomeric racemates or diastereomeric racemates can be separated by conventional methods, for example by column chromatography, thin layer chromatography and high performance liquid chromatography.

Equivalents considered - one of ordinary skill in the art will appreciate that compound (I) may also exist in the form of tautomers. The tautomeric form of the compound (I) may include, but is not limited to, the structure represented by the following formula (VI):

Typical compounds of the invention include, but are not limited to:

Or a pharmaceutically acceptable salt thereof.

The present invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, the process comprising:

The compound of the formula (IA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (IB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of, under basic conditions, a compound of the formula (I); wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; A, B, D, E, ring X, n, R ¹ to R ⁷ The definition is as described in the general formula (I).

The present invention relates to a process for the preparation of a compound of the formula (II) or a pharmaceutically acceptable salt thereof, the process comprising:

The compound of the formula (IIA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (IIB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of a basic condition, a compound of the formula (II) is obtained, wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; A, B, D, E, ring X, R ¹ and R ⁵ are as defined Said in the formula (II).

The present invention relates to a process for the preparation of a compound of the formula (III) or a pharmaceutically acceptable salt thereof, the process comprising:

The compound of the formula (IIA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (IIIB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of a reaction under basic conditions, a compound of the formula (III) is obtained; wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; A, B, Y, Z, J, G, R ¹ is as defined Said in (III).

The present invention relates to a process for the preparation of a compound of the formula (IV) or a pharmaceutically acceptable salt thereof, the process comprising:

The compound of the formula (IIA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (IB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of a basic condition, a compound of the formula (IV); wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; A, B, Y, Z, J, G, R ¹ and R ⁵ are defined. As described in the general formula (IV).

The present invention relates to a process for the preparation of a compound of the formula (V) or a pharmaceutically acceptable salt thereof, the process comprising:

The compound of the formula (IIA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (VB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of a basic condition, a compound of the formula (V) is obtained, wherein: R ^{a is} selected from a halogen, a hydroxyl group or an alkoxy group; and A, B, D, E, R ¹ and R ⁵ are as defined in the formula ( Said in V).

Another aspect of the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting PARP.

Another aspect of the invention relates to a method of inhibiting PARP comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use as an adjuvant in the treatment of cancer or for sensitizing tumor cells to ionizing radiation or chemotherapy the use of.

Another aspect of the invention relates to a compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an adjuvant or a drug for making tumor cells sensitive to ionizing radiation or chemotherapy during cancer treatment .

Another aspect of the invention relates to a compound of the formula (I) of the invention, or a pharmaceutically acceptable salt thereof, as a medicament for inhibiting PARP.

Another aspect of the invention relates to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, liver cancer Or colon cancer, wherein the drug is further administered in combination with a therapeutically effective amount of a drug selected from the group consisting of: temozolomide ( TMZ ), doxorubicin, paclitaxel (Taxol, Paclitaxel), Cisplatin, Carboplatin ), dacarbazine, topotecan, irinotecan, gemcitabine or bevacizumab.

Another aspect of the present invention relates to a method of treating cancer, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer or ovarian cancer , pancreatic cancer, prostate cancer, liver cancer or colon cancer, wherein the compound of the formula (I) or a pharmaceutically acceptable salt thereof is further used in combination with a therapeutically effective amount of a drug selected from the group consisting of temozolomide and doxorubicin , paclitaxel, cisplatin, carboplatin, dacarbazine, topotecan, irinotecan, gemcitabine or bevacizumab.

Another aspect of the invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which is a medicament for treating cancer, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, liver cancer or colon cancer Wherein the drug is further administered in combination with a therapeutically effective amount of a drug selected from the group consisting of temozolomide, doxorubicin, paclitaxel, cisplatin, carboplatin, dacarbazine, topotecan, irinotecan, gemcitabine or bevacizole anti.

Further, another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient thereof . The pharmaceutical composition can be used as a drug for inhibiting PARP, or as an adjuvant in cancer treatment or as a drug for making tumor cells sensitive to ionizing radiation or chemotherapy, or as a drug for treating cancer. Use of the pharmaceutical composition for the preparation of a medicament for inhibiting PARP. The pharmaceutical composition is useful in the preparation of a medicament for use in the treatment of cancer or as a medicament for sensitizing tumor cells to ionizing radiation or chemotherapy. Use of the pharmaceutical composition for the preparation of a medicament for treating cancer, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer or colon cancer, wherein the composition is further combined with a therapeutically effective dose of a drug selected from the group consisting of Applications: Temozolomide, doxorubicin, paclitaxel, cisplatin, carboplatin, dacarbazine, topotecan, irinotecan, gemcitabine or bevacizumab.

Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

"Alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group preferably having 1 to 12 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and t-butyl groups. , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2 ,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3 - dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl , 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl 2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl , and its various branched isomers. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Second butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methyl Butyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2 - dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4- Methyl amyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl. , alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C( O) OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O )NR ⁹ R ¹⁰ .

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises 3 Up to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

"Spirocycloalkyl" means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkane, depending on the number of common spiro atoms between the ring and the ring. base. More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include

"Fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include

"Bridge cycloalkyl" refers to 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The π-electron system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Thio, heterocycloalkylthio, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -OR ⁸ , -C(O)OR ⁵ , -OC(O)R ⁵ , -O(CH ₂ ) _p C(O)OR ⁵ , -C(O)R ⁵ , -S (O) _m R ⁸ , -NHC(O)R ⁵ , -NR ⁶ R ⁷ , -OC(O)NR ⁶ R ⁷ or -C(O)NR ⁶ R ⁷ .

"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S (O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O)m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, sharing a single atom (called a spiro atom) between the monocyclic rings, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) _m The hetero atom (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include

"Fused heterocyclyl" refers to 5 to 20 members, each ring in the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more a bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member double ring heterogeneous Ring base. Non-limiting examples of fused heterocyclic groups include

"Bridge heterocyclyl" refers to a 5 to 14 member, any two rings sharing two polycyclic heterocyclic groups of atoms that are not directly bonded, these may contain one or more double bonds, but none of the rings are fully conjugated A π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:

Wait. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Thio, heterocycloalkylthio, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated π-electron system (ie, having adjacent pairs) The ring of a carbon atom is preferably a 6 to 10 member such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S (O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 members. The heteroaryl group is preferably 5 or 6 members such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane. Thio group, alkylamino group, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Thio, heterocycloalkylthio, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ .

"Hydroxy" refers to an -OH group.

"Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -NH _2.

"Cyano" means -CN.

"Nitro" means -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Oxo" means =O.

"Carboxylic acid" means -C(O)OH.

"Carboxylic acid ester" means -C(O)O(alkyl) or (cycloalkyl).

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity.

m, n and R ⁸ to R ¹⁰ are as defined in the compound of the formula (I).

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, the process comprising: the invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, Methods include:

The compound of the formula (IA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (IB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of, under basic conditions, a compound of the formula (I); wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; A, B, D, E, ring X, n, R ¹ to R ⁷ The definition is as described in the general formula (I).

A method for preparing a compound of the formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the formula (IIA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (IIB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of a basic condition, a compound of the formula (II) is obtained, wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; A, B, D, E, ring X, R ¹ and R ⁵ are as defined Said in the formula (II).

A method for preparing a compound of the formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the formula (IIA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (IIIB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of, under basic conditions, a compound of the formula (III); wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; and A, B, Y, Z, J, G and R ¹ are as defined Said in (III).

A method of preparing a compound of the formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the formula (IIA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (IB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of a basic condition, a compound of the formula (IV); wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; A, B, Y, Z, J, G, R ¹ and R ⁵ are defined. As described in the general formula (IV).

A method of preparing a compound of the formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the formula (IIA) is optionally hydrolyzed to a carboxylic acid and a compound of the formula (VB) or a salt thereof in a condensation reagent such as benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate In the presence of a basic condition, a compound of the formula (V) is obtained, wherein: R ^{a is} selected from a halogen, a hydroxyl group or an alkoxy group; and A, B, D, E, R ¹ and R ⁵ are as defined in the formula ( Said in V).

The above condensation reaction is optionally carried out in a carboxylic acid (including a compound of the formula (IA) and the formula (IIA)) and an amine (general formula (IB), formula (IIB), formula (IIIB), formula (IVB) And the compound of the general formula (VB)) are carried out under a condensation reagent and a basic condition, and the condensation reagent used is selected from the group consisting of N,N-dicyclohexylcarbodiimide and N,N-diisopropylcarbodiimide. Amine, O -benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), etc., preferably O -benzotriazole-N,N,N', N'-tetramethyluronium tetrafluoroborate (TBTU); basic conditions are provided by an organic base or an inorganic base selected from, for example, diisopropylethylamine, pyridine, triethylamine, hexahydropyridine, N- Methylpiperazine, 4-dimethylaminopyridine, etc., preferably diisopropylethylamine; the solvent used is selected from the group consisting of toluene, benzene, dichloromethane, tetrahydrofuran, chloroform N,N-dimethylformamide or The above solvent composition mixture or the like is preferably N,N-dimethylformamide; the reaction temperature is controlled at -80 ° C to 100 ° C, preferably 0 ° C to 60 ° C; the reaction time is generally controlled from 1 minute to 72 ° Hours, preferably from 15 minutes to 24 hours.

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus. The solvent was deuterated dimethyl hydrazine (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl. Base decane (TMS).

The measurement of MS was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

High performance liquid phase (HPLC) measurements were performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a WaterS 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column).

The IC ₅₀ value was determined using a NovoStar plate reader (BMG, Germany).

Thin layer chromatography gelatinized sheets use Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheets. The specifications of thin layer chromatography (TLC) used for thin layer chromatography are 0.15mm to 0.2mm. The specifications for thin layer chromatography separation and purification are 0.4mm to 0.5. Mm.

Column chromatography generally uses Yantai Yellow Sea 200 to 300 mesh silicone as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be used by companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Suiyuan Chemical Technology and Dari Chemicals. Buy out.

Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen atmosphere or an argon atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

Purification compounds using a column chromatography eluent system and a thin layer chromatography developer system include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, the volume ratio of the solvent according to the compound The polarity is adjusted to adjust, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.

Example 1

4-[[4-fluoro-3-(6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl )-phenyl]methyl]-2 H -pyridazin-1-one

first step

1,2,3,4,5,7,7 a -octahydropyrrolo[3,4- c ]pyridin-6-one

5-Oxo-1,3,3 a ,4,6,6 a -hexahydrocyclopenta[ c ]pyrrole-2-carboxylic acid tert-butyl ester 1 a (1 g, 4.40 mmol) under ice bath Dissolved in 10 mL of concentrated hydrochloric acid, sodium azide (0.69 g, 10.60 mmol) was added and allowed to react at room temperature for 12 hours. Concentrate under reduced pressure, add saturated sodium bicarbonate solution until the pH of the reaction mixture was 9 and extracted with dichloromethane (100 mL×2). The organic phase was combined and concentrated under reduced pressure. The obtained residue was purified to give 1,2,3,4,5,7,7 a -octahydropyrrolo[3,4- c ]pyridin-6-one 1b (0.20 g, tan solid). 35.0%.

MS m/z (ESI): 141.1 [M+1]

Second step

4-[[4-fluoro-3-(6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl )-phenyl]methyl]-2 H -pyridazin-1-one

Dissolving 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol, prepared by the known method "Patent WO2004080976") Add benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), 1,2 to 10 mL of N,N-dimethylformamide ,3,4,5,7,7 a -octahydropyrrolo[3,4- c ]pyridin-6-one 1b (85 mg, 0.60 mmol) and triethylamine (0.2 mL, 1 mmol), reaction 12 hour. Filtration and concentration of the filtrate under reduced pressure, and the residue obtained was purified by silica gel chromatography to afford 4-[[4-fluoro-3-(6-oxo-3,3 a ,4,5,7, 7 a -Hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl)-phenyl]methyl]-2 H -pyridazin-1-one 1 (120 mg, pale yellow solid) , Yield: 55.0%.

MS m/z (ESI): 421.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.60 ( br . s, 1H), 8.24 - 8.26 (m, 1H), 7.96-7.99 (m, 1H), 7.82-7.89 (m, 2H), 7.50-7.70 (m, 1H), 7.38-7.42 (m, 2H), 7.18-7.21 (m, 1H), 4.31 (m, 2H), 3.72-3.76 (m, 1H), 2.88-3.36 (m, 4H) ), 1.95-2.34(m,3H),1.10-1.14(m,2H)

Example 2

4-[[3-[(8 aR )-4-oxo-1,3,6,7,8,8 a -hexahydropyrrolo[1,2- a ]pyryl-2-carbonyl]-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

(2 R )-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[( 2R )-Pyrrolidin-2-yl]-methanol 2a (4 g, 39.50 mmol) was dissolved in 50 mL dichloromethane, triethylamine (11 mL, 80 mmol) Di-tert-butyl dicarbonate (12.90 g, 59 mmol) was reacted for 3 hours. Concentrated under reduced pressure, by column chromatography on silica gel eluting A surfactant system resulting residue, to give (2 R) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester 2b (7.01 g, pale Yellow oil), Yield: 88.0%.

MS m/z (ESI+23): 224.2 [M+23]

Second step

(2 R )-2-carbamimidyrrolidine-1-carboxylic acid tert-butyl ester

The grass chloroform (0.8 mL, 8 mmol) was dissolved in 5 mL of dichloromethane, and the reaction mixture was cooled to -78 ° C, dimethyl hydrazide (14 mL, 14 mmol) was added dropwise and stirred for 15 min. 3 mL of ( 2R )-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester 2b (400 mg, 2 mmol) in dichloromethane was added dropwise at 78 ° C, and stirred for 15 minutes, then triethylamine was added. (2 mL, 14 mmol), stirring was continued for 15 minutes, then warmed to 0 ° C for 15 min. 80 mL of petroleum ether was added, washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system B to give (2 R )- 2-Methylpyridylpyrrolidine-1-carboxylic acid tert-butyl ester 2c (349 mg, pale yellow oil), yield: 87.7%.

MS m/z (ESI): 199.8 [M+1]

third step

( 2R )-2-[[(2-ethoxy-2-oxo-ethyl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester

(2 R )-2-Methylpyridylpyrrolidine-1-carboxylic acid tert-butyl ester 2c (500 mg, 2.50 mmol) was dissolved in 30 mL of dichloromethane, and ethyl glycinate hydrochloride (526 mg) was added. , 3.80 mmol), after stirring for 30 minutes, sodium triethoxysulfonate hydride (1.59 g, 7.50 mmol) was added and the mixture was reacted for 12 hours. Add 30 mL of water, extract with methylene chloride (30 mL×2), combine with organic phase, wash with saturated sodium chloride solution (15 mL×2), dry over anhydrous sodium sulfate, filtered, The resulting residue was purified by column chromatography using eluent B to give ( 2R )-2-[[(2-ethoxy-2-oxo-ethyl)amino]methyl]pyrrolidin-1- T-butyl formate 2d (611 mg, pale yellow oil), yield: 85.2%.

MS m/z (ESI): 287.2 [M+1]

the fourth step

(8 aR )-2,3,6,7,8,8 a -hexahydro-1 H -pyrrolo[1,2- a ]pyrazin-4-one

( 2R )-2-[[(2-ethoxy-2-oxo-ethyl)amino]methyl]pyrrolidine-1-carboxylic acid tert-butyl ester 2d (611 mg, 2.10 mmol) and 3 mL of trifluoroacetic acid was dissolved in 10 mL of dichloromethane and reacted for 12 hours. Concentrate under reduced pressure, add 40 mL of dichloromethane, add 1 M sodium hydroxide solution until the pH of the reaction solution is 12 to 13, separate the liquid, extract the aqueous phase with dichloromethane (20 mL × 3), and combine the organic phase. The mixture was washed with a saturated sodium chloride solution (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography to afford (8 aR )-2. 3,6,7,8,8 a -Hexahydro- 1H -pyrrolo[1,2- a ]pyrazin-4-one 2e (105 mg, brown oil), yield: 35.0%.

MS m/z (ESI): 141.1 [M+1]

the fifth step

4-[[3-[(8 aR )-4-oxo-1,3,6,7,8,8 a -hexahydropyrrolo[1,2- a ]pyrazine-2-carbonyl]-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol) in 6 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (340 mg, 0.90 mmol), (8 aR )-2,3,6,7,8, 8 a -Hexahydro-1 H -pyrrolo[1,2- a ]pyrazin-4-one 2e (105 mg, 0.75 mmol) and N,N-diisopropylethylamine (260 μL, 1.50 mmol) , reaction for 12 hours. After adding 20 mL of water and extracting with dichloromethane (30 mL×3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by eluent column chromatography with eluent system A. , 4-[[3-[(8 aR )-4-oxo-1,3,6,7,8,8 a -hexahydropyrrolo[1,2- a ]pyrazine-2-carbonyl] 4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 2 (20 mg, pale yellow solid), yield: 9.0%.

MS m/z (ESI): 421.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.45 ( br . s, 1H), 8.47 (d, 1H), 7.79 (m, 2H), 7.76 (m, 1H), 7.35 (m, 2H), 7.29 (t, 1H), 4.28 (s, 2H), 4.05 (m, 1H), 3.85 (m, 1H), 3.69 (m, 2H), 3.52 (m, 2H), 2.64 (m, 1H), 2.04 ( m, 2H), 1.87 (m, 2H)

Example 3

4-[[3-[(8 aR )-6-oxo-1,3,4,7,8,8 a -hexahydropyrrolo[1,2- a ]pyrazine-2-carbonyl]-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

Methyl [(2 R )-5-oxopyrrolidin-2-yl]methanesulfonate

(5 R )-5-(Hydroxymethyl)pyrrolidin-2-one 3a (4 g, 43.40 mmol) was dissolved in 150 mL chloroform, triethylamine (35 mL, 260.40 mmol) After 10 minutes, methanesulfonium chloride (20 mL, 217 mmol) was added and allowed to react at room temperature for 3 hours. Add 100 mL of dichloromethane, wash with saturated sodium bicarbonate solution (20 mL), saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and then filtered, and the filtrate is concentrated under reduced pressure. A release agent system resulting residue was purified to give [(2 R) -5- oxo-pyrrolidine-2-yl] methyl methanesulfonate 3b (3.50 g, pale yellow solid), yield: 42.0%.

MS m/z (ESI): 194.0 [M+1]

Second step

(5 R )-5-[(benzyl(2-hydroxyethyl)amino)methyl]pyrrolidin-2-one

Methyl [( 2R )-5-oxopyrrolidin-2-yl]methanesulfonate 3b (1 g, 5.17 mmol) and 2-benzylamino-ethanol (3 g, 20.68 mmol) were added to the microwave. In the tube, the reaction was carried out for 40 minutes under microwave conditions at 130 °C. After adding 20 mL of dichloromethane and 20 mL of water, the mixture was separated and the aqueous phase was extracted with dichloromethane (20 mL×2). The organic phase was combined and washed with saturated sodium chloride (20 mL) The filtrate was concentrated under reduced pressure, and the obtained residue was purified eluting with eluent column chromatography to afford (5 R )-5-[(benzyl(2-hydroxyethyl)amino)methyl]pyrrolidine. 2-ketone 3c (640 mg, pale yellow oil), yield: 50.0%.

MS m/z (ESI): 249.1 [M+1]

third step

2-[Benzyl-[[(2 R )-5-oxopyrrolidin-2-yl]methyl]amino]methanesulfonate

(5 R )-5-[(benzyl(2-hydroxyethyl)amino)methyl]pyrrolidin-2-one 3c (640 mg, 2.58 mmol) was dissolved in 10 mL of chloroform and triethylamine was added (0.8 mL, 5.15 mmol), methanesulfonium chloride (0.4 mL, 5.15 mmol) was added in an ice bath and allowed to react at room temperature for 6 hours. After adding 20 mL of a saturated sodium hydrogencarbonate solution, the mixture was separated and the aqueous phase was extracted with dichloromethane (20 mL×2). [[(2 R )-5-Oxopyrrolidin-2-yl]methyl]amino]methanesulfonate ethyl ester 3d (180 mg, mp.

the fourth step

(8 aR) -2- benzyl -1,3,4,7,8,8 a - hexahydro-pyrrolo [1,2- a] pyrazin-6-one

2-[Benzyl-[[(2 R )-5-oxopyrrolidin-2-yl]methyl]amino]methanesulfonate ethyl ester 3d (180 mg, 0.55 mmol) was dissolved in 10 mL acetonitrile A mixture of sodium hydride and mineral oil (30 mg, 60%, 0.72 mmol) was added and reacted for 4 hours. Pour into 30 mL of ice water, extract with methylene chloride (20 mL×3), and combine with organic phase, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue obtained by column chromatography was purified by eluent system A to give (8 aR )-2-benzyl-1,3,4,7,8,8 a -hexahydropyrrolo[1,2- a ]pyridin. Pyrazin-6-one 3e (90 mg, light yellow oil), yield: 71.0%.

MS m/z (ESI): 231.1 [M+1]

the fifth step

(8 aR) -2,3,4,7,8,8 a - hexahydro-pyrrolo [1,2- a] pyrazin-6-one

Dissolve (8 aR )-2-benzyl-1,3,4,7,8,8 a -hexahydropyrrolo[1,2- a ]pyrazine-6-one 3e (90 mg, 0.39 mmol) 20 mg of 10% palladium on carbon and ammonium formate (172 mg, 2.74 mmol) were added to 5 mL of methanol and refluxed for 3 hours. The filter cake was washed with 10 mL of methanol, the filtrate was concentrated under reduced pressure, to give (8 aR) -2,3,4,7,8,8 a - hexahydro-pyrrolo [1,2- a] pyrazine-6 Ketone 3f (55 mg, colorless oil), yield: 100.0%.

MS m/z (ESI): 141.1 [M+1]

Step 6

4-[[3-[(8 aR )-6-oxo-1,3,4,7,8,8 a -hexahydropyrrolo[1,2- a ]pyrazine-2-carbonyl]-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (106 mg, 0.36 mmol) in 10 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (205 mg, 0.54 mmol), (8 aR )-2,3,4,7,8, 8 a -Hexahydropyrrolo[1,2- a ]pyrazine-6-one 3f (55 mg, 0.39 mmol) and N,N-diisopropylethylamine (130 μL, 0.72 mmol). Concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent A purification system residues to give 4 - [[3 - [( 8 aR) -6- oxo -1,3,4,7,8,8 a - Hexahydropyrrolo[1,2- a ]pyrazine-2-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one 3 (30 mg, pale yellow solid) Rate: 20.0%.

MS m/z (ESI): 421.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.59 ( br . s, 1H), 8.27 (d, 1H), 7.78 (m, 3H), 7.45 (m, 3H), 4.62 (m, 1H) ), 4.33 (s, 2H), 4.08 (m, 1H), 3.75 (m, 1H), 3.52 (m, 1H), 3.17 (m, 1H), 2.89 (m, 4H), 2.27 (m, 2H)

Example 4

4-[[3-[1-benzyl-3,3 a ,4,6,7,7 a -hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carbonyl]-4- Fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

3-(2-methoxy-2-oxo-ethyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

4-Oxo-piperidine-1-carboxylic acid tert-butyl ester 4a (20 g, 100.50 mmol) was dissolved in 180 mL of tetrahydrofuran, and 2 M diisopropylamino lithium tetrahydrofuran / n-glycol was added at -78 °C. Alkyl/ethylbenzene solution (75 mL, 150 mmol) was stirred for 30 min. chloroacetic acid methyl ester (13 mL, 150 mmol) After adding 100 mL of water and extracting with ethyl acetate (200 mL×3), the organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent system B to give 3-(2-methoxy-2-oxo-ethyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester 4b (26.56 g , reddish brown oil), yield: 97.2%.

MS m/z (ESI): 172.1 [M-100+1]

Second step

Tert-butyl 4-hydroxy-3-(2-hydroxyethyl)piperidine-1-carboxylate

3-(2-methoxy-2-oxo-ethyl)-4-oxo-piperidine-1-carboxylic acid tert-butyl ester 4b (3 g, 11 mmol) was dissolved in 30 mL of tetrahydrofuran and added Lithium borohydride (730 mg, 33 mmol) was reacted at 40 ° C for 3 hours and at room temperature for 48 hours. Add 10 mL of saturated ammonium chloride solution, filter, and concentrate the filtrate under reduced pressure. Add 50 mL of ethyl acetate, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, The residue obtained was purified by eluent column chromatography eluting to afford 4-hydroxy-3-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester 4c (2.31 g, brown oil ), yield: 85.8%.

third step

4-methanesulfonyloxy-3-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester

3-Hydroxy-3-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester 4c (500 mg, 2.04 mmol) was dissolved in 15 mL dichloromethane and triethylamine (850 μL, 6.12 mmol) After stirring for 10 minutes in an ice bath, methanesulfonium chloride (380 μL, 4.89 mmol) was added and reacted for 1 hour. It was washed with a saturated ammonium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 4-methylsulfonyloxy-3-(2-methylsulfonyloxyethyl)piperidine. 1-butylic acid tert-butyl ester 4d (614 mg, light brown oil), yield: 75.0%.

the fourth step

1-benzyl-3,3 a ,4,6,7,7 a -hexahydro-2H-pyrrolo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester

4-Methanesulfonyloxy-3-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester 4d (305 mg, 0.76 mmol) was dissolved in benzylamine (407 mg, 3.80 mmol) In the reaction, the reaction was carried out at 70 ° C for 2.5 hours. 15 mL of ethyl acetate and 2.5 mL of 5 M sodium hydroxide solution were added, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by eluent column chromatography using eluent system A. To give 1-benzyl-3,3 a ,4,6,7,7 a -hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 4e (181 mg , pale yellow oil), Yield: 75.0%.

MS m/z (ESI): 317.2 [M+1]

the fifth step

1-benzyl-2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride

1-Benzyl-3,3 a ,4,6,7,7 a -hexahydro-2H-pyrrolo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 4e (181 mg, 0.57 mmol Dissolved in 2 mL of dichloromethane, and added 3 mL of 2M hydrogen chloride in 1,4-dioxane for 12 hours. Concentration under reduced pressure gave crude 1-benzyl-2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride 4f (181 mg, Yellow oil), the product was directly subjected to the next reaction without purification.

Step 6

4-[[3-[1-benzyl-3,3 a ,4,6,7,7 a -hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carbonyl]-4- Fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (115 mg, 0.38 mmol) in 6 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (260 mg, 0.68 mmol), crude 1-benzyl-2,3,3 a ,4, 5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride 4f (144 mg, 0.57 mmol) and N,N-diisopropylethylamine (350 μL, 1.90 mmol), Reaction for 12 hours. After adding 20 mL of water and extracting with dichloromethane (20 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4-[[3-[1-benzyl-3,3 a ,4,6,7,7 a -hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carbonyl]-4- fluoro - phenyl] methyl] -2 H - phthalazin-1-one 4 (38 mg, pale yellow solid), yield: 20.0%.

MS m/z (ESI): 497.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.50 ( br . s, 1H), 8.47 (d, 1H), 7.77 (m, 3H), 7.33 (m, 7H), 7.01 (m, 1H), 4.26 (s, 2H), 4.17 (m, 1H), 3.86 (m, 2H), 3.73 (s, 2H), 3.31 (m, 2H), 2.75 (m, 2H), 2.28 (s, 3H), 2.18 ( s, 1H), 4.97 (s, 1H)

Example 5

4 - [[4-fluoro-3- [1- (3-pyridylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [3,2- c] Pyridine-5-carbonyl]-phenyl]methyl]-2 H -pyridazin-1-one

first step

1-(3-pyridylmethyl)-3,3 a ,4,6,7,7 a -hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester

Dissolving 4-methylsulfonyloxy-3-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester 4d (719 mg, 1.79 mmol) in C -pyridin-3-yl- Methylamine (968 mg, 8.95 mmol) was reacted at 70 ° C for 2.5 hours. Add 30 mL of ethyl acetate, wash with 5M sodium hydroxide solution (20 mL × 3), separate the liquid, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. A system resulting residue was purified to give 1- (3-pyridylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [3,2- c] pyridine-5 - tert-butyl formate 5a (200 mg, light yellow oil), yield: 35.7%.

MS m/z (ESI): 318.2 [M+1]

Second step

1-(3-pyridylmethyl)-2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride

1-(3-Pyridylmethyl)-3,3 a ,4,6,7,7 a -hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 5a (200 mg, 0.63 mmol) was dissolved in 3 mL of dichloromethane, and 6 mL of 2M hydrogen chloride in 1,4-dioxane was added and reacted for 12 hours. Concentration under reduced pressure gave crude 1-(3-pyridylmethyl)-2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride 5b (181 mg, light yellow oil).

third step

4-- [[4-fluoro-3- [1- (3-pyridinylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [3,2- c] Pyridine-5-carbonyl]-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol) in 6 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (342 mg, 0.90 mmol), crude 1-(3-pyridylmethyl)-2,3, 3 a , 4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride 5b (160 mg, 0.63 mmol) and N,N-diisopropylethylamine (430 μL , 2.50 mmol), reaction for 12 hours. After adding 10 mL of water and extracting with ethyl acetate (15 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4 - [[4-fluoro-3- [1- (3-pyridylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [3,2- c] pyridine-5-carbonyl] - phenyl] methyl] -2 H - phthalazin-1-one 5 (20 mg, pale yellow solid), yield: 8.0%.

MS m/z (ESI): 498.4 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.90 ( br. s, 1H), 8.59 (m, 2H), 8.47 (d, 1H), 7.75 (m, 3H), 7.31 (m, 4H), 7.06 (m, 1H), 4.27 (s, 2H), 4.14 (m, 1H), 3.93 (m, 2H), 3.74 (m, 1H), 3.30 (m, 1H), 2.77 (m, 1H), 2.54 ( m,1H), 2.30 (m, 2H), 2.25 (m, 1H), 1.92 (s, 1H), 1.29 (m, 3H)

Example 6

8-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzylidene]-6,7,9,9 a -tetrahydro-1 H - Pyrazino[2,1- c ][1,4]oxazin-4-one

first step

4-benzyloxycarbonylpiperazine-2-carboxylic acid

Piperazine-2-carboxylic acid 6a (4 g, 30.70 mmol) was dissolved in 30 mL of water, 60 mL of copper sulfate pentahydrate (3.84 g, 15.35 mmol) was added, and 30 mL of benzyl chloroformate was added dropwise in an ice bath. mL, 36.90 mmol) of 1,4-dioxane solution. The pH of the reaction solution was adjusted to be greater than 7 (sodium bicarbonate was added as needed) and allowed to react at room temperature for 12 hours. Filtration, the filter cake was washed with ice water (10 mL), ethyl acetate (10 mL), ethyl acetate (10 mL), and dried in vacuo to give crude 4-benzyloxycarbonylpiperazine-2-carboxylic acid 6b (8 g, The blue solid), the product was directly subjected to the next reaction without purification.

Second step

Piperazine-1,3-dicarboxylic acid-1-benzyl ester-3-methyl ester

Add 30 mL of methanol to a 100 mL eggplant bottle, add dichlorohydrazine (2.7 mL, 37.50 mmol) dropwise on ice, stir for 30 minutes, and add the crude 4-benzyloxycarbonylpiperazine-2-carboxylic acid 6b (1.98). g, 7.50 mmol), refluxed for 3 hours, concentrated under reduced pressure to give crude piperazine-1,3-dicarboxylic acid 1-benzyl-3-carbomethoxy ester 6c (4.20 g, yellow oil), was used without Purification proceeds directly to the next reaction.

MS m/z (ESI): 279.1 [M+1]

third step

3-(hydroxymethyl)piperazine-1-carboxylic acid benzyl ester

The crude piperazine-1,3-dicarboxylic acid-1-benzyl ester-3-methyl ester 6c (4.20 g, 15 mmol) was dissolved in 20 mL of tetrahydrofuran, and the mixture was stirred, and then lithium borohydride (0.65 g, 30 mmol) ), react at room temperature for 12 hours. Add 10 mL of acetone, concentrate under reduced pressure, add 20 mL of water, extract with dichloromethane (20 mL×3), combine the organic phase, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter The filtrate was concentrated under reduced pressure to give 3-(hydroxymethyl)piperazine-1-carboxylic acid benzyl ester 6d (1.80 g, colourless oil).

MS m/z (ESI): 251.1 [M+1]

the fourth step

Benzyl 4-(2-chloroethyl)-3-(hydroxymethyl)piperazine-1-carboxylate

Benzyl 3-(hydroxymethyl)piperazine-1-carboxylate 6d (1.80 g, 7 mmol) was dissolved in dichloromethane (30 mL), and then triethylamine (3 mL, 21 mmol) 10 mL of chloroacetic acid chloride (0.6 mL, 8.40 mmol) in dichloromethane was reacted at room temperature for 2 hours. Add 30 mL of water, separate the liquid, extract the aqueous phase with dichloromethane (50 mL×3), combine the organic phases, and wash with saturated sodium bicarbonate solution (20 mL×2) and saturated sodium chloride solution (20 mL× 2) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and purifying the obtained residue by eluent column chromatography to afford 4-(2-chloroethyl) 3-(hydroxymethyl) Piperazine-1-carboxylate 6e (650 mg, colorless oil), yield: 28.0%.

MS m/z (ESI): 327 [M+1]

the fifth step

4-oxo-6,7,9,9a-tetrahydro-1 H -pyrazino[2,1- c ][1,4]oxazine-8-carboxylic acid benzyl ester

Benzyl 4-(2-chloroethenyl)-3-(hydroxymethyl)piperazine-1-carboxylate 6e (650 mg, 2 mmol) was dissolved in 5 mL of N,N-dimethylformamide Under ice bath, a mixture of sodium hydride and mineral oil (192 mg, 60%, 4 mmol) was added and allowed to react at room temperature for 12 hours. After adding 20 mL of water and extracting with ethyl acetate (50 mL × 3), the organic phase was combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, in the resulting purified chromatography developing solvent system B residue, to give 4-oxo -6,7,9,9 a - tetrahydro -1 H - pyrazino [2,1- c] [1,4] oxazine -8-Benzyl benzoate 6f (180 mg, white solid), yield: 31.0%.

MS m/z (ESI): 291.1 [M+1]

Step 6

1,6,7,8,9,9 a -hexahydropyrazino[2,1- c ][1,4]oxazin-4-one

4-oxo-6,7,9,9 a -tetrahydro-1 H -pyrazino[2,1- c ][1,4]oxazine-8-carboxylic acid benzyl ester 6f (180 mg, 0.62 Methyl) was dissolved in 20 mL of methanol, 50 mg of 10% palladium on carbon was added, and hydrogen was replaced three times for 4 hours. Filtration and concentration of the filtrate under reduced pressure gave crude 1,6,7,8,9,9 a -hexahydropyrazino[2,1- c ][1,4]oxazin-4-one 6 g (100 mg, The product was obtained as a colorless oil.

Seventh step

8-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzylidene]-6,7,9,9 a -tetrahydro-1 H - Pyrazino[2,1- c ][1,4]oxazin-4-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1 c (150 mg, 0.50 mmol) in 5 mL of N,N-dimethyl To the guanamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), crude 1,6,7,8,9,9 a - Hexahydropyrazino[2,1- c ][1,4]oxazin-4-one 6g (100 mg, 0.64 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol), Reaction for 12 hours. After adding 20 mL of water and extracting with dichloromethane (20 mL×3), the organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate Chromatography to purify the obtained residue in the solvent system A to give 8-[2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl]-6. 7,9,9 a -tetrahydro-1 H -pyrazino[2,1- c ][1,4]oxazin-4-one 6 (200 mg, white solid), yield: 92.0%.

MS m/z (ESI): 437.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.45 ( br . s, 1H), 8.49-8.46 (m, 1H), 7.81-7.70 (m, 3H), 7.39-7.34 (m, 2H), 7.10- 7.03(m,1H), 4.68-4.58(m,2H), 4.29(s,2H), 4.20-4.05(m,3H),3.74-3.38(m,4H),3.21-3.18(m,1H), 2.78-2.68(m,1H)

Example 7

4-[[3-(1,3,3 a ,4,5,6,7,7 a -octahydroisoindol-2-carbonyl)-4-fluoro-phenyl]methyl]-2 H - Pyridazine-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol) in 20 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol), octahydro-isoindole (75 mg, 0.60 mmol) and N were added. N-diisopropylethylamine (0.2 mL, 1 mmol) was reacted for 12 hours. Concentration under reduced pressure, and the residue obtained was purified by a thin layer chromatography to afford 4-[[3-(1,3,3 a ,4,5,6,7,7 a - octahydroisoindole). 2-carbonyl) -4-fluoro - phenyl] methyl] -2 H - phthalazin-1 -one 7 (76 mg, white solid), yield: 37.6%.

MS m/z (ESI): 406.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.02 ( br . s, 1H), 8.51 (d, 1H), 7.82 (m, 3H), 7.60 (m, 1H), 7.39 (m, 1H), 7.07 (m, 1H), 4.31 (s, 2H), 4.25 (m, 1H), 3.74 (m, 1H), 3.53 (m, 3H), 3.32 (m, 1H), 3.20 (m, 2H), 3.16 ( m, 2H), 2.35 (m, 2H), 1.57 (m, 2H)

Example 8

4-[[3-(5,7-Dihydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]-benzoic acid 1c (150 mg, 0.50 mmol) in 10 mL of N,N-dimethyl In the decylamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), 6,7-dihydro-5 H -pyrrolo[3, 4- B ]pyridine hydrochloride (116 mg, 0.60 mmol) and N,N-diisopropylethylamine (350 μL, 2 mmol). Add 30 mL of water, extract with methylene chloride (50 mL × 3), and combine the organic phase, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, Chromatography to purify the obtained residue in the solvent system A to give 4-[[3-(5,7-dihydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl] Base]-2 H -phthalazin-1-one 8 (200 mg, white solid), yield: 100.0%.

MS m/z (ESI): 401.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.45 ( br. s, 1H), 8.56-8.43 (m, 2H), 7.82-7.62 (m, 4H), 7.53-7.35 (m, 2H), 7.31 7.18 (m, 1H), 7.12-7.08 (m, 1H), 5.01 (S, 2H), 4.67 (s, 2H), 4.30 (s, 2H)

Example 9

4-[[3-(3,3 a ,4,6,7,7a-hexahydro-2 H -furo[3,2- c ]pyridine-5-carbonyl)-4-fluoro-phenyl]- ]]-2 H -pyridazin-1-one

first step

3-hydroxy-3-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester

Dissolving 3-hydroxy-3-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester 4c (550 mg, 2.24 mmol) in 5 mL of dichloromethane, and adding N,N-diisopropyl Ethylamine (0.8 mL, 4.48 mmol) was stirred in an ice-bath for 10 min, and then succinyl chloride (260 μL, 2.47 mmol) was added and allowed to react at room temperature for 2 hours. Washed with a saturated aqueous solution of ammonium chloride (1 mL), dried over anhydrous sodium sulfate, filtered, filtered, evaporated, evaporated. T-butyl 2-methylsulfonyloxyethyl)piperidine-1-carboxylate 9a (50 mg, yellow oil), yield: 6.9%.

MS m/z (ESI): 224 [M-100+1]

Second step

3,3 a ,4,6,7,7 a -hexahydro-2 H -furo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester

Dissolve tert-butyl 4-hydroxy-3-(2-methanesulfonyloxyethyl)piperidine-1-carboxylate 9a (800 mg, 2.50 mmol) in 10 mL of tetrahydrofuran, add sodium hydride under ice bath Mix with mineral oil (119 mg, 60%, 3 mmol) for 3 hours. Add 0.5 mL of a saturated ammonium chloride solution, concentrate under reduced pressure, and purify the residue by eluent column chromatography using eluent column chromatography to give 3,3 a , 4,6,7,7 a -hexahydro-2 H -furo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 9b (200 mg, colorless oil), yield: 35.0%.

MS m/z (ESI): 128.2 [M-100+1]

third step

2,3,3 a ,4,5,6,7,7 a -octahydrofuro[3,2- c ]pyridine hydrochloride

Dissolve 3,3 a , 4,6,7,7a-hexahydro-2 H -furo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 9b (200 mg, 0.10 mmol) in 2 mL In a solution of 2 M hydrogen chloride in 1,4-dioxane, the reaction was carried out for 12 hours. Concentration under reduced pressure gave crude 2,3,3 a ,4,5,6,7,7 a- octahydrofuro[3,2- c ]pyridine hydrochloride 9c (181 mg, pale yellow oil) The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 128.1 [M+1]

the fourth step

4-[[3-(3,3 a ,4,6,7,7 a -hexahydro-2 H -furo[3,2- c ]pyridine-5-carbonyl)-4-fluoro-phenyl] Methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), crude 2,3,3 a ,4,5,6,7 , 7 a - octahydro-furo [3,2- c] pyridine hydrochloride 9c (76 mg, 0.60 mmol) and N, N- diisopropylethylamine (360μL, 2 mmol), for 12 hours. After adding 20 mL of water and extracting with dichloromethane (20 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4-[[3-(3,3 a ,4,6,7,7 a -hexahydro-2 H -furo[3,2- c ]pyridine-5-carbonyl)-4-fluoro-phenyl] methyl] -2 H - phthalazin-1-one 9 (40 mg, white solid), yield: 20.0%.

MS m/z (ESI): 408.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.06 ( br . s, 1H), 8.45-8.47 (m, 1H), 7.73-7.79 (m, 3H), 7.27-7.32 (m, 2H), 7.00 -7.05 (m, 1H), 5.57 (m, 1H), 4.27 (s, 2H), 4.21 (m, 1H), 3.71-3.74 (m, 2H), 2.28-2.33 (m, 4H), 1.26-1.30 (m, 4H)

Example 10

7-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzylidene]-5,6,8,8 a -tetrahydro-1 H - Oxazo[3,4- a ]pyrazin-3-one

first step

3-oxo-5,6,8,8 a -tetrahydro-1 H -oxazolo[3,4- a ]pyrazine-7-carboxylic acid benzyl ester

Benzyl 3-(hydroxymethyl)piperazine-1-carboxylate 6d (500 mg, 2 mmol) was dissolved in 30 mL of 1,2-dichloroethane and N,N-diisopropylethylamine was added ( 0.5 mL, 3 mmol). Triphosgene (296 mg, 1 mmol) was added and reacted at 50 ° C for 12 hours. Add 30 mL of water, separate the liquid, extract the aqueous phase with dichloromethane (50 mL × 3), combine the organic phase, wash with saturated sodium chloride solution (25 mL × 2), dry over anhydrous sodium sulfate, filter, filtrate decompression Concentration to give the crude 3-oxo-5,6,8,8 a -tetrahydro-1 H -oxazolo[3,4- a ]pyrazine-7-carboxylic acid benzyl ester 10a (551 mg, colorless oil The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 277.1 [M+1]

Second step

1,5,6,7,8,8 a -hexahydrooxazolo[3,4- a ]pyrazin-3-one

Dissolve the crude 3-oxo-5,6,8,8 a -tetrahydro-1 H -oxazolo[3,4- a ]pyrazine-7-carboxylic acid benzyl ester 10 a (551 mg, 2 mmol) 100 mg of 10% palladium on carbon was added to 50 mL of methanol, and hydrogen was replaced three times for 3 hours. Filtration and concentration of the filtrate under reduced pressure afforded crude, 1,5,6,7,8,8 a -hexahydrooxazole [3,4- a ]pyrazin-3-one 10b (284 mg, colorless oil) The product was directly subjected to the next reaction without purification.

third step

7-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzylidene]-5,6,8,8 a -tetrahydro-1 H - Oxazo[3,4- a ]pyrazin-3-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), crude 1,5,6,7,8,8 a -6 Hydrocarbazolo[3,4- a ]pyrazin-3-one 10b (150 mg, 1 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol) were reacted for 12 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc) The resulting residue was purified by thin layer chromatography using a solvent system A to give 7-[2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl ] -5,6,8,8 a - tetrahydro -1 H - oxazolo [3,4- a] pyrazin-3-one 10 (65 mg, white solid), yield: 31.0%.

MS m/z (ESI): 423.1 [M+1]

¹H NMR (400 MHz, CDCl₃): δ 10.52 (Br. s,,1H), 8.51-8.49 (m, 1H), 7.84-7.78 (m, 3H), 7.45-7.39 (m, 2H), 7.18-7.10 (m, 1H), 4.95-4.82 (m, 1H) , 4.57-4.47 (m, 1H), 4.35 (s, 2H), 4.12-3.54 (m, 5H), 3.21-3.15 (m, 2H)

Example 11

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl] Methyl]-2 H -pyridazin-1-one

first step

6-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a ,5,7,7 a -6 Hydrogen-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol) in 20 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol), octahydro-pyrrolo[3,4- b ]pyridine-1 was added. -T-butyl formate (136 mg, 0.60 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol). Concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give 6- [2-fluoro-5 - [(4-oxo -3 H - phthalazin-1-yl) methyl] benzene Methotyl]-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester 11a (58 mg, brown oil The yield was 23.0%.

MS m/z (ESI): 407.2 [M-100+1]

Second step

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl] Methyl]-2 H -pyridazin-1-one

6-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a ,5,7,7 a - Hexahydro- 2H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester 11a (58 mg, 0.11 mmol) was dissolved in 2 mL of 2M hydrogen chloride in 1,4-dioxane. 12 hours. The saturated sodium bicarbonate solution was added dropwise until the pH of the reaction mixture was 9 and extracted with dichloromethane (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate and filtered The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel eluting to afford 4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrole). and [3,4- b] pyridine-6-carbonyl) -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 11 (5 mg, white solid), yield: 10.9%.

MS m/z (ESI): 407.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.03 ( br . s, 1H), 8.50 (d, 1H), 7.82 (m, 3H), 7.30 (m, 1H), 7.29 (m, 1H), 7.01 (m, 1H), 4.31 (s, 2H), 4.16 (m, 1H), 3.76 (m, 4H), 3.25 (m, 3H), 3.07 (m, 2H), 2.70 (m, 1H), 2.09 ( m, 2H)

Example 12

4-[[3-(3,3 a ,4,6,7,7 a -hexahydro-2 H -thieno[3,2- c ]pyridine-5-carbonyl)-phenyl]methyl]- 2 H -pyridazine-1-one

first step

6,7-dihydro-4 H -thieno[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester

Dissolve 4,5,6,7-tetrahydrothieno[3,2- c ]pyridine 12a (1 g, 5.70 mmol) in 30 mL of dichloromethane and add N,N-diisopropylethylamine ( 3 mL, 17.10 mmol) and di-tert-butyl dicarbonate (3.10 g, 14.20 mmol) were reacted for 2 hours. Add 30 mL of saturated ammonium chloride solution, extract with methylene chloride (50 mL×2), and combine the organic phase, washed with saturated sodium chloride solution (25 mL×2), dried over anhydrous sodium sulfate The crude product, 6,7-dihydro- 4H -thieno[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 12b (1.40 g, m. reaction.

Second step

3,3 a ,4,6,7,7 a -hexahydro-2 H -thieno[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester

The crude 6,7-dihydro- 4H -thieno[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 12b (500 mg, 2.10 mmol) was dissolved in 30 mL of methanol and 20% hydr. Palladium on carbon (1.62 g, 2.30 mmol), three times in hydrogen, and reacted at 50 ° C for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded 3,3 a ,4,6,7,7 a -hexahydro- 2H -thieno[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 12c (50 mg , colorless oil), yield: 10.0%.

MS m/z (ESI): 188.1 [M-56+1]

third step

2,3,3 a ,4,5,6,7,7 a -octahydrothieno[3,2- c ]pyridine hydrochloride

3,3 a , 4,6,7,7 a -hexahydro-2 H -thieno[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 12c (200 mg, 0.82 mmol) was dissolved in 3 In a solution of mL 2 M hydrogen chloride in 1,4-dioxane, the reaction was carried out for 12 hours. Concentration under reduced pressure gave crude 2,3,3 a ,4,5,6,7,7 a- octahydrothieno[3,2- c ]pyridine hydrochloride 12d (118 mg, white solid) The next reaction was carried out directly by purification.

MS m/z (ESI): 144.1 [M+1]

the fourth step

4-[[3-(3,3 a ,4,6,7,7 a -hexahydro-2 H -thieno[3,2- c ]pyridine-5-carbonyl)-phenyl]methyl]- 2 H -pyridazine-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol) in 10 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), crude 2,3,3 a ,4,5,6,7 , 7 a - octahydro-thieno [3,2- c] pyridine hydrochloride 12d (65 mg, 0.45 mmol) and N, N- diisopropylethylamine (260μL, 1.50 mmol), for 12 hours. After concentration under reduced pressure, a solution of 20 mL of saturated aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane (50 mL×2). The organic phase was combined and washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography to afford 4-[[3-(3,3 a ,4,6,7,7 a -hexahydro- 2H -thiophene) [3,2- c] pyridine-5-carbonyl) - phenyl] methyl] -2 H - phthalazin-1-one 12 (60 mg, white solid), yield: 28.0%.

MS m/z (ESI): 424.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.61 ( br . s, 1H), 8.46-8.49 (m, 1H), 7.71-7.78 (m, 3H), 7.29-7.31 (m, 2H), 7.01 -7.05 (m, 1H), 4.29 (s, 2H), 3.46-3.75 (m, 4H), 2.81-3.25 (m, 4H), 1.74-2.47 (m, 4H)

Example 13

4-[[3-(1,1-dioxo-3,3 a ,4,6,7,7 a -hexahydro-2 H -thieno[3,2- c ]pyridine-5-carbonyl) -4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(3,3 a ,4,6,7,7 a -hexahydro-2 H -thieno[3,2- c ]pyridine-5-carbonyl)-phenyl]methyl] -2 H -phthalazin-1-one 12 (20 mg, 0.05 mmol) was dissolved in 10 mL acetonitrile and 5 mL water was added. Potassium peroxymonosulfate complex salt (87 mg, 0.14 mmol) and sodium carbonate (45 mg, 0.42 mmol) were mixed and added to the above solution in portions for 4 hours. Add 50 mL of dichloromethane, stir for 10 minutes, separate the liquid, and extract the aqueous phase with dichloromethane (15 mL). The organic phase is combined and concentrated under reduced pressure to give 4-[[3-(1,1-dioxo-) 3,3 a ,4,6,7,7 a -hexahydro-2 H -thieno[3,2- c ]pyridine-5-carbonyl)-4-fluoro-phenyl]methyl]-2 H - Pyridazin-1-one 13 (22 mg, white solid), yield: 96.5%.

MS m/z (ESI): 456.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.57 ( br. s, 1H), 8.24 - 8.26 (m, 1H), 7.82-7.97 (m, 3H), 7.39-7.43 (m, 2H), 7.20- 7.25 (m, 1H), 4.31-4.33 (m, 2H), 2.68-3.37 (m, 6H), 1.22-1.98 (m, 6H)

Example 14

4-[[3-(3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazin-6-carbonyl)-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

3-bromo-4-(2-hydroxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

2,5-Dihydropyrrole-1-carboxylic acid tert-butyl ester 14a (9.50 g, 56.14 mmol, prepared by a known method " Organic Process Research & Development, 2009, 13(3), 638-640 ") Dissolved in 50 mL of ethylene glycol, N-bromosinium imine (10.99 g, 61.75 mmol) was added in 10 portions and reacted for 12 hours. After adding 100 mL of water and extracting with ethyl acetate (100 mL × 3), the organic phase was combined, washed with saturated sodium chloride solution (25 mL × 2), dried over anhydrous sodium sulfate, filtered, Bromo-4-(2-hydroxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester 14b (12 g, reddish brown oil), yield: 72.3%.

MS m/z (ESI): 254 [M-56+1]

Second step

3-bromo-4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1-carboxylic acid tert-butyl ester

3-Bromo-4-(2-hydroxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester 14b (12 g, 38.69 mmol) was dissolved in 100 mL of toluene and triethylamine (8.1 mL, 58.03 mmol) And 4-dimethylaminopyridine (0.50 g, 4 mmol), p-toluenesulfonyl chloride (10.06 g, 58.03 mmol) was added and the mixture was reacted for 12 hours. Add 100 mL of water, separate the liquid, and extract the aqueous phase with ethyl acetate (100 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (25 mL×2), dried over anhydrous sodium sulfate Concentration, the residue obtained was purified by eluent column chromatography using eluent system B to give 3-bromo-4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1-carboxylic acid. Tributyl ester 14c (14.30 g, colorless oil), yield: 79.6%.

third step

4-benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester

3-Bromo-4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1-carboxylic acid tert-butyl ester 14c (14.30 g, 30.78 mmol) was dissolved in 80 mL of p-xylene Benzylamine (3.30 g, 30.78 mmol) was added and reacted at 140 ° C for 5 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc) , 4-benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester 14d (7.50 g, light brown oil), yield: 76.0%.

MS m/z (ESI): 319.2 [M+1]

the fourth step

4-benzyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine

4-Benzyl--2,3,4 a, 5,7,7 a - hexahydro - pyrrolo [3,4- b] [1,4] oxazine-6-carboxylic acid tert-butyl ester 14d (500 Mg, 1.57 mmol) was dissolved in 10 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added for 2 hours. Concentrate under reduced pressure, add 10 mL of saturated sodium bicarbonate solution, and extract with dichloromethane (20 mL×2), and the organic phase is combined, washed with saturated sodium chloride solution (15 mL×2), dried over anhydrous sodium sulfate, filtered, filtrate Concentration under reduced pressure gave crude 4-benzyl-3,4 a ,5,6,7,7 a -hexahydro- 2H -pyrrolo[3,4- b ][1,4]oxazine 14e (340 Mg, colorless oil), the product was taken to the next step without purification.

the fifth step

4-[[3-(4-benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carbonyl)- 4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.50 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol), crude 4-benzyl-3,4 a ,5,6, 7,7 a -Hexahydro- 2H -pyrrolo[3,4- b ][1,4]oxazine 14e (220 mg, 1 mmol) and N,N-diisopropylethylamine (0.2 mL, 1 mmol), reaction for 12 hours. Add 20 mL of water, extract with methylene chloride (50 mL × 3), and combine the organic phase, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, A purification chromatography using a developing solvent system resulting residue, to give 4 - [[3- (4-benzyl--2,3,4 a, 5,7,7 a - hexahydro-pyrrolo [3,4- b] [1,4] oxazine-6-carbonyl) -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 14f (200 mg, white solid), yield: 80.0%.

MS m/z (ESI): 499.2 [M+1]

Step 6

4-[[3-(3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazin-6-carbonyl)-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(4-benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carbonyl) -4-Fluoro-phenyl]methyl]-2 H -phthalazin-1-one 14f (200 mg, 0.40 mmol) was dissolved in 30 mL of methanol, 20 mg 10% palladium/carbon was added, and hydrogen was replaced three times, 35 The reaction was carried out at ° C for 3 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography to afford 4-[[3-(3,4,4 a ,5,7,7 a -hexahydro-2 H - Pyrrolo[3,4- b ][1,4]oxazin-6-carbonyl)-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one 14 (45 mg, white solid) , Yield: 27.0%.

MS m/z (ESI): 409.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.51 ( br. s, 1H), 8.45-8.49 (m, 1H), 7.70-7.81 (m, 3H), 7.37-7.41 (m, 1H), 7.26- 7.31 (m, 1H), 6.99-7.06 (m, 1H), 4.28 (d, 2H), 3.95-4.10 (m, 1H), 3.81-3.90 (m, 1H), 3.67-3.78 (m, 2H), 3.47-3.64 (m, 3H), 3.22-3.36 (m, 1H), 3.01-3.21 (m, 1H), 2.64-2.75 (m, 1H)

Example 15

4 - [[4-fluoro-3- [2 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [ 3,4- c ]pyridine-5-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one

first step

2 - [[(4-methoxyphenyl) methyl] -3,3 a, 4,5,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridine-6 ketone

Dissolve 1,2,3,4,5,7,7a-octahydropyrrolo[3,4- c ]pyridin-6-one 1b (300 mg, 2.14 mmol) in 10 mL of acetonitrile and add 1-( Bromomethyl)-4-methoxy-benzene (644 mg, 3.21 mmol) and potassium carbonate (886 mg, 6.42 mmol) were reacted at 80 ° C for 4 hours. Filtered, and the filtrate was concentrated under reduced pressure to give 2 - [[(4-methoxyphenyl) methyl] -3,3 a, 4,5,7,7 a - hexahydro -1 H - pyrrolo [3, 4- c ]pyridine-6-one 15a (700 mg, light brown solid), yield: 100.0%.

MS m/z (ESI): 261.1 [M+1]

Second step

2-[(4-Methoxyphenyl)methyl]-1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine

2 - [[(4-methoxyphenyl) methyl] -3,3 a, 4,5,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridine-6 The ketone 15a (200 mg, 0.52 mmol) was dissolved in 12 mL of tetrahydrofuran, lithium aluminum hydride (50 mg, 1.16 mmol) was added, and the reaction was carried out at 70 ° C for 2 hours, and the reaction was continued at 50 ° C for 12 hours. Add 0.1 mL of water and 0.1 mL of 10% sodium hydroxide solution, centrifuge, and concentrate the supernatant under reduced pressure to give 2-[(4-methoxyphenyl)methyl]-1,3,3 a ,4,5 , 6,7,7 a - octahydro-pyrrolo [3,4- c] pyridin-15b (127 mg, light brown oil) yield: 67.1%.

MS m/z (ESI): 247.2 [M+1]

third step

4 - [[4-fluoro-3- [2 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [ 3,4- c ]pyridine-5-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (130 mg, 0.43 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (290 mg, 0.78 mmol), 2-[(4-methoxyphenyl)methyl] -1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine 15b (127 mg, 0.52 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.29 mmol), reaction for 12 hours. After adding 15 mL of water and extracting with ethyl acetate (15 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. - [[4-fluoro-3- [2 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3 , 4- c ]pyridine-5-carbonyl]phenyl]methyl]-2 H -phthalazin-1-one 15 (21 mg, pale yellow solid), yield: 9.5%.

MS m/z (ESI): 527.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.6 ( br. s, 1H), 8.48 (d, 1H), 7.72 (m, 3H), 7.27 (m, 3H), 7.01 (dd, 1H), 6.92(d,1H), 6.86(m,2H), 4.28(s,2H), 3.78(m,5H), 3.64(m,2H), 3.31(m,2H),2.91(m,2H),2.58 (m, 2H), 2.42 (m, 2H), 2.23 (m, 1H), 1.90 (m, 1H)

Example 16

4-[[4-fluoro-3-(2-methyl-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-5-carbonyl Phenyl]methyl]-2 H -pyridazin-1-one

first step

6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester

Dissolve 1,2,3,4,5,7,7 a -octahydropyrrolo[3,4- c ]pyridin-6-one 1b (300 mg, 2.14 mmol) in 12 mL of dichloromethane and add N,N-Diisopropylethylamine (0.7 mL, 4.18 mmol) and di-tert-butyl dicarbonate (560 mg, 2.57 mmol) were reacted for 12 hours. Add 5 mL of water, extract with methylene chloride (10 mL × 3), combine the organic phase, wash with a saturated sodium chloride solution (30 mL × 2), dry over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified by column chromatography using eluent system A to give 6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine. 2-butylic acid tert-butyl ester 16a (406 mg, yellow solid), yield: 78.9%.

Second step

2-methyl-1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine

6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 16a (300 mg, 1.24 Methyl) was dissolved in 15 mL of tetrahydrofuran, lithium aluminum hydride (194 mg, 5.24 mmol) was added, and the reaction was carried out at 70 ° C for 2 hours, and the reaction was continued at 50 ° C for 12 hours. Add 0.5 mL of water and 0.5 mL of 10% sodium hydroxide solution, centrifuge, and concentrate the supernatant under reduced pressure to give 2-methyl-1,3,3 a ,4,5,6,7,7 a -octahydropyrrole. [3,4- c ]pyridine 16b (130 mg, colorless oil), yield: 76.0%.

MS m/z (ESI): 141.2 [M+1]

third step

4-[[4-fluoro-3-(2-methyl-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-5-carbonyl Phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1 c (260 mg, 0.89 mmol) in 10 mL of N,N-dimethyl To the guanamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (600 mg, 1.60 mmol), 2-methyl-1,3,3 a ,4, 5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine 16b (150 mg, 1.10 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.25 mmol), reaction 12 hour. Concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent A purification system residues to give 4 - [[4-fluoro-3- (2-methyl -3,3 a, 4,6,7,7 a - Hexahydro-1 H -pyrrolo[3,4- c ]pyridine-5-carbonyl)phenyl]methyl]-2 H -phthalazin-1-one 16 (83 mg, pale yellow solid), yield: 19.2%.

MS m/z (ESI): 421.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 8.37 (d, 1H), 7.94 (d, 1H), 7.85 (m, 2H), 7.47 (m, 1H), 7.31 (m, 1H), 7.15 ( t,1H), 4.38 (S, 2H), 3.73 (m, 1H), 3.42 (m, 1H), 3.16 (m, 1H), 2.91 (m, 2H), 2.56 (m, 2H), 2.40 (m) , 2H), 2.32 (s, 3H), 2.10 (m, 1H), 1.90 (m, 1H), 1.73 (m, 1H)

Example 17

4-[[3-[1(cyclopropylcarbonyl)-3,4,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ]pyridine-6-carbonyl]-4-fluoro -phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 11 (100 mg, 0.25 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (68 μL, 0.50 mmol) was added, and cyclopropyl hydrazine chloride was added at 0 °C. (33 μL, 0.37 mmol), reacted for 1 hour. After adding 20 mL of water and extracting with dichloromethane (20 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4-[[3-[1(cyclopropylcarbonyl)-3,4,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ]pyridine-6-carbonyl]-4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 17 (10 mg, white solid), yield: 8.6%.

MS m/z (ESI): 475.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.27 ( br . s, 1H), 8.51 (d, 1H), 7.82 (m, 3H), 7.41 (m, 1H), 7.30 (m, 2H), 4.32 (s, 2H), 4.15 (m, 1H), 3.86 (m, 2H), 3.68 (m, 2H), 3.53 (m, 1H), 3.10 (m, 1H), 3.01 (m, 1H), 2.32 ( m,1H), 1.92 (m, 4H), 1.04 (m, 2H), 0.85 (m, 2H)

Example 18

4-[[4-fluoro-3-(4-methyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6 -carbonyl)-phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazin-6-carbonyl)- 4-Fluoro-phenyl]methyl]-2 H -phthalazin-1-one 14 (38 mg, 0.10 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and 40% formaldehyde solution (21 μL, 0.30 mmol). After stirring for 2 hours, sodium triethoxysulfonate hydride (64 mg, 0.30 mmol) was added and the mixture was reacted for 12 hours. Add 30 mL of water, extract with methylene chloride (50 mL×3), and combine with EtOAc (EtOAc) The obtained residue was purified with a developing solvent system A to give 4-[[4-fluoro-3-(4-methyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b] [1,4] oxazine-6-carbonyl) - phenyl] methyl] -2 H - phthalazin-1-one 18 (21 mg, white solid), yield: 50.0%.

MS m/z (ESI): 423.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.43-8.49 (m, 1H), 7.68-7.79 (m, 3H), 7.27-7.42 (m, 2H), 6.98-7.08 (m, 1H), 5.67 ( d,1H), 4.25-4.32 (m, 2H), 4.00-4.16 (m, 1H), 3.82-3.92 (m, 1H), 3.74-3.81 (m, 1H), 3.57-3.74 (m, 3H), 3.36-3.52(m,1H),3.23-3.34(m,1H), 2.59-2.76(m,1H),2.42(s,3H)

Example 19

4-[[4-fluoro-3-[1-(pyrrolidin-2-carbonyl)-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b Pyridine-6-carbonyl]-phenyl]methyl]-2 H -pyridazin-1-one

first step

Pyrrolidine-2-carboxylic acid-1-carboxylic acid tert-butyl ester

Pyrrolidine-2-carboxylic acid 19a (6 g, 50 mmol) was dissolved in 30 mL of methanol, then triethylamine (22 mL, 160 mmol) 78 mmol), react at room temperature for 5 hours. Concentration under reduced pressure gave the crude pyridane-2-carboxylic acid-l-carboxylic acid tert-butyl ester 19b (11 g, colorless oil).

Second step

2-[6-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a ,5,7,7 A -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carbonylpyrrolidin-1-carboxylic acid tert-butyl ester

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 11 (110 mg, 0.27 mmol) was dissolved in 10 mL of N,N-dimethylformamide and benzotriazole-N,N,N' was added. , N'-tetramethylurea hexafluorophosphate (152 mg, 0.40 mmol), crude pyrrolidine-2-carboxylic acid-1-carboxylic acid tert-butyl ester 19b (117 mg, 0.54 mmol) and N,N-diiso Propylethylamine (0.1 mL, 0.54 mmol) was reacted for 12 hours. Add 30 mL of water, extract with ethyl acetate (50 mL × 3), and combine the organic phases, and then wash with a saturated aqueous solution of ammonium chloride (50 mL) and saturated sodium chloride (50 mL) The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography to afford 2-[6-[2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl) )methyl]benzimidyl]-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carbonyl]pyrrolidine-1- T-butyl formate 19c (100 mg, white solid), yield: 61.0%.

MS m/z (ESI): 604.3 [M+1]

third step

4-[[4-fluoro-3-[1-(pyrrolidin-2-carbonyl)-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b Pyridine-6-carbonyl]-phenyl]methyl]-2 H -pyridazin-1-one

2-[6-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzylidene]-3,4,4 a ,5,7, 7 a - hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carbonylpyrrolidin-1-carboxylic acid tert-butyl ester 19c (100 mg, 0.16 mmol) dissolved in 30 mL of 2M hydrogen chloride 1 In a 4-dioxane solution, the reaction was carried out for 12 hours. The organic layer was concentrated under reduced pressure. The resulting residue was purified to give 4-[[4-fluoro-3-[1-(pyrrolidin-2-carbonyl)-3,4,4 a ,5,7,7 a -hexahydro-2 H. - pyrrolo [3,4- b] pyridine-6-carbonyl] - phenyl] methyl] -2 H - phthalazin-1-one 19 (32 mg, white solid), yield: 38.6%.

MS m/z (ESI): 504.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.39-8.48 (m, 1H), 7.70-7.86 (m, 3H), 7.28-7.45 (m, 2H), 7.00-7.10 (m, 1H), 4.28 (s, 2H), 3.72-3.85 (m, 1H), 3.56-3.71 (m, 3H), 3.40-3.55 (m, 2H), 2.95-3.15 (m, 1H), 2.44-2.71 (m, 1H) , 2.00-2.34 (m, 3H), 1.69-1.97 (m, 9H)

Example 20

4 - [[4-fluoro-3- [1 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [ 3,2- c ]pyridine-5-carbonyl]-phenyl]methyl]-2 H -pyridazin-1-one

first step

1 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [3,2- c] pyridine-5-carboxylic acid Third butyl ester

4-Methanesulfonyloxy-3-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester 4d (250 mg, 0.62 mmol) was dissolved in 5 mL of tetrahydrofuran and added (4 -Methoxyphenyl)methanamine (256 mg, 1.87 mmol), reacted under microwave conditions at 120 °C for 20 min. After cooling to room temperature, 50 mL of ethyl acetate was added, and washed with 5 M sodium hydroxide solution (15 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A resulting residue was purified to give 1 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [3,2 c ] Pyridin-5-carboxylic acid tert-butyl ester 20a (170 mg, colorless oil), yield: 79.0%.

MS m/z (ESI): 347.2 [M+1]

Second step

1-[(4-Methoxyphenyl)methyl]-2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride

1 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [3,2- c] pyridine-5 The third butyl formate 20a (130 mg, 0.38 mmol) was dissolved in 1.5 mL of dichloromethane, and 1.5 mL of a 2M solution of hydrogen chloride in 1,4-dioxane was added and reacted for 12 hours. Concentration under reduced pressure gave the crude 1-[(4-methoxyphenyl)methyl]-2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c Pyridine hydrochloride 20b (92 mg, light yellow oil).

MS m/z (ESI): 247.1 [M+1]

third step

4 - [[4-fluoro-3- [1 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [ 3,2- c ]pyridine-5-carbonyl]-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1 c (100 mg, 0.31 mmol) in 5 mL of N,N-dimethyl To the guanamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (118 mg, 0.56 mmol), crude 1-[(4-methoxyphenyl) A was added. 2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride 20b (92 mg, 0.38 mmol) and N,N-di Isopropylethylamine (270 μL, 0.94 mmol) was reacted for 12 hours. After adding 20 mL of water and extracting with ethyl acetate (15 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4 - [[4-fluoro-3- [1 - [(4-methoxyphenyl) methyl] -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [ 3,2- c ]pyridine-5-carbonyl]-phenyl]methyl]-2 H -phthalazin-1-one 20 (13 mg, pale yellow solid).

MS m/z (ESI): 527.3 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.83 (m, 2H), 7.51 (m, 1H), 7.43 (m, 2H), 7.28 (d, 1H), 7.17 (m, 1H), 7.01 (m, 2H), 4.37 (s, 2H), 4.17 (m, 3H), 3.82 (s, 2H), 3.75 (m, 1H), 3.08 ( m, 2H), 2.42 (m, 2H), 2.19 (m, 1H), 1.95 (m, 1H), 1.30 (m, 5H)

Example 21

4-[[4-fluoro-3-(5-methyl-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl Phenyl]methyl]-2 H -pyridazin-1-one

first step

5-methyl-6-oxo-1,3,3 a ,4,7,7 a -hexahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester

6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 16a (12.79 g, 53.20 Methyl acetate was dissolved in 30 mL of N,N-dimethylformamide, and a mixture of sodium hydride and mineral oil (2.34 g, 60%, 58.50 mmol) was added in an ice bath, stirred for 30 minutes, and methyl iodide (10 mL, 15.90 mmol), react for 3 hours. Concentrated under reduced pressure, added 20 mL of ice water, extracted with ethyl acetate (20 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. A resulting residue was purified to give 5-methyl-6-oxo -1,3,3 a, 4,7,7 a - hexahydro-pyrrolo [3,4- c] pyridine-2-carboxylic acid tertiary butyl Ester 21a (6.35 g, pale yellow oil), yield: 47.1%.

MS m/z (ESI): 199.1 [M-56+1]

Second step

5-methyl-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-6-one hydrochloride

5-methyl-6-oxo-1,3,3 a ,4,7,7 a -hexahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 21a (80 mg, 0.32 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of 2 M hydrogen chloride in 1,4-dioxane was added and reacted for 12 hours. Concentration under reduced pressure gave crude 5-methyl-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-6-one hydrochloride 21b ( 50 mg, white solid), the product was taken to the next step without purification.

third step

5-methyl-1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine

The crude 5-methyl-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-6-one hydrochloride 21b (49 mg, 0.32 Methyl) was dissolved in 5 mL of tetrahydrofuran, lithium aluminum hydride (50 mg, 1.26 mmol) was added, and the reaction was carried out at 70 ° C for 3 hours, and the reaction was continued at 50 ° C for 12 hours. 50 mL of dichloromethane, 0.5 mL of water and 0.5 mL of 10% sodium hydroxide solution were added, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 5-methyl-1,2,3,3 a ,4 , 6,7,7 a - octahydro-pyrrolo [3,4- c] pyridin-21c (45 mg, colorless oil), was used without purification in the next step.

MS m/z (ESI): 141.1 [M+1]

the fourth step

4-[[4-fluoro-3-(5-methyl-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl Phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (90 mg, 0.29 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (195 mg, 0.52 mmol) was added, and the crude product was 5-methyl-1,2,3,3 a . 4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine 21c (70 mg, 0.32 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol), for 12 hours . After adding 15 mL of water and extracting with ethyl acetate (15 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4-[[4-fluoro-3-(5-methyl-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl ) phenyl] methyl] -2 H - phthalazin-1-one 21 (28 mg, pale yellow solid), yield: 23.3%.

MS m/z (ESI): 421.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 8.36 (d, 1H), 7.94 (d, 1H), 7.86 (m, 2H), 7.48 (s, 1H), 7.37 (m, 1H), 7.16 (m, 1H), 4.58 (s, 2H), 3.62 (m, 1H), 3.55 (m, 1H), 3.43 (m, 1H), 3.26 (m, 1H), 3.19 (m, 1H), 2.77 ( m, 3H), 2.59 (s, 1H), 2.54 (s, 3H), 2.49 (m, 1H), 1.99 (m, 1H), 1.81 (m, 1H)

Example 22

4-[[4-fluoro3-(1-pyrimidin-2-yl-3,3 a ,4,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- c ]pyridine-6 -carbonyl)phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 11 (110 mg, 0.25 mmol) was dissolved in 20 mL of N-methylpyrrolidone, 2-chloropyrimidine (40 mg, 0.38 mmol) was added, and microwave conditions at 200 °C The reaction was carried out for 2 hours. Concentrate under reduced pressure, add 80 mL of ethyl acetate, EtOAc (EtOAc) (EtOAc) Concentration, the resulting residue was purified by thin layer chromatography eluting to afford 4-[[4-fluoro 3-(1-pyrimidin-2-yl-3,3 a ,4,5,7,7 a - hexahydro -2 H - pyrrolo [3,4- c] pyridine-6-carbonyl) phenyl] methyl] -2 H -, white solid), yield phthalazin-1-one 22 (35 mg: 29.0 %.

MS m/z (ESI): 485.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.21 ( br . s, 1H), 8.49-8.44 (m, 1H), 8.35 (d, 1H), 8.29 (d, 1H), 7.79-7.71 (m) , 3H), 7.41-7.35 (m, 1H), 7.32-7.22 (m, 1H), 7.07-6.98 (m, 1H), 6.57-6.50 (m, 1H), 4.28 (d, 2H), 3.71-3.65 (m, 1H), 3.46-3.30 (m, 2H), 2.85 (m, 2H), 2.41-2.36 (m, 2H), 2.07-1.99 (m, 2H), 1.62-1.43 (m, 3H)

Example 23

4-[[4-fluoro3-(1-methyl-2-yl-3,3 a ,4,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- c ]pyridine- 6-carbonyl)phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 11 (150 mg, 0.37 mmol) was dissolved in 20 mL of 1,2-dichloroethane, and 0.1 mL of acetic acid and 40% formaldehyde solution (53 μL, 0.75 mmol) was added. ). After stirring for 2 hours, sodium triethoxysulfonate borohydride (160 mg, 0.75 mmol) was added and the mixture was reacted for 48 hours. Add 50 mL of dichloromethane, and wash with saturated sodium bicarbonate solution (50 mL), water (50 mL), brine (50 mL) The resulting residue was purified by layer chromatography to afford 4-[[4-fluoro 3-(1-methyl-2-yl-3,3 a ,4,5,7,7 a -hexahydro- 2 H - pyrrolo [3,4- c] pyridine-6-carbonyl) phenyl] methyl] -2 H - phthalazin-1-one 23 (35 mg, white solid), yield: 22.6%.

MS m/z (ESI): 421.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.25 ( br . s, 1H), 8.49-8.44 (m, 1H), 7.80-7.71 (m, 3H), 7.45-7.39 (m, 1H), 7.32 7.25 (m, 1H), 7.07-7.00 (m, 1H), 4.28 (d, 2H), 3.66 (d, 1H), 3.64-3.57 (m, 1H), 3.45-3.36 (m, 1H), 3.33 3.22(m,1H),2.81-265(m,1H), 2.36(s,3H), 2.17-2.09(m,2H),1.87-1.75(m,1H),1.73-1.53(m,4H)

Example 24

4-[[3-(3,4,6,7,9,9 a -hexahydro-1 H -pyrazino[2,1- c ][1,4]oxazin-8-carbonyl)-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

1,3,4,6,7,8,9,9 a -octahydropyrazino[2,1- c ][1,4]oxazine

The 1,6,7,8,9,9 a - hexahydropyrazino [2,1- c] [1,4] oxazin-4-one 6g (100 mg, 0.64 mmol) was dissolved in 10 mL of tetrahydrofuran Lithium aluminum hydride (50 mg, 1.28 mmol) was added and reacted at 40 ° C for 12 hours. Add 30 mL of dichloromethane and 0.5 mL of 10% sodium hydroxide solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give 1,3,4,6,7,8,9,9 a -octahydropyridyl Pyrazino[2,1- c ][1,4]oxazine 24a (60 mg, yellow oil), yield: 66.6%.

Second step

4-[[3-(3,4,6,7,9,9 a -hexahydro-1 H -pyrazino[2,1- c ][1,4]oxazin-8-carbonyl)-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (150 mg, 0.51 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (319 mg, 0.84 mmol), 1,3,4,6,7,8,9,9 was added. A -octahydropyrazino[2,1- c ][1,4]oxazine 24a (60 mg, 0.42 mmol) and N,N-diisopropylethylamine (162 mg, 1.26 mmol), reaction 48 hour. Add 10 mL of water, extract with methylene chloride (25 mL × 3), combine the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and purified by eluent column chromatography with eluent system A , 4-[[3-(3,4,6,7,9,9 a -hexahydro-1 H -pyrazino[2,1- c ][1,4]oxazin-8-carbonyl) 4-fluoro - phenyl] methyl] -2 H - phthalazine (10 mg, white solid), yield of 24 l-one: 5.0%.

MS m/z (ESI): 423.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.10 ( br. S, 1H), 8.52 - 8.42 (m, 1H), 7.71 - 7.65 (m, 5H), 7.21 - 7.16 (m, 1H), 4.21. s, 2H), 3.75-3.57 (m, 4H), 2.78-2.48 (m, 9H)

Example 25

4-[[3-(5-Amino-1,3,3 a ,4,5,6,7,7 a -octahydroisoindol-2-carbonyl)-4-fluoro-phenyl]methyl ]-2 H -pyridazin-1-one

first step

2,3,3 a ,4,7,7 a -hexahydro-1 H -isoindole

Lithium aluminum hydride (3.75 g, 132 mmol) was added portionwise to 150 mL of tetrahydrofuran under ice bath, 3 a , 4,7,7 a -tetrahydroisoindole-1,3-one 25a (5 g , 33 mmol) was dissolved in 100 mL of tetrahydrofuran and slowly added dropwise to the above reaction solution. The mixture was naturally warmed to room temperature and reacted at 40 ° C for 12 hours. Under ice bath, 20 mL of water and 40 g of anhydrous sodium sulfate were added, filtered, and the filter cake was washed with dichloromethane (50 mL×2) to give crude 2,3,3 a ,4,7,7 a -hexahydro- 1 H -isoindole 25b (4 g, light yellow oil).

Second step

1,3,3 a ,4,7,7 a - hexahydroisoindole-2-carboxylic acid tert-butyl ester

The crude 2,3,3 a ,4,7,7 a -hexahydro-1 H -isoindole 25b (5 g, 40 mmol) was dissolved in 100 mL of tetrahydrofuran and triethylamine (8.3 mL, 60 mmol) Under ice bath, di-tert-butyl dicarbonate (10 g, 45 mmol) was added and reacted at room temperature for 12 hours. After adding 150 mL of water and extracting with ethyl acetate (150 mL × 3), the organic phase was combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. 3 a , 4,7,7 a - hexahydroisoindole-2-carboxylic acid tert-butyl ester 25c (8 g, orange oil), yield: 89.6%.

third step

5-hydroxy-1,3,3 a ,4,5,6,7,7 a - octahydroisoindole-2-carboxylic acid tert-butyl ester

Dissolve 1,3,3 a , 4,7,7 a - hexahydroisoindole-2-carboxylic acid tert-butyl ester 25c (8 g, 36 mmol) in 80 mL of tetrahydrofuran, add 36 under ice bath A solution of 1 M borane in tetrahydrofuran was added to room temperature and allowed to react for 12 hours. Under ice bath, 20 mL of methanol, 13.3 mL of 3M sodium hydroxide solution and 13.3 mL of 30% hydrogen peroxide were added and reacted at 60 ° C for 1.5 hours. After cooling to room temperature, it was extracted with ethyl acetate (150 mL×3), EtOAcjjjjjjjjjjjjjj -1,3,3 a ,4,5,6,7,7 a - octahydroisoindole-2-carboxylic acid tert-butyl ester 25d (10 g, light yellow oil), product The next step is to react.

the fourth step

6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -isoindole-2-carboxylic acid tert-butyl ester

The crude 5-hydroxy-1,3,3 a ,4,5,6,7,7 a -octahydroisoindole-2-carboxylic acid tert-butyl ester 25d (2 g, 8.30 mmol) was dissolved in 70 mL two To the methyl chloride, pyridinium chlorochromate (2.86 g, 13.30 mmol) and 3 g of diatomaceous earth were added and reacted for 72 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system B to give 6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H - Isoindole-2-carboxylic acid tert-butyl ester 25e (700 mg, light yellow oil), yield 35.0%.

MS m/z (ESI): 184.1 [M-56+1]

the fifth step

1,2,3,3 a ,4,6,7,7 a - octahydroisoindole-5-one

Dissolve 6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -isoindole-2-carboxylic acid tert-butyl ester 25e (700 mg, 2.93 mmol) in 11 mL 2M A solution of hydrogen chloride in 1,4-dioxane was reacted for 14 hours. Concentrated under reduced pressure to give crude 1,2,3,3 a, 4,6,7,7 a - octahydro-isoindol-5-one 25f (600 mg, brown oil), was used without purification for The next step is to react.

Step 6

4-[[4-fluoro3-(6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -isoindole-2-carbonyl)-phenyl]methyl] -2 H -pyridazin-1-one

The crude 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (572 mg, 2 mmol) was dissolved in 5 mL of N,N-dimethyl To the guanamine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.10 g, 2.88 mmol), 1,2,3,3 a ,4,6,7 was added. , 7 a - octahydroisoindole-5-one 25f (400 mg, 2.88 mmol) and N,N-diisopropylethylamine (0.7 mL, 4 mmol). Concentration under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A to give crude 4-[[4-fluoro 3-(6-oxo-3,3 a ,4,5,7,7) a - hexahydro -1 H - isoindole-2-carbonyl) - phenyl] methyl] -2 H - phthalazin-1-one 25g (1.20 g, brown oil), was used without purification for The next step is to react.

MS m/z (ESI): 420.2 [M+1]

Seventh step

4-[[3-(5-Amino-1,3,3 a ,4,5,6,7,7 a -octahydroisoindol-2-carbonyl)-4-fluoro-phenyl]methyl ]-2 H -pyridazin-1-one

The crude product 4-[[4-fluoro-3-(6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -isoindole-2-carbonyl)-phenyl] methyl] -2 H - phthalazin-1-one 25g (100 mg, 0.24 mmol) was dissolved in 5 mL of methanol, was added ammonium formate (30 mg, 0.48 mmol). After stirring for 2 hours, sodium triethoxysulfonate hydride (153 mg, 0.72 mmol) was added and the mixture was reacted for 48 hours. Concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent A purification system residues to give 4 - [[3- (5-amino -1,3,3 a, 4,5,6,7,7 a - octahydro-isoindole-2-carbonyl) -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 25 (5 mg, white solid), yield: 5.0%.

MS m/z (ESI): 421.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.01 ( br. s, 1H), 8.51 (d, 1H), 7.83 (m, 3H), 7.40 (m, 2H), 7.08 (m, 1H), 4.31 (s, 2H), 3.99 (m, 2H), 3.74 (m, 2H), 3.53 (s, 2H), 2.46 (m, 3H), 1.66 (m, 3H)

Example 26

4 - [[3- [2- (cyclopropylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridine-5 Carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

2-(cyclopropylmethyl)-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-6-one

1,2,3,4,5,7,7 a -octahydropyrrolo[3,4- c ]pyridin-6-one 1b (220 mg, 1.57 mmol) was dissolved in 6 mL of acetonitrile, followed by the addition of carbonic acid Potassium (650 mg, 4.71 mmol) and 0.5 mL of bromomethylcyclopropane (167 μL, 1.73 mmol) in acetonitrile were reacted for 56 hours. The filtrate was concentrated under reduced pressure to give crude 2- (cyclopropylmethyl) -3,3 a, 4,5,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridin - 6-keto 26a (280 mg, light brown oil).

MS m/z (ESI): 195.1 [M+1]

Second step

2-(cyclopropylmethyl)-1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine

The crude 2-(cyclopropylmethyl)-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-6-one 26a (100 mg , 0.64 mmol) was dissolved in 10 mL of tetrahydrofuran, lithium aluminum hydride (50 mg, 1.28 mmol) was added, and the reaction was refluxed for 12 hours. 30 mL of dichloromethane and 0.5 mL of 10% sodium hydroxide solution were added, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(cyclopropylmethyl)-1,3,3 a ,4,5 , 6,7,7 a - octahydro-pyrrolo [3,4- c] pyridin-26b (140 mg, yellow oil). yield: 63.0%.

MS m/z (ESI): 181.2 [M+1]

third step

4 - [[3- [2- (cyclopropylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridine-5 Carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

2-Fluoro-5-[(4-oxo- 3H -phthalazin-1-yl)methyl]benzoic acid 1c (232 mg, 0.78 mmol) was dissolved in 10 mL of N,N-dimethylformamide To the amine, 1-hydroxybenzotriazole (53 mg, 0.39 mmol), 2-(cyclopropylmethyl)-1,3,3 a ,4,5,6,7,7 a -octahydropyrrole And [3,4- c ]pyridine 26b (140 mg, 0.78 mmol), 1-ethyl-(3-dimethylaminopropyl)carbenium diimine hydrochloride (223 mg, 1.17 mmol) and Triethylamine (216 μL, 1.56 mmol) was reacted for 12 hours. Concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent A purification system residues to give 4 - [[3- [2- (cyclopropylmethyl) -3,3 a, 4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-5-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one 26 (30 mg, white solid ), yield: 8.4%.

MS m/z (ESI): 461.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.34 ( br . s, 1H), 8.45 (s, 1H), 7.83-7.72 (m, 4H), 7.31 (s, 1H), 7.04 (s, 1H) , 4.28 (s, 2H), 3.45-3.38 (m, 3H), 3.10 (m, 1H), 2.94 - 2.79 (m, 3H), 2.65 (d, 3H), 1.97 (s, 1H), 1.76 (s , 3H), 1.27-1.23 (q, 1H), 0.78-0.70 (t, 2H), 0.43-0.37 (m, 2H)

Example 27

4-[[4-fluoro-3-(1-isopropyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-6- Carbonyl)phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 11 (80 mg, 0.20 mmol) was dissolved in 7 mL of 1 -dichloroethane and 2-methylpropanal (43 mg, 0.59 mmol) After stirring for 5 hours, sodium triethoxysulfonate borohydride (208 mg, 0.99 mmol) was added, and the reaction was carried out for 24 hours, and sodium triethoxysulfonate hydride (100 mg, 0.45 mmol) was added thereto, and the mixture was refluxed for 3 hours. After adding 15 mL of water and extracting with dichloromethane (25 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4-[[4-fluoro-3-(1-isopropyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-6- carbonyl) phenyl] methyl] -2 H - phthalazin-1-one 27 (8 mg, yellow solid), yield: 10.0%.

MS m/z (ESI): 463.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.00 ( br . s, 1H), 8.41-8.37 (m, 1H), 7.72-7.68 (m, 4H), 7.41 (m, 1H), 7.22. m, 1H), 4.20 (s, 2H), 2.94-2.19 (m, 9H), 1.81-1.62 (m, 6H), 0.92 (s, 3H), 0.91 (s, 3H)

Example 28

4-[[3-(1-cyclopropyl-3,3 a ,4,6,7,7a-hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carbonyl)-4- Fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

1-cyclopropyl-3,3 a ,4,6,7,7a-hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester

Dissolving 4-methylsulfonyloxy-3-(2-methanesulfonyloxyethyl)piperidine-1-carboxylic acid tert-butyl ester 4d (818 mg, 2.04 mmol) in 5 mL of tetrahydrofuran, adding cyclopropane The amine (350 mg, 6.12 mmol) was reacted under microwave conditions at 110 ° C for 30 minutes. It was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by eluent column chromatography with eluent column A to give 1-cyclopropyl-3,3 a ,4,6,7,7 a -hexahydro- 2H -pyrrolo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 28a (90 mg, colorless oil), yield: 16.6%.

MS m/z (ESI): 267.2 [M+1]

Second step

1-cyclopropyl-2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride

1-cyclopropyl-3,3 a ,4,6,7,7 a -hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carboxylic acid tert-butyl ester 28a (90 mg, 0.34 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of 2 M hydrogen chloride in 1,4-dioxane was added and reacted for 12 hours. Concentration under reduced pressure gave crude 1-cyclopropyl-2,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride 28b (92 mg, Light yellow oil), the product was taken to the next step without purification.

third step

4-[[3-(1-cyclopropyl-3,3 a ,4,6,7,7 a -hexahydro-2 H -pyrrolo[3,2- c ]pyridine-5-carbonyl)-4 -fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (91 mg, 0.31 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (209 mg, 0.56 mmol), crude 1-cyclopropyl-2,3,3 a ,4 ,5,6,7,7 a -octahydropyrrolo[3,2- c ]pyridine hydrochloride 28b (92 mg, 0.34 mmol) and N,N-diisopropylethylamine (265 μL, 1.53 mmol) , reaction for 12 hours. Add 20 mL of water, and extract with ethyl acetate (15 mL × 3). The organic phase is combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered and evaporated. A purification chromatography using a developing solvent system resulting residue, to give 4 - [[3- (1-cyclopropyl -3,3 a, 4,6,7,7 a - hexahydro -2 H - pyrrolo [3 , 2- c ] Pyridin-5-carbonyl)-4-fluoro-phenyl]methyl]-2 H -phthalazin-1-one 28 (9 mg, pale yellow solid).

MS m/z (ESI): 447.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 8.36 (d, 1H), 7.95 (d, 1H), 7.88 (m, 2H), 7.50 (m, 1H), 7.29 (m, 1H), 7.17 (m, 1H), 4.58 (s, 1H), 4.39 (d, 2H), 4.16 (m, 1H), 3.75 (m, 1H), 3.03 (m, 2H), 2.51 (m, 2H), 2.32 ( m,1H), 2.20 (m, 2H), 1.97 (m, 2H), 1.59 (m, 1H), 0.85 (m, 2H), 0.73 (m, 1H), 0.64 (m, 1H)

Example 29

4 - [[3- [5- (cyclopropylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridin-2 Carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

3-(cyclopropylmethyl)-6-oxo-1,3,3 a ,4,7,7 a -hexahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester

6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 16a (300 mg, 1.25 Methyl acetate was dissolved in 8 mL of N,N-dimethylformamide, and a mixture of sodium hydride and mineral oil (90 mg, 60%, 2.25 mmol) was added in an ice bath, stirred for 30 minutes, and bromomethylcyclopropane was added. 240 μL, 2.50 mmol), stirring was continued for 30 minutes, and the reaction was allowed to proceed to room temperature for 3 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. 6-oxo-1,3,3 a ,4,7,7 a -hexahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 29a (400 mg, light brown oil) The product was directly subjected to the next reaction without purification.

MS m/z (ESI): 239.1 [M-56+1]

Second step

5-(cyclopropylmethyl)-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-6-one hydrochloride

The crude 5- (cyclopropylmethyl) -6-oxo -1,3,3 a, 4,7,7 a - hexahydro-pyrrolo [3,4- c] pyridine-2-carboxylic acid tertiary butyl Ester 29a (400 mg, 1.25 mmol) was dissolved in 6 mL of dichloromethane, and 6 mL of 2M hydrogen chloride in 1,4-dioxane was added and reacted for 12 hours. Concentration under reduced pressure gave crude 5-(cyclopropylmethyl)-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-6-one The hydrochloride 29b (418 mg, yellow oil) was taken to the next step without purification.

third step

5-(cyclopropylmethyl)-1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine

The crude product 5-(cyclopropylmethyl)-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-6-one hydrochloride 29b (418 Mg, 1.25 mmol) was dissolved in 10 mL of tetrahydrofuran, lithium aluminum hydride (190 mg, 5 mmol) was added, and the reaction was carried out at 70 ° C for 3 hours, and the reaction was continued at 50 ° C for 12 hours. 50 mL of dichloromethane, 0.5 mL of water and 0.5 mL of 10% sodium hydroxide solution were added, stirred for 30 minutes, filtered, and the filtrate was dried over anhydrous sodium sulfate. -1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine 29c (225 mg, colorless oil), product One step reaction.

the fourth step

4 - [[3- [5- (cyclopropylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridin-2 Carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (300 mg, 1.13 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (760 mg, 2.34 mmol), crude 5-(cyclopropylmethyl)-1,2, 3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine 29c (225 mg, 1.25 mmol) and N,N-diisopropylethylamine (580 μL, 3.39 mmol) ), reacted for 12 hours. After adding 15 mL of water and extracting with ethyl acetate (25 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4 - [[3- [5- (cyclopropylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridin-2 carbonyl] -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 29 (90 mg, pale yellow solid), yield: 36.5%.

MS m/z (ESI): 461.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.51 ( br . s, 1H), 8.46 (d, 1H), 7.77 (m, 3H), 7.38 (m, 1H), 7.31 (m, 1H), 7.04(m,1H), 4.64(m,1H), 4.29(d,2H), 3.74(m,1H), 3.68(m,1H), 3.42(m,2H),3.01(m,2H),2.55 (m, 4H), 1.89 (m, 2H), 1.66 (m, 1H), 1.11 (m, 1H), 0.69 (m, 2H), 0.36 (m, 2H)

Example 30

4-[[3-(1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridin-5-carbonyl)-4-fluoro-phenyl] Methyl]-2 H -pyridazin-1-one

first step

1,3,3 a ,4,5,6,7,7 a - octahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester

6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 16a (50 mg, 0.21 Methyl acetate was dissolved in 2 mL of tetrahydrofuran, and a solution of borane in tetrahydrofuran (1 mL, 1.04 mmol) was added. 0.2 mL of water was added dropwise, and concentrated under reduced pressure to give a crude tris(1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 30a (20 mg, white solid), product was used in the next step without isolation.

MS m/z (ESI): 227.1 [M+1]

Second step

4-[[3-(1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridin-5-carbonyl)-4-fluoro-phenyl] Methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (23 mg, 0.18 mmol) in 1 mL of N,N-dimethylformamide To the amine, 1-ethyl-(3-dimethylaminopropyl)carbonium diimine hydrochloride (51 mg, 0.27 mmol), 1-hydroxybenzotriazole (12 mg, 0.089 mmol) ,1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 30a (40 mg, 0.18 mmol) and triethyl Amine (49 μL, 0.35 mmol) was reacted for 12 hours. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography. 5 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane was added to the residue, and the reaction was carried out for 12 hours. Concentration under reduced pressure, and the residue obtained was purified by EtOAc (EtOAc) eluting to afford 4-[[3-(1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[ 3,4- c] pyridine-5-carbonyl) -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 30 (20 mg, white solid), yield: 27.4%.

MS m/z (ESI): 407.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 8.38 (d, 1H), 7.98 (d, 1H), 7.91-7.84 (m, 2H), 7.51-7.49 (m, 2H), 7.18 (t, 1H) ), 4.40 (s, 2H), 4.27-4.13 (m, 1H), 3.55-3.36 (m, 3H), 3.22-3.10 (m, 3H), 2.63 - 2.45 (m, 3H), 1.93-1.63 (m , 2H)

Example 31

4-[[3-(5-Dimethylamino-1,3,3 a ,4,5,6,7,7 a -octahydroisoindol-2-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -pyridazin-1-one

4-[[3-(5-Amino-1,3,3 a ,4,5,6,7,7 a -hexahydroisoindol-2-carbonyl)-4-fluoro-phenyl]- Base]-2 H -phthalazin-1-one 25 (100 mg, 0.24 mmol) dissolved in 5 mL of methanol, 40% formaldehyde solution (24 μL, 0.26 mmol) and sodium triethoxysulfonate (153 mg) , 0.72 mmol), reaction for 12 hours. Concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent A purification system residues to give 4 - [[3- (5-dimethylamino -1,3,3 a, 4,5,6,7, 7 a - octahydro-isoindol-2-carbonyl) -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 31 (50 mg, white solid), yield: 46.5%.

MS m/z (ESI): 449.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.53 ( br . s, 1H), 7.47 (m, 1H), 7.80 (m, 3H), 7.33 (m, 2H), 7.05 (m, 1H), 4.30 (m, 2H), 3.69 (m, 2H), 3.50 (m, 2H), 3.47 (m, 1H), 2.66 (m, 6H), 2.23 (m, 2H), 2.16 (m, 2H), 1.94 (m, 2H), 1.49 (m, 2H)

Example 32

4-[[3-[1-(cyclopropylmethyl)-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-6- Carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

The crude product 4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-benzene yl] methyl] -2 H - phthalazin-1-one 11 (200 mg, 0.50 mmol) was dissolved in 50 mL of acetonitrile was added potassium carbonate (140 mg, 1 mmol) and bromomethyl cyclopropane (100 mg, 0.75 mmol), reacted at 82 ° C for 3 hours. Filtration, the filter cake was washed with 30 mL of dichloromethane, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc) eluting to afford 4-[[3-[1-(cyclopropylmethyl)- 3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-6-carbonyl]-4-fluoro-phenyl]methyl]-2 H - Pyridazin-1-one 32 (60 mg, white solid), yield: 28.3%.

MS m/z (ESI): 461.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.48 (m, 1H), 7.71 (m, 3H), 7.69 (m, 2H), 7.02 (m, 1H), 4.28 (d, 2H), 4.16 (d) , 2H), 3.70 (d, 2H), 3.49 (m, 2H), 3.15 (m, 1H), 2.69 (m, 1H), 2.33 (m, 1H), 1.76 (m, 2H), 1.70 (m, 2H), 1.44 (m, 1H), 0.49 (m, 5H)

Example 33

4-[[3-(1-ethyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-6-carbonyl)-4- Fluoro-phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 11 (100 mg, 0.25 mmol) was dissolved in 30 mL of acetonitrile and potassium carbonate (70 mg, 0.50 mmol) and ethyl iodide (60 mg, 0.38 mmol) The reaction was carried out at 75 ° C for 2 hours. Filtration, the filter cake was washed with 30 mL of dichloromethane, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc) a , 5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl]methyl]-2 H -pyridazine-1- Ketone 33 (31 mg, white solid), Yield: 28.7%.

MS m/z (ESI): 435.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.38 (m, 1H), 7.89 (m, 3H), 7.44 (m, 2H), 7.20 (m, 1H), 4.40 (s, 2H), 3.94 (m) , 2H), 3.48 (m, 2H), 3.18 (m, 3H), 2.97 (m, 2H), 1.79 (m, 5H), 1.29 (m, 3H)

Example 34

4-[[3-(5-ethyl-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl)-4- Fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

3-ethyl-6-oxo-1,3,3 a ,4,7,7 a -hexahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester

6-oxo-3,3 a ,4,5,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 16a (300 mg, 1.24 Methyl acetate was dissolved in 5 mL of N,N-dimethylformamide, sodium hydride (74 mg, 1.86 mmol) was added at 0 ° C, reacted at 0 ° C for 0.5 hours, reacted at room temperature for 1.2 hours, and added with ethyl iodide (252 μL, 3.12 mmol), react for 3 hours. After adding 20 mL of water and extracting with ethyl acetate (20 mL × 3), the organic phase was combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, 3--6-oxo-1,3,3 a ,4,7,7 a -hexahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 34a (365 mg, yellow liquid), The product was used in the next step without isolation.

MS m/z (ESI): 213.1 [M-56+1]

Second step

5-ethyl-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-6-one hydrochloride

The crude 5-ethyl-6-oxo-1,3,3 a ,4,7,7 a -hexahydropyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester 34a (620 mg , 2.50 mmol) was dissolved in 8 mL of dichloromethane, and 5 mL of 6.5 M hydrogen chloride in 1,4-dioxane was added and reacted for 12 hours. Concentration under reduced pressure gave crude 5-ethyl-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-6-one hydrochloride 34b ( 420 mg, yellow solid), product was used in the next step without isolation.

MS m/z (ESI): 213.1 [M-56+1]

third step

5-ethyl-1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine

The crude 5-ethyl-2,3,3 a ,4,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-6-one hydrochloride 34b (420 mg, 2.50) Methyl) was dissolved in 25 mL of tetrahydrofuran, and lithium tetrahydroaluminum (285 mg, 7.50 mmol) was added at 0 ° C, reacted at 70 ° C for 3 hours, and reacted at 50 ° C for 12 hours. 0.3 mL of 5 M sodium hydroxide solution, 0.7 mL of water and 50 mL of dichloromethane were added, and the mixture was filtered through basic aluminum oxide, and the filtrate was concentrated under reduced pressure to give crude 5-ethyl-1, 2, 3, 3 a , 4 , 6,7,7 a - octahydro-pyrrolo [3,4- c] pyridin-34c (432 mg, light brown oil), the product was used directly without isolation in the next step.

the fourth step

4-[[3-(5-ethyl-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl)-4- Fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (620 mg, 2.08 mmol) in 8 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.41 g, 3.74 mmol) was added, and the crude product was 5-ethyl-1,2,3,3 a . 4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine 34c (432 mg, 2.50 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.24 mmol), reaction 12 hour. After adding 25 mL of water and extracting with ethyl acetate (20 mL × 3), the organic phase was combined, washed with a saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue obtained was purified by eluent system A to give 4-[[3-(5-ethyl-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3, 4- c ]pyridine-2-carbonyl)-4-fluoro-phenyl]methyl]-2 H -phthalazin-1-one 34 (260 mg, light red solid), yield: 28.8%.

MS m/z (ESI): 435.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.13 ( br. s, 1H), 8.46 (d, 1H), 7.76 (m, 3H), 7.37 (m, 1H), 7.28 (m, 1H), 7.03 (t, 1H), 4.28 (d, 2H), 3.65 (m, 1H), 3.59 (m, 1H), 3.32 (m, 1H), 3.29 (m, 1H), 2.40 (m, 6H), 1.95 ( m, 2H), 1.73 (s, 2H), 1.58 (m, 1H), 1.41 (m, 2H)

Example 35

4-[[3-(4-ethyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carbonyl)- 4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester

3-Benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester 14d (500 mg , 1.57 mmol) was dissolved in 20 mL of methanol, 20 mg of 10% palladium on carbon was added, and hydrogen was replaced three times for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave 3,4,4 a ,5,7,7 a -hexahydro- 2H -pyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid Butyl ester 35a (230 mg, colorless oil), yield: 64.0%.

Second step

4-ethyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester

3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester 35a (300 mg, 1.31 mmol) was dissolved in 10 mL of acetonitrile, and potassium carbonate (543 mg, 3.93 mmol) and ethyl iodide (0.2 mL, 1.97 mmol) were sequentially added and reacted at 80 ° C for 3 hours. Filtration, the filter cake was washed with 30 mL of acetonitrile, and the filtrate was concentrated under reduced pressure to give crude 4-ethyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1, 4] Oxazine-6-carboxylic acid tert-butyl ester 35b (400 mg, yellow solid), the product was used in the next step without isolation.

third step

4-ethyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine hydrochloride

The crude 4-ethyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester 35b (400 Mg, 1.31 mmol) was dissolved in 20 mL of 6.5 M hydrogen chloride in 1,4-dioxane for 12 hours. Concentrated under reduced pressure to afford crude 4-ethyl -3,4 a, 5,6,7,7 a - hexahydro -2 H - pyrrolo [3,4- b] [1,4] oxazine hydrochloride 35c (400 mg, brown solid), product was used in the next step without isolation.

MS m/z (ESI): 157.1 [M+1]

the fourth step

4-[[3-(4-ethyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carbonyl)- 4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (250 mg, 0.84 mmol) in 5 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (477 mg, 1.26 mmol), crude 4-ethyl-3,4 a ,5,6, 7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine hydrochloride 35c (400 mg, 1 mmol) and N,N-diisopropylethylamine ( 0.3 mL, 1.68 mmol), reacted for 12 hours. Add 30 mL of water, extract with dichloromethane (30 mL×3), combine the organic phases, concentrate under reduced pressure, add 50 mL of ethyl acetate, and wash with saturated sodium bicarbonate (40 mL) and saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,, a , 5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carbonyl)-4-fluoro-phenyl]methyl]-2 H -pyridazine- 1-ketone 35 (70 mg, white solid), yield: 5.5%.

MS m/z (ESI): 437.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.40 ( br . s, 1H), 8.48 (m, 1H), 7.78 (m, 3H), 7.40 (m, 1H), 7.29 (m, 1H), 7.05 (m,1H), 4.29 (m, 2H), 3.66 (m, 10H), 2.59 (m, 2H), 1.17 (t, 3H)

Example 36

4-[[3-[4-(cyclopropylmethyl)-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine- 6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

3-(cyclopropylmethyl)-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester

3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester 35a (330 mg, 1.45 mmol) was dissolved in 30 mL of acetonitrile, and potassium carbonate (530 mg, 4.35 mmol) and bromomethylcyclopropane (391 mg, 2.90 mmol) were sequentially added and reacted at 82 ° C for 3 hours. Filtration, the filter cake was washed with 30 mL of dichloromethane, and the filtrate was concentrated under reduced pressure to give crude 4-(cyclopropylmethyl)-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3, 4- b ][1,4]oxazol-6-carboxylic acid tert-butyl ester 36a (300 mg, white solid), product was used in the next step without isolation.

Second step

4-(cyclopropylmethyl)-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine hydrochloride

The crude 4-(cyclopropylmethyl)-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carboxylic acid Butyl ester 36a (300 mg, 1 mmol) was dissolved in 20 mL of 6.5 M hydrogen chloride in 1,4-dioxane and allowed to react for 12 hours. Concentrated under reduced pressure to give crude 4- (cyclopropylmethyl) -3,4 a, 5,6,7,7 a - hexahydro -2 H - pyrrolo [3,4- b] [1,4] Oxazine hydrochloride 36b (260 mg, colorless oil) was used for the next step without isolation.

third step

4-[[3-[4-(cyclopropylmethyl)-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine- 6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (300 mg, 1 mmol) in 20 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (570 mg, 1.50 mmol), crude 4-(cyclopropylmethyl)-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine hydrochloride 36b (260 mg, 1 mmol) and N,N-diiso Propylethylamine (0.5 mL, 3 mmol) was reacted for 12 hours. Add 50 mL of water, extract with dichloromethane (50 mL × 3), combine the organic phases, concentrate under reduced pressure, add 100 mL of ethyl acetate, and wash with saturated sodium bicarbonate (40 mL) and saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -phthalazin-1-one 36 (185 mg, white solid), yield: 40.0%.

MS m/z (ESI): 463.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.48 (m, 1H), 7.78 (m, 3H), 7.39 (m, 2H), 7.05 (m, 1H), 4.27 (s, 2H), 3.89 (m) , 1H), 3.76 (m, 4H), 3.51 (m, 2H), 3.12 (m, 1H), 2.71 (m, 2H), 2.42 (m, 2H), 0.89 (m, 1H), 0.50 (m, 2H), 0.16 (m, 2H)

Example 37

4 - [[3- [2- (2-aminoethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridine-5 -carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

N-[2-[5-[2-fluoro-5-[(4-oxo-3 H -pyridazin-1-yl)methyl]benzylidene]-3,3 a ,4,6 ,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-2-yl]ethyl]carbamic acid tert-butyl ester

4-[[3-(1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridin-5-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 30 (80 mg, 0.19 mmol) was dissolved in 10 mL of acetonitrile, followed by potassium carbonate (82 mg, 0.59 mmol), sodium iodide (15 mg, 0.098 mmol) And N-(2-chloroethyl)carbamic acid tert-butyl ester (53 mg, 0.29 mmol), refluxed for 4 hours, and reacted at 50 ° C for 12 hours. Filtration, the filter cake was washed with 20 mL of dichloromethane, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by thin layer chromatography to afford to afford N-[2-[5-[2-fluoro-5-[ (4-oxo -3 H - phthalazin-1-yl) methyl] benzoyl-yl] -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3, 4- c ]pyridin-2-yl]ethyl]aminocarbamic acid tert-butyl ester 37a (30 mg, white solid), yield: 27.8%.

MS m/z (ESI): 550.2 [M+1]

Second step

4 - [[3- [2- (2-aminoethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridine-5 -carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

N-[2-[5-[2-fluoro-5-[(4-oxo-3 H -pyridazin-1-yl)methyl]benzylidene]-3,3 a , 4, 6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridin-2-yl]ethyl]carbamic acid tert-butyl ester 37a (30 mg, 0.054 mmol) dissolved in 3 mL In dichloromethane, 3 mL of a 6.5 M solution of hydrogen chloride in 1,4-dioxane was added and reacted for 12 hours. Concentrate under reduced pressure, add 20 mL of dichloromethane, 0.1 mL of 5M sodium hydroxide solution, 3 mL of methanol, and a saturated solution of sodium carbonate to make the pH of the reaction mixture to 9 and dry over anhydrous sodium sulfate. A layer chromatography and the obtained residue was purified by developing solvent system, to give 4 - [[3- [2- (2-aminoethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c] pyridine-5- carbonyl] -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 37 (15 mg, pale yellow solid), yield : 62.5%.

MS m/z (ESI): 448.0 [M-1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.88 (S, 1H), 8.28 (d, 1H), 8.15 (m, 1H), 7.93 (m, 1H), 7.13 (d, 1H), 7.06 (d) , 1H), 6.45 (m, 1H), 3.95 (m, 1H), 3.83 (s, 2H), 2.29 (m, 2H), 2.22 (m, 2H), 1.94 (m, 8H), 1.26 (m, 4H)

Example 38

4 - [[4-fluoro-3- [2- (2-hydroxyethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c Pyridine-5-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridin-5-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 30 (100 mg, 0.21 mmol) was dissolved in 10 mL of acetonitrile, followed by potassium carbonate (101 mg, 0.74 mmol) and bromoethanol (46 mg, 0.37 mmol) , reaction for 24 hours. Concentration under reduced pressure, the residue obtained was purified by silica gel eluting to afford 4-[[4-(4-(2-hydroxyethyl)-3,3 a ,4,6 ,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-5-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one 38 (20 mg, white solid ), yield: 18.2%.

MS m/z (ESI): 451.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 8.37 (s, 1H), 7.78 (t, 1H), 7.88 (m, 2H), 7.48 (m, 1H), 7.36 (d, 1H), 7.16 (t, 1H), 4.59 (m, 1H), 4.39 (s, 2H), 4.10 (s, 2H), 3.84 (m, 2H), 3.66 (m, 2H), 3.43 (m, 1H), 3.39 ( m, 2H), 3.20 (m, 2H), 2.68 (m, 2H), 1.94 (m, 2H), 1.76 (m, 2H), 1.66 (m, 1H)

Example 39

4-[[3-[(4 aS ,7 aS )-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4- b ]pyridine-6-carbonyl]-4 -fluoro-phenyl]methyl]-2 H -indolyl-1-one

first step

6-benzylpyrrolo[3,4- b ]pyridine-5,7-dione

Pyridine-2,3-dicarboxylic acid 39a (10 g, 59.80 mmol) was dissolved in 20 mL of acetic anhydride, and reacted at 110 ° C for 4 hours, and concentrated under reduced pressure to give a white solid furo[3,4- b ]pyridine-5 , 7-diketone.

The furo[3,4- b ]pyridine-5,7-dione was dissolved in 10 mL of benzylamine at 0 ° C, reacted at 180 ° C for 0.5 hour, added with 20 mL of acetic anhydride at 110 ° C, and reacted at 110 ° C for 2 hours. After cooling in an ice bath, ethanol was added to recrystallize, a white solid was precipitated, filtered, and the filter cake was washed with ethanol to give 6-benzylpyrrolo[3,4- b ]pyridine-5,7-dione 39b (7 g, white Solid), Yield: 49.2%.

Second step

6-Benzyl-1,2,3,4,4 a ,7 a -hexahydropyrrolo[3,4- b ]pyridine-5,7-dione

6-Benzylpyrrolo[3,4- b ]pyridine-5,7-dione 39b (11 g, 46.20 mmol) was dissolved in 200 mL of methanol, and 1.10 g of 10% palladium/carbon was added for hydrogenation by hydrogenation. 12 hours. Filtration, the filter cake was washed with 100 mL of methanol, and the filtrate was concentrated under reduced pressure. The residue obtained was separated from eluent system A by basic alumina column chromatography to give 6-benzyl-1,2,3,4,4 a , 7 a -hexahydropyrrolo[3,4- b ]pyridine-5,7-dione 39c (10 g, pale yellow oil), yield: 89.2%.

MS m/z (ESI): 245.1 [M+1]

third step

6-Benzyl-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine

6-Benzyl-1,2,3,4,4 a ,7 a -hexahydropyrrolo[3,4- b ]pyridine-5,7-dione 39c (5 g, 20 mmol) was dissolved in 120 Lithium tetrahydroaluminum (7.60 g, 20 mmol) was added portionwise in mL tetrahydrofuran at 0 ° C, and reacted at 75 ° C for 6 hours. After cooling in an ice bath, 12.9 mL of water and 100 mL of dichloromethane were added, 20% sodium hydroxide solution was added dropwise until a white precipitate appeared, and the filtrate was washed with 50 mL of dichloromethane, and the filtrate was concentrated under reduced pressure to give crude 6-benzyl. group -1,2,3,4,4 a, 5,7,7 a - octahydro-pyrrolo [3,4- b] pyridin-39d (4 g, pale yellow oil) and the product used directly without isolation In the next step of the reaction.

MS m/z (ESI): 217.2 [M+1]

the fourth step

(4 aS ,7 aS )-6-benzyl-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine

D(-)-tartaric acid (1.38 g, 9.20 mmol) was dissolved in 5 mL of N,N-dimethylformamide, dissolved at 80 ° C to dissolve completely, and 1 mL of crude 6-benzyl-1,2 was added. ,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine 39d (1 g, 4.60 mmol) in N,N-dimethylformamide solution, 80 ° C After stirring for 15 minutes, the solution turned dark green, cooled to 0 ° C, stirred for 1 hour, no solid precipitated, 5 mL of ethylene glycol monomethyl ether was added, and a white solid precipitated. Filtration, filter cake washed with 5 mL N,N-dimethylformamide, add 2 mL of ethylene glycol monomethyl ether, stir for 10 minutes, filter, filter cake dissolved in 5 mL water, add 0.8 mL 45% KOH soda solution, stirred for 10 minutes, tert-butyl methyl ether and extracted with (6 mL × 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, to give (4 aS, 7 aS) -6 -benzyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4- b ]pyridine 39e (0.25 g, colorless oil), yield: 25.0%.

the fifth step

(4 aS ,7 aS )-6-benzyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester

(4 aS ,7 aS )-6-benzyl-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine 39e (120 mg, 0.56 Methyl acetate was dissolved in 20 mL of dichloromethane, and 4-dimethylaminopyridine (136 mg, 1.11 mmol) and di-tert-butyl dicarbonate (182 mg, 0.83 mmol) were added and reacted for 4 hours. After adding 20 mL of water, the mixture was separated and the aqueous phase was extracted with methylene chloride (20 mL × 3). The organic phase was combined, washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate Obtaining (4 aS ,7 aS )-6-benzyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid Butyrate 39f (150 mg, pale yellow liquid), yield: 85.4%.

MS m/z (ESI): 317.2 [M+1]

Step 6

(4 aS ,7 aS )-2,3,4,4 a ,5,6,7,7 a - octahydropyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester

(4 aS ,7 aS )-6-benzyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid Butyl ester 39f (150 mg, 0.47 mmol) was dissolved in 10 mL of methanol, and 15 mg of 10% palladium on carbon was added and replaced with hydrogen three times for 12 hours. Filtration, the filter cake was washed with 20 mL of methanol, and the filtrate was concentrated under reduced pressure to give (4 aS , 7 aS )-2,3,4,4 a ,5,6,7,7 a -octahydropyrrolo[3,4 - b ] pyridine-1-carboxylic acid tert-butyl ester 39 g (100 mg, pale yellow liquid), yield: 93.5%.

Seventh step

(4 aS ,7 aS )-6-[2-fluoro-5-[(4-oxo-3 H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a , 5,7,7 a -hexahydro-2 H -pyrrolo[3,4- c ]pyridine-1-carboxylic acid tert-butyl ester

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (132 mg, 0.44 mmol) in 2 mL of N,N-dimethylformamide In the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (251 mg, 0.66 mmol), (4 aS , 7 aS )-2,3,4,4 was added. a , 5,6,7,7 a - octahydropyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester 39g (100 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.2 mL, 0.88 mmol), reaction for 12 hours. Concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A residue purified to afford (4 aS, 7 aS) -6- [2- fluoro-5 - [(4-oxo -3 H - phthalazin - 1-yl)methyl]benzhydryl]-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- c ]pyridine-1-carboxylic acid tert-butyl Ester 39h (40 mg, white solid), yield: 17.9%.

Eighth step

4-[[3-[(4 aS ,7 aS )-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl] -4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

(4 aS ,7 aS )-6-[2-fluoro-5-[(4-oxo-3 H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a , 5,7,7 a -hexahydro-2 H -pyrrolo[3,4- c ]pyridine-1-carboxylic acid tert-butyl ester 39h (50 mg, 0.099 mmol) dissolved in 5 mL of 6.5 M hydrogen chloride 1, 4-Dioxane solution, reaction for 4 hours. Concentrated under reduced pressure, 1 mL of aqueous ammonia, concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent A purification system residues to give 4 - [[3 - [( 4 aS, 7 aS) -1,2,3, 4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one 39 (5 mg, pale yellow solid), yield: 12.5%.

MS m/z (ESI): 407.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 11.30 ( br . s, 1H), 8.47 (m, 1H), 7.76 (m, 3H), 7.40 (m, 1H), 7.27 (m, 1H), 7.04 (m, 1H), 4, 27 (m, 2H), 3.70 (m, 2H), 3.50 (m, 2H), 3, 20 (m, 2H), 2.25 (m, 1H), 2.00 (m, 2H) ),1.63 (m, 2H)

Example 40

4 - [[4-fluoro-3- [2- (2-pyridylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c Pyridine-5-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridin-5-carbonyl)-4-fluoro-phenyl ]Methyl]-2 H -phthalazin-1-one 30 (80 mg, 0.19 mmol) was dissolved in 10 mL of 1 -dichloroethane and pyridine-2-carbaldehyde (32 mg, 0.30 mmol). The reaction was refluxed for 1 hour. After cooling to room temperature, sodium cyanoborohydride (25 mg, 0.39 mmol) was added and the mixture was reacted for 12 hours. 15 mL of a saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane (15 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue, to give 4 - [[4-fluoro-3- [2- (2-pyridylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3 , 4- c ]pyridine-5-carbonyl]phenyl]methyl]-2 H -phthalazin-1-one 40 (27 mg, white solid), yield: 27.8%.

MS m/z (ESI): 498.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.65 (d, 1H), 8.44 (d, 1H), 7.74 (m, 5H), 7.30 (m, 3H), 7.01 (m, 2H), 4.31 (s) , 2H), 4.27 (s, 2H), 3.40 (m, 2H), 3.12 (m, 2H), 2.75 (m, 2H), 2.56 (m, 2H), 1.90 (m, 2H), 1.71 (m, 2H)

Example 41

4-[[3-[(4 aR ,7 aR )-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl] -4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

(4 aR ,7 aR )-6-benzyl-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine

L(+)-tartaric acid (1.38 g, 9.20 mmol) was dissolved in 4 mL of N,N-dimethylformamide, dissolved at 80 ° C to dissolve completely, and 1 mL of crude 6-benzyl-1,2 was added. ,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine 39d (1 g, 4.60 mmol) in N,N-dimethylformamide solution, 80 ° C After stirring for 15 minutes and stirring at room temperature for 1 hour, 6 mL of ethylene glycol monomethyl ether was added, and a white solid precipitated. Filtration, the filter cake was washed with 5 mL of N,N-dimethylformamide, 2 mL of ethylene glycol monomethyl ether was added to the filter cake, stirred for 10 minutes, filtered, and the filter cake was dissolved in 5 mL of water, and 0.8 mL was added. % sodium hydroxide solution, stirred for 5 minutes, extracted with methyl tert-butyl ether (6 mL × 3), combined organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (4 aR , 7 aR )-6-benzyl-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine 41 a (120 mg, colorless oil) Rate: 12.0%.

Second step

(4 aR ,7 aR )-6-benzyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester

(4 aR ,7 aR )-6-benzyl-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine 41a (700 mg, 3.20 Methyl acetate was dissolved in 10 mL of dichloromethane, and triethylamine (1.4 mL, 9.60 mmol) and di-tert-butyl dicarbonate (1.05 g, 4.80 mmol) were added and reacted for 12 hours. The reaction solution was washed with a saturated aqueous solution of ammonium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with eluent system A to give (4 aR , 7 aR - 6-benzyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester 41b (1 g, Yellow solid), Yield: 98.9%.

MS m/z (ESI): 317.2 [M+1]

third step

(4 aR ,7 aR )-2,3,4,4 a ,5,6,7,7 a - octahydropyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester

(4 aR , 7 aR )-6-benzyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid Butyl ester 41b (1 g, 3.16 mmol) was dissolved in 20 mL of methanol, and 0.10 g of 10% palladium on carbon was added, and hydrogen was replaced three times for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded crude (4 aR , 7 aR )-2,3,4,4 a ,5,6,7,7 a -octahydropyrrolo[3,4- b ]pyridine-1- The third butyl formate 41c (800 mg, white solid) was taken to the next step without purification.

MS m/z (ESI): 226.9 [M+1]

the fourth step

(4 aR ,7 aR )-6-[2-fluoro-5-[(4-oxo-3 H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a , 5,7,7 a -hexahydro-2 H -pyrrolo[3,4- c ]pyridine-1-carboxylic acid tert-butyl ester

Dissolving 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (1.05 g, 3.53 mmol) in 20 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2 g, 5.29 mmol), crude (4 aR , 7 aR )-2,3,4, 4a,5,6,7,7a-octahydropyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester 41c (800 mg, 3.53 mmol) and N,N-diisopropylethylamine ( 1.3 mL, 7.06 mmol), reaction for 12 hours. Concentrate under reduced pressure, add 40 mL of water, EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by eluent column chromatography using eluent column chromatography to give (4 aR , 7 aR )-6-[2-fluoro-5-[(4-oxo-3 H -pyridazine-1) -yl)methyl]benzhydryl]-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- c ]pyridine-1-carboxylic acid tert-butyl ester 41d (1.20 g, yellow solid), yield: 70.8%.

MS m/z (ESI): 407.1 [M-100+1]

the fifth step

4-[[3-[(4 aR ,7 aR )-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl] -4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

(4 aR ,7 aR )-6-[2-fluoro-5-[(4-oxo-3 H -pyridazin-1-yl)methyl]benzylidene]-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- c ]pyridine-1-carboxylic acid tert-butyl ester 41d (1.20 g, 2.36 mmol) dissolved in 20 mL of 6.5 M hydrogen chloride 1,4 In a dioxane solution, the reaction was carried out for 12 hours. Concentrated under reduced pressure, 20 mL of dichloromethane was added, and aqueous ammonia was added dropwise until the solid was completely dissolved. Drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure, and purifying the residue obtained from the solvent system A to obtain 4-[[3-[(4 aR ,7 aR )-1,2,3, 4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one 41 (360 mg, pale yellow solid), yield: 37.5%.

MS m/z (ESI): 407.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.60 ( br . S, 1H), 8.24 - 8.26 (m, 1H), 7.81 - 7.95 (m, 3H), 7.41 - 7.46 (m, 2H), 7.21-7.26 (m, 1H), 4.33 (S, 2H), 3.54-3.65 (m, 3H), 3.41-3.44 (m, 1H), 3.13-3.17 (m, 3H), 2.77-3.06 (m, 1H) ), 1.44-1.69 (m, 4H)

Example 42

4-[[3-[1-(2-Aminoethyl)-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-6 -carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

N-(2-bromoethyl)aminocarbamic acid tert-butyl ester

Dissolve 2-bromoethylamine hydrobromide 42a (11 g, 53.60 mmol) in 120 mL of methanol and add triethylamine (40 mL, 161 mmol) and dibutyl succinate (23.40 g, 107 mmol The mixture was stirred at 60 ° C for 30 minutes and at room temperature for 12 hours. Concentrate under reduced pressure, add 150 mL of ethyl acetate, add 80 mL of 1M hydrochloric acid, and separate the organic phase. Wash with water (40 mL), saturated sodium bicarbonate (40 mL) and saturated sodium chloride (40 mL) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and purifying the obtained residue by eluent column chromatography to afford N-(2-bromoethyl)carbamic acid tert-butyl ester 42b (10.50) g, colorless oil), yield: 85.7%.

MS m/z (ESI+23): 170.1 [M-56+1]

Second step

N-[2-[6-[2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a ,5, 7,7 a - hexahydro-2 H -pyrrolo[3,4- b ]pyridin-1-yl]ethyl]carbamic acid tert-butyl ester

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl ]Methyl]-2 H -pyridazin-1-one 11 (210 mg, 0.50 mmol) was dissolved in 50 mL of acetonitrile and added N-(2-bromoethyl)carbamic acid tert-butyl ester 42b (168 mg , 0.75 mmol) and potassium carbonate (350 mg, 2.50 mmol), refluxed for 7 hours. Filtration, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel eluting with the solvent system A to give N-[2-[6-[2-fluoro-5-[(4-oxo-3 H -pyridazine) -1-yl)methyl]benzhydryl]-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridin-1-yl]B Tert-butyl carbamic acid tert-butyl ester 42c (150 mg, white solid), yield: 54.5%.

third step

4-[[3-[1-(2-Aminoethyl)-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-6 -carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

N-[2-[6-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a ,5 ,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridin-1-yl]ethyl]carbamic acid tert-butyl ester 42c (150 mg, 0.27 mmol) dissolved in 2 mL 2 In a solution of M hydrogen chloride in 1,4-dioxane, the reaction was carried out for 12 hours. Concentrated under reduced pressure, 50 mL of dichloromethane and 20 mL of saturated sodium carbonate solution were added, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography. The residue gives 4-[[3-[1-(2-aminoethyl)-3,4,4 a ,5,7,7 a -hexahydro- 2H -pyrrolo[3,4- b ] pyridine-6-carbonyl] -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 42 (35 mg, white solid), yield: 28.7%.

MS m/z (ESI): 450.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.31 (m, 1H), 7.88 (m, 3H), 7.52 (m, 2H), 7.23 (m, 1H), 4.35 (s, 2H), 3.44 (m) , 4H), 3.22 (m, 3H), 3.01 (m, 2H), 2.58 (m, 1H), 2.28 (m, 1H), 1.45 (m, 5H)

Example 43

4-[[4-fluoro-3-[1-(3-pyridylmethyl)-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b Pyridine-6-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -phthalazin-1-one 11 (150 mg, 0.37 mmol) was dissolved in 10 mL of 1,2-dichloroethane, pyridine-3-carbaldehyde (47.40 mg, 0.44 mmol) and Acetic acid (0.1 mL, 0.002 mmol) was reacted for 5 hrs, and sodium triethyloxy borohydride (234 mg, 1.11 mmol). Add 30 mL of water, extract with methylene chloride (50 mL×3), and combine with EtOAc (EtOAc) The obtained residue was purified with a solvent system A to give 4-[[4-fluoro-3-[1-(3-pyridylmethyl)-3,4,4 a ,5,7,7 a -hexahydro- 2 H - pyrrolo [3,4- b] pyridine-6-carbonyl] phenyl] methyl] -2 H - phthalazin-1-one 43 (80 mg, white solid), yield: 43.7%.

MS m/z (ESI): 498.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 11.21 ( br. s, 1H), 8.63 (m, 3H), 7.80 (m, 4H), 7.33 (m, 1H), 7.30 (m, 2H), 7.09 (m, 1H), 4.32 (m, 2H), 4.32 (m, 2H), 3.96 (m, 1H), 3.68 (m, 3H), 3.41 (m, 2H), 3.17 (m, 2H), 2.68 ( m, 1H), 2.51 (m, 1H), 2.24 (m, 1H), 1.68 (m, 5H)

Example 44

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)phenyl]methyl]-2 H -pyridazin-1-one

first step

6-[3-[(4-oxo-3 H -pyridazin-1-yl)methyl]benzylidene]-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester

3-[(4-Oxo- 3H -phthalazin-1-yl)methyl]benzoic acid 44a (300 mg, 1.07 mmol, prepared by the known method "Patent WO2004080976") was dissolved in 20 mL of N , N-dimethylformamide, benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate (528 mg, 1.61 mmol), octahydro-pyrrolo[3 , 4- b ]pyridine-3-carboxylic acid tert-butyl ester (242 mg, 1.07 mmol) and N,N-diisopropylethylamine (0.6 mL, 3.21 mmol). Concentration under reduced pressure, and the residue obtained was purified by silica gel chromatography to afford 6-[3-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl] -3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester 44b (400 mg, white solid), yield : 76.6%.

MS m/z (ESI): 389.2 [M-100+1]

Second step

4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine-6-carbonyl)phenyl]methyl]-2 H -pyridazin-1-one

6-[2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzhydryl]-3,4,4 a ,5,7,7 a - Hexahydro-2H-pyrrolo[3,4- b ]pyridine-1-carboxylic acid tert-butyl ester 44b (400 mg, 0.82 mmol) was dissolved in 2 mL of 2M hydrogen chloride in 1,4-dioxane, reaction 12 hour. The saturated sodium bicarbonate solution was added dropwise until the pH of the reaction mixture was 9 and extracted with dichloromethane (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate and filtered The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel eluting to afford 4-[[3-(1,2,3,4,4 a ,5,7,7 a -octahydropyrrole). and [3,4- b] pyridine-6-carbonyl) phenyl] methyl] -2 H - phthalazin-1-one 44 (80 mg, white solid), yield: 25.1%.

MS m/z (ESI): 389.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.37 ( br. s, 1H), 8.50 (m, 1H), 7.78 (m, 3H), 7.54 (m, 4H), 4.36 (s, 2H), 3.77 (m, 4H), 2.67 (m, 1H), 2.21 (m, 2H), 1.65 (m, 5H)

Example 45

4-[[3-(5,7-Dihydropyrrolo[3,4- b ]pyridine-6-carbonyl)phenyl]methyl]-2 H -pyridazin-1-one

3-[(4-Oxo-3 H -pyridazin-1-yl)methyl]benzoic acid 44a (212 mg, 0.76 mmol) was dissolved in 10 mL of N,N-dimethylformamide and added Benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (375 mg, 1.14 mmol), 6,7-dihydro-5 H -pyrrolo[3,4- b ] Pyridine (100 mg, 0.83 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.28 mmol). Add 30 mL of water, extract with methylene chloride (50 mL × 3), and combine the organic phase, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, Chromatography to purify the obtained residue in the solvent system A to give 4-[[3-(5,7-dihydropyrrolo[3,4- b ]pyridin-6-carbonyl)phenyl]methyl]-2 H - pyridazin-1-one 45 (99 mg, white solid), yield: 34.0%.

MS m/z (ESI): 383.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.11 ( b r. s, 1H), 8.56 (m, 2H), 7.81 (m, 4H), 7.55 (m, 3H), 7.30 (m, 2H), 5.06(s,2H), 4.80(s,2H), 4.39(s,2H)

Example 46

4-[[3-(1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine-2-carbonyl)-4-fluoro-phenyl] Methyl]-2 H -pyridazin-1-one

first step

O5-benzyl O2-tert-butyl 3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2,5-dicarboxylate

Dissolve 1,3,3 a , 4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine-2-carboxylic acid tert-butyl ester 30a (200 mg, 0.89 mmol) in 5 Triethylamine (369 μL, 2.66 mmol) was added to mL dichloromethane. Benzyl chloroformate (189 μL, 1.33 mmol) was added dropwise at 0 ° C and allowed to react at room temperature for 12 hours. 3 mL of dichloromethane and 10 mL of water were added, and the organic phase was separated, washed with a saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give O5-benzyl O2- Tributyl 3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2,5-dicarboxylate 46a (250 mg, yellow oil (product), yield: 78.0%.

MS m/z (ESI): 261.1 [M-100+1]

Second step

1,2,3,3 a ,4,6,7,7 a - octahydropyrrolo[3,4- c ]pyridine-5-carboxylic acid benzyl ester trifluoroacetate

O5-benzyl O2-tert-butyl 3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2,5-dicarboxylate 46a (250 mg, 0.69 mmol) was dissolved in trifluoroacetic acid (386 μL, 2.78 mmol) and reacted for 0.5 h. Concentration under reduced pressure gave crude 1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine-5-carboxylate trifluoroacetate 46b (260 mg , yellow oil), the product was directly subjected to the next reaction without purification.

third step

2- [2-fluoro-5 - [(4-oxo -3 H - phthalazin-1-yl) methyl] benzoyl-yl] -3,3 a, 4,6,7,7 a - six Hydrogen-1 H -pyrrolo[3,4- c ]pyridine-5-carboxylic acid benzyl ester

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (207 mg, 0.69 mmol) in 5 mL of N,N-dimethylformamide To the amine, 1-hydroxybenzotriazole (54 mg, 0.40 mmol), crude 1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine -5-Benzyl benzoate trifluoroacetate 46b (260 mg, 0.69 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (199 mg, 1.04 mmol) , reaction for 12 hours. Concentration under reduced pressure, the residue obtained was purified by silica gel eluting to afford 2-[2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzene Methotyl]-3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-5-carboxylic acid benzyl ester 46c (35 mg, yellow solid) Yield: 9.3%.

MS m/z (ESI): 541.2 [M+1]

the fourth step

4-[[3-(1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine-2-carbonyl)-4-fluoro-phenyl] Methyl]-2 H -pyridazin-1-one

2- [2-fluoro-5 - [(4-oxo -3 H - phthalazin-1-yl) methyl] benzoyl-yl] -3,3 a, 4,6,7,7 a - Hexahydro-1 H -pyrrolo[3,4- c ]pyridine-5-carboxylic acid benzyl ester 46c (300 mg, 0.55 mmol) was dissolved in 10 mL of methanol, and 50 mg of 10% palladium/carbon was added and replaced with hydrogen three times. Reaction for 5 hours. Filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by a thin layer chromatography to afford 4-[[3-(1,3,3 a ,4,5,6,7,7 a -8-hydrogen) Pyrrolo[3,4- c ]pyridine-2-carbonyl)-4-fluoro-phenyl]methyl]-2 H -phthalazin-1-one 46 (134 mg, white solid), yield: 60.0% .

MS m/z (ESI): 407.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 8.38 (d, 1H), 7.94 (m, 1H), 7.78 (m, 2H), 7.50 (m, 1H), 7.37 (m, 1H), 7.17 ( Dd, 1H), 4.58 (m, 1H), 4.39 (s, 2H), 3.74 (m, 1H), 3.60 (m, 1H), 3.45 (m, 1H), 3.24 (m, 1H), 3.20 (m) , 2H), 3.17 (m, 1H), 2.73 (m, 1H), 2.64 (m, 1H), 2.05 (m, 1H), 1.88 (m, 1H), 1.67 (m, 1H)

Example 47

4-[[3-(5,7-Dihydropyrrole[3,4- b ]pyrazine-6-carbonyl)-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

2,3-di(bromomethyl)pyrazine

2,3-Dimethylpyrazine 47a (4 g, 0.037 mol) was dissolved in 100 mL of carbon tetrachloride, and N-bromosuccinimide (19 g, 0.11 mol) and azobis Nitrile (0.60 g, 3.69 mmol) was refluxed at 80 ° C for 6 hours and at 50 ° C for 12 hours. Filtration, the filter cake was washed with dichloromethane (20 mL×2), the filtrate was washed with saturated sodium thiosulfate solution (20 mL×2), and the filtrate was concentrated under reduced pressure to give 2,3-di(bromomethyl)pyrazine. 47b (6 g, yellow oil), yield: 66.0%.

MS m/z (ESI): 266.9 [M+1]

Second step

6-trityl-5,7-dihydropyrrolo[3,4- b ]pyrazine

Dissolve 2,3-bis(bromomethyl)pyrazine 47 b (400 mg, 1.51 mmol) in 20 mL of N,N-dimethylformamide and add 5 mL of tritylamine (1.18 g, 4.52 mmol) of N,N-dimethylformamide solution. At 0 ° C, 1 mL of N,N-diisopropylethylamine was added and the reaction was carried out for 1 hour. Add 100 mL of water, extract with ethyl acetate (100 mL×3), combine the organic phases, wash with saturated ammonium chloride solution (50 mL×2), saturated sodium chloride solution (50 mL×2), anhydrous sulfuric acid sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, to give crude 6-trityl-5,7-dihydro-pyrrolo [3,4- b] pyrazin-47c (800 mg, brown solid) was used without further purification Carry out the next reaction.

MS m/z (ESI): 363.1 [M+1]

third step

6,7-Dihydro-5 H -pyrrolo[3,4- b ]pyrazine

The crude 6-trityl-5,7-dihydropyrrolo[3,4- b ]pyrazine 47c (250 mg, 0.69 mmol) was dissolved in 15 mL of 2M hydrogen chloride in methanol and reacted for 12 hours. Concentration under reduced pressure gave crude EtOAc (3,4-dihydro- 5H -pyrrolo[3,4-b]pyrazine 47d (80 mg, brown oil).

the fourth step

4-[[3-(5,7-Dihydropyrrolo[3,4- b ]pyrazine-6-carbonyl)-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (246 mg, 0.83 mmol) in 10 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (391 mg, 1.03 mmol) was added, and the crude 6,7-dihydro-5 H -pyrrolo[3 , 4- b ]pyrazine 47d (80 mg, 0.69 mmol) and N,N-diisopropylethylamine (178 mg, 1.38 mmol). The organic layer was combined with EtOAc (EtOAc) (EtOAc) The resulting residue was purified by thin layer chromatography using a solvent system A to give 4-[[3-(5,7-dihydropyrrolo[3,4- b ]pyrazine-6-carbonyl)-4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 47 (42 mg, white solid), yield: 15.2%.

MS m/z (ESI): 402.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.04 ( br . s, 1H), 8.44-8.49 (m, 3H), 7.73-7.80 (m, 3H), 7.40-7.42 (m, 2H), 7.11 -7.15(m,1H),5.06(s,2H),4.73(s,2H),4.31(s,2H)

Example 48

4-[4-Fluoro-3-(4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1,5- d ][1,4]oxazin-7-carbonyl)benzyl]-2 H -pyridazin-1-one

first step

4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1,5- d ][1,4]oxazine salt Acid salt

5 a , 6,8,8 a -tetrahydropyrrolo[3,4- b ][1,2,3]triazolo[1,5- d ][1,4]oxazine-7 (4 H )-carboxylic acid tert-butyl ester 48a (1.20 g, 4.50 mmol, prepared by the known method "patent WO2009071657") was dissolved in 20 mL of 2M hydrogen chloride in 1,4-dioxane for 12 hours. Concentration under reduced pressure gave crude 4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1,5- d ][1 , 4] Oxazine hydrochloride 48b (1.10 g, brown solid), the product was taken directly to the next reaction without purification.

Second step

4-[4-Fluoro-3-(4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1,5- d ][1,4]oxazin-7-carbonyl)benzyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (300 mg, 1 mmol) in 10 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (568 mg, 1.50 mmol), crude 4,5 a ,6,7,8,8 a - Hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1,5- d ][1,4]oxazine hydrochloride 48b (303 mg, 1.50 mmol) and N,N Diisopropylethylamine (0.6 mL, 3 mmol) was reacted for 12 hours. Concentrate under reduced pressure, add 50 mL of water, EtOAc (EtOAc (EtOAc) A thin layer chromatography and the obtained residue was purified by developing solvent system, to give 4- [4-fluoro -3- (4,5 a, 6,7,8,8a- hexahydropyrrolo [3,4- b] [ 1,2,3]triazolo[1,5- d ][1,4]oxazin-7-carbonyl)benzyl]-2 H -phthalazin-1-one 48 (320 mg, white solid) Yield: 71.7%.

MS m/z (ESI): 447.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.59 ( br . s, 1H), 8.25-8.27 (m, 1H), 7.82-7.98 (m, 3H), 7.67 (s, 1H), 7.46- 7.48 (m, 2H), 7.28-7.29 (m, 1H), 5.29-5.33 (m, 1H), 5.02-5.08 (m, 1H), 4.36-4.57 (m, 1H), 4.35 (s, 2H), 4.15-4.34(m,1H), 3.95-4.05(m,1H), 3.59-3.63(m,2H),3.13-3.15(m,1H)

Example 49

4-[[4-fluoro-3-(2-methyl-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)phenyl]methyl]-2 H -pyridazine- 1-ketone

2-Fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (600 mg, 2.04 mmol) was dissolved in 15 mL of N,N-dimethylform. To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.39 g, 3.67 mmol), 2-methyl-6,7-dihydro-5 H- Pyrrolo[3,4- d ]pyrimidine 49a (304 mg, 2.25 mmol, prepared by the known method "Patent WO2006127530") and N,N-diisopropylethylamine (1.8 mL, 10.20 mmol), reaction 12 hours. Concentration under reduced pressure, and the residue obtained was purified by silica gel eluting to afford 4-[[4-fluoro-3-(2-methyl-5,7-dihydropyrrolo[3,4- d ] pyrimidine-6-carbonyl) phenyl] methyl] -2 H - phthalazin-1-one 49 (100 mg, white solid), yield: 11.8%.

MS m/z (ESI): 416.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.16 ( br . s, 1H), 8.65 (s, 1H), 8.47 (d, 1H), 7.78 (m, 3H), 7.39 (m, 2H), 7.12 (t, 1H), 4.96 (m, 2H), 4.70 (m, 1H), 4.63 (m, 1H), 4.30 (m, 2H), 2.73 (s, 3H)

Example 50

4 - [[4-fluoro-3- [5- (3-pyridylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c Pyridine-2-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine-2-carbonyl)-4-fluoro-phenyl ]Methyl]-2 H -phthalazin-1-one 46 (90 mg, 0.22 mmol) was dissolved in 15 mL of 1,2-dichloroethane, then pyridine-3-carbaldehyde (36 mg, 0.33 mmol) Reaction for 1.5 hours. After cooling to room temperature, sodium cyanoborohydride (28 mg, 0.44 mmol) was added and allowed to react for 12 hours. After adding 20 mL of a saturated ammonium chloride solution, the mixture was extracted with dichloromethane (20 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate The resulting residue was purified by thin layer chromatography eluting to afford 4-[[4-fluoro-3-[5-(3-pyridylmethyl)-3,3 a ,4,6,7, 7 a -Hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one 50 (31 mg, white solid) Rate: 28.4%.

MS m/z (ESI): 498.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 8.67 (d, 1H), 8.56 (t, 1H), 8.36 (d, 1H), 8.04 (m, 1H), 7.97 (d, 1H), 7.87 (m, 2H), 7.49 (m, 3H), 7.16 (t, 1H), 4.40 (s, 2H), 4.08 (s, 2H), 3.66 (m, 2H), 3.58 (m, 1H), 3.40 ( m, 2H), 2.96 (m, 4H), 2.04 (m, 1H), 1.88 (m, 1H), 1.63 (m, 1H)

Example 51

4 - [[4-fluoro-3- [2- (3-pyridylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3,4- c Pyridine-5-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,2,3,3 a ,4,6,7,7 a -octahydropyrrolo[3,4- c ]pyridin-5-carbonyl)-4-fluoro-phenyl ]Methyl]-2 H -phthalazin-1-one 30 (100 mg, 0.25 mmol) was dissolved in 20 mL of 1,2 dichloroethane, pyridine-3-carbaldehyde (50 mg, 0.44 mmol) was added and reflux Reaction for 3 hours. After cooling to room temperature, sodium cyanoborohydride (50 mg, 0.61 mmol) was added and allowed to react for 12 hours. 15 mL of a saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane (20 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography The residue, to give 4 - [[4-fluoro-3- [2- (3-pyridylmethyl) -3,3 a, 4,6,7,7 a - hexahydro -1 H - pyrrolo [3 , 4- c ]pyridine-5-carbonyl]phenyl]methyl]-2 H -phthalazin-1-one 51 (21 mg, pale yellow solid), yield: 17.3%.

MS m/z (ESI): 498.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.62 (s, 1H), 8.54 (s, 1H), 8.47 (d, 1H), 7.75 (m, 3H), 7.27 (m, 4H), 7.01 (m) , 1H), 4.29 (s, 2H), 3.77 (s, 2H), 3.64 (s, 2H), 3.52 (m, 1H), 3.30 (m, 2H), 2.82 (m, 2H), 2.55 (m, 2H), 2.42 (m, 2H), 2.23 (m, 1H)

Example 52

4-[[3-[(4 aR ,7 aR )-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine -6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

(4a R ,7a R )-6-benzyl-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine

(4 aR ,7 aR )-6-benzyl-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine 41a (2.30 g, 10.60 Ment) dissolved in 50 mL of 1,2-dichloroethane, added 37% formaldehyde solution (2.6 mL, 31.90 mmol), reacted for 2 hours, and added sodium triethoxysulfonate (11.20 g, 53 mmol). Reaction for 12 hours. 1 M sodium hydroxide solution was added dropwise to the reaction solution to pH 8, extracted with dichloromethane (40 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product (4a R, 7a R )-6-benzyl-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine 52a (2.30 g, shallow Yellow oil), the product was directly subjected to the next reaction without purification.

MS m/z (ESI): 231.2 [M+1]

Second step

(4 aR ,7 aR )-1-methyl-2,3,4,4 a ,5,6,7,7 a -octahydropyrrolo[3,4- b ]pyridine

The crude product (4 aR , 7 aR )-6-benzyl-1-methyl-3,4,4a,5,7,7a-hexahydro- 2H -pyrrolo[3,4- b ]pyridine 52a ( 2.30 g, 10 mmol) was dissolved in 20 mL of methanol, and 0.23 g of 10% palladium on carbon was added and replaced with hydrogen three times for 12 hours. The filtrate was concentrated under reduced pressure to give a crude product (4 aR, 7 aR) -1- methyl -2,3,4,4 a, 5,6,7,7 a - octahydro-pyrrolo [3,4- b Pyridine 52b (1.10 g, yellow solid), product was taken to the next step without purification.

MS m/z (ESI): 141.1 [M+1]

third step

4-[[3-[(4 aR ,7 aR )-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine -6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolving 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (2.30 g, 7.80 mmol) in 40 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.40 g, 11.70 mmol), crude (4 aR , 7 aR )-1-methyl-2 was added. ,3,4,4 a ,5,6,7,7 a -octahydropyrrolo[3,4- b ]pyridine 52b (1.10 mg, 7.80 mmol) and N,N-diisopropylethylamine (4.3 mL, 23.40 mmol), reaction for 12 hours. Concentrate under reduced pressure, add 40 mL of water, extract with dichloromethane (40 mL×3), and combine the organic phases and wash with saturated sodium bicarbonate solution (30 mL×2) and saturated sodium chloride solution (30 mL×2) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and purifying the residue by eluent column chromatography using eluent column chromatography, and further purifying the residue by using thin layer chromatography to develop the residue to obtain 4 -[[3-[(4 aR ,7 aR )-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine- 6- carbonyl] -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 52 (1.10 g, white solid), yield: 33.6%.

MS m/z (ESI): 421.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.55 ( br. s, 1H), 8.46 (d, 1H), 7.74-7.78 (m, 4H), 7.29-7.31 (m, 1H), 7.00-7.05 ( m,1H), 4.28 (s, 2H), 3.67-3.96 (m, 2H), 3.31-3.49 (m, 2H), 2.79-2.94 (m, 1H), 2.56 (s, 3H), 2.22 (m, 1H), 1.26-1.85 (m, 6H)

Example 53

4-[[3-[(4 aS ,7 aS )-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine -6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step

(4a S ,7a S )-6-benzyl-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine

(4 aS ,7 aS )-6-benzyl-1,2,3,4,4 a ,5,7,7 a -octahydropyrrolo[3,4- b ]pyridine 39e (1.17 g, 5.40 Methyl) dissolved in 25 mL of 1,2-dichloroethane, added 37% formaldehyde solution (1.3 mL, 16.20 mmol), reacted for 2 hours, and added sodium triethoxysulfonate (5.70 g, 27 mmol). Reaction for 12 hours. 1M sodium hydroxide solution was added dropwise to the reaction solution to pH 8, extracted with dichloromethane (40 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product (4a S, 7a S )-6-benzyl-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine 53a (1 g, pale yellow Oily), the product was directly subjected to the next reaction without purification.

Second step

(4 aS ,7 aS )-1-methyl-2,3,4,4 a ,5,6,7,7 a -octahydropyrrolo[3,4- b ]pyridine

Crude (4a S ,7a S )-6-benzyl-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine 53a (1 g, 4.30 mmol) was dissolved in 10 mL of methanol, and 0.10 g of 10% palladium/carbon was added, and hydrogen was replaced three times for 12 hours. Filtration and concentration of the filtrate under reduced pressure afforded crude (4 aS , 7 aS )-1-methyl-2,3,4,4 a ,5,6,7,7 a -octahydropyrrolo[3,4- b Pyridine 53b (0.60 g, light yellow oil).

MS m/z (ESI): 141.1 [M+1]

third step

4-[[3-[(4 aS ,7 aS )-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine -6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolving 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (1.27 g, 4.27 mmol) in 10 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.40 g, 6.40 mmol), crude (4 aS , 7 aS )-1-methyl-2 was added. ,3,4,4 a ,5,6,7,7 a -octahydropyrrolo[3,4- b ]pyridine 53b (0.60 g, 4.27 mmol) and N,N-diisopropylethylamine (2.4 mL, 12.80 mmol), reaction for 12 hours. Concentrate under reduced pressure, add 40 mL of water, extract with dichloromethane (40 mL×3), and combine the organic phases and wash with saturated sodium bicarbonate solution (30 mL×2) and saturated sodium chloride solution (30 mL×2) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and purifying the residue by eluent column chromatography using eluent column chromatography, and further purifying the residue by using thin layer chromatography to develop the residue to obtain 4 -[[3-[(4 aS ,7 aS )-1-methyl-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ]pyridine- 6- carbonyl] -4-fluoro - phenyl] methyl] -2 H - phthalazin-1-one 53 (0.60 g, white solid), yield: 33.3%.

MS m/z (ESI): 421.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.67 ( br . s, 1H), 8.45 (d, 1H), 7.74-7.81 (m, 4H), 7.29-7.30 (m, 1H), 7.00-7.05 (m, 1H), 4.29 (s, 2H), 3.66-3.99 (m, 2H), 3.31-3.46 (m, 2H), 2.81-2.96 (m, 1H), 2.56 (s, 3H), 2.23 (m) , 1H), 1.26-1.86 (m, 6H)

Example 54

4-[[4-fluoro-3-[2-(trifluoromethyl)-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl]phenyl]methyl]-2 H -pyridazine-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (250 mg, 0.87 mmol) in 10 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (989 g, 2.61 mmol), 2-(trifluoromethyl)-6,7-dihydrogen was added. -5 H - pyrrolo [3,4- d] pyrimidine 54a (200 mg, 1.04 mmol, using well-known methods "patent WO2006127530" preparation derived) and N, N- diisopropylethylamine (756μL, 4.35 mmol ), reacted for 12 hours. Concentration under reduced pressure, the residue obtained was purified using EtOAc EtOAc EtOAc (EtOAc) , 4- d] pyrimidine-6-carbonyl] phenyl] methyl] -2 H - phthalazin-1-one 54 (35 mg, yellow solid), yield: 8.6%.

MS m/z (ESI): 470.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.69 ( br . s, 1H), 8.71 (d, 1H), 8.46 (m, 1H), 7.79 (m, 3H), 7.42 (m, 2H), 7.13(t,1H), 5.07(m,2H),4.77(m,2H),4.32(s,2H)

Example 55

4-[[4-fluoro-3-(1-oxo-5,7-dihydropyrrolo[3,4- b ]pyridine-6-carbonyl)phenyl]methyl]-2 H -pyridazine-1 -ketone

first step

5,7-dihydropyrrolo[3,4- b ]pyridine-6-carboxylic acid tert-butyl ester

Dissolve 6,7-dihydro- 5H -pyrrolo[3,4- b ]pyridine hydrochloride 8a (313 g, 2 mmol) in 30 mL of methanol and add triethylamine (1 mL, 7 mmol) Under ice bath, di-tert-butyl dicarbonate (655 mg, 3 mmol) was added and reacted at room temperature for 6 hours. Concentration under reduced pressure gave crude 5,7-dihydropyrrolo[3,4- b ]pyridin-6-carboxylic acid tert-butyl ester 55a (450 mg, as a colourless oil). .

Second step

1-butyl-5,7-dihydropyrrolo[3,4- b ]pyridine-6-carboxylic acid tert-butyl ester

The crude 5,7-dihydropyrrolo[3,4- b ]pyridine-6-carboxylic acid tert-butyl ester 55a (330 mg, 1.50 mmol) was dissolved in 20 mL of dichloromethane and m-chloroperoxybenzoic acid was added. (345 mg, 2 mmol), reaction for 16 hours. Add 50 mL of saturated sodium carbonate solution, extract with methylene chloride (50 mL×3), and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give crude-1 -5,7-dihydropyrrole [3,4- b ]pyridine-6-carboxylic acid tert-butyl ester 55b (250 mg, white solid).

third step

1-oxidized-6,7-dihydro-5 H -pyrrolo[3,4- b ]pyridine hydrochloride

Dissolve 1-oxide-5,7-dihydropyrrolo[3,4- b ]pyridine-6-carboxylic acid tert-butyl ester 55b (931 mg, 4 mmol) in 20 mL of 2 M hydrogen chloride 1,4-two The reaction was carried out for 16 hours in a methylene chloride solution. Concentrated under reduced pressure to give crude 1- oxide 6,7-dihydro -5 H - pyrrolo [3,4- b] pyridine hydrochloride 55c (690mg, white solid) was used without purification in the next step .

the fourth step

4-[[4-fluoro-3-(1-oxo-5,7-dihydropyrrolo[3,4- b ]pyridine-6-carbonyl)phenyl]methyl]-2 H -pyridazine-1 -ketone

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (300 mg, 1 mmol) in 20 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (570 mg, 1.50 mmol), crude 1-oxidized-6,7-dihydro-5 H - Pyrrolo[3,4- b ]pyridine hydrochloride 55c (175 mg, 1 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). Concentrate under reduced pressure, add 80 mL of saturated sodium carbonate solution, extract with dichloromethane (50 mL×3), combine the organic phase, concentrate under reduced pressure, add 100 mL of ethyl acetate, then water (30 mL × 2), saturated The sodium chloride solution was washed (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by thin layer chromatography to afford 4-[[4-fluoro-3-( 1-Oxo-5,7-dihydropyrrolo[3,4- b ]pyridine-6-carbonyl)phenyl]methyl]-2 H -phthalazin-1-one 55 (60 mg, white solid) Yield: 14.4%.

MS m/z (ESI): 417.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.27 ( br . s, 1H), 8.55-8.45 (m, 2H), 7.79-7.76 (m, 3H), 7.74-7.66 (m, 1H), 7.40 -7.37(m,2H),7.14-7.12(m,1H),7.11-7.09(m,1H),5.02(s,2H),4.68(s,2H),4.31(s,2H)

Example 56

4-[[3-(5,7-Dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (250 mg, 0.87 mmol) in 10 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (593 mg, 1.57 mmol), 6,7-dihydro-5 H -pyrrolo[3, 4- d ]pyrimidine hydrochloride 56a (135 mg, 1.04 mmol, obtained by the well-known method "patent WO2006127530") and N,N-diisopropylethylamine (756 μL, 4.35 mmol) were reacted for 12 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc) The residue obtained is purified by thin layer chromatography using a solvent system A to give 4-[[3-(5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)-4-fluoro- phenyl] methyl] -2 H - phthalazin-1-one 56 (36.72 mg, white solid), yield: 10.5%.

MS m/z (ESI): 402.1 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 9.05 (d, 1H), 8.64 (d, 1H), 8.36 (d, 1H), 7.90 (s, 1H), 7.86 (m, 2H), 7.51 ( m, 2H), 7.23 (t, 1H), 5.18 (s, 1H), 5.03 (s, 1H), 4.75 (s, 1H), 4.67 (s, 1H), 4.42 (s, 2H)

Example 57

4 - [[4-fluoro-3- [5 - [[6- (trifluoromethyl) -3-pyridinyl] methyl] -3,3 a, 4,6,7,7 a - hexahydro - 1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl]phenyl]methyl]-2 H -pyridazin-1-one

4-[[3-(1,3,3 a ,4,5,6,7,7 a -octahydropyrrolo[3,4- c ]pyridine-2-carbonyl)-4-fluoro-phenyl ]methyl]-2 H -pyridazin-1-one 46 (80 mg, 0.20 mmol) was dissolved in 15 mL of 1,2-dichloroethane, and 6-(trifluoromethyl)pyridine-3-carbaldehyde was added. 63 mg, 0.35 mmol), refluxed for 2 hours. After cooling to room temperature, sodium cyanoborohydride (32 mg, 0.50 mmol) was added and allowed to react for 12 hours. After adding 20 mL of a saturated ammonium chloride solution and extracting with ethyl acetate (20 mL × 3), the organic phase was combined, washed with a saturated sodium chloride solution (15 mL × 2), dried over anhydrous sodium sulfate The resulting residue was purified by a thin layer chromatography eluting to afford 4-[[4-fluoro-3-[5-[[6-(trifluoromethyl)-3-pyridyl]methyl]- 3,3 a ,4,6,7,7 a -hexahydro-1 H -pyrrolo[3,4- c ]pyridine-2-carbonyl]phenyl]methyl]-2 H -pyridazine-1- Ketone 57 (17 mg, white solid), yield: 15.3%.

MS m/z (ESI): 566.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.62 (s, 1H), 8.70 (d, 1H), 8.26 (d, 1H), 7.95-7.75 (m, 6H), 7.47-7.27 (m) , 2H), 4.64 (s, 2H), 3.58 (s, 2H), 3.56-3.36 (m, 2H), 3.35-3.17 (m, 2H), 2.98-2.93 (m, 1H), 2.33 (br, 2H) ), 2.14 (br, 2H), 1.70 (s, 1H), 1.50 (br, 2H)

Example 58

4-[[4-fluoro-3-[2-[(2-methyl-3-pyridyl)oxy]-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl] Phenyl]methyl]-2 H -pyridazin-1-one

first step

2-methylisothiourea iodate

The thiourea (122 g, 1.61 mmol) was dissolved in 814 mL of methanol, and then the mixture was evaporated. Concentrated under reduced pressure, the residue was washed with 200 mL of ether and 100 mL of methanol, concentrated under reduced pressure to give 2-methyl-isothiourea hydroiodide 58a (325 g, white solid), yield: 92.8%.

Second step

2-methylmercapto-5 H -pyrrole[3,4- d ]pyrimidin-6(7 H )-carboxylic acid tert-butyl ester

3-Oxopyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 5.4 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethylamine (6.6 mL, 49.36 mmol) The mixture was refluxed for 2 hr.

The above yellow solid was dissolved in 40 mL of ethanol, and 2-methylthiourea 58a (2.35 g, 10.80 mmol) and sodium ethoxide (0.55 g, 8.10 mmol) were successively added, and the reaction was refluxed for 5 hours, and reacted at 50 ° C for 12 hours. The reaction was refluxed for 4 hours. Add 30 mL of saturated sodium chloride solution, extract with ethyl acetate (30 mL×3), combine the organic phase, dry over anhydrous sodium sulfate, and then filtered, and then the filtrate is concentrated under reduced pressure. The obtained residue was purified to give 2-carbazyl- 5H -pyrrole[3,4- d ]pyrimidine-6( 7H )-carboxylic acid tert-butyl ester 58b (500 mg, white solid).

MS m/z (ESI): 268.1 [M+1]

third step

2-methanesulfonyl-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester

2-Mercapto-5 H -pyrrole[3,4- d ]pyrimidin-6(7 H )-carboxylic acid tert-butyl ester 58b (100 mg, 0.37 mmol) was dissolved in 10 mL dichloromethane and cooled to 0 At ° C, 3 mL of m-chloroperoxybenzoic acid (193 mg, 0.78 mmol) in dichloromethane was added dropwise, and the mixture was reacted at 0 ° C for 1 hour and at room temperature for 15 hours. Add 40 mL of a mixed solvent of saturated sodium sulfite solution and saturated sodium bicarbonate solution (V/V = 1/1), extract with dichloromethane (40 mL × 2), and combine the organic phases and wash with brine (20 mL) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and purifying the obtained residue by eluent column chromatography to give 2-methanesulfonyl-5,7-dihydropyrrolo[3,4 -d] Pyrimidine-6-carboxylic acid tert-butyl ester 58c (90 mg, white solid), yield: 80.4%.

MS m/z (ESI): 300.1 [M+1]

the fourth step

2-[(2-methyl-3-pyridyl)oxy]-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester

2-Methanesulfonyl-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester 58c (100 mg, 0.33 mmol), 2-methylpyridin-3-ol (36.50 mg, 0.33 mmol) and potassium carbonate (46.10 mg, 0.33 mmol) were dissolved in 6 mL of N,N-dimethylformamide and reacted at 80 ° C for 1 hour. After adding 20 mL of water and extracting with ethyl acetate (30 mL × 3), the organic phase was combined, washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by eluent system B to give 2-[(2-methyl-3-pyridyl)oxy]-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6- T-butyl formate 58d (71.40 mg, white solid), yield: 65.1%.

MS m/z (ESI): 329.1 [M+1]

the fifth step

2-[(2-methyl-3-pyridyl)oxy]-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidine hydrochloride

2-[(2-Methyl-3-pyridyl)oxy]-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester 58d (80 mg, 0.24 mmol Dissolved in 5 mL of dichloromethane, and added 5 mL of a 2.5 M solution of hydrogen chloride in 1,4-dioxane for 12 hours. Concentration under reduced pressure gave crude 2-[(2-methyl-3-pyridyl)oxy]-6,7-dihydro- 5H -pyrrolo[3,4- d ]pyrimidine hydrochloride 58e (56 Mg, off-white solid), the product was used in the next step without isolation.

MS m/z (ESI): 229.1 [M+1]

Step 6

4-[[4-fluoro-3-[2-[(2-methyl-3-pyridyl)oxy]-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl] Phenyl]methyl]-2 H -pyridazin-1-one

Dissolving 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (70 mg, 0.23 mmol) in 8 mL of N,N-dimethylform To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (160 mg, 0.41 mmol), crude 2-[(2-methyl-3-pyridyl) was added. Oxy ]-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidine hydrochloride 58e (56 mg, 0.24 mmol) and N,N-diisopropylethylamine (200 μL, 1.15) Methyl), reaction for 12 hours. After adding 15 mL of water and extracting with ethyl acetate (20 mL × 3), the organic phase was combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, Chromatography to purify the obtained residue in the solvent system A to give 4-[[4-fluoro-3-[2-[(2-methyl-3-pyridyl)oxy]-5,7-dihydropyrrole. [3,4- d] pyrimidine-6-carbonyl] phenyl] methyl] -2 H - phthalazin-1-one 58 (51 mg, white solid), yield: 42.9%.

MS m/z (ESI): 509.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.61 (s, 1H), 8.47 (d, 1H), 8.38 (d, 1H), 8.26 (d, 1H), 7.78 (s, 1H), 7.93-7.73 (m, 2H), 7.60 (t, 1H), 7.55-7.35 (m, 2H), 7.34-7.23 (m, 2H), 4.83 (s, 1H), 4.76 (s, 1H), 4.55 ( s,1H), 4.51(s,1H), 4.34(d,2H), 2.27(s,3H)

Example 59

4-[[4-fluoro-3-(2-methylsulfonyl-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)phenyl]methyl]-2 H -indole Pyrazin-1-one

first step

2-Methanesulfonyl-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidine hydrochloride

Dissolving 2-methanesulfonyl-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester 58c (100 mg, 0.33 mmol) in 6 mL of 2.5 M hydrogen chloride. In a 4-dioxane solution, the reaction was carried out for 18 hours. Concentration under reduced pressure gave crude 2-methanesulfonyl-6,7-dihydro- 5H -pyrrolo[3,4- d ]pyrimidine hydrochloride 59a (78.80 mg, white solid). Used in the next step of the reaction.

Second step

4-[[4-fluoro-3-(2-methylsulfonyl-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)phenyl]methyl]-2 H -indole Pyrazin-1-one

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (100 mg, 0.34 mmol) in 4 mL of N,N-dimethylformamide To the amine, 1-ethyl-(3-dimethylaminopropyl)carbonium diimine hydrochloride (95 mg, 0.50 mmol), 2-methanesulfonyl-6,7-dihydro- 5 H -pyrrolo[3,4- d ]pyrimidine hydrochloride 59a (78.80 mg, 0.34 mmol), 1-hydroxybenzotriazole (54 mg, 0.40 mmol) and N,N-diisopropylethylamine (130 mg, 1.01 mmol), reaction for 12 hours. Concentrate under reduced pressure, add 80 mL of ethyl acetate, and then wash with water (20 mL × 3) The resulting residue was purified to give 4-[[4-fluoro-3-(2-methylsulfonyl-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)phenyl. ] methyl] -2 H - phthalazin-1-one 59 (60 mg, white solid), yield: 37.5%.

MS m/z (ESI): 480.1 [M+1]

¹ H NMR (400 MHz, CDCl 3 ): δ 8.89-8.73 (d, 1H), 8.48-8.45 (m, 1H), 7.81-7.76 (m, 3H), 7.44-7.41 (m, 2H), 7.14 ( t,1H),5.13-5.11(d,2H),4.85-4.80(d,2H),4.32(s,2H),3.38-3.34(d,3H)

Example 60

4-[4-Fluoro-3-(4,5 a ,6,7,8,8 a -hexahydropyrrolo(4-methyl)-[3,4- b ][1,2,3] Zizo[1,5- d ][1,4]oxazine-7-carbonyl)benzyl]-2 H -pyridazin-1-one

first step

6-oxa-3-azabicyclo[3.1.0]cyclohexane-3-carboxylic acid tert-butyl ester

2,5-Dihydropyrrole-1-carboxylic acid tert-butyl ester 14a (2 g, 11.80 mmol) was dissolved in 40 mL of dichloromethane under ice-bath, and m-chloroperoxybenzoic acid (3.47 g, 14.10 mmol) was added. ), react at room temperature for 12 hours. Filtration, the filter cake was washed with petroleum ether, and the filtrate was washed with saturated sodium bicarbonate solution (20 mL×3) and saturated sodium chloride solution (20 mL) and concentrated under reduced pressure to give crude 6-oxa-3-aza. Bicyclo[3.1.0]cyclohexane-3-carboxylic acid tert-butyl ester 60a (2 g, light yellow oil) was used for the next step without isolation.

Second step

3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester

The crude 6-oxa-3-azabicyclo[3.1.0]cyclohexane-3-carboxylic acid tert-butyl ester 60a (2 g, 10.78 mmol) was dissolved in 40 mL of methanol and water (V/V=8 :1) To a mixed solvent, ammonium chloride (1.26 g, 23.60 mmol) and sodium azide (2.10 g, 32.34 mmol) were added, and the mixture was reacted at 80 ° C for 7 hours. After adding 30 mL of a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate (50 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give crude 3-azide-4-hydroxy-pyrrolidine. 1-butylic acid tert-butyl ester 60b (1.60 g, brown oil) was used for the next step without isolation.

MS m/z (ESI): 129.1 [M-100+1]

third step

3-azido-4-but-2-ynyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester

The crude 3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester 60b (0.50 g, 2.19 mmol) was dissolved in 10 mL of tetrahydrofuran under ice bath, and a mixture of sodium hydride and mineral oil (0.14 g) was added. , 60%, 3.28 mmol), react for 30 minutes, add 1-bromo-2-butyne (0.3 mL, 3.28 mmol), and react at room temperature for 12 hours. After adding 10 mL of water and 30 mL of a saturated ammonium chloride solution, the mixture was extracted with ethyl acetate (50 mL×3). Butan-2-alkyneoxy-pyrrolidine-1-carboxylic acid tert-butyl ester 60c (1.60 g, brown oil) was used for the next step without isolation.

MS m/z (ESI): 181.1 [M-100+1]

the fourth step

5 a ,6,8,8 a -tetrahydropyrrolo(4-methyl)-[3,4- b ][1,2,3]triazolo[1,5- d ][1,4] Oxazine-7( 4H )-carboxylic acid tert-butyl ester

The crude 3-azido-4-but-2-ynyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester 60c (0.60 g, 2.10 mmol) was dissolved in 12 mL of xylene and reacted at 140 ° C for 7 hours. Concentration under reduced pressure gave the crude 5a ,6,8,8 a -tetrahydropyrrolo(4-methyl)-[3,4- b ][1,2,3]triazolo[1,5- d [1,4]oxazine-7( 4H )-carboxylic acid tert- butyl ester 60d (0.60 g, brown solid), product was used in the next step without isolation.

MS m/z (ESI): 281.2 [M+1]

the fifth step

4,5 a ,6,7,8,8 a -hexahydropyrrolo(4-methyl)-[3,4- b ][1,2,3]triazolo[1,5- d ][ 1,4]oxazine hydrochloride

The crude product 5 a , 6,8,8 a -tetrahydropyrrolo(4-methyl)-[3,4- b ][1,2,3]triazolo[1,5- d ][1, 4] Oxazin-7( 4H )-carboxylic acid tert- butyl ester 60d (600 mg, 2.10 mmol) was dissolved in 10 mL of 2.5 M hydrogen chloride in 1,4-dioxane for 4 hours. Concentration under reduced pressure gave crude 4,5 a ,6,7,8,8 a -hexahydropyrrolo(4-methyl)-[3,4- b ][1,2,3]triazolo[1 , 5- d ][1,4]oxazine hydrochloride 60e (0.46 g, brown solid).

MS m/z (ESI): 181.1 [M+1]

Step 6

4-[4-Fluoro-3-(4,5 a ,6,7,8,8 a -hexahydropyrrolo(4-methyl)-[3,4- b ][1,2,3] Zizo[1,5- d ][1,4]oxazine-7-carbonyl)benzyl]-2 H -pyridazin-1-one

Dissolving 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (275 mg, 0.93 mmol) in 10 mL of N,N-dimethylformamide Add 4,5 a ,6,7,8,8 a -hexahydropyrrolo(4-methyl)-[3,4- b ][1,2,3]triazolo[1,5- d ][1,4]oxazine hydrochloride 60e (300 mg, 1.38 mmol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (523 mg, 1.38 mmol) N,N-diisopropylethylamine (0.5 mL, 2.76 mmol) was reacted for 12 hours. The organic layer was combined with EtOAc (EtOAc) (EtOAc) The residue obtained was purified by the solvent system A to give 4-[4-fluoro-3-(4,5 a ,6,7,8,8 a -hexahydropyrrolo(4-methyl)-[3, 4- b ][1,2,3]triazolo[1,5- d ][1,4]oxazin-7-carbonyl)benzyl]-2 H -pyridazin-1-one 60 (170 mg , white solid), Yield: 40.0%.

MS m/z (ESI): 461.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.99 (s, 1H), 8.45-8.48 (m, 1H), 7.73-7.82 (m, 3H), 7.38-7.40 (m, 2H), 7.10-7.12 ( m, 1H), 5.31-5.22 (m, 1H), 5.00-5.19 (m, 1H), 4.22-4.30 (m, 4H), 4.19-4.20 (m, 1H), 3.60-3.72 (m, 3H), 2.29(s,3H)

Example 61 4-[[4-fluoro-3-(2-carbamimido-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)phenyl]methyl]-2 H -pyridazine- 1-ketone

first step 2-mercapto-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidine hydrochloride

Dissolve 2-methylmercapto-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester 58b (100 mg, 0.37 mmol) in 4 mL of dichloromethane and add 3 mL A solution of 2.5 M hydrogen chloride in 1,4-dioxane was reacted for 12 hours. Concentration under reduced pressure gave crude 2-carbazin-6,7-dihydro- 5H -pyrrolo[3,4- d ]pyrimidine hydrochloride 61a (45 mg, yellow solid). The next step is the reaction.

Second step 4-[[4-fluoro-3-(2-carbamimido-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)phenyl]methyl]-2 H -pyridazine- 1-ketone

Dissolve 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (100 mg, 0.37 mmol) in 5 mL of N,N-dimethylformamide To the amine, the crude 2-mercapto-6,7-dihydro- 5H -pyrrolo[3,4- d ]pyrimidine hydrochloride 61a (62 mg, 0.37 mmol), 1-hydroxybenzotriazole ( 230 mg, 0.61 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.70 mmol) were reacted for 12 hours. Add 10 mL of water, and extract with ethyl acetate (20 mL×3). The organic phase is combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate Chromatography to purify the obtained residue in the solvent system A to give 4-[[4-fluoro-3-(2-carbamido-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl) phenyl] methyl] -2 H - phthalazin-1-one 61 (30 mg, white solid), yield: 19.7%.

MS m/z (ESI): 448.1 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.61 (s, 1H), 8.51 (d, 1H), 8.25 (d, 1H), 7.97 (d, 1H), 7.96-7.79 (m, 1H) , 7.78-7.73 (m, 1H), 7.56-7.36 (m, 2H), 7.36-7.17 (m, 1H), 4.75 (s, 2H), 4.52 (d, 2H), 4.35 (s, 2H), 2.52 (s, 3H)

Example 62 4-[[3-[(4 aS ,7 aR )-4-methyl-fluoro-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b ][1,4] Oxazine-6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step (4 aS ,7 aR )-4-benzyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine

Dissolve L-(+)-tartaric acid (5.15 g, 34.36 mmol) in 30 mL of methanol, heat to 60 ° C, and add 10 mL of 4-benzyl-3,4 a ,5,6,7,7 a a solution of hexahydro- 2H -pyrrolo[3,4- b ][1,4]oxazine 14e (7.50 g, 34.36 mmol) in methanol, cooled to 49 ° C and allowed to react for 30 min. After cooling to 0 ° C, filtration, the solid was washed with a cooled mixture of 300 mL of ethanol and methanol (V/V = 2:1). The obtained crude product was recrystallized from 50 mL of methanol, and the recrystallized mother liquid was concentrated under reduced pressure to give residue. The solution was dissolved in 50 mL of water, and 6 M sodium hydroxide solution was added dropwise until the pH of the reaction solution was 12, and the mixture was extracted with dichloromethane (100 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, (4 aS ,7 aR )-4-benzyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine 62a (1.60 g, colorless oil), yield: 42.6%.

Second step (4 aS ,7 aR )-4-benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid Tributyl ester

(4 aS ,7 aR )-4-benzyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine 62a (1.60 g, 7.30 mmo1) was dissolved in 50 mL of dichloromethane, and di-tert-butyl dicarbonate (2.40 g, 11 mmol) and triethylamine (2 mL, 14.60 mmol) were added and reacted for 12 hours. Was added 50 mL of saturated ammonium chloride solution and extracted with dichloromethane (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product (4 aS, 7 aR) -4- benzyl group -2,3,4 a, 5,7,7 a - hexahydro-pyrrolo [3,4- b] [1,4] oxazine-6-carboxylic acid tert-butyl ester 62b (3.07 g, colorless oil The product was used in the next step without isolation.

third step (4 aS ,7 aR )-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid third Butyl ester

The crude product (4 aS , 7 aR )-4-benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6- The third butyl formate 62b (3.07 g, 9.60 mmol) was dissolved in 100 mL of methanol, 300 mg of 10% palladium on carbon was added, three times of hydrogen was exchanged, and the reaction was carried out at 2 bar for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to give crude. 4 aS ,7 aR )-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tertidine Ester 62c (2 g, colorless oil) was used for the next step without isolation.

the fourth step (4 aS ,7 aR )-4-methyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carboxylic acid Tributyl ester

Crude (4 aS , 7 aR )-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazin-6-carboxylic acid The third butyl ester 62c (2g, 8.76mmol) was dissolved in 100mL of dichloroethane, added with 37% formaldehyde solution (1.40g, 17.52mmol), reacted for 1 hour, cooled to 0 ° C, and added sodium triethyl sulfonium borohydride. (4.64 g, 21.90 mmol), reacted at room temperature for 12 hours. 80 mL of a saturated sodium carbonate solution was added, and the mixture was extracted with dichloromethane (100 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give crude (4 as , 7 aR )-4-methyl- 2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester 62d (1.80 g, colorless oil) The product was used in the next step without isolation.

the fifth step (4 aS ,7 aR )-4-methyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine salt Acid salt

Crude (4 aS , 7 aR )-4-methyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6- The third butyl formate 62d (1.80 g, 7.40 mmol) was dissolved in 50 mL of 4 M hydrogen chloride in 1,4-dioxane for 12 hours. Concentration under reduced pressure gave crude (4 aS ,7 aR )-4-methyl-3,4 a ,5,6,7,7 a -hexahydro- 2H -pyrrolo[3,4- b ][ 1,4] Oxazine hydrochloride 62e (1.76 g, white solid).

Step 6 4-[[3-[(4 aS ,7 aR )-4-methyl-fluoro-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b ][1,4] Oxazine-6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolving 2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1c (2.45 g, 8.20 mmol) in 60 mL of N,N-dimethylformamide Add benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (3.73 g, 9.80 mmol), N,N-diisopropylethylamine (4.7 mL, 28.7 mmol) And crude (4 aS ,7 aR )-4-methyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4] Oxazine hydrochloride 62e (1.76 g, 8.20 mmol) was reacted for 12 hours. 100 mL of saturated sodium carbonate solution and 100 mL of dichloromethane were added, the organic phase was separated, concentrated under reduced pressure, and the residue was evaporated to ethyl acetate (100 mL). The sodium solution was washed (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system A to give 4-[[3-[(4) aS ,7 aR )-4-methyl-fluoro-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carbonyl]-4 - fluoro - phenyl] methyl] -2 H - phthalazin-1-one 62 (2.80 g, white solid), yield: 80.9%.

MS m/z (ESI): 423.2 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.46 (s, 1H), 8.52-8.50 (m, 1H), 7.82-7.80 (m, 3H), 7.44-7.42 (m, 1H), 7.36-7.34 ( m, 1H), 7.09-7.06 (m, 1H), 4.33-4.31 (m, 2H), 4.18-4.07 (m, 1H), 3.95-3.65 (m, 5H), 3.53-3.46 (m, 2H), 3.33-3.18(m,2H), 2.49(s,3H)

Example 63 4-[[4-fluoro-3-(2-methoxy-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)phenyl]methyl]-2 H -pyridazine 1-ketone

first step 2-methoxy-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester

2-Methanesulfonyl-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester 58c (50 mg, 0.17 mmol) was dissolved in 4 mL of methanol for 10 min. Add a mixture of sodium hydride and mineral oil (10 mg, 60%, 0.22 mmol), react for 3 hours, add 0.5 mL of water, concentrate under reduced pressure, add 70 mL of ethyl acetate, water (10 mL) and saturated sodium chloride The solution (15 mL x 2) was washed. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude 2-oxo-5,7-dihydro-pyrrolo [3,4- d] pyrimidine-6-carboxylic acid tert-butyl ester 63a (30 Mg, brown oil), the product was used in the next step without isolation.

MS m/z (ESI): 252.1 [M+1]

Second step 2-methoxy-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidine hydrochloride

Dissolve 2-methoxy-5,7-dihydropyrrolo[3,4- d ]pyrimidine-6-carboxylic acid tert-butyl ester 63a (78 mg, 0.31 mmol) in 2 mL of dichloromethane and add 2 A solution of 2.5 M hydrogen chloride in 1,4-dioxane was reacted for 12 hours. Concentration under reduced pressure gave crude 2-methoxy-6,7-dihydro- 5H -pyrrolo[3,4- d ]pyrimidine hydrochloride 63b (31 mg, white solid). In the next step of the reaction.

third step 4-[[4-fluoro-3-(2-methoxy-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl)phenyl]methyl]-2 H -pyridazine 1-ketone

Dissolving 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (90 mg, 0.30 mmol) in 8 mL of N,N-dimethylformamide To the amine, the crude 2-methoxy-6,7-dihydro- 5H -pyrrolo[3,4- d ]pyrimidine hydrochloride 63b (50 mg, 0.31 mmol), 1-hydroxybenzotriazole was added. Monohydrate (210 mg, 0.56 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.55 mmol) were reacted for 12 hours. After adding 15 mL of water and extracting with ethyl acetate (25 mL × 3), the organic phase was combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, Chromatography to purify the obtained residue in the solvent system A to give 4-[[4-fluoro-3-(2-methoxy-5,7-dihydropyrrolo[3,4- d ]pyrimidin-6-carbonyl ) phenyl] methyl] -2 H - phthalazin-1-one 63 (20 mg, white solid), yield: 11.5%.

MS m/z (ESI): 432.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 12.59 (s, 1H), 8.45 (d, 1H), 8.25 (d, 1H), 7.97 (d, 1H), 7.99-7.79 (m, 1H) , 7.78-7.64 (m, 1H), 7.57-7.37 (m, 2H), 7.35-7.17 (m, 1H), 4.73 (d, 2H), 4.49 (d, 2H), 4.35 (s, 2H), 3.89 (s, 3H)

Example 64 4-[[3-[(4 aR ,7 aS )-4-methyl-fluoro-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b ][1,4] Oxazine-6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

first step (4 aR ,7 aS )-4-benzyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine

Dissolve D-(-)-tartaric acid (5.15 g, 34.36 mmol) in 30 mL of methanol, heat to 60 ° C, and add 10 mL of 4-benzyl-3,4 a ,5,6,7,7 a a solution of hexahydro- 2H -pyrrolo[3,4- b ][1,4]oxazine 14e (7.50 g, 34.36 mmol) in methanol, cooled to 49 ° C and allowed to react for 30 min. After cooling to 0 ° C, filtration, the solid was washed with a cooled mixture of 300 mL of ethanol and methanol (V/V = 2:1). The obtained crude product was recrystallized from 50 mL of methanol, and the recrystallized mother liquid was concentrated under reduced pressure to give residue. The solution was dissolved in 50 mL of water, and 6 M sodium hydroxide solution was added dropwise until the pH of the reaction solution was 12, and the mixture was extracted with dichloromethane (100 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, (4 aR ,7 aS )-4-benzyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine 64a (1.80 g, colorless oil), yield: 48.0%.

Second step (4 aR ,7 aS )-4-benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid Tributyl ester

(4 aR ,7 aS )-4-benzyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine 64a (1.80 g, 8.20 mmol) was dissolved in 40 mL of dichloromethane, and di-n-butyl dicarbonate (2.70 g, 12.40 mmol) and triethylamine (2.3 mL, 16.40 mmol). Add 50 mL of saturated ammonium chloride solution, extract with methylene chloride (100 mL×3), combine the organic phase, dried over anhydrous sodium sulfate, and filtered, and then the filtrate is concentrated under reduced pressure to give crude (4 aR , 7 aS )-4-benzyl Base-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester 64b (2.60 g, colorless oil The product was used in the next step without isolation.

third step (4 aR ,7 aS )-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid third Butyl ester

The crude product (4 aR , 7 aS )-4-benzyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6- The third butyl formate 64b (2.60 g, 8.16 mmol) was dissolved in 60 mL of methanol, 260 mg of 10% palladium on carbon was added, three times of hydrogen was exchanged, and the reaction was carried out at 2 bar for 4 hours, and the filtrate was concentrated under reduced pressure to give a crude product. 4 aR ,7 aS )-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tertidine Ester 64c (1.80 g, colorless oil) was used for the next step without isolation.

the fourth step (4 aR ,7 aS )-4-methyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid Tributyl ester

Crude (4 aR , 7 aS )-3,4,4 a ,5,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazin-6-carboxylic acid The third butyl ester 64c (1.80 g, 7.88 mmol) was dissolved in 60 mL of dichloroethane, added with 37% formaldehyde solution (1 mL, 11.80 mmol), reacted for 1 hour, cooled to 0 ° C, and added triethylsulfonium boron. Sodium hydride (5 g, 23.60 mmol) was reacted at room temperature for 12 hours. 80 mL of saturated sodium carbonate solution was added, and the mixture was extracted with dichloromethane (100 mL×3). The organic phase was combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give crude (4 aR , 7 aS )-4-methyl-2 ,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazine-6-carboxylic acid tert-butyl ester 64d (2 g, colorless oil), The product was used in the next step without isolation.

the fifth step (4 aR ,7 aS )-4-methyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4]oxazine salt Acid salt

Crude (4 aR , 7 aS )-4-methyl-2,3,4 a ,5,7,7 a -hexahydropyrrolo[3,4- b ][1,4]oxazin-6- The third butyl formate 64d (2 g, 8.25 mmol) was dissolved in 50 mL of 4M hydrogen chloride in 1,4-dioxane and allowed to react for 24 hours. Concentration under reduced pressure gave crude (4 aR , 7 as )-4-methyl-3,4 a ,5,6,7,7 a -hexahydro- 2H -pyrrolo[3,4- b ][1 4] Oxazine hydrochloride 64e (1.76 g, white solid).

Step 6 4-[[3-[(4 aR ,7 aS )-4-methyl-fluoro-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b ][1,4] Oxazine-6-carbonyl]-4-fluoro-phenyl]methyl]-2 H -pyridazin-1-one

Dissolving 2-fluoro-5-[(4-oxo- 3H -pyridazin-1-yl)methyl]benzoic acid 1c (2.09 g, 7 mmol) in 60 mL of N,N-dimethylformamide To the amine, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.18 g, 8.40 mmol), N,N-diisopropylethylamine (4 mL, 24.50) was added. Ment) and (4 aR ,7 aS )-4-methyl-3,4 a ,5,6,7,7 a -hexahydro-2 H -pyrrolo[3,4- b ][1,4] Oxazine hydrochloride 64e (1.52 g, 7 mmol) was reacted for 24 hours. 100 mL of saturated sodium carbonate solution and 100 mL of dichloromethane were added, the organic phase was separated, concentrated under reduced pressure, and the residue was evaporated to ethyl acetate (100 mL). The sodium solution was washed (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography with eluent system A to give 4-[[3-[(4) aR ,7 aS )-4-methyl-fluoro-2,3,4a,5,7,7a-hexahydropyrrolo[3,4- b ][1,4]oxazin-6-carbonyl]-4 - fluoro - phenyl] methyl] -2 H - phthalazin-1-one 64 (1.50 g, white solid), yield: 50.8%.

MS m/z (ESI): 423.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.46 (S, 1H), 8.52-8.50 (m, 1H), 7.82-7.80 (m, 3H), 7.44-7.42 (m, 1H), 7.36-7.34 ( m, 1H), 7.09-7.06 (m, 1H), 4.33-4.31 (m, 2H), 4.18-4.07 (m, 1H), 3.95-3.65 (m, 5H), 3.53-3.46 (m, 2H), 3.33-3.18(m,2H), 2.49(s,3H)

Example 65 4-[4-Fluoro-3-((5 aR ,8 aR )-4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3] Triazolo[1,5- d ][1,4]oxazin-7-carbonyl)benzyl]-2 H -pyridazin-1-one

4-[4-Fluoro-3-(4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1,5 - d ][1,4]oxazine-7-carbonyl)benzyl]-2 H -phthalazin-1-one 48 (550 mg, 1.23 mmol) was purified by HPLC to afford 4-[4-fluoro -3-((5 aR ,8 aR )-4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1, 5- d] [1,4] oxazine-7-carbonyl) benzyl] -2 H - phthalazin-1-one 65 (240 mg, white solid), yield: 99.9%.

MS m/z (ESI): 446.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD- d ₄ ): δ 8.35-8.38 (d, 1H), 7.82-7.96 (m, 3H), 7.63 (s, 1H), 7.46-7.53 (m, 1H), 7.44-7.45 (m, 1H), 7.20-7.45 (m, 1H), 5.27-5.35 (m, 1H), 5.06-5.15 (m, 1H), 4.57-4.61 (m, 1H), 4.40 (s, 2H) ), 4.13-4.16 (m, 2H), 3.49-3.74 (m, 3H)

Example 66 4-[4-Fluoro-3-((5 aS, 8 aS )-4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3] Triazolo[1,5- d ][1,4]oxazin-7-carbonyl)benzyl]-2 H -pyridazin-1-one

4-[4-Fluoro-3-(4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1,5 - d ][1,4]oxazine-7-carbonyl)benzyl]-2 H -phthalazin-1-one 48 (550 mg, 1.23 mmol) was purified by HPLC to afford 4-[4-fluoro -3-((5 aS ,8 aS )-4,5 a ,6,7,8,8 a -hexahydropyrrolo[3,4- b ][1,2,3]triazolo[1, 5- d] [1,4] oxazine-7-carbonyl) benzyl] -2 H - phthalazin-1-one 66 (290 mg, white solid), yield: 99.9%.

MS m/z (ESI): 446.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD- d ₄ ): δ 8.35-8.37 (d, 1H), 7.83-7.96 (m, 3H), 7.62 (s, 1H), 7.46-7.53 (m, 1H) , 7.44-7.45 (m, 1H), 7.20-7.45 (m, 1H), 5.28-5.35 (m, 1H), 5.06-5.16 (m, 1H), 4.61-4.63 (m, 1H), 4.40 (s, 2H), 4.12-4.16 (m, 2H), 3.50-3.74 (m, 3H)

Test case: Biological evaluation Example 1 PARP enzyme activity assay

The following in vitro screening assays were used to determine the inhibition of PARP enzyme activity by the compounds of the invention.

The experiments described below were carried out by using the TREVIGEN HT F homologous poly(Adenosine diphosphate-ribose) polymerase inhibitor kit (TREVIGEN HT F homogeneous PARP Inhibition Assay Kit, Cat. No. 4690-096-K) to determine the compound of the invention against PARP. Inhibition of enzyme activity. The experiment is based on the PARP-related DNA repair process that consumes NAD ⁺ , and NAD ⁺ is used in another reaction to catalyze the non-fluorescent active matrix to a highly fluorescent active molecule, so by measuring the enhancement of the fluorescent signal, The level of NAD ⁺ in the reaction system was known to calculate the degree of inhibition of PARP enzyme activity by the test compound.

The detailed operation of the experiment and the preparation of the reagents used, such as reaction mix, circulation mix, buffer, etc., can refer to TREVIGEN HT F homopoly (Adenosine diphosphate) - Ribose) Polymerase Inhibition Kit Instructions.

The experimental procedure is briefly described as follows: The test compound is dissolved in dimethyl hydrazine and subsequently diluted to the desired concentration for the experiment with 1x buffer. First, 25 μL of a 200 nM, NAD ⁺ solution was added to a round bottom 96-well plate, followed by the addition of 1 μL of the test compound solution and a duplicate well control. Then, 25 μL of a reaction mixture containing DNA, PARP enzyme and reaction buffer was added to each well. After incubating for 30 minutes at room temperature, 50 μL of the loop reaction mixture was added to each well, and incubated at room temperature for 15 to 40 minutes in the dark. Subsequently, 50 μL of the stop solution was added, and the fluorescence value (Ex544 nm, Em 590 nm) of each well was read on a microplate reader. The inhibition rate of PARP enzyme activity by the compound can be calculated by the NAD ⁺ standard curve equation.

IC ₅₀ values for compounds may be obtained by calculating the inhibition rate at different concentrations.

Example 2 cell proliferation inhibition experiment

The following experiment was conducted to determine the proliferation inhibitory activity of the compound of the present invention against the triple negative phenotype of breast cancer cell line MDA-MB-436 cells under in vitro conditions.

The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against a triple negative phenotype of breast cancer cells, and the inhibitory activity of the compound can be expressed by an IC ₅₀ value.

The experimental protocol is briefly described as follows: First, DMEM F12 is supplemented with 10% FBS (all purchased from Gibco) as a complete medium, and MDA-MB-231 and MDA-MB-436 cells are at a suitable cell density (eg 3000/mL medium). The cells were seeded on a 96-well culture plate and cultured overnight in a constant temperature incubator at 37 ° C under 5% CO ₂ . Test compounds were first dissolved in DMSO and subsequently diluted to the concentration required for the experiment in medium without FBS. After the cells were attached, the original medium was replaced with fresh medium supplemented with a series of gradient concentrations of test compound (typically 7 or 9 concentration points). Thereafter, the cell culture plate was further cultured for 72 hours at 37 ° C under 5% CO ₂ . After 72 hours, the inhibitory activity of the compound against cell proliferation was measured by the method of CCK8 (Cell Counting Kit-8, Cat. No.: CK04, available from Dojindo).

IC ₅₀ values for compounds may be obtained by calculating the test compound at various concentrations for inhibition of cell proliferation values.

Conclusion: The preferred compounds of the present invention have significant inhibitory activity against MDA-MB-436 cells in inhibiting proliferation.

Pharmacokinetic evaluation Test Example 1 Pharmacokinetic tests of the compounds of Example 8, Example 18 and Example 62 of the present invention 1. Summary

SD rats were used as test animals, and the concentration of the drug in plasma at different times after the administration of the compound of Example 8, the compound of Example 18 and the compound of Example 62 by intragastric administration and intravenous injection were determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2, the test plan 2.1 Test drugs

Example 8 compound, Example 18 compound and Example 62 compound

2.2 Test animals

24 healthy adult SD rats, male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2003-0002.

2.3 Drug preparation

Oral administration group: Weigh a certain amount of the drug, add 0.5 mL of dimethyl hydrazine to dissolve, then add physiological saline to 10 mL, and configure it to 1.5 mg/mL; intravenous administration group: weigh the appropriate amount of medicine, then add 0.5% sodium carboxymethylcellulose was formulated into a 1.5 mg/mL suspension.

2.4 administration

Twenty-four healthy adult SD rats, half male and half female, were intragastrically administered after fasting overnight. The doses were all 15.0 mg/kg and the administration volume was 10 mL/kg.

2.5 Sample Collection

The gavage administration group: 0.2 mL of blood collected from the eyelids before and after administration and 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 7.0, 9.0, 12.0, 24.0 hours after administration, and placed in a heparinized test tube At 3500 rpm, the plasma was separated by centrifugation for 20 minutes, stored at -20 ° C, and fed 2 hours after administration.

Intravenous administration group: 0.2 mL from the eyelids before and 2 minutes after administration, 0.5 minutes, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours, placed in heparinized tubes At 3500 rpm, the plasma was separated by centrifugation for 20 minutes and stored at 20 °C.

3. Operation

Take 20 μL of rat blank plasma at each time after administration, add 50 μL of internal standard solution, 140 μL of methanol, mix and vortex for 3 minutes, centrifuge for 10 minutes (13500 rpm), and take 20 μL of supernatant for LC- MS/MS analysis. The main pharmacokinetic parameters were calculated using DAS 2.0 software.

4, pharmacokinetic parameters results The pharmacokinetic parameters of the compounds of the invention are as follows:

Conclusion: The compound of the present invention has better drug metabolism data and the pharmacokinetic properties are obviously improved.

Antitumor effect evaluation Test Example 1 Tests the antitumor effect of the compound of the present invention on mice Experimental purpose

The efficacy of the compound of the present invention in combination with temozolomide (TMZ) on human colon cancer SW620 xenograft tumor nude mice was tested.

2. Test drug Example compound 3. Experimental animals

BALB/cA-nude nude mice, SPF, 16 to 20 g, sputum, purchased from Shanghai Sip. Bikai Experimental Animals Co., Ltd. Certificate No.: SCXK (Shanghai) 2008-0016.

4. Experimental steps 4.1 The nude mouse laboratory environment was adapted for three days. 4.2 Nude mice were subcutaneously inoculated with colon cancer SW620 cells (5×10 ⁶ /piece), and the tumors were grown for 10 days and grown to 339±132 mm ^{3 and the} animals were randomly divided into groups (d0). The dosages and dosing schedules are shown in the table below. The tumor volume was measured 2 to 3 times a week, weighed, and data were recorded. The tumor volume (V) is calculated as:

V=1/2×a×b ²

Where a and b represent length and width, respectively.

Tumor inhibition rate (%) = (C-T) / C (%)

Among them: T and C are the tumor volume of the experimental group (test compound) and the blank control group at the end of the experiment.

5. Dosing schedule, dose and experimental results

Conclusion: The tumor inhibition rate % data range indicates: "+": 50% to 60%; "++": 60% to 80%; "+++": 80% to 100%. The compound to be tested of the present invention combined with TMZ has a good tumor inhibition rate for colon cancer SW620 cells, and most of them are higher than 60%.

Claims (27)

A compound of the formula (I) or a pharmaceutically acceptable salt thereof: Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituted by a substituent selected from a halogen, a hydroxyl group, an alkyl group or an alkoxy group; R ^{5 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an oxo group, C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl or alkoxy. Substituted ; R ⁶ and R ⁷ are each independently selected from hydrogen atoms, alkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, ^{heteroaryl, -C (O) OR 8,} -OC (O R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ , or R ⁶ and R ⁷ together form an oxo group; ring atoms D or E are each independently selected from C or N atoms; when n is 1, D and E are bonded to each other to form 6 Up to 10 membered ring X, when cyclized, in accordance with the valence bond theory, the 6 to 10 membered ring X is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group aryl or heteroaryl is independently optionally further substituted with one or more substituents selected from alkyl, halo, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzyl, oxo, -OR ^8, - C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O Substituted by a substituent of R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group And the heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkane , Cycloalkyl, heterocyclyl, aryl, heteroaryl, ^{oxo, -C (O) OR 8,} -OC (O) R 8, -O (CH 2) p C (O) OR 8, -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ Substituted by a substituent; when n is 2, D and E are bonded to each other to form a 5- to 10-membered ring X, which conforms to the valence bond theory, and the 5- to 10-membered ring X is selected from a cycloalkyl group and a heterocyclic group. Or a heteroaryl group, wherein the cycloalkyl, heterocyclic or heteroaryl group is each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ Substituted with a substituent of -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ , wherein Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocycle. Base, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) Substituted with a substituent of _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ ; R ^{8 is} selected from a hydrogen atom, An alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from one or more Substituted with a substituent of an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, An alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from one or more Substituted by a substituent of an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or, R ⁹ and R ¹⁰ are bonded to a nitrogen atom The atom forms a heterocyclic group, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group is optionally further selected from one or more selected from the group consisting of an alkyl group, a halogen, and a hydroxyl group. , alkoxy, cycloalkyl, heterocyclic, aryl, Substituted by a substituent of a heteroaryl, carboxylic acid or carboxylic acid ester; m is 0, 1 or 2; n is 1 or 2; and p is 0, 1 or 2. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to the invention of claim 1, which comprises a compound of the formula (II) or a pharmaceutically acceptable salt thereof: Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, An aryl or heteroaryl group, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituted by a substituent selected from a halogen, a hydroxyl group, an alkyl group or an alkoxy group; R ^{5 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an oxo group, C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl or alkoxy. Substituted The ring atoms D or E are each independently selected from C or N atoms; D and E are bonded to each other to form a 6 to 10 membered ring X, which conforms to the valence bond theory, and the 6 to 10 membered ring X is selected from cycloalkyl groups. Or a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cycloalkane , heterocyclic, aryl, heteroaryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O) OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR Substituted by a substituent of ⁹ R ¹⁰ wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ is substituted with a substituent; ^{R. 8} is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group Wherein the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocycle Substituted with a substituent of a aryl group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocycle Substituted with a substituent of a aryl group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or, R ⁹ and R ¹⁰ form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclyl optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituted by a substituent of a heteroaryl, carboxylic acid or carboxylic acid ester; m is 0, 1 or 2; and p is 0, 1 or 2. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to the invention of claim 2, which comprises a compound of the formula (III) or a pharmaceutically acceptable salt thereof: Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituents selected from halogen, hydroxy, alkyl or alkoxy are substituted; Y, Z, G and J are each independently selected from N or C atoms; provided that Y, Z, G or J are not simultaneously N atoms, at the same time, any three ring atoms that are arbitrarily connected cannot be N atoms at the same time; when Y, Z, G and J are selected from N atoms, there is no substitution; when Y, Z, G and J are selected from C atoms Wherein, Y, Z, G and J are each independently optionally further selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a benzyl group, an oxo group, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ , wherein alkyl, alkoxy, cycloalkyl, heterocyclic Or an aryl, heteroaryl or benzyl group, each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -C (O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O) Substituted with a substituent of R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ ; R ^{8 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic ring a aryl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy Substituted by a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester R ⁹ or R ¹⁰ are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each Independently optionally further substituted with one or more substituents selected from alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters; Alternatively, R ⁹ and R ¹⁰ form a heterocyclic group with the attached nitrogen atom, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group is optionally further Substituted by one or more substituents selected from alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid ester; m is selected from 0,1 Or 2; and p is selected from 0, 1 or 2. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to the invention of claim 2, which comprises a compound of the formula (IV) or a pharmaceutically acceptable salt thereof: Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituted by a substituent selected from a halogen, a hydroxyl group, an alkyl group or an alkoxy group; R ^{5 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an oxo group, C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl or alkoxy. Substituted ; Y, Z, G, and J are each independently selected from O atoms, N (R ¹¹⁾ or ^{C (R 11) (R 12} ); with the proviso that, Y, Z, G or J are not both N (R ¹¹⁾ Meanwhile, the arbitrarily connected three ring atoms cannot be N(R ¹¹ ) at the same time; and, when Y, Z, J or G is selected from N(R ¹¹ ) or C(R ¹¹ )(R ¹² ), any adjacent The two ring atoms may form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; R ^{8 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by a substituent of a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by a substituent of a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or R ⁹ and R ¹⁰ together with the nitrogen atom attached form a heterocyclyl, wherein the heterocyclyl contains within one or more N, O or S (O) _m hetero atoms, and the heterocyclic group optionally further substituted with one Or a plurality of substituents selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ¹¹ and R ¹² are each independently Selected from hydrogen atom, alkyl group, halogen, hydroxyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, benzyl group, oxo group, -OR ⁸ , -C(O)OR ⁸ , -OC(O) R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC (O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further one or more Selected from alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O ( CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R Substituted by a substituent of ¹⁰ or -C(O)NR ⁹ R ¹⁰ ; m is selected from 0, 1 or 2; and p is selected from 0, 1 or 2. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 4, wherein: A and B together with the carbon atom to which they are bonded form a cycloalkyl group, a heterocyclic group or an aryl group. Or a heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, hetero Cyclo, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC Substituting (O) R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently Selected from hydrogen atom, halogen, hydroxy, alkyl, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further substituted with one or more substituents selected from halogen, hydroxy, alkyl or alkoxy; R ^{5 is} selected from Hydrogen atom, hydroxyl group, alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, oxo, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optional Further substituted with one or more substituents selected from halogen, hydroxy, alkyl or alkoxy; Y, Z, G and J are each independently selected from an O atom, N(R ¹¹ ) or C(R ¹¹ ) (R ¹² ); wherein: J is an O atom or N(R ¹¹ ), G is C(R ¹¹ )(R ¹² ), Z is C(R ¹¹ )(R ¹² ), Y is an O atom, N(R ¹¹ ) or C(R ¹¹ )(R ¹² ); J is C(R ¹¹ )(R ¹² ), G is N(R ¹¹ ) or C(R ¹¹ )(R ¹² ), and Z is C(R ¹¹ ) (R ¹² ), Y is C(R ¹¹ )(R ¹² ); J is C(R ¹¹ )(R ¹² ), G is C(R ¹¹ )(R ¹² ), and Z is N(R ¹¹ ) or C (R ¹¹ )(R ¹² ), Y is C(R ¹¹ )(R ¹² ); and, when Y, Z, J or G is selected from N(R ¹¹ ) or C(R ¹¹ )(R ¹² ), any The adjacent two ring atoms may form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; and R ^{8 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. Wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is, independently, each optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl , substituted aryl, heteroaryl, carboxylic acid or carboxylic ester is replaced; ¹⁰ is independently selected from a hydrogen atom or R ⁹ R, an alkyl group a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl groups, Substituted by a substituent of a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or, R ⁹ and R ¹⁰ form a hetero atom with a nitrogen atom to which it is bonded a cyclic group wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group is optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy Substituted by a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ¹¹ and R ¹² are each independently selected from a hydrogen atom, an alkyl group, a halogen, a hydroxyl group, a cycloalkane , heterocyclic, aryl, heteroaryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O) OR ⁸ , -C(O)R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ , wherein alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected from one or more Alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ Substituted by a substituent; m is selected from 0, 1 or 2; and p is selected from 0, 1 or 2. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to the first aspect of the invention, which comprises a compound of the formula (V) or a pharmaceutically acceptable salt thereof: Wherein: A and B together with the carbon atom to which they are attached form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently optionally further One or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)OR ⁸ , -OC(O)R ⁸ ,- O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O) Substituted by a substituent of NR ⁹ R ¹⁰ ; R ¹ , R ² , R ³ or R ⁴ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group, a cyano group, an alkoxy group, a cycloalkyl group, a heterocyclic group, An aryl or heteroaryl group, -C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl or alkoxy group is each independently optionally further one or more Substituted by a substituent selected from a halogen, a hydroxyl group, an alkyl group or an alkoxy group; R ^{5 is} selected from a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an oxo group, C(O)OR ⁸ , -C(O)R ⁸ or -C(O)NR ⁹ R ¹⁰ , wherein the alkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl or alkoxy. Substituted D and E are each independently selected from N or C atoms; D and E are bonded to each other to form a 5 to 10 membered ring X, which is valence-bonded in the ring, and the 5 to 10 membered ring X is selected from cycloalkyl, hetero a cycloalkyl or heteroaryl group, wherein the cycloalkyl, heterocyclyl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, cycloalkyl, heterocyclyl, aryl , heteroaryl, benzyl, oxo, -OR ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O) Substituted by a substituent of R ⁸ , -S(O) _m R ⁸ , -NHC(O)R ⁸ , -NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ or -C(O)NR ⁹ R ¹⁰ Wherein alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl are each independently optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, cycloalkyl, Heterocyclyl, aryl, heteroaryl, oxo, -C(O)OR ⁸ , -OC(O)R ⁸ , -O(CH ₂ ) _p C(O)OR ⁸ , -C(O)R _{^{8, -S (O) m R}} 8, -NHC (O) R 8, -NR 9 R 10, -OC (O) NR 9 R 10 or -C (O) NR ⁹ R ¹⁰ substituted with a substituent; R ⁸ is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, The radical, heterocyclyl, aryl or heteroaryl are each, independently, optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituting a substituent of a carboxylic acid or a carboxylic acid ester; R ⁹ or R ¹⁰ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group or the cycloalkane The radical, heterocyclyl, aryl or heteroaryl are each, independently, optionally further selected from one or more selected from the group consisting of alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituting a substituent of a carboxylic acid or a carboxylic acid ester; or, R ⁹ and R ¹⁰ form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid Substituted by an ester substituent; m is selected from 0, 1 or 2; and p is 0, 1 or 2. The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, wherein A and B together with the carbon atom to be bonded form an aryl group. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as described in claim 7, wherein A and B together with the carbon atom to which they are attached form a phenyl group. The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ¹ is a hydrogen atom. The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ¹ is a halogen, preferably a fluorine atom. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to the invention of claim 10, wherein R ¹ is a fluorine atom. The compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ or R ⁴ are each independently hydrogen, as defined in any one of claims 1 to 6 atom. The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ² , R ³ or R ⁴ are each independently a hydrogen atom, R ¹ is a halogen. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to the invention of claim 13, wherein R ¹ is a fluorine atom. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁶ or R ⁷ are each independently a hydrogen atom, or R ⁶ and R ⁷ together form an oxygen, as claimed in claim 1 generation. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to the invention of claim 1, wherein the compound is selected from the group consisting of: A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 of the patent application, which comprises: The compound of the formula (IA) is optionally hydrolyzed to a carboxylic acid and reacted with a compound of the formula (IB) or a salt thereof to give a compound of the formula (I): wherein: R ^{a is} selected from halogen, hydroxy or alkoxy; A, B, D, E, ring X, n, R ¹ to R ⁷ are as defined in the first item of the patent application. A pharmaceutical composition comprising a compound of the formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or a pharmaceutically acceptable carrier Shape agent. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, or the use of the pharmaceutical composition according to claim 18, It is used in the preparation of drugs that inhibit PARP. The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 18, A drug that inhibits PARP. A method of inhibiting PARP, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, Or the pharmaceutical composition as described in claim 18 of the patent application. The use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or the use of the pharmaceutical composition according to claim 18, It is used in the preparation of a drug as an adjuvant in cancer treatment or for making tumor cells sensitive to ionizing radiation or chemotherapy. The compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 18, An adjuvant used in cancer treatment or a drug used to make tumor cells sensitive to ionizing radiation or chemotherapy. A compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 18, in the preparation of a treatment Use in a medicament for cancer, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, liver cancer or colon cancer. The compound of the formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or the pharmaceutical composition according to claim 18, A medicament for treating cancer, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, liver cancer or colon cancer. A method for treating cancer, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16. Or the pharmaceutical composition as described in claim 18 of the patent application. The use according to any one of the preceding claims, wherein the medicament is further used in combination with a therapeutically effective amount of a drug selected from the group consisting of temozolomide, doxorubicin, paclitaxel, cisplatin, carboplatin , dacarbazine, topotecan, irinotecan, gemcitabine or bevacizumab.