Compounds as parp7 inhibitors

Abstract

The present application provides compounds as PARP7 inhibitors, in particular, the present application provides a compound of the following formula (I), or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates thereof. The compound can be used for treating or preventing diseases or disorders associated with the activity or expression amount of PARP7.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry; specifically, it relates to a novel class of derivatives containing tricyclic heteroaryl groups, their synthesis methods, and their application as a PARP7 inhibitor in the preparation of drugs for the treatment of tumors and other related diseases. Background Technology

[0002] ADP-ribosylation is a type of post-translational modification involving multiple amino acid residues. Ribosylation leads to the reversible attachment of ADP-ribose to substrate proteins, regulating various physiological functions such as gene expression, protein degradation, and cellular stress responses. It is mediated by members of the PARP (Poly(ADP-ribose) polymerases) family. The human PARP family comprises 17 members. Based on catalytic mechanisms and activities, PARP family proteins can be divided into three classes: one class catalyzes the multi-ADP ribosylation of substrates, including PARP1, PARP2, PARP5a, and PARP5b; another class catalyzes the single-ADP ribosylation of substrates, including PARP3, PARP4, PARP7, and PARP12; PARP13 is unique, as its catalytic activity has not been observed in vivo or in vitro. PARP1 has become an effective target in DNA damage-related tumor types, and currently, four PARP1 inhibitor anti-tumor drugs are on the market, with several others in clinical trials.

[0003] PARP7 plays a crucial role in neuronal development, stem cell maintenance, antiviral infection, and cancer. PARP7 expression is regulated by transcription factors and signaling pathways, including the transcription factor AHR (Aryl hydrocarbon receptor), androgen receptor, HIF1 (Hypoxia inducible factor 1), and the platelet-derived growth factor signaling pathway. AHR is a ligand-activated transcription factor involved in regulating physiological processes such as pro-inflammatory responses and foreign body metabolism. AHR can be activated by various ligands, such as the endogenous tryptophan metabolite kynurenine and TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin). AHR activation induces the expression of various metabolism-related genes, such as cytochrome P450A1 and P450B1. AHR-induced PARP7 expression acts as a negative feedback regulator of AHR, inhibiting its transcriptional activation activity.

[0004] The PARP7 gene is located on chromosome 3 (3q25), a locus frequently amplified in squamous cell carcinoma. Genome association studies have identified the 3q25 locus as a susceptibility site for ovarian cancer, suggesting that PARP7 plays a role in this cancer type. Mechanistically, PARP7 may regulate microtubule stability through ribosylation of Tubulin, and inhibit the type I interferon signaling pathway, thereby suppressing the body's anti-tumor immunity and promoting tumor growth and survival.

[0005] PARP7 is highly expressed in the brain. Knockout of PARP7 in mice leads to abnormal development of the cerebral cortex and reduced proliferation and migration of neural progenitor cells. PARP7 also plays an important role in maintaining the expression of stem cell genes such as Nanog, Sox2, Stella, and Zfp42. Under PARP7 deficiency, embryonic stem cells struggle to maintain stemness and exhibit a tendency to differentiate. PARP7 can also modify the liver X receptor (LXR), co-activating the LXR signaling pathway and promoting physiological processes such as cholesterol and lipid metabolism. TBK1 (TANK-binding kinase 1) is a major kinase in the pattern recognition receptor signaling pathway, mediating the activation of type I interferon and antiviral immunity. PARP7 inhibits TBK1 activation by ribosylating TBK1, thereby suppressing the innate antiviral immune response.

[0006] Given its role in innate immune responses, PARP7's role in tumor immunity is receiving increasing attention. Abnormally expressed or activated PARP7 can suppress innate immune responses, thereby inhibiting T cell-mediated anti-tumor immunity. In large-scale gene screening, PARP7 has also been identified as an inhibitor of T cell activation. Knocking out PARP7 in melanoma cells enhances the proliferation and growth of co-cultured T cells.

[0007] In summary, PARP7 is a promising target for treating multiple disease types, including tumors and viruses. Summary of the Invention

[0008] The purpose of this invention is to provide a novel class of PARP7 inhibitors.

[0009] In a first aspect, the present invention provides a compound, or an optical isomer thereof, of the structure shown in formula (I), a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate:

[0010]

[0011] In formula (I):

[0012] A is selected from -NR 3 -、-O-、-CR 4 R5 - or 3- to 8-membered heterocyclic groups; wherein, R 3 Selected from hydrogen or C 1-4 Alkyl; R 4 and R 5 Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0013] B is selected from -CR 6 R 7 - or chemical bond; where R 6 and R 7 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 Alkyl, 4- to 8-membered heterocyclic, or 4- to 8-membered heterocyclic C 1-4 Alkyl; or R 6 and R 7 Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocyclic group, which contains one or two heteroatoms selected from N, O, and S;

[0014] D is selected from -(CR) 8 R 9 ) p -Y-(CR 10 R 11 ) q -; where Y is selected from -O-, -NR 12 -、-CR 13 R 14 -、C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; each R 8 and R 9 Each is independently selected from hydrogen, halogen, hydroxyl, or C. 1-4 Alkyl groups; each R 10 and R 11 Each is independently selected from hydrogen, halogen, hydroxyl, or C. 1-4 Alkyl; or R 8 and R 9 The carbon atom or R connected to it 10 and R11 Together with the carbon atom it is attached to, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocyclic group, which contains one or two heteroatoms selected from N, O, and S; R 12 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, or 4- to 8-membered heterocyclic groups; R 13 and R 14 Each is independently selected from hydrogen, halogen, or C. 1-4 Alkyl; or R 13 and R 14 Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocyclic group, which contains one or two heteroatoms selected from N, O, and S;

[0015] E is selected from chemical bonds or -C(O)-;

[0016] F is selected from chemical bonds or -NR b -; where R b Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 8-membered heterocyclic, aryl, heteroaryl, C(O)R c , or S(O)2R c ; or R b With R 10 Or R 11 Together with the nitrogen atom, carbon atom, and E, it forms a 4- to 8-membered heterocyclic group, which contains one N atom and 0 or one heteroatom selected from N, O, and S; R c Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, or 4- to 8-membered heterocyclic groups; R b Or R c The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups described herein are optionally substituted by one or more substituents selected from the group consisting of: halogens, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 8-membered heterocyclic groups, NR d R d ,CN,OR d SR d C(O)R t , or S(O)2R t Each R dEach can be either hydrogen or C. 1-4 Alkyl; R t Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 4- to 8-membered heterocyclic, aryl, or heteroaryl;

[0017] G is selected from N or CR e Among them, R e Selected from hydrogen or C 1-4 alkyl;

[0018] Each R a Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl, hydroxyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkyl, NR h R h CN; each R h Each can be independently hydrogen or C 1-4 Alkyl; or two R h Together with the nitrogen atom it is attached to, it forms a 3- to 8-membered heterocyclic group, which contains one or two N atoms and one or more heteroatoms selected from O and S; or two R atoms attached to the same carbon atom. a Together with carbon atoms, they form C=M; where M is selected from O or CR. j R k Among them, R j and R k Each is independently selected from the following group: hydrogen, halogen, or C. 1-4 Alkyl group; or two R atoms attached to different carbon atoms a They are connected together to form a bridge ring structure;

[0019] T is selected from N or CR 15 Among them, R 15 Selected from hydrogen, halogen, or C 1-4 alkyl;

[0020] X and Z are each independently selected from N or CR;

[0021] Each R is independently selected from hydrogen, halogen, C. 1-4 Alkyl, C 1-4Haloalkyl, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 Cycloalkylynyl, 3- to 8-membered heterocyclic ynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic, NR h R h CN, NO2, SR h C(O)R t C(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t Among them, R h and R t The definition is as described above;

[0022] R 1 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 Haloalkenyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkyl, or C 1-4 Halogenated alkoxy C 1-4 alkyl;

[0023] R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group;

[0024] m and n are each independently selected from 0, 1, or 2;

[0025] k is selected from 0, 1, or 2;

[0026] h is selected from 0, 1, 2, 3, or 4;

[0027] Or the structural fragment in equation (I) Selected from the following formula:

[0028]

[0029] Where d is selected from 0, 1, or 2; e is selected from 1, 2, 3, or 4;

[0030] Unless otherwise specified, each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is optionally and independently substituted by 1 to 3 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, CN, NO2, OR h SR h NR h R h C(O)R t C(O)OR h C(O)NR h R h NR h C(O)R t NR h S(O)2R t , or S(O)2R t The prerequisite is that the resulting chemical structure is stable and meaningful; among them, R h and R t The definition is as described above;

[0031] Unless otherwise specified, the aryl group mentioned above is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group; the cyclic structure is a saturated or unsaturated cyclic group containing heteroatoms or not containing heteroatoms.

[0032] In another preferred embodiment, equation (I) is equivalent to equation (IIA):

[0033]

[0034] Q is selected from -NR 16 -、-O-、-CR 17 R 18 -; where R 16 Selected from hydrogen, C 1-4 Alkyl, C 3-6Cycloalkyl, 3- to 8-membered heterocyclic, aryl, heteroaryl, C(O)R t , or S(O)2R t ;R 17 and R 18 Each is independently selected from hydrogen, halogen, or C. 1-4 alkyl;

[0035] f and g are each independently selected from 0, 1, or 2; the prerequisite is that f and g cannot be 0 at the same time.

[0036] j and t are each independently selected from 0, 1, or 2;

[0037] The definitions of the other groups are as described above.

[0038] In another preferred embodiment, equation (I) is equation (IIIA):

[0039]

[0040] p is selected from 0, 1, or 2;

[0041] j and t are each independently selected from 0, 1, or 2;

[0042] The definitions of the other groups are as described above.

[0043] In another preferred embodiment, equation (I) is equation (IVA):

[0044]

[0045] R 6 and R 7 Each is independently selected from hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 Alkyl, 4- to 8-membered heterocyclic, or 4- to 8-membered heterocyclic C 1-4 alkyl;

[0046] p is selected from 0, 1, or 2;

[0047] j and t are each independently selected from 0, 1, or 2;

[0048] The definitions of the other groups are as described above.

[0049] In another preferred embodiment, equation (I) is equation (VA):

[0050]

[0051] R b The definition is as described above;

[0052] The definitions of each group are as described above.

[0053] In another preferred embodiment, equation (I) is equation (VIA):

[0054]

[0055] R b Selected from C 3-6 Cycloalkyl, 4- to 8-membered heterocyclic, aryl, or heteroaryl; wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of: halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 8-membered heterocyclic groups, NR d R d ,CN,OR d SR d C(O)R t , or S(O)2R t Among them, R t Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, or 4- to 8-membered heterocyclic groups; each R d Each can be either hydrogen or C. 1-4 alkyl;

[0056] q is selected from 0, 1, 2, or 3;

[0057] The definitions of the other groups are as described above.

[0058] In another preferred embodiment, equation (I) is equation (VIIA):

[0059]

[0060] R c Selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, or 4- to 8-membered heterocyclic group; wherein the alkyl, alkenyl, ynyl, cycloalkyl, and heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of: halogen, C 1-4Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 8-membered heterocyclic groups, NR d R d ,CN,OR d SR d C(O)R t , or S(O)2R t ;

[0061] j is selected from 0, 1, or 2;

[0062] The definitions of the other groups are as described above.

[0063] In another preferred embodiment, equation (I) is equation (VIIIA):

[0064]

[0065] R 1 Selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group;

[0066] R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkynyl group;

[0067] R 8 R 9 R 10 R 11 Each is independently selected from hydrogen, hydroxyl, and C. 1-4 alkyl;

[0068] X is selected from N or CR;

[0069] R is independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 Cycloalkylynyl, 3- to 8-membered heterocyclic ynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic groups, CN.

[0070] In another preferred embodiment, equation (I) is equation (IXA):

[0071]

[0072] R 1 Selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group;

[0073] R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkynyl group;

[0074] R 6 and R 7 Each is independently selected from hydrogen and C. 1-4 alkyl;

[0075] R 8 R 9 R 10 R 11 Each is independently selected from hydrogen, hydroxyl, and C. 1-4 alkyl;

[0076] X is selected from N or CR;

[0077] R is independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 Cycloalkylynyl, 3- to 8-membered heterocyclic ynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic groups, CN.

[0078] In another preferred embodiment, equation (I) is equation (XA):

[0079]

[0080] R b Selected from C 3-6 Cycloalkyl, 4- to 8-membered heterocyclic, aryl, or heteroaryl; wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of: halogen, C 1-4 Alkyl, NR d R d ,CN,OR d C(O)R t , or S(O)2R t Among them, R t Selected from C 1-4Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, or 4- to 8-membered heterocyclic groups; each R d Each can be either hydrogen or C. 1-4 alkyl;

[0081] R 1 Selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group;

[0082] R 2 Selected from hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkynyl group;

[0083] R 6 and R 7 Each is independently selected from hydrogen and C. 1-4 Alkyl; R 8 R 9 R 10 R 11 Each is independently selected from hydrogen, hydroxyl, and C. 1-4 Alkyl; or

[0084] R 6 and R 7 The carbon atom and R connected to it 8 and R 9 The carbon atom or R connected to it 10 and R 11 Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocyclic group, which contains one or two heteroatoms selected from N, O, and S;

[0085] X is selected from N or CR;

[0086] R is independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6 Cycloalkylynyl, 3- to 8-membered heterocyclic ynyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic groups, CN.

[0087] In another preferred embodiment,

[0088] R1 Selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group; R 2 For H;

[0089] X is selected from N or CH;

[0090] R is independently selected from trifluoromethyl, CN, and C. 2-4 alkynyl group, C 3-6 Cycloalkylynyl, 3- to 8-membered heterocyclic ynyl, C 3-6 Cycloalkyl.

[0091] In another preferred embodiment, equation (I) is equation (XIA):

[0092]

[0093] R 1 Selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 2-4 alkynyl group;

[0094] R 2 Selected from hydrogen;

[0095] R 6 and R 7 Each is independently selected from hydrogen and C. 1-4 alkyl;

[0096] R 8 R 9 R 10 R 11 Each is independently selected from hydrogen, hydroxyl, and C. 1-4 alkyl;

[0097] Or R 6 and R 7 The carbon atom and R connected to it 8 and R 9 The carbon atom or R connected to it 10 and R 11 Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group or a 4- to 8-membered heterocyclic group, which contains one or two heteroatoms selected from N, O, and S;

[0098] X is selected from N or CH;

[0099] R are each independently selected from C 2-4 alkynyl group, C 2-4 Halogenated alkynyl group, C 3-6Cycloalkylynyl, 3- to 8-membered heterocyclic ynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic groups.

[0100] In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0101]

[0102]

[0103]

[0104] "*" indicates a chiral center.

[0105] A second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier.

[0106] A third aspect of the invention provides the use of a compound, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate, as described in the first aspect of the invention, for the preparation of a pharmaceutical composition for treating diseases, conditions, or symptoms associated with PARP7 activity or expression levels.

[0107] In another preferred embodiment, the disease, symptom, or condition is selected from the group consisting of: multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, monocytic leukemia, splenomegaly with polycythemia, eosinophilic syndrome, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck cancer, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, stomach cancer, and various hematologic malignancies and solid tumors, as well as various types of heart disease, viral infections, neurodegenerative diseases, inflammation, and pain, especially those disease types associated with PARP7 overexpression or abnormal activation. Detailed Implementation

[0108] Through long-term and in-depth research, the inventors unexpectedly discovered a class of novel compounds as PARP7 inhibitors, along with their preparation methods and applications. The compounds of this invention can be applied to the treatment of various diseases related to the activity of ADP and glycosyltransferases. Based on the above findings, the inventors completed this invention.

[0109] the term

[0110] Unless otherwise specified, the word “or” as used in this article has the same meaning as “and / or” (referring to both “or” and “and”).

[0111] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0112] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, either alone or as part of other substituents, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number definiteness (e.g., C...), it is used to indicate a carbon atom number. 1-10 When ), it refers to the alkyl group containing 1-10 carbon atoms. For example, C 1-8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0113] As used herein, the term "alkenyl," whether alone or as part of other substituents, refers to a straight-chain or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number definiteness (e.g., C...), it signifies a carbon chain group. 2-8 When ), it refers to the alkenyl group containing 2-8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0114] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of other substituents. The alkynyl group can be straight-chain or branched, or a combination thereof. When the alkynyl group is preceded by a carbon number limit (e.g., C...), it is considered a alkynyl group. 2-8 When alkynyl is used, it means that the alkynyl group contains 2-8 carbon atoms. For example, the term "C 2-8 "Alynyl" refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0115] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number determination (e.g., C...), it is used to indicate the presence of a carbon number limit (e.g., C...). 3-10 When ), it refers to the cycloalkyl group containing 3-10 carbon atoms. In some preferred embodiments, the term "C" is used. 3-8"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a single carbon atom (called a spiro atom). These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to a fully carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. All atoms in the cycloalkyl group are carbon atoms. The following are some examples of cycloalkyl groups; the present invention is not limited to the cycloalkyl groups described below.

[0116]

[0117] Unless otherwise stated, the terms used in the specification and claims have the following meanings. "Aryl" refers to a monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent group must be on a carbon atom of a ring having a conjugated π-electron system. Aryl groups can be substituted or unsubstituted. Some examples of aryl groups are given below; the invention is not limited to the aryl groups described below.

[0118]

[0119] "Heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms (optionally nitrogen, oxygen, and sulfur), or a polycyclic group consisting of a heterocyclic group (containing one or more heteroatoms, optional nitrogen, oxygen, and sulfur) fused with an aryl group, with the linking site located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below; however, this invention is not limited to the heteroaryl groups described below.

[0120]

[0121] "Heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups. "Spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system; one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic groups" refer to polycyclic heterocyclic groups in which any two rings share two non-directly connected atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, while the remaining ring atoms are carbon. If a saturated ring and an aromatic ring are present simultaneously in the heterocyclic group (for example, a saturated ring and an aromatic ring fused together), the point of attachment to the parent ring must be on the saturated ring. Note: When the point of attachment to the parent ring is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. Below are some examples of heterocyclic groups; this invention is not limited to the heterocyclic groups described below.

[0122]

[0123] As used herein, the term "halogen" refers to F, Cl, Br, and I, either alone or as part of other substituents.

[0124] As used herein, the term "substitution" (with or without the "arbitrarily" modified) refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, i.e., two rings sharing a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. The substituents include, for example (but are not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8Aldehyde group, C 2-10 Acyl group, C 2-10 Ester group, amino group.

[0125] For convenience and to conform to common understanding, the terms "arbitrary substitution" or "optional substitution" apply only to sites that can be substituted by substituents, and do not include chemically impossible substitutions.

[0126] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" means a salt suitable for contact with the tissues of an object (e.g., a human) without producing undesirable side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes salts of the compounds of the present invention having acidic groups (e.g., potassium, sodium, magnesium, calcium salts) or salts of the compounds of the present invention having basic groups (e.g., sulfates, hydrochlorides, phosphates, nitrates, carbonates).

[0127] use:

[0128] The present invention provides the use of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients for the inhibition of PARP7.

[0129] The compound of this invention can be used as a PARP7 inhibitor.

[0130] This invention is a single inhibitor of PARP7, which aims to prevent, alleviate, or cure diseases by regulating the enzyme activity of PARP7. The diseases referred to include multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, monocytic leukemia, splenomegaly with polycythemia, eosinophilic syndrome, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck cancer, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, gastric cancer, and various hematologic malignancies and solid tumors, as well as various types of heart disease, viral infections, neurodegenerative diseases, inflammation, and pain, especially those diseases associated with PARP7 overexpression or abnormal activation.

[0131] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates thereof and / or compositions thereof, can be formulated together with pharmaceutically acceptable excipients or carriers to obtain compositions that can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections, sterile powders, etc. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (added), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular weight polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic), and lubricants (such as magnesium stearate, glycerin and talc). In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound or pharmaceutical composition of the present invention administered to the patient is not fixed and is usually given at a pharmaceutically effective dose. Simultaneously, the actual amount of compound administered can be determined by the physician based on the actual situation, including the condition being treated, the chosen route of administration, the actual compound administered, and the patient's individual condition. The dosage of the compound of the present invention depends on the specific purpose of treatment, the route of administration, the patient's condition, and the physician's judgment. The proportion or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, and route of administration.

[0132] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions.

[0133] General synthetic methods for compounds

[0134] The reagents and conditions for each compound synthesis step can be those conventionally used in this type of preparation method in the art. After the compound structures of this invention are disclosed, the selection of reactants, solvents, bases, amounts of compounds used, reaction temperatures, reaction times, etc., can be made by those skilled in the art based on their knowledge. The compounds of this invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art; such combinations can be easily performed by those skilled in the art.

[0135] Pharmaceutical Compositions and Administration

[0136] Because the compounds of the present invention have excellent inhibitory activity against an ADP ribosyltransferase, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to PARP7 activity or expression levels.

[0137] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0138] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0139] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0140] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0141] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0142] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0143] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0144] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0145] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0146] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0147] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0148] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0149] The main advantages of this invention include:

[0150] 1. A compound as shown in Formula I is provided.

[0151] 2. A novel PARP7 inhibitor is provided, as well as its preparation and application, wherein the inhibitor can inhibit the activity of PARP7 at extremely low concentrations.

[0152] 3. A class of pharmaceutical compositions for treating diseases related to PARP7 activity is provided.

[0153] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0154] Some representative compounds of the present invention can be prepared by the following synthetic methods. In each of the following reaction formulas, the reagents and conditions of each step can be selected from those conventionally used in this type of preparation method in the art. After the compound structures of the present invention are disclosed, the above selection can be made by those skilled in the art based on their knowledge in the art.

[0155] Example:

[0156] Some of the compounds of this invention can be prepared by the following methods.

[0157] abbreviation

[0158] Boc2O = ditert-butyl dicarbonate

[0159] Cs₂CO₃ = Cesium carbonate

[0160] DCM = dichloromethane

[0161] DIPEA = N,N-Diisopropylamine

[0162] DMA = N,N-dimethylacetamide

[0163] DMF = N,N-dimethylformamide

[0164] DMSO = dimethyl sulfoxide

[0165] EtOAc = Ethyl acetate

[0166] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0167] SEM = 2-(trimethylsilyl)ethoxymethyl

[0168] PMB = 4-Methoxybenzyl

[0169] TEA = Triethylamine

[0170] TFA = Trifluoroacetic acid

[0171] TsOH = 4-Methylbenzenesulfonic acid

[0172] Desmartin oxidant = 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzyl-3-(1H)-one

[0173] Example 1: Preparation of Compound 1

[0174]

[0175] Compound 1a (1.0 g, 5.48 mmol), compound 1b (1.02 g, 5.48 mmol), and potassium carbonate (1.51 g, 10.96 mmol) were added to N-methylpyrrolidone (8 mL) and heated to 80 °C with stirring for 2 hours. After the reaction mixture cooled to room temperature, it was diluted with water. The mixture was extracted with ethyl acetate (3 x 25 mL), and the resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give a white solid compound 1c (1.71 g, 94% yield). MS m / z 333.3 [M+H] + .

[0176] Compound 1c (1.71 g, 5.15 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of a 4 M, 6 mL solution of 1,4-dioxane hydrogen chloride. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered and washed with dichloromethane to give a white solid product 1d (1.54 g, 100% yield). MS m / z 233.3 [M+H] + .

[0177] Compound 1d (100 mg, 0.29 mmol) and triethylamine (148 mg, 1.46 mmol) were dissolved in dichloromethane (3 mL), and the mixture was stirred at -40 °C. Acrylic anhydride 1e (44 mg, 0.35 mmol) was then slowly added dropwise. The reaction mixture was stirred at -40 °C for 30 minutes. After the reaction was complete, the mixture was allowed to rise to room temperature and then diluted with water. The mixture was extracted with dichloromethane (3 x 15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 8:1) to give a white solid product 1f (77 mg, 92% yield). MS m / z 287.2 [M+H] + .

[0178] Compound 1f (77 mg, 0.27 mmol), 1 g (101 mg, 0.54 mmol), and cesium carbonate (105 mg, 0.32 mmol) were added sequentially to acetonitrile (3 mL), and the mixture was heated to 60 °C and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:ethyl acetate = 3:1) to give a colorless oily product 1 h (47 mg, yield 37%). MS m / z 474.5 [M+H] + .

[0179] Compound 1h (47 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), and then a 1,4-dioxane solution of hydrogen chloride (4 M, 0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, an appropriate amount of ammonia was added to adjust the pH to approximately 7. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1, 2% ammonia) to give a white solid product 1i (33 mg, yield 89%). MS m / z 374.4 [M+H] + .

[0180] Compound 1j was synthesized using the method described in patent US20190330194.

[0181] Compound 1j (31 mg, 0.10 mmol), compound 1i (33 mg, 0.09 mmol), and triethylamine (40 mg, 0.40 mmol) were added sequentially to acetonitrile (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a white solid product 1k (32 mg, yield 55%). MS m / z 656.7 [M+H] + .

[0182] Compound 1k (32 mg, 0.05 mmol) was added to trifluoroacetic acid (1.5 mL), followed by the addition of trifluoromethanesulfonic acid (5 drops). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, a suitable amount of ammonia was added to adjust the pH to approximately 7. The mixture was extracted with dichloromethane (3 × 15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a white solid product 1 (8 mg, yield 31%). 1 H NMR (500MHz, CDCl3) δ10.10(s,1H),8.52(s,2H),8.11(s,1H),6.35-6.15(m,1H),3.96-3.89(m,4H),3.84(t,J=6 .1Hz,2H),3.73-3.70(m,2H),3.57-3.51(m,4H),2.61(t,J=6.1Hz,2H),1.04-1.02(m,2H),1.01-0.99(m,2H)ppm. MS m / z 536.5[M+H] + .

[0183] Example 2: Preparation of Compound 2

[0184]

[0185] Compound 2a (0.500 g, 3.62 mmol), compound 1b (0.675 g, 3.62 mmol), and potassium carbonate (0.850 g, 6.12 mmol) were added to DMA (10 mL) and heated to 80 °C with stirring for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with water (10 mL × 2). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-10% ethyl acetate / petroleum ether) to give a white solid product 2b (0.7 g, yield 67%). 1 H NMR (500MHz, CDCl3) δ8.42(d,J=2.2Hz,1H),7.64(dd,J=9.0,2.2Hz,1H),6.60(d,J=9.0Hz,1H),3.74–3.64(m,4H),3.62–3.45(m,4H),1.49(s,9H)ppm.

[0186] Compound 2b (200 mg, 0.69 mmol) and 1,4-dioxane (1 mL, 4 mmol) in 4N HCl were dissolved in dichloromethane (5 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and dried under vacuum to give compound 2c (156 mg, 100% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.43(s,2H),8.56(d,J=2.2Hz,1H),7.96(dd,J=9.0,2.2Hz,1H),7.03(d,J=9.0Hz,1H),4.00–3.84(m,4H),3.17(s,4H)ppm.

[0187] Compound 2c (177 mg, 0.78 mmol) and triethylamine (316 mg, 3.13 mmol) were dissolved in dichloromethane (6 mL), and the mixture was stirred at -40 °C, followed by slow dropwise addition of acrylic anhydride 1e (128 mg, 1.02 mmol). The reaction mixture was stirred at -40 °C for 1 hour. After the reaction was complete, the mixture was allowed to rise to room temperature and then diluted with water. The mixture was extracted with dichloromethane (3 × 20 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 10:1) to give a white solid product 2d (154 mg, yield 81%).

[0188] Compound 2d (154 mg, 0.64 mmol), 1 g (238 mg, 1.27 mmol), and cesium carbonate (248 mg, 0.76 mmol) were added sequentially to acetonitrile (4 mL), and the mixture was heated to 65 °C and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:ethyl acetate = 3:1) to give a white solid product 2e (50 mg, yield 17%). MS m / z 430.5 [M+H] + .

[0189] Compound 2e (50 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), and then a 1,4-dioxane solution of HCl (4 M, 0.5 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, an appropriate amount of ammonia was added to adjust the pH to approximately 7. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1, 2% ammonia) to give a white solid product 2f (28 mg, yield 81%). MS m / z 330.4 [M+H] + .

[0190] Compound 1j (30 mg, 0.09 mmol), compound 2f (28 mg, 0.08 mmol), and triethylamine (39 mg, 0.39 mmol) were added sequentially to acetonitrile (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give 2 g (12 mg, yield 23%) of a white solid product. MS m / z 612.7 [M+H] + .

[0191] 2 g (12 mg, 0.02 mmol) of the compound was added to 1 mL of trifluoroacetic acid, followed by 3 drops of trifluoromethanesulfonic acid. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, a suitable amount of ammonia was added to adjust the pH to approximately 7. The mixture was extracted with dichloromethane (3 × 15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a white solid product 1 (2 mg, yield 21%). MS m / z 492.4 [M+H] + .

[0192] Example 3: Preparation of Compound 3

[0193]

[0194] Compound 3a (0.200 g, 1.29 mmol), compound 1b (0.240 g, 1.29 mmol), and cesium carbonate (0.840 g, 2.58 mmol) were added to DMA (10 mL) and heated to 80 °C with stirring for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (10 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to give a white solid product 3b (0.320 g, yield 82%). MS m / z 305.39 [M+H] + .

[0195] Compound 3b (220 mg, 0.72 mmol) and 1,4-dioxane (1 mL, 4 mmol) of 4N hydrogen chloride were dissolved in dichloromethane (1 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and dried under vacuum to give compound 3c (176 mg, 100% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ9.38(s,2H),8.31(s,2H),4.00-3.96(m,4H),3.19(brs,4H),1.92-1.80(m,1H),0.97-0.93(m,2H),0.76-0.68(m,2H)ppm. MS m / z 205.31[M+H] + .

[0196] Compound 3c (150 mg, 0.63 mmol) and triethylamine (192 mg, 1.89 mmol) were dissolved in dichloromethane (5 mL), and the mixture was stirred at -40 °C, followed by slow dropwise addition of acrylic anhydride 1e (87 mg, 0.69 mmol). The reaction mixture was stirred at -40 °C for 1 hour. After the reaction was complete, the mixture was allowed to rise to room temperature and then diluted with water. The mixture was extracted with dichloromethane (3 × 20 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a white solid product 3d (162 mg, 99% yield). MS m / z 259.4 [M+H] + .

[0197] Compound 3d (162 mg, 0.63 mmol), compound 3e (220 mg, 1.25 mmol), and cesium carbonate (245 mg, 0.75 mmol) were added sequentially to acetonitrile (4 mL), and the mixture was heated to 65 °C and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:ethyl acetate = 3:1) to give a white solid product 3f (183 mg, yield 67%). MS m / z 434.6 [M+H] + .

[0198] Compound 3f (183 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), and then a 1,4-dioxane solution of hydrogen chloride (4 M, 1.0 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, an appropriate amount of ammonia was added to adjust the pH to approximately 7. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 2% ammonia) to give 3 g (100 mg, yield 71%) of a white solid product. MS m / z 334.5 [M+H] + .

[0199] Compound a was synthesized using the method described in patent US20190330194.

[0200] Compound a (57 mg, 0.18 mmol), compound 3 g (50 mg, 0.15 mmol), and triethylamine (46 mg, 0.45 mmol) were added sequentially to acetonitrile (2.5 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a yellow oily product 3 h (95 mg, purity 85%, yield 87%). MS m / z 616.7 [M+H] + .

[0201] Compound 3h (95 mg, 85% purity, 0.13 mmol) was added to trifluoroacetic acid (1.5 mL), followed by the addition of trifluoromethanesulfonic acid (4 drops). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, a suitable amount of ammonia was added to adjust the pH to approximately 7. The mixture was extracted with dichloromethane (3 × 15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give a white solid product 3 (20 mg, yield 31%). 1H NMR (500MHz, CDCl3) δ10.35(s,1H),8.14(s,2H),7.66(s,1H),5.87-5.80(m,1H),3.95-3.76(m,7H),3.72-3.68(m,2H),3.66-3.63( m,1H),3.55-3.48(m,3H),2.64(t,J=6.3Hz,2H),1.77-1.68(m,1H),1.30(d,J=6.6Hz,3H),0.95-0.90(m,2H),0.62-0.58(m,2H)ppm. MS m / z 496.5[M+H] + .

[0202] Example 4: Preparation of Compound 4

[0203]

[0204] Compound 4 was prepared by replacing the corresponding structural fragments, following a method similar to that used in Example 7.

[0205] Example 5: Preparation of Compound 5

[0206]

[0207] Compound 5 was prepared by replacing the corresponding structural fragments, following a method similar to that used in Example 7.

[0208] Example 6: Preparation of Compound 6

[0209]

[0210] Compound 6 was prepared by replacing the corresponding structural fragments, following a method similar to that used in Example 7.

[0211] Example 7: Preparation of Compound 7

[0212]

[0213] Compound 7a (600 mg, 4.11 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and potassium persulfate (2.15 g, 6.21 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was filtered, the filtrate was diluted with water, extracted twice with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude yellow oily compound 7b (426 mg) was used directly in the next reaction.

[0214] Compound 7b (200 mg, 1.72 mmol) and compound 1d (461 mg, 1.72 mmol) were dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (877 mg, 6.88 mmol) was added dropwise, followed by 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (981 mg, 2.58 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give a white solid compound 7c (420 mg, 74% yield). MS m / z 331.0 [M+H] + .

[0215] Compound 7c (100 mg, 0.30 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) were dissolved in dichloromethane (3 mL), and methanesulfonyl chloride (52 g, 0.45 mmol) was added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give a yellow solid compound 7d (112 mg, yield 91%). MS m / z 408.9 [M+H] + .

[0216] Compound 7d (112 mg, 0.28 mmol) was dissolved in methyl tert-butyl ether (5 mL), and potassium tert-butoxide (38 mg, 0.34 mmol) was added under ice bath conditions. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give a yellow solid compound 7e (71 mg, 83% yield). 1 H NMR (500MHz, CDCl3) δ8.52(s,2H),6.60(s,1H),3.98-3.93(m,4H),3.84-3.65(m,4H),1.47-1.42(m,2H),1.24-1.20(m,2H). MS m / z 313.1[M+H] + .

[0217] Compound 3e (25 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydrogen (60%, 7.5 mg, 0.19 mmol) was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 20 minutes, and then compound 7e (30 mg, 0.10 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give a yellow solid compound 7f (44 mg, 94% yield). MS m / z 488.1 [M+H] + .

[0218] Compound 7f (44 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and dioxane hydrochloride (0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a yellow oily compound 7 g (30 mg, yield 86%). 1 H NMR(500MHz,CD3OD)δ8.60(s,2H),4.03-3.89(m,4H),3.76-3.66(m,4H),3.58-3.52(m,1H),3.36-3.32(m, 1H), 3.13-3.05 (m, 1H), 2.86 (d, J = 2.1Hz, 2H), 1.10 (d, J = 6.6Hz, 3H), 0.94-0.88 (m, 2H), 0.70-0.63 (m, 2H). MS m / z 388.1[M+H] + .

[0219] Compound 7 g (30 mg, 0.08 mmol) and compound b (38 mg, 0.11 mmol) were dissolved in acetonitrile (2 mL), and then N,N-diisopropylethylamine (31 mg, 0.24 mmol) was added dropwise. The reaction mixture was heated and stirred at 40 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography to give a yellow oily compound 7 h (15 mg, yield 29%). MS m / z 680.0 [M+H] + .

[0220] Compound 7h (15 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (0.5 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography to give compound 7 (1 mg, 8% yield) as a white solid. 1 H NMR(500MHz,CD3OD)δ8.59(s,2H),7.90(s,1H),4.11-4.06(m,1H),3.97-3.89(m,4H),3.71-3.66(m,4H),3.60-3. 56(m,1H),3.40-3.30(m,1H),2.86(d,J=5.1Hz,2H),1.23(d,J=6.6Hz,3H),0.88-0.84(m,2H),0.69-0.66(m,2H). MS m / z 550.0[M+H] + .

[0221] Example 8: Preparation of Compound 8

[0222]

[0223] Compound 8a (1.03 g, 5.0 mmol) was dissolved in N,N-dimethylformamide (10 mL) and cooled to 0 °C. Sodium hydroxide (60%, 240 mg, 6 mmol) was added, and the reaction was carried out for 15 minutes. Tert-butyl bromoacetate 8b (732 mg, 6.0 mmol) was added, and the reaction was slowly brought to room temperature for 16 hours. The reaction was quenched with saturated sodium carbonate solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:2) to give compound 8c (250 mg, yield 17%).

[0224] Compound 8c (250 mg, 0.65 mmol) was dissolved in trifluoroacetic acid (2 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound 8d (140 mg, yield 82%). 1 H NMR(500MHz,DMSO-d6)δ12.57(s,1H),7.90-7.78(m,4H),4.50-4.38(m,1H),3.97(d ,J=2.8Hz,2H),3.91(t,J=9.6Hz,1H),3.68-3.66(m,1H),1.36(d,J=7.1Hz,3H)ppm.

[0225] Compound 4b (245 mg, 1.0 mmol) was dissolved in ethanol (5 mL), and a solution of 1,4-dioxane hydrogen chloride (4 M, 0.5 mL) and cyclopropylamine (114 mg, 2.0 mmol) were added. Sodium cyanoborohydride (126 mg, 2.0 mmol) was then added, and the reaction was carried out at room temperature for 16 hours. The reaction was quenched with saturated sodium carbonate solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give compound 8f (140 mg, 50% yield). 1 H NMR (500MHz, CDCl3) δ8.45 (d, J = 0.6Hz, 2H), 4.71-4.67 (m, 2H), 3.19-3.03 (m, 2H), 2.93-2.89 (m, 1H) ,2.24-2.12(m,1H),2.10-1.95(m,2H),1.35-1.32(m,2H),0.54-0.42(m,2H),0.38-0.27(m,2H)ppm.

[0226] Compound 8f (70 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (1 mL), and compound 8d (79 mg, 0.3 mmol), triethylamine (75 mg, 0.75 mmol), and HATU (140 mg, 0.37 mmol) were added. The reaction was carried out at room temperature for 16 hours. The reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were extracted with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:7) to give compound 8 g (80 mg, yield 60%). MS m / z 532.7 [M+H] +

[0227] 8 g (40 mg, 0.075 mmol) of the compound was dissolved in methanol (1 mL), and water and hydrazine (80%, 0.1 mL) were added. The mixture was heated to 35 °C and reacted for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1, 1% ammonia) to give compound 8h (20 mg, yield 66%). 1 H NMR (500MHz, CD3OD) δ8.54(s,2H),4.96(d,J=13.6Hz,2H),4.44(d,J=2.1Hz,2H),4.18-4.07(m,1H),3.65-3.59(m,1H),3.44-3.31(m,2H),2. 97(t,J=12.9Hz,2H),2.71-2.61(br,1H),2.18-2.06(m,2H),1.84-1.77(m,2H),1.21-1.15(m,3H),0.92-0.85(m,2H),0.84-0.77(m,2H)ppm.

[0228] Compound 8h (10 mg, 0.025 mmol) was dissolved in acetonitrile (1 mL), and compound b (synthesized using the method described in patent US20210024502, 10 mg, 0.03 mmol) and triethylamine (12 mg, 0.12 mmol) were added. The mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 8i (10 mg, yield 57%). 1H NMR (500MHz, CD3OD) δ8.55 (s, 2H), 8.05 (s, 1H), 5.35 (s, 2H), 4.97 (d, J = 13.5Hz, 2H),4.42(d,J=4.4Hz,2H),4.28–4.07(m,2H),3.75–3.64(m,3H),3.61-3.53(m, 1H),2.98(t,J=12.1Hz,2H),2.68-2.57(m,1H),2.14-2.02(m,2H),1.86-1.74(m ,2H),1.39-1.26(m,3H),0.94-0.91(m,2H),0.90-0.80(m,4H),0.01(s,9H)ppm.

[0229] Compound 8i (7 mg, 0.01 mmol) was dissolved in trifluoroacetic acid (0.5 mL) and reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting mixture was redissolved in dichloromethane. A small amount of ammonia was added to adjust the pH to alkalinity, and the mixture was purified by preparative silica gel thin-layer chromatography (dichloromethane:methanol = 20:1) to give target compound 8 (5.13 mg, 90% yield). 1 H NMR (500MHz, CD3OD) δ8.54(s,2H),7.99(s,1H),4.96(d,J=13.5Hz,2H),4.42(d,J=5.5Hz,2H),4.24–4.07(m,2H),3.68-3.63(m,1H),3.58-3.55(m ,1H),2.97(t,J=12.3Hz,2H),2.63(br,1H),2.14-2.05(m,2H),1.81-1.7 9(m,2H),1.29(d,J=6.5Hz,3H),0.89-0.85(m,2H),0.83-0.76(m,2H)ppm.

[0230] Example 9: Preparation of Compound 9

[0231]

[0232] Compound 4b (245 mg, 1.0 mmol) was dissolved in ethanol (5 mL), a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.5 mL) and Compound 9a (146 mg, 2.0 mmol) were added, followed by sodium cyanoborohydride (126 mg, 2.0 mmol), and the reaction was carried out at room temperature for 16 hours. The reaction was quenched by adding saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting mixture was separated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford Compound 9b (70 mg, yield 23%). 1 ¹H NMR (500 MHz, CDCl₃) δ 8.47 (s, 2H), 4.85 (t, J = 6.9 Hz, 2H), 4.75-4.73 (m, 2H), 4.48 (t, J = 6.4 Hz, 2H), 4.15-4.10 (m, 1H), 3.11-2.99 (m, 2H), 2.83-2.79 (m, 1H), 1.91-1.85 (m, 2H), 1.40-1.29 (m, 2H) ppm.

[0233] Compound 9b (50 mg, 0.166 mmol) was dissolved in N,N-dimethylformamide (1 mL), Compound 8d (44 mg, 0.166 mmol) and triethylamine (50 mg, 0.5 mmol) were added, followed by HATU (95 mg, 0.25 mmol), and the reaction was carried out at room temperature for 16 hours. Water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:7) to afford Compound 9c (50 mg, yield 55%). MS m / z 548.6 [M+H] + .

[0234] Compound 9c (30 mg, 0.054 mmol) was dissolved in methanol (1 mL), hydrazine hydrate (80% aqueous solution, 0.1 mL) was added, and the mixture was heated to 35°C and reacted for 16 hours. The reaction mixture was concentrated under pressure, and the resulting mixture was separated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford Compound 9d (8 mg, yield 40%). MS m / z 418.5 [M+H] + .

[0235] Compound 9d (5 mg, crude product) was dissolved in acetonitrile (1 mL), and compound b (4 mg, 0.12 mmol) and triethylamine (6 mg, 0.06 mmol) were added. The reaction was carried out at room temperature for 16 hours. The reaction was quenched with water, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 9e (4 mg, 73% yield). Compound 9e (2.0 mg, 0.03 mmol) was dissolved in tetrabutylammonium fluoride (0.5 mL), and one drop of ethylenediamine was added. The mixture was placed in a sealed tube and heated to 85 °C for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative silica gel thin-layer chromatography (petroleum ether:ethyl acetate = 1:3) to give target compound 9 (0.67 mg, 40% yield). MS m / z 580.5 [M+H] + .

[0236] Example 10: Preparation of Compound 10

[0237]

[0238] Compound 3e (1 g, 5.71 mmol), compound 10a (2.39 g, 11.41 mmol), and tetrabutylammonium hydrogen sulfate (186 mg, 0.57 mmol) were dissolved in sodium hydroxide solution (25%, 9.13 g). The reaction mixture was stirred overnight at 65 °C. After the reaction was complete, ethyl acetate was added for dilution. The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a yellow oily product 10b (750 mg, yield 43%). MS m / z 326.0 [M + Na] + .

[0239] Compound 10b (750 mg, 2.47 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude product 10c, which was directly used for the next reaction. MS m / z 120.0 [M+H] + .

[0240] Crude product 10c (theoretical yield: 295 mg, 2.47 mmol) and compound b (814 mg, 2.47 mmol) were dissolved in acetonitrile (8 mL), and then N,N-diisopropylethylamine (960 mg, 7.43 mmol) was added. The reaction mixture was stirred at 40 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 6:1) to give a yellow oily product 10d (390 mg, yield 38%). MS m / z 434.0 [M+Na] + .

[0241] Under nitrogen protection, compound 10d (50 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and Dysmartin oxidant (103 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium carbonate solution and saturated sodium sulfite solution were added sequentially. The mixture was extracted with dichloromethane (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product 10e was directly used in the next reaction.

[0242] Crude products 10e (theoretical yield: 50 mg, 0.12 mmol) and 10f (synthesized using the method in WO2016077375, 30 mg, 0.12 mmol) were dissolved in dichloromethane (3 mL), and acetic acid (7 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was placed at 0 °C, and sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added. The reaction mixture was stirred at room temperature for another 30 minutes. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with dichloromethane (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 10 g (3 mg, yield 4%) of a colorless oily product. MS m / z 640.6 [M+H] + .

[0243] Under ice-water bath conditions, 10 g (3 mg, 0.005 mmol) of the compound was dissolved in 1.5 mL of dichloromethane, and N,N-diisopropylethylamine (2 mg, 0.014 mmol) was added with stirring. Then, a 1 mL dichloromethane dilution of acetyl chloride (0.4 mg, 0.005 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 15 minutes. After the reaction was complete, a small amount of methanol was added to quench the reaction. The mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a white solid product 10i (2 mg, yield 63%). MS m / z 682.2 [M+H] + .

[0244] Compound 10i (2 mg, 0.003 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added. The reaction mixture was stirred at room temperature for 20 minutes. After the reaction mixture was concentrated under reduced pressure, it was dissolved in methanol (1 mL), and 2 drops of ammonia were added. The mixture was stirred at room temperature for 2 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give a white solid product 10 (1 mg, yield 62%). MS m / z 552.1 [M+H] + .

[0245] Example 11: Preparation of Compound 11

[0246]

[0247] Compound 11 was synthesized using the same method as compound 10, yielding compound 11 (0.8 mg, white solid) from compound 10 g. 1 H NMR (500MHz, CD3OD) δ8.54(s,2H),7.91(s,1H),6.19(dd,J=16.7,1.8Hz,1H),5.77-5.63(m,2H),4.97(d,J=12.5Hz,2H),4.45-4.35(m,1H), 4.23-4.08(m,2H),3.64-3.46(m,5H),3.04-2.92(m,2H),2.06-1.99(m ,1H),1.95-1.82(m,1H),1.81-1.74(m,2H),1.23(d,J=5.7Hz,3H)ppm. MS m / z 564.0[M+H] + .

[0248] Example 12: PARP7 enzyme inhibitory activity test

[0249] Prepare histone-coated 384-well plates: Add 25 μL of histone solution to each well and incubate overnight at 4°C. Wash the histone-coated 384-well plates three times with PBST solution. Add 50 μL of blocking solution to each well and block at room temperature for 1 hour. Then wash the 384-well plates three times with PBST solution. Prepare a 10 mM stock solution of the compound using 100% DMSO and dilute it serially. Transfer 5 μL of the compound to each well. Prepare PARP7 enzyme solution ((BPS, Cat. No. 80527)) and incubate at 25°C for 10 minutes. Transfer 10 μL of the enzyme solution to each well and incubate with the compound at room temperature for 10 minutes. Add 10 μL of 2.5x Biotin-NAD+ (R&D, Cat. No. 6573) to each well and incubate at 25°C for 60 minutes. Wash the 384-well plates three times with PBST solution. Add 20 μL of anti-poly(ADP-ribose) rabbit monoclonal antibody and incubate at room temperature for 1.5 hours, washing three times with PBST solution. Then add 20 μL of horseradish peroxidase-linked anti-rabbit IgG diluted 1:2000 and incubate at room temperature for 1 hour. Wash the 384-well plate three times with PBST solution. Add 25 μL of a 1:1 mixture of Femto-ECL substrate A and Femto-ECL substrate B (THERMO PIERCE, Cat. No. 37074), and immediately read the fluorescence values ​​using Envision. Calculate the inhibition rate of the compound in Excel using the formula inhibition% = (Max - Signal) / (Max - Min) * 100. Where max refers to the value of the DMSO control and min refers to the value of the enzyme-free control. Fit the curve using XL-Fit software and calculate the IC50. 50 The formula is: Y = Bottom + (Top - Bottom) / (1 + (IC) 50 / X)*HillSlope). Y is the percentage inhibition rate, and X is the concentration of the compound. The activities of some representative compounds are shown in Table 1.

[0250] Table 1 PARP7 enzyme inhibitory activity

[0251] 1 The inhibition rate at 12.5 nM was 95%. 3 <![CDATA[IC 50 <1nM]]> 7 The inhibition rate at 12.5 nM was 70%. 8 <![CDATA[IC 50 <1nM]]>

[0252] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof: 。 2. A pharmaceutical composition, characterized in that, It comprises the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Used to prepare pharmaceutical compositions for treating diseases, conditions, or symptoms related to PARP7 activity or expression levels.

4. The use as described in claim 3, characterized in that, The diseases, symptoms, or conditions described are selected from the following group: multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, monocytic leukemia, splenomegaly with polycythemia, eosinophilic syndrome, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck cancer, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, stomach cancer, heart disease, viral infections, neurodegenerative diseases, inflammation, and pain.

5. The use as described in claim 3, characterized in that, The disease, symptom, or condition is a type of disease associated with PARP7 overexpression or abnormal activation.

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