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WO2022188889A1 - Composé utile en tant qu'inhibiteur de parp7 - Google Patents

Composé utile en tant qu'inhibiteur de parp7 Download PDF

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Publication number
WO2022188889A1
WO2022188889A1 PCT/CN2022/080732 CN2022080732W WO2022188889A1 WO 2022188889 A1 WO2022188889 A1 WO 2022188889A1 CN 2022080732 W CN2022080732 W CN 2022080732W WO 2022188889 A1 WO2022188889 A1 WO 2022188889A1
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Prior art keywords
alkyl
hydrogen
cycloalkyl
compound
alkynyl
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PCT/CN2022/080732
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Chinese (zh)
Inventor
张汉承
贾薇
蔡聪聪
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Hangzhou Innogate Pharma Co Ltd
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Hangzhou Innogate Pharma Co Ltd
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Priority to CN202280021065.7A priority Critical patent/CN117425648A/zh
Priority to CN202211105078.0A priority patent/CN116789647A/zh
Publication of WO2022188889A1 publication Critical patent/WO2022188889A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to a novel derivative containing a tricyclic heteroaryl group, its synthesis method and its use as a PARP7 inhibitor in the preparation of medicines for the treatment of tumors and other related diseases applications in .
  • ADP ribosylation is a kind of post-translational modification on various amino acid residues. Ribosylation leads to the reversible attachment of ADP ribose to the substrate protein, and regulates various physiological functions such as gene expression, protein degradation and cellular stress response. , mediated by members of the PARP (Poly(ADP-ribose)polymerases) family.
  • the human PARP family contains 17 members. According to the catalytic mode and activity, the PARP family proteins can be divided into three categories. One class catalyzes the multi-ADP ribosylation of substrates, including PARP1, PARP2, PARP5a, and PARP5b; one class catalyzes the substrates.
  • PARP1 has become an effective target in DNA damage-related tumor types.
  • PARP1 inhibitor anti-tumor drugs There are currently four PARP1 inhibitor anti-tumor drugs on the market, and multiple PARP1 inhibitors are in clinical trials.
  • PARP7 plays an important role in neuronal development, stem cell maintenance, resistance to viral infection, and cancer.
  • the expression of PARP7 is regulated by transcription factors and signaling pathways, including transcription factors AHR (Aryl hydrogen receptor), androgen receptor, HIF1 (Hypoxia inducible factor 1) and platelet-derived growth factor signaling pathways.
  • AHR is a ligand-activated transcription factor involved in the regulation of physiological processes such as pro-inflammatory responses and foreign body metabolism.
  • AHR can be activated by a variety of ligands, such as endogenous tryptophan metabolites kynurenine and TCDD (2,3,7,8tetrachlorodibenzo-p-dioxin).
  • AHR Activation of AHR induces the expression of various metabolism-related genes, such as cytochrome P450A1 and P450B1.
  • AHR-induced expression of PARP7 as a negative feedback regulator of AHR, inhibits the transcriptional activation activity of AHR.
  • the PARP7 gene is located on chromosome 3 (3q25), a locus that is frequently amplified in squamous cancer types. Genomic association assays identified the 3q25 locus as a susceptibility locus for ovarian cancer, suggesting a role for PARP7 in this cancer type. Mechanistically, PARP7 may regulate the stability of tubulin by ribosylating Tubulin, as well as inhibit the type 1 interferon signaling pathway, inhibit the body's anti-tumor immunity, and promote tumor growth and survival.
  • PARP7 is highly expressed in the brain. Knockout of PARP7 in mice results in abnormal cortical development and reduced proliferation and migration of neural progenitors. PARP7 also plays an important role in maintaining the expression of stemness genes such as Nanog, Sox2, Stella and Zfp42. In the absence of PARP7, the stemness of embryonic stem cells is difficult to maintain, showing a tendency to differentiate. PARP7 can also modify the liver X receptor (LXR), co-activate the LXR signaling pathway, and promote physiological processes such as cholesterol and fat metabolism. TBK1 (TANK binding kinase 1) is a major kinase in the pattern recognition receptor signaling pathway, mediating the activation of type 1 interferon and antiviral immunity. PARP7 inhibits the innate antiviral immune response by ribosylating TBK1 and inhibiting the activation of TBK1.
  • LXR liver X receptor
  • TBK1 TANK binding kinase 1
  • PARP7 inhibits
  • PARP7 Based on the role of PARP7 in the innate immune response, the role of PARP7 in tumor immunity has also received increasing attention. Aberrantly expressed or activated PARP7 can inhibit T cell-mediated antitumor immunity by inhibiting the innate immune response. In a large-scale genetic screen, PARP7 was also identified as a suppressor of T cell activation. Knockdown of PARP7 in melanoma cells enhanced proliferation and growth of co-cultured T cells.
  • PARP7 is a promising target for anti-tumor and viral diseases.
  • the object of the present invention is to provide a new class of PARP7 inhibitors.
  • the first aspect of the present invention provides a compound of the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof. :
  • A is selected from -NR 3 -, -O-, -CR 4 R 5 -, or 3- to 8-membered heterocyclyl; wherein, R 3 is selected from hydrogen or C 1-4 alkyl; R 4 and R 5 each independently selected from hydrogen, halogen, or C 1-4 alkyl;
  • R 6 and R 7 are each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkane group, C 3-6 cycloalkyl C 1-4 alkyl, 4- to 8-membered heterocyclyl, or 4- to 8-membered heterocyclyl C 1-4 alkyl; or R 6 and R 7 and their The attached carbon atoms together form a 3- to -6-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S;
  • D is selected from -(CR 8 R 9 ) p -Y-(CR 10 R 11 ) q -; wherein, Y is selected from -O-, -NR 12 -, -CR 13 R 14 -, C 3-6 cycloalkane radical, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; each R8 and R9 are each independently selected from hydrogen, halogen, hydroxy, or C 1-4 alkyl; each R 10 and R 11 are each independently selected from hydrogen, halogen, hydroxy, or C 1-4 alkyl; or to which R 8 and R 9 are attached Carbon atoms, or R 10 and R 11 together with the carbon atoms to which they are attached form a 3- to -6-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group, the heterocyclic group contains 1 or 2 members selected from the group consisting of A heteroatom of
  • E is selected from chemical bonds or -C(O)-;
  • F is selected from chemical bonds or -NR b -; wherein, R b is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclic group, aryl group, heteroaryl group, C(O)R c , or S(O) 2 R c ; or R b and R 10 or R 11 and the nitrogen atom and carbon atom to which they are connected together with E to form a 4- to 8-membered heterocyclic group, this heterocyclic group contains 1 N atom and 0 or 1 heteroatom selected from N, O, S; R c is selected from C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8- membered heterocyclic group; the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, and hetero
  • G is selected from N or CR e ; wherein, R e is selected from hydrogen or C 1-4 alkyl;
  • T is selected from N or CR 15 ; wherein, R 15 is selected from hydrogen, halogen, or C 1-4 alkyl;
  • X and Z are each independently selected from N or CR;
  • Each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2 -4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy Oxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, NR h Rh , CN, NO 2 , SR h , C(O)R t , C(O)OR h , C(O)NR h Rh , NR h C(O)R t , NR h S(O) 2 R t , or S(O ) 2
  • R 1 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 halo Alkynyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 haloalkoxy C 1-4 alkyl;
  • R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl;
  • n are each independently selected from 0, 1, or 2;
  • k is selected from 0, 1, or 2;
  • h is selected from 0, 1, 2, 3, or 4;
  • each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is optionally and each independently selected from 1-3 groups each independently selected from the following Substituent substitution of the group: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, NO2, ORh , SRh , NRhRh , C(O) Rt , C(O ) ORh , C ( O ) NRhRh , NR h C(O)R t , NR h S(O) 2 R t , or S(O) 2 R t , provided that the chemical structure formed is stable and meaningful; where Rh and R t
  • the above-mentioned aryl group 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 Saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic groups.
  • formula (I) is formula (IIA):
  • Q is selected from -NR 16 -, -O-, -CR 17 R 18 -; wherein, R 16 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocycle R 17 and R 18 are each independently selected from hydrogen , halogen , or C 1-4 alkyl;
  • f and g are each independently selected from 0, 1, or 2; provided that f and g cannot be 0 at the same time;
  • j and t are each independently selected from 0, 1, or 2;
  • formula (I) is formula (IIIA):
  • p is selected from 0, 1, or 2;
  • j and t are each independently selected from 0, 1, or 2;
  • formula (I) is formula (IVA):
  • R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 1-4 alkoxy C 1- 4 alkyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, 4- to 8-membered heterocyclyl, or 4- to 8- membered heterocyclyl C 1-4 alkyl;
  • p is selected from 0, 1, or 2;
  • j and t are each independently selected from 0, 1, or 2;
  • formula (I) is formula (VA):
  • R b is as defined above;
  • formula (I) is formula (VIA):
  • R b is selected from C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl are any optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, NR d R d , CN, OR d , SR d , C(O)R t , or S(O) 2 R t ; wherein R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; each R d is independently hydrogen or C 1-4 alkyl;
  • q is selected from 0, 1, 2, or 3;
  • formula (I) is formula (VIIA):
  • R c is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; the alkyl , alkenyl, alkynyl, cycloalkyl and heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-4alkyl , C2-4alkenyl , C2- 4alkynyl , C3-6cycloalkyl , 4- to 8-membered heterocyclyl, NRdRd , CN, ORd , SRd , C ( O) Rt , or S(O ) 2R t ;
  • j is selected from 0, 1, or 2;
  • formula (I) is formula (VIIIA):
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
  • R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
  • X is selected from N or CR
  • R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  • formula (I) is formula (IXA):
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl
  • R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
  • X is selected from N or CR
  • R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  • formula (I) is formula (XA):
  • R b is selected from C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl are any optionally substituted with 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) 2 R t ; wherein, R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; each R d is each independently hydrogen or C 1-4 alkyl;
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl;
  • R 8 , R 9 , R 10 , R 11 are each independently selected from hydrogen, hydroxyl, C 1-4 alkyl ; or
  • the carbon atom to which R 6 and R 7 are attached, the carbon atom to which R 8 and R 9 are attached, or the carbon atom to which R 10 and R 11 are attached together form a 3- to -6-membered cycloalkyl, or a 4- to 8-membered heterocyclic group, this heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S;
  • X is selected from N or CR
  • R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is H;
  • X is selected from N or CH
  • R is each independently selected from trifluoromethyl, CN, C2-4alkynyl , C3-6cycloalkylalkynyl , 3- to 8-membered heterocyclylalkynyl, C3-6cycloalkyl .
  • formula (I) is formula (XIA):
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is selected from hydrogen
  • R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl
  • R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
  • X is selected from N or CH
  • R is each independently selected from C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 3-6 cycloalkane base, 3- to 8-membered heterocyclyl.
  • the compound of formula (I) is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated Derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.
  • the third aspect of the present invention provides a compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof. , for preparing a pharmaceutical composition for treating diseases, disorders or conditions related to the activity or expression of PARP7.
  • the disease, disorder 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, and monocytic leukemia , polycythemia splenomegaly, eosinophilic leukemia syndrome, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer , prostate cancer, glioblastoma, ovarian cancer, head and neck cancer, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, stomach cancer and other hematological and solid tumors, as well as various types of heart disease, viral infection, neurodegenerative disease, inflammation and pain, especially those disease types associated with PARP7 overexpression or abnormal activation.
  • the inventors After long-term and in-depth research, the inventors have unexpectedly discovered a class of compounds with novel structures as PARP7 inhibitors, as well as their preparation methods and applications.
  • the compounds of the present invention can be applied to the treatment of various diseases related to the activities of the ADP and glycosyltransferases. Based on the above findings, the inventors have completed the present invention.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • alkyl refers to a straight chain (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched chain groups .
  • a carbon number limitation eg, C 1-10
  • C 1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
  • alkenyl refers to a straight 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 limitation (eg, C2-8 ), it means that the alkenyl group contains 2-8 carbon atoms.
  • 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 the like group.
  • alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be straight or branched, or a combination thereof.
  • a carbon number limitation eg, C 2-8 alkynyl
  • C 2-8 alkynyl refers to straight or branched chain alkynyl groups having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
  • cycloalkyl refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group having saturated or partially saturated .
  • a cycloalkyl group is preceded by a carbon number limitation (eg C 3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
  • C 3-8 cycloalkyl refers to saturated or partially unsaturated monocyclic or bicycloalkyl having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclo pentyl, cycloheptyl, or similar groups.
  • “Spirocycloalkyl” refers to a bicyclic or polycyclic group in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more double bonds, but none of the rings have fully conjugated pi electrons system.
  • “Fused cycloalkyl” refers to an all-carbobicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more bicyclic bonds, but none of the rings have a fully conjugated pi electron system.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system .
  • the atoms contained in the cycloalkyl group are all carbon atoms.
  • the following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl.
  • the aryl ring can 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 must be in a conjugated pi-electron system on the carbon atom of the ring.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group containing one to more heteroatoms A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the attachment site is located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.
  • Heterocyclyl 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.
  • monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
  • Polycyclic heterocyclyl refers to heterocyclyl including spiro, fused and bridged rings.
  • “Spirocyclic heterocyclyl” refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, the remaining ring atoms are carbon.
  • “Fused-ring heterocyclyl” 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 no A ring has a fully conjugated pi electron system and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
  • “Bridged heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system , and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If both saturated and aromatic rings are present in the heterocyclyl group (for example, the saturated and aromatic rings are fused together), the point of attachment to the parent must be on the saturated ring. Note: When the point of attachment to the parent is on an aromatic ring, it is called a heteroaryl group, not a heterocyclyl group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
  • halogen refers to F, Cl, Br, and I.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, an optionally substituted group may have at any substitutable position of the group a substituent selected from a specified group, which may be the same or different at each position.
  • a cyclic substituent such as a heterocyclyl
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl , aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amino group.
  • a pharmaceutically acceptable salt refers to a salt suitable for contact with the tissue of a subject (eg, a human) without undue side effects.
  • a pharmaceutically acceptable salt of a compound of the present invention includes a salt of a compound of the present invention that has an acidic group (eg, potassium, sodium, magnesium, calcium) or has a basic salts of compounds of the invention (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates).
  • the present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates , the use of a pharmaceutically acceptable carrier or excipient for inhibiting PARP7.
  • the compounds of the present invention are useful as a PARP7 inhibitor.
  • the present invention is a single inhibitor of PARP7, and achieves the purpose of preventing, relieving or curing diseases by regulating the enzymatic activity of PARP7.
  • Indicated diseases include multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, monocytic leukemia, polycythemia splenomegaly, eosinophilic leukemia syndrome, fibrosis Sarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck cancer , cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, gastric cancer and other hematological tumors and solid tumors, as well as various
  • compositions may be combined with pharmaceutically acceptable excipients or The carriers are formulated together and the resulting compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases.
  • the compositions may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions. Sterile powder, etc.
  • the pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants such as magnesium stearate, glycerin and talc.
  • disintegrants such as starch, croscarmellose sodium, complex silicates and high molecular polyethylene glycol
  • granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic
  • lubricants such as magnesium stearate, glycerin and talc.
  • the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders.
  • the amount of a compound or pharmaceutical composition of the present invention administered to a patient is not fixed, but is usually administered in a pharmaceutically effective amount. Meanwhile, the amount of the compound actually administered can be determined by the physician according to the actual situation, including the condition to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like.
  • the dosage of a compound of the present invention will depend upon the particular use of the treatment, the mode of administration, the patient's condition, and the judgment of the physician.
  • the ratio or concentration of a compound of the present invention in a pharmaceutical composition depends on a variety of factors, including dosage, physicochemical properties, route of administration, and the like.
  • the reagents and conditions of each compound synthesis step can be selected from the conventional reagents or conditions in the art for such preparation methods.
  • the reactants, solvents, bases, the amount of the used compound, the reaction temperature, and the required reaction conditions Selection of time and the like can be performed by those skilled in the art according to the knowledge in the art.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
  • compositions and methods of administration are provided.
  • the compound of the present invention Since the compound of the present invention has excellent inhibitory activity against an ADP ribosyltransferase, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention
  • the pharmaceutical composition in which the compound of the invention is the main active ingredient can be used for the treatment, prevention and alleviation of diseases related to the activity or expression of PARP7.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • 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.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • 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.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • a PARP7 inhibitor with novel structure, preparation and application thereof, the inhibitor can inhibit the activity of PARP7 at a very low concentration.
  • a pharmaceutical composition for treating diseases related to PARP7 activity is provided.
  • Some representative compounds of the present invention can be prepared by the following synthetic methods.
  • the reagents and conditions of each step can be selected from conventional reagents or conditions in the field for such preparation methods.
  • the above selection can be made by those skilled in the art according to the knowledge in the art.
  • Some compounds of the present invention can be prepared by the following methods.
  • DIPEA N,N-diisopropylamine
  • HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate
  • Compound 1j was synthesized by the method of patent US20190330194.
  • Compound 5 was prepared by referring to a method similar to Example 7, substituting the corresponding structural fragment.
  • Compound 6 was prepared by referring to a method similar to Example 7, substituting the corresponding structural fragment.

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Abstract

La présente invention concerne un composé utile en tant qu'inhibiteur de PARP7. Plus particulièrement, la présente invention concerne un composé ayant une structure telle que représentée par la formule (I), ou un isomère optique, un sel pharmaceutiquement acceptable, un promédicament, un dérivé deutéré, un hydrate ou un solvate de celui-ci. Le composé peut être utilisé pour traiter ou prévenir des maladies ou des troubles associés à l'activité ou au niveau d'expression de PARP7.
PCT/CN2022/080732 2021-03-12 2022-03-14 Composé utile en tant qu'inhibiteur de parp7 Ceased WO2022188889A1 (fr)

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WO2024149234A1 (fr) * 2023-01-10 2024-07-18 Angel Pharmaceutical Co., Ltd. Inhibiteurs de parp7 et leurs utilisations
WO2024152855A1 (fr) * 2023-01-17 2024-07-25 中国药科大学 Inhibiteur de parp de pyridazinone, son procédé de préparation, et composition pharmaceutique et son utilisation
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WO2024149234A1 (fr) * 2023-01-10 2024-07-18 Angel Pharmaceutical Co., Ltd. Inhibiteurs de parp7 et leurs utilisations
WO2024152855A1 (fr) * 2023-01-17 2024-07-25 中国药科大学 Inhibiteur de parp de pyridazinone, son procédé de préparation, et composition pharmaceutique et son utilisation
WO2025210243A1 (fr) * 2024-04-04 2025-10-09 Katholieke Universiteit Leuven Composés antiviraux

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