CN117425648A - Compounds as PARP7 inhibitors - Google Patents
Compounds as PARP7 inhibitors Download PDFInfo
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- CN117425648A CN117425648A CN202280021065.7A CN202280021065A CN117425648A CN 117425648 A CN117425648 A CN 117425648A CN 202280021065 A CN202280021065 A CN 202280021065A CN 117425648 A CN117425648 A CN 117425648A
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- Prior art keywords
- alkyl
- cycloalkyl
- hydrogen
- alkynyl
- halogen
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- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
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- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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Classifications
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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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- 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
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Abstract
The present invention provides compounds as PARP7 inhibitorsSpecifically, the invention provides a compound with a structure shown in the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate and solvate thereof. The compounds are useful for the treatment or prevention of diseases or conditions associated with PARP7 activity or expression levels.
Description
The present invention relates to the field of pharmaceutical chemistry; in particular, the invention relates to a novel tricyclic heteroaryl-containing derivative, a synthesis method thereof and application of the derivative serving as a PARP7 inhibitor in preparation of medicaments for treating various diseases such as tumors and the like.
ADP ribosylation is a post-translational modification at various amino acid residues, which results in the reversible attachment of ADP ribose to a substrate protein, regulating various physiological functions such as gene expression, protein degradation, and cellular stress response, mediated by PARP (Poly (ADP-ribose) family members. The human PARP family contains 17 members, and PARP family proteins can be divided into three classes, depending on catalytic means and activity, one class of which catalyzes the multiple ADP ribosylation of substrates, including PARP1, PARP2, PARP5a and PARP5b; mono ADP ribosylation of a class of catalytic substrates including PARP3, PARP4, PARP7, PARP12, and the like; PARP13 is special and has no catalytic activity in vitro or in vivo. PARP1 has become an effective target in tumor types related to DNA damage, four types of PARP1 inhibitor antitumor drugs are currently marketed, and a plurality of PARP1 inhibitors are in clinical trials.
PARP7 plays an important role in neuronal development, stem cell maintenance, antiviral infection and cancer. PARP7 expression is regulated by transcription factors and signaling pathways, including transcription factor AHR (Aryl hydrocarbon receptor), androgen receptor, HIF1 (Hypoxia inducible factor 1), and platelet-derived growth factor signaling pathway, among others. AHR is a ligand-activated transcription factor involved in regulating physiological processes such as pro-inflammatory response and foreign body metabolism. AHR may be activated by a variety of ligands, such as the endogenous tryptophan metabolites kynurenine and TCDD (2, 3,7, 8-tetrahydrodbenzo-p-dioxan), among others. Activation of AHR induces expression of a variety of metabolism-related genes, such as cytochromes P450A1 and P450B1, and the like. AHR-induced expression of PARP7 is used as a negative feedback regulator of AHR to inhibit transcriptional activation activity of AHR.
The PARP7 gene is located on chromosome 3 (3 q 25), a locus that is most amplified in squamous cancer types. Genomic association experiments identified the 3q25 locus as a susceptible site for ovarian cancer, suggesting that PARP7 plays a role in this cancer class. Mechanically, PARP7 may regulate Tubulin stability, inhibit one type of interferon signaling pathway, inhibit body's anti-tumor immunity, and promote tumor growth and survival by ribosylating Tubulin.
PARP7 is expressed higher in the brain. Following PARP7 knockout in mice, mice have brain cortical dysplasia, and reduced proliferation and migration of neural progenitor cells. PARP7 also plays an important role in maintaining the expression of dry genes such as Nanog, sox2, stilla and Zfp 42. In the absence of PARP7, embryonic stem cells are difficult to maintain in their stem properties, exhibiting a tendency to differentiate. PARP7 can also modify Liver X Receptors (LXRs), coactivate LXR signaling pathways, and promote physiological processes such as cholesterol and fat metabolism. TBK1 (TANK binding kinase 1) is the major kinase in the pattern recognition receptor signaling pathway, mediating the activation of interferon type one and antiviral immunity. PARP7 inhibits activation of TBK1 by ribosylating TBK1, thereby inhibiting innate anti-viral immune response.
Based on the role of PARP7 in innate immune responses, the role of PARP7 in tumor immunity is also of increasing concern. Abnormally expressed or activated PARP7 may inhibit T cell mediated anti-tumor immunity by inhibiting the innate immune response. PARP7 was also identified as an inhibitor of T cell activation in large-scale gene screening. Knocking out PARP7 in melanoma cells can enhance proliferation and growth of co-cultured T cells.
In conclusion, PARP7 is a promising target against various disease types such as tumor and virus.
Disclosure of Invention
The object of the present invention is to provide a novel class of PARP7 inhibitors.
In a first aspect of the present invention, there is provided a compound having the structure shown in formula (I) below, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof:
in formula (I):
a is selected from-NR 3 -、-O-、-CR 4 R 5 -or a 3-to 8-membered heterocyclyl; wherein R is 3 Selected from hydrogen or C 1-4 An alkyl group; r is R 4 And R is 5 Each independently selected from hydrogen, halogen, or C 1-4 An alkyl group;
b is selected from-CR 6 R 7 -or a chemical bond; wherein R is 6 And R is 7 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 Cycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 4-to 8-membered heterocyclyl, or 4-to 8-membered heterocyclyl C 1-4 An alkyl group; or R is 6 And R is 7 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl 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 the group consisting of-O-, -NR 12 -、-CR 13 R 14 -、C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; each R is 8 And R is 9 Each independently selected from hydrogen, halogen, hydroxy, or C 1-4 An alkyl group; each R is 10 And R is 11 Each independently selected from hydrogen, halogen, hydroxy, or C 1-4 An alkyl group; or R is 8 And R is 9 To which is attached a carbon atom, or R 10 And R is 11 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S; r is R 12 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; r is R 13 And R is 14 Each independently selected from hydrogen, halogen, or C 1-4 An alkyl group; or R is 13 And R is 14 Together with the carbon atom to which they are attached form a 3-to-6-membered cycloalkyl group, or a 4-to 8-membered heterocyclyl group containing 1 or 2 members selected from N, O,A heteroatom of S;
e is selected from a bond or-C (O) -;
f is selected from a bond or-NR b -; wherein R is b Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) R c Or S (O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the Or R is b And R is R 10 Or R is 11 And the nitrogen atom, carbon atom and E to which they are attached together form a 4-to 8-membered heterocyclic group containing 1N atom and 0 or 1 heteroatom selected from N, O, S; r is R c Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; r is R b Or R is c The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups described in (a) are 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 The method comprises the steps of carrying out a first treatment on the surface of the Each R is d Each independently is hydrogen or C 1-4 An alkyl group; r is R t Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl;
g is selected from N or CR e The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is e Selected from hydrogen or C 1-4 An alkyl group;
each R is a Each 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, hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkoxy C 1-4 Alkyl, NR h R h CN; each R is h Each independently is hydrogen, or C 1-4 An alkyl group; or two R h Together with the nitrogen atom to which it is attached, form a 3-to-8-membered heterocyclic group containing 1 or 2N atoms and 0 or 1 heteroatom selected from O, S; or two R's attached to the same carbon atom a Together with the carbon atoms, form c=m; wherein M is selected from O or CR j R k The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is j And R is k Each independently selected from the group consisting of: hydrogen, halogen, or C 1-4 An alkyl group; or two R's bound to different carbon atoms a Are connected together to form a bridge ring structure;
t is selected from N or CR 15 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 15 Selected from hydrogen, halogen, or C 1-4 An alkyl group;
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 C 1-4 Alkyl, C 1-4 Haloalkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, NR h R h 、CN、NO 2 、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) 2 R t Or S (O) 2 R t The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is h And R is t Is defined as above;
R 1 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 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 An alkyl group;
R 2 selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl;
m and 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;
or structural fragments of formula (I)Selected from the following formulae:
wherein d is selected from 0, 1, or 2; e is selected from 1, 2, 3, or 4;
wherein, unless otherwise specified, each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is optionally and each independently substituted with 1 to 3 substituents each independently selected from the group consisting of: 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, NO 2 、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) 2 R t Or S (O) 2 R t Provided that the chemical structure formed is stable and meaningful; wherein R is h And R is t Is defined as above;
unless otherwise specified, the above aryl groups are aromatic groups having 6 to 12 carbon atoms; heteroaryl is a 5-to 15-membered (preferably 5-to 12-membered) heteroaryl group; the cyclic structure is a saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic group.
In another preferred embodiment, formula (I) is formula (IIA):
q is selected from-NR 16 -、-O-、-CR 17 R 18 -; wherein R is 16 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) R t Or S (O) 2 R t ;R 17 And R is 18 Each independently selected from hydrogen, halogen, or C 1-4 An alkyl group;
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;
the other groups are as defined above.
In another preferred embodiment, 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;
the other groups are as defined above.
In another preferred embodiment, formula (I) is formula (IVA):
R 6 And R is 7 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 An alkyl group;
p is selected from 0, 1, or 2;
j and t are each independently selected from 0, 1, or 2;
the other groups are as defined above.
In another preferred embodiment, formula (I) is formula (VA):
R b is as defined above;
the definition of each group is as described above.
In another preferred embodiment, formula (I) is formula (VIA):
R b selected from C 3-6 Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are 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 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is t Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; each R is d Each independently is hydrogen or C 1-4 An alkyl group;
q is selected from 0, 1, 2, or 3;
the other groups are as defined above.
In another preferred embodiment, formula (I) is formula (VIIA):
R c selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups are 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 ;
j is selected from 0, 1, or 2;
the other groups are as defined above.
In another preferred embodiment, formula (I) is formula (VIIIA):
R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl;
R 2 selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkynyl;
R 8 、R 9 、R 10 、R 11 each independently selected from hydrogen, hydroxy, C 1-4 An alkyl group;
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.
In another preferred embodiment, formula (I) is formula (IXA):
R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl;
R 2 selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkynyl;
R 6 and R is 7 Each independently selected from hydrogen, C 1-4 An alkyl group;
R 8 、R 9 、R 10 、R 11 each independently selected from hydrogen, hydroxy, C 1-4 An alkyl group;
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.
In another preferred embodiment, formula (I) is formula (XA):
R b selected from C 3-6 Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are 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 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is t Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; each R is d Each independently is hydrogen or C 1-4 An alkyl group;
R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl;
R 2 selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkynyl;
R 6 and R is 7 Each independently selected from hydrogen, C 1-4 An alkyl group; r is R 8 、R 9 、R 10 、R 11 Each independently selected from hydrogen, hydroxy, C 1- 4 An alkyl group; or (b)
R 6 And R is 7 To which is attached a carbon atom, R 8 And R is 9 To which is attached a carbon atom, or R 10 And R is 11 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl containing 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.
In a further preferred embodiment of the present invention,
R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl; r is R 2 Is H;
x is selected from N or CH;
r is each independently selected from trifluoromethyl, CN, C 2-4 Alkynyl, C 3-6 Cycloalkylalkynyl, 3-to 8-membered heterocyclylalkynyl, C 3-6 Cycloalkyl groups.
In another preferred embodiment, formula (I) is formula (XIA):
R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl;
R 2 selected from hydrogen;
R 6 and R is 7 Each independently selected from hydrogen, C 1-4 An alkyl group;
R 8 、R 9 、R 10 、R 11 each independently selected from hydrogen, hydroxy, C 1-4 An alkyl group;
or R is 6 And R is 7 To which is attached a carbon atom, R 8 And R is 9 To which is attached a carbon atom, or R 10 And R is 11 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S;
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 Cycloalkyl, 3-to 8-membered heterocyclyl.
In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:
"×" indicates chiral centers.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the first aspect of the invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, and a pharmaceutically acceptable carrier.
In a third aspect of the present invention there is provided the use of a compound according to the first aspect of the present invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, for the manufacture of a pharmaceutical composition for the treatment of a disease, disorder or condition associated with PARP7 activity or expression level.
In another preferred embodiment, 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 lymphoid leukemia, monocytic leukemia, splenomegaly, eosinophilia syndrome, fibrosarcoma, salivary gland carcinoma, liver cancer, rectal cancer, bladder cancer, laryngeal carcinoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous 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 hematological and solid tumors, as well as various types of heart diseases, viral infections, neurodegenerative diseases, inflammation and pain, and the like, particularly those associated with PARP7 overexpression or abnormal activation.
The inventor has studied intensively for a long time, and has unexpectedly found a compound with a novel structure as PARP7 inhibitor, and a preparation method and application thereof. The compounds of the invention may be used in the treatment of various diseases associated with the activities of the ADP and glycosyltransferases. Based on the above findings, the inventors have completed the present invention.
Terminology
Unless specifically stated otherwise, references herein to "or" have the same meaning as "and/or" refer to "or" and ".
Unless otherwise specified, each chiral carbon atom (chiral center) of all compounds of the invention may optionally be in the R configuration or S configuration, or a mixture of R and S configurations.
As used herein, the term "alkyl" alone or as part of another substituent refers to a straight chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched groups. Having a limit of the number of carbon atoms before the alkyl group (e.g. C 1-10 ) When used, the term alkyl is defined as having 1 to 10 carbon atoms. For example, C 1-8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
As used herein, the term "alkenyl" alone or as part of another substituent refers to a straight or branched chain carbon chain group having at least one carbon-carbon double bond. Alkenyl groups may be substituted or unsubstituted. Having a limit on the number of carbon atoms before the alkenyl group (e.g. C 2-8 ) When used, means that the alkenyl group contains 2 to 8 carbon atoms. For example, C 2-8 Alkenyl refers to alkenyl groups containing 2 to 8 carbon atoms and includes ethenyl, propenyl, 1, 2-butenyl, 2, 3-butenyl, butadienyl, or the like.
As used herein, the term "alkynyl" alone or as part of another substituent refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be straight or branched, or a combination thereof. Having a definition of the number of carbon atoms before alkynyl (e.g. C 2-8 Alkynyl) means that the alkynyl contains 2 to 8 carbon atoms. For example, the term "C 2-8 Alkynyl "refers to straight or branched chain alkynyl groups having 2 to 8 carbon atoms and includes ethynyl, propynyl, isopropoxynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or the like.
As used herein, the term "cycloalkyl" alone or as part of another substituent refers to a group having a saturated or partially saturated unit ring, bicyclic or polycyclic (fused, bridged or spiro) ring system. When a cycloalkyl group has a defined number of carbon atoms (e.g. C 3-10 ) When referring to cycloalkyl groups, said cycloalkyl groups contain 3 to 10 carbon atoms. In some preferred embodiments, the term "C 3-8 Cycloalkyl "refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "spirocycloalkyl" refers to a bicyclic or polycyclic group having a single carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. "fused ring alkyl" refers to an all-carbon bi-or multi-cyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. "bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. The atoms contained in the cycloalkyl are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited to the cycloalkyl groups described below.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-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, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted. The following are examples of aryl groups, and the present invention is not limited to the following aryl groups.
"heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a polycyclic group containing a heterocyclic group (containing one or more heteroatoms selected from nitrogen, oxygen and sulfur) fused to an aryl group, with the attachment site located on the aryl group. Heteroaryl groups may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the heteroaryl groups described below.
"heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Polycyclic heterocyclyl refers to heterocyclyl groups including spiro, fused and bridged rings. "Spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (referred to as the spiro atom) with the 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 heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system, and in which one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon. "bridged heterocyclic group" refers to a polycyclic heterocyclic group wherein any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system, and wherein one or more of the 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 (e.g., the saturated and aromatic rings are fused together), the point of attachment to the parent must be at the saturated ring. And (3) injection: when the point of attachment to the parent is on an aromatic ring, it is referred to as heteroaryl, and not as heterocyclyl. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
As used herein, the term "halogen" refers to F, cl, br, and I, alone or as part of other substituents.
As used herein, the term "substituted" (with or without "optionally" modification) means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, i.e., two rings have one common carbon atom. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such as (but not limited to): c (C) 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxy, carboxyl (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl, C 2-10 Ester groups, amino groups.
For convenience and in accordance with conventional understanding, the terms "optionally substituted" or "optionally substituted" are used only to refer to sites that can be substituted with substituents, and do not include those that are not chemically realizable.
As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with tissue of a subject (e.g., a human) without undue adverse side effects. In some embodiments, pharmaceutically acceptable salts of certain compounds of the invention include salts of the compounds of the invention having an acidic group (e.g., potassium, sodium, magnesium, calcium) or salts of the compounds of the invention having a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).
The application is as follows:
the present invention provides the use of a class of compounds of formula (I), or deuterated derivatives thereof, salts, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients thereof, for inhibiting PARP 7.
The compounds of the present invention are useful as a PARP7 inhibitor.
The invention is a single inhibitor of PARP7, and achieves the aim of preventing, relieving or curing diseases by regulating the enzyme activity of PARP 7. The diseases include multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphoid leukemia, monocytic leukemia, splenomegaly, eosinophilia syndrome, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous 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 other various types of hematological and solid tumors, as well as various types of heart diseases, viral infections, neurodegenerative diseases, inflammation and pain, etc., especially those associated with PARP7 overexpression or abnormal activation.
The compounds of the present invention and deuterated derivatives thereof, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates and/or compositions thereof, may be formulated with pharmaceutically acceptable excipients or carriers and the resulting compositions may be administered to mammals, such as men, women and animals, in vivo for the treatment of conditions, symptoms and diseases. The composition may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, and sterile injectable solutions. Sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin (augmentation), glycine, disintegrants (e.g., starch, croscarmellose sodium, complex silicates, and polymeric polyethylene glycols), granulating binders (e.g., polyvinylpyrrolidone, sucrose, gelatin, and acacia), and lubricants (e.g., magnesium stearate, glycerol, 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, powders. The amount of the compound or pharmaceutical composition of the present invention administered to a patient is not fixed and is typically administered in a pharmaceutically effective amount. Meanwhile, the amount of the compound actually administered may be decided by a physician according to the actual circumstances, including the condition to be treated, the administration route selected, the actual compound administered, the individual condition of the patient, etc. The dosage of the compounds of the invention will depend on the particular use being treated, the mode of administration, the condition of the patient, and the judgment of the physician. The proportion or concentration of the compounds of the invention in the pharmaceutical composition depends on a variety of factors including the dosage, physicochemical properties, route of administration, etc.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions.
General synthetic method of compound
The reagents and conditions for the synthesis steps of each compound can be selected from reagents or conditions conventional in the art for such preparation methods, and after the structure of the compound of the present invention is disclosed, the selection of reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc. can be performed by those skilled in the art according to the knowledge in the art. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent inhibitory activity against an ADP-ribosyltransferase, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention and alleviation of diseases associated with PARP7 activity or expression level.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 5-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), and emulsifying agent (such as sodium hydroxide, etc ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
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. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, 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 released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include 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 as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-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 nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration 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 which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 5 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The main advantages of the invention include:
1. there is provided a compound of formula I.
2. Provides a PARP7 inhibitor with novel structure, and preparation and application thereof, wherein the PARP7 inhibitor can inhibit the activity of PARP7 at very low concentration.
3. A pharmaceutical composition for treating diseases associated with PARP7 activity is provided.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Some representative compounds of the present invention may be prepared by the following synthetic methods, in which the reagents and conditions for each step may be selected from those conventionally used in the art for such preparation methods, and the above selections may be made by one skilled in the art based on the knowledge of the art after the structure of the compounds of the present invention is disclosed.
Examples:
some of the compounds of the present invention can be prepared by the following method.
Abbreviations (abbreviations)
Boc 2 O=di-tert-butyl dicarbonate
Cs 2 CO 3 Cesium carbonate
Dcm=dichloromethane
Dipea=n, N-diisopropylamine
DMA = N, N-dimethylacetamide
Dmf=n, N-dimethylformamide
DMSO = dimethyl sulfoxide
EtOAc = ethyl acetate
HATU = 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxohexafluorophosphate
Sem=2- (trimethylsilyl) ethoxymethyl
Pmb=4-methoxybenzyl group
Tea=triethylamine
TFA = trifluoroacetic acid
Tsoh=4-methylbenzenesulfonic acid
Dessmartin oxidant = 1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-phenyliodic-3- (1H) -one
EXAMPLE 1 preparation of Compound 1
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℃for stirring for 2 hours. After the reaction solution was cooled to room temperature, water was added to dilute. The mixture was extracted with ethyl acetate (3×25 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 column chromatography on silica gel (petroleum ether: ethyl acetate=15:1) to give compound 1c (1.71 g, yield 94%) as a white solid. MS m/z 333.3[ M+H ]] + 。
Compound 1c (1.71 g,5.15 mmol) was dissolved in dichloromethane (15 mL) and then a solution of hydrogen chloride in 1, 4-dioxane (4M, 6 mL) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and washed with methylene chloride to obtain a white solid product 1d (1.54 g, yield 100%). MS m/z 233.3[ M+H ] ] + 。
Compound 1d (100 mg,0.29 mmol) and triethylamine (148 mg,1.46 mmol) were dissolved in dichloromethane (3 mL), and stirred at-40℃and then acrylic anhydride 1e (44 mg,0.35 mmol) was slowly added dropwise. The reaction mixture was stirred at-40℃for 30 minutes. After the reaction is completed, the temperature is raised to room temperature, and water is added into the reaction mixture for dilution. 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 is subjected to silica gelColumn chromatography separation and purification (dichloromethane: ethyl acetate=8:1) gave product 1f as a white solid (77 mg, 92% yield). MS m/z 287.2[ M+H ]] + 。
Compound 1f (77 mg,0.27 mmol), 1g (101 mg,0.54 mmol) and cesium carbonate (105 mg,0.32 mmol) were added sequentially to acetonitrile (3 mL), heated to 60 ℃ and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: ethyl acetate=3:1) to give a colorless oily product 1h (47 mg, yield 37%). MS m/z 474.5[ M+H ]] + 。
Compound 1h (47 mg,0.10 mmol) was dissolved in dichloromethane (2 mL) and a 1, 4-dioxane solution of hydrogen chloride (4M, 0.5 mL) was added and the mixture was stirred at room temperature for 2 h. After the reaction is completed, adding a proper amount of ammonia water to adjust the pH to about 7. The mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (dichloromethane: methanol=25:1, 2% aqueous ammonia) to give product 1i (33 mg, yield 89%) as a white solid. MS m/z 374.4[ M+H ] ] + 。
Compound 1j was synthesized using the procedure of patent US 20190330194.
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 stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol=25:1) to give product 1k (32 mg, yield 55%) as a white solid. MS m/z 656.7[ M+H ]] + 。
Compound 1k (32 mg,0.05 mmol) was added to trifluoroacetic acid (1.5 mL), and trifluoromethanesulfonic acid (5 drops) was further added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction is finished, a proper amount of ammonia water is added dropwise to adjust the pH to about 7. The mixture was extracted with dichloromethane (3X 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 column chromatography on silica gel (dichloromethane: methanol=25:1) to give product 1 as a white solid (8 mg, yield 31%). 1 H NMR(500MHz,CDCl 3 )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] + 。
EXAMPLE 2 preparation of Compound 2
Compound 2a (0.500 g,3.62 mmol), compound 1b (0.6755 g,3.62 mmol) and potassium carbonate (0.850 g,6.12 mmol) were added to DMA (10 mL) and heated to 80 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (40 mL), washed with water (10 ml×2), and the organic layer was dried over sodium sulfate, filtered, and concentrated, and the crude product was purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether) to give product 2b (0.7 g, yield 67%) as a white solid. 1 H NMR(500MHz,CDCl 3 )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。
Compound 2b (200 mg,0.69 mmol) and 4N HCl in 1, 4-dioxane (1 mL,4 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and dried in vacuo to give compound 2c (156 mg, yield 100%) as a white solid. 1 H NMR(500MHz,DMSO-d 6 )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。
Compound 2c (177 mg,0.78 mmol) and triethylamine (316 mg,3.13 mmol) were dissolved in dichloromethane (6 mL), and stirred at-40℃and then acrylic anhydride 1e (128 mg,1.02 mmol) was slowly added dropwise. The reaction mixture was stirred at-40℃for 1 hour. After the reaction is completed, the temperature is raised to room temperature, and water is added into the reaction mixture for dilution. The mixture was extracted with dichloromethane (3X 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 column chromatography on silica gel (dichloromethane: ethyl acetate=10:1) to give product 2d as a white solid (154 mg, yield 81%).
Compound 2d (154 mg,0.64 mmol), 1g (238 mg,1.27 mmol) and cesium carbonate (248 mg,0.76 mmol) were added sequentially to acetonitrile (4 mL), heated to 65 ℃ and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: ethyl acetate=3:1) to give product 2e (50 mg, yield 17%) as a white solid. MS m/z 430.5[ M+H ] ] + 。
Compound 2e (50 mg,0.10 mmol) was dissolved in dichloromethane (2 mL) and HCl in 1, 4-dioxane (4M, 0.5 mL) was added and the mixture stirred at room temperature for 2 hours. After the reaction is completed, adding a proper amount of ammonia water to adjust the pH to about 7. The mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (dichloromethane: methanol=25:1, 2% aqueous ammonia) to give product 2f as a white solid (28 mg, yield 81%). MS m/z 330.4[ M+H ]] + 。
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 stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol=25:1) to give 2g (12 mg, yield 23%) of a white solid product. MS m/z 612.7[ M+H ]] + 。
2g (12 mg,0.02 mmol) of the compound was added to trifluoroacetic acid (1 mL), and trifluoromethanesulfonic acid (3 drops) was further added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction is finished, a proper amount of ammonia water is added dropwise to adjust the pH to about 7. The mixture was extracted with dichloromethane (3X 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 column chromatography on silica gel (dichloromethane: methanol=25:1) to give product 1 as a white solid (2 mg, yield 21%). MS m/z 492.4[ M+H ] ] + 。
EXAMPLE 3 preparation of Compound 3
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℃and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (10 ml×3), dried over sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (0-20% ethyl acetate/petroleum ether) to give product 3b as a white solid (0.320 g, yield 82%). MS m/z 305.39[ M+H ]] + 。
Compound 3b (220 mg,0.72 mmol) and 4N 1, 4-dioxane (1 mL,4 mmol) of 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 in vacuo to give compound 3c (176 mg, yield 100%) as a white solid. 1 H NMR(500MHz,DMSO-d 6 )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] + 。
Compound 3c (150 mg,0.63 mmol) and triethylamine (192 mg,1.89 mmol) were dissolved in dichloromethane (5 mL), and stirred at-40℃and then acrylic anhydride 1e (87 mg,0.69 mmol) was slowly added dropwise. The reaction mixture was stirred at-40℃for 1 hour. After the reaction is completed, the temperature is raised to room temperature, and water is added into the reaction mixture for dilution. The mixture was extracted with dichloromethane (3X 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 column chromatography on silica gel (dichloromethane: methanol=20:1) to give 3d (162 mg, 99% yield) as a white solid. MS m/z 259.4[ M+H ] ] + 。
Compound 3d (162 mg,0.63 mmol), compound 3e (220 mg,1.25 mmol) and cesium carbonate (248 mg,0.75 mmol) were added sequentially to acetonitrile (4 mL), heated to 65 ℃ and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane: ethyl acetate=3:1) to obtain a white solid product 3f (183 mg, yield 67%). MS m/z 434.6[ M+H ]] + 。
Compound 3f (183 mg,0.42 mmol) was dissolved in dichloromethane (4 mL), and a 1, 4-dioxane solution (4M, 1.0 mL) of hydrogen chloride was further added, and the mixture was stirred at room temperature for 2 hours. To be reactedAnd after that, adding a proper amount of ammonia water to adjust the pH to about 7. The mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (dichloromethane: methanol=20:1, 2% aqueous ammonia) to give 3g (100 mg, yield 71%) of a white solid product. MS m/z 334.5[ M+H ]] + 。
Compound a was synthesized using the procedure of patent US 20190330194.
Compound a (57 mg,0.18 mmol), compound 3g (50 mg,0.15 mmol) and triethylamine (46 mg,0.45 mmol) were successively added to acetonitrile (2.5 mL), and 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 (95 mg, purity 85%, yield 87%). MS m/z 616.7[ M+H ] ] + 。
Compound 3h (95 mg, 85% purity, 0.13 mmol) was added to trifluoroacetic acid (1.5 mL), and trifluoromethanesulfonic acid (4 drops) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction is finished, a proper amount of ammonia water is added dropwise to adjust the pH to about 7. The mixture was extracted with dichloromethane (3X 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 column chromatography on silica gel (dichloromethane: methanol=25:1) to give product 3 as a white solid (20 mg, yield 31%). 1 H NMR(500MHz,CDCl 3 )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] + 。
EXAMPLE 4 preparation of Compound 4
Compound 4 was prepared by substituting the corresponding structural fragment by a method similar to example 7.
EXAMPLE 5 preparation of Compound 5
Compound 5 was prepared by substituting the corresponding structural fragment by a method similar to example 7.
EXAMPLE 6 preparation of Compound 6
Compound 6 was prepared by substituting the corresponding structural fragment by a method similar to example 7.
EXAMPLE 7 preparation of Compound 7
Compound 7a (600 mg,4.11 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), followed by addition of potassium hydrogen persulfate (2.15 g,6.21 mmol). 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 crude yellow oily compound 7b (426 mg) was directly used in the next reaction.
Compound 7b (200 mg,1.72 mmol), compound 1d (463mg, 1.72 mmol) were dissolved in acetonitrile (10 mL), N, N-diisopropylethylamine (877 mg,6.88 mmol) was added dropwise, and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (981 mg,2.58 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to give compound 7c (420 mg, yield 74%) as a white solid. MS m/z 331.0[ M+H ]] + 。
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 (5) was added dropwise under ice-bath2g,0.45 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to give compound 7d (112 mg, yield 91%) as a yellow solid. MS m/z 408.9[ M+H ]] + 。
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. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to give compound 7e (71 mg, yield 83%) as a yellow solid. 1 H NMR(500MHz,CDCl 3 )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] + 。
Compound 3e (25 mg,0.14 mmol) was dissolved in tetrahydrofuran (3 mL) and sodium hydrogen (60%, 7.5mg,0.19 mmol) was added under ice-bath. The reaction mixture was stirred for 20 min in an ice bath and 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 separated and purified by silica gel column chromatography to give compound 7f (44 mg, yield 94%) as a yellow solid. MS m/z 488.1[ M+H ] ] + 。
Compound 7f (44 mg,0.09 mmol) was dissolved in dichloromethane (3 mL) and dioxane hydrochloride (0.5 mL) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and 7g (30 mg, yield 86%) of a yellow oily compound was obtained by separation and purification through silica gel column chromatography. 1 H NMR(500MHz,CD 3 OD)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] + 。
7g (30 mg,0.08 mmol) of compound, b (38 mg,0.11 mmol) was dissolved in acetonitrile (2 mL), and N, N-diisopropylethylamine (31 mg,0.24 mmol) was added dropwise. The reaction mixture was heated at 40℃and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the yellow oily compound was isolated and purified by preparative thin layer plate for 7h (15 mg, yield 29%). MS m/z 680.0[ M+H ]] + 。
Will be combinedThe material 7h (15 mg,0.02 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and then separated and purified by a preparative thin layer plate to give compound 7 (1 mg, yield 8%) as a white solid. 1 H NMR(500MHz,CD 3 OD)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] + 。
EXAMPLE 8 preparation of Compound 8
Compound 8a (1.03 g,5.0 mmol) was dissolved in N, N-dimethylformamide (10 mL) cooled to 0deg.C, sodium hydrogen (60%, 240mg,6 mmol) was added and reacted for 15 min, tert-butyl bromoacetate 8b (730 mg,6.0 mmol) was added and the reaction was allowed to slowly warm to room temperature for 16 h. The aqueous phase was extracted twice with ethyl acetate, 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 column chromatography on silica gel (petroleum ether: ethyl acetate=8:2) to give compound 8c (250 mg, yield 17%).
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 obtained crude product was purified by silica gel column chromatography to give compound 8d (140 mg, yield 82%). 1 H NMR(500MHz,DMSO-d 6 )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。
Compound 4b (245 mg,1.0 mmol) was dissolved in ethanol (5 mL), a solution of hydrogen chloride in 1, 4-dioxane (4M, 0.5 mL) and cyclopropylamine (114 mg,2.0 mmol) were added, and sodium cyanoborohydride (126 mg,2.0 mmol) was added and reacted at room temperature for 16 hours. Adding saturated sodium carbonate water solution for quenching, and using acetic acid for water phaseThe ethyl ester was extracted twice, 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=10:1) to give compound 8f (140 mg, yield 50%). 1 H NMR(500MHz,CDCl 3 )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。
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 and reacted at room temperature for 16 hours. Quenched with water, the aqueous phase was extracted with ethyl acetate, and 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 column chromatography on silica gel (petroleum ether: ethyl acetate=3:7) to give 8g (80 mg, yield 60%) of the compound. MS m/z 532.7[ M+H ] ] +
8g (40 mg,0.075 mmol) of the compound was dissolved in methanol (1 mL), water and hydrazine (80%, 0.1 mL) were added, and the mixture was heated to 35℃to react for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (dichloromethane: methanol=10:1, 1% aqueous ammonia) to give compound 8h (20 mg, yield 66%). 1 H NMR(500MHz,CD 3 OD)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。
Compound 8h (10 mg,0.025 mmol) was dissolved in acetonitrile (1 mL) and compound b (synthesized using the procedure in patent US20210024502, 10mg,0.03 mmol) and triethylamine (12 mg,0.12 mmol) were added and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 8i (10 mg, yield 57%). 1 H NMR(500MHz,CD 3 OD)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。
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, the resulting mixture was redissolved in methylene chloride, a small amount of aqueous ammonia was added to adjust to basicity, and the mixture was separated and purified by preparative silica gel thin layer plate (methylene chloride: methanol=20:1) to give the objective compound 8 (5.13 mg, yield 90%). 1 H NMR(500MHz,CD 3 OD)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),1.81-1.79(m,2H),1.29(d,J=6.5Hz,3H),0.89–0.85(m,2H),0.83-0.76(m,2H)ppm。
EXAMPLE 9 preparation of Compound 9
Compound 4b (245 mg,1.0 mmol) was dissolved in ethanol (5 mL), a 1, 4-dioxane solution of hydrogen chloride (4M, 0.5 mL) and compound 9a (146 mg,2.0 mmol) were added, and sodium cyanoborohydride (126 mg,2.0 mmol) was further added and reacted at room temperature for 16 hours. Saturated aqueous sodium carbonate was added to quench the mixture, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give compound 9b (70 mg, yield 23%). 1 H NMR(500MHz,CDCl 3 )δ8.47(s,2H),4.85(t,J=6.9Hz,2H),4.75-4.73(m,2H),4.48(t,J=6.4Hz,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。
Compound 9b (50 mg,0.166 mmol) was dissolved in N, N-dimethylformamide (1 mL), compound 8d (44 mg,0.166 mmol), triethylamine (50 mg,0.5 mmol) and HATU (9) were added5mg,0.25 mmol) and reacted at room temperature for 16 hours. The mixture was quenched with water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:7) to give compound 9c (50 mg, yield 55%). MS m/z 548.6[ M+H ]] + 。
Compound 9c (30 mg,0.054 mmol) was dissolved in methanol (1 mL), and hydrazine hydrate (80% aqueous solution, 0.1 mL) was added and the mixture was heated to 35℃to react for 16 hours. The reaction mixture was concentrated under pressure, and the obtained mixture was purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give compound 9d (8 mg, yield 40%). MS m/z 418.5[ M+H ]] + 。
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 to react at room temperature for 16 hours. The mixture was quenched with water, the aqueous phase was extracted twice with ethyl acetate, 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 isolated and purified by preparative silica gel thin layer plate (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 tetra-n-butylammonium fluoride (0.5 mL), one drop of ethylenediamine was added dropwise, and the mixture was placed in a sealed tube and heated to 85℃for reaction for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative silica gel thin layer plate separation (petroleum ether: ethyl acetate=1:3) to give the objective compound 9 (0.67 mg, yield 40%). MS m/z 580.5[ M+H ] ] + 。
EXAMPLE 10 preparation of Compound 10
Compound 3e (1 g,5.71 mmol), compound 10a (2.39 g,11.41 mmol) and tetrabutylammonium bisulfate (186 mg,0.57 mmol) were dissolved in sodium hydroxide solution (25%, 9.13 g) and the reaction mixture was stirred overnight at 65 ℃. After the reaction is completed, ethyl acetate is added for dilution. Mixed liquidExtracted with ethyl acetate (3X 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 obtained was isolated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=5:1) to give product 10b as a yellow oil (750 mg, yield 43%). MS m/z 326.0[ M+Na] + 。
Compound 10b (750 mg,2.47 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product 10c which is directly subjected to the next reaction. MS m/z 120.0[ M+H ]] + 。
The crude product 10c (theoretical yield: 295mg,2.47 mmol) and compound b (814 mg,2.47 mmol) were dissolved in acetonitrile (8 mL) and N, N-diisopropylethylamine (960 mg,7.43 mmol) was added and the reaction mixture stirred at 40℃for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The crude product obtained was isolated and purified by column chromatography on silica gel (dichloromethane: ethyl acetate=6:1) to give the product 10d as a yellow oil (390 mg, yield 38%). MS M/z434.0[ M+Na ] + 。
Compound 10d (50 mg,0.12 mmol) was dissolved in dichloromethane (2 mL) under nitrogen, and dessert-martin oxidant (103 mg,0.24 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. And after the reaction is finished, sequentially adding a saturated sodium carbonate solution and a saturated sodium sulfite solution. The mixture was extracted with dichloromethane (3X 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 obtained was directly subjected to the next reaction.
The crude products 10e (theoretical yield: 50mg,0.12 mmol) and 10f (synthesized using the method in WO2016077375, 30mg,0.12 mmol) were dissolved in dichloromethane (3 mL) and acetic acid (7 mg,0.12 mmol) was added and the reaction stirred at room temperature for 1 hour. The reaction solution was allowed to stand at 0℃and sodium triacetoxyborohydride (78 mg,0.37 mmol) was added thereto, and the reaction solution was stirred at room temperature for another 30 minutes. And adding water to quench after the reaction is finished. The mixture was extracted with dichloromethane (3X 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 is passed through a silica gel column layerIsolation and purification by chromatography (dichloromethane: methanol=20:1) afforded the product as a colourless oil 10g (3 mg, yield 4%). MS m/z 640.6[ M+H ] ] + 。
10g (3 mg,0.005 mmol) of the compound was dissolved in methylene chloride (1.5 mL) under ice-water bath, and N, N-diisopropylethylamine (2 mg,0.014 mmol) was added thereto and stirred. A further 10h (0.4 mg,0.005 mmol) of acetyl chloride in methylene chloride diluent (1 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 15 minutes. And adding a small amount of methanol to quench after the reaction is finished. The mixture was concentrated under reduced pressure. The crude product obtained was purified by preparative thin layer chromatography (dichloromethane: methanol=20:1) to give product 10i as a white solid (2 mg, 63% yield). MS m/z 682.2[ M+H ]] + 。
Compound 10i (2 mg, 0.003mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.2 mL) was added and the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (1 mL), and 2 drops of ammonia were added dropwise, followed by stirring at room temperature for 2 minutes. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol=20:1) to give product 10 as a white solid (1 mg, yield 62%). MS m/z 552.1[ M+H ]] + 。
EXAMPLE 11 preparation of Compound 11
Synthesis of Compound 11 referring to the method for synthesizing Compound 10, compound 11 (0.8 mg, white solid) is obtained from 10g of Compound. 1 H NMR(500MHz,CD 3 OD)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] + 。
Example 12 PARP7 enzyme inhibition Activity assay
Preparation of histone coated 384 well plates: 25 μl of the mixture was used in the groupThe protein solution was added to 384-well plates and incubated overnight at 4 ℃. The histone-coated 384-well plates were washed three times with PBST solution, 50 μl of blocking solution was added to each well, blocked for 1 hour at room temperature, and then the 384-well plates were washed three times with PBST solution. The compounds were prepared as 10mM stock solutions in 100% DMSO and diluted according to a concentration gradient. mu.L of the compound was transferred to 384 well plates. PARP7 enzyme solution ((BPS, cat.No.80527)) was prepared and incubated at 25 ℃ for ten minutes. Transfer 10 μl of enzyme solution to 384 well plates and incubate with compound for ten minutes at room temperature. mu.L of 2.5 XBiotin-NAD+ (R) was added&D, cat.no. 6573) into each well, incubation was carried out for 60 minutes at 25 ℃. The 384 well plates were washed three times with PBST solution. mu.L of anti-poly/mono-ADP ribose rabbit mab was added and incubated for 1.5 hours at room temperature and washed three times with PBST solution. Then 20. Mu.L of horseradish peroxidase-conjugated anti-rabbit IgG at 1:2000 was added and incubated for 1 hour at room temperature. The 384 well plates were washed three times with PBST solution. Add 25. Mu.L of 1:1 mixed Femto-ECL substrate A and Femto-ECL substrate B (THERMO PIERCE, cat.No.37074) and immediately read fluorescence values using Envision. The inhibition of the compounds was calculated in Excel using the formula inhibition% = (Max-Signal)/(Max-Min) x 100. Where max refers to the value of DMSO control and min refers to the value of no enzyme activity control. Fitting curves and calculating IC using XL-Fit software 50 . The formula is: y=bottom+ (Top-Bottom)/(1+ (IC) 50 X) HillSlope). Y is the percent inhibition and X is the concentration of the compound. The activities of some of the representative compounds are shown in table 1.
TABLE 1 PARP7 enzyme inhibitory Activity
Compounds of formula (I) | IC 50 or inhibition rate |
1 | Inhibition of 12.5nM is 95% |
3 | IC 50 <1nM |
7 | Inhibition of 12.5nM is 70% |
8 | IC 50 <1nM |
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (16)
- A compound of the structure shown in formula (I) or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof:in formula (I):a is selected from-NR 3 -、-O-、-CR 4 R 5 -or a 3-to 8-membered heterocyclyl; wherein R is 3 Selected from hydrogen or C 1-4 An alkyl group; r is R 4 And R is 5 Each independently selected from hydrogen, halogen, or C 1-4 An alkyl group;b is selected from-CR 6 R 7 -or a chemical bond; wherein R is 6 And R is 7 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 Cycloalkyl, C 3-6 Cycloalkyl C 1-4 Alkyl, 4-to 8-membered heterocyclyl, or 4-to 8-membered heterocyclyl C 1-4 An alkyl group; or R is 6 And R is 7 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl 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 the group consisting of-O-, -NR 12 -、-CR 13 R 14 -、C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, or heteroaryl; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; each R is 8 And R is 9 Each independently selected from hydrogen, halogen, hydroxy, or C 1-4 An alkyl group; each R is 10 And R is 11 Each independently selected from hydrogen, halogen, hydroxy, or C 1-4 An alkyl group; or R is 8 And R is 9 To which is attached a carbon atom, or R 10 And R is 11 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S; r is R 12 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; r is R 13 And R is 14 Each independently selected from hydrogen, halogen, or C 1-4 An alkyl group; or R is 13 And R is 14 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S;E is selected from a bond or-C (O) -;f is selected from a bond or-NR b -; wherein R is b Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) R c Or S (O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the Or R is b And R is R 10 Or R is 11 And the nitrogen atom, carbon atom and E to which they are attached together form a 4-to 8-membered heterocyclic group containing 1N atom and 0 or 1 heteroatom selected from N, O, S; r is R c Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; r is R b Or R is c The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups described in (a) are 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 The method comprises the steps of carrying out a first treatment on the surface of the Each R is d Each independently is hydrogen or C 1-4 An alkyl group; r is R t Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl;g is selected from N or CR e The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is e Selected from hydrogen or C 1-4 An alkyl group;each R is a Each 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, hydroxy C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Alkoxy C 1-4 Alkyl, NR h R h CN; each R is h Each independently is hydrogen, or C 1-4 An alkyl group; or two R h Together with the nitrogen atom to which it is attached, form a 3-to-8-membered heterocyclic group containing 1 or 2N atoms and 0 or 1 heteroatom selected from O, S; or two R's attached to the same carbon atom a Together with the carbon atoms, form c=m; wherein M is selected from O or CR j R k The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is j And R is k Each independently selected from the group consisting of: hydrogen, halogen, or C 1-4 An alkyl group; or two R's bound to different carbon atoms a Are connected together to form a bridge ring structure;t is selected from N or CR 15 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 15 Selected from hydrogen, halogen, or C 1-4 An alkyl group;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 C 1-4 Alkyl, C 1-4 Haloalkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl,NR h R h 、CN、NO 2 、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) 2 R t Or S (O) 2 R t The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is h And R is t Is defined as above;R 1 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 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 An alkyl group;R 2 selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl;m and 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;or structural fragments of formula (I)Selected from the following formulae:wherein d is selected from 0, 1, or 2; e is selected from 1, 2, 3, or 4;therein unless otherwise specifiedIllustratively, each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is optionally and each independently substituted with 1-3 substituents each independently selected from the group consisting of: 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, NO 2 、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) 2 R t Or S (O) 2 R t Provided that the chemical structure formed is stable and meaningful; wherein R is h And R is t Is defined as above;unless otherwise specified, the above aryl groups are aromatic groups having 6 to 12 carbon atoms; heteroaryl is a 5-to 15-membered (preferably 5-to 12-membered) heteroaryl group; the cyclic structure is a saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic group.
- The compound as set forth in claim 1, wherein formula (I) is formula (IIA):q is selected from-NR 16 -、-O-、-CR 17 R 18 -; wherein R is 16 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, aryl, heteroaryl, C (O) R t Or S (O) 2 R t ;R 17 And R is 18 Each independently selected from hydrogen, halogenOr C 1-4 An alkyl group;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;the other groups are defined in claim 1.
- The compound of claim 1, wherein 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;the other groups are defined in claim 1.
- The compound of claim 1, wherein formula (I) is formula (IVA):R 6 and R is 7 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 An alkyl group;p is selected from 0, 1, or 2;j and t are each independently selected from 0, 1, or 2;the other groups are defined in claim 1.
- The compound of claim 1, wherein formula (I) is formula (VA):R b is defined as in claim 1;the definition of each group is as defined in claim 4.
- The compound of claim 1, wherein formula (I) is formula (VIA):R b selected from C 3-6 Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are 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 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is t Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; each R is d Each independently is hydrogen or C 1-4 An alkyl group;q is selected from 0, 1, 2, or 3;the definition of the other groups is as defined in claim 4.
- The compound of claim 1, wherein formula (I) is formula (VIIA):R c selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups are 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 ;j is selected from 0, 1, or 2;the definition of the other groups is as defined in claim 4.
- The compound of claim 1, wherein formula (I) is formula (VIIIA):R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl;R 2 selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkynyl;R 8 、R 9 、R 10 、R 11 each independently selected from hydrogen, hydroxy, C 1-4 An alkyl group;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.
- The compound of claim 1, wherein formula (I) is formula (IXA):R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl;R 2 selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkynyl;R 6 and R is 7 Each independently selected from hydrogen, C 1-4 An alkyl group;R 8 、R 9 、R 10 、R 11 each independently selected from hydrogen, hydroxy, C 1-4 An alkyl group;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 Cycloalkyl alkynyl, 3-to 8-membered heterocyclylalkynyl、C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 3-to 8-membered heterocyclyl, CN.
- The compound of claim 1, wherein formula (I) is formula (XA):R b selected from C 3-6 Cycloalkyl, 4-to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are 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 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is t Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or a 4-to 8-membered heterocyclyl; each R is d Each independently is hydrogen or C 1-4 An alkyl group;R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl;R 2 selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkynyl;R 6 and R is 7 Each independently selected from hydrogen, C 1-4 An alkyl group; r is R 8 、R 9 、R 10 、R 11 Each independently selected from hydrogen, hydroxy, C 1- 4 An alkyl group; or (b)R 6 And R is 7 To which is attached a carbon atom, R 8 And R is 9 To which is attached a carbon atom, or R 10 And R is 11 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl containing 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.
- A compound according to any one of claims 1 to 10,R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl; r is R 2 Is H;x is selected from N or CH;r is each independently selected from trifluoromethyl, CN, C 2-4 Alkynyl, C 3-6 Cycloalkylalkynyl, 3-to 8-membered heterocyclylalkynyl, C 3-6 Cycloalkyl groups.
- The compound of claim 1, wherein formula (I) is formula (XIA):R 1 selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 2-4 Alkynyl;R 2 selected from hydrogen;R 6 and R is 7 Each independently selected from hydrogen, C 1-4 An alkyl group;R 8 、R 9 、R 10 、R 11 each independently selected from hydrogen, hydroxy, C 1-4 An alkyl group;or R is 6 And R is 7 To which is attached a carbon atom, R 8 And R is 9 To which is attached a carbon atom, or R 10 And R is 11 Together with the carbon atom to which it is attached, form a 3-to-6 membered cycloalkyl, or a 4-to 8-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S;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 Cycloalkyl, 3-to 8-membered heterocyclyl.
- A compound according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:"×" indicates chiral centers.
- A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, and a pharmaceutically acceptable carrier.
- Use of a compound according to any one of claims 1 to 13, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, for the preparation of a pharmaceutical composition for the treatment of a disease, disorder or condition associated with PARP7 activity or expression level.
- The use according to claim 15, wherein 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 lymphoid leukemia, monocytic leukemia, splenomegaly, eosinophilia syndrome, fibrosarcoma, salivary gland carcinoma, liver cancer, rectal cancer, bladder cancer, laryngeal carcinoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous 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 hematological and solid tumors, as well as various types of heart diseases, viral infections, neurodegenerative diseases, inflammation and pain, and the like, particularly those associated with PARP7 overexpression or abnormal activation.
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