CN118496203A - Quinoxaline compound and medical application thereof - Google Patents
Quinoxaline compound and medical application thereof Download PDFInfo
- Publication number
- CN118496203A CN118496203A CN202410342919.2A CN202410342919A CN118496203A CN 118496203 A CN118496203 A CN 118496203A CN 202410342919 A CN202410342919 A CN 202410342919A CN 118496203 A CN118496203 A CN 118496203A
- Authority
- CN
- China
- Prior art keywords
- methyl
- quinoxalin
- carboxamide
- oxo
- piperazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- -1 Quinoxaline compound Chemical class 0.000 title claims description 360
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title description 2
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- 125000000217 alkyl group Chemical group 0.000 claims description 20
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- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses quinoxaline compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts of the compounds, and definition of R 1、R2、R3、R4、R5 and n are detailed in the specification. In addition, the invention also discloses a medicine taking the compound, isomer, solvate, deuterated derivative and salt thereof as active ingredients and application thereof in preparing diseases related to PARP-1 such as cancers.
Description
Technical Field
The invention relates to quinoxaline compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts of the compounds, medicaments using the compounds or the salts thereof as active ingredients, and application of the quinoxaline compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts of the compounds as PARP1 inhibitors in treating cancers.
Background
PARP is a multifunctional protein post-translational modification enzyme that is widely present in eukaryotic cells. In mammalian cells, the PARP family has 17 members, whereas the members involved in DNA damage repair processes are only PARP1, PARP2 and PARP33, with PARP1 being the primary member involved in DNA repair processes and PARP2 and PARP3 being less involved.
When PARP function is damaged or inhibited, DNA single-strand break is continuously present, which is easy to cause pause of replication fork and DNA double-strand break, so that damaged DNA replicas appear and accumulate gradually, and finally, replication fork collapse can be caused, and cells can not replicate normally.
PARP1 can be activated during cancer treatment to repair chemotherapy-induced DNA damage and generally results in drug resistance and sustained tumor growth. Thus, PARP-1 inhibitors can be used as chemotherapeutic potentiators in combination with DNA damaging chemotherapeutics, and can also be used as single agents in some tumor types.
In addition to the capability of PARP to repair damaged DNA, another set of repair system in the cell, such as homologous recombination pathway mediated by the oncogene BRCA1/2, can repair DNA damage and maintain chromosome stability. In the case that some germ line tumor patients such as ovarian cancer, fallopian tube cancer, primary peritoneal cancer and the like carry BRCA1/2 mutant genes, that is, BRCA1/2 defects exist, and correspondingly, compensation mechanisms are lacking, and PARP functions are damaged or inhibited, the tumor cells cannot repair DNA damage, and finally cell death is caused.
PARP inhibitors have shown excellent clinical efficacy in patients with homologous recombination-deficient cancers, however hematological toxicity and other toxicities limit the use of such drugs, whether single-drug or combination therapy. Recent literature suggests that this part of the adverse effects may result from the inhibition of PARP2 by PARP inhibitors already on the market, but PARP2 is not essential for therapeutic efficacy. Thus, it is necessary to design selective inhibitors in order to overcome the side effects of existing PARP inhibitors and to construct next generation PARP inhibitors.
Inhibition of PARP family enzymes has been used as a strategy to inactivate complementary DNA repair pathways and selectively kill cancer cells. Many preclinical and clinical studies have shown that tumor cells with deleterious alterations of BRCA1 or BRCA2, a key tumor suppressor protein involved in Homologous Recombination (HR) to repair double strand DNA breaks (DSB), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. The Homologous Recombination Repair (HRR) pathway of such tumors is inadequate and its survival depends on the function of the PARP enzyme. Although PARP inhibitor therapy targets mainly BRCA mutated cancers, PARP inhibitors have been tested clinically in non-BRCA mutated tumors that exhibit Homologous Recombination Defects (HRDs).
PARP inhibitors with increased selectivity for PARP1 may increase clinical efficacy and reduce side effects compared to other clinical PARP1/2 inhibitors. The strong selective inhibition of PARP1 will result in the capture of PARP1 on DNA, which leads to DNA Double Strand Breaks (DSBs) by collapsing the replication fork in S phase. Efficient capture of PARP1-DNA in tumor cells with HRD selectivity.
Thus, there is an unmet medical need for effective and safe PARP inhibitors. In particular, they are selective inhibitors of PARP 1.
Disclosure of Invention
Applicants have found that the quinoxalines described herein surprisingly have PARP inhibitory activity and are therefore useful in the treatment of diseases and conditions in which PARP function is of pathological significance. Furthermore, the quinoxaline compounds described herein are unexpectedly highly selective for PARP1 over other PARP family members (such as PARP2, PARP3, PARP5a and PARP 6). Furthermore, the quinoxalines described herein have advantageously low hERG activity.
A first object of the present invention is to provide a compound of formula (I):
isomers, solvates, deuterated derivatives, and pharmaceutically acceptable salts thereof;
Wherein:
r 1 is hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, optionally substituted with deuterium;
R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 1-10 alkoxy, and optionally substituted with halogen, C1-C3 alkyl, C 1-10 alkoxy, deuterium;
R 3 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, which groups may be optionally substituted with deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
R 4 is hydrogen, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl, optionally substituted with deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
R 5 is hydrogen, C 1-10 alkyl, and when the carbon atom connected with R 5 is connected with 2 substituents, the carbon atom connected with the R 5 can form a 3-6 membered ring;
n is independently selected from 0, 1, 2 or 3;
More specifically, compounds of the structure of formula (I) include, but are not limited to, the following structures:
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-ethyl-5- (4- ((2-ethyl-3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) -6- (trifluoromethyl) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) -6- (difluoromethyl) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-chloro-N- (methyl-d 3) pyridine-2-carboxamide;
n- (methyl-d 3) 5- (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-chloro-N- (methyl-d 3 - (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-chloro-N- (methyl-d 3) -5- (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
N- (methyl-d 3) -5- (4- ((3-oxo-2-propyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-chloro-N- (methyl-d 3) -5- (4- ((3-oxo-2-propyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-2-propyl-3, 4-dihydroquinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-2-ethyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
5- (4- ((2- (1, 1-difluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (2, 2-difluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (2, 2-difluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (2-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2- (2-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
n- (methyl-d 3) -5- (4- ((3-oxo-2- (2, 2-trifluoroethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-hydro-2- (2, 2 trifluoroethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-methyl-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N-methyl-5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl- d -2) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-isopropyl-3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-3-oxo-4H-oxin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-3-oxo-4H-quinoxalin-6 yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-methyl-N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N-methyl-5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine amide;
5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N-methylpyridine-2-carboxamide;
5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6- (difluoromethyl) -5- (4- (2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-methyl-5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
6-chloro-5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2, 5 dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-chloro-5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-fluoropyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-methylpyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-methylpyridine-2-carboxamide;
6-chloro-5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
(R) -6-fluoro-5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
(S) -6-fluoro-5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
(R) -5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
(S) -5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (1, 1-difluoroethyl) -5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-oxo-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N-methylpyridine-2-carboxamide;
6-chloro-5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-methyl-3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6- (difluoromethyl) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-chloro-5- (4- ((2-methyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
n- (ethyl-2, 2-d 3) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
n- (ethyl-2, 2-d 3) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methylpyridine-2-carboxamide;
5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
4-chloro-5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-chloro-5- (4- ((5-fluoro-3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d z) pyridine-2-carboxamide;
5- (4- ((2- (difluoromethyl) -5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2 isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6 yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6- (difluoromethyl) -5- (4- (2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6- (difluoromethyl) -5- (4- (2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
(S) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide;
(S) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
(S) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide;
(S) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N, 6-dimethylpyridine-2-carboxamide;
(S) -6-fluoro-N-methyl-5- (2-methyl-4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
(S) -5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
(S) -5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
(S) -5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-N-methylpyridine-2-carboxamide;
(R) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
Or (R) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide;
isomers, solvates, deuterated derivatives, and pharmaceutically acceptable salts thereof;
Wherein:
terminology of art
The term "alkyl" refers to straight or branched alkyl groups having 1 to 12 carbon atoms in the chain, examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups considered to be equivalent to any of the foregoing examples in light of the teachings provided by those of ordinary skill in the art and text.
The term "alkoxy" refers to an alkyl group as defined above bonded to an oxygen atom. The alkoxy group is attached to the parent structure via an oxygen atom.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, and the like. Preferably C2-10 alkenyl, preferably C2-6 alkenyl, most preferably C2-4 alkenyl, most preferably vinyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, alkylamino, halogen, hydroxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy.
The term "amino" refers to an-NH 2 group or a mono or dialkylamino group.
The term cycloalkyl refers to saturated and partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or exploded polycyclic carbocycles, each carbon atom having 3 to 12 ring atoms. Illustrative examples of cycloalkyl groups include the following entities in the form of suitable bonding moieties:
The term "heteroaryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (the ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities in the form of suitable bonding moieties:
The term "aryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic ring containing C5-C20 s and free of heteroatoms nitrogen, oxygen, sulfur, and the like, typical aromatic groups include, but are not limited to, residues derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably comprising 3 to 12 ring atoms, of which 1 to 4 heteroatoms, more preferably the heterocycloalkyl ring comprises 3 to 10 ring atoms, and more preferably the heterocycloalkyl ring comprises 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, morpholinyl tetrahydrofuranyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. The heterocycle may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, haloalkyl, alkoxy, alkylamino, halogen, hydroxy, amino, oxo, alkylamino, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, hydroxyalkyl, carboxy or carboxylate.
The term "halogen" means chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo. The term "haloalkyl" refers to an alkyl group as defined above, substituted with one or more halogen atoms.
In a second aspect, the present invention provides a method for preparing a compound, isomer, deuterated derivative of the structure of formula (I), specifically as described in the examples.
In the embodiments provided herein, the compounds of the present invention, if containing basic groups, may be salified with acids and salts of the compounds of the present invention may be prepared using methods well known to those skilled in the art.
Common acid salts include organic acid salts and inorganic acid salts. Typically, the organic acid salts that are relatively common are citrate, fumarate, oxalate, malate, lactate, sulfonate (e.g., camphorsulfonate, p-toluenesulfonate, methanesulfonate, etc.), and the like; inorganic acid salts include hydrohalic acid salts, sulfate salts, phosphate salts, nitrate salts, and the like. For example, methanesulfonic acid, trifluoromethanesulfonic acid salt may be formed with lower alkylsulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, etc.; para-toluene sulfonate, benzene sulfonate, etc. may be formed with aryl sulfonic acids such as benzene sulfonic acid or para-toluene sulfonic acid; with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid, etc., to form corresponding salts; glutamate or aspartate may be formed with amino acids such as glutamate or aspartate. Corresponding salts may also be formed with inorganic acids such as hydrohalic acids (e.g., hydrofluoric, hydrobromic, hydroiodic, hydrochloric), nitric, carbonic, sulfuric or phosphoric acids, and the like.
In a third aspect, the present invention provides a medicament utilizing a compound of the structure of formula (I), isomers, solvates, deuterated derivatives, or pharmaceutically acceptable salts or solvates thereof, of the present invention as an active ingredient. The above-mentioned drugs may further contain one or more pharmaceutically acceptable carriers including diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like which are usual in the pharmaceutical field, and flavoring agents, sweeteners and the like may be added as necessary. The medicine of the invention can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection and the like, and the medicines of the various forms can be prepared according to the conventional methods in the pharmaceutical field.
In a fourth aspect, the present invention provides a compound of formula (I), an isomer, a solvate, a deuterated derivative or a pharmaceutically acceptable salt thereof, for use in a medicament for the treatment of PARP 1-related neoplasms selected from any of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, and lung cancer.
Detailed Description
The following description of the embodiments of the invention will be given by way of example only, and it will be appreciated by those skilled in the art that various modifications and substitutions of the corresponding features may be made in accordance with the teachings of the prior art, while remaining within the scope of the invention as claimed
Example 1, 5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Step 1, 4- (1-methoxy-1-oxobutan-2-yl) amino) -3-nitrobenzoic acid ethyl ester
10G of methyl 4-fluoro-3-nitro-benzoate as raw material, 8.49g of methyl(s) -2-aminobutyrate hydrochloride and 19.47g of diisopropylethylamine were added to 40ml of methanol solution, and the system was orange-colored and stirred at room temperature. After the reaction was completed, methanol was removed, the system was extracted 3 times with methylene chloride and water, washed 3 times with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated to give a yellow oily substance.
Step 2, 3-amino-4- ((1-methoxy-1-oxobutan-2-yl) amino) benzoic acid ethyl ester
15.65G of the raw material from step 1 are dissolved in 150ml of methanol, 150ml of water and 55.19g of sodium dithionite are added, the temperature is raised to 60 ℃ and the mixture is stirred, and the system is pale yellow. After the reaction, 300ml of ice water is added to stir for 30min, and light yellow solid is obtained through suction filtration.
ESI MS m/z：311.12[M+1]+
Step 3, 2-ethyl-3-oxo-2, 4-dihydro-1H-quinoxaline-6-carboxylic acid ethyl ester
7G of the raw material in step 2 was dissolved in 60ml of water, and 60ml of water and 6.4g of sodium periodate were added, and the temperature was raised to 80℃and stirred, and the system was gradually changed to brown yellow. 180ml of ice water is added into the system after the reaction is finished, the mixture is stirred for 30 minutes, and 5g of brown yellow solid is obtained through suction filtration.
ESI MS m/z：247.10[M+1]+
Step 4, 3-ethyl-7- (hydroxymethyl) -1H-quinoxalin-2-one
Lithium aluminum hydride 2g was added to tetrahydrofuran 30ml at 0℃under nitrogen protection, then intermediate 4g of step 3 was added, and the resulting mixture was stirred at 60℃for 2.0 hours. The reaction mixture was quenched by dropwise addition of an appropriate amount of water, the solid was filtered, washed with diethyl ether, and chromatographed on a solid column, which was dried under vacuum to give 3.3g of intermediate.
ESI MS m/z：205.09[M+1]+
Step 5, 5- (4- ((2-ethyl-3-oxo-3, 4-dihydroquinolin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine amide
Thionyl chloride 2ml was added dropwise to the intermediate of step 4, 2.0g, 0.1ml of N, N-dimethylformamide in 30ml of dichloromethane, stirred at room temperature for 3 hours, the reaction mixture was concentrated to dryness to give 7- (chloromethyl) -3-ethylquinolin-2 (1H) -one, diisopropylethylamine 3ml, N- (methyl-d 3) -5- (piperazin-1-yl) picolinamide 2g were dissolved in acetonitrile 50ml, stirred at 80℃for 2 hours, concentrated to dryness, stirred with aqueous sodium bicarbonate, extracted with ethyl acetate, washed with water, dried, filtered, and the residue was column chromatographed to give the objective 2.1g.
1H NMR(400MHz,DMSO-d6)δ12.25(1H,bs),8.37(1H,s),8.27(1H,d),7.83(1H,d),7.69(1H,d),7.41-7.37(1H,m),7.30-7.23(2H,m),3.62(2H,s),3.37-3.30(overlapped with water 4H,m),2.80(2H,q),2.58-2.53(4H,m),1.22(3H,t).
ESI MS m/z：410.23[M+1]+
Example 2, 6-Ethyl-5- (4- ((2-Ethyl-3-oxo-4H-quinoxalin 6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 12.
ESI MS m/z：438.26[M+1]+
Example 3, 5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) -6- (trifluoromethyl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：478.22[M+1]+
Example 4, 5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) -6- (difluoromethyl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：460.23[M+1]+
Example 5, 5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：428.22[M+1]+
Example 6, 5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：424.25[M+1]+
Example 7, 5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-chloro-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：443.19[M+1]+
Example 8N- (methyl-d 3) 5- (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：450.19[M+1]+
Example 9, 6-chloro-N- (methyl-d 3) 5- (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：484.15[M+1]+
Example 10, 6-chloro-N- (methyl-d 3) -5- (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：468.18[M+1]+
Example 11, N- (methyl-d 3) -5- (4- ((3-oxo-2-propyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
1H NMR(400MHz,DMSO-d6)δ12.16(1H,bs),8.36(1H,s),8.26(1H,d),7.83(1H,d),7.67(d,1H),7.41-7.35(m,1H),7.29-7.20(m,2H),3.60(s,2H),3.37-3.31(m,overlapped with water 4H),2.75(2H,t),2.57-2.52(4H,m),1.77-1.66(2H,m),0.96(3H,t);
ESI MS m/z：424.25[M+1]+
Example 12, 6-chloro-N- (methyl-d 3) -5- (4- ((3-oxo-2-propyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：458.21[M+1]+
Example 13, 6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-2-propyl-3, 4-dihydroquinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：442.24[M+1]+
Example 14, 6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-2-ethyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
1H NMR(400MHz,DMSO-d6)δ1.22(3H,t),2.61-2.54(4H,m),2.80(2H,q),3.21-3.14(4H,m),3.62(2H,s),7.29-7.22(2H,m),7.60-7.54(1H,m),7.69(1H,d),7.85(1H,d),8.36(1H,s),12.25(1H,s);
ESI MS m/z：446.21[M+1]+
Example 15, 5- (4- ((2- (1, 1-difluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：446.21[M+1]+
Example 16, 5- (4- ((2- (2, 2-difluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：446.21[M+1]+
Example 17, 5- (4- ((2- (2, 2-difluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：464.20[M+1]+
Example 18, 5- (4- ((2- (2-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：428.22[M+1]+
Example 19, 6-fluoro-5- (4- ((2- (2-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：446.21[M+1]+
Example 20, N- (methyl-d 3) -5- (4- ((3-oxo-2- (2, 2-trifluoroethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：464.20[M+1]+
Example 21, 6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-2- (2, 2-trifluoroethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 1.
ESI MS m/z：482.19[M+1]+
Example 22, 6-fluoro-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Step 1, 5-bromo-6-fluoropyridine carboxylic acid methyl ester
5G of 5-bromopiperidine methyl ester as a raw material and 15g of silver difluoride were added to 50ml of anhydrous acetonitrile under nitrogen protection, and reacted at room temperature for 6 hours. After completion of the reaction, insoluble matter was removed by celite, and the solid was washed with 60ml of acetonitrile, and the filtrate was collected, concentrated to dryness under reduced pressure, and the residue was dissolved in 50ml of methylene chloride and washed with saturated brine 3 times. The organic layer was then dried over anhydrous sodium sulfate, suction filtered, and spun-dried to give 5g of a white solid product.
1H NMR(400MHz,DMSO-d6)δ3.89(3H，s)，7.92(1H，dd)，8.50(1H，dd)；
Step 2, 4- (2-fluoro-6- (methoxycarbonyl) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester
5G of the intermediate from step 1, 5.96g of tert-butyl piperazine-1-carboxylate were added to 60ml of 1, 4-dioxane, 18g of cesium carbonate were added, 1.25g Ruphos Pd G3 g of cesium carbonate was added under nitrogen protection, and the reaction was stirred under nitrogen protection at 80℃overnight. After the completion of the reaction, 50ml of water was added to quench the reaction, followed by celite, and washing with 40ml of 1, 4-dioxane, the filtrate was collected, and the 1, 4-dioxane was removed by concentration under reduced pressure. The remaining filtrate was extracted 3 times with ethyl acetate and the organic phases were combined. Drying with anhydrous sodium sulfate, suction filtering, concentrating under reduced pressure, purifying with column, eluting with petroleum ether and ethyl acetate system, and obtaining yellow solid product 5.3g.
1HNMR(400MHz,DMSO-d6)δ1.44(9H,s),3.22-3.15(4H,m),3.52-3.45(4H,m),3.83(3H,s),7.55(1H,dd),7.93(1H,dd);
Step 3, 5- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -6-fluoropyridine-2-carboxylic acid
5.3G of the intermediate from step 2 was added to 10ml of tetrahydrofuran, and 0.59g of sodium hydroxide was dissolved in 10ml of water to the system, and reacted at room temperature for 4 hours. After the reaction was completed, THF was removed by concentration under reduced pressure. The pH was adjusted to 2 with concentrated hydrochloric acid, extracted 3 times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated to dryness under reduced pressure to give 4.9g of the objective.
1HNMR(400MHz,DMSO-d3)δ1.42(9H,s),3.20-3.11(4H,m),3.53-3.44(4H,m),7.53(1H,dd),7.90(1H,d),12.98(1H,s);
Step 4, 4- (2-fluoro-6- ((methyl-d 3) carbamoyl) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester
4.9G of intermediate step 3, 1.23g of deuterated methylamine hydrochloride are added to 15ml of ethyl acetate. 22.5g of 50% ethyl acetate solution of propylphosphoric anhydride, 4.5g of diisopropylZ amine were added thereto, and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated to dryness under reduced pressure to give 4.2g of a product.
Step 5, 6-fluoro-N- (methyl-d 3) -5- (piperazin-1-yl) pyridine amide
2G of the mixture obtained in the step 3 was added with 10ml of 10M ethanol hydrochloride solution, and the mixture was stirred at room temperature for 2 hours. And (5) finishing the reaction. The reaction system was concentrated to dryness under reduced pressure. The product 6-fluoro-N- (methyl-d 3) -5- (piperazin-1-yl) pyridine amide dihydrochloride was obtained as a yellow solid 1.1g.
Step 6, 5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
0.10G of 7- (bromomethyl) -3-methylquinolin-2 (1H) -one and 0.5ml of diisopropylethylamine were dissolved in 10ml of acetonitrile, the mixture was stirred at 80℃for 2 hours, concentrated to dryness, stirred with an aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with water, dried, filtered and the residue was subjected to column chromatography to give 0.12g of the objective compound.
1H NMR(400MHz,DMSO-d6)δ2.39(3H,s),2.60-2.54(4H,m),3.21-3.14(4H,m),3.62(2H,s),7.28-7.22(2H,m),7.60-7.54(1H,m),7.66(1H,d),7.84(1H,dd),8.36(1H,s),12.26(1H,bs);
ESI MS m/z：414.21[M+1]+
Example 23, 6-methyl-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
1H NMR(400MHz,DMSO-d6)δ12.26(1H,s),8.38(1H：bs),7.82-7.77(1H,m),7.68-7.64(1H,m),7.51-7.46(1H,m),7.29-7.22(2H,m),3.64(2H,s),2.99-2.93(4H,m),2.62-2.55(4H,m),2.50(3H,overlapped with DMSO,s),2.40(3H,s);
ESI MS m/z：410.23[M+1]+
Example 24, N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
1HNMR(400MHz,DMSO-d6)δ12.34(1H,bs),8.37(1H,bs),8.27-8.23(1H,m),7.84-7.80(1H,m),7.67-7.63(1H,m),7.40-7.36(1H,m),7.34-7.24(2H,m),3.61(2H,s),3.38-3.30(4H,m),2.64-2.54(4H,m),2.38(3H,s);
ESI MS m/z：396.21[M+1]+
Example 25, 6-fluoro-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：416.22[M+1]+
Example 26, 6-fluoro-N-methyl-5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：413.20[M+1]+
EXAMPLE 27N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：398.23[M+1]+
Example 28, 6-fluoro-5- (4- ((2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m./z：442.24[M+1]+
Example 29, 5- (4- ((2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：438.26[M+1]+
Example 30, 5- (4- ((2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：424.253[M+1]+
Example 31, 5- (4- ((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：440.2[M+1]+
Example 32, 5- (4- ((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：436.25[M+1]+
Example 33, 5- (4- ((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：422.23[M+1]+
Example 34, 6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：400.19[M+1]+
Example 35, 6-methyl-N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：396.21[M+1]+
Example 36N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z，382.20[M+1]+
Example 37, 6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：402.20[M+1]+
Example 38, 6-fluoro-N-methyl-5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：399.18[M+1]+
Example 39, 6-fluoro-5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：430.20[M+1]+
Example 40, 5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine amide
Synthesized by the method of reference example 1.
ESI MS m/z：412.21[M+1]+
Example 41, 5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：426.23[M+1]+
Example 42, 6-fluoro-5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：432.21[M+1]+
Example 43, 6-fluoro-5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N-methylpyridine-2-carboxamide
Synthesized by the method of reference example 1.
ESI MS m/z：429.19[M+1]+
Example 44, 5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Step 1, 2- ((4-bromo-3-fluoro-2-nitrophenyl) amino) butanoic acid methyl ester
165Ml of diisopropylethylamine was slowly added to a stirred solution of 37.4g of 1-bromo-2, 4-difluoro-3-nitrobenzene and 24.3g of methyl-2-aminobutyrate hydrochloride in 350ml of N, N-dimethylformamide, and stirred for 8 hours. After dilution with water, extraction with ethyl acetate and concentration of the product under reduced pressure gave 23.6g of methyl 2- (4-bromo-3-fluoro-2-nitro-phenylamino) butyrate.
ESI MS m/z：335.0[M+1]+
Step 2, 7-bromo-3-ethyl-8-fluoro-3, 4-dihydro-1H-quinoxalin-2-one
Sodium hydrosulfite and methyl 2- (4-bromo-3-fluoro-2-nitro-phenylamino) butyrate 12.5 g were added to a 100mL mixture of methanol. Stirring was carried out at room temperature for 2h, the solid was filtered and washed with methanol. The solvent was removed in vacuo, diluted with ethyl acetate and basified with aqueous sodium bicarbonate. The organic layer was separated, washed with water, dried over sodium sulfate and concentrated to give the crude product. 100ml of methanol was added to the solid, stirred for 10 minutes, and filtered to obtain 8.8g of the objective substance.
Step 3, 7-bromo-3-ethyl-8-fluoro-1H-quinoxalin-2-one
DDQ 10g was added to step 2 intermediate 8.6g in dichloromethane 200ml and stirred at room temperature for 2 hours. The solvent was removed, 150mL of methanol was added to the solid, and stirred for 30 minutes. The solid was filtered, washed with 30mL of methanol, 50mL of water was added, then 60mL of sodium bicarbonate was slowly added, and the mixture was stirred overnight at room temperature, the stirring stopped, the solid was filtered, and washed with water to give the objective 4.5g.
Step 4, 3-ethyl-8-fluoro-7-hydroxymethyl-1H-quinoxalin-2-one
Xphos Pd G2 (1.121 g,1.43 mmol) was added to a solution of step 3 intermediate 7.7g and (tributyltin) methanol 10.0g in 120ml of 1, 4-dioxane and the reaction mixture stirred at 90 h. The solvent was removed in vacuo, 80ml of diethyl ether was added and stirred for 30min, and the solid was washed with 50ml of diethyl ether to give 3.2g of a white solid.
1H NMR(400MHz,DMSO-d6)δ1.21(3H,t),2.81(2H,q).4.64(2H,br d),5.39(1H,t),7.32(1H,br t),7.55(1H,d),12.41(1H,br s);
ESI MS m/z：223.08[M+1]+
Step 5, 3-ethyl-8-fluoro-7-bromomethyl-1H-quinoxalin-2-one
1.0G of intermediate 3 was added to 4ml of HCl, the temperature was raised to 80℃and stirred, after 3 hours the reaction was completed, added to ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to give 0.5g of the objective.
Step 6, 5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine amide
Diisopropylethylamine 20.90mL, 5g of the intermediate in step 5 and 7.0g of 6-methyl-N- (methyl-d 3) -5- (piperazin-1-yl) pyridine amide hydrochloride were added to acetonitrile 20mL, the reaction mixture was stirred under 60) for 2 hours, the reaction was completed, a solid was precipitated, filtered, washed with acetonitrile, the solid was filtered off, washed with sodium carbonate water, and then with water, and the filtrate was filtered to obtain the objective 7.6g.
1H NMR(400MHz,DMSO-d6)δ1.23(3H,t),2.48(3H,s),2.62(4H,br s),2.76-2.88(5H,m),2.95(4H,br s),3.73(2H,s),7.31(1H,t),7.47(1H,d),7.56(1H,d),7.79(1H,d),8.41(1H,q),12.44(1H,s)
ESI MS m/z：442.24[M+1]+
Example 45, 6- (difluoromethyl) -5- (4- (2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(500MHz,DMSO-d6)δ1.21(3H,t),2.62(4H,br d),2.75-2.83(2H,m),2.97-3.02(4H,m),3.73(2H,s),7.03-7.26(1H,t),7.31(1H,br d),7.56(1H,br d),7.84(1H,d),8.08(1H,d),8.37(1H,q),12.44(1H,br d)
ESI MS m/z：478.22[M+1]+
Example 46, 5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide
Step 1:5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) picolinic acid methyl ester
Diisopropylethylamine 0.5mL was added to a suspension of 7- (bromomethyl-d 2) -3-ethyl-8-fluoroquinolin-2 (1H) -one 680mg and 5- (piperazin-1-yl) picolinate 700mg in acetonitrile (5 mL). The reaction mixture was stirred at 60℃for 2 hours, the solvent was removed in vacuo and the residue was purified by chromatography on silica gel eluting with methylene chloride/methanol (5:1) to give 516mg of intermediate.
Step 2:5- (4- ((2-ethyl-5-fluoro-3-oxo-3, 4-dihydroquinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine amide
10ML of ammonia in methanol (7N) was added to 300mg of step 1 intermediate. The resulting suspension was stirred at 50℃for 24 hours. The obtained residue was purified by a silica gel column to obtain 167mg of an objective substance.
1H NMR(400NHz,DMSO-d6)δ1.24(3H,t),2.56-2.62(4H,m),2.81(2H,q),3.33-3.40(4H,m),7.26-7.34(2H,m),7.36(1H,dd),7.56(1H,d),7.75(1H,br d),7.84(1H,d),8.28(1H,d),12.44(1H,br s)
ESI MS m/z：413.20[M+1]+
Example 47, 6-methyl-5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(500MHz,DMSO-d6)δ1.23(3H,br t),2.46-2.48(3H,m),2.53-2.68(4H,m),2.83(2H,q),2.93(4H,br s),7.31(1H,br t),7.39-7.50(2H,m),7.54(1H,br d),7.78(2H,br d),12.40(1H,br s)
ESI MS m/z：427.21[M+1]+
Example 48, 5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHz,DMSO-d6)61.23(3H,t),2.58-2.64(4H,m),2.82(2H,q),3.15-3.20(4H,m),3.72(2H,s),7.28-7.33(1H,m),7.53-7.58(2H,m),7.83-7.86(1H,m),8.38-8.44(1H,m),12.46(1H,s)
ESI MS m/z：446.21[M+1]+
Example 49, 6-chloro-5- (4- ((2-ethyl-5-fluoro-3-oxo-1H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400NHz,DMSO-d6)δ1.22(3H,t)2.57-2.65(4H,m),2.76-2.86(5H,m),3.05-3.15(4H,m),3.72(2H,s),7.29(1H,t),7.55(1H,d).7.65(1H,d),7.93(1H,d),8.40-8.45(1H,m),12.45(1H,s);
ESI MS m/z：462.18[M+1]+
Example 50, 5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHz,DMSO-d6 ) Δ1.21 (3 h, t), 2.54-2.62 (4 h, m), 2.76-2.86 (2 h, m), 3.06-3.15 (4 h, m, combined as water peaks), 3.68 (2 h, s), 7.28 (1 h, t), 7.36 (1 h, dd), 7.55 (1 h, d), 7.82 (1 h, d), 8.24 (1 h, d), 8.36-8.42 (1 h, m), 12.43 (1 h, s);
ESI MS m/z：428.22[M+1]+
Example 51, 5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
To 185mg of a suspension of 7- (bromomethyl) -3, 8-dimethyl-1H-quinoxalin-2-one was added hydrobromic acid, ACN (5 ml), 167mg of 6-fluoro-N- (methyl-d 3) -5- (piperazin-1-yl) pyridine amide hydrochloride and 0.5 ml of diisopropylamine ethyl, and the reaction mixture was stirred at 70℃for 1 hour to obtain a pale yellow suspension. The suspension was cooled to room temperature, the solid was collected by filtration, washed 3 times with acetonitrile and dried to give 85mg of the objective.
1HNMR(400MHz,DMSO-d6)δ2.06(3H,brs),2.43(3H,brd),2.57(4H,brs),3.15(4H,brs),3.62(2H,brs),7.24(1H,brd).7.43-7.67(2H,m),7.84(1H,brd),8.37(1H,brs),11.14-11.97(1H,m);
ESI MS m/z：428.22[M+1]+
Example 52, 5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
1HNMR(400MHz,DMSO-d6)δ2.44(3H,s),2.56(3H,s),3.25-3.56(6Hm)3.87-4.01(2H,m),4.56(2Hbrs),7.47-7.71(3Hm),7.96(1H,brd),8.34(1H,brd),8.58(1H,brs),11.27(1H,brs),11.52-11.92(1H,m)
ESI MS m/z：410.23[M+1]+
Example 53, 6-chloro-5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
1HNMR(400NHz,DMSO-d6)62.42(3H,s),2.41(3H,s),2.55-2.61(4H,m),3.06-3.10(4H,m),3.61(2H,s),7.25(1H,d),7.52(1H,d),7.66(1H,d),7.91(1H,d),8.42-8.45(1H,m),11.57(1H,s);
ESI MS m/z：444.19[M+1]+
Example 54, 5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
1HNMR(400MHz DMSO-d6)δ2.41(3H,s),2.42(3H,s),2.47(3H,s),2.56-2.63(4H,m),2.88-2.94(4H,m),3.63(2H,s),7.25(1H,d),7.47(1H,d),7.52(1H,d),7.79(1H,d),8.38-8.44(1H,m),11.57(1H,s)
ESI MS m/z：424.25[M+1]+
Example 55, 5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-fluoropyridine-2-carboxamide
Prepared by the method of reference example 44.
1HNMR(400MHz,DMSO-d6)δ2.41(3H,s),2.42(3H,s),2.56(4H,brs),3.14(4H,brs),7.22(1H,d),7.45(1H,brs),7.47-7.58(2H,m),7.77(1H,brs)7.85(1H,br d).11.16-11.70(1H,m)：
ESI MS m/z：413.20[M+1]+
Example 56, 5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-methylpyridine-2-carboxamide
Prepared by the method of reference example 44.
1HNMR(400NHz DMSO-d6)δ2.41(3H,s),2.45-2.48(3Hm),2.51-2.64(4Hm),2.92(4H,br s),7.28(1H,t),7.43-7.54(3H,m),7.76-7.83(2H,m),12.43(1H,br s);
ESI MS m/z：413.20[M+1]+
Example 57, 5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-methylpyridine-2-carboxamide
Prepared by the method of reference example 44.
1HNMR(400NHzDMSO-d6)δ2.42(3H,s)2.45(3H,s),2.49(3H,s).2.58(4H,br s),2.93(4H,brs),7.24(1H,br d).7.42(1H,brs),7.46(1H,brd).7.51(1H,brd),7.78(2H,brd),10.54-11.23(1H,m)
ESI MS m/z：409.22[M+1]+
Example 58, 6-chloro-5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
1HNMR(400MHz,DMSO-d6)δ1.22(3H,t),2.67(4H,brs),2.78-2.92(2H,m),3.14(4H,brs),7.45(1H,d).7.67(2H,dd).7.92(1H,d),8.41(1H,q),10.78-11.42(1H,m);
ESI MS m/z：478.15[M+1]+
Example 59, 5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
1HNMR(400MHz,DMSO-d6)δ1.23(3Ht)2.63(4Hbrs),2.84(2Hq),3.18(4H,brs),3.72(2Hs),7.42(1H,d).7.52-7.62(1H,m),7.70(1H,d).7.84(1H,d).8.39(1H,q)11.19-11.51(1H,m);
ESI MS m/z：462.18[M+1]+
Example 60, 5- (4- ((5-chloro 2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
1H NMR(400MHz DMSO-d6)δ1.23(3H,t),2.85(2H,q).3.24-3.37(8H,m,merged into water peak).4.41-4.62(2H,m),7.44(1H,dd),7.56(1H,br d),7.79-7.90(2H,m),8.33(1H,d),8.44(1H,br d),11.86-12.21(1H,m);
ESI MS m/z：444.199[M+1]+
Example 61, 5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Diisopropylethylamine (0.5 mL) was added to a stirred suspension of 6-methyl-N- (methyl-d 3) -5-piperazin-1-ylpyridin-2-carboxamide dihydrochloride (480 mg), and 7- (bromomethyl) -8-chloro-3-ethyl-1H-quinolin-2-one (480 mg), acetonitrile (5 mL), and stirred at 70 ℃ for 2H to give a suspension. The mixture was cooled to room temperature, filtered to give a solid, washed with water and dried to give 356mg of the objective.
1H NMR(400MHz,DMSO-d6)δ1.23(3H,t),2.64(4H,br s),2.84(2H,m),2.94(4H,br s),3.38(3H,s,overlapped water peak),3.76(2H,s),7.46(2H,dd),7.72(1H,d),7.78(1H,d),8.41(1H,br d),11.59-1.99(1H,m);
ESI MS m/z：458.21[M+1]+
Examples 62, 63, (S/R) -6-fluoro-5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHz,DMSO-d6)δ1.53-1.72(3H,m),3.54-3.90(8H,m),4.56(2H,br s),5.78-6.21(1H,m),7.61-7.82(3H,m),7.86(1H,d),8.44(1H,brd),11.40-11.85(1H-m),12.79-13.13(1H,m);
ESI MS m/z：464.20[M+1]+
Examples 64, 65, (R/S) -5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1HNMR(400MHz,DMSO-d6)δ1.41-1.70(3H,m),2.49(3H,s),2.55-2.69(4H,m),,2.95(4H,br s),3.76(2H,s),5.84-6.22(1H,m),7.18-7.42(1H,m),7.48(1H,d),7.66(1H,d),7.79(1H,d),8.41(1H,br d),11.66-12.88(1H,m);
ESI MS m/z：460.23[M+1]+
Example 66, 5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-l-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Diisopropylethylamine 0.2mL, N- (methyl-d 3) -5- (piperazin-1-yl) pyridine amide dihydrochloride 90.5mg and 7- (bromomethyl) -8-chloro-3-methyl-1H-quinoxalin-2-one 88mg were added to a mixture of acetonitrile (4 mL), and stirred at 70℃for 3H. The mixture was concentrated, and column chromatography was performed to obtain 85mg of the objective substance.
ESI MS m/z：430.18[M+1]+
Example 67, 5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHz,DMSO-d6)δ2.37-2.47(3H,m),2.64(4H,br s),3.14-3.23(4H,m),3.75(2H,s),7.46(1H,d),7.58(1H,dd),7.67(1H,d),7.84(1H,d),8.41(1H,br d),10.72-12.11(1H,m);
ESI MS m/z：448.17[M+1]+
Example 68, 5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
ESI MS m/z：444.19[M+1]+
Example 69, 5- (4- ((2- (1, 1-difluoroethyl) -5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide salt s
Synthesized by the method of reference example 44.
ESI MS m/z：478.22[M+1]+
Example 70, 6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Step 1, 2- ((4-bromo-3-fluoro-2-nitrophenyl) amino) propanoic acid methyl ester
1.63G of diisopropylethylamine was slowly added to a stirred solution of 1g of 1-bromo-2, 4-difluoro-3-nitrobenzene and 0.65g of alanine methyl ester hydrochloride in 5ml of N, N-dimethylformamide, stirred at room temperature, diluted with water and extracted 3 times with dichloromethane, the organic phases were combined, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and then chromatographed through a silica gel column to give 0.8g of an orange-yellow oil.
1H NMR(400MHz,DMSO-d6)δ7.69(1H,dd),7.27(1H,d),6.74(1H,dd),4.56-4.48(1H,m),3.69(3H,s),1.45(3H,d);
Step 2, 7-bromo-3-methyl-8-fluoro-3, 4-dihydro-1H-quinoxalin-2-one
0.81G of zinc powder was slowly added to a stirred solution of 0.5g of the intermediate from step 1 and 0.83g of ammonium chloride in 8ml of methanol and 0.2g of water at 0℃in an ice bath, and the mixture was stirred at room temperature. After the reaction of the raw materials was completed, the system was suction-filtered, and the filter cake was washed with a 20% solution of methanol in methylene chloride, and the filtrate was concentrated to give a tan solid, water was added to the solid, and extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed 3 times with saturated common salt water, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to give a crude product. To a single-necked flask containing the crude product, 1ml of ethyl acetate and 1ml of methanol were added, and 2 drops of 1, 4-dioxane of 4N hydrogen chloride was added dropwise, followed by stirring at room temperature for 1 hour, and after concentrating under reduced pressure, silica gel was passed through a column to obtain 0.3g.
Step 3, 7-bromo-3-methyl-8-fluoro-1H-quinoxalin-2-one
DDQ 1g was added to step 2 intermediate 0.3g in 10ml of dichloromethane and stirred at room temperature for 2 hours. The solvent was removed, 15mL of methanol was added to the solid, and stirred for 30 minutes. The solid was filtered, washed with 5mL of methanol, 50 mL of water was added, then 60mL of sodium bicarbonate was slowly added, and the mixture was stirred overnight at room temperature, the stirring stopped, the solid was filtered, and washed with water to give the objective 0.2g.
1H NMR(400MHz,DMSO-d6)δ12.60(1H，s)，7.54-7.46(2H，m)，2.41(3H，s)；
Step 4, 3-methyl-8-fluoro-7-hydroxymethyl-1H-quinoxalin-2-one
Xphos Pd G2 (1.121 g,1.43 mmol) was added to a solution of 7-bromo-3-methyl-8-fluoro-1H-quinoxalin-2-one 0.1g and (tributyltin) methanol 0.138g in 5ml of 1, 4-dioxane and the reaction mixture was stirred at 90℃for 4 hours. The solvent was removed in vacuo, 10ml of diethyl ether was added and stirred for 30min, and the solid was washed with 10ml of diethyl ether to give 0.12g of a white solid.
1HNMR.(400MHz,DMSO-d6)δ12.41(1H,s),7.53-7.50(1H,m),7.35-7.30(1H,m),5.42-5.38(1H,m),4.63(2H,d),2.41(3H,s);
Step 5, 3-methyl-8-fluoro-7-bromomethyl-1H-quinoxalin-2-one
8-Fluoro-7- (hydroxymethyl) -3-methyl-1H-quinoxalin-2-one 0.12g,5ml aqueous hydrobromic acid (48%), 80℃for 3H, ice water was added, extracted with dichloromethane and dried. Filtration and concentration gave 0.26g of a white solid.
Step 6, 6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
To the flask was added 0.26g of the intermediate of step 5, 0.24g of 6-fluoro-N- (methyl-d 3) -5- (piperazin-1-yl) pyridine amide dihydrochloride, 10ml of acetonitrile, 0.2ml of diisopropylethylamine was added at room temperature, and stirred at 70℃for 4 hours. The solvent was removed under reduced pressure, the residue was subjected to column chromatography to give 0.3g of a product.
1HNMR(400MHz DMSO-d6)δ2.42(s,3H),2.64-2.54(m,4H),3.21-3.12(m,4H),3.70(s,2H),7.32-7.25(m,1H),7.59-7.49(m,2H),7.84(d,1H),8.36(s,1H),12.45(bs,1H);
ESI MS m/z：432.20[M+1]+
Example 71, 6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1HNMR(400MHz DMSO-d6)δδ2.42(s,3H),2.63-2.54(m,4H),3.21-3.14(m,4H),7.31-7.25(m,1H),7.58-7.48(m,2H),7.84(d,1H),8.36(s,1H),12.44(bs,1H);
ESI MS m/z：434.21[M+1]+
Example 72, 6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N-methylpyridine-2-carboxamide
Synthesized by the method of reference example 44.
ESI MS m/z：431.19[1M+1]+
Example 73, 6-chloro-5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Thionyl chloride 2ml was added dropwise to intermediate 8-fluoro-7- (hydroxymethyl) -3-methoxyquinoxalin-2 (IH) -one 1.5g, 0.1ml of N, N-dimethylformamide in dichloromethane 20ml, stirred at room temperature for 3 hours, and the reaction mixture was concentrated to dryness to give 7- (chloromethyl) -8-fluoro-3-methoxyquinoxalin-2 (1H) -one. 7- (chloromethyl) -8-fluoro-3-methoxyquinoxalin-2 (1H) -one, diisopropylethylamine 2.5ml, 6-chloro-N- (methyl-d 3) -5- (piperazin-1-yl) pyridine amide 1.5g was dissolved in acetonitrile 25ml, stirred for 2 hours at 80 ℃, concentrated to dryness, stirred with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed with water, dried, filtered and the residue was column chromatographed to give the objective 1.6g.
1H NMR(400MHZ,DMSO-d6)δ2.57-2.66(4H,m),3.06-3.14(4H,m),3.70(2H,s),3.96(3H,s),7.21-7.30(m,1H),7.36(d,1H),7.65(d,1H),7.92(d,1H),8.43(d,1H),12.46(s,1H);
ESI MS m/z：464.16[1M+1]+
Example 74, 5- (4- ((2-ethyl-5-methyl-3-oxo-41H-quinoxalin-6-yl) methyl) piperazin-l-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHZ,DMSO-d6)δ1.21(3H,t),2.43(3H,s),2.51(3H,s),5.54-2.58(4H,m),2.73-2.86(2H,m),2.87-2.93(4H,m),3.63(2H,s),7.24(1H,d),7.46(1H,d),7.53(1H,d),7.77(1H,d),8.38(1H,d),11.52(1H,s);
ESI MS m/z：438.26[M+1]+
Example 75, 5- (4- ((2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1HNMR(400MHZ,DMSO-d6)δ1.20(3H,t),2.41(3H,s),2.49-2.59(4H,m),2.70-2.81(5H,m),3.08-3.16(4H,m),3.59(2H,s),7.22(1H,d),7.47-7.60(2H,m),7.82(1H,dd),8.37(1H,d),11.52(1H,s);
ESI MS m/z：442.24[M+1]+
Example 76, 5- (4- ((2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHZ,DMSO-d3)δ1.17-1.26(3H,m),2.42(3H,s),2.48-2.56(4H,m),2.70-2.81(2H,m),3.31-3.34(4H,m),3.60(2H,s),7.26(1H,d),7.39(1H,d),7.54(1H,d),7.83(1H,d),8.27(1H,s),8.36(1H,s).11.52(1H,s);
ESI MS m/z：424.25[M+1]+
Example 77, 6- (difluoromethyl) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Diisopropylamine 0.52mL was added to a stirred mixture of 3-methyl-8-fluoro-7-bromomethyl-1H-quinoxalin-2-one 200mg and 6- (difluoromethyl) -5- (piperazin-1-yl) -N- (methyl-d 3) picolinamide dihydrochloride 250.6mg and 5mL acetonitrile, and the resulting mixture was stirred at 70℃for 2 hours. Concentrating to dryness, adding sodium bicarbonate water solution, stirring, extracting with ethyl acetate, washing with water, drying, filtering, and performing column chromatography on the residue to obtain 84mg of the target product.
1H NMR(500MHz,DMSO-d6)δ2.36(3H,s),2.66(4H,brs),3.03(4H,brd),3.71(2H,s),7.04-7.28(2H,m),7.41(1H,brd),7.85(1H,d),8.08(1H,d),8.39(1H,q),12.27-12.63(1H,m);
ESI MS m/z：464.20[M+1]+
Example 78, 6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide
Step 1, 6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) picolinic acid methyl ester
800Mg of 7- (bromomethyl-d 2) -3-methyl-8-fluoro-1H-quinoxalin-2-one, 1200mg of methyl 6-fluoro-5- (piperazin-1-yl) picolinate hydrochloride, 25mL of acetonitrile and 0.2mL of diisopropylethylamine were added, and the reaction mixture was heated to 70℃for 2 hours. The reaction mixture was cooled to room temperature, concentrated and the crude solid was purified. 0.96g of the target product was obtained.
ESI MS m/z：432.17[M+1]+
Step 2, 6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-3, 4-dihydroquinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine amide
10.3Ml of ammonia (7N ammonia in methanol) was added to the intermediate of step 1, 0.5g was added to a 50ml round bottom flask, sealed and stirred at room temperature for 24 hours to give 200mg of pure product. The filtrate was concentrated in vacuo, and the resulting white solid was slurried in 4ml of methanol and filtered to give 237mg of the objective.
1H NMR(500MHz,DMSO-d6)δ2.43(3H,s),2.60(4H,br s),3.12-3.25(4H,m),7.28(1H,br t),7.44(1H,br s),7.48-7.56(2H,m),7.75(1H,br s),7.86(1H,br d),12.34(1H,br s);
ESI MS m/z：417.12[M+1]+
Example 79, 6-chloro-5- (4- ((2-methyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHz,DMSO-d6)δ2.43(3H,s),2.59-2.65(4H,m),3.08-3.17(4H,m),3.71(2H,s),7.31(1H,t),7.52(1H,d),7.64(1H,d),7.92(1H,d),8.42-8.48(1H,m),12.46(1H,s)
ESI MS m/z：448.17[M+1]+
Example 80, 5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHz,DMSO-d6)δ2.43(3H,s),2.48(3H,s),2.56-2.63(4H,m),2.92-2.97(4H,m),3.73(2H,s),7.31(1H,t),7.46(1,d),7.53(1H,d),7.78(1H,d),8.39-8.45(1H,m),12.47(1H,s);
ESI MS m/z：428.22[M+1]+
Example 81, 5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1HNMR(400MHz,DMSO-d6)δ12.45(1H,bs),8.35(1H,bs),8.25(1H,d),7.82(1H,d),7.52(1H,d),7.39-7.35(1H,m),7.32-7.27(m,1H),3.69(2H,s),3.30(4H,ovedapped with water m),2.61-2.53(4H,m),2.42(3H,s);
ESI MS m/z：414.21[M+1]+
Example 82N- (ethyl-2, 2-d 3) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHZ,DMSO-d6)δ2.40(3H,s),2.52-2.62(4H,m),3.17-3.27(4H,m),3.25(2H,q),3.68(2H,s),7.27(1H,t),7.49-7.56(2H,m),7.82(1H,d),8.44(1H.d),12.46(1H,s);
ESI MS m/z：446.21[M+1]+
Example 83, N- (ethyl-2, 2-d 3) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methylpyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400NHZ,DMSO-d6)δ2.42(3H,s),2.51(3H,s),2.55-2.62(4H,m),2.86-2.96(4H,m),3.31(2H,q),3.71(2H,s),7.26(1H,t),7.46(1H,d),7.51(1H,d),7.76(1H,d),8.40(1H,t),12.42(1H,s);
ESI MS m/z：442.24[M+1]+
Example 84, 5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHZ,DMSO-d6)δ2.51(3H,s),2.57-2.64(4H,m),2.90-2.96(4H,m),3.76(2H,s),7.42(1H,t),7.46(1H,d),7.71(1H,d),7.78(1H,d),8.38-8.42(1H,m),13.21(1H,brs),
ESI MS m/z：482.19[M+1]+
Example 85, 6-fluoro-5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400NHZ,DMSO-d6)δ2.58-2.64(4H,m),3.13-3.22(4H,m),3.76(2H,s),7.38(1H,t),7.55(1H,dd),7.72(1H,d),7.83(1H,dd),8.38-8.43(1H,m),13.38(1H,brs);
ESI MS m/z：486.17[M+1]+
Example 86, 4-chloro 5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 14.
1H NMR(400MHZ,DMSO-d6)δ2.61-2.66(4H,m),3.08-3.14(4H,m),3.76(2H,s),7.41(1H,t),7.65(1H,d),7.73(1H,d),7.92(1H,d),8.41-8.43(1H,m),13.25(1H,brs);
ESI MS m/z：501.14[M+1]+
Example 87, 5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 44.
1H NMR(400MHZ,DMSO-d6)δ2.51-2.56(4H,m),3.26-3.35(4H,m),3.73(2H,s),7.31(1H,t),7.41(1H,dd),7.64(1H,d),7.82(1H,d),8.28(1H,d),8.37-8.41(1H,m);
ESI MS m/z：468.18[M+1]+
Example 88, 5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Step 1, 4-bromo-3-fluoro-benzene-1, 2-diamine
20G of sodium hydrosulfite was added to 7.3g of 4-bromo-3-fluoro-2-nitroaniline and 60ml of methanol. The mixture was stirred at reflux for 3 hours. The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3X 50 ml), washed with water (100 ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by column chromatography to give 5.38g of 4-bromo-3-fluoro-benzene-1.2-diamine.
ESI MS m/z：204.97[M+1]+
Step 2, 7-bromo-8-fluoro-1H-quinoxalin-2-one
3.2G of ethyl 2-oxoacetate was added to 30ml of toluene of 2.2g of 4-bromo-3-fluoro-benzene-1.2 diamine. The resulting mixture was stirred at 100℃for 60 minutes. The solvent was removed under reduced pressure and the precipitate was collected by filtration, washed with 5ml of ethyl acetate and dried under vacuum to give 1.6g.
ESI MS m/z：242.95[M+1]+
Step 3, 8-fluoro-7- (hydroxymethyl) -1H-quinoxalin-2-one
0.2G of chloro [ (n-butylbis (1-adamantyl) phosphine) -2- (2-aminobiphenyl) ] palladium was added to (tributylenemethanol 1.70g, 7-bromo-8-fluoro-1H-quinoxalin-2-one 1.5g and 1, 4-dioxane (30 mL). After the mixture was stirred under nitrogen at 100℃for 18 hours, it was washed with water, and the aqueous layer was extracted with ethyl acetate (3X 60 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed, followed by column chromatography to give 520mg of the objective.
ESI MS m/z：195.05[M+1]+
Step4, 5- (4- ((5-fluoro-3-oxo-4-H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine amide
Thionyl chloride 0.5mL was added to a solution of 8-fluoro-7- (hydroxymethyl) -1H-quinoxalin-2-one 320mg in dichloromethane 3 mL. The resulting mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. To NMP3.0ml of the mixture were added diisopropylamine 0.5ml and 280mg of N- (methyl-ds) -5-piperazin-1-ylpyridine-2-carboxamide, and the resulting mixture was stirred at 80℃for 1 hour, washed with water (100 ml), and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by filtration, and the objective 234mg was obtained by column chromatography.
1H NMR(400MHz,DMSO-d6)δ2.56-2.60(4H,m),3.29-3.33(4H,m),3.72(2H,s),7.31-7.43(2H,m),7.62(1H,d),7.81(1H,d),8.21(1H,s),8.26(1H,d),8.38-8.42(1H,m);
ESI MS m/z：400.19[M+1]+
Example 89, 6-chloro 5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 88.
1H NMR(400MHz,DMSO-d6)δ2.59-2.65(4H,m),3.08-3.13(4H,m),3.72(2H,s),7.34(1H,dd),7.62(1H,d),7.64(1H,d),7.92(1H,d),8.21(1H,s),8.41-8.44(1H,m),12.57(1H,s);
ESI MS m/z：434.15[M+1]+
Example 90, 5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 88.
1H NMR(400MHz,DMSO-d6)δ2.47(3H,s),2.55-2.65(4H,s),2.93-2.98(4H,m),3.72(2H,s),7.31-7.39(1H,m),7.48(1H,d),7.62(1H,d),7.77(1H,d),8.18(1H,s),8.39-8.44(1H,m),12.54(1H,s);
ESI MS m/z：414.21[M+1]+
Example 91, 6-fluoro-5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 88.
ESI MS m/z：418.18[M+1]+
Example 92, 5- (4- ((2- (difluoromethyl) -5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 88.
1H NMR(400MHz,DMSO-d6)δ2.48(3H,s),2.61-2.65(4H,m),2.91-2.98(4H,m),3.75(2H,s),7.07(1H,t),7.38(1H,t),7.49(1H,d),7.71(1H,d),7.80(1H,d),8.41(1H,q),13.02(1H,s);
ESI MS m/z：464.20[M+1]+
Example 93, 5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Step 1, 4-bromo-3-fluoro-benzene-1, 2-diamine
8G of sodium hydrosulfite was added to 3.0g of 4-bromo-3-fluoro-2-nitroaniline and dissolved in 30ml of methanol. The resulting mixture was refluxed for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO 4, filtered and evaporated to give 2.4g of 4-bromo-3-fluoro-benzene-1, 2-diamine.
1H NMR(400MHz,DMSO-d6)δ4.66(2H，s)，4.94(2H，s)，6.31(1H，dd)，6.55(1H，dd)；
Step 2, 7-bromo-8-fluoro-3-methoxy-1H-quinoxalin-2-one
2.4G of methyl 2, 2-trimethoxyacetate was added to a solution of 1.5g of 4-bromo-3-fluorobenzene-1, 2-diamine and 0.45g of ytterbium (tris ((trifluoromethyl) sulfonyl) oxy) in 20ml of toluene at room temperature. The resulting mixture was stirred at 100℃for 5h and the solvent was removed under reduced pressure. Washing with water, extraction with ethyl acetate and column chromatography gave 0.65g of 7-bromo-8-fluoro-3-methoxy-1H-quinoxalin-2-one.
Step 3, 8-fluoro-7- (hydroxymethyl) 3-methoxy-1H-quinoxalin-2-one
1.6G of (tributyltin group) methanol, 600.0mg of 7-bromo-8-fluoro-3-methoxyquinoxalin-2 (1H) -one and 73mg of chloro [ (n-butyldi (1-adamantyl) phosphine) -2- (2-aminobiphenyl) ] palladium are added to 20ml of dioxane, the mixture is stirred at 100℃for 6 hours under nitrogen protection, then filtered, concentrated under reduced pressure to remove the solvent, and the crude product is purified by column chromatography, and 254mg of 8-fluoro-7- (hydroxymethyl) -3-methoxy-1H-quinoxalin-2-one is obtained by drying.
Step 4, 7-chloromethyl-8-fluoro-3-methoxy-1H-quinoxalin-2-one
To a solution of step 4 intermediate 200.0mg in 50ml of diethyl ether was added 8ml of thionyl chloride at room temperature. The resulting mixture was stirred at room temperature for 8 hours. The solvent was removed to give 178mg of 7- (chloromethyl) -8-fluoro-3-methoxy-1H-quinoxalin-2-one, which was used directly in the next step.
1H NMR(400MHz,DMSO-d6)δ3.96(3H，s)，4.87(2H，s).7.27-7.42(2H，m)，12.60(1H，s)
ESI MS m/z(ES+)[M+H]+＝243.03
Step 5, 5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
To 10ml of acetonitrile at room temperature, 150mg of the intermediate of step 4, 200mg of N- (methyl-d 3) -5-piperazin-1-ylpyridine-2-carboxamide and 0.5ml of diisopropylethylamine were added, and the mixture was stirred at 60℃for 6 hours, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to give 163.0mg of the objective compound.
1H NMR(400MHz,DMSO-d6)δ2.52-2.58(4H,m),3.18-3.44(4H,m),3.65(2H,s),3.94(3H,s),7.11-7.27(1H,m),7.26-7.41(2H,m),7.82(1H,d),8.24(1H,d),8.38(1H,q),12.31(1H,s);
ESI MS m/z：430.20[M+1]+
Example 94, 6-fluoro-5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 93.
1H NMR(400MHz,DMSO-d6)δ2.54-2.59(4H,m),3.10-3.18(4H,m),3.66(2H,s),395(3H,s),7.18-7.28(1H,m),7.35(1H,d),7.54(1H,dd),7.78-7.87(1H,m),8.41(1H,d),12.50(1H,s);
ESI MS m/z：448.19[M[M+1]+
Example 95, 5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 93.
1H NMR(400MHz,DMSO-d6)δ2.49(3H s),2.57-2.63(4H,m),2.91-2.95(4H,m),3.68(2H,s),3.98(3H,s),7.26(1H,t),7.37(1H,d),7.46(1H,d),7.78(1H,d),8.44(1H,q),12.52(1H,s);
ESI MS m/z：444.22[M+1]+
Example 96, 6-fluoro-5- (4- ((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 93.
1H NMR(400MHz,DMSO-d6)1.23(6H,d),2.54-2.65(4H,m),3.13-3.24(4H,m),3.35-3.53(1H,m),3.72(2H,s),7.32(1H,t),7.51-7.57(2H,m),7.83(1H,d),8.37-8.41(1H,m),12.47(1H,brs);
ESI MS m/z：460.23[M+1]+
Example 97, 5- (4- ((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 93.
1H NMR(400MHz,DMSO-d6)δ1.21(6H,d),2.45-2.47(3H,m),2.51-2.66(4H,m),2.93(4H,brs),3.37-3.51(1H,m),3.72(2H,s),7.28(1H,t),7.47(1H,d),7.55(1H,d),7.78(1H,d),8.38-8.45(1H,m),12.45(1H,s);
ESI MS m/z：456.25[M+1]+
Example 98, 5- (4- ((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 93.
1H NMR(400MHz,DMSO-d6)δ1.23(6H,d),2.51-2.60(4H,m),3.243.29(4H,m),3.373.51(1H,m),3.71(2H,s),7.32(1H,t),7.37(1H,dd),7.56(1H,d),7.83(1H,d),8.25(1H,d),8.37(1H,br d),12.45(1H,br s);
ESI MS m/z：442.24[M+1]+
Example 99, 5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 93.
1H NMR(400MHz,DMSO-d6)δ1.05-1.12(4H,m),2.53-2.62(4H,m),2.72(1H,s),3.12-3.22(4H,m),3.68(2H,s),7.25(1H,t),7.44(1H,d),7.56(1H,dd),7.85(1H,d),8.38(1H,brd),12.45(1H,br s);
ESI MS m/z：458.21[M+1]+
Example 100, 5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 93.
1H NMR(400MHz,DMSO-d6)1.03-1.15(4H,m),2.46-2.49(3H,m),2.52-2.65(4H,m),2.65-2.75(1H,m),2.80(3H,d),2.94(4H,br s),3.71(2H,s),7.26(1H,t),7.40-7.50(2H,m),7.79(1H,d),8.37-8.44(1H,m),12.46(1H,s).;19FNMR(471NHz,DMSO-d6)-135.54(1F,s);
ESI MS m/z：454.24[M+1]+
Example 101, 5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 93.
1H NMR(400MHz,DMSO-d6)δ1.04-1.15(4H,m),2.54-2.61(4H,m),2.64-2.80(2H,m),3.69(2H,s),7.26(1H,brt),7.39(1H,dd),7.41(1H,d),7.83(1H,d),8.26(1H,d),8.36-8.40(1H,m),12.39-12.51(1H,m);
ESI MS m/z：440.22[M+1]+
Example 102, 5- (4- ((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide
Step 1, 7-bromo-3-methoxy-8-methyl-1H-quinoxalin-2-one
Methyl 4-bromo-3-methylbenzene-1, 2-diamine 0.9g, 2-trimethoxyacetate 1.4g, ytterbium (III) triflate 0.540g, under nitrogen protection, the mixture was stirred at 100℃and cooled to room temperature, the solid was collected by filtration, washed with methanol and dried to give 1.8g of 7-bromo-3-methoxy-8-methyl-quinoxalin-2 (1H) -one.
Step 2, 7- (hydroxymethyl) -3-methoxy-8-methyl-1H-quinoxalin-2-one
1.8G of (tributylstannyl) methanol, 1.0g of 7-bromo-3-methoxy-8-methyl-1H-quinoxaline-one and Xphos PdG 2.0 g of 0.452g are added to a 100mL reaction flask, 30mL of 1-dioxane is added, and the mixture is stirred overnight at 80 ℃ under nitrogen protection, a black mixture is obtained, the solvent is removed under reduced pressure, the residue is purified on a silica gel column and then the product is slurried in 10mL of methanol, the solid is collected by filtration and dried, thus obtaining 750mg of the target compound.
1H NMR(400MHz,DMSO-d6)δ2.31(3H,s),3.92-4.02(3H,m),4.57(2H,d),5.15(1H,t),728(1H,d),7.38(1H,d),11.58(1H,br s);
ESI MS m/z：211.08[M+1]+
Step 3, 7- (bromomethyl) -3-methoxy-8-methyl-1H-quinoxalin-2-one
600Mg of 7-hydroxymethyl-3-methoxy-8-methyl-1H-quinoxalin-2-one and 180mg of 1, 2-tetrabromo-1, 2-dichloroethane are added to 20mL of methylene chloride, the mixture is stirred at room temperature for 4 hours, the solvent is removed under reduced pressure, the residue is suspended in 15mL of diethyl ether, filtration, washing of the solid with diethyl ether, washing of the solid suspension with water, filtration and drying are carried out to obtain the objective 0.42g.
ESI MS m/z：285.00[M+1]+
Step 4, 5- (4- ((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine amide
250Mg of 6-methyl-N- (methyl-d 3) -5- (piperazin-1-yl) pyridine carboxamide dihydrochloride and 258mg of 7- (bromomethyl) -3-methoxy-8-methyl-1H-quinoxalin-2-one are added to 5mL of acetonitrile, then to 0.6mL of diisopropylethylamine, the mixture is stirred for 2H at 70℃to give a clear solution, the mixture is cooled to room temperature, the solid is collected by filtration, washed with acetonitrile, water and dried to give 167mg of the objective.
1H NMR(400MHz,DMSO-d6)δ2.42(3H,s),2.48(3H,s),256(4H,br s),2.92(4H,brs).3.61(2H,s),3.94(3H,s),7.17(1H,d),7.36(1H,d),7.45(1H,d),7.77(1H,d),8.41(1H,q),11.57(1H,br s);
ESI MS m/z：440.24[M+1]+
Example 103, 6-fluoro-5- (4- ((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 102.
1H NMR(400MHz,DMSO-d6)δ2.41(3H,s),2.54(4H,br s),3.15(4H,br s),3.57(2H,s),3.94(3H,s),7.16(1H,br d),7.34(1H,br d),7.51-7.61(1H,m),7.82(1H,br d),8.37(1H,br d),11.57(1H,s);
ESI MS m/z：444.22[M+1]+
Example 104, 6- (difluoromethyl) -5- (4- (2-methoxy-5-methyl-3-oxo-4-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
167Mg of 6- (difluoromethyl) -N- (methyl-d 3) -5-piperazin-1-ylpyridine-2-carboxamide dihydrochloride and 160mg of 7- (bromomethyl) -3-methoxy-8-methyl-1H-quinoxalin-2-one are added to 6ml of acetonitrile, the mixture is stirred for 2H at 70 ℃, the solution is clarified, the mixture is cooled to room temperature to obtain a suspension, the solid is collected by filtration, washed with acetonitrile, water and dried to obtain 142mg of the target compound.
1H NMR(400MHz,DMSO-d6)δ2.42(3H,s),2.58(4H,br s),2.96(4H,br s),3.61(2H,s),3.94(3H,s),6.93-7.27(2H,m),7.34(1H,d),7.84(1H,br d),8.07(1H,d),8.37(1H,br d),11.59(1H,br s);
ESI MS m/z：476.22[M+1]+
Example 105, 6- (difluoromethyl) -5- (4- (2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Synthesized by the method of reference example 102.
1H NMR(400MHz,DMSO-d6)δ2.41(3H,s),2.42(3H,s),2.61(4H,br s),2.97(4H,br d),3.62(2H,s),6.96-7.23(1H,m),724-7.28(1H,m),7.52(1H,d),7.86(1H,d),8.07(1H,d),8.37(1H,brd),11.53(1H,brs);
ESI MS m/z：460.23[M+1]+
Example 106, (S) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：443.19[M+1]+
Example 107 (S) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：446.21[M+1]+
Example 108 (S) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：425.20[M+1]+
Example 109, (S) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N, 6-dimethylpyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：439.22[M+1]+
Example 110 (S) -6-fluoro-N-methyl-5- (2-methyl-4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：425.20[M+1]+
Example 111, (S) -5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：460.23[M+1]+
Example 112, (S) -5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：472.23[M+1]+
Example 113 (S) -5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-N-methylpyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：469.21[M+1]+
Example 114, (R) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：446.21[M+1]+
Example 115 (R) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide
Prepared by the method of reference example 44.
ESI MS m/z：443.19[M+1]+
EXAMPLE 116 inhibition of PARP by Compounds
Method 1: compound samples were dissolved in DMSO to prepare 10mM stock solutions, and then the compounds were added to the screening system at a concentration ranging from 0.1nM to 10 μm, diluted according to a 3-fold gradient, and two wells were made for each concentration. The experimental results are converted into the activity percentages, the drug concentration is taken as an abscissa, the corresponding enzyme activity percentage of each concentration is taken as an ordinate, a dose-response curve is drawn, the GRAPHPAD PRISM is used for nonlinear regression, and the IC50 value of the tested compound on PARP-1 enzyme inhibition is calculated. The specific operation steps are as follows:
The target compounds were tested for their PARP-1 enzyme inhibitory activity in 96 well plates. Each well was pre-diluted with histone (20 ug/mL) in 100uL PBS buffer (10 mM sodium dihydrogen phosphate, 10mM disodium hydrogen phosphate, 150mM sodium chloride, pH 7.4) and incubated overnight at 4 ℃. Thereafter, 100. Mu.M NAD+ and 25. Mu.M biotinylated NAD+ diluted in 30uL buffer (50 mM Tris,2mM magnesium chloride, pH 8.0) and 200nM sDNA were added per well, followed by 5. Mu.L of test compound or solvent control at different concentrations. After 20uL (5 ng) PARP-1 was added per well at 30℃for 1h, 50uL HRP was added, and after 30min incubation, 100uL buffer (0.1M H 2O2 citrate buffer, pH 5.4) was added to terminate the reaction, and the chemiluminescent values were detected on a SpectraMax M5 instrument. The percentage of enzyme activity was calculated according to the following formula:
Percent enzyme activity (%) = (OD dosing well-OD background)/(OD control well-OD background) ×100% parp1/2 trapping
Method 2: experimental protocol
Assay buffer composition: 10mM phosphate buffer (pH 7.9), 50mM NaCl,1mM EDTA,0.05%Brij-35,1mM DTT
Compound preparation: compounds were dissolved by DMSO and diluted in gradient. And diluting the compound to the test concentration by using an assay buffer, and vibrating for 15min by using a seismograph.
Enzyme preparation: PARP1/PARP2 enzyme was diluted to 4X using assay buffer while GST-TB was added. The prepared enzyme was added to the assay plate at 4 μl per well.
DSB DNA preparation: DSB DNA was diluted to 4X using assay buffer and 4 μl per well was added to the assay plate.
The test compounds were added to the assay plate at 4. Mu.L per well and incubated with enzymes etc. for 1 hour in a room temperature incubator.
NAD preparation: NAD was diluted to 4X using an assay buffer, 4. Mu.L per well was added to the assay plate and incubated for 10 minutes at room temperature.
And (3) detection: the final value is read by Envision 2105.
The experimental results are shown in Table 1
TABLE 1 test compounds at the enzyme level vs PARP-1 IC 50 values
Note that: + shows IC50 values at 50 nM; ++ showing IC50 values at 5nM
The compound of example 70 and the like are suggested to have higher inhibition or capturing capacity on PARP1 than AZD-9574.
EXAMPLE 117 proliferation inhibition of Compounds on human tumor cells
Cell preparation: DLD-1BRCA2 (-/-), UWB1.289, UWB1.289BRCA1+, MDA-MB-43, cells were cultured by ATCC recommended medium.
Compound preparation: compounds were dissolved by DMSO and diluted in gradient. 40nL of compound was transferred to the experimental plate by ECHO.
The appropriate cell density was selected for plating, 40. Mu.L was added evenly to the plates and incubated for 7 days in an incubator at 37 ℃.
The assay plate was left at room temperature for 30 minutes, 20. Mu.L of detection reagent (CELLTITER GLO ASSAY KIT) was added and incubated at room temperature for 30 minutes.
And (3) detection: the final value is read by Envision 2105.
Results: the compound of the embodiment has obvious inhibition effect on the tumor cells, and is obviously superior to AZD-2281 and AZD-9574.
TABLE 2 proliferation inhibition of test compounds on human tumor cells IC 50 values
Note that: + shows IC50 values at 500 nM; ++ shows IC50 values at 30 nM; ++ show IC50 value at 5 nM.
Example 118 rat pharmacokinetic test of Compounds of the invention
1. Purpose of test
The pharmacokinetic parameters of the compound were calculated by examining the drug concentration of inventive example 1 in plasma samples after intravenous and oral administration of inventive example 1, respectively, to male SD rats.
2. Materials and methods
2.1 Animal test
2.2 Reagents for test
In the embodiment 1 of the invention, the self-made part is made.
2.3 Formulations for administration
Intravenous and oral administration solutions were formulated:
5.383mg of the compound of example 1 of the present invention was weighed into an EP tube, and then 0.538mL of DMSO, 0.538mL of NMP, 1.615mL of Solutol and 8.075mL of physiological saline (ratio: 5:5:15:75, v/v/v/v) were added thereto, and vortexing was performed to sufficiently dissolve it, thereby obtaining a colorless clear solution having a final actual concentration of 0.500 mg.mL-1.
5.383mg×100％÷10.766mL＝0.500mg·mL-1
2.4 Laboratory animals
SD rats purchased from si Bei Fu (beijing) biotechnology limited, experimental animal production license number: SCXK (Beijing) 2019-0010. The laboratory animals were kept in the laboratory. Rat information is shown in table 3.
TABLE 3 rat information,
2.5 Animal test design
The rats were tested, 6 healthy SD rats were selected and divided into 2 groups of 3 rats each for oral and intravenous administration, 0h prior to administration, 0.0833 (i.e., intravenous only) after administration, about 0.25mL of whole blood was collected from the orbital venous plexus of the rats at 0.25,0.5,1,2,4,6,8 and 24 hours, placed in a centrifuge tube containing EDTA-K2 anticoagulation, and immediately after collection placed in crushed ice. Centrifuging at 2000g for 10min within 0.5 hr, packaging the whole blood plasma, and placing into another clean centrifuge tube. The actual blood taking time of the sample (containing 2 hours) within 2 hours is within +/-1 minute of the theoretical blood taking time, the actual blood taking time of the sample after two hours is within +/-5 minutes of the theoretical blood taking time, and the transport condition of the plasma sample is ice box transport. The rat test conditions are shown in Table 4.
Table 4 rat test conditions
Note that: m: male, male; r: rat, rat.
Oral and intravenous administration was performed according to the relevant SOP.
2.6 Collection of Whole blood samples
About 0.25mL of whole blood was collected from the orbital venous plexus of SD rats after administration according to the time points specified in the animal test design table, and placed in a 1.5mL centrifuge tube containing EDTA-K2. Centrifuging the collected whole blood at 2000g and 4deg.C for 10min, packaging the whole blood plasma, placing into another clean centrifuge tube, and immediately storing in a refrigerator at-20deg.C for testing.
3. Test results
The test results are shown in Table 5.
Table 5 pharmacokinetic parameters of example 1 in plasma after single oral administration of SD rats (5 mg. Kg -1, N=3)
Note that: f% = PO AUC 0～t_D_obs/Mean IV AUC0～t_D_obs ×100.
Results: example 70 compound rats were exposed to greater than AZD-9574 oral administration.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (11)
1. A compound of formula (I):
isomers, solvates, deuterated derivatives, and pharmaceutically acceptable salts thereof;
Wherein:
r 1 is hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, optionally substituted with deuterium;
R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 1-10 alkoxy, and optionally substituted with halogen, C1-C3 alkyl, C 1-10 alkoxy, deuterium;
R 3 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, which groups may be optionally substituted with deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
R 4 is hydrogen, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl, optionally substituted with deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
R 5 is hydrogen, C 1-10 alkyl, and when the carbon atom connected with R 5 is connected with 2 substituents, the carbon atom connected with the R 5 can form a 3-6 membered ring;
n is independently selected from 0, 1, 2 or 3.
2. The compound of claim 1, wherein the compound of formula (I) includes, but is not limited to, the following structures:
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-ethyl-5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) -6- (trifluoromethyl) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) -6- (difluoromethyl) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-chloro-N- (methyl-d 3) pyridine-2-carboxamide;
n- (methyl-d 3) 5- (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-chloro-N- (methyl-d 3 - (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-chloro-N- (methyl-d 3) -5- (4- ((2- (trifluoromethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
N- (methyl-d 3) -5- (4- ((3-oxo-2-propyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-chloro-N- (methyl-d 3) -5- (4- ((3-oxo-2-propyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-hydro-2-propyl-3, 4-dihydroquinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-2-ethyl-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
5- (4- ((2- (1, 1-difluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (2, 2-difluoroethyl) -3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (2, 2 difluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (2-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2- (2-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
n- (methyl-d 3) -5- (4- ((3-oxo-2- (2, 2-trifluoroethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6 oxy-N- (methyl-d 3) -5- (4- ((3-oxo-2- (2, 2-trifluoroethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-methyl-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N-methyl-5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
N- (methyl-d 3) -5- (4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-3-oxo-4H-oxin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-methyl-N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
N- (methyl-d 3) -5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N- (methyl-d 3) -5- (4- ((3-hydro-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-N-methyl-5- (4- ((3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-methoxy-3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine amide;
5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N-methylpyridine-2-carboxamide;
5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6- (difluoromethyl) -5- (4- (2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-methyl-5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d j) pyridine-2-carboxamide;
6-chloro-5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-chloro-5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-fluoropyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-methylpyridine-2-carboxamide;
5- (4- ((2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -6-methylpyridine-2-carboxamide;
6-chloro-5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
(R) -6-fluoro-5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
(S) -6-fluoro-5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
(R) -5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
(S) -5- (4- ((5-fluoro-2- (1-fluoroethyl) -3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (1, 1-difluoroethyl) -5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) -N-methylpyridine-2-carboxamide;
6-chloro-5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6- (difluoromethyl) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl-d 2) piperazin-1-yl) pyridine-2-carboxamide;
6-chloro-5- (4- ((2-methyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
n- (ethyl-2, 2-d 3) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
n- (ethyl-2, 2-d 3) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methylpyridine-2-carboxamide;
5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
4-chloro-5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-3-oxo-2- (trifluoromethyl) -4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6 chloro-5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2- (difluoromethyl) -5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-methoxy-3-hydro-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
5- (4- ((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -6-methyl-N- (methyl-d 3) pyridine-2-carboxamide;
6-fluoro-5- (4- ((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6- (difluoromethyl) -5- (4- (2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
6- (difluoromethyl) -5- (4- (2, 5-dimethyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
(S) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide;
(S) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide;
(S) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide;
(S) -5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N, 6-dimethylpyridine-2-carboxamide;
(S) -6-fluoro-N-methyl-5- (2-methyl-4- ((2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) piperazin-1-yl) pyridine-2-carboxamide;
(S) -5- (4- ((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
(S) -5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-N- (methyl-d 3) pyridine-2-carboxamide;
(S) -5- (4- ((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -6-fluoro-N-methylpyridine-2-carboxamide;
(R) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N- (methyl-d 3) pyridine-2-carboxamide or
(R) -6-fluoro-5- (4- ((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl) methyl) -2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide;
Isomers, solvates, deuterated derivatives, and pharmaceutically acceptable salts thereof.
3. A pharmaceutical composition comprising a compound, isomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any of claims 1-2.
4. The composition of claim 3, further comprising a pharmaceutically acceptable carrier, excipient, diluent, or combination thereof.
5. The pharmaceutical composition according to claim 4 for use in the treatment of cancer.
6. A pharmaceutical composition according to claim 5, wherein the cancer lacks an HR dependent DNADSB repair pathway.
7. The pharmaceutical composition of claim 5, wherein the cancer cell has a BRCA1 or BRCA2 deficient phenotype.
8. A pharmaceutical composition according to claim 5, wherein the cancer is heterozygous for a mutant line in a gene encoding a component of the HR dependent DNADSB repair pathway.
9. The pharmaceutical composition of claim 5, wherein the cancer is heterozygous for a mutant line in BRCA1 and/or BRCA 2.
10. The pharmaceutical composition according to claim 5, wherein the cancer cells include, but are not limited to, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, and lung cancer.
11. Use of a pharmaceutical composition according to claims 3-10 for the preparation of a medicament for the prevention or treatment of diseases related to PARP-1.
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