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WO2025168048A1 - Composé ayant une structure à triple liaison, et composition pharmaceutique associée et utilisation associée - Google Patents

Composé ayant une structure à triple liaison, et composition pharmaceutique associée et utilisation associée

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Publication number
WO2025168048A1
WO2025168048A1 PCT/CN2025/076194 CN2025076194W WO2025168048A1 WO 2025168048 A1 WO2025168048 A1 WO 2025168048A1 CN 2025076194 W CN2025076194 W CN 2025076194W WO 2025168048 A1 WO2025168048 A1 WO 2025168048A1
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Prior art keywords
mmol
compound
heteroatoms
alkyl
partially unsaturated
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Pending
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PCT/CN2025/076194
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English (en)
Chinese (zh)
Inventor
许祖盛
夏林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Yingli Pharmaceutical Co Ltd
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Shanghai Yingli Pharmaceutical Co Ltd
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Publication of WO2025168048A1 publication Critical patent/WO2025168048A1/fr
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • C07D221/12—Phenanthridines
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a triple-bond structure compound, a pharmaceutical composition thereof and application thereof.
  • PARP poly(ADPribose) polymerase family
  • PARP is overexpressed in diseases such as tumors, inflammation-related diseases, autoimmune diseases, neurodegenerative diseases, and metabolic stress.
  • diseases such as tumors, inflammation-related diseases, autoimmune diseases, neurodegenerative diseases, and metabolic stress.
  • PARP inhibitors can produce a synergistic lethal effect on tumors with breast cancer susceptibility gene (BRCA) mutations. They can target tumor cells with homologous recombination repair (HRR) defects, thereby killing tumor cells more effectively.
  • BRCA mutations were first discovered in ovarian cancer and breast cancer. Prostate cancer and pancreatic cancer are also related to BRCA gene mutations.
  • PARP inhibitors are expected to become ideal drugs for cancer treatment and have broad research significance. In recent years, several PARP inhibitors have been approved by the FDA for the treatment of tumors. These marketed PARP inhibitors have low selectivity. While inhibiting PARP-1, they also affect PARP-2, and all have significant adverse reactions. Studies have found that the loss of PARP-2 shortens the lifespan of mouse red blood cells and impairs the differentiation of erythroid progenitor cells, leading to chronic anemia. Ischemic damage can cause neuronal damage, and chemical damage makes pancreatitis more likely to occur. In addition, spermatogenesis, adipogenesis, and thymogenesis are also impaired in PARP-2 single knockout mice.
  • the technical problem to be solved by the present invention is to provide a highly selective inhibitor that not only meets the requirements of tumor treatment but also helps to reduce the adverse reactions caused by the inhibition of PARP-2.
  • the present invention provides a triple-bond structure compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a crystal form thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof:
  • D 1 is CL D1 -R 6 , N, NR or S;
  • D 2 is absent, CL D2 -R 7 or N, wherein when D 1 is S or NR, D 2 is absent;
  • D 3 is CL D3 -R 8 or N;
  • D 4 is absent, O, S, N, NR 4 or -C(R 4 R 5 );
  • D 5 is CL D5 -R 9 or N;
  • R 1 is hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 1-6 alkyl substituted by one or more halogens;
  • Ring A is phenyl, "3-8 membered cycloalkenyl", “3-8 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S” or "5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S";
  • R 1 and R 4 are independently hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 1-6 alkyl substituted by one or more halogens; or, R 4 and L D1 -R 6 together with the carbon atom to which they are attached form an optionally substituted phenyl or a "5-6 membered aryl group containing 1-4 heteroatoms independently selected from O, N, and S";
  • M is -NR a -, R 5 and Ra are absent, and R 4 is hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 1-6 alkyl substituted by one or more halogens;
  • D 4 is NR 4
  • R 1 and R 2 are independently hydrogen, halogen, C 1-6 alkyl, -CN, -OR, -SR, -N(R) 2 , -NO 2 , -COOR, -C(O)N(R) 2 , -OC(O)R', -OC(O)N(R) 2 , -OC(O)OR, -OSO 2 R', -OSO 2 N(R) 2 , -N(R)C(O)R', -S(O)R', -S(O) 2 R', -SO 2 N(R) 2 , -SO 3 R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) 2 , -NRC(
  • Ring A' is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from O, N and S;
  • R a is hydrogen or
  • L R3 is a connecting bond or a C 1-6 alkylene group
  • R3 is hydrogen or an optionally substituted C1-6 alkyl group, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclyl group, a 6-10 membered saturated or partially unsaturated bicyclic carbocyclyl group, a phenyl group, an 8-10 membered bicyclic aryl group, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclyl group containing 1-3 heteroatoms independently selected from O, N and S, a 6-10 membered saturated or partially unsaturated bicyclic heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S, a 5-6 membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S, or an 8-10 membered bicyclic heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S;
  • R 4 and R 5 are independently hydrogen, halogen, -CN, -OR, -SR, -N(R) 2 , -NO 2 , -C(O)R', -COOR, -C(O)N(R) 2 , -OC(O)R', -OC(O)N(R) 2 , -OC(O)OR, -OSO 2 R', -OSO 2 N(R) 2 , -N(R)C(O)R', -S(O)R', -S(O) 2 R', -SO 2 N(R) 2 , -SO 3 R', -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) 2 , -NRC(O)N(R) 2 , -NRS(O)N(R) 2 , -NRS(O)R', -NRS(O) 2 N(R
  • RL is hydrogen, -CN, -OR L1 or an optionally substituted C 1-6 alkyl group
  • RL1 is hydrogen, C1-6 alkyl or halogen-substituted C1-6 alkyl
  • Each L is independently a linking bond, a C 1-6 alkylene group, or a C 1-6 alkylene group substituted by one or more halogens;
  • L D1 , L D2 , L D3 and L D5 are independently a connecting bond or an optionally substituted C 1-6 alkylene group;
  • X is a linking bond, -C(O)-, O or NR x ;
  • R x is hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
  • Ring C is C 6-10 aryl, "3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, N and S", “5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S”, “9-10 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from O, N and S" or dihydropyridinyl;
  • each R C1 is independently hydrogen, oxo, halogen, -CN, -OR, -SR, -N(R) 2 , -N + (R) 3 , -NO 2 , -C(O)R′, -COOR, -C(O)N(R) 2 , -OC(O)R′, -OC(O)N(R) 2 , -OC(O)OR, -OSO 2 R′, -OSO 2 N(R) 2 , -N(R)C(O)R′, -N(R)SO 2 R′, -S(O)R′, -S(O) 2 R′, -SO 2 N(R) 2 , -SO 3 R′, -NHOR, -C(O)NR(OR), -NRC(O)OR, -NRC(O)N(R) 2 , -C( ⁇ NR m )NR′, -C( ⁇ NR m )N
  • Each R is independently hydrogen, C 1-6 alkyl, -OC 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S” or "4-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", said C 1-6 alkyl, -OC 1-6 alkyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, 6-8 membered saturated or partially unsaturated bicyclic carbocyclic group, "3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S” or "4-10 membered saturated or partially unsaturated heterobicyclic group containing
  • Each R' is independently an optionally substituted or unsubstituted C1-6 alkyl group, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, a 6-10 membered saturated or partially unsaturated bicyclic carbocyclic group, a "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, which are independently selected from O, N and S", a "6-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms, which are independently selected from O, N and S", a "5-6 membered heteroaryl group containing 1-4 heteroatoms, which are independently selected from O, N and S", or a "8-10 membered bicyclic heteroaryl group containing 1-4 heteroatoms, which are independently selected from O, N and S", or,
  • R' and the N atom to which they are connected form a "3-7 membered saturated or partially unsaturated monoheterocyclic group containing 1-3 heteroatoms, one of which is N, and the other heteroatoms are independently selected from O, N and S";
  • Each R m is independently -OH, -CN or R;
  • p and n are independently 0, 1, 2 or 3;
  • D1 is CL D1 - R6 or N
  • D 4 is absent, O, S, N, NR 4 or -C(R 4 R 5 );
  • R 1 is hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 1-6 alkyl substituted by one or more halogens;
  • R 1 and R 4 are independently hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 1-6 alkyl substituted by one or more halogens; or, R 4 and L D1 -R 6 together with the carbon atom to which they are attached form an optionally substituted phenyl or a "5-6 membered aryl group containing 1-4 heteroatoms independently selected from O, N, and S";
  • Ring C is C 6-10 aryl, "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S" or dihydropyridyl;
  • RC is -LC- RC1 ;
  • Each L C is independently a linking bond, a C 1-6 alkylene group, or a C 1-6 alkylene group substituted by one or more halogen groups;
  • Each R C1 is independently hydrogen, oxo, halogen, -CN, -N(R) 2 , -OC 1-6 alkyl, -C(O)N(R) 2 , C 1-6 alkyl substituted by one or more halogens, "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S", or the above groups are optionally substituted by any of the following groups: C 1-6 alkyl;
  • each R is independently hydrogen, C 1-6 alkyl, C 6-10 aryl, -OC 1-6 alkyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group, "a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from O, N and S", "a 4-10 membered saturated or partially unsaturated heterobicyclic group containing 1-4 heteroatoms independently selected from O, N and S", and the C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic group is optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkyl substituted with cyano, -OC 1-6 alkyl, C 3-8 cycloalkyl and C 1-6 alkyl substituted with hydroxy ;
  • n 0, 1, or 2;
  • p and n are independently 0, 1 or 2;
  • q 0, 1, 2, or 3.
  • D 1 is CL D1 -R 6 or N;
  • D 2 is CL D2 -R 7 or N;
  • D 3 is CL D3 -R 8 ;
  • D 4 is absent, O, S, N, NR 4 or -C(R 4 R 5 );
  • R 1 is C 1-6 alkyl or C 1-6 alkyl substituted by one or more halogens;
  • Ring A is phenyl, "3-8 membered cycloalkenyl” or “5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S"; m is 0, 1 or 2, L is a linker or C 1-6 alkylene, RA1 is C 1-6 alkyl, C 1-6 alkyl substituted by one or more halogens, or halogen;
  • R 1 and R 4 are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 1-6 alkyl substituted by one or more halogens;
  • M is -NR a -, R 5 and Ra are absent, and R 4 is C 1-6 alkyl;
  • M is -C(R 1 R 2 )- or -N(R a )-, D 4 is O or -C(R 4 R 5 );
  • R 1 and R 2 are independently hydrogen or C 1-6 alkyl;
  • R a is C 3-8 cycloalkyl;
  • R 4 and R 5 are independently hydrogen;
  • L D1 , L D and L D3 are independently connecting bonds
  • R 6 , R 7 and R 8 are independently hydrogen or halogen
  • X is a linking bond, -C(O)-, O or NR x ;
  • RC is -LC- RC1 ;
  • Each R C1 is independently hydrogen, oxo, halogen, -CN, -N(R) 2 , -C(O)N(R) 2 , "5-12 membered heteroaryl containing 1-3 heteroatoms independently selected from O, N and S", or the above groups are optionally substituted by any of the following groups: C 1-6 alkyl;
  • the present invention also provides a use of the aforementioned triple-bond structure compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its solvate of a pharmaceutically acceptable salt, its crystal form, its stereoisomer, its tautomer or its isotope compound in the preparation of PARP inhibitor drugs.
  • the C 3-8 cycloalkyl group may be a C 3-6 cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • YL230769-269 8300 mg, 25.751 mmol
  • 10% palladium on carbon 4100 mg, 38.527 mmol
  • ethanol 60 mL
  • the reaction solution was filtered, and the filtrate was concentrated to yield YL230769-270 (4800 mg, 16.307 mmol, 63.33%).
  • YL230769-272 (3900 mg, 15.708 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4278.88 mg, 18.850 mmol), and 1,4-dioxane (65 mL) were added in sequence. Under nitrogen, the mixture was reacted at 110°C for 3 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated, and then saturated aqueous sodium bicarbonate solution was added. The mixture was filtered and the filter cake was dried to obtain YL230769-274 (2440 mg, 9.908 mmol, 63.07%). LC-MS (ESI): m/z 247.2 (M+H) + .
  • YL230769-274 (2440 mg, 9.908 mmol) and tetrahydrofuran (50 mL) were added sequentially. Under nitrogen, the mixture was cooled to 0°C, and then lithium aluminum tetrahydride solution (19.816 mL, 19.816 mmol) was slowly added dropwise. The reaction was continued at this temperature for 1 hour. LCMS indicated the reaction was complete.
  • Zinc powder 54.57 g, 834.631 mmol
  • YL230783-167-A 33.5 g, 104.329 mmol
  • ammonium chloride 44.64 g, 834.631 mmol
  • methanol 360 mL
  • water 18 mL
  • the remaining solid residue was filtered and rinsed with a large amount of methanol:dichloromethane (1:5) solution.
  • the filtrate was concentrated and then diluted with ethyl acetate and water.
  • the organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • YL230783-171-A (29.5 g, 113.864 mmol) was dissolved in dichloromethane (1100 mL), and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (31.02 g, 136.637 mmol) was added all at once. The reaction was continued at room temperature for 2 hours. After the reaction was completed, the reaction solvent was removed by evaporation, and a large amount of saturated sodium bicarbonate was added to quench the reaction. The mixture was stirred at room temperature overnight and filtered. The filter cake was rinsed with a large amount of water and then with diethyl ether.
  • YL230783-172-A (10 g, 38.901 mmol) and XPhos Pd G2 (1.53 g, 1.945 mmol) were dissolved in 1,2-dioxane (200 mL) at room temperature and replaced with nitrogen. (tributyltin)methanol (14.99 g, 46.682 mmol) was then added and replaced with nitrogen again. The temperature was then raised to 80°C for 11 hours. After completion of the reaction, the solvent was removed by rotary evaporation.
  • YL230783-173-A (3.05 g, 14.650 mmol) was dissolved in HBr-H2O (48%, 600 mL) at room temperature and then heated to 80°C for 3 days. After the reaction, the remaining reaction solvent was removed, ethyl acetate and water were added for dilution, and the mixture was filtered. The filtrate was extracted again with a large amount of ethyl acetate. The organic phases were combined, washed with water and saturated NaCl, and the organic layer solvent was dried. The residue was re-added with a large amount of ethyl acetate and acetonitrile, sonicated, and filtered.
  • YL230804-108-A1 (1.40 g, 4.86 mmol) was added to a concentrated H 2 SO 4 solution (15 mL) and allowed to react at room temperature for 2 hours. The reaction solution was cooled to 0°C, and then the aqueous solution was slowly added dropwise. A white solid precipitated, which was filtered and the filter cake was vacuum dried to obtain YL230774-451 (1.00 g, 85.02% yield).
  • triphenylphosphine (0.29 g, 1.09 mmol) and Pd(Ph3P) 2Cl2 (0.43 g, 0.55 mmol) were added to a mixture of YL230774-405 (5.00 g, 18.23 mmol), pinacol diboron (5.09 g, 20.06 mmol), and potassium carbonate (3.78 g, 27.35 mmol) in 1,4-dioxane (100 mL). The mixture was heated to 80°C for 5 hours. The reaction mixture was filtered through a celite filter cake, and the filtrate was concentrated and dried in vacuo to yield YL230774-407 (5.00 g, crude product).
  • Trifluoromethanesulfonic anhydride (10.92 g, 38.69 mmol) was slowly added to a solution of methyl 2-oxocyclopentane-1-carboxylate (5.00 g, 35.17 mmol) and DIEA (6.82 g, 52.76 mmol) in dichloromethane (70 mL) at -78°C. The mixture was stirred for 0.5 hours after addition, then warmed to room temperature and reacted for 1.5 hours. The reaction mixture was quenched with water, and the organic phase was separated and concentrated.
  • XPhos Pd G2 (1.15 g, 1.46 mmol) was added to a mixture of YL230774-405 (4.00 g, 14.59 mmol), (4-(methoxycarbonyl)-2-nitrophenyl)boronic acid (3.94 g, 17.50 mmol), and cesium carbonate (9.51 g, 29.17 mmol) in 1,4-dioxane (80 mL). The mixture was heated to 80°C for 4 hours.
  • Lithium aluminum hydride (1.6 mL, 1 M) in tetrahydrofuran (THF) was added dropwise to a solution of YL230774-411 (200 mg, 0.82 mmol) in THF (10 mL) in an ice-water bath at 0°C.
  • the reaction was maintained at 0°C for 1.5 hours.
  • the reaction mixture was quenched at 0°C with 1 drop of water, followed by 3 drops of sodium hydroxide solution.
  • anhydrous sodium sulfate (0.1 g, Na2SO4 ) was added and stirred for 30 minutes. The mixture was filtered, and the filter cake was rinsed with THF several times.
  • YL230804-039-A (29.3 g, 96.978 mmol) was dissolved in tetrahydrofuran (120 mL) and water (120 mL). The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Sodium periodate (45.63 mL, 213.352 mmol) was added and allowed to react at room temperature for 2 hours. The reaction mixture was quenched with aqueous sodium thiosulfate, diluted with water, and extracted with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate , filtered, and evaporated to dryness to obtain compound YL230804-045-A (25.2 g, 99.57%).
  • YL230804-045-A (25.2 g, 96.541 mmol) was dissolved in ethanol (250 mL), and ethyl 3,3-diethoxypropionate (73.46 g, 386.163 mmol) and stannous chloride (91.53 g, 482.703 mmol) were added. The mixture was allowed to react at 80°C overnight. The reaction mixture was spin-dried and poured into aqueous sodium bicarbonate . Extraction was performed with ethyl acetate.
  • YL230804-046-A (1.9 g, 6.107 mmol) was dissolved in 1,4-dioxane (20 mL), and (tributyltin)methanol (2.16 g, 6.717 mmol) and XPhos Pd G2 (38 mg, 0.048 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed overnight at 80°C.
  • YL230804-051-A (0.8 g, 3.074 mmol) was dissolved in tetrahydrofuran (15 mL).
  • Bis(2-methoxyethyl)aminosulfur trifluoride (2.72 g, 12.296 mmol) was added at 0°C and allowed to react at 50°C for 2 hours.
  • the reaction solution was diluted with saturated aqueous ammonium chloride and ethyl acetate.
  • the organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • YL230783-189-A (1.6 g, 6.318 mmol) and anhydrous tetrahydrofuran (340 mL) were added to the reaction flask, and the mixture was cooled to 0°C.
  • a 1 M solution of lithium aluminum hydride in tetrahydrofuran (15.8 mL, 15.794 mmol) was then slowly added. The mixture was stirred at 0°C for 1.5 hours.
  • the mixture was quenched with 20 mL of ethyl acetate, followed by the addition of 5 mL of water.
  • the resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness.
  • YL230783-192-A 500 mg, 2.220 mmol
  • dichloromethane 110 mL
  • DMF 0.018 mL, 0.222 mmol
  • the atmosphere was replaced with nitrogen and the temperature was lowered to 0°C.
  • thionyl chloride 1584.37 mg, 13.319 mmol was slowly added dropwise. After the addition, the mixture was heated to room temperature and stirred for 1 hour.
  • YL230804-145-A1 (1 g, 3.636 mmol) was dissolved in 1,4-dioxane (15 mL), and (tributyltin)methanol (1.28 g, 3.999 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G2) (0.14 g, 0.182 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 80°C overnight.
  • YL230769-377 (3130 mg, 9.902 mmol), sodium hydroxide (594.10 mg, 14.852 mmol), and N,N-dimethylacetamide (30 mL) were added sequentially. Under nitrogen, the mixture was allowed to react at room temperature for 1 hour. The temperature was then raised to 120°C and allowed to react for 18 hours. LCMS indicated the reaction was complete.
  • methyl cyclopropylacetate 210.41 mg, 1.642 mmol
  • tetrahydrofuran 10 mL
  • the mixture was cooled to -78°C, followed by the addition of lithium bis(trimethylsilylamide) (3.830 mL).
  • the reaction was continued at this temperature for 30 minutes, followed by the addition of YL230769-405 (220 mg, 1.094 mmol).
  • the reaction was continued at -78°C for 30 minutes, then the temperature was slowly raised to room temperature and the reaction was continued for 18 hours.
  • XPhos Pd G2 (Cas: 1310584-14-5, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)) (72 mg, 0.091 mmol) was added to a solution of YL230774-387 (250 mg, 0.909 mmol) and (tributyltin)methanol (350 mg, 1.09 mmol) in 1,4-dioxane (5 mL). The mixture was heated to 80°C for 2 hours.
  • Methyl 2-pyrrolidine (2 g, 15.984 mmol), 1-bromo-2,4-difluoro-3-nitrobenzene (4.18 g, 17.582 mmol), and cesium carbonate (11.46 g, 35.164 mmol) were dissolved in DMF (60 mL) at room temperature and reacted for 5 hours.
  • the mixture was diluted with ethyl acetate and water, and the organic phase was separated.
  • the aqueous phase was extracted with ethyl acetate.
  • the organic phases were combined, washed with a saturated sodium chloride solution and then with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • YL230784-484-C1 2000 mg, 5.600 mmol
  • acetic acid 20 mL
  • iron powder 1563 mg, 28.001 mmol
  • the mixture was heated to 75°C under nitrogen and reacted for 3 hours.
  • the mixture was filtered, rinsed with a large amount of methanol, and the filter cake was slurried with methanol.
  • the mixture was filtered, the filtrates were combined, concentrated to dryness under reduced pressure, slurried with methanol, filtered, and dried under vacuum to obtain YL230784-485-C1 (1.3 g, 4.625 mmol, 82.59%).
  • YL230784-485-C1 500 mg, 1.779 mmol
  • dioxane 10 mL
  • (tributyltin)methanol 685 mg, 2.135 mmol
  • chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) 140 mg, 0.178 mmol
  • YL230784-492-C1 50 mg, 0.215 mmol
  • dichloromethane 5 mL
  • N,N-dimethylformamide 0.05 mL
  • the mixture was cooled to 0°C under nitrogen and thionyl chloride (153 mg, 1.292 mmol) was added dropwise.
  • the mixture was then allowed to react at room temperature overnight.
  • the mixture was quenched with saturated sodium bicarbonate and extracted with dichloromethane.
  • the organic phase was separated and the aqueous phase was extracted with dichloromethane.
  • YL230769-283 (111 mg, 0.498 mmol), N-methylpropargylamine (41.34 mg, 0.598 mmol), potassium iodide (16.55 mg, 0.100 mmol), N,N-diisopropylethylamine (322.15 mg, 2.492 mmol), and acetonitrile (10 mL) were added sequentially. Under nitrogen, the mixture was reacted at 80°C for 2 hours. LCMS indicated a successful reaction.
  • N-methyl-5-bromopicolinamide (645 mg, 2.999 mmol), N-tert-butoxycarbonylaminopropyne (558.59 mg, 3.599 mmol), cuprous iodide (1142.43 mg, 5.999 mmol), potassium iodide (497.88 mg, 2.999 mmol), N,N-diisopropylethylamine (1938.30 mg, 14.997 mmol), tetrakistriphenylphosphine palladium (693.19 mg, 0.600 mmol), and N,N-dimethylformamide (20 mL).
  • YL230769-315 45.87 mg, 0.2424 mmol
  • YL230769-283 45 mg, 0.202 mmol
  • N,N-diisopropylethylamine 52.22 mg, 0.404 mmol
  • potassium iodide 6.71 mg, 0.040 mmol
  • acetonitrile 3 mL
  • YL230769-316 140 mg, 0.491 mmol
  • 3-bromopropyne 70.06 mg, 0.589 mmol
  • potassium carbonate 101.74 mg, 0.736 mmol
  • potassium iodide 16.29 mg, 0.098 mmol
  • acetonitrile 10 mL
  • YL230769-317 47 mg, 0.145 mmol
  • N-methyl-5-bromopicolinamide 37.51 mg, 0.174 mmol
  • cuprous iodide 55.37 mg, 0.291 mmol
  • potassium iodide 24.13 mg, 0.145 mmol
  • N,N-diisopropylethylamine 93.94 mg, 0.727 mmol
  • tetrakistriphenylphosphine palladium 33.60 mg, 0.029 mmol
  • N,N-dimethylformamide 5 mL
  • cuprous iodide 89 mg, 0.47 mmol
  • Pd(Ph3P)2Cl2 181 mg, 0.23 mmol
  • 5-bromo-N-methylpicolinamide 500 mg, 2.33 mmol
  • prop-2- en -1- ol 0.15 mL, 2.56 mmol
  • triethylamine 5 mL
  • the reaction mixture was heated to 70°C for 2 hours.
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • YL230769-283 100 mg, 0.449 mmol
  • cyclopropylamine 256 mg, 4.491 mmol
  • DIEA 116.1 mg, 0.898 mmol
  • potassium iodide 15 mg, 0.09 mmol
  • Acetonitrile (2 mL) was added, the atmosphere was replaced with nitrogen, and the reaction was carried out at 80°C for 2 hours.
  • YL230804-031-A (90 mg, 0.370 mmol), 3-bromopropyne (44 mg, 0.370 mmol), and potassium carbonate (102 mg, 0.740 mmol) were added to a reaction flask.
  • DMF 3 mL
  • YL230804-033-1 (55 mg, 0.195 mmol), N-methyl-5-bromopicolinamide (46.1 mg, 0.215 mmol), cuprous iodide (74.5 mg, 0.391 mmol), DIEA (126.3 mg, 0.977 mmol) and tetrakis(triphenylphosphine)palladium (45.2 mg, 0.039 mmol) were added to a reaction flask, and DMF (5 mL) was added. The atmosphere was replaced with nitrogen, and the mixture was reacted at 100° C. for 1.5 hours.
  • Potassium iodide (6 mg, 0.038 mmol) was added to a solution of YL230783-142 (40 mg, 0.19 mmol), N-methyl-2-propyn-1-amine (16 mg, 0.23 mmol), and DIEA (N-ethyl-N-isopropylpropan-2-amine) (73 mg, 0.57 mmol) in acetonitrile (4 mL). The mixture was heated to 80°C for 2 hours.
  • YL230783-174-A 550 mg, 2.029 mmol
  • potassium iodide 168.39 mg, 1.014 mmol
  • acetonitrile 120 mL
  • N,N-diisopropylethylamine 1311.14 mg, 10.144 mmol
  • N-methylpropargylamine 280.43 mg, 4.058 mmol
  • YL230783-175-A 200 mg, 0.771 mmol
  • YL230774-364-A1 197.74 mg, 0.849 mmol
  • copper iodide 293.81 mg, 1.543 mmol
  • potassium iodide (128.05 mg, 0.771 mmol
  • tetrakistriphenylphosphine palladium 178.28 mg, 0.154 mmol
  • the temperature was then raised to 100°C and the reaction was allowed to react for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated NaCl, dried over anhydrous Na2SO4 , filtered, and evaporated to dryness.
  • YL230783-175-A 150 mg, 0.579 mmol
  • 4-iodobenzene-1-carbonitrile 158.99 mg, 0.694 mmol
  • copper iodide 220.36 mg, 1.157 mmol
  • potassium carbonate 319.81 mg, 2.314 mmol
  • potassium iodide (128.05 mg, 0.771 mmol
  • allylpalladium(II) chloride dimer 42.34 mg, 0.116 mmol
  • the organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • the organic phases were combined, washed with water and saturated NaCl, dried over anhydrous Na2SO4 , filtered, and evaporated to dryness.
  • the crude product was purified (Welch Xtimate C18, 21.2*250mm, 10um, water (10mM trifluoroacetic acid)/acetonitrile, flow rate 30mL/min, column temperature 25°C, detection wavelength 254nm), neutralized with saturated sodium bicarbonate under ice bath, and then extracted with ethyl acetate.
  • the temperature was then raised to 100°C and the reaction was allowed to react for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated NaCl, dried over anhydrous Na2SO4 , filtered, and evaporated to dryness.
  • YL230783-180-A 300 mg, 1.135 mmol
  • dichloromethane (30 mL) 30 mL
  • trifluoroacetic acid 1.5 mL
  • the mixture was diluted with dichloromethane and water and extracted. Since the target product was highly water-soluble and almost completely dissolved in the aqueous layer, the aqueous phase was lyophilized to directly obtain the target compound YL230783-183-A as an oil.
  • YL230783-174-A 120 mg, 0.443 mmol
  • YL230783-183-A 72.68 mg, 0.443 mmol
  • potassium iodide 73.48 mg, 0.443 mmol
  • acetonitrile 20 mL
  • N,N-diisopropylethylamine 286.07 mg, 2.213 mmol
  • YL230774-374 (200 mg, 0.76 mmol) was added to a 4 M 1,4-dioxane hydrochloride solution (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain YL230774-376 (150 mg, 98.76% yield).
  • Tetraethoxytitanium 44 mg, 0.19 mmol was added to a mixture of YL230774-376 (40 mg, 0.19 mmol) and YL230774-366 (47 mg, 0.23 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (164 mg, 0.78 mmol) was added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was quenched with methanol, concentrated under reduced pressure, and purified by preparative HPLC ( NH4HCO3 ) to give YL230774-377 (15 mg, yield 21.82%).
  • YL230769-274 100 mg, 0.449 mmol
  • acetonitrile 5 mL
  • N-methylpropargylamine 46 mg, 0.674 mmol
  • potassium iodide 15 mg, 0.090 mmol
  • N,N-diisopropylethylamine 290 mg, 2.245 mmol
  • the mixture was heated to 80°C for 2 hours.
  • the mixture was diluted with water and ethyl acetate, and the layers were separated.
  • the aqueous layer was extracted twice with ethyl acetate.
  • the combined organic phases were washed with brine, dried, and concentrated under reduced pressure.
  • YL230784-300-C1 100 mg, 0.422 mmol
  • dioxane 5 mL
  • di-tert-butyl dicarbonate 276 mg, 1.265 mmol
  • 4-dimethylaminopyridine 10 mg, 0.084 mmol
  • YL230784-310-C1 110 mg, 0.326 mmol
  • triethylamine 6 mL
  • dimethyl sulfoxide 1 mL
  • YL230784-300-C1 83 mg, 0.326 mmol
  • cuprous iodide 12 mg, 0.065 mmol
  • bistriphenylphosphine palladium dichloride 22 mg, 0.033 mmol
  • YL230784-294-C1 (6.15 g, 21.419 mmol), tetrahydrofuran (30 mL) and potassium tert-butoxide (2.64 g, 23.561 mmol) were added in sequence, and the temperature was raised to 60° C. under nitrogen protection for reaction for 2 days.
  • the reaction solution was quenched by adding 1 M citric acid solution and filtered.
  • YL230784-327-C1 55 mg, 0.155 mmol
  • triethylamine 3 mL
  • dimethyl sulfoxide 0.5 mL
  • YL230784-300-C1 59 mg, 0.232 mmol
  • cuprous iodide 6 mg, 0.031 mmol
  • bistriphenylphosphine palladium dichloride 12 mg, 0.015 mmol
  • YL230784-329-C1 45 mg, 0.085 mmol
  • dichloromethane 3 mL
  • trifluoroacetic acid 1 mL
  • YL230804-031-A (90 mg, 0.370 mmol), 3-bromopropyne (44 mg, 0.370 mmol), and potassium carbonate (102 mg, 0.740 mmol) were added to a reaction flask.
  • DMF 3 mL
  • YL230804-082-A (20 mg, 0.069 mmol) was dissolved in acetonitrile (2 mL), and YL230774-417-A (21 mg, 0.104 mmol), N,N-diisopropylethylamine (45 mg, 0.346 mmol), and potassium iodide (1.15 mg, 0.007 mmol) were added. The mixture was reacted at 80°C for 2 hours. The reaction solution was dried to obtain compound YL230804-085-A (5.8 mg).
  • YL230804-066-A (620 mg, 2.278 mmol) was dissolved in ethanol (8 mL), and hydrazine hydrate (402 mg, 6.835 mmol, 85%) was added. The atmosphere was replaced with nitrogen and the reaction was carried out at 70°C for 2 hours. The reaction solution was cooled to room temperature and poured into ice water, whereupon a white solid precipitated. The resulting solid was filtered, washed with water, filtered again, and evaporated to dryness to obtain compound YL230804-068-A (500 mg, 89.22%).
  • YL230804-068-A 500 mg, 2.074 mmol was dissolved in tetrahydrofuran (10 mL), replaced with N2 , and cooled to 0°C.
  • Sodium hydride 125 mg, 3.111 mmol was added and allowed to react at room temperature for 0.5 h.
  • 2-(Trimethylsilyl)ethoxymethyl chloride 520 mg, 3.111 mmol was added and allowed to react at room temperature for 2 h.
  • the reaction solution was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with ethyl acetate.
  • YL230804-084-A (620 mg, 1.675 mmol) was dissolved in N,N-dimethylformamide (10 mL), and tert-butyl methyl(prop-2-yn-1-yl)carbamate (425 mg, 2.513 mmol), cuprous iodide (638 mg, 3.35 mmol), N,N-diisopropylethylamine (1.08 g, 8.375 mmol), tetrakistriphenylphosphine palladium (387 mg, 0.335 mmol), and sodium iodide (50 mg, 0.335 mmol) were added. The reaction was allowed to react at 120°C for 6 hours.
  • YL230804-125-A (40 mg, 0.146 mmol) was dissolved in 1,4-dioxane (0.5 mL) and water (0.1 mL).
  • YL230774-467-A1 (21 mg, 0.104 mmol), cesium carbonate (143 mg, 0.438 mmol), XPHOS (14 mg, 0.029 mmol), and palladium acetate (3.3 mg, 0.015 mmol) were added and reacted at 100°C for 1 hour.
  • the reaction solution was dried and purified by normal phase column chromatography to obtain compound YL230804-130-A (YL-27054) (3.2 mg).
  • ESI: (m/z) 411.3 [M+H] + .
  • YL230804-125-A (40 mg, 0.146 mmol) was dissolved in 1,4-dioxane (0.5 mL) and water (0.1 mL).
  • YL230774-473-A1 (189 mg, 0.438 mmol, 79%), cesium carbonate (143 mg, 0.438 mmol), XPHOS (14 mg, 0.029 mmol), and palladium acetate (3.3 mg, 0.015 mmol) were added and reacted at 100°C for 1 hour.
  • the reaction solution was dried and purified by normal phase column chromatography and preparative chromatography to obtain compound 20 (5.3 mg).
  • ESI: (m/z) 429.2 [M+H] + .
  • YL230804-125-A 400 mg, 1.022 mmol, 70% purity
  • 1,4-dioxane 8 mL
  • (tributyltin)methanol 360 mg, 1.124 mmol
  • XPhos Pd G2 11.5 mg, 0.015 mmol
  • the atmosphere was purged with nitrogen and the reaction was allowed to proceed at 80°C overnight.
  • the reaction solution was extracted with ethyl acetate and water.
  • YL230804-082-A (20 mg, 0.082 mmol), YL230783-234-A (19 mg, 0.086 mmol), N,N-diisopropylethylamine (32 mg, 0.246 mmol) and potassium iodide (1.3 mg, 0.008 mmol) were added to a reaction flask, acetonitrile (2 mL) was added, the nitrogen atmosphere was replaced, and the reaction was carried out at 80° C. for 2 hours.
  • YL230804-145-A1 (1 g, 3.636 mmol) was dissolved in 1,4-dioxane (15 mL), and (tributyltin)methanol (1.28 g, 3.999 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Xphos Pd G2) (0.14 g, 0.182 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 80°C overnight.
  • YL230804-152-A 200 mg, 0.727 mmol was dissolved in 1,4-dioxane (10 mL), and (tributyltin)methanol (257 mg, 0.800 mmol) and Xphos Pd G2 (28.5 mg, 0.036 mmol) were added. The atmosphere was purged with nitrogen and the reaction was allowed to proceed overnight at 80°C. Ethyl acetate and water were added, the layers separated, and the aqueous phase was extracted with ethyl acetate.
  • YL230804-161-A (100 mg, 0.444 mmol) was dissolved in dichloromethane (8 mL), and 1 drop of DMF was added. The atmosphere was replaced with nitrogen ( N2 ), and the temperature was lowered to 0°C. Thionyl chloride ( 315 mg, 2.653 mmol) was added, and the reaction was allowed to react at room temperature overnight. The reaction solution was cooled to 0°C, neutralized with saturated aqueous sodium bicarbonate, and extracted with dichloromethane/methanol (10/1).
  • YL230784-361 500 mg, 1.670 mmol
  • dioxane 5 mL
  • dioxane hydrochloride solution 5 mL
  • the reaction solution was concentrated under reduced pressure, neutralized by adding ammonia methanol solution, and concentrated under reduced pressure to obtain the crude product YL230784-367-C1 (465 mg, 2.334 mmol, 139.72%); LC-MS (ESI): m/z 200.2 (M+H) + ;
  • Methyl 5-bromo-6-fluoropicolinate 500 mg, 2.137 mmol was dissolved in a solution of methanol (10 mL) and water (10 mL). Potassium hydroxide (240 mg, 4.273 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3-4 by adding dilute hydrochloric acid (2 M). The solution was extracted several times with a mixture of dichloromethane and methanol. The organic phase was separated, concentrated, and dried under vacuum to obtain compound YL230804-167-A (520 mg, crude product); LC-MS (ESI): m/z 218.0 (M+H) + ;
  • YL230804-167-A (520 mg, 2.364 mmol) was dissolved in DMF (10 mL), and DIEA (916 mg, 7.091 mmol), HATU (1.35 g, 3.545 mmol), and cyclopropylamine (150 mg, 2.60 mmol) were added.
  • DIEA 916 mg, 7.091 mmol
  • HATU 1.35 g, 3.545 mmol
  • cyclopropylamine 150 mg, 2.60 mmol
  • YL230804-168-A 200 mg, 0.772 mmol was dissolved in triethylamine (5 mL) and dimethyl sulfoxide (1 mL).
  • Pd(Ph 3 P) 2 Cl 2 54.2 mg, 0.077 mmol
  • cuprous iodide 29 mg, 0.154 mmol
  • tert-butyl methyl(propan-2-yl)carbamate 144 mg, 0.849 mmol
  • YL230804-170-A 50 mg, 0.144 mmol was added to a 1,4-dioxane hydrochloride solution (2 mL, 4 M) and allowed to react at room temperature for 1 hour. The reaction mixture was concentrated to yield YL230804-172-A (40 mg, crude product). LC-MS (ESI): m/z 225.1 (M+H) + ;
  • YL230804-172-A 34 mg, 0.123 mmol was dissolved in acetonitrile, DIEA (53 mg, 0.410 mmol) was added, and the mixture was stirred at room temperature for 20 minutes.
  • YL230804-141-A (20 mg, 0.082 mmol) and potassium iodide (1.4 mg, 0.008 mmol) were then added, and the mixture was stirred at 80°C for 2 hours.
  • YL230804-166-A 200 mg, 0.730 mmol was dissolved in DMF (5 mL) and methanol (5 mL), and triethylamine (0.3 mL, 2.189 mmol) and Pd(dppf)Cl 2 (107 mg, 0.146 mmol) were added.
  • the mixture was protected by carbon monoxide gas and reacted at 80° C. for 30 hours.
  • the mixture was extracted with ethyl acetate and water, and the organic phase was separated. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • YL230804-169-A (100 mg, 0.395 mmol) was dissolved in methanol (3 mL) and water (3 mL). Potassium hydroxide (44 mg, 0.790 mmol) was added and the mixture was heated to 50°C for 2 hours. The pH was adjusted to 4-5 with 1N dilute hydrochloric acid. The mixture was extracted with dichloromethane/methanol (10/1). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain YL230804-175-A (180 mg, crude product). LC-MS (ESI): m/z 239.9 (M+H) + ;
  • YL230804-175-A 25 mg, 0.084 mmol was dissolved in DMF (3 mL), and DIEA (32 mg, 0.251 mmol) and HATU (48 mg, 0.125 mmol) were added. The mixture was stirred at room temperature for 20 minutes, and then YL230769-421-A (28 mg, 0.125 mmol) was added. The mixture was reacted at room temperature for 1 hour.
  • methyl 5-bromo-6-methylpicolinate (460 mg, 1.999 mmol) and a solution of methylamine in ethanol (5 mL) were added sequentially. Under nitrogen, the mixture was allowed to react at room temperature for 18 hours. LCMS analysis indicated a successful reaction, and the reaction solution was directly dried to yield YL230769-363 (458 mg, 1.999 mmol, 99.99%); LC-MS (ESI): m/z 231.0 (M+H) + .
  • YL230769-376 100 mg, 0.315 mmol
  • dichloromethane 10 mL
  • trifluoroacetic acid 1 mL, 13.059 mmol
  • the reaction was continued at room temperature for 2 hours.
  • LCMS indicated the reaction was complete.
  • the reaction solution was concentrated, and then ammonia methanol solution was added. After stirring for 30 minutes, the solution was concentrated to yield YL230769-385 (68 mg, 0.313 mmol, 99.34%); LC-MS (ESI): m/z 218.3 (M+H) + .
  • YL230769-385 26 mg, 0.120 mmol
  • YL230769-384 31.79 mg, 0.120 mmol
  • potassium iodide 3.97 mg, 0.024 mmol
  • N,N-diisopropylethylamine 77.33 mg, 0.598 mmol
  • acetonitrile 10 mL
  • YL230769-379 250 mg, 1.004 mmol
  • ethylene glycol (10 mL) 10 mL
  • the mixture was reacted at 165°C for 3 hours under nitrogen.
  • YL230769-418 843 mg, 2.264 mmol
  • tert-butyl methyl(prop-2-yn-1-yl)carbamate 574.73 mg, 3.396 mmol
  • cuprous iodide 862.45 mg, 4.528 mmol
  • potassium iodide 375.86 mg, 2.264 mmol
  • N,N-diisopropylethylamine 1463.27 mg, 11.321 mmol
  • tetrakistriphenylphosphine palladium 523.31 mg, 0.453 mmol
  • N,N-dimethylformamide 30 mL.
  • YL230769-427 36 mg, 0.165 mmol
  • YL230769-429 45.58 mg, 0.198 mmol
  • N,N-diisopropylethylamine 63.97 mg, 0.495 mmol
  • O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 94.10 mg, 0.247 mmol
  • N,N-dimethylformamide 5 mL
  • YL230769-283 37 mg, 0.166 mmol
  • YL230769-429 45.91 mg, 0.199 mmol
  • potassium iodide 5.52 mg, 0.033 mmol
  • N,N-diisopropylethylamine 107.38 mg, 0.831 mmol
  • acetonitrile 10 mL
  • YL230783-191-A (1.14 g, 6.758 mmol), cuprous iodide (0.86 g, 4.506 mmol), potassium iodide (0.75 g, 4.506 mmol), and tetrakistriphenylphosphine palladium (1.04 g, 0.901 mmol) were dissolved in DMF (75 mL) at room temperature and replaced with nitrogen. N,N-diisopropylethylamine (2.91 g, 22.528 mmol) was then added and replaced with nitrogen again. The temperature was then raised to 100°C for 1 hour. After the reaction, the mixture was diluted with ethyl acetate and water.
  • YL230783-195-A 700 mg, 2.178 mmol
  • dichloromethane 25 mL
  • trifluoroacetic acid 2.5 mL, 32.648 mmol
  • excess trifluoroacetic acid was neutralized by adding sodium hydroxide solution (1 M).
  • the mixture was then diluted with dichloromethane and water and extracted.
  • the organic solvent was evaporated to obtain the target compound YL230783-199-A (700 mg, 1.266 mmol, 58.10%).
  • YL230783-198-A 80 mg, 0.328 mmol
  • YL230783-199-A 87.16 mg, 0.394 mmol
  • potassium iodide 54.50 mg, 0.328 mmol
  • acetonitrile 30 mL
  • N,N-diisopropylethylamine 212.15 mg, 1.641 mmol
  • the reaction was continued at 80°C for 1.5 hours.
  • the mixture was diluted with ethyl acetate and water.
  • the organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • YL230783-198-A (89 mg, 0.365 mmol), YL230783-234-A (96.53 mg, 0.438 mmol), and KI (60.63 mg, 0.365 mmol) were dissolved in acetonitrile (60 mL).
  • DIEA (236.02 mg, 1.826 mmol) was then added and the reaction continued at 80°C for 1.5 hours.
  • the mixture was diluted with ethyl acetate and water.
  • the organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • the organic phases were combined, washed with water, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and evaporated to dryness.
  • the mixture was diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • YL230783-244-A (1.5 g, 5.900 mmol) and anhydrous tetrahydrofuran (55 mL) were added to the reaction flask.
  • the mixture was cooled to 0°C, and then lithium aluminum hydride tetrahydrofuran solution (1 M) (11.8 mL) was slowly added.
  • the mixture was stirred at 0°C for 2 hours. After the reaction was completed, it was quenched with 20 mL of ethyl acetate, and then 5 mL of water was added. The resulting mixture was spin-dried to dryness.
  • YL230783-195-A (1 g, 3.112 mmol), dichloromethane (30 mL), and trifluoroacetic acid (3 mL, 39.177 mmol) were added to a reaction flask and stirred at room temperature for 2 hours. After completion of the reaction, excess trifluoroacetic acid was neutralized by adding ammonia methanol (7 M) solution. The mixture was then diluted with dichloromethane and water, extracted, and the organic solvent was evaporated to obtain the target compound YL230783-250-A (5.5 g, 1.539 mmol, 49.46%) as a salt.
  • YL230783-251-A 250 mg, 1.022 mmol
  • YL230783-250-A 2448.88 mg, 1.328 mmol
  • potassium iodide 169.61 mg, 1.022 mmol
  • acetonitrile 120 mL
  • N,N-diisopropylethylamine 132.06 mg, 1.022 mmol
  • the mixture was diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • Methyl 6-chloro-5-nitropyridine-3-carboxylate (3.4 g, 15.699 mmol) was dissolved in ethanol (330 mL) and saturated aqueous ammonium chloride (110 mL) at room temperature. Iron powder (5.26 g, 94.192 mmol) was then added and the reaction mixture was heated to 80°C for 3 hours. After completion, the solvent was removed by vortexing, the reaction mixture was diluted with ethyl acetate and water, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • YL230783-249-A (3.2 g, 17.150 mmol), 2-(methoxycarbonyl)phenylboronic acid (6.17 g, 34.300 mmol), SPhos Pd G2 (1.24 g, 1.715 mmol) and potassium phosphate (10.92 g, 51.450 mmol) were dissolved in 1,4-dioxane (370 mL), and the temperature was raised to 100°C for overnight reaction. After the reaction, the reaction solution was vortexed and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • YL230783-254-A 80 mg, 0.315 mmol
  • tetrahydrofuran 25 mL
  • 1M lithium aluminum hydride solution in tetrahydrofuran 15.8 mL, 15.794 mmol
  • the mixture was stirred at room temperature for 1 hour.
  • the reaction was quenched with 10 mL of ethyl acetate and then 3 mL of water was added.
  • the resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness.
  • YL230783-259-A 60 mg, 0.245 mmol
  • YL230783-250-A 434.02 mg, 0.294 mmol
  • potassium iodide 40.71 mg, 0.245 mmol
  • acetonitrile 60 mL
  • N,N-diisopropylethylamine 158.47 mg, 1.226 mmol
  • the mixture was diluted with ethyl acetate and water, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • Methyl 4-amino-2-picolinate (3.6 g, 23.661 mmol) and N-bromosuccinimide (4.21 g, 23.661 mmol) were dissolved in 1,2-dichloroethane (120 mL) and the reaction was continued at room temperature for 2 hours. After completion, the solvent was evaporated and the residue was purified by automated column chromatography (Biotage) (mobile phase: dichloromethane/methanol 100/5 to 100/7) to obtain compound YL230783-255-A (5.5 g, 22.376 mmol, 94.57%).
  • YL230783-255-A (5.5 g, 23.804 mmol), 2-(methoxycarbonyl)phenylboronic acid (8.57 g, 47.609 mmol), SPhos Pd G2 (3.43 g, 4.761 mmol) and potassium phosphate (15.16 g, 71.413 mmol) were dissolved in 1,4-dioxane (620 mL) and then heated to 100°C for overnight reaction. After the reaction, the reaction solution was vortexed and diluted with ethyl acetate and water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • YL230783-257-A (90 mg, 0.354 mmol) and tetrahydrofuran (50 mL) were added to a reaction flask.
  • the mixture was cooled to 0°C, followed by the slow addition of 2.85 mL of a 1 M lithium aluminum hydride solution in tetrahydrofuran.
  • the mixture was stirred at room temperature for 4 hours.
  • the reaction was quenched with 12 mL of ethyl acetate, followed by the addition of 5 mL of water.
  • the resulting mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness.
  • YL230783-262-A 75 mg, 0.307 mmol
  • YL230783-250-A (678.15 mg, 0.460 mmol)
  • potassium iodide 50.88 mg, 0.307 mmol
  • acetonitrile 60 mL
  • N,N-diisopropylethylamine 396.18 mg, 3.065 mmol
  • the reaction mixture was diluted with ethyl acetate and water.
  • the organic phase was separated, and the aqueous phase was extracted with ethyl acetate.
  • LAH (CAS: 16853-85-3) (2 mL, 1 M, 2.07 mmol) was added dropwise to a mixture of YL230774-468 (300 mg, 1.04 mmol) in tetrahydrofuran (10 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched with water (0.1 mL) at 0°C, followed by sodium hydroxide solution (0.1 mL). After stirring for 10 minutes, anhydrous sodium sulfate (0.1 g, Na 2 SO 4 ) was added and stirred for 30 minutes.
  • YL230774-470 (2.18 g, 9.860 mmol) was added to a mixture of potassium bromomethyl trifluoroborate (1.80 g, 8.964 mmol) and potassium iodide (0.07 g, 0.448 mmol) in ACN (50 mL) and heated to 70°C for 16 hours. The reaction mixture was concentrated to remove acetonitrile and washed with methyl tert-butyl ether to obtain YL230774-473 (3.9 g, crude product). (ESI): m/z 304.2 [MH] - .
  • XPhos Pd G2 (CAS: 1310584-14-5) (8.07 mg, 0.010 mmol) was added to a mixture of YL230774-460 (30 mg, 0.10 mmol), YL230774-473 (88.97 mg, 0.206 mmol), and cesium carbonate (100.68 mg, 0.309 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL). The mixture was heated to 100°C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate.
  • YL230774-464 (5 mg, 0.009 mmol) was added to trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.1 mL) and heated to 100°C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution until weakly alkaline, extracted with dichloromethane, and the organic phase separated. After concentration, the organic phase was purified by reverse phase chromatography (C18, NH 4 HCO 3 ) to afford compound 42 (0.5 mg, 13.37% yield). (ESI): m/z 416.3 [M+H] + .
  • YL230804-108 (1.40 g, 4.86 mmol) was added to concentrated H2SO4 (15 mL) and allowed to react at room temperature for 2 hours. The reaction solution was cooled to 0°C, and then the aqueous solution was slowly added dropwise. A white solid precipitated, which was filtered and the filter cake was vacuum dried to yield YL230774-451 (1.00 g, 85.02% yield).
  • Tetraisopropoxytitanium (CAS: 546-68-9) (57 mg, 0.20 mmol) was added to a mixture of YL230774-398 (90 mg, 0.20 mmol) and YL230774-400 (44 mg, 0.20 mmol) in tetrahydrofuran (1 mL) and stirred at room temperature for 0.5 hour.
  • Sodium triacetylborohydride (212 mg, 1.00 mmol) was then added and allowed to react at room temperature for 16 hours. The reaction mixture was quenched with methanol and filtered through celite.
  • NMMO 87 mg, 0.74 mmol
  • YL230774-348 200 mg, 0.74 mmol
  • acetonitrile 4 mL
  • the reaction was quenched with water and extracted with dichloromethane.
  • YL240807-039-A 60 mg, 0.160 mmol was added to a 1,4-dioxane hydrochloride solution (2 mL, 4 M) and allowed to react at room temperature for 1 hour. The reaction mixture was concentrated to yield YL230804-189-A (45 mg, crude product).
  • YL240807-039-A 60 mg, 0.160 mmol was dissolved in a hydrochloric acid-dioxane solution (2 mL) and allowed to react at room temperature for 1 hour. The reaction solution was dried under vacuum to afford compound YL230804-189-A (45 mg, 90.33%).
  • ESI: (m/z) 290.2 [M+H] + ;
  • YL240807-045-A was obtained by replacing cis-3-methoxycyclobutylamine with cyclopropylamine using the method for synthesizing YL230804-172-A in Example 25;
  • YL230769-434 (1023 mg, 3.873 mmol), (tributyltin)methanol (1492.39 mg, 4.648 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (304.44 mg, 0.387 mmol), and 1,4-dioxane (30 mL). The mixture was reacted at 80°C for 12 hours under nitrogen. LCMS indicated the reaction was complete.
  • YL230769-436 (538 mg, 2.499 mmol), dichloromethane (30 mL), and N,N-dimethylformamide (0.010 mL, 0.125 mmol) in sequence. Under nitrogen, the mixture was cooled to 0°C, and then thionyl chloride (1783.99 mg, 14.997 mmol) was slowly added. The reaction was continued for 1 hour, then the temperature was raised to room temperature and the reaction was continued for 11 hours. LCMS indicated the reaction was complete. Saturated sodium bicarbonate and dichloromethane were slowly added to the reaction solution.
  • YL230769-437 (23.4 mg, 0.100 mmol), YL240807-045-A (35.01 mg, 0.120 mmol), potassium iodide (3.32 mg, 0.020 mmol), N,N-diisopropylethylamine (64.71 mg, 0.501 mmol), and acetonitrile (10 mL). Under nitrogen, the mixture was reacted at 80°C for 3 hours. LCMS indicated the reaction was complete, and the reaction solution was directly concentrated and prepared using a reverse-phase alkaline method to obtain compound YL230769-443 (compound 52) (31 mg, 0.063 mmol, 63.37%).
  • Example 53 The method of Example 37 was used to obtain the following compounds 53, 54 and 55:
  • Lithium aluminum hydride (1M) in tetrahydrofuran (0.69 mL, 0.689 mmol) was added dropwise to a mixture of YL240807-055 (100 mg, 0.345 mmol) in tetrahydrofuran (4 mL) in a 0°C ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched with water (1 drop) at 0°C, followed by the addition of sodium hydroxide solution (3 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.05 g , Na2SO4 ) was added and stirred for 30 minutes.
  • ESI: (m/z) 227.2 [M+H] + ;
  • methyl 6-chloro-5-nitronicotinate 2000 mg, 9.234 mmol
  • ethanol 30 mL
  • iron powder 2578 mg, 46.172 mmol
  • ammonium chloride 1481 mg, 27.703 mmol
  • water 5 mL
  • the mixture was heated to 70°C under nitrogen and reacted for 2 hours.
  • the mixture was filtered hot, rinsed with hot ethanol, and concentrated under reduced pressure.
  • the iron powder was slurried with dichloromethane, filtered, and the filtrate was combined with the solid, water was added, and the layers were separated.
  • YL230784-419-C1 (1.34 g, 7.182 mmol) and dioxane hydrochloride solution (20 mL) were added sequentially, and the mixture was reacted at room temperature for 2 hours under nitrogen protection. The mixture was concentrated under reduced pressure to obtain YL230784-421-C1 (1570 mg, 7.039 mmol, 98.01%).
  • YL230784-421-C1 250 mg, 1.121 mmol
  • 1,4-dioxane 10 mL
  • water 1 mL
  • methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzoate 740 mg, 2.242 mmol
  • chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) 80 mg, 0.112 mmol
  • potassium phosphate 774 mg, 3.363 mmol
  • YL230784-432-C1 85 mg, 0.264 mmol
  • tetrahydrofuran 5 mL
  • 1 M lithium aluminum hydride solution in tetrahydrofuran 1.3 mL
  • the mixture was then allowed to warm to room temperature and allowed to react for 1 hour.
  • the mixture was quenched with ethyl acetate, and 1.5 mL of water was added.
  • the mixture was stirred for 30 minutes, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure.
  • YL230804-293-A 160 mg, 0.544 mmol was added to a 1,4-dioxane hydrochloride solution (3 mL, 4 M) and allowed to react at room temperature for 1 hour. After concentration, the reaction mixture was adjusted to alkalinity with 7 M amine methanol and dried to afford YL230804-308-A (100 mg, crude).
  • YL230804-264-A 40 mg, 0.160 mmol
  • DIEA 62 mg, 0.479 mmol
  • YL230804-308-A 37 mg, 0.191 mmol
  • potassium iodide 2.6 mg, 0.016 mmol
  • Lithium aluminum hydride (1M) in tetrahydrofuran (1.0 mL, 1.04 mmol) was added dropwise to a mixture of YL240807-175 (150 mg, crude) in tetrahydrofuran (10 mL) at 0°C in an ice-water bath. The mixture was maintained at 0°C for 1.5 hours. The reaction mixture was quenched by the addition of water (1 drop) at 0°C, followed by the addition of sodium hydroxide solution (3 drops). After stirring for 10 minutes, anhydrous sodium sulfate (0.05 g, Na 2 SO 4 ) was added and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield YL240807-178 (150 mg, crude, 13.9% purity). (ESI): m/z 262.2 [M+H] + .

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  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé ayant une structure à triple liaison, et une composition pharmaceutique associée et l'utilisation associée. La présente invention concerne un composé ayant une structure à triple liaison telle que représentée par la formule I, un sel pharmaceutiquement acceptable de celui-ci, un solvate de celui-ci, un solvate du sel pharmaceutiquement acceptable de celui-ci, une forme cristalline de celui-ci, un stéréoisomère de celui-ci, un tautomère de celui-ci, ou un composé isotope de celui-ci. En tant qu'inhibiteur hautement sélectif, le composé ayant la structure à triple liaison de la présente invention peut non seulement satisfaire aux exigences d'un traitement de tumeur, mais aide également à réduire des réactions néfastes provoquées par l'inhibition de PARP-2.
PCT/CN2025/076194 2024-02-08 2025-02-07 Composé ayant une structure à triple liaison, et composition pharmaceutique associée et utilisation associée Pending WO2025168048A1 (fr)

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