WO2023125812A1 - Substituted pyrimidone derivative, and pharmaceutical composition and medical use thereof - Google Patents

Substituted pyrimidone derivative, and pharmaceutical composition and medical use thereof Download PDF

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Publication number
WO2023125812A1
WO2023125812A1 PCT/CN2022/143403 CN2022143403W WO2023125812A1 WO 2023125812 A1 WO2023125812 A1 WO 2023125812A1 CN 2022143403 W CN2022143403 W CN 2022143403W WO 2023125812 A1 WO2023125812 A1 WO 2023125812A1
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alkyl
ring
compound
cycloalkyl
alkoxy
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PCT/CN2022/143403
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French (fr)
Chinese (zh)
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李鑫
胡斌
赵志明
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Publication of WO2023125812A1 publication Critical patent/WO2023125812A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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 invention relates to the technical field of medicine, in particular to a substituted pyrimidinone derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition and a pharmaceutical application thereof.
  • Macrophage colony-stimulating factor 1 receptor belongs to the type III receptor tyrosine kinase family, and its ligand is macrophage colony-stimulating factor 1 (CSF-1).
  • the CSF1/CSF-1R signal transduction pathway is critical for the differentiation and survival of macrophages.
  • TAMs tumor-associated macrophages
  • TAMs are a class of immune cell subsets with high plasticity, which can be polarized like M1 and M2 types.
  • M1 cells can secrete interleukin-12 (IL-12) and IL-23, produce nitric oxide (NO), reactive oxygen species (ROS) and other cell killing, pro-inflammatory and chemokines, which play a role in tumor cells. Killing effect; M2 cells can secrete chemokines, inflammatory factors and matrix remodeling enzymes such as CCL17, CCL18, M-CSF, IL-6, IL-10 and matrix metalloproteinase (MMP), promote tumor proliferation, inhibit T cells, activate NK cells.
  • IL-12 interleukin-12
  • IL-23 produce nitric oxide (NO), reactive oxygen species (ROS) and other cell killing, pro-inflammatory and chemokines, which play a role in tumor cells. Killing effect; M2 cells can secrete chemokines, inflammatory factors and matrix remodeling enzymes such as CCL17, CCL18, M
  • the purpose of the present invention is to provide a substituted pyrimidinone derivative with high activity and good selectivity to CSF-1R.
  • the first aspect of the present invention provides a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • Z 1 is CR z1 or N
  • Z 2 is CR z2 or N
  • Z 3 is CR z3 or N
  • Z 1 , Z 2 , and Z 3 are not N at the same time
  • Z 4 is CR z4 or N;
  • Z 5 is CR z5 or N; and
  • Z 4 and Z 5 are not N at the same time;
  • Z 6 is CR z6 or N
  • R z1 , R z2 , R z3 , R z4 , R z5 , and R z6 are independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl ( preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl ), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 al
  • Ring A is a benzene ring or a 5- to 10-membered heteroaromatic ring
  • L is hydrogen, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -NR 03 R 04 , -C(O ) NR 01 R 02 or 5 to 6 membered heteroaryl ring; wherein the C 1-8 alkyl, 5 to 6 membered heteroaryl ring are each independently unsubstituted or are independently selected from 1, 2 or 3
  • the following substituents are substituted: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2- 4 alkynyl, hydroxy substituted C 1-3 alkyl, hydroxy substituted C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR 03 R 04 , - SO 2 C 1-3 alkyl, -S(O)C 1-3 al
  • R is hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C (O) NR 01 R 02 , -NR 03 R 04 or -SO 2 C 1-8 alkyl; wherein the C 1-8 alkyl is unsubstituted or 1, 2 or 3 independently selected from the following Substituent group substitution: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR 03 R 04 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl,
  • R 03 and R 04 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)C 1-8 alkyl ( Preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)C 3-8 cycloalkyl (preferably -C(O) C 3-6 cycloalkyl), -C(O)NR 01 R 02 , -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C (O)OC 1-3 alkyl), SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5
  • n 0, 1, 2 or 3;
  • R 1 and R 2 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -NR 05 R 06 , -C(O)OC 1-8 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -C (O) C 1-8 alkyl (preferably -C (O) C 1-6 alkyl, more preferably -C (O) C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 3 to 8 membered heterocycle; wherein the C 1-8 alkyl, 3 to 8 membered heterocycle are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkeny
  • R 05 and R 06 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)C 1-3 alkyl, -C(O)C 3-8 cycloalkyl (preferably -C(O)C 3-6 cycloalkyl), -C(O) NR 01 R 02 , -C(O)OC 1-3 alkyl , -SO 2 C 1-3 alkyl, -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5 to 6 membered heteroaryl ring; wherein said C 1-8 alkyl, C 3-8 cycloalkyl, 5 to 6 membered heteroaryl ring are each independently unsubstituted or replaced by 1, 2 or 3 substituents independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine),
  • R 1 and R 2 respectively form the structure shown in formula (i) together with the nitrogen atom and carbon atom connected to them: where X is -(CR q1 R q2 ) m -, -(CR q3 R q4 ) t1 -O-(CR q5 R q6 ) t2 -, -(CR q7 R q8 ) t3 -NR q0 -(CR q9 R q10 ) t4 -;
  • n 1, 2, 3 or 4;
  • t1, t2, t3, t4 are each independently 0, 1, 2 or 3; t1, t2 are not 0 at the same time; t3, t4 are not 0 at the same time;
  • R q1 and R q2 are each independently hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR 01 R 02 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)
  • R q3 , R q4 , R q5 , R q6 , R q7 , R q8 , R q9 , R q10 are each independently hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1 -8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O) NR 01 R 02 , -C(O)C 1-8 alkyl (preferably
  • R q0 is hydrogen, deuterium, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkane group), -C(O)NR 01 R 02 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1- 3 alkyl) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl , C 3-8 cycloalkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, nitro , hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C
  • R 01 and R 02 are independently hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R a1 and R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1 and R b1 together with the connected nitrogen atom form a 4- to 6-membered saturated monohetero ring; the 4 to 6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, nitrate radical, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 Alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), - C(O)N(
  • Z 1 is CR z1 or N;
  • Z 2 is CR z2 ;
  • Z 3 is CR z3 .
  • Z 1 is CR z1 ;
  • Z 2 is CR z2 ;
  • Z 3 is CR z3 .
  • Z 1 is N;
  • Z 2 is CR z2 ;
  • Z 3 is CR z3 .
  • Z 1 is CR z1 ;
  • Z 2 is CR z2 ;
  • Z 3 is N.
  • Z 1 is CR z1 ;
  • Z 2 is N;
  • Z 3 is CR z3 .
  • Z 4 is CR z4 ;
  • Z 5 is CR z5 .
  • Z 1 is CR z1 ;
  • Z 2 is CR z2 ;
  • Z 3 is CR z3 ;
  • Z 4 is CR z4 ;
  • Z 5 is CR z5 .
  • Z 1 is N;
  • Z 2 is CR z2 ;
  • Z 3 is CR z3 ;
  • Z 4 is CR z4 ;
  • Z 5 is CR z5 .
  • Z6 is N.
  • the 5- to 10-membered heteroaryl ring in the ring A is a 5- to 10-membered nitrogen-containing heteroaryl ring.
  • the ring A is a 5-6 membered nitrogen-containing heteroaryl ring (preferably a 5-6 membered nitrogen-containing heteroaryl ring) or an 8-10 membered nitrogen-containing heteroaryl ring (preferably a 9-10 membered A nitrogen-containing heteroaromatic ring, more preferably a pyrido 5- to 6-membered nitrogen-containing heteroaromatic ring).
  • the 5 to 6-membered nitrogen-containing heteroaryl ring in the ring A is a thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2 ,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring , 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, Pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, 1,2,3-triazine ring, 1,3,5
  • the ring A is a pyridine ring, a pyrimidine ring or a pyridopyrrole ring (preferably a pyridine ring).
  • the R 03 is hydrogen;
  • R 04 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O) C 1- 3 alkyl, -C(O)C 3-8 cycloalkyl (preferably -C(O)C 3-6 cycloalkyl), -C(O)NR 01 R 02 , -C(O )OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5 to 6-membered heteroaromatic ring; wherein said C 1-8 alkyl, -C(O)C 1-3 alkyl, C 3-8 cycloalkyl,
  • the 5 to 6 membered heteroaromatic rings are each independently unsubstituted or substituted with 1, 2 or 3 substituents each independently
  • the 5 to 6-membered heteroaromatic ring in L is a thiophene ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxa Oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring
  • the L is hydrogen, difluoromethyl, trifluoromethyl, -NH 2 , -NHCH 3 ,
  • R 1 is hydrogen or C 1-3 alkyl (preferably methyl or ethyl).
  • R 2 is -NR 05 R 06 .
  • the R 05 is hydrogen;
  • R 06 is hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl (preferably cyclopropyl); wherein the C 1-3 alkyl,
  • Each C3-6 cycloalkyl group is independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, - NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, - OC(O)C 1-3 alkyl, C 3-6 cycloalkyl
  • the 3-7 membered saturated or partially unsaturated monoheterocyclic ring formed by R 05 , R 06 and the connected nitrogen atom is an azetidine ring, a tetrahydropyrrole ring or a piperidine ring.
  • the R 2 is hydrogen, methyl, amino,
  • the compound having the structure shown in formula (I) is selected from one of the following compounds:
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides the compound described in the first aspect of the present invention, or its pharmaceutically acceptable salt, or its stereoisomer and the pharmaceutical composition described in the second aspect of the present invention in the preparation of treatment or prevention and Use in medicine for diseases associated with or mediated by CSF-1R activity.
  • the fourth aspect of the present invention provides a method for treating diseases related to or mediated by CSF-1R activity, the method comprising administering to patients an effective amount of the compound described in the first aspect of the present invention, or Its pharmaceutically acceptable salt, or its stereoisomer, or the pharmaceutical composition as described in the second aspect of the present invention.
  • the disease associated with or mediated by CSF-IR activity is cancer, such as solid tumors and hematological tumors.
  • Alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups.
  • C 1-8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group; non-limiting examples of the alkyl group include: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethyl propyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-d
  • Alkynyl refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups with one or more carbon-carbon triple bonds
  • C 2-8 alkynyl refers to alkynyl groups with 2 to 8 carbon atoms, preferably C 2-6 alkynyl, more preferably C2-4 alkynyl, similarly defined; non-limiting examples include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, etc.
  • Cycloalkyl and “cycloalkyl ring” are used interchangeably and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group, which may be fused with an aryl or heteroaryl group. Cycloalkyl rings can be optionally substituted. In certain embodiments, cycloalkyl rings contain one or more carbonyl groups, such as oxo groups.
  • C 3-8 cycloalkyl refers to a monocyclic cycloalkyl group with 3 to 8 carbon atoms
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc.
  • Heterocycloalkyl and “heterocycloalkyl ring” are used interchangeably and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which may be combined with an aryl or heteroaryl fused. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, heterocycloalkyl rings contain one or more carbonyl or thiocarbonyl groups, eg, groups comprising oxo and thioxo.
  • 3 to 8 membered heterocycloalkyl refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, preferably 4 to 8-membered heterocycloalkyl. More preferred is a 3 to 6 membered heterocycloalkyl group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. More preferred is a 4 to 6 membered heterocycloalkyl group having 4 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl , oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetra Hydropyranyl, azetidin-2-one, oxetane-2-one, dihydrofuran-2(3H)-one, pyrrolidin-2-one, pyrrolidin- 2,5-diketone, dihydrofuran-2,5-diketone, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazin-2-one, morphine Lin-3-
  • Aryl and “aromatic ring” are used interchangeably and both refer to an all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, which Can be fused to a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring or heteroaryl.
  • C 6-10 aryl refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl, and the like.
  • Heteroaryl and “heteroaromatic ring” are used interchangeably and both refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having shared 6 or 10 ⁇ electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. Heteroaryl rings can be optionally substituted.
  • “5 to 10 membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • “5 to 6 membered heteroaryl” means a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadi Azolyl, 1,2,5-ox
  • 8 to 10 membered heteroaryl means a bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include indolyl, iso Indolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzisofuryl, benzimidazole, benzoxazolyl, benziso Oxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido [2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthyridinyl,
  • Heteroatom means nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Fused” refers to a structure in which two or more rings share one or more bonds.
  • Alkoxy means -O-alkyl, wherein alkyl is as defined above. It is preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, most preferably C 1-3 alkoxy. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, pentyloxy, and the like.
  • Cycloalkyloxy means an -O-cycloalkyl group in which cycloalkyl is as defined above. It is preferably C 3-8 cycloalkyloxy, more preferably C 3-6 cycloalkyloxy. Non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • a bond means that the two groups connected by it are connected by a covalent bond.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Halo refers to a group in which one or more (eg 1, 2, 3, 4 or 5) hydrogens are replaced by a halogen.
  • Amino means NH 2
  • cyano means CN
  • nitro means NO 2
  • benzyl means -CH 2 -phenyl
  • oxo O
  • carboxy means -C (O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • hydroxyl refers to -OH
  • mercapto refers to SH
  • the structure of "cyclopropylene” is:
  • saturated or partially unsaturated monocyclic ring means a saturated or partially unsaturated all-carbon monocyclic ring system, where "partially unsaturated” means a ring portion that includes at least one double or triple bond, and “partially unsaturated” is intended to encompass Rings with multiple sites of unsaturation, but are not intended to include aryl or heteroaryl moieties as defined herein.
  • saturated or partially unsaturated monocyclic rings contain one or more carbonyl groups, such as oxo groups.
  • 3 to 7 membered saturated or partially unsaturated monocyclic ring has 3 to 7 ring carbon atoms, preferably a saturated or partially unsaturated monocyclic ring having 3 to 6 ring carbon atoms, more preferably 3 to 6 ring carbon atoms saturated monocycle.
  • Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, Cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.
  • “Saturated or partially unsaturated monoheterocyclic ring” means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer from 0 to 2 ), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • the "3- to 7-membered saturated or partially unsaturated monoheterocyclic ring” has 3 to 7 ring atoms, of which 1, 2 or 3 ring atoms are the above-mentioned heteroatoms.
  • 3 to 6 membered saturated or partially unsaturated monoheterocycles having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms as mentioned above, more preferably 5 to 6 ring atoms, of which 1 or 2 are A 5- to 6-membered saturated or partially unsaturated monoheterocycle whose atoms are the aforementioned heteroatoms, most preferably a 5- or 6-membered saturated monoheterocycle.
  • Non-limiting examples of saturated monoheterocyclic rings include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings , oxazolidine ring, piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, nitrogen Heterocyclobutane-2-one ring, oxetane-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, dihydro Furan-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran-2
  • Non-limiting examples of partially unsaturated monoheterocyclic rings include 1,2-dihydroazetidinium rings, 1,2-dihydrooxetidine rings, 2,5-dihydro-1H- Pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2, 3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4 ,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1,3-
  • Substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently replaced by the corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently replaced by the corresponding number of substituents of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • C 1-8 alkyl, C 3-8 cycloalkyl can be substituted by a group of substituents, which means that when it is further preferably C 1-6 alkyl, C 1-3 alkyl, C In the case of 3-6 cycloalkyl, C 1-6 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl may also be substituted by substituents of the above group.
  • substituted substituents independently selected from " in the present invention means that when more than one hydrogen on the group is replaced by a substituent, the types of the substituents may be the same or different, so The selected substituents are each independent species.
  • X is (CR q1 R q2 ) m , when m is 2, that is, X is CR q1 R q2 -CR q1 R q2 , where two R q1 can be the same or different, and two R q2 can be the same or different, for separate species.
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 following groups independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more Preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferred halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, halogenated C 1-8 alkyl substituted amino, acetyl, hydroxyl, hydroxymethyl , hydroxyethyl, carboxyl
  • any two "preferred” may be independent of each other.
  • R 3 when the same substituent appears multiple times, it can be independently selected from different groups. If the general formula contains multiple R 3 s , R 3 can be independently selected from different groups.
  • the "number of ring atoms” means the number of structural compounds (for example, monocyclic compounds, condensed ring compounds, crosslinked compounds, carbocyclic compounds, heterocyclic compounds) that constitute the ring itself in which atoms are bonded to form a ring.
  • the number of atoms within an atom When the ring is substituted by a substituent, the atoms included in the substituent are not included in the ring-forming atoms.
  • the substituent abbreviations correspond to: n-normal, sec-secondary, i-iso, t-tertiary, o-ortho, m-inter, p-pair, Me methyl, Et ethyl, Pr propyl , Butyl, Am n-pentyl, Hx hexyl, Cy cyclohexyl.
  • linking site when the linking site is not specified in the group, it means that an optional linkable site in the group is used as the linking site.
  • the fused site when the fused site is not specified in the group, it means that the optional fused site in the group is used as the fused site, preferably two or more positions in the ortho position in the group are fused location.
  • the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, buccal and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, syrups and the like.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions and the like.
  • the above-mentioned dosage forms can be made from the active compound and one or more carriers or excipients through common pharmaceutical methods.
  • the aforementioned carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compounds can form solutions or suspensions with the above-mentioned carriers.
  • “Pharmaceutically acceptable carrier” means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary preparation or excipient of any type, which is compatible with the patient, preferably a mammal , more preferably a human, suitable for delivering the active agent to the target site of interest without terminating the activity of the agent.
  • Active substance of the present invention or “active compound of the present invention” refers to a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, which has a higher CSF-1R selection inhibitory activity.
  • compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of a compound to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of a compound of the present invention that will elicit a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc.
  • the therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or its prodrug contained in the said pharmaceutical composition of the present invention or said pharmaceutical composition Preferably it is 0.1 mg-5 g/kg (body weight).
  • Patient means an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • Treating means alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing its development, or alleviating to some extent one or more symptoms of a disease or disorder.
  • the "pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • a pharmaceutically acceptable acid addition salt refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts with inorganic bases and salts with organic bases. These salts can be prepared by methods known in the art.
  • solvate refers to the complex formed by the compound of the present invention and a solvent. They are either reacted in the solvent or precipitated or crystallized from the solvent. For example, a complex formed with water is called a "hydrate”. Solvates of compounds of formula (I) are within the scope of the present invention.
  • the compound represented by formula (I) of the present invention contains one or more chiral centers, it can exist in different optically active forms.
  • a compound of formula (I) contains one chiral center, the compound contains a pair of enantiomers.
  • the two enantiomers of the compound as well as the mixture of the pair of enantiomers, such as the racemic mixture, are also within the protection scope of the present invention.
  • Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • the compound includes enantiomers and diastereomers.
  • Enantiomers and diastereomers of the compound and mixtures of enantiomers, mixtures of diastereomers, and mixtures of enantiomers and diastereomers Also within the protection scope of the present invention. Enantiomers and diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the present invention provides methods for preparing compounds of formula (I), which can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with methods described in the present invention. Solvents, temperatures and other reaction conditions given in this invention can be varied according to the skill in the art. The reactions can be used sequentially to provide compounds of the invention, or they can be used to synthesize fragments which are subsequently added by methods described herein and/or by methods known in the art.
  • the compounds described in the present invention can be synthesized by using appropriate alternative starting materials using methods similar to those described below or the exemplary methods described in the Examples, or relevant publications used by those skilled in the art.
  • Starting materials for the synthesis of the compounds described in this invention can be synthesized or can be obtained from commercial sources.
  • the compounds described in this invention and other related compounds with different substituents can be synthesized using techniques and starting materials known to those skilled in the art.
  • General methods for preparing compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified with reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.
  • novel substituted pyrimidinone derivatives which have high selective inhibitory activity on CSF-1R, and thus can be used for the treatment and/or prevention of CSF-1R activity-related or mediated by CSF-1R activity. Drugs that cause disease.
  • LC-MS Agilent 1290 HPLC System/6130/6150 MS liquid mass spectrometry (manufacturer: Agilent), column Waters BEH/CHS, 50 ⁇ 2.1mm, 1.7 ⁇ m.
  • Adopt ISCO Combiflash-Rf75 or Rf200 automatic column passing instrument Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
  • thin layer chromatography TLC
  • LC-MS LC-MS
  • column chromatography can be used for compound purification.
  • the developer system used in column chromatography or TLC can be selected from: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system, etc., the volume ratio of the solvent is based on the polarity of the compound Adjust differently.
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • DIEA N,N-diisopropylethylamine
  • FA formic acid
  • TEA triethylamine
  • EA ethyl acetate
  • PE petroleum ether
  • KHMDS bis(trimethylsilyl) potassium amide
  • NaHMDS bis(trimethylsilyl) sodium amide
  • NMP N-methylpyrrolidone
  • m-CPBA m-chloroperbenzoic acid
  • TFA trifluoroacetic acid
  • MsOH methanesulfonic acid
  • DMAP 4-dimethylaminopyridine
  • BINAP (2R,3S)-2,2'-bisdiphenylphosphino-1,1' -binaphthyl
  • NBS N-bromosuccinimide
  • NCS N-chloros
  • room temperature means about 20-30°C.
  • Step 1 Dissolve 5-bromo-2-chloro-4-methoxypyrimidine (1.0g, 4.5mmol) and isopropylamine (1.06g, 18.01mmol) in dry tetrahydrofuran (10mL), and add three Ethylamine (910 mg, 9.0 mmol).
  • the reaction solution was microwaved at 70°C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated to remove THF, water (100 mL) was added to the residue, and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (120 mL x 2), dried over sodium sulfate and concentrated to obtain compound v2-1 (1.0 g).
  • ESI-MS: m/z 246.0 [M+H] + .
  • Step 2 Dissolve compound v2-1 (900mg, 3.67mmol), pinacol diboronate (1.87g, 7.35mmol) and potassium acetate (1.08g, 11.02mmol) in 1,4-dioxane (20mL ), Pd 2 (PPh 3 ) 2 Cl 2 (260 mg, 0.37 mmol) was added to the above solution. After nitrogen replacement, the reaction solution was stirred at 85°C for 16 hours. The reaction solution was cooled to room temperature, added with water (100 mL), and extracted with ethyl acetate (30 mL x 3).
  • Step 1 Dissolve 5-bromo-2,4-dichloropyrimidine (36g, 0.158mol) and LiOH (13.3g, 0.316mmol) in THF (1000mL) and H 2 O (100mL), and replace the reaction solution with nitrogen Stir overnight at room temperature to obtain compound v4-1.
  • ESI-MS: m/z 208.9 [M+H] + .
  • Step 4 compound v4-3 (7.8g, 31.8mol), pinacol diboronate (1.61g, 63.6mol), x-phos (1.3g, 3.18mmol), potassium acetate (9.35g, 95.4mmol) and Pd 2 (dba) 3 (1.45 g, 1.59 mmol) were dissolved in 1,4-dioxane (80 mL), and the reaction solution was stirred at 70° C. for 3 hours after nitrogen replacement to obtain compound v4.
  • ESI-MS: m/z 294.0 [M+H] + .
  • Step 1 Dissolve 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (1.5g, 6.7mmol) in dioxane (30mL), and add (R )-1-methoxypropan-2-amine (1.1 g, 10 mmol), DIEA (2.6 g, 13 mmol). The reaction solution was stirred at 80° C. for 2 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Step 2 (R)-5-bromo-2-((1-methoxypropan-2-yl)amino)-3-methylpyrimidin-4(3H)-one ((1.2g, 4.0mmol) , dissolved in dioxane (25mL), and bis-pinacolyl diboron (2.0g, 8.0mmol), potassium acetate (1.2g, 12.0mmol), tris(dibenzylideneacetone) were added to the above solution ) Dipalladium (183mg, 0.2mmol), 2-bicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl (190mg, 0.4mmol).
  • Step 2 Dissolve compound v5-1 (1.5 g, 5.7 mmol), palladium on carbon (150 mg,) in methanol (100 mL), keep the solution at room temperature, and stir for 16 hours under hydrogen atmosphere. Concentration gave compound v5 (1 g).
  • LC-MS: m/z 175.1 [M+H] + .
  • Embodiment 1 the preparation of compound L1
  • Step 2 Compound 1-1 (160 mg, 0.49 mmol), compound v2 (104 mg, 0.49 mmol) were dissolved in 1,4-dioxane (5 mL). To the above solution was added a solution of potassium carbonate (135 mg, 0.98 mmol) dissolved in water (0.5 mL) and Pd(dppf) Cl2 (36 mg, 0.05 mmol). After nitrogen replacement, the reaction solution was stirred overnight at 108°C. The reaction solution was cooled to room temperature and concentrated to remove 1,4-dioxane. Water (10 mL) was added to the residue, and extracted with dichloromethane (20 mL x 3).
  • Embodiment 2 the preparation of compound L2
  • Step 2 Dissolve compound 2-1 (1.0 g, 6.1 mmol) in ethyl acetate (150 mL), add m-CPBA (3.1 g, 15.3 mmol, 85% purity) to the above solution, and stir at room temperature for 16 hours . After filtering, the filter cake was washed with a small amount of ethyl acetate to obtain compound 2-2 (810 mg).
  • ESI-MS: m/z 179.9 [M+H] + .
  • Step 4 compound 2-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 2-4.
  • ESI-MS: m/z 329.0 [M+H] + .
  • Step 5 compound 2-4 and intermediate v1 are used as raw materials, referring to the preparation method in step 1 of Example 1, to obtain the product L2.
  • ESI-MS: m/z 486.1 [M+H] + .
  • Embodiment 3 the preparation of compound L3
  • Step 3 Compound 3-2 and 2-chloroquinolin-6-ol are used as raw materials, referring to the preparation method in Step 1 of Example 1, to obtain Compound 3-3.
  • LC-MS: m/z 353.1 [M+H] + .
  • Step 4 compound 3-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound L3.
  • LC-MS: m/z 484.1 [M+H] + .
  • Embodiment 4 the preparation of compound L4
  • Step 1 Using 2-chloroquinolin-6-ol and intermediate v4 as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound 4-1.
  • LC-MS: m/z 311.1 [M+H] + .
  • Step 2 compound 4-1 and intermediate v3 are used as raw materials, referring to the preparation method in step 1 of Example 1, to obtain compound L4.
  • LC-MS: m/z 498.1 [M+H] + .
  • Embodiment 5 the preparation of compound L5
  • Step 1 using intermediate v8 and 2-chloro-6-hydroxy-quinoline as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound 5-1.
  • Step 3 using compound 5-2 and compound v1-1 as raw materials, refer to the preparation method in step 2 of Example 1 to obtain the product L5.
  • ESI-MS: m/z 524.4 [M+H].
  • Embodiment 6 the preparation of compound L6
  • Step 1 Dissolve concentrated sulfuric acid (49g, 500mmol) in water (30mL), add 4-amino-3-fluorophenol (6.3g, 50mmol), glycerin (36.8g, 400mmol) and nitrobenzene (18.4g, 75mmol ). The reaction solution was stirred at 140°C for 4 hours, cooled to room temperature, added to ice water, and neutralized with saturated aqueous sodium bicarbonate solution. The mixture was filtered, and the filter cake was washed with petroleum ether to obtain compound 6-1 (3.0 g).
  • Step 6 compound 6-5 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 6-6.
  • ESI-MS: m/z 329.0 [M+H] + .
  • Step 7 compound 6-6 and intermediate v1 are used as raw materials, referring to the preparation method in step 1 of Example 1, to obtain the product L6.
  • ESI-MS: m/z 486.1 [M+H] + .
  • Embodiment 7 the preparation of compound L7
  • Step 2 Using compound 7-1 as a raw material, refer to the preparation method in step 3 of Example 2 to obtain compound 7-2 (1.3 g).
  • ESI-MS: m/z 194.9 [M+H] + .
  • Step 3 Compound 7-2 (400mg, 2.03mmol) was dissolved in chloroform (5mL), boron tribromide (1.5mL) was added to the above solution, and the reaction solution was stirred in an oil bath at 60°C for 24 hours after nitrogen replacement . The reaction solution was cooled to 0°C, quenched with methanol, and then concentrated. The residue was purified by a C18 reverse column to obtain compound 7-3 (180 mg, yield 39.4%).
  • ESI-MS: m/z 224.8[M+H] +
  • Step 4 compound 7-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 7-4.
  • ESI-MS: m/z 312.1 [M+H] + .
  • Step 5 Compound 7-4 (180 mg, 579 ⁇ mol) was dissolved in NMP (4 mL), and potassium carbonate (239 mg, 1.74 mmol) and intermediate v1 (205 mg, 1.16 mmol) were added. The reaction solution was stirred at 110° C. for 16 hours, and the crude product was purified by preparative HPLC (TFA) to obtain compound L7 (83 mg, yield 46%).
  • ESI-MS: m/z 469.0 [M+H] + .
  • Embodiment 8 the preparation of compound L8
  • Step 1 Dissolve 4-amino-3-methylphenol (1g, 6.90mmol), (E)-3-ethoxyacryloyl chloride (0.971g, 7.25mmol) in tetrahydrofuran (50mL), and react after nitrogen replacement The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to remove tetrahydrofuran to obtain Compound 8-1 (1 g).
  • ESI-MS: m/z 222.0 [M+H] + .
  • Step 3 Using compound 8-2 as a raw material, refer to the preparation method in step 3 of Example 2 to obtain compound 8-3 (170 mg).
  • ESI-MS: m/z 194.0 [M+H] + .
  • Step 4 compound 8-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 8-4.
  • ESI-MS: m/z 325.0 [M+H] + .
  • Step 6 compound 8-5 and compound v1-1 were used as raw materials, and the product L8 was obtained by referring to the preparation method in step 2 of Example 1.
  • Embodiment 9 the preparation of compound L9
  • Step 3 Using compound 9-2, refer to the preparation method in step 3 of Example 2 to obtain compound 9-3 (200 mg).
  • Step 4 compound 9-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 9-4.
  • LC-MS, m/z 325.1 [M+H] + .
  • Embodiment 10 the preparation of compound L10
  • Embodiment 11 Preparation of Compound L11
  • Step 1 Dissolve 4-amino-2,6-difluorophenol (1.45g, 10.0mmol) and pyridine (1.56g, 20.0mmol) in tetrahydrofuran (100mL), and add (E)-3- Ethoxyacryloyl chloride (1.4g, 10.5mmol), stirred at room temperature for 24 hours. Concentration gave compound 11-1.
  • ESI-MS: m/z 244.0 [M+H] + .
  • Step 3 Using compound 11-2 as a raw material, refer to the preparation method in step 3 of Example 2 to obtain compound 11-3 (720 mg).
  • ESI-MS: m/z 215.9[M+H] + .
  • Step 4 compound 11-3 and compound v4 were used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 11-4.
  • ESI-MS: m/z 347.0 [M+H] + .
  • Step 5 Compound 11-4 (500 mg, 1.4 mmol) was dissolved in NMP (10 mL), and potassium carbonate (597 mg, 4.3 mmol) and 2-bromo-4-fluoropyridine (761 mg, 4.3 mmol) were added. The reaction solution was stirred at 90° C. for 24 hours, and purified by a C18 reverse column to obtain the product compound 11-5 (301 mg, yield 41.5%).
  • ESI-MS: m/z 503.9 [M+H] + .
  • Step 6 compound 11-5 and compound v1-1 were used as raw materials, and the product L11 was obtained by referring to the preparation method in step 2 of Example 1.
  • Embodiment 12 the preparation of compound L12
  • Step 1 6-bromo-2-chloroquinazoline (1g), biboronic acid pinacol ester (1.36g), potassium acetate (806mg) and Pd(dppf)Cl 2 (301mg) were dissolved in 1,4-bis In oxane (50 mL), the reaction solution was replaced with nitrogen and stirred at 70° C. for 2 hours to obtain compound 12-1.
  • ESI-MS: m/z 291.0 [M+H] + .
  • Step 3 compound 12-2 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 12-3.
  • ESI-MS: m/z 311.0 [M+H] + .
  • Step 5 using compound 12-4 and compound v1-1 as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound L12.
  • ESI-MS: m/z 469.0 [M+H] + .
  • Embodiment 13 Preparation of compound L13
  • Step 1 Compound 4-1 (890mg, 2.87mmol) was dissolved in NMP (15mL), and potassium carbonate (1.6g, 11.48mmol) and 2-bromo-4-fluoropyridine (758mg, 4.3mmol) were added. After nitrogen replacement, the reaction solution was stirred overnight in an oil bath at 90°C. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain a crude product.
  • Step 2 compound 13-1 (150mg, 0.32mmol), X-phos (61mg, 0.128mmol), acetamide (38mg, 0.64mmol), cesium carbonate (312mg, 0.96mmol) and Pd 2 (dba) 3 (59mg , 0.064 mmol) was dissolved in 1,4-dioxane (8 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Embodiment 14 Preparation of Compound L14
  • Step 1 Compound 4-1 (750mg, 2.4mmol) was dissolved in DMF (10mL), and the reaction solution was cooled to 0°C. NaH (106mg, 2.7mmol) was added slowly, and the reaction solution was stirred at 0°C for 1h. Then 2,4-dichloropyrimidine (394mg, 2.7mmol) was added, and the reaction solution was stirred at room temperature for 3h.
  • Embodiment 15 Preparation of Compound L15
  • Step 1 Dissolve 2-bromo-3-amino-5-fluoropyridine (2g, 9.6mmol) in THF (9mL), add triethylamine (3.1mL, 21.6mmol), benzyl acrylate (1.3mL, 14.4 mmol), palladium acetate (0.3g, 1.3mmol) and triphenylphosphine (0.6g, 2.2mmol).
  • the reaction solution was stirred at 140° C. for 2 hours in a microwave reactor.
  • the reaction solution was cooled to room temperature, the residue was added to water (150 mL), and extracted with ethyl acetate (150 mL x 2).
  • Step 2 Compound 15-1 (1.5g, 7.5mmol) was dissolved in acetic acid (15mL), and tributylphosphine (1.9mL, 7.5mmol) was added to the above solution. After nitrogen replacement, the reaction solution was stirred at 110°C 2 hours. After the reaction solution was filtered, the residue was washed with ethyl acetate and concentrated to obtain compound 15-2 (500 mg).
  • Step 3 Compound 15-2 (500 mg) was dissolved in 1,4-dioxane (15 mL), and POCl 3 (1 mL, 27.5 mmol) was added to the above solution. The reaction solution was stirred at 110° C. for 5 hours. After the reaction solution was concentrated, the residue was dissolved in dichloromethane, added to ice water (150 mL), and extracted with dichloromethane (150 mL x 2).
  • Step 4 compound 15-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 15-4.
  • ESI-MS: m/z 314.0 [M+H] + .
  • Embodiment 16 Preparation of Compound L16
  • Embodiment 17 Preparation of Compound L17
  • Step 1 Compound 13-1 and 1-Boc-pyrazole-4-boronic acid pinacol ester were used as raw materials, referring to the preparation method in Step 2 of Example 1, to obtain Compound 17-1.
  • ESI-MS: m/z 554.0 [M+H] + .
  • Embodiment 18 Preparation of compound L18
  • Embodiment 19 Preparation of Compound L19
  • Step 2 Dissolve compound 19-1 (1.5g, 7.39mmol) in DMF (8mL), add triethylamine (1.64g, 16.3mmol), benzyl acrylate (1.80g, 11.1mmol), palladium acetate (213mg , 0.96mmol) and triphenylphosphine (445mg, 1.70mmol), the reaction solution was stirred in a microwave reactor at 140°C for 2 hours after nitrogen replacement. The reaction solution was cooled to room temperature, the residue was added to water (150 mL), and extracted with ethyl acetate (150 mL x 2).
  • ESI-MS: m/z 177.0 [M+H] + .
  • Step 5 compound 19-4 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 19-5.
  • ESI-MS: m/z 326.1 [M+H] + .
  • ESI-MS: m/z 469.0 [M+H] + .
  • Embodiment 20 Preparation of Compound L20
  • Step 1 Add 2-bromo-4-fluoropyridine (2g, 11.4mmol) into a dry 50mL three-necked flask under the protection of nitrogen, drop to -78°C, add n-butyllithium solution (5.5mL, 13.7mmol ) and reacted for 30 minutes, acetone (1.58 g, 27.2 mmol) was added to the above solution to keep the temperature at -78° C. for 1 hour, and then returned to room temperature.
  • 2-bromo-4-fluoropyridine (2g, 11.4mmol) into a dry 50mL three-necked flask under the protection of nitrogen, drop to -78°C, add n-butyllithium solution (5.5mL, 13.7mmol ) and reacted for 30 minutes, acetone (1.58 g, 27.2 mmol) was added to the above solution to keep the temperature at -78° C. for 1 hour, and then returned to room temperature.
  • Step 2 Compound 20-1 (56mg, 0.36mmol), Compound 4-1 (112mg, 0.36mmol) and potassium carbonate (149mg, 1.08mmol) were dissolved in NMP (3mL), and the solution was heated to 100°C and stirred for 16h . After the reaction was monitored by LCMS, it was concentrated, prepared in reverse phase, and lyophilized to obtain compound L20 (50 mg, yield 31.2%).
  • Embodiment 21 Preparation of Compound L21
  • Step 1 Compound 4-1 (600 mg, 1.90 mmol) was dissolved in NMP (20 mL), and potassium carbonate (1.0 g, 7.60 mmol) and 2-nitro-4-chloropyridine (360 mg, 2.90 mmol) were added. After nitrogen replacement, the reaction solution was stirred overnight in an oil bath at 90°C. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain a crude product.
  • NMP 20 mL
  • potassium carbonate 1.0 g, 7.60 mmol
  • 2-nitro-4-chloropyridine 360 mg, 2.90 mmol
  • Embodiment 22 Preparation of Compound L22
  • Step 1 Compound 4-1 (367 mg, 1.18 mmol) was dissolved in acetic acid (15 mL), and liquid bromine (199 mg, 1.24 mmol) was added. The reaction solution was stirred at room temperature for 3 hours, the product was precipitated and filtered to obtain compound 22-1 (360 mg, yield 83%).
  • ESI-MS: m/z 388.9 [M+H] + ..
  • Step 4 compound 22-3 and compound v1-1 were used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 22-4.
  • Embodiment 23 Preparation of compound L23
  • Step 1 Dissolve compound L22 (240mg, 0.44mmol) and sodium hydroxide (200mg, 5.0mmol) in methanol (40mL), add water (10mL) to the above solution, and stir the reaction solution in an oil bath at 80°C for 3 Hour.
  • ESI-MS: m/z 512.2 [M+H] + .
  • Embodiment 24 Preparation of compound L24
  • Step 2 compound 24-1 (63mg, 0.14mmol), BocNH 2 (162mg, 1.4mmol), Pd 2 dba 3 (26mg, 0.03mmol), x-Phos (27mg, 0.06mmol) and cesium carbonate (114mg, 0.35mmol) was dissolved in 1,4-dioxane (2mL), the solution was heated to 100°C and stirred for 16h. After the reaction was monitored by LCMS, it was concentrated, prepared in reverse phase, and lyophilized to obtain compound L24 (11 mg, yield 18%).
  • Embodiment 25 Preparation of compound L25
  • Embodiment 26 Preparation of Compound L26
  • Embodiment 27 Preparation of compound L27
  • Embodiment 28 Preparation of compound L28
  • Embodiment 29 Preparation of Compound L29
  • Step 2 Dissolve compound 29-1 (1.60g, 7.66mmol), sodium 4-methylbenzenesulfinate (2.86g, 16.05mmol) in DMF (80.0mL), and add potassium cyanide ( 1.25g, 19.2mmol). After nitrogen replacement, the reaction solution was stirred in an oil bath at 130° C. for 19 hours. After the reaction solution was cooled to room temperature, it was added dropwise to ice water and extracted with ethyl acetate (320 mL x 3).
  • Step 4 compound 29-3 and compound v4 were used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 29-4.
  • ESI-MS: m/z 350.1 [M+H] + .
  • ESI-MS: m/z 336.1 [M+H] + .
  • Step 7 Compound 29-6 (60 mg, 0.122 mmol) and compound v1-1 were used as raw materials, and the product L29 was obtained by referring to the preparation method in Step 2 of Example 1.
  • Embodiment 30 Preparation of compound L30
  • Step 2 Dissolve compound 31-3 (466mg, 1.5mmol) and diethyl oxalate (1.64g, 11.2mmol) in a mixed solvent of tetrahydrofuran (4.0mL) and ethanol (8.0mL), and add sodium ethoxide to the above solution (153mg, 2.25mmol), stirred at room temperature for 3 hours. Neutralize with dilute hydrochloric acid and concentrate to obtain compound 31-4.
  • ESI-MS: m/z 412.0 [M+H] + .
  • Step 7 compound 31-6 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound L 31.
  • Step 1 Dissolve compound 4-1 (450mg, 1.45mmol) in DMF (10mL), add 2,4-dichloro-3-fluoropyridine (240mg, 1.45mmol) and sodium bicarbonate (365mg ,4.35mmol). The reaction solution was stirred at 60° C. for 3 days. Water (60 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (120 mL x 2), dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 34-1.
  • ESI-MS: m/z 440.1 [M+H] + .
  • Step 2 Dissolve compound 34-1 (260mg, 0.6mmol), benzophenone imine (160mg, 0.886mmol) in 1,4-dioxane (6mL), and add cesium carbonate ( 482 mg, 1.48 mmol), Xantphos (34 mg, 0.06 mmol) and Pd 2 (dba) 3 (54 mg, 0.06 mmol). After nitrogen replacement, the reaction solution was stirred in an oil bath at 100° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated to remove 1,4-dioxane. The residue was added with water (20 mL), extracted with dichloromethane (35 mL x 3).
  • Step 1 intermediate v7 and 2-chloro-6-hydroxy-quinoline as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound 38-1.
  • Step 2 Dissolve compound 38-1 (1.0g, 2.9mmol) in DMF (20mL), add 2-bromo-4-fluoropyridine (1.55g, 8.8mmol) and potassium carbonate (1.2g ,8.8mmol). The reaction solution was stirred at 90°C for 16 hours. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Step 3 Dissolve compound 38-2 (200mg, 0.4mmol) in dioxane (10mL), add acetamide (143mg, 2.4mmol), cesium carbonate (782mg, 2.4mmol), Pd 2 (dba) 3 (37 mg, 0.04 mmol), X-PHOS (38 mg, 0.08 mmol). After nitrogen replacement, the reaction solution was stirred at 80°C for 3 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Embodiment 40 Preparation of compound L40
  • Step 2 compound 40-1(2) (100mg, 0.21mmol), X-phos (61mg, 0.128mmol), acetamide (74mg, 1.26mmol) cesium carbonate (409.5mg, 1.26mmol) and Pd 2 (dba) 3 (59mg, 0.064mmol) was dissolved in 1,4-dioxane (5mL), and the reaction solution was stirred at 85°C for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Step 1 compound 40-1 (100mg, 0.21mmol), X-phos (61mg, 0.128mmol), tert-butyl carbamate (147mg, 1.26mmol) cesium carbonate (409.5mg, 1.26mmol) and Pd 2 (dba ) 3 (59mg, 0.064mmol) was dissolved in 1,4-dioxane (5mL), and the reaction solution was stirred at 85°C for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain compound 41-1.
  • ESI-MS: m/z 404.0 [M+H] + .
  • Step 1 5-bromo-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (2.0g, 8.5mmol) and isopropanol pinacol borate (3.16g, 17.0 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to -78°C, and 2.5 M n-butyllithium n-hexane solution (6.8 mL, 17.0 mmol) was slowly added dropwise. The reaction was stirred at -78°C for 1 hour. The completion of the reaction was monitored by LCMS, and the reaction solution was slowly added to ethanol (100 mL) at -78° C. to quench the reaction. The reaction system was neutralized with 1M hydrochloric acid and concentrated to obtain compound 42-1.
  • ESI-MS: m/z 201.1 [M+H] + .
  • Step 2 Compound 42-1 and 2-chloroquinoline-6-ol were used as raw materials, and the compound 42-2 was obtained by referring to the preparation method in Step 2 of Example 1.
  • ESI-MS: m/z 300.1 [M+H] + .
  • Step 4 compound 42-3 (500mg, 1.1mmol), X-Phos (105mg, 0.22mmol), acetamide (390mg, 6.6mmol), cesium carbonate (2.15g, 6.6mmol) and Pd 2 (dba) 3 (100 mg, 0.11 mmol) was dissolved in 1,4-dioxane (50 mL), and the reaction solution was stirred at 90° C. for 17 hours after nitrogen replacement.
  • Step 5 Dissolve compound 42-4 (130mg, 0.3mmol), pyrrolidine (210mg, 3.0mmol) and potassium carbonate (207mg, 1.5mmol) in 1,4-dioxane (10mL), seal the tube and heat to 140°C and stirred for 17 hours. It was filtered, concentrated, and purified by preparative HPLC (5% aqueous ammonium bicarbonate/acetonitrile) to obtain compound L45 (17 mg, yield 12.5%) and compound L42 (7.0 mg, yield 5.6%).
  • Step 1 Dissolve compound 38-2 (300mg, 0.6mmol) in dioxane (10mL), add tert-butyl carbamate (281mg, 2.4mmol), cesium carbonate (782mg, 2.4mmol) to the above solution ), Pd 2 (dba) 3 (54mg, 0.06mmol), X-PHOS (50mg, 0.12mmol). After nitrogen replacement, the reaction solution was stirred at 70°C for 3 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3).
  • Step 2 Compound 43-1 (200 mg, 0.12 mmol) was dissolved in dioxane (10 mL), and HCl/dioxane (4M, 10 mL,) was added to the above solution. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated to remove dioxane, and the residue was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain product L43 (30 mg, yield 18.3%).
  • Step 1 Dissolve compound 5-2 (300mg, 0.57mmol) in dioxane (10mL), add tert-butyl carbamate (270mg, 2.3mmol), cesium carbonate (750mg, 2.3mmol) to the above solution ), Pd 2 (dba) 3 (53 mg, 0.06 mmol), X-PHOS (53 mg, 0.11 mmol). After nitrogen replacement, the reaction solution was stirred at 70°C for 3 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3).
  • Step 1 Using the intermediate compound v9 and 2-chloro-6-hydroxyquinoline as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound 48-1.
  • ESI-MS: m/z 309.1 [M+H] + .
  • Step 2 Using compound 48-1 and 4-fluoro-2-bromopyridine as raw materials, refer to the preparation method in step 2 of Example 5 to obtain compound 48-2.
  • ESI-MS: m/z 464.0 [M+H] + .
  • Step 3 Using compound 48-2 and tert-butyl carbamate as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 48-3 (115 mg, yield 66.8%).
  • ESI-MS: m/z 501.2 [M+H] + .
  • Step 4 Using compound 48-3 as a raw material, refer to the preparation method in Step 3 of Example 1 and the preparation method in Step 2 of Example 43 to obtain the product L48 (26 mg, yield 42%).
  • Step 1 Using compound 48-2 and acetamide as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 50-1.
  • ESI-MS: m/z 443.1 [M+H] + .
  • Step 2 Using compound 50-1 as a raw material, refer to the preparation method in Step 3 of Example 1 to obtain the product L50.
  • Step 1 Dissolve 5-bromo-2-chloro-4-methoxypyrimidine (4.0g, 17.9mmol) in dioxane (50mL), and add 3-aminobutane-1- Alcohol (4g, 45mmol), DIEA (7g, 54mmol). The reaction solution was stirred at 80°C for 16 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Step 2 Compound 52-1 (3 g, 10.9 mmol) was dissolved in concentrated sulfuric acid (10 mL), and the reaction solution was stirred at 90° C. for 1 hour. Add ethyl acetate (50mL) and water (50mL) to the reaction solution after cooling, adjust the pH to 8 with saturated sodium bicarbonate solution, wash the organic phase three times with saturated brine (30mL), dry over sodium sulfate and evaporate the solvent to obtain compound 52-2 (1.5 g, 56.6% yield).
  • ESI-MS: m/z 244.1 [M+H] + .
  • Step 3 Dissolve compound 52-2 (1.5g, 6.17mmol) in tetrahydrofuran (30mL), add di-tert-butyl dicarbonate (3.9g, 18mmol), TEA (1.8g, 18mmol), DMAP to the above solution (146 mg, 1.2 mmol). The reaction solution was stirred at 60°C for 16 hours. The reaction solution was concentrated to remove THF, and water (20 mL) was added to the residue, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Step 4 Dissolve compound 52-3 (2g, 5.83mmol) in dioxane (40mL), add bis-pinacolyl diboron (4.5g, 17.5mmol), potassium acetate ( 1.7 g, 17.5 mmol), Pd(PPh 3 ) 2 Cl 2 (400 mg, 0.6 mmol). After nitrogen substitution, the reaction solution was stirred at 85° C. for 1 hour. After the reaction liquid was cooled, the solid was removed by filtration, washed with dioxane (20 mL), and the solvent was distilled off to obtain compound 52-4.
  • ESI-MS: m/z 254.1 [M+H-56] + .
  • Step 5 Compound 52-4 and 2-chloro-6-hydroxy-quinoline were used as raw materials, referring to the preparation method in Step 2 of Example 1, to obtain Compound 52-5 (1.2 g, yield 63.9%).
  • ESI-MS: m/z 409.2 [M+H] + .
  • Step 6 Dissolve compound 52-5 (700mg, 1.7mmol) in DMF (15mL), add 2-bromo-4-fluoropyridine (900mg, 5.1mmol), potassium carbonate (700mg, 5.1mmol) to the above solution ). The reaction solution was stirred at 90°C for 16 hours. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • 2-bromo-4-fluoropyridine 900mg, 5.1mmol
  • potassium carbonate 700mg, 5.1mmol
  • Step 7 Using compound 52-6 and tert-butyl carbamate as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 52-7.
  • ESI-MS: m/z 601.2 [M+H] + .
  • Step 1 Using 2-chloroquinolin-6-ol and intermediate v2 as raw materials, refer to the preparation method in Step 2 of Example 1 to obtain compound 54-1 (520 mg, yield 51.4%).
  • ESI-MS: m/z 311.1 [M+H] + .
  • Step 2 Using compound 54-1 and 4-fluoro-2-bromopyridine as raw materials, refer to the preparation method in step 2 of Example 5 to obtain compound 54-2 (240 mg).
  • ESI-MS: m/z 466.0 [M+H] + .
  • Step 3 Using compound 54-2 and acetamide as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 54-3 (135 mg, yield 71%).
  • Step 4 Using compound 54-3 as a raw material, refer to the preparation method in Step 3 of Example 1 to obtain the product L54 (12.5 mg, yield 14.5%).
  • Step 1 Using compound 52-6 and acetamide as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 55-1.
  • ESI-MS: m/z 543.2 [M+H] + .
  • Step 2 Dissolve 4-chloro-2-(difluoromethyl)pyridine (100mg) in DMF (1mL), add potassium carbonate (83mg, 0.6mmol) to the above solution, compound 4-1 (112mg, 0.36 mmol). The reaction solution was stirred under microwave at 120°C for 5 hours. After the reaction solution was cooled, water (10 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was subjected to preparative HPLC (NH4HCO3) to obtain compound L56 (6.0 mg, yield 3.8%).
  • Step 1 Using compound 54-2 and tert-butyl carbamate as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 58-1.
  • ESI-MS: m/z 503.2 [M+H] + .
  • Step 2 Using compound 58-1 as a raw material, refer to the preparation method in Step 3 of Example 1 and the preparation method in Step 2 of Example 43 to obtain the product L58.
  • ESI-MS: m/z 389.2 [M+H] + .
  • Step 1 Using 5-bromo-2-chloro-4-methoxypyrimidine and 1-aminopropanol as raw materials, refer to the preparation method in Step 1-6 of Example 52 to obtain compound 59-6.
  • ESI-MS: m/z 552.0 [M+H] + .
  • Step 7 Using compound 59-6 and acetamide as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 59-7.
  • ESI-MS: m/z 529.2 [M+H] + .
  • Step 10 Using compound 59-7 as a raw material, refer to the preparation method in step 2 of Example 43 to obtain the product L59 (15 mg, yield 14%).
  • Embodiment 60 Preparation of compound L60
  • Step 1 Dissolve acetamide (390 mg, 6.6 mmol) in DMF (10 mL) under ice-cooling, and add NaH (264 mg, 6.6 mmol) to the above solution. The reaction solution was stirred under ice bath for 15 minutes. 5-Chloro-2-fluoro-4-iodopyridine (850 mg, 3.3 mmol) was added to the above solution, and stirred overnight at room temperature. Add water (20mL) to the reaction solution, and extract with ethyl acetate (20mL x 3). The organic phases were combined and washed with saturated brine (30 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Step 2 Dissolve N-(5-chloro-4-iodopyridin-2-yl)acetamide (40mg, 0.13mmol) in DMF (1mL), and add compound 4-1 (62mg, 0.2 mmol), cesium carbonate (88 mg, 0.26 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (40 mg, 0.2 mmol). After nitrogen replacement, the reaction solution was stirred at 100° C. for 16 hours. After the reaction solution was cooled, water (10 mL) was added and extracted with ethyl acetate (10 mL x 3).
  • Embodiment 62 Preparation of compound L62
  • Step 1 Dissolve acetamide (350mg, 6.25mmol) in DMF (20mL). After nitrogen replacement, add NaH (335mg, 8.37mmol, 60%) to the above solution in batches under ice bath. Stir under ice bath for 30 minutes, add 2,3-difluoro-4-iodopyridine (1.0 g, 4.17 mmol), and stir the reaction solution at room temperature for 16 hours. Water (100 mL) was concentrated to the reaction liquid, and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (150mL x 2), dried over sodium sulfate and evaporated to remove the solvent.
  • Step 2 N-(3-fluoro-4-iodo-2-yl)acetamide (140mg, 0.774mmol), compound 4-1 (160mg, 0.52mmol) and cesium carbonate (505mg, 1.55mmol) were dissolved in DMF (3 mL), after nitrogen replacement, copper iodide (100 mg, 0.52 mmol) and TMHD (185 mg, 1.03 mmol) were added to the above solution. Nitrogen was replaced again, and the reaction solution was stirred at 80° C. for 18 hours. The reaction solution was concentrated after cooling to room temperature, water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (40 mL x 3).
  • Embodiment 63 Preparation of Compound L63
  • Step 2 compound 63-1 (322mg, 1.0mmol), 2,2,6,6-tetramethylheptane-3,5-dione (46mg, 0.25mmol), N-(3-fluoro-4- Iodopyridin-2-yl)acetamide (421mg, 1.5mmol), cesium carbonate (652mg, 2.0mmol) and cuprous iodide (95mg, 0.5mmol) were dissolved in N-methylpyrrolidone (15mL), and reacted after nitrogen replacement The solution was stirred at 90°C for 72 hours.
  • Embodiment 67 Preparation of Compound L67
  • Step 3 compound 67-2 (25mg, 0.05mmol), x-phos (2.4mg, 0.005mmol), acetamide (18mg, 0.3mmol) and cesium carbonate (49mg, 0.15mmol) and Pd 2 (dba) 3 (5 mg, 0.005 mmol) was dissolved in 1,4-dioxane (2 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated.
  • Embodiment 68 Preparation of Compound L68
  • ESI-MS: m/z 508.0 [M+H] + .
  • Step 3 compound 68-2 (135mg, 0.27mmol), x-phos (50mg, 0.1mmol), acetamide (63mg, 1.07mmol) cesium carbonate (347mg, 1.07mmol) and Pd 2 (dba) 3 (49g , 0.05 mmol) was dissolved in 1,4-dioxane (8 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Embodiment 69 Preparation of Compound L69
  • Step 2 Dissolve compound 77-1 (450mg, 2.22mmol), bis(pinacolate) diboron (618.5mg, 3.32mmol) in THF (5mL), cool the system to -78°C, and add to the above solution Added n-butyllithium solution (1.33mL, 3.32mmol) into the mixture, kept the system at -78°C and stirred for 1 hour, then gradually raised to room temperature, overnight, quenched by adding a small amount of ethanol, and directly spin-dried to obtain compound 77-2.
  • Step 3 Compound 77-2 and 2-chloro-6-hydroxyquinoline were used as raw materials, referring to the preparation method in Step 2 of Example 1, to obtain Compound 77-3.
  • ESI-MS: m/z 268.0 [M+H] + .
  • Step 4 Compound 77-3 (330mg, 1.23mmol), 2-bromo-4-fluoropyridine (326mg, 1.85mmol), potassium carbonate (341mg, 2.47mmol) were added to DMF (5mL), and the reaction solution was heated at 80°C Stirring was continued for 16 hours. After filtration, the residue was purified by C18 reverse column to obtain compound 77-4 (200 mg, yield 38.4%).
  • ESI-MS: m/z 422.9 [M+H] + .
  • Step 5 Compound 77-4 (200mg, 0.47mmol), acetamide (165mg, 2.8mmol), Pd 2 dba 3 (43mg, 0.05mmol), X-phos (45mg, 0.09mmol), cesium carbonate (913mg, 2.8 mmol) was dissolved in 1,4-dioxane (5 mL), and after replacing nitrogen, the reaction solution was stirred at 80°C for 16 hours. The product compound L77 (18 mg, yield 21%) was obtained by preparative HPLC (NH4HCO3).
  • Step 2 Dissolve compound 79-1 (1.0g, 5.3mmol), triisopropyl borate (2g, 10.6mmol) in tetrahydrofuran (20mL) under a dry ice ethanol bath, and add 2.5M n- Butyllithium (4.2ml, 10.6mmol). The reaction solution was stirred at -78°C for 3 hours under the protection of nitrogen, and stirred at room temperature for one hour. The reaction solution was adjusted to pH 6 with 1N HCl, and extracted three times with ethyl acetate.
  • Step 3 Compound 79-2 and 2-chloro-6-hydroxy-quinoline were used as raw materials, referring to the preparation method in Step 2 of Example 1, to obtain Compound 79-3.
  • ESI-MS: m/z 253.0 [M+H] + .
  • Step 5 Compound 79-4 (200mg, 0.49mmol) was dissolved in dioxane (5mL), and acetamide (115mg, 1.96mmol), cesium carbonate (640mg, 1.96mmol), Pd 2 (dba) 3 (45 mg, 0.049 mmol), X-PHOS (47 mg, 0.098 mmol). After nitrogen replacement, the reaction solution was stirred at 80°C for 4 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • Step 2 using compound 80-1 and compound v1-1 as raw materials, referring to the preparation method in step 2 of Example 1, the product L80 was obtained.
  • ESI-MS: m/z 480.3 [M+H] + .
  • Step 1 5-bromo-2-chloro-3-methylpyrimidin-4 (3H)-one (5g, 0.02mol), ethylamine hydrochloride (2.5g, 0.03mol) and DIEA (10.4g, 0.08 mmol) was dissolved in THF (35 mL), and the reaction solution was stirred overnight at 65° C. after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate/water (30 mL x 3).
  • Step 2 will synthesize 5-bromo-2-(ethylamino)-3-methylpyrimidin-4(3H)-one (3.7g, 16mmol), (Boc) 2 O (10.5g, 48mmol), TEA (4.8 g, 48 mmol) and DMAP (390 mg, 3.2 mmol) were dissolved in THF (200 mL). After nitrogen replacement, the reaction solution was stirred overnight in an oil bath at 65°C. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3).
  • Step 3 tert-butyl (5-bromo-1-methyl-6-oxyl-1,6-dihydropyrimidin-2-yl) (ethyl) carbamate (4.7g, 14.2mmol), Isopropanol pinacol borate (5.26g, 28.3mmol) was dissolved in THF (80mL), and n-butyllithium (2.5M, 11.3mL) was added slowly at -78°C. The reaction solution was reacted at -78°C for 2 h and then warmed to room temperature.
  • Step 4 2-chloro-6-hydroxy-quinoline (2g, 11.1mmol) and tert-butylethyl (1-methyl-6-oxo-5-(4,4,5,5-tetramethyl 1,3,2-Dioxybenzaldehyde-2-yl)-1,6-dihydropyrimidin-2-yl)carbamate (9.4g, 16.7mmol), dissolved in 1,4-diox Hexacyclic (120 mL), potassium carbonate (4.6 g, 33.3 mmol), water (12 mL) and Pd(dppf)Cl2 (811 mg, 1.0 mol) were added to the solution. After nitrogen replacement, the reaction solution was stirred in an oil bath at 75° C. for 3 hours.
  • Step 5 Dissolve N-(3-fluoro-4-iodopyridin-2-yl)acetamide (500 mg, 1.78 mmol) in acetic acid (10 mL), and add hydrochloric acid solution (1 mL) to the above solution. The reaction solution was stirred at 60°C for 16 hours.
  • Step 6 Mix 3-fluoro-4-iodopyridin-2-amine (410mg, 1.72mmol), tert-butylethyl (5-(6-hydroxyquinolin-2-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-2-yl) carbamate (450mg, 1.14mmol) and potassium carbonate (1.11g, 3.41mmol) were dissolved in NMP (10mL), and after nitrogen replacement, the above solution was Added cuprous iodide (215 mg, 1.14 mmol) and TMHD (418 mg, 2.27 mmol). Nitrogen was replaced again, and the reaction solution was stirred at 100° C. for 18 hours.
  • ESI-MS: m/z 507.0 [M+H] + .
  • Step 1 5-(6-((2-bromopyridin-4-yl)oxy)quinolin-2-yl)-N-isopropyl-4-methoxypyrimidin-2-amine (125mg, 0.269mmol), methyl carbamate (40mg, 0.537mmol) and cesium carbonate (263mg, 0.807mmol) were dissolved in 1,4-dioxane (4mL), then X-phos (13mg, 0.027mmol) and Pd 2 (dba) 3 (25 mg, 0.027 mmol). After nitrogen replacement, the reaction solution was stirred at 90°C for 16 hours.
  • Step 2 Dissolve 87-1 (80 mg, 0.174 mmol) in acetic acid (2 mL), and add hydrobromic acid (281 mg, 1.39 mmol, 40%) to the above solution. The reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated. Triethylamine (0.5 mL) was added to the residue, followed by DMF (2.5 mL), filtered, and the filtrate was subjected to preparative HPLC (FA) to obtain the product L87 (25.2 mg, yellow solid, yield 32.5% ).
  • Step 2 Dissolve 89-1 (600mg, 1.11mmol), tert-butyl carbamate (1.3g, 11.1mmol) and cesium carbonate (1.09mg, 3.33mmol) in 1,4-dioxane (15mL) , under nitrogen protection, X-phos (53mg, 0.11mmol) and Pd 2 (dba) 3 (102mg, 0.11mmol) were added to the above solution. The reaction solution was stirred at 90°C for 16 hours.
  • Step 3 Dissolve 89-2 (350mg, 0.67mmol) in dichloromethane (10mL), and add trifluoroacetic acid (3mL). The reaction was stirred at room temperature for 1.5 hours. Water (60 mL) was added to the reaction solution, and the aqueous phase was washed with ethyl acetate (200 mL).
  • Step 1 tert-butyl (5-(6-((2-bromopyridin-4-yl)oxy)quinolin-2-yl)-1-methyl-6-oxyl-1,6-di Hydropyrimidin-2-yl) (ethyl) carbamate (prepared according to the method of compound 86-1, 210mg, 0.38mmol), x-phos (72mg, 0.152mmol), methyl carbamate (85.5mg, 1.14 mmol), cesium carbonate (370mg, 1.14mmol) and Pd 2 (dba) 3 (70mg, 0.076mmol) were dissolved in 1,4-dioxane (15mL), and the reaction solution was stirred at 85°C for 3 Hour.
  • Step 2 tert-butyl (5-(6-((2-acetylaminopyridin-4-yl)oxy)quinolin-2-yl)-1-methyl-6-oxyl-1,6- Dihydropyrimidin-2-yl)(ethyl)carbamate (200 mg, 0.36 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2.5 mL) was added to the solution. After nitrogen replacement, the reaction solution was stirred at 85°C for 3 hours. After the reaction, adjust to neutral with saturated NaHCO 3 solution, and filter. The solid was slurried with methanol/dichloromethane to afford compound L83 (28 mg, 17% yield).
  • Step 1 5-(6-hydroxy-1,8-naphthyridin-2-yl)-2-(isopropylamino)-3-methyl-4(3H)-pyrimidinone (400mg, 1.28mmol), 2-Bromo-4-fluoropyridine (340mg, 1.93mmol), potassium carbonate (354mg, 2.57mmol) were added to DMF (5mL), and the reaction solution was stirred at 80°C for 16 hours.
  • Step 2 5-(6-((2-bromopyridin-4-yl)oxy)-1,8-naphthyridin-2-yl)-2-(isopropylamino)-3-methyl- 4(3H)-pyrimidinone (100mg, 0.2mmol), methyl carbamate (96mg, 1.28mmol), Pd 2 dba 3 (18.3mg, 0.02mmol), X-phos (19.1mg, 0.04mmol), cesium carbonate (174mg, 0.54mmol) was dissolved in 1,4-dioxane (2mL), and the reaction solution was stirred at 100°C for 16 hours after replacing nitrogen.
  • Embodiment 98 Preparation of Compound L98
  • Step 1 Add 19-6 (425mg, 1.37mmol) and cesium carbonate (1.24g, 4.11mmol) into DMF (9mL), and add 2,3,4-trichloropyridine (250mg, 1.37mmol) to the above solution .
  • the reaction solution was stirred at 90°C for 17 hours.
  • ESI-MS: m/z 456.9 [M+H] + .
  • Step 2 98-1 (350mg, 0.768mmol), tert-butyl carbamate (900mg, 7.67mmol) and cesium carbonate (750mg, 2.3mmol) were dissolved in 1,4-dioxane (9mL), nitrogen Under protection, X-phos (36.5 mg, 0.077 mmol) and Pd 2 (dba) 3 (71 mg, 0.077 mmol) were added to the above solution. The reaction solution was stirred at 100°C for 24 hours.
  • Embodiment 99 Preparation of Compound L99
  • Step 3 Dissolve 99-2 in 1,4-dioxane hydrochloric acid solution (5 mL), and after nitrogen replacement, the reaction solution was stirred at 20° C. for 2 hours.
  • the product L99 25 mg, yellow solid, yield 11.6% was obtained by preparative HPLC (FA).
  • Embodiment 100 Preparation of Compound L100
  • Step 2 Dissolve 100-1 in dichloromethane (6 mL), add trifluoroacetic acid (1.5 mL) dropwise at room temperature, and stir the reaction solution at 20° C. for 1.5 hours. The reaction solution was concentrated, and the pH of the residue was adjusted to 7-8 with saturated sodium bicarbonate solution, filtered, and the mixture was concentrated. The residue was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain the product L100 (19.5 mg, yellow solid, yield 14.8%).
  • Embodiment 101 Preparation of Compound L101
  • Embodiment 102 Preparation of compound L102
  • Embodiment 103 Preparation of Compound L103
  • ESI-MS: m/z 437.9 [M+H] + .
  • Embodiment 104 Preparation of Compound L104
  • Embodiment 105 Preparation of Compound L105
  • Step 2 105-1 (450 mg, 2 mmol) was dissolved in 40% HBr acetic acid (40 mL) and 40% HBr aqueous solution (10 mL), and the reaction solution was stirred at 130° C. for 12 hours after nitrogen replacement.
  • ESI-MS: m/z 284.0 [M+H] + .
  • Step 4 105-3 (260mg, 0.6mmol), x-phos (114mg, 0.24mmol), tert-butyl carbamate (421.7mg, 3.6mmol) cesium carbonate (1.1g, 3.6mmol) and Pd 2 (dba ) 3 (110 mg, 0.12 mmol) was dissolved in 1,4-dioxane (20 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. Filtration, concentration, and EA/PE slurry gave the crude product 105-4 (200 mg, yellow solid).
  • ESI-MS: m/z 409.9[M+H-100] +
  • Embodiment 106 Preparation of Compound L106
  • ESI-MS: m/z 439.9 [M+H] + .
  • Step 2 106-1 (100mg, 0.23mmol), x-phos (44mg, 0.092mmol), acetamide (81.4mg, 1.38mmol), cesium carbonate (224mg, 0.69mmol) and Pd 2 (dba) 3 ( 42mg, 0.046mmol) was dissolved in 1,4-dioxane (20mL), and the reaction solution was stirred at 85°C for 3 hours after nitrogen replacement. It was filtered, concentrated, and purified by preparative HPLC (0.1% aqueous formic acid/acetonitrile) to obtain the product L106 (4 mg, yield 4.1%).
  • Embodiment 107 Preparation of compound L107
  • ESI-MS: m/z 431.0 [M+H] + .
  • Embodiment 108 Preparation of Compound L108
  • ESI-MS: m/z 389.0 [M+H] + .
  • ESI-MS: m/z 545.8 [M+H] + .
  • Step 3 108-2 (100mg, 0.18mmol), x-phos (35mg, 0.074mmol), acetamide (32mg, 0.55mmol) cesium carbonate (180mg, 0.55mmol) and Pd 2 (dba) 3 (34mg, 0.0368 mmol) was dissolved in 1,4-dioxane (5 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and then filtered. The organic phase was concentrated and then PE slurried to obtain the crude product 108-3 (80 mg, yellow solid).
  • ESI-MS: m/z 523.0[M+H] +
  • Step 4 Dissolve 108-3 (80 mg, 0.15 mmol) in TFA (5 mL). After nitrogen replacement, the reaction solution was stirred at 65°C for 12 hours. After the reaction was completed, it was adjusted to neutral with saturated NaHCO 3 solution, then concentrated by filtration, and the residue was purified by HPLC (0.1% FA) to obtain L108 (13 mg, yellow solid, yield 22%).
  • Embodiment 109 Preparation of Compound L109
  • Step 1 Dissolve 5-(6-hydroxyquinolin-2-yl)-3-methyl-2-(methylamino)pyrimidin-4(3H)-one (200mg, 0.7mmol) in DMF (5mL) , NaH (42 mg, 1.05 mmol) was added to the above solution. The reaction solution was stirred under ice bath for 15 minutes, and then 2,4-dichloropyrimidine (156 mg, 1.05 mmol) was added to the above solution. Stir at room temperature for two hours. The reaction solution was adjusted to pH 7 with saturated ammonium chloride solution, and extracted three times with ethyl acetate.
  • Step 2 109-1 (120mg, 0.30mmol), 1-methyl-1H-pyrazol-4-amine hydrochloride (81mg, 0.61mmol), cesium carbonate (293mg, 0.9mmol), 2-bicyclohexyl Phosphine-2',4',6'-triisopropylbiphenyl (28mg, 0.06mmol), tris(dibenzylideneacetone)dipalladium (28mg, 0.03mmol) in dioxane (5mL) , and the reaction solution was stirred at 100° C. for 16 hours after nitrogen replacement.
  • Embodiment 110 Preparation of compound L110
  • Step 2 110-1 (130mg, 0.304mmol), tert-butyl carbamate (356mg, 3.04mmol) and cesium carbonate (298mg, 0.91mmol) were dissolved in 1,4-dioxane (4mL), nitrogen Under protection, X-phos (14.5 mg, 0.03 mmol) and Pd 2 (dba) 3 (28 mg, 0.03 mmol) were added to the above solution. The reaction solution was stirred at 110° C. for 20 hours.
  • Embodiment 111 Preparation of Compound L111
  • Step 1 Dissolve 2-(2-(ethylamino)-4-methoxypyrimidin-5-yl)quinolin-6-ol (750mg, 2.5mmol) in DMF (20mL) and add to the above solution 2-Bromo-4-fluoropyridine (1.3 g, 7.5 mmol), potassium carbonate (1.0 g, 7.5 mmol) were added. The reaction solution was stirred at 90°C for 16 hours. Add water (20mL) to the reaction solution and extract with ethyl acetate (30mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent.
  • 2-Bromo-4-fluoropyridine 1.3 g, 7.5 mmol
  • potassium carbonate 1.0 g, 7.5 mmol
  • Step 2 Dissolve 111-1 (183 mg, 0.88 mmol) in dioxane (5 mL), and add ((6-1,1'-bis(diphenylphosphino)ferrocene dichloro Palladium (II) (29mg, 0.04mmol), potassium carbonate (3.4g, 1.32mmol). After nitrogen replacement, the reaction solution was stirred at 80°C for 16 hours. The reaction solution was concentrated to remove dioxane, and water (20mL ), extracted with ethyl acetate (30mL x3).
  • Embodiment 112 Preparation of Compound L112
  • Step 1 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (500mg, 2.24mmol), methylamine hydrochloride (268mg, 2.69mmol) and DIEA (289mg, 6.72mmol) It was dissolved in THF (5 mL), and the reaction solution was reacted overnight at room temperature to obtain 112-1 (500 mg, white solid, yield 89%).
  • ESI-MS: m/z 250.1, 252.0 [M+H] + .
  • Step 2 Dissolve 112-1 (350mg, 1.4mmol), x-phos (66mg, 0.14mmol), potassium acetate (411mg, 4.2mmol) and Pd 2 (dba) 3 (64mg, 0.07mmol) in 1,4 - In dioxane (10 mL), the reaction solution was replaced with nitrogen and stirred at 70° C. for 5 hours to obtain a reaction solution of compound 112-2. After the LCMS monitoring reaction, there is no need for post-processing, and it can be directly put into the next step.
  • Embodiment 113 Preparation of Compound L113
  • ESI-MS: m/z 452.1 [M+H] + .
  • Step 2 113-1 (100mg, 0.22mmol), x-phos (42mg, 0.08mmol), acetamide (39mg, 0.66mmol) cesium carbonate (218mg, 0.66mmol) and Pd 2 (dba) 3 (40mg, 0.04 mmol) was dissolved in 1,4-dioxane (5 mL), and the reaction solution was stirred at 85° C. for 1 hour after nitrogen replacement. It was filtered, concentrated, and purified by preparative HPLC (0.1% aqueous formic acid/acetonitrile) to obtain the product L113 (37 mg, yellow solid, yield 38.9%).
  • Embodiment 114 Preparation of Compound L114
  • Step 1 5-(6-hydroxyquinolin-2-yl)-3-methyl-2-(methylamino)pyrimidin-4(3H)-one (282mg, 1.0mmol) was dissolved in DMF (2.0 mL), potassium carbonate (276mg, 2.0mmol) and potassium tert-butoxide (112mg, 1.0mmol) were added, and stirred at room temperature for 5 minutes. Add 2,3,4-trifluoropyridine (200mg, 1.5mmol) and react at room temperature for 2 hours.
  • Embodiment 115 Preparation of Compound L115
  • Embodiment 116 Preparation of Compound L116
  • Step 1 Dissolve 2,3-difluoropyridine (11.5g, 100mmol) in anhydrous tetrahydrofuran (200mL), cool to -78°C, and slowly add 2.5M n-butyllithium n-hexane solution (42mL, 105mmol ). The reaction was stirred at -78°C for 1 hour. Hexachloroethane (26g, 110mmol) was added, and the reaction solution was reacted at -78°C for 1 hour. The completion of the reaction was monitored by TLC, and the reaction was quenched with saturated aqueous ammonium chloride solution (200mL), extracted with ether (300mL x 2), and dried.
  • Step 2 4-chloro-2,3-difluoropyridine (13g, 87.2mmol), anhydrous potassium fluoride (20.2g, 349mmol) and tetramethylammonium chloride (1.9g, 17.4mmol) were added to di Methyl sulfoxide (100 mL) was replaced with nitrogen, and heated to 150° C. in an oil bath under nitrogen protection and stirred for 17 hours. The reaction liquid was cooled to room temperature and distilled under reduced pressure (70°C, 0.02MPa) to obtain 2,3,4-trifluoropyridine (5.5g, yield 47%).
  • ESI-MS: m/z 421.9 [M-PMB+1] + .
  • Embodiment 117 Preparation of Compound L117
  • ESI-MS: m/z 541.3 [M+H] + .
  • Step 3 Dissolve 117-2 (80mg, 0.15mmol) in acetonitrile (2.0mL), add methyl chloroformate (21mg, 0.22mmol) and indium powder (3.0mg, 0.03mmol), heat to 30°C and stir 72 hours. Concentration afforded 117-3 (used directly in the next step).
  • ESI-MS: m/z 599.0 [M+H] + .
  • Embodiment 118 Preparation of Compound L118
  • Embodiment 119 Preparation of compound L119
  • Step 1 2-(dimethylamino)-5-(6-hydroxyquinolin-2-yl)-3-methylpyrimidin-4(3H)-one (prepared according to the method of compound 4-1, 90mg, 0.30mmol), 2,3,4-trifluoropyridine (60%) (100mg, 0.45mmol), potassium carbonate (124.2mg, 0.90mmol) and potassium tert-butoxide (84mg, 0.75mmol) were dissolved in DMF (5mL) , the reaction solution was stirred at 95° C. for 1 h after nitrogen replacement.
  • Step 2 Dissolve 119-1 (60mg, 0.146mmol), PMB-NH 2 (60mg, 0.439mmol) and DIEA (75mg, 0.584mmol) in NMP (5mL), and stir the reaction solution at 140°C for 12h after nitrogen replacement .
  • ESI-MS: m/z 527.0 [M+H] + .
  • Step 3 119-2 was dissolved in TFA (5 mL), and the reaction solution was stirred at 60° C. for 30 min after nitrogen replacement. After the reaction was completed, it was concentrated, and the residue was purified by HPLC (0.1% NaHCO 3 ) to obtain the product L119 (20 mg, yellow solid, yield 48.8%).
  • ESI-MS: m/z 407.1[M+H] + .
  • Embodiment 120 Preparation of Compound L120
  • Step 2 Dissolve 120-1 (85mg, 0.192mmol), tert-butyl carbamate (226mg, 1.93mmol) and cesium carbonate (188mg, 0.576mmol) in 1,4-dioxane (3mL), nitrogen Under protection, X-phos (10 mg, 0.02 mmol) and Pd 2 (dba) 3 (18 mg, 0.02 mmol) were added to the above solution. The reaction solution was stirred at 110° C. for 20 hours.
  • Embodiment 121 Preparation of compound L121
  • Step 1 Dissolve 5-(6-hydroxyquinolin-2-yl)-2-(isopropylamino)-3-methylpyrimidin-4(3H)-one (500mg, 1.61mmol) in DMF (10mL) , the reaction solution was stirred at room temperature for 30 minutes after nitrogen replacement. Then 1a (224 mg, 1.61 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. The residue was added to water (20 mL), extracted with ethyl acetate (20 mL x 2).
  • Embodiment 122 Preparation of Compound L122
  • Embodiment 123 Preparation of Compound L123
  • Embodiment 124 Preparation of Compound L124
  • Step 2 124-1 (43mg, 0.56mmol), cesium carbonate (182.5mg, 0.56mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13mg, 0.028mmol ) and tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol) were dissolved in dioxane (5 mL), and the reaction solution was stirred at 100° C. for 1 h after nitrogen replacement. The reaction solution was cooled to room temperature and filtered, the organic phase was concentrated and the residue was purified by HPLC (0.1% FA) to obtain the product L124 (4 mg, yellow solid).
  • Embodiment 125 Preparation of Compound L125
  • Step 1 tert-butyl ethyl (5-(6-hydroxyl-1,8-naphthyridin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl ) carbamate (refer to tert-butylethyl (5-(6-hydroxyquinolin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino
  • Preparation method of formic acid ester Dissolve 300mg, 0.756mmol) in DMF (6.0mL), add potassium carbonate (205mg, 1.5mmol) and potassium tert-butoxide (92mg, 0.756mmol), stir at room temperature for 5 minutes.
  • Step 2 Dissolve 125-1 (150mg, 0.294mmol), (4-methoxyphenyl)methanamine (160mg, 1.18mmol) and cesium carbonate (288mg, 0.88mmol) in 1,4-dioxane (6 mL), under nitrogen protection, X-phos (14 mg, 0.03 mmol) and Pd 2 (dba) 3 (27 mg, 0.03 mmol) were added to the above solution. The reaction solution was stirred at 120°C for 26 hours.
  • Embodiment 126 Preparation of Compound L126
  • Step 1 tert-butyl ethyl (5-(6-hydroxyl-1,8-naphthyridin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl ) carbamate (200mg, 0.504mmol) and potassium carbonate (200mg, 1.48mmol) were added to DMF (5mL), and 2,3,4-trichloropyridine (100mg, 0.55mmol) was added to the above solution. The reaction solution was stirred at 90°C for 16 hours.
  • ESI-MS: m/z 542.9 [M+H] + .
  • Step 3 Dissolve 126-2 (65 mg, 0.124 mmol) in dichloromethane (3 mL), and add trifluoroacetic acid (0.75 mL) dropwise into the above solution at room temperature. The reaction solution was stirred at 20°C for 1 hour. Water (25 mL) was added to the reaction solution, and the aqueous phase was washed with ethyl acetate (50 mL).
  • test compound was prepared into 100X DMSO solution with the concentration required for the experiment, and 50 nl of the prepared compound solution was added in a 384-well plate (Corning 3575), wherein 100% inhibition control well (C1), 0% inhibition control well (C2) and DMSO was added to 100% phosphorylation control wells (C3).
  • %Pho (1-((ERX C3520nm-C3450nm)/((C1450nm-C3450nm)+ERX(C3520nm-C1520nm))))x100%
  • Inhibition rate (IR) (1-% Photest compound)/(% Pho C2) x 100%
  • This experiment was detected by ELISA method.
  • THP-1 cells in the logarithmic growth phase plant them in a 96-well plate (Costar 3894) at an appropriate concentration of 45 ⁇ L, add 5 ⁇ L of DMSO solutions of test compounds at different concentrations (only DMSO is added to the control wells), and store at 37 ° C, 5% Cultivate under CO 2 conditions.
  • DMSO solutions of test compounds at different concentrations (only DMSO is added to the control wells)
  • DMSO solutions of test compounds only DMSO is added to the control wells
  • store at 37 ° C, 5% Cultivate under CO 2 conditions After 1 hour, add 10 ⁇ L hMCSF PBS solution (Peprotech 300-25) (blank wells only add PBS), incubate at room temperature for 5 minutes, take it out, and directly add 60 ⁇ L 2X cell lysate (CST 9806S) ( CST 5872S), shake at 800rpm for 1 minute, and store at -80°C until use.
  • the Capture solution was prepared, 100 ⁇ L per well was added to a high binding 96-well plate (Costar 42592), and incubated overnight at room temperature.
  • Inhibition% [1-(Total mean(Inhibitor)–total mean(background))/(Total mean(blank)–total mean(background))] ⁇ 100%
  • the compound of table 2 is to the inhibitory activity of THP-1 cell CSF-1R phosphorylation level
  • the LC/MS/MS method was used to determine the drug concentration in the blood plasma of mice at different times after intravenous injection and oral gavage administration of each test compound, to study the pharmacokinetic behavior of each test compound in mice, and to evaluate its Pharmacokinetic characteristics.
  • mice healthy adult male ICR mice (weight 25-40g, 12 mice, the mice in the intravenous injection group were free to drink water and food, and the intragastric administration group was fasted overnight, and free to drink water and food after 4 hours of administration), provided by Beijing Vital Provided by River Laboratory Animal Co.LTD;
  • Administration method and dose select animals that meet the experimental requirements before administration, and weigh the marks. ICR mouse tail vein administration (2mg/kg, 5% DMSO+30% (10% Solutol HS15) + 65% (20% Captisol, pH 7.4)) and intragastric administration (10mg/kg, 5% DMSO+ 30% (10% Solutol HS15) + 65% (20% Captisol, pH 7.4)).
  • Blood sample collection Before collecting blood samples, bind the mice, each administered mouse at the scheduled blood collection time point (intravenous administration: respectively at 0.083, 0.25, 0.5, 1, 2, 4, 7 days after administration) , 24h blood collection, a total of 8 time points; intragastric administration: blood collection at 0.083, 0.25, 0.5, 1, 2, 4, 7, 24h after administration, a total of 8 time points), blood collection through the canthus vein About 100 ⁇ L.
  • the whole blood was transferred to a 1.5mL test tube pre-added with K 2 EDTA (Sigma-ACDRICH, WXBB0768), centrifuged for 6min (8000rpm, 4°C), and the plasma was separated. The whole process was completed within 15min after blood collection. All samples need to be stored in a -20°C freezer until sample analysis.
  • Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry (model: Triple QuadTM 4000), and the chromatographic column was Waters XBridge-C18 (2.1 ⁇ 50mm, 3.5 ⁇ m).
  • Preparation of standard curve prepare a standard curve with a linear range of 1.00-3000 ng/mL of the compound to be tested in blank ICR mouse plasma matrix, and prepare quality control samples with concentrations of 3, 500, 2400 ng/mL at low, middle and high concentrations.

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Abstract

The present application relates to a substituted pyrimidone derivative, and a pharmaceutically acceptable salt, stereoisomer, pharmaceutical composition and medical use thereof. The substituted pyrimidone derivative is a compound having a structure represented by formula (I), and the compound has significant CSF-1R selective inhibitory activity, and is very practical.

Description

取代的嘧啶酮衍生物、其药物组合物及医药上的用途Substituted pyrimidinone derivatives, their pharmaceutical compositions and their use in medicine
相关申请related application
本申请要求2021年12月31日申请的，申请号为202111678390.4，名称为“取代的嘧啶酮衍生物、其药物组合物及医药上的用途”的中国专利申请的优先权，在此将其全文引入作为参考。This application claims the priority of the Chinese patent application filed on December 31, 2021, with the application number 202111678390.4, entitled "Substituted pyrimidinone derivatives, their pharmaceutical composition and their use in medicine", the full text of which is hereby Incorporated by reference.
技术领域technical field
本发明涉及医药技术领域，特别涉及一种取代的嘧啶酮衍生物、其药学上可接受的盐、立体异构体、药物组合物及医药上的用途。The invention relates to the technical field of medicine, in particular to a substituted pyrimidinone derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition and a pharmaceutical application thereof.
背景技术Background technique
巨噬细胞集落刺激因子1受体(CSF-1R)属于Ⅲ型受体酪氨酸激酶家族，配体为巨噬细胞集落刺激因子1(CSF-1)。CSF1/CSF-1R的信号转导通路对巨噬细胞的分化和存活至关重要。在各类实体肿瘤中，CSF1/CSF-1R的过表达广泛存在，对肿瘤相关的巨噬细胞(TAMs)的调控，在肿瘤恶性增殖、转移和微环境调控等方面发挥着重要的作用。Macrophage colony-stimulating factor 1 receptor (CSF-1R) belongs to the type III receptor tyrosine kinase family, and its ligand is macrophage colony-stimulating factor 1 (CSF-1). The CSF1/CSF-1R signal transduction pathway is critical for the differentiation and survival of macrophages. In various solid tumors, the overexpression of CSF1/CSF-1R exists widely, and it plays an important role in the regulation of tumor-associated macrophages (TAMs) in the malignant proliferation, metastasis and microenvironmental regulation of tumors.
TAMs是一类具有较高可塑性的免疫细胞亚群，能够像M1型和M2型进行极化。其中M1型细胞能够分泌白细胞介素-12(IL-12)和IL-23，产生一氧化氮(NO)、活性氧(ROS)等细胞杀伤、促炎及趋化因子，对肿瘤细胞起到杀伤作用；M2型细胞能够分泌CCL17、CCL18、M-CSF、IL-6、IL-10及基质金属蛋白酶(MMP)等趋化因子、炎症因子以及基质重塑的酶类，促进肿瘤增殖，抑制T细胞，激活NK细胞。TAMs are a class of immune cell subsets with high plasticity, which can be polarized like M1 and M2 types. Among them, M1 cells can secrete interleukin-12 (IL-12) and IL-23, produce nitric oxide (NO), reactive oxygen species (ROS) and other cell killing, pro-inflammatory and chemokines, which play a role in tumor cells. Killing effect; M2 cells can secrete chemokines, inflammatory factors and matrix remodeling enzymes such as CCL17, CCL18, M-CSF, IL-6, IL-10 and matrix metalloproteinase (MMP), promote tumor proliferation, inhibit T cells, activate NK cells.
研究表明，阻断CSF1/CSF-1R通路可显著降低巨噬细胞在肿瘤部位的浸润，抑制巨噬细胞向M2型TAMs极化，提高细胞毒性T细胞活性，从而抑制肿瘤生长增殖、减少肿瘤转移。因此，通过抑制CSF-1R信号传导来抑制巨噬细胞的存活或活化有望成为癌症免疫疗法的一种重要策略。因此开发新的高活性和高选择性的CSF-1R抑制剂具有重要的临床意义。Studies have shown that blocking the CSF1/CSF-1R pathway can significantly reduce the infiltration of macrophages in tumor sites, inhibit the polarization of macrophages to M2 TAMs, and increase the activity of cytotoxic T cells, thereby inhibiting tumor growth and proliferation and reducing tumor metastasis . Therefore, inhibiting macrophage survival or activation by inhibiting CSF-1R signaling is expected to be an important strategy for cancer immunotherapy. Therefore, it is of great clinical significance to develop new highly active and highly selective CSF-1R inhibitors.
发明内容Contents of the invention
本发明的目的是提供一种对CSF-1R活性高、选择性好的取代的嘧啶酮衍生物。The purpose of the present invention is to provide a substituted pyrimidinone derivative with high activity and good selectivity to CSF-1R.
本发明第一方面提供了一种具有式(I)所示的结构的化合物、或其药学上可接受的盐、或其立体异构体：The first aspect of the present invention provides a compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
Figure PCTCN2022143403-appb-000001
Figure PCTCN2022143403-appb-000001
其中，in,
Z 1为CR z1或N；Z 2为CR z2或N；Z 3为CR z3或N；且Z 1、Z 2、Z 3不同时为N； Z 1 is CR z1 or N; Z 2 is CR z2 or N; Z 3 is CR z3 or N; and Z 1 , Z 2 , and Z 3 are not N at the same time;
Z 4为CR z4或N；Z 5为CR z5或N；且Z 4、Z 5不同时为N； Z 4 is CR z4 or N; Z 5 is CR z5 or N; and Z 4 and Z 5 are not N at the same time;
Z 6为CR z6或N； Z 6 is CR z6 or N;
R z1、R z2、R z3、R z4、R z5、R z6分别独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1- 3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-OC(O)C 1- 8烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-C(O)NR 01R 02或-NR a1R b1；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1- 3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷 基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R z1 , R z2 , R z3 , R z4 , R z5 , and R z6 are independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl ( preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl ), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1 -6 alkyl, more preferably -C(O)OC 1-3 alkyl) , -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -C(O)NR 01 R 02 or -NR a1 R b1 ; wherein the C 1-8 alkyl, C 3-8 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium , halogen (preferably fluorine or chlorine), cyano , nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogen Substituted C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O )NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6-membered heterocycloalkyl;
环A为苯环或5至10元杂芳环；Ring A is a benzene ring or a 5- to 10-membered heteroaromatic ring;
L为氢、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-NR 03R 04、-C(O)NR 01R 02或5至6元杂芳环；其中所述C 1-8烷基、5至6元杂芳环各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2- 4烯基、C 2-4炔基、羟基取代C 1-3烷基、羟基取代的C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR 03R 04、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； L is hydrogen, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -NR 03 R 04 , -C(O ) NR 01 R 02 or 5 to 6 membered heteroaryl ring; wherein the C 1-8 alkyl, 5 to 6 membered heteroaryl ring are each independently unsubstituted or are independently selected from 1, 2 or 3 The following substituents are substituted: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2- 4 alkynyl, hydroxy substituted C 1-3 alkyl, hydroxy substituted C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR 03 R 04 , - SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1 -3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
R 0为氢、氰基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)NR 01R 02、-NR 03R 04或-SO 2C 1-8烷基；其中所述C 1-8烷基为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR 03R 04、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R is hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C (O) NR 01 R 02 , -NR 03 R 04 or -SO 2 C 1-8 alkyl; wherein the C 1-8 alkyl is unsubstituted or 1, 2 or 3 independently selected from the following Substituent group substitution: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR 03 R 04 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
R 03、R 04分别独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)C 3-8环烷基(优选为-C(O)C 3-6环烷基)、-C(O)NR 01R 02、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 3-8环烷基(优选为-SO 2C 3-6环烷基)、C 3-8环烷基(优选为C 3-6环烷基)或5至6元杂芳环；其中所述C 1-8烷基、-C(O)C 1-8烷基、C 3-8环烷基、5至6元杂芳环各自独立地为未被取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R 03 and R 04 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)C 1-8 alkyl ( Preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)C 3-8 cycloalkyl (preferably -C(O) C 3-6 cycloalkyl), -C(O)NR 01 R 02 , -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C (O)OC 1-3 alkyl), SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5 to 6 membered heteroaromatic ring; wherein The C 1-8 alkyl, -C(O)C 1-8 alkyl, C 3-8 cycloalkyl, and 5 to 6 membered heteroaromatic rings are each independently unsubstituted or replaced by 1, 2 or 3 Substituents each independently selected from the group consisting of: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkene Base, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 -SO 2 C 1-3 alkyl, -S(O)C 1 -3 Alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3- 6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
n为0、1、2或3；n is 0, 1, 2 or 3;
R 1、R 2分别独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-NR 05R 06、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)或3至8元杂环；其中所述C 1-8烷基、3至8元杂环各自独立地为未被取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR 05R 06、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、-C 1-3烷基OC 1-3烷基和3至6元杂环； R 1 and R 2 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -NR 05 R 06 , -C(O)OC 1-8 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -C (O) C 1-8 alkyl (preferably -C (O) C 1-6 alkyl, more preferably -C (O) C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 3 to 8 membered heterocycle; wherein the C 1-8 alkyl, 3 to 8 membered heterocycle are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, halogenated C 1-3 alkoxy, -NR 05 R 06 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, -C 1-3 alkyl OC 1-3 alkyl and 3 to 6 membered heterocycle;
R 05、R 06分别独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1-3烷基、-C(O)C 3- 8环烷基(优选为-C(O)C 3-6环烷基)、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、-SO 2C 3-8环烷基(优选为-SO 2C 3-6环烷基)、C 3-8环烷基(优选为C 3-6环烷基)或5至6元杂芳环；其中所述C 1-8烷基、C 3-8环烷基、5至6元杂芳环各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1- 3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；或者R 05、R 06与相连接的氮原子形成3至7元饱和或部分不饱和单杂环；其中所述3至7元饱和或部分不饱和单杂环为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、C 1-3烷氧基取代的C 1-3烷基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1- 3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R 05 and R 06 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)C 1-3 alkyl, -C(O)C 3-8 cycloalkyl (preferably -C(O)C 3-6 cycloalkyl), -C(O) NR 01 R 02 , -C(O)OC 1-3 alkyl , -SO 2 C 1-3 alkyl, -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5 to 6 membered heteroaryl ring; wherein said C 1-8 alkyl, C 3-8 cycloalkyl, 5 to 6 membered heteroaryl ring are each independently unsubstituted or replaced by 1, 2 or 3 substituents independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2- 4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O )C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O ) OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6-membered heterocycloalkyl; or R 05 , R 06 form a 3 to 7-membered saturated or partially unsaturated monoheterocyclic ring with the connected nitrogen atom; wherein the 3 to 6 The 7-membered saturated or partially unsaturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy substituted C 1-3 alkyl, halogenated C 1 -3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1- 3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered hetero Cycloalkyl;
或者R 1、R 2分别与其相连接的氮原子、碳原子共同形成式(i)所示结构：
Figure PCTCN2022143403-appb-000002
其中X为-(CR q1R q2) m-、-(CR q3R q4) t1-O-(CR q5R q6) t2-、-(CR q7R q8) t3-NR q0-(CR q9R q10) t4-； Or R 1 and R 2 respectively form the structure shown in formula (i) together with the nitrogen atom and carbon atom connected to them:
Figure PCTCN2022143403-appb-000002
where X is -(CR q1 R q2 ) m -, -(CR q3 R q4 ) t1 -O-(CR q5 R q6 ) t2 -, -(CR q7 R q8 ) t3 -NR q0 -(CR q9 R q10 ) t4 -;
m为1、2、3或4；m is 1, 2, 3 or 4;
t1、t2、t3、t4各自独立地为0、1、2或3；t1、t2不同时为0；t3、t4不同时为0；t1, t2, t3, t4 are each independently 0, 1, 2 or 3; t1, t2 are not 0 at the same time; t3, t4 are not 0 at the same time;
R q1、R q2各自独立地为氢、氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 2-4烯基、C 2-4炔基、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR 01R 02、-C(O)C 1-8 烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-8烷基，更优选为-OC(O)C 1-8烷基)、-NR a1R b1；或者R q1、R q2与相连接的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述C 1-8烷基、C 3-6环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、3至7元饱和或部分不饱和单环、3至7元饱和或部分不饱和单杂环各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q1 and R q2 are each independently hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR 01 R 02 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O)OC 1 -8 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -OC (O) C 1-8 alkyl (preferably - OC(O)C 1-8 alkyl, more preferably -OC(O)C 1-8 alkyl), -NR a1 R b1 ; or R q1 , R q2 and the connected carbon atoms together form 3 to 7 One-membered saturated or partially unsaturated monocyclic ring or 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, 3 to 7 membered saturated or partially unsaturated monocyclic ring, 3 to 7 membered saturated or partially unsaturated monoheterocyclic ring are each independently unsubstituted or replaced by 1 , 2 or 3 substituents independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkane Oxygen, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkane radical, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3 -6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
R q3、R q4、R q5、R q6、R q7、R q8、R q9、R q10各自独立地为氢、氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR 01R 02、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1- 6烷基，更优选为-C(O)OC 1-3烷基)； R q3 , R q4 , R q5 , R q6 , R q7 , R q8 , R q9 , R q10 are each independently hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1 -8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O) NR 01 R 02 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C( O) OC 1-8 alkyl (preferably -C (O) OC 1- 6 alkyl, more preferably -C (O) OC 1-3 alkyl);
R q0为氢、氘、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、-C(O)NR 01R 02、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)；其中所述C 1-8烷基、C 3-8环烷基各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q0 is hydrogen, deuterium, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkane group), -C(O)NR 01 R 02 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1- 3 alkyl) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl , C 3-8 cycloalkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, nitro , hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkane Oxygen, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
R 01、R 02分别独立地为氢或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)； R 01 and R 02 are independently hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
R a1、R b1各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基；或者R a1、R b1与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 R a1 and R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1 and R b1 together with the connected nitrogen atom form a 4- to 6-membered saturated monohetero ring; the 4 to 6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, nitrate radical, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 Alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), - C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3- 6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
在一些实施例中，Z 1为CR z1或N；Z 2为CR z2；Z 3为CR z3。 In some embodiments, Z 1 is CR z1 or N; Z 2 is CR z2 ; Z 3 is CR z3 .
在一些实施例中，Z 1为CR z1；Z 2为CR z2；Z 3为CR z3。 In some embodiments, Z 1 is CR z1 ; Z 2 is CR z2 ; Z 3 is CR z3 .
在一些实施例中，Z 1为N；Z 2为CR z2；Z 3为CR z3。 In some embodiments, Z 1 is N; Z 2 is CR z2 ; Z 3 is CR z3 .
在一些实施例中，Z 1为CR z1；Z 2为CR z2；Z 3为N。 In some embodiments, Z 1 is CR z1 ; Z 2 is CR z2 ; Z 3 is N.
在一些实施例中，Z 1为CR z1；Z 2为N；Z 3为CR z3。 In some embodiments, Z 1 is CR z1 ; Z 2 is N; Z 3 is CR z3 .
在一些实施例中，Z 4为CR z4；Z 5为CR z5。 In some embodiments, Z 4 is CR z4 ; Z 5 is CR z5 .
在一些实施例中，Z 1为CR z1；Z 2为CR z2；Z 3为CR z3；Z 4为CR z4；Z 5为CR z5。 In some embodiments, Z 1 is CR z1 ; Z 2 is CR z2 ; Z 3 is CR z3 ; Z 4 is CR z4 ; Z 5 is CR z5 .
在一些实施例中，Z 1为N；Z 2为CR z2；Z 3为CR z3；Z 4为CR z4；Z 5为CR z5。 In some embodiments, Z 1 is N; Z 2 is CR z2 ; Z 3 is CR z3 ; Z 4 is CR z4 ; Z 5 is CR z5 .
在一些实施例中，Z 6为N。 In some embodiments, Z6 is N.
在一些实施例中，所述环A中的5至10元杂芳环为5至10元含氮杂芳环。In some embodiments, the 5- to 10-membered heteroaryl ring in the ring A is a 5- to 10-membered nitrogen-containing heteroaryl ring.
在一些实施例中，所述环A为5至6元含氮杂芳环(优选为5至6元含氮杂芳环)或8至10元含氮杂芳环(优选为9至10元含氮杂芳环，更优选为吡啶并5至6元含氮杂芳环)。In some embodiments, the ring A is a 5-6 membered nitrogen-containing heteroaryl ring (preferably a 5-6 membered nitrogen-containing heteroaryl ring) or an 8-10 membered nitrogen-containing heteroaryl ring (preferably a 9-10 membered A nitrogen-containing heteroaromatic ring, more preferably a pyrido 5- to 6-membered nitrogen-containing heteroaromatic ring).
在一些实施例中，所述环A中的5至6元含氮杂芳环为噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环、1,2,3-三嗪环、1,3,5-均三嗪环、1,3,4-三嗪环或四嗪环。In some embodiments, the 5 to 6-membered nitrogen-containing heteroaryl ring in the ring A is a thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2 ,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring , 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, Pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, 1,2,3-triazine ring, 1,3,5-s-triazine ring, 1,3,4-triazine ring or tetra oxazine ring.
在一些实施例中，所述环A为吡啶环、嘧啶环或吡啶并吡咯环(优选为吡啶环)。In some embodiments, the ring A is a pyridine ring, a pyrimidine ring or a pyridopyrrole ring (preferably a pyridine ring).
在一些实施例中，式(I)中
Figure PCTCN2022143403-appb-000003
为
Figure PCTCN2022143403-appb-000004
(优选为
Figure PCTCN2022143403-appb-000005
)。 In some embodiments, in formula (I)
Figure PCTCN2022143403-appb-000003
for
Figure PCTCN2022143403-appb-000004
(preferably
Figure PCTCN2022143403-appb-000005
).
在一些实施例中，所述R 03为氢；R 04为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1- 3烷基、-C(O)C 3-8环烷基(优选为-C(O)C 3-6环烷基)、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、- SO 2C 3-8环烷基(优选为-SO 2C 3-6环烷基)、C 3-8环烷基(优选为C 3-6环烷基)或5至6元杂芳环；其中所述C 1-8烷基、-C(O)C 1-3烷基、C 3-8环烷基、5至6元杂芳环各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 In some embodiments, the R 03 is hydrogen; R 04 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O) C 1- 3 alkyl, -C(O)C 3-8 cycloalkyl (preferably -C(O)C 3-6 cycloalkyl), -C(O)NR 01 R 02 , -C(O )OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5 to 6-membered heteroaromatic ring; wherein said C 1-8 alkyl, -C(O)C 1-3 alkyl, C 3-8 cycloalkyl, The 5 to 6 membered heteroaromatic rings are each independently unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, - NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, - OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
在一些实施例中，所述L中的5至6元杂芳环为噻吩环、呋喃环、噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环或四嗪环；所述5至6元杂芳环为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基(优选为甲基)、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、羟基取代的C 1-3烷基、羟基取代的C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR 03R 04、-SO 2C 1-3烷基(优选为-SO 2CH 3)、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 In some embodiments, the 5 to 6-membered heteroaromatic ring in L is a thiophene ring, a furan ring, a thiazole ring, an isothiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxa Oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring An azole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring or a tetrazine ring; the 5 to 6-membered heteroaryl ring is unsubstituted or is independently selected from 1, 2 or 3 The following substituents are substituted: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl (preferably methyl), C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy substituted C 1-3 alkyl, hydroxy substituted C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR 03 R 04 , -SO 2 C 1-3 alkyl (preferably -SO 2 CH 3 ), -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C( O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
在一些实施例中，所述L为氢、二氟甲基、三氟甲基、-NH 2、-NHCH 3、
Figure PCTCN2022143403-appb-000006
Figure PCTCN2022143403-appb-000007
In some embodiments, the L is hydrogen, difluoromethyl, trifluoromethyl, -NH 2 , -NHCH 3 ,
Figure PCTCN2022143403-appb-000006
Figure PCTCN2022143403-appb-000007
在一些实施例中，R 1为氢或C 1-3烷基(优选为甲基或乙基)。 In some embodiments, R 1 is hydrogen or C 1-3 alkyl (preferably methyl or ethyl).
在一些实施例中，R 2为-NR 05R 06。 In some embodiments, R 2 is -NR 05 R 06 .
在一些实施例中，所述R 05为氢；R 06为氢、C 1-3烷基或C 3-6环烷基(优选为环丙烷基)；其中所述C 1- 3烷基、C 3-6环烷基各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 In some embodiments, the R 05 is hydrogen; R 06 is hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl (preferably cyclopropyl); wherein the C 1-3 alkyl, Each C3-6 cycloalkyl group is independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, - NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, - OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
在一些实施例中，所述R 05、R 06与相连接的氮原子形成的3至7元饱和或部分不饱和单杂环为氮杂环丁烷环、四氢吡咯环或哌啶环。 In some embodiments, the 3-7 membered saturated or partially unsaturated monoheterocyclic ring formed by R 05 , R 06 and the connected nitrogen atom is an azetidine ring, a tetrahydropyrrole ring or a piperidine ring.
在一些实施例中，所述R 2为氢、甲基、氨基、
Figure PCTCN2022143403-appb-000008
Figure PCTCN2022143403-appb-000009
Figure PCTCN2022143403-appb-000010
In some embodiments, the R 2 is hydrogen, methyl, amino,
Figure PCTCN2022143403-appb-000008
Figure PCTCN2022143403-appb-000009
Figure PCTCN2022143403-appb-000010
在一些实施例中，所述式(I)中的
Figure PCTCN2022143403-appb-000011
为
Figure PCTCN2022143403-appb-000012
Figure PCTCN2022143403-appb-000013
In some embodiments, in the formula (I)
Figure PCTCN2022143403-appb-000011
for
Figure PCTCN2022143403-appb-000012
Figure PCTCN2022143403-appb-000013
在一些实施例中，所述式(I)中
Figure PCTCN2022143403-appb-000014
为
Figure PCTCN2022143403-appb-000015
Figure PCTCN2022143403-appb-000016
In some embodiments, in the formula (I)
Figure PCTCN2022143403-appb-000014
for
Figure PCTCN2022143403-appb-000015
Figure PCTCN2022143403-appb-000016
可选地，所述具有式(I)所示的结构的化合物选自如下化合物中的一种：Optionally, the compound having the structure shown in formula (I) is selected from one of the following compounds:
Figure PCTCN2022143403-appb-000017
Figure PCTCN2022143403-appb-000017
Figure PCTCN2022143403-appb-000018
Figure PCTCN2022143403-appb-000018
Figure PCTCN2022143403-appb-000019
Figure PCTCN2022143403-appb-000019
Figure PCTCN2022143403-appb-000020
Figure PCTCN2022143403-appb-000020
Figure PCTCN2022143403-appb-000021
Figure PCTCN2022143403-appb-000021
Figure PCTCN2022143403-appb-000022
Figure PCTCN2022143403-appb-000022
Figure PCTCN2022143403-appb-000023
Figure PCTCN2022143403-appb-000023
Figure PCTCN2022143403-appb-000024
Figure PCTCN2022143403-appb-000024
Figure PCTCN2022143403-appb-000025
Figure PCTCN2022143403-appb-000025
Figure PCTCN2022143403-appb-000026
Figure PCTCN2022143403-appb-000026
本发明第二方面提供了一种药物组合物，其包括本发明第一方面所述的化合物、或其药学上可接受的盐、或其立体异构体，以及药学可接受的载体。The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
本发明第三方面提供了本发明第一方面所述的化合物、或其药学上可接受的盐、或其立体异构体以及本发明第二方面所述的药物组合物在制备治疗或预防与CSF-1R活性相关的或由CSF-1R活性介导的疾病的药物中的应用。The third aspect of the present invention provides the compound described in the first aspect of the present invention, or its pharmaceutically acceptable salt, or its stereoisomer and the pharmaceutical composition described in the second aspect of the present invention in the preparation of treatment or prevention and Use in medicine for diseases associated with or mediated by CSF-1R activity.
本发明第四方面提供了一种治疗与CSF-1R活性相关的或由CSF-1R活性介导的疾病的方法，所述方法包括给予患者有效量的本发明第一方面所述的化合物、或其药学上可接受的盐、或其立体异构体，或如本发明第二方面所述药物组合物。在某些实施方案中，与CSF-1R活性相关的或由CSF-1R活性介导的疾病是癌症，例如实体瘤和血液瘤。The fourth aspect of the present invention provides a method for treating diseases related to or mediated by CSF-1R activity, the method comprising administering to patients an effective amount of the compound described in the first aspect of the present invention, or Its pharmaceutically acceptable salt, or its stereoisomer, or the pharmaceutical composition as described in the second aspect of the present invention. In certain embodiments, the disease associated with or mediated by CSF-IR activity is cancer, such as solid tumors and hematological tumors.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.
具体实施方式Detailed ways
下面将结合本申请实施例中的附图，对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。The following will clearly and completely describe the technical solutions in the embodiments of the application with reference to the drawings in the embodiments of the application. Apparently, the described embodiments are only some of the embodiments of the application, not all of them. Based on the embodiments in this application, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the scope of protection of this application.
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文中在本申请的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本申请。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this application belongs. The terms used herein in the specification of the application are only for the purpose of describing specific embodiments, and are not intended to limit the application.
本发明人经过广泛而深入的研究，意外地发现了这类取代的嘧啶酮衍生物，其具有显著的CSF-1R选择抑制活性。因此该系列化合物有望开发成为用于治疗和/或预防CSF-1R介导的疾病的药物。在此基础上，发明人完成了本发明。After extensive and in-depth research, the present inventors unexpectedly discovered such substituted pyrimidinone derivatives, which have significant CSF-1R selective inhibitory activity. Therefore, the series of compounds are expected to be developed into medicines for treating and/or preventing diseases mediated by CSF-1R. On this basis, the inventors have completed the present invention.
术语定义Definition of Terms
为了能够更清楚地理解本发明的技术内容，下面对本发明的术语作进一步说明。In order to understand the technical content of the present invention more clearly, the terms of the present invention will be further described below.
“烷基”指直链和支链的饱和的脂族烃基。“C 1-8烷基”是指具有1至8个碳原子的烷基，优选为C 1-6烷基，更优选为C 1-3烷基；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。 "Alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups. "C 1-8 alkyl" refers to an alkyl group having 1 to 8 carbon atoms, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group; non-limiting examples of the alkyl group include: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethyl propyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl Base, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3, 3-Dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2- Methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.
“烯基”指直链或支链的具有一个或多个碳碳双键(C＝C)的不饱和脂族烃基，“C 2-8烯基”指具有2至8个碳原子的烯基，优选为C 2-6烯基，更优选为C 2-4烯基，定义类似；非限制性实施例包括乙烯基、丙烯基、异丙烯基、正丁烯基、异丁烯基、戊烯基、己烯基等。 "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C=C), and "C 2-8 alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms. Group, preferably C2-6 alkenyl, more preferably C2-4 alkenyl, similarly defined; non-limiting examples include vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl base, hexenyl, etc.
“炔基”指直链和支链的具有一个或多个碳碳三键的不饱和脂族烃基，“C 2-8炔基”指具有2至8个碳原子的炔基，优选为C 2-6炔基，更优选为C 2-4炔基，定义类似；非限制性实施例包括乙炔基、丙炔基、正丁炔基、异丁炔基、戊炔基、己炔基等。 "Alkynyl" refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups with one or more carbon-carbon triple bonds, and "C 2-8 alkynyl" refers to alkynyl groups with 2 to 8 carbon atoms, preferably C 2-6 alkynyl, more preferably C2-4 alkynyl, similarly defined; non-limiting examples include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, etc. .
“环烷基”和“环烷基环”可互换使用，均指饱和单环、双环或多环环状烃基，该基团可以与芳基或杂芳基稠合。环烷基环可以任选地被取代。在某些实施方案中，环烷基环含有一个或多个羰基，例如氧代的基团。“C 3-8环烷基”是指具有3至8个碳原子的单环环烷基，环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丁酮、环戊酮、环戊烷-1,3-二酮等。优选为C 3-6环烷基，包括环丙基、环丁基、环戊基和环己基。 "Cycloalkyl" and "cycloalkyl ring" are used interchangeably and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group, which may be fused with an aryl or heteroaryl group. Cycloalkyl rings can be optionally substituted. In certain embodiments, cycloalkyl rings contain one or more carbonyl groups, such as oxo groups. "C 3-8 cycloalkyl" refers to a monocyclic cycloalkyl group with 3 to 8 carbon atoms, non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. Preferred is C 3-6 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
“杂环烷基”和“杂环烷基环”可互换使用，均指包含至少一个选自氮、氧和硫的杂原子的环烷基，该基团可以与芳基或杂芳基稠合。杂环烷基环可以任选地被取代。在某些实施方案中，杂环烷基环含有一个或多个羰基或硫代羰基，例如包含氧代和硫代的基团。“3至8元杂环烷基”是指具有3至8个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子的单环环状烃基，优选为4至8元杂环烷基。更优选为3至6元杂环烷基，其具有3至6个环原子，其中1或2个环原子为选自氮、氧和硫的杂原子。更优选为4至6元杂环烷基，其具有4至6个环原子，其中1或2个环原子为选自氮、氧和硫的杂原子。单环杂环烷基的非限制性实施例包括氮丙环基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、四 氢呋喃基、四氢噻吩基、四氢吡咯基、噁唑烷基、二氧戊环基、哌啶基、哌嗪基、吗啉基、二氧六环基、硫代吗啉基、硫代吗啉-1,1-二氧化物、四氢吡喃基、氮杂环丁烷-2-酮基、氧杂环丁烷-2-酮基、二氢呋喃-2(3H)-酮基、吡咯烷-2-酮基、吡咯烷-2,5-二酮基、二氢呋喃-2,5-二酮基、哌啶-2-酮基、四氢-2H-吡喃-2-酮基、哌嗪-2-酮基、吗啉-3-酮基等。"Heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which may be combined with an aryl or heteroaryl fused. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, heterocycloalkyl rings contain one or more carbonyl or thiocarbonyl groups, eg, groups comprising oxo and thioxo. "3 to 8 membered heterocycloalkyl" refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, preferably 4 to 8-membered heterocycloalkyl. More preferred is a 3 to 6 membered heterocycloalkyl group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. More preferred is a 4 to 6 membered heterocycloalkyl group having 4 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of monocyclic heterocycloalkyl groups include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl , oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetra Hydropyranyl, azetidin-2-one, oxetane-2-one, dihydrofuran-2(3H)-one, pyrrolidin-2-one, pyrrolidin- 2,5-diketone, dihydrofuran-2,5-diketone, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazin-2-one, morphine Lin-3-one group and so on.
“芳基”和“芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，该基团可以与环烷基环、杂环烷基环、环烯基环、杂环烯基环或杂芳基稠合。“C 6- 10芳基”指具有6至10个碳原子的单环或双环芳基，芳基的非限制性实施例包括苯基、萘基等。 "Aryl" and "aromatic ring" are used interchangeably and both refer to an all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, which Can be fused to a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring or heteroaryl. "C 6-10 aryl" refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl, and the like.
“杂芳基”和“杂芳环”可互换使用，均指具有环碳原子和环杂原子的单环、双环或多环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。本发明中，杂芳基还包括上述杂芳环与一个或多个环烷基环、杂环烷基环、环烯基环、杂环烯基环或芳环稠合的环系统。杂芳环可以任选地被取代。“5至10元杂芳基”是指具有5至10个环原子，其中1、2、3或4个环原子为杂原子的单环或双环杂芳基。“5至6元杂芳基”是指具有5至6个环原子，其中1、2、3或4个环原子为杂原子的单环杂芳基，非限制性实施例包括噻吩基、呋喃基、噻唑基、异噻唑基、咪唑基、噁唑基、吡咯基、吡唑基、三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、四唑基、异噁唑基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基。“8至10元杂芳基”是指具有8至10个环原子，其中1、2、3或4个环原子为杂原子的双环杂芳基，非限制性实施例包括吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基、嘌呤基、吡啶并[3,2-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[4,3-d]嘧啶基、1,8-萘啶基、1,7-萘啶基、1,6-萘啶基、1,5-萘啶基、喋啶基、喹啉基、异喹啉基、噌啉基、喹喔啉基、酞嗪基和喹唑啉基。“杂原子”是指氮、氧或硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。"Heteroaryl" and "heteroaromatic ring" are used interchangeably and both refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having shared 6 or 10 π electrons), wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the present invention, heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. Heteroaryl rings can be optionally substituted. "5 to 10 membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. "5 to 6 membered heteroaryl" means a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadi Azolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazine base. "8 to 10 membered heteroaryl" means a bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include indolyl, iso Indolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzisofuryl, benzimidazole, benzoxazolyl, benziso Oxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido [2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. "Heteroatom" means nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
“稠合”是指两个或多个环共用一个或多个键的结构。"Fused" refers to a structure in which two or more rings share one or more bonds.
“烷氧基”指-O-烷基，其中烷基的定义如上所述。优选C 1-8烷氧基，更优选C 1-6烷氧基，最优选C 1- 3烷氧基。非限制性实施例包含甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。 "Alkoxy" means -O-alkyl, wherein alkyl is as defined above. It is preferably C 1-8 alkoxy, more preferably C 1-6 alkoxy, most preferably C 1-3 alkoxy. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, pentyloxy, and the like.
“环烷基氧基”指-O-环烷基，其中环烷基的定义如上所述。优选C 3-8环烷基氧基，更优选C 3-6环烷基氧基。非限制性实施例包含环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。 "Cycloalkyloxy" means an -O-cycloalkyl group in which cycloalkyl is as defined above. It is preferably C 3-8 cycloalkyloxy, more preferably C 3-6 cycloalkyloxy. Non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
“一个键”指由其连接的两个基团通过一个共价键连接。"A bond" means that the two groups connected by it are connected by a covalent bond.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。"Halo" refers to a group in which one or more (eg 1, 2, 3, 4 or 5) hydrogens are replaced by a halogen.
“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苯甲基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CHOHCH 3，“羟基”指-OH，“巯基”指SH，“亚环丙基”结构为：
Figure PCTCN2022143403-appb-000027
"Amino" means NH 2 , "cyano" means CN, "nitro" means NO 2 , "benzyl" means -CH 2 -phenyl, "oxo" means =O, "carboxy" means -C (O)OH, "acetyl" refers to -C(O)CH 3 , "hydroxymethyl" refers to -CH 2 OH, "hydroxyethyl" refers to -CH 2 CH 2 OH or -CHOHCH 3 , "hydroxyl" refers to -OH, "mercapto" refers to SH, and the structure of "cyclopropylene" is:
Figure PCTCN2022143403-appb-000027
“饱和或部分不饱和单环”是指饱和或部分不饱和的全碳单环系统，其中“部分不饱和”是指包括至少一个双键或三键的环部分，“部分不饱和”意图涵盖具有多个不饱和位点的环，但并不意图包括如本文所定义的芳基或杂芳基部分。在某些实施方案中，饱和或部分不饱和单环含有一个或多个羰基，例如氧代的基团。“3至7元饱和或部分不饱和单环”具有3到7个环碳原子，优选具有3到6个环碳原子的饱和或部分不饱和单环，更优选具有3到6个环碳原子的饱和单环。饱和或部分不饱和单环的非限制性实施例包括环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环戊酮环、环戊烷-1,3-二酮环等。"Saturated or partially unsaturated monocyclic ring" means a saturated or partially unsaturated all-carbon monocyclic ring system, where "partially unsaturated" means a ring portion that includes at least one double or triple bond, and "partially unsaturated" is intended to encompass Rings with multiple sites of unsaturation, but are not intended to include aryl or heteroaryl moieties as defined herein. In certain embodiments, saturated or partially unsaturated monocyclic rings contain one or more carbonyl groups, such as oxo groups. "3 to 7 membered saturated or partially unsaturated monocyclic ring" has 3 to 7 ring carbon atoms, preferably a saturated or partially unsaturated monocyclic ring having 3 to 6 ring carbon atoms, more preferably 3 to 6 ring carbon atoms saturated monocycle. Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, Cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.
“饱和或部分不饱和单杂环”是指饱和或部分不饱和单环中的1、2或3个环碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。 “3至7元饱和或部分不饱和单杂环”具有3到7个环原子，其中1、2或3个环原子为上述杂原子。优选具有3到6个环原子，其中1或2个环原子为上述杂原子的3至6元饱和或部分不饱和单杂环，更优选具有5到6个环原子，其中1或2个环原子为上述杂原子的5至6元饱和或部分不饱和单杂环，最优选为5或6元饱和单杂环。饱和单杂环的非限制性实施例包括环氧丙烷环、氮杂环丁烷环、氧杂环丁烷环、四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、吡咯啉环、噁唑烷环、哌嗪环、二氧戊环、二氧六环、吗啉环、硫代吗啉环、硫代吗啉-1,1-二氧化物、四氢吡喃环、氮杂环丁烷-2-酮环、氧杂环丁烷-2-酮环、吡咯烷-2-酮环、吡咯烷-2,5-二酮环、哌啶-2-酮环、二氢呋喃-2(3H)-酮环、二氢呋喃-2,5-二酮环、四氢-2H-吡喃-2-酮环、哌嗪-2-酮环、吗啉-3-酮环。部分不饱和单杂环的非限制性实施例包括1,2-二氢氮杂环丁二烯环、1,2-二氢氧杂环丁二烯环、2,5-二氢-1H-吡咯环、2,5-二氢呋喃环、2,3-二氢呋喃环、2,3-二氢-1H-吡咯环、3,4-二氢-2H-吡喃环、1,2,3,4-四氢吡啶环、3,6-二氢-2H-吡喃环、1,2,3,6-四氢吡啶环、4,5-二氢-1H-咪唑环、1,4,5,6-四氢嘧啶环、3,4,7,8-四氢-2H-1,4,6-噁二唑嗪环、1,6-二氢嘧啶环、4,5,6,7-四氢-1H-1,3-二氮杂
Figure PCTCN2022143403-appb-000028
环、2,5,6,7-四氢-1,3,5-噁二氮杂
Figure PCTCN2022143403-appb-000029
环等。 "Saturated or partially unsaturated monoheterocyclic ring" means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer from 0 to 2 ), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. The "3- to 7-membered saturated or partially unsaturated monoheterocyclic ring" has 3 to 7 ring atoms, of which 1, 2 or 3 ring atoms are the above-mentioned heteroatoms. Preferably 3 to 6 membered saturated or partially unsaturated monoheterocycles having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms as mentioned above, more preferably 5 to 6 ring atoms, of which 1 or 2 are A 5- to 6-membered saturated or partially unsaturated monoheterocycle whose atoms are the aforementioned heteroatoms, most preferably a 5- or 6-membered saturated monoheterocycle. Non-limiting examples of saturated monoheterocyclic rings include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings , oxazolidine ring, piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, nitrogen Heterocyclobutane-2-one ring, oxetane-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, dihydro Furan-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran-2-one ring, piperazin-2-one ring, morpholin-3-one ring . Non-limiting examples of partially unsaturated monoheterocyclic rings include 1,2-dihydroazetidinium rings, 1,2-dihydrooxetidine rings, 2,5-dihydro-1H- Pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2, 3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4 ,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1,3-diazepine
Figure PCTCN2022143403-appb-000028
Cyclo, 2,5,6,7-tetrahydro-1,3,5-oxadiazepine
Figure PCTCN2022143403-appb-000029
Ring etc.
“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently replaced by the corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently replaced by the corresponding number of substituents of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
本申请中，“C 1-8烷基、C 3-8环烷基”可以被一组取代基取代，意味着当其进一步优选为C 1-6烷基、C 1-3烷基、C 3-6环烷基时，C 1-6烷基、C 1-3烷基、C 3-6环烷基也可以被上述组的取代基取代。 In the present application, "C 1-8 alkyl, C 3-8 cycloalkyl" can be substituted by a group of substituents, which means that when it is further preferably C 1-6 alkyl, C 1-3 alkyl, C In the case of 3-6 cycloalkyl, C 1-6 alkyl, C 1-3 alkyl, C 3-6 cycloalkyl may also be substituted by substituents of the above group.
除非另有定义，本发明所述“各自独立地选自……的取代基”是指当基团上的一个以上的氢被取代基取代时，所述的取代基种类可以相同或不同，所选自的取代基为各自独立的种类。Unless otherwise defined, the "substituents independently selected from ..." in the present invention means that when more than one hydrogen on the group is replaced by a substituent, the types of the substituents may be the same or different, so The selected substituents are each independent species.
除非另有定义，本发明所述“……相同或不同，且各自独立地为……”是指当通式中存在一个以上的相同取代基团时，该基团可以相同或不同，为各自独立的种类。例如X为(CR q1R q2) m，当m为2时，即X为CR q1R q2-CR q1R q2，其中的两个R q1可以相同或不同，两个R q2可以相同或不同，为各自独立的种类。 Unless otherwise defined, "...the same or different, and each independently is..." in the present invention means that when there are more than one identical substituent groups in the general formula, the groups may be the same or different, and are each separate species. For example, X is (CR q1 R q2 ) m , when m is 2, that is, X is CR q1 R q2 -CR q1 R q2 , where two R q1 can be the same or different, and two R q2 can be the same or different, for separate species.
除非另有定义，本文任一基团可以是取代的或未取代的。上述基团被取代时，取代基优选为1至5个以下基团，独立地选自氰基、卤素(优选氟或氯)、C 1-8烷基(优选C 1-6烷基，更优选C 1-3烷基)、C 1-8烷氧基(优选C 1-6烷氧基，更优选C 1-3烷氧基)、卤代C 1-8烷基(优选卤代C 1-6烷基，更优选卤代C 1-3烷基)、C 3-8环烷基(优选C 3-6环烷基)、卤代C 1-8烷氧基(优选卤代C 1-6烷氧基，更优选卤代C 1-3烷氧基)、C 1-8烷基取代的氨基、卤代C 1-8烷基取代的氨基、乙酰基、羟基、羟甲基、羟乙基、羧基、硝基、C 6-10芳基(优选苯基)、C 3-8环烷基氧基(优选为C 3-6环烷基氧基)、C 2-8烯基(优选C 2-6烯基，更优选C 2-4烯基)、C 2-8炔基(优选C 2-6炔基，更优选C 2-4炔基)、-CONR 01R 02、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环、4至6元饱和或不饱和单环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环，其中R 01、R 02各自独立地为氢或C 1-3烷基。 Unless otherwise defined, any group herein may be substituted or unsubstituted. When the above groups are substituted, the substituents are preferably 1 to 5 following groups independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more Preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferred halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, halogenated C 1-8 alkyl substituted amino, acetyl, hydroxyl, hydroxymethyl , hydroxyethyl, carboxyl, nitro, C 6-10 aryl (preferably phenyl), C 3-8 cycloalkyloxy (preferably C 3-6 cycloalkyloxy), C 2-8 alkene Group (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-8 alkynyl (preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl), -CONR 01 R 02 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -CHO, -OC(O )C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 aryl, such as -SO 2 -benzene base), -COC 6-10 aryl (preferably -COC 6 aryl, such as -CO-phenyl), 4 to 6 membered saturated or unsaturated monoheterocyclic ring, 4 to 6 membered saturated or unsaturated monocyclic ring, 5 to 6 membered monocyclic heteroaryl ring, 8 to 10 membered bicyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring or bridged heterocyclic ring, wherein R 01 and R 02 are each independently hydrogen or C 1- 3 alkyl.
本发明中，一个方案中出现两个或更多个“优选”时，任意的两个“优选”可以是彼此独立的。In the present invention, when two or more "preferred" appear in one solution, any two "preferred" may be independent of each other.
本发明中，在本发明中，同一取代基多次出现时，可独立选自不同基团。如通式含有多个R 3，则R 3可独立选自不同基团。 In the present invention, in the present invention, when the same substituent appears multiple times, it can be independently selected from different groups. If the general formula contains multiple R 3 s , R 3 can be independently selected from different groups.
在本发明中，“环原子数”表示原子键合成环状而得到的结构化合物(例如，单环化合物、稠环化合物、交联化合物、碳环化合物、杂环化合物)的构成该环自身的原子之中的原子数。该环被取代基所取代时，取代基所包含的原子不包括在成环原子内。关于以下所述的“环原子数”，在没有特别说明的条件下也是同样的。例如，苯环的环原子数为6，萘环的环原子数为10，噻吩基的环原子数为5。In the present invention, the "number of ring atoms" means the number of structural compounds (for example, monocyclic compounds, condensed ring compounds, crosslinked compounds, carbocyclic compounds, heterocyclic compounds) that constitute the ring itself in which atoms are bonded to form a ring. The number of atoms within an atom. When the ring is substituted by a substituent, the atoms included in the substituent are not included in the ring-forming atoms. The same applies to the "number of ring atoms" described below unless otherwise specified. For example, the number of ring atoms of a benzene ring is 6, the number of ring atoms of a naphthalene ring is 10, and the number of ring atoms of a thienyl group is 5.
在本发明中，取代基缩写对应为：n-正，sec-仲，i-异，t-叔，o-邻，m-间，p-对，Me甲基，Et乙基，Pr丙基，Bu丁基，Am正戊基，Hx己基，Cy环己基。In the present invention, the substituent abbreviations correspond to: n-normal, sec-secondary, i-iso, t-tertiary, o-ortho, m-inter, p-pair, Me methyl, Et ethyl, Pr propyl , Butyl, Am n-pentyl, Hx hexyl, Cy cyclohexyl.
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。The various substituent groups described herein above may themselves be substituted by groups described herein.
本文所述的饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代 表性的取代情况如下所示：When the saturated monoheterocycle described herein is substituted, the positions of the substituents can be in their possible chemical positions, and the representative substitution situations of the exemplary monoheterocycle are as follows:
Figure PCTCN2022143403-appb-000030
Figure PCTCN2022143403-appb-000030
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2022143403-appb-000031
表示与其他原子的连接。 Where "Sub" represents various substituents described herein;
Figure PCTCN2022143403-appb-000031
Indicates connections to other atoms.
本发明中，基团中未指明连接位点时，表示基团中任选可连接位点作为连接位点。In the present invention, when the linking site is not specified in the group, it means that an optional linkable site in the group is used as the linking site.
本发明中，基团中未指明稠合位点时，表示基团中任选可稠合位点作为稠合位点，优选基团中处于邻位的两个或多个位点为稠合位点。In the present invention, when the fused site is not specified in the group, it means that the optional fused site in the group is used as the fused site, preferably two or more positions in the ortho position in the group are fused location.
药物组合物pharmaceutical composition
通常本发明化合物或其药学可接受的盐、或其溶剂化物、或其立体异构体可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。Usually, the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, buccal and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, syrups and the like. The compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions and the like. The above-mentioned dosage forms can be made from the active compound and one or more carriers or excipients through common pharmaceutical methods. The aforementioned carriers need to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compounds can form solutions or suspensions with the above-mentioned carriers.
“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。"Pharmaceutically acceptable carrier" means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary preparation or excipient of any type, which is compatible with the patient, preferably a mammal , more preferably a human, suitable for delivering the active agent to the target site of interest without terminating the activity of the agent.
“本发明的活性物质”或“本发明的活性化合物”是指本发明式(I)化合物、或其药学上可接受的盐、或其溶剂化物、或其立体异构体，其具有较高的CSF-1R选择抑制活性。"Active substance of the present invention" or "active compound of the present invention" refers to a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, which has a higher CSF-1R selection inhibitory activity.
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。The compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice. The "therapeutically effective amount" of a compound to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。"Therapeutically effective amount" refers to the amount of a compound of the present invention that will elicit a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc.
本发明的所述药物组合物或所述药用组合物中含有的本发明化合物或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或其前药的治疗有效量优选为0.1mg-5g/kg(体重)。The therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or its prodrug contained in the said pharmaceutical composition of the present invention or said pharmaceutical composition Preferably it is 0.1 mg-5 g/kg (body weight).
“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。"Patient" means an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。"Treating" means alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing its development, or alleviating to some extent one or more symptoms of a disease or disorder.
所述“药学上可接受的盐”包括药学可接受的酸加成盐和药学可接受的碱加成盐。药学上可接受的酸加成盐是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。这些盐可通过本专业已知的方法制备。The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A pharmaceutically acceptable acid addition salt refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.
“药学可接受的碱加成盐”，包括但不限于无机碱的盐、有机碱的盐。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases and salts with organic bases. These salts can be prepared by methods known in the art.
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于本发明范围之内。The "solvate" mentioned in the present invention refers to the complex formed by the compound of the present invention and a solvent. They are either reacted in the solvent or precipitated or crystallized from the solvent. For example, a complex formed with water is called a "hydrate". Solvates of compounds of formula (I) are within the scope of the present invention.
当本发明式(I)所示的化合物含有一个或多个手性中心时，可以以不同的光学活性形式存在。当式(I)化合物含有一个手性中心时，该化合物包含一对对映异构体。该化合物的两个对映异构体以及该一对对映异构体的混合物，如外消旋混合物也在本发明的保护范围内。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式(I)化合物含有多于一个手性中心时，该化合物包含对映异构体和非对映异构体。该化合物的所有对映异构体和非对映异构体，以及对映异构体的混合物，非对映异构体的混合物，以及对映异构体和非对映异构体的混合物也在本发明的保护范围内。对映异构体、非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。When the compound represented by formula (I) of the present invention contains one or more chiral centers, it can exist in different optically active forms. When a compound of formula (I) contains one chiral center, the compound contains a pair of enantiomers. The two enantiomers of the compound as well as the mixture of the pair of enantiomers, such as the racemic mixture, are also within the protection scope of the present invention. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula (I) contains more than one chiral center, the compound includes enantiomers and diastereomers. All enantiomers and diastereomers of the compound, and mixtures of enantiomers, mixtures of diastereomers, and mixtures of enantiomers and diastereomers Also within the protection scope of the present invention. Enantiomers and diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.
制备方法Preparation
本发明提供了式(I)化合物的制备方法，使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本发明描述的方法组合可以合成式(I)化合物。本发明给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。所述反应可以按顺序使用，以提供本发明的化合物，或者它们可以用于合成片段，所述片段通过本发明所描述的方法和/或本领域已知的方法随后加入。The present invention provides methods for preparing compounds of formula (I), which can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with methods described in the present invention. Solvents, temperatures and other reaction conditions given in this invention can be varied according to the skill in the art. The reactions can be used sequentially to provide compounds of the invention, or they can be used to synthesize fragments which are subsequently added by methods described herein and/or by methods known in the art.
本发明描述的化合物可以使用与下述类似的方法或实施例中所述的示例性方法，或本领域技术人员所用的相关公开文献，通过使用适当的可选择的起始原料合成化合物。用于合成本发明所描述的化合物的起始原料可以被合成或可以从商业来源获得。本发明描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本发明公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本发明提供的分子中的各种部分。The compounds described in the present invention can be synthesized by using appropriate alternative starting materials using methods similar to those described below or the exemplary methods described in the Examples, or relevant publications used by those skilled in the art. Starting materials for the synthesis of the compounds described in this invention can be synthesized or can be obtained from commercial sources. The compounds described in this invention and other related compounds with different substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods for preparing compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified with reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.
本发明的主要优点在于：The main advantages of the present invention are:
提供了一系列结构新颖的取代的嘧啶酮衍生物，其对CSF-1R具有较高的选择抑制活性，因此可用作治疗和/或预防与CSF-1R活性相关的或由CSF-1R活性介导的疾病的药物。Provided are a series of novel substituted pyrimidinone derivatives, which have high selective inhibitory activity on CSF-1R, and thus can be used for the treatment and/or prevention of CSF-1R activity-related or mediated by CSF-1R activity. Drugs that cause disease.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental method that does not indicate specific condition in the following examples, usually according to conventional conditions such as people such as Sambrook, molecular cloning: the condition described in the laboratory handbook (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer suggested conditions. Percentages and parts are by weight unless otherwise indicated. Unless otherwise defined, terms used herein have the same meanings as those skilled in the art are familiar with. In addition, any methods and materials similar or equivalent to those described can also be applied in the present invention.
试剂与仪器Reagents and Instruments
1HNMR：Bruker AVANCE-400核磁仪，内标为四甲基硅烷(TMS)。 1 HNMR: Bruker AVANCE-400 nuclear magnetic analyzer, the internal standard is tetramethylsilane (TMS).
LC-MS：Agilent 1290 HPLC System/6130/6150 MS液质联用质谱仪(生产商：安捷伦)，柱子Waters BEH/CHS，50×2.1mm，1.7μm。LC-MS: Agilent 1290 HPLC System/6130/6150 MS liquid mass spectrometry (manufacturer: Agilent), column Waters BEH/CHS, 50×2.1mm, 1.7μm.
制备高效液相色谱(pre-HPLC)：GX-281(生产商：吉尔森)。Preparative high performance liquid chromatography (pre-HPLC): GX-281 (manufacturer: Gilson).
采用ISCO Combiflash-Rf75或Rf200型自动过柱仪，Agela 4g、12g、20g、40g、80g、120g一次性硅胶柱。Adopt ISCO Combiflash-Rf75 or Rf200 automatic column passing instrument, Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
已知的起始原料可以采用或按照本领域已知的方法来合成，或可以购自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)和达瑞化学品等公司。Known starting materials can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Darui Chemicals, etc. company.
实施例中，反应进程的监测可采用薄层色谱法(TLC)或者LC-MS，化合物纯化可采用柱层析。柱层析或TLC所用的展开剂体系可选自：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系、石油醚和乙酸乙酯体系和丙酮体系等，溶剂的体积比根据化合物的极性不同而进行调节。In the embodiments, thin layer chromatography (TLC) or LC-MS can be used for monitoring the reaction progress, and column chromatography can be used for compound purification. The developer system used in column chromatography or TLC can be selected from: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system, etc., the volume ratio of the solvent is based on the polarity of the compound Adjust differently.
如本文所用，DMF：N,N-二甲基甲酰胺；DMSO：二甲基亚砜；THF：四氢呋喃；DIEA：N,N-二异丙基乙胺；FA：甲酸；TEA：三乙胺；EA：乙酸乙酯；PE：石油醚；KHMDS：双(三甲基硅烷基)氨基钾；NaHMDS：二(三甲基硅基)氨基钠；NMP：N-甲基吡咯烷酮；m-CPBA：间氯过苯甲酸；TFA：三氟乙酸；MsOH：甲磺酸；DMAP：4-二甲氨基吡啶；BINAP：(2R,3S)-2,2'-双二苯膦基-1,1'-联萘，NBS：N-溴代丁二酰亚胺，NCS：N-氯代丁二酰亚胺，Pd 2(dba) 3：三(二亚苯甲基丙酮)二钯，Pd(dppf)Cl 2：[1,1'-双(二苯基磷)二茂铁]二氯化钯，Pd(PPh 3) 2Cl 2：二(三苯基膦)二氯化钯，Pd(PPh 3) 4：四(三苯基膦)钯，PdCl 2(CH 3CN) 2：二氯二(乙腈)钯，DPPA：叠氮磷酸二苯酯，DBU：1,8-二氮杂二环十一碳-7-烯，TBAF：四丁基氟化铵，Na Ascorbate：抗坏血酸钠，t-BuXPhosPd-G3：甲磺酸(2-二叔丁基膦基-2'，4'，6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)，X-PHOS：2-二环己基膦-2',4',6'-三异丙基联苯，XantPhos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；HATU：2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。 As used herein, DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; THF: tetrahydrofuran; DIEA: N,N-diisopropylethylamine; FA: formic acid; TEA: triethylamine ; EA: ethyl acetate; PE: petroleum ether; KHMDS: bis(trimethylsilyl) potassium amide; NaHMDS: bis(trimethylsilyl) sodium amide; NMP: N-methylpyrrolidone; m-CPBA: m-chloroperbenzoic acid; TFA: trifluoroacetic acid; MsOH: methanesulfonic acid; DMAP: 4-dimethylaminopyridine; BINAP: (2R,3S)-2,2'-bisdiphenylphosphino-1,1' -binaphthyl, NBS: N-bromosuccinimide, NCS: N-chlorosuccinimide, Pd 2 (dba) 3 : tris(dibenzylideneacetone) dipalladium, Pd(dppf )Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, Pd(PPh 3 ) 2 Cl 2 : bis(triphenylphosphine)palladium dichloride, Pd(PPh 3 ) 4 : Tetrakis(triphenylphosphine) palladium, PdCl 2 (CH 3 CN) 2 : dichlorobis(acetonitrile) palladium, DPPA: diphenylphosphoryl azide, DBU: 1,8-diazabicyclo Undec-7-ene, TBAF: tetrabutylammonium fluoride, Na Ascorbate: sodium ascorbate, t-BuXPhosPd-G3: methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), X-PHOS: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, XantPhos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene; HATU: 2-(7-azabenzotriazepine azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
如本文所用，室温是指约20-30℃。As used herein, room temperature means about 20-30°C.
中间体v1的制备Preparation of intermediate v1
Figure PCTCN2022143403-appb-000032
Figure PCTCN2022143403-appb-000032
以2-溴-4-氟吡啶和化合物v1-1为原料，参考实施例1步骤2的制备方法，得到中间体v1(820mg)。ESI-MS:m/z＝177.9[M+H] +。 Using 2-bromo-4-fluoropyridine and compound v1-1 as raw materials, referring to the preparation method in step 2 of Example 1, intermediate v1 (820 mg) was obtained. ESI-MS: m/z = 177.9 [M+H] + .
中间体v2的制备Preparation of intermediate v2
Figure PCTCN2022143403-appb-000033
Figure PCTCN2022143403-appb-000033
步骤1、将5-溴-2-氯-4-甲氧基嘧啶(1.0g,4.5mmol)和异丙胺(1.06g,18.01mmol)溶于干燥四氢呋喃(10mL)中，向上述溶液中加入三乙胺(910mg,9.0mmol)。反应液在70℃下微波2小时。待反应液冷却至室温，浓缩除去四氢呋喃，残余物中加水(100mL)，用乙酸乙酯萃取(80mL x 3)。有机相合并后用饱和盐水(120mL x 2)洗涤，硫酸钠干燥后浓缩得到化合物v2-1(1.0g)。ESI-MS:m/z＝246.0[M+H] +。 Step 1. Dissolve 5-bromo-2-chloro-4-methoxypyrimidine (1.0g, 4.5mmol) and isopropylamine (1.06g, 18.01mmol) in dry tetrahydrofuran (10mL), and add three Ethylamine (910 mg, 9.0 mmol). The reaction solution was microwaved at 70°C for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated to remove THF, water (100 mL) was added to the residue, and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (120 mL x 2), dried over sodium sulfate and concentrated to obtain compound v2-1 (1.0 g). ESI-MS: m/z = 246.0 [M+H] + .
步骤2、将化合物v2-1(900mg,3.67mmol)，联硼酸频那醇酯(1.87g,7.35mmol)和醋酸钾(1.08g,11.02mmol)溶于1,4-二氧六环(20mL)中，向上述溶液中加入Pd 2(PPh 3) 2Cl 2(260mg，0.37mmol)。氮气置换后反应液在85℃下搅拌16小时。反应液冷却至室温，加水(100mL)，乙酸乙酯(30mL x 3)萃取。有机相合并，水洗(10mL x 2)，饱和盐水洗(10mL)，硫酸钠干燥，过滤。滤液浓缩干，残余物先通过硅胶柱层析纯化(石油醚：乙酸乙酯＝5:1到1:1梯度洗脱)。所得产品再用C18反相柱纯化得到中间体v2(800mg)。ESI-MS:m/z＝212.2[M+H] +。 Step 2. Dissolve compound v2-1 (900mg, 3.67mmol), pinacol diboronate (1.87g, 7.35mmol) and potassium acetate (1.08g, 11.02mmol) in 1,4-dioxane (20mL ), Pd 2 (PPh 3 ) 2 Cl 2 (260 mg, 0.37 mmol) was added to the above solution. After nitrogen replacement, the reaction solution was stirred at 85°C for 16 hours. The reaction solution was cooled to room temperature, added with water (100 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (10 mL x 2), washed with saturated brine (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to dryness, and the residue was first purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1 gradient elution). The obtained product was purified by C18 reverse phase column to obtain intermediate v2 (800mg). ESI-MS: m/z = 212.2 [M+H] + .
中间体v3的制备Preparation of intermediate v3
Figure PCTCN2022143403-appb-000034
Figure PCTCN2022143403-appb-000034
2-(4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-基)乙醇和2-溴-4-氟吡啶为原料，参考实施例 1步骤2的制备方法，得到中间体v3(120mg)。LC-MS m/z＝208.1[M+H] +。 1H NMR(DMSO-d6,400MHz):δ(ppm)：8.53(dd,J＝5.2Hz,J＝9.2Hz,1H),7.62(dd,J＝3.6Hz,J＝10.8Hz,1H),7.11-7.07(m,1H),4.93(t,J＝5.6Hz,1H),4.18(t,J＝5.6Hz,2H),3.76(q,J＝5.6Hz,3H)。 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol and 2-bromo-4 - Fluoropyridine was used as raw material, referring to the preparation method in step 2 of Example 1, to obtain intermediate v3 (120 mg). LC-MS m/z = 208.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 8.53 (dd, J=5.2Hz, J=9.2Hz, 1H), 7.62 (dd, J=3.6Hz, J=10.8Hz, 1H), 7.11-7.07 (m, 1H), 4.93 (t, J=5.6Hz, 1H), 4.18 (t, J=5.6Hz, 2H), 3.76 (q, J=5.6Hz, 3H).
中间体v4的制备Preparation of intermediate v4
Figure PCTCN2022143403-appb-000035
Figure PCTCN2022143403-appb-000035
步骤1、将5-溴-2,4-二氯嘧啶(36g,0.158mol)和LiOH(13.3g,0.316mmol)溶于THF(1000mL)和H 2O(100mL)中，氮气置换后反应液在室温下搅拌过夜得到化合物v4-1。ESI-MS：m/z＝208.9[M+H] +。 Step 1. Dissolve 5-bromo-2,4-dichloropyrimidine (36g, 0.158mol) and LiOH (13.3g, 0.316mmol) in THF (1000mL) and H 2 O (100mL), and replace the reaction solution with nitrogen Stir overnight at room temperature to obtain compound v4-1. ESI-MS: m/z = 208.9 [M+H] + .
步骤2、将碘甲烷(33g,0.158mol)加入上述化合物v4-1的反应液中。氮气置换后在室温下搅拌1天。反应结束后旋蒸除去THF，水相用乙酸乙酯萃取(100mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，通过硅胶柱层析纯化(PE:EA＝5:1)洗脱，得到化合物v4-2(18.3g)。ESI-MS：m/z＝223.0[M+H] +。 Step 2. Add iodomethane (33 g, 0.158 mol) into the reaction solution of the above-mentioned compound v4-1. After nitrogen substitution, the mixture was stirred at room temperature for 1 day. After the reaction, THF was removed by rotary evaporation, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, evaporated the solvent, and purified by silica gel column chromatography (PE:EA=5:1) to obtain compound v4-2 (18.3 g). ESI-MS: m/z = 223.0 [M+H] + .
步骤3、将化合物v4-2(18.3g,0.08mol)，异丙胺(14.8g,0.25mol)和DIEA(32g,0.25mol)溶于THF(80mL)中，氮气置换后反应液在室温下反应过夜。LC-MS监测反应结束后浓缩，得到化合物v4-3(18g)。ESI-MS：m/z＝246.1[M+H] +。 Step 3. Compound v4-2 (18.3g, 0.08mol), isopropylamine (14.8g, 0.25mol) and DIEA (32g, 0.25mol) were dissolved in THF (80mL), and the reaction solution was reacted at room temperature after nitrogen replacement overnight. After the reaction was monitored by LC-MS, it was concentrated to obtain compound v4-3 (18 g). ESI-MS: m/z = 246.1 [M+H] + .
步骤4、将化合物v4-3(7.8g,31.8mol)，联硼酸频那醇酯(1.61g,63.6mol)，x-phos(1.3g，3.18mmol)，乙酸钾(9.35g,95.4mmol)和Pd 2(dba) 3(1.45g，1.59mmol)溶于1,4-二氧六环(80mL)中，氮气置换后反应液在70℃下搅拌3小时得到化合物v4。ESI-MS：m/z＝294.0[M+H] +。 Step 4, compound v4-3 (7.8g, 31.8mol), pinacol diboronate (1.61g, 63.6mol), x-phos (1.3g, 3.18mmol), potassium acetate (9.35g, 95.4mmol) and Pd 2 (dba) 3 (1.45 g, 1.59 mmol) were dissolved in 1,4-dioxane (80 mL), and the reaction solution was stirred at 70° C. for 3 hours after nitrogen replacement to obtain compound v4. ESI-MS: m/z = 294.0 [M+H] + .
中间体v7的制备Preparation of intermediate v7
Figure PCTCN2022143403-appb-000036
Figure PCTCN2022143403-appb-000036
步骤1、将5-溴-2-氯-3-甲基嘧啶-4(3H)-酮(1.5g,6.7mmol)，溶于二氧六环(30mL)中，向上述溶液中加入(R)-1-甲氧基丙烷-2-胺(1.1g,10mmol)，DIEA(2.6g,13mmol)。反应液在80℃下搅拌2小时。反应液浓缩除去二氧六环，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1到2:1梯度洗脱)得到产物(R)-5-溴-2-((1-甲氧基丙烷-2-基)氨基)-3-甲基嘧啶-4(3H)-酮(1.2g,黄色固体，产率65.2％)。ESI-MS:Rt＝0.92min，m/z＝276.1[M+H] +. 1H NMR(CDCl3,300MHz):δ7.94(s,1H),5.12-5.11(m,1H),4.34-4.32(m,1H),3.58-3.54(m,1H),3.48(s,3H),3.43(s,3H),1.96(s,1H),1.32(d,J＝6.6Hz,3H). Step 1. Dissolve 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (1.5g, 6.7mmol) in dioxane (30mL), and add (R )-1-methoxypropan-2-amine (1.1 g, 10 mmol), DIEA (2.6 g, 13 mmol). The reaction solution was stirred at 80° C. for 2 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1 to 2:1 gradient elution) to obtain the product ( R)-5-bromo-2-((1-methoxypropan-2-yl)amino)-3-methylpyrimidin-4(3H)-one (1.2 g, yellow solid, 65.2% yield). ESI-MS: Rt＝0.92min, m/z＝276.1[M+H] + . 1 H NMR (CDCl3, 300MHz): δ7.94(s, 1H), 5.12-5.11(m, 1H), 4.34- 4.32(m,1H),3.58-3.54(m,1H),3.48(s,3H),3.43(s,3H),1.96(s,1H),1.32(d,J=6.6Hz,3H).
步骤2、将(R)-5-溴-2-((1-甲氧基丙烷-2-基)氨基)-3-甲基嘧啶-4(3H)-酮((1.2g,4.0mmol)，溶于二氧六环(25mL)中，向上述溶液中加入双联频哪醇基二硼(2.0g,8.0mmol)，醋酸钾(1.2g,12.0mmol)，三(二亚苄基丙酮)二钯(183mg,0.2mmol),2-双环己基膦-2',4',6'-三异丙基联苯(190mg,0.4mmol)。氮气置换后反应液在70℃下搅拌3小时。反应液冷却后过滤除去固体，固体用二氧六环洗涤(20mL)，蒸除溶剂，残余物直接使用在下一步。ESI-MS:Rt＝0.56min，m/z＝242.2[M+H] +. Step 2, (R)-5-bromo-2-((1-methoxypropan-2-yl)amino)-3-methylpyrimidin-4(3H)-one ((1.2g, 4.0mmol) , dissolved in dioxane (25mL), and bis-pinacolyl diboron (2.0g, 8.0mmol), potassium acetate (1.2g, 12.0mmol), tris(dibenzylideneacetone) were added to the above solution ) Dipalladium (183mg, 0.2mmol), 2-bicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl (190mg, 0.4mmol). After nitrogen replacement, the reaction solution was stirred at 70°C for 3 hours The reaction solution was cooled and filtered to remove the solid, the solid was washed with dioxane (20 mL), the solvent was evaporated, and the residue was used directly in the next step. ESI-MS: Rt=0.56min, m/z=242.2[M+H] + .
中间体v8的制备Preparation of intermediate v8
Figure PCTCN2022143403-appb-000037
Figure PCTCN2022143403-appb-000037
参考中间体v7的制备方法，区别在于用(R)-2-(甲氧甲基)-吡咯烷替换(R)-1-甲氧基丙烷-2-胺，得到中间体v8，ESI-MS:m/z＝268.1[M+H] +。 Refer to the preparation method of intermediate v7, the difference is that (R)-2-(methoxymethyl)-pyrrolidine is used to replace (R)-1-methoxypropane-2-amine to obtain intermediate v8, ESI-MS :m/z=268.1[M+H] + .
中间体v9的制备Preparation of intermediate v9
Figure PCTCN2022143403-appb-000038
Figure PCTCN2022143403-appb-000038
参考中间体v2的制备方法，区别在于用环丙胺替换异丙胺，得到中间体v9，MS:m/z＝210.1[M+H] +。中间体v5的制备 Referring to the preparation method of intermediate v2, the difference is that isopropylamine is replaced by cyclopropylamine to obtain intermediate v9, MS: m/z=210.1[M+H] + . Preparation of intermediate v5
Figure PCTCN2022143403-appb-000039
Figure PCTCN2022143403-appb-000039
步骤1、将中间体v1(4.9g,27.8mmol)溶于DMF(50mL)中，0℃下加入钠氢(2.23g,55.7mmol)并搅拌半小时，随后加入苄醇(6.0g,55.7mmol)，搅拌12小时。LCMS监测反应结束后，浓缩后残余物加入乙酸乙酯(120mL)稀释，水洗，通过硅胶柱层析纯化得到化合物v5-1(1.5g)。LC-MS m/z＝266.1[M+H] +。 Step 1. Dissolve intermediate v1 (4.9g, 27.8mmol) in DMF (50mL), add sodium hydrogen (2.23g, 55.7mmol) at 0°C and stir for half an hour, then add benzyl alcohol (6.0g, 55.7mmol ), stirred for 12 hours. After the reaction was monitored by LCMS, the concentrated residue was diluted with ethyl acetate (120 mL), washed with water, and purified by silica gel column chromatography to obtain compound v5-1 (1.5 g). LC-MS m/z = 266.1 [M+H] + .
步骤2、将化合物v5-1(1.5g,5.7mmol)，钯碳(150mg,)溶于甲醇(100mL)中，溶液保持室温，氢气氛围下搅拌16小时。浓缩得到化合物v5(1g)。LC-MS：m/z＝175.1[M+H] +。 Step 2. Dissolve compound v5-1 (1.5 g, 5.7 mmol), palladium on carbon (150 mg,) in methanol (100 mL), keep the solution at room temperature, and stir for 16 hours under hydrogen atmosphere. Concentration gave compound v5 (1 g). LC-MS: m/z = 175.1 [M+H] + .
实施例1：化合物L1的制备Embodiment 1: the preparation of compound L1
Figure PCTCN2022143403-appb-000040
Figure PCTCN2022143403-appb-000040
步骤1、将中间体化合物v1(300mg,1.69mmol)和2-氯-6-羟基喹啉(305mg，1.69mmol)溶于NMP(5mL)中，再加入碳酸钾(468mg，3.39mmol)。反应液在140℃搅拌5小时。反应液冷却后加水(20mL)，用乙酸乙酯(20mL x 3)萃取。有机相合并后用饱和盐水(5mL)洗涤，硫酸钠干燥浓缩，纯化得到化合物1-1(90mg)。ESI-MS：m/z＝337.3[M+H] +。 Step 1. Intermediate compound v1 (300mg, 1.69mmol) and 2-chloro-6-hydroxyquinoline (305mg, 1.69mmol) were dissolved in NMP (5mL), and potassium carbonate (468mg, 3.39mmol) was added. The reaction solution was stirred at 140°C for 5 hours. After the reaction solution was cooled, water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (5 mL), dried over sodium sulfate, concentrated, and purified to obtain compound 1-1 (90 mg). ESI-MS: m/z = 337.3 [M+H] + .
步骤2、将化合物1-1(160mg,0.49mmol)，化合物v2(104mg，0.49mmol)溶于1，4-二氧六环(5mL)中。向上述溶液中加入碳酸钾(135mg,0.98mmol)溶于水(0.5mL)的溶液和Pd(dppf)Cl 2(36mg，0.05mmol)。氮气置换后反应液在108℃搅拌过夜。反应液冷却至室温，浓缩除去1，4-二氧六环。残余物中加水(10mL)，用二氯甲烷(20mL x 3)萃取。有机相合并，用饱和盐水(10mL)洗涤，硫酸钠干燥后浓缩，纯化得到化合物1-2(120mg)。ESI-MS：m/z＝468.2[M+H] +。 Step 2. Compound 1-1 (160 mg, 0.49 mmol), compound v2 (104 mg, 0.49 mmol) were dissolved in 1,4-dioxane (5 mL). To the above solution was added a solution of potassium carbonate (135 mg, 0.98 mmol) dissolved in water (0.5 mL) and Pd(dppf) Cl2 (36 mg, 0.05 mmol). After nitrogen replacement, the reaction solution was stirred overnight at 108°C. The reaction solution was cooled to room temperature and concentrated to remove 1,4-dioxane. Water (10 mL) was added to the residue, and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over sodium sulfate, concentrated, and purified to obtain compound 1-2 (120 mg). ESI-MS: m/z = 468.2 [M+H] + .
步骤3、将化合物1-2(120mg,0.257mmol)溶于乙酸(3mL)中，再加40％氢溴酸(208mg，1.03mmol)。反应液在90℃搅拌4小时。反应液冷却后浓缩除去乙酸，残余物中加入二氯甲烷(10mL)，水(10mL)和饱和碳酸钠水溶液(5mL)。再用二氯甲烷(20mL x 3)萃取，有机相合并，用饱和盐水(5mL)洗涤，硫酸钠干燥后浓缩，纯化得到化合物1-3(100mg)。ESI-MS：m/z＝454.2[M+H] +。 Step 3. Compound 1-2 (120 mg, 0.257 mmol) was dissolved in acetic acid (3 mL), and 40% hydrobromic acid (208 mg, 1.03 mmol) was added. The reaction solution was stirred at 90°C for 4 hours. After cooling, the reaction solution was concentrated to remove acetic acid, and dichloromethane (10 mL), water (10 mL) and saturated aqueous sodium carbonate solution (5 mL) were added to the residue. Then extracted with dichloromethane (20mL x 3), the organic phases were combined, washed with saturated brine (5mL), dried over sodium sulfate, concentrated, and purified to obtain compound 1-3 (100mg). ESI-MS: m/z = 454.2 [M+H] + .
步骤4、将化合物1-3(100mg,0.22mmol)溶于DMF(3mL)中，再加入碳酸钾(91mg，0.66mmol)和碘甲烷(94mg，0.66mmol)。反应液在室温搅拌2小时。反应液浓缩，纯化得到产物L1(50mg)。ESI-MS：m/z＝468.2[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：8.78(s,1H),8.47-8.41(m,2H),8.28-8.26(m,2H),8.05(d,J＝9.2Hz,1H),7.98(s,1H),7.68(d,J＝2.4Hz,1H),7.56(dd,J＝8.8,2.4Hz,1H),7.31(d,J＝2.4Hz,1H),7.18(d,J＝7.6Hz,1H),6.78(dd,J＝6.0,2.4Hz,1H),4.42-4.34(m,1H),3.85(s,3H),3.41(s,3H),1.26(d,J＝6.8Hz,6H)。 Step 4. Compound 1-3 (100 mg, 0.22 mmol) was dissolved in DMF (3 mL), and potassium carbonate (91 mg, 0.66 mmol) and iodomethane (94 mg, 0.66 mmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated and purified to obtain product L1 (50 mg). ESI-MS: m/z = 468.2 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 8.78 (s, 1H), 8.47-8.41 (m, 2H), 8.28-8.26 (m, 2H), 8.05 (d, J = 9.2Hz ,1H),7.98(s,1H),7.68(d,J=2.4Hz,1H),7.56(dd,J=8.8,2.4Hz,1H),7.31(d,J=2.4Hz,1H),7.18 (d,J=7.6Hz,1H),6.78(dd,J=6.0,2.4Hz,1H),4.42-4.34(m,1H),3.85(s,3H),3.41(s,3H),1.26( d, J=6.8Hz, 6H).
实施例2：化合物L2的制备Embodiment 2: the preparation of compound L2
Figure PCTCN2022143403-appb-000041
Figure PCTCN2022143403-appb-000041
步骤1、浓硫酸(98g,1.0mol)溶于水(50mL)中，加入4-氨基-2-氟苯酚(6.3g,50mmol)，甘油(73.6g,800mmol)和硝基苯(18.4g,150mmol)。反应液140℃下搅拌3小时，冷却至室温后加入冰水中，用饱和碳酸氢钠水溶液调制中性。混合物过滤，滤饼用石油醚洗涤得到化合物2-1(12.0g)。ESI-MS：m/z＝164.0[M+H] +。 Step 1. Dissolve concentrated sulfuric acid (98g, 1.0mol) in water (50mL), add 4-amino-2-fluorophenol (6.3g, 50mmol), glycerin (73.6g, 800mmol) and nitrobenzene (18.4g, 150mmol). The reaction solution was stirred at 140°C for 3 hours, cooled to room temperature, added to ice water, and neutralized with saturated aqueous sodium bicarbonate solution. The mixture was filtered, and the filter cake was washed with petroleum ether to obtain compound 2-1 (12.0 g). ESI-MS: m/z = 164.0 [M+H] + .
步骤2、将化合物2-1(1.0g,6.1mmol)溶于乙酸乙酯(150mL)中，向上述溶液中加入m-CPBA(3.1g,15.3mmol,85％纯度)，室温下搅拌16小时。过滤，滤饼少量乙酸乙酯洗涤，得到化合物2-2(810mg)。ESI-MS：m/z＝179.9[M+H] +。 Step 2. Dissolve compound 2-1 (1.0 g, 6.1 mmol) in ethyl acetate (150 mL), add m-CPBA (3.1 g, 15.3 mmol, 85% purity) to the above solution, and stir at room temperature for 16 hours . After filtering, the filter cake was washed with a small amount of ethyl acetate to obtain compound 2-2 (810 mg). ESI-MS: m/z = 179.9 [M+H] + .
步骤3、将化合物2-2(850mg,4.75mmol)溶于三氯氧磷(50mL)中。80℃下反应3小时。纯化得到化合物2-3(230mg)。ESI-MS：m/z＝197.9[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：10.83(brs,1H),8.29(d,J＝8.4Hz,1H),7.72(d,J＝12.0Hz,1H),7.46(d,J＝8.4Hz,1H),7.42(d,J＝9.6Hz,1H)。 Step 3. Compound 2-2 (850 mg, 4.75 mmol) was dissolved in phosphorus oxychloride (50 mL). The reaction was carried out at 80° C. for 3 hours. Purification gave compound 2-3 (230 mg). ESI-MS: m/z = 197.9 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 10.83 (brs, 1H), 8.29 (d, J = 8.4Hz, 1H), 7.72 (d, J = 12.0Hz, 1H), 7.46 ( d, J = 8.4Hz, 1H), 7.42 (d, J = 9.6Hz, 1H).
步骤4、化合物2-3和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物2-4。ESI-MS：m/z＝329.0[M+H] +。 Step 4, compound 2-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 2-4. ESI-MS: m/z = 329.0 [M+H] + .
步骤5、化合物2-4和中间体v1为原料，参考实施例1步骤1的制备方法，得到产物L2。ESI-MS:m/z＝486.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：8.80(s,1H),8.48(d,J＝9.2Hz,1H),8.42(d,J＝5.6Hz,1H),8.31-8.28(m,2H),7.99(s,1H),7.95-7.90(m,2H),7.33(d,J＝1.6Hz,1H),7.21(d,J＝7.6Hz,1H),6.81(dd,J＝5.6,2.0Hz,1H),4.42-4.34(m,1H),3.85(s,3H),3.41(s,3H),1.26(d,J＝6.8Hz,6H)。 Step 5, compound 2-4 and intermediate v1 are used as raw materials, referring to the preparation method in step 1 of Example 1, to obtain the product L2. ESI-MS: m/z = 486.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 8.80 (s, 1H), 8.48 (d, J = 9.2Hz, 1H), 8.42 (d, J = 5.6Hz, 1H), 8.31- 8.28(m,2H),7.99(s,1H),7.95-7.90(m,2H),7.33(d,J=1.6Hz,1H),7.21(d,J=7.6Hz,1H),6.81(dd , J=5.6, 2.0Hz, 1H), 4.42-4.34(m, 1H), 3.85(s, 3H), 3.41(s, 3H), 1.26(d, J=6.8Hz, 6H).
实施例3：化合物L3的制备Embodiment 3: the preparation of compound L3
Figure PCTCN2022143403-appb-000042
Figure PCTCN2022143403-appb-000042
步骤1、将2-(甲硫基)嘧啶-4-醇(5.0g,35.2mmol)，1-甲基-4-氨基-吡唑盐酸盐(5.5g，42.2mmol)加入二乙二醇二甲醚(50mL)中。氮气置换后反应液在140℃下搅拌16小时。反应液冷却至室温，浓缩除去溶剂，得到化合物3-1(6.0g)。LC-MS：m/z＝192.0[M+H] +。 Step 1. Add 2-(methylthio)pyrimidin-4-ol (5.0g, 35.2mmol), 1-methyl-4-amino-pyrazole hydrochloride (5.5g, 42.2mmol) to diethylene glycol in dimethyl ether (50 mL). The reaction liquid was stirred at 140° C. for 16 hours after nitrogen replacement. The reaction liquid was cooled to room temperature, and concentrated to remove the solvent to obtain compound 3-1 (6.0 g). LC-MS: m/z = 192.0 [M+H] + .
步骤2、将化合物3-1(1.0g)加入到POCl 3(10mL)中，反应液在100℃下搅拌16小时。反应液冷却室温后浓缩，乙酸乙酯(20mL)稀释后加入到冰水中淬灭，用饱和碳酸钠溶液调节pH值到8。乙酸乙酯(50mL x 2)萃取，饱和食盐水(50mL)洗涤，无水硫酸钠干燥后浓缩，通过柱层析纯化得到化合物3-2(100mg)。LC-MS：m/z＝210.0[M+H] +。 1H NMR(DMSO-d6,300MHz):δ(ppm)：9.09(s,1H),8.40(d,J＝5.1Hz,1H),7.89(s,1H),7.49(s,1H),6.86(d,J＝5.1Hz,1H),3.84(s,3H)。 Step 2. Compound 3-1 (1.0 g) was added into POCl 3 (10 mL), and the reaction solution was stirred at 100° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated, diluted with ethyl acetate (20 mL) and added to ice water to quench, and the pH value was adjusted to 8 with saturated sodium carbonate solution. Extracted with ethyl acetate (50mL x 2), washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 3-2 (100mg). LC-MS: m/z = 210.0 [M+H] + . 1 H NMR (DMSO-d6, 300MHz): δ (ppm): 9.09 (s, 1H), 8.40 (d, J = 5.1Hz, 1H), 7.89 (s, 1H), 7.49 (s, 1H), 6.86 (d, J = 5.1 Hz, 1H), 3.84 (s, 3H).
步骤3、化合物3-2和2-氯喹啉-6-醇为原料，参考实施例1步骤1的制备方法，得到化合物3-3。 LC-MS：m/z＝353.1[M+H] +。 Step 3: Compound 3-2 and 2-chloroquinolin-6-ol are used as raw materials, referring to the preparation method in Step 1 of Example 1, to obtain Compound 3-3. LC-MS: m/z = 353.1 [M+H] + .
步骤4、化合物3-3和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物L3。LC-MS：m/z＝484.1[M+H] +。 1H NMR(DMSO-d6,400MHz):δ(ppm)：9.55(s,1H),8.77(s,1H),8.45(d,J＝8.8Hz,1H),8.33-8.29(m,2H),8.08(s,1H),7.79(s,1H),7.61(d,J＝8.0Hz,1H),7.18(d,J＝7.6Hz,1H),7.05(s,1H),6.63(s,1H),6.47(d,J＝2.4Hz,1H),4.38(q,J＝6.8Hz,1H),3.76(s,3H),3.41(s,3H),1.26(d,J＝6.8Hz,6H)。 Step 4, compound 3-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound L3. LC-MS: m/z = 484.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 9.55 (s, 1H), 8.77 (s, 1H), 8.45 (d, J = 8.8Hz, 1H), 8.33-8.29 (m, 2H) ,8.08(s,1H),7.79(s,1H),7.61(d,J=8.0Hz,1H),7.18(d,J=7.6Hz,1H),7.05(s,1H),6.63(s, 1H), 6.47(d, J=2.4Hz, 1H), 4.38(q, J=6.8Hz, 1H), 3.76(s, 3H), 3.41(s, 3H), 1.26(d, J=6.8Hz, 6H).
实施例4：化合物L4的制备Embodiment 4: the preparation of compound L4
Figure PCTCN2022143403-appb-000043
Figure PCTCN2022143403-appb-000043
步骤1、2-氯喹啉-6-醇和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物4-1。LC-MS：m/z＝311.1[M+H] +。 1H NMR(DMSO-d6,400MHz):δ(ppm)：9.85(s,1H),8.65(s,1H),8.27(d,J＝8.4Hz,1H),8.04(d,J＝8.4Hz,1H),7.79(d,J＝8.8Hz,1H),7.26(dd,J＝2.4Hz,J＝8.8Hz,1H),7.08-7.05(m,2H),4.39-4.29(m,1H),3.39(s,3H),1.24(d,J＝6.4Hz,6H)。 Step 1. Using 2-chloroquinolin-6-ol and intermediate v4 as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound 4-1. LC-MS: m/z = 311.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 9.85 (s, 1H), 8.65 (s, 1H), 8.27 (d, J = 8.4Hz, 1H), 8.04 (d, J = 8.4Hz ,1H),7.79(d,J=8.8Hz,1H),7.26(dd,J=2.4Hz,J=8.8Hz,1H),7.08-7.05(m,2H),4.39-4.29(m,1H) , 3.39 (s, 3H), 1.24 (d, J=6.4Hz, 6H).
步骤2、化合物4-1和中间体v3为原料，参考实施例1步骤1的制备方法，得到化合物L4。LC-MS：m/z＝498.1[M+H] +。 1H NMR(DMSO-d6,400MHz):δ(ppm)：8.77(s,1H),8.45(d,J＝8.8Hz,1H),8.41(d,J＝6.0Hz,1H),8.27(s,1H),8.26(d,J＝8.8Hz,1H),8.04(d,J＝8.8Hz,1H),8.00(s,1H),7.68(d,J＝4.2Hz,1H),7.57(dd,J＝2.8Hz,J＝8.8Hz,1H),7.33(d,J＝2.4Hz,1H),7.21(d,J＝7.6Hz,1H),6.78(dd,J＝2.8Hz,J＝6.0Hz,1H),4.93(t,J＝5.2Hz,1H),4.40-4.35(m,1H),4.15(t,J＝5.6Hz,2H),3.74(q,J＝5.2Hz,2H),3.43(s,3H),1.26(d,6H)。 Step 2, compound 4-1 and intermediate v3 are used as raw materials, referring to the preparation method in step 1 of Example 1, to obtain compound L4. LC-MS: m/z = 498.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 8.77 (s, 1H), 8.45 (d, J = 8.8Hz, 1H), 8.41 (d, J = 6.0Hz, 1H), 8.27 (s ,1H),8.26(d,J=8.8Hz,1H),8.04(d,J=8.8Hz,1H),8.00(s,1H),7.68(d,J=4.2Hz,1H),7.57(dd , J=2.8Hz, J=8.8Hz, 1H), 7.33(d, J=2.4Hz, 1H), 7.21(d, J=7.6Hz, 1H), 6.78(dd, J=2.8Hz, J=6.0 Hz,1H),4.93(t,J=5.2Hz,1H),4.40-4.35(m,1H),4.15(t,J=5.6Hz,2H),3.74(q,J=5.2Hz,2H), 3.43(s,3H), 1.26(d,6H).
实施例5：化合物L5的制备Embodiment 5: the preparation of compound L5
Figure PCTCN2022143403-appb-000044
Figure PCTCN2022143403-appb-000044
步骤1、中间体v8和2-氯-6-羟基-喹啉为原料，参考实施例1步骤2的制备方法，得到化合物5-1。H NMR(CD 3OD,300MHz):δ8.44(s,1H),8.05(s,2H),7.89(d,J＝9.0Hz,1H),7.29(dd,J＝2.7Hz,J＝8.7Hz 1H),7.11(s,1H),4.63(s,1H),3.72-3.69(m,1H),3.54(s,3H),3.50-3.43(m,3H),3.33(s,3H),2.20-1.81(m,4H)。 Step 1, using intermediate v8 and 2-chloro-6-hydroxy-quinoline as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound 5-1. H NMR (CD 3 OD, 300MHz): δ8.44(s, 1H), 8.05(s, 2H), 7.89(d, J=9.0Hz, 1H), 7.29(dd, J=2.7Hz, J=8.7 Hz 1H),7.11(s,1H),4.63(s,1H),3.72-3.69(m,1H),3.54(s,3H),3.50-3.43(m,3H),3.33(s,3H), 2.20-1.81(m,4H).
步骤2、将化合物5-1(850mg,2.3mmol)溶于DMF(20mL)中，向上述溶液中加入2-溴-4-氟吡啶(1.2g,6.96mmol)，碳酸钾(960mg,6.96mmol)。反应液在90℃下搅拌16小时。反应液加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，通过柱层析纯化得到化合物5-2(800mg)。ESI-MS:，m/z＝522.1[M+H].Step 2. Dissolve compound 5-1 (850mg, 2.3mmol) in DMF (20mL), add 2-bromo-4-fluoropyridine (1.2g, 6.96mmol), potassium carbonate (960mg, 6.96mmol) to the above solution ). The reaction solution was stirred at 90°C for 16 hours. Add water (20mL) to the reaction solution and extract with ethyl acetate (30mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, evaporated to remove the solvent, and purified by column chromatography to obtain compound 5-2 (800 mg). ESI-MS:, m/z=522.1[M+H].
步骤3、化合物5-2和化合物v1-1为原料，参考实施例1步骤2的制备方法，得到产物L5。ESI-MS:m/z＝524.4[M+H]。H NMR(DMSO-d6,400MHz):δ8.75(s,1H),8.45-8.41(m,2H),8.31(d,J＝8.8Hz,1H),8.26(s,1H),8.06(d,J＝9.2Hz,1H),7.98(s,1H),7.70(d,J＝2.8Hz,1H),7.58(dd,J＝2.4Hz,J＝9.2Hz,1H),7.32(d,J＝2.0Hz,1H),6.79(dd,J＝2.4Hz,J＝5.6Hz,1H),4.58(s,1H),3.85(s,3H),3.63-3.61(m,1H).3.61-3.53(m,2H),3.44(s,3H),3.39-3.33(m,1H),3.27(s,3H).2.16-2.12(m,1H),1.97-1.96(m,1H),1.79-1.71(m,2H)。Step 3, using compound 5-2 and compound v1-1 as raw materials, refer to the preparation method in step 2 of Example 1 to obtain the product L5. ESI-MS: m/z = 524.4 [M+H]. H NMR(DMSO-d6,400MHz):δ8.75(s,1H),8.45-8.41(m,2H),8.31(d,J＝8.8Hz,1H),8.26(s,1H),8.06(d ,J=9.2Hz,1H),7.98(s,1H),7.70(d,J=2.8Hz,1H),7.58(dd,J=2.4Hz,J=9.2Hz,1H),7.32(d,J =2.0Hz,1H),6.79(dd,J=2.4Hz,J=5.6Hz,1H),4.58(s,1H),3.85(s,3H),3.63-3.61(m,1H).3.61-3.53 (m,2H),3.44(s,3H),3.39-3.33(m,1H),3.27(s,3H).2.16-2.12(m,1H),1.97-1.96(m,1H),1.79-1.71 (m,2H).
实施例6：化合物L6的制备Embodiment 6: the preparation of compound L6
Figure PCTCN2022143403-appb-000045
Figure PCTCN2022143403-appb-000045
步骤1、浓硫酸(49g,500mmol)溶于水(30mL)中，加入4-氨基-3-氟苯酚(6.3g,50mmol)，甘油(36.8g,400mmol)和硝基苯(18.4g,75mmol)。反应液140℃下搅拌4小时，冷却至室温后加入冰水中，用饱和碳酸氢钠水溶液调制中性。混合物过滤，滤饼用石油醚洗涤得到化合物6-1(3.0g)。Step 1. Dissolve concentrated sulfuric acid (49g, 500mmol) in water (30mL), add 4-amino-3-fluorophenol (6.3g, 50mmol), glycerin (36.8g, 400mmol) and nitrobenzene (18.4g, 75mmol ). The reaction solution was stirred at 140°C for 4 hours, cooled to room temperature, added to ice water, and neutralized with saturated aqueous sodium bicarbonate solution. The mixture was filtered, and the filter cake was washed with petroleum ether to obtain compound 6-1 (3.0 g).
步骤2、将化合物6-1(1.0g,6.13mmol)溶于DMF(5mL)中，加入叔丁醇钾(721mg,6.44mmol)后反应液在室温搅拌20min，随后加入溴化苄(1.15g,6.75mmol)。反应液在80℃下搅拌4小时。反应液冷却室温，残余物加入水(50mL)，用乙酸乙酯(50mL x 2)萃取。有机相合并，饱和盐水(50mL)洗涤，硫酸钠干燥后浓缩，通过柱层析纯化得到化合物6-2(850mg)。ESI-MS:m/z＝254.0[M+H] +。 Step 2. Dissolve compound 6-1 (1.0g, 6.13mmol) in DMF (5mL), add potassium tert-butoxide (721mg, 6.44mmol) and stir the reaction solution at room temperature for 20min, then add benzyl bromide (1.15g ,6.75mmol). The reaction solution was stirred at 80°C for 4 hours. The reaction solution was cooled to room temperature, the residue was added to water (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, concentrated, and purified by column chromatography to obtain compound 6-2 (850 mg). ESI-MS: m/z = 254.0 [M+H] + .
步骤3、将化合物6-2(850mg,3.36mmol)溶于乙酸乙酯(10mL)中，向上述溶液中加入m-CPBA(2.7g,13.4mmol,85％purity)，氮气置换后反应液在室温下搅拌16小时。残余物加入饱和亚硫酸钠水溶液(50mL)，用乙酸乙酯(50mL x 2)萃取。有机相合并，饱和盐水(50mL)洗涤，通过柱纯化得到化合物6-3(340mg)。ESI-MS：m/z＝270.0[M+H] +。 Step 3. Dissolve compound 6-2 (850mg, 3.36mmol) in ethyl acetate (10mL), add m-CPBA (2.7g, 13.4mmol, 85% purity) to the above solution, and replace the reaction solution with nitrogen in Stir at room temperature for 16 hours. The residue was added with saturated aqueous sodium sulfite (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), and purified by column to obtain compound 6-3 (340 mg). ESI-MS: m/z = 270.0 [M+H] + .
步骤4、将化合物6-3(340mg,1.26mmol)和DMF(46mg,632μmol)，溶于二氯甲烷(5mL)中，向上述溶液中加入三氯氧磷(232mg,1.52mmol)。氮气置换后反应液在室温下搅拌16小时。通过柱层析纯化得到化合物6-4(210mg)。ESI-MS：m/z＝287.9[M+H] +。 Step 4. Compound 6-3 (340 mg, 1.26 mmol) and DMF (46 mg, 632 μmol) were dissolved in dichloromethane (5 mL), and phosphorus oxychloride (232 mg, 1.52 mmol) was added to the above solution. After nitrogen replacement, the reaction solution was stirred at room temperature for 16 hours. Purification by column chromatography gave compound 6-4 (210 mg). ESI-MS: m/z = 287.9 [M+H] + .
步骤5、将化合物6-4(210mg,729μmol)溶于二氯甲烷(3mL)中，向上述溶液中加入三溴化硼(1mL,17％in DCM)。氮气置换后反应液在0℃下搅拌2小时。反应液甲醇淬灭后通过C18反向柱纯化得到化合物6-5(135mg)。ESI-MS：m/z＝197.9[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：10.60(brs,1H),8.29(d,J＝8.8Hz,1H),7.53(d,J＝8.8Hz,1H),7.20(d,J＝12.0Hz,1H),7.07(s,1H)。 Step 5. Compound 6-4 (210 mg, 729 μmol) was dissolved in dichloromethane (3 mL), and boron tribromide (1 mL, 17% in DCM) was added to the above solution. After nitrogen substitution, the reaction solution was stirred at 0° C. for 2 hours. The reaction solution was quenched with methanol and purified by C18 reverse column to obtain compound 6-5 (135 mg). ESI-MS: m/z = 197.9 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 10.60 (brs, 1H), 8.29 (d, J = 8.8Hz, 1H), 7.53 (d, J = 8.8Hz, 1H), 7.20 ( d, J = 12.0 Hz, 1H), 7.07 (s, 1H).
步骤6、化合物6-5和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物6-6。ESI-MS：m/z＝329.0[M+H] +。 Step 6, compound 6-5 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 6-6. ESI-MS: m/z = 329.0 [M+H] + .
步骤7、化合物6-6和中间体v1为原料，参考实施例1步骤1的制备方法，得到产物L6。ESI-MS:m/z＝486.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：8.84(s,1H),8.61-8.57(m,2H),8.50(s,1H),8.39(d,J＝8.8Hz,1H),8.20(s,1H),7.69(s,1H),7.68(d,J＝8.0Hz,1H),7.62(s,1H),7.38(d,J＝7.2Hz,1H),7.18(d,J＝6.4Hz,1H),4.42-4.37(m,1H),3.90(s,3H),3.42(s,3H),1.27(d,J＝6.8Hz,6H)。 Step 7, compound 6-6 and intermediate v1 are used as raw materials, referring to the preparation method in step 1 of Example 1, to obtain the product L6. ESI-MS: m/z = 486.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 8.84 (s, 1H), 8.61-8.57 (m, 2H), 8.50 (s, 1H), 8.39 (d, J = 8.8Hz, 1H ),8.20(s,1H),7.69(s,1H),7.68(d,J=8.0Hz,1H),7.62(s,1H),7.38(d,J=7.2Hz,1H),7.18(d , J=6.4Hz, 1H), 4.42-4.37(m, 1H), 3.90(s, 3H), 3.42(s, 3H), 1.27(d, J=6.8Hz, 6H).
实施例7：化合物L7的制备Embodiment 7: the preparation of compound L7
Figure PCTCN2022143403-appb-000046
Figure PCTCN2022143403-appb-000046
步骤1、将4-甲氧基苯-1,2-二胺(5.0g,36.2mmol)和乙醛酸乙酯(8.1g,39.8mmol)溶于乙醇(50mL)中。反应液回流16小时后冷却至室温，浓缩除去乙醇，残余物用石油醚：乙酸乙酯＝10:1(30mL)打浆得到化合物7-1(5.0g,产率78.5％)。ESI-MS：m/z＝177.0[M+H] +。 Step 1. Dissolve 4-methoxybenzene-1,2-diamine (5.0 g, 36.2 mmol) and ethyl glyoxylate (8.1 g, 39.8 mmol) in ethanol (50 mL). The reaction solution was refluxed for 16 hours, cooled to room temperature, concentrated to remove ethanol, and the residue was slurried with petroleum ether: ethyl acetate = 10:1 (30 mL) to obtain compound 7-1 (5.0 g, yield 78.5%). ESI-MS: m/z = 177.0 [M+H] + .
步骤2、以化合物7-1为原料，参考实施例2步骤3的制备方法，得到化合物7-2(1.3g)。ESI-MS:m/z＝194.9[M+H] +。 1H NMR(CDCl 3,400MHz):δ(ppm)：8.72(s,1H),7.90(d,J＝9.2Hz,1H),7.45(dd,J＝9.2Hz,2.8Hz,1H),7.39(d,J＝2.8Hz,1H),3.98(s,3H)。 Step 2. Using compound 7-1 as a raw material, refer to the preparation method in step 3 of Example 2 to obtain compound 7-2 (1.3 g). ESI-MS: m/z = 194.9 [M+H] + . 1 H NMR (CDCl 3 , 400MHz): δ (ppm): 8.72 (s, 1H), 7.90 (d, J = 9.2Hz, 1H), 7.45 (dd, J = 9.2Hz, 2.8Hz, 1H), 7.39 (d, J=2.8Hz, 1H), 3.98(s, 3H).
步骤3、将化合物7-2(400mg,2.03mmol)溶于氯仿(5mL)中，向上述溶液中加入三溴化硼(1.5mL)，氮气置换后反应液在60℃油浴中搅拌24小时。反应液冷却至0℃，甲醇淬灭后后浓缩，残余物通过C18反向柱纯化得到化合物7-3(180mg,产率39.4％)。ESI-MS：m/z＝224.8[M+H] + Step 3. Compound 7-2 (400mg, 2.03mmol) was dissolved in chloroform (5mL), boron tribromide (1.5mL) was added to the above solution, and the reaction solution was stirred in an oil bath at 60°C for 24 hours after nitrogen replacement . The reaction solution was cooled to 0°C, quenched with methanol, and then concentrated. The residue was purified by a C18 reverse column to obtain compound 7-3 (180 mg, yield 39.4%). ESI-MS: m/z=224.8[M+H] +
步骤4、化合物7-3和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物7-4。ESI-MS：m/z＝312.1[M+H] +。 Step 4, compound 7-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 7-4. ESI-MS: m/z = 312.1 [M+H] + .
步骤5、将化合物7-4(180mg,579μmol)溶于NMP(4mL)中，再加入碳酸钾(239mg,1.74mmol)和中间体v1(205mg,1.16mmol)。反应液在110℃搅拌16小时，粗品用制备HPLC(TFA)纯化得到化合物L7(83mg，产率46％)。ESI-MS:m/z＝469.0[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：9.76(s,1H),8.74(s,1H),8.57(d,J＝6.4Hz,1H),8.48(s,1H),8.17(s,1H),8.16(d,J＝9.2Hz,1H),7.88(d,J＝2.8Hz,1H),7.73(dd,J＝9.2Hz,2.8Hz,1H),7.62(d,J＝2.4Hz,1H),7.38(d,J＝8.0Hz,1H),7.15(dd,J＝6.4Hz,2.4Hz,1H),4.43-4.37(m,1H),3.89(s,3H),3.43(s,3H),1.27(d,J＝6.8Hz,6H)。 Step 5. Compound 7-4 (180 mg, 579 μmol) was dissolved in NMP (4 mL), and potassium carbonate (239 mg, 1.74 mmol) and intermediate v1 (205 mg, 1.16 mmol) were added. The reaction solution was stirred at 110° C. for 16 hours, and the crude product was purified by preparative HPLC (TFA) to obtain compound L7 (83 mg, yield 46%). ESI-MS: m/z = 469.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 9.76 (s, 1H), 8.74 (s, 1H), 8.57 (d, J=6.4Hz, 1H), 8.48 (s, 1H), 8.17(s,1H),8.16(d,J=9.2Hz,1H),7.88(d,J=2.8Hz,1H),7.73(dd,J=9.2Hz,2.8Hz,1H),7.62(d, J＝2.4Hz, 1H), 7.38(d, J＝8.0Hz, 1H), 7.15(dd, J＝6.4Hz, 2.4Hz, 1H), 4.43-4.37(m, 1H), 3.89(s, 3H) , 3.43 (s, 3H), 1.27 (d, J=6.8Hz, 6H).
实施例8：化合物L8的制备Embodiment 8: the preparation of compound L8
Figure PCTCN2022143403-appb-000047
Figure PCTCN2022143403-appb-000047
步骤1、将4-氨基-3-甲基苯酚(1g，6.90mmol),(E)-3-乙氧基丙烯酰氯(0.971g,7.25mmol)溶于四氢呋喃(50mL)中，氮气置换后反应液在室温下搅拌2小时。反应液浓缩除去四氢呋喃，得到化合物8-1(1g)。ESI-MS：m/z＝222.0[M+H] +。 Step 1. Dissolve 4-amino-3-methylphenol (1g, 6.90mmol), (E)-3-ethoxyacryloyl chloride (0.971g, 7.25mmol) in tetrahydrofuran (50mL), and react after nitrogen replacement The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to remove tetrahydrofuran to obtain Compound 8-1 (1 g). ESI-MS: m/z = 222.0 [M+H] + .
步骤2、将化合物8-1(1g,4.52mmol)溶于MsOH(10mL)中，反应液在室温下搅拌2小时。反应结束后将反应液倒入冰水中淬灭，饱和碳酸氢钠溶液调节pH至7，混合液用乙酸乙酯四氢呋喃混合液(10:1)(30mL x3)萃取。有机相合并，用饱和盐水(5mL)洗涤，硫酸钠干燥后浓缩，残余物通过硅胶柱层析纯化得到化合物8-2(490mg,产率61.5％)。ESI-MS：m/z＝176.0[M+H] +。 Step 2. Compound 8-1 (1 g, 4.52 mmol) was dissolved in MsOH (10 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched by pouring into ice water, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate tetrahydrofuran mixture (10:1) (30 mL x3). The organic phases were combined, washed with saturated brine (5 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 8-2 (490 mg, yield 61.5%). ESI-MS: m/z = 176.0 [M+H] + .
步骤3、以化合物8-2为原料，参考实施例2步骤3的制备方法，得到化合物8-3(170mg)。ESI-MS：m/z＝194.0[M+H] +。 Step 3. Using compound 8-2 as a raw material, refer to the preparation method in step 3 of Example 2 to obtain compound 8-3 (170 mg). ESI-MS: m/z = 194.0 [M+H] + .
步骤4、化合物8-3和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物8-4。ESI-MS：m/z＝325.0[M+H] +。 Step 4, compound 8-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 8-4. ESI-MS: m/z = 325.0 [M+H] + .
步骤5、将化合物8-4(30mg,0.093mmol)溶于NMP(3mL)中，再加入碳酸钾(52mg，0.372mmol)和2-溴-4-氟吡啶(25mg，0.14mmol)。氮气置换后反应液在70℃油浴中搅拌5小时。反应液冷却至室温，反应液加水(5mL)，用乙酸乙酯萃取(20mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，得到化合物8-5(45mg)。ESI-MS：m/z＝482.9[M+H] +。 Step 5. Compound 8-4 (30 mg, 0.093 mmol) was dissolved in NMP (3 mL), and potassium carbonate (52 mg, 0.372 mmol) and 2-bromo-4-fluoropyridine (25 mg, 0.14 mmol) were added. After nitrogen replacement, the reaction solution was stirred in an oil bath at 70° C. for 5 hours. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to obtain compound 8-5 (45 mg). ESI-MS: m/z = 482.9 [M+H] + .
步骤6、化合物8-5和化合物v1-1为原料，参考实施例1步骤2的制备方法，得到产物L8。ESI-MS：m/z＝482.0[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：8.88(s,1H),8.49(d,J＝8.8Hz,1H),8.40(d,J＝5.6Hz,1H),8.24(t,J＝7.2Hz,2H),7.98(s,1H),7.5(d,J＝2Hz,1H),7.45(s,1H),7.31(d,J＝2.5Hz,1H),7.16(d,J＝8Hz,1H),6.76(dd,J＝10Hz,1H),4.42-4.33(m,1H),3.85(s,3H),3.41(s,3H),2.76(s,3H),1.26(d,J＝6.8Hz,6H)。 Step 6, compound 8-5 and compound v1-1 were used as raw materials, and the product L8 was obtained by referring to the preparation method in step 2 of Example 1. ESI-MS: m/z = 482.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 8.88 (s, 1H), 8.49 (d, J = 8.8Hz, 1H), 8.40 (d, J = 5.6Hz, 1H), 8.24 ( t, J=7.2Hz, 2H), 7.98(s, 1H), 7.5(d, J=2Hz, 1H), 7.45(s, 1H), 7.31(d, J=2.5Hz, 1H), 7.16(d ,J=8Hz,1H),6.76(dd,J=10Hz,1H),4.42-4.33(m,1H),3.85(s,3H),3.41(s,3H),2.76(s,3H),1.26 (d, J=6.8Hz, 6H).
实施例9：化合物L9的制备Embodiment 9: the preparation of compound L9
Figure PCTCN2022143403-appb-000048
Figure PCTCN2022143403-appb-000048
步骤1、将2-甲基-4-氨基苯酚(10.0g,0.08mol)溶于THF(200mL)中，加入吡啶(9.36g,0.12mol)，3-乙氧基丙烯酰氯(11.4g,0.09mol)，反应液在室温搅拌2小时。LCMS监测反应结束后，浓缩，残余物用乙酸乙酯打浆得到化合物9-1(13.0g,产率73.5％)。LC-MS m/z＝222.0[M+H] +。 1H NMR(DMSO-d6,300MHz):δ(ppm)：9.40(s,1H),9.02(s,1H),7.42(d,J＝12.3Hz,1H),7.29(s,1H),7.23(d,J＝8.4Hz,1H),6.69(d,J＝8.4Hz,1H),5.50(d,J＝12.3Hz,1H),3.93(q,J＝6.9Hz,1H),2.1(s,3H),1.28(t,J＝6.9Hz,3H)。 Step 1. Dissolve 2-methyl-4-aminophenol (10.0g, 0.08mol) in THF (200mL), add pyridine (9.36g, 0.12mol), 3-ethoxyacryloyl chloride (11.4g, 0.09 mol), the reaction solution was stirred at room temperature for 2 hours. After the reaction was monitored by LCMS, it was concentrated, and the residue was slurried with ethyl acetate to obtain compound 9-1 (13.0 g, yield 73.5%). LC-MS m/z = 222.0 [M+H] + . 1 H NMR (DMSO-d6, 300MHz): δ (ppm): 9.40 (s, 1H), 9.02 (s, 1H), 7.42 (d, J = 12.3Hz, 1H), 7.29 (s, 1H), 7.23 (d, J=8.4Hz, 1H), 6.69(d, J=8.4Hz, 1H), 5.50(d, J=12.3Hz, 1H), 3.93(q, J=6.9Hz, 1H), 2.1(s , 3H), 1.28 (t, J=6.9Hz, 3H).
步骤2、将化合物9-1(13.0g,0.58mol)溶于甲磺酸(100mL)中，反应液在室温搅拌2小时。LCMS监测反应结束后，倒入冰水中，用饱和碳酸钠溶液调节pH值到8。过滤，用乙酸乙酯打浆得到化合物9-2(8.5g,产率82.5％)。LC-MS：m/z＝176.0[M+H] +。 Step 2. Compound 9-1 (13.0 g, 0.58 mol) was dissolved in methanesulfonic acid (100 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was monitored by LCMS, it was poured into ice water, and the pH value was adjusted to 8 with saturated sodium carbonate solution. Filtration and beating with ethyl acetate gave compound 9-2 (8.5 g, yield 82.5%). LC-MS: m/z = 176.0 [M+H] + .
步骤3、以化合物9-2，参考实施例2步骤3的制备方法，得到化合物9-3(200mg)。 1H NMR(DMSO-d6,300MHz):δ(ppm)：10.28(s,1H),8.19(d,J＝6.3Hz,1H),7.69(s,1H),7.37(d,J＝6.6Hz 1H),7.20(s,1H),2.23(s,3H)。 Step 3. Using compound 9-2, refer to the preparation method in step 3 of Example 2 to obtain compound 9-3 (200 mg). 1 H NMR(DMSO-d6,300MHz):δ(ppm):10.28(s,1H),8.19(d,J=6.3Hz,1H),7.69(s,1H),7.37(d,J=6.6Hz 1H), 7.20(s,1H), 2.23(s,3H).
步骤4、化合物9-3和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物9-4。LC-MS，m/z＝325.1[M+H] +。 Step 4, compound 9-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 9-4. LC-MS, m/z = 325.1 [M+H] + .
步骤5、将化合物9-4(180mg,0.55mmol)，中间体v1(195mg,1.10mmol)和碳酸钾(228mg,1.65mmol)溶于NMP(3mL)中，溶液加热至110℃，搅拌16h。LC-MS监测反应结束后，浓缩，反相制备，冻干，得到化合物L9(20.0mg,产率7.5％)。LC-MS，m/z＝482.3[M+H] +。 1H NMR(DMSO-d6,400MHz):δ(ppm)：8.75(s,1H),8.39(s,1H),8.37(s,1H),8.23(s,1H),8.21(d,J＝9.2Hz,1H),7.96(s,1H),7.95(s,1H),7.61(s,1H),7.16(d,J＝8.0Hz,1H),7.26(d,J＝2.4Hz,1H),6.7(dd,J＝2.4Hz,J＝5.6Hz,1H),4.42-4.33(m,1H),3.84(s,3H),3.40(s,3H),2.35(s,3H),1.26(d,J＝6.4Hz,6H)。 Step 5. Compound 9-4 (180mg, 0.55mmol), intermediate v1 (195mg, 1.10mmol) and potassium carbonate (228mg, 1.65mmol) were dissolved in NMP (3mL), and the solution was heated to 110°C and stirred for 16h. After the reaction was monitored by LC-MS, it was concentrated, prepared in reverse phase, and lyophilized to obtain compound L9 (20.0 mg, yield 7.5%). LC-MS, m/z = 482.3 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 8.75 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.21 (d, J= 9.2Hz, 1H), 7.96(s, 1H), 7.95(s, 1H), 7.61(s, 1H), 7.16(d, J=8.0Hz, 1H), 7.26(d, J=2.4Hz, 1H) ,6.7(dd,J=2.4Hz,J=5.6Hz,1H),4.42-4.33(m,1H),3.84(s,3H),3.40(s,3H),2.35(s,3H),1.26( d, J=6.4Hz, 6H).
实施例10：化合物L10的制备Embodiment 10: the preparation of compound L10
Figure PCTCN2022143403-appb-000049
Figure PCTCN2022143403-appb-000049
将化合物4-1(200mg,0.65mmol)，4-氯-N-甲基吡啶-2-甲酰胺(220mg,0.64mmol)和碳酸钾(220mg,1.95mmol)溶于NMP(3mL)中，溶液加热至110℃，搅拌16h。LCMS监测反应结束后，浓缩，反相制备，冻干，得到化合物L10(30mg,产率10.3％)。LC-MS m/z＝445.0[M+H] +。 1H NMR(DMSO-d6,400MHz):δ(ppm)：8.79(s,2H),8.55(d,J＝5.6Hz,1H),8.48(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.07(d,J＝8.8Hz,1H),7.75(d,J＝2.4Hz,1H),7.58(dd,J＝2.8Hz,J＝8.8Hz,1H),7.48(d,J＝2.4Hz,1H),7.24(dd,J＝2.4Hz,J＝5.6Hz,1H),7.18(d,J＝7.6Hz,1H),4.40-4.35(m,1H),3.41(s,3H),2.78(d,J＝5.2Hz,3H),1.26(d,J＝6.8Hz,6H)。 Compound 4-1 (200mg, 0.65mmol), 4-chloro-N-methylpyridine-2-carboxamide (220mg, 0.64mmol) and potassium carbonate (220mg, 1.95mmol) were dissolved in NMP (3mL), and the solution Heated to 110°C and stirred for 16h. After the reaction was monitored by LCMS, it was concentrated, prepared in reverse phase, and lyophilized to obtain compound L10 (30 mg, yield 10.3%). LC-MS m/z = 445.0 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ (ppm): 8.79 (s, 2H), 8.55 (d, J = 5.6Hz, 1H), 8.48 (d, J = 8.8Hz, 1H), 8.27 (d ,J=8.8Hz,1H),8.07(d,J=8.8Hz,1H),7.75(d,J=2.4Hz,1H),7.58(dd,J=2.8Hz,J=8.8Hz,1H), 7.48(d, J=2.4Hz, 1H), 7.24(dd, J=2.4Hz, J=5.6Hz, 1H), 7.18(d, J=7.6Hz, 1H), 4.40-4.35(m, 1H), 3.41 (s, 3H), 2.78 (d, J=5.2Hz, 3H), 1.26 (d, J=6.8Hz, 6H).
实施例11：化合物L11的制备Embodiment 11: Preparation of Compound L11
Figure PCTCN2022143403-appb-000050
Figure PCTCN2022143403-appb-000050
步骤1、将4-氨基-2,6-二氟苯酚(1.45g,10.0mmol)和吡啶(1.56g,20.0mmol)溶于四氢呋喃(100mL)中，向上述溶液中加入(E)-3-乙氧基丙烯酰氯(1.4g,10.5mmol)，室温下搅拌24小时。浓缩得到化合物11-1。ESI-MS：m/z＝244.0[M+H] +。 Step 1. Dissolve 4-amino-2,6-difluorophenol (1.45g, 10.0mmol) and pyridine (1.56g, 20.0mmol) in tetrahydrofuran (100mL), and add (E)-3- Ethoxyacryloyl chloride (1.4g, 10.5mmol), stirred at room temperature for 24 hours. Concentration gave compound 11-1. ESI-MS: m/z = 244.0 [M+H] + .
步骤2、将化合物11-1(2.43g,10.0mmol)溶于甲磺酸(15mL)中，室温下搅拌17小时。将反应液缓慢加入到冰水(150mL)中，过滤，固体水洗，干燥，得到化合物11-2(1.8g,产率92％)。ESI-MS：m/z＝198.0[M+H] +。 Step 2. Compound 11-1 (2.43 g, 10.0 mmol) was dissolved in methanesulfonic acid (15 mL), and stirred at room temperature for 17 hours. The reaction solution was slowly added to ice water (150 mL), filtered, the solid was washed with water, and dried to obtain compound 11-2 (1.8 g, yield 92%). ESI-MS: m/z = 198.0 [M+H] + .
步骤3、以化合物11-2为原料，参考实施例2步骤3的制备方法，得到化合物11-3(720mg)。ESI-MS：m/z＝215.9[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.39(d,J＝8.8Hz,1H),7.69(dd,J＝11.2,1.2Hz,1H),7.59(d,J＝8.8Hz,1H)。 Step 3. Using compound 11-2 as a raw material, refer to the preparation method in step 3 of Example 2 to obtain compound 11-3 (720 mg). ESI-MS: m/z=215.9[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.39 (d, J=8.8Hz, 1H), 7.69 (dd, J=11.2, 1.2Hz, 1H), 7.59 (d, J = 8.8Hz, 1H).
步骤4、化合物11-3和化合物v4为原料，参考实施例1步骤2的制备方法，得到化合物11-4。ESI-MS：m/z＝347.0[M+H] +。 Step 4, compound 11-3 and compound v4 were used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 11-4. ESI-MS: m/z = 347.0 [M+H] + .
步骤5、将化合物11-4(500mg,1.4mmol)溶于NMP(10mL)中，加入碳酸钾(597mg,4.3mmol)和2-溴-4-氟吡啶(761mg,4.3mmol)。反应液在90℃搅拌24小时，通过C18反向柱纯化得到产物化合物11-5(301mg，产率41.5％)。ESI-MS:m/z＝503.9[M+H] +。 Step 5. Compound 11-4 (500 mg, 1.4 mmol) was dissolved in NMP (10 mL), and potassium carbonate (597 mg, 4.3 mmol) and 2-bromo-4-fluoropyridine (761 mg, 4.3 mmol) were added. The reaction solution was stirred at 90° C. for 24 hours, and purified by a C18 reverse column to obtain the product compound 11-5 (301 mg, yield 41.5%). ESI-MS: m/z = 503.9 [M+H] + .
步骤6、化合物11-5和化合物v1-1为原料，参考实施例1步骤2的制备方法，得到产物L11。ESI-MS:m/z＝504.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.85(s,1H),8.62(d,J＝8.8Hz,1H),8.46-8.41(m,2H),8.29(s,1H),8.01(s,1H),7.84(d,J＝11.2Hz,1H),7.36(d,J＝2.4Hz,1H),7.30(d,J＝8.0Hz,1H),6.89(dd,J＝5.6,2.4Hz,1H),4.42-4.37(m,1H),3.85(s,3H),3.41(s,3H),1.26(d,J＝6.4Hz,6H)。 Step 6, compound 11-5 and compound v1-1 were used as raw materials, and the product L11 was obtained by referring to the preparation method in step 2 of Example 1. ESI-MS: m/z＝504.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.85(s, 1H), 8.62 (d, J＝8.8Hz, 1H), 8.46 -8.41(m,2H),8.29(s,1H),8.01(s,1H),7.84(d,J=11.2Hz,1H),7.36(d,J=2.4Hz,1H),7.30(d, J=8.0Hz,1H),6.89(dd,J=5.6,2.4Hz,1H),4.42-4.37(m,1H),3.85(s,3H),3.41(s,3H),1.26(d,J = 6.4Hz, 6H).
实施例12：化合物L12的制备Embodiment 12: the preparation of compound L12
Figure PCTCN2022143403-appb-000051
Figure PCTCN2022143403-appb-000051
步骤1、将6-溴-2-氯喹唑啉(1g)，联硼酸频那醇酯(1.36g)，醋酸钾(806mg)和Pd(dppf)Cl 2(301mg)溶于1,4-二氧六环(50mL)中，氮气置换后反应液在70℃下搅拌2小时得到化合物12-1。ESI-MS：m/z＝291.0[M+H] +。 Step 1, 6-bromo-2-chloroquinazoline (1g), biboronic acid pinacol ester (1.36g), potassium acetate (806mg) and Pd(dppf)Cl 2 (301mg) were dissolved in 1,4-bis In oxane (50 mL), the reaction solution was replaced with nitrogen and stirred at 70° C. for 2 hours to obtain compound 12-1. ESI-MS: m/z = 291.0 [M+H] + .
步骤2、将NaOH(182mg)，H 2O 2(520mg)和H 2O(50mL)加入到化合物12-1的反应液中，反应液在室温下搅拌3小时。反应结束后向反应液中加入Na 2SO 3溶液淬灭，混合液用乙酸乙酯(50mL x3)萃取。有机相合并，用饱和盐水(5mL)洗涤，硫酸钠干燥后浓缩，残余物通过硅胶柱层析纯化得到化合物12-2(430mg)。ESI-MS：m/z＝180.9[M+H] +。 Step 2. NaOH (182 mg), H 2 O 2 (520 mg) and H 2 O (50 mL) were added to the reaction solution of compound 12-1, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, Na 2 SO 3 solution was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 12-2 (430 mg). ESI-MS: m/z = 180.9 [M+H] + .
步骤3、化合物12-2和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物12-3。 ESI-MS：m/z＝311.0[M+H] +。 Step 3, compound 12-2 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 12-3. ESI-MS: m/z = 311.0 [M+H] + .
步骤4、将化合物12-3(600mg)溶于NMP(10mL)中，再加入碳酸钾(1.06g)和2-溴-4-氟吡啶(373.5mg，2.12mmol)。氮气置换后反应液在100℃油浴中搅拌过夜。反应液冷却至室温，反应液加水(5mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，用C18反向柱纯化得到化合物12-4(236mg)。ESI-MS：m/z＝466.9[M+H] +。 Step 4. Compound 12-3 (600 mg) was dissolved in NMP (10 mL), and potassium carbonate (1.06 g) and 2-bromo-4-fluoropyridine (373.5 mg, 2.12 mmol) were added. After nitrogen replacement, the reaction solution was stirred overnight in an oil bath at 100°C. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, evaporated to remove the solvent, and purified with a C18 reverse column to obtain compound 12-4 (236 mg). ESI-MS: m/z = 466.9 [M+H] + .
步骤5、化合物12-4和化合物v1-1为原料，参考实施例1步骤2的制备方法，得到化合物L12。ESI-MS：m/z＝469.0[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：9.53(s,1H),8.52(s,1H),8.44(d,J＝6Hz,1H),8.27(s,1H),8.02(d,J＝8.8Hz,1H),7.99(s,1H),7.84-7.80(m,2H),7.34(d,J＝2.4Hz,1H),7.13(d,J＝7.6Hz,1H),6.85(dd,J＝5.6Hz,1H),4.41-4.32(m,1H),3.85(s,3H),3.38(s,3H),1.25(d,J＝6.8Hz,6H)。 Step 5, using compound 12-4 and compound v1-1 as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound L12. ESI-MS: m/z = 469.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 9.53 (s, 1H), 8.52 (s, 1H), 8.44 (d, J=6Hz, 1H), 8.27 (s, 1H), 8.02 (d,J=8.8Hz,1H),7.99(s,1H),7.84-7.80(m,2H),7.34(d,J=2.4Hz,1H),7.13(d,J=7.6Hz,1H) , 6.85 (dd, J = 5.6Hz, 1H), 4.41-4.32 (m, 1H), 3.85 (s, 3H), 3.38 (s, 3H), 1.25 (d, J = 6.8Hz, 6H).
实施例13：化合物L13的制备Embodiment 13: Preparation of compound L13
Figure PCTCN2022143403-appb-000052
Figure PCTCN2022143403-appb-000052
步骤1、将化合物4-1(890mg,2.87mmol)溶于NMP(15mL)中，再加入碳酸钾(1.6g，11.48mmol)和2-溴-4-氟吡啶(758mg，4.3mmol)。氮气置换后反应液在90℃油浴中搅拌过夜。反应液冷却至室温，反应液加水(5mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，得到粗产物。粗品用C18反向柱纯化(乙腈：水＝5:95到80:20梯度洗脱)得到化合物13-1(700mg，产率52.3％)。ESI-MS：m/z＝465.9[M+H] +。 Step 1. Compound 4-1 (890mg, 2.87mmol) was dissolved in NMP (15mL), and potassium carbonate (1.6g, 11.48mmol) and 2-bromo-4-fluoropyridine (758mg, 4.3mmol) were added. After nitrogen replacement, the reaction solution was stirred overnight in an oil bath at 90°C. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain a crude product. The crude product was purified by C18 reverse column (acetonitrile: water = 5:95 to 80:20 gradient elution) to obtain compound 13-1 (700 mg, yield 52.3%). ESI-MS: m/z = 465.9 [M+H] + .
步骤2、化合物13-1(150mg,0.32mmol)，X-phos(61mg，0.128mmol)，乙酰胺(38mg，0.64mmol)，碳酸铯(312mg,0.96mmol)和Pd 2(dba) 3(59mg，0.064mmol)溶于1,4-二氧六环(8mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，粗品用C18反向柱制备(乙腈:水＝5:95到80:20梯度洗脱)得到化合物L13(38mg，产率26.7％)。ESI-MS:m/z＝445.3[M+H] +。 1H NMR(400MHz,DMSO-D6):δ(ppm)：10.57(s,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.26(d,J＝8.9Hz,1H),8.22(d,J＝5.7Hz,1H),8.03(d,J＝9.1Hz,1H),7.74–7.68(m,2H),7.54(dd,J＝5.5,2.5Hz,1H),7.18(d,J＝7.5Hz,1H),6.76(dd,J＝5.5,2.2Hz,1H),4.40-4.35(m,1H),3.41(s,3H),2.03(s,3H),1.26(d,J＝6.6Hz,6H)。 Step 2, compound 13-1 (150mg, 0.32mmol), X-phos (61mg, 0.128mmol), acetamide (38mg, 0.64mmol), cesium carbonate (312mg, 0.96mmol) and Pd 2 (dba) 3 (59mg , 0.064 mmol) was dissolved in 1,4-dioxane (8 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50mL), dried over sodium sulfate and evaporated to remove the solvent. The crude product was prepared on a C18 reverse column (acetonitrile:water=5:95 to 80:20 gradient elution) to obtain compound L13 (38mg, yield rate 26.7%). ESI-MS: m/z = 445.3 [M+H] + . 1 H NMR (400MHz, DMSO-D6): δ (ppm): 10.57(s, 1H), 8.78(s, 1H), 8.46(d, J=8.8Hz, 1H), 8.26(d, J=8.9Hz ,1H),8.22(d,J=5.7Hz,1H),8.03(d,J=9.1Hz,1H),7.74–7.68(m,2H),7.54(dd,J=5.5,2.5Hz,1H) ,7.18(d,J=7.5Hz,1H),6.76(dd,J=5.5,2.2Hz,1H),4.40-4.35(m,1H),3.41(s,3H),2.03(s,3H), 1.26 (d, J=6.6Hz, 6H).
实施例14：化合物L14的制备Embodiment 14: Preparation of Compound L14
Figure PCTCN2022143403-appb-000053
Figure PCTCN2022143403-appb-000053
步骤1、将化合物4-1(750mg,2.4mmol)溶于DMF(10mL)中，反应液冷却至0℃。缓慢加入NaH(106mg,2.7mmol)，反应液在0℃搅拌1h。然后加入2,4-二氯嘧啶(394mg,2.7mmol),反应液在室温搅拌3h，LCMS检测反应结束后,冰水(30mL)淬灭反应，乙酸乙酯萃取(200mL x 2)，有机相用无水硫酸钠干燥，浓缩，柱层析(PE:EA＝1:1)得到化合物14-1(550mg,产率54.1％)。ESI-MS:m/z＝422.9[M+H] +。 Step 1. Compound 4-1 (750mg, 2.4mmol) was dissolved in DMF (10mL), and the reaction solution was cooled to 0°C. NaH (106mg, 2.7mmol) was added slowly, and the reaction solution was stirred at 0°C for 1h. Then 2,4-dichloropyrimidine (394mg, 2.7mmol) was added, and the reaction solution was stirred at room temperature for 3h. After the reaction was detected by LCMS, the reaction was quenched with ice water (30mL), extracted with ethyl acetate (200mL x 2), and the organic phase was It was dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=1:1) gave compound 14-1 (550 mg, yield 54.1%). ESI-MS: m/z = 422.9 [M+H] + .
步骤2、将化合物14-1(200mg,0.47mmol)，1H-吡唑-4-胺(78mg,0.94mmol)和溶于正丁醇(2mL)中，封管加热至140℃，搅拌0.5h。LCMS监测反应结束后，浓缩，反相柱制备(C18)，冻干，得到化合物L14(3.0mg,产率1.3％)。ESI-MS:m/z＝470.0[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：8.80(s,1H),8.46(d,J＝8.8Hz,1H),8.32(s,1H),8.27(d,J＝8.8Hz,2H),8.02(d,J＝9.2Hz,1H),7.76(s,1H),7.60(d,J＝6.0Hz,1H),7.18-7.17(m,2H),6.41(d,J＝5.6Hz,1H),4.39-4.37(m,1H),3.41(s,3H),1.26(d,J＝6.8Hz,6H)。 Step 2. Dissolve compound 14-1 (200mg, 0.47mmol), 1H-pyrazol-4-amine (78mg, 0.94mmol) and n-butanol (2mL), seal the tube and heat to 140°C, stirring for 0.5h . After the reaction was monitored by LCMS, it was concentrated, prepared by reverse phase column (C18), and lyophilized to obtain compound L14 (3.0 mg, yield 1.3%). ESI-MS: m/z = 470.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 8.80 (s, 1H), 8.46 (d, J = 8.8Hz, 1H), 8.32 (s, 1H), 8.27 (d, J = 8.8 Hz,2H),8.02(d,J=9.2Hz,1H),7.76(s,1H),7.60(d,J=6.0Hz,1H),7.18-7.17(m,2H),6.41(d,J =5.6Hz, 1H), 4.39-4.37(m, 1H), 3.41(s, 3H), 1.26(d, J=6.8Hz, 6H).
实施例15：化合物L15的制备Embodiment 15: Preparation of Compound L15
Figure PCTCN2022143403-appb-000054
Figure PCTCN2022143403-appb-000054
步骤1、将2-溴-3-氨基-5-氟吡啶(2g,9.6mmol)溶于THF(9mL)中，加入三乙胺(3.1mL,21.6mmol)，丙烯酸苄酯(1.3mL,14.4mmol)，醋酸钯(0.3g,1.3mmol)和三苯基膦(0.6g,2.2mmol)。反应液在微波反应器中140℃搅拌2小时。反应液冷却室温，残余物加入水(150mL)，用乙酸乙酯(150mL x 2)萃取。有机相合并，饱和盐水(250mL)洗涤，硫酸钠干燥后浓缩，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝3:1到1:1梯度洗脱)得到化合物15-1(1.76g,产率93％)。ESI-MS:m/z＝273.0[M+H] +。 Step 1. Dissolve 2-bromo-3-amino-5-fluoropyridine (2g, 9.6mmol) in THF (9mL), add triethylamine (3.1mL, 21.6mmol), benzyl acrylate (1.3mL, 14.4 mmol), palladium acetate (0.3g, 1.3mmol) and triphenylphosphine (0.6g, 2.2mmol). The reaction solution was stirred at 140° C. for 2 hours in a microwave reactor. The reaction solution was cooled to room temperature, the residue was added to water (150 mL), and extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (250 mL), dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1 gradient elution) to obtain compound 15-1 ( 1.76g, yield 93%). ESI-MS: m/z = 273.0 [M+H] + .
步骤2、将化合物15-1(1.5g,7.5mmol)溶于乙酸(15mL)中，向上述溶液中加入三丁基膦(1.9mL,7.5mmol).氮气置换后反应液在110℃下搅拌2小时。反应液过滤后残余物用乙酸乙酯洗涤浓缩得到化合物15-2(500mg)。Step 2. Compound 15-1 (1.5g, 7.5mmol) was dissolved in acetic acid (15mL), and tributylphosphine (1.9mL, 7.5mmol) was added to the above solution. After nitrogen replacement, the reaction solution was stirred at 110°C 2 hours. After the reaction solution was filtered, the residue was washed with ethyl acetate and concentrated to obtain compound 15-2 (500 mg).
步骤3、将化合物15-2(500mg)溶于1，4-二氧六环(15mL)中，向上述溶液中加入POCl 3(1mL,27.5mmol).反应液在110℃下搅拌5小时。反应液浓缩后残余物用二氯甲烷溶解后加入冰水中(150mL)，用二氯甲烷(150mL x 2)萃取。有机相合并，饱和盐水(250mL)洗涤，硫酸钠干燥后浓缩，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝2:1到石油醚：乙酸乙酯：二氯甲烷＝1:1:1洗脱)得到化合物15-3(300mg,产率58.4％)。 Step 3. Compound 15-2 (500 mg) was dissolved in 1,4-dioxane (15 mL), and POCl 3 (1 mL, 27.5 mmol) was added to the above solution. The reaction solution was stirred at 110° C. for 5 hours. After the reaction solution was concentrated, the residue was dissolved in dichloromethane, added to ice water (150 mL), and extracted with dichloromethane (150 mL x 2). The organic phases were combined, washed with saturated brine (250 mL), dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to petroleum ether: ethyl acetate: dichloromethane = 1: 1:1 elution) to obtain compound 15-3 (300 mg, yield 58.4%).
步骤4、化合物15-3和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物15-4。ESI-MS：m/z＝314.0[M+H] +。 Step 4, compound 15-3 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 15-4. ESI-MS: m/z = 314.0 [M+H] + .
步骤5、将化合物15-4(156mg,500μmol)溶于NMP(4mL)中，再加入碳酸铯(489mg,1.5mmol)和中间体v5(131mg,0.75mmol)。反应液在110℃搅拌12小时，粗品用制备HPLC(TFA)纯化得到产物L15(60mg，产率25.6％)。ESI-MS:m/z＝469.0[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ(ppm)：8.81(s,1H),8.66-8.45(m,3H),8.33(s,1H),8.12-8.04(m,2H),7.62-7.56(m,2H),7.24-7.14(m,2H),4.43-4.39(m,1H),3.90(s,3H),3.43(s,3H),1.28(d,J＝8.8Hz,6H)。 Step 5. Compound 15-4 (156 mg, 500 μmol) was dissolved in NMP (4 mL), and cesium carbonate (489 mg, 1.5 mmol) and intermediate v5 (131 mg, 0.75 mmol) were added. The reaction solution was stirred at 110° C. for 12 hours, and the crude product was purified by preparative HPLC (TFA) to obtain product L15 (60 mg, yield 25.6%). ESI-MS: m/z = 469.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ (ppm): 8.81 (s, 1H), 8.66-8.45 (m, 3H), 8.33 (s, 1H), 8.12-8.04 (m, 2H), 7.62 -7.56(m,2H),7.24-7.14(m,2H),4.43-4.39(m,1H),3.90(s,3H),3.43(s,3H),1.28(d,J＝8.8Hz,6H ).
实施例16：化合物L16的制备Embodiment 16: Preparation of Compound L16
Figure PCTCN2022143403-appb-000055
Figure PCTCN2022143403-appb-000055
将化合物14-1(200mg,0.47mmol)，4-胺基异噁唑(73mg,0.94mmol)溶于正丁醇(2mL)中，封管加热至100℃，搅拌0.5h。LCMS监测反应结束后，浓缩，反相柱制备(0.5％碳酸氢铵和乙腈)，冻干，得到产物L16(25.0mg,产率11.3％)。LC-MS:m/z＝471.0[M+H] +。1H NMR(DMSO-d6,400MHz):δ(ppm)：9.75(brs,1H),8.81(s,1H),8.49-8.27(m,4H),8.05(d,J＝8.8Hz,1H),7.79(s,1H),7.62(d,J＝8.0Hz,1H),7.18(d,J＝4.4Hz,1H),6.60(d,J＝5.6Hz,2H),4.40-4.36(m,1H),3.40(s,3H),1.26(d,J＝6.8Hz,6H)。 Compound 14-1 (200mg, 0.47mmol), 4-aminoisoxazole (73mg, 0.94mmol) was dissolved in n-butanol (2mL), heated to 100°C with sealed tube, and stirred for 0.5h. After the reaction was monitored by LCMS, it was concentrated, prepared by reverse-phase column (0.5% ammonium bicarbonate and acetonitrile), and lyophilized to obtain the product L16 (25.0 mg, yield 11.3%). LC-MS: m/z = 471.0 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ (ppm): 9.75 (brs, 1H), 8.81 (s, 1H), 8.49-8.27 (m, 4H), 8.05 (d, J = 8.8Hz, 1H), 7.79(s,1H),7.62(d,J=8.0Hz,1H),7.18(d,J=4.4Hz,1H),6.60(d,J=5.6Hz,2H),4.40-4.36(m,1H ), 3.40 (s, 3H), 1.26 (d, J=6.8Hz, 6H).
实施例17：化合物L17的制备Embodiment 17: Preparation of Compound L17
Figure PCTCN2022143403-appb-000056
Figure PCTCN2022143403-appb-000056
步骤1、化合物13-1和1-Boc-吡唑-4-硼酸频哪醇酯为原料，参考实施例1步骤2的制备方法，得到化合物17-1。ESI-MS：m/z＝554.0[M+H] +。 Step 1. Compound 13-1 and 1-Boc-pyrazole-4-boronic acid pinacol ester were used as raw materials, referring to the preparation method in Step 2 of Example 1, to obtain Compound 17-1. ESI-MS: m/z = 554.0 [M+H] + .
步骤2、将化合物17-1(350mg,0.63mmol)溶于二氯甲烷(15mL)中，再加入TFA(10ml)和苯甲醚(5ml)。氮气置换后反应液在室温下搅拌3h。反应结束后，向反应液加NaHCO 3溶液中和，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，得到粗产物。粗品用C18反向柱制备得到产物L17(200mg)。ESI-MS：m/z＝454.0[M+H] +。 1H NMR(400MHz,DMSO-D6):δ(ppm)：13.06(s,1H),8.78(s,1H),8.43(m,2H),8.33(s,1H),8.26(d,J＝8.9Hz,1H),8.04(d,J＝8.7Hz,2H),7.67(s,1H),7.56(dd,J＝9.0,2.4Hz,1H),7.42(d,J＝1.7Hz,1H),7.17(d,J＝7.4Hz,1H),6.76(m,1H),4.38(dd,J＝13.5,6.8Hz,1H),3.41(s,3H),1.26(d,J＝6.6Hz,6H)。 Step 2. Compound 17-1 (350mg, 0.63mmol) was dissolved in dichloromethane (15mL), and TFA (10ml) and anisole (5ml) were added. After nitrogen replacement, the reaction solution was stirred at room temperature for 3 h. After the reaction was completed, NaHCO 3 solution was added to the reaction liquid for neutralization, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain a crude product. The crude product was prepared on a C18 reverse column to give the product L17 (200 mg). ESI-MS: m/z = 454.0 [M+H] + . 1 H NMR (400MHz, DMSO-D6): δ (ppm): 13.06 (s, 1H), 8.78 (s, 1H), 8.43 (m, 2H), 8.33 (s, 1H), 8.26 (d, J= 8.9Hz, 1H), 8.04(d, J=8.7Hz, 2H), 7.67(s, 1H), 7.56(dd, J=9.0, 2.4Hz, 1H), 7.42(d, J=1.7Hz, 1H) ,7.17(d,J=7.4Hz,1H),6.76(m,1H),4.38(dd,J=13.5,6.8Hz,1H),3.41(s,3H),1.26(d,J=6.6Hz, 6H).
实施例18：化合物L18的制备Embodiment 18: Preparation of compound L18
Figure PCTCN2022143403-appb-000057
Figure PCTCN2022143403-appb-000057
将化合物L17(100mg,10.22mmol)，TEA(16mg,0.66mmol)溶于二氯甲烷(50mL)中。向上述溶液中加入甲基磺酰氯(30mg,0.26mmol)。氮气置换后反应液在室温下中搅拌1小时。浓缩除去二氯甲烷，残余物中加水(10mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，粗品用C18反向柱制备(乙腈:水＝5:95到80:20梯度洗脱)得到化合物L18(26mg)。ESI-MS：m/z＝532.0[M+H] +。 1H NMR(400MHz,DMSO-D6):δ(ppm)：8.89(s,1H),8.78(s,1H),8.53–8.48(m,2H),8.46(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.05(d,J＝9.1Hz,1H),7.70(d,J＝2.7Hz,1H),7.67(d,J＝2.3Hz,1H),7.56(dd,J＝9.0,2.7Hz,1H),7.17(d,J＝7.6Hz,1H),6.92(dd,J＝5.7,2.4Hz,1H),4.38(m,6.7Hz,1H),3.59(s,3H),3.41(s,3H),1.26(d,J＝6.6Hz,6H)。 Compound L17 (100 mg, 10.22 mmol), TEA (16 mg, 0.66 mmol) was dissolved in dichloromethane (50 mL). To the above solution was added methanesulfonyl chloride (30 mg, 0.26 mmol). After nitrogen substitution, the reaction solution was stirred at room temperature for 1 hour. Concentrate to remove dichloromethane, add water (10 mL) to the residue, and extract with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The crude product was prepared on a C18 reverse column (acetonitrile:water=5:95 to 80:20 gradient elution) to obtain compound L18 (26 mg). ESI-MS: m/z = 532.0 [M+H] + . 1 H NMR (400MHz, DMSO-D6): δ (ppm): 8.89 (s, 1H), 8.78 (s, 1H), 8.53–8.48 (m, 2H), 8.46 (d, J = 8.8Hz, 1H) ,8.27(d,J=8.8Hz,1H),8.05(d,J=9.1Hz,1H),7.70(d,J=2.7Hz,1H),7.67(d,J=2.3Hz,1H),7.56 (dd, J=9.0,2.7Hz,1H),7.17(d,J=7.6Hz,1H),6.92(dd,J=5.7,2.4Hz,1H),4.38(m,6.7Hz,1H),3.59 (s, 3H), 3.41 (s, 3H), 1.26 (d, J=6.6Hz, 6H).
实施例19：化合物L19的制备Embodiment 19: Preparation of Compound L19
Figure PCTCN2022143403-appb-000058
Figure PCTCN2022143403-appb-000058
步骤1、将5-甲氧基吡啶-2-胺(1.9g,15.4mmol)溶于乙酸(10mL)中，缓慢加入溴(2.47g,15.4mmol)的乙酸(10mL)溶液。室温下搅拌17小时。氨水中和，用乙酸乙酯(200mL x 2)萃取。有机相合并，饱和盐水(250mL)洗涤，硫酸钠干燥后浓缩，得到化合物19-1(1.5g,产率47.6％)。ESI-MS:m/z＝204.9[M+H] +。 1H NMR(CDCl 3,400MHz):δ(ppm)：7.76(d,J＝2.4Hz,1H),7.36(d,J＝2.4Hz,1H),4.65(brs,2H),3.78(s,3H)。 Step 1. Dissolve 5-methoxypyridin-2-amine (1.9g, 15.4mmol) in acetic acid (10mL), and slowly add bromine (2.47g, 15.4mmol) in acetic acid (10mL). Stir at room temperature for 17 hours. Neutralize with ammonia water and extract with ethyl acetate (200mL x 2). The organic phases were combined, washed with saturated brine (250 mL), dried over sodium sulfate and concentrated to obtain compound 19-1 (1.5 g, yield 47.6%). ESI-MS: m/z = 204.9 [M+H] + . 1 H NMR (CDCl 3 , 400MHz): δ (ppm): 7.76 (d, J = 2.4Hz, 1H), 7.36 (d, J = 2.4Hz, 1H), 4.65 (brs, 2H), 3.78 (s, 3H).
步骤2、将化合物19-1(1.5g,7.39mmol)溶于DMF(8mL)中，加入三乙胺(1.64g,16.3mmol)，丙烯酸苄酯(1.80g,11.1mmol)，醋酸钯(213mg,0.96mmol)和三苯基膦(445mg,1.70mmol)，氮气置换后反应液在微波反应器中140℃搅拌2小时。反应液冷却室温，残余物加入水(150mL)，用乙酸乙酯(150mL x 2)萃取。有机相合并，饱和盐水(250mL)洗涤，硫酸钠干燥后浓缩，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝3:1到1:1梯度洗脱)得到化合物19-2(1.2g,产率57.2％)。ESI-MS:m/z＝285.0[M+H] +。 Step 2. Dissolve compound 19-1 (1.5g, 7.39mmol) in DMF (8mL), add triethylamine (1.64g, 16.3mmol), benzyl acrylate (1.80g, 11.1mmol), palladium acetate (213mg , 0.96mmol) and triphenylphosphine (445mg, 1.70mmol), the reaction solution was stirred in a microwave reactor at 140°C for 2 hours after nitrogen replacement. The reaction solution was cooled to room temperature, the residue was added to water (150 mL), and extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (250 mL), dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 to 1:1 gradient elution) to obtain compound 19-2 ( 1.2 g, yield 57.2%). ESI-MS: m/z = 285.0 [M+H] + .
步骤3、将化合物19-2(1.2g,4.23mmol)溶于甲醇(5mL)中，向上述溶液中加入甲醇钾(1.0g,12.7mmol)，氮气置换后反应液在60℃下搅拌2小时。反应液浓缩后残余物通过C18反向柱纯化(乙腈：水＝30:70到35:65梯度洗脱)得到化合物19-3(900mg)。ESI-MS：m/z＝177.0[M+H] +。 Step 3. Compound 19-2 (1.2g, 4.23mmol) was dissolved in methanol (5mL), potassium methoxide (1.0g, 12.7mmol) was added to the above solution, and the reaction solution was stirred at 60°C for 2 hours after nitrogen replacement . After the reaction solution was concentrated, the residue was purified by a C18 reverse column (acetonitrile:water=30:70 to 35:65 gradient elution) to obtain compound 19-3 (900 mg). ESI-MS: m/z = 177.0 [M+H] + .
步骤4、化合物19-3为原料，参考实施例2步骤3的制备方法，得到化合物19-4(180mg)。ESI-MS：m/z＝195.0[M+H] +。 Step 4. Compound 19-3 was used as the starting material. Referring to the preparation method in Step 3 of Example 2, Compound 19-4 (180 mg) was obtained. ESI-MS: m/z = 195.0 [M+H] + .
步骤5、化合物19-4和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物19-5。ESI-MS：m/z＝326.1[M+H] +。 Step 5, compound 19-4 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 19-5. ESI-MS: m/z = 326.1 [M+H] + .
步骤6、将化合物19-5(180mg,554μmol)溶于二氯甲烷(3mL)中，向上述溶液中加入三溴化硼(1mL)。氮气置换后反应液在室温下搅拌3小时。反应液甲醇淬灭后浓缩残余物通过C18反向柱纯化(乙腈：水＝35:65到40:60梯度洗脱)得到化合物19-6(125mg,产率72.6％)。ESI-MS：m/z＝312.1[M+H] +。 Step 6. Compound 19-5 (180 mg, 554 μmol) was dissolved in dichloromethane (3 mL), and boron tribromide (1 mL) was added to the above solution. After nitrogen replacement, the reaction solution was stirred at room temperature for 3 hours. The reaction solution was quenched with methanol and the concentrated residue was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain compound 19-6 (125 mg, yield 72.6%). ESI-MS: m/z = 312.1 [M+H] + .
步骤7、将化合物19-6(30mg,0.096mol)溶于NMP(3mL)中，向上述溶液中加入碳酸钾(53mg,0.384mmol)和中间体v1(20mg,0.115mol)。氮气置换后反应液在110℃搅拌3小时。反应液浓缩后残余物通过C18反向柱制备(乙腈：水＝35:65到40:60梯度洗脱)得到化合物L19(125mg,产率72.6％)。ESI-MS：m/z＝469.0[M+H] +。 1H NMR(400MHz,DMSO-D6):δ(ppm)：9.03(d,J＝16.8Hz,2H),8.65(d,J＝8.9Hz,1H),8.54(s,2H),8.38(s,2H),8.10(s,1H),7.55(s,2H),7.10(s,1H),4.45(m,1H),3.87(s,3H),3.45(s,3H),1.28(d,J＝6.6Hz,6H)。 Step 7. Compound 19-6 (30 mg, 0.096 mol) was dissolved in NMP (3 mL), and potassium carbonate (53 mg, 0.384 mmol) and intermediate v1 (20 mg, 0.115 mol) were added to the above solution. After nitrogen replacement, the reaction solution was stirred at 110°C for 3 hours. After the reaction solution was concentrated, the residue was prepared by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain compound L19 (125 mg, yield 72.6%). ESI-MS: m/z = 469.0 [M+H] + . 1 H NMR (400MHz, DMSO-D6): δ (ppm): 9.03 (d, J = 16.8Hz, 2H), 8.65 (d, J = 8.9Hz, 1H), 8.54 (s, 2H), 8.38 (s ,2H),8.10(s,1H),7.55(s,2H),7.10(s,1H),4.45(m,1H),3.87(s,3H),3.45(s,3H),1.28(d, J=6.6Hz, 6H).
实施例20：化合物L20的制备Embodiment 20: Preparation of Compound L20
Figure PCTCN2022143403-appb-000059
Figure PCTCN2022143403-appb-000059
步骤1、将2-溴-4-氟吡啶(2g,11.4mmol)加入一个干燥后的氮气保护下的50mL三口烧瓶中，降至-78℃,加入正丁基锂溶液(5.5mL,13.7mmol)并反应30分钟，向上述溶液中加入丙酮(1.58g,27.2mmol)保持温度在-78℃并保持1小时，之后恢复至室温。LCMS监测反应结束后，浓缩，有机相合并，饱和盐水(50mL)洗涤，硫酸钠干燥，浓缩后残余物通过硅胶柱层析纯化得到化合物20-1(350mg,产率20％)。LC-MS m/z＝156.0[M+H] +。 Step 1. Add 2-bromo-4-fluoropyridine (2g, 11.4mmol) into a dry 50mL three-necked flask under the protection of nitrogen, drop to -78°C, add n-butyllithium solution (5.5mL, 13.7mmol ) and reacted for 30 minutes, acetone (1.58 g, 27.2 mmol) was added to the above solution to keep the temperature at -78° C. for 1 hour, and then returned to room temperature. After the reaction was monitored by LCMS, it was concentrated, the organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and the concentrated residue was purified by silica gel column chromatography to obtain compound 20-1 (350 mg, yield 20%). LC-MS m/z = 156.0 [M+H] + .
步骤2、将化合物20-1(56mg,0.36mmol)，化合物4-1(112mg,0.36mmol)和碳酸钾(149mg,1.08mmol)溶于NMP(3mL)中，溶液加热至100℃，搅拌16h。LCMS监测反应结束后，浓缩，反相制备，冻干，得到化合物L20(50mg,产率31.2％)。LC-MS m/z＝446.1[M+H] +， 1H NMR(DMSO-d 6,300MHz):δ8.88(s,1H),8.80(s,1H),8.48(d,J＝9.0Hz,1H),8.36(d,J＝5.4Hz,1H),8.29(d,J＝8.8Hz,1H),8.07(d,J＝9.4Hz,1H),7.64(d,J＝5.6Hz,1H),7.53(dd,J＝2.7Hz,J＝2.7Hz,1H),6.75(d,J＝5.4Hz,1H),5.40(s,1H),4.37-4.44(m,1H),3.44(s,3H),1.66(s,6H),1.29(d,J＝6.6Hz,6H)。 Step 2. Compound 20-1 (56mg, 0.36mmol), Compound 4-1 (112mg, 0.36mmol) and potassium carbonate (149mg, 1.08mmol) were dissolved in NMP (3mL), and the solution was heated to 100°C and stirred for 16h . After the reaction was monitored by LCMS, it was concentrated, prepared in reverse phase, and lyophilized to obtain compound L20 (50 mg, yield 31.2%). LC-MS m/z=446.1[M+H] + , 1 H NMR (DMSO-d 6 , 300MHz): δ8.88(s, 1H), 8.80(s, 1H), 8.48(d, J=9.0 Hz,1H),8.36(d,J=5.4Hz,1H),8.29(d,J=8.8Hz,1H),8.07(d,J=9.4Hz,1H),7.64(d,J=5.6Hz, 1H), 7.53(dd, J=2.7Hz, J=2.7Hz, 1H), 6.75(d, J=5.4Hz, 1H), 5.40(s, 1H), 4.37-4.44(m, 1H), 3.44( s, 3H), 1.66 (s, 6H), 1.29 (d, J=6.6Hz, 6H).
实施例21：化合物L21的制备Embodiment 21: Preparation of Compound L21
Figure PCTCN2022143403-appb-000060
Figure PCTCN2022143403-appb-000060
步骤1、将化合物4-1(600mg,1.90mmol)溶于NMP(20mL)中，再加入碳酸钾(1.0g，7.60mmol)和2-硝基-4-氯吡啶(360mg，2.90mmol)。氮气置换后反应液在90℃油浴中搅拌过夜。反应液冷却至室温，反应液加水(5mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，得到粗产物。粗品用C18反向柱纯化(乙腈：水＝5:95到80:20梯度洗脱)得到化合物21-1(350mg，产率42.6％)。ESI-MS:m/z＝433.0[M+H] +。 Step 1. Compound 4-1 (600 mg, 1.90 mmol) was dissolved in NMP (20 mL), and potassium carbonate (1.0 g, 7.60 mmol) and 2-nitro-4-chloropyridine (360 mg, 2.90 mmol) were added. After nitrogen replacement, the reaction solution was stirred overnight in an oil bath at 90°C. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain a crude product. The crude product was purified by C18 reverse column (acetonitrile: water = 5:95 to 80:20 gradient elution) to obtain compound 21-1 (350 mg, yield 42.6%). ESI-MS: m/z = 433.0 [M+H] + .
步骤2、将化合物21-1(500mg，1.15mmol)，Pd/C(50mg)溶于甲醇(250mL)中。氢气置换后反应液在室温下中搅拌12小时。反应结束后过滤浓缩。粗品用C18反向柱制备(乙腈:水＝5:95到80:20梯度洗脱)得到化合物L21(300mg，65％)。ESI-MS:m/z＝403.0[M+H] +。 1H NMR(400MHz,DMSO-D6):δ(ppm)：8.76(s,1H),8.44(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.02(d,J＝9.2Hz,1H),7.84(d,J＝6Hz,1H),7.63(d,J＝2.4Hz,1H),7.50(dd,J＝6.4,2.8Hz,1H),7.18(d,J＝7.6Hz,1H),6.23(dd,J＝3.6,2.4Hz,1H),5.95(s,2H),5.88(d,J＝2.0Hz,1H),4.37(m,1H),3.41(s,3H),1.26(d,J＝6.4Hz,6H)。 Step 2. Compound 21-1 (500 mg, 1.15 mmol), Pd/C (50 mg) was dissolved in methanol (250 mL). After hydrogen replacement, the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated by filtration. The crude product was prepared on a C18 reverse column (acetonitrile:water=5:95 to 80:20 gradient elution) to obtain compound L21 (300 mg, 65%). ESI-MS: m/z = 403.0 [M+H] + . 1 H NMR (400MHz, DMSO-D6): δ (ppm): 8.76 (s, 1H), 8.44 (d, J = 8.8Hz, 1H), 8.26 (d, J = 8.8Hz, 1H), 8.02 (d ,J=9.2Hz,1H),7.84(d,J=6Hz,1H),7.63(d,J=2.4Hz,1H),7.50(dd,J=6.4,2.8Hz,1H),7.18(d, J＝7.6Hz, 1H), 6.23(dd, J＝3.6, 2.4Hz, 1H), 5.95(s, 2H), 5.88(d, J＝2.0Hz, 1H), 4.37(m, 1H), 3.41( s, 3H), 1.26 (d, J=6.4Hz, 6H).
实施例22：化合物L22的制备Embodiment 22: Preparation of Compound L22
Figure PCTCN2022143403-appb-000061
Figure PCTCN2022143403-appb-000061
步骤1、将化合物4-1(367mg,1.18mmol)溶于乙酸(15mL)中，加入液溴(199mg,1.24mmol)。反应液在室温下搅拌3小时，产物析出，过滤，得到化合物22-1(360mg，产率83％)。ESI-MS:m/z＝388.9[M+H] +.。 Step 1. Compound 4-1 (367 mg, 1.18 mmol) was dissolved in acetic acid (15 mL), and liquid bromine (199 mg, 1.24 mmol) was added. The reaction solution was stirred at room temperature for 3 hours, the product was precipitated and filtered to obtain compound 22-1 (360 mg, yield 83%). ESI-MS: m/z = 388.9 [M+H] + ..
步骤2、将化合物22-1(325mg,0.83mmol)，二异丙基乙胺(321mg,2.49mmol)和Pd(dppf)Cl 2(61mg,0.08mmol)溶于DMF(50mL)中，向上述溶液中加入乙醇(50mL)，反应体系抽真空，一氧化碳置换，重复三次，在一氧化碳保护下，95℃油浴中搅拌17小时。反应液冷却至室温，浓缩，反相柱层析(乙腈：水＝3:97到50:50梯度洗脱)纯化，得到化合物22-2(232mg，产率73％)。ESI-MS:m/z＝383.1[M+H] +。 Step 2. Dissolve compound 22-1 (325mg, 0.83mmol), diisopropylethylamine (321mg, 2.49mmol) and Pd(dppf)Cl 2 (61mg, 0.08mmol) in DMF (50mL), and add to the above Add ethanol (50 mL) to the solution, vacuumize the reaction system, replace with carbon monoxide, repeat three times, and stir in an oil bath at 95° C. for 17 hours under the protection of carbon monoxide. The reaction solution was cooled to room temperature, concentrated, and purified by reverse phase column chromatography (acetonitrile: water = 3:97 to 50:50 gradient elution) to obtain compound 22-2 (232 mg, yield 73%). ESI-MS: m/z = 383.1 [M+H] + .
步骤3、将化合物22-2(211mg,0.55mmol)，碳酸钾(228mg,1.65mmol)和2-溴-4-氟吡啶(291mg,1.65mmol)溶于的NMP(8mL)，80℃下反应17小时。反相柱层析纯化，得到化合物22-3(275mg，产率93％)。ESI-MS：m/z＝540.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.84(s,1H),8.60(d,J＝9.2Hz,1H),8.33(d,J＝9.2Hz,1H),8.29(d,J＝5.6Hz,1H),8.19(d,J＝8.8Hz,1H),7.67(d,J＝8.8Hz,1H),7.28(d,J＝7.2Hz,1H),7.21(d,J＝2.4Hz,1H),7.03(dd,J＝5.6,2.4Hz,1H),4.15-4.36(m,1H),4.30(q,J＝7.2Hz,2H),3.41(s,3H),1.26(d,J＝6.8Hz,6H),1.11(t,J＝7.2Hz,1H)。 Step 3. Dissolve compound 22-2 (211mg, 0.55mmol), potassium carbonate (228mg, 1.65mmol) and 2-bromo-4-fluoropyridine (291mg, 1.65mmol) in NMP (8mL), react at 80°C 17 hours. Purified by reverse phase column chromatography to obtain compound 22-3 (275 mg, yield 93%). ESI-MS: m/z=540.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.84(s, 1H), 8.60 (d, J=9.2Hz, 1H), 8.33 (d, J=9.2Hz, 1H), 8.29(d, J=5.6Hz, 1H), 8.19(d, J=8.8Hz, 1H), 7.67(d, J=8.8Hz, 1H), 7.28(d ,J=7.2Hz,1H),7.21(d,J=2.4Hz,1H),7.03(dd,J=5.6,2.4Hz,1H),4.15-4.36(m,1H),4.30(q,J= 7.2Hz, 2H), 3.41(s, 3H), 1.26(d, J=6.8Hz, 6H), 1.11(t, J=7.2Hz, 1H).
步骤4、化合物22-3和化合物v1-1为原料，参考实施例1步骤2的制备方法，得到化合物22-4。ESI-MS:m/z＝540.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.84(s,1H),8.59(d,J＝9.2Hz,1H),8.38(d,J＝5.6Hz,1H),8.30(d,J＝9.2Hz,1H),8.26(s,1H),8.17(d,J＝8.8Hz,1H),7.97(s,1H),7.62(d,J＝8.8Hz,1H),7.26-7.25(m,2H),6.69(dd,J＝5.6,2.4Hz,1H),4.42-4.36(m,1H),4.30(q,J＝7.2Hz,2H),3.85(s,3H),3.41(s,3H),1.26(d,J＝6.8Hz,6H),1.11(t,J＝7.2Hz,1H)。 Step 4, compound 22-3 and compound v1-1 were used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 22-4. ESI-MS: m/z＝540.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.84(s, 1H), 8.59 (d, J＝9.2Hz, 1H), 8.38 (d,J=5.6Hz,1H),8.30(d,J=9.2Hz,1H),8.26(s,1H),8.17(d,J=8.8Hz,1H),7.97(s,1H),7.62 (d, J=8.8Hz, 1H), 7.26-7.25(m, 2H), 6.69(dd, J=5.6, 2.4Hz, 1H), 4.42-4.36(m, 1H), 4.30(q, J=7.2 Hz, 2H), 3.85(s, 3H), 3.41(s, 3H), 1.26(d, J=6.8Hz, 6H), 1.11(t, J=7.2Hz, 1H).
实施例23：化合物L23的制备Embodiment 23: Preparation of compound L23
Figure PCTCN2022143403-appb-000062
Figure PCTCN2022143403-appb-000062
步骤1、将化合物L22(240mg,0.44mmol)和氢氧化钠(200mg,5.0mmol)溶于甲醇(40mL)中，向上述溶液中加入水(10mL)，反应液在80℃油浴中搅拌3小时。利用1.0M盐酸中和反应液，反相柱层析(乙腈：水＝3:97到30:70梯度洗脱)纯化，得到化合物23-1(190mg，产率80％)。ESI-MS:m/z＝512.2[M+H] +。 Step 1. Dissolve compound L22 (240mg, 0.44mmol) and sodium hydroxide (200mg, 5.0mmol) in methanol (40mL), add water (10mL) to the above solution, and stir the reaction solution in an oil bath at 80°C for 3 Hour. The reaction solution was neutralized with 1.0M hydrochloric acid and purified by reverse phase column chromatography (acetonitrile:water=3:97 to 30:70 gradient elution) to obtain compound 23-1 (190 mg, yield 80%). ESI-MS: m/z = 512.2 [M+H] + .
步骤2、将化合物23-1(185mg,0.36mmol),HATU(205mg,0.54mmol)，氯化铵(58mg,1.08mmol)和DIEA(278mg,2.16mmol)溶于DMF(5.0mL)中，室温下搅拌17小时。反相柱层析(乙腈：水＝5:95到70:30梯度洗脱)纯化，得到化合物L23(141mg，产率77％)。ESI-MS:m/z＝511.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.81(s,1H),8.55(d,J＝9.2Hz,1H),8.37(d,J＝5.6Hz,1H),8.23(s,1H),8.21(d,J＝8.8Hz,1H),8.05-8.02(m,2H),7.96(s,1H),7.82(s,1H),7.50(d,J＝5.6Hz,1H),7.24(d,J＝2.4Hz,1H),7.21(d,J＝8.8Hz,1H),6.72(dd,J＝5.6,2.4Hz,1H),4.41-4.34(m,1H),3.85(s,3H),3.41(s,3H),1.26(d,J＝6.4Hz,6H)。 Step 2, compound 23-1 (185mg, 0.36mmol), HATU (205mg, 0.54mmol), ammonium chloride (58mg, 1.08mmol) and DIEA (278mg, 2.16mmol) were dissolved in DMF (5.0mL), room temperature Stirring was continued for 17 hours. Purification by reverse phase column chromatography (acetonitrile: water = 5:95 to 70:30 gradient elution) gave compound L23 (141 mg, yield 77%). ESI-MS: m/z＝511.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.81(s, 1H), 8.55 (d, J＝9.2Hz, 1H), 8.37 (d,J=5.6Hz,1H),8.23(s,1H),8.21(d,J=8.8Hz,1H),8.05-8.02(m,2H),7.96(s,1H),7.82(s, 1H), 7.50(d, J=5.6Hz, 1H), 7.24(d, J=2.4Hz, 1H), 7.21(d, J=8.8Hz, 1H), 6.72(dd, J=5.6, 2.4Hz, 1H), 4.41-4.34 (m, 1H), 3.85 (s, 3H), 3.41 (s, 3H), 1.26 (d, J=6.4Hz, 6H).
实施例24：化合物L24的制备Embodiment 24: Preparation of compound L24
Figure PCTCN2022143403-appb-000063
Figure PCTCN2022143403-appb-000063
步骤1、将2,3,4-三氯吡啶(100mg,0.55mmol),化合物4-1(171mg,0.55mmol)和碳酸铯(537mg, 1.15mmol)溶于DMF(2mL)中，溶液加热至70℃，搅拌12h。LCMS监测反应结束后，浓缩，反相制备，冻干，得到化合物24-1(70mg,产率28％)。LC-MS：m/z＝456.1[M+H] +。 Step 1, 2,3,4-trichloropyridine (100mg, 0.55mmol), compound 4-1 (171mg, 0.55mmol) and cesium carbonate (537mg, 1.15mmol) were dissolved in DMF (2mL), and the solution was heated to 70°C, stirring for 12h. After the reaction was monitored by LCMS, it was concentrated, prepared in reverse phase, and freeze-dried to obtain compound 24-1 (70 mg, yield 28%). LC-MS: m/z = 456.1 [M+H] + .
步骤2、将化合物24-1(63mg,0.14mmol)，BocNH 2(162mg,1.4mmol),Pd 2dba 3(26mg,0.03mmol),x-Phos(27mg,0.06mmol)和碳酸铯(114mg,0.35mmol)溶于1,4-二氧六环(2mL)中，溶液加热至100℃，搅拌16h。LCMS监测反应结束后，浓缩，反相制备，冻干，得到化合物L24(11mg,产率18％)。LC-MS m/z＝437.0[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ8.77(s,1H),8.44(d,J＝8.8Hz,1H),8.24(d,J＝8.8Hz,1H),8.01(d,J＝9.2Hz,1H),7.80(d,J＝5.6Hz,1H),7.58(d,J＝2.8Hz,1H),7.52(dd,J＝2.8Hz,J＝2.8Hz,1H),7.16(d,J＝7.6Hz,1H),6.43(s,1H),6.11(d,J＝5.2Hz,1H),4.33-4.42(m,1H),3.40(s,3H),1.26(s,6H)。 Step 2, compound 24-1 (63mg, 0.14mmol), BocNH 2 (162mg, 1.4mmol), Pd 2 dba 3 (26mg, 0.03mmol), x-Phos (27mg, 0.06mmol) and cesium carbonate (114mg, 0.35mmol) was dissolved in 1,4-dioxane (2mL), the solution was heated to 100°C and stirred for 16h. After the reaction was monitored by LCMS, it was concentrated, prepared in reverse phase, and lyophilized to obtain compound L24 (11 mg, yield 18%). LC-MS m/z=437.0[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ8.77(s, 1H), 8.44(d, J=8.8Hz, 1H), 8.24( d,J=8.8Hz,1H),8.01(d,J=9.2Hz,1H),7.80(d,J=5.6Hz,1H),7.58(d,J=2.8Hz,1H),7.52(dd, J＝2.8Hz, J＝2.8Hz, 1H), 7.16(d, J＝7.6Hz, 1H), 6.43(s, 1H), 6.11(d, J＝5.2Hz, 1H), 4.33-4.42(m, 1H), 3.40(s,3H), 1.26(s,6H).
实施例25：化合物L25的制备Embodiment 25: Preparation of compound L25
Figure PCTCN2022143403-appb-000064
Figure PCTCN2022143403-appb-000064
将化合物L23(120mg,0.23mmol)和三聚氯氰(87mg,0.47mmol)溶于DMF(5mL)中，室温下搅拌17小时。乙酸乙酯稀释(20mL)，饱和碳酸氢钠水溶液洗涤(20mL)，饱和食盐水洗涤(20mL x 3)。无水硫酸钠干燥，浓缩，高效液相制备色谱纯化，得到化合物L25(45mg，产率39％)。ESI-MS:m/z＝493.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.84(s,1H),8.75(d,J＝9.2Hz,1H),8.49(d,J＝5.6Hz,1H),8.41(d,J＝9.2Hz,1H),8.32-8.30(m,2H),8.02(s,1H),7.67(d,J＝9.2Hz,1H),7.45(d,J＝2.0Hz,1H),7.29(d,J＝7.6Hz,1H),6.95(dd,J＝5.6,2.4Hz,1H),4.42-4.36(m,1H),3.86(s,3H),3.42(s,3H),1.26(d,J＝6.4Hz,6H)。 Compound L23 (120 mg, 0.23 mmol) and cyanuric chloride (87 mg, 0.47 mmol) were dissolved in DMF (5 mL), and stirred at room temperature for 17 hours. Dilute with ethyl acetate (20 mL), wash with saturated aqueous sodium bicarbonate (20 mL), and wash with saturated brine (20 mL x 3). Dry over anhydrous sodium sulfate, concentrate, and purify by HPLC to obtain compound L25 (45 mg, yield 39%). ESI-MS: m/z＝493.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.84(s, 1H), 8.75 (d, J＝9.2Hz, 1H), 8.49 (d, J=5.6Hz, 1H), 8.41(d, J=9.2Hz, 1H), 8.32-8.30(m, 2H), 8.02(s, 1H), 7.67(d, J=9.2Hz, 1H) ,7.45(d,J=2.0Hz,1H),7.29(d,J=7.6Hz,1H),6.95(dd,J=5.6,2.4Hz,1H),4.42-4.36(m,1H),3.86( s, 3H), 3.42 (s, 3H), 1.26 (d, J=6.4Hz, 6H).
实施例26：化合物L26的制备Embodiment 26: Preparation of Compound L26
Figure PCTCN2022143403-appb-000065
Figure PCTCN2022143403-appb-000065
将化合物4-1(80mg,0.258mmol)，溶于DMF(150mL)中，在氮气保护，0℃下加入NaH(19mg,0.48mmol)。反应液在冰浴下搅拌30分钟。然后室温下加入4-氯嘧啶-2-胺，将反应液升高到75℃，搅拌5小时。待反应液冷却至室温，加入水(1mL)淬灭，过滤，收集滤液。将滤液通过制备HPLC(NH 4HCO 3)得到产物L26(45.4mg，产率43.6％)。ESI-MS:m/z＝404.0[M+H] +.H NMR(DMSO-d 6,400MHz):δ8.78(s,1H),8.44(d,J＝8.8Hz,1H),8.25(d,J＝8.8Hz,1H),8.15(d,J＝5.6Hz,1H),7.98(d,J＝9.2Hz,1H),7.69(d,J＝2.4Hz,1H),7.52(dd,J＝9.2Hz,1H),7.16(d,J＝7.6Hz,1H),6.62(s,2H),6.21(d,J＝7.6Hz,1H),4.38-4.36(m,1H),3.41(s,3H),1.27(s,3H),1.26(s,3H)。 Compound 4-1 (80 mg, 0.258 mmol) was dissolved in DMF (150 mL), and NaH (19 mg, 0.48 mmol) was added at 0°C under nitrogen protection. The reaction solution was stirred under ice bath for 30 minutes. Then 4-chloropyrimidin-2-amine was added at room temperature, and the reaction liquid was raised to 75° C. and stirred for 5 hours. After the reaction solution was cooled to room temperature, it was quenched by adding water (1 mL), filtered, and the filtrate was collected. The filtrate was passed through preparative HPLC (NH 4 HCO 3 ) to obtain the product L26 (45.4 mg, 43.6% yield). ESI-MS: m/z=404.0[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ8.78(s, 1H), 8.44(d, J=8.8Hz, 1H), 8.25( d,J=8.8Hz,1H),8.15(d,J=5.6Hz,1H),7.98(d,J=9.2Hz,1H),7.69(d,J=2.4Hz,1H),7.52(dd, J＝9.2Hz, 1H), 7.16(d, J＝7.6Hz, 1H), 6.62(s, 2H), 6.21(d, J＝7.6Hz, 1H), 4.38-4.36(m, 1H), 3.41( s,3H), 1.27(s,3H), 1.26(s,3H).
实施例27：化合物L27的制备Embodiment 27: Preparation of compound L27
Figure PCTCN2022143403-appb-000066
Figure PCTCN2022143403-appb-000066
将化合物13-1(150mg,0.32mmol)，X-phos(61mg，0.128mmol)，甲基磺酰胺(152mg，1.6mmol)碳酸铯(416mg,1.28mmol)和Pd 2(dba) 3(59mg，0.064mmol)溶于1,4-二氧六环(10mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，粗品用C18反向柱制备(乙腈:水＝5:95到80:20梯度洗脱)得到化合物L27(30mg，产率19.4％)。ESI-MS:m/z＝481.2[M+H] +。 1H NMR(400MHz,DMSO-D6):δ(ppm)：8.78(s,1H),8.47(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.06(dd,J＝11.7,7.6Hz,2H),7.72(d,J＝2.7Hz,1H),7.55(dd,J＝9.1,2.7Hz,1H),7.18(d,J＝7.6Hz,1H),6.62(dd,J＝6.1,2.3Hz,1H),6.48(d,J＝2.2Hz,1H),4.38(m,1H),3.41(s,3H),3.11(s,3H),1.26(d,J＝6.6Hz,6H)。 Compound 13-1 (150mg, 0.32mmol), X-phos (61mg, 0.128mmol), methylsulfonamide (152mg, 1.6mmol) cesium carbonate (416mg, 1.28mmol) and Pd 2 (dba) 3 (59mg, 0.064 mmol) was dissolved in 1,4-dioxane (10 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50mL), dried over sodium sulfate and evaporated to remove the solvent. The crude product was prepared on a C18 reverse column (acetonitrile:water=5:95 to 80:20 gradient elution) to obtain compound L27 (30mg, yield rate of 19.4%). ESI-MS: m/z = 481.2 [M+H] + . 1 H NMR (400MHz, DMSO-D6): δ (ppm): 8.78 (s, 1H), 8.47 (d, J = 8.8Hz, 1H), 8.27 (d, J = 8.8Hz, 1H), 8.06 (dd ,J=11.7,7.6Hz,2H),7.72(d,J=2.7Hz,1H),7.55(dd,J=9.1,2.7Hz,1H),7.18(d,J=7.6Hz,1H),6.62 (dd,J=6.1,2.3Hz,1H),6.48(d,J=2.2Hz,1H),4.38(m,1H),3.41(s,3H),3.11(s,3H),1.26(d, J=6.6Hz, 6H).
实施例28：化合物L28的制备Embodiment 28: Preparation of compound L28
Figure PCTCN2022143403-appb-000067
Figure PCTCN2022143403-appb-000067
将化合物13-1(400mg,0.86mmol)，X-phos(818mg，1.72mmol)，环丙烷磺酰胺(1g，8.6mmol)，碳酸铯(2.8g,8.6mmol)和Pd 2(dba) 3(59mg，0.064mmol)溶于DMF(10mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，粗品用C18反向柱制备(乙腈:水＝5:95到80:20梯度洗脱)得到化合物L28(15mg，产率27％)。ESI-MS:m/z＝471.3[M+H] +。 1H NMR(400MHz,DMSO-D6):δ(ppm)：10.85(s,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.24(dd,J＝12.6,7.3Hz,2H),8.03(d,J＝9.1Hz,1H),7.69(dd,J＝4.7,2.5Hz,2H),7.53(dd,J＝9.1,2.7Hz,1H),7.17(d,J＝7.6Hz,1H),6.78(dd,J＝5.7,2.4Hz,1H),4.38(dq,J＝13.3,6.7Hz,1H),3.41(s,3H),1.99–1.92(m,1H),1.26(d,J＝6.6Hz,6H),0.77–0.70(m,4H)。 Compound 13-1 (400 mg, 0.86 mmol), X-phos (818 mg, 1.72 mmol), cyclopropanesulfonamide (1 g, 8.6 mmol), cesium carbonate (2.8 g, 8.6 mmol) and Pd 2 (dba) 3 ( 59mg, 0.064mmol) was dissolved in DMF (10mL), and the reaction solution was stirred at 85°C for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and evaporated to remove the solvent. The crude product was prepared on a C18 reverse column (acetonitrile:water=5:95 to 80:20 gradient elution) to obtain compound L28 (15 mg, yield rate 27%). ESI-MS: m/z = 471.3 [M+H] + . 1 H NMR (400MHz, DMSO-D6): δ (ppm): 10.85 (s, 1H), 8.78 (s, 1H), 8.46 (d, J = 8.8Hz, 1H), 8.24 (dd, J = 12.6, 7.3Hz, 2H), 8.03(d, J=9.1Hz, 1H), 7.69(dd, J=4.7, 2.5Hz, 2H), 7.53(dd, J=9.1, 2.7Hz, 1H), 7.17(d, J＝7.6Hz, 1H), 6.78(dd, J＝5.7, 2.4Hz, 1H), 4.38(dq, J＝13.3, 6.7Hz, 1H), 3.41(s, 3H), 1.99–1.92(m, 1H ), 1.26 (d, J=6.6Hz, 6H), 0.77–0.70 (m, 4H).
实施例29：化合物L29的制备Embodiment 29: Preparation of Compound L29
Figure PCTCN2022143403-appb-000068
Figure PCTCN2022143403-appb-000068
步骤1、将2,4-二氯-6-甲氧基喹啉(5.0g,21.9mmol)和甲磺酸(10.5g，110mmol)溶于乙醇(200mL)和水(10mL)中，将反应液回流两天。待反应液冷却室温，将其滴加到冰水中，用NaOH(2M/L)调节PH值4～6。过滤，收集滤饼，用水清洗滤饼。将残余物通过硅胶柱层析纯化得到化合物29-1(1.6g)。ESI-MS:m/z＝210[M+H] +。 Step 1, 2,4-dichloro-6-methoxyquinoline (5.0g, 21.9mmol) and methanesulfonic acid (10.5g, 110mmol) were dissolved in ethanol (200mL) and water (10mL), and the reaction The liquid was refluxed for two days. After the reaction solution was cooled to room temperature, it was added dropwise to ice water, and the pH value was adjusted to 4-6 with NaOH (2M/L). Filter, collect the filter cake, and wash the filter cake with water. The residue was purified by silica gel column chromatography to obtain compound 29-1 (1.6 g). ESI-MS: m/z = 210 [M+H] + .
步骤2、将化合物29-1(1.60g,7.66mmol)，4-甲基苯亚磺酸钠(2.86g，16.05mmol)溶于DMF(80.0mL)中，向上述溶液中加入氰化钾(1.25g,19.2mmol)。氮气置换后反应液在130℃油浴中搅拌19小时。待反应液冷却室温，将其滴加到冰水中，用乙酸乙酯(320mL x 3)萃取。有机相合并，用饱和盐水(350mL x 2)洗涤，硫酸钠干燥后浓缩，残余物通过C18反向柱纯化(乙腈：水＝35:65到48:52梯度洗脱)得到化合物29-2(390mg，产率26％)。ESI-MS：m/z＝201.0[M+H] +。 Step 2. Dissolve compound 29-1 (1.60g, 7.66mmol), sodium 4-methylbenzenesulfinate (2.86g, 16.05mmol) in DMF (80.0mL), and add potassium cyanide ( 1.25g, 19.2mmol). After nitrogen replacement, the reaction solution was stirred in an oil bath at 130° C. for 19 hours. After the reaction solution was cooled to room temperature, it was added dropwise to ice water and extracted with ethyl acetate (320 mL x 3). The organic phases were combined, washed with saturated brine (350mL x 2), dried over sodium sulfate and concentrated, and the residue was purified by C18 reverse column (acetonitrile:water=35:65 to 48:52 gradient elution) to obtain compound 29-2 ( 390 mg, yield 26%). ESI-MS: m/z = 201.0 [M+H] + .
步骤3、化合物29-2为原料，参考实施例2步骤3的制备方法，得到化合物29-3(300mg)。ESI-MS:m/z＝201.0[M+H] +。 Step 3. Compound 29-2 was used as the raw material. Referring to the preparation method in Step 3 of Example 2, Compound 29-3 (300 mg) was obtained. ESI-MS: m/z = 201.0 [M+H] + .
步骤4、化合物29-3和化合物v4为原料，参考实施例1步骤2的制备方法，得到化合物29-4。ESI-MS:m/z＝350.1[M+H] +。 Step 4, compound 29-3 and compound v4 were used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound 29-4. ESI-MS: m/z = 350.1 [M+H] + .
步骤5、将化合物29-4(270mg,0.77mmol)溶于DCM(10mL)中，浴冰下加入三氟化硼(1.2mL,37.7mmol)。反应液在室温下搅拌17小时。浓缩除去DCM，残余物通过C18反向柱纯化(乙腈：水＝30:70到55:45梯度洗脱)得到化合物29-5。ESI-MS:m/z＝336.1[M+H] +。 Step 5. Compound 29-4 (270 mg, 0.77 mmol) was dissolved in DCM (10 mL), and boron trifluoride (1.2 mL, 37.7 mmol) was added under ice bath. The reaction was stirred at room temperature for 17 hours. Concentrate to remove DCM, and the residue is purified by C18 reverse column (acetonitrile:water=30:70 to 55:45 gradient elution) to obtain compound 29-5. ESI-MS: m/z = 336.1 [M+H] + .
步骤6、将化合物29-5(190mg,0.567mmol)和4-氟-2-溴吡啶溶于DMF(6mL)中，室温下加入碳酸铯(560mg,1.7mmol)。反应液在90℃油浴中搅拌3小时。反应液冷却至室温，残余物通过C18反向柱纯化(乙腈：水＝45:55到58:42梯度洗脱)得到化合物29-6(75mg，产率28％)。ESI-MS:m/z＝491.0[M+H] +。 Step 6. Compound 29-5 (190 mg, 0.567 mmol) and 4-fluoro-2-bromopyridine were dissolved in DMF (6 mL), and cesium carbonate (560 mg, 1.7 mmol) was added at room temperature. The reaction solution was stirred in an oil bath at 90°C for 3 hours. The reaction solution was cooled to room temperature, and the residue was purified by C18 reverse column (acetonitrile:water=45:55 to 58:42 gradient elution) to obtain compound 29-6 (75 mg, yield 28%). ESI-MS: m/z = 491.0 [M+H] + .
步骤7、化合物29-6(60mg,0.122mmol)和化合物v1-1为原料，参考实施例1步骤2的制备方法，得到产物L29。ESI-MS:m/z＝493.3[M+H] +.HNMR(DMSO-d 6,400MHz):δ8.99(s,1H),8.46(d,J＝5.6Hz,1H),8.27(s,1H),8.17(d,J＝8.8Hz,1H),8.10(s,1H),7.99(s,1H),7.83-7.79(m,2H),7.36(d,J＝2.4Hz,1H),7.22(d,J＝7.6Hz,1H),6.88-6.86(m,1H),4.38-4.35(m,1H),3.85(s,3H),3.40(s,3H),1.28(s,3H),1.26(s,3H)。 Step 7: Compound 29-6 (60 mg, 0.122 mmol) and compound v1-1 were used as raw materials, and the product L29 was obtained by referring to the preparation method in Step 2 of Example 1. ESI-MS: m/z＝493.3[M+H] + .HNMR (DMSO-d 6 , 400MHz): δ8.99(s, 1H), 8.46(d, J＝5.6Hz, 1H), 8.27(s ,1H),8.17(d,J=8.8Hz,1H),8.10(s,1H),7.99(s,1H),7.83-7.79(m,2H),7.36(d,J=2.4Hz,1H) ,7.22(d,J＝7.6Hz,1H),6.88-6.86(m,1H),4.38-4.35(m,1H),3.85(s,3H),3.40(s,3H),1.28(s,3H ), 1.26(s,3H).
实施例30：化合物L30的制备Embodiment 30: Preparation of compound L30
Figure PCTCN2022143403-appb-000069
Figure PCTCN2022143403-appb-000069
将化合物L29(17mg,0.035mmol)溶于DMSO(1mL)和THF(0.2mL)中，加入氢氧化钠(2mg,0.05mmol)和双氧水(23mg,0.21mmol,30％)。反应液在室温下搅拌2小时。反应液经过制备HPLC(TFA)得到产物L30(6mg，，产率34％)。ESI-MS:m/z＝511.3[M+H] +.H NMR(DMSO-d 6,400MHz):δ8.49(d,J＝6.0Hz,1H),8.44(s,1H),8.36(s,1H),8.12(d,J＝9.2Hz,1H),8.07(s,1H),8.03(s,1H),7.85(d,J＝14.8Hz,2H),7.68(d,J＝8.4Hz,1H),7.44(s,1H),7.27(s,1H),7.04(d,J＝6.8Hz,1H),6.94(s,1H),4.34-4.31(m,1H),3.88(s,3H),3.38(s,3H),1.27(s,3H),1.26(s,3H)。 Compound L29 (17 mg, 0.035 mmol) was dissolved in DMSO (1 mL) and THF (0.2 mL), and sodium hydroxide (2 mg, 0.05 mmol) and hydrogen peroxide (23 mg, 0.21 mmol, 30%) were added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was subjected to preparative HPLC (TFA) to obtain the product L30 (6 mg, yield 34%). ESI-MS: m/z=511.3[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ8.49(d, J=6.0Hz, 1H), 8.44(s, 1H), 8.36( s,1H),8.12(d,J=9.2Hz,1H),8.07(s,1H),8.03(s,1H),7.85(d,J=14.8Hz,2H),7.68(d,J=8.4 Hz, 1H), 7.44(s, 1H), 7.27(s, 1H), 7.04(d, J=6.8Hz, 1H), 6.94(s, 1H), 4.34-4.31(m, 1H), 3.88(s ,3H), 3.38(s,3H), 1.27(s,3H), 1.26(s,3H).
实施例31：化合物L31的制备Example 31: Preparation of Compound L31
Figure PCTCN2022143403-appb-000070
Figure PCTCN2022143403-appb-000070
步骤1、将化合物v5(800mg,4.57mmol),2-氟-4-甲基-5-硝基吡啶(856mg,5.5mmol)，叔丁醇钾(512mg,4.57mmol)，溶于DMF(5mL)中，溶液常温下搅拌12小时。LCMS监测反应结束后，浓缩后残余物加入乙酸乙酯(40mL)稀释，水洗，有机相浓缩，通过硅胶柱层析纯化(石油醚：乙酸乙酯＝1:1洗脱)得到化合物31-3(1.0g,产率70.3％)。LC-MS m/z＝312.0[M+H] +。 Step 1. Dissolve compound v5 (800mg, 4.57mmol), 2-fluoro-4-methyl-5-nitropyridine (856mg, 5.5mmol), potassium tert-butoxide (512mg, 4.57mmol) in DMF (5mL ), the solution was stirred at room temperature for 12 hours. After the reaction was monitored by LCMS, after concentration, the residue was diluted with ethyl acetate (40 mL), washed with water, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 elution) to obtain compound 31-3 (1.0 g, yield 70.3%). LC-MS m/z = 312.0 [M+H] + .
步骤2、将化合物31-3(466mg,1.5mmol)和草酸二乙酯(1.64g,11.2mmol)溶于四氢呋喃(4.0mL)和乙醇(8.0mL)混合溶剂中，向上述溶液中加入乙醇钠(153mg,2.25mmol)，室温下搅拌3小时。稀盐酸中和，浓缩得到化合物31-4。ESI-MS：m/z＝412.0[M+H] +。 Step 2. Dissolve compound 31-3 (466mg, 1.5mmol) and diethyl oxalate (1.64g, 11.2mmol) in a mixed solvent of tetrahydrofuran (4.0mL) and ethanol (8.0mL), and add sodium ethoxide to the above solution (153mg, 2.25mmol), stirred at room temperature for 3 hours. Neutralize with dilute hydrochloric acid and concentrate to obtain compound 31-4. ESI-MS: m/z = 412.0 [M+H] + .
步骤3、将化合物31-4(131mg,0.32mmol)溶于乙腈(5mL)中，加入硼氢化钠(6mg,0.16mmol)，室温下搅拌1小时。加入乙酸(5mL)，升温至65℃，加入铁粉(6mg,0.16mmol)，反应液在65℃下反应2小时。过滤，浓缩，反相柱层析(乙腈：水＝5:95到50:50梯度洗脱)，得到化合物31-5(35mg,产率32％)。ESI-MS：m/z＝338.0[M+H] +。 Step 3. Dissolve compound 31-4 (131 mg, 0.32 mmol) in acetonitrile (5 mL), add sodium borohydride (6 mg, 0.16 mmol), and stir at room temperature for 1 hour. Acetic acid (5 mL) was added, the temperature was raised to 65°C, iron powder (6 mg, 0.16 mmol) was added, and the reaction solution was reacted at 65°C for 2 hours. Filtration, concentration, and reverse-phase column chromatography (acetonitrile: water = 5:95 to 50:50 gradient elution) gave compound 31-5 (35 mg, yield 32%). ESI-MS: m/z = 338.0 [M+H] + .
步骤4、化合物31-5为原料，参考实施例2步骤3的制备方法，得到化合物31-6(30mg)。 1H NMR(DMSO-d 6,400MHz):δ9.18(s,1H),8.53(d,J＝9.2Hz,1H),8.47(d,J＝5.6Hz,1H),8.28(s,1H),7.99(s,1H),7.87(d,J＝9.2Hz,1H),7.77(s,1H),7.42(d,J＝2.0Hz,1H),6.94(d,J＝5.6,2.0Hz,1H),3.86(s,3H)。 Step 4. Compound 31-5 was used as the starting material. Referring to the preparation method in Step 3 of Example 2, Compound 31-6 (30 mg) was obtained. 1 H NMR (DMSO-d 6 , 400MHz): δ9.18(s, 1H), 8.53(d, J=9.2Hz, 1H), 8.47(d, J=5.6Hz, 1H), 8.28(s, 1H ),7.99(s,1H),7.87(d,J=9.2Hz,1H),7.77(s,1H),7.42(d,J=2.0Hz,1H),6.94(d,J=5.6,2.0Hz ,1H), 3.86(s,3H).
步骤7、化合物31-6和中间体v4为原料，参考实施例1步骤2的制备方法，得到化合物L 31。ESI-MS：m/z＝469.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ9.18(s,1H),8.83(s,1H),8.70(d,J＝8.8Hz,1H),8.58(d,J＝6.4Hz,1H),8.47(s,1H),8.40(d,J＝8.8Hz,1H),8.17(s,1H),7.77(s,1H),7.66(s,1H),7.34(d,J＝7.6Hz,1H),7.21-7.20(m,1H),4.42-4.37(m,1H),3.90(s,3H),3.42(s,3H),1.26(d,J＝6.4Hz,6H)。 Step 7, compound 31-6 and intermediate v4 are used as raw materials, referring to the preparation method in step 2 of Example 1, to obtain compound L 31. ESI-MS: m/z=469.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.18(s, 1H), 8.83(s, 1H), 8.70(d, J= 8.8Hz, 1H), 8.58(d, J=6.4Hz, 1H), 8.47(s, 1H), 8.40(d, J=8.8Hz, 1H), 8.17(s, 1H), 7.77(s, 1H) ,7.66(s,1H),7.34(d,J=7.6Hz,1H),7.21-7.20(m,1H),4.42-4.37(m,1H),3.90(s,3H),3.42(s,3H ), 1.26 (d, J=6.4Hz, 6H).
实施例32：化合物L32的制备Example 32: Preparation of compound L32
Figure PCTCN2022143403-appb-000071
Figure PCTCN2022143403-appb-000071
将化合物4-1(100mg,0.32mmol)，4-氯-1H-吡咯并[2,3-b]吡啶(98mg,0.64mmol)，三乙胺(32mg,0.32mmol)和三氟乙酸(36mg,0.32mmol)混合，加热至140℃，反应48小时。高效制备液相色 谱纯化(0.5％碳酸氢铵水溶液/乙腈)得到产物L32(21mg,产率15％)。ESI-MS：m/z＝427.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ11.78(s,1H),8.77(s,1H),8.43(d,J＝8.8Hz,1H),8.23(d,J＝8.8Hz,1H),8.13(d,J＝5.6Hz,1H),8.03(d,J＝9.2Hz,1H),7.64(d,J＝2.8Hz,1H),7.58(dd,J＝9.2,2.8Hz,1H),7.36(dd,J＝3.2,2.4Hz,1H),7.16(d,J＝7.6Hz,1H),6.57(d,J＝5.6Hz,1H),6.20(dd,J＝3.2,1.6Hz,1H),4.42-4.33(m,1H),3.41(s,3H),1.26(d,J＝6.8Hz,6H)。 Compound 4-1 (100mg, 0.32mmol), 4-chloro-1H-pyrrolo[2,3-b]pyridine (98mg, 0.64mmol), triethylamine (32mg, 0.32mmol) and trifluoroacetic acid (36mg , 0.32mmol) were mixed, heated to 140°C, and reacted for 48 hours. Purification by HPLC (0.5% aqueous ammonium bicarbonate/acetonitrile) gave the product L32 (21 mg, 15% yield). ESI-MS: m/z=427.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ11.78(s, 1H), 8.77(s, 1H), 8.43(d, J= 8.8Hz, 1H), 8.23(d, J=8.8Hz, 1H), 8.13(d, J=5.6Hz, 1H), 8.03(d, J=9.2Hz, 1H), 7.64(d, J=2.8Hz ,1H),7.58(dd,J=9.2,2.8Hz,1H),7.36(dd,J=3.2,2.4Hz,1H),7.16(d,J=7.6Hz,1H),6.57(d,J= 5.6Hz, 1H), 6.20 (dd, J = 3.2, 1.6Hz, 1H), 4.42-4.33 (m, 1H), 3.41 (s, 3H), 1.26 (d, J = 6.8Hz, 6H).
实施例33：化合物L33的制备Example 33: Preparation of compound L33
Figure PCTCN2022143403-appb-000072
Figure PCTCN2022143403-appb-000072
将化合物13-1(400mg,0.86mmol)，X-phos(818mg，1.72mmol)，环丙烷磺酰胺(1g，8.6mmol)，碳酸铯(2.8g,8.6mmol)和Pd 2(dba) 3(59mg，0.064mmol)溶于DMF(10mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，纯化得到化合物L33(10mg)。ESI-MS:m/z＝507.0[M+H] +。 1H NMR(400MHz,DMSO-D6):δ(ppm)：8.79(s,1H),8.48(d,J＝8.8Hz,1H),8.28(d,J＝8.9Hz,1H),8.05(d,J＝9.1Hz,2H),7.74(s,1H),7.56(dd,J＝9.1,2.5Hz,1H),7.19(d,J＝7.5Hz,1H),6.61(d,J＝28.2Hz,2H),4.38(m,1H),3.41(s,3H),1.26(d,J＝6.6Hz,6H),0.90(s,4H)。 Compound 13-1 (400 mg, 0.86 mmol), X-phos (818 mg, 1.72 mmol), cyclopropanesulfonamide (1 g, 8.6 mmol), cesium carbonate (2.8 g, 8.6 mmol) and Pd 2 (dba) 3 ( 59mg, 0.064mmol) was dissolved in DMF (10mL), and the reaction solution was stirred at 85°C for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to obtain compound L33 (10 mg). ESI-MS: m/z = 507.0 [M+H] + . 1 H NMR (400MHz, DMSO-D6): δ (ppm): 8.79 (s, 1H), 8.48 (d, J = 8.8Hz, 1H), 8.28 (d, J = 8.9Hz, 1H), 8.05 (d ,J=9.1Hz,2H),7.74(s,1H),7.56(dd,J=9.1,2.5Hz,1H),7.19(d,J=7.5Hz,1H),6.61(d,J=28.2Hz , 2H), 4.38 (m, 1H), 3.41 (s, 3H), 1.26 (d, J=6.6Hz, 6H), 0.90 (s, 4H).
实施例34：化合物L34的制备Example 34: Preparation of compound L34
Figure PCTCN2022143403-appb-000073
Figure PCTCN2022143403-appb-000073
步骤1、将化合物4-1(450mg,1.45mmol)溶于DMF(10mL)中，向上述溶液中加入2,4-二氯-3-氟吡啶(240mg,1.45mmol)和碳酸氢钠(365mg,4.35mmol)。反应液在60℃下搅拌3天。反应液中加水(60mL)，用乙酸乙酯萃取(50mL x 3)。有机相合并后用饱和盐水(120mL x 2)洗涤，硫酸钠干燥后浓缩，残余物通过硅胶柱层析纯化得到化合物34-1。ESI-MS:m/z＝440.1[M+H] +。 Step 1. Dissolve compound 4-1 (450mg, 1.45mmol) in DMF (10mL), add 2,4-dichloro-3-fluoropyridine (240mg, 1.45mmol) and sodium bicarbonate (365mg ,4.35mmol). The reaction solution was stirred at 60° C. for 3 days. Water (60 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (120 mL x 2), dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 34-1. ESI-MS: m/z = 440.1 [M+H] + .
步骤2、将化合物34-1(260mg,0.6mmol),二苯甲酮亚胺(160mg，0.886mmol)溶于1，4-二氧六环(6mL)中，向上述溶液中加入碳酸铯(482mg,1.48mmol)，Xantphos(34mg,0.06mmol)和Pd 2(dba) 3(54mg,0.06mmol)。氮气置换后反应液在100℃油浴中搅拌16小时。反应液冷却至室温，浓缩除去1，4-二氧六环。残余物加水(20mL)，用二氯甲烷(35mL x 3)萃取。有机相合并，用饱和盐水(50mL x 3)洗涤，硫酸钠干燥后浓缩，残余物通过硅胶柱层析纯化得到化合物34-2(160mg)。ESI-MS:m/z＝585.2[M+H] +。 Step 2. Dissolve compound 34-1 (260mg, 0.6mmol), benzophenone imine (160mg, 0.886mmol) in 1,4-dioxane (6mL), and add cesium carbonate ( 482 mg, 1.48 mmol), Xantphos (34 mg, 0.06 mmol) and Pd 2 (dba) 3 (54 mg, 0.06 mmol). After nitrogen replacement, the reaction solution was stirred in an oil bath at 100° C. for 16 hours. The reaction solution was cooled to room temperature and concentrated to remove 1,4-dioxane. The residue was added with water (20 mL), extracted with dichloromethane (35 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 34-2 (160 mg). ESI-MS: m/z = 585.2 [M+H] + .
步骤3、将化合物34-2(160mg，0.274mmol)溶于甲醇(3mL)中，0℃下，向上述溶液中加入盐酸(0.4mL)。反应液室温搅拌1小时。浓缩除去甲醇。残余物加三乙胺(0.6mL)，浓缩后,残余物再经过制备HPLC(NH 4HCO 3)得到化合物L34(7.5mg)。ESI-MS：m/z＝421.0[M+H] +。H NMR(DMSO-d 6,400MHz):δ8.76(s,1H),8.43(d,J＝9.2Hz,1H),8.24(d,J＝8.8Hz,1H),8.00(d,J＝8.4Hz,1H),7.68(d,J＝5.6Hz,1H),7.62-7.56(m,2H),7.17(d,J＝7.6Hz,1H),6.64(s,2H),6.23-6.22(m,1H),4.40-4.35(m,1H),3.40(s,3H),1.26(s,3H),1.25(s,3H)。 Step 3. Compound 34-2 (160 mg, 0.274 mmol) was dissolved in methanol (3 mL), and hydrochloric acid (0.4 mL) was added to the above solution at 0°C. The reaction solution was stirred at room temperature for 1 hour. Concentrate to remove methanol. Triethylamine (0.6 mL) was added to the residue, and after concentration, the residue was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain compound L34 (7.5 mg). ESI-MS: m/z = 421.0 [M+H] + . H NMR (DMSO-d 6 , 400MHz): δ8.76(s, 1H), 8.43(d, J=9.2Hz, 1H), 8.24(d, J=8.8Hz, 1H), 8.00(d, J= 8.4Hz, 1H), 7.68(d, J=5.6Hz, 1H), 7.62-7.56(m, 2H), 7.17(d, J=7.6Hz, 1H), 6.64(s, 2H), 6.23-6.22( m,1H), 4.40-4.35(m,1H), 3.40(s,3H), 1.26(s,3H), 1.25(s,3H).
实施例35：化合物L35的制备Example 35: Preparation of compound L35
Figure PCTCN2022143403-appb-000074
Figure PCTCN2022143403-appb-000074
将化合物19-6(100mg,0.32mmol)溶于NMP(4mL)中，向上述溶液中加入碳酸钾(88mg,0.52mmol)和4-氯-N-甲基吡啶酰胺(88mg,0.52mmol)。氮气置换后反应液在110℃搅拌12小时。反应液浓缩后残余物通过C18反向柱制备得到化合物L35(3mg,)。ESI-MS：m/z＝446.0[M+H] +. 1H NMR(400MHz,DMSO-D6)δ8.98(d,J＝3.0Hz,1H),8.87(s,1H),8.81(q,J＝4.7Hz,1H),8.64(d,J＝8.7Hz,1H),8.58(d,J＝5.6Hz,1H),8.36(d,J＝8.8Hz,1H),8.28(d,J＝3.0Hz,1H),7.56(d,J＝2.6Hz,1H),7.32(dd,J＝5.6,2.6Hz,1H),7.28(d,J＝7.7Hz,1H),4.46–4.38(m,1H),3.42(s,3H),2.80(d,J＝4.9Hz,3H),1.27(d,J＝6.6Hz,6H)。 Compound 19-6 (100 mg, 0.32 mmol) was dissolved in NMP (4 mL), and potassium carbonate (88 mg, 0.52 mmol) and 4-chloro-N-methylpicolinamide (88 mg, 0.52 mmol) were added to the above solution. After nitrogen replacement, the reaction solution was stirred at 110°C for 12 hours. After the reaction solution was concentrated, the residue was prepared through a C18 reverse column to obtain compound L35 (3 mg,). ESI-MS: m/z=446.0[M+H] + . 1 H NMR (400MHz, DMSO-D6) δ8.98(d, J=3.0Hz, 1H), 8.87(s, 1H), 8.81(q ,J=4.7Hz,1H),8.64(d,J=8.7Hz,1H),8.58(d,J=5.6Hz,1H),8.36(d,J=8.8Hz,1H),8.28(d,J =3.0Hz,1H),7.56(d,J=2.6Hz,1H),7.32(dd,J=5.6,2.6Hz,1H),7.28(d,J=7.7Hz,1H),4.46–4.38(m , 1H), 3.42 (s, 3H), 2.80 (d, J=4.9Hz, 3H), 1.27 (d, J=6.6Hz, 6H).
实施例36：化合物L36的制备Example 36: Preparation of compound L36
Figure PCTCN2022143403-appb-000075
Figure PCTCN2022143403-appb-000075
将化合物13-1(150mg,0.32mmol)，X-phos(152mg，0.32mmol)，丙酰胺(140mg，1.92mmol)碳酸铯(624mg,1.92mmol)和Pd 2(dba) 3(146mg，0.16mmol)溶于1,4-二氧六环(10mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，粗品用C18反向柱制备(乙腈:水＝5:95到80:20梯度洗脱)得到化合物L36(38mg，产率26.7％)。ESI-MS:m/z＝459.1[M+H] +。 1H NMR(400MHz,DMSO-D6)δ10.49(s,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.27(d,J＝8.7Hz,1H),8.22(d,J＝5.7Hz,1H),8.04(d,J＝9.1Hz,1H),7.71(dd,J＝15.6,2.5Hz,2H),7.54(dd,J＝9.1,2.7Hz,1H),7.17(d,J＝7.6Hz,1H),6.77(dd,J＝5.7,2.4Hz,1H),4.40-4.35(m,1H),3.41(s,3H),2.33(q,7.5Hz,2H),1.26(d,J＝6.6Hz,6H),0.98(t,J＝7.5Hz,3H)。 Compound 13-1 (150mg, 0.32mmol), X-phos (152mg, 0.32mmol), propionamide (140mg, 1.92mmol) cesium carbonate (624mg, 1.92mmol) and Pd 2 (dba) 3 (146mg, 0.16mmol ) was dissolved in 1,4-dioxane (10 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50mL), dried over sodium sulfate and evaporated to remove the solvent. The crude product was prepared on a C18 reverse column (acetonitrile:water=5:95 to 80:20 gradient elution) to obtain compound L36 (38mg, yield rate 26.7%). ESI-MS: m/z = 459.1 [M+H] + . 1 H NMR (400MHz, DMSO-D6) δ10.49(s, 1H), 8.78(s, 1H), 8.46(d, J=8.8Hz, 1H), 8.27(d, J=8.7Hz, 1H), 8.22(d, J=5.7Hz, 1H), 8.04(d, J=9.1Hz, 1H), 7.71(dd, J=15.6, 2.5Hz, 2H), 7.54(dd, J=9.1, 2.7Hz, 1H ),7.17(d,J=7.6Hz,1H),6.77(dd,J=5.7,2.4Hz,1H),4.40-4.35(m,1H),3.41(s,3H),2.33(q,7.5Hz , 2H), 1.26 (d, J=6.6Hz, 6H), 0.98 (t, J=7.5Hz, 3H).
实施例37：化合物L37的制备Example 37: Preparation of compound L37
Figure PCTCN2022143403-appb-000076
Figure PCTCN2022143403-appb-000076
将化合物13-1(50mg,0.107mmol)，x-phos(52mg，0.107mmol)，2-羟基乙酰胺(48mg，0.64mmol)碳酸铯(208mg,0.64mmol)和Pd 2(dba) 3(49mg，0.535mmol)溶于1,4-二氧六环(6mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，用C18反向柱制备得到化合物L37(13mg，产率27.6％)。ESI-MS:m/z＝461.0[M+H] +。 1H NMR(400MHz,DMSO-D6)δ9.76(s,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.24(d,J＝5.7Hz,1H),8.04(d,J＝9.1Hz,1H),7.72(dd,J＝6.5,2.5Hz,2H),7.55(dd,J＝9.1,2.7Hz,1H),7.18(d,J＝7.6Hz,1H),6.81(dd,J＝5.7,2.4Hz,1H),4.42–4.33(m,1H),3.98(s,2H),3.41(s,3H),1.26(d,J＝6.6Hz,6H)。 Compound 13-1 (50mg, 0.107mmol), x-phos (52mg, 0.107mmol), 2-hydroxyacetamide (48mg, 0.64mmol) cesium carbonate (208mg, 0.64mmol) and Pd 2 (dba) 3 (49mg , 0.535 mmol) was dissolved in 1,4-dioxane (6 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. Compound L37 (13 mg, yield 27.6%) was prepared by a C18 reverse column. ESI-MS: m/z = 461.0 [M+H] + . 1 H NMR (400MHz, DMSO-D6) δ9.76(s, 1H), 8.78(s, 1H), 8.46(d, J=8.8Hz, 1H), 8.27(d, J=8.8Hz, 1H), 8.24(d, J=5.7Hz, 1H), 8.04(d, J=9.1Hz, 1H), 7.72(dd, J=6.5, 2.5Hz, 2H), 7.55(dd, J=9.1, 2.7Hz, 1H ),7.18(d,J=7.6Hz,1H),6.81(dd,J=5.7,2.4Hz,1H),4.42–4.33(m,1H),3.98(s,2H),3.41(s,3H) , 1.26 (d, J=6.6Hz, 6H).
实施例38：化合物L38的制备Example 38: Preparation of compound L38
Figure PCTCN2022143403-appb-000077
Figure PCTCN2022143403-appb-000077
步骤1、中间体v7和2-氯-6-羟基-喹啉为原料，参考实施例1步骤2的制备方法，得到化合物38-1。ESI-MS:m/z＝341.1[M+H].H NMR(DMSO-d6,300MHz):δ9.94(s,1H),8.66(s,1H),8.28(d,J＝8.4Hz,1H),8.06(d,J＝8.7Hz,1H),7.82(d,J＝9.3Hz,1H),7.30-7.27(m,1H),7.13(d,J＝10.2Hz,1H),4.51-4.47(m,1H),3.56-3.51(m,1H),3.42(s,3H),3.31(s,3H),1.91(s,1H),1.23(d,J＝6.6Hz,3H)。Step 1, intermediate v7 and 2-chloro-6-hydroxy-quinoline as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound 38-1. ESI-MS: m/z＝341.1[M+H].H NMR (DMSO-d6, 300MHz): δ9.94(s, 1H), 8.66(s, 1H), 8.28(d, J＝8.4Hz, 1H), 8.06(d, J=8.7Hz, 1H), 7.82(d, J=9.3Hz, 1H), 7.30-7.27(m, 1H), 7.13(d, J=10.2Hz, 1H), 4.51- 4.47 (m, 1H), 3.56-3.51 (m, 1H), 3.42 (s, 3H), 3.31 (s, 3H), 1.91 (s, 1H), 1.23 (d, J=6.6Hz, 3H).
步骤2、将化合物38-1(1.0g,2.9mmol)，溶于DMF(20mL)中，向上述溶液中加入2-溴-4-氟吡啶(1.55g,8.8mmol)，碳酸钾(1.2g,8.8mmol)。反应液在90℃下搅拌16小时。反应液加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1到1:1梯度洗脱)得到化合物38-2(1.0g，产率68.7％)。ESI-MS:m/z＝496.0[M+H] +。 Step 2. Dissolve compound 38-1 (1.0g, 2.9mmol) in DMF (20mL), add 2-bromo-4-fluoropyridine (1.55g, 8.8mmol) and potassium carbonate (1.2g ,8.8mmol). The reaction solution was stirred at 90°C for 16 hours. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1 gradient elution) to obtain compound 38 -2 (1.0 g, yield 68.7%). ESI-MS: m/z = 496.0 [M+H] + .
步骤3、将化合物38-2(200mg,0.4mmol)，溶于二氧六环(10mL)中，向上述溶液中加入乙酰氨(143mg,2.4mmol)，碳酸铯(782mg,2.4mmol)，Pd 2(dba) 3(37mg,0.04mmol),X-PHOS(38mg,0.08mmol)。氮气置换后反应液在80℃下搅拌3小时。反应液浓缩除去二氧六环，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物经过制备HPLC(NH 4HCO 3)得到化合物L38(40mg，产率20.8％).ESI-MS:m/z＝475.0[M+H]. 1H NMR(DMSO-d6,400MHz):δ10.56(s,1H),8.79(s,1H),8.45(d,J＝8.4Hz,1H),8.27(d,J＝4.8Hz,1H),8.22(d,J＝6.0Hz,1H),8.04(d,J＝9.2Hz,1H),7.73(d,J＝4Hz,1H),7.69(d,J＝2.4Hz 1H),7.55(dd,J＝2.8Hz,J＝9.6Hz,1H),7.20(d,J＝8.0Hz,1H),6.76(dd,J＝2.4Hz,J＝6.0Hz,1H),4.53-4.46(m,1H),3.54-3.50(m,1H),3.41(s,3H).3.38-3.37(m,1H),3.34(s,3H),2.03(s,3H),1.22(d,J＝6.8Hz,3H)。 Step 3. Dissolve compound 38-2 (200mg, 0.4mmol) in dioxane (10mL), add acetamide (143mg, 2.4mmol), cesium carbonate (782mg, 2.4mmol), Pd 2 (dba) 3 (37 mg, 0.04 mmol), X-PHOS (38 mg, 0.08 mmol). After nitrogen replacement, the reaction solution was stirred at 80°C for 3 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain compound L38 (40 mg, yield 20.8%).ESI-MS: m/z =475.0[M+H]. 1 H NMR (DMSO-d6, 400MHz): δ10.56(s, 1H), 8.79(s, 1H), 8.45(d, J=8.4Hz, 1H), 8.27(d ,J=4.8Hz,1H),8.22(d,J=6.0Hz,1H),8.04(d,J=9.2Hz,1H),7.73(d,J=4Hz,1H),7.69(d,J= 2.4Hz 1H), 7.55(dd, J=2.8Hz, J=9.6Hz, 1H), 7.20(d, J=8.0Hz, 1H), 6.76(dd, J=2.4Hz, J=6.0Hz, 1H) ,4.53-4.46(m,1H),3.54-3.50(m,1H),3.41(s,3H).3.38-3.37(m,1H),3.34(s,3H),2.03(s,3H),1.22 (d, J=6.8Hz, 3H).
实施例39：化合物L39的制备Example 39: Preparation of Compound L39
Figure PCTCN2022143403-appb-000078
Figure PCTCN2022143403-appb-000078
将化合物5-2(150mg,0.29mmol)，溶于二氧六环(5mL)中，向上述溶液中加入乙酰氨(102mg,1.7mmol)，碳酸铯(560mg,1.7mmol)，Pd 2(dba) 3(27mg,0.03mmol),X-PHOS(29mg,0.06mmol)。氮气置换后反应液在80℃下搅拌4小时。反应液浓缩除去二氧六环，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物经过制备HPLC(NH 4HCO 3)得到产物L39(40mg，产率27.8％).ESI-MS:m/z＝501.1[M+H] +。 11H NMR(DMSO-d6,400MHz):δ10.5(s,1H),8.76(s,1H),8.45(d,J＝9.2Hz,1H),8.30(d,J＝8.8Hz,1H),8.22(d,J＝5.6Hz,1H),8.05(d,J＝8.8Hz,1H),7.73-7.70(m,2H),7.57-7.54(m,1H),6.76(dd,J＝2.4Hz,J＝5.6Hz,1H),4.59-4.57(m,1H),3.63-3.56(m,1H),3.55-3.52(m,2H),3.44(s,3H).3.37-3.36(m,1H),3.27(s,3H),2.15-2.13(m,1H),2.02(s,3H).1.97-1.96(m,1H),1.78-1.70(m,1H)。 Compound 5-2 (150mg, 0.29mmol) was dissolved in dioxane (5mL), and acetamide (102mg, 1.7mmol), cesium carbonate (560mg, 1.7mmol), Pd 2 (dba ) 3 (27mg, 0.03mmol), X-PHOS (29mg, 0.06mmol). After nitrogen replacement, the reaction solution was stirred at 80°C for 4 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain the product L39 (40 mg, yield 27.8%).ESI-MS: m/z =501.1[M+H] + . 11 H NMR(DMSO-d6,400MHz):δ10.5(s,1H),8.76(s,1H),8.45(d,J=9.2Hz,1H),8.30(d,J=8.8Hz,1H) ,8.22(d,J=5.6Hz,1H),8.05(d,J=8.8Hz,1H),7.73-7.70(m,2H),7.57-7.54(m,1H),6.76(dd,J=2.4 Hz,J＝5.6Hz,1H),4.59-4.57(m,1H),3.63-3.56(m,1H),3.55-3.52(m,2H),3.44(s,3H).3.37-3.36(m, 1H), 3.27(s, 3H), 2.15-2.13(m, 1H), 2.02(s, 3H). 1.97-1.96(m, 1H), 1.78-1.70(m, 1H).
实施例40：化合物L40的制备Embodiment 40: Preparation of compound L40
Figure PCTCN2022143403-appb-000079
Figure PCTCN2022143403-appb-000079
步骤1、将化合物19-6(600mg,1.9mmol)溶于NMP(10mL)中，向上述溶液中加入碳酸钾(786mg,5.7mmol)和2-溴-4-氟吡啶(512mg,2.9mmol)。氮气置换后反应液在90℃搅拌12小时。反应液浓缩后残余物通过C18反向柱制备得到化合物40-1(200mg,产率22％)。ESI-MS：m/z＝467.0[M+H] +。 Step 1, Dissolve compound 19-6 (600mg, 1.9mmol) in NMP (10mL), add potassium carbonate (786mg, 5.7mmol) and 2-bromo-4-fluoropyridine (512mg, 2.9mmol) to the above solution . After nitrogen substitution, the reaction solution was stirred at 90° C. for 12 hours. After the reaction solution was concentrated, the residue was prepared through a C18 reverse column to obtain compound 40-1 (200 mg, yield 22%). ESI-MS: m/z = 467.0 [M+H] + .
步骤2、化合物40-1(2)(100mg,0.21mmol)，X-phos(61mg，0.128mmol)，乙酰胺(74mg，1.26mmol)碳酸铯(409.5mg,1.26mmol)和Pd 2(dba) 3(59mg，0.064mmol)溶于1,4-二氧六环(5mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，粗品用C18反向柱制备得到化合物L40(22.4mg，，产率24％)。ESI-MS:m/z＝446.0[M+H] +。 1H NMR(400MHz,DMSO-D6)δ10.62(s,1H),8.93(d,J＝3.0Hz,1H),8.86(s,1H),8.62(d,J＝8.7Hz,1H),8.35(d,J＝8.8Hz,1H),8.25(d,J＝5.7Hz,1H),8.22(d,J＝3.0Hz,1H),7.77(d,J＝2.1Hz,1H),7.27(d,J＝7.9Hz,1H),6.83(dd,J＝5.7,2.4Hz,1H),4.47–4.36(m,1H),3.42(s,3H),2.04(s,3H),1.26(d,J＝6.6Hz,6H)。 Step 2, compound 40-1(2) (100mg, 0.21mmol), X-phos (61mg, 0.128mmol), acetamide (74mg, 1.26mmol) cesium carbonate (409.5mg, 1.26mmol) and Pd 2 (dba) 3 (59mg, 0.064mmol) was dissolved in 1,4-dioxane (5mL), and the reaction solution was stirred at 85°C for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The crude product was prepared on a C18 reverse column to obtain compound L40 (22.4 mg, yield 24%). ESI-MS: m/z = 446.0 [M+H] + . 1 H NMR (400MHz, DMSO-D6) δ10.62(s, 1H), 8.93(d, J=3.0Hz, 1H), 8.86(s, 1H), 8.62(d, J=8.7Hz, 1H), 8.35(d, J=8.8Hz, 1H), 8.25(d, J=5.7Hz, 1H), 8.22(d, J=3.0Hz, 1H), 7.77(d, J=2.1Hz, 1H), 7.27( d,J=7.9Hz,1H),6.83(dd,J=5.7,2.4Hz,1H),4.47–4.36(m,1H),3.42(s,3H),2.04(s,3H),1.26(d , J=6.6Hz, 6H).
实施例41：化合物L41的制备Example 41: Preparation of Compound L41
Figure PCTCN2022143403-appb-000080
Figure PCTCN2022143403-appb-000080
步骤1、将化合物40-1(100mg,0.21mmol)，X-phos(61mg，0.128mmol)，氨基甲酸叔丁酯(147mg，1.26mmol)碳酸铯(409.5mg,1.26mmol)和Pd 2(dba) 3(59mg，0.064mmol)溶于1,4-二氧六环(5mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，得化合物41-1。 Step 1, compound 40-1 (100mg, 0.21mmol), X-phos (61mg, 0.128mmol), tert-butyl carbamate (147mg, 1.26mmol) cesium carbonate (409.5mg, 1.26mmol) and Pd 2 (dba ) 3 (59mg, 0.064mmol) was dissolved in 1,4-dioxane (5mL), and the reaction solution was stirred at 85°C for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain compound 41-1.
步骤2、将化合物41-1(100mg,0.21mmol)溶于DMF(5mL)中，向混合液中加入TFA(5mL)和CH 2Cl 2(10mL)，氮气置换后反应液在室温下搅拌5小时。反应结束后蒸除溶剂，粗品用C18反向柱制备(乙腈:水＝5:95到75:25梯度洗脱)得到化合物L41(20mg，产率25％)。ESI-MS:m/z＝404.0[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝3.0Hz,1H),8.86(s,1H),8.63(d,J＝8.7Hz,1H),8.38(d,J＝8.8Hz,1H),8.26(d,J＝3.0Hz,1H),7.93(d,J＝6.4Hz,1H),7.30(d,J＝7.7Hz,1H),6.77(s,2H),6.51(dd,J＝6.4,2.3Hz,1H),6.06(d,J＝2.3Hz,1H),4.45–4.37(m,1H),3.42(s,3H),1.26(d,J＝6.6Hz,6H)。 Step 2. Compound 41-1 (100mg, 0.21mmol) was dissolved in DMF (5mL), TFA (5mL) and CH 2 Cl 2 (10mL) were added to the mixture, and the reaction solution was stirred at room temperature for 5 Hour. After the reaction, the solvent was evaporated, and the crude product was prepared by C18 reverse column (acetonitrile:water=5:95 to 75:25 gradient elution) to obtain compound L41 (20 mg, yield 25%). ESI-MS: m/z = 404.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.93(d, J=3.0Hz, 1H), 8.86(s, 1H), 8.63(d, J=8.7Hz, 1H), 8.38(d, J=8.8 Hz,1H),8.26(d,J=3.0Hz,1H),7.93(d,J=6.4Hz,1H),7.30(d,J=7.7Hz,1H),6.77(s,2H),6.51( dd,J=6.4,2.3Hz,1H),6.06(d,J=2.3Hz,1H),4.45–4.37(m,1H),3.42(s,3H),1.26(d,J=6.6Hz,6H ).
实施例42：化合物L42的制备和化合物L45的制备Example 42: Preparation of Compound L42 and Preparation of Compound L45
Figure PCTCN2022143403-appb-000081
Figure PCTCN2022143403-appb-000081
步骤1、将5-溴-3-甲基-2-(甲硫基)嘧啶-4(3H)-酮(2.0g,8.5mmol)和异丙醇频哪醇硼酸酯(3.16g,17.0mmol)溶于无水四氢呋喃(100mL)中，冷却至-78℃，缓慢滴加2.5M的正丁基锂正己烷溶液(6.8mL,17.0mmol)。反应液在-78℃下搅拌1小时。LCMS监测反应完毕，将反应液缓慢加入到-78℃的乙醇(100mL)中淬灭反应，1M盐酸中和反应体系，浓缩，得到化合物42-1。ESI-MS:m/z＝201.1[M+H] +。 Step 1, 5-bromo-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (2.0g, 8.5mmol) and isopropanol pinacol borate (3.16g, 17.0 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to -78°C, and 2.5 M n-butyllithium n-hexane solution (6.8 mL, 17.0 mmol) was slowly added dropwise. The reaction was stirred at -78°C for 1 hour. The completion of the reaction was monitored by LCMS, and the reaction solution was slowly added to ethanol (100 mL) at -78° C. to quench the reaction. The reaction system was neutralized with 1M hydrochloric acid and concentrated to obtain compound 42-1. ESI-MS: m/z = 201.1 [M+H] + .
步骤2、化合物42-1和2-氯喹啉-6-酚为原料，参考实施例1步骤2的制备方法，得到化合物42-2。ESI-MS:m/z＝300.1[M+H] +。 Step 2: Compound 42-1 and 2-chloroquinoline-6-ol were used as raw materials, and the compound 42-2 was obtained by referring to the preparation method in Step 2 of Example 1. ESI-MS: m/z = 300.1 [M+H] + .
步骤3、将化合物42-2(8.5mmol)，碳酸钾(8.2g,59.5mmol)和2-溴-4-氟吡啶(8.97g,51.0mmol)溶于的DMF(50mL)，90℃下反应17小时。乙酸乙酯(300mL)稀释，饱和食盐水洗涤(300mL x 4)，干燥浓缩，硅胶柱层析(DCM：EA＝5:1到1:1梯度洗脱)纯化，得到化合物42-3(1.5g,三步总产率39％)。ESI-MS：m/z＝457.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.80(s,1H),8.42(d,J＝8.8Hz,1H),8.39(d,J＝8.8Hz,1H),8.31(d,J＝6.0Hz,1H),8.14(d,J＝9.6Hz,1H),7.82(d,J＝2.4Hz,1H),7.64(dd,J＝9.6,2.4Hz,1H),7.29(d,J＝2.4Hz,1H),7.11(dd,J＝6.0,2.4Hz,1H),3.57(s,3H),2.66(s,3H)。 Step 3. Dissolve compound 42-2 (8.5mmol), potassium carbonate (8.2g, 59.5mmol) and 2-bromo-4-fluoropyridine (8.97g, 51.0mmol) in DMF (50mL), react at 90°C 17 hours. Diluted with ethyl acetate (300mL), washed with saturated brine (300mL x 4), dried and concentrated, and purified by silica gel column chromatography (DCM:EA=5:1 to 1:1 gradient elution) to obtain compound 42-3 (1.5 g, three-step total yield 39%). ESI-MS: m/z=457.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.80(s, 1H), 8.42(d, J=8.8Hz, 1H), 8.39 (d, J=8.8Hz, 1H), 8.31(d, J=6.0Hz, 1H), 8.14(d, J=9.6Hz, 1H), 7.82(d, J=2.4Hz, 1H), 7.64(dd ,J=9.6,2.4Hz,1H),7.29(d,J=2.4Hz,1H),7.11(dd,J=6.0,2.4Hz,1H),3.57(s,3H),2.66(s,3H) .
步骤4、将化合物42-3(500mg,1.1mmol)，X-Phos(105mg,0.22mmol)，乙酰胺(390mg，6.6mmol)，碳酸铯(2.15g,6.6mmol)和Pd 2(dba) 3(100mg，0.11mmol)溶于1,4-二氧六环(50mL)中，氮气置换后反应液在90℃下搅拌17小时。反应液冷却至室温，乙酸乙酯(200mL)稀释，饱和食盐水(100mL)洗涤，干燥，浓缩，硅胶柱层析(DCM：EA＝2:1到1:1梯度洗脱)纯化，得到化合物42-4(305mg，产率64％)。ESI-MS:m/z＝434.1[M+H] +。 Step 4, compound 42-3 (500mg, 1.1mmol), X-Phos (105mg, 0.22mmol), acetamide (390mg, 6.6mmol), cesium carbonate (2.15g, 6.6mmol) and Pd 2 (dba) 3 (100 mg, 0.11 mmol) was dissolved in 1,4-dioxane (50 mL), and the reaction solution was stirred at 90° C. for 17 hours after nitrogen replacement. The reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with saturated brine (100 mL), dried, concentrated, and purified by silica gel column chromatography (DCM:EA=2:1 to 1:1 gradient elution) to obtain compound 42-4 (305 mg, 64% yield). ESI-MS: m/z = 434.1 [M+H] + .
步骤5、将化合物42-4(130mg,0.3mmol)，吡咯烷(210mg,3.0mmol)和碳酸钾(207mg,1.5mmol)溶于1,4-二氧六环(10mL)中，封管加热至140℃，搅拌17小时。过滤，浓缩，高效液相制备色谱(5％碳酸氢铵水溶液/乙腈)纯化，得到化合物L45(17mg，产率12.5％)和化合物L42(7.0mg，产率5.6％)。Step 5. Dissolve compound 42-4 (130mg, 0.3mmol), pyrrolidine (210mg, 3.0mmol) and potassium carbonate (207mg, 1.5mmol) in 1,4-dioxane (10mL), seal the tube and heat to 140°C and stirred for 17 hours. It was filtered, concentrated, and purified by preparative HPLC (5% aqueous ammonium bicarbonate/acetonitrile) to obtain compound L45 (17 mg, yield 12.5%) and compound L42 (7.0 mg, yield 5.6%).
化合物L45:ESI-MS:m/z＝457.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.57(s,1H),8.76(s,1H),8.48(d,J＝8.8Hz,1H),8.28(d,J＝8.8Hz,1H),8.22(d,J＝5.6Hz,1H),8.04(d,J＝8.8Hz,1H),7.72(d,J＝2.4Hz,1H),7.71(d,J＝2.8Hz,1H),7.54(dd,J＝8.8,2.8Hz,1H),6.76(dd,J＝5.6,2.4Hz,1H),3.63(t,J＝6.4Hz,4H),3.49(s,3H),2.03(s,3H),1.90(t,J＝6.4Hz,4H)。 Compound L45: ESI-MS: m/z=457.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.57(s, 1H), 8.76(s, 1H), 8.48(d ,J=8.8Hz,1H),8.28(d,J=8.8Hz,1H),8.22(d,J=5.6Hz,1H),8.04(d,J=8.8Hz,1H),7.72(d,J =2.4Hz, 1H), 7.71(d, J=2.8Hz, 1H), 7.54(dd, J=8.8, 2.8Hz, 1H), 6.76(dd, J=5.6, 2.4Hz, 1H), 3.63(t , J=6.4Hz, 4H), 3.49(s, 3H), 2.03(s, 3H), 1.90(t, J=6.4Hz, 4H).
化合物L42:ESI-MS:m/z＝415.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):8.82(s,1H),8.54(d,J＝8.8Hz,1H),8.41(d,J＝5.6Hz,1H),8.17(d,J＝8.8Hz,1H),7.98(d,J＝7.2Hz,1H),7.89(s,1H),7.75-7.73(m,2H),7.66(d,J＝8.8Hz,1H),6.75(dd,J＝7.2,2.4Hz,1H),6.15(d,J＝2.0Hz,1H),3.66-3.65(m,4H),3.51(s,3H),1.91(t,J＝6.4Hz,4H)。 Compound L42: ESI-MS: m/z=415.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): 8.82(s, 1H), 8.54(d, J=8.8Hz, 1H), 8.41(d, J=5.6Hz, 1H), 8.17(d, J=8.8Hz, 1H), 7.98(d, J=7.2Hz, 1H), 7.89(s, 1H), 7.75-7.73(m, 2H ),7.66(d,J=8.8Hz,1H),6.75(dd,J=7.2,2.4Hz,1H),6.15(d,J=2.0Hz,1H),3.66-3.65(m,4H),3.51 (s, 3H), 1.91 (t, J = 6.4Hz, 4H).
实施例43：化合物L43的制备Example 43: Preparation of compound L43
Figure PCTCN2022143403-appb-000082
Figure PCTCN2022143403-appb-000082
步骤1、将化合物38-2(300mg,0.6mmol)，溶于二氧六环(10mL)中，向上述溶液中加入氨基甲酸叔丁酯(281mg,2.4mmol)，碳酸铯(782mg,2.4mmol)，Pd 2(dba) 3(54mg,0.06mmol),X-PHOS(50mg,0.12mmol)。氮气置换后反应液在70℃下搅拌3小时。反应液浓缩除去二氧六环，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过C18反向柱纯化(乙腈：水＝5到70梯度洗脱)得到化合物43-1(200mg，产率59.1％).ESI-MS:m/z＝533.2[M+H] +。 Step 1. Dissolve compound 38-2 (300mg, 0.6mmol) in dioxane (10mL), add tert-butyl carbamate (281mg, 2.4mmol), cesium carbonate (782mg, 2.4mmol) to the above solution ), Pd 2 (dba) 3 (54mg, 0.06mmol), X-PHOS (50mg, 0.12mmol). After nitrogen replacement, the reaction solution was stirred at 70°C for 3 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by C18 reverse column (acetonitrile: water = 5 to 70 gradient elution) to obtain compound 43-1 (200 mg, yield 59.1%). ESI-MS: m/z = 533.2 [M+H] + .
步骤2、将化合物43-1(200mg,0.12mmol)溶于二氧六环(10mL)中，向上述溶液中加入HCl/dioxane(4M,10mL,).。反应液在室温下搅拌3小时。反应液浓缩除去二氧六环，残余物经过制 备HPLC(NH 4HCO 3)得到产物L43(30mg，产率18.3％).ESI-MS:m/z＝433.0[M+H].H NMR(DMSO-d6,400MHz):δ8.75(s,1H),8.43(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.20(d,J＝9.2Hz,1H),7.84(d,J＝5.6Hz,1H),7.63(d,J＝2.8Hz,1H),7.51(dd,J＝2.8Hz,J＝9.2Hz,1H),7.18(d,J＝8.0Hz 1H),6.24(dd,J＝2.4Hz,J＝6.0Hz 1H),5.93(s,2H),5.89(s,1H),4.51-4.47(m,1H),3.53-3.49(m,1H).3.41(s,3H),3.38-3.35(m,2H),3.34(s,3H),1.22(d,J＝6.8Hz,3H)。 Step 2. Compound 43-1 (200 mg, 0.12 mmol) was dissolved in dioxane (10 mL), and HCl/dioxane (4M, 10 mL,) was added to the above solution. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated to remove dioxane, and the residue was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain product L43 (30 mg, yield 18.3%). ESI-MS: m/z=433.0 [M+H].H NMR ( DMSO-d6,400MHz):δ8.75(s,1H),8.43(d,J=8.8Hz,1H),8.26(d,J=8.8Hz,1H),8.20(d,J=9.2Hz,1H ), 7.84(d, J=5.6Hz, 1H), 7.63(d, J=2.8Hz, 1H), 7.51(dd, J=2.8Hz, J=9.2Hz, 1H), 7.18(d, J=8.0 Hz 1H),6.24(dd,J=2.4Hz,J=6.0Hz 1H),5.93(s,2H),5.89(s,1H),4.51-4.47(m,1H),3.53-3.49(m,1H ). 3.41 (s, 3H), 3.38-3.35 (m, 2H), 3.34 (s, 3H), 1.22 (d, J=6.8Hz, 3H).
实施例44：化合物L44的制备Example 44: Preparation of Compound L44
Figure PCTCN2022143403-appb-000083
Figure PCTCN2022143403-appb-000083
步骤1、将化合物5-2(300mg,0.57mmol)，溶于二氧六环(10mL)中，向上述溶液中加入氨基甲酸叔丁酯(270mg,2.3mmol)，碳酸铯(750mg,2.3mmol)，Pd 2(dba) 3(53mg,0.06mmol),X-PHOS(53mg,0.11mmol)。氮气置换后反应液在70℃下搅拌3小时。反应液浓缩除去二氧六环，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过C18反向柱纯化(乙腈：水＝5到70梯度洗脱)得到化合物44-1(150mg，产率47.0％).ESI-MS:m/z＝559.2[M+H] +。 Step 1. Dissolve compound 5-2 (300mg, 0.57mmol) in dioxane (10mL), add tert-butyl carbamate (270mg, 2.3mmol), cesium carbonate (750mg, 2.3mmol) to the above solution ), Pd 2 (dba) 3 (53 mg, 0.06 mmol), X-PHOS (53 mg, 0.11 mmol). After nitrogen replacement, the reaction solution was stirred at 70°C for 3 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by C18 reverse column (acetonitrile: water = 5 to 70 gradient elution) to obtain compound 44-1 (150 mg, yield 47.0%). ESI-MS: m/z = 559.2 [M+H] + .
步骤2、以化合物44-1为原料，参考实施例43步骤2的制备方法，得到产物L44(30mg，产率24.3％).ESI-MS:m/z＝459.1[M+H].H NMR(DMSO-d6,400MHz):δ8.74(s,1H),8.43(d,J＝8.8Hz,1H),8.30(d,J＝8.8Hz,1H),8.04(d,J＝9.2Hz,1H),7.85(d,J＝6.0Hz,1H),7.66(d,J＝2.4Hz,1H),7.52(dd,J＝2.8Hz,J＝8.8Hz,1H),6.27(dd,J＝2.0Hz,J＝5.6Hz 1H),6.06(s,2H),5.91(s,1H),4.59-4.56(m,1H),3.63-3.59(m,1H).3.53-3.51(m,2H),3.44(s,3H),3.27(s,3H),2.15-2.13(m,2H).1.98-1.97(m,1H),1.78-1.70(m,2H)。Step 2. Using compound 44-1 as a raw material, refer to the preparation method in step 2 of Example 43 to obtain the product L44 (30mg, yield 24.3%).ESI-MS: m/z=459.1[M+H].H NMR (DMSO-d6,400MHz):δ8.74(s,1H),8.43(d,J=8.8Hz,1H),8.30(d,J=8.8Hz,1H),8.04(d,J=9.2Hz, 1H), 7.85(d, J=6.0Hz, 1H), 7.66(d, J=2.4Hz, 1H), 7.52(dd, J=2.8Hz, J=8.8Hz, 1H), 6.27(dd, J= 2.0Hz,J＝5.6Hz 1H),6.06(s,2H),5.91(s,1H),4.59-4.56(m,1H),3.63-3.59(m,1H).3.53-3.51(m,2H) ,3.44(s,3H),3.27(s,3H),2.15-2.13(m,2H).1.98-1.97(m,1H),1.78-1.70(m,2H).
实施例46：化合物L46的制备和化合物L47的制备Example 46: Preparation of Compound L46 and Preparation of Compound L47
Figure PCTCN2022143403-appb-000084
Figure PCTCN2022143403-appb-000084
将化合物42-4(200mg,0.46mmol)，乙胺盐酸盐(1.9g,23.0mmol)和碳酸钾(3.18g,23.0mmol)溶于1,4-二氧六环(10mL)中，封管加热至140℃，搅拌47小时。过滤，浓缩，高效液相制备色谱(0.1％三氟乙酸水溶液/乙腈)纯化，得到化合物L47(15mg，产率7.5％)和化合物L46(17mg，产率9.5％)。Compound 42-4 (200mg, 0.46mmol), ethylamine hydrochloride (1.9g, 23.0mmol) and potassium carbonate (3.18g, 23.0mmol) were dissolved in 1,4-dioxane (10mL), sealed The tube was heated to 140°C and stirred for 47 hours. It was filtered, concentrated, and purified by preparative HPLC (0.1% aqueous trifluoroacetic acid/acetonitrile) to obtain compound L47 (15 mg, yield 7.5%) and compound L46 (17 mg, yield 9.5%).
化合物L47:ESI-MS:m/z＝431.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.65(s,1H),8.98(s,1H),8.59-8.50(m,2H),8.27-8.20(m,3H),7.85(s,1H),7.73-7.72(m,2H),6.83-6.81(m,1H),3.58-3.52(m,2H),3.44(s,3H),2.04(s,3H),1.22(t,J＝7.2Hz,3H)。 Compound L47:ESI-MS:m/z=431.0[M+H] + . 1 H NMR(DMSO-d 6 ,400MHz):δ10.65(s,1H),8.98(s,1H),8.59-8.50 (m,2H),8.27-8.20(m,3H),7.85(s,1H),7.73-7.72(m,2H),6.83-6.81(m,1H),3.58-3.52(m,2H),3.44 (s, 3H), 2.04 (s, 3H), 1.22 (t, J=7.2Hz, 3H).
化合物L46:ESI-MS:m/z＝389.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.76(s,1H),8.44(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.01(d,J＝8.8Hz,1H),7.84(d,J＝5.6Hz,1H),7.63(d,J＝2.4Hz,1H),7.60(t,J＝5.6Hz,1H),7.50(dd,J＝8.8,2.4Hz,1H),6.23(dd,J＝5.6,2.4Hz,1H),5.93(s,2H),5.88(d,J＝2.4Hz,1H),3.52-3.45(m,2H),3.39(s,3H),1.20(t,J＝7.2Hz,3H)。 Compound L46: ESI-MS: m/z=389.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.76(s, 1H), 8.44(d, J=8.8Hz, 1H ),8.26(d,J=8.8Hz,1H),8.01(d,J=8.8Hz,1H),7.84(d,J=5.6Hz,1H),7.63(d,J=2.4Hz,1H), 7.60(t, J=5.6Hz, 1H), 7.50(dd, J=8.8, 2.4Hz, 1H), 6.23(dd, J=5.6, 2.4Hz, 1H), 5.93(s, 2H), 5.88(d , J=2.4Hz, 1H), 3.52-3.45(m, 2H), 3.39(s, 3H), 1.20(t, J=7.2Hz, 3H).
实施例48：化合物L48的制备Example 48: Preparation of Compound L48
Figure PCTCN2022143403-appb-000085
Figure PCTCN2022143403-appb-000085
步骤1、以中间体化合物v9和2-氯-6-羟基喹啉为原料，参考实施例1步骤2的制备方法，得到化合物48-1。ESI-MS：m/z＝309.1[M+H] +。 Step 1. Using the intermediate compound v9 and 2-chloro-6-hydroxyquinoline as raw materials, refer to the preparation method in step 2 of Example 1 to obtain compound 48-1. ESI-MS: m/z = 309.1 [M+H] + .
步骤2、以化合物48-1和4-氟-2-溴吡啶为原料，参考实施例5步骤2的制备方法，得到化合物48-2。ESI-MS:m/z＝464.0[M+H] +。 Step 2. Using compound 48-1 and 4-fluoro-2-bromopyridine as raw materials, refer to the preparation method in step 2 of Example 5 to obtain compound 48-2. ESI-MS: m/z = 464.0 [M+H] + .
步骤3、以化合物48-2和氨基甲酸叔丁酯为原料，参考实施例13步骤2的制备方法，得到化合 物48-3(115mg，产率66.8％)。ESI-MS:m/z＝501.2[M+H] +。 Step 3. Using compound 48-2 and tert-butyl carbamate as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 48-3 (115 mg, yield 66.8%). ESI-MS: m/z = 501.2 [M+H] + .
步骤4、以化合物48-3为原料，参考实施例1步骤3的制备方法，以及实施例43步骤2的制备方法，得到产物L48(26mg，产率42％)。ESI-MS:m/z＝387.2[M+H] +.HNMR(DMSO-d 6,400MHz):δ11.31(s,1H),8.82(s,1H),8.46(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.02(d,J＝9.2Hz,1H),7.84(d,J＝5.6Hz,1H),7.63(d,J＝2.4Hz,1H),7.50(d,J＝9.2Hz,1H),6.23(d,J＝6.0Hz,1H),5.94(s,2H),5.90(d,J＝2.0Hz,1H),2.78-2.72(m,1H),0.79-0.77(m,2H),0.59-0.56(m,2H)。 Step 4. Using compound 48-3 as a raw material, refer to the preparation method in Step 3 of Example 1 and the preparation method in Step 2 of Example 43 to obtain the product L48 (26 mg, yield 42%). ESI-MS: m/z＝387.2[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ11.31(s, 1H), 8.82(s, 1H), 8.46(d, J＝8.8Hz ,1H),8.27(d,J=8.8Hz,1H),8.02(d,J=9.2Hz,1H),7.84(d,J=5.6Hz,1H),7.63(d,J=2.4Hz,1H ),7.50(d,J=9.2Hz,1H),6.23(d,J=6.0Hz,1H),5.94(s,2H),5.90(d,J=2.0Hz,1H),2.78-2.72(m ,1H), 0.79-0.77(m,2H),0.59-0.56(m,2H).
实施例49：化合物L49的制备Example 49: Preparation of Compound L49
Figure PCTCN2022143403-appb-000086
Figure PCTCN2022143403-appb-000086
将化合物L21(90mg,0.22mmol)，氘代乙酰胺(21mg，0.27mmol)和NaH(16mg，0.66mmol)溶于1,4-二氧六环(2mL)中，氮气置换后反应液在室温下搅拌1小时。反应结束后用乙酸乙酯(30mL x3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，用C18反向柱制备得到化合物L49(8.3mg，产率8.6％)。ESI-MS:m/z＝448.0[M+H] +。 1H NMR(400MHz,DMSO-D6)δ10.56(s,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.24(dd,J＝13.3,7.2Hz,2H),8.03(d,J＝9.3Hz,1H),7.71(dd,J＝10.7,1.7Hz,2H),7.54(dd,J＝9.0,2.4Hz,1H),7.18(d,J＝7.1Hz,1H),6.75(d,J＝3.3Hz,1H),4.40–4.35(m,1H),3.41(s,3H),1.26(d,J＝6.5Hz,6H)。 Compound L21 (90mg, 0.22mmol), deuterated acetamide (21mg, 0.27mmol) and NaH (16mg, 0.66mmol) were dissolved in 1,4-dioxane (2mL), and the reaction solution was replaced with nitrogen at room temperature Stir for 1 hour. After the reaction was completed, it was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. Compound L49 (8.3 mg, yield 8.6%) was prepared by a C18 reverse column. ESI-MS: m/z = 448.0 [M+H] + . 1 H NMR (400MHz, DMSO-D6) δ10.56(s, 1H), 8.78(s, 1H), 8.46(d, J=8.8Hz, 1H), 8.24(dd, J=13.3, 7.2Hz, 2H ), 8.03(d, J=9.3Hz, 1H), 7.71(dd, J=10.7, 1.7Hz, 2H), 7.54(dd, J=9.0, 2.4Hz, 1H), 7.18(d, J=7.1Hz , 1H), 6.75 (d, J = 3.3Hz, 1H), 4.40–4.35 (m, 1H), 3.41 (s, 3H), 1.26 (d, J = 6.5Hz, 6H).
实施例50：化合物L50的制备Example 50: Preparation of Compound L50
Figure PCTCN2022143403-appb-000087
Figure PCTCN2022143403-appb-000087
步骤1、以化合物48-2和乙酰胺为原料，参考实施例13步骤2的制备方法，得到化合物50-1。ESI-MS:m/z＝443.1[M+H] +。 Step 1. Using compound 48-2 and acetamide as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 50-1. ESI-MS: m/z = 443.1 [M+H] + .
步骤2、以化合物50-1为原料，参考实施例1步骤3的制备方法，得到产物L50。ESI-MS:m/z＝49429.2[M+H] +.HNMR(DMSO-d 6,400MHz):δ10.55(s,1H),8.82(s,1H),8.48(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.22(d,J＝5.6Hz,1H),8.04(d,J＝8.8Hz,1H),7.73(d,J＝2.0Hz,1H),7.69(d,J＝2.4Hz,1H),7.54(d,J＝8.8Hz,1H),6.75(d,J＝5.6Hz,1H),2.78-2.72(m,1H),2.03(s,3H),0.79-0.77(m,2H),0.59-0.56(m,2H)。 Step 2. Using compound 50-1 as a raw material, refer to the preparation method in Step 3 of Example 1 to obtain the product L50. ESI-MS: m/z＝49429.2[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ10.55(s, 1H), 8.82(s, 1H), 8.48(d, J＝8.8Hz ,1H),8.27(d,J=8.8Hz,1H),8.22(d,J=5.6Hz,1H),8.04(d,J=8.8Hz,1H),7.73(d,J=2.0Hz,1H ),7.69(d,J=2.4Hz,1H),7.54(d,J=8.8Hz,1H),6.75(d,J=5.6Hz,1H),2.78-2.72(m,1H),2.03(s ,3H), 0.79-0.77(m,2H), 0.59-0.56(m,2H).
实施例51：化合物L51的制备和化合物L53的制备Example 51: Preparation of Compound L51 and Preparation of Compound L53
Figure PCTCN2022143403-appb-000088
Figure PCTCN2022143403-appb-000088
将化合物42-4(190mg,0.44mmol)和环丙胺(501mg,8.8mmol)溶于三乙胺三氟乙酸盐(10mL)中，封管加热至100℃，搅拌48小时。乙酸乙酯稀释(200mL)，饱和食盐水洗涤(200mL x 3)，干燥，浓缩，高效液相制备色谱(0.1％％甲酸水溶液/乙腈)纯化，得到化合物L53(67mg，产率34.5％)和化合物L51(19mg,产率10.8％)。Compound 42-4 (190 mg, 0.44 mmol) and cyclopropylamine (501 mg, 8.8 mmol) were dissolved in triethylamine trifluoroacetate (10 mL), sealed and heated to 100°C, and stirred for 48 hours. Diluted with ethyl acetate (200mL), washed with saturated brine (200mL x 3), dried, concentrated, and purified by preparative high-performance liquid chromatography (0.1%% aqueous formic acid/acetonitrile) to obtain compound L53 (67mg, yield 34.5%) and Compound L51 (19 mg, yield 10.8%).
化合物L53:ESI-MS:m/z＝443.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.55(s,1H),8.80(s,1H),8.45(d,J＝8.4Hz,1H),8.27(d,J＝8.4Hz,1H),8.22(d,J＝5.6Hz,1H),8.04(d,J＝8.8Hz,1H),7.72(d,J＝2.4Hz,1H),7.69(d,J＝2.4Hz,1H),7.59(d,J＝3.2Hz,1H),7.54(d,J＝8.8,2.4Hz,1H),6.76(dd,J＝5.6,2.4Hz,1H),3.37(s,3H),2.95-2.90(m,1H),2.03(s,3H),0.80-0.75(m,2H),0.69-0.65(m,2H)。 Compound L53: ESI-MS: m/z=443.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.55(s, 1H), 8.80(s, 1H), 8.45(d ,J=8.4Hz,1H),8.27(d,J=8.4Hz,1H),8.22(d,J=5.6Hz,1H),8.04(d,J=8.8Hz,1H),7.72(d,J =2.4Hz,1H),7.69(d,J=2.4Hz,1H),7.59(d,J=3.2Hz,1H),7.54(d,J=8.8,2.4Hz,1H),6.76(dd,J =5.6, 2.4Hz, 1H), 3.37(s, 3H), 2.95-2.90(m, 1H), 2.03(s, 3H), 0.80-0.75(m, 2H), 0.69-0.65(m, 2H).
化合物L51:ESI-MS:m/z＝401.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.78(s,1H),8.43(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.02(d,J＝9.2Hz,1H),7.84(d,J＝5.6Hz,1H),7.63(d,J＝2.4Hz,1H),7.57(d,J＝2.8Hz,1H),7.50(d,J＝9.2,2.8Hz,1H),6.23(dd,J＝5.6,2.4Hz,1H),5.94(s,2H),5.89(d,J＝2.4Hz,1H),3.37(s,3H),2.94-2.90(m,1H),0.80-0.75(m,2H),0.68-0.65(m,2H)。 Compound L51: ESI-MS: m/z=401.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.78(s, 1H), 8.43(d, J=8.8Hz, 1H ),8.26(d,J=8.8Hz,1H),8.02(d,J=9.2Hz,1H),7.84(d,J=5.6Hz,1H),7.63(d,J=2.4Hz,1H), 7.57(d, J=2.8Hz, 1H), 7.50(d, J=9.2, 2.8Hz, 1H), 6.23(dd, J=5.6, 2.4Hz, 1H), 5.94(s, 2H), 5.89(d , J=2.4Hz, 1H), 3.37(s, 3H), 2.94-2.90(m, 1H), 0.80-0.75(m, 2H), 0.68-0.65(m, 2H).
实施例52：化合物L52的制备Example 52: Preparation of Compound L52
Figure PCTCN2022143403-appb-000089
Figure PCTCN2022143403-appb-000089
步骤1、将5-溴-2-氯-4-甲氧基嘧啶(4.0g,17.9mmol)，溶于二氧六环(50mL)中，向上述溶液中加入3-氨基丁烷-1-醇(4g,45mmol)，DIEA(7g,54mmol)。反应液在80℃下搅拌16小时。反应液浓缩除去二氧六环，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1到2:1梯度洗脱)得到化合物52-1(3.0g，产率60.9％)。ESI-MS:m/z＝276.0[M+H] +。 Step 1. Dissolve 5-bromo-2-chloro-4-methoxypyrimidine (4.0g, 17.9mmol) in dioxane (50mL), and add 3-aminobutane-1- Alcohol (4g, 45mmol), DIEA (7g, 54mmol). The reaction solution was stirred at 80°C for 16 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 2:1 gradient elution) to obtain compound 52 -1 (3.0 g, yield 60.9%). ESI-MS: m/z = 276.0 [M+H] + .
步骤2、将化合物52-1(3g,10.9mmol)，溶于浓硫酸(10mL)中，反应液在90℃下搅拌1小时。反应液冷却后加入乙酸乙酯(50mL)，水(50mL)，用饱和碳酸氢钠溶液调节pH到8，有机相由饱和食盐水(30mL)洗涤三次,硫酸钠干燥后蒸除溶剂，得到化合物52-2(1.5g,产率56.6％)。ESI-MS:m/z＝244.1[M+H] +。 Step 2. Compound 52-1 (3 g, 10.9 mmol) was dissolved in concentrated sulfuric acid (10 mL), and the reaction solution was stirred at 90° C. for 1 hour. Add ethyl acetate (50mL) and water (50mL) to the reaction solution after cooling, adjust the pH to 8 with saturated sodium bicarbonate solution, wash the organic phase three times with saturated brine (30mL), dry over sodium sulfate and evaporate the solvent to obtain compound 52-2 (1.5 g, 56.6% yield). ESI-MS: m/z = 244.1 [M+H] + .
步骤3、将化合物52-2(1.5g,6.17mmol)溶于四氢呋喃(30mL)中，向上述溶液中加入二碳酸二叔丁酯(3.9g,18mmol)，TEA(1.8g,18mmol)，DMAP(146mg,1.2mmol)。反应液在60℃下搅拌16小时。反应液浓缩除去四氢呋喃，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1到3:1梯度洗脱)得到化合物52-3(2g，产率94.5％)。ESI-MS:m/z＝288.0[M+H-56] +。 Step 3. Dissolve compound 52-2 (1.5g, 6.17mmol) in tetrahydrofuran (30mL), add di-tert-butyl dicarbonate (3.9g, 18mmol), TEA (1.8g, 18mmol), DMAP to the above solution (146 mg, 1.2 mmol). The reaction solution was stirred at 60°C for 16 hours. The reaction solution was concentrated to remove THF, and water (20 mL) was added to the residue, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1 gradient elution) to obtain compound 52 -3 (2 g, yield 94.5%). ESI-MS: m/z = 288.0 [M+H-56] + .
步骤4、将化合物52-3(2g,5.83mmol)，溶于二氧六环(40mL)中，向上述溶液中加入双联频哪醇基二硼(4.5g,17.5mmol)，醋酸钾(1.7g,17.5mmol)，Pd(PPh 3) 2Cl 2(400mg,0.6mmol)。氮气置换后反应液在85℃下搅拌1小时。反应液冷却后过滤除去固体，固体用二氧六环洗涤(20mL)，蒸除溶剂，得到化合物52-4。ESI-MS:m/z＝254.1[M+H-56] +。 Step 4. Dissolve compound 52-3 (2g, 5.83mmol) in dioxane (40mL), add bis-pinacolyl diboron (4.5g, 17.5mmol), potassium acetate ( 1.7 g, 17.5 mmol), Pd(PPh 3 ) 2 Cl 2 (400 mg, 0.6 mmol). After nitrogen substitution, the reaction solution was stirred at 85° C. for 1 hour. After the reaction liquid was cooled, the solid was removed by filtration, washed with dioxane (20 mL), and the solvent was distilled off to obtain compound 52-4. ESI-MS: m/z = 254.1 [M+H-56] + .
步骤5、化合物52-4和2-氯-6-羟基-喹啉为原料，参考实施例1步骤2的制备方法，得到化合物52-5(1.2g,产率63.9％)。ESI-MS:m/z＝409.2[M+H] +。 Step 5. Compound 52-4 and 2-chloro-6-hydroxy-quinoline were used as raw materials, referring to the preparation method in Step 2 of Example 1, to obtain Compound 52-5 (1.2 g, yield 63.9%). ESI-MS: m/z = 409.2 [M+H] + .
步骤6、将化合物52-5(700mg,1.7mmol)，溶于DMF(15mL)中，向上述溶液中加入2-溴-4-氟吡啶(900mg,5.1mmol)，碳酸钾(700mg,5.1mmol)。反应液在90℃下搅拌16小时。反应液加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1到3:1梯度洗脱)得到化合物52-6(900mg，产率94.03％)。ESI-MS:m/z＝564.1[M+H] +。 Step 6. Dissolve compound 52-5 (700mg, 1.7mmol) in DMF (15mL), add 2-bromo-4-fluoropyridine (900mg, 5.1mmol), potassium carbonate (700mg, 5.1mmol) to the above solution ). The reaction solution was stirred at 90°C for 16 hours. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1 gradient elution) to obtain compound 52 -6 (900 mg, yield 94.03%). ESI-MS: m/z = 564.1 [M+H] + .
步骤7、以化合物52-6和氨基甲酸叔丁酯为原料，参考实施例13步骤2的制备方法，得到化合物52-7。ESI-MS:m/z＝601.2[M+H] +。 Step 7. Using compound 52-6 and tert-butyl carbamate as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 52-7. ESI-MS: m/z = 601.2 [M+H] + .
步骤8、以化合物52-7为原料，参考实施例43步骤2的制备方法，得到产物L52(20mg，产率6.2％).ESI-MS:m/z＝401.0[M+H].H NMR(DMSO-d6,400MHz):δ8.84(s,1H),8.57-8.54(m,2H),8.30(d,J＝8.8Hz,1H),8.07(d,J＝9.2Hz,1H),7.90(d,J＝5.6Hz,1H),7.67(d,J＝2.4Hz,1H),7.54(dd,J＝2.4Hz,J＝8.8Hz,1H),6.28(dd,J＝2.4Hz,J＝6.0Hz 1H),5.99(s,2H),5.95(s,1H),4.31-4.28(m,1H),3.79-3.75(m,1H),3.68-3.66(m,1H).2.20-2.15(m,1H),1.70-1.68(m,1H),1.30(d,J＝6.4Hz 3H)。Step 8. Using compound 52-7 as a raw material, refer to the preparation method in step 2 of Example 43 to obtain the product L52 (20mg, yield 6.2%).ESI-MS: m/z=401.0[M+H].H NMR (DMSO-d6,400MHz):δ8.84(s,1H),8.57-8.54(m,2H),8.30(d,J＝8.8Hz,1H),8.07(d,J＝9.2Hz,1H), 7.90(d, J=5.6Hz, 1H), 7.67(d, J=2.4Hz, 1H), 7.54(dd, J=2.4Hz, J=8.8Hz, 1H), 6.28(dd, J=2.4Hz, J＝6.0Hz 1H),5.99(s,2H),5.95(s,1H),4.31-4.28(m,1H),3.79-3.75(m,1H),3.68-3.66(m,1H).2.20- 2.15(m,1H),1.70-1.68(m,1H),1.30(d,J＝6.4Hz 3H).
实施例54：化合物L54的制备Example 54: Preparation of Compound L54
Figure PCTCN2022143403-appb-000090
Figure PCTCN2022143403-appb-000090
步骤1、以2-氯喹啉-6-醇和中间体v2为原料，参考实施例1步骤2的制备方法，得到化合物54- 1(520mg，产率51.4％)。ESI-MS：m/z＝311.1[M+H] +。 Step 1. Using 2-chloroquinolin-6-ol and intermediate v2 as raw materials, refer to the preparation method in Step 2 of Example 1 to obtain compound 54-1 (520 mg, yield 51.4%). ESI-MS: m/z = 311.1 [M+H] + .
步骤2、以化合物54-1和4-氟-2-溴吡啶为原料，参考实施例5步骤2的制备方法，得到化合物54-2(240mg)。ESI-MS:m/z＝466.0[M+H] +。 Step 2. Using compound 54-1 and 4-fluoro-2-bromopyridine as raw materials, refer to the preparation method in step 2 of Example 5 to obtain compound 54-2 (240 mg). ESI-MS: m/z = 466.0 [M+H] + .
步骤3、以化合物54-2和乙酰胺为原料，参考实施例13步骤2的制备方法，得到化合物54-3(135mg，产率71％)。ESI-MS:m/z＝445.2[M+H] +.HNMR(DMSO-d 6,400MHz):δ10.57(s,1H),8.83(s,1H),8.43(s,1H),8.31(d,J＝8.8Hz,1H),8.23(d,J＝6.0Hz,1H),8.08(d,J＝6.8Hz,1H),8.01(d,J＝8.8Hz,1H),7.73-7.71(m,2H),7.58-7.55(m,1H),6.77(d,J＝5.2Hz,1H),4.22(s,1H),4.00(s,3H),2.03(s,3H),1.22(s,3H),1.20(s,3H)。 Step 3. Using compound 54-2 and acetamide as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 54-3 (135 mg, yield 71%). ESI-MS: m/z＝445.2[M+H] + .HNMR(DMSO-d 6 ,400MHz):δ10.57(s,1H),8.83(s,1H),8.43(s,1H),8.31 (d,J=8.8Hz,1H),8.23(d,J=6.0Hz,1H),8.08(d,J=6.8Hz,1H),8.01(d,J=8.8Hz,1H),7.73-7.71 (m,2H),7.58-7.55(m,1H),6.77(d,J=5.2Hz,1H),4.22(s,1H),4.00(s,3H),2.03(s,3H),1.22( s,3H), 1.20(s,3H).
步骤4、以化合物54-3为原料，参考实施例1步骤3的制备方法，得到产物L54(12.5mg，产率14.5％)。ESI-MS:m/z＝431.2[M+H] +.HNMR(DMSO-d 6,400MHz):δ10.55(s,1H),8.81(s,1H),8.47(d,J＝8.8Hz,1H),8.36(s,1H),8.26(d,J＝8.8Hz,1H),8.22(d,J＝6.0Hz,1H),8.03(d,J＝9.2Hz,1H),7.73(d,J＝1.6Hz,1H),7.68(d,J＝2.4Hz,1H),7.53(d,J＝8.8Hz,1H),7.49-7.39(m,1H),6.75(d,J＝5.6Hz,1H),4.14-4.12(m,1H),2.03(s,3H),1.22(s,3H),1.19(s,3H)。 Step 4. Using compound 54-3 as a raw material, refer to the preparation method in Step 3 of Example 1 to obtain the product L54 (12.5 mg, yield 14.5%). ESI-MS: m/z＝431.2[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ10.55(s, 1H), 8.81(s, 1H), 8.47(d, J＝8.8Hz ,1H),8.36(s,1H),8.26(d,J=8.8Hz,1H),8.22(d,J=6.0Hz,1H),8.03(d,J=9.2Hz,1H),7.73(d ,J=1.6Hz,1H),7.68(d,J=2.4Hz,1H),7.53(d,J=8.8Hz,1H),7.49-7.39(m,1H),6.75(d,J=5.6Hz ,1H), 4.14-4.12(m,1H), 2.03(s,3H), 1.22(s,3H), 1.19(s,3H).
实施例55：化合物L55的制备Example 55: Preparation of Compound L55
Figure PCTCN2022143403-appb-000091
Figure PCTCN2022143403-appb-000091
步骤1、将以化合物52-6和乙酰胺为原料，参考实施例13步骤2的制备方法，得到化合物55-1。ESI-MS:m/z＝543.2[M+H] +。 Step 1. Using compound 52-6 and acetamide as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 55-1. ESI-MS: m/z = 543.2 [M+H] + .
步骤2、以化合物55-1为原料，参考实施例43步骤2的制备方法，得到产物L55.ESI-MS:m/z＝443.2[M+H].H NMR(DMSO-d6,400MHz):δ10.56(s,1H),δ8.80s,1H),8.54-8.50(m,2H),8.25-8.21(m,2H),8.02(d,J＝8.8Hz,1H),7.72-7.69(m,2H),7.52(dd,J＝2.8Hz,J＝9.2Hz,1H),6.75(dd,J＝2.4Hz,J＝5.6Hz,1H),4.26-4.23(m,1H),3.73-3.63(m,2H),2.14-2.09(m,1H),2.07(s,3H),1.68-1.60(m,1H),1.24(d,J＝6.4Hz 3H)。Step 2. Using compound 55-1 as a raw material, refer to the preparation method in step 2 of Example 43 to obtain the product L55.ESI-MS: m/z=443.2[M+H].H NMR (DMSO-d6, 400MHz): δ10.56(s, 1H), δ8.80s, 1H), 8.54-8.50(m, 2H), 8.25-8.21(m, 2H), 8.02(d, J＝8.8Hz, 1H), 7.72-7.69( m,2H),7.52(dd,J=2.8Hz,J=9.2Hz,1H),6.75(dd,J=2.4Hz,J=5.6Hz,1H),4.26-4.23(m,1H),3.73- 3.63 (m, 2H), 2.14-2.09 (m, 1H), 2.07 (s, 3H), 1.68-1.60 (m, 1H), 1.24 (d, J=6.4Hz 3H).
实施例56：化合物L56的制备Example 56: Preparation of Compound L56
Figure PCTCN2022143403-appb-000092
Figure PCTCN2022143403-appb-000092
步骤1、在干冰乙醇浴下，将4-氯-2-吡啶甲醛(1.0g,7.09mmol)，溶于二氯甲烷(20mL)中，向上述溶液中加入二乙胺基三氟化硫(2.2g,14.14mmol)。反应液在-78℃下搅拌2小时。反应液加入饱和碳酸氢钠调节Ph到8，用二氯甲烷萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，)得到4-氯-2-(二氟甲基)吡啶(100mg)。ESI-MS:m/z＝164.0[M+H] +。 Step 1. Dissolve 4-chloro-2-pyridinecarbaldehyde (1.0g, 7.09mmol) in dichloromethane (20mL) under a dry ice ethanol bath, and add diethylaminosulfur trifluoride ( 2.2g, 14.14mmol). The reaction was stirred at -78°C for 2 hours. The reaction solution was adjusted to pH 8 by adding saturated sodium bicarbonate, and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to obtain 4-chloro-2-(difluoromethyl)pyridine (100 mg). ESI-MS: m/z = 164.0 [M+H] + .
步骤2、将4-氯-2-(二氟甲基)吡啶(100mg)，溶于DMF(1mL)中，向上述溶液中加入碳酸钾(83mg,0.6mmol)，化合物4-1(112mg,0.36mmol)。反应液在微波120℃下搅拌5小时。反应液冷却后加水(10mL),用乙酸乙酯萃取(20mL x 3)。有机相合并后用饱和盐水(30mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物经过制备HPLC(NH4HCO3)得到化合物L56(6.0mg，产率3.8％).ESI-MS:m/z＝438.2[M+H].H NMR(DMSO-d6,400MHz):δ8.78(s,1H),δ8.59(d,J＝5.6Hz,1H),8.47(d,J＝8.8Hz,1H),8.28(d,J＝8.8Hz,1H),8.07(d,J＝8.8Hz,1H),7.76(d,J＝2.4Hz,1H),7.58(dd,J＝2.4Hz,J＝8.8Hz,1H),7.26(d,J＝1.6Hz,1H),7.20-7.06(m,2H),7.06-6.79(m,1H),4.40-4.35(m,1H),3.41(s,3H),1.26(d,J＝6.4Hz,6H)。Step 2. Dissolve 4-chloro-2-(difluoromethyl)pyridine (100mg) in DMF (1mL), add potassium carbonate (83mg, 0.6mmol) to the above solution, compound 4-1 (112mg, 0.36 mmol). The reaction solution was stirred under microwave at 120°C for 5 hours. After the reaction solution was cooled, water (10 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was subjected to preparative HPLC (NH4HCO3) to obtain compound L56 (6.0 mg, yield 3.8%). ESI-MS: m/z=438.2 [M+H].H NMR(DMSO-d6,400MHz):δ8.78(s,1H),δ8.59(d,J＝5.6Hz,1H),8.47(d,J＝8.8Hz,1H) ,8.28(d,J=8.8Hz,1H),8.07(d,J=8.8Hz,1H),7.76(d,J=2.4Hz,1H),7.58(dd,J=2.4Hz,J=8.8Hz ,1H),7.26(d,J=1.6Hz,1H),7.20-7.06(m,2H),7.06-6.79(m,1H),4.40-4.35(m,1H),3.41(s,3H), 1.26 (d, J=6.4Hz, 6H).
实施例57：化合物L57的制备Example 57: Preparation of compound L57
Figure PCTCN2022143403-appb-000093
Figure PCTCN2022143403-appb-000093
以化合物13-1和1-甲基脲为原料，参考实施例13步骤2的制备方法，得到产物L57ESI-MS:m/z＝460.3[M+H] +。 1H NMR(400MHz,DMSO-D6)δ9.14(s,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.10(d,J＝6.0Hz,1H),8.03(d,J＝9.2Hz,1H),7.92(d,J＝5.6Hz,1H),7.68(d,J＝2.8Hz,1H),7.54-7.51(m,1H),7.17(d,J＝7.2Hz,1H),6.96(d,J＝2.4Hz,1H),6.63(d,J＝6.0Hz,1H),4.39-4.35(m,1H),3.41(s,3H),2.68-2.66(m,3H),1.27(s,3H),1.25(s,3H)。 Using compound 13-1 and 1-methylurea as raw materials, referring to the preparation method in step 2 of Example 13, the product L57 was obtained by ESI-MS: m/z=460.3[M+H] + . 1 H NMR (400MHz, DMSO-D6) δ9.14(s, 1H), 8.78(s, 1H), 8.46(d, J=8.8Hz, 1H), 8.27(d, J=8.8Hz, 1H), 8.10(d, J=6.0Hz, 1H), 8.03(d, J=9.2Hz, 1H), 7.92(d, J=5.6Hz, 1H), 7.68(d, J=2.8Hz, 1H), 7.54- 7.51(m,1H),7.17(d,J=7.2Hz,1H),6.96(d,J=2.4Hz,1H),6.63(d,J=6.0Hz,1H),4.39-4.35(m,1H ), 3.41(s,3H), 2.68-2.66(m,3H), 1.27(s,3H), 1.25(s,3H).
实施例58：化合物L58的制备Example 58: Preparation of Compound L58
Figure PCTCN2022143403-appb-000094
Figure PCTCN2022143403-appb-000094
步骤1、以化合物54-2和氨基甲酸叔丁酯为原料，参考实施例13步骤2的制备方法，得到化合物58-1。ESI-MS:m/z＝503.2[M+H] +。 Step 1. Using compound 54-2 and tert-butyl carbamate as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 58-1. ESI-MS: m/z = 503.2 [M+H] + .
步骤2、以化合物58-1为原料，参考实施例1步骤3的制备方法以及实施例43步骤2的制备方法，得到产物L58。ESI-MS:m/z＝389.2[M+H] +。HNMR(DMSO-d 6,400MHz):δ10.90(s,1H),8.81(s,1H),8.44(d,J＝8.4Hz,1H),8.26(d,J＝8.8Hz,1H),8.01(d,J＝8.8Hz,1H),7.84(d,J＝5.6Hz,1H),7.63(d,J＝5.6Hz,1H),7.50(d,J＝8.8Hz,1H),6.85(s,1H),6.23(d,J＝6.0Hz,1H),5.93(s,2H),5.89(d,J＝2.0Hz,1H),4.15-4.10(m,1H),1.20(s,3H),1.19(s,3H)。 Step 2. Using compound 58-1 as a raw material, refer to the preparation method in Step 3 of Example 1 and the preparation method in Step 2 of Example 43 to obtain the product L58. ESI-MS: m/z = 389.2 [M+H] + . HNMR(DMSO-d 6 ,400MHz):δ10.90(s,1H),8.81(s,1H),8.44(d,J＝8.4Hz,1H),8.26(d,J＝8.8Hz,1H), 8.01(d, J=8.8Hz, 1H), 7.84(d, J=5.6Hz, 1H), 7.63(d, J=5.6Hz, 1H), 7.50(d, J=8.8Hz, 1H), 6.85( s,1H),6.23(d,J=6.0Hz,1H),5.93(s,2H),5.89(d,J=2.0Hz,1H),4.15-4.10(m,1H),1.20(s,3H ), 1.19(s,3H).
实施例59：化合物L59的制备Example 59: Preparation of compound L59
Figure PCTCN2022143403-appb-000095
Figure PCTCN2022143403-appb-000095
步骤1、以5-溴-2-氯-4-甲氧基嘧啶和1-氨基丙醇为原料，参考实施例52步骤1-6的制备方法，得到化合物59-6。ESI-MS:m/z＝552.0[M+H] +。 Step 1. Using 5-bromo-2-chloro-4-methoxypyrimidine and 1-aminopropanol as raw materials, refer to the preparation method in Step 1-6 of Example 52 to obtain compound 59-6. ESI-MS: m/z = 552.0 [M+H] + .
步骤7、以化合物59-6和乙酰胺为原料，参考实施例13步骤2的制备方法，得到化合物59-7。ESI-MS:m/z＝529.2[M+H] +。 Step 7. Using compound 59-6 and acetamide as raw materials, refer to the preparation method in step 2 of Example 13 to obtain compound 59-7. ESI-MS: m/z = 529.2 [M+H] + .
步骤10、以化合物59-7为原料，参考实施例43步骤2的制备方法，得到产物L59(15mg，产率14％)。ESI-MS:m/z＝429.2[M+H] +.HNMR(DMSO-d 6,400MHz):δ10.55(s,1H),8.79(s,1H),8.52(d,J＝8.8Hz,1H),8.24(d,J＝8.8Hz,1H),8.21(d,J＝6.0Hz,1H),8.02(d,J＝9.2Hz,1H),7.72(d,J＝2.0Hz,1H),7.67(d,J＝2.4Hz,1H),7.52(dd,J＝2.8Hz，9.2Hz,1H)，6.75(dd,J＝2.4Hz，6.0Hz,1H),3.97(t,J＝6.0Hz,2H),3.33(s,2H),2.63-21.98(m,5H)。 Step 10. Using compound 59-7 as a raw material, refer to the preparation method in step 2 of Example 43 to obtain the product L59 (15 mg, yield 14%). ESI-MS: m/z＝429.2[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ10.55(s, 1H), 8.79(s, 1H), 8.52(d, J＝8.8Hz ,1H),8.24(d,J=8.8Hz,1H),8.21(d,J=6.0Hz,1H),8.02(d,J=9.2Hz,1H),7.72(d,J=2.0Hz,1H ), 7.67(d, J=2.4Hz, 1H), 7.52(dd, J=2.8Hz, 9.2Hz, 1H), 6.75(dd, J=2.4Hz, 6.0Hz, 1H), 3.97(t, J= 6.0Hz, 2H), 3.33(s, 2H), 2.63-21.98(m, 5H).
实施例60：化合物L60的制备Embodiment 60: Preparation of compound L60
Figure PCTCN2022143403-appb-000096
Figure PCTCN2022143403-appb-000096
步骤1、在冰浴下，将乙酰胺(390mg,6.6mmol)溶于DMF(10mL)中，向上述溶液中加入NaH(264mg，6.6mmol)。反应液在冰浴下搅拌15分钟。向上述溶液中加入5-氯-2-氟-4-碘吡啶(850mg,3.3mmol)，在室温下搅拌过夜。反应液加水(20mL),用乙酸乙酯萃取(20mL x 3)。有机相合并后用饱和盐水(30mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过C18反向柱纯化(乙腈：水＝5到70梯度洗脱)得到N-(5-氯-4-碘吡啶-2-基)乙酰胺。ESI-MS:m/z＝296.9[M+H] +。 Step 1. Dissolve acetamide (390 mg, 6.6 mmol) in DMF (10 mL) under ice-cooling, and add NaH (264 mg, 6.6 mmol) to the above solution. The reaction solution was stirred under ice bath for 15 minutes. 5-Chloro-2-fluoro-4-iodopyridine (850 mg, 3.3 mmol) was added to the above solution, and stirred overnight at room temperature. Add water (20mL) to the reaction solution, and extract with ethyl acetate (20mL x 3). The organic phases were combined and washed with saturated brine (30 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by C18 reverse column (acetonitrile: water = 5 to 70 gradient elution) to obtain N-(5-chloro-4- iodopyridin-2-yl)acetamide. ESI-MS: m/z = 296.9 [M+H] + .
步骤2、将N-(5-氯-4-碘吡啶-2-基)乙酰胺(40mg,0.13mmol)，溶于DMF(1mL)中，向上述溶液中加入化合物4-1(62mg,0.2mmol)，碳酸铯(88mg,0.26mmol)，2,2,6,6-四甲基-3,5-庚二酮(40mg,0.2mmol)。在氮气置换后，反应液在100℃下搅拌16小时。反应液冷却后加水(10mL),用乙酸乙酯萃取(10mL x 3)。有机相合并后用饱和盐水(20mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物经过Pre-TLC和甲醇打浆得到化合物L60(4.0mg，产率6.45％).ESI-MS:m/z＝479.2[M+H].H NMR(DMSO-d6,400MHz):δ10.67(s,1H),δ8.79(s,J＝5.6Hz,1H),8.47(d,J＝8.8Hz,1H),8.42(s,1H),8.26(d,J＝8.8Hz,1H),8.05(d,J＝9.2Hz,1H),7.72(d,J＝2.4Hz,1H),7.68(s,1H),7.58(dd,J＝2.8Hz,J＝9.2Hz,1H),7.18(d,J＝7.6Hz 1H),4.39-4.37(m,1H),3.41(s,3H).1.96(s,3H).1.26(d,J＝6.8Hz,6H)。Step 2. Dissolve N-(5-chloro-4-iodopyridin-2-yl)acetamide (40mg, 0.13mmol) in DMF (1mL), and add compound 4-1 (62mg, 0.2 mmol), cesium carbonate (88 mg, 0.26 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (40 mg, 0.2 mmol). After nitrogen replacement, the reaction solution was stirred at 100° C. for 16 hours. After the reaction solution was cooled, water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was subjected to Pre-TLC and methanol beating to obtain compound L60 (4.0 mg, yield 6.45%). ESI-MS: m/z = 479.2[M+H].H NMR(DMSO-d6,400MHz):δ10.67(s,1H),δ8.79(s,J＝5.6Hz,1H),8.47(d,J＝8.8Hz,1H ),8.42(s,1H),8.26(d,J=8.8Hz,1H),8.05(d,J=9.2Hz,1H),7.72(d,J=2.4Hz,1H),7.68(s,1H ),7.58(dd,J＝2.8Hz,J＝9.2Hz,1H),7.18(d,J＝7.6Hz 1H),4.39-4.37(m,1H),3.41(s,3H).1.96(s, 3H). 1.26 (d, J=6.8Hz, 6H).
实施例61：化合物L61的制备Example 61: Preparation of Compound L61
Figure PCTCN2022143403-appb-000097
Figure PCTCN2022143403-appb-000097
将化合物42-4(100mg,0.23mmol)和哌啶(200mg,2.3mmol)溶于1,4-二氧六环(5mL)中，向上述溶液中加入碳酸铯(750mg，2.3mmol)和碳酸钾(317.4mg，2.3mmol)。反应液在80℃下搅拌12小时。反应液冷却室温后后通过制备HPLC(NH 4OAc)得到产物L61(3mg,产率2.8％)。ESI-MS:m/z＝471.3[M+H] +.H NMR(DMSO-d 6,400MHz):δ10.56(s,1H),8.75(s,1H),8.44(d,J＝8.4Hz,1H),8.32(d,J＝8.8Hz,1H),8.23(d,J＝5.6Hz,1H),8.08(d,J＝9.2Hz,1H),7.72(t,J＝2.8Hz,2H),7.57(dd,J＝2.4Hz,9.2Hz,1H),6.77(dd,J＝2.0Hz,5.6Hz,1H),3.48(s,3H),3.00(t,J＝6.0Hz,2H),2.03(s,3H),1.65(s,8H)。 Compound 42-4 (100mg, 0.23mmol) and piperidine (200mg, 2.3mmol) were dissolved in 1,4-dioxane (5mL), cesium carbonate (750mg, 2.3mmol) and carbonic acid were added to the above solution Potassium (317.4 mg, 2.3 mmol). The reaction solution was stirred at 80° C. for 12 hours. After the reaction solution was cooled to room temperature, the product L61 (3 mg, yield 2.8%) was obtained by preparative HPLC (NH 4 OAc). ESI-MS: m/z＝471.3[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ10.56(s, 1H), 8.75(s, 1H), 8.44(d, J＝8.4 Hz,1H),8.32(d,J=8.8Hz,1H),8.23(d,J=5.6Hz,1H),8.08(d,J=9.2Hz,1H),7.72(t,J=2.8Hz, 2H), 7.57(dd, J=2.4Hz, 9.2Hz, 1H), 6.77(dd, J=2.0Hz, 5.6Hz, 1H), 3.48(s, 3H), 3.00(t, J=6.0Hz, 2H ), 2.03(s,3H), 1.65(s,8H).
实施例62：化合物L62的制备Embodiment 62: Preparation of compound L62
Figure PCTCN2022143403-appb-000098
Figure PCTCN2022143403-appb-000098
步骤1、将乙酰胺(350mg,6.25mmol)溶于DMF(20mL)中，氮气置换后，冰浴下向上述溶液中分批加入NaH(335mg,8.37mmol,60％)。冰浴下搅拌30分钟，加入2,3-二氟-4-碘吡啶(1.0g,4.17mmol)，反应液在室温下搅拌16小时。向反应液浓加水(100mL)，用乙酸乙酯萃取(80mL x 3)。有机相合并后用饱和盐水(150mL x 2)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过C18反向柱纯化(乙腈：水＝50:50到55:45梯度洗脱)得到产物N-(3-氟-4-碘-2-基)乙酰胺(450mg，产率38％)。ESI-MS:m/z＝281.0[M+H] +。 Step 1. Dissolve acetamide (350mg, 6.25mmol) in DMF (20mL). After nitrogen replacement, add NaH (335mg, 8.37mmol, 60%) to the above solution in batches under ice bath. Stir under ice bath for 30 minutes, add 2,3-difluoro-4-iodopyridine (1.0 g, 4.17 mmol), and stir the reaction solution at room temperature for 16 hours. Water (100 mL) was concentrated to the reaction liquid, and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine (150mL x 2), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by a C18 reverse column (acetonitrile:water=50:50 to 55:45 gradient elution) to obtain the product N- (3-Fluoro-4-iodo-2-yl)acetamide (450 mg, 38% yield). ESI-MS: m/z = 281.0 [M+H] + .
步骤2、将N-(3-氟-4-碘-2-基)乙酰胺(140mg,0.774mmol),化合物4-1(160mg,0.52mmol)和碳酸铯(505mg,1.55mmol)溶于DMF(3mL)中，置换氮气后，向上述溶液中加入碘化亚铜(100mg，0.52mmol)和TMHD(185mg，1.03mmol)。再次置换氮气，反应液在80℃下搅拌18小时。反应液冷却室温后浓缩，向反应液加水(50mL)，用乙酸乙酯萃取(40mL x 3)。有机相合并后用饱和盐水(50mL x 2)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过C18反向柱纯化得到粗产物，再经过制备HPLC(TFA)得到产物L62(8.4mg,产率3.5％)。ESI-MS:m/z＝463.3[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ10.35(s,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.26(d,J＝8.4Hz,1H),8.10(d,J＝7.2Hz,1H),8.05(d,J＝9.2Hz,1H),7.71(d,J＝2.4Hz,1H),7.61(d,J＝9.2Hz,1H),7.18(d,J＝7.6Hz,1H),6.90-6.87(m,1H),4.40-4.35(m,1H),3.41(s,3H),2.10(s,3H),1.26(s,3H),1.25(s,3H)。 Step 2, N-(3-fluoro-4-iodo-2-yl)acetamide (140mg, 0.774mmol), compound 4-1 (160mg, 0.52mmol) and cesium carbonate (505mg, 1.55mmol) were dissolved in DMF (3 mL), after nitrogen replacement, copper iodide (100 mg, 0.52 mmol) and TMHD (185 mg, 1.03 mmol) were added to the above solution. Nitrogen was replaced again, and the reaction solution was stirred at 80° C. for 18 hours. The reaction solution was concentrated after cooling to room temperature, water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (40 mL x 3). The organic phases were combined and washed with saturated brine (50mL x 2), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by C18 reverse column to obtain the crude product, and then the product L62 (8.4mg, yield 3.5%). ESI-MS: m/z = 463.3 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.35(s, 1H), 8.78(s, 1H), 8.46(d, J=8.8Hz, 1H), 8.26(d, J=8.4Hz, 1H ), 8.10(d, J=7.2Hz, 1H), 8.05(d, J=9.2Hz, 1H), 7.71(d, J=2.4Hz, 1H), 7.61(d, J=9.2Hz, 1H), 7.18(d,J=7.6Hz,1H),6.90-6.87(m,1H),4.40-4.35(m,1H),3.41(s,3H),2.10(s,3H),1.26(s,3H) ,1.25(s,3H).
实施例63：化合物L63的制备Embodiment 63: Preparation of Compound L63
Figure PCTCN2022143403-appb-000099
Figure PCTCN2022143403-appb-000099
步骤1、将化合物42-2(500mg,1.67mmol)和吡咯烷(3.56g,50.16mmol)溶于三乙胺三氟乙酸盐(10mL)中，封管加热至100℃，搅拌48小时。乙酸乙酯稀释(100mL)，饱和食盐水洗涤(100mL x3)，干燥，浓缩，反相柱层析(乙腈：水＝5:95到70:30梯度洗脱)纯化，得到化合物63-1(490mg，产率91％)。ESI-MS:m/z＝323.2[M+H] +。 Step 1. Dissolve compound 42-2 (500 mg, 1.67 mmol) and pyrrolidine (3.56 g, 50.16 mmol) in triethylamine trifluoroacetate (10 mL), seal the tube and heat to 100° C., and stir for 48 hours. Diluted with ethyl acetate (100 mL), washed with saturated brine (100 mL x3), dried, concentrated, and purified by reverse phase column chromatography (acetonitrile: water = 5:95 to 70:30 gradient elution) to obtain compound 63-1 ( 490 mg, yield 91%). ESI-MS: m/z = 323.2 [M+H] + .
步骤2、将化合物63-1(322mg,1.0mmol)，2,2,6,6-四甲基庚-3,5-二酮(46mg,0.25mmol)，N-(3-氟-4-碘吡啶-2-基)乙酰胺(421mg，1.5mmol)，碳酸铯(652mg,2.0mmol)和碘化亚铜(95mg，0.5mmol)溶于N-甲基吡咯烷酮15mL)中，氮气置换后反应液在90℃下搅拌72小时。反应液冷却至室温，乙酸乙酯(100mL)萃取，饱和食盐水(100mL x 3)洗涤，干燥，浓缩，反相柱层析纯化，得到化合物L63(50mg，产率10％)。ESI-MS:m/z＝475.3[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.35(s,1H),8.76(s,1H),8.48(d,J＝8.8Hz,1H),8.28(d,J＝8.8Hz,1H),8.11(d,J＝5.6Hz,1H),8.05(d,J＝8.8Hz,1H),7.72(d,J＝2.8Hz,1H),7.62(dd,J＝8.8,2.8Hz,1H),6.91(dd,J＝6.0,5.6Hz,1H),3.63(t,J＝6.4Hz,4H),3.49(s,3H),2.10(s,3H),1.91-1.88(m,4H)。 Step 2, compound 63-1 (322mg, 1.0mmol), 2,2,6,6-tetramethylheptane-3,5-dione (46mg, 0.25mmol), N-(3-fluoro-4- Iodopyridin-2-yl)acetamide (421mg, 1.5mmol), cesium carbonate (652mg, 2.0mmol) and cuprous iodide (95mg, 0.5mmol) were dissolved in N-methylpyrrolidone (15mL), and reacted after nitrogen replacement The solution was stirred at 90°C for 72 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (100 mL), washed with saturated brine (100 mL x 3), dried, concentrated, and purified by reverse phase column chromatography to obtain compound L63 (50 mg, yield 10%). ESI-MS: m/z＝475.3[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.35(s, 1H), 8.76(s, 1H), 8.48(d, J＝ 8.8Hz, 1H), 8.28(d, J=8.8Hz, 1H), 8.11(d, J=5.6Hz, 1H), 8.05(d, J=8.8Hz, 1H), 7.72(d, J=2.8Hz ,1H),7.62(dd,J=8.8,2.8Hz,1H),6.91(dd,J=6.0,5.6Hz,1H),3.63(t,J=6.4Hz,4H),3.49(s,3H) , 2.10 (s, 3H), 1.91-1.88 (m, 4H).
实施例67：化合物L67的制备Embodiment 67: Preparation of Compound L67
Figure PCTCN2022143403-appb-000100
Figure PCTCN2022143403-appb-000100
步骤1、将化合物42-2(200mg,0.67mmol)和2,2,2-三氟乙胺(3.3g,33.4mmol)溶于TEA/TFA混合溶液(摩尔比1:1)(7mL)中，氮气置换后反应液在110℃下搅拌过夜。反应液冷却至室温后浓缩，残余物通过C18反向柱提纯得到化合物67-1(50mg)。ESI-MS：m/z＝351.0[M+H] +。 Step 1. Compound 42-2 (200mg, 0.67mmol) and 2,2,2-trifluoroethylamine (3.3g, 33.4mmol) were dissolved in TEA/TFA mixed solution (molar ratio 1:1) (7mL) , and the reaction solution was stirred overnight at 110° C. after nitrogen replacement. The reaction solution was cooled to room temperature and concentrated, and the residue was purified by C18 reverse column to obtain compound 67-1 (50 mg). ESI-MS: m/z = 351.0 [M+H] + .
步骤2、将化合物67-1(50mg,0.143mmol)溶于DMF(3mL)中，向溶液中加入碳酸铯(140mg,0.43mmol)和2-溴-4-氟吡啶(50mg,0.286mmol)。氮气置换后反应液在90℃搅拌过夜。反应液浓缩后，残余物通过C18反向柱提纯得到化合物67-2(25mg)。ESI-MS：m/z＝505.9[M+H] +。 Step 2. Compound 67-1 (50 mg, 0.143 mmol) was dissolved in DMF (3 mL), and cesium carbonate (140 mg, 0.43 mmol) and 2-bromo-4-fluoropyridine (50 mg, 0.286 mmol) were added to the solution. After nitrogen replacement, the reaction solution was stirred overnight at 90°C. After the reaction solution was concentrated, the residue was purified by C18 reverse column to obtain compound 67-2 (25 mg). ESI-MS: m/z = 505.9 [M+H] + .
步骤3、将化合物67-2(25mg,0.05mmol)，x-phos(2.4mg，0.005mmol)，乙酰胺(18mg，0.3mmol)和碳酸铯(49mg,0.15mmol)和Pd 2(dba) 3(5mg，0.005mmol)溶于1,4-二氧六环(2mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后浓缩。残余物经过制备HPLC(0.1％甲酸水溶液)得到化合物67(5.5mg，产率22.9％)。ESI-MS：m/z＝485.2[M+H] +。 1H NMR(DMSO-d 6，400MHz)δ10.56(s,1H),8.75(s,1H),8.42(d,J＝8.8Hz,1H),8.30(d,J＝8.8Hz,1H),8.22(d,J＝6.0Hz,1H),8.06(d,J＝9.2Hz,1H),7.73(d,J＝2.0Hz,1H),7.71(d,J＝2.4Hz,1H),7.56(dd,J＝8.8Hz,1H),6.76(d,J＝6.0Hz,1H),4.35-4.31(m,1H),3.47(s,3H),2.03(s,3H)。 Step 3, compound 67-2 (25mg, 0.05mmol), x-phos (2.4mg, 0.005mmol), acetamide (18mg, 0.3mmol) and cesium carbonate (49mg, 0.15mmol) and Pd 2 (dba) 3 (5 mg, 0.005 mmol) was dissolved in 1,4-dioxane (2 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated. The residue was subjected to preparative HPLC (0.1% aqueous formic acid) to obtain compound 67 (5.5 mg, yield 22.9%). ESI-MS: m/z = 485.2 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz) δ10.56(s, 1H), 8.75(s, 1H), 8.42(d, J=8.8Hz, 1H), 8.30(d, J=8.8Hz, 1H) ,8.22(d,J=6.0Hz,1H),8.06(d,J=9.2Hz,1H),7.73(d,J=2.0Hz,1H),7.71(d,J=2.4Hz,1H),7.56 (dd, J=8.8Hz, 1H), 6.76 (d, J=6.0Hz, 1H), 4.35-4.31(m, 1H), 3.47(s, 3H), 2.03(s, 3H).
实施例68：化合物L68的制备Embodiment 68: Preparation of Compound L68
Figure PCTCN2022143403-appb-000101
Figure PCTCN2022143403-appb-000101
步骤1、将化合物42-2(350mg,1.17mmol)和环己胺(1.1g,11.7mmol)溶于TEA/TFA混合溶液(摩尔比1:1)(5mL)中，氮气置换后反应液在100℃下搅拌过夜。反应液冷却至室温后浓缩，残余物通过C18反向柱提纯(乙腈：水＝35:65到40:60梯度洗脱)得到得到化合物68-1(130mg，产率31.8％)。ESI-MS：m/z＝351.0[M+H] +。 Step 1. Dissolve compound 42-2 (350mg, 1.17mmol) and cyclohexylamine (1.1g, 11.7mmol) in TEA/TFA mixed solution (molar ratio 1:1) (5mL), and replace the reaction solution with nitrogen in Stir overnight at 100°C. The reaction solution was cooled to room temperature and concentrated, and the residue was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain compound 68-1 (130 mg, yield 31.8%). ESI-MS: m/z = 351.0 [M+H] + .
步骤2、将化合物68-1(130mg,0.37mmol)溶于NMP(5mL)中，向溶液中加入碳酸钾(102.5mg,0.74mmol)和2-溴-4-氟吡啶(78.5mg,0.44mmol)。氮气置换后反应液在90℃搅拌过夜。反应液浓缩后残余物通过C18反向柱提纯(乙腈：水＝35:65到40:60梯度洗脱)得到化合物68-2(135mg,产率72.3％)。ESI-MS：m/z＝508.0[M+H] +。 Step 2. Dissolve compound 68-1 (130mg, 0.37mmol) in NMP (5mL), add potassium carbonate (102.5mg, 0.74mmol) and 2-bromo-4-fluoropyridine (78.5mg, 0.44mmol ). After nitrogen replacement, the reaction solution was stirred overnight at 90°C. After the reaction solution was concentrated, the residue was purified by a C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain compound 68-2 (135 mg, yield 72.3%). ESI-MS: m/z = 508.0 [M+H] + .
步骤3、将化合物68-2(135mg,0.27mmol)，x-phos(50mg，0.1mmol)，乙酰胺(63mg，1.07mmol)碳酸铯(347mg,1.07mmol)和Pd 2(dba) 3(49g，0.05mmol)溶于1,4-二氧六环(8mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，氮气置换后反应液在90℃搅拌过夜。反应液浓缩后残余物经过制备HPLC(0.1％甲酸水溶液)得到化合物L68(40mg产率31％)。ESI-MS：m/z＝485.3[M+H] +。 1H NMR(DMSO-d 6，400MHz)δ8.77(s,1H),8.45(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.22(d,J＝5.7Hz,1H),8.03(d,J＝9.1Hz,1H),7.72(d,J＝2.0Hz,1H),7.69(d,J＝2.7Hz,1H),7.53(dd,J＝9.1,2.7Hz,1H),7.13(d,J＝7.8Hz,1H),6.75(dd,J＝5.7,2.4Hz,1H),4.15–3.94(m,1H),3.41(s,3H),2.03(s,3H),1.93(d,J＝11.2Hz,2H),1.77(d,J＝12.9Hz,2H),1.64(d,J＝13.0Hz,1H),1.36(m,5H),1.14(m,1H)。 Step 3, compound 68-2 (135mg, 0.27mmol), x-phos (50mg, 0.1mmol), acetamide (63mg, 1.07mmol) cesium carbonate (347mg, 1.07mmol) and Pd 2 (dba) 3 (49g , 0.05 mmol) was dissolved in 1,4-dioxane (8 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. After nitrogen replacement, the reaction solution was stirred overnight at 90°C. After the reaction solution was concentrated, the residue was subjected to preparative HPLC (0.1% formic acid aqueous solution) to obtain compound L68 (40 mg, yield 31%). ESI-MS: m/z = 485.3 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz) δ8.77(s, 1H), 8.45(d, J=8.8Hz, 1H), 8.26(d, J=8.8Hz, 1H), 8.22(d, J= 5.7Hz, 1H), 8.03(d, J=9.1Hz, 1H), 7.72(d, J=2.0Hz, 1H), 7.69(d, J=2.7Hz, 1H), 7.53(dd, J=9.1, 2.7Hz, 1H), 7.13(d, J=7.8Hz, 1H), 6.75(dd, J=5.7, 2.4Hz, 1H), 4.15–3.94(m, 1H), 3.41(s, 3H), 2.03( s,3H),1.93(d,J=11.2Hz,2H),1.77(d,J=12.9Hz,2H),1.64(d,J=13.0Hz,1H),1.36(m,5H),1.14( m, 1H).
实施例69：化合物L69的制备Embodiment 69: Preparation of Compound L69
Figure PCTCN2022143403-appb-000102
Figure PCTCN2022143403-appb-000102
将化合物42-4(245mg,0.56mmol)和(1R,2R)-2-氨基环己醇(651mg,5.65mmol)溶于1,4-二氧六环(10mL)中，向上述溶液中加入碳酸铯(1.84g，5.65mmol)和碳酸钾(780mg，5.65mmol)。反应液在80℃下搅拌12小时。反应液冷却室温后后通过制备HPLC(NH 4OAc)得到产物L69(3mg，产率1.1％)。ESI-MS:m/z＝501.3[M+H] +.H NMR(DMSO-d 6,400MHz):δ10.59(s,1H),8.80(s,1H),8.49(d,J＝11.6Hz,1H),8.30-8.24(m,2H),8.06(d,J＝12.4Hz,1H),7.74(dd,J＝2.8Hz,14.4Hz,2H),7.56(dd,J＝3.2Hz,12.0Hz,1H),7.18(d,J＝10.4Hz,1H),6.78(dd,J＝2.8Hz,7.6Hz,1H),4.79(d,J＝5.6Hz,1H),4.00-3.94(m,1H),3.59(s,1H),3.47(s,3H),2.06(s,3H),1.96(s,2H),1.71(s,2H),1.31(s,4H)。 Compound 42-4 (245mg, 0.56mmol) and (1R,2R)-2-aminocyclohexanol (651mg, 5.65mmol) were dissolved in 1,4-dioxane (10mL), and added to the above solution Cesium carbonate (1.84g, 5.65mmol) and potassium carbonate (780mg, 5.65mmol). The reaction solution was stirred at 80° C. for 12 hours. After the reaction solution was cooled to room temperature, the product L69 (3 mg, yield 1.1%) was obtained by preparative HPLC (NH 4 OAc). ESI-MS: m/z＝501.3[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ10.59(s, 1H), 8.80(s, 1H), 8.49(d, J＝11.6 Hz,1H),8.30-8.24(m,2H),8.06(d,J=12.4Hz,1H),7.74(dd,J=2.8Hz,14.4Hz,2H),7.56(dd,J=3.2Hz, 12.0Hz, 1H), 7.18(d, J=10.4Hz, 1H), 6.78(dd, J=2.8Hz, 7.6Hz, 1H), 4.79(d, J=5.6Hz, 1H), 4.00-3.94(m ,1H), 3.59(s,1H), 3.47(s,3H), 2.06(s,3H), 1.96(s,2H), 1.71(s,2H), 1.31(s,4H).
实施例70：化合物L70的制备Example 70: Preparation of Compound L70
Figure PCTCN2022143403-appb-000103
Figure PCTCN2022143403-appb-000103
步骤1、将化合物59-6(180mg,0.33mmol)和Boc胺(234mg,2.0mmol)，Pd 2dba 3(30mg,0.03mmol)，X-phos(32mg,0.07mmol)，碳酸铯(270mg，0.8mmol)溶于1,4-二氧六环(10mL)中，置换氮气后，反应液在80℃下搅拌16小时。得到化合物70-1。反应液直接用于下一步。ESI-MS:m/z＝487.2[M-100+1] +。 Step 1. Compound 59-6 (180mg, 0.33mmol) and Bocamine (234mg, 2.0mmol), Pd 2 dba 3 (30mg, 0.03mmol), X-phos (32mg, 0.07mmol), cesium carbonate (270mg, 0.8 mmol) was dissolved in 1,4-dioxane (10 mL), and after replacing nitrogen, the reaction solution was stirred at 80°C for 16 hours. Compound 70-1 was obtained. The reaction solution was directly used in the next step. ESI-MS: m/z = 487.2 [M-100+1] + .
步骤2、将上述反应液过滤，加入盐酸/1,4-二氧六环(2mL),反应液在常温下搅拌1.5小时，冷却至室温后通过制备HPLC(NH 4OAc)得到产物L70(5mg，产率4％)。ESI-MS:m/z＝387.2[M+H] +.H NMR(DMSO-d 6,400MHz):δ8.77(s,1H),8.50(d,J＝9.2Hz,1H),8.45(s,1H),8.24(d,J＝8.8Hz,1H),8.01(d,J＝8.8Hz,1H),7.84(d,J＝3.5Hz,1H),7.62(d,J＝2.4Hz,1H),7.48(dd,J＝2.8Hz,8.8Hz,1H),6.24(dd,J＝2.0Hz,5.6Hz,1H),5.97(s,2H),5.89(d,J＝2.0Hz,1H),3.96(t,J＝6.0Hz,2H),1.99(t,J＝6.0Hz,2H)。 Step 2. Filter the above reaction solution, add hydrochloric acid/1,4-dioxane (2mL), stir the reaction solution at room temperature for 1.5 hours, cool to room temperature and obtain the product L70 (5mg , yield 4%)). ESI-MS: m/z=387.2[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ8.77(s, 1H), 8.50(d, J=9.2Hz, 1H), 8.45( s,1H),8.24(d,J=8.8Hz,1H),8.01(d,J=8.8Hz,1H),7.84(d,J=3.5Hz,1H),7.62(d,J=2.4Hz, 1H), 7.48(dd, J=2.8Hz, 8.8Hz, 1H), 6.24(dd, J=2.0Hz, 5.6Hz, 1H), 5.97(s, 2H), 5.89(d, J=2.0Hz, 1H ), 3.96(t, J=6.0Hz, 2H), 1.99(t, J=6.0Hz, 2H).
实施例72：化合物L72的制备Example 72: Preparation of Compound L72
Figure PCTCN2022143403-appb-000104
Figure PCTCN2022143403-appb-000104
将化合物42-4(150mg,0.34mmol)和(S)-3-氟吡咯烷盐酸盐(1.3g,10.4mmol)溶于三乙胺三氟乙酸盐(10mL)中，封管加热至120℃，搅拌48小时。乙酸乙酯稀释(100mL)，饱和食盐水洗涤(100mL x3)，干燥，浓缩，高效液相制备色谱(0.1％甲酸水溶液/乙腈)纯化，得到化合物L72(15mg，产率9.1％)。ESI-MS:m/z＝475.3[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.56(s,1H),8.76(s,1H),8.46(d,J＝8.8Hz,1H),8.30(d,J＝8.8Hz,1H),8.22(d,J＝5.6Hz,1H),8.06(d,J＝8.8Hz,1H),7.73-7.70(m,2H),7.55(dd,J＝8.8,2.4Hz,1H),6.76(dd,J＝5.6,2.4Hz,1H),5.43(d,J＝53.2Hz,1H),4.10-3.71(m,4H),3.51(s,3H),2.33-2.07(m,2H),2.03(s,3H))。 Compound 42-4 (150mg, 0.34mmol) and (S)-3-fluoropyrrolidine hydrochloride (1.3g, 10.4mmol) were dissolved in triethylamine trifluoroacetate (10mL), sealed and heated to 120°C, stirring for 48 hours. Diluted with ethyl acetate (100 mL), washed with saturated brine (100 mL x3), dried, concentrated, and purified by preparative HPLC (0.1% aqueous formic acid/acetonitrile) to obtain compound L72 (15 mg, yield 9.1%). ESI-MS: m/z＝475.3[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.56(s, 1H), 8.76(s, 1H), 8.46(d, J＝ 8.8Hz, 1H), 8.30(d, J=8.8Hz, 1H), 8.22(d, J=5.6Hz, 1H), 8.06(d, J=8.8Hz, 1H), 7.73-7.70(m, 2H) ,7.55(dd,J=8.8,2.4Hz,1H),6.76(dd,J=5.6,2.4Hz,1H),5.43(d,J=53.2Hz,1H),4.10-3.71(m,4H), 3.51(s,3H),2.33-2.07(m,2H),2.03(s,3H)).
实施例74：化合物L74的制备Example 74: Preparation of compound L74
Figure PCTCN2022143403-appb-000105
Figure PCTCN2022143403-appb-000105
将化合物13-1(50mg,0.11mmol)，X-phos(5.5mg，0.011mmol)，氨基甲酸甲酯(48mg，0.65mmol)和碳酸铯(105mg,0.32mmol)和Pd 2(dba) 3(10mg，0.011mmol)溶于1,4-二氧六环(2mL)中，氮气置换后反应液在85℃下搅拌5小时。反应液冷却至室温后用乙酸乙酯(25mL x 3)萃取。有机相合并后用饱和盐水(30mL x 2)洗涤，硫酸钠干燥后浓缩，粗品用制备HPLC(NH 4HCO 3)得到产物L74(14.3mg，产率29.2％)。ESI-MS：m/z＝361.2[M+H] +。 1H NMR(400MHz,DMSO-D6)δ10.27(s,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.18(d,J＝5.6Hz,1H),8.04(d,J＝9.2Hz,1H),7.70(d,J＝2.8Hz,1H),7.55(dd,J＝2.8,8.8Hz,1H),7.18(d,J＝7.6Hz,1H),6.96(d,J＝2.4Hz,1H),6.74(d,J＝5.6Hz,1H),4.41-4.35(m,1H),3.59(s,3H),3.38(s,3H),1.26(d,J＝6.4Hz,6H)。 Compound 13-1 (50mg, 0.11mmol), X-phos (5.5mg, 0.011mmol), methyl carbamate (48mg, 0.65mmol) and cesium carbonate (105mg, 0.32mmol) and Pd 2 (dba) 3 ( 10mg, 0.011mmol) was dissolved in 1,4-dioxane (2mL), and the reaction solution was stirred at 85°C for 5 hours after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate (25 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over sodium sulfate and concentrated. The crude product was obtained by preparative HPLC (NH 4 HCO 3 ) to obtain the product L74 (14.3 mg, yield 29.2%). ESI-MS: m/z = 361.2 [M+H] + . 1 H NMR (400MHz, DMSO-D6) δ10.27(s, 1H), 8.78(s, 1H), 8.46(d, J=8.8Hz, 1H), 8.27(d, J=8.8Hz, 1H), 8.18(d, J=5.6Hz, 1H), 8.04(d, J=9.2Hz, 1H), 7.70(d, J=2.8Hz, 1H), 7.55(dd, J=2.8, 8.8Hz, 1H), 7.18(d, J=7.6Hz, 1H), 6.96(d, J=2.4Hz, 1H), 6.74(d, J=5.6Hz, 1H), 4.41-4.35(m, 1H), 3.59(s, 3H ), 3.38 (s, 3H), 1.26 (d, J=6.4Hz, 6H).
实施例75：化合物L75的制备Example 75: Preparation of Compound L75
Figure PCTCN2022143403-appb-000106
Figure PCTCN2022143403-appb-000106
将化合物42-4(150mg,0.35mmol)，3,3-二氟吡咯盐酸盐(993mg,6.92mmol)溶于三氟乙酸和三乙胺的混合离子液体中(5mL/5mL)中。反应液在120℃下搅拌12小时。反应液冷却室温后后通过制备HPLC(NH 4OAc)得到产物L75(3mg)。ESI-MS:m/z＝493.2[M+H] +.H NMR(DMSO-d 6,400MHz):δ10.56(s,1H),8.75(s,1H),8.45(d,J＝8.8Hz,1H),8.32(d,J＝8.8Hz,1H),8.22(d,J＝5.6Hz,1H),8.07(d,J＝8.8Hz,1H),7.72(t,J＝2.8Hz,2H),7.56(dd,J＝2.8Hz,9.2Hz,1H),6.77(dd,J＝2.4Hz,6.0Hz,1H),4.09(t,J＝13.2Hz,2H),3.88(t,J＝7.2Hz,2H),3.50(s,3H),2.03(s,5H)。 Compound 42-4 (150 mg, 0.35 mmol), 3,3-difluoropyrrole hydrochloride (993 mg, 6.92 mmol) was dissolved in a mixed ionic liquid of trifluoroacetic acid and triethylamine (5 mL/5 mL). The reaction solution was stirred at 120° C. for 12 hours. After the reaction solution was cooled to room temperature, the product L75 (3 mg) was obtained by preparative HPLC (NH 4 OAc). ESI-MS: m/z＝493.2[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ10.56(s, 1H), 8.75(s, 1H), 8.45(d, J＝8.8 Hz,1H),8.32(d,J=8.8Hz,1H),8.22(d,J=5.6Hz,1H),8.07(d,J=8.8Hz,1H),7.72(t,J=2.8Hz, 2H), 7.56(dd, J=2.8Hz, 9.2Hz, 1H), 6.77(dd, J=2.4Hz, 6.0Hz, 1H), 4.09(t, J=13.2Hz, 2H), 3.88(t, J =7.2Hz, 2H), 3.50(s, 3H), 2.03(s, 5H).
实施例76：化合物L76的制备Example 76: Preparation of Compound L76
Figure PCTCN2022143403-appb-000107
Figure PCTCN2022143403-appb-000107
将化合物L63(30mg,0.06mmol)溶于正丁醇(5mL)中，加入浓盐酸(1.0mL)，加热至50℃，搅拌3小时，1M氢氧化钠水溶液中和，浓缩，高效液相制备色谱(0.1％甲酸水溶液/乙腈)纯化，得到化合物L76(15mg，产率55％)。ESI-MS:m/z＝433.2[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.74(s,1H),8.45(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.01(d,J＝8.4Hz,1H),7.68(d,J＝5.6Hz,1H),7.56-7.54(m,2H),6.33(s,2H),6.22(dd,J＝5.2,5.6Hz,1H),3.63(t,J＝6.4Hz,4H),3.49(s,3H),1.91-1.88(m,4H)。 Dissolve compound L63 (30mg, 0.06mmol) in n-butanol (5mL), add concentrated hydrochloric acid (1.0mL), heat to 50°C, stir for 3 hours, neutralize with 1M aqueous sodium hydroxide solution, concentrate, and perform HPLC preparation Purification by chromatography (0.1% aqueous formic acid/acetonitrile) afforded compound L76 (15 mg, 55% yield). ESI-MS: m/z＝433.2[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.74(s, 1H), 8.45(d, J＝8.8Hz, 1H), 8.26 (d, J=8.8Hz, 1H), 8.01(d, J=8.4Hz, 1H), 7.68(d, J=5.6Hz, 1H), 7.56-7.54(m, 2H), 6.33(s, 2H) , 6.22 (dd, J=5.2, 5.6Hz, 1H), 3.63 (t, J=6.4Hz, 4H), 3.49 (s, 3H), 1.91-1.88 (m, 4H).
实施例77：化合物L77的制备Example 77: Preparation of Compound L77
Figure PCTCN2022143403-appb-000108
Figure PCTCN2022143403-appb-000108
步骤1、将5-溴-2-甲基-4(1H)-嘧啶酮(800mg,4.2mmol)溶于DMF(8mL)中，体系降温至-78℃后，向上述溶液中加入NaHMDS(3.2mL,6.3mmol)。反应液在-78℃下搅拌0.5小时,继续向体系中加入碘甲烷(1.2g,8.4mmol)，反应逐渐升至室温，加水(5mL)淬灭，残余物通过C18反向柱纯化得到化合物77-1(460mg，产率54％)。ESI-MS:m/z＝202.9[M+H] +。 Step 1. Dissolve 5-bromo-2-methyl-4(1H)-pyrimidinone (800mg, 4.2mmol) in DMF (8mL), and after cooling the system to -78°C, add NaHMDS (3.2 mL, 6.3mmol). The reaction solution was stirred at -78°C for 0.5 hours, then methyl iodide (1.2 g, 8.4 mmol) was added to the system, the reaction was gradually raised to room temperature, quenched by adding water (5 mL), and the residue was purified by C18 reverse column to obtain compound 77 -1 (460 mg, 54% yield). ESI-MS: m/z = 202.9 [M+H] + .
步骤2、将化合物77-1(450mg,2.22mmol)，双(频哪醇合)二硼(618.5mg,3.32mmol)溶于THF(5mL)中，体系降温至-78℃后，向上述溶液中加入正丁基锂溶液(1.33mL,3.32mmol)，体系保持-78℃并搅拌1小时后，逐渐升至室温，过夜，加入少量乙醇淬灭，直接旋干得到化合物77-2。Step 2. Dissolve compound 77-1 (450mg, 2.22mmol), bis(pinacolate) diboron (618.5mg, 3.32mmol) in THF (5mL), cool the system to -78°C, and add to the above solution Added n-butyllithium solution (1.33mL, 3.32mmol) into the mixture, kept the system at -78°C and stirred for 1 hour, then gradually raised to room temperature, overnight, quenched by adding a small amount of ethanol, and directly spin-dried to obtain compound 77-2.
步骤3、化合物77-2和2-氯-6-羟基喹啉为原料，参考实施例1步骤2的制备方法，得到化合物77-3。ESI-MS:m/z＝268.0[M+H] +。 Step 3: Compound 77-2 and 2-chloro-6-hydroxyquinoline were used as raw materials, referring to the preparation method in Step 2 of Example 1, to obtain Compound 77-3. ESI-MS: m/z = 268.0 [M+H] + .
步骤4、将化合物77-3(330mg,1.23mmol)，2-溴-4-氟吡啶(326mg,1.85mmol)，碳酸钾(341mg,2.47mmol)加入DMF(5mL)中，反应液在80℃下搅拌16小时。过滤，残余物通过C18反向柱纯化得到化合物77-4(200mg，产率38.4％)。ESI-MS:m/z＝422.9[M+H] +。 Step 4. Compound 77-3 (330mg, 1.23mmol), 2-bromo-4-fluoropyridine (326mg, 1.85mmol), potassium carbonate (341mg, 2.47mmol) were added to DMF (5mL), and the reaction solution was heated at 80°C Stirring was continued for 16 hours. After filtration, the residue was purified by C18 reverse column to obtain compound 77-4 (200 mg, yield 38.4%). ESI-MS: m/z = 422.9 [M+H] + .
步骤5、将化合物77-4(200mg,0.47mmol)，乙酰胺(165mg,2.8mmol)，Pd 2dba 3(43mg,0.05mmol)，X-phos(45mg,0.09mmol)，碳酸铯(913mg，2.8mmol)溶于1,4-二氧六环(5mL)中，置换氮气后，反应液在80℃下搅拌16小时。经过制备HPLC(NH4HCO3)得到产物化合物L77(18mg，产率21％)。ESI-MS:m/z＝402.2[M+H] +.H NMR(DMSO-d 6,400MHz):δ10.59(s,1H),8.74(s,1H),8.40(q,J＝9.2Hz,2H),8.24(d,J＝6.0Hz,1H),8.14(d,J＝9.2Hz,1H),7.77-7.74(m,2H),7.61(dd,J＝2.4Hz,6.4Hz,1H),6.78(dd,J＝2.4Hz,3.2Hz,1H),3.59(s,3H),2.62(s,3H),2.03(s,3H)。 Step 5. Compound 77-4 (200mg, 0.47mmol), acetamide (165mg, 2.8mmol), Pd 2 dba 3 (43mg, 0.05mmol), X-phos (45mg, 0.09mmol), cesium carbonate (913mg, 2.8 mmol) was dissolved in 1,4-dioxane (5 mL), and after replacing nitrogen, the reaction solution was stirred at 80°C for 16 hours. The product compound L77 (18 mg, yield 21%) was obtained by preparative HPLC (NH4HCO3). ESI-MS: m/z=402.2[M+H] + .H NMR(DMSO-d 6 ,400MHz):δ10.59(s,1H),8.74(s,1H),8.40(q,J=9.2 Hz, 2H), 8.24(d, J=6.0Hz, 1H), 8.14(d, J=9.2Hz, 1H), 7.77-7.74(m, 2H), 7.61(dd, J=2.4Hz, 6.4Hz, 1H), 6.78(dd, J=2.4Hz, 3.2Hz, 1H), 3.59(s, 3H), 2.62(s, 3H), 2.03(s, 3H).
实施例79：化合物L79的制备Example 79: Preparation of compound L79
Figure PCTCN2022143403-appb-000109
Figure PCTCN2022143403-appb-000109
步骤1、将3-溴吡啶-2-醇(5.0g,28.5mmol)溶于二氧六环(50mL)中，向上述溶液中加入碘甲烷(40.8g,142.5mmol)，叔丁醇钾(6.45g,57.5mmol)。反应液在70℃下搅拌16小时。反应液浓缩除 去二氧六环，残余物中加水(30mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过硅胶柱层析纯化得到化合物79-1(5.0g，产率92.5％)。ESI-MS:m/z＝187.9[M+H] +。 Step 1, 3-bromopyridin-2-ol (5.0g, 28.5mmol) was dissolved in dioxane (50mL), and methyl iodide (40.8g, 142.5mmol) was added to the above solution, potassium tert-butoxide ( 6.45 g, 57.5 mmol). The reaction solution was stirred at 70°C for 16 hours. The reaction solution was concentrated to remove dioxane, water (30 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel column chromatography to obtain compound 79-1 (5.0 g, yield 92.5%). ESI-MS: m/z = 187.9 [M+H] + .
步骤2、在干冰乙醇浴下，将化合物79-1(1.0g,5.3mmol)，硼酸三异丙酯(2g,10.6mmol)溶于四氢呋喃(20mL)中，向上述溶液中加入2.5M的正丁基锂(4.2ml,10.6mmol)。反应液在氮气保护下-78℃搅拌3小时,室温搅拌一小时。反应液用1N HCl调pH值到6，用乙酸乙酯萃取三次。有机相用饱和食盐水洗涤，然后用无水硫酸钠干燥，过滤，后蒸除溶剂，残余物通过反相柱层析纯化得到化合物79-2(450mg，产率54.3％)。ESI-MS:m/z＝154.0[M+H].Step 2. Dissolve compound 79-1 (1.0g, 5.3mmol), triisopropyl borate (2g, 10.6mmol) in tetrahydrofuran (20mL) under a dry ice ethanol bath, and add 2.5M n- Butyllithium (4.2ml, 10.6mmol). The reaction solution was stirred at -78°C for 3 hours under the protection of nitrogen, and stirred at room temperature for one hour. The reaction solution was adjusted to pH 6 with 1N HCl, and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated, and the residue was purified by reverse phase column chromatography to obtain compound 79-2 (450 mg, yield 54.3%). ESI-MS: m/z=154.0[M+H].
步骤3、化合物79-2和2-氯-6-羟基-喹啉为原料，参考实施例1步骤2的制备方法，得到化合物79-3。ESI-MS:m/z＝253.0[M+H] +。 Step 3: Compound 79-2 and 2-chloro-6-hydroxy-quinoline were used as raw materials, referring to the preparation method in Step 2 of Example 1, to obtain Compound 79-3. ESI-MS: m/z = 253.0 [M+H] + .
步骤4、将化合物79-3(200mg,0.79mmol)，溶于DMF(5mL)中，向上述溶液中加入2-溴-4-氟吡啶(417mg,2.37mmol)，碳酸钾(327mg,2.37mmol)。反应液在90℃下搅拌16小时。反应液加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过Pre-TLC纯化得到化合物79-4(200mg，产率62.02％)。ESI-MS:m/z＝407.9[M+H] +。 Step 4. Dissolve compound 79-3 (200mg, 0.79mmol) in DMF (5mL), add 2-bromo-4-fluoropyridine (417mg, 2.37mmol), potassium carbonate (327mg, 2.37mmol) to the above solution ). The reaction solution was stirred at 90°C for 16 hours. Water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by Pre-TLC to obtain compound 79-4 (200 mg, yield 62.02%). ESI-MS: m/z = 407.9 [M+H] + .
步骤5、将化合物79-4(200mg,0.49mmol)，溶于二氧六环(5mL)中，向上述溶液中加入乙酰胺(115mg,1.96mmol)，碳酸铯(640mg,1.96mmol)，Pd 2(dba) 3(45mg,0.049mmol),X-PHOS(47mg,0.098mmol)。氮气置换后反应液在80℃下搅拌4小时。反应液浓缩除去二氧六环，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物经过制备HPLC(NH 4HCO 3)得到产物L79(24mg，产率12.68％).ESI-MS:m/z＝387.2[M+H].H NMR(DMSO-d6,400MHz):δ10.56(s,1H),8.58(d,J＝8.8Hz,1H),8.43(dd,J＝2.0Hz,J＝6.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.23(d,J＝5.6Hz,1H),8.11(d,J＝9.2Hz,1H),7.74(s,2H),7.59(dd,J＝2.4Hz,J＝8.8Hz,1H),6.77(dd,J＝2.4Hz,J＝6.0Hz,1H),6.48(t,J＝6.8Hz,1H),3.59(s,3H),2.03(s,3H)。 Step 5. Compound 79-4 (200mg, 0.49mmol) was dissolved in dioxane (5mL), and acetamide (115mg, 1.96mmol), cesium carbonate (640mg, 1.96mmol), Pd 2 (dba) 3 (45 mg, 0.049 mmol), X-PHOS (47 mg, 0.098 mmol). After nitrogen replacement, the reaction solution was stirred at 80°C for 4 hours. The reaction solution was concentrated to remove dioxane, water (20 mL) was added to the residue, and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain the product L79 (24 mg, yield 12.68%).ESI-MS: m/z =387.2[M+H].H NMR(DMSO-d6,400MHz):δ10.56(s,1H),8.58(d,J=8.8Hz,1H),8.43(dd,J=2.0Hz,J= 6.8Hz, 1H), 8.34(d, J=8.8Hz, 1H), 8.23(d, J=5.6Hz, 1H), 8.11(d, J=9.2Hz, 1H), 7.74(s, 2H), 7.59 (dd, J=2.4Hz, J=8.8Hz, 1H), 6.77(dd, J=2.4Hz, J=6.0Hz, 1H), 6.48(t, J=6.8Hz, 1H), 3.59(s, 3H ), 2.03(s,3H).
实施例80：化合物L80的制备Example 80: Preparation of Compound L80
Figure PCTCN2022143403-appb-000110
Figure PCTCN2022143403-appb-000110
步骤1、将化合物63-1(140mg,0.435mmol)和碳酸钾(180mg,1.3mmol)溶于DMF(4mL)中，向上述溶液中加入2-溴-4-氟吡啶(153mg,0.87mmol)。反应液在90℃下搅拌16小时，反应液冷却室温后，通过C18反向柱纯化(乙腈：水＝55:45到70:30梯度洗脱)得到化合物80-1(100mg，产率48％)。ESI-MS:m/z＝477.2[M+H] +。 Step 1. Compound 63-1 (140mg, 0.435mmol) and potassium carbonate (180mg, 1.3mmol) were dissolved in DMF (4mL), and 2-bromo-4-fluoropyridine (153mg, 0.87mmol) was added to the above solution . The reaction solution was stirred at 90°C for 16 hours. After the reaction solution was cooled to room temperature, it was purified by C18 reverse column (acetonitrile:water=55:45 to 70:30 gradient elution) to obtain compound 80-1 (100mg, yield 48% ). ESI-MS: m/z = 477.2 [M+H] + .
步骤2、化合物80-1和化合物v1-1为原料，参考实施例1步骤2的制备方法，得到产物L80。ESI-MS：m/z＝480.3[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ8.76(s,1H),8.47(d,J＝8.8Hz,1H),8.42(d,J＝5.6Hz,1H),8.29(d,J＝8.4Hz,1H),8.26(s,1H),8.05(d,J＝9.2Hz,1H),7.98(s,1H),7.69(d,J＝2.8Hz,1H),7.57(d,J＝8.0Hz,1H),7.32(d,J＝2.4Hz,1H),6.78(d,J＝5.6,1H),3.85(s,3H),3.60-3.62(m,4H),3.49(s,3H),1.91-1.88(m,4H)。 Step 2, using compound 80-1 and compound v1-1 as raw materials, referring to the preparation method in step 2 of Example 1, the product L80 was obtained. ESI-MS: m/z = 480.3 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.76(s, 1H), 8.47(d, J=8.8Hz, 1H), 8.42(d, J=5.6Hz, 1H), 8.29(d, J =8.4Hz,1H),8.26(s,1H),8.05(d,J=9.2Hz,1H),7.98(s,1H),7.69(d,J=2.8Hz,1H),7.57(d,J =8.0Hz,1H),7.32(d,J=2.4Hz,1H),6.78(d,J=5.6,1H),3.85(s,3H),3.60-3.62(m,4H),3.49(s, 3H), 1.91-1.88 (m, 4H).
实施例86：化合物L86的制备Example 86: Preparation of Compound L86
Figure PCTCN2022143403-appb-000111
Figure PCTCN2022143403-appb-000111
步骤1、将5-溴-2-氯-3-甲基嘧啶-4(3H)-酮(5g,0.02mol)，乙胺盐酸盐(2.5g，0.03mol)和DIEA(10.4g,0.08mmol)溶于THF(35mL)中，氮气置换后反应液在65℃下搅拌过夜。反应液冷却至室温后用乙酸乙酯/水(30mL x 3)萃取。合并有机相，用饱和盐水(5mL)洗涤，硫酸钠干燥后浓缩，得到产物5-溴-2-(乙氨基)-3-甲基嘧啶-4(3H)-酮(4.1g,黄色固体，产率88.7％)。ESI-MS：m/z＝233.9[M+H] +。 Step 1, 5-bromo-2-chloro-3-methylpyrimidin-4 (3H)-one (5g, 0.02mol), ethylamine hydrochloride (2.5g, 0.03mol) and DIEA (10.4g, 0.08 mmol) was dissolved in THF (35 mL), and the reaction solution was stirred overnight at 65° C. after nitrogen replacement. The reaction solution was cooled to room temperature and extracted with ethyl acetate/water (30 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over sodium sulfate and concentrated to give the product 5-bromo-2-(ethylamino)-3-methylpyrimidin-4(3H)-one (4.1 g, yellow solid, Yield 88.7%). ESI-MS: m/z = 233.9 [M+H] + .
步骤2、将合成5-溴-2-(乙氨基)-3-甲基嘧啶-4(3H)-酮(3.7g,16mmol)，(Boc) 2O(10.5g，48mmol)，TEA(4.8g,48mmol)和DMAP(390mg,3.2mmol)溶于THF(200mL)中。氮气置换后反应液在65℃油浴中搅拌过夜。反应液冷却至室温，反应液加水(5mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，得到粗产物。粗产物通过硅胶柱层析纯化(PE:EA＝5:1洗脱)得到产物叔丁基(5-溴-1-甲基-6-氧基-1,6-二氢嘧啶-2-基)(乙基)氨基甲酸酯(5.0g，黄色固体，产率94.4％)。ESI-MS：m/z＝353.9[M+23] +。 Step 2, will synthesize 5-bromo-2-(ethylamino)-3-methylpyrimidin-4(3H)-one (3.7g, 16mmol), (Boc) 2 O (10.5g, 48mmol), TEA (4.8 g, 48 mmol) and DMAP (390 mg, 3.2 mmol) were dissolved in THF (200 mL). After nitrogen replacement, the reaction solution was stirred overnight in an oil bath at 65°C. The reaction solution was cooled to room temperature, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was evaporated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA=5:1 elution) to obtain the product tert-butyl (5-bromo-1-methyl-6-oxyl-1,6-dihydropyrimidin-2-yl ) (ethyl) carbamate (5.0 g, yellow solid, 94.4% yield). ESI-MS: m/z = 353.9 [M+23] + .
步骤3、将叔丁基(5-溴-1-甲基-6-氧基-1,6-二氢嘧啶-2-基)(乙基)氨基甲酸酯(4.7g,14.2mmol)，异丙醇频哪醇硼酸酯(5.26g，28.3mmol)溶于THF(80mL)中，在-78℃下缓慢加入正丁基锂(2.5M,11.3mL)。反应液-78℃下反应2h后升至室温。LCMS监测反应结束后浓缩，得到粗产物叔丁基乙基(1-甲基-6-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-1,6-二氢嘧啶-2-基)氨基甲酸酯。ESI-MS：m/z＝282.0[M+H] +。 Step 3, tert-butyl (5-bromo-1-methyl-6-oxyl-1,6-dihydropyrimidin-2-yl) (ethyl) carbamate (4.7g, 14.2mmol), Isopropanol pinacol borate (5.26g, 28.3mmol) was dissolved in THF (80mL), and n-butyllithium (2.5M, 11.3mL) was added slowly at -78°C. The reaction solution was reacted at -78°C for 2 h and then warmed to room temperature. LCMS monitors and concentrates after the completion of the reaction to obtain the crude product tert-butylethyl (1-methyl-6-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxobenzene formaldehyde-2-yl)-1,6-dihydropyrimidin-2-yl)carbamate. ESI-MS: m/z = 282.0 [M+H] + .
步骤4、将2-氯-6-羟基-喹啉(2g,11.1mmol)和叔丁基乙基(1-甲基-6-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-1,6-二氢嘧啶-2-基)氨基甲酸酯(9.4g,16.7mmol)，溶于1，4-二氧六环(120mL)中，向溶液中加入碳酸钾(4.6g,33.3mmol)，水(12mL)和Pd(dppf)Cl2(811mg,1.0mol)。氮气置换后反应液在75℃油浴中搅拌3小时。反应液冷却至室温，浓缩除去1，4-二氧六环，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1到5:1梯度洗脱)得到产物叔丁基乙基(5-(6-羟基喹啉-2-基)-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)氨基甲酸酯(3.8g,黄色固体，产率86.36％)。ESI-MS：m/z＝397.0[M+H] +。 Step 4, 2-chloro-6-hydroxy-quinoline (2g, 11.1mmol) and tert-butylethyl (1-methyl-6-oxo-5-(4,4,5,5-tetramethyl 1,3,2-Dioxybenzaldehyde-2-yl)-1,6-dihydropyrimidin-2-yl)carbamate (9.4g, 16.7mmol), dissolved in 1,4-diox Hexacyclic (120 mL), potassium carbonate (4.6 g, 33.3 mmol), water (12 mL) and Pd(dppf)Cl2 (811 mg, 1.0 mol) were added to the solution. After nitrogen replacement, the reaction solution was stirred in an oil bath at 75° C. for 3 hours. The reaction solution was cooled to room temperature, concentrated to remove 1,4-dioxane, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 5:1 gradient elution) to obtain the product tert-butyl ethyl Dihydropyrimidin-2-yl (5-(6-hydroxyquinolin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)carbamate (3.8g, yellow solid, yield rate of 86.36%). ESI-MS: m/z = 397.0 [M+H] + .
步骤5、将N-(3-氟-4-碘吡啶-2-基)乙酰胺(500mg,1.78mmol)溶于乙酸(10mL)中，向上述溶液中加入盐酸溶液(1mL)。反应液在60℃搅拌16小时。反应液浓缩除去乙酸，残余物中加三乙胺(1mL)，浓缩，加入DMF(10mL)，过滤，滤液通过C18反向柱纯化(乙腈：水＝15:85到30:70梯度洗脱)得到3-氟-4-碘吡啶-2-胺(320mg，白色固体，产率75.3％)。ESI-MS:m/z＝238.9[M+H] +。 Step 5. Dissolve N-(3-fluoro-4-iodopyridin-2-yl)acetamide (500 mg, 1.78 mmol) in acetic acid (10 mL), and add hydrochloric acid solution (1 mL) to the above solution. The reaction solution was stirred at 60°C for 16 hours. The reaction solution was concentrated to remove acetic acid, triethylamine (1 mL) was added to the residue, concentrated, DMF (10 mL) was added, filtered, and the filtrate was purified by a C18 reverse column (acetonitrile: water = 15:85 to 30:70 gradient elution) 3-Fluoro-4-iodopyridin-2-amine (320 mg, white solid, 75.3% yield) was obtained. ESI-MS: m/z = 238.9 [M+H] + .
步骤6、将3-氟-4-碘吡啶-2-胺(410mg,1.72mmol)，叔丁基乙基(5-(6-羟基喹啉-2-基)-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)氨基甲酸酯(450mg,1.14mmol)和碳酸钾(1.11g，3.41mmol)溶于NMP(10mL)中，置换氮气后，向上述溶液中加入碘化亚铜(215mg，1.14mmol)和TMHD(418mg，2.27mmol)。再次置换氮气，反应液在100℃下搅拌18小时。反应液冷却室温后浓缩，向反应液加水(80mL)，用乙酸乙酯萃取(50mL x 3)。有机相合并后用饱和盐水(80mL x 2)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过C18反向柱纯化(乙腈：水＝45:55到55:45梯度洗脱)得到粗产物86-1(40mg,黄色固体)。ESI-MS:m/z＝507.0[M+H] +。 Step 6. Mix 3-fluoro-4-iodopyridin-2-amine (410mg, 1.72mmol), tert-butylethyl (5-(6-hydroxyquinolin-2-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-2-yl) carbamate (450mg, 1.14mmol) and potassium carbonate (1.11g, 3.41mmol) were dissolved in NMP (10mL), and after nitrogen replacement, the above solution was Added cuprous iodide (215 mg, 1.14 mmol) and TMHD (418 mg, 2.27 mmol). Nitrogen was replaced again, and the reaction solution was stirred at 100° C. for 18 hours. The reaction solution was concentrated after cooling to room temperature, water (80 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (80mL x 2), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by a C18 reverse column (acetonitrile:water=45:55 to 55:45 gradient elution) to obtain the crude product 86 -1 (40 mg, yellow solid). ESI-MS: m/z = 507.0 [M+H] + .
步骤7、将化合物86-1(40.0g,0.079mmol)溶于二氯甲烷(2mL)中，向上述溶液中加入三氟乙酸(0.5mL)，反应液在室温下搅拌1小时。浓缩除去二氯甲烷，残余物加三乙胺(0.3mL)，浓缩，加入DMF(1mL)，过虑后收集滤液，通过制备HPLC(NH 4HCO 3)得到产物L86(10.5mg，黄色固体，产率32.8％)。ESI-MS：m/z＝407.2[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ8.76(s,1H),8.43(d,J＝8.8Hz,1H),8.24(d,J＝8.4Hz,1H),8.00(d,J＝8.4Hz,1H),7.68(d,J＝5.2Hz,1H),7.59-7.54(m,3H),6.33(s,2H),6.23-6.21(m,1H),3.05-3.47(m,2H),3.39(s,3H),1.20(t,J＝7.2Hz,3H). Step 7. Compound 86-1 (40.0 g, 0.079 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added to the above solution, and the reaction solution was stirred at room temperature for 1 hour. Concentrate to remove dichloromethane, add triethylamine (0.3 mL) to the residue, concentrate, add DMF ( 1 mL ), collect the filtrate after filtration, and obtain the product L86 (10.5 mg, yellow solid, yield rate of 32.8%). ESI-MS: m/z = 407.2 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.76(s, 1H), 8.43(d, J=8.8Hz, 1H), 8.24(d, J=8.4Hz, 1H), 8.00(d, J =8.4Hz,1H),7.68(d,J=5.2Hz,1H),7.59-7.54(m,3H),6.33(s,2H),6.23-6.21(m,1H),3.05-3.47(m, 2H), 3.39(s, 3H), 1.20(t, J=7.2Hz, 3H).
实施例87：化合物L87的制备Example 87: Preparation of Compound L87
Figure PCTCN2022143403-appb-000112
Figure PCTCN2022143403-appb-000112
步骤1、将5-(6-((2-溴吡啶-4-基)氧基)喹啉-2-基)-N-异丙基-4-甲氧基嘧啶-2-胺(125mg,0.269mmol),氨基甲酸甲酯(40mg,0.537mmol)和碳酸铯(263mg,0.807mmol)溶于1,4-二氧六环(4mL)中，再加入X-phos(13mg,0.027mmol)和Pd 2(dba) 3(25mg,0.027mmol)。氮气置换后反应液在90℃下搅拌16小时。反应液浓缩后，残余物通过硅胶柱层析纯化(二氯甲烷：甲醇＝20:1到12:1梯度洗脱)得到产物87-1(110g，黄色固体，产率88％)。ESI-MS:m/z＝461.0[M+H] +。 Step 1, 5-(6-((2-bromopyridin-4-yl)oxy)quinolin-2-yl)-N-isopropyl-4-methoxypyrimidin-2-amine (125mg, 0.269mmol), methyl carbamate (40mg, 0.537mmol) and cesium carbonate (263mg, 0.807mmol) were dissolved in 1,4-dioxane (4mL), then X-phos (13mg, 0.027mmol) and Pd 2 (dba) 3 (25 mg, 0.027 mmol). After nitrogen replacement, the reaction solution was stirred at 90°C for 16 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 12:1 gradient elution) to obtain product 87-1 (110 g, yellow solid, yield 88%). ESI-MS: m/z = 461.0 [M+H] + .
步骤2、将87-1(80mg,0.174mmol)溶于乙酸(2mL)中，向上述溶液中加入氢溴酸(281mg,1.39mmol,40％)。反应液在60℃下搅拌16小时。反应液冷却室温后浓缩，向残余物加入三乙胺(0.5mL)，再加入DMF(2.5mL),过滤，滤液经制备HPLC(FA)得到产物L87(25.2mg,黄色固体，产率32.5％)。ESI-MS:m/z＝447.3[M+H] +.HNMR(DMSO-d 6,400MHz):δ10.88(s,1H),10.27(s,1H),8.81(s,1H),8.46(d,J＝8.4Hz,1H),8.26(d,J＝8.0Hz,1H),8.18(d,J＝5.6Hz,1H),8.04(d,J＝9.2Hz,1H),7.70(s,1H),7.55(d,J＝9.2Hz,1H),7.45(d,J＝2.4Hz,1H),6.75-6.73(m,2H),4.15-4.10(m,1H),3.59(s,3H),1.23(s,3H),1.19(s,3H)。 Step 2. Dissolve 87-1 (80 mg, 0.174 mmol) in acetic acid (2 mL), and add hydrobromic acid (281 mg, 1.39 mmol, 40%) to the above solution. The reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated. Triethylamine (0.5 mL) was added to the residue, followed by DMF (2.5 mL), filtered, and the filtrate was subjected to preparative HPLC (FA) to obtain the product L87 (25.2 mg, yellow solid, yield 32.5% ). ESI-MS: m/z＝447.3[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ10.88(s,1H),10.27(s,1H),8.81(s,1H),8.46 (d, J=8.4Hz, 1H), 8.26(d, J=8.0Hz, 1H), 8.18(d, J=5.6Hz, 1H), 8.04(d, J=9.2Hz, 1H), 7.70(s ,1H),7.55(d,J=9.2Hz,1H),7.45(d,J=2.4Hz,1H),6.75-6.73(m,2H),4.15-4.10(m,1H),3.59(s, 3H), 1.23(s,3H), 1.19(s,3H).
实施例89：化合物L89的制备Example 89: Preparation of Compound L89
Figure PCTCN2022143403-appb-000113
Figure PCTCN2022143403-appb-000113
步骤1、将叔丁基乙基(5-(6-羟基喹啉-2-基)-1-甲基-6-氧基-1,6-二氢嘧啶-2-基)氨基甲酸酯(800mg,2.02mmol)和碳酸铯(1.98g,6.06mmol)加入DMF(16mL)中，向上述溶液中加入2,3,4-三氯吡啶(400mg,2.21mmol)。反应液在100℃搅拌16小时。反应液过滤，滤液经C18反向柱纯化(乙腈：水＝50:50到100:0梯度洗脱)得到产物89-1(600mg，黄色固体，产率55％)。ESI-MS:m/z＝541.9[M+H] +。 Step 1, tert-butyl ethyl (5-(6-hydroxyquinolin-2-yl)-1-methyl-6-oxyl-1,6-dihydropyrimidin-2-yl)carbamate (800mg, 2.02mmol) and cesium carbonate (1.98g, 6.06mmol) were added to DMF (16mL), and 2,3,4-trichloropyridine (400mg, 2.21mmol) was added to the above solution. The reaction solution was stirred at 100°C for 16 hours. The reaction solution was filtered, and the filtrate was purified by C18 reverse column (acetonitrile:water=50:50 to 100:0 gradient elution) to obtain product 89-1 (600 mg, yellow solid, yield 55%). ESI-MS: m/z = 541.9 [M+H] + .
步骤2、将89-1(600mg,1.11mmol)，氨基甲酸叔丁酯(1.3g,11.1mmol)和碳酸铯(1.09mg,3.33mmol)溶于1，4-二氧六环(15mL)中，氮气保护下，向上述溶液中加入X-phos(53mg,0.11mmol)和Pd 2(dba) 3(102mg,0.11mmol)。反应液在90℃下搅拌16小时。反应液冷却室温后浓缩，残余物通过硅胶柱层析纯化(二氯甲烷：甲醇＝20:1到12:1梯度洗脱)得到产物89-2(390mg,黄色固体，产率67.5％)。ESI-MS:m/z＝522.9[M+H] +。 Step 2. Dissolve 89-1 (600mg, 1.11mmol), tert-butyl carbamate (1.3g, 11.1mmol) and cesium carbonate (1.09mg, 3.33mmol) in 1,4-dioxane (15mL) , under nitrogen protection, X-phos (53mg, 0.11mmol) and Pd 2 (dba) 3 (102mg, 0.11mmol) were added to the above solution. The reaction solution was stirred at 90°C for 16 hours. The reaction solution was concentrated after cooling to room temperature, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 12:1 gradient elution) to obtain product 89-2 (390 mg, yellow solid, yield 67.5%). ESI-MS: m/z = 522.9 [M+H] + .
步骤3、将89-2(350mg,0.67mmol)溶于二氯甲烷(10mL)中，再加入三氟乙酸(3mL)。反应液在室温下搅拌1.5小时。反应液加水(60mL)，用乙酸乙酯(200mL)洗涤水相。随后水相用碳酸氢钠饱和水溶液调节pH值到8，乙酸乙酯(200mL x 2)萃取，有机相合并，用饱和盐水(300mL)洗涤，硫酸钠干燥后浓缩，得到粗产物，再用甲醇重结晶得到产物L89(38.3mg,黄色固体，产率13.5％)。ESI-MS:m/z＝423.2[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.87(s,1H),8.49(d,J＝8.8Hz,1H),8.41(d,J＝8.8Hz,1H),8.15(d,J＝8.8Hz,1H),8.05(s,1H),7.87(d,J＝8.8Hz,1H),7.87(dd,J＝9.2Hz,1H),6.99(s,2H),6.23(d,J＝6.0Hz,1H),3.62-3.55(m,2H),3.43(s,3H),1.23-1.20(m,3H)。 Step 3. Dissolve 89-2 (350mg, 0.67mmol) in dichloromethane (10mL), and add trifluoroacetic acid (3mL). The reaction was stirred at room temperature for 1.5 hours. Water (60 mL) was added to the reaction solution, and the aqueous phase was washed with ethyl acetate (200 mL). Then the aqueous phase was adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate (200mL x 2), the organic phases were combined, washed with saturated brine (300mL), dried over sodium sulfate and concentrated to obtain a crude product, which was then washed with methanol Recrystallization gave the product L89 (38.3 mg, yellow solid, yield 13.5%). ESI-MS: m/z＝423.2[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.87(s, 1H), 8.49 (d, J＝8.8Hz, 1H), 8.41 (d,J=8.8Hz,1H),8.15(d,J=8.8Hz,1H),8.05(s,1H),7.87(d,J=8.8Hz,1H),7.87(dd,J=9.2Hz , 1H), 6.99(s, 2H), 6.23(d, J=6.0Hz, 1H), 3.62-3.55(m, 2H), 3.43(s, 3H), 1.23-1.20(m, 3H).
参照上述实施例方法合成以下实施例中的化合物：Synthesize the compound in the following examples with reference to the above-mentioned example method:
Figure PCTCN2022143403-appb-000114
Figure PCTCN2022143403-appb-000114
Figure PCTCN2022143403-appb-000115
Figure PCTCN2022143403-appb-000115
Figure PCTCN2022143403-appb-000116
Figure PCTCN2022143403-appb-000116
Figure PCTCN2022143403-appb-000117
Figure PCTCN2022143403-appb-000117
实施例83：化合物L83的制备Example 83: Preparation of Compound L83
Figure PCTCN2022143403-appb-000118
Figure PCTCN2022143403-appb-000118
步骤1、将叔丁基(5-(6-((2-溴吡啶-4-基)氧基)喹啉-2-基)-1-甲基-6-氧基-1,6-二氢嘧啶-2-基)(乙基)氨基甲酸酯(参照化合物86-1的方法制备，210mg,0.38mmol)，x-phos(72mg，0.152mmol)，氨基甲酸甲酯(85.5mg，1.14mmol)，碳酸铯(370mg,1.14mmol)和Pd 2(dba) 3(70mg，0.076mmol)溶于1,4-二氧六环(15mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后用乙酸乙酯(30mL x 3)萃取。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过硅胶柱层析纯化(PE:EA＝8:1到EA:MeOH＝10:1梯度洗脱)得到产物叔丁基乙基(5-(6-((甲氧羰基)氨基)吡啶-4-基)氧基喹啉-2-基)-1-甲基-6-氧基-1,6-二氢嘧啶-2-基)氨基甲酸酯(200mg,黄色固体，产率96.0％)。ESI-MS：m/z＝547.1[M+H] +。 Step 1, tert-butyl (5-(6-((2-bromopyridin-4-yl)oxy)quinolin-2-yl)-1-methyl-6-oxyl-1,6-di Hydropyrimidin-2-yl) (ethyl) carbamate (prepared according to the method of compound 86-1, 210mg, 0.38mmol), x-phos (72mg, 0.152mmol), methyl carbamate (85.5mg, 1.14 mmol), cesium carbonate (370mg, 1.14mmol) and Pd 2 (dba) 3 (70mg, 0.076mmol) were dissolved in 1,4-dioxane (15mL), and the reaction solution was stirred at 85°C for 3 Hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (PE:EA=8:1 to EA:MeOH=10:1 gradient elution) to obtain the product tert-Butylethyl(5-(6-((methoxycarbonyl)amino)pyridin-4-yl)oxyquinolin-2-yl)-1-methyl-6-oxyl-1,6-di Hydropyrimidin-2-yl)carbamate (200mg, yellow solid, yield 96.0%). ESI-MS: m/z = 547.1 [M+H] + .
步骤2、将叔丁基(5-(6-((2-乙酰氨基吡啶-4-基)氧基)喹啉-2-基)-1-甲基-6-氧基-1,6-二氢嘧啶-2-基)(乙基)氨基甲酸酯(200mg,0.36mmol)溶于二氯甲烷(10mL)中，向溶液中加入三氟乙酸(2.5mL)。氮气置换后反应液在85℃下搅拌3小时。反应结束后用饱和NaHCO 3溶液调至中性，并过滤。固体用甲醇/二氯甲烷打浆，得到化合物L83(28mg,产率17％)。ESI-MS：m/z＝447.2[M+H] +。 1H NMR(DMSO-d 6,400MHz)δ10.26(br,1H),8.79(s,1H),8.46(d,J＝8.8Hz,1H),8.27(d,J＝8.7Hz,1H),8.18(d,J＝5.7Hz,1H),8.04(d,J＝9.1Hz,1H),7.70(d,J＝2.7Hz,1H),7.54(dd,J＝9.1,2.7Hz,1H),7.45(d,J＝2.3Hz,1H),6.73(dd,J＝5.7,2.3Hz,1H),3.59(s,3H),3.49(q,J＝7.1Hz,2H),3.40(s,3H),1.21(t,J＝7.1Hz,3H). Step 2, tert-butyl (5-(6-((2-acetylaminopyridin-4-yl)oxy)quinolin-2-yl)-1-methyl-6-oxyl-1,6- Dihydropyrimidin-2-yl)(ethyl)carbamate (200 mg, 0.36 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2.5 mL) was added to the solution. After nitrogen replacement, the reaction solution was stirred at 85°C for 3 hours. After the reaction, adjust to neutral with saturated NaHCO 3 solution, and filter. The solid was slurried with methanol/dichloromethane to afford compound L83 (28 mg, 17% yield). ESI-MS: m/z = 447.2 [M+H] + . 1 H NMR (DMSO-d 6, 400MHz) δ10.26(br, 1H), 8.79(s, 1H), 8.46(d, J=8.8Hz, 1H), 8.27(d, J=8.7Hz, 1H) ,8.18(d,J=5.7Hz,1H),8.04(d,J=9.1Hz,1H),7.70(d,J=2.7Hz,1H),7.54(dd,J=9.1,2.7Hz,1H) ,7.45(d,J=2.3Hz,1H),6.73(dd,J=5.7,2.3Hz,1H),3.59(s,3H),3.49(q,J=7.1Hz,2H),3.40(s, 3H), 1.21(t, J=7.1Hz, 3H).
实施例92：化合物L92的制备Example 92: Preparation of Compound L92
Figure PCTCN2022143403-appb-000119
Figure PCTCN2022143403-appb-000119
步骤1、将5-(6-羟基-1,8-萘啶-2-基)-2-(异丙基氨基)-3-甲-4(3H)-嘧啶酮(400mg,1.28mmol)，2-溴-4-氟吡啶(340mg,1.93mmol)，碳酸钾(354mg,2.57mmol)加入DMF(5mL)中，反应液在80℃下搅拌16小时。过滤，残余物通过C18反向柱纯化(乙腈：水＝35:65到40:60梯度洗脱)得到产物5-(6-((2-溴吡啶-4-基)氧基)-1,8-萘啶-2-基)-2-(异丙基氨基)-3-甲基-4(3H)-嘧啶酮(200mg，褐色固体，产率33.4％)。ESI-MS:m/z＝467[M+H] +。 Step 1. 5-(6-hydroxy-1,8-naphthyridin-2-yl)-2-(isopropylamino)-3-methyl-4(3H)-pyrimidinone (400mg, 1.28mmol), 2-Bromo-4-fluoropyridine (340mg, 1.93mmol), potassium carbonate (354mg, 2.57mmol) were added to DMF (5mL), and the reaction solution was stirred at 80°C for 16 hours. Filtration, the residue was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain the product 5-(6-((2-bromopyridin-4-yl)oxy)-1, 8-Naphthyridin-2-yl)-2-(isopropylamino)-3-methyl-4(3H)-pyrimidinone (200 mg, brown solid, 33.4% yield). ESI-MS: m/z = 467 [M+H] + .
步骤2、将5-(6-((2-溴吡啶-4-基)氧基)-1,8-萘啶-2-基)-2-(异丙基氨基)-3-甲基-4(3H)-嘧啶酮(100mg, 0.2mmol)，氨基甲酸甲酯(96mg,1.28mmol)，Pd 2dba 3(18.3mg,0.02mmol)，X-phos(19.1mg,0.04mmol)，碳酸铯(174mg，0.54mmol)溶于1,4-二氧六环(2mL)中，置换氮气后，反应液在100℃下搅拌16小时。经过制备HPLC(NH 4HCO 3)得到化合物L92(10mg，产率10.1％)。ESI-MS:m/z＝462.2[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.36(s,1H),8.94(d,J＝3.2Hz,1H),8.87(s,1H),8.62(d,J＝8.8Hz,1H),8.36(d,J＝8.8Hz,1H),8.24-8.21(m,2H),7.49(d,J＝2.0Hz,1H),7.29(d,J＝8.0Hz,1H),6.81(dd,J＝5.6Hz,2.4Hz,1H),4.46-4.37(m,1H),3.73(s,3H),3.61(s,3H),1.26(d,J＝6.8Hz,6H). Step 2, 5-(6-((2-bromopyridin-4-yl)oxy)-1,8-naphthyridin-2-yl)-2-(isopropylamino)-3-methyl- 4(3H)-pyrimidinone (100mg, 0.2mmol), methyl carbamate (96mg, 1.28mmol), Pd 2 dba 3 (18.3mg, 0.02mmol), X-phos (19.1mg, 0.04mmol), cesium carbonate (174mg, 0.54mmol) was dissolved in 1,4-dioxane (2mL), and the reaction solution was stirred at 100°C for 16 hours after replacing nitrogen. Compound L92 (10 mg, yield 10.1%) was obtained by preparative HPLC (NH 4 HCO 3 ). ESI-MS: m/z＝462.2[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.36(s, 1H), 8.94 (d, J＝3.2Hz, 1H), 8.87 (s,1H),8.62(d,J=8.8Hz,1H),8.36(d,J=8.8Hz,1H),8.24-8.21(m,2H),7.49(d,J=2.0Hz,1H) ,7.29(d,J=8.0Hz,1H),6.81(dd,J=5.6Hz,2.4Hz,1H),4.46-4.37(m,1H),3.73(s,3H),3.61(s,3H) ,1.26(d,J=6.8Hz,6H).
实施例98：化合物L98的制备Embodiment 98: Preparation of Compound L98
Figure PCTCN2022143403-appb-000120
Figure PCTCN2022143403-appb-000120
步骤1、将19-6(425mg,1.37mmol)和碳酸铯(1.24g,4.11mmol)加入DMF(9mL)中，向上述溶液中加入2,3,4-三氯吡啶(250mg,1.37mmol)。反应液在90℃搅拌17小时。反应液过滤，滤液经C18反向柱纯化(乙腈：水＝25:75到75:25梯度洗脱)得到产物98-1(400mg，黄色固体，产率64.4％)。ESI-MS:m/z＝456.9[M+H] +。 Step 1. Add 19-6 (425mg, 1.37mmol) and cesium carbonate (1.24g, 4.11mmol) into DMF (9mL), and add 2,3,4-trichloropyridine (250mg, 1.37mmol) to the above solution . The reaction solution was stirred at 90°C for 17 hours. The reaction solution was filtered, and the filtrate was purified by C18 reverse column (acetonitrile:water=25:75 to 75:25 gradient elution) to obtain product 98-1 (400 mg, yellow solid, yield 64.4%). ESI-MS: m/z = 456.9 [M+H] + .
步骤2、将98-1(350mg,0.768mmol)，氨基甲酸叔丁酯(900mg,7.67mmol)和碳酸铯(750mg,2.3mmol)溶于1，4-二氧六环(9mL)中，氮气保护下，向上述溶液中加入X-phos(36.5mg,0.077mmol)和Pd 2(dba) 3(71mg,0.077mmol)。反应液在100℃下搅拌24小时。反应液冷却室温后浓缩，残余物通过硅胶柱层析纯化(二氯甲烷：甲醇＝20:1到12:1梯度洗脱)得到粗产物，粗产物通过C18反向柱纯化(NH 4HCO 3)得到产物L98(24.2mg,黄色固体，产率7.2％)。ESI-MS:m/z＝438.0[M+H] +.H NMR(DMSO-d 6,400MHz):δ8.93(d,J＝3.2Hz,1H),8.85(s,1H),8.59(d,J＝8.4Hz,1H),8.34(d,J＝8.8Hz,1H),8.08(d,J＝3.2Hz,1H),7.84(d,J＝5.6Hz,1H),7.26(d,J＝7.6Hz,1H),6.51(s,2H),6.23(d,J＝5.6Hz,1H),4.45-4.37(m,1H),3.41(s,3H),1.26(d,J＝6.8Hz,6H)。 Step 2, 98-1 (350mg, 0.768mmol), tert-butyl carbamate (900mg, 7.67mmol) and cesium carbonate (750mg, 2.3mmol) were dissolved in 1,4-dioxane (9mL), nitrogen Under protection, X-phos (36.5 mg, 0.077 mmol) and Pd 2 (dba) 3 (71 mg, 0.077 mmol) were added to the above solution. The reaction solution was stirred at 100°C for 24 hours. The reaction solution was concentrated after cooling to room temperature, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 12:1 gradient elution) to obtain a crude product, which was purified by a C18 reverse column (NH 4 HCO 3 ) afforded the product L98 (24.2 mg, yellow solid, 7.2% yield). ESI-MS: m/z=438.0[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ8.93(d, J=3.2Hz, 1H), 8.85(s, 1H), 8.59( d,J=8.4Hz,1H),8.34(d,J=8.8Hz,1H),8.08(d,J=3.2Hz,1H),7.84(d,J=5.6Hz,1H),7.26(d, J＝7.6Hz, 1H), 6.51(s, 2H), 6.23(d, J＝5.6Hz, 1H), 4.45-4.37(m, 1H), 3.41(s, 3H), 1.26(d, J＝6.8 Hz, 6H).
实施例99：化合物L99的制备Embodiment 99: Preparation of Compound L99
Figure PCTCN2022143403-appb-000121
Figure PCTCN2022143403-appb-000121
步骤1、将叔丁基乙基(5-(6-羟基喹啉-2-基)-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)氨基甲酸酯(400mg,1.0mmol)，2,4-二氯嘧啶(224mg,1.5mmol)，DIEA(387mg,3.0mmol)加入NMP(5mL)中，反应液在60℃下搅拌16小时。残余物通过C18反向柱纯化(乙腈：水＝35:65到40:60梯度洗脱)得到产物99-1(368mg，类白色固体，产率72.3％)。ESI-MS:m/z＝509.2[M+H] +。 Step 1, tert-butyl ethyl (5-(6-hydroxyquinolin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)carbamate (400mg, 1.0mmol), 2,4-dichloropyrimidine (224mg, 1.5mmol), DIEA (387mg, 3.0mmol) were added to NMP (5mL), and the reaction solution was stirred at 60°C for 16 hours. The residue was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain product 99-1 (368 mg, off-white solid, yield 72.3%). ESI-MS: m/z = 509.2 [M+H] + .
步骤2、将99-1(232mg,0.46mmol)，1-甲基-1H-吡唑-4-胺盐酸盐(73mg,0.55mmol)，Pd 2dba 3(41mg,0.05mmol)，X-phos(43mg,0.09mmol)，碳酸铯(525mg，1.6mmol)溶于1,4-二氧六环(5mL)中，置换氮气后，反应液在100℃下搅拌16小时。过滤得到产物99-2。ESI-MS:m/z＝570.0[M+H] +。 Step 2, 99-1 (232mg, 0.46mmol), 1-methyl-1H-pyrazol-4-amine hydrochloride (73mg, 0.55mmol), Pd 2 dba 3 (41mg, 0.05mmol), X- Phos (43mg, 0.09mmol) and cesium carbonate (525mg, 1.6mmol) were dissolved in 1,4-dioxane (5mL). After replacing nitrogen, the reaction solution was stirred at 100°C for 16 hours. Filtration afforded product 99-2. ESI-MS: m/z = 570.0 [M+H] + .
步骤3、将99-2溶于1,4-二氧六环盐酸溶液(5mL)中，置换氮气后，反应液在20℃下搅拌2小时。经过制备HPLC(FA)得到产物L99(25mg，黄色固体，产率11.6％)。ESI-MS:m/z＝470.1[M+H] +.H NMR(DMSO-d 6,400MHz):δ9.56(s,1H),8.78(s,1H),8.47(d,J＝8.8Hz,1H),8.33-8.29(m,2H),8.07(s,1H),7.79(s,1H),7.62-7.59(m,2H),7.06(s,1H),6.64(s,1H),6.46(d,J＝5.2Hz,1H),3.53-3.46(m,1H),3.40(s,3H),3.02(s,3H),1.21(t,J＝7.2Hz,3H)。 Step 3. Dissolve 99-2 in 1,4-dioxane hydrochloric acid solution (5 mL), and after nitrogen replacement, the reaction solution was stirred at 20° C. for 2 hours. The product L99 (25 mg, yellow solid, yield 11.6%) was obtained by preparative HPLC (FA). ESI-MS: m/z＝470.1[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ9.56(s, 1H), 8.78(s, 1H), 8.47(d, J＝8.8 Hz,1H),8.33-8.29(m,2H),8.07(s,1H),7.79(s,1H),7.62-7.59(m,2H),7.06(s,1H),6.64(s,1H) , 6.46 (d, J = 5.2Hz, 1H), 3.53-3.46 (m, 1H), 3.40 (s, 3H), 3.02 (s, 3H), 1.21 (t, J = 7.2Hz, 3H).
实施例100：化合物L100的制备Embodiment 100: Preparation of Compound L100
Figure PCTCN2022143403-appb-000122
Figure PCTCN2022143403-appb-000122
步骤1、将99-1(200mg,0.39mmol)，4-氨基-1H-吡唑-1-羧酸叔丁酯(86mg,0.47mmol)， Pd 2dba 3(36mg,0.04mmol)，X-phos(19mg,0.04mmol)，碳酸铯(385mg，1.18mmol)溶于1,4-二氧六环(5mL)中，置换氮气后，反应液在100℃下搅拌16小时。将混合物浓缩，残留物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝5:1到1:1梯度洗脱)得到产物100-1(190mg，黄色固体，产率73％)。ESI-MS:m/z＝656.1[M+H] +。 Step 1, 99-1 (200mg, 0.39mmol), tert-butyl 4-amino-1H-pyrazole-1-carboxylate (86mg, 0.47mmol), Pd 2 dba 3 (36mg, 0.04mmol), X- Phos (19mg, 0.04mmol) and cesium carbonate (385mg, 1.18mmol) were dissolved in 1,4-dioxane (5mL). After replacing nitrogen, the reaction solution was stirred at 100°C for 16 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1 to 1:1 gradient elution) to obtain product 100-1 (190 mg, yellow solid, yield 73%). ESI-MS: m/z = 656.1 [M+H] + .
步骤2、将100-1溶于二氯甲烷(6mL)中，室温下滴加三氟乙酸(1.5mL)，反应液在20℃下搅拌1.5小时。将反应液浓缩，用饱和碳酸氢钠溶液将残留物的Ph调至7～8，过滤，浓缩混合物。残留物经过制备HPLC(NH 4HCO 3)得到产物L100(19.5mg，黄色固体，产率14.8％)。ESI-MS:m/z＝456.1[M+H] +.H NMR(DMSO-d 6,400MHz):δ12.15(s,1H),9.53(s,1H),8.81(s,1H),8.46(d,J＝8.8Hz,1H),8.33(d,J＝5.2Hz,1H),8.27(d,J＝8.8Hz,1H),8.04(d,J＝9.2Hz,1H),7.76(d,J＝2.4Hz,1H),7.61-7.59(m,2H),7.18(s,1H),6.41(d,J＝5.2Hz,1H),3.51-3.48(m,2H),3.40(s,3H),1.23-1.19(m,3H)。 Step 2. Dissolve 100-1 in dichloromethane (6 mL), add trifluoroacetic acid (1.5 mL) dropwise at room temperature, and stir the reaction solution at 20° C. for 1.5 hours. The reaction solution was concentrated, and the pH of the residue was adjusted to 7-8 with saturated sodium bicarbonate solution, filtered, and the mixture was concentrated. The residue was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain the product L100 (19.5 mg, yellow solid, yield 14.8%). ESI-MS: m/z=456.1[M+H] + .H NMR(DMSO-d 6 ,400MHz):δ12.15(s,1H),9.53(s,1H),8.81(s,1H), 8.46(d, J=8.8Hz, 1H), 8.33(d, J=5.2Hz, 1H), 8.27(d, J=8.8Hz, 1H), 8.04(d, J=9.2Hz, 1H), 7.76( d,J=2.4Hz,1H),7.61-7.59(m,2H),7.18(s,1H),6.41(d,J=5.2Hz,1H),3.51-3.48(m,2H),3.40(s ,3H), 1.23-1.19(m,3H).
实施例101：化合物L101的制备Embodiment 101: Preparation of Compound L101
Figure PCTCN2022143403-appb-000123
Figure PCTCN2022143403-appb-000123
将14-1(230mg,0.55mmol),碳酸钾(152mg,1.1mmol)，Pd(dppf)Cl 2(40mg,0.055mmol)和1-甲基-1H-吡唑-4-硼酸频哪醇酯(170mg,0.82mmol)溶入1，4-二氧六环/水(15mL/1.5mL)中。氮气置换后反应液在75℃油浴中搅拌3小时。反应液冷却至室温，浓缩除去1，4-二氧六环，残余物通过甲醇/二氯甲烷打浆，得到产物L101(97mg,黄色固体，产率37.6％)。ESI-MS：m/z＝469.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.80(s,1H),8.64(d,J＝6.0Hz,1H),8.47(d,J＝8.8Hz,1H),8.28(d,J＝8.8Hz,1H),8.13(d,J＝9.2Hz,1H),8.04(d,J＝8.8Hz,1H),7.83(s,1H),7.79(d,J＝2.8Hz,1H),7.63(dd,J＝8.8,2.4Hz,1H),7.17(d,J＝7.6Hz,1H),6.87(d,J＝5.6Hz,1H),4.41-4.34(m,1H),3.84(s,3H),3.41(s,3H),1.26(d,J＝6.8Hz,6H). 14-1 (230mg, 0.55mmol), potassium carbonate (152mg, 1.1mmol), Pd(dppf)Cl 2 (40mg, 0.055mmol) and 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (170mg, 0.82mmol) was dissolved in 1,4-dioxane/water (15mL/1.5mL). After nitrogen replacement, the reaction solution was stirred in an oil bath at 75° C. for 3 hours. The reaction solution was cooled to room temperature, concentrated to remove 1,4-dioxane, and the residue was slurried with methanol/dichloromethane to obtain product L101 (97 mg, yellow solid, yield 37.6%). ESI-MS: m/z=469.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.80(s, 1H), 8.64(d, J=6.0Hz, 1H), 8.47 (d,J=8.8Hz,1H),8.28(d,J=8.8Hz,1H),8.13(d,J=9.2Hz,1H),8.04(d,J=8.8Hz,1H),7.83(s ,1H),7.79(d,J=2.8Hz,1H),7.63(dd,J=8.8,2.4Hz,1H),7.17(d,J=7.6Hz,1H),6.87(d,J=5.6Hz ,1H),4.41-4.34(m,1H),3.84(s,3H),3.41(s,3H),1.26(d,J=6.8Hz,6H).
实施例102：化合物L102的制备Embodiment 102: Preparation of compound L102
Figure PCTCN2022143403-appb-000124
Figure PCTCN2022143403-appb-000124
步骤1、将19-6(330mg,1.06mmol)，2,4-二氯嘧啶(237mg,1.59mmol)，碳酸钾(414mg,3.0mmol)加入DMF(6mL)中，反应液在90℃下搅拌16小时。残余物通过C18反向柱纯化(乙腈：水＝25:75到70:30梯度洗脱)得到产物102-1(300mg，类白色固体，产率62.1％)。Step 1. Add 19-6 (330mg, 1.06mmol), 2,4-dichloropyrimidine (237mg, 1.59mmol), potassium carbonate (414mg, 3.0mmol) into DMF (6mL), and stir the reaction solution at 90°C 16 hours. The residue was purified by C18 reverse column (acetonitrile:water=25:75 to 70:30 gradient elution) to obtain product 102-1 (300 mg, off-white solid, yield 62.1%).
步骤2、将102-1(270mg,0.64mmol)，1-甲基-1H-吡唑-4-胺盐酸盐(124mg,1.28mmol)，Pd 2dba 3(59mg,0.06mmol)，X-phos(30mg,0.06mmol)，碳酸铯(624mg，1.9mmol)溶于1,4-二氧六环(10mL)中，置换氮气后，反应液在110℃下搅拌16小时。残余物通过C18反向柱纯化(乙腈：水＝35:65到40:60梯度洗脱)得到粗产物。粗产物经过制备HPLC(NH 4HCO 3)得到产物L102(7.4mg，黄色固体，产率2.4％)。ESI-MS:m/z＝485.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ9.62-9.25(m,1H),8.98(d,J＝2.4Hz,1H),8.87(s,1H),8.64(d,J＝8.8Hz,1H),8.41-8.32(m,3H),7.79-6.78(m,1H),7.27(d,J＝13.2Hz,1H),7.04-6.64(m,1H),6.55(d,J＝6.8Hz,1H),4.42(d,J＝6.0Hz,1H),3.42(s,3H),3.09(s,3H),1.26(t,J＝8.0Hz,6H)。 Step 2, 102-1 (270mg, 0.64mmol), 1-methyl-1H-pyrazol-4-amine hydrochloride (124mg, 1.28mmol), Pd 2 dba 3 (59mg, 0.06mmol), X- Phos (30mg, 0.06mmol), cesium carbonate (624mg, 1.9mmol) were dissolved in 1,4-dioxane (10mL), and after replacing nitrogen, the reaction solution was stirred at 110°C for 16 hours. The residue was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain crude product. The crude product was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain product L102 (7.4 mg, yellow solid, yield 2.4%). ESI-MS: m/z＝485.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.62-9.25 (m, 1H), 8.98 (d, J＝2.4Hz, 1H) ,8.87(s,1H),8.64(d,J=8.8Hz,1H),8.41-8.32(m,3H),7.79-6.78(m,1H),7.27(d,J=13.2Hz,1H), 7.04-6.64(m,1H),6.55(d,J=6.8Hz,1H),4.42(d,J=6.0Hz,1H),3.42(s,3H),3.09(s,3H),1.26(t , J=8.0Hz, 6H).
实施例103：化合物L103的制备Embodiment 103: Preparation of Compound L103
Figure PCTCN2022143403-appb-000125
Figure PCTCN2022143403-appb-000125
步骤1、将5-(6-羟基喹啉-2-基)-3-甲基-2-(甲胺基)嘧啶-4(3H)-酮(参照化合物4-1方法制备，100mg,0.355mmol)，2-溴-4-氟吡啶(105mg,0.60mmol)，碳酸钾(122mg,0.89mmol)加入DMF(3mL)中，反应液在90℃下搅拌16小时。将反应液过滤，残余物通过C18反向硅胶柱纯化(乙腈：水＝25:75到100:0梯度洗脱)得到产物103-1(80mg，产率52％)。ESI-MS:m/z＝437.9[M+H] +。 Step 1, 5-(6-hydroxyquinolin-2-yl)-3-methyl-2-(methylamino)pyrimidin-4(3H)-one (prepared by referring to the method of compound 4-1, 100mg, 0.355 mmol), 2-bromo-4-fluoropyridine (105mg, 0.60mmol), potassium carbonate (122mg, 0.89mmol) were added to DMF (3mL), and the reaction solution was stirred at 90°C for 16 hours. The reaction solution was filtered, and the residue was purified by C18 reverse silica gel column (acetonitrile:water=25:75 to 100:0 gradient elution) to obtain product 103-1 (80 mg, yield 52%). ESI-MS: m/z = 437.9 [M+H] + .
步骤2、将103-1(80mg,0.183mmol)，氨基甲酸甲酯(41mg,0.55mmol)，Pd 2dba 3(18mg,0.02mmol)，X-phos(9mg,0.02mmol)，碳酸铯(180mg，0.55mmol)溶于1,4-二氧六环(3mL)中，置换氮气后，反应液在110℃下搅拌18小时。残余物通过C18反向硅胶柱纯化(乙腈：水＝25:75到100:0梯 度洗脱)得到粗产物。粗产物经过制备HPLC(NH 4HCO 3)得到产物L103(7.3mg，产率9.3％)。ESI-MS:m/z＝433.1[M+H] +.H NMR(DMSO-d 6,400MHz):δ10.26(s,1H),8.80(s,1H),8.47(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.18(d,J＝5.2Hz,1H),8.05(d,J＝9.2Hz,1H),7.70(d,J＝2.8Hz,1H),7.59-7.53(m,2H),7.45(d,J＝2.4Hz,1H),6.73(dd,J＝5.8Hz,1H),3.59(s,3H),3.40(s,3H),2.96(d,J＝2.8Hz,3H). Step 2, 103-1 (80mg, 0.183mmol), methyl carbamate (41mg, 0.55mmol), Pd 2 dba 3 (18mg, 0.02mmol), X-phos (9mg, 0.02mmol), cesium carbonate (180mg , 0.55 mmol) was dissolved in 1,4-dioxane (3 mL), and after replacing nitrogen, the reaction solution was stirred at 110°C for 18 hours. The residue was purified by C18 reverse silica gel column (acetonitrile:water=25:75 to 100:0 gradient elution) to obtain crude product. The crude product was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain the product L103 (7.3 mg, 9.3% yield). ESI-MS: m/z＝433.1[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ10.26(s, 1H), 8.80(s, 1H), 8.47(d, J＝8.8 Hz,1H),8.27(d,J=8.8Hz,1H),8.18(d,J=5.2Hz,1H),8.05(d,J=9.2Hz,1H),7.70(d,J=2.8Hz, 1H),7.59-7.53(m,2H),7.45(d,J=2.4Hz,1H),6.73(dd,J=5.8Hz,1H),3.59(s,3H),3.40(s,3H), 2.96(d,J=2.8Hz,3H).
实施例104：化合物L104的制备Embodiment 104: Preparation of Compound L104
Figure PCTCN2022143403-appb-000126
Figure PCTCN2022143403-appb-000126
将5-(6-(2-溴吡啶-4-基)氧基)喹啉-2-基)-4-甲氧基-N，N-二甲基嘧啶-2-胺(参照化合物54-2的方法制备，100mg,0.22mmol)，x-phos(22mg，0.044mmol)，乙酰胺(38.3mg，0.66mmol)碳酸铯(215mg,0.66mmol)和Pd 2(dba) 3(32.2mg，0.044mmol)溶于1,4-二氧六环(5mL)中，氮气置换后反应液在85℃下搅拌6小时。反应液冷却至室温后过滤，有机相浓缩后甲醇打浆得到产物L104(42mg，产率37.8％)。ESI-MS：m/z＝431.1[M+H] +. 1H NMR(DMSO-d 6,400MHz)δ10.58(s,1H),8.76(s,1H),8.45(d,J＝8.8Hz,1H),8.31(d,J＝9.2Hz,1H),8.22(d,J＝4.5Hz,1H),8.06(d,J＝9.2Hz,1H),7.72(d,J＝4.8Hz,2H),7.57-7.54(m,1H),6.77-6.75(m,1H),3.48(s,3H),3.0(s,6H),3.02(s,3H)。 5-(6-(2-bromopyridin-4-yl)oxy)quinolin-2-yl)-4-methoxy-N,N-dimethylpyrimidin-2-amine (reference compound 54- 2, 100mg, 0.22mmol), x-phos (22mg, 0.044mmol), acetamide (38.3mg, 0.66mmol) cesium carbonate (215mg, 0.66mmol) and Pd 2 (dba) 3 (32.2mg, 0.044 mmol) was dissolved in 1,4-dioxane (5 mL), and the reaction solution was stirred at 85° C. for 6 hours after nitrogen replacement. The reaction solution was cooled to room temperature and then filtered. The organic phase was concentrated and then slurried with methanol to obtain the product L104 (42 mg, yield 37.8%). ESI-MS: m/z=431.1[M+H] + . 1 H NMR (DMSO-d 6, 400MHz) δ10.58(s,1H),8.76(s,1H),8.45(d,J=8.8 Hz,1H),8.31(d,J=9.2Hz,1H),8.22(d,J=4.5Hz,1H),8.06(d,J=9.2Hz,1H),7.72(d,J=4.8Hz, 2H), 7.57-7.54(m,1H), 6.77-6.75(m,1H), 3.48(s,3H), 3.0(s,6H), 3.02(s,3H).
实施例105：化合物L105的制备Embodiment 105: Preparation of Compound L105
Figure PCTCN2022143403-appb-000127
Figure PCTCN2022143403-appb-000127
步骤1、将2-氯-6-甲氧基-1,8-萘啶(550mg,2.8mmol)，3-甲基-2-(甲胺基)-5-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)嘧啶-4(3H)-酮(1g,3.4mmol)，Pd(dppf)Cl 2(205mg,0.28mmol)和碳酸钾(773mg,5.6mmol)溶于二氧六环/水(15/1.5mL)中，氮气置换后反应液在70℃下搅拌3小时。LCMS监测反应结束后浓缩，EA重结晶，得到产物105-1(960mg，黄色固体)。ESI-MS：m/z＝298.0[M+H] +。 Step 1, 2-chloro-6-methoxy-1,8-naphthyridine (550mg, 2.8mmol), 3-methyl-2-(methylamino)-5-(4,4,5,5 -Tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)pyrimidin-4(3H)-one (1 g, 3.4 mmol), Pd(dppf)Cl 2 (205 mg, 0.28 mmol) and potassium carbonate (773mg, 5.6mmol) was dissolved in dioxane/water (15/1.5mL), and the reaction solution was stirred at 70°C for 3 hours after nitrogen replacement. After the reaction was monitored by LCMS, it was concentrated and EA was recrystallized to obtain the product 105-1 (960 mg, yellow solid). ESI-MS: m/z = 298.0 [M+H] + .
步骤2、将105-1(450mg,2mmol)，溶于40％HBr乙酸(40mL)和40％HBr水溶液(10mL)中，氮气置换后反应液在130℃下搅拌12小时。LCMS监测反应结束后无需后处理，浓缩除去溶剂，残余物通过C18反向柱提纯(乙腈:水＝5:95到70:30梯度洗脱)得到产物105-2(400mg，黄色固体，50％)。ESI-MS：m/z＝284.0[M+H] +。 Step 2. 105-1 (450 mg, 2 mmol) was dissolved in 40% HBr acetic acid (40 mL) and 40% HBr aqueous solution (10 mL), and the reaction solution was stirred at 130° C. for 12 hours after nitrogen replacement. LCMS monitors that no post-treatment is required after the reaction is completed, the solvent is concentrated and removed, and the residue is purified by a C18 reverse column (acetonitrile:water=5:95 to 70:30 gradient elution) to obtain the product 105-2 (400mg, yellow solid, 50% ). ESI-MS: m/z = 284.0 [M+H] + .
步骤3、将105-2(250mg,0.89mmol)溶于DMF(10mL)中，向溶液中加入碳酸铯(860mg,2.64mmol)和2,3,4-三氯吡啶(176mg,0.97mmol)。氮气置换后反应液在90℃搅拌过夜。反应液浓缩后残余物通过C18反向柱提纯(乙腈:水＝35:65到40:60梯度洗脱)得到105-3(250mg,黄色固体,产率66.4％)。ESI-MS：m/z＝429.1[M+H] +。 Step 3. Dissolve 105-2 (250mg, 0.89mmol) in DMF (10mL), and add cesium carbonate (860mg, 2.64mmol) and 2,3,4-trichloropyridine (176mg, 0.97mmol) to the solution. After nitrogen replacement, the reaction solution was stirred overnight at 90°C. After the reaction solution was concentrated, the residue was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 105-3 (250 mg, yellow solid, yield 66.4%). ESI-MS: m/z = 429.1 [M+H] + .
步骤4、将105-3(260mg,0.6mmol)，x-phos(114mg，0.24mmol)，氨基甲酸叔丁酯(421.7mg，3.6mmol)碳酸铯(1.1g,3.6mmol)和Pd 2(dba) 3(110mg，0.12mmol)溶于1,4-二氧六环(20mL)中，氮气置换后反应液在85℃下搅拌3小时。过滤，浓缩，EA/PE打浆，得到粗产物105-4(200mg,黄色固体)。ESI-MS：m/z＝409.9[M+H-100] + Step 4, 105-3 (260mg, 0.6mmol), x-phos (114mg, 0.24mmol), tert-butyl carbamate (421.7mg, 3.6mmol) cesium carbonate (1.1g, 3.6mmol) and Pd 2 (dba ) 3 (110 mg, 0.12 mmol) was dissolved in 1,4-dioxane (20 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. Filtration, concentration, and EA/PE slurry gave the crude product 105-4 (200 mg, yellow solid). ESI-MS: m/z=409.9[M+H-100] +
步骤5、将105-4(200mg,0.39mmol)和TFA(4mL)加入CH 2Cl 2(20mL)中。氮气置换后反应液在室温下搅拌1h。反应液浓缩后残余物通过pre-HPLC(0.1％TFA水溶液)提纯得到L105(12mg,产率7.5％)。ESI-MS：m/z＝410.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ9.27(d,J＝3.2Hz,1H),8.87(s,1H),8.60(d,J＝8.8Hz,1H),8.34(d,J＝8.8Hz,1H),8.07(d,J＝3.2Hz,1H),7.84(d,J＝5.2Hz,1H),7.67(s,1H),6.51(s,2H),6.22(d,J＝5.2Hz,1H),3.39(s,3H),2.97(s,3H). Step 5. Add 105-4 (200 mg, 0.39 mmol) and TFA (4 mL) into CH 2 Cl 2 (20 mL). After nitrogen replacement, the reaction solution was stirred at room temperature for 1 h. After the reaction solution was concentrated, the residue was purified by pre-HPLC (0.1% TFA aqueous solution) to obtain L105 (12 mg, yield 7.5%). ESI-MS: m/z=410.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.27(d, J=3.2Hz, 1H), 8.87(s, 1H), 8.60 (d,J=8.8Hz,1H),8.34(d,J=8.8Hz,1H),8.07(d,J=3.2Hz,1H),7.84(d,J=5.2Hz,1H),7.67(s ,1H),6.51(s,2H),6.22(d,J=5.2Hz,1H),3.39(s,3H),2.97(s,3H).
实施例106：化合物L106的制备Embodiment 106: Preparation of Compound L106
Figure PCTCN2022143403-appb-000128
Figure PCTCN2022143403-appb-000128
步骤1、将105-2(150mg,0.89mmol)溶于NMP(10mL)中，向溶液中加入碳酸钾(220mg,1.59mmol)和2-溴-4-氟吡啶(93mg,0.53mmol)。氮气置换后反应液在90℃搅拌过夜。反应液浓缩后残余物通过C18反向柱提纯(乙腈:水＝35:65到40:60梯度洗脱)得到106-1(100mg,黄色固体,产率43％)。ESI-MS：m/z＝439.9[M+H] +。 Step 1. Dissolve 105-2 (150mg, 0.89mmol) in NMP (10mL), and add potassium carbonate (220mg, 1.59mmol) and 2-bromo-4-fluoropyridine (93mg, 0.53mmol) to the solution. After nitrogen replacement, the reaction solution was stirred overnight at 90°C. After the reaction solution was concentrated, the residue was purified by a C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 106-1 (100 mg, yellow solid, yield 43%). ESI-MS: m/z = 439.9 [M+H] + .
步骤2、将106-1(100mg,0.23mmol)，x-phos(44mg，0.092mmol)，乙酰胺(81.4mg，1.38mmol)，碳酸铯(224mg,0.69mmol)和Pd 2(dba) 3(42mg，0.046mmol)溶于1,4-二氧六环(20mL)中，氮气置换后反应液在85℃下搅拌3小时。过滤，浓缩，高效液相制备色谱(0.1％甲酸水溶液/乙腈)纯化得到产物L106(4mg，产率4.1％)。ESI-MS：m/z＝418.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.61(s,1H),8.92(d,J＝2.8Hz,1H),8.89(s,1H),8.63(d,J＝5.2Hz,1H),8.35(d,J＝7.2Hz,1H),8.25(d,J＝6.0Hz,1H),8.21(d,J＝2.8Hz,1H),7.76(d,J＝2.4Hz,1H),7.68(s,1H),6.82(dd,J＝5.6,2.4Hz,1H),3.40(s,3H),2.97(s,3H),2.04(s,3H)。 Step 2, 106-1 (100mg, 0.23mmol), x-phos (44mg, 0.092mmol), acetamide (81.4mg, 1.38mmol), cesium carbonate (224mg, 0.69mmol) and Pd 2 (dba) 3 ( 42mg, 0.046mmol) was dissolved in 1,4-dioxane (20mL), and the reaction solution was stirred at 85°C for 3 hours after nitrogen replacement. It was filtered, concentrated, and purified by preparative HPLC (0.1% aqueous formic acid/acetonitrile) to obtain the product L106 (4 mg, yield 4.1%). ESI-MS: m/z=418.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.61(s, 1H), 8.92(d, J=2.8Hz, 1H), 8.89 (s,1H),8.63(d,J=5.2Hz,1H),8.35(d,J=7.2Hz,1H),8.25(d,J=6.0Hz,1H),8.21(d,J=2.8Hz ,1H),7.76(d,J=2.4Hz,1H),7.68(s,1H),6.82(dd,J=5.6,2.4Hz,1H),3.40(s,3H),2.97(s,3H) ,2.04(s,3H).
实施例107：化合物L107的制备Embodiment 107: Preparation of compound L107
Figure PCTCN2022143403-appb-000129
Figure PCTCN2022143403-appb-000129
步骤1、将2-(2-(乙氨基)-4-甲氧基嘧啶-5-基)喹啉-6-醇(参照化合物54-1的方法制备，100mg,0.338mmol)，4-氯-N-甲基吡啶酰胺(115mg,0.676mmol)，碳酸钾(140mg,1.01mmol)加入DMF(3mL)中，反应液在100℃下搅拌18小时。将反应液过滤，残余物通过C18反向硅胶柱纯化(乙腈：水＝25:75到90:10梯度洗脱)得到产物107-1(80mg，黄色固体，产率55％)。ESI-MS:m/z＝431.0[M+H] +。 Step 1, 2-(2-(ethylamino)-4-methoxypyrimidin-5-yl)quinolin-6-ol (prepared according to the method of compound 54-1, 100mg, 0.338mmol), 4-chloro -N-methylpicolinamide (115mg, 0.676mmol), potassium carbonate (140mg, 1.01mmol) were added to DMF (3mL), and the reaction solution was stirred at 100°C for 18 hours. The reaction solution was filtered, and the residue was purified by C18 reverse silica gel column (acetonitrile:water=25:75 to 90:10 gradient elution) to obtain product 107-1 (80 mg, yellow solid, yield 55%). ESI-MS: m/z = 431.0 [M+H] + .
步骤2、将107-1(80mg,0.186mmol)溶于乙酸(2mL)中，向上述溶液中加入氢溴酸(0.4mL,40％)。反应液在60℃下搅拌16小时。反应液冷却室温后浓缩，向残余物加入三乙胺(0.5mL)，再加入DMF(2.5mL),过滤，滤液经制备HPLC(NH 4HCO 3)得到产物L107(24.0mg，产率31.2％)。ESI-MS:m/z＝417.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ11.18(s,1H),8.82-8.78(m,2H),8.55(d,J＝5.6Hz,1H),8.50(d,J＝8.4Hz,1H),8.27(d,J＝8.8Hz,1H),8.07(d,J＝9.2Hz,1H),7.75(s,1H),7.58(d,J＝7.6Hz,1H),7.48(d,J＝2.4Hz,1H),7.25(dd,J＝5.6Hz,1H),6.95(s,1H),3.42-3.35(m,2H),2.79(d,J＝4.8Hz,3H),1.15(t,J＝7.2Hz,3H). Step 2. Dissolve 107-1 (80 mg, 0.186 mmol) in acetic acid (2 mL), and add hydrobromic acid (0.4 mL, 40%) to the above solution. The reaction solution was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated. Triethylamine (0.5 mL) was added to the residue, followed by DMF (2.5 mL), filtered, and the filtrate was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain the product L107 (24.0 mg, yield 31.2% ). ESI-MS: m/z＝417.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ11.18(s, 1H), 8.82-8.78(m, 2H), 8.55(d, J＝5.6Hz, 1H), 8.50(d, J＝8.4Hz, 1H), 8.27(d, J＝8.8Hz, 1H), 8.07(d, J＝9.2Hz, 1H), 7.75(s, 1H) ,7.58(d,J=7.6Hz,1H),7.48(d,J=2.4Hz,1H),7.25(dd,J=5.6Hz,1H),6.95(s,1H),3.42-3.35(m, 2H), 2.79(d, J=4.8Hz, 3H), 1.15(t, J=7.2Hz, 3H).
实施例108：化合物L108的制备Embodiment 108: Preparation of Compound L108
Figure PCTCN2022143403-appb-000130
Figure PCTCN2022143403-appb-000130
步骤1、将42-2(300mg,1mmol)，PMBNH 2(686.50mg，5mmol)溶于TEA/TFA混合溶液中(10mL)中，氮气置换后反应液在125℃下搅拌过夜。反应液浓缩后残余物通过C18反向柱提纯(乙腈：水＝35:65到40:60梯度洗脱)得到108-1(150mg,黄色固体,产率38.6％)。ESI-MS：m/z＝389.0[M+H] +。 Step 1. 42-2 (300mg, 1mmol), PMBNH 2 (686.50mg, 5mmol) were dissolved in TEA/TFA mixed solution (10mL), and the reaction solution was stirred at 125°C overnight after nitrogen replacement. After the reaction solution was concentrated, the residue was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 108-1 (150 mg, yellow solid, yield 38.6%). ESI-MS: m/z = 389.0 [M+H] + .
步骤2、将108-1(150mg,0.38mmol)溶于NMP(3mL)中，向溶液中加入碳酸钾(110mg,0.81mmol)和2-溴-4-氟吡啶(114mg,0.65mmol)。氮气置换后反应液在90℃搅拌过夜。反应液浓缩后残余物通过C18反向柱提纯(乙腈：水＝35:65到40:60梯度洗脱)得到108-2(100mg,黄色固体,产率34.8％)。ESI-MS：m/z＝545.8[M+H] +。 Step 2. Dissolve 108-1 (150mg, 0.38mmol) in NMP (3mL), and add potassium carbonate (110mg, 0.81mmol) and 2-bromo-4-fluoropyridine (114mg, 0.65mmol) to the solution. After nitrogen replacement, the reaction solution was stirred overnight at 90°C. After the reaction solution was concentrated, the residue was purified by a C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 108-2 (100 mg, yellow solid, yield 34.8%). ESI-MS: m/z = 545.8 [M+H] + .
步骤3、将108-2(100mg,0.18mmol)，x-phos(35mg，0.074mmol)，乙酰胺(32mg，0.55mmol)碳酸铯(180mg,0.55mmol)和Pd 2(dba) 3(34mg，0.0368mmol)溶于1,4-二氧六环(5mL)中，氮气置换后反应液在85℃下搅拌3小时。反应液冷却至室温后过滤，有机相浓缩后PE打浆得到粗产物108-3(80mg,黄色固体)。ESI-MS：m/z＝523.0[M+H] + Step 3, 108-2 (100mg, 0.18mmol), x-phos (35mg, 0.074mmol), acetamide (32mg, 0.55mmol) cesium carbonate (180mg, 0.55mmol) and Pd 2 (dba) 3 (34mg, 0.0368 mmol) was dissolved in 1,4-dioxane (5 mL), and the reaction solution was stirred at 85° C. for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and then filtered. The organic phase was concentrated and then PE slurried to obtain the crude product 108-3 (80 mg, yellow solid). ESI-MS: m/z=523.0[M+H] +
步骤4、将108-3(80mg,0.15mmol)溶于TFA(5mL)中。氮气置换后反应液在65℃下搅拌12小时。反应结束后用饱和NaHCO 3溶液调至中性后过滤浓缩，残余物通过HPLC(0.1％FA)提纯，得到L108(13mg,黄色固体，产率22％). 1H NMR(DMSO-d 6,400MHz)δ10.55(s,1H),8.76(s,1H),8.49(d,J＝8.8Hz,1H),8.25(d,J＝9.6Hz,1H),8.21(d,J＝5.6Hz,1H),8.03(d,J＝9.2Hz,1H),7.72(d,J＝2.0Hz,1H),7.68-7.65(m,3H),7.52(dd,J＝9.2,2.8Hz,1H),6.74(dd,J＝5.6,2.4Hz,1H),3.40(s,3H),2.03(s,3H)。 Step 4. Dissolve 108-3 (80 mg, 0.15 mmol) in TFA (5 mL). After nitrogen replacement, the reaction solution was stirred at 65°C for 12 hours. After the reaction was completed, it was adjusted to neutral with saturated NaHCO 3 solution, then concentrated by filtration, and the residue was purified by HPLC (0.1% FA) to obtain L108 (13 mg, yellow solid, yield 22%). 1 H NMR (DMSO-d 6, 400MHz) δ10.55(s, 1H), 8.76(s, 1H), 8.49(d, J＝8.8Hz, 1H), 8.25(d, J＝9.6Hz, 1H), 8.21(d, J＝5.6Hz ,1H),8.03(d,J=9.2Hz,1H),7.72(d,J=2.0Hz,1H),7.68-7.65(m,3H),7.52(dd,J=9.2,2.8Hz,1H) , 6.74 (dd, J=5.6, 2.4Hz, 1H), 3.40 (s, 3H), 2.03 (s, 3H).
实施例109：化合物L109的制备Embodiment 109: Preparation of Compound L109
Figure PCTCN2022143403-appb-000131
Figure PCTCN2022143403-appb-000131
步骤1、将5-(6-羟基喹啉-2-基)-3-甲基-2-(甲氨基)嘧啶-4(3H)-酮(200mg,0.7mmol)溶于DMF(5mL)中，向上述溶液中加入NaH(42mg,1.05mmol)。反应液在冰浴下搅拌15分钟,然后向上述溶液中加入2,4-二氯嘧啶(156mg,1.05mmol)。室温搅拌两小时。反应液用饱和氯化铵溶液调pH值到7，用乙酸乙酯萃取三次。有机相用饱和食盐水洗涤，然后用无水硫酸钠干燥，过滤，后蒸除溶剂，残余物通过打浆纯化(乙酸乙酯：甲醇＝1:1)得到产物109-1(120mg,黄色固体，产率43.4％)。ESI-MS:m/z＝395.1[M+H]。Step 1. Dissolve 5-(6-hydroxyquinolin-2-yl)-3-methyl-2-(methylamino)pyrimidin-4(3H)-one (200mg, 0.7mmol) in DMF (5mL) , NaH (42 mg, 1.05 mmol) was added to the above solution. The reaction solution was stirred under ice bath for 15 minutes, and then 2,4-dichloropyrimidine (156 mg, 1.05 mmol) was added to the above solution. Stir at room temperature for two hours. The reaction solution was adjusted to pH 7 with saturated ammonium chloride solution, and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated, and the residue was purified by beating (ethyl acetate:methanol=1:1) to obtain the product 109-1 (120mg, yellow solid, Yield 43.4%). ESI-MS: m/z = 395.1 [M+H].
步骤2、将109-1(120mg,0.30mmol)，1-甲基-1H-吡唑-4-胺盐酸盐(81mg,0.61mmol)，碳酸铯(293mg,0.9mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(28mg,0.06mmol)，三(二亚苄基丙酮)二钯(28mg,0.03mmol)溶于二氧六环(5mL)中，氮气置换后反应液在100℃下搅拌16小时。反应液浓缩除去二氧六环，残余物中加水(10mL)，用乙酸乙酯萃取(20mL x 3)。有机相合并后用饱和盐水(30mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物经过制备HPLC(NH4HCO3)得到产物L109(26mg，黄色固体，产率19.0％).ESI-MS:m/z＝456.1[M+H]. 1H NMR(DMSO-d6,400MHz):δ9.55(s,1H),8.40(s,1H),8.79(s,1H),8.47(d,J＝8.8Hz,1H),8.33-8.29(m,2H),8.10-8.08(m,1H),7.79(s,1H),7.60(d,J＝8.8Hz,1H),7.05(s,1H),6.61(s,1H),6.46(d,J＝5.2Hz,1H),3.37(s,3H),3.01-2.95(m,6H)。 Step 2, 109-1 (120mg, 0.30mmol), 1-methyl-1H-pyrazol-4-amine hydrochloride (81mg, 0.61mmol), cesium carbonate (293mg, 0.9mmol), 2-bicyclohexyl Phosphine-2',4',6'-triisopropylbiphenyl (28mg, 0.06mmol), tris(dibenzylideneacetone)dipalladium (28mg, 0.03mmol) in dioxane (5mL) , and the reaction solution was stirred at 100° C. for 16 hours after nitrogen replacement. The reaction solution was concentrated to remove dioxane, water (10 mL) was added to the residue, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was subjected to preparative HPLC (NH4HCO3) to obtain the product L109 (26 mg, yellow solid, yield 19.0%). ESI-MS: m/z =456.1[M+H]. 1 H NMR(DMSO-d6,400MHz):δ9.55(s,1H),8.40(s,1H),8.79(s,1H),8.47(d,J=8.8Hz ,1H),8.33-8.29(m,2H),8.10-8.08(m,1H),7.79(s,1H),7.60(d,J=8.8Hz,1H),7.05(s,1H),6.61( s, 1H), 6.46 (d, J=5.2Hz, 1H), 3.37 (s, 3H), 3.01-2.95 (m, 6H).
实施例110：化合物L110的制备Embodiment 110: Preparation of compound L110
Figure PCTCN2022143403-appb-000132
Figure PCTCN2022143403-appb-000132
步骤1、将5-(6-羟基喹啉-2-基)-3-甲基-2-(甲胺基)嘧啶-4(3H)-酮(130mg,0.461mmol)和碳酸铯(451mg,1.28mmol)加入DMF(3mL)中，向上述溶液中加入2,3,4-三氯吡啶(88mg,0.484mmol)。反应液在90℃搅拌16小时。反应液过滤，滤液经C18反向柱纯化(乙腈：水＝25:75到75:25梯度洗脱)得到产物110-1(130mg，黄色固体，产率68％)。ESI-MS:m/z＝427.9[M+H] +。 Step 1. Combine 5-(6-hydroxyquinolin-2-yl)-3-methyl-2-(methylamino)pyrimidin-4(3H)-one (130mg, 0.461mmol) and cesium carbonate (451mg, 1.28mmol) was added to DMF (3mL), and 2,3,4-trichloropyridine (88mg, 0.484mmol) was added to the above solution. The reaction solution was stirred at 90°C for 16 hours. The reaction solution was filtered, and the filtrate was purified by a C18 reverse column (acetonitrile:water=25:75 to 75:25 gradient elution) to obtain product 110-1 (130 mg, yellow solid, yield 68%). ESI-MS: m/z = 427.9 [M+H] + .
步骤2、将110-1(130mg,0.304mmol)，氨基甲酸叔丁酯(356mg,3.04mmol)和碳酸铯(298mg,0.91mmol)溶于1，4-二氧六环(4mL)中，氮气保护下，向上述溶液中加入X-phos(14.5mg,0.03mmol)和Pd 2(dba) 3(28mg,0.03mmol)。反应液在110℃下搅拌20小时。反应液冷却室温后浓缩，残余物通过硅胶柱层析纯化(二氯甲烷：甲醇＝20:1到12:1梯度洗脱)得到粗产物，粗产物经过制备HPLC(NH 4HCO 3)得到产物L110(11.3mg,黄色固体，产率9.1％)。ESI-MS:m/z＝409.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.78(s,1H),8.44(d,J＝8.8Hz,1H),8.25(d,J＝8.8Hz,1H),8.02(d,J＝9.2Hz,1H),7.80(d,J＝6.0Hz,1H),7.58(d,J＝3.2Hz,2H),7.52(dd,J＝9.6,2.8Hz,1H),6.44(s,2H),6.11(d,J＝6.0Hz,1H),3.39(s,3H),2.95(d,J＝4.0Hz,3H)。 Step 2, 110-1 (130mg, 0.304mmol), tert-butyl carbamate (356mg, 3.04mmol) and cesium carbonate (298mg, 0.91mmol) were dissolved in 1,4-dioxane (4mL), nitrogen Under protection, X-phos (14.5 mg, 0.03 mmol) and Pd 2 (dba) 3 (28 mg, 0.03 mmol) were added to the above solution. The reaction solution was stirred at 110° C. for 20 hours. The reaction solution was cooled to room temperature and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 12:1 gradient elution) to obtain a crude product, which was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain the product L110 (11.3 mg, yellow solid, 9.1% yield). ESI-MS: m/z＝409.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.78(s, 1H), 8.44(d, J＝8.8Hz, 1H), 8.25 (d, J=8.8Hz, 1H), 8.02(d, J=9.2Hz, 1H), 7.80(d, J=6.0Hz, 1H), 7.58(d, J=3.2Hz, 2H), 7.52(dd , J=9.6, 2.8Hz, 1H), 6.44(s, 2H), 6.11(d, J=6.0Hz, 1H), 3.39(s, 3H), 2.95(d, J=4.0Hz, 3H).
实施例111：化合物L111的制备Embodiment 111: Preparation of Compound L111
Figure PCTCN2022143403-appb-000133
Figure PCTCN2022143403-appb-000133
步骤1、将2-(2-(乙氨基)-4-甲氧基嘧啶-5-基)喹啉-6-醇(750mg,2.5mmol)，溶于DMF(20mL)中，向上述溶液中加入2-溴-4-氟吡啶(1.3g,7.5mmol)，碳酸钾(1.0g,7.5mmol)。反应液在90℃下搅拌16小时。反应液加水(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过硅胶柱层析纯化(石油醚：乙酸乙酯＝10:1到1:1梯度洗脱)得到产物111-1(700mg,黄色固体，产率61.1％)。ESI-MS:m/z＝452.0[M+H]。Step 1. Dissolve 2-(2-(ethylamino)-4-methoxypyrimidin-5-yl)quinolin-6-ol (750mg, 2.5mmol) in DMF (20mL) and add to the above solution 2-Bromo-4-fluoropyridine (1.3 g, 7.5 mmol), potassium carbonate (1.0 g, 7.5 mmol) were added. The reaction solution was stirred at 90°C for 16 hours. Add water (20mL) to the reaction solution and extract with ethyl acetate (30mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1 gradient elution) to obtain the product 111 -1 (700 mg, yellow solid, yield 61.1%). ESI-MS: m/z = 452.0 [M+H].
步骤2、将111-1(183mg,0.88mmol)溶于二氧六环(5mL)中，向上述溶液中加入((6-1,1'-二(二苯膦基)二茂铁二氯化钯(II)(29mg,0.04mmol)，碳酸钾(3.4g,1.32mmol)。氮气置换后反应液在80℃下搅拌16小时。反应液浓缩除去二氧六环，残余物中加水(20mL)，用乙酸乙酯萃取(30mL x3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物通过C18反向柱纯化(乙腈：水＝5到70梯度洗脱)得到产物111-2(120mg，黄色固体，产率60.2％).ESI-MS:m/z＝453.9 [M+H]。Step 2. Dissolve 111-1 (183 mg, 0.88 mmol) in dioxane (5 mL), and add ((6-1,1'-bis(diphenylphosphino)ferrocene dichloro Palladium (II) (29mg, 0.04mmol), potassium carbonate (3.4g, 1.32mmol). After nitrogen replacement, the reaction solution was stirred at 80°C for 16 hours. The reaction solution was concentrated to remove dioxane, and water (20mL ), extracted with ethyl acetate (30mL x3). The combined organic phases were washed with saturated brine (50mL), dried over sodium sulfate and evaporated to remove the solvent, and the residue was purified by a C18 reverse column (acetonitrile: water=5 to 70 gradient wash De) gave product 111-2 (120 mg, yellow solid, yield 60.2%). ESI-MS: m/z=453.9 [M+H].
步骤3、将111-2((100mg,0.22mmol)溶于氢溴酸的醋酸溶液(1mL),醋酸(5mL),水(1mL)中,反应液在60℃下搅拌16小时。反应液加入饱和碳酸氢钠中和(20mL)，用乙酸乙酯萃取(30mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，残余物经过制备HPLC(NH4HCO3)得到产物L111(22mg，白色固体，产率22.7％).ESI-MS:m/z＝440.1[M+H]. 1H NMR(DMSO-d6,400MHz):δ10.45-9.90(m,1H),8.81(s,1H),8.47(d,J＝8.8Hz,1H),8.41(d,J＝5.6Hz,1H),8.27-8.26(m,2H),8.04(d,J＝9.2Hz,1H),7.97(s,1H),7.68(d,J＝2.4Hz,1H),7.56(dd,J＝2.8Hz,J＝9.2Hz,1H),7.31(d,J＝2.4Hz,1H),6.78(dd,J＝2.4Hz,J＝5.6Hz,1H),3.85(s,3H),3.42-3.31(m,2H),1.15(t，J＝7.2Hz,3H).。 Step 3. Dissolve 111-2 ((100mg, 0.22mmol) in hydrobromic acid in acetic acid solution (1mL), acetic acid (5mL), water (1mL), and stir the reaction solution at 60°C for 16 hours. Add the reaction solution to Saturated sodium bicarbonate neutralized (20mL), extracted with ethyl acetate (30mL x 3). The combined organic phases were washed with saturated brine (50mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was obtained by preparative HPLC (NH4HCO3) Product L111 (22 mg, white solid, yield 22.7%).ESI-MS: m/z=440.1[M+H]. 1 H NMR (DMSO-d6, 400MHz): δ10.45-9.90 (m, 1H) ,8.81(s,1H),8.47(d,J=8.8Hz,1H),8.41(d,J=5.6Hz,1H),8.27-8.26(m,2H),8.04(d,J=9.2Hz, 1H),7.97(s,1H),7.68(d,J=2.4Hz,1H),7.56(dd,J=2.8Hz,J=9.2Hz,1H),7.31(d,J=2.4Hz,1H) , 6.78(dd, J=2.4Hz, J=5.6Hz, 1H), 3.85(s, 3H), 3.42-3.31(m, 2H), 1.15(t, J=7.2Hz, 3H).
实施例112：化合物L112的制备Embodiment 112: Preparation of Compound L112
Figure PCTCN2022143403-appb-000134
Figure PCTCN2022143403-appb-000134
步骤1、将5-溴-2-氯-3-甲基嘧啶-4(3H)-酮(500mg,2.24mmol)，甲胺盐酸盐(268mg,2.69mmol)和DIEA(289mg,6.72mmol)溶于THF(5mL)中，反应液在室温下反应过夜，得到112-1(500mg，白色固体，产率89％)。ESI-MS：m/z＝250.1,252.0[M+H] +。 Step 1, 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (500mg, 2.24mmol), methylamine hydrochloride (268mg, 2.69mmol) and DIEA (289mg, 6.72mmol) It was dissolved in THF (5 mL), and the reaction solution was reacted overnight at room temperature to obtain 112-1 (500 mg, white solid, yield 89%). ESI-MS: m/z = 250.1, 252.0 [M+H] + .
步骤2、将112-1(350mg,1.4mmol)，x-phos(66mg，0.14mmol)，乙酸钾(411mg,4.2mmol)和Pd 2(dba) 3(64mg，0.07mmol)溶于1,4-二氧六环(10mL)中，氮气置换后反应液在70℃下搅拌5小时得到化合物112-2的反应液。LCMS监测反应结束后无需后处理，直接投入下一步。ESI-MS：m/z＝216.0[M+H-82] +。 Step 2. Dissolve 112-1 (350mg, 1.4mmol), x-phos (66mg, 0.14mmol), potassium acetate (411mg, 4.2mmol) and Pd 2 (dba) 3 (64mg, 0.07mmol) in 1,4 - In dioxane (10 mL), the reaction solution was replaced with nitrogen and stirred at 70° C. for 5 hours to obtain a reaction solution of compound 112-2. After the LCMS monitoring reaction, there is no need for post-processing, and it can be directly put into the next step. ESI-MS: m/z = 216.0 [M+H-82] + .
步骤3、2-氯喹啉-6-醇(250mg,1.4mmol),碳酸钾(579mg,4.2mmol)，水(2mL)和Pd(dppf)Cl 2(102mg,0.14mmol)加入到步骤2得到的112-2的反应液中。氮气置换后反应液在75℃油浴中搅拌3小时。反应液冷却至室温，浓缩除去1，4-二氧六环，残余物通过C18反向柱提纯(乙腈:水＝5:95到60:40梯度洗脱)得到产物112-3(300mg,黄色固体，产率68.3％)。ESI-MS：m/z＝315.1[M+H] +。 Step 3, 2-chloroquinolin-6-ol (250mg, 1.4mmol), potassium carbonate (579mg, 4.2mmol), water (2mL) and Pd(dppf)Cl 2 (102mg, 0.14mmol) were added to the obtained 112-2 in the reaction solution. After nitrogen replacement, the reaction solution was stirred in an oil bath at 75° C. for 3 hours. The reaction solution was cooled to room temperature, concentrated to remove 1,4-dioxane, and the residue was purified by C18 reverse column (acetonitrile:water=5:95 to 60:40 gradient elution) to obtain the product 112-3 (300 mg, yellow Solid, 68.3% yield). ESI-MS: m/z = 315.1 [M+H] + .
步骤4、将112-3(150mg,0.48mmol)溶于DMF(10mL)中，向溶液中加入叔丁醇钾(160.5mg,1.44mmol)和2-溴-4-氟吡啶(126mg,0.72mmol)。反应液在室温下搅拌10分钟。反应液浓缩后残余物通过C18反向柱提纯(乙腈:水＝35:65到40:60梯度洗脱)得到112-4(100mg,黄色固体,产率44.6％)。ESI-MS：m/z＝470.1[M+H] +。 Step 4. Dissolve 112-3 (150mg, 0.48mmol) in DMF (10mL), add potassium tert-butoxide (160.5mg, 1.44mmol) and 2-bromo-4-fluoropyridine (126mg, 0.72mmol ). The reaction was stirred at room temperature for 10 minutes. After the reaction solution was concentrated, the residue was purified by a C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 112-4 (100 mg, yellow solid, yield 44.6%). ESI-MS: m/z = 470.1 [M+H] + .
步骤5、将112-4(100mg,0.21mmol)，x-phos(10mg，0.02mmol)，乙酰胺(37mg，0.63mmol)碳酸铯(205mg,0.63mmol)和Pd 2(dba) 3(9.6mg，0.01mmol)溶于1,4-二氧六环(5mL)中，氮气置换后反应液在85℃下搅拌1小时。过滤，浓缩，高效液相制备色谱(0.1％甲酸水溶液/乙腈)纯化得到产物L112(32mg,黄色固体，产率33.5％)。ESI-MS：m/z＝449.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.55(s,1H),8.76(s,1H),8.45(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.22(d,J＝6.0Hz,1H),8.04(d,J＝9.2Hz,1H),7.81(s,1H),7.72(d,J＝2.0Hz,1H),7.69(d,J＝2.8Hz,1H),7.54(dd,J＝6.4Hz,1H),6.75(dd,J＝5.7,3.2Hz,1H),4.70-4.56(m,2H),3.80-3.73(m,2H),3.43(s,3H),2.03(s,3H)。 Step 5, 112-4 (100mg, 0.21mmol), x-phos (10mg, 0.02mmol), acetamide (37mg, 0.63mmol) cesium carbonate (205mg, 0.63mmol) and Pd 2 (dba) 3 (9.6mg , 0.01 mmol) was dissolved in 1,4-dioxane (5 mL), and the reaction solution was stirred at 85° C. for 1 hour after nitrogen replacement. It was filtered, concentrated, and purified by preparative HPLC (0.1% aqueous formic acid/acetonitrile) to obtain the product L112 (32 mg, yellow solid, yield 33.5%). ESI-MS: m/z=449.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.55(s, 1H), 8.76(s, 1H), 8.45(d, J= 8.8Hz, 1H), 8.27(d, J=8.8Hz, 1H), 8.22(d, J=6.0Hz, 1H), 8.04(d, J=9.2Hz, 1H), 7.81(s, 1H), 7.72 (d,J=2.0Hz,1H),7.69(d,J=2.8Hz,1H),7.54(dd,J=6.4Hz,1H),6.75(dd,J=5.7,3.2Hz,1H),4.70 -4.56(m,2H),3.80-3.73(m,2H),3.43(s,3H),2.03(s,3H).
实施例113：化合物L113的制备Embodiment 113: Preparation of Compound L113
Figure PCTCN2022143403-appb-000135
Figure PCTCN2022143403-appb-000135
步骤1、将112-3(100mg,0.32mmol)溶于DMF(10mL)中，向溶液中加入碳酸钾(132mg,0.96mmol)和2-溴-4-氟吡啶(84mg,0.48mmol)。氮气置换后反应液在80℃搅拌过夜。反应液浓缩后残余物通过C18反向柱提纯(乙腈:水＝35:65到40:60梯度洗脱)得到113-1(100mg,黄色固体,产率70.4％)。ESI-MS：m/z＝452.1[M+H] +。 Step 1. Dissolve 112-3 (100mg, 0.32mmol) in DMF (10mL), and add potassium carbonate (132mg, 0.96mmol) and 2-bromo-4-fluoropyridine (84mg, 0.48mmol) to the solution. After nitrogen replacement, the reaction solution was stirred overnight at 80°C. After the reaction solution was concentrated, the residue was purified by a C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 113-1 (100 mg, yellow solid, yield 70.4%). ESI-MS: m/z = 452.1 [M+H] + .
步骤2、将113-1(100mg,0.22mmol)，x-phos(42mg，0.08mmol)，乙酰胺(39mg，0.66mmol)碳酸铯(218mg,0.66mmol)和Pd 2(dba) 3(40mg，0.04mmol)溶于1,4-二氧六环(5mL)中，氮气置换后反应 液在85℃下搅拌1小时。过滤，浓缩，高效液相制备色谱(0.1％甲酸水溶液/乙腈)纯化得到产物L113(37mg,黄色固体，产率38.9％)。ESI-MS：m/z＝429.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ10.55(s,1H),8.68(s,1H),8.39(d,J＝8.8Hz,1H),8.27(d,J＝8.8Hz,1H),8.22(d,J＝5.6Hz,1H),7.99(d,J＝9.2Hz,1H),7.72(s,1H),7.69(d,J＝2.8Hz,1H),7.54(dd,J＝6.4Hz,1H),6.75(dd,J＝5.7,3.2Hz,1H),4.21(t,J＝9.2,2H),3.85(t,J＝8.8,2H),3.28(s,3H),2.03(s,3H)。 Step 2, 113-1 (100mg, 0.22mmol), x-phos (42mg, 0.08mmol), acetamide (39mg, 0.66mmol) cesium carbonate (218mg, 0.66mmol) and Pd 2 (dba) 3 (40mg, 0.04 mmol) was dissolved in 1,4-dioxane (5 mL), and the reaction solution was stirred at 85° C. for 1 hour after nitrogen replacement. It was filtered, concentrated, and purified by preparative HPLC (0.1% aqueous formic acid/acetonitrile) to obtain the product L113 (37 mg, yellow solid, yield 38.9%). ESI-MS: m/z=429.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ10.55(s, 1H), 8.68(s, 1H), 8.39(d, J= 8.8Hz, 1H), 8.27(d, J=8.8Hz, 1H), 8.22(d, J=5.6Hz, 1H), 7.99(d, J=9.2Hz, 1H), 7.72(s, 1H), 7.69 (d,J=2.8Hz,1H),7.54(dd,J=6.4Hz,1H),6.75(dd,J=5.7,3.2Hz,1H),4.21(t,J=9.2,2H),3.85( t,J=8.8,2H), 3.28(s,3H), 2.03(s,3H).
实施例114：化合物L114的制备Embodiment 114: Preparation of Compound L114
Figure PCTCN2022143403-appb-000136
Figure PCTCN2022143403-appb-000136
步骤1、将5-(6-羟基喹啉-2-基)-3-甲基-2-(甲胺基)嘧啶-4(3H)-酮(282mg,1.0mmol)溶于的DMF(2.0mL)，加入碳酸钾(276mg,2.0mmol)和叔丁醇钾(112mg,1.0mmol)，室温下下搅拌5分钟。加入2,3,4-三氟吡啶(200mg,1.5mmol)，室温下下反应2小时。过滤，滤液C18反相柱层析纯化(0.1％三氟乙酸水溶液/乙腈＝95:5到20:80梯度洗脱)得到114-1(345mg,黄色固体，产率87％)。ESI-MS：m/z＝395.9[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.80(s,1H),8.48(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.06(d,J＝9.2Hz,1H),7.94(d,J＝6.0Hz,1H),7.78(d,J＝2.8Hz,1H),7.64(dd,J＝9.2,2.8Hz,1H),7.60(brs,1H),7.00(t,J＝5.6Hz,1H),3.39(s,3H),2.95(d,J＝2.0Hz,3H)。 Step 1, 5-(6-hydroxyquinolin-2-yl)-3-methyl-2-(methylamino)pyrimidin-4(3H)-one (282mg, 1.0mmol) was dissolved in DMF (2.0 mL), potassium carbonate (276mg, 2.0mmol) and potassium tert-butoxide (112mg, 1.0mmol) were added, and stirred at room temperature for 5 minutes. Add 2,3,4-trifluoropyridine (200mg, 1.5mmol) and react at room temperature for 2 hours. After filtration, the filtrate was purified by C18 reverse phase column chromatography (0.1% trifluoroacetic acid aqueous solution/acetonitrile=95:5 to 20:80 gradient elution) to obtain 114-1 (345 mg, yellow solid, yield 87%). ESI-MS: m/z＝395.9[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.80(s, 1H), 8.48 (d, J＝8.8Hz, 1H), 8.26 (d, J=8.8Hz, 1H), 8.06(d, J=9.2Hz, 1H), 7.94(d, J=6.0Hz, 1H), 7.78(d, J=2.8Hz, 1H), 7.64(dd , J=9.2, 2.8Hz, 1H), 7.60 (brs, 1H), 7.00 (t, J=5.6Hz, 1H), 3.39 (s, 3H), 2.95 (d, J=2.0Hz, 3H).
步骤2、将114-1(345mg,0.87mmol)，对甲氧基苄胺(359mg,2.6mmol)和二异丙基乙胺(449mg，3.5mmol)溶于N-甲基吡咯烷酮(10mL)中，氮气置换后反应液在140℃下搅拌17小时。反应液减压浓缩，得到114-2(粗产物，直接用于下一步反应)。ESI-MS:m/z＝513.0[M+H] +。 Step 2. Dissolve 114-1 (345mg, 0.87mmol), p-methoxybenzylamine (359mg, 2.6mmol) and diisopropylethylamine (449mg, 3.5mmol) in N-methylpyrrolidone (10mL) , and the reaction solution was stirred at 140° C. for 17 hours after nitrogen replacement. The reaction solution was concentrated under reduced pressure to obtain 114-2 (crude product, directly used in the next reaction). ESI-MS: m/z = 513.0 [M+H] + .
步骤3、将114-2(粗产物,0.87mmol)溶于三氟乙酸(10mL)中，加热至65℃，搅拌1小时。浓缩，C18反相柱层析纯化(0.1％三氟乙酸水溶液/乙腈＝95:5到30:70梯度洗脱)，浓缩除去乙腈，1.0M碳酸钾水溶液调节pH至8，产物析出，过滤，大量水洗涤，干燥，得到L114(180mg,黄色固体)。ESI-MS:m/z＝393.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.78(s,1H),8.43(d,J＝8.8Hz,1H),8.24(d,J＝8.8Hz,1H),8.01(d,J＝8.8Hz,1H),7.68(d,J＝5.6Hz,1H),7.58-7.53(m,3H),6.33(brs,2H),6.22(dd,J＝5.6,5.2Hz,1H),3.39(s,3H),2.95(d,J＝4.4Hz,3H).。 Step 3. Dissolve 114-2 (crude product, 0.87 mmol) in trifluoroacetic acid (10 mL), heat to 65° C., and stir for 1 hour. Concentrate, purify by C18 reverse-phase column chromatography (0.1% trifluoroacetic acid aqueous solution/acetonitrile=95:5 to 30:70 gradient elution), concentrate to remove acetonitrile, adjust pH to 8 with 1.0M potassium carbonate aqueous solution, the product is precipitated, filtered, Washed with plenty of water and dried to give L114 (180 mg, yellow solid). ESI-MS: m/z＝393.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.78(s, 1H), 8.43(d, J＝8.8Hz, 1H), 8.24 (d,J=8.8Hz,1H),8.01(d,J=8.8Hz,1H),7.68(d,J=5.6Hz,1H),7.58-7.53(m,3H),6.33(brs,2H) , 6.22 (dd, J = 5.6, 5.2Hz, 1H), 3.39 (s, 3H), 2.95 (d, J = 4.4Hz, 3H).
实施例115：化合物L115的制备Embodiment 115: Preparation of Compound L115
Figure PCTCN2022143403-appb-000137
Figure PCTCN2022143403-appb-000137
将5-(6-(2-溴吡啶-4-基)氧基)喹啉-2-基)-2-(二甲氨基)-3-甲基嘧啶-(3H)-酮(参照化合物13-1的方法制备，100mg,0.22mmol)，氨基甲酸酯(66mg，0.85mmol)，碳酸铯(287mg,0.88mmol)，x-phos(42mg，0.088mmol)和Pd 2(dba) 3(40mg，0.044mmol)溶于二氧六环(5mL)中，氮气置换后反应液在100℃搅拌1h。反应液冷却至室温后过滤，有机相浓缩后残余物通过HPLC(0.1％FA)提纯,得到产物L115(12mg,黄色固体)。ESI-MS：m/z＝447.1[M+H] +. 1H NMR(400MHz,DMSO)δ10.27(s,1H),8.76(s,1H),8.46(d,J＝8.8Hz,1H),8.32(d,J＝8.8Hz,1H),8.19(d,J＝5.7Hz,1H),8.07(d,J＝9.1Hz,1H),7.72(d,J＝2.6Hz,1H),7.57(dd,J＝9.1,2.7Hz,1H),7.45(d,J＝2.2Hz,1H),6.74(dd,J＝5.7,2.3Hz,1H),3.59(s,3H),3.48(s,3H),3.01(s,6H)。 5-(6-(2-bromopyridin-4-yl)oxy)quinolin-2-yl)-2-(dimethylamino)-3-methylpyrimidin-(3H)-one (reference compound 13 -1 prepared by the method, 100mg, 0.22mmol), carbamate (66mg, 0.85mmol), cesium carbonate (287mg, 0.88mmol), x-phos (42mg, 0.088mmol) and Pd 2 (dba) 3 (40mg , 0.044 mmol) was dissolved in dioxane (5 mL), and the reaction solution was stirred at 100° C. for 1 h after nitrogen replacement. The reaction solution was cooled to room temperature and filtered, the organic phase was concentrated and the residue was purified by HPLC (0.1% FA) to obtain the product L115 (12 mg, yellow solid). ESI-MS: m/z=447.1[M+H] + . 1 H NMR (400MHz, DMSO) δ10.27(s, 1H), 8.76(s, 1H), 8.46(d, J=8.8Hz, 1H ),8.32(d,J=8.8Hz,1H),8.19(d,J=5.7Hz,1H),8.07(d,J=9.1Hz,1H),7.72(d,J=2.6Hz,1H), 7.57(dd, J=9.1,2.7Hz,1H),7.45(d,J=2.2Hz,1H),6.74(dd,J=5.7,2.3Hz,1H),3.59(s,3H),3.48(s ,3H), 3.01(s,6H).
实施例116：化合物L116的制备Embodiment 116: Preparation of Compound L116
Figure PCTCN2022143403-appb-000138
Figure PCTCN2022143403-appb-000138
步骤1、将2,3-二氟吡啶(11.5g,100mmol)溶于无水四氢呋喃(200mL)中，冷却至-78℃，缓慢滴加2.5M的正丁基锂正己烷溶液(42mL,105mmol)。反应液在-78℃下搅拌1小时。加入六氯乙烷(26g,110mmol)，将反应液在-78℃下反应1小时，TLC监测反应完毕，饱和氯化铵水溶液(200mL)淬灭反应，乙醚萃取(300mL x 2)，干燥，浓缩，得到4-氯-2,3-二氟吡啶(粗品，黄色油状物，直接用于下一步反应)。 1H NMR(CDCl 3,400MHz):δ7.89(d,J＝5.2Hz,1H),7.25(t,J＝5.2Hz,1H)。 Step 1. Dissolve 2,3-difluoropyridine (11.5g, 100mmol) in anhydrous tetrahydrofuran (200mL), cool to -78°C, and slowly add 2.5M n-butyllithium n-hexane solution (42mL, 105mmol ). The reaction was stirred at -78°C for 1 hour. Hexachloroethane (26g, 110mmol) was added, and the reaction solution was reacted at -78°C for 1 hour. The completion of the reaction was monitored by TLC, and the reaction was quenched with saturated aqueous ammonium chloride solution (200mL), extracted with ether (300mL x 2), and dried. Concentration gave 4-chloro-2,3-difluoropyridine (crude product, yellow oil, directly used in the next reaction). 1 H NMR (CDCl 3 , 400MHz): δ7.89 (d, J=5.2Hz, 1H), 7.25 (t, J=5.2Hz, 1H).
步骤2、将4-氯-2,3-二氟吡啶(13g,87.2mmol)，无水氟化钾(20.2g,349mmol)和四甲基氯化铵(1.9g,17.4mmol)加入到二甲亚砜(100mL)中，氮气置换，在氮气保护下，加热至150℃油浴中搅拌17小时。反应液冷却至室温，减压蒸馏(70℃，0.02MPa)，得到2,3,4-三氟吡啶(5.5g，产率47％)。 1H NMR(CDCl 3,400MHz):δ7.95(dd,J＝5.6,6.4Hz,1H),7.25(dt,J＝8.4,5.2Hz,1H)。 Step 2, 4-chloro-2,3-difluoropyridine (13g, 87.2mmol), anhydrous potassium fluoride (20.2g, 349mmol) and tetramethylammonium chloride (1.9g, 17.4mmol) were added to di Methyl sulfoxide (100 mL) was replaced with nitrogen, and heated to 150° C. in an oil bath under nitrogen protection and stirred for 17 hours. The reaction liquid was cooled to room temperature and distilled under reduced pressure (70°C, 0.02MPa) to obtain 2,3,4-trifluoropyridine (5.5g, yield 47%). 1 H NMR (CDCl 3 , 400 MHz): δ7.95 (dd, J=5.6, 6.4 Hz, 1H), 7.25 (dt, J=8.4, 5.2 Hz, 1H).
步骤3、将19-6(500mg,1.6mmol)溶于的DMF(10mL)，加入碳酸钾(447mg,3.2mmol)和叔丁醇钾(179mg,1.6mmol)，室温下下搅拌5分钟。加入2,3,4-三氟吡啶(3)(319mg,2.4mmol)，室温下下反应2小时。过滤，滤液C18反相柱层析纯化(0.1％三氟乙酸水溶液/乙腈＝95:5到20:80梯度洗脱)得到116-1(350mg,黄色固体，产率51％)。ESI-MS：m/z＝424.9[M+H] +. Step 3. Dissolve 19-6 (500 mg, 1.6 mmol) in DMF (10 mL), add potassium carbonate (447 mg, 3.2 mmol) and potassium tert-butoxide (179 mg, 1.6 mmol), and stir at room temperature for 5 minutes. 2,3,4-Trifluoropyridine (3) (319 mg, 2.4 mmol) was added and reacted at room temperature for 2 hours. After filtration, the filtrate was purified by C18 reverse phase column chromatography (0.1% aqueous trifluoroacetic acid/acetonitrile=95:5 to 20:80 gradient elution) to obtain 116-1 (350 mg, yellow solid, yield 51%). ESI-MS: m/z=424.9[M+H] + .
步骤4、将116-1(350mg,0.82mmol)，对甲氧基苄胺(339mg,2.47mmol)和二异丙基乙胺(423mg，3.28mmol)溶于N-甲基吡咯烷酮(5mL)中，氮气置换后反应液在140℃下搅拌8小时。反应液减压浓缩，C18反相柱层析纯化(0.1％三氟乙酸水溶液/乙腈＝95:5到20:80梯度洗脱)，得到116-2(210mg,黄色固体，产率47％)。ESI-MS:m/z＝421.9[M-PMB+1] +。 Step 4. Dissolve 116-1 (350mg, 0.82mmol), p-methoxybenzylamine (339mg, 2.47mmol) and diisopropylethylamine (423mg, 3.28mmol) in N-methylpyrrolidone (5mL) , and the reaction solution was stirred at 140° C. for 8 hours after nitrogen replacement. The reaction solution was concentrated under reduced pressure and purified by C18 reverse phase column chromatography (0.1% aqueous trifluoroacetic acid/acetonitrile=95:5 to 20:80 gradient elution) to obtain 116-2 (210 mg, yellow solid, yield 47%) . ESI-MS: m/z = 421.9 [M-PMB+1] + .
步骤5、将116-2(210mg,0.39mmol)溶于三氟乙酸(10mL)中，加热至65℃，搅拌17小时。浓缩，C18反相柱层析纯化(0.1％三氟乙酸水溶液/乙腈＝95:5到40:60梯度洗脱)，浓缩除去乙腈，1.0M碳酸氢钠水溶液调节pH至8，产物析出，过滤，大量水洗涤，干燥，得到L116(110mg,黄色固体，产率67％)。ESI-MS:m/z＝422.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.95(d,J＝3.2Hz,1H),8.84(s,1H),8.58(d,J＝8.4Hz,1H),8.34(d,J＝8.4Hz,1H),8.07(d,J＝3.2Hz,1H),7.71(d,J＝5.6Hz,1H),7.25(d,J＝7.6Hz,1H),6.40(s,2H),6.31(dd,J＝5.6,5.2Hz,1H),4.43-4.38(m,1H),3.41(s,3H),1.26(d,J＝6.4Hz,6H)。 Step 5. Dissolve 116-2 (210 mg, 0.39 mmol) in trifluoroacetic acid (10 mL), heat to 65° C., and stir for 17 hours. Concentrate, purify by C18 reverse phase column chromatography (0.1% trifluoroacetic acid aqueous solution/acetonitrile=95:5 to 40:60 gradient elution), concentrate to remove acetonitrile, adjust the pH to 8 with 1.0M aqueous sodium bicarbonate solution, and precipitate the product, filter , washed with a large amount of water and dried to obtain L116 (110 mg, yellow solid, yield 67%). ESI-MS: m/z＝422.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.95(d, J＝3.2Hz, 1H), 8.84(s, 1H), 8.58 (d, J=8.4Hz, 1H), 8.34(d, J=8.4Hz, 1H), 8.07(d, J=3.2Hz, 1H), 7.71(d, J=5.6Hz, 1H), 7.25(d ,J=7.6Hz,1H),6.40(s,2H),6.31(dd,J=5.6,5.2Hz,1H),4.43-4.38(m,1H),3.41(s,3H),1.26(d, J=6.4Hz, 6H).
实施例117：化合物L117的制备Embodiment 117: Preparation of Compound L117
Figure PCTCN2022143403-appb-000139
Figure PCTCN2022143403-appb-000139
步骤1、将4-1(131mg,0.42mmol)溶于的DMF(5.0mL)，加入碳酸钾(116mg,0.84mmol)和叔丁醇钾(47mg,0.42mmol)，室温下下搅拌5分钟。加入2,3,4-三氟吡啶(75mg,0.5mmol)，室温下反应2小时。过滤，滤液C18反相柱层析纯化(0.1％三氟乙酸水溶液/乙腈＝95:5到20:80梯度洗脱)得到117-1(110mg,黄色固体，产率62％)。ESI-MS：m/z＝424.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.79(s,1H),8.48(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.06(d,J＝9.2Hz,1H),7.94(d,J＝5.6Hz,1H),7.78(d,J＝2.8Hz,1H),7.64(dd,J＝9.6,2.8Hz,1H),7.18(d,J＝7.6Hz,1H),7.00(t,J＝5.6Hz,1H),4.40-4.35(m,1H),3.41(s,3H),1.26(d,J＝6.8Hz,6H)。 Step 1. Dissolve 4-1 (131 mg, 0.42 mmol) in DMF (5.0 mL), add potassium carbonate (116 mg, 0.84 mmol) and potassium tert-butoxide (47 mg, 0.42 mmol), and stir at room temperature for 5 minutes. Add 2,3,4-trifluoropyridine (75mg, 0.5mmol) and react at room temperature for 2 hours. After filtration, the filtrate was purified by C18 reverse-phase column chromatography (0.1% aqueous trifluoroacetic acid/acetonitrile=95:5 to 20:80 gradient elution) to obtain 117-1 (110 mg, yellow solid, yield 62%). ESI-MS: m/z=424.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.79(s, 1H), 8.48(d, J=8.8Hz, 1H), 8.26 (d, J=8.8Hz, 1H), 8.06(d, J=9.2Hz, 1H), 7.94(d, J=5.6Hz, 1H), 7.78(d, J=2.8Hz, 1H), 7.64(dd ,J=9.6,2.8Hz,1H),7.18(d,J=7.6Hz,1H),7.00(t,J=5.6Hz,1H),4.40-4.35(m,1H),3.41(s,3H) , 1.26 (d, J=6.8Hz, 6H).
步骤2、将117-1(100mg,0.24mmol)，对甲氧基苄胺(97mg,0.71mmol)和二异丙基乙胺(122mg，0.94mmol)溶于N-甲基吡咯烷酮(5mL)中，氮气置换后反应液在140℃下搅拌17小时。反应液减压浓缩，C18反相柱层析纯化(0.5％三氟乙酸水溶液/乙腈＝95:5到50:50梯度洗脱)，得到117-2(85mg，黄色固体，产率67％)。ESI-MS:m/z＝541.3[M+H] +。 Step 2. Dissolve 117-1 (100mg, 0.24mmol), p-methoxybenzylamine (97mg, 0.71mmol) and diisopropylethylamine (122mg, 0.94mmol) in N-methylpyrrolidone (5mL) , and the reaction solution was stirred at 140° C. for 17 hours after nitrogen replacement. The reaction solution was concentrated under reduced pressure and purified by C18 reverse phase column chromatography (0.5% aqueous trifluoroacetic acid/acetonitrile=95:5 to 50:50 gradient elution) to obtain 117-2 (85 mg, yellow solid, yield 67%) . ESI-MS: m/z = 541.3 [M+H] + .
步骤3、将117-2(80mg,0.15mmol)溶于乙腈(2.0mL)中，加入氯甲酸甲酯(21mg,0.22mmol)和铟粉(3.0mg,0.03mmol)，加热至30℃，搅拌72小时。浓缩，得到117-3(直接用于下一步)。ESI-MS:m/z＝599.0[M+H] +。 Step 3. Dissolve 117-2 (80mg, 0.15mmol) in acetonitrile (2.0mL), add methyl chloroformate (21mg, 0.22mmol) and indium powder (3.0mg, 0.03mmol), heat to 30°C and stir 72 hours. Concentration afforded 117-3 (used directly in the next step). ESI-MS: m/z = 599.0 [M+H] + .
步骤4、将117-3(粗产物,0.15mmol)溶于三氟乙酸(5mL)中，加热至60℃，搅拌17小时。浓缩，高效制备液相色谱纯化(0.1％甲酸水溶液/乙腈)，冻干，得到L117(17mg,黄色固体，产率12.5％)。ESI-MS:m/z＝479.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ9.97(brs,1H),8.78(s,1H),8.46(d,J＝8.8Hz,1H),8.25(d,J＝8.8Hz,1H),8.08(d,J＝5.6Hz,1H),8.04(d,J＝9.2Hz,1H),7.71(d,J＝2.8Hz,1H),7.61(dd,J＝9.2,2.8Hz,1H),7.17(brs,1H),6.89(t,J＝5.6Hz,1H),4.39-4.36(m,1H),3.68(s,3H),3.41(s,3H),1.25(t,J＝6.4Hz,6H)。 Step 4. Dissolve 117-3 (crude product, 0.15 mmol) in trifluoroacetic acid (5 mL), heat to 60° C., and stir for 17 hours. Concentrate, purify by HPLC (0.1% aqueous formic acid/acetonitrile), and lyophilize to obtain L117 (17 mg, yellow solid, yield 12.5%). ESI-MS: m/z＝479.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.97(brs, 1H), 8.78(s, 1H), 8.46(d, J＝ 8.8Hz, 1H), 8.25(d, J=8.8Hz, 1H), 8.08(d, J=5.6Hz, 1H), 8.04(d, J=9.2Hz, 1H), 7.71(d, J=2.8Hz ,1H),7.61(dd,J=9.2,2.8Hz,1H),7.17(brs,1H),6.89(t,J=5.6Hz,1H),4.39-4.36(m,1H),3.68(s, 3H), 3.41(s, 3H), 1.25(t, J=6.4Hz, 6H).
实施例118：化合物L118的制备Embodiment 118: Preparation of Compound L118
Figure PCTCN2022143403-appb-000140
Figure PCTCN2022143403-appb-000140
步骤1、将2-(乙氨基)-5-(6-羟基-1,8-萘啶-2-基)-3-甲基嘧啶-4(3H)-酮(参照化合物19-6的方法制备，200mg,0.67mmol)溶于NMP(5mL)中，向溶液中加入碳酸钾(185mg,1.34mmol)和2-溴-4-氟吡啶(142mg,0.81mmol)。氮气置换后反应液在90℃搅拌过夜。反应液浓缩后残余物通过C18反向柱提纯(乙腈：水＝35:65到40:60梯度洗脱)得到118-1(50mg,黄色固体,产率16.5％)。ESI-MS：m/z＝452.8[M+H] +。 Step 1, 2-(ethylamino)-5-(6-hydroxy-1,8-naphthyridin-2-yl)-3-methylpyrimidin-4(3H)-one (refer to the method of compound 19-6 Preparation, 200mg, 0.67mmol) was dissolved in NMP (5mL), potassium carbonate (185mg, 1.34mmol) and 2-bromo-4-fluoropyridine (142mg, 0.81mmol) were added to the solution. After nitrogen replacement, the reaction solution was stirred overnight at 90°C. After the reaction solution was concentrated, the residue was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 118-1 (50 mg, yellow solid, yield 16.5%). ESI-MS: m/z = 452.8 [M+H] + .
步骤2、将118-1(65mg,0.14mmol)，1-甲基-1H-吡唑-4-硼酸(45mg，0.22mmol)，碳酸钾(40mg,0.28mmol)和Pd(dppf)Cl 2(10mg，0.014mmol)溶于1,4-二氧六环/水(5/0.5mL)中，氮气置换后反应液在75℃下搅拌3小时。反应液冷却至室温后过滤，有机相浓缩后残余物通过HPLC(0.1％FA)提纯,得到产物L118(12mg,黄色固体)。ESI-MS：m/z＝455.1[M+H] +. 1H NMR(DMSO-d 6,400MHz)δ8.95(d,J＝3.2Hz,1H),8.86(s,1H),8.60(d,J＝8.8Hz,1H),8.45(d,J＝5.6Hz,1H),8.35(d,J＝8.8Hz,1H),8.28(s,1H),8.19(d,J＝2.8Hz,1H),7.99(s,1H),7.68(s,1H),7.38(d,J＝2.0Hz,1H),6.89(dd,J＝5.2,2.4Hz,1H),3.85(s,3H),3.51(q,J＝7.2Hz,2H),3.40(s,3H),1.12(t,J＝7.2Hz,3H)。 Step 2, 118-1 (65mg, 0.14mmol), 1-methyl-1H-pyrazole-4-boronic acid (45mg, 0.22mmol), potassium carbonate (40mg, 0.28mmol) and Pd(dppf)Cl 2 ( 10mg, 0.014mmol) was dissolved in 1,4-dioxane/water (5/0.5mL), and the reaction solution was stirred at 75°C for 3 hours after nitrogen replacement. The reaction solution was cooled to room temperature and filtered, the organic phase was concentrated and the residue was purified by HPLC (0.1% FA) to obtain the product L118 (12 mg, yellow solid). ESI-MS: m/z=455.1[M+H] + . 1 H NMR (DMSO-d 6, 400MHz) δ8.95(d, J=3.2Hz, 1H), 8.86(s, 1H), 8.60( d,J=8.8Hz,1H),8.45(d,J=5.6Hz,1H),8.35(d,J=8.8Hz,1H),8.28(s,1H),8.19(d,J=2.8Hz, 1H),7.99(s,1H),7.68(s,1H),7.38(d,J=2.0Hz,1H),6.89(dd,J=5.2,2.4Hz,1H),3.85(s,3H), 3.51(q, J=7.2Hz, 2H), 3.40(s, 3H), 1.12(t, J=7.2Hz, 3H).
实施例119：化合物L119的制备Embodiment 119: Preparation of compound L119
Figure PCTCN2022143403-appb-000141
Figure PCTCN2022143403-appb-000141
步骤1、将2-(二甲氨基)-5-(6-羟基喹啉-2-基)-3-甲基嘧啶-4(3H)-酮(参照化合物4-1的方法制备，90mg,0.30mmol)，2,3,4-三氟吡啶(60％)(100mg，0.45mmol)，碳酸钾(124.2mg,0.90mmol)和叔丁醇钾(84mg，0.75mmol)溶于DMF(5mL)中，氮气置换后反应液在95℃搅拌1h。反应液浓缩后残余物通过C18反向柱提纯(乙腈：水＝35:65到40:60梯度洗脱)得到119-1(60mg,黄色固体,产率48％)。ESI-MS：m/z＝410.1[M+H]+。Step 1. 2-(dimethylamino)-5-(6-hydroxyquinolin-2-yl)-3-methylpyrimidin-4(3H)-one (prepared according to the method of compound 4-1, 90mg, 0.30mmol), 2,3,4-trifluoropyridine (60%) (100mg, 0.45mmol), potassium carbonate (124.2mg, 0.90mmol) and potassium tert-butoxide (84mg, 0.75mmol) were dissolved in DMF (5mL) , the reaction solution was stirred at 95° C. for 1 h after nitrogen replacement. After the reaction solution was concentrated, the residue was purified by a C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 119-1 (60 mg, yellow solid, yield 48%). ESI-MS: m/z = 410.1 [M+H]+.
步骤2、将119-1(60mg,0.146mmol)，PMB-NH 2(60mg，0.439mmol)和DIEA(75mg，0.584mmol)溶于NMP(5mL)中，氮气置换后反应液在140℃搅拌12h。反应液通过C18反向柱提纯(乙腈：水＝35:65到40:60梯度洗脱)得到119-2(50mg,黄色固体,产率66.7％)。ESI-MS：m/z＝527.0[M+H] +。 Step 2. Dissolve 119-1 (60mg, 0.146mmol), PMB-NH 2 (60mg, 0.439mmol) and DIEA (75mg, 0.584mmol) in NMP (5mL), and stir the reaction solution at 140°C for 12h after nitrogen replacement . The reaction solution was purified by C18 reverse column (acetonitrile:water=35:65 to 40:60 gradient elution) to obtain 119-2 (50 mg, yellow solid, yield 66.7%). ESI-MS: m/z = 527.0 [M+H] + .
步骤3、将119-2溶于TFA(5mL)中，氮气置换后反应液在60℃搅拌30min。反应结束后浓缩，残余物通过HPLC(0.1％NaHCO 3)提纯,得到产物L119(20mg,黄色固体，产率48.8％)。ESI-MS：m/z＝407.1[M+H] +. 1H NMR(400MHz,DMSO)δ8.74(s,1H),8.43(d,J＝8.8Hz,1H),8.29(d,J＝8.7Hz,1H),8.03(d,J＝10.3Hz,1H),7.69(d,J＝5.6Hz,1H),7.62–7.50(m,2H),6.34(s,2H),6.23(t,J＝5.5Hz,1H),3.47(s,3H),3.00(s,6H)。 Step 3. 119-2 was dissolved in TFA (5 mL), and the reaction solution was stirred at 60° C. for 30 min after nitrogen replacement. After the reaction was completed, it was concentrated, and the residue was purified by HPLC (0.1% NaHCO 3 ) to obtain the product L119 (20 mg, yellow solid, yield 48.8%). ESI-MS: m/z＝407.1[M+H] + . 1 H NMR (400MHz, DMSO) δ8.74(s, 1H), 8.43(d, J＝8.8Hz, 1H), 8.29(d, J =8.7Hz,1H),8.03(d,J=10.3Hz,1H),7.69(d,J=5.6Hz,1H),7.62–7.50(m,2H),6.34(s,2H),6.23(t , J=5.5Hz, 1H), 3.47(s, 3H), 3.00(s, 6H).
实施例120：化合物L120的制备Embodiment 120: Preparation of Compound L120
Figure PCTCN2022143403-appb-000142
Figure PCTCN2022143403-appb-000142
步骤1、将2-(二甲氨基)-5-(6-羟基喹啉-2-基)-3-甲基嘧啶-4(3H)-酮(100mg,0.34mmol)和碳酸铯(330mg,1.01mmol)加入DMF(3mL)中，向上述溶液中加入2,3,4-三氯吡啶(68mg,0.37mmol)。反应液在90℃搅拌16小时。反应液过滤，滤液经C18反向柱纯化(乙腈：水＝25:75到100:0梯度洗脱)得到产物120-1(85mg，黄色固体，产率57％)。ESI-MS:m/z＝441.8[M+H] +。 Step 1. Combine 2-(dimethylamino)-5-(6-hydroxyquinolin-2-yl)-3-methylpyrimidin-4(3H)-one (100mg, 0.34mmol) and cesium carbonate (330mg, 1.01 mmol) was added to DMF (3 mL), and 2,3,4-trichloropyridine (68 mg, 0.37 mmol) was added to the above solution. The reaction solution was stirred at 90°C for 16 hours. The reaction solution was filtered, and the filtrate was purified by a C18 reverse column (acetonitrile:water=25:75 to 100:0 gradient elution) to obtain product 120-1 (85 mg, yellow solid, yield 57%). ESI-MS: m/z = 441.8 [M+H] + .
步骤2、将120-1(85mg,0.192mmol)，氨基甲酸叔丁酯(226mg,1.93mmol)和碳酸铯(188mg,0.576mmol)溶于1，4-二氧六环(3mL)中，氮气保护下，向上述溶液中加入X-phos(10mg,0.02mmol)和Pd 2(dba) 3(18mg,0.02mmol)。反应液在110℃下搅拌20小时。反应液冷却室温后浓缩，残余物通过硅胶柱层析纯化(二氯甲烷：甲醇＝20:1到12:1梯度洗脱)得到粗产物，粗产物经过制备HPLC(NH 4HCO 3)得到产物L120(15.0mg,黄色固体，产率18.5％)。ESI-MS:m/z＝423.0[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.80(s,1H),8.46(d,J＝8.8Hz,1H),8.39(d,J＝8.8Hz,1H),8.12(d,J＝9.2Hz,1H),7.85(d,J＝5.6Hz,1H),7.67(d,J＝2.8Hz,1H),7.61(dd,J＝9.2,2.4Hz,1H),6.83(s,2H), 6.22(d,J＝6.0Hz,1H),3.48(s,3H),3.04(s,6H)。 Step 2. Dissolve 120-1 (85mg, 0.192mmol), tert-butyl carbamate (226mg, 1.93mmol) and cesium carbonate (188mg, 0.576mmol) in 1,4-dioxane (3mL), nitrogen Under protection, X-phos (10 mg, 0.02 mmol) and Pd 2 (dba) 3 (18 mg, 0.02 mmol) were added to the above solution. The reaction solution was stirred at 110° C. for 20 hours. The reaction solution was cooled to room temperature and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 12:1 gradient elution) to obtain a crude product, which was subjected to preparative HPLC (NH 4 HCO 3 ) to obtain the product L120 (15.0 mg, yellow solid, 18.5% yield). ESI-MS: m/z＝423.0[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.80(s, 1H), 8.46 (d, J＝8.8Hz, 1H), 8.39 (d, J=8.8Hz, 1H), 8.12(d, J=9.2Hz, 1H), 7.85(d, J=5.6Hz, 1H), 7.67(d, J=2.8Hz, 1H), 7.61(dd , J=9.2, 2.4Hz, 1H), 6.83(s, 2H), 6.22(d, J=6.0Hz, 1H), 3.48(s, 3H), 3.04(s, 6H).
实施例121：化合物L121的制备Embodiment 121: Preparation of compound L121
Figure PCTCN2022143403-appb-000143
Figure PCTCN2022143403-appb-000143
步骤1、将5-(6-羟基喹啉-2-基)-2-(异丙胺基)-3-甲基嘧啶-4(3H)-酮(500mg,1.61mmol)溶于DMF(10mL)中，氮气置换后反应液在室温搅拌30分钟。然后加入1a(224mg，1.61mmol),反应液在室温搅拌1小时。残余物加入水(20mL)，用乙酸乙酯(20mL x 2)萃取。有机相合并，饱和盐水(20mL)洗涤，硫酸钠干燥后浓缩，残余物通过C18反向柱纯化(乙腈：水＝30:70到35:65梯度洗脱)得到产物121-1(400mg,黄色固体,产率60.15％)。ESI-MS:m/z＝413.9[M+H] +。 Step 1. Dissolve 5-(6-hydroxyquinolin-2-yl)-2-(isopropylamino)-3-methylpyrimidin-4(3H)-one (500mg, 1.61mmol) in DMF (10mL) , the reaction solution was stirred at room temperature for 30 minutes after nitrogen replacement. Then 1a (224 mg, 1.61 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. The residue was added to water (20 mL), extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over sodium sulfate and concentrated, and the residue was purified by C18 reverse column (acetonitrile: water = 30:70 to 35:65 gradient elution) to obtain product 121-1 (400 mg, yellow solid, yield 60.15%). ESI-MS: m/z = 413.9 [M+H] + .
步骤2、将121-1(100mg,0.24mmol)溶于DMSO(1mL)中，加入双氧水(30％,1mL)，碳酸钾(100mg,0.72mmol),反应液在室温搅拌2小时。残余物加入水(10mL)，过滤，用水洗涤，收集固体，固体通过C18反向柱制备(FA)得到L121(30mg,黄色固体,产率29.0％)。ESI-MS:m/z＝432.1[M+H] +. 1H NMR(400MHz,DMSO)δ8.82-8.79(m,2H),8.47(d,J＝8.4Hz,1H),8.27(d,J＝8.8Hz,1H),8.03(d,J＝9.2Hz,1H),7.94(s,1H),7.99(s,1H),7.75(s,1H),7.62(dd,J＝2.4Hz,J＝9.2Hz 1H),7.29(d,J＝5.6Hz,1H),7.18(d,J＝7.6Hz,1H),4.40-4.35(m,1H)3.40(s,3H),1.26(d,J＝6.4Hz,6H)。 Step 2. Dissolve 121-1 (100mg, 0.24mmol) in DMSO (1mL), add hydrogen peroxide (30%, 1mL), potassium carbonate (100mg, 0.72mmol), and stir the reaction solution at room temperature for 2 hours. The residue was added to water (10 mL), filtered, washed with water, and the solid was collected, which was prepared by C18 reverse column preparation (FA) to give L121 (30 mg, yellow solid, yield 29.0%). ESI-MS: m/z＝432.1[M+H] + . 1 H NMR (400MHz, DMSO) δ8.82-8.79(m, 2H), 8.47(d, J＝8.4Hz, 1H), 8.27(d ,J=8.8Hz,1H),8.03(d,J=9.2Hz,1H),7.94(s,1H),7.99(s,1H),7.75(s,1H),7.62(dd,J=2.4Hz ,J=9.2Hz 1H),7.29(d,J=5.6Hz,1H),7.18(d,J=7.6Hz,1H),4.40-4.35(m,1H),3.40(s,3H),1.26(d , J=6.4Hz, 6H).
实施例122：化合物L122的制备Embodiment 122: Preparation of Compound L122
Figure PCTCN2022143403-appb-000144
Figure PCTCN2022143403-appb-000144
将叔丁基(5-(6-(2-溴吡啶-4-基)氧基)-1,8-萘啶-2-基)-1-甲基-6-氧基-1,6-二氢嘧啶-2-基)(乙基)氨基甲酸酯(参照化合物86-1的方法制备，60mg,0.11mmol)，x-phos(8.2mg，0.022mmol)，氨基甲酸甲酯(24.8mg，0.33mmol)，碳酸铯(108mg,0.33mmol)和Pd 2(dba) 3(7.3mg，0.01mmol)溶于1,4-二氧六环(5mL)中，氮气置换后反应液在85℃下搅拌1小时。过滤，浓缩，粗产品以DCM溶解，加入5ml TFA在室温下搅拌1小时，浓缩，高效液相制备色谱(0.1％甲酸水溶液/乙腈)纯化得到产物L122(21mg,白色固体，产率27.6％)。ESI-MS：m/z＝448.1[M+H] +. 1H NMR(DMSO-d 6,400MHz)δ10.34(s,1H),8.94(d,J＝2.8Hz,1H),8.87(s,1H),8.62(d,J＝8.8Hz,1H),8.36(d,J＝8.8Hz,1H),8.27-8.21(m,2H),7.70(t,J＝5.2Hz,1H),7.49(d,J＝2.4Hz,1H),6.81(dd,J＝2.4,6.0Hz,1H),3.61(s,3H),3.55-3.48(m,2H),3.41(s,3H),1.21(t,J＝7.2Hz,1H). tert-Butyl(5-(6-(2-bromopyridin-4-yl)oxy)-1,8-naphthyridin-2-yl)-1-methyl-6-oxyl-1,6- Dihydropyrimidin-2-yl) (ethyl) carbamate (prepared according to the method of compound 86-1, 60mg, 0.11mmol), x-phos (8.2mg, 0.022mmol), methyl carbamate (24.8mg , 0.33mmol), cesium carbonate (108mg, 0.33mmol) and Pd 2 (dba) 3 (7.3mg, 0.01mmol) were dissolved in 1,4-dioxane (5mL), and the reaction solution was heated at 85°C after nitrogen replacement Stir for 1 hour. Filtration, concentration, the crude product was dissolved in DCM, added 5ml TFA, stirred at room temperature for 1 hour, concentrated, and purified by HPLC (0.1% aqueous formic acid/acetonitrile) to obtain the product L122 (21mg, white solid, yield 27.6%) . ESI-MS: m/z=448.1[M+H] + . 1 H NMR (DMSO-d 6, 400MHz) δ10.34(s, 1H), 8.94(d, J=2.8Hz, 1H), 8.87( s,1H),8.62(d,J=8.8Hz,1H),8.36(d,J=8.8Hz,1H),8.27-8.21(m,2H),7.70(t,J=5.2Hz,1H), 7.49(d,J=2.4Hz,1H),6.81(dd,J=2.4,6.0Hz,1H),3.61(s,3H),3.55-3.48(m,2H),3.41(s,3H),1.21 (t,J=7.2Hz,1H).
实施例123：化合物L123的制备Embodiment 123: Preparation of Compound L123
Figure PCTCN2022143403-appb-000145
Figure PCTCN2022143403-appb-000145
将叔丁基(5-(6-(2-溴吡啶-4-基)氧基)-1,8-萘啶-2-基)-1-甲基-6-氧基-1,6-二氢嘧啶-2-基)(乙基)氨基甲酸酯(80mg,0.15mmol)，x-phos(15mg，0.03mmol)，1-甲基脲(33.7mg，0.45mmol)碳酸铯(147mg,0.45mmol)和Pd 2(dba) 3(22mg，0.03mmol)溶于1,4-二氧六环(5mL)中，氮气置换后反应液在85℃下搅拌1小时。过滤，浓缩，粗产品以DCM溶解，加入5ml TFA在室温下搅拌1小时，浓缩，高效液相制备色谱(0.1％甲酸水溶液/乙腈)纯化得到产物L123(24mg,白色固体，产率28.9％)。ESI-MS：m/z＝447.1[M+H] +. 1H NMR(DMSO-d 6,400MHz)δ9.17(s,1H),8.92(d,J＝3.2Hz,1H),8.86(s,1H),8.62(d,J＝8.8Hz,1H),8.36(d,J＝8.8Hz,1H),8.21(d,J＝2.8Hz,2H),8.14(d,J＝2.8Hz,1H),7.88(d,J＝3.2Hz,1H),7.71-7.68(m,1H),7.01(d,J＝2.0Hz,1H),6.72-6.69(m,1H),3.52-3.49(m,2H),3.40(s,3H),2.67(d,J＝4.8Hz,3H),1.21(d,J＝7.2Hz,1H). tert-Butyl(5-(6-(2-bromopyridin-4-yl)oxy)-1,8-naphthyridin-2-yl)-1-methyl-6-oxyl-1,6- Dihydropyrimidin-2-yl) (ethyl) carbamate (80mg, 0.15mmol), x-phos (15mg, 0.03mmol), 1-methylurea (33.7mg, 0.45mmol) cesium carbonate (147mg, 0.45 mmol) and Pd 2 (dba) 3 (22 mg, 0.03 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction solution was stirred at 85° C. for 1 hour after nitrogen replacement. Filtration, concentration, the crude product was dissolved in DCM, added 5ml TFA and stirred at room temperature for 1 hour, concentrated, and purified by HPLC (0.1% aqueous formic acid/acetonitrile) to obtain the product L123 (24mg, white solid, yield 28.9%) . ESI-MS: m/z=447.1[M+H] + . 1 H NMR (DMSO-d 6, 400MHz) δ9.17(s, 1H), 8.92(d, J=3.2Hz, 1H), 8.86( s,1H),8.62(d,J=8.8Hz,1H),8.36(d,J=8.8Hz,1H),8.21(d,J=2.8Hz,2H),8.14(d,J=2.8Hz, 1H), 7.88(d, J=3.2Hz, 1H), 7.71-7.68(m, 1H), 7.01(d, J=2.0Hz, 1H), 6.72-6.69(m, 1H), 3.52-3.49(m ,2H),3.40(s,3H),2.67(d,J=4.8Hz,3H),1.21(d,J=7.2Hz,1H).
实施例124：化合物L124的制备Embodiment 124: Preparation of Compound L124
Figure PCTCN2022143403-appb-000146
Figure PCTCN2022143403-appb-000146
步骤1、将105-2(60mg,0.21mmol)，溶于DMF(2mL)中，向上述溶液中加入2-溴-4-氟吡啶 (73.8mg,0.42mmol)，碳酸钾(57.9mg,0.42mmol)。反应液在90℃下搅拌16小时。反应液加水(5mL)，用乙酸乙酯萃取(10mL x 3)。有机相合并后用饱和盐水(50mL)洗涤，硫酸钠干燥后蒸除溶剂，，残余物通过Pre-TLC纯化(石油醚：乙酸乙酯＝2:1梯度洗脱)得到124-1(60mg,黄色固体，产率65.2％)。ESI-MS:m/z＝439.8[M+H].Step 1. Dissolve 105-2 (60 mg, 0.21 mmol) in DMF (2 mL), add 2-bromo-4-fluoropyridine (73.8 mg, 0.42 mmol), potassium carbonate (57.9 mg, 0.42 mmol). The reaction solution was stirred at 90°C for 16 hours. Add water (5mL) to the reaction solution and extract with ethyl acetate (10mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over sodium sulfate and evaporated to remove the solvent. The residue was purified by Pre-TLC (petroleum ether: ethyl acetate = 2:1 gradient elution) to obtain 124-1 (60 mg, Yellow solid, 65.2% yield). ESI-MS: m/z=439.8[M+H].
步骤2、将124-1(43mg，0.56mmol)，碳酸铯(182.5mg,0.56mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(13mg，0.028mmol)和三(二亚苄基丙酮)二钯(13mg，0.014mmol)溶于二氧六环(5mL)中，氮气置换后反应液在100℃搅拌1h。反应液冷却至室温后过滤，有机相浓缩后残余物通过HPLC(0.1％FA)提纯,得到产物L124(4mg,黄色固体)。ESI-MS:m/z＝434.1[M+H]. 1H NMR(DMSO-d6,400MHz):δ10.37(s,1H),8.98-8.96(m,2H),8.64(d,J＝8.8Hz,1H),8.46(d,J＝8.8Hz,1H),8.28(d,J＝2.8Hz,1H),8.23(d,J＝5.6Hz,1H),7.92(s,1H),7.50(d,J＝2.0Hz,1H),6.83(dd,J＝2.4Hz,J＝5.6Hz,1H),3.61(s,3H),3.42(s,3H),3.00(d,J＝3.6Hz,1H). Step 2, 124-1 (43mg, 0.56mmol), cesium carbonate (182.5mg, 0.56mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (13mg, 0.028mmol ) and tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol) were dissolved in dioxane (5 mL), and the reaction solution was stirred at 100° C. for 1 h after nitrogen replacement. The reaction solution was cooled to room temperature and filtered, the organic phase was concentrated and the residue was purified by HPLC (0.1% FA) to obtain the product L124 (4 mg, yellow solid). ESI-MS: m/z＝434.1[M+H]. 1 H NMR (DMSO-d6, 400MHz): δ10.37(s, 1H), 8.98-8.96(m, 2H), 8.64(d, J＝ 8.8Hz, 1H), 8.46(d, J=8.8Hz, 1H), 8.28(d, J=2.8Hz, 1H), 8.23(d, J=5.6Hz, 1H), 7.92(s, 1H), 7.50 (d,J=2.0Hz,1H),6.83(dd,J=2.4Hz,J=5.6Hz,1H),3.61(s,3H),3.42(s,3H),3.00(d,J=3.6Hz ,1H).
实施例125：化合物L125的制备Embodiment 125: Preparation of Compound L125
Figure PCTCN2022143403-appb-000147
Figure PCTCN2022143403-appb-000147
步骤1、将叔丁基乙基(5-(6-羟基-1,8-萘啶-2-基)-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)氨基甲酸酯(参照叔丁基乙基(5-(6-羟基喹啉-2-基)-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)氨基甲酸酯的制备方法制备，300mg,0.756mmol)溶于的DMF(6.0mL)，加入碳酸钾(205mg,1.5mmol)和叔丁醇钾(92mg,0.756mmol)，室温下下搅拌5分钟。加入2,3,4-三氟吡啶(250mg,1.89mmol)，室温下下反应2小时。过滤，滤液C18反相柱层析纯化(0.1％三氟乙酸水溶液/乙腈＝95:5到20:80梯度洗脱)得到产物125-1(180mg,黄色固体，产率46.7％)。ESI-MS：m/z＝511.0[M+H] +。 Step 1, tert-butyl ethyl (5-(6-hydroxyl-1,8-naphthyridin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl ) carbamate (refer to tert-butylethyl (5-(6-hydroxyquinolin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino Preparation method of formic acid ester: Dissolve 300mg, 0.756mmol) in DMF (6.0mL), add potassium carbonate (205mg, 1.5mmol) and potassium tert-butoxide (92mg, 0.756mmol), stir at room temperature for 5 minutes. Add 2,3,4-trifluoropyridine (250mg, 1.89mmol) and react at room temperature for 2 hours. After filtration, the filtrate was purified by C18 reverse phase column chromatography (0.1% aqueous trifluoroacetic acid/acetonitrile=95:5 to 20:80 gradient elution) to obtain product 125-1 (180 mg, yellow solid, yield 46.7%). ESI-MS: m/z = 511.0 [M+H] + .
步骤2、将125-1(150mg,0.294mmol)，(4-甲氧基苯基)甲胺(160mg,1.18mmol)和碳酸铯(288mg,0.88mmol)溶于1，4-二氧六环(6mL)中，氮气保护下，向上述溶液中加入X-phos(14mg,0.03mmol)和Pd 2(dba) 3(27mg,0.03mmol)。反应液在120℃下搅拌26小时。反应液冷却室温后浓缩，残余物通过C18反相柱层析纯化(0.1％三氟乙酸水溶液/乙腈＝95:5到20:80梯度洗脱)得到产物125-2(50mg,黄色固体，产率32％)。ESI-MS:m/z＝528.0[M+H] +。 Step 2. Dissolve 125-1 (150mg, 0.294mmol), (4-methoxyphenyl)methanamine (160mg, 1.18mmol) and cesium carbonate (288mg, 0.88mmol) in 1,4-dioxane (6 mL), under nitrogen protection, X-phos (14 mg, 0.03 mmol) and Pd 2 (dba) 3 (27 mg, 0.03 mmol) were added to the above solution. The reaction solution was stirred at 120°C for 26 hours. The reaction solution was concentrated after cooling to room temperature, and the residue was purified by C18 reverse-phase column chromatography (0.1% aqueous trifluoroacetic acid/acetonitrile=95:5 to 20:80 gradient elution) to obtain product 125-2 (50 mg, yellow solid, yield rate 32%). ESI-MS: m/z = 528.0 [M+H] + .
步骤3、将125-2(50mg,0.095mmol)溶于三氟乙酸(2mL)，加热至60℃，搅拌17小时。浓缩，残留物通过HPLC(FA)，冻干，得到产物L125(17.5mg,黄色固体，产率43％)。ESI-MS:m/z＝408.0[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ9.02(d,J＝3.2Hz,1H),8.94(s,1H),8.61(d,J＝8.8Hz,1H),8.46(d,J＝8.4Hz,1H),8.18(d,J＝2.8Hz,1H),7.93(s,1H),7.75(d,J＝6.0Hz,1H),6.78(s,2H),6.41(t,J＝6.0Hz,1H),3.57-3.50(m,2H),3.42(s,3H),1.27-1.20(m,3H)。 Step 3. Dissolve 125-2 (50 mg, 0.095 mmol) in trifluoroacetic acid (2 mL), heat to 60° C., and stir for 17 hours. After concentration, the residue was passed through HPLC (FA), and lyophilized to obtain the product L125 (17.5 mg, yellow solid, yield 43%). ESI-MS: m/z = 408.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.02(d, J=3.2Hz, 1H), 8.94(s, 1H), 8.61(d, J=8.8Hz, 1H), 8.46(d, J =8.4Hz,1H),8.18(d,J=2.8Hz,1H),7.93(s,1H),7.75(d,J=6.0Hz,1H),6.78(s,2H),6.41(t,J =6.0Hz, 1H), 3.57-3.50(m, 2H), 3.42(s, 3H), 1.27-1.20(m, 3H).
实施例126：化合物L126的制备Embodiment 126: Preparation of Compound L126
Figure PCTCN2022143403-appb-000148
Figure PCTCN2022143403-appb-000148
步骤1、将叔丁基乙基(5-(6-羟基-1,8-萘啶-2-基)-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)氨基甲酸酯(200mg,0.504mmol)和碳酸钾(200mg,1.48mmol)加入DMF(5mL)中，向上述溶液中加入2,3,4-三氯吡啶(100mg,0.55mmol)。反应液在90℃搅拌16小时。反应液过滤，滤液经C18反向柱纯化(乙腈：水＝25:75到100:0梯度洗脱)得到产物126-1(150mg，黄色固体，产率54.8％)。ESI-MS:m/z＝542.9[M+H] +。 Step 1, tert-butyl ethyl (5-(6-hydroxyl-1,8-naphthyridin-2-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl ) carbamate (200mg, 0.504mmol) and potassium carbonate (200mg, 1.48mmol) were added to DMF (5mL), and 2,3,4-trichloropyridine (100mg, 0.55mmol) was added to the above solution. The reaction solution was stirred at 90°C for 16 hours. The reaction solution was filtered, and the filtrate was purified by a C18 reverse column (acetonitrile:water=25:75 to 100:0 gradient elution) to obtain product 126-1 (150 mg, yellow solid, yield 54.8%). ESI-MS: m/z = 542.9 [M+H] + .
步骤2、将126-1(130mg,0.24mmol)，氨基甲酸叔丁酯(280mg,2.4mmol)和碳酸铯(235mg,0.72mmol)溶于1，4-二氧六环(4mL)中，氮气保护下，向上述溶液中加入X-phos(14mg,0.03mmol)和Pd 2(dba) 3(27mg,0.03mmol)。反应液在100℃下搅拌24小时。反应液冷却室温后浓缩，残余物通过硅胶柱层析纯化(二氯甲烷：甲醇＝20:1到12:1梯度洗脱)得到126-2(65mg,黄色固体，产率52％)。ESI-MS:m/z＝523.9[M+H] +。 Step 2, 126-1 (130mg, 0.24mmol), tert-butyl carbamate (280mg, 2.4mmol) and cesium carbonate (235mg, 0.72mmol) were dissolved in 1,4-dioxane (4mL), nitrogen Under protection, X-phos (14 mg, 0.03 mmol) and Pd 2 (dba) 3 (27 mg, 0.03 mmol) were added to the above solution. The reaction solution was stirred at 100°C for 24 hours. The reaction solution was concentrated after cooling to room temperature, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 12:1 gradient elution) to obtain 126-2 (65 mg, yellow solid, yield 52%). ESI-MS: m/z = 523.9 [M+H] + .
步骤3、将126-2(65mg,0.124mmol)溶于二氯甲烷(3mL)，室温下向上述溶液中滴入三氟乙酸(0.75mL)。反应液在20℃下搅拌1小时。反应液加水(25mL)，用乙酸乙酯(50mL)洗涤水相。随后水相用碳酸氢钠饱和水溶液调节pH值到8，乙酸乙酯(40mL x 3)萃取，有机相合并，用饱和盐水(300mL)洗涤，硫酸钠干燥后浓缩，经过制备HPLC(FA)得到产物L126(15.2mg,黄色固体，产率29％)。ESI-MS:m/z＝424.0[M+H] +.H NMR(DMSO-d 6,400MHz):δ8.93(d,J＝3.2Hz,1H),8.85(s,1H),8.59(d,J＝8.8Hz,1H),8.34(d,J＝9.2Hz,1H),8.08(d,J＝3.2Hz,1H),7.84(d,J＝4.2Hz,1H),7.70(t,J＝5.6Hz, 1H),6.52(s,2H),6.23(d,J＝6.0Hz,1H),3.54-3.40(m,2H),3.36(s,3H),1.21(t,J＝6.0Hz,3H)。 Step 3. Dissolve 126-2 (65 mg, 0.124 mmol) in dichloromethane (3 mL), and add trifluoroacetic acid (0.75 mL) dropwise into the above solution at room temperature. The reaction solution was stirred at 20°C for 1 hour. Water (25 mL) was added to the reaction solution, and the aqueous phase was washed with ethyl acetate (50 mL). Then the aqueous phase was adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate (40mL x 3), the organic phases were combined, washed with saturated brine (300mL), dried over sodium sulfate, concentrated, and obtained by preparative HPLC (FA) Product L126 (15.2 mg, yellow solid, 29% yield). ESI-MS: m/z=424.0[M+H] + .H NMR (DMSO-d 6 , 400MHz): δ8.93(d, J=3.2Hz, 1H), 8.85(s, 1H), 8.59( d,J=8.8Hz,1H),8.34(d,J=9.2Hz,1H),8.08(d,J=3.2Hz,1H),7.84(d,J=4.2Hz,1H),7.70(t, J＝5.6Hz, 1H), 6.52(s, 2H), 6.23(d, J＝6.0Hz, 1H), 3.54-3.40(m, 2H), 3.36(s, 3H), 1.21(t, J＝6.0 Hz, 3H).
测试例1：对CSF-1R激酶活性的测定Test Example 1: Determination of Kinase Activity of CSF-1R
本实验使用Z’lyte的方法检测化合物对CSF-1R活性的抑制，所用试剂为Z'-LYTE TM Kinase Assay Kit-Tyrosine 1 Peptide(Invitrogen PV3190)，CSF-1R(Invitrogen PV3249)。 In this experiment, Z'lyte method was used to detect the inhibition of CSF-1R activity by compounds, and the reagents used were Z'-LYTE TM Kinase Assay Kit-Tyrosine 1 Peptide (Invitrogen PV3190), CSF-1R (Invitrogen PV3249).
通过下述方法测定受试化合物对CSF-1R酶活性的抑制作用：Measure the inhibitory effect of test compound on CSF-1R enzymatic activity by following method:
测试化合物用实验所需浓度配制成100X的DMSO溶液，在384孔板(Corning 3575)中加入50nl配制好的化合物溶液，其中100％inhibition对照孔(C1)，0％inhibition对照孔(C2)和100％phosphorylation对照孔(C3)加入DMSO。配制1X缓冲液，并用1X缓冲液配制2X的CSF-1R酶/底物稀释液，2X的磷酸化底物稀释液和2X ATP稀释液，每孔中分别加入5μL的2X CSF-1R酶/底物稀释液和5μL的2X ATP稀释液，其中100％inhibition对照孔加入5μL的1X缓冲液和5μL的2X CSF-1R酶/底物稀释液，0％inhibition对照孔加入5μL的2X ATP稀释液和5μL的2X CSF-1R酶/底物稀释液，100％phosphorylation对照孔加入5μL的2X的磷酸化底物稀释液和5μL的1X缓冲液。震荡混匀后，于25℃孵育1小时；加入5μL Z’lyte试剂盒中的development solution检测磷酸化水平，震荡混匀，25℃孵育1小时，用Envision荧光酶标仪测定各孔化学发光强度。The test compound was prepared into 100X DMSO solution with the concentration required for the experiment, and 50 nl of the prepared compound solution was added in a 384-well plate (Corning 3575), wherein 100% inhibition control well (C1), 0% inhibition control well (C2) and DMSO was added to 100% phosphorylation control wells (C3). Prepare 1X buffer, and use 1X buffer to prepare 2X CSF-1R enzyme/substrate dilution, 2X phosphorylated substrate dilution and 2X ATP dilution, and add 5 μL of 2X CSF-1R enzyme/substrate to each well 100% inhibition control wells were added with 5 μL of 1X buffer and 5 μL of 2X CSF-1R enzyme/substrate dilution, and 0% inhibition control wells were added with 5 μL of 2X ATP dilution and 5 μL of 2X CSF-1R enzyme/substrate dilution, 100% phosphorylation control wells were added with 5 μL of 2X phosphorylation substrate dilution and 5 μL of 1X buffer. After shaking and mixing, incubate at 25°C for 1 hour; add 5 μL of the development solution in the Z'lyte kit to detect the phosphorylation level, shake and mix, incubate at 25°C for 1 hour, and measure the chemiluminescence intensity of each well with an Envision fluorescent microplate reader .
％Pho＝(1-((ERX C3520nm-C3450nm)/((C1450nm-C3450nm)+ERX(C3520nm-C1520nm))))x100％%Pho=(1-((ERX C3520nm-C3450nm)/((C1450nm-C3450nm)+ERX(C3520nm-C1520nm))))x100%
Inhibition rate(IR)＝(1-％Photest compound)/(％Pho C2)x100％Inhibition rate (IR) = (1-% Photest compound)/(% Pho C2) x 100%
针对各测试化合物各设2个平行孔，计算平均值。将计算得到的抑制率用XLFIT 5.0软件(英国IDBS公司)拟合计算半数抑制浓度IC 50。测得的本发明上述化合物对CSF-1R酶的抑制活性的IC 50值见表1-1和表1-2。 Two parallel wells were set up for each test compound, and the average value was calculated. The calculated inhibition rate was fitted with XLFIT 5.0 software (IDBS, UK) to calculate the half maximal inhibitory concentration IC 50 . See Table 1-1 and Table 1-2 for the measured IC 50 values of the inhibitory activity of the above-mentioned compounds of the present invention on CSF-1R enzyme.
表1-1化合物对CSF-1R激酶的抑制活性The inhibitory activity of table 1-1 compound to CSF-1R kinase
Figure PCTCN2022143403-appb-000149
Figure PCTCN2022143403-appb-000149
表1-2化合物对CSF-1R激酶的抑制活性The inhibitory activity of table 1-2 compound to CSF-1R kinase
L91L91 0.0650.065 L92L92 0.0240.024
L93L93 0.0260.026 L94L94 0.0500.050
L95L95 0.0230.023 L98L98 0.0210.021
L99L99 0.0510.051 L100L100 0.0320.032
L101L101 0.0730.073 L102L102 0.1300.130
L103L103 0.0290.029 L104L104 0.0110.011
L105L105 0.0290.029 L106L106 0.1010.101
L107L107 0.0740.074 L109L109 0.0240.024
L110L110 0.0120.012 L111L111 0.0150.015
L112L112 0.0210.021 L113L113 0.1680.168
L114L114 0.0380.038 L115L115 0.0270.027
L116L116 0.0330.033 L117L117 0.0990.099
L118L118 0.0260.026 L119L119 0.0230.023
L120L120 0.0300.030 L123L123 0.0560.056
L124L124 0.1200.120  the  the
由表1-1和1-2可知，本发明实施例化合物对CSF-1R激酶具有较高的抑制活性。It can be seen from Tables 1-1 and 1-2 that the compounds of the examples of the present invention have relatively high inhibitory activity on CSF-1R kinase.
测试例2：对THP-1细胞CSF-1R磷酸化水平的抑制Test Example 2: Inhibition of CSF-1R Phosphorylation Level in THP-1 Cells
本实验用ELISA方法检测。This experiment was detected by ELISA method.
1.THP-1细胞处理1. THP-1 cell treatment
取对数生长期THP-1细胞，以适当浓度45μL铺种于96孔板中(Costar 3894)，加入5μL不同浓度的测试化合物的DMSO溶液(对照孔只加DMSO)，于37℃，5％CO 2条件下培养，1小时后，加入10μL hMCSF的PBS溶液(Peprotech 300-25)(空白孔只加PBS)，室温孵育5分钟后，取出，直接加入60μL 2X细胞裂解液(CST 9806S)(CST 5872S)，800rpm振荡1分钟，储存于-80℃待用。 Take THP-1 cells in the logarithmic growth phase, plant them in a 96-well plate (Costar 3894) at an appropriate concentration of 45 μL, add 5 μL of DMSO solutions of test compounds at different concentrations (only DMSO is added to the control wells), and store at 37 ° C, 5% Cultivate under CO 2 conditions. After 1 hour, add 10 μL hMCSF PBS solution (Peprotech 300-25) (blank wells only add PBS), incubate at room temperature for 5 minutes, take it out, and directly add 60 μL 2X cell lysate (CST 9806S) ( CST 5872S), shake at 800rpm for 1 minute, and store at -80°C until use.
2.检测步骤2. Detection steps
按照磷酸化CSF-1R的ELISA检测试剂盒(R&D DYC3268E)配制Capture溶液，每孔100μL加入high binding 96孔板中(Costar 42592)，室温孵育过夜。300μL PBST清洗四次，加入封闭液(1％BSA PBS溶液)(Genview FA016-100G)，室温孵育2小时，300μL PBST清洗四次；加入100μL细胞样本，室温孵育2小时，300μL PBST清洗四次；加入100μL anti-pY-HRP溶液，室温孵育2小时，300μL PBST清洗四次；加入100μL ELISA反应底物TMB，室温孵育30分钟，加入50μL 2N的H 2SO 4溶液终止反应。于Infinite M1000荧光酶标仪(Tecan)上读取OD值，吸收波长为450nm和570nm。 According to the phosphorylated CSF-1R ELISA detection kit (R&D DYC3268E), the Capture solution was prepared, 100 μL per well was added to a high binding 96-well plate (Costar 42592), and incubated overnight at room temperature. Wash four times with 300 μL PBST, add blocking solution (1% BSA in PBS solution) (Genview FA016-100G), incubate at room temperature for 2 hours, wash four times with 300 μL PBST; add 100 μL cell samples, incubate at room temperature for 2 hours, wash four times with 300 μL PBST; Add 100 μL anti-pY-HRP solution, incubate at room temperature for 2 hours, wash with 300 μL PBST four times; add 100 μL ELISA reaction substrate TMB, incubate at room temperature for 30 minutes, add 50 μL 2N H 2 SO 4 solution to terminate the reaction. The OD value was read on an Infinite M1000 fluorescent microplate reader (Tecan), and the absorption wavelengths were 450 nm and 570 nm.
2.3数据分析2.3 Data analysis
加DMSO不加hMCSF为背景，加DMSO及hMCSF为空白对照。Add DMSO without hMCSF as the background, add DMSO and hMCSF as the blank control.
Inhibition％＝[1-(Total mean(Inhibitor)–total mean(背景))/(Total mean(空白)–total mean(背景))]×100％Inhibition%＝[1-(Total mean(Inhibitor)–total mean(background))/(Total mean(blank)–total mean(background))]×100％
2.4将计算得到的抑制率用XLFIT 5.0软件计算出IC 50值，参见表2。 2.4 Use XLFIT 5.0 software to calculate the IC 50 value from the calculated inhibition rate, see Table 2.
表2化合物对THP-1细胞CSF-1R磷酸化水平的抑制活性The compound of table 2 is to the inhibitory activity of THP-1 cell CSF-1R phosphorylation level
Figure PCTCN2022143403-appb-000150
Figure PCTCN2022143403-appb-000150
Figure PCTCN2022143403-appb-000151
Figure PCTCN2022143403-appb-000151
由表2可知，本发明实施例化合物对THP-1细胞CSF-1R磷酸化水平具有较高的抑制活性。It can be seen from Table 2 that the compounds of the examples of the present invention have relatively high inhibitory activity on the phosphorylation level of CSF-1R in THP-1 cells.
测试例3：小鼠体内药代试验Test Example 3: In vivo pharmacokinetic test in mice
应用LC/MS/MS法测定小鼠分别静脉注射给药和口服灌胃给药各测试化合物后不同时刻血浆中的药物浓度，研究各测试化合物在小鼠体内的药代动力学行为，评价其药动学特征。The LC/MS/MS method was used to determine the drug concentration in the blood plasma of mice at different times after intravenous injection and oral gavage administration of each test compound, to study the pharmacokinetic behavior of each test compound in mice, and to evaluate its Pharmacokinetic characteristics.
实验方案：Experimental program:
试验动物：健康成年雄性ICR小鼠(体重25-40g，12只，静脉注射组小鼠自由饮水和饮食，灌胃给药组禁食过夜，给药4h后自由饮水和饮食)，由Beijing Vital River Laboratory Animal Co.LTD提供；Experimental animals: healthy adult male ICR mice (weight 25-40g, 12 mice, the mice in the intravenous injection group were free to drink water and food, and the intragastric administration group was fasted overnight, and free to drink water and food after 4 hours of administration), provided by Beijing Vital Provided by River Laboratory Animal Co.LTD;
给药方式与剂量：给药前挑选符合实验要求的动物，称重标记。ICR小鼠尾静脉给药(2mg/kg,5％DMSO+30％(10％Solutol HS15)+65％(20％Captisol，pH 7.4))和灌胃给药(10mg/kg,5％DMSO+30％(10％Solutol HS15)+65％(20％Captisol，pH 7.4))。Administration method and dose: select animals that meet the experimental requirements before administration, and weigh the marks. ICR mouse tail vein administration (2mg/kg, 5% DMSO+30% (10% Solutol HS15) + 65% (20% Captisol, pH 7.4)) and intragastric administration (10mg/kg, 5% DMSO+ 30% (10% Solutol HS15) + 65% (20% Captisol, pH 7.4)).
血样采集：采集血样前，绑定小鼠，每一只给药的小鼠在预定的采血时间点(静脉给药：分别于给药后的0.083，0.25，0.5，1，2，4，7，24h采血，共8个时间点；灌胃给药：分别于给药后的0.083，0.25，0.5，1，2，4，7，24h采血，共8个时间点)，通过眼眦静脉采血约100μL。全血转移至预先加入K 2EDTA(Sigma-ACDRICH，WXBB0768)的1.5mL试管中，离心6min(8000rpm,4℃)，分离出血浆，整个过程在采血后15min内完成。所有的样品都需要存放于-20℃冰箱直至样品分析。 Blood sample collection: Before collecting blood samples, bind the mice, each administered mouse at the scheduled blood collection time point (intravenous administration: respectively at 0.083, 0.25, 0.5, 1, 2, 4, 7 days after administration) , 24h blood collection, a total of 8 time points; intragastric administration: blood collection at 0.083, 0.25, 0.5, 1, 2, 4, 7, 24h after administration, a total of 8 time points), blood collection through the canthus vein About 100 μL. The whole blood was transferred to a 1.5mL test tube pre-added with K 2 EDTA (Sigma-ACDRICH, WXBB0768), centrifuged for 6min (8000rpm, 4°C), and the plasma was separated. The whole process was completed within 15min after blood collection. All samples need to be stored in a -20°C freezer until sample analysis.
分析方法：采用液相色谱-串联质谱法(型号：Triple QuadTM 4000)分析血浆样品，色谱柱为：Waters XBridge-C18(2.1×50mm,3.5μm)。Analysis method: Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry (model: Triple QuadTM 4000), and the chromatographic column was Waters XBridge-C18 (2.1×50mm, 3.5μm).
标准曲线的配制：配制待测化合物在空白ICR小鼠血浆基质中线性范围为1.00-3000ng/mL的标准曲线，同时配制浓度为3，500，2400ng/mL的低中高浓度的质控样品。Preparation of standard curve: prepare a standard curve with a linear range of 1.00-3000 ng/mL of the compound to be tested in blank ICR mouse plasma matrix, and prepare quality control samples with concentrations of 3, 500, 2400 ng/mL at low, middle and high concentrations.
生物样品的处理：将冻存的血浆样品放置湿冰上解冻，待样品解冻后，放置涡旋仪上涡旋5min。取20μL血浆样品、标准曲线及质控指控样品加至96孔板中，再加入200μL含内标地塞米松(品牌：NIFDC，批号:6TUC-T4C2，配制浓度2000ng/mL)的乙腈沉淀蛋白，涡旋混合5min，然后在3700rpm，4℃离心15min，提取上清同样条件下二次离心，最后进2μL上清溶液进行LC-MS/MS分析。结果如表3所示。Processing of biological samples: thaw the frozen plasma samples on wet ice, and vortex for 5 minutes after the samples are thawed. Take 20 μL of plasma samples, standard curve and quality control samples and add them to a 96-well plate, then add 200 μL of acetonitrile protein precipitation containing internal standard dexamethasone (brand: NIFDC, batch number: 6TUC-T4C2, prepared concentration 2000ng/mL), Vortex and mix for 5 minutes, then centrifuge at 3700 rpm, 4°C for 15 minutes, extract the supernatant and centrifuge twice under the same conditions, and finally add 2 μL of the supernatant solution for LC-MS/MS analysis. The results are shown in Table 3.
表3.化合物小鼠口服给药(10mg/kg)药代动力学参数Table 3. Compound mice oral administration (10mg/kg) pharmacokinetic parameters
Figure PCTCN2022143403-appb-000152
Figure PCTCN2022143403-appb-000152
由表3可知，本申请化合物具有良好的口服吸收特性。It can be seen from Table 3 that the compound of the present application has good oral absorption characteristics.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, should be considered as within the scope of this specification.
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对申请专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。The above-mentioned embodiments only express several implementation modes of the present application, and the description thereof is relatively specific and detailed, but should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the scope of protection of the patent application should be based on the appended claims.

Claims (22)

  1. 一种具有式(I)所示的结构的化合物、或其药学上可接受的盐、或其立体异构体：A compound having a structure shown in formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
    Figure PCTCN2022143403-appb-100001
    Figure PCTCN2022143403-appb-100001
    其中，in,
    Z 1为CR z1或N；Z 2为CR z2或N；Z 3为CR z3或N；且Z 1、Z 2、Z 3不同时为N； Z 1 is CR z1 or N; Z 2 is CR z2 or N; Z 3 is CR z3 or N; and Z 1 , Z 2 , and Z 3 are not N at the same time;
    Z 4为CR z4或N；Z 5为CR z5或N；且Z 4、Z 5不同时为N； Z 4 is CR z4 or N; Z 5 is CR z5 or N; and Z 4 and Z 5 are not N at the same time;
    Z 6为CR z6或N； Z 6 is CR z6 or N;
    R z1、R z2、R z3、R z4、R z5、R z6分别独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1- 3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-OC(O)C 1- 8烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-C(O)NR 01R 02或-NR a1R b1；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1- 3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R z1 , R z2 , R z3 , R z4 , R z5 , and R z6 are independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl ( preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl ), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1 -6 alkyl, more preferably -C(O)OC 1-3 alkyl) , -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -C(O)NR 01 R 02 or -NR a1 R b1 ; wherein the C 1-8 alkyl, C 3-8 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium , halogen (preferably fluorine or chlorine), cyano , nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogen Substituted C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O )NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6-membered heterocycloalkyl;
    环A为苯环或5至10元杂芳环；Ring A is a benzene ring or a 5- to 10-membered heteroaromatic ring;
    L为氢、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-NR 03R 04、-C(O)NR 01R 02或5至6元杂芳环；其中所述C 1-8烷基、5至6元杂芳环各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2- 4烯基、C 2-4炔基、羟基取代C 1-3烷基、羟基取代的C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR 03R 04、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； L is hydrogen, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -NR 03 R 04 , -C(O ) NR 01 R 02 or 5 to 6 membered heteroaryl ring; wherein the C 1-8 alkyl, 5 to 6 membered heteroaryl ring are each independently unsubstituted or are independently selected from 1, 2 or 3 The following substituents are substituted: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2- 4 alkynyl, hydroxy substituted C 1-3 alkyl, hydroxy substituted C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR 03 R 04 , - SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1 -3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    R 0为氢、氰基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)NR 01R 02、-NR 03R 04或-SO 2C 1-8烷基；其中所述C 1-8烷基为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR 03R 04、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R is hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C (O) NR 01 R 02 , -NR 03 R 04 or -SO 2 C 1-8 alkyl; wherein the C 1-8 alkyl is unsubstituted or 1, 2 or 3 independently selected from the following Substituent group substitution: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR 03 R 04 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    R 03、R 04分别独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)C 3-8环烷基(优选为-C(O)C 3-6环烷基)、-C(O)NR 01R 02、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 3-8环烷基(优选为-SO 2C 3-6环烷基)、C 3-8环烷基(优选为C 3-6环烷基)或5至6元杂芳环；其中所述C 1-8烷基、-C(O)C 1-8烷基、C 3-8环烷基、5至6元杂芳环各自独立地为未被取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R 03 and R 04 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)C 1-8 alkyl ( Preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)C 3-8 cycloalkyl (preferably -C(O) C 3-6 cycloalkyl), -C(O)NR 01 R 02 , -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C (O)OC 1-3 alkyl), SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5 to 6 membered heteroaromatic ring; wherein The C 1-8 alkyl, -C(O)C 1-8 alkyl, C 3-8 cycloalkyl, and 5 to 6 membered heteroaromatic rings are each independently unsubstituted or replaced by 1, 2 or 3 Substituents each independently selected from the group consisting of: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkene Base, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 -SO 2 C 1-3 alkyl, -S(O)C 1 -3 Alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3- 6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    R 1、R 2分别独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-NR 05R 06、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)或3至8元杂环；其中所述C 1-8烷基、3至8元杂环各自独立地为未被取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR 05R 06、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6 环烷基、C 3-6环烷基氧基、-C 1-3烷基OC 1-3烷基和3至6元杂环； R 1 and R 2 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -NR 05 R 06 , -C(O)OC 1-8 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -C (O) C 1-8 alkyl (preferably -C (O) C 1-6 alkyl, more preferably -C (O) C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 3 to 8 membered heterocycle; wherein the C 1-8 alkyl, 3 to 8 membered heterocycle are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, halogenated C 1-3 alkoxy, -NR 05 R 06 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, -C 1-3 alkyl OC 1-3 alkyl and 3 to 6 membered heterocycle;
    R 05、R 06分别独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1-3烷基、-C(O)C 3- 8环烷基(优选为-C(O)C 3-6环烷基)、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、-SO 2C 3-8环烷基(优选为-SO 2C 3-6环烷基)、C 3-8环烷基(优选为C 3-6环烷基)或5至6元杂芳环；其中所述C 1-8烷基、C 3-8环烷基、5至6元杂芳环各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1- 3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；或者R 05、R 06与相连接的氮原子形成3至7元饱和或部分不饱和单杂环；其中所述3至7元饱和或部分不饱和单杂环为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、C 1-3烷氧基取代的C 1-3烷基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1- 3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R 05 and R 06 are independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)C 1-3 alkyl, -C(O)C 3-8 cycloalkyl (preferably -C(O)C 3-6 cycloalkyl), -C (O)NR 01 R 02 , -C(O)OC 1-3 alkyl , -SO 2 C 1-3 alkyl, -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5 to 6 membered heteroaryl ring; wherein said C 1-8 alkyl, C 3-8 cycloalkyl, 5 to 6 membered heteroaryl ring are each independently unsubstituted or replaced by 1, 2 or 3 substituents independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2- 4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O )C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O ) OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy group and 3 to 6 membered heterocycloalkyl group; or R 05 , R 06 form a 3 to 7 membered saturated or partially unsaturated monoheterocyclic ring with the connected nitrogen atom; wherein the 3 to 6 membered heterocycloalkyl group; The 7-membered saturated or partially unsaturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy substituted C 1-3 alkyl, halogenated C 1 -3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1- 3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered hetero Cycloalkyl;
    或者R 1、R 2分别与其相连接的氮原子、碳原子共同形成式(i)所示结构：
    Figure PCTCN2022143403-appb-100002
    其中X为-(CR q1R q2) m-、-(CR q3R q4) t1-O-(CR q5R q6) t2-、-(CR q7R q8) t3-NR q0-(CR q9R q10) t4-；     Or R 1 and R 2 respectively form the structure shown in formula (i) together with the nitrogen atom and carbon atom connected to them:
    Figure PCTCN2022143403-appb-100002
    where X is -(CR q1 R q2 ) m -, -(CR q3 R q4 ) t1 -O-(CR q5 R q6 ) t2 -, -(CR q7 R q8 ) t3 -NR q0 -(CR q9 R q10 ) t4 -;
    m为1、2、3或4；m is 1, 2, 3 or 4;
    t1、t2、t3、t4各自独立地为0、1、2或3；t1、t2不同时为0；t3、t4不同时为0；t1, t2, t3, t4 are each independently 0, 1, 2 or 3; t1, t2 are not 0 at the same time; t3, t4 are not 0 at the same time;
    R q1、R q2各自独立地为氢、氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 2-4烯基、C 2-4炔基、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR 01R 02、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-8烷基，更优选为-OC(O)C 1-8烷基)、-NR a1R b1；或者R q1、R q2与相连接的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述C 1-8烷基、C 3-6环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、3至7元饱和或部分不饱和单环、3至7元饱和或部分不饱和单杂环各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q1 and R q2 are each independently hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR 01 R 02 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O)OC 1 -8 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -OC (O) C 1-8 alkyl (preferably - OC(O)C 1-8 alkyl, more preferably -OC(O)C 1-8 alkyl), -NR a1 R b1 ; or R q1 , R q2 and the connected carbon atoms together form 3 to 7 One-membered saturated or partially unsaturated monocyclic ring or 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, 3 to 7 membered saturated or partially unsaturated monocyclic ring, 3 to 7 membered saturated or partially unsaturated monoheterocyclic ring are each independently unsubstituted or replaced by 1 , 2 or 3 substituents independently selected from the following group: deuterium, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkane Oxygen, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkane radical, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3 -6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    R q3、R q4、R q5、R q6、R q7、R q8、R q9、R q10各自独立地为氢、氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR 01R 02、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1- 6烷基，更优选为-C(O)OC 1-3烷基)； R q3 , R q4 , R q5 , R q6 , R q7 , R q8 , R q9 , R q10 are each independently hydrogen, deuterium, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1 -8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O) NR 01 R 02 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C( O) OC 1-8 alkyl (preferably -C (O) OC 1- 6 alkyl, more preferably -C (O) OC 1-3 alkyl);
    R q0为氢、氘、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、-C(O)NR 01R 02、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)；其中所述C 1-8烷基、C 3-8环烷基各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q0 is hydrogen, deuterium, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkane group), -C(O)NR 01 R 02 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1- 3 alkyl) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl , C 3-8 cycloalkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, nitro , hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkane Oxygen, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    R 01、R 02分别独立地为氢或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)； R 01 and R 02 are independently hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
    R a1、R b1各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基；或者R a1、R b1与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 R a1 and R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1 and R b1 together with the connected nitrogen atom form a 4- to 6-membered saturated monohetero ring; the 4 to 6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, nitrate radical, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 Alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), - C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3- 6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述Z 1为CR z1；Z 2为CR z2；Z 3为CR z3。 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said Z 1 is CR z1 ; Z 2 is CR z2 ; Z 3 is CR z3 .
  3. 如权利要求1-2任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述Z 4为CR z4；Z 5为CR z5。 The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said Z 4 is CR z4 ; Z 5 is CR z5 .
  4. 如权利要求2所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述Z 2为CR z2；Z 3为CR z3；Z 4为CR z4；Z 5为CR z5。 The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said Z 2 is CR z2 ; Z 3 is CR z3 ; Z 4 is CR z4 ; Z 5 is CR z5 .
  5. 如权利要求1-4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述Z 6为N。 The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said Z 6 is N.
  6. 如权利要求1-5任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述环A中的5至10元杂芳环为5至10元含氮杂芳环。The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the 5 to 10 membered heteroaromatic ring in the ring A is 5 to 10-membered nitrogen-containing heteroaromatic ring.
  7. 如权利要求6所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述环A为5至6元含氮杂芳环(优选为5至6元含氮杂芳环)或8至10元含氮杂芳环(优选为9至10元含氮杂芳环，更优选为吡啶并5至6元含氮杂芳环)。The compound according to claim 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the ring A is a 5 to 6 member nitrogen-containing heteroaromatic ring (preferably 5 to 6 member nitrogen-containing heteroaryl ring) or 8-10 membered nitrogen-containing heteroaryl ring (preferably 9-10 membered nitrogen-containing heteroaryl ring, more preferably pyrido 5-6 membered nitrogen-containing heteroaryl ring).
  8. 如权利要求7所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述环A为吡啶环、嘧啶环或吡啶并吡咯环(优选为吡啶环)。The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the ring A is a pyridine ring, a pyrimidine ring or a pyridopyrrole ring (preferably a pyridine ring) .
  9. 如权利要求1-8任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述式(I)中
    Figure PCTCN2022143403-appb-100003
    为
    Figure PCTCN2022143403-appb-100004
    The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein in the formula (I)
    Figure PCTCN2022143403-appb-100003
    for
    Figure PCTCN2022143403-appb-100004
  10. 如权利要求1-9任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述R 03为氢；R 04为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1-3烷基、-C(O)C 3-8环烷基(优选为-C(O)C 3-6环烷基)、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、-SO 2C 3-8环烷基(优选为-SO 2C 3-6环烷基)、C 3-8环烷基(优选为C 3-6环烷基)或5至6元杂芳环；其中所述C 1-8烷基、-C(O)C 1-3烷基、C 3-8环烷基、5至6元杂芳环各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said R 03 is hydrogen; R 04 is hydrogen, C 1-8 Alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)C 1-3 alkyl, -C(O)C 3-8 cycloalkyl (preferably -C(O)C 3-6 cycloalkyl), -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 C 3-8 cycloalkyl (preferably -SO 2 C 3-6 cycloalkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 5 to 6 membered heteroaromatic ring; wherein The C 1-8 alkyl, -C(O)C 1-3 alkyl, C 3-8 cycloalkyl, and 5 to 6 membered heteroaryl rings are each independently unsubstituted or replaced by 1, 2 or 3 Substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl , C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O ) C 1 -3 Alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3- 6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
  11. 如权利要求1-10任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述L中的5至6元杂芳环为噻吩环、呋喃环、噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环或四嗪环；所述5至6元杂芳环为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基(优选为甲基)、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、羟基取代的C 1-3烷基、羟基取代的C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR 03R 04、-SO 2C 1-3烷基(优选为-SO 2CH 3)、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1- 3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the 5 to 6-membered heteroaromatic ring in L is a thiophene ring, Furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1, 2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring Diazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring or tetra an oxazine ring; the 5-6 membered heteroaromatic ring is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl , carboxyl, C 1-3 alkyl (preferably methyl), C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy substituted C 1-3 alkyl, hydroxy substituted C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR 03 R 04 , -SO 2 C 1-3 alkyl (preferably -SO 2 CH 3 ), -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1- 3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3-6 membered heterocycloalkyl.
  12. 如权利要求1-11任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述L为氢、二氟甲基、三氟甲基、-NH 2、-NHCH 3、
    Figure PCTCN2022143403-appb-100005
    Figure PCTCN2022143403-appb-100006
    Figure PCTCN2022143403-appb-100007
    The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said L is hydrogen, difluoromethyl, trifluoromethyl, -NH 2 , -NHCH 3 ,
    Figure PCTCN2022143403-appb-100005
    Figure PCTCN2022143403-appb-100006
    Figure PCTCN2022143403-appb-100007
  13. 如权利要求1-12任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述R 1为氢或C 1-3烷基。 The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said R 1 is hydrogen or C 1-3 alkyl.
  14. 如权利要求1-13任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述R 2为-NR 05R 06。 The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said R 2 is -NR 05 R 06 .
  15. 如权利要求14所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述R 05为氢；R 06为氢、C 1-3烷基或C 3-6环烷基(优选为环丙烷基)；其中所述C 1-3烷基、C 3-6环烷基各自独立地为未取代或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟或氯)、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR 01R 02、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 The compound according to claim 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said R 05 is hydrogen; R 06 is hydrogen, C 1-3 alkyl or C 3 -6 cycloalkyl (preferably cyclopropyl); wherein said C 1-3 alkyl, C 3-6 cycloalkyl are each independently unsubstituted or are independently selected from the following by 1, 2 or 3 Substituent group substitution: deuterium, halogen (preferably fluorine or chlorine), cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR 01 R 02 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl groups.
  16. 如权利要求1-15任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述R 2为氢、甲基、氨基、
    Figure PCTCN2022143403-appb-100008
    Figure PCTCN2022143403-appb-100009
    The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein said R is hydrogen, methyl, amino,
    Figure PCTCN2022143403-appb-100008
    Figure PCTCN2022143403-appb-100009
  17. 如权利要求1-16任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述式(I)中的
    Figure PCTCN2022143403-appb-100010
    为
    Figure PCTCN2022143403-appb-100011
    Figure PCTCN2022143403-appb-100012
    Figure PCTCN2022143403-appb-100013
    The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that, in the formula (I)
    Figure PCTCN2022143403-appb-100010
    for
    Figure PCTCN2022143403-appb-100011
    Figure PCTCN2022143403-appb-100012
    Figure PCTCN2022143403-appb-100013
  18. 如权利要求1-17任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述式(I)中
    Figure PCTCN2022143403-appb-100014
    为
    Figure PCTCN2022143403-appb-100015
    Figure PCTCN2022143403-appb-100016
    The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein in the formula (I)
    Figure PCTCN2022143403-appb-100014
    for
    Figure PCTCN2022143403-appb-100015
    Figure PCTCN2022143403-appb-100016
  19. 如权利要求1-18任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，所述具有式(I)所示的结构的化合物选自如下化合物中的一种：The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound having the structure shown in formula (I) is selected from the following One of the compounds:
    Figure PCTCN2022143403-appb-100017
    Figure PCTCN2022143403-appb-100017
    Figure PCTCN2022143403-appb-100018
    Figure PCTCN2022143403-appb-100018
    Figure PCTCN2022143403-appb-100019
    Figure PCTCN2022143403-appb-100019
    Figure PCTCN2022143403-appb-100020
    Figure PCTCN2022143403-appb-100020
    Figure PCTCN2022143403-appb-100021
    Figure PCTCN2022143403-appb-100021
    Figure PCTCN2022143403-appb-100022
    Figure PCTCN2022143403-appb-100022
    Figure PCTCN2022143403-appb-100023
    Figure PCTCN2022143403-appb-100023
    Figure PCTCN2022143403-appb-100024
    Figure PCTCN2022143403-appb-100024
    Figure PCTCN2022143403-appb-100025
    Figure PCTCN2022143403-appb-100025
    Figure PCTCN2022143403-appb-100026
    Figure PCTCN2022143403-appb-100026
  20. 一种药物组合物，其特征在于，包括权利要求1-19中任一项所述的化合物、或其药学上可接受的盐、或其立体异构体；以及药学可接受的载体。A pharmaceutical composition, characterized by comprising the compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.
  21. 一种权利要求1-19任一所述的化合物、或其药学上可接受的盐、或其立体异构体，或权利要求20所述的药物组合物在制备治疗或预防与CSF-1R活性相关的或由CSF-1R活性介导的疾病的药物中的应用。A compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition according to claim 20 in the preparation of a treatment or prevention with CSF-1R activity Drug application for diseases related or mediated by CSF-1R activity.
  22. 如权利要求21所述的应用，其特征在于，所述与CSF-1R活性相关的或由CSF-1R活性介导的疾病为癌症。The use according to claim 21, characterized in that the disease related to or mediated by CSF-1R activity is cancer.
PCT/CN2022/143403 2021-12-31 2022-12-29 Substituted pyrimidone derivative, and pharmaceutical composition and medical use thereof WO2023125812A1 (en)

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CN101300258A (en) * 2005-09-14 2008-11-05 詹森药业有限公司 5-OXO-5,8-dihydro-pyrido-pyrimidines as inhibitors of C-FMS kinase
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US20140275085A1 (en) * 2013-03-15 2014-09-18 Deciphera Pharmaceuticals, Llc 2-aminopyrimidin-6-ones and analogs exhibiting anti-cancer and anti-proliferative activities
US20140323478A1 (en) * 2013-04-30 2014-10-30 Afraxis Holdings, Inc. Serine/threonine kinase inhibitors
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