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WO2022160931A1 - Pyridopyrimidine derivative, preparation method therefor and use thereof - Google Patents

Pyridopyrimidine derivative, preparation method therefor and use thereof Download PDF

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Publication number
WO2022160931A1
WO2022160931A1 PCT/CN2021/135230 CN2021135230W WO2022160931A1 WO 2022160931 A1 WO2022160931 A1 WO 2022160931A1 CN 2021135230 W CN2021135230 W CN 2021135230W WO 2022160931 A1 WO2022160931 A1 WO 2022160931A1
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Prior art keywords
alkyl
cycloalkyl
ethyl
alkoxy
general formula
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PCT/CN2021/135230
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French (fr)
Chinese (zh)
Inventor
张盼盼
周林
叶成
钱文建
陈磊
Original Assignee
浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Application filed by 浙江海正药业股份有限公司, 上海昂睿医药技术有限公司 filed Critical 浙江海正药业股份有限公司
Priority to CN202180081504.9A priority Critical patent/CN116546985A/en
Publication of WO2022160931A1 publication Critical patent/WO2022160931A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems

Definitions

  • the present invention relates to a substituted pyridopyrimidine derivative, its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an SOS1 inhibitor.
  • RAS genes are widely present in various eukaryotes such as mammals, fruit flies, fungi, nematodes and yeast, and have important physiological functions in various life systems.
  • the mammalian RAS gene family has three members, namely H- RAS, K-RAS and N-RAS, various RAS genes have similar structures, all composed of four exons, distributed on the DNA of about 30kb in length.
  • Their encoded products are monomeric globular proteins with a relative molecular mass of 21 kDa.
  • the activation and inactivation states of RAS proteins have a significant impact on life processes such as cell growth, differentiation, proliferation and apoptosis.
  • This protein is a membrane-bound guanine nucleotide-binding protein with weak GTPase activity, which regulates RAS through GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in normal physiological activities
  • GAPs GTPase activating proteins
  • GEFs guanine nucleotide exchange factors
  • RAS protein when combines with GTP to form RAS-GTP, it is in the active state.
  • GTPase activating protein can dephosphorylate RAS-GTP into RAS-GDP, and then inactivate; the inactivated RAS-GDP is in guanine.
  • nucleotide exchange factors Under the action of nucleotide exchange factors, it is converted into active RAS-GTP, thereby activating a series of downstream pathways such as RAF/MER/ERK and PI3K/AKT/mTOR.
  • the RAS gene is also closely related to various human diseases, especially in cancer, RAS is an oncogene that frequently mutates, among which KRAS subtype gene mutations account for 86% of the total number of RAS gene mutations, about 90% of pancreatic cancer, Different degrees of KRAS gene mutation occur in 30%-40% of colon cancers and 15-20% of lung cancers. Given the prevalence of KRAS gene mutations, this target has always been the focus of drug development workers. Since the publication of the clinical results of AMG-510, which directly acts on the KRAS-G12C target, the research on KRAS inhibitors has set off a boom at home and abroad.
  • the SOS (Son of sevenless homolog) protein was originally discovered in Drosophila studies and is a guanosine-releasing protein encoded by the SOS gene.
  • Humans have two SOS homologues, hSOS1 and hSOS2, both of which are members of the guanine nucleotide exchange factor family with 70% homology. Although they are highly similar in structure and sequence, their physiological There are some differences in functionality.
  • hSOS1 protein is 150kDa in size and is a multi-structural protein domain composed of 1333 amino acids, including N-terminal protein domain (HD), multiple homology domains, helical linker (HL), RAS exchange sequence (REM) and rich C-terminal domain of proline.
  • HD N-terminal protein domain
  • HL helical linker
  • REM RAS exchange sequence
  • hSOS1 There are two binding sites on hSOS1 with RAS protein, namely catalytic site and allosteric site.
  • the catalytic site binds to the RAS protein on the RAS-GDP complex to promote guanine nucleotide exchange
  • the allosteric site binds
  • the RAS protein on the RAS-GTP complex further enhances the catalytic effect, and then participates in and activates the signal transduction of RAS family proteins.
  • Studies have shown that inhibition of SOS1 not only completely inhibited the RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also resulted in a 50% reduction in phospho-ERK activity in mutant KRAS cell lines.
  • inhibition of SOS1 can also reduce the activity of RAS, thereby treating various cancers caused by RAS gene mutation or RAS protein overactivation, including pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma tumor, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer , chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma, etc.
  • pancreatic cancer lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma tumor, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer,
  • the present invention provides a substituted pyridopyrimidine compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl, 9-10 membered bicyclic aryl or 9-10 membered fused ring;
  • R 2 is selected from halogen, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, -OR 4 , -C(O)R 5 , -NR 6 C(O)R 7 , -CH 2 NR 8 R 9 , -C(O)NR 8 R 9 , or -NR 8 R 9 ; wherein, the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from R 10 ;
  • R 3 is selected from hydrogen atom, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl or -C(O)R 5 ; wherein , the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are optionally further substituted by one or more substituents selected from R 10 ;
  • R 5 is each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-11 membered heterocyclyl, -NR 8 R 9 ; wherein said alkyl, cycloalkyl or heterocyclyl
  • the cyclic group is optionally further substituted with one or more substituents selected from hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy;
  • R 6 is selected from hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl
  • R 11 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected from one or more halogen, cyano, hydroxyl, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or 4-11-membered heterocyclic group substituents; the 4-11-membered heterocyclic group is optional is further substituted by C 1 -C 3 alkyl or C 1 -C 3 alkoxy;
  • R 12 and R 13 are each independently selected from hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl;
  • R 14 is selected from halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl or -C(O)R 15 ; wherein said The alkyl, alkoxy or hydroxyalkyl groups are optionally further substituted by one or more selected from halogen, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 ,
  • R 15 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected by one or more selected from halogen, hydroxyl, cyano, C 1 - C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or substituents of 4-11-membered heterocyclic groups;
  • n 1, 2 or 3.
  • a preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (II-1), (II- 2)
  • R 1 , R 2 , R 3 and m are defined as described in the general formula (I).
  • a preferred embodiment of the present invention is a compound represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring B is selected from C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3 or 4;
  • Rings A, R 1 , R 3 , R 10 and m are as defined in general formula (I).
  • a preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (IV-1), (IV- 2)
  • ring A, R 1 , R 3 , R 6 , R 7 , R 8 , R 9 and m are as defined in general formula (I).
  • a preferred embodiment of the present invention is a compound represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • ring A, R 1 , R 3 , R 4 and m are as defined in general formula (I).
  • a preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (VI-1), (VI- 2), the compound shown in (VI-3) or (VI-4) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
  • Rings A, R 1 , R 3 , R 8 , R 9 and m are as defined in general formula (I).
  • a preferred version of the present invention is a compound represented by general formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
  • R 10 and n are as defined in general formula (III).
  • the compound of general formula (I) is selected from:
  • the present invention provides a pharmaceutical composition containing effective doses of general formula (I), (II-1), (II-2), (II-3), (III), The compound described in (IV-1), (IV-2), (V), (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer thereof, Tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.
  • the present invention provides a kind of general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), ( The compound described in VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof Use of compounds in the preparation of SOS1 inhibitors.
  • the present invention also provides a general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V),
  • the compound described in (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a drug thereof Use of the composition in the preparation of a medicament for the treatment of diseases mediated by SOS1, wherein the diseases mediated by SOS1 are preferably RAS family protein signaling pathway-dependent related cancers, cancers caused by SOS1 mutations or caused by SOS1 mutations
  • the hereditary disease; wherein said disease mediated by SOS1 is preferably pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute Myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical
  • the present invention further provides a general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V),
  • the compound described in (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a drug thereof Use of the composition in the preparation of a medicament for treating RAS family protein signal transduction pathway-dependent related cancer, cancer caused by SOS1 mutation or hereditary disease caused by SOS1 mutation.
  • the present invention provides a kind of general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), ( The compound described in VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof
  • lung cancer colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer , cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma drugs.
  • Alkyl when taken as a group or part of a group is meant to include C1 - C20 straight or branched chain aliphatic hydrocarbon groups. Preferably it is a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged and spirocyclic carbocyclic rings. Preferably it is C 3 -C 12 cycloalkyl, more preferably C 3 -C 8 cycloalkyl, most preferably C 3 -C 6 cycloalkyl.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl groups can be substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and a single carbon atom (called a spiro atom) is shared between the monocyclic rings, and the ring may contain one or more Aromatic systems with multiple double bonds, but none of the rings have fully conjugated pi electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthryl.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-dicyclo[3.2.1]octyl Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl “heterocycle,” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclyl in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, fused, bridged and spirocyclic. It preferably has a 5 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur.
  • Examples of “monocyclic heterocyclyl” include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpho Linyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, piperazinyl, hexahydropyrimidinyl,
  • Monocyclic heterocyclyl groups may be substituted or unsubstituted.
  • “Spiroheterocyclyl” refers to a 5- to 18-membered polycyclic group with two or more cyclic structures, and the single rings share one atom with each other, and the ring may contain one or more double bonds, but Aromatic systems in which none of the rings has fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) n (wherein n is selected from 0, 1, or 2), and the remaining ring atoms for carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • Spirocycloalkyl groups are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl according to the number of spiro atoms shared between rings, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl Heterospiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,
  • Spiroheterocyclyl can be substituted or unsubstituted.
  • Fused heterocyclyl refers to a polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings is fully conjugated
  • a pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon.
  • n is selected from 0, 1 or 2
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0] Hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridged heterocyclyl” refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures that share two atoms that are not directly connected to each other, and one or more rings may be Aromatic systems containing one or more double bonds but none of the rings have fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo cyclo[3.3.2]decyl,
  • Bridged heterocyclyl groups can be substituted or unsubstituted.
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzom- Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoin
  • Heteroaryl groups can be substituted or unsubstituted.
  • “Fused ring” refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring is not completely conjugated A pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more heteroatoms selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2), and the remaining ring atoms are carbon .
  • the condensed ring preferably includes a bicyclic or tricyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • C 1 -C 6 hydroxyalkyl refers to a hydroxy substituted C 1 -C 6 alkyl group.
  • C 1 -C 6 haloalkyl refers to a halogen substituted C 1 -C 6 alkyl group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • DMSO dimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • BOP refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.
  • DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • DCC refers to dicyclohexylcarbodiimide.
  • EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • PdCl2 (dppf) refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • Pd( PPh3 ) 2Cl2 refers to bis(triphenylphosphine)palladium dichloride .
  • Pd2(dba )3 refers to tris(dibenzylideneacetone)dipalladium.
  • XantPhos refers to 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.
  • HATU refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • 9-BBN refers to 9-borabicyclo[3.3.1]nonane.
  • SPhos-Pd-G3 refers to methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1' - Biphenyl-2-yl)palladium(II).
  • leaving group is an atom or functional group that is removed from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions.
  • the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that is broken off with a pair of electrons from the substrate molecule is called the leaving group.
  • Groups that readily accept electrons and have a strong ability to withstand negative charges are good leaving groups. When the pKa of the conjugated acid of the leaving group is smaller, the easier it is for the leaving group to detach from other molecules.
  • Common leaving groups include, but are not limited to, halo, methanesulfonyl, -OTs, or -OH.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g., olefinic) bonds.
  • “Pharmaceutically acceptable salts” refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt formed with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the present invention provides a preparation method of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IA) and compound (IB) undergo condensation reaction under the condition of a condensing agent, preferably BOP condensing agent, DCC condensing agent, EDCI condensing agent and HATU condensing agent, to obtain the compound of general formula (I); when R 1 When containing a nitro group, it can be further reduced to an amino group;
  • a condensing agent preferably BOP condensing agent, DCC condensing agent, EDCI condensing agent and HATU condensing agent
  • R 1 , R 2 , R 3 and m are as described in the general formula (I).
  • the present invention provides a preparation method of compounds of general formula (II-1), (II-2), (II-3) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
  • the methods described include:
  • the compound of general formula (IA) and the compound (IIB-2) are respectively subjected to a condensation reaction to obtain the general formula (II-2); the compound of (II-2) can be further rationally transformed;
  • Described condensing agent is preferably BOP condensing agent, DCC condensing agent, EDCI condensing agent or HATU condensing agent;
  • the rational transformation includes, when R 1 contains a nitro group, the nitro group can be further reduced to an amino group;
  • R 1 , R 2 , R 3 and m are as described in the general formulae (II-1), (II-2), (II-3).
  • the present invention provides a preparation method of a compound of general formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • X is selected from halogen, preferably bromine
  • M is selected from H, -B(OH) 2 , -BF3K , -MgX or
  • Ring B is selected from C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;
  • Rings A, R 1 , R 3 , R 10 , m and n are as defined in general formula (III).
  • the present invention provides a preparation method of a compound of general formula (IV-1), (IV-2) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said method comprising:
  • the compound of general formula (IIIA) and compound (IVB-1) are subjected to a cross-coupling reaction under metal catalysis to obtain the compound of general formula (IV-1); the compound of (IV-1) can be further rationally transformed;
  • compound (IV-2) are subjected to a cross-coupling reaction under metal catalysis to obtain compound (IV-2); compound (IV-2) can be further rationally transformed;
  • X is selected from halogen, preferably bromine
  • Ring A, R 1 , R 3 , R 6 , R 7 , R 8 , R 9 and m are as defined in general formulae (IV-1) and (IV-2).
  • the present invention provides a preparation method of a compound of general formula (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIIA) and compound (VB) are subjected to a cross-coupling reaction under metal catalysis to obtain the compound of general formula (V); when R 1 contains a nitro group, it can be further reduced to an amino group.
  • X is selected from halogen, preferably bromine
  • Rings A, R 1 , R 3 , R 4 and m are as defined in general formula (V).
  • the compound of general formula (IIIA) reacts with pinacol biboronate under metal catalysis to obtain the compound of general formula (VC); the compound of general formula (VC) is oxidized to obtain the compound of general formula (VD); the compound of general formula (VD) and The compound of general formula (VE) undergoes a nucleophilic substitution reaction to obtain the compound of general formula (V);
  • X is selected from halogen, preferably bromine
  • L is selected from leaving groups, preferably p-toluenesulfonate and halogen;
  • Rings A, R 1 , R 3 , R 4 and m are as defined in general formula (V).
  • the present invention provides a compound of general formula (VI-1), (VI-2), (VI-3), (VI-4) or a stereoisomer, tautomer or pharmaceutically acceptable compound thereof
  • the preparation method of salt, described method comprises:
  • the compound of general formula (IIIA) is subjected to carbonylation reaction under metal catalysis to obtain the compound of general formula (VIB-1); the compound of general formula (VIB-1) is hydrolyzed to generate carboxylic acid to obtain the compound of general formula (VIC); further react with HNR 8 R 9 undergoes a condensation reaction under the condition of a condensing agent to obtain a compound of general formula (VI-1);
  • the compound of the general formula (IIIA) is subjected to a cross-coupling reaction under metal catalysis, and hydrolyzed to obtain the compound of the general formula (VIB-2); the compound of the general formula (VIB-2) undergoes reductive amination reaction with HNR 8 R 9 , and Through further resolution, compounds (VI-2) and (VI-3) are obtained;
  • the compound of general formula (VIA) is obtained under metal catalysis to obtain the compound of general formula (VIB-3); the compound of (VIB-3) is subjected to substitution reaction to obtain the compound of general formula (VI-4);
  • X is selected from halogen, preferably bromine
  • Ring A, R 1 , R 3 , R 8 , R 9 and m are defined as in the general formula (VI-1).
  • the present invention provides a kind of preparation method of compound of general formula (IA), described method comprises:
  • R 2 and R 3 are as defined in the general formula (I).
  • the present invention provides a preparation method of a compound of general formula (IB), the method comprising:
  • the bromide (IB-1) compound undergoes a metal-catalyzed cross-coupling reaction (such as Stille coupling reaction) to convert the ethyl ketone intermediate (IB-2) compound; the ethyl ketone intermediate (IB-2) compound is combined with a chiral sulfonic acid
  • the imide undergoes a reduction reaction to form a chiral sulfonimide (IB-3) compound; the chiral sulfonimide (IB-3) compound is reduced by sodium borohydride or 9-BBN to give the separable main product (IB -4) and a diastereomeric mixture of the minor product (IB-5); the enantiomer (IB-4) compound was reacted with HCl/1,4-dioxane solution to remove the sulfinyl group, The chiral benzylamine hydrochloride (IB) compound is obtained.
  • R 1 , ring A and m are as defined in general formula (I).
  • Mass spectrum is obtained by LC/MS instrument, and the ionization mode can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • CD3OD Deuterated methanol.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
  • Test Example 1 Test that the compound of the present invention blocks the binding of SOS1 to KRAS G12C protein
  • the following method was used to determine the ability of the compounds of the invention to block the interaction of SOS1 with KRAS G12C protein under in vitro conditions.
  • This method uses the KRAS-G12C/SOS1BINDING ASSAY KITS kit (Cat. No. 63ADK000CB16PEG) from Cisbio Company.
  • Kit instructions for detailed experimental operation, please refer to the kit instructions.
  • Table 1 IC 50 data of the compounds of the present invention blocking the interaction between SOS1 and KRAS G12C protein

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Abstract

The present invention relates to a substituted pyridopyrimidine derivative, a preparation method therefor, and the use of a pharmaceutical composition containing the derivative in medicine. In particular, the present invention relates to a substituted pyridopyrimidine derivative as represented by general formula (I), a preparation method therefor, a pharmaceutically acceptable salt thereof, and the use of same as therapeutic agents, in particular as SOS1 inhibitors, wherein the definition of each substituent in the general formula (I) is the same as the definition in the description.

Description

吡啶并嘧啶类衍生物及其制备方法和用途Pyridopyrimidine derivatives and preparation method and use thereof 技术领域technical field
本发明涉及一种取代的吡啶并嘧啶类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为SOS1抑制剂的用途。The present invention relates to a substituted pyridopyrimidine derivative, its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an SOS1 inhibitor.
背景技术Background technique
RAS基因广泛存在于各种真核生物如哺乳类、果蝇、真菌、线虫及酵母中,在各种生命体系中具有重要的生理功能,哺乳动物的RAS基因家族有三个成员,分别是H-RAS、K-RAS和N-RAS,各种RAS基因具有相似的结构,均由四个外显子组成,分布于全长约30kb的DNA上。它们的编码产物为相对分子质量21kDa的单体球状蛋白质。RAS蛋白的激活和非激活状态对细胞生长、分化、增殖和凋亡等生命进程有着重大的影响。该蛋白是一种膜结合的鸟嘌呤核苷酸结合蛋白,具有弱的GTP酶活性,在正常生理活动中,通过GTP酶活化蛋白(GAPs)和鸟嘌呤核苷酸交换因子(GEFs)调节RAS的活性状态,当RAS蛋白与GTP结合形成RAS-GTP时为激活状态,GTP酶活化蛋白可以使RAS-GTP去磷酸化转变成RAS-GDP,进而失活;失活的RAS-GDP在鸟嘌呤核苷酸交换因子作用下又转变成有活性的RAS-GTP,从而激活RAF/MER/ERK和PI3K/AKT/mTOR等一系列下游通路。RAS genes are widely present in various eukaryotes such as mammals, fruit flies, fungi, nematodes and yeast, and have important physiological functions in various life systems. The mammalian RAS gene family has three members, namely H- RAS, K-RAS and N-RAS, various RAS genes have similar structures, all composed of four exons, distributed on the DNA of about 30kb in length. Their encoded products are monomeric globular proteins with a relative molecular mass of 21 kDa. The activation and inactivation states of RAS proteins have a significant impact on life processes such as cell growth, differentiation, proliferation and apoptosis. This protein is a membrane-bound guanine nucleotide-binding protein with weak GTPase activity, which regulates RAS through GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in normal physiological activities In the active state, when RAS protein combines with GTP to form RAS-GTP, it is in the active state. GTPase activating protein can dephosphorylate RAS-GTP into RAS-GDP, and then inactivate; the inactivated RAS-GDP is in guanine. Under the action of nucleotide exchange factors, it is converted into active RAS-GTP, thereby activating a series of downstream pathways such as RAF/MER/ERK and PI3K/AKT/mTOR.
RAS基因同时也与人类的各种疾病密切相关,尤其在癌症方面,RAS是经常出现突变的致癌基因,其中KRAS亚型基因突变占到RAS基因突变总数的86%,约90%的胰腺癌,30%-40%的结肠癌、15-20%的肺癌中均出现不同程度的KRAS基因突变。鉴于KRAS基因突变的普遍性,该靶点一直是药物研发工作者关注的方向。从直接作用于KRAS-G12C靶点的AMG-510临床结果的公布开始,KRAS抑制剂的研究在国内外掀起一股热潮。The RAS gene is also closely related to various human diseases, especially in cancer, RAS is an oncogene that frequently mutates, among which KRAS subtype gene mutations account for 86% of the total number of RAS gene mutations, about 90% of pancreatic cancer, Different degrees of KRAS gene mutation occur in 30%-40% of colon cancers and 15-20% of lung cancers. Given the prevalence of KRAS gene mutations, this target has always been the focus of drug development workers. Since the publication of the clinical results of AMG-510, which directly acts on the KRAS-G12C target, the research on KRAS inhibitors has set off a boom at home and abroad.
SOS(Son of sevenless homolog)蛋白最初是在果蝇研究中被发现,是由SOS基因编码的鸟苷释放蛋白。人类有2种SOS同源体,hSOS1和hSOS2,二者都是鸟嘌呤核苷酸交换因子家族的成员,具有70%的同源性,尽管它们在结构和序列上高度相似,但各自的生理功能存在一定差异。hSOS1蛋白大小为150kDa,是由1333个氨基酸组成的多结构蛋白域,包含N端蛋白结构域(HD)、多个同源结构域、螺旋接头(HL)、RAS交换序列(REM)和富含脯氨酸的C端结构域。hSOS1上有2个与RAS蛋白的结合位点,分别是催化位点和变构位点,催化位点结合RAS-GDP复合物上的RAS蛋白促进鸟嘌呤核苷酸交换,变构位点结 合RAS-GTP复合物上的RAS蛋白进一步增强催化作用,进而参与并激活RAS家族蛋白的信号转导。有研究表明,对SOS1的抑制不仅能够对野生型KRAS细胞中的RAS-RAF-MEK-ERK通路产生完全抑制,在突变的KRAS细胞系中,也能导致磷酸-ERK的活性降低50%。因此,对SOS1的抑制也能够降低RAS的活性,从而治疗由RAS基因突变或RAS蛋白过度激活导致的各种癌症,包括胰腺癌、肺癌、结肠直肠癌、胆管上皮癌、多发性骨髓瘤、黑色素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、子宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞性白血病、肝细胞癌、乳癌、卵巢癌、前列腺癌、成胶质细胞瘤、肾癌及肉瘤等。The SOS (Son of sevenless homolog) protein was originally discovered in Drosophila studies and is a guanosine-releasing protein encoded by the SOS gene. Humans have two SOS homologues, hSOS1 and hSOS2, both of which are members of the guanine nucleotide exchange factor family with 70% homology. Although they are highly similar in structure and sequence, their physiological There are some differences in functionality. hSOS1 protein is 150kDa in size and is a multi-structural protein domain composed of 1333 amino acids, including N-terminal protein domain (HD), multiple homology domains, helical linker (HL), RAS exchange sequence (REM) and rich C-terminal domain of proline. There are two binding sites on hSOS1 with RAS protein, namely catalytic site and allosteric site. The catalytic site binds to the RAS protein on the RAS-GDP complex to promote guanine nucleotide exchange, and the allosteric site binds The RAS protein on the RAS-GTP complex further enhances the catalytic effect, and then participates in and activates the signal transduction of RAS family proteins. Studies have shown that inhibition of SOS1 not only completely inhibited the RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also resulted in a 50% reduction in phospho-ERK activity in mutant KRAS cell lines. Therefore, inhibition of SOS1 can also reduce the activity of RAS, thereby treating various cancers caused by RAS gene mutation or RAS protein overactivation, including pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma tumor, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer , chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma, etc.
市场上还未有选择性地针对于SOS1的药物上市,但已经公布了一系列相关专利,其中包括BI公司的WO2018115380A1,WO2019122129A1,Bayer公司的WO2019201848A1,Revolution公司的WO2020180768A1,WO2020180770A1等,目前处于临床试验阶段的药物为BI-1701963。但这些对于抗肿瘤研究是远远不够的,仍有必要研究和开发新的选择性SOS1激酶抑制剂,来解决未满足的医疗需求。There are no drugs selectively targeting SOS1 on the market, but a series of related patents have been published, including BI's WO2018115380A1, WO2019122129A1, Bayer's WO2019201848A1, Revolution's WO2020180768A1, WO2020180770A1, etc., which are currently in clinical trials The drug in stage is BI-1701963. However, these are far from enough for anti-tumor research, and there is still a need to research and develop new selective SOS1 kinase inhibitors to address unmet medical needs.
发明内容SUMMARY OF THE INVENTION
针对上述的技术问题,本发明提供一种通式(I)所示的一种取代的吡啶并嘧啶类化合物或其立体异构体、互变异构体或其可药用的盐:In view of the above-mentioned technical problems, the present invention provides a substituted pyridopyrimidine compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021135230-appb-000001
Figure PCTCN2021135230-appb-000001
其中:in:
环A选自C 6-C 10芳基、5-10元杂芳基、9-10元双环杂环基、9-10元双环芳基或9-10元稠合环; Ring A is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl, 9-10 membered bicyclic aryl or 9-10 membered fused ring;
R 1相同或不同,各自独立地选自氢原子、卤素、氰基、氨基、硝基、C 1-C 6烷基、C 3-C 6环烷基、4-11元杂环基、C 6-C 10芳基、5-10元杂芳基;其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、氰基、羟基、氨基、=O的取代基所取代; R 1 are the same or different, each independently selected from hydrogen atom, halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-11 membered heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further selected from one or more halogens, cyano groups , substituted by substituents of hydroxy, amino, and =O;
R 2选自卤素、氰基、C 1-C 6烷基、C 3-C 10环烷基、4-11元杂环基、C 6-C 10芳基、5-10元杂芳基、-OR 4、-C(O)R 5、-NR 6C(O)R 7、-CH 2NR 8R 9、-C(O)NR 8R 9
Figure PCTCN2021135230-appb-000002
或-NR 8R 9;其中,所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自R 10的取代基所取代;
R 2 is selected from halogen, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, -OR 4 , -C(O)R 5 , -NR 6 C(O)R 7 , -CH 2 NR 8 R 9 , -C(O)NR 8 R 9 ,
Figure PCTCN2021135230-appb-000002
or -NR 8 R 9 ; wherein, the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from R 10 ;
R 3选自氢原子、C 1-C 6烷基、C 1-C 3烷氧基、C 3-C 10环烷基、5-10元杂芳基或-C(O)R 5;其中,所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自R 10的取代基所取代; R 3 is selected from hydrogen atom, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl or -C(O)R 5 ; wherein , the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are optionally further substituted by one or more substituents selected from R 10 ;
R 4选自氢原子、C 1-C 6烷基、C 3-C 6环烷基或4-11元杂环基;其中所述的烷基或环烷基任选进一步被一个或多个选自氘原子、羟基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、杂环基、=O、-N(CH 3) 2或-N(C 2H 5) 2的取代基所取代;所述的4-11元杂环基任选进一步被一个或多个选自羟基、卤素、氰基、C 1-C 6烷氧基或=O的取代基所取代; R 4 is selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a 4-11 membered heterocyclic group; wherein the alkyl or cycloalkyl group is optionally further modified by one or more selected from deuterium atom, hydroxyl, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, heterocyclyl, =O, -N( CH3 ) 2 or -N( C2H 5 ) substituted by the substituent of 2 ; the 4-11-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, C 1 -C 6 alkoxy or =O replaced;
R 5各自独立地选自C 1-C 6烷基、C 3-C 6环烷基、4-11元杂环基、-NR 8R 9;其中所述的烷基、环烷基或杂环基任选进一步被一个或多个选自羟基、卤素、氰基、氨基、C 1-C 6烷氧基的取代基所取代; R 5 is each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-11 membered heterocyclyl, -NR 8 R 9 ; wherein said alkyl, cycloalkyl or heterocyclyl The cyclic group is optionally further substituted with one or more substituents selected from hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy;
R 6选自氢、C 1-C 3烷基或C 3-C 6环烷基; R 6 is selected from hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl;
R 7选自C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基、5-10元杂芳基或4-11元杂环基;其中所述的烷基、环烷基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、氰基、氨基、C 1-C 6烷氧基的取代基所取代;所述的杂环基任选进一步被一个或多个选自羟基、卤素、氰基、C 1-C 6烷基、C 3-C 6环氧基、C 1-C 3烷氧基或=O的取代基所取代; R 7 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-10-membered heteroaryl or 4-11-membered heterocyclyl; radical, cycloalkyl, aryl or heteroaryl optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, amino, C 1 -C 6 alkoxy; the heterocycle is optionally further substituted by one or more substituents selected from hydroxy, halogen, cyano, C1 - C6 alkyl, C3 - C6 epoxy, C1 - C3 alkoxy or =O replace;
R 8和R 9各自独立地选自氢原子或C 1-C 6烷基;其中所述的烷基任选进一步被一个或多个选自羟基、卤素、氰基、氨基、C 1-C 6烷氧基、-N(CH 3) 2、-N(C 2H 5) 2、4-11元杂环基或=O的取代基所取代;所述的4-11元杂环基任选进一步被一个或多个选自羟基、卤素、氰基、C 1-C 6烷基、C 3-C 6环氧基、C 1-C 3烷氧基或=O的取代基所取代; R 8 and R 9 are each independently selected from a hydrogen atom or a C 1 -C 6 alkyl group; wherein said alkyl group is optionally further selected from one or more of hydroxyl, halogen, cyano, amino, C 1 -C 6 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 , 4-11-membered heterocyclic group or a substituent of =O; the 4-11-membered heterocyclic group is any is further substituted with one or more substituents selected from hydroxyl, halogen, cyano, C1 - C6 alkyl, C3 - C6 epoxy, C1 - C3 alkoxy or =O;
或者,R 8和R 9与它们相连接的原子一起形成一个含N的4-11元杂环基,所述的4-11元杂环基任选进一步被一个或多个=O或R 14的取代基所取代; Alternatively, R 8 and R 9 together with the atoms to which they are attached form an N-containing 4-11 membered heterocyclyl optionally further modified by one or more =O or R 14 substituted by the substituent;
R 10各自独立地选自卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6羟基烷基、C 3-C 6环烷基、=O、-C(O)R 11或-CH 2C(O)NR 12R 13;其中所述的烷基、烷氧基、羟基烷基或环烷基任选进一步被一个或多个选自卤素、氰基、C 1-C 3烷氧基、-N(CH 3) 2、-N(C 2H 5) 2 或4-11元杂环基的取代基所取代;所述的4-11元杂环基任选进一步被一个或多个C 1-C 3烷基或C 1-C 3烷氧基的取代基所取代; R 10 is each independently selected from halogen, cyano, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl , =O, -C(O)R 11 or -CH 2 C(O)NR 12 R 13 ; wherein said alkyl, alkoxy, hydroxyalkyl or cycloalkyl is optionally further modified by one or more substituted with a substituent selected from halogen, cyano, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or 4-11-membered heterocyclic group; the said The 4-11 membered heterocyclyl is optionally further substituted by one or more C 1 -C 3 alkyl or C 1 -C 3 alkoxy substituents;
R 11选自C 1-C 6烷基或C 3-C 6环烷基;其中所述的烷基或环烷基任选进一步被一个或多个选自卤素、氰基、羟基、C 1-C 3烷氧基、-N(CH 3) 2、-N(C 2H 5) 2或4-11元杂环基的取代基所取代;所述的4-11元杂环基任选进一步被C 1-C 3烷基或C 1-C 3烷氧基所取代; R 11 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected from one or more halogen, cyano, hydroxyl, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or 4-11-membered heterocyclic group substituents; the 4-11-membered heterocyclic group is optional is further substituted by C 1 -C 3 alkyl or C 1 -C 3 alkoxy;
R 12和R 13各自独立地选自氢、C 1-C 3烷基或C 3-C 6环烷基; R 12 and R 13 are each independently selected from hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl;
或者,R 12和R 13与它们相连接的原子一起形成含N的4-11元杂环基;其中所述的杂环基任选进一步被一个或多个选自卤素、氰基、羟基、C 1-C 6烷氧基、C 1-C 6羟基烷基、C 1-C 6含卤烷基、C 3-C 6环烷基或=O的取代基所取代; Alternatively, R 12 and R 13 together with the atoms to which they are attached form an N-containing 4-11 membered heterocyclic group; wherein said heterocyclic group is optionally further selected from one or more groups selected from halogen, cyano, hydroxyl, substituted by C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or a substituent of =O;
R 14选自卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6羟基烷基或-C(O)R 15;其中所述的烷基、烷氧基或羟基烷基任选进一步被一个或多个选自卤素、C 1-C 3烷氧基、-N(CH 3) 2、-N(C 2H 5) 2R 14 is selected from halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl or -C(O)R 15 ; wherein said The alkyl, alkoxy or hydroxyalkyl groups are optionally further substituted by one or more selected from halogen, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 ,
Figure PCTCN2021135230-appb-000003
的取代基所取代;
Figure PCTCN2021135230-appb-000003
substituted by the substituent;
R 15选自C 1-C 6烷基或C 3-C 6环烷基;其中所述烷基或环烷基任选进一步被一个或多个选自卤素、羟基、氰基、C 1-C 3烷氧基、-N(CH 3) 2、-N(C 2H 5) 2或4-11元杂环基的取代基所取代; R 15 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected by one or more selected from halogen, hydroxyl, cyano, C 1 - C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or substituents of 4-11-membered heterocyclic groups;
m为1、2或3。m is 1, 2 or 3.
本发明的优选方案,一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(II-1)、(II-2)、(II-3)所示的化合物或其立体异构体、互变异构体或其可药用的盐:A preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (II-1), (II- 2) The compound shown in (II-3) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
Figure PCTCN2021135230-appb-000004
Figure PCTCN2021135230-appb-000004
其中:R 1、R 2、R 3和m的定义如通式(I)中所述。 wherein: R 1 , R 2 , R 3 and m are defined as described in the general formula (I).
本发明的优选方案,一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(III)所示的化合物或其立体异构体、互变异构体或其可药用的盐:A preferred embodiment of the present invention is a compound represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2021135230-appb-000005
Figure PCTCN2021135230-appb-000005
其中:in:
环B选自C 3-C 10环烷基、4-11元杂环基、C 6-C 10芳基或5-10元杂芳基; Ring B is selected from C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;
n选自0、1、2、3或4;n is selected from 0, 1, 2, 3 or 4;
环A、R 1、R 3、R 10和m的定义如通式(I)中所述。 Rings A, R 1 , R 3 , R 10 and m are as defined in general formula (I).
本发明的优选方案,一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(IV-1)、(IV-2)所示的化合物或其立体异构体、互变异构体或其可药用的盐:A preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (IV-1), (IV- 2) The compound shown or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure PCTCN2021135230-appb-000006
Figure PCTCN2021135230-appb-000006
其中:环A、R 1、R 3、R 6、R 7、R 8、R 9和m的定义如通式(I)中所述。 wherein: ring A, R 1 , R 3 , R 6 , R 7 , R 8 , R 9 and m are as defined in general formula (I).
本发明的优选方案,一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(V)所示的化合物或其立体异构体、互变异构体或其可药用的盐:A preferred embodiment of the present invention is a compound represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
Figure PCTCN2021135230-appb-000007
Figure PCTCN2021135230-appb-000007
其中:环A、R 1、R 3、R 4和m的定义如通式(I)中所述。 wherein: ring A, R 1 , R 3 , R 4 and m are as defined in general formula (I).
本发明的优选方案,一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药 用的盐,其为通式(VI-1)、(VI-2)、(VI-3)或(VI-4)所示的化合物或其立体异构体、互变异构体或其可药用的盐:A preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (VI-1), (VI- 2), the compound shown in (VI-3) or (VI-4) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
Figure PCTCN2021135230-appb-000008
Figure PCTCN2021135230-appb-000008
其中:in:
环A、R 1、R 3、R 8、R 9和m的定义如通式(I)中所述。 Rings A, R 1 , R 3 , R 8 , R 9 and m are as defined in general formula (I).
本发明的优选方案,一种通式(III)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其中:A preferred version of the present invention is a compound represented by general formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
Figure PCTCN2021135230-appb-000009
选自以下基团:
Figure PCTCN2021135230-appb-000009
selected from the following groups:
Figure PCTCN2021135230-appb-000010
Figure PCTCN2021135230-appb-000010
其中:R 10和n的定义如通式(III)中所述。 wherein: R 10 and n are as defined in general formula (III).
在本发明的优选方案中,通式(I)所述的化合物选自:In a preferred embodiment of the present invention, the compound of general formula (I) is selected from:
Figure PCTCN2021135230-appb-000011
Figure PCTCN2021135230-appb-000011
Figure PCTCN2021135230-appb-000012
Figure PCTCN2021135230-appb-000012
Figure PCTCN2021135230-appb-000013
Figure PCTCN2021135230-appb-000013
Figure PCTCN2021135230-appb-000014
Figure PCTCN2021135230-appb-000014
或其立体异构体、互变异构体或其可药用的盐。or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
注:如果在画出的结构和给出的该结构的名称之间有差异,则画出的结构将给予更大的权重。NOTE: If there is a discrepancy between the drawn structure and the given name of that structure, the drawn structure will be given greater weight.
更进一步,本发明提供一种药物组合物,所述的药物组合物含有有效剂量的通式(I)、(II-1)、(II-2)、(II-3)、(III)、(IV-1)、(IV-2)、(V)、(VI-1)、(VI-2)、(VI-3)或(VI-4)所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。Further, the present invention provides a pharmaceutical composition containing effective doses of general formula (I), (II-1), (II-2), (II-3), (III), The compound described in (IV-1), (IV-2), (V), (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer thereof, Tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.
本发明提供一种通式(I)、(II-1)、(II-2)、(II-3)、(III)、(IV-1)、(IV-2)、(V)、(VI-1)、(VI-2)、(VI-3)或(VI-4)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备SOS1抑制剂中的用途。The present invention provides a kind of general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), ( The compound described in VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof Use of compounds in the preparation of SOS1 inhibitors.
本发明还提供一种通式(I)、(II-1)、(II-2)、(II-3)、(III)、(IV-1)、(IV-2)、(V)、(VI-1)、(VI-2)、(VI-3)或(VI-4)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗由SOS1介导的疾病的药物中的用途,其中所述的由SOS1介导的疾病优选为RAS家族蛋白信号传导通路依赖性相关的癌症、SOS1突变导致的癌症或SOS1突变导致的遗传性疾病;其中所述的由SOS1介导的疾病优选为胰腺癌、肺癌、结肠直肠癌、胆管上皮癌、多发性骨髓瘤、黑色素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、子宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞性白血病、肝细胞癌、乳癌、卵巢癌、前列腺癌、成胶质细胞瘤、肾癌及肉瘤。The present invention also provides a general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), The compound described in (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a drug thereof Use of the composition in the preparation of a medicament for the treatment of diseases mediated by SOS1, wherein the diseases mediated by SOS1 are preferably RAS family protein signaling pathway-dependent related cancers, cancers caused by SOS1 mutations or caused by SOS1 mutations The hereditary disease; wherein said disease mediated by SOS1 is preferably pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute Myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovary cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma.
本发明进一步提供一种通式(I)、(II-1)、(II-2)、(II-3)、(III)、(IV-1)、(IV-2)、(V)、(VI-1)、(VI-2)、(VI-3)或(VI-4)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗RAS家族蛋白信号传导通路依赖性相关的癌症、SOS1突变导致的癌症或SOS1突变导致的遗传性疾病的药物中的用途。The present invention further provides a general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), The compound described in (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a drug thereof Use of the composition in the preparation of a medicament for treating RAS family protein signal transduction pathway-dependent related cancer, cancer caused by SOS1 mutation or hereditary disease caused by SOS1 mutation.
本发明提供一种通式(I)、(II-1)、(II-2)、(II-3)、(III)、(IV-1)、(IV-2)、(V)、(VI-1)、(VI-2)、(VI-3)或(VI-4)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗胰腺癌、肺癌、结肠直肠癌、胆管上皮癌、多发性骨髓瘤、黑色素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、子宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞性白血病、肝细胞癌、乳癌、卵巢癌、前列腺癌、成胶质细胞瘤、肾癌及肉瘤的药物中的用途。The present invention provides a kind of general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), ( The compound described in VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof In preparation for the treatment of pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer , cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma drugs.
发明的详细说明Detailed description of the invention
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:Unless stated to the contrary, some terms used in the specification and claims of the present invention are defined as follows:
“烷基”当作一基团或一基团的一部分时是指包括C 1-C 20直链或者带有支链的脂肪烃基团。优选为C 1-C 10烷基,更优选为C 1-C 6烷基。烷基基团的实施例包括但不限于甲基、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、2,3-二甲基丁基等。烷基可以是取代或未取代的。 "Alkyl" when taken as a group or part of a group is meant to include C1 - C20 straight or branched chain aliphatic hydrocarbon groups. Preferably it is a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C 3-C 12环烷基,更优选为C 3-C 8环烷基,最优选为C 3-C 6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。环烷基可以是取代或未取代的。 "Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged and spirocyclic carbocyclic rings. Preferably it is C 3 -C 12 cycloalkyl, more preferably C 3 -C 8 cycloalkyl, most preferably C 3 -C 6 cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl groups can be substituted or unsubstituted.
“螺环烷基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个碳原子(称螺原子)的多环基团,环内可以含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基,优选为单螺和双螺环烷基,优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于:螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and a single carbon atom (called a spiro atom) is shared between the monocyclic rings, and the ring may contain one or more Aromatic systems with multiple double bonds, but none of the rings have fully conjugated pi electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
“稠环烷基”指5至18元,含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,优选为6至12元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷 基。“稠环烷基”的非限制性实施例包括但不限于:二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。"Fused cycloalkyl" refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthryl.
“桥环烷基”指5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,优选为6至12元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更优选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。"Bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-dicyclo[3.2.1]octyl Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用,都是指非芳香性杂环基,其中一个或多个成环的原子是杂原子,如氧、氮、硫原子等,包括单环、多环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双环或三环,其可以包含1,2或3个选自氮、氧和/或硫中的原子。"Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclyl in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, fused, bridged and spirocyclic. It preferably has a 5 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur.
“单环杂环基”的实例包括但不限于吗啉基、氧杂环丁烷基、硫代吗啉基、四氢呋喃基、四氢吡喃基、1,1-二氧代-硫代吗啉基、哌啶基、2-氧代-哌啶基、吡咯烷基、2-氧代-吡咯烷基、哌嗪-2-酮基、哌嗪基、六氢嘧啶基、Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpho Linyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, piperazinyl, hexahydropyrimidinyl,
Figure PCTCN2021135230-appb-000015
Figure PCTCN2021135230-appb-000015
单环杂环基可以是取代或未取代的。Monocyclic heterocyclyl groups may be substituted or unsubstituted.
“螺杂环基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个原子的多环基团,环内可以含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O) n(其中n选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于:1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基、5-氧杂螺[2.4]庚基、 "Spiroheterocyclyl" refers to a 5- to 18-membered polycyclic group with two or more cyclic structures, and the single rings share one atom with each other, and the ring may contain one or more double bonds, but Aromatic systems in which none of the rings has fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) n (wherein n is selected from 0, 1, or 2), and the remaining ring atoms for carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. Spirocycloalkyl groups are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl according to the number of spiro atoms shared between rings, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl Heterospiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,
Figure PCTCN2021135230-appb-000016
Figure PCTCN2021135230-appb-000016
螺杂环基可以是取代或未取代的。Spiroheterocyclyl can be substituted or unsubstituted.
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O) n(其中n选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于:八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基,3-氮杂二环[3.1.0]己基,八氢苯并[b][1,4]二噁英(dioxine)。 "Fused heterocyclyl" refers to a polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings is fully conjugated A pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0] Hexyl, octahydrobenzo[b][1,4]dioxine.
“桥杂环基”指5至14元,5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接的原子的多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O) n(其中n选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更优选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于:2-氮杂二环[2.2.1]庚基,2-氮杂二环[2.2.2]辛基、2-氮杂二环[3.3.2]癸基、 "Bridged heterocyclyl" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures that share two atoms that are not directly connected to each other, and one or more rings may be Aromatic systems containing one or more double bonds but none of the rings have fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo cyclo[3.3.2]decyl,
Figure PCTCN2021135230-appb-000017
Figure PCTCN2021135230-appb-000017
桥杂环基可以是取代或未取代的。Bridged heterocyclyl groups can be substituted or unsubstituted.
“芳基”是指含有一个或者两个环的碳环芳香系统,其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基,比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基,更优选芳基为苯基和萘基,最优选为苯基。芳基可以是取代或未取 代的。 "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups. Aryl groups can be substituted or unsubstituted.
“杂芳基”是指芳香族5至6元单环或8至10元双环,其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基,吡啶基,2-氧代-1,2-二氢吡啶基,哒嗪基,嘧啶基,吡嗪基,噻吩基,异噁唑基,噁唑基,噁二唑基,咪唑基,吡咯基,吡唑基,三唑基,四氮唑基,噻唑基,异噻唑基,1,2,3-噻二唑基,苯并间二氧杂环戊烯基,苯并噻吩基、苯并咪唑基,吲哚基,异吲哚基,1,3-二氧代-异吲哚基,喹啉基,吲唑基,苯并异噻唑基,苯并噁唑基、苯并异噁唑基、吡啶酮基、"Heteroaryl" refers to an aromatic 5 to 6 membered monocyclic or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzom- Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoyl Isothiazolyl, benzoxazolyl, benzisoxazolyl, pyridinone,
Figure PCTCN2021135230-appb-000018
Figure PCTCN2021135230-appb-000018
杂芳基可以是取代或未取代的。Heteroaryl groups can be substituted or unsubstituted.
“稠合环”是指两个或两个以上环状结构彼此共用一对原子的多环基团,一个或多个环可以含有一个或多个双键,但至少一个环不具有完全共轭的π电子的芳香系统,其中环原子选自0个、一个或多个选自氮、氧或S(O) r(其中r选自0、1或2)的杂原子,其余环原子为碳。稠合环优选包括双环或三环的稠合环,其中双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环。优选为7至14元,更优选为8至10元。“稠合环”的实施 例包括但不限于: "Fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring is not completely conjugated A pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more heteroatoms selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2), and the remaining ring atoms are carbon . The condensed ring preferably includes a bicyclic or tricyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
Figure PCTCN2021135230-appb-000019
Figure PCTCN2021135230-appb-000019
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C 1-C 6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。 "Alkoxy" refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
“C 1-C 6羟基烷基”指羟基取代的C 1-C 6烷基。 "C 1 -C 6 hydroxyalkyl" refers to a hydroxy substituted C 1 -C 6 alkyl group.
“C 1-C 6含卤烷基”指卤素取代的C 1-C 6烷基。 "C 1 -C 6 haloalkyl" refers to a halogen substituted C 1 -C 6 alkyl group.
“羟基”指-OH基团。"Hydroxy" refers to the -OH group.
“卤素”是指氟、氯、溴和碘。"Halogen" refers to fluorine, chlorine, bromine and iodine.
“氨基”指-NH 2"Amino" refers to -NH2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO 2"Nitro" refers to -NO2 .
“苄基”指-CH 2-苯基。 "Benzyl" refers to -CH2 -phenyl.
“DMSO”指二甲基亚砜。"DMSO" refers to dimethyl sulfoxide.
“DMF”指N,N-二甲基甲酰胺。"DMF" refers to N,N-dimethylformamide.
“BOP”指苯并三氮唑-1-基氧基三(二甲氨基)磷鎓六氟磷酸盐。"BOP" refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.
“DBU”指1,8-二氮双环[5.4.0]十一-7-烯。"DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.
“DCC”指二环己基碳二亚胺。"DCC" refers to dicyclohexylcarbodiimide.
“EDCI”指1-(3-二甲基氨基丙基)-3-乙基碳二亚胺。"EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
“PdCl 2(dppf)”指[1,1'-双(二苯基膦基)二茂铁]二氯化钯。 " PdCl2 (dppf)" refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
“RuPhos-Pd-G 3”指甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)。 "RuPhos-Pd-G 3 " methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1' - Biphenyl-2-yl)palladium(II).
“Pd(PPh 3) 2Cl 2”指双(三苯基膦)二氯化钯。 "Pd( PPh3 ) 2Cl2 " refers to bis(triphenylphosphine)palladium dichloride .
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。 "Pd2(dba )3 " refers to tris(dibenzylideneacetone)dipalladium.
“XantPhos”指4,5-双二苯基膦-9,9-二甲基氧杂蒽。"XantPhos" refers to 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.
“HATU”指2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。"HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
“9-BBN”指9-硼双环[3.3.1]壬烷。"9-BBN" refers to 9-borabicyclo[3.3.1]nonane.
“SPhos-Pd-G3”指甲烷磺酸(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)。"SPhos-Pd-G3" refers to methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1' - Biphenyl-2-yl)palladium(II).
“离去基团(leaving group)”,或称离去基,在化学反应中从一较大分子中脱离的原子或官能基,是亲核取代反应与消除反应中应用的术语。在亲核取代反应中,被亲核试剂进攻的反应物称为底物(substrate),而从底物分子中带着一对电子断裂出去的原子或原子团称为离去基团。易接受电子、承受负电荷能力强的基团是好的离去基团。当离去基团共轭酸的pKa越小,离去基团越容易从其他分子中脱离。原因是因为当其共轭酸的pKa越小,相应离去基团不需和其他原子结合,以阴离子(或电中性离去基团)的形式存在的趋势也就增强。常见的离去基团包括但不限于卤素、甲磺酰基、-OTs或-OH。"Leaving group", or leaving group, is an atom or functional group that is removed from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions. In the nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that is broken off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to withstand negative charges are good leaving groups. When the pKa of the conjugated acid of the leaving group is smaller, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugated acid is smaller, the corresponding leaving group does not need to be combined with other atoms, and the tendency to exist in the form of an anion (or a neutral leaving group) is also enhanced. Common leaving groups include, but are not limited to, halo, methanesulfonyl, -OTs, or -OH.
“取代的”指基团中的一个或多个氢原子,优选为最多5个,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" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g., olefinic) bonds.
本说明书所述的“取代”或“取代的”,如无特别指出,均是指基团可被一个或多个取代基所取代。"Substituted" or "substituted" mentioned in this specification, unless otherwise specified, means that the group may be substituted by one or more substituents.
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。"Pharmaceutically acceptable salts" refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. The pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt formed with a suitable acid.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients Form. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
本发明化合物的合成方法Synthetic method of the compound of the present invention
为了完成本发明的目的,本发明采用如下技术方案:In order to accomplish the purpose of the present invention, the present invention adopts following technical scheme:
本发明提供了一种通式(I)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法包括:The present invention provides a preparation method of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021135230-appb-000020
Figure PCTCN2021135230-appb-000020
通式(IA)化合物与(IB)化合物在缩合剂的条件下,优选为BOP缩合剂、DCC缩合剂、EDCI缩合剂和HATU缩合剂,发生缩合反应得到通式(I)化合物;当R 1含有硝基时,可以进一步还原成氨基; The compound of general formula (IA) and compound (IB) undergo condensation reaction under the condition of a condensing agent, preferably BOP condensing agent, DCC condensing agent, EDCI condensing agent and HATU condensing agent, to obtain the compound of general formula (I); when R 1 When containing a nitro group, it can be further reduced to an amino group;
R 1、R 2、R 3和m的定义如通式(I)中所述。 The definitions of R 1 , R 2 , R 3 and m are as described in the general formula (I).
本发明提供了一种通式(II-1)、(II-2)、(II-3)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法包括:The present invention provides a preparation method of compounds of general formula (II-1), (II-2), (II-3) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof. The methods described include:
Figure PCTCN2021135230-appb-000021
Figure PCTCN2021135230-appb-000021
Figure PCTCN2021135230-appb-000022
Figure PCTCN2021135230-appb-000022
通式(IA)化合物分别与(IIB-1)化合物在缩合剂的条件下,发生缩合反应,得到通式(II-1);(II-1)化合物可以进一步发生合理转化;Under the condition of a condensing agent, the compound of general formula (IA) and compound (IIB-1) are respectively subjected to a condensation reaction to obtain general formula (II-1); the compound of (II-1) can be further rationally transformed;
通式(IA)化合物分别与(IIB-2)化合物在缩合剂的条件下,发生缩合反应,得到通式(II-2);(II-2)化合物可以进一步发生合理转化;Under the condition of a condensing agent, the compound of general formula (IA) and the compound (IIB-2) are respectively subjected to a condensation reaction to obtain the general formula (II-2); the compound of (II-2) can be further rationally transformed;
通式(IA)化合物分别与(IIB-3)化合物在缩合剂的条件下,发生缩合反应,得到通式(II-1);(II-2)化合物可以进一步发生合理转化;Under the condition of a condensing agent, the compound of general formula (IA) and compound (IIB-3) undergo a condensation reaction to obtain general formula (II-1); the compound of (II-2) can be further transformed reasonably;
其中:in:
所述的缩合试剂优选为BOP缩合剂、DCC缩合剂、EDCI缩合剂或HATU缩合剂;Described condensing agent is preferably BOP condensing agent, DCC condensing agent, EDCI condensing agent or HATU condensing agent;
所述的合理转化包括,当R 1含有硝基时,该硝基可以进一步还原成氨基; The rational transformation includes, when R 1 contains a nitro group, the nitro group can be further reduced to an amino group;
R 1、R 2、R 3和m的定义如通式(II-1)、(II-2)、(II-3)中所述。 The definitions of R 1 , R 2 , R 3 and m are as described in the general formulae (II-1), (II-2), (II-3).
本发明提供了一种通式(III)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法包括:The present invention provides a preparation method of a compound of general formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
Figure PCTCN2021135230-appb-000023
Figure PCTCN2021135230-appb-000023
通式(IIIA)化合物与(IIIB)化合物在金属催化下进行交叉耦合反应得到通式(III)化合物;当R 1含有硝基时,可以进一步还原成氨基。(III)化合物可以进一步发生合理转化。其中: The compound of general formula (IIIA) and compound (IIIB) are subjected to a cross-coupling reaction under metal catalysis to obtain the compound of general formula (III); when R 1 contains a nitro group, it can be further reduced to an amino group. Compound (III) can be further rationally transformed. in:
X选自卤素,优选为溴;X is selected from halogen, preferably bromine;
M选自H、-B(OH) 2、-BF 3K、-MgX或
Figure PCTCN2021135230-appb-000024
M is selected from H, -B(OH) 2 , -BF3K , -MgX or
Figure PCTCN2021135230-appb-000024
环B选自C 3-C 10环烷基、4-11元杂环基、C 6-C 10芳基或5-10元杂芳基; Ring B is selected from C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;
环A、R 1、R 3、R 10、m和n的定义如通式(III)中所述。 Rings A, R 1 , R 3 , R 10 , m and n are as defined in general formula (III).
本发明提供了一种通式(IV-1)、(IV-2)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法包括:The present invention provides a preparation method of a compound of general formula (IV-1), (IV-2) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said method comprising:
Figure PCTCN2021135230-appb-000025
Figure PCTCN2021135230-appb-000025
通式(IIIA)化合物与(IVB-1)化合物,在金属催化下进行交叉耦合反应,得到通式(IV-1)化合物;(IV-1)化合物可以进一步发生合理转化;The compound of general formula (IIIA) and compound (IVB-1) are subjected to a cross-coupling reaction under metal catalysis to obtain the compound of general formula (IV-1); the compound of (IV-1) can be further rationally transformed;
通式(IIIA)化合物与(IVB-2)化合物,在金属催化下进行交叉耦合反应,得到(IV-2)化合物;(IV-2)化合物可以进一步发生合理转化;The compound of general formula (IIIA) and compound (IVB-2) are subjected to a cross-coupling reaction under metal catalysis to obtain compound (IV-2); compound (IV-2) can be further rationally transformed;
其中:in:
X选自卤素,优选为溴;X is selected from halogen, preferably bromine;
环A、R 1、R 3、R 6、R 7、R 8、R 9和m的定义如通式(IV-1)和(IV-2)中所述。 Ring A, R 1 , R 3 , R 6 , R 7 , R 8 , R 9 and m are as defined in general formulae (IV-1) and (IV-2).
本发明提供了一种通式(V)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法包括:The present invention provides a preparation method of a compound of general formula (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:
方案一:Option One:
Figure PCTCN2021135230-appb-000026
Figure PCTCN2021135230-appb-000026
通式(IIIA)化合物与(VB)化合物,在金属催化下进行交叉耦合反应,得到通式(V)化合物;当R 1含有硝基时,可以进一步还原成氨基。 The compound of general formula (IIIA) and compound (VB) are subjected to a cross-coupling reaction under metal catalysis to obtain the compound of general formula (V); when R 1 contains a nitro group, it can be further reduced to an amino group.
其中:in:
X选自卤素,优选为溴;X is selected from halogen, preferably bromine;
环A、R 1、R 3、R 4和m的定义如通式(V)中所述。 Rings A, R 1 , R 3 , R 4 and m are as defined in general formula (V).
方案二:Option II:
Figure PCTCN2021135230-appb-000027
Figure PCTCN2021135230-appb-000027
通式(IIIA)化合物与联硼酸频那醇酯在金属催化下反应,得到通式(VC)化合物;通式(VC)化合物氧化后得到通式(VD)化合物;通式(VD)化合物与通式(VE)化合物发生亲核取代反应,得到通式(V)化合物;The compound of general formula (IIIA) reacts with pinacol biboronate under metal catalysis to obtain the compound of general formula (VC); the compound of general formula (VC) is oxidized to obtain the compound of general formula (VD); the compound of general formula (VD) and The compound of general formula (VE) undergoes a nucleophilic substitution reaction to obtain the compound of general formula (V);
其中:in:
X选自卤素,优选为溴;X is selected from halogen, preferably bromine;
L选自离去基团,优选为对甲苯磺酸酯基和卤素;L is selected from leaving groups, preferably p-toluenesulfonate and halogen;
环A、R 1、R 3、R 4和m的定义如通式(V)中所述。 Rings A, R 1 , R 3 , R 4 and m are as defined in general formula (V).
本发明提供了一种通式(VI-1)、(VI-2)、(VI-3)、(VI-4)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法包括:The present invention provides a compound of general formula (VI-1), (VI-2), (VI-3), (VI-4) or a stereoisomer, tautomer or pharmaceutically acceptable compound thereof The preparation method of salt, described method comprises:
Figure PCTCN2021135230-appb-000028
Figure PCTCN2021135230-appb-000028
通式(IIIA)化合物在金属催化下进行插羰反应,得到通式(VIB-1)化合物;通式(VIB-1)化合物水解生成羧酸,得到通式(VIC)化合物;进一步与HNR 8R 9在缩合剂的条件下发生缩合反应,得到通式(VI-1)化合物; The compound of general formula (IIIA) is subjected to carbonylation reaction under metal catalysis to obtain the compound of general formula (VIB-1); the compound of general formula (VIB-1) is hydrolyzed to generate carboxylic acid to obtain the compound of general formula (VIC); further react with HNR 8 R 9 undergoes a condensation reaction under the condition of a condensing agent to obtain a compound of general formula (VI-1);
通式(IIIA)化合物在金属催化下进行交叉偶联反应,并通过水解,得到通式(VIB-2)化合物;通式(VIB-2)化合物与HNR 8R 9发生还原胺化反应,并通过进一步拆分,得到(VI-2)和(VI-3)化合物; The compound of the general formula (IIIA) is subjected to a cross-coupling reaction under metal catalysis, and hydrolyzed to obtain the compound of the general formula (VIB-2); the compound of the general formula (VIB-2) undergoes reductive amination reaction with HNR 8 R 9 , and Through further resolution, compounds (VI-2) and (VI-3) are obtained;
通式(VIA)化合物在金属催化下,得到通式(VIB-3)化合物;(VIB-3)化合物进行取代反应,得到通式(VI-4)化合物;The compound of general formula (VIA) is obtained under metal catalysis to obtain the compound of general formula (VIB-3); the compound of (VIB-3) is subjected to substitution reaction to obtain the compound of general formula (VI-4);
其中:in:
X选自卤素,优选为溴;X is selected from halogen, preferably bromine;
环A、R 1、R 3、R 8、R 9和m的定义如通式(VI-1)中所述。 Ring A, R 1 , R 3 , R 8 , R 9 and m are defined as in the general formula (VI-1).
本发明提供了一种通式(IA)化合物的制备方法,所述方法包括:The present invention provides a kind of preparation method of compound of general formula (IA), described method comprises:
Figure PCTCN2021135230-appb-000029
Figure PCTCN2021135230-appb-000029
通式(SM-1)化合物或通式(SM-2)化合物或通式(SM-3)化合物发生环化反应,得到通式(IA)化合物;The compound of general formula (SM-1) or the compound of general formula (SM-2) or the compound of general formula (SM-3) undergoes a cyclization reaction to obtain the compound of general formula (IA);
其中:R 2和R 3的定义如通式(I)中所述。 wherein: R 2 and R 3 are as defined in the general formula (I).
本发明提供了一种通式(IB)化合物的制备方法,所述方法包括:The present invention provides a preparation method of a compound of general formula (IB), the method comprising:
Figure PCTCN2021135230-appb-000030
Figure PCTCN2021135230-appb-000030
溴化物(IB-1)化合物进行金属催化的交叉偶联反应(例如Stille偶联反应)转化为乙酮中间体(IB-2)化合物;乙酮中间体(IB-2)化合物与手性磺酰亚胺发生还原反应形成手性磺酰亚胺(IB-3)化合物;手性磺酰亚胺(IB-3)化合物经硼氢化钠或9-BBN还原,得到可分离的主要产物(IB-4)和次要产物(IB-5)的非对映异构体混合物;对映体(IB-4)化合物与HCl/1,4-二氧六 环溶液反应,脱去亚磺酰基,得到手性苄胺的盐酸盐(IB)化合物。The bromide (IB-1) compound undergoes a metal-catalyzed cross-coupling reaction (such as Stille coupling reaction) to convert the ethyl ketone intermediate (IB-2) compound; the ethyl ketone intermediate (IB-2) compound is combined with a chiral sulfonic acid The imide undergoes a reduction reaction to form a chiral sulfonimide (IB-3) compound; the chiral sulfonimide (IB-3) compound is reduced by sodium borohydride or 9-BBN to give the separable main product (IB -4) and a diastereomeric mixture of the minor product (IB-5); the enantiomer (IB-4) compound was reacted with HCl/1,4-dioxane solution to remove the sulfinyl group, The chiral benzylamine hydrochloride (IB) compound is obtained.
其中:R 1、环A和m的定义如通式(I)中所述。 wherein: R 1 , ring A and m are as defined in general formula (I).
具体实施方式Detailed ways
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.
实施例Example
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。 1H NMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。 The examples give the preparation and related structural identification data of the representative compounds represented by formula (I). It must be noted that the following examples are used to illustrate the present invention rather than limit it. The 1 H NMR spectrum was measured with a Bruker instrument (400 MHz), and the chemical shifts were expressed in ppm. A tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. When coupling constants are provided, they are in Hz.
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。Mass spectrum is obtained by LC/MS instrument, and the ionization mode can be ESI or APCI.
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
在下列实例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于上海皓鸿生物医药科技有限公司,上海韶远试剂有限公司,上海毕得医药科技有限公司,萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and various starting materials and reagents were obtained from commercially available or synthesized according to known methods without further purification. For direct use, unless otherwise specified, commercially available manufacturers include but are not limited to Shanghai Haohong Biomedical Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., Saen Chemical Technology (Shanghai) Co., Ltd. and Shanghai Lingkai Pharmaceutical Technology Co., Ltd., etc.
CD 3OD:氘代甲醇。 CD3OD : Deuterated methanol.
CDCl 3:氘代氯仿。 CDCl 3 : deuterated chloroform.
DMSO-d 6:氘代二甲基亚砜。 DMSO-d 6 : deuterated dimethyl sulfoxide.
氮气氛是指反应瓶连接一个约1L容积的氮气气球。Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
实施例中无特殊说明,反应中的溶液是指水溶液。There is no special description in the examples, and the solution in the reaction refers to an aqueous solution.
对化合物进行纯化,采用硅胶柱层析洗脱剂体系和薄层色谱法;其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行调节,如醋酸或三乙胺等。To purify the compound, use silica gel column chromatography eluent system and thin layer chromatography; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagents can also be added for adjustment, such as acetic acid or Triethylamine, etc.
中间体A-1的合成Synthesis of Intermediate A-1
Figure PCTCN2021135230-appb-000031
Figure PCTCN2021135230-appb-000031
第一步first step
2-氨基-5-溴-6-甲氧基烟酸甲酯A-1b的合成Synthesis of 2-amino-5-bromo-6-methoxynicotinic acid methyl ester A-1b
在反应瓶中加入2-氨基-6-甲氧基-烟酸甲酯A-1a(1.5g,根据文献Synlett(2011),(2),203-206制备)、碳酸氢钠(2.08g)和二氯甲烷(20mL),降温至0℃,缓慢滴加液溴(1.97g)的二氯甲烷溶液(10mL),保持0℃下反应1小时。LC-MS检测原料转化完全。加入50mL水,以饱和亚硫酸氢钠溶液淬灭反应,以二氯甲烷(50mL×2)萃取,合并有机相,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:石油醚/乙酸乙酯=20:1),得到2-氨基-5-溴-6-甲氧基烟酸甲酯A-1b(2.0g),产率93%。2-Amino-6-methoxy-nicotinic acid methyl ester A-1a (1.5g, prepared according to literature Synlett (2011), (2), 203-206), sodium bicarbonate (2.08g) were added to the reaction flask and dichloromethane (20 mL), the temperature was lowered to 0°C, a solution of bromine (1.97 g) in dichloromethane (10 mL) was slowly added dropwise, and the reaction was maintained at 0°C for 1 hour. Complete conversion of starting material was detected by LC-MS. 50 mL of water was added, the reaction was quenched with saturated sodium bisulfite solution, extracted with dichloromethane (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification by chromatography (eluent: petroleum ether/ethyl acetate = 20:1) to obtain methyl 2-amino-5-bromo-6-methoxynicotinate A-1b (2.0 g), yield 93%.
MS m/z(ESI):261.0[M+1]MS m/z(ESI): 261.0[M+1]
第二步second step
2-乙酰基亚酰胺基-5-溴-6-甲氧基烟酸甲酯A-1c的合成Synthesis of 2-acetylimido-5-bromo-6-methoxynicotinic acid methyl ester A-1c
在反应瓶中加入2-氨基-5-溴-6-甲氧基烟酸甲酯A-1b(800mg)和乙腈(8mL),加入4M HCl/1,4-二氧六环溶液(16mL),升温至60℃反应24小时。LC-MS检测原料转化完全。减压浓缩除去一半溶剂后,加入50mL乙醚,搅拌,析出白色固体,继续搅拌1小时,过滤,将固体烘干,得到2-乙酰基亚酰胺基-5-溴-6-甲氧基烟酸甲酯A-1c(650mg),产率70%。To the reaction flask were added methyl 2-amino-5-bromo-6-methoxynicotinate A-1b (800 mg) and acetonitrile (8 mL), and 4M HCl/1,4-dioxane solution (16 mL) was added , the temperature was raised to 60 °C and the reaction was carried out for 24 hours. Complete conversion of starting material was detected by LC-MS. After concentrating under reduced pressure to remove half of the solvent, add 50 mL of diethyl ether, stir to precipitate a white solid, continue to stir for 1 hour, filter, and dry the solid to obtain 2-acetylimido-5-bromo-6-methoxynicotinic acid Methyl ester A-1c (650 mg), 70% yield.
MS m/z(ESI):302.0[M+1]MS m/z(ESI): 302.0[M+1]
第三步third step
6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮A-1的合成Synthesis of 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1
在100mL反应瓶中依次加入2-乙酰基亚酰胺基-5-溴-6-甲氧基烟酸甲酯A-1c(500mg)、乙醇(20mL)和碳酸氢钠(695mg),回流反应2小时。TLC检测原料消失后,加入200mL二氯甲烷/甲醇(V:V=10:1)的混合溶剂,用水(100mL)洗涤1次,以无水硫酸钠干燥,过滤,减压浓缩,得到6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮A-1(330mg),产率74%。MS m/z(ESI):270.0[M+1]Into a 100mL reaction flask were sequentially added 2-acetylimido-5-bromo-6-methoxynicotinic acid methyl ester A-1c (500mg), ethanol (20mL) and sodium bicarbonate (695mg), and the reaction was carried out under reflux for 2 Hour. After TLC detected the disappearance of the raw materials, 200 mL of a mixed solvent of dichloromethane/methanol (V:V=10:1) was added, washed once with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6- Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (330 mg), 74% yield. MS m/z(ESI): 270.0[M+1]
中间体A-2的合成Synthesis of Intermediate A-2
6-溴-2-甲基-1H-吡啶并[2,3-d]嘧啶-4-酮A-2的合成Synthesis of 6-bromo-2-methyl-1H-pyrido[2,3-d]pyrimidin-4-one A-2
Figure PCTCN2021135230-appb-000032
Figure PCTCN2021135230-appb-000032
在100mL烧瓶中加入2-氨基-5-溴-吡啶-3-羧酸A-2a(2g)和乙酸酐(20mL),140℃下反应2小时。TLC检测原料转化完全。减压浓缩,加入20mL氨水,100℃下反应6个小 时。反应液中有大量白色固体析出。TLC检测中间体反应完全,过滤,将滤饼烘干,得到6-溴-2-甲基-1H-吡啶并[2,3-d]嘧啶-4-酮A-2(1.5g),产率67%。2-Amino-5-bromo-pyridine-3-carboxylic acid A-2a (2 g) and acetic anhydride (20 mL) were added to a 100 mL flask, and the reaction was carried out at 140° C. for 2 hours. Complete conversion of starting material was detected by TLC. Concentrate under reduced pressure, add 20 mL of ammonia water, and react at 100°C for 6 hours. A large amount of white solid was precipitated in the reaction solution. TLC detected that the intermediate reaction was complete, filtered, and dried the filter cake to obtain 6-bromo-2-methyl-1H-pyrido[2,3-d]pyrimidin-4-one A-2 (1.5g), which was rate 67%.
MS m/z(ESI):240.0[M+1]MS m/z(ESI): 240.0[M+1]
中间体A-3的合成Synthesis of Intermediate A-3
Figure PCTCN2021135230-appb-000033
Figure PCTCN2021135230-appb-000033
将6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮A-1(1.00g,3.72mmol)、吗啡啉(647.51mg,7.43mmol)、RuPhos-G3(311mg,0.37mmol)、叔丁醇钠(713.50mg,7.43mmol)依次加入到四氢呋喃(20mL)中,抽换氮气三次,于100℃下持续搅拌反应12小时。恢复室温后,减压浓缩除去溶剂,加入乙酸乙酯(100mL),水洗(30mL×3),合并有机相,饱和食盐水溶液(30mL)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩,硅胶拌样,柱层析分离纯化(洗脱剂:二氯甲烷/甲醇=20:1),得到7-甲氧基-2-甲基-6-吗啡啉-吡啶并[2,3-d]嘧啶-4(3H)-酮A-3(800mg),产率78%。6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (1.00 g, 3.72 mmol), morpholine (647.51 mg, 7.43 mmol), RuPhos-G3 (311 mg, 0.37 mmol), and sodium tert-butoxide (713.50 mg, 7.43 mmol) were successively added to tetrahydrofuran (20 mL), purged with nitrogen three times, and continued to stir the reaction at 100° C. for 12 hours. After returning to room temperature, concentrated under reduced pressure to remove the solvent, added ethyl acetate (100 mL), washed with water (30 mL×3), combined the organic phases, washed with saturated brine solution (30 mL), dried the organic phase with anhydrous sodium sulfate, filtered, and reduced pressure. Concentrated, mixed with silica gel, and separated and purified by column chromatography (eluent: dichloromethane/methanol=20:1) to obtain 7-methoxy-2-methyl-6-morpholine-pyrido[2,3 -d]pyrimidin-4(3H)-one A-3 (800 mg), 78% yield.
MS m/z(ESI):276.9[M+1]MS m/z(ESI): 276.9[M+1]
中间体C-1的合成Synthesis of Intermediate C-1
(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1的合成(R)-6-Bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3 Synthesis of -d]pyrimidin-4-amine C-1
Figure PCTCN2021135230-appb-000034
Figure PCTCN2021135230-appb-000034
在15mL反应瓶中加入6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮A-1(300mg)、(R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺B-1(300mg,根据公开文献Cancer Discov2021;11:142-157.制备)、BOP(638.65mg)、DBU(507mg)和N,N-二甲基甲酰胺(2mL),室温下搅拌反应3小时。反应结束后,加入100mL乙酸乙酯,以水(50mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:石油醚/乙酸乙酯=3:1),得到(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(170mg),产率31%。Into a 15mL reaction flask was added 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (300mg), (R)-1- (3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine B-1 (300 mg, prepared according to published literature Cancer Discov 2021; 11:142-157.), BOP (638.65 mg), DBU (507 mg) and N,N-dimethylformamide (2 mL), and the reaction was stirred at room temperature for 3 hours. After the reaction, 100 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent). : petroleum ether/ethyl acetate=3:1) to obtain (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl) yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine C-1 (170 mg) in 31% yield.
MS m/z(ESI):486.0[M+1]MS m/z(ESI): 486.0[M+1]
中间体C-2的合成Synthesis of Intermediate C-2
(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺A-2的合成(R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine-4- Synthesis of Amine A-2
Figure PCTCN2021135230-appb-000035
Figure PCTCN2021135230-appb-000035
在100mL烧瓶中加入6-溴-2-甲基-1H-吡啶并[2,3-d]嘧啶-4-酮A-2(1.5g)、(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐B-2(1.69g,根据公开专利CN 111372932A制备)、BOP(5.53g)、DBU(2.85g)和N,N-二甲基甲酰胺(20mL),室温下搅拌反应5小时。TLC检测原料反应完全。加入乙酸乙酯和水,萃取,分液,有机相用饱和食盐水洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:石油醚/乙酸乙酯=3:1),得到(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-2(1.7g),产率66%。Into a 100 mL flask was added 6-bromo-2-methyl-1H-pyrido[2,3-d]pyrimidin-4-one A-2 (1.5 g), (R)-1-(3-(difluoro) Methyl)-2-fluorophenyl)ethane-1-amine hydrochloride B-2 (1.69g, prepared according to published patent CN 111372932A), BOP (5.53g), DBU (2.85g) and N,N- Dimethylformamide (20 mL) was stirred at room temperature for 5 hours. TLC detected that the reaction of the raw materials was complete. Ethyl acetate and water were added, extracted, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: Petroleum ether/ethyl acetate = 3:1) to give (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl Pyrido[2,3-d]pyrimidin-4-amine C-2 (1.7 g), 66% yield.
MS m/z(ESI):412.1[M+2]MS m/z(ESI): 412.1[M+2]
中间体C-3的合成Synthesis of Intermediate C-3
(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-3的合成(R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido[2,3- d] Synthesis of Pyrimidine-4-amine C-3
Figure PCTCN2021135230-appb-000036
Figure PCTCN2021135230-appb-000036
在15mL反应瓶中加入6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮A-1(400mg,1.48mmol)、(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐B-2(501.27mg,2.22mmol),BOP(982.54mg,2.22mmol)、DBU(676.42mg,4.44mmol)和DMSO(5mL),室温下搅拌反应12小时。加入100mL乙酸乙酯,以水(50mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:石油醚/乙酸乙酯=3:1),得到(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-3(350mg),产率54%。Into a 15 mL reaction flask was added 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (400 mg, 1.48 mmol), (R) -1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride B-2 (501.27 mg, 2.22 mmol), BOP (982.54 mg, 2.22 mmol), DBU ( 676.42 mg, 4.44 mmol) and DMSO (5 mL), and the reaction was stirred at room temperature for 12 hours. 100 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate = 3:1) to give (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2 -Methylpyrido[2,3-d]pyrimidin-4-amine C-3 (350 mg), 54% yield.
MS m/z(ESI):441.0[M+1]MS m/z(ESI): 441.0[M+1]
中间体B-3的合成Synthesis of Intermediate B-3
(R)-3-(1-氨基乙基)-2-甲基苯甲腈盐酸盐B-3的合成Synthesis of (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride B-3
Figure PCTCN2021135230-appb-000037
Figure PCTCN2021135230-appb-000037
第一步first step
(S,Z)-N-(1-(3-溴-2-甲基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺的合成Synthesis of (S,Z)-N-(1-(3-bromo-2-methylphenyl)ethylene)-2-methylpropane-2-sulfonimide
在250mL烧瓶中加入1-(3-溴-2-甲基苯基)乙烷-1-酮(12g,56.32mmol),(R)-2-甲基丙烷-2-磺酰亚胺(8.87g,73.22mmol),钛酸四乙酯(19.27g,84.48mmol),四氢呋喃100mL,置换氮气3次,80度下反应7小时。恢复室温后,加水30mL,硅藻土过滤,乙酸乙酯洗涤,水洗三次,无水硫酸钠干燥,过滤浓缩,硅胶拌样,过柱机过柱得到(S,Z)-N-(1-(3-溴-2-甲基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺14g,产率79%。Into a 250 mL flask was added 1-(3-bromo-2-methylphenyl)ethane-1-one (12 g, 56.32 mmol), (R)-2-methylpropane-2-sulfonimide (8.87 g g, 73.22 mmol), tetraethyl titanate (19.27 g, 84.48 mmol), 100 mL of tetrahydrofuran, replaced nitrogen three times, and reacted at 80 degrees for 7 hours. After returning to room temperature, add 30 mL of water, filter through celite, wash with ethyl acetate, wash three times with water, dry over anhydrous sodium sulfate, filter and concentrate, mix with silica gel, and pass through a column machine to obtain (S,Z)-N-(1- (3-Bromo-2-methylphenyl)ethylene)-2-methylpropane-2-sulfonimide 14 g, yield 79%.
MS m/z(ESI):316.1[M+1]MS m/z(ESI): 316.1[M+1]
第二步second step
(S)-N-((R)-1-(3-溴-2-甲基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺的合成Synthesis of (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonimide
在250mL反应瓶中加入(S,Z)-N-(1-(3-溴-2-甲基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺(7g,22.13mmol),四氢呋喃30mL),于冰浴下缓慢加入0.5M 9-BBN的四氢呋喃溶液80mL,恢复室温反应继续反应5小时。送LC-MS检测原料消失,加入饱和氯化铵溶液淬灭,浓缩除去四氢呋喃,加入乙酸乙酯,水洗三次,无水硫酸钠干燥。过柱机过柱纯化得到(S)-N-((R)-1-(3-溴-2-甲基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺6.0g,产率85%。Into a 250mL reaction flask was added (S,Z)-N-(1-(3-bromo-2-methylphenyl)ethylene)-2-methylpropane-2-sulfonimide (7g, 22.13 g mmol), tetrahydrofuran 30mL), slowly add 0.5M tetrahydrofuran solution 80mL of 9-BBN under ice bath, return to room temperature and continue to react for 5 hours. Send LC-MS to detect the disappearance of raw materials, add saturated ammonium chloride solution to quench, concentrate to remove tetrahydrofuran, add ethyl acetate, wash with water three times, and dry over anhydrous sodium sulfate. Purified by column machine to obtain (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonimide 6.0g , the yield is 85%.
MS m/z(ESI):318.2[M+1]MS m/z(ESI): 318.2[M+1]
第三步third step
(R)-1-(3-溴-2-甲基苯基)乙烷-1-胺盐酸盐的合成Synthesis of (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine hydrochloride
在25mL反应瓶中加入(S)-N-((R)-1-(3-溴-2-甲基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺(4g,12.57mmol),加入氯化氢/二氧六环溶液10mL,室温下搅拌。LC-MS检测原料反应完全,浓缩溶剂,加入乙醚搅拌,析出(R)-1-(3-溴-2-甲基苯基)乙烷-1-胺盐酸盐1.8g,产率58%。MS m/z(ESI):214.0[M+1]In a 25mL reaction flask was added (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonimide (4g, 12.57 mmol), 10 mL of hydrogen chloride/dioxane solution was added, and the mixture was stirred at room temperature. LC-MS detected that the reaction of the raw materials was complete, the solvent was concentrated, diethyl ether was added to stir, and 1.8 g of (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine hydrochloride was precipitated, with a yield of 58%. . MS m/z(ESI): 214.0[M+1]
第四步the fourth step
(R)-(1-(3-溴-2-甲基苯基)乙基)氨基甲酸叔丁酯的合成Synthesis of tert-butyl (R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate
在100mL烧瓶中加入(R)-1-(3-溴-2-甲基苯基)乙烷-1-胺盐酸盐(1.3g,5.2mmol)二碳酸二叔丁酯(1.19g,10.90mmol)和二氯甲烷8mL),冰浴下缓慢加入二异丙基乙胺(1.34g,10.4mmol),室温下反应3小时。加入300mL二氯甲烷,水洗三次,无水硫酸钠干燥, 过柱机过柱纯化得到(R)-(1-(3-溴-2-甲基苯基)乙基)氨基甲酸叔丁酯3.0g,产率93%。Into a 100 mL flask was added (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine hydrochloride (1.3 g, 5.2 mmol) di-tert-butyl dicarbonate (1.19 g, 10.90 g mmol) and dichloromethane 8 mL), slowly added diisopropylethylamine (1.34 g, 10.4 mmol) under ice bath, and reacted at room temperature for 3 hours. 300 mL of dichloromethane was added, washed three times with water, dried over anhydrous sodium sulfate, and purified by passing through a column machine to obtain (R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamic acid tert-butyl ester 3.0 g, 93% yield.
MS m/z(ESI):314.1[M+1]MS m/z(ESI): 314.1[M+1]
第五步the fifth step
(R)-(1-(3-氰基-2-甲基苯基)乙基)氨基甲酸叔丁酯的合成Synthesis of tert-butyl (R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate
在50mL烧瓶中加入(R)-(1-(3-溴-2-甲基苯基)乙基)氨基甲酸叔丁酯(2g,6.37mmol),Zn(CN) 2(1.49g,12.73mmol),Pd(PPh 3) 4(735.52mg,636.50μmol),DMF(8mL,置换氮气三次,于140度下反应8小时。恢复室温后加入乙酸乙酯,水洗三次,无水硫酸钠干燥,过柱机过柱得(R)-(1-(3-氰基-2-甲基苯基)乙基)氨基甲酸叔丁酯0.8g,产率49%。 In a 50 mL flask was added (R)-(1-(3-bromo-2-methylphenyl)ethyl) tert-butyl carbamate (2 g, 6.37 mmol), Zn(CN) 2 (1.49 g, 12.73 mmol) ), Pd(PPh 3 ) 4 (735.52 mg, 636.50 μmol), DMF (8 mL, nitrogen was replaced three times, and the reaction was carried out at 140 degrees for 8 hours. After returning to room temperature, ethyl acetate was added, washed three times with water, dried over anhydrous sodium sulfate, and passed Column machine was used to obtain tert-butyl (R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate 0.8 g with a yield of 49%.
MS m/z(ESI):261.2[M+1]MS m/z(ESI): 261.2[M+1]
第六步Step 6
(R)-3-(1-氨基乙基)-2-甲基苯甲腈盐酸盐B-3的合成Synthesis of (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride B-3
在100mL烧瓶中加入(R)-(1-(3-氰基-2-甲基苯基)乙基)氨基甲酸叔丁酯(4.5g,17.29mmol)和4M氯化氢/二氧六环溶液20mL,室温下反应5小时,析出白色固体析出。加入乙醚,过滤,得(R)-3-(1-胺基乙基)-2-甲基苯甲腈盐酸盐3.0g,产率89%。Into a 100 mL flask were added tert-butyl (R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate (4.5 g, 17.29 mmol) and 20 mL of 4M hydrogen chloride/dioxane solution , reacted at room temperature for 5 hours, and a white solid was precipitated. Diethyl ether was added and filtered to obtain (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride 3.0 g with a yield of 89%.
MS m/z(ESI):161.1[M+1]MS m/z(ESI): 161.1[M+1]
中间体B-4的合成Synthesis of Intermediate B-4
(R)-3-(1-氨基乙基)苯甲腈盐酸盐B-4的合成Synthesis of (R)-3-(1-aminoethyl)benzonitrile hydrochloride B-4
Figure PCTCN2021135230-appb-000038
Figure PCTCN2021135230-appb-000038
第一步first step
(R,E)-N-(1-(3-氰基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺的合成Synthesis of (R,E)-N-(1-(3-cyanophenyl)ethylene)-2-methylpropane-2-sulfonimide
于反应瓶中加入3-乙酰基苯甲腈(1.2g,8.27mmol),(R)-2-甲基丙烷-2-磺酰亚胺(1.80g,14.88mmol),钛酸四乙酯(3.77g,16.53mmol)和四氢呋喃50mL),置换氮气3次,80度反应7小时。LC-MS检测原料反应完全,加入水(50mL)硅藻土过滤,滤饼用乙酸乙酯(50mL)洗涤,收集滤液减压浓缩,所得残余物加入乙酸乙酯(200mL),水洗(100mL),无水硫酸钠干燥,过滤,减压浓缩,所得残余物过柱机过柱得到(R,E)-N-(1-(3-氰基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺1.8g,产率87%。3-acetylbenzonitrile (1.2g, 8.27mmol), (R)-2-methylpropane-2-sulfonimide (1.80g, 14.88mmol), tetraethyl titanate ( 3.77 g, 16.53 mmol) and tetrahydrofuran 50 mL), replaced with nitrogen 3 times, and reacted at 80 degrees for 7 hours. LC-MS detected that the reaction of the raw materials was complete, water (50 mL) was added for diatomaceous earth filtration, the filter cake was washed with ethyl acetate (50 mL), the filtrate was collected and concentrated under reduced pressure, the obtained residue was added to ethyl acetate (200 mL), washed with water (100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the obtained residue was passed through a column machine to obtain (R,E)-N-(1-(3-cyanophenyl)ethylene)-2-methyl Propane-2-sulfonimide 1.8 g, yield 87%.
MS m/z(ESI):249.2[M+1]MS m/z(ESI): 249.2[M+1]
第二步second step
(R)-N-((R)-1-(3-氰基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺的合成Synthesis of (R)-N-((R)-1-(3-cyanophenyl)ethyl)-2-methylpropane-2-sulfonimide
于50反应瓶中加入(R,E)-N-(1-(3-氰基苯基)亚乙基)-2-甲基丙烷-2-磺酰亚胺(1.0g, 4.03mmol)和四氢呋喃20mL,于冰浴下缓慢加入0.5M 9-BBN的四氢呋喃溶液16mL,恢复室温反应继续反应5小时。送LC-MS检测原料消失,加入饱和氯化铵溶液淬灭,浓缩除去四氢呋喃,加入乙酸乙酯,水洗三次,无水硫酸钠干燥。过柱机过柱纯化得到(R)-N-((R)-1-(3-氰基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺600mg,产率60%。Into a 50 reaction flask was added (R,E)-N-(1-(3-cyanophenyl)ethylene)-2-methylpropane-2-sulfonimide (1.0g, 4.03mmol) and 20 mL of tetrahydrofuran, 16 mL of 0.5M 9-BBN solution in tetrahydrofuran was slowly added under an ice bath, and the reaction was continued for 5 hours after returning to room temperature. Send LC-MS to detect the disappearance of raw materials, add saturated ammonium chloride solution to quench, concentrate to remove tetrahydrofuran, add ethyl acetate, wash with water three times, and dry over anhydrous sodium sulfate. Purified by column machine to obtain (R)-N-((R)-1-(3-cyanophenyl)ethyl)-2-methylpropane-2-sulfonimide 600mg, yield 60% .
MS m/z(ESI):251.1[M+1]MS m/z(ESI): 251.1[M+1]
第三步third step
(R)-3-(1-氨基乙基)苯甲腈盐酸盐的合成Synthesis of (R)-3-(1-aminoethyl)benzonitrile hydrochloride
于25mL反应瓶中加入(R)-N-((R)-1-(3-氰基苯基)乙基)-2-甲基丙烷-2-磺酰亚胺(600mg,2.40mmol)和1,4-二氧六环10mL,缓慢滴加4M氯化氢/二氧六环溶液3mL,室温搅拌反应3小时。LCMS显示反应完全,反应液减压浓缩,所得残余物加入乙醚(20mL),搅拌析出固体,过滤,收集滤饼干燥,得(R)-3-(1-氨基乙基)苯甲腈盐酸盐B-4(420mg,产率96%)。Into a 25mL reaction flask was added (R)-N-((R)-1-(3-cyanophenyl)ethyl)-2-methylpropane-2-sulfonimide (600mg, 2.40mmol) and 10 mL of 1,4-dioxane was slowly added dropwise with 3 mL of 4M hydrogen chloride/dioxane solution, and the reaction was stirred at room temperature for 3 hours. LCMS showed that the reaction was complete, the reaction solution was concentrated under reduced pressure, diethyl ether (20 mL) was added to the obtained residue, the solid was precipitated by stirring, filtered, and the filter cake was collected and dried to obtain (R)-3-(1-aminoethyl)benzonitrile hydrochloride Salt B-4 (420 mg, 96% yield).
MS m/z(ESI):147.1[M+1]MS m/z(ESI): 147.1[M+1]
中间体C-4的合成Synthesis of Intermediate C-4
(R)-3-(1-((6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈C-4的合成(R)-3-(1-((6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methyl Synthesis of benzonitrile C-4
Figure PCTCN2021135230-appb-000039
Figure PCTCN2021135230-appb-000039
在25mL反应瓶中加入6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮A-1(400mg,1.48mmol)、(R)-3-(1-氨基乙基)-2-甲基苯甲腈盐酸盐B-3(308.5mg,1.93mmol),BOP(982.54mg,2.22mmol)、DBU(676.42mg,4.44mmol)和DMSO(5mL),室温下搅拌反应12小时。加入100mL乙酸乙酯,以水(50mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:石油醚/乙酸乙酯=3:1),得到(R)-3-(1-((6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈C-4(270mg),产率45%。6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (400 mg, 1.48 mmol), (R) was added to a 25 mL reaction flask -3-(1-Aminoethyl)-2-methylbenzonitrile hydrochloride B-3 (308.5 mg, 1.93 mmol), BOP (982.54 mg, 2.22 mmol), DBU (676.42 mg, 4.44 mmol) and DMSO (5 mL), and the reaction was stirred at room temperature for 12 hours. 100 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate = 3:1) to give (R)-3-(1-((6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl) Amino)ethyl)-2-methylbenzonitrile C-4 (270 mg), 45% yield.
MS m/z(ESI):412.1[M+1]MS m/z(ESI): 412.1[M+1]
中间体C-5的合成Synthesis of Intermediate C-5
(R)-3-(1-((6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)苯甲腈C-5的合成(R)-3-(1-((6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)benzonitrile C- Synthesis of 5
Figure PCTCN2021135230-appb-000040
Figure PCTCN2021135230-appb-000040
在25mL反应瓶中加入6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮A-1(400mg,1.48mmol)、(R)-3-(1-氨基乙基)苯甲腈盐酸盐B-4(352.4mg,1.93mmol),BOP(982.54mg,2.22mmol)、DBU(676.42mg,4.44mmol)和DMSO(5mL),室温下搅拌反应12小时。加入100mL乙酸乙酯,以水(50mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:石油醚/乙酸乙酯=3:1),得到(R)-3-(1-((6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈C-4(240mg),产率41%。6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (400 mg, 1.48 mmol), (R) was added to a 25 mL reaction flask -3-(1-aminoethyl)benzonitrile hydrochloride B-4 (352.4 mg, 1.93 mmol), BOP (982.54 mg, 2.22 mmol), DBU (676.42 mg, 4.44 mmol) and DMSO (5 mL), The reaction was stirred at room temperature for 12 hours. 100 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate = 3:1) to give (R)-3-(1-((6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl) Amino)ethyl)-2-methylbenzonitrile C-4 (240 mg), 41% yield.
MS m/z(ESI):398.1[M+1]MS m/z(ESI): 398.1[M+1]
实施例1Example 1
N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-4-胺1的合成N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran- Synthesis of 3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1
Figure PCTCN2021135230-appb-000041
Figure PCTCN2021135230-appb-000041
Figure PCTCN2021135230-appb-000042
Figure PCTCN2021135230-appb-000042
第一步first step
(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶并[2,3-d]嘧啶-4-胺1a的合成(R)-7-Methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(4,4,5, Synthesis of 5-Tetramethyl-1,3,2-dioxaboran-2-yl)pyrido[2,3-d]pyrimidin-4-amine 1a
在25mL反应瓶中,加入(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(160mg)、联硼酸频那醇酯(125.34mg)、Pd(dppf)Cl 2(24mg)和乙酸钾(64mg),加入1,4-二氧六环(3mL),置换氮气3次,于100℃下反应8小时。反应结束后,反应液通过硅藻土过滤,将滤液减压浓缩,加入50mL乙酸乙酯,以水(50mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到粗品(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶并[2,3-d]嘧啶-4-胺1a(170mg),直接用于下一步反应。 In a 25mL reaction vial, add (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl ) pyrido[2,3-d]pyrimidin-4-amine C-1 (160 mg), pinacol diboronate (125.34 mg), Pd(dppf)Cl 2 (24 mg) and potassium acetate (64 mg) were added 1,4-dioxane (3 mL) was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 8 hours. After the reaction, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (R)-7-Methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(4,4,5, 5-Tetramethyl-1,3,2-dioxaboran-2-yl)pyrido[2,3-d]pyrimidin-4-amine 1a (170 mg) was used directly in the next reaction.
第二步second step
(R)-7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[2,3-d]嘧啶-6-醇1b的合成(R)-7-Methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3- d] Synthesis of Pyrimidine-6-ol 1b
在25mL单口瓶中加入(R)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶并[2,3-d]嘧啶-4-胺1a(160mg)、氢氧化钠(120mg)和四氢呋喃(10mL),缓慢加入双氧水(102mg),室温下反应1小时,LC-MS检测原料转化完全。加入10mL饱和硫代硫酸钠溶液淬灭反应,滴加1M稀盐酸调节pH至中性,以乙酸乙酯(50mL)萃取,有机相以水(50mL)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到粗品(R)-7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[2,3-d]嘧啶-6-醇1b(120mg),直接用于下一步反应。Add (R)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-( 4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)pyrido[2,3-d]pyrimidin-4-amine 1a (160 mg), sodium hydroxide (120 mg) and tetrahydrofuran (10 mL), slowly added hydrogen peroxide (102 mg), reacted at room temperature for 1 hour, and LC-MS detected the complete conversion of the raw materials. 10 mL of saturated sodium thiosulfate solution was added to quench the reaction, 1M dilute hydrochloric acid was added dropwise to adjust the pH to neutral, extracted with ethyl acetate (50 mL), the organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, Concentration under reduced pressure gave crude (R)-7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyridine and [2,3-d]pyrimidin-6-ol 1b (120 mg) was used directly in the next reaction.
MS m/z(ESI):424.1[M+1]MS m/z(ESI): 424.1[M+1]
第三步third step
7-甲氧基-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(((S)-四氢呋喃-3-基)氧基)吡 啶并[2,3-d]嘧啶-4-胺1d的合成7-Methoxy-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran Synthesis of -3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1d
在反应瓶中加入(R)-7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[2,3-d]嘧啶-6-醇1b(200mg)、(R)-四氢呋喃-3-基对甲苯磺酸酯1c(171.70mg)、碳酸钾(130.59mg)和N,N-二甲基甲酰胺(6mL),升温至60℃反应8小时。LC-MS检测原料消失。加入20mL乙酸乙酯,以水(30mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=50:1),得到7-甲氧基-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-4-胺1d(90mg),产率39%。Add (R)-7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido to the reaction flask [2,3-d]pyrimidin-6-ol 1b (200 mg), (R)-tetrahydrofuran-3-yl p-toluenesulfonate 1c (171.70 mg), potassium carbonate (130.59 mg) and N,N-dimethylformaldehyde formamide (6 mL), the temperature was raised to 60° C. and reacted for 8 hours. The disappearance of starting material was detected by LC-MS. 20 mL of ethyl acetate was added, washed with water (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane). /methanol = 50:1) to give 7-methoxy-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)- 6-(((S)-Tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1d (90 mg), 39% yield.
MS m/z(ESI):494.2[M+1]MS m/z(ESI): 494.2[M+1]
第四步the fourth step
N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-4-胺1的合成N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran- Synthesis of 3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1
在反应瓶中加入7-甲氧基-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-4-胺1d(100mg)、铁粉(56.59mg)、四氢呋喃(3mL)、乙醇(3mL)和1M稀盐酸(1mL),升温至100℃,反应3小时。LC-MS检测原料转化完全。滴加碳酸氢钠溶液调节pH至中性,过滤,将滤液减压浓缩,加入15mL乙酸乙酯,以水(30mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=50:1),得到N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)吡啶并[2,3-d]嘧啶-4-胺1(50mg),产率53%。Add 7-methoxy-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(( to the reaction flask (S)-Tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1d (100 mg), iron powder (56.59 mg), tetrahydrofuran (3 mL), ethanol (3 mL) and 1M Dilute hydrochloric acid (1 mL) was heated to 100° C. and reacted for 3 hours. Complete conversion of starting material was detected by LC-MS. Sodium bicarbonate solution was added dropwise to adjust the pH to neutral, filtered, the filtrate was concentrated under reduced pressure, 15 mL of ethyl acetate was added, washed with water (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=50:1) to obtain N-((R)-1-(3-amino-5-(trifluoromethyl) )phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1 (50 mg), 53% yield.
MS m/z(ESI):464.2[M+1]MS m/z(ESI): 464.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.08(d,J=7.9Hz,1H),8.02(s,1H),6.85(d,J=10.6Hz,2H),6.70(s,1H),5.59-5.52(m,3H),5.14(s,1H),3.97(s,3H),3.97-3.95(m,1H),3.93-3.76(m,3H),2.37(s,3H),2.36-2.28(m,1H),2.07-2.01(m,1H),1.55(d,J=7.0Hz,3H)ppm. 1 H NMR (400MHz, DMSO-d 6 )δ8.08(d,J=7.9Hz,1H),8.02(s,1H),6.85(d,J=10.6Hz,2H),6.70(s,1H) ,5.59-5.52(m,3H),5.14(s,1H),3.97(s,3H),3.97-3.95(m,1H),3.93-3.76(m,3H),2.37(s,3H),2.36 -2.28(m,1H),2.07-2.01(m,1H),1.55(d,J=7.0Hz,3H)ppm.
实施例2Example 2
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-吗啉基吡啶并[2,3-d]嘧啶-4-胺2的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-morpholinopyrido[2, Synthesis of 3-d]pyrimidin-4-amine 2
Figure PCTCN2021135230-appb-000043
Figure PCTCN2021135230-appb-000043
Figure PCTCN2021135230-appb-000044
Figure PCTCN2021135230-appb-000044
第一步first step
(R)-7-甲氧基-2-甲基-6-吗啉基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺2b的合成(R)-7-Methoxy-2-methyl-6-morpholinyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2 Synthesis of ,3-d]pyrimidin-4-amine 2b
于15mL烧瓶中加入(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(100mg)、吗啡啉(21.5mg)、Pd 2(dba) 3(37.7mg)、XantPhos(47.6mg)、碳酸铯(134.02mg)和1,4-二氧六环(3mL),置换氮气3次,升温至90℃,氮气氛下反应5小时。反应结束后。反应液通过硅藻土过滤,将滤液减压浓缩,加入50mL乙酸乙酯,以水(50mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=40:1),得到(R)-7-甲氧基-2-甲基-6-吗啉基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺2a(50mg),产率49%。 Into a 15mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine [2,3-d]pyrimidin-4-amine C-1 (100 mg), morpholine (21.5 mg), Pd 2 (dba) 3 (37.7 mg), XantPhos (47.6 mg), cesium carbonate (134.02 mg) and 1,4-dioxane (3 mL), nitrogen was replaced 3 times, the temperature was raised to 90° C., and the reaction was carried out under nitrogen atmosphere for 5 hours. after the reaction is over. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was washed with silica gel Column chromatography was further separated and purified (eluent: dichloromethane/methanol=40:1) to obtain (R)-7-methoxy-2-methyl-6-morpholinyl-N-(1-( 3-Nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 2a (50 mg), 49% yield.
MS m/z(ESI):493.2[M+1]MS m/z(ESI): 493.2[M+1]
第二步second step
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-吗啉基吡啶并[2,3-d]嘧啶-4-胺2的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-morpholinopyrido[2, Synthesis of 3-d]pyrimidin-4-amine 2
于15mL烧瓶中加入(R)-7-甲氧基-2-甲基-6-吗啉基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺2a(50mg)、铁粉(28.35mg)、四氢呋喃(2mL)、乙醇(2mL)和1M稀盐酸(1mL),升温至100℃反应3小时。反应结束后,以饱和碳酸氢钠溶液调节pH至中性,反应液通过硅藻土过滤,将滤液减压浓缩,加入50mL乙酸乙酯,以水(50mL×3)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=40:1),得到(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-吗啉基吡啶并[2,3-d]嘧啶-4-胺2(5mg),产率10%。Add (R)-7-methoxy-2-methyl-6-morpholinyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl to a 15 mL flask ) pyrido[2,3-d]pyrimidin-4-amine 2a (50mg), iron powder (28.35mg), tetrahydrofuran (2mL), ethanol (2mL) and 1M dilute hydrochloric acid (1mL), the temperature was raised to 100°C for reaction 3 Hour. After the reaction, the pH was adjusted to neutrality with saturated sodium bicarbonate solution, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), and washed with anhydrous sodium sulfate. Dry, filter, and concentrate under reduced pressure, and the obtained residue is further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain (R)-N-(1-(3-amino) -5-(Trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-morpholinopyrido[2,3-d]pyrimidin-4-amine 2 (5 mg) , the yield is 10%.
MS m/z(ESI):463.0[M+1]MS m/z(ESI): 463.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.86(d,J=7.8Hz,1H),8.15(s,1H),6.87(d,J=6.0Hz,2H),6.76(s,1H),5.69(t,J=7.3Hz,1H),4.11(s,3H),3.79(s,4H),3.14(s,4H),2.57(s,3H),1.62(d,J=7.1Hz,3H)ppm. 1 H NMR (400MHz, DMSO-d 6 )δ9.86(d,J=7.8Hz,1H),8.15(s,1H),6.87(d,J=6.0Hz,2H),6.76(s,1H) ,5.69(t,J=7.3Hz,1H),4.11(s,3H),3.79(s,4H),3.14(s,4H),2.57(s,3H),1.62(d,J=7.1Hz, 3H)ppm.
实施例3Example 3
(R)-1-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-6-基)乙-1-酮3的合成(R)-1-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2, Synthesis of 3-d]pyrimidin-6-yl)ethan-1-one 3
Figure PCTCN2021135230-appb-000045
Figure PCTCN2021135230-appb-000045
第一步first step
(R)-6-(1-乙氧基乙烯基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺3b的合成(R)-6-(1-Ethoxyvinyl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl Synthesis of pyrido[2,3-d]pyrimidin-4-amine 3b
于25mL圆底单口烧瓶中加入(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(200mg)和1,4-二氧六环(5mL),加入三丁基(1-乙氧基乙烯)锡3a(160.4mg)和Pd(PPh 3) 2Cl 2(26mg)和三乙胺(93.7mg),置换氮气3次,100℃下反应4小时。反应结束后,冷却至室温,硅藻土过滤,将滤液减压浓缩,加入50mL乙酸乙酯,水(50mL×3)洗涤三次,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=40:1),得到(R)-6-(1-乙氧基乙烯基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺3b(150mg),产率85%。 Add (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethane to a 25mL round-bottomed single-necked flask yl)pyrido[2,3-d]pyrimidin-4-amine C-1 (200 mg) and 1,4-dioxane (5 mL), tributyl(1-ethoxyethylene)tin 3a ( 160.4 mg), Pd(PPh 3 ) 2 Cl 2 (26 mg) and triethylamine (93.7 mg), replaced with nitrogen three times, and reacted at 100° C. for 4 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL × 3) three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain residual The compound was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain (R)-6-(1-ethoxyvinyl)-7-methoxy-2- Methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 3b (150 mg), yield 85 %.
MS m/z(ESI):478.2[M+1]MS m/z(ESI): 478.2[M+1]
第二步second step
(R)-1-(7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[2,3-d]嘧啶-6-基)乙-1-酮3c的合成(R)-1-(7-Methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2 Synthesis of ,3-d]pyrimidin-6-yl)ethan-1-one 3c
在25mL反应瓶中加入(R)-6-(1-乙氧基乙烯基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺3b(150mg)、1,4-二氧六环(2.50mL)和稀盐酸(3M,2.50mL),室温下搅拌反应3小时。LC-MS检测原料消失。加入50mL乙酸乙酯,以水(50mL×3)洗涤三次,以无水硫酸钠干燥,过滤,减压浓缩,得到(R)-1-(7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[2,3-d]嘧啶-6-基)乙-1-酮3c(100mg),产率71%,直接用于下一步反应。Add (R)-6-(1-ethoxyvinyl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl) into a 25mL reaction flask yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 3b (150 mg), 1,4-dioxane (2.50 mL) and dilute hydrochloric acid (3M, 2.50 mL), room temperature The reaction was stirred for 3 hours. The disappearance of starting material was detected by LC-MS. 50 mL of ethyl acetate was added, washed three times with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-1-(7-methoxy-2-methyl-4- ((1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)ethan-1-one 3c (100 mg) , the yield was 71%, which was directly used in the next reaction.
MS m/z(ESI):450.1[M+1]MS m/z(ESI): 450.1[M+1]
第三步third step
(R)-1-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-6-基)乙-1-酮3的合成(R)-1-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2, Synthesis of 3-d]pyrimidin-6-yl)ethan-1-one 3
于15mL烧瓶中加入(R)-1-(7-甲氧基-2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)吡啶并[2,3-d]嘧啶-6-基)乙-1-酮3c(100mg)、铁粉(62.1mg)、四氢呋喃(2mL)、乙醇(2mL)和稀盐酸(1M,1mL),升温至100℃反应3小时。反应结束后,以饱和碳酸氢钠溶液调节pH至中性,反应液通过硅藻土过滤,将滤液减压浓缩,加入50mL乙酸乙酯,以水(50mL×3)洗涤,有机相以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=40:1),得到(R)-1-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-6-基)乙-1-酮3(40mg),产率43%。Add (R)-1-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino to a 15 mL flask )pyrido[2,3-d]pyrimidin-6-yl)ethan-1-one 3c (100 mg), iron powder (62.1 mg), tetrahydrofuran (2 mL), ethanol (2 mL) and dilute hydrochloric acid (1 M, 1 mL) , and the temperature was raised to 100 °C for 3 hours. After the reaction, the pH was adjusted to neutral with saturated sodium bicarbonate solution, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), and the organic phase was dried with anhydrous dried over sodium sulfate, filtered and concentrated under reduced pressure, the obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain (R)-1-(4-(( 1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)ethyl -1-one 3 (40 mg), 43% yield.
MS m/z(ESI):420.1[M+1]MS m/z(ESI): 420.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.15(s,1H),8.85(d,J=7.9Hz,1H),6.88(s,1H),6.84(s,1H),6.70(s,1H),5.55-5.50(m,1H),4.05(s,3H),2.62(s,3H),2.41(s,3H),1.53(d,J=7.0Hz,3H)ppm. 1 H NMR (400MHz, DMSO-d 6 ) δ 9.15(s, 1H), 8.85(d, J=7.9Hz, 1H), 6.88(s, 1H), 6.84(s, 1H), 6.70(s, 1H), 5.55-5.50(m, 1H), 4.05(s, 3H), 2.62(s, 3H), 2.41(s, 3H), 1.53(d, J=7.0Hz, 3H)ppm.
实施例4Example 4
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-d]嘧啶-4-胺4的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(1-methyl-1H- Synthesis of Pyrazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine 4
Figure PCTCN2021135230-appb-000046
Figure PCTCN2021135230-appb-000046
第一步first step
(R)-7-甲氧基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺4b的合成(R)-7-Methoxy-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(1-(3-nitro-5-(trifluoromethyl) Synthesis of yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 4b
于25mL烧瓶中加入(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(120mg)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑4a(102.70mg)、RuPhos-Pd-G3(20.67mg)、碳酸钠(78.47mg)、二氧六环(2mL)和去离子水(0.2mL),置换氮气三次,升温至95℃反应5小时。反应结束后,冷却至室温,反应液通过硅藻土过滤,将滤液减压浓缩,加入50mL乙酸乙酯,以水(50mL×3)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=40:1),得到(R)-7-甲氧基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺4b(100mg),产率83%。Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine Do[2,3-d]pyrimidin-4-amine C-1 (120 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Alk-2-yl)-1H-pyrazole 4a (102.70 mg), RuPhos-Pd-G3 (20.67 mg), sodium carbonate (78.47 mg), dioxane (2 mL) and deionized water (0.2 mL), The nitrogen was replaced three times, and the temperature was raised to 95° C. to react for 5 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain (R)-7-methoxy-2-methyl-6-(1-methyl) yl)-1H-pyrazol-4-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidine-4- Amine 4b (100 mg), 83% yield.
MS m/z(ESI):488.2[M+1]MS m/z(ESI): 488.2[M+1]
第二步second step
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-d]嘧啶-4-胺4的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(1-methyl-1H- Synthesis of Pyrazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine 4
于15mL烧瓶中加入(R)-7-甲氧基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺4b(100mg)、铁粉(57.29mg)、四氢呋喃(2mL)、乙醇(2mL)和稀盐酸(1M,1mL),升温至100℃反应4小时。反应结束后,以饱和碳酸氢钠溶液调节pH至中性,过滤,将滤液减压浓缩,加入50mL乙酸乙酯,以水(50mL×3)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=30:1),得到(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-d]嘧啶-4-胺4(20mg),产率21%。Into a 15mL flask was added (R)-7-methoxy-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(1-(3-nitro-5 -(Trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 4b (100 mg), iron powder (57.29 mg), tetrahydrofuran (2 mL), ethanol (2 mL) and dilute Hydrochloric acid (1M, 1 mL) was heated to 100°C and reacted for 4 hours. After the reaction, the pH was adjusted to neutral with saturated sodium bicarbonate solution, filtered, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), dried with anhydrous sodium sulfate, filtered, and reduced in pressure Concentrated, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=30:1) to obtain (R)-N-(1-(3-amino-5-(trifluoro) Methyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidine-4 - Amine 4 (20 mg), 21% yield.
MS m/z(ESI):458.2[M+1]MS m/z(ESI): 458.2[M+1]
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.27(d,J=7.9Hz,1H),8.20(s,1H),8.05(s,1H),6.86(d,J=6.2Hz,2H),6.71(s,1H),5.56(s,3H),4.07(s,3H),3.92(s,3H),2.40(s,3H),1.57(d,J=7.0Hz,3H)ppm. 1 H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.27(d,J=7.9Hz,1H),8.20(s,1H),8.05(s,1H),6.86(d,J =6.2Hz, 2H), 6.71(s, 1H), 5.56(s, 3H), 4.07(s, 3H), 3.92(s, 3H), 2.40(s, 3H), 1.57(d, J=7.0Hz ,3H)ppm.
实施例5Example 5
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(3,4-二甲氧基苯基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺5的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,4-dimethoxyphenyl)-7-methoxy- Synthesis of 2-Methylpyrido[2,3-d]pyrimidin-4-amine 5
Figure PCTCN2021135230-appb-000047
Figure PCTCN2021135230-appb-000047
第一步first step
(R)-6-(3,4-二甲氧基苯基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺5b的合成(R)-6-(3,4-Dimethoxyphenyl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)benzene) Synthesis of yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 5b
于25mL烧瓶中加入(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(60mg)、(3,4-二甲氧基苯基)硼酸5a(44.91mg)、RuPhos-Pd-G3(10.33mg)、碳酸钠(39.24mg)、1,4-二氧六环(2mL)和去离子水(0.2mL),置换氮气三次,升温至95℃反应5小时。反应结束后,冷却至室温,反应液通过硅藻土过滤,将滤液减压浓缩,加入50mL乙酸乙酯,以水(50mL×3)洗涤,以无水硫酸钠干燥,过滤,减压浓缩, 得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=40:1),得到粗品(R)-6-(3,4-二甲氧基苯基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺5b(53.6mg),产率80%。Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine [2,3-d]pyrimidin-4-amine C-1 (60 mg), (3,4-dimethoxyphenyl)boronic acid 5a (44.91 mg), RuPhos-Pd-G3 (10.33 mg), carbonic acid Sodium (39.24 mg), 1,4-dioxane (2 mL) and deionized water (0.2 mL) were replaced with nitrogen three times, and the temperature was raised to 95° C. to react for 5 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain crude product (R)-6-(3,4-dimethoxyphenyl)-7 -Methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 5b (53.6 mg), 80% yield.
MS m/z(ESI):544.2[M+1]MS m/z(ESI): 544.2[M+1]
第二步second step
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(3,4-二甲氧基苯基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺5的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,4-dimethoxyphenyl)-7-methoxy- Synthesis of 2-Methylpyrido[2,3-d]pyrimidin-4-amine 5
在50mL反应瓶中加入(R)-6-(3,4-二甲氧基苯基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺5b(67.00mg)、10%钯炭催化剂(20mg)和甲醇(10mL),置换氢气三次,50℃反应过夜。反应结束后,反应液用硅藻土过滤,将滤液减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=30:1),得到(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(3,4-二甲氧基苯基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺5(19mg),产率30%。Add (R)-6-(3,4-dimethoxyphenyl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-() to a 50 mL reaction flask Trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 5b (67.00 mg), 10% palladium on carbon catalyst (20 mg) and methanol (10 mL), replaced with hydrogen three times, 50 °C reaction overnight. After the reaction, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=30:1) to obtain (R) -N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,4-dimethoxyphenyl)-7-methoxy-2-methyl pyrido[2,3-d]pyrimidin-4-amine 5 (19 mg), 30% yield.
MS m/z(ESI):514.2[M+1]MS m/z(ESI): 514.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ10.01(d,J=7.9Hz,1H),8.92(s,1H),7.24(d,J=2.1Hz,1H),7.19(dd,J=8.2,2.1Hz,1H),7.12(d,J=8.5Hz,1H),6.89(d,J=11.3Hz,2H),6.75(s,1H),5.67(q,J=7.0Hz,1H),4.09(s,3H),3.82(s,3H),3.81(s,3H),2.62(s,3H),1.61(d,J=7.0Hz,3H)ppm. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (d, J=7.9 Hz, 1H), 8.92 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.19 (dd, J= 8.2, 2.1Hz, 1H), 7.12 (d, J=8.5Hz, 1H), 6.89 (d, J=11.3Hz, 2H), 6.75 (s, 1H), 5.67 (q, J=7.0Hz, 1H) ,4.09(s,3H),3.82(s,3H),3.81(s,3H),2.62(s,3H),1.61(d,J=7.0Hz,3H)ppm.
实施例6Example 6
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-吗啡啉吡啶并[2,3-d]嘧啶-4-胺6的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-morpholinepyrido[2,3 Synthesis of -d]pyrimidin-4-amine 6
Figure PCTCN2021135230-appb-000048
Figure PCTCN2021135230-appb-000048
于15mL烧瓶中加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-3(150.00mg,339.95μmol)、吗啡啉(59.23mg,679.90μmol)、Pd 2(dba) 3 (31.13mg,33.99μmol)、XantPhos(39.34mg,67.99μmol)、叔丁醇钠(97.92mg,1.02mmol)和1,4-二氧六环(2mL),置换氮气三次,升温至100℃反应过夜。LC-MS检测原料反应完全。硅藻土过滤,使用乙酸乙酯洗涤,收集滤液,水洗三次,无水硫酸钠干燥,过滤,减压浓缩除去溶剂,得到的残留物用硅胶柱层析分离纯化(洗脱剂:二氯甲烷/甲醇=20:1),得到(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-吗啡啉吡啶并[2,3-d]嘧啶-4-胺6(13mg),产率9%。 In a 15 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (150.00 mg, 339.95 μmol), morpholine (59.23 mg, 679.90 μmol), Pd 2 (dba) 3 (31.13 mg, 33.99 μmol), XantPhos (39.34 mg, 67.99 μmol), sodium tert-butoxide (97.92 mg, 1.02 mmol) and 1,4-dioxane (2 mL), replaced with nitrogen three times, and heated to 100° C. to react overnight. LC-MS detected that the reaction of the starting materials was complete. Filter through celite, wash with ethyl acetate, collect the filtrate, wash with water three times, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained residue is separated and purified by silica gel column chromatography (eluent: dichloromethane). /methanol = 20:1) to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6 - Morpholinepyrido[2,3-d]pyrimidin-4-amine 6 (13 mg), 9% yield.
MS m/z(ESI):448.2[M+1]MS m/z(ESI): 448.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.39-8.24(m,1H),8.00(s,1H),7.67(t,J=7.5Hz,1H),7.50(t,J=7.2Hz,1H),7.30(t,J=7.7Hz,1H),7.24(t,J=54.4Hz,1H),5.79(t,J=7.2Hz,1H),3.98(s,3H),3.79(t,J=4.5Hz,4H),3.11(q,J=3.3Hz,4H),2.32(s,3H),1.60(d,J=7.0Hz,3H)ppm. 1 H NMR (400MHz, DMSO-d 6 )δ8.39-8.24(m,1H),8.00(s,1H),7.67(t,J=7.5Hz,1H),7.50(t,J=7.2Hz, 1H), 7.30(t, J=7.7Hz, 1H), 7.24(t, J=54.4Hz, 1H), 5.79(t, J=7.2Hz, 1H), 3.98(s, 3H), 3.79(t, J=4.5Hz, 4H), 3.11 (q, J=3.3Hz, 4H), 2.32 (s, 3H), 1.60 (d, J=7.0Hz, 3H) ppm.
实施例7Example 7
(R)-6-环丙基-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺7的合成(R)-6-Cyclopropyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine- Synthesis of 4-amine 7
Figure PCTCN2021135230-appb-000049
Figure PCTCN2021135230-appb-000049
于25mL封管中加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-2(300mg)和1,4-二氧六环(10mL),加入环丙基硼酸7a(84.6mg)、Pd(dppf)Cl 2(48mg)和碳酸铯(641.8mg),置换氮气3次,100℃反应4个小时。反应液使用硅藻土过滤,浓缩,加入乙酸乙酯,水洗三遍,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=30:1),得到(R)-6-环丙基-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺7(80mg),产率33%。 Add (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3- d] Pyrimidine-4-amine C-2 (300 mg) and 1,4-dioxane (10 mL) were added cyclopropylboronic acid 7a (84.6 mg), Pd(dppf)Cl 2 (48 mg) and cesium carbonate ( 641.8 mg), replaced nitrogen three times, and reacted at 100°C for 4 hours. The reaction solution was filtered through celite, concentrated, added with ethyl acetate, washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane). Methane/methanol=30:1) to give (R)-6-cyclopropyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyridine and [2,3-d]pyrimidin-4-amine 7 (80 mg), 33% yield.
MS m/z(ESI):373.1[M+1]MS m/z(ESI): 373.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.82(d,J=2.3Hz,1H),8.58(d,J=7.2Hz,1H),8.41(d,J=2.4Hz,1H),7.66(t,J=7.5Hz,1H),7.50(t,J=7.2Hz,1H),7.28(t,J=7.7Hz,1H),7.24(t,J=54.4Hz,1H),5.77(p,J=7.0Hz,1H),2.35(s,3H),2.15-2.07(m,1H),1.60(d,J=7.0Hz,3H),1.10-1.07(m,2H),0.94-0.83(m,2H)ppm. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.82 (d, J=2.3Hz, 1H), 8.58 (d, J=7.2Hz, 1H), 8.41 (d, J=2.4Hz, 1H), 7.66 (t, J=7.5Hz, 1H), 7.50 (t, J=7.2Hz, 1H), 7.28 (t, J=7.7Hz, 1H), 7.24 (t, J=54.4Hz, 1H), 5.77 (p , J=7.0Hz, 1H), 2.35(s, 3H), 2.15-2.07(m, 1H), 1.60(d, J=7.0Hz, 3H), 1.10-1.07(m, 2H), 0.94-0.83( m,2H)ppm.
实施例8Example 8
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-((4-甲基哌嗪-1-基)甲基)吡啶并[2,3-d]嘧啶-4-胺8的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-((4-methylpiperazine Synthesis of -1-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine 8
Figure PCTCN2021135230-appb-000050
Figure PCTCN2021135230-appb-000050
在15mL烧瓶中加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-3(120.0mg,0.27mmol)、((4-甲基哌嗪-1-基)甲基)三氟硼酸钾(119.7mg,0.54mmol)、SPhos-Pd-G3(11.9mg,0.014mmol)、四氢呋喃(6mL)和蒸馏水(0.6mL),升温至100℃反应6个小时。LC-MS监测原料转化完全。硅藻土过滤,乙酸乙酯洗涤,水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化(洗脱剂:二氯甲烷/甲醇=30:1),得(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-((4-甲基哌嗪-1-基)甲基)吡啶并[2,3-d]嘧啶-4-胺8(47mg),产率37%。In a 15 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (120.0 mg, 0.27 mmol), ((4-methylpiperazin-1-yl)methyl)potassium trifluoroborate (119.7 mg, 0.54 mmol) , SPhos-Pd-G3 (11.9 mg, 0.014 mmol), tetrahydrofuran (6 mL) and distilled water (0.6 mL), and the temperature was raised to 100° C. to react for 6 hours. Complete conversion of starting material was monitored by LC-MS. Filtered with celite, washed with ethyl acetate, washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the obtained residue was separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=30:1 ) to get (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-((4-methyl) ylpiperazin-1-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine 8 (47 mg) in 37% yield.
MS m/z(ESI):475.3[M+1]MS m/z(ESI): 475.3[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.50(d,J=7.3Hz,1H),7.67(t,J=7.5Hz,1H),7.49(t,J=7.2Hz,1H),7.29(t,J=7.7Hz,1H),7.23(t,J=54.4Hz,1H),5.77(t,J=7.2Hz,1H),3.95(s,3H),3.51(d,J=5.8Hz,2H),2.46-2.39(m,8H),2.33(s,3H),2.15(s,3H),1.59(d,J=7.0Hz,3H)ppm. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.60 (s, 1H), 8.50 (d, J=7.3Hz, 1H), 7.67 (t, J=7.5Hz, 1H), 7.49 (t, J= 7.2Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 5.77(t, J=7.2Hz, 1H), 3.95(s, 3H), 3.51 (d, J=5.8Hz, 2H), 2.46-2.39(m, 8H), 2.33(s, 3H), 2.15(s, 3H), 1.59(d, J=7.0Hz, 3H) ppm.
实施例9Example 9
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin- 4-amine
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-(吡咯-1-基)吡啶并[2,3-d]嘧啶-4-胺9的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(pyrrol-1-yl)pyridine Synthesis of [2,3-d]pyrimidin-4-amine 9
Figure PCTCN2021135230-appb-000051
Figure PCTCN2021135230-appb-000051
于25mL烧瓶中加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-3(100mg,0.23mmol)、吡咯(32.2mg,0.45mmol)、Pd 2(dba) 3(41.5mg,0.045mmol)、XantPhos(52.5mg,0.091mmol)、叔丁醇钠(65.3mg,0.68mmol)和1,4-二氧六环(5mL),置换氮气三次,升温至95℃反应过夜。LC-MS监测原料转化完全。硅藻土过滤,乙酸乙酯洗涤,水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-(吡咯-1-基)吡啶并[2,3-d]嘧啶-4-胺9(7.8mg),产率8%。 In a 25 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (100 mg, 0.23 mmol), pyrrole (32.2 mg, 0.45 mmol), Pd 2 (dba) 3 (41.5 mg, 0.045 mmol), XantPhos (52.5 mg, 0.091 mmol), sodium tert-butoxide (65.3 mg, 0.68 mmol) and 1,4-dioxane (5 mL), nitrogen was replaced three times, the temperature was raised to 95° C. to react overnight. Complete conversion of starting material was monitored by LC-MS. Filter through celite, wash with ethyl acetate, wash three times with water, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography to obtain (R)-N-(1-(3- (Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(pyrrol-1-yl)pyrido[2,3-d]pyrimidine-4- Amine 9 (7.8 mg), 8% yield.
MS m/z(ESI):432.2[M+1]MS m/z(ESI): 432.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ9.70(d,J=7.2Hz,1H),7.73(t,J=7.6Hz,1H),7.65(s,1H),7.57(t,J=7.2Hz,1H),7.37(d,J=7.0Hz,1H),7.24(t,J=54.4Hz,1H),5.91(t,J=7.1Hz,1H),4.07(s,3H),3.55-3.35(m,7H),1.95(s,4H),1.67(d,J=7.0Hz,3H)ppm. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.70 (d, J=7.2 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.57 (t, J= 7.2Hz, 1H), 7.37(d, J=7.0Hz, 1H), 7.24(t, J=54.4Hz, 1H), 5.91(t, J=7.1Hz, 1H), 4.07(s, 3H), 3.55 -3.35(m,7H),1.95(s,4H),1.67(d,J=7.0Hz,3H)ppm.
实施例10Example 10
(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperazin-1-yl)ethan-1-one(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6- yl)piperazin-1-yl)ethan-1-one
(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-6-基)哌嗪-1-基)乙-1-酮10的合成(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido Synthesis of [2,3-d]pyrimidin-6-yl)piperazin-1-yl)ethan-1-one 10
Figure PCTCN2021135230-appb-000052
Figure PCTCN2021135230-appb-000052
Figure PCTCN2021135230-appb-000053
Figure PCTCN2021135230-appb-000053
于反应瓶中加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-3(50mg,0.11mmol)、1-(哌嗪-1-)乙烷-1-酮(29.1mg,0.23mmol)、Pd 2(dba) 3(10.4mg,0.011μmol)、XantPhos(13.1mg,0.022μmol)、叔丁醇钠(32.7mg,3.4mmol)和1,4-二氧六环(2mL),置换氮气三次,升温至95℃反应过夜。LC-MS监测原料转化完全,硅藻土过滤,乙酸乙酯洗涤,水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物硅胶拌样,柱层析分离纯化,得到(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-6-基)哌嗪-1-基)乙-1-酮10(35mg),产率57%。 Add (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido into the reaction flask [2,3-d]pyrimidin-4-amine C-3 (50 mg, 0.11 mmol), 1-(piperazin-1-)ethan-1-one (29.1 mg, 0.23 mmol), Pd 2 (dba) 3 (10.4 mg, 0.011 μmol), XantPhos (13.1 mg, 0.022 μmol), sodium tert-butoxide (32.7 mg, 3.4 mmol) and 1,4-dioxane (2 mL), replace nitrogen three times, and heat up to 95 ° C React overnight. LC-MS monitored the complete conversion of the raw materials, filtered through celite, washed with ethyl acetate, washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was mixed with silica gel and separated and purified by column chromatography to obtain (R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2 ,3-d]pyrimidin-6-yl)piperazin-1-yl)ethan-1-one 10 (35 mg) in 57% yield.
MS m/z(ESI):489.3[M+1]MS m/z(ESI): 489.3[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.27(d,J=7.3Hz,1H),8.02(s,1H),7.66(t,J=7.4Hz,1H),7.50(t,J=7.1Hz,1H),7.29(t,J=7.7Hz,1H),7.24(t,J=54.4Hz,1H),5.78(t,J=7.2Hz,1H),3.99(s,3H),3.63(d,J=5.4Hz,4H),3.17-2.96(m,4H),2.32(s,3H),2.06(s,3H),1.59(d,J=7.1Hz,3H)ppm. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (d, J=7.3 Hz, 1H), 8.02 (s, 1H), 7.66 (t, J=7.4 Hz, 1H), 7.50 (t, J= 7.1Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.24(t, J=54.4Hz, 1H), 5.78(t, J=7.2Hz, 1H), 3.99(s, 3H), 3.63 (d, J=5.4Hz, 4H), 3.17-2.96(m, 4H), 2.32(s, 3H), 2.06(s, 3H), 1.59(d, J=7.1Hz, 3H) ppm.
实施例11Example 11
(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d ]pyrimidin-4-amine
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(4-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-4-胺11的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazine- Synthesis of 1-yl)pyrido[2,3-d]pyrimidin-4-amine 11
Figure PCTCN2021135230-appb-000054
Figure PCTCN2021135230-appb-000054
第一步first step
(R)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5- (trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine(R)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5- (trifluoromethyl)phenyl)ethyl)pyrido[2,3-d ]pyrimidin-4-amine
(R)-7-甲氧基-2-甲基-6-(4-甲基哌嗪-1-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺11a的合成(R)-7-Methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5-(trifluoromethyl)benzene) Synthesis of yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 11a
于25mL烧瓶中加入(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(100mg,0.2mmol)、1-甲基哌嗪(41.20mg,0.4mmol)、Pd 2(dba) 3(37.7mg,0.04mmol)、XantPhos(47.60mg,0.08mmol)、碳酸铯(167.5mg,0.5mmol)和1,4-二氧六环(2mL),置换氮气三次,升温至95℃反应过夜。LC-MS监测原料转化完全,硅藻土过滤,乙酸乙酯洗涤,水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-7-甲氧基-2-甲基-6-(4-甲基哌嗪-1-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺11a(25mg),产率24%。 Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine [2,3-d]pyrimidin-4-amine C-1 (100 mg, 0.2 mmol), 1-methylpiperazine (41.20 mg, 0.4 mmol), Pd 2 (dba) 3 (37.7 mg, 0.04 mmol) , XantPhos (47.60 mg, 0.08 mmol), cesium carbonate (167.5 mg, 0.5 mmol) and 1,4-dioxane (2 mL), nitrogen was replaced three times, and the temperature was raised to 95° C. to react overnight. LC-MS monitored the complete conversion of the raw materials, filtered through celite, washed with ethyl acetate, washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)- 7-Methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl ) pyrido[2,3-d]pyrimidin-4-amine 11a (25 mg) in 24% yield.
MS m/z(ESI):506.2[M+1]MS m/z(ESI): 506.2[M+1]
第二步second step
(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d ]pyrimidin-4-amine
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(4-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-4-胺11的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazine- Synthesis of 1-yl)pyrido[2,3-d]pyrimidin-4-amine 11
于10mL反应瓶中加入(R)-7-甲氧基-2-甲基-6-(4-甲基哌嗪-1-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺11a(25mg,0.05mmol)、1M盐酸(1mL)、铁粉(13.8mg,0.25mmol)、四氢呋喃(2mL),于100℃下反应1个小时。TLC检测原料转化完全。碳酸氢钠溶液调节pH为中性,过滤,乙酸乙酯洗涤,有机相水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(4-甲基哌嗪-1-基)吡啶并[2,3-d]嘧啶-4-胺11(2.1mg),收率9%。Add (R)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5-( Trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 11a (25 mg, 0.05 mmol), 1 M hydrochloric acid (1 mL), iron powder (13.8 mg, 0.25 mmol), tetrahydrofuran (2 mL), reacted at 100°C for 1 hour. Complete conversion of starting material was detected by TLC. The sodium bicarbonate solution was adjusted to neutral pH, filtered, washed with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R) -N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl) ) pyrido[2,3-d]pyrimidin-4-amine 11 (2.1 mg), 9% yield.
MS m/z(ESI):475.9[M+1]MS m/z(ESI): 475.9[M+1]
实施例12Example 12
(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methylpyrido[ 2,3-d]pyrimidin-4-amine
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺12的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7 Synthesis of -methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 12
Figure PCTCN2021135230-appb-000055
Figure PCTCN2021135230-appb-000055
Figure PCTCN2021135230-appb-000056
Figure PCTCN2021135230-appb-000056
第一步first step
(R)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(R)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-
(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine
(R)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺12a的合成(R)-6-(3,6-Dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(tris) Synthesis of fluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 12a
于25mL烧瓶中加入(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(120mg,0.25mmol)、2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-频哪醇硼烷(103.7mg,0.5mmol)、RuPhos-Pd-G3(20.7mg,0.025mmol)、碳酸钠(78.5mg,0.75mmol)、1,4-二氧六环(4mL)和蒸馏水(0.4mL),置换氮气三次,升温至95℃反应过夜。LC-MS监测原料转化完全,硅藻土过滤,乙酸乙酯洗涤,水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺12a(97mg),产率81%。Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine Por[2,3-d]pyrimidin-4-amine C-1 (120 mg, 0.25 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5 -Tetramethyl-1,3,2-pinacolborane (103.7mg, 0.5mmol), RuPhos-Pd-G3 (20.7mg, 0.025mmol), sodium carbonate (78.5mg, 0.75mmol), 1,4 -Dioxane (4 mL) and distilled water (0.4 mL), replaced with nitrogen three times, heated to 95°C and reacted overnight. LC-MS monitored the complete conversion of the raw materials, filtered through celite, washed with ethyl acetate, washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)- 6-(3,6-Dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl) Phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 12a (97 mg) in 81% yield.
MS m/z(ESI):490.2[M+1]MS m/z(ESI): 490.2[M+1]
第二步second step
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺12的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7 Synthesis of -methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 12
于10mL烧瓶中加入(R)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺12a(90mg,0.18mmol)、铁粉(51.4mg,0.92mmol)、1M盐酸(1mL)、四氢呋喃(2mL)和乙醇(2mL),升温至100度反应2小时。TLC检测原料转化完全,碳酸氢钠溶液调节pH为中性,过滤,乙酸乙酯洗涤,有机相水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺12(18mg),产率22%Add (R)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro) to a 10 mL flask -5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 12a (90 mg, 0.18 mmol), iron powder (51.4 mg, 0.92 mmol), 1 M hydrochloric acid ( 1 mL), tetrahydrofuran (2 mL) and ethanol (2 mL), the temperature was raised to 100 degrees and reacted for 2 hours. The complete conversion of the raw materials was detected by TLC, the pH of the sodium bicarbonate solution was adjusted to neutral, filtered, washed with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography Purification to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl )-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 12 (18 mg), 22% yield
MS m/z(ESI):460.2[M+1]MS m/z(ESI): 460.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.53(s,1H),8.38(d,J=7.9Hz,1H),6.87(s,1H),6.84(s,1H),6.70(s,1H),6.18(s,1H),5.55(s,2H),5.51(d,J=7.8Hz,1H),4.25(d,J=3.3Hz,2H),3.96(s,3H),3.82(t,J=5.5Hz,2H),2.62-2.46(m,2H),2.39(s,3H),1.53(d,J=7.0Hz,3H)ppm. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.53(s, 1H), 8.38(d, J=7.9Hz, 1H), 6.87(s, 1H), 6.84(s, 1H), 6.70(s, 1H), 6.18(s, 1H), 5.55(s, 2H), 5.51(d, J=7.8Hz, 1H), 4.25(d, J=3.3Hz, 2H), 3.96(s, 3H), 3.82( t, J=5.5Hz, 2H), 2.62-2.46 (m, 2H), 2.39 (s, 3H), 1.53 (d, J=7.0Hz, 3H) ppm.
实施例13Example 13
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-4-amine
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-(四氢-2H-吡喃-4-基)吡啶并[2,3-d]嘧啶-4-胺13的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(tetrahydro-2H-pyran Synthesis of -4-yl)pyrido[2,3-d]pyrimidin-4-amine 13
Figure PCTCN2021135230-appb-000057
Figure PCTCN2021135230-appb-000057
第一步first step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methylpyrido[2 ,3-d]pyrimidin-4-amine
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺13a的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7 Synthesis of -methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 13a
于50mL烧瓶中加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-3(100mg,0.23mmol)、2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-频哪醇硼烷(95.2mg,0.46mmol)、RuPhos-Pd-G3(19.0mg,0.023mmol)、碳酸钠(72.1mg,0.69mmol)、1,4-二氧六环(5mL)和蒸馏水(0.5mL),置换氮气三次,升温至95℃反应过夜。LC-MS监测原料转化完全,硅藻土过滤,乙酸乙酯洗涤,水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺13a(80mg),产率80%。In a 50 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (100 mg, 0.23 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- Tetramethyl-1,3,2-pinacolborane (95.2 mg, 0.46 mmol), RuPhos-Pd-G3 (19.0 mg, 0.023 mmol), sodium carbonate (72.1 mg, 0.69 mmol), 1,4- Dioxane (5 mL) and distilled water (0.5 mL) were replaced with nitrogen three times, and the temperature was raised to 95° C. to react overnight. LC-MS monitored the complete conversion of the raw materials, filtered through celite, washed with ethyl acetate, washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)- N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy -2-Methylpyrido[2,3-d]pyrimidin-4-amine 13a (80 mg), 80% yield.
MS m/z(ESI):445.2[M+1]MS m/z(ESI): 445.2[M+1]
第二步second step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-4-amine
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-(四氢-2H-吡喃-4-基)吡啶并[2,3-d]嘧啶-4-胺13的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(tetrahydro-2H-pyran Synthesis of -4-yl)pyrido[2,3-d]pyrimidin-4-amine 13
在50mL反应瓶中加入(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺13a(80mg,0.18mmol)、10%钯炭催化剂(95mg)和乙醇(40mL),置换氢气三次后,40℃下反应过夜。硅藻土过滤,乙酸乙酯洗涤,得到的残留物经制备HPLC分离纯化,得到(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-(四氢-2H-吡喃-4-基)吡啶并[2,3-d]嘧啶-4-胺13(38mg),产率48%。Add (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran- 4-yl)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 13a (80 mg, 0.18 mmol), 10% palladium on carbon catalyst (95 mg) and ethanol (40 mL) , after replacing the hydrogen three times, the reaction was carried out at 40 °C overnight. Celite filtration, washing with ethyl acetate, the obtained residue was separated and purified by preparative HPLC to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- 7-Methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine 13 (38 mg), 48% yield.
MS m/z(ESI):447.2[M+1]MS m/z(ESI): 447.2[M+1]
实施例14Example 14
(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)tetrahydro-2H-pyran-4-ol(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)tetrahydro -2H-pyran-4-ol
(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-6-基)四氢-2H-吡喃-4-醇14的合成(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2, Synthesis of 3-d]pyrimidin-6-yl)tetrahydro-2H-pyran-4-ol 14
Figure PCTCN2021135230-appb-000058
Figure PCTCN2021135230-appb-000058
于50mL烧瓶中加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-3(100mg,0.23mmol)和四氢呋喃(5mL),置换氮气三次,冷却至-78℃,缓慢滴加入2.5mol/L正丁基锂/正己烷溶液(0.5mL),-78℃下保温反应1小时。缓慢加入1-甲基哌啶-4-酮(38.5mg,3.4mmol),恢复至室温反应1小时。加入饱和氯化铵溶液淬灭反应,加入乙酸乙酯,水洗三次,用饱和食盐水洗一次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-6-基)四氢-2H-吡喃-4-醇14(2mg),产率2%。In a 50 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (100 mg, 0.23 mmol) and tetrahydrofuran (5 mL), replaced nitrogen three times, cooled to -78 °C, and slowly added 2.5 mol/L n-butyllithium/n-hexane dropwise alkane solution (0.5 mL), and the reaction was incubated at -78°C for 1 hour. 1-Methylpiperidin-4-one (38.5 mg, 3.4 mmol) was slowly added, and the reaction was returned to room temperature for 1 hour. Saturated ammonium chloride solution was added to quench the reaction, ethyl acetate was added, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to obtain ( R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3 -d]pyrimidin-6-yl)tetrahydro-2H-pyran-4-ol 14 (2 mg), 2% yield.
MS m/z(ESI):463.2[M+1]MS m/z(ESI): 463.2[M+1]
实施例15Example 15
(R)-2-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-基)-N,N-二甲基乙酰胺15的合成(R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d Synthesis of ]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide 15
(R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3- d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide(R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3 ,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide
Figure PCTCN2021135230-appb-000059
Figure PCTCN2021135230-appb-000059
第一步first step
tert-butyl(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylatetert-butyl(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3 ,6-dihydropyridine-1(2H)-carboxylate
(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯15a的合成(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidine- Synthesis of 6-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester 15a
于25mL烧瓶中,加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-2(500mg,1.22mmol)、N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(751.9mg,2.43mmol)、Pd(dppf)Cl 2(177.9mg,0.24mmol)、磷酸钾(516.2mg,2.4mmol)、1,4-二氧六环(8mL)和蒸馏水(0.8mL),于微波下110℃反应4小时。LC-MS检测原料转化完全。硅藻土过滤,乙酸乙酯洗涤,有机相水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯15a(500mg),产率80%。 In a 25 mL flask, add (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3- d] Pyrimidine-4-amine C-2 (500mg, 1.22mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (751.9mg, 2.43mmol), Pd ( dppf) Cl 2 (177.9 mg, 0.24 mmol), potassium phosphate (516.2 mg, 2.4 mmol), 1,4-dioxane (8 mL) and distilled water (0.8 mL), reacted under microwave at 110° C. for 4 hours. Complete conversion of starting material was detected by LC-MS. Filter through celite, wash with ethyl acetate, wash the organic phase three times with water, once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography to obtain (R)-4 -(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)- 3,6-Dihydropyridine-1(2H)-carboxylate tert-butyl ester 15a (500 mg), 80% yield.
MS m/z(ESI):514.2[M+1]MS m/z(ESI): 514.2[M+1]
第二步second step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3- d]pyrimidin-4-amine
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(1,2,3,6-四氢吡啶-4-基)吡啶并[2,3-d]嘧啶-4-胺15b的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridine-4 Synthesis of -yl)pyrido[2,3-d]pyrimidin-4-amine 15b
于50mL反应瓶中,加入(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯15a(500mg,0.97mmol)、加入1,4-二氧六环(10mL)、加入4M氯化氢/1,4-二氧六环溶液(5mL),室温下反应3小时。TLC监测原料消失。减压除去溶剂至少量,加入乙醚析出固体,过滤,烘干固体,得到(R)-N-(1-(3- (二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(1,2,3,6-四氢吡啶-4-基)吡啶并[2,3-d]嘧啶-4-胺15b的盐酸盐(400mg)。In a 50 mL reaction flask, add (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2 ,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester 15a (500 mg, 0.97 mmol), 1,4-dioxane (10 mL) was added , 4M hydrogen chloride/1,4-dioxane solution (5 mL) was added, and the reaction was carried out at room temperature for 3 hours. The disappearance of starting material was monitored by TLC. At least a small amount of solvent was removed under reduced pressure, diethyl ether was added to separate out the solid, filtered, and the solid was dried to obtain (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2- Methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine 15b hydrochloride salt (400 mg).
MS m/z(ESI):414.2[M+1]MS m/z(ESI): 414.2[M+1]
第三步third step
(R)-2-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-基)-N,N-二甲基乙酰胺15的合成(R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d Synthesis of ]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide 15
(R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide(R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3 ,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide
于25mL烧瓶中,加入(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(1,2,3,6-四氢吡啶-4-基)吡啶并[2,3-d]嘧啶-4-胺15b的盐酸盐(50mg,0.12mmol)、2-溴-N,N-二甲基-乙酰胺(20.1mg,0.12mmol)、碳酸钾(50.1mg,0.36mmol)和乙腈(5mL),50℃下反应过夜。反应液加入乙酸乙酯,水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-2-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-基)-N,N-二甲基乙酰胺15(20mg),产率30%。In a 25mL flask, add (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6 - Tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine 15b hydrochloride (50 mg, 0.12 mmol), 2-bromo-N,N-dimethyl-acetamide ( 20.1 mg, 0.12 mmol), potassium carbonate (50.1 mg, 0.36 mmol) and acetonitrile (5 mL) were reacted at 50°C overnight. The reaction solution was added with ethyl acetate, washed with water three times, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)-2-(4-( 4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3, 6-Dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide 15 (20 mg), 30% yield.
MS m/z(ESI):499.2[M+1]MS m/z(ESI): 499.2[M+1]
实施例16Example 16
(R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropanenitrile(R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3 ,6-dihydropyridin-1(2H)-yl)-3-oxopropanenitrile
(R)-3-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-基)-3-氧代丙腈16的合成(R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d Synthesis of ]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropionitrile 16
Figure PCTCN2021135230-appb-000060
Figure PCTCN2021135230-appb-000060
于25mL烧瓶中,加入(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(1,2,3,6-四氢吡啶-4-基)吡啶并[2,3-d]嘧啶-4-胺15b的盐酸盐(50mg,0.12mmol)、2-氰基乙酸(20.6mg,0.24mmol)、EDCI(46.4mg,0.24mmol)和二氯甲烷(7mL),室温条件下反应4小时。加入 二氯甲烷,水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-3-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-基)-3-氧代丙腈16(20mg),产率35%。In a 25mL flask, add (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6 - Tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine 15b hydrochloride (50 mg, 0.12 mmol), 2-cyanoacetic acid (20.6 mg, 0.24 mmol), EDCI ( 46.4 mg, 0.24 mmol) and dichloromethane (7 mL), reacted at room temperature for 4 hours. Dichloromethane was added, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)-3-(4-(4- ((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6- Dihydropyridin-1(2H)-yl)-3-oxopropionitrile 16 (20 mg) in 35% yield.
MS m/z(ESI):481.2[M+1]MS m/z(ESI): 481.2[M+1]
实施例17Example 17
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2,3-d]pyrimidin-4-amine
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(2-吗啉基乙氧基)吡啶并[2,3-d]嘧啶-4-胺17的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2 Synthesis of ,3-d]pyrimidin-4-amine 17
Figure PCTCN2021135230-appb-000061
Figure PCTCN2021135230-appb-000061
第一步first step
(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-ol(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-醇17a的合成(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-ol(R)-4-((1 Synthesis of -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-ol 17a
于25mL烧瓶中,加入(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺C-2(800mg,1.95mmol)、Pd(dppf)Cl 2(317.7mg,0.39mmol)、联硼酸频那醇酯(988.1mg,3.89mmol)、乙酸钾(381.9mg,3.89mmol)和1,4-二氧六环(8mL),置换氮气三次,于100℃下反应过夜。降至室温后,硅藻土过滤,乙酸乙酯洗涤,有机相水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,减压除去溶剂,加入四氢呋喃(10mL)、蒸馏水(3mL)和30%双氧水溶液(2mL)和氢氧化钠(698.26mg,17.46mmol),室温下反应过夜。TLC检测原料转化完全。加入乙酸乙酯,水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,减压除去溶剂,真空干燥,得到粗品(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-醇17a(650mg),产率96%。 In a 25 mL flask, add (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3- d] Pyrimidine-4-amine C-2 (800mg, 1.95mmol), Pd(dppf)Cl 2 (317.7mg, 0.39mmol), Biboronate pinacol ester (988.1mg, 3.89mmol), Potassium acetate (381.9mg , 3.89 mmol) and 1,4-dioxane (8 mL), replaced nitrogen three times, and reacted at 100 °C overnight. After cooling to room temperature, celite was filtered, washed with ethyl acetate, the organic phase was washed three times with water, washed with saturated brine once, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and tetrahydrofuran (10 mL), distilled water (3 mL) and 30% hydrogen peroxide were added. The solution (2 mL) and sodium hydroxide (698.26 mg, 17.46 mmol) were reacted overnight at room temperature. Complete conversion of starting material was detected by TLC. Ethyl acetate was added, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and dried in vacuo to obtain crude product (R)-4-((1-(3-(difluoromethyl)-2) -Fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-ol 17a (650 mg) in 96% yield.
MS m/z(ESI):349.1[M+1]MS m/z(ESI): 349.1[M+1]
第二步second step
(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2,3-d]pyrimidin-4-amine
(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(2-吗啉基乙氧基)吡啶并[2,3-d]嘧啶-4-胺17的合成(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2 Synthesis of ,3-d]pyrimidin-4-amine 17
在25mL烧瓶中,加入(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-醇17a(80mg,0.23mmol)、4-(2-氯乙基)吗啡啉(68.7mg,0.46mmol)、碘化钾(3.8mg,0.023mmol)、碳酸钾(63.5mg,0.46mmol)和DMF(5mL),于70℃下反应3小时。TLC检测原料转化完全。加入乙酸乙酯,水洗三次,饱和食盐水洗一次,无水硫酸钠干燥,过滤,干燥,得到的残留物用硅胶柱层析分离纯化,得到(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(2-吗啉基乙氧基)吡啶并[2,3-d]嘧啶-4-胺17(11mg),产率11%。In a 25 mL flask, add (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d ] Pyrimidine-6-ol 17a (80mg, 0.23mmol), 4-(2-chloroethyl)morpholine (68.7mg, 0.46mmol), potassium iodide (3.8mg, 0.023mmol), potassium carbonate (63.5mg, 0.46mmol) ) and DMF (5 mL) were reacted at 70°C for 3 hours. Complete conversion of starting material was detected by TLC. Ethyl acetate was added, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried, and the obtained residue was separated and purified by silica gel column chromatography to obtain (R)-N-(1-(3-(bis). Fluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2,3-d]pyrimidin-4-amine 17 (11 mg) , the yield is 11%.
MS m/z(ESI):462.2[M+1]MS m/z(ESI): 462.2[M+1]
实施例18Example 18
(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3 -yl)pyrido[2,3-d]pyrimidin-4-amine
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基团)吡啶并[2,3-d]嘧啶-4-胺18的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl-3, Synthesis of 9-diazaspiro[5.5]undecan-3-yl)pyrido[2,3-d]pyrimidin-4-amine 18
Figure PCTCN2021135230-appb-000062
Figure PCTCN2021135230-appb-000062
第一步first step
(R)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine(R)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl) )ethyl)pyrido[2,3-d]pyrimidin-4-amine
(R)-7-甲氧基-2-甲基-6-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺18a的合成(R)-7-Methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(1-(3 -Synthesis of nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 18a
于25mL烧瓶中加入(R)-6-溴-7-甲氧基-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺C-1(150mg)、3-甲基-3,9-二氮杂螺[5.5]十一烷(102.70mg)、Pd 2(dba) 3(28.3mg)、XantPhos(35.7mg)、碳酸铯(301.5mg)和二氧六环(5mL),置换氮气三次,升温至100℃反应6小时。反应结束后,冷却至室温,反应液通过硅藻土过滤,将滤液减压浓缩,加入50mL乙酸乙酯,以水(25mL×3)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=9:1),得到(R)-7-甲氧基-2-甲基-6-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺18a(50mg),产率29%。 Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine [2,3-d]pyrimidin-4-amine C-1 (150 mg), 3-methyl-3,9-diazaspiro[5.5]undecane (102.70 mg), Pd 2 (dba) 3 (28.3 mg), XantPhos (35.7 mg), cesium carbonate (301.5 mg) and dioxane (5 mL), nitrogen was replaced three times, and the temperature was raised to 100° C. to react for 6 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=9:1) to obtain (R)-7-methoxy-2-methyl-6-(9-methyl) yl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[ 2,3-d]pyrimidin-4-amine 18a (50 mg), 29% yield.
MS m/z(ESI):574.3[M+1]MS m/z(ESI): 574.3[M+1]
第二步second step
(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)pyrido[2,3-d]pyrimidin-4-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3 -yl)pyrido[2,3-d]pyrimidin-4-amine
(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基团)吡啶并[2,3-d]嘧啶-4-胺18的合成(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl-3, Synthesis of 9-diazaspiro[5.5]undecan-3-yl)pyrido[2,3-d]pyrimidin-4-amine 18
于10mL烧瓶中加入(R)-7-甲氧基-2-甲基-6-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)吡啶并[2,3-d]嘧啶-4-胺18a(50mg)、铁粉(24mg)、1M盐酸(1mL)、四氢呋喃(2mL)和乙醇(2mL),升温至100度反应2小时。TLC检测原料转化完全,碳酸氢钠溶液调节pH为中性,过滤,乙酸乙酯洗涤,有机相水洗三次,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析分离纯化,得到(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基团)吡啶并[2,3-d]嘧啶-4-胺18(17mg),产率36%。In a 10 mL flask was added (R)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N- (1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 18a (50mg), iron powder (24mg), 1M hydrochloric acid (1 mL), tetrahydrofuran (2 mL) and ethanol (2 mL), and the temperature was raised to 100 degrees to react for 2 hours. The complete conversion of the raw materials was detected by TLC, the pH of the sodium bicarbonate solution was adjusted to neutral, filtered, washed with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography Purification to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl) -3,9-Diazaspiro[5.5]undecan-3-yl)pyrido[2,3-d]pyrimidin-4-amine 18 (17 mg), 36% yield.
MS m/z(ESI):544.3[M+1]MS m/z(ESI): 544.3[M+1]
实施例19Example 19
(R)-3-(1-((7-methoxy-2-methyl-6-morpholinopyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile(R)-3-(1-((7-methoxy-2-methyl-6-morpholinopyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-吗啡啉吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈19的合成(R)-3-(1-((7-Methoxy-2-methyl-6-morpholinepyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methyl Synthesis of Benzonitrile 19
Figure PCTCN2021135230-appb-000063
Figure PCTCN2021135230-appb-000063
第一步first step
在50ml烧瓶中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈C-4(60mg,145.53μmol),吗啡啉(43.69mg,353.55μmol),Pd 2(dba) 3(13.32mg,14.55μmol),BINAP(18.12mg,29.11μmol)和二氧六环5m,置换氮气三次,升温至100度反应6小时。LC-MS显示原料反应完全,硅藻土过滤,浓缩,加入乙酸乙酯100mL,水洗(25mL×3),无水硫酸钠干燥,过滤浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=19:1),得(R)-3-(1-((7-甲氧基-2-甲基-6-吗啡啉吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈19 26mg,产率43%。MS m/z(ESI):419.2[M+1] In a 50ml flask was added (R)-3-(1-((6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino)ethyl) -2-methylbenzonitrile C-4 (60 mg, 145.53 μmol), morpholine (43.69 mg, 353.55 μmol), Pd 2 (dba) 3 (13.32 mg, 14.55 μmol), BINAP (18.12 mg, 29.11 μmol) With 5m of dioxane, nitrogen was replaced three times, and the temperature was raised to 100 degrees to react for 6 hours. LC-MS showed that the reaction of the raw materials was complete, celite was filtered, concentrated, 100 mL of ethyl acetate was added, washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was further separated and purified by silica gel column chromatography ( Eluent: dichloromethane/methanol=19:1) to give (R)-3-(1-((7-methoxy-2-methyl-6-morpholinopyrido[2,3-d) ]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile 19 26 mg, 43% yield. MS m/z(ESI): 419.2[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.35(d,J=6.9Hz,1H),7.97(s,1H),7.77(d,J=7.8Hz,1H),7.63(d,J=7.6Hz,1H),7.36(t,J=7.8Hz,1H),5.63(t,J=7.0Hz,1H),3.97(s,3H),3.78(t,J= 4.6Hz,4H),3.10(q,J=3.4Hz,4H),2.70(s,3H),2.32(s,3H),1.54(d,J=7.0Hz,3H)ppm. 1 H NMR(400MHz, DMSO-d 6 )δ8.35(d,J=6.9Hz,1H),7.97(s,1H),7.77(d,J=7.8Hz,1H),7.63(d,J= 7.6Hz, 1H), 7.36(t, J=7.8Hz, 1H), 5.63(t, J=7.0Hz, 1H), 3.97(s, 3H), 3.78(t, J= 4.6Hz, 4H), 3.10 (q, J=3.4Hz, 4H), 2.70 (s, 3H), 2.32 (s, 3H), 1.54 (d, J=7.0Hz, 3H) ppm.
实施例20Example 20
(R)-3-(1-((7-methoxy-2-methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile(R)-3-(1-((7-methoxy-2-methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyrido[2,3-d]pyrimidin-4- yl)amino)ethyl)-2-methylbenzonitrile
(R)-3-(1-((7-甲氧基-2-甲基-6-(3-氧代-9-氮杂螺[5.5]十一烷-9-基)吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈20的合成(R)-3-(1-((7-Methoxy-2-methyl-6-(3-oxo-9-azaspiro[5.5]undecan-9-yl)pyrido[2 Synthesis of ,3-d]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile 20
Figure PCTCN2021135230-appb-000064
Figure PCTCN2021135230-appb-000064
在50ml烧瓶中加入(R)-3-(1-((6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈C-4(75.00mg,181.91μmol),3-氧代-9-氮杂螺[5.5]十一烷盐酸盐(62.77mg,327.45μmol),Pd 2(dba) 3(16.65mg,18.19μmol),X-PHOS(17.34mg,36.38μmol),叔丁醇钠(69.93mg,727.66μmol)和二氧六环4mL,置换氮气三次,升温至100度反应6小时。LC-MS显示原料反应完全,硅藻土过滤,浓缩,加入乙酸乙酯100mL,水洗(25mL×3),无水硫酸钠干燥,过滤浓缩,得到的残留物用硅胶柱层析进一步分离纯化(洗脱剂:二氯甲烷/甲醇=19:1),得(R)-3-(1-((7-甲氧基-2-甲基-6-(3-氧代-9-氮杂螺[5.5]十一烷-9-基)吡啶并[2,3-d]嘧啶-4-基)氨基)乙基)-2-甲基苯甲腈20 30mg,产率33%。 In a 50ml flask was added (R)-3-(1-((6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino)ethyl) -2-methylbenzonitrile C-4 (75.00 mg, 181.91 μmol), 3-oxo-9-azaspiro[5.5]undecane hydrochloride (62.77 mg, 327.45 μmol), Pd 2 (dba ) 3 (16.65mg, 18.19μmol), X-PHOS (17.34mg, 36.38μmol), sodium tert-butoxide (69.93mg, 727.66μmol) and dioxane 4mL, replaced nitrogen three times, heated to 100 degrees and reacted for 6 hours . LC-MS showed that the reaction of the raw materials was complete, celite was filtered, concentrated, 100 mL of ethyl acetate was added, washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was further separated and purified by silica gel column chromatography ( Eluent: dichloromethane/methanol=19:1) to obtain (R)-3-(1-((7-methoxy-2-methyl-6-(3-oxo-9-aza) Spiro[5.5]undecan-9-yl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile 20 30 mg, 33% yield.
MS m/z(ESI):487.3[M+1]MS m/z(ESI): 487.3[M+1]
1H NMR(400MHz,DMSO-d6)δ8.31(d,J=7.0Hz,1H),7.97(s,1H),7.77(d,J=7.8Hz, 1 H NMR(400MHz, DMSO-d6)δ8.31(d,J=7.0Hz,1H),7.97(s,1H),7.77(d,J=7.8Hz,
1H),7.63(d,J=7.7Hz,1H),7.36(t,J=7.8Hz,1H),5.63(p,J=7.1Hz,1H),3.96(s,3H),3.60(t,J=5.3Hz,4H),3.05(q,J=4.5Hz,4H),2.70(s,3H),2.32(s,3H),1.67(d,J=5.6Hz,3H),1H), 7.63(d, J=7.7Hz, 1H), 7.36(t, J=7.8Hz, 1H), 5.63(p, J=7.1Hz, 1H), 3.96(s, 3H), 3.60(t, J=5.3Hz, 4H), 3.05(q, J=4.5Hz, 4H), 2.70(s, 3H), 2.32(s, 3H), 1.67(d, J=5.6Hz, 3H),
1.52(t,J=6.6Hz,8H)ppm.1.52(t,J=6.6Hz,8H)ppm.
生物学评价Biological evaluation
测试例1、本发明化合物阻断SOS1与KRAS G12C蛋白结合的测试Test Example 1. Test that the compound of the present invention blocks the binding of SOS1 to KRAS G12C protein
以下方法用于测定本发明化合物在体外条件下阻断SOS1与KRAS G12C蛋白相互作用的能力。本方法使用Cisbio公司的KRAS-G12C/SOS1BINDING ASSAY KITS试剂盒(货号63ADK000CB16PEG),详细实验操作可参考试剂盒说明书。The following method was used to determine the ability of the compounds of the invention to block the interaction of SOS1 with KRAS G12C protein under in vitro conditions. This method uses the KRAS-G12C/SOS1BINDING ASSAY KITS kit (Cat. No. 63ADK000CB16PEG) from Cisbio Company. For detailed experimental operation, please refer to the kit instructions.
将实验流程简述如下:使用diluent buffer(货号62DLBDDF)配置Tag1-SOS1和Tag2- KRAS-G12C蛋白为5X的工作液浓度备用。受试化合物溶解于DMSO中制备为10mM贮存液,随后使用diluent buffer进行稀释备用。首先向孔中加入2μL受试化合物(反应体系终浓度为10000nM-0.1nM),随后加入4μL Tag1-SOS1 5X的工作液和4μL Tag2-KRAS-G12C 5X的工作液,离心并混匀,静置15分钟;随后加入10μL预混匀的anti-Tag1-Tb 3+和anti-Tag2-XL665,室温下孵育2小时;最后使用酶标仪以TF-FRET模式上测定在304nM的激发波长下,各孔发射波长为620nM和665nM的荧光强度,并计算各孔665/620的荧光强度比值。通过与对照组(0.1%DMSO)的荧光强度比值进行比较,计算受试化合物在各浓度下的百分比抑制率,并通过GraphPad Prism 5软件以受试化合物浓度对数值-抑制率进行非线性回归分析,获得化合物的IC 50值,见表1。 The experimental process is briefly described as follows: Use diluent buffer (Cat. No. 62DLBDDF) to configure the working solution concentration of Tag1-SOS1 and Tag2-KRAS-G12C proteins to 5X for use. Test compounds were dissolved in DMSO to prepare 10 mM stock solutions, which were then diluted with diluent buffer for use. First add 2μL of the test compound to the well (final concentration of the reaction system is 10000nM-0.1nM), then add 4μL of Tag1-SOS1 5X working solution and 4μL of Tag2-KRAS-G12C 5X working solution, centrifuge and mix well, let stand 15 minutes; then add 10 μL of pre-mixed anti-Tag1-Tb 3+ and anti-Tag2-XL665, and incubate for 2 hours at room temperature; finally, use a microplate reader to measure at the excitation wavelength of 304nM in TF-FRET mode. Wells emit fluorescence intensities at wavelengths of 620 nM and 665 nM, and the ratio of 665/620 fluorescence intensities for each well is calculated. By comparing the fluorescence intensity ratio with the control group (0.1% DMSO), the percentage inhibition rate of the test compound at each concentration was calculated, and the numerical-inhibition rate was subjected to nonlinear regression analysis with the test compound concentration by GraphPad Prism 5 software. , the IC50 values of the compounds were obtained, see Table 1.
表1本发明化合物阻断SOS1与KRAS G12C蛋白相互作用的IC 50数据 Table 1 IC 50 data of the compounds of the present invention blocking the interaction between SOS1 and KRAS G12C protein
化合物编号Compound number SOS1/IC 50(nM) SOS1/ IC50 (nM)
11 16.716.7
22 12.812.8
33 37.437.4
44 50.150.1
55 30.330.3
66 29.929.9
77 6.56.5
88 24.724.7
99 25.925.9
1111 18.818.8
1212 51.851.8
1313 15.615.6
1515 54.154.1
1616 37.637.6
1919 32.432.4
2020 52.452.4
结论:从表1可以看出,本发明化合物对于SOS1与KRAS G12C蛋白相互作用具有较强的阻断作用。Conclusion: It can be seen from Table 1 that the compound of the present invention has a strong blocking effect on the interaction between SOS1 and KRAS G12C protein.

Claims (12)

  1. 一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐:A compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021135230-appb-100001
    Figure PCTCN2021135230-appb-100001
    其中:in:
    环A选自C 6-C 10芳基、5-10元杂芳基、9-10元双环杂环基、9-10元双环芳基或9-10元稠合环; Ring A is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl, 9-10 membered bicyclic aryl or 9-10 membered fused ring;
    R 1相同或不同,各自独立地选自氢原子、卤素、氰基、氨基、硝基、C 1-C 6烷基、C 3-C 6环烷基、4-11元杂环基、C 6-C 10芳基、5-10元杂芳基;其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、氰基、羟基、氨基、=O的取代基所取代; R 1 are the same or different, each independently selected from hydrogen atom, halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-11 membered heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further selected from one or more halogens, cyano groups , substituted by substituents of hydroxy, amino, and =O;
    R 2选自卤素、氰基、C 1-C 6烷基、C 3-C 10环烷基、4-11元杂环基、C 6-C 10芳基、5-10元杂芳基、-OR 4、-C(O)R 5、-NR 6C(O)R 7、-CH 2NR 8R 9、-C(O)NR 8R 9
    Figure PCTCN2021135230-appb-100002
    或-NR 8R 9;其中,所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自R 10的取代基所取代;
    R 2 is selected from halogen, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, -OR 4 , -C(O)R 5 , -NR 6 C(O)R 7 , -CH 2 NR 8 R 9 , -C(O)NR 8 R 9 ,
    Figure PCTCN2021135230-appb-100002
    or -NR 8 R 9 ; wherein, the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from R 10 ;
    R 3选自氢原子、C 1-C 6烷基、C 1-C 3烷氧基、C 3-C 10环烷基、5-10元杂芳基或-C(O)R 5;其中,所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自R 10的取代基所取代; R 3 is selected from hydrogen atom, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl or -C(O)R 5 ; wherein , the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are optionally further substituted by one or more substituents selected from R 10 ;
    R 4选自氢原子、C 1-C 6烷基、C 3-C 6环烷基或4-11元杂环基;其中所述的烷基或环烷基任选进一步被一个或多个选自氘原子、羟基、卤素、氰基、C 1-C 6烷基、C 1-C 6烷氧基、杂环基、=O、-N(CH 3) 2或-N(C 2H 5) 2的取代基所取代;所述的4-11元杂环基任选进一步被一个或多个选自羟基、卤素、氰基、C 1-C 6烷氧基或=O的取代基所取代; R 4 is selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a 4-11 membered heterocyclic group; wherein the alkyl or cycloalkyl group is optionally further modified by one or more selected from deuterium atom, hydroxyl, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, heterocyclyl, =O, -N( CH3 ) 2 or -N( C2H 5 ) substituted by the substituent of 2 ; the 4-11-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, C 1 -C 6 alkoxy or =O replaced;
    R 5各自独立地选自C 1-C 6烷基、C 3-C 6环烷基、4-11元杂环基、-NR 8R 9;其中所述的烷基、环烷基或杂环基任选进一步被一个或多个选自羟基、卤素、氰基、氨 基、C 1-C 6烷氧基的取代基所取代; R 5 is each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-11 membered heterocyclyl, -NR 8 R 9 ; wherein said alkyl, cycloalkyl or heterocyclyl The cyclic group is optionally further substituted with one or more substituents selected from hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy;
    R 6选自氢、C 1-C 3烷基或C 3-C 6环烷基; R 6 is selected from hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl;
    R 7选自C 1-C 6烷基、C 3-C 6环烷基、C 6-C 10芳基、5-10元杂芳基或4-11元杂环基;其中所述的烷基、环烷基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、氰基、氨基、C 1-C 6烷氧基的取代基所取代;所述的杂环基任选进一步被一个或多个选自羟基、卤素、氰基、C 1-C 6烷基、C 3-C 6环氧基、C 1-C 3烷氧基或=O的取代基所取代; R 7 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-10-membered heteroaryl or 4-11-membered heterocyclyl; radical, cycloalkyl, aryl or heteroaryl optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, amino, C 1 -C 6 alkoxy; the heterocycle is optionally further substituted by one or more substituents selected from hydroxy, halogen, cyano, C1 - C6 alkyl, C3 - C6 epoxy, C1 - C3 alkoxy or =O replace;
    R 8和R 9各自独立地选自氢原子或C 1-C 6烷基;其中所述的烷基任选进一步被一个或多个选自羟基、卤素、氰基、氨基、C 1-C 6烷氧基、-N(CH 3) 2、-N(C 2H 5) 2、4-11元杂环基或=O的取代基所取代;所述的4-11元杂环基任选进一步被一个或多个选自羟基、卤素、氰基、C 1-C 6烷基、C 3-C 6环氧基、C 1-C 3烷氧基或=O的取代基所取代; R 8 and R 9 are each independently selected from a hydrogen atom or a C 1 -C 6 alkyl group; wherein said alkyl group is optionally further selected from one or more of hydroxyl, halogen, cyano, amino, C 1 -C 6 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 , 4-11-membered heterocyclic group or a substituent of =O; the 4-11-membered heterocyclic group is any is further substituted with one or more substituents selected from hydroxyl, halogen, cyano, C1 - C6 alkyl, C3 - C6 epoxy, C1 - C3 alkoxy or =O;
    或者,R 8和R 9与它们相连接的原子一起形成一个含N的4-11元杂环基,所述的4-11元杂环基任选进一步被一个或多个=O或R 14的取代基所取代; Alternatively, R 8 and R 9 together with the atoms to which they are attached form an N-containing 4-11 membered heterocyclyl optionally further modified by one or more =O or R 14 substituted by the substituent;
    R 10各自独立地选自卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6羟基烷基、C 3-C 6环烷基、=O、-C(O)R 11或-CH 2C(O)NR 12R 13;其中所述的烷基、烷氧基、羟基烷基或环烷基任选进一步被一个或多个选自卤素、氰基、C 1-C 3烷氧基、-N(CH 3) 2、-N(C 2H 5) 2或4-11元杂环基的取代基所取代;所述的4-11元杂环基任选进一步被一个或多个C 1-C 3烷基或C 1-C 3烷氧基的取代基所取代; R 10 is each independently selected from halogen, cyano, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl , =O, -C(O)R 11 or -CH 2 C(O)NR 12 R 13 ; wherein said alkyl, alkoxy, hydroxyalkyl or cycloalkyl is optionally further modified by one or more substituted with a substituent selected from halogen, cyano, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or 4-11-membered heterocyclic group; the said The 4-11 membered heterocyclyl is optionally further substituted by one or more C 1 -C 3 alkyl or C 1 -C 3 alkoxy substituents;
    R 11选自C 1-C 6烷基或C 3-C 6环烷基;其中所述的烷基或环烷基任选进一步被一个或多个选自卤素、氰基、羟基、C 1-C 3烷氧基、-N(CH 3) 2、-N(C 2H 5) 2或4-11元杂环基的取代基所取代;所述的4-11元杂环基任选进一步被C 1-C 3烷基或C 1-C 3烷氧基所取代; R 11 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected from one or more halogen, cyano, hydroxyl, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or 4-11-membered heterocyclic group substituents; the 4-11-membered heterocyclic group is optional is further substituted by C 1 -C 3 alkyl or C 1 -C 3 alkoxy;
    R 12和R 13各自独立地选自氢、C 1-C 3烷基或C 3-C 6环烷基; R 12 and R 13 are each independently selected from hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl;
    或者,R 12和R 13与它们相连接的原子一起形成含N的4-11元杂环基;其中所述的杂环基任选进一步被一个或多个选自卤素、氰基、羟基、C 1-C 6烷氧基、C 1-C 6羟基烷基、C 1-C 6含卤烷基、C 3-C 6环烷基或=O的取代基所取代; Alternatively, R 12 and R 13 together with the atoms to which they are attached form an N-containing 4-11 membered heterocyclic group; wherein said heterocyclic group is optionally further selected from one or more groups selected from halogen, cyano, hydroxyl, substituted by C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or a substituent of =O;
    R 14选自卤素、羟基、氰基、氨基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6羟基烷基或-C(O)R 15;其中所述的烷基、烷氧基或羟基烷基任选进一步被一个或多个选自卤素、C 1-C 3烷氧基、-N(CH 3) 2、-N(C 2H 5) 2R 14 is selected from halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl or -C(O)R 15 ; wherein said The alkyl, alkoxy or hydroxyalkyl groups are optionally further substituted by one or more selected from halogen, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 ,
    Figure PCTCN2021135230-appb-100003
    的取代基所取代;
    Figure PCTCN2021135230-appb-100003
    substituted by the substituent;
    R 15选自C 1-C 6烷基或C 3-C 6环烷基;其中所述烷基或环烷基任选进一步被一个或多个选自卤素、羟基、氰基、C 1-C 3烷氧基、-N(CH 3) 2、-N(C 2H 5) 2或4-11元杂环基的取代基所取代; R 15 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected by one or more selected from halogen, hydroxyl, cyano, C 1 - C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or substituents of 4-11-membered heterocyclic groups;
    m为1、2或3。m is 1, 2 or 3.
  2. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(II-1)、(II-2)、(II-3)所示的化合物或其立体异构体、互变异构体或其可药用的盐:The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (II-1), (II-2) ), the compound shown in (II-3) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
    Figure PCTCN2021135230-appb-100004
    Figure PCTCN2021135230-appb-100004
    其中:R 1、R 2、R 3和m的定义如权利要求1中所述。 wherein: R 1 , R 2 , R 3 and m are as defined in claim 1 .
  3. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(III)所示的化合物或其立体异构体、互变异构体或其可药用的盐:The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a stereoisomer thereof Isomers, tautomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2021135230-appb-100005
    Figure PCTCN2021135230-appb-100005
    其中:in:
    环B选自C 3-C 10环烷基、4-11元杂环基、C 6-C 10芳基或5-10元杂芳基; Ring B is selected from C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;
    n选自0、1、2、3或4;n is selected from 0, 1, 2, 3 or 4;
    环A、R 1、R 3、R 10和m的定义如权利要求1中所述。 Rings A, R 1 , R 3 , R 10 and m are as defined in claim 1 .
  4. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体或 其可药用的盐,其为通式(IV-1)、(IV-2)所示的化合物或其立体异构体、互变异构体或其可药用的盐:The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (IV-1), (IV-2) ) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
    Figure PCTCN2021135230-appb-100006
    Figure PCTCN2021135230-appb-100006
    其中:环A、R 1、R 3、R 6、R 7、R 8、R 9和m的定义如权利要求1中所述。 wherein: ring A, R 1 , R 3 , R 6 , R 7 , R 8 , R 9 and m are as defined in claim 1 .
  5. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(V)所示的化合物或其立体异构体、互变异构体或其可药用的盐:The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V) or a stereoisomer thereof Isomers, tautomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2021135230-appb-100007
    Figure PCTCN2021135230-appb-100007
    其中:环A、R 1、R 3、R 4和m的定义如权利要求1中所述。 wherein: Rings A, R 1 , R 3 , R 4 and m are as defined in claim 1 .
  6. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(VI-1)、(VI-2)、(VI-3)或(VI-4)所示的化合物或其立体异构体、互变异构体或其可药用的盐:The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (VI-1), (VI-2) ), (VI-3) or (VI-4) compounds or their stereoisomers, tautomers or their pharmaceutically acceptable salts:
    Figure PCTCN2021135230-appb-100008
    Figure PCTCN2021135230-appb-100008
    其中:in:
    环A、R 1、R 3、R 8、R 9和m的定义如权利要求1中所述。 Rings A, R 1 , R 3 , R 8 , R 9 and m are as defined in claim 1 .
  7. 根据权利要求3所述的通式(III)所示的化合物或其立体异构体、互变异构体或其可药用的盐,其中:The compound represented by the general formula (III) according to claim 3 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein:
    Figure PCTCN2021135230-appb-100009
    选自以下基团:
    Figure PCTCN2021135230-appb-100009
    selected from the following groups:
    Figure PCTCN2021135230-appb-100010
    Figure PCTCN2021135230-appb-100010
    其中:R 10和n的定义如权利要求1中所述。 wherein: R 10 and n are as defined in claim 1.
  8. 根据权利要求1~7中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中所述的化合物为:The compound according to any one of claims 1 to 7 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is:
    Figure PCTCN2021135230-appb-100011
    Figure PCTCN2021135230-appb-100011
    Figure PCTCN2021135230-appb-100012
    Figure PCTCN2021135230-appb-100012
  9. 一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1~8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合物。A pharmaceutical composition containing an effective dose of the compound according to any one of claims 1 to 8 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers, excipients or their combinations.
  10. 根据权利要求1~8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求9所述的药物组合物在制备SOS1抑制剂中的用途。The compound according to any one of claims 1 to 8 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of SOS1 inhibitors use in.
  11. 根据权利要求1~8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求9所述的药物组合物在制备治疗由SOS1介导的疾病的药物中的用途,其中所述的由SOS1介导的疾病优选为RAS家族蛋白信号传导通路依赖性相关的癌症、SOS1突变导致的癌症或SOS1突变导致的遗传性疾病。The compound according to any one of claims 1 to 8 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 is prepared for the treatment of SOS1 The use in medicine for mediated diseases, wherein the diseases mediated by SOS1 are preferably RAS family protein signaling pathway-dependent related cancers, cancers caused by SOS1 mutations, or genetic diseases caused by SOS1 mutations.
  12. 根据权利要求11所述的用途,其中所述的由SOS1介导的疾病选自胰腺癌、肺癌、结肠直肠癌、胆管上皮癌、多发性骨髓瘤、黑色素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、子宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞性白血病、肝细胞癌、乳癌、卵巢癌、前列腺癌、成胶质细胞瘤、肾癌及肉瘤。The use according to claim 11, wherein the disease mediated by SOS1 is selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, Thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma , breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma.
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