WO2022160931A1 - Dérivé de pyridopyrimidine, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyridopyrimidine, son procédé de préparation et son utilisation Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
ethyl
alkoxy
general formula
Prior art date
Application number
PCT/CN2021/135230
Other languages
English (en)
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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/zh
Publication of WO2022160931A1 publication Critical patent/WO2022160931A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de pyridopyrimidine substitué, son procédé de préparation, et l'utilisation d'une composition pharmaceutique contenant le dérivé en médecine. En particulier, la présente invention concerne un dérivé de pyridopyrimidine substitué représenté par la formule générale (I), un procédé de préparation associé, un sel pharmaceutiquement acceptable de celui-ci, et l'utilisation de ceux-ci en tant qu'agents thérapeutiques, en particulier en tant qu'inhibiteurs de SOS1, la définition de chaque substituant dans la formule générale (I) étant la même que celle dans la description.
PCT/CN2021/135230 2021-01-28 2021-12-03 Dérivé de pyridopyrimidine, son procédé de préparation et son utilisation WO2022160931A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180081504.9A CN116546985A (zh) 2021-01-28 2021-12-03 吡啶并嘧啶类衍生物及其制备方法和用途

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202110116295 2021-01-28
CN202110116295.9 2021-01-28
CN202110641104 2021-06-09
CN202110641104.0 2021-06-09

Publications (1)

Publication Number Publication Date
WO2022160931A1 true WO2022160931A1 (fr) 2022-08-04

Family

ID=82652956

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/135230 WO2022160931A1 (fr) 2021-01-28 2021-12-03 Dérivé de pyridopyrimidine, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN116546985A (fr)
WO (1) WO2022160931A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11648254B2 (en) 2021-03-02 2023-05-16 Kumquat Biosciences Inc. Substituted pyrido[2,3-d]pyrimidines as inhibitors of Ras pathway signaling
WO2024027762A1 (fr) * 2022-08-05 2024-02-08 上海艾力斯医药科技股份有限公司 Composé à cycles fusionnés, son procédé de préparation et son utilisation
US11912708B2 (en) 2022-04-20 2024-02-27 Kumquat Biosciences Inc. Macrocyclic heterocycles and uses thereof
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019122129A1 (fr) * 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Nouvelles pyridopyrimidinones à substitution benzylamino et dérivés à utiliser en tant qu'inhibiteurs de sos1
CN113801114A (zh) * 2020-06-11 2021-12-17 江苏恒瑞医药股份有限公司 稠合二环杂芳基类衍生物、其制备方法及其在医药上的应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107400092B (zh) * 2016-05-20 2021-08-24 浙江海正药业股份有限公司 嘧啶类衍生物及其制备方法和其在医药上的用途
JP7219218B2 (ja) * 2016-12-22 2023-02-07 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規のベンジルアミノ置換キナゾリンおよびｓｏｓ１阻害剤としての誘導体
WO2019027765A1 (fr) * 2017-08-02 2019-02-07 Northwestern University Composés de pyrimidine fusionnés substitués et leurs utilisations
MA56020A (fr) * 2019-05-31 2022-04-06 Chiesi Farm Spa Dérivés de pyridopyrimidines utilisés en tant qu'inhibiteurs de p2x3
CN116323623A (zh) * 2020-09-18 2023-06-23 拜耳公司 作为SOS1抑制剂的吡啶并[2,3-d]嘧啶-4-胺
CN114539245A (zh) * 2020-11-26 2022-05-27 上海翰森生物医药科技有限公司 含嘧啶并环类衍生物调节剂、其制备方法和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019122129A1 (fr) * 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Nouvelles pyridopyrimidinones à substitution benzylamino et dérivés à utiliser en tant qu'inhibiteurs de sos1
CN113801114A (zh) * 2020-06-11 2021-12-17 江苏恒瑞医药股份有限公司 稠合二环杂芳基类衍生物、其制备方法及其在医药上的应用

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11648254B2 (en) 2021-03-02 2023-05-16 Kumquat Biosciences Inc. Substituted pyrido[2,3-d]pyrimidines as inhibitors of Ras pathway signaling
US11912708B2 (en) 2022-04-20 2024-02-27 Kumquat Biosciences Inc. Macrocyclic heterocycles and uses thereof
WO2024027762A1 (fr) * 2022-08-05 2024-02-08 上海艾力斯医药科技股份有限公司 Composé à cycles fusionnés, son procédé de préparation et son utilisation
WO2024074827A1 (fr) 2022-10-05 2024-04-11 Sevenless Therapeutics Limited Nouveaux traitements de la douleur

Also Published As

Publication number Publication date
CN116546985A (zh) 2023-08-04

Similar Documents

Publication Publication Date Title
WO2022160931A1 (fr) Dérivé de pyridopyrimidine, son procédé de préparation et son utilisation
EP2920183B1 (fr) Thiéno[3,2-c]pyridin-4(5h)-ones utiles comme inhibiteurs de bet
KR20210018204A (ko) 면역조절제로서 복소환형 화합물
CA3177261A1 (fr) Compose de benzothiazolyle biaryle, son procede de preparation et son utilisation
WO2015127872A1 (fr) Dérivés de 1,5-diamine phénylène 2,4-disubstitués et leurs applications, compositions pharmaceutiques et compositions pharmaceutiquement acceptables préparées à partir de ces dérivés
WO2014140077A1 (fr) Furopyridines utilisées en tant qu'inhibiteurs de bromodomaine
CN111793068A (zh) 杂芳基化合物和其用途
WO2021143701A1 (fr) Composé hétérocyclique de pyrimidine-4(3h)-cétone, son procédé de préparation et son utilisation en médecine et en pharmacologie
CN111094289B (zh) 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用
WO2016173557A1 (fr) Composé ayant une activité d'inhibition de kinase, procédé de préparation et utilisations
KR20170063734A (ko) Mk2 억제제 및 이의 용도
WO2016011979A1 (fr) Dérivé 7h-pyrrolo[2,3-d]pyrimidine 2,4-disubstituté, procédé de préparation et utilisation médicinale de ce dernier
JP6797923B2 (ja) Ａｌｋおよびｓｒｐｋ阻害剤ならびに使用方法
CN109721599B (zh) 一类氨基取代含氮稠环化合物及其制备方法和用途
WO2022135590A1 (fr) Composés pyrimido-hétérocycliques, et leur procédé de préparation et leur utilisation
WO2017101796A1 (fr) Dérivé de phtalazinone, et procédé de préparation et utilisation associés
WO2018010514A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de fgfr
WO2022170952A1 (fr) Dérivé de pyridazinone polycyclique servant d'inhibiteur de sos1, son procédé de préparation et son utilisation
JP2023538091A (ja) Ｂｔｋ阻害剤としての複素環式化合物
CN115427035A (zh) Enl/af9 yeats抑制剂
WO2019085894A1 (fr) Composé cyclique fusionné contenant de l'azote, son procédé de préparation et son utilisation
WO2022105921A1 (fr) Composé pyrimido-hétérocyclique, son procédé de préparation et son utilisation
WO2018205916A1 (fr) Inhibiteur de fgfr4, préparation et utilisation associées
WO2023036252A1 (fr) Dérivé de pyrrolopyrimidine ou de pyrrolopyridine et son utilisation médicale
WO2022127827A1 (fr) Inhibiteur de mutation de protéine krasg12c et son procédé de préparation, composition pharmaceutique et son application

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21922521

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202180081504.9

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21922521

Country of ref document: EP

Kind code of ref document: A1