Classifications

• • 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
• • 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
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to a novel pyrimidine-4(3H)-one heterocyclic compound or a pharmaceutically acceptable salt thereof that regulates or inhibits the activity of SHP2, a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, and
• the method for preparing the compound or its pharmaceutically acceptable salt and the compound or its pharmaceutically acceptable salt or a pharmaceutical composition containing the compound or its pharmaceutically acceptable salt are prepared for the treatment and/or prevention of SHP2
• SHP2 (Src Homology 2 domain-containing Phosphatase 2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 (Protein Tyrosine Phosphatase Nonreceptor type 11) gene.
• SHP2 contains two SH2 domains (Src Homology domain), a PTP domain (Protein Tyrosine Phosphatase domain) and a C-terminal tail. Under normal conditions, SHP2 is in a self-inhibitory conformation, and its N-SH2 binds to PTP, blocking the substrate channel at the catalytic site of PTP, thereby inhibiting the activity of PTP.
• SH2 binds to bisphosphotyrosine peptides (such as IRS-1)
• the autoinhibitory interaction of SH2-PTP is released, PTP catalytic sites are exposed, SHP2 is activated, and tyrosine dephosphorylation is catalyzed reaction.
• SHP2 is widely expressed. As an oncogene, it mediates the activation of a variety of cancer-causing signal transduction channels, such as the RAS-ERK, PI3K-AKT and JAK-STAT pathways, and promotes the survival and proliferation of cancer cells. SHP2 can bind to and dephosphorylate RAS, increase RAS-RAF association, and activate downstream cell proliferation signals. SHP2 also mediates the compensatory activation pathway after MEK and other kinases are inhibited, thereby promoting tumor resistance (Ruess DA, et al., Nat. Med. 2018, 24, 954-960). Therefore, the activation of SHP2 is closely related to the occurrence of many diseases, such as leukemia, melanoma, breast cancer, lung cancer, colon cancer, neuroblastoma, hepatocellular carcinoma and so on.
• diseases such as leukemia, melanoma, breast cancer, lung cancer, colon cancer, neuroblastoma, hepatocellular carcinoma and so on.
• SHP2 also plays an important role in the immune checkpoint channel of PD-1 and BTLA (B-and T-Lymphocyte Attenuator), not only inhibiting T-cell activation but also promoting T-cell disability (Li J, et al., Cancer Res. 2015, 75, 508-518).
• SHP2 As an anti-tumor target, SHP2 has attracted a lot of attention.
• the SHP2 catalytic site inhibitor Due to the high protein sequence homology of the PTP catalytic site and the high hydrophilicity of the PTP catalytic pocket, the SHP2 catalytic site inhibitor has poor selectivity, poor cell permeability, and low bioavailability.
• the discovery of Novartis allosteric inhibitor SHP099 (Chen Y, et al., Nature 2016, 535, 148-52) provides a new channel for the development of highly specific oral SHP2 inhibitors.
• many companies have published some patent applications for SHP2 inhibitors, including WO2015107495, WO2016203405, WO2018057884, WO2018013597, WO2017211303, etc.
• the present invention designs a compound having a structure represented by the general formula (I), and finds that the compound having such a structure exhibits an excellent SHP2 activity inhibitory effect.
• the present invention provides a compound represented by general formula (I) or its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers and mixtures thereof as SHP2 inhibitors:
• Ring A is a benzene ring or a 6-membered heteroaromatic ring
• ring B is a 5-membered heteroaromatic ring fused with ring A.
• the benzene ring and heteroaromatic ring are optionally selected from D, halogen, and cyano.
• R 1 is H, D, cyano, C 1-2 alkyl, cyclopropyl, -OR a , -NR a R b or -C(O)NR a R b , the alkyl and cyclopropyl
• One or more hydrogens are optionally substituted by one or more D or fluorine;
• R 2 is H, C 1-2 alkyl or cyclopropyl, one or more hydrogens of said alkyl and cyclopropyl are optionally substituted by one or more selected from D, fluorine or hydroxyl;
• R 4a and R 4b are each independently selected from H, D, halo, cyano, -OR a, -NR a R b , -C (O) R a, -C (O) NR a R b, C 1- 6 alkyl group, C 3-6 cycloalkyl group, 4-7 membered heterocyclic group or 5-6 membered heteroaryl group, but R 4a and R 4b cannot be cyano, -OR a or -NR a R b at the same time,
• the alkyl group, cycloalkyl group, heterocyclic group and heteroaryl group are optionally selected by one or more selected from D, halogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered heteroaryl group, -OR a , -NR a R b , -C(O)R a or -C(
• R 5a , R 5b , R 6a and R 6b are each independently selected from H, D, fluorine or methyl;
• R a and R b are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group, said alkyl, cycloalkyl and heterocyclic group are optionally selected by One or more substituents selected from D, fluorine, cyano, oxo, hydroxyl, -OCH 3 or -NH 2 are substituted.
• One embodiment of the present invention relates to the compound represented by the above general formula (I) or its pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, which are described in the general formula (II)
• Ring A is a benzene ring or a 6-membered heteroaromatic ring
• ring B is a 5-membered heteroaromatic ring fused with ring A.
• the benzene ring and heteroaromatic ring are optionally selected from D, halogen, and cyano.
• R 1 is H, D, cyano, C 1-2 alkyl, -OR a or -NR a R b , and one or more hydrogens of the alkyl group are optionally substituted by one or more D or fluorine;
• R 2 is H or C 1-2 alkyl, one or more hydrogens of the alkyl are optionally substituted by one or more D or fluorine;
• R 4a and R 4b are each independently selected from H, D, halogen, cyano, -OR a , -NR a R b , -C(O)NR a R b , C 1-6 alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or 5-6 membered heteroaryl, but R 4a and R 4b cannot be cyano, -OR a or -NR a R b at the same time, the alkyl, cycloalkyl , Heterocyclyl and heteroaryl are optionally selected by one or more selected from D, halogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -OR a , -NR a R b , -C(O)R a or -C(O)NR a R b substituents; R 4a and
• R a and R b are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group, said alkyl, cycloalkyl and heterocyclic group are optionally selected by One or more substituents selected from D, fluorine, cyano, oxo, hydroxyl, -OCH 3 or -NH 2 are substituted.
• Another embodiment of the present invention relates to the compound represented by the above general formula (I) or its pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, which are represented by the general formula (III)
• Ring A is a benzene ring or a 6-membered heteroaromatic ring
• ring B is a 5-membered heteroaromatic ring fused with ring A.
• the benzene ring and heteroaromatic ring are optionally selected from D, halogen, and cyano.
• X is -O- or -CR 8a R 8b -;
• R 1 is H, D, cyano, C 1-2 alkyl or -NR a R b , and one or more hydrogens of the alkyl group are optionally substituted by one or more D or fluorine;
• R 2 is H or C 1-2 alkyl, one or more hydrogens of the alkyl are optionally substituted by one or more D or fluorine;
• R 7a , R 7b , R 8a , R 8b , R 9a and R 9b are each independently selected from H, D, halogen, cyano, C 1-2 alkyl or -OR c , one or more of the alkyl groups Each hydrogen is optionally substituted by one or more selected from D, fluorine or hydroxyl, but R 7a and R 7a , R 8a and R 8b , R 9a and R 9b optionally cannot be -OR c at the same time;
• R a and R b are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocyclic group, said alkyl, cycloalkyl and heterocyclic group are optionally selected by One or more substituents selected from D, fluorine, cyano, oxo, hydroxyl, -OCH 3 or -NH 2 ;
• R c is H or C 1-2 alkyl, and one or more hydrogens of the alkyl are optionally substituted by one or more D or fluorine.
• Another embodiment of the present invention relates to the compound represented by the above general formula (I) or its pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, which are represented by the general formula (IV)
• Ring A is a benzene ring or a 6-membered heteroaromatic ring
• ring B is a 5-membered heteroaromatic ring fused with ring A.
• the benzene ring and heteroaromatic ring are optionally selected from D, halogen, and cyano. , Oxo, C 1-2 alkyl, -OR a or -NR a R b substituents, wherein one or more hydrogens of the alkyl group are optionally substituted by one or more D or fluorine;
• X is -O- or -CH 2 -;
• R 1 is independently selected from H, D, C 1-2 alkyl or -NR a R b , one or more hydrogens of the alkyl group are optionally substituted by one or more D or fluorine;
• R 2 is H or a C 1-2 alkyl group, one or more hydrogens of the alkyl group are optionally substituted by one or more D or fluorine;
• R 7 is H, D or C 1-2 alkyl, one or more hydrogens of said alkyl are optionally substituted by one or more D or fluorine;
• R a and R b are each independently H or C 1-2 alkyl, and one or more hydrogens of the alkyl group are optionally substituted with one or more D or fluorine.
• the present invention further relates to the compound represented by the above general formula (I), wherein the compound is selected from:
• the compound of the present invention can effectively inhibit the activity of SHP2, and preferably has an IC 50 of less than 50 nM.
• the compound of the present invention has a significant inhibitory effect on the proliferation of NCI-H358 cells, and preferably its IC 50 is less than 1000 nM.
• Another aspect of the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof Forms and pharmaceutically acceptable carriers and excipients.
• the present invention further relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, and at least An additional drug, wherein the at least one additional drug includes, but is not limited to, chemotherapeutic drugs, targeted drugs, DNA synthesis inhibitors, antibody drugs, antibody drug conjugates, anti-tumor drugs, immunosuppressants, and the like.
• Another aspect of the present invention also relates to the compound represented by the general formula (I) or its pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, or the pharmaceutical composition in the preparation of medicines
• the drug is used to treat or prevent SHP2-mediated related diseases, wherein the diseases include but are not limited to leukemia, Noonan syndrome, leopard spot syndrome, neuroblastoma, lung cancer, breast cancer, colon cancer , Esophageal cancer, stomach cancer, head and neck cancer, etc.
• the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, freeze-dried preparations, injections and the like.
• the pharmaceutical preparation of the present invention can be administered in the form of a dosage unit containing a predetermined amount of active ingredient per dosage unit.
• a dosage unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and particularly preferably 5 mg to 500 mg of the compound of the present invention according to the condition to be treated, the method of administration, and the age, weight and condition of the patient.
• methods known in the pharmaceutical field can be used to prepare this type of pharmaceutical preparations, such as mixing the active ingredient with one or more excipients and/or adjuvants.
• compositions of the present invention may be suitable for administration by any desired suitable method, such as oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (Including subcutaneous, intramuscular, intravenous or intradermal) method of administration.
• oral including oral or sublingual
• rectal including oral or sublingual
• nasal including oral, sublingual or transdermal
• vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
• C xy means the range of carbon atoms, where x and y are both integers, for example, C 3-8 cycloalkyl means a cycloalkyl group with 3-8 carbon atoms, that is, with 3, 4, 5, 6, Cycloalkyl groups of 7 or 8 carbon atoms. It should also be understood that “C 3-8 "also includes any sub-range therein, such as C 3-7 , C 3 6 , C 4-7 , C 4-6 , C 5-6 and the like.
• Alkyl refers to a saturated linear or branched hydrocarbon group containing 1 to 20 carbon atoms, for example, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
• alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl Group, 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-dimethylbutyl, 1,3-Dimethylbutyl, 2-ethylbutyl, etc.
• Cycloalkyl or carbocyclic refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms.
• the cycloalkyl group may be a single carbon ring, and usually contains 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms.
• Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
• Cycloalkyl groups can also be fused, bridged or spiro-bonded bi- or tricyclic rings, such as decahydronaphthyl, bicyclo[2.2.2]octane, spiro[3.3]heptane and the like.
• Heterocyclic group or heterocyclic ring refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group, which includes 3 to 20 ring atoms, for example, 3 to 14, 3 to 12, 3 to 10 1, 3 to 8, 3 to 6, or 5 to 6 ring atoms, of which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include The ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
• It preferably includes 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, more preferably 4 to 7 ring atoms, more preferably 4 to 6 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4 It is a heteroatom, more preferably 1 to 3 are heteroatoms, and most preferably 1 to 2 are heteroatoms.
• Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, oxbutanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorphyl Linyl, homopiperazinyl, azetidine, etc.
• Polycyclic heterocyclic groups include fused, bridged or spiro heterocyclic groups, such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 3,8- Diazabicyclo[3.2.1]octane, 5-azaspiro[2.4]heptane, 2-oxa-7-azaspiro[3.5]nonane, etc.
• Aryl or aromatic ring refers to an aromatic monocyclic or condensed polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, and most preferably phenyl.
• the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
• Non-limiting examples include:
• Heteroaryl or heteroaromatic ring refers to a heteroaromatic system containing 5 to 14 ring atoms, where 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably heteroaryl is 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrakis Azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and the like.
• the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples
• Halogen refers to fluorine, chlorine, bromine or iodine.
• Cyano refers to -CN.
• heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the expression includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
• substitution means that one or more hydrogen atoms in the group, preferably 5, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
• the substituents include, but are not limited to, halogen, cyano, nitro, oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclic group, phenyl, 5 -6-membered heteroaryl and so on.
• “Isomers” refer to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called “stereoisomers”. Stereoisomers include optical isomers, geometric isomers and conformational isomers.
• the compounds of the present invention may exist in the form of optical isomers.
• Optical isomers include enantiomers and diastereomers.
• Enantiomers means that two stereoisomers are mirror images of each other but not superimposable with each other.
• a racemic mixture or racemate refers to a mixture of equal numbers of left and right enantiomers of a chiral molecule.
• Diastereoisomers means that two stereoisomers are not mirror images of each other and cannot be superimposed.
• optical isomer When the optical isomer is a single isomer and its absolute configuration is determined, it is the absolute configuration of "R” or “S” according to the configuration of the substituent on the chiral carbon atom; when the absolute configuration of the optical isomer The configuration is not determined, and it is (+) or (-) according to the measured optical rotation value.
• Methods of preparing and separating optical isomers are known in the art.
• the compounds of the present invention may also exist in geometric isomers.
• the present invention considers various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around a carbon-carbon double bond or carbon-nitrogen bond are designated as Z or E configuration, and substituents around a cycloalkyl or heterocyclic ring are designated as cis or trans configuration.
• the compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.
• the present invention includes any tautomeric or stereoisomeric forms and mixtures thereof, and is not limited to any one of the tautomeric or stereoisomeric forms used in the naming or chemical structural formula of the compound.
• isotopes refer to all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms that have the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as but not limited to 2 H(D), 3 H, 13 C, 14 C, 15 N, respectively , 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
• the isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples using appropriate isotope-labeled reagents instead of non-isotopically-labeled reagents. Such compounds have various potential uses, for example as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
• Deuterium (D) is a preferred isotope of the present invention. For example, hydrogen in methyl, methylene or methine can be replaced by deuterium.
• the compounds of the present invention can be administered in the form of prodrugs.
• Prodrug refers to a derivative of the biologically active compound of the invention that is converted into a derivative of the biologically active compound of the present invention under physiological conditions in the living body, for example, by oxidation, reduction, hydrolysis, etc. (each of them utilizes enzymes or is performed without the participation of enzymes).
• prodrugs are compounds in which the amino group in the compound of the present invention is acylated, alkylated or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or
• the hydroxyl group is acylated, alkylated, phosphorylated or converted into borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy Or wherein the carboxyl group is esterified or amidated, or wherein the sulfhydryl group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to the target and/or to the cytosol of the cell.
• a carrier molecule such as a peptide
• “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to salts made from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids.
• the present invention also includes their corresponding pharmaceutically acceptable salts. Therefore, the compounds of the invention containing acidic groups can exist in the form of salts and can be used in accordance with the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids.
• the compounds of the present invention containing basic groups can exist in the form of salts and can be used in the form of their addition salts with inorganic or organic acids according to the present invention.
• suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propylene Acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, Adipic acid and other acids known to those skilled in the art.
• the present invention also includes internal salts or betaines in addition to the salt forms mentioned.
• Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting these with organic or inorganic acids or bases in a solvent or dispersant or by anion exchange or cation exchange with other salts.
• “Pharmaceutical composition” refers to containing one or more of the compounds described herein or their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, and other components such as pharmaceutically acceptable carriers And excipients.
• the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
• terapéuticaally effective amount refers to the amount of the compound of the present invention that can effectively inhibit the function of SHP2 and/or treat or prevent the disease.
• patient refers to mammals, especially humans.
• the present invention also provides a method for preparing the compound.
• the preparation of the compound of the general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way.
• the compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and the methods of the present invention can be used.
• the product obtained in each step of the reaction is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation and the like.
• the starting materials and chemical reagents required for synthesis can be conventionally synthesized or purchased according to literature (available on SciFinder).
• the heterocyclic compound of the general formula (I) of the present invention can be synthesized according to the route described in Method A: 1) A1 is substituted with NH in piperidine compound A2 under base catalysis or condensation reaction with a condensing agent to obtain an intermediate A3; 2) A3 then reacts with the sulfhydryl group on the 5,6-fused heteroaromatic ring through Buchwald coupling reaction to produce the product A4.
• the type of heterocyclic compounds described by the general formula (I) of the present invention can be synthesized according to the route described in Method B: 1) A1 and A2a undergo substitution reaction under base catalysis or condensation reaction with a condensing agent to obtain intermediate A3a; 2) The ketone group in A3a and (R)-2-methylpropane-2-sulfinamide undergo reductive amination to form A5a; 3) A5a and the sulfhydryl group on the 5,6-fused heteroaromatic ring are formed by Buchwald coupling reaction A6a; 4) A6a is deprotected in an acidic environment to obtain product A4a.
• the starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Coupling Chemicals And other chemical companies.
• the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
• NMR nuclear magnetic resonance
• MS mass spectrometry
• DMSO-d 6 deuterated dimethyl sulfoxide
• CDC1 3 deuterated chloroform
• CD 3 OD deuterated methanol
• the internal standard is Tetramethylsilane (TMS)
• TMS Tetramethylsilane
• ESI Agilent SQD mass spectrometer
• HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Poroshell120EC-C18, 50 ⁇ 3.0mm, 2.7 ⁇ m column) or Waters Arc high pressure liquid chromatograph (Sunfire C18, 150 ⁇ 4.6mm, 5 ⁇ m column).
• reaction temperature is room temperature (20-30°C).
• the reactions are all carried out under an argon atmosphere or a nitrogen atmosphere.
• the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
• the hydrogen atmosphere means that the reaction flask is evacuated and then filled with hydrogen (repeated 3 times), and then a hydrogen balloon with a volume of about 1L is connected.
• the microwave reaction uses a CEM Discover-SP type microwave reactor.
• the monitoring of the reaction process in the examples uses Agilent liquid mass spectrometry (1260/6120), or thin layer chromatography (TLC), and the thickness of the silica gel plate used is 0.15-0.2 mm (Qingdao Ocean GF254).
• the compound is purified by column chromatography or thin layer chromatography, wherein the column chromatography uses Qingdao Ocean’s 200-300 mesh silica gel, and the thin layer chromatography uses Qingdao Ocean’s GF254 silica gel plate with a thickness of 0.4 to 0.5 mm.
• Column chromatography or thin layer chromatography developing solvent system usually has a) dichloromethane and methanol system, b) petroleum ether and ethyl acetate system, or as shown in the examples.
• the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine or other acidic or alkaline reagents can also be added for further adjustment.
• the purification of the compound also used Waters mass spectrometry guided automatic preparation system (mass detector: SQD2), according to the polarity of the compound, an appropriate acetonitrile/water (containing 0.1% trifluoroacetic acid or formic acid, or 0.05% ammonia) gradient was used in 20mL/ The flow rate of min was used to elute the reversed-phase high pressure column (XBridge-C18, 19 ⁇ 150mm, 5 ⁇ m).
• 1N diluted hydrochloric acid can be added after purification using an automatic preparation system, and then the solvent can be removed under reduced pressure to obtain hydrochloride.
• DMF refers to N,N-dimethylformamide
• DIPEA N,N-diisopropylethylamine
• DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.
• NBS N-bromosuccinimide
• NIS refers to N-iodosuccinimide.
• XantPhos refers to 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene.
• the abbreviation Pd 2 (dba) 3 refers to tris(dibenzylideneacetone)dipalladium.
• Carter condensing agent refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.
• 2,4-Dichloro-5-iodopyrimidine 1a (8.0g, 29.1mmol) was dissolved in tetrahydrofuran (100mL), sodium hydroxide solution (1N, 45mL) was added at 0°C, the reaction mixture was warmed to room temperature and stirred for 16 hours .
• the pH was adjusted to acidity with citric acid, and extraction was performed with ethyl acetate (60 mL ⁇ 3).
• the organic phases were combined and washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, and dissolved under reduced pressure to obtain the target product 1b (6.7 g, solid), yield: 91%.
• a methanol solution (30%, 158 mg, 0.88 mmol) of sodium methoxide (30%, 158 mg, 0.88 mmol) was added to a methanol (20 mL) solution of 1 g (200 mg, 0.8 mmol), and the mixture was stirred at room temperature for 2 hours. Solubility was removed under reduced pressure to obtain the target product for 1 h (100 mg, solid), with a yield of 73%. The product was used directly in the next reaction without purification.
• the organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the solvent was removed under reduced pressure.
• Potassium tert-butoxide (204 mg, 1.82 mmol) was added to the solution of 2b (240 mg, 0.91 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 2 hours. It was acidified to pH 4 with hydrochloric acid (6N), and extracted with ethyl acetate (20 mL). The organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and desolventized under reduced pressure to obtain the target product 2c (130 mg, solid), yield: 87%.
• a methanol solution (30%, 443.5 mg, 2.46 mmol) of sodium methoxide (30%, 443.5 mg, 2.46 mmol) was added to a methanol (20 mL) solution of 3b (560 mg, 2.24 mmol), and the mixture was stirred at 30°C for 1 hour. Solubility was removed under reduced pressure to obtain the target product 3c (200 mg, solid), yield: 51%. The product was used directly in the next reaction without purification.
• a methanol solution (30%, 182 mg, 1.01 mmol) of sodium methoxide (30%, 182 mg, 1.01 mmol) was added to a methanol (20 mL) solution of 4d (230 mg, 0.92 mmol), and the mixture was stirred at 30°C for 4 hours. The solvent was removed under reduced pressure to obtain the target product 4e (150 mg, solid), with a yield of 95%. The product was used directly in the next reaction without purification.
• a methanol solution (30%, 317 mg, 1.76 mmol) of sodium methoxide (30%, 317 mg, 1.76 mmol) was added to a methanol (20 mL) solution of 5b (400 mg, 1.6 mmol), and the mixture was stirred at room temperature for 2 hours.
• the reaction mixture was poured into water (100 mL), the pH was adjusted to weakly acidic with citric acid, and extracted with ethyl acetate (30 mL ⁇ 3).
• the organic phases were combined and washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure.
• Potassium tert-butoxide (672 mg, 6.0 mmol) was added to the solution of 6b (500 mg, 2.0 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hours. It was acidified to pH 4 with hydrochloric acid (6N) and extracted with dichloromethane (20 mL). The organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure to obtain the target product 6c (300 mg, solid), yield: 100%.
• Trimethyloxonium tetrafluoroborate (733 mg, 4.95 mmol) was added to a solution of 7b (760 mg, 3.3 mmol) in ethyl acetate (15 mL) under ice cooling, and the reaction mixture was stirred at room temperature for 4 hours. Add petroleum ether (30 mL) to dilute, stir for 10 minutes, and filter. The filtrate was added with ethyl acetate (20 mL), and washed with sodium bicarbonate solution (30 mL ⁇ 3) and saturated brine (20 mL ⁇ 3).
• a methanol solution (30%, 93 mg, 0.52 mmol) of sodium methoxide (30%, 93 mg, 0.52 mmol) was added to a methanol (20 mL) solution of 7d (140 mg, 0.47 mmol), and the mixture was stirred at 30°C for 32 hours. The solvent was removed under reduced pressure to obtain the target product 7e (100 mg, solid), with a yield of 96%. The product was used directly in the next reaction without purification.
• a methanol solution (30%, 45.5 mg, 0.25 mmol) of sodium methoxide (30%, 45.5 mg, 0.25 mmol) was added to a methanol (3 mL) solution of 8 g (60 mg, 0.21 mmol), and the mixture was stirred at 30°C for 4 hours. Solubility was removed under reduced pressure to obtain the target product for 8h (40 mg, solid), yield: 92%. The product was directly used in the next reaction without purification.
• a methanol solution (30%, 130 mg, 0.72 mmol) of sodium methoxide (30%, 130 mg, 0.72 mmol) was added to a methanol (20 mL) solution of 9d (195 mg, 0.60 mmol), and the mixture was stirred at 30°C for 16 hours. The solvent was removed under reduced pressure to obtain the target product 9e (220 mg, solid, crude product). The product was used directly in the next reaction without purification.
• Oxalyl chloride (27.6 g, 218.9 mmol) was added dropwise to dichloromethane (500 mL) at -30°C, the temperature was lowered to -78°C, and dimethyl sulfoxide (21.7 g, 278.6 mmol) was added dropwise. After the reaction mixture was stirred at -78°C for 30 minutes, a solution of 10b (35 g, 199 mmol) in dichloromethane (100 mL) was slowly added and stirred for 1 hour. Triethylamine (100.5g, 995mmol) was added dropwise, stirring was continued at -78°C for 30 minutes, and then stirred at room temperature overnight.
• a tetrahydrofuran solution (1M, 193 mL, 193 mmol) of tetrabutylammonium fluoride (1M, 193 mL, 193 mmol) was added to a tetrahydrofuran (400 mL) solution of 10e (55 g, 128.5 mmol), and the mixture was stirred at room temperature for 2 hours.
• Dilute with saturated sodium bicarbonate solution and water (100 mL, 1/2 v/v) add ethyl acetate (200 mL), separate the layers, and extract the aqueous phase with ethyl acetate (200 mL ⁇ 3).
• the reaction mixture 10g (8.5g, 32.9mmol), Dess-Martin oxidant (27.4g, 64.56mmol) and dichloromethane (200mL) were stirred at 0°C for 2 hours.
• Saturated sodium bicarbonate solution and saturated sodium thiosulfate solution (100mL, 1/1v/v) were added, stirred vigorously, and separated.
• the aqueous phase was extracted with dichloromethane (200 mL ⁇ 3).
• the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
• reaction mixture 10j (60mg, 0.15mmol), (R)-2-methylpropane-2-sulfinamide (36.3mg, 0.3mmol), tetraethyl titanate (137mg, 0.6mmol) and tetrahydrofuran (5mL) Heat to 90°C and stir for 4 hours. Cool to 0°C, add methanol (2 mL) and lithium borohydride in tetrahydrofuran (2.0M, 0.15 mL, 0.3 mmol), and stir for 1 hour. Water (5 mL) and dichloromethane (20 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL ⁇ 3).
• the aqueous phase was extracted with dichloromethane (10 mL ⁇ 3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure.
• a tetrahydrofuran solution (1M, 303 mL, 303 mmol) of tetrabutylammonium fluoride (1M, 303 mL, 303 mmol) was added to a solution of 11e (90 g, 223 mmol) in tetrahydrofuran (1300 mL), and the mixture was stirred at room temperature overnight.
• Dilute with saturated sodium bicarbonate solution and water (800 mL, 1/2 v/v) add ethyl acetate (800 mL), separate the layers, and extract the aqueous phase with ethyl acetate (500 mL ⁇ 3).
• Dissolve 12a (86 mg, 0.166 mmol) in methanol (5 mL), add a dioxane solution of hydrogen chloride (4.0 M, 1 mL), and stir at room temperature for 1 hour. Concentrated under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography to obtain the target product 12 (16.8 mg, solid), yield: 19%.
• reaction mixture 1-benzyl-4-methylpiperidine-4-carbonitrile 16a (2g, 9.3mmol), di-tert-butyl dicarbonate (6.1g, 27.9mmol), nickel chloride hexahydrate (2.2g, 9.3 mmol) and methanol (50 mL) were stirred at room temperature for 15 minutes. Cool to 0°C, add sodium borohydride (1.77 g, 46.5 mmol), warm to room temperature, and stir for 8 hours. The solvent was removed under reduced pressure, and the residue was suspended in methylene chloride and filtered.
• reaction mixture 17c (180mg, 0.35mmol), 2c (70mg, 0.42mmol), DIPEA (135mg, 1.05mmol), Pd 2 (dba) 3 (32mg, 0.035mmol), XantPhos (20mg, 0.035mmol) and dioxygen
• Potassium tert-butoxide (224 mg, 2 mmol) was added to a solution of 1 g (250 mg, 1 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 2 hours. It was quenched with water and washed with ethyl acetate. The aqueous phase was acidified to pH 4 with hydrochloric acid (6N) and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure to obtain the target product 18a (100 mg, solid), yield: 67%.
• reaction mixture 17c (180mg, 0.35mmol), 18a (63mg, 0.42mmol), DIPEA (135mg, 1.05mmol), Pd 2 (dba) 3 (32mg, 0.035mmol), XantPhos (20mg, 0.035mmol) and dioxy
• Recombinant human SHP2 full-length protein was expressed and purified by Tsinghua University's protein purification and identification platform, and the double phosphorylated polypeptide (H2N-LN(pY)IDLDLV-(dPEG8)LST(pY)ASINFQK-amide) was synthesized by GenScript Biotechnology Co., Ltd.
• the alternative substrate DiFMUP was purchased from Thermo Fisher Scientific (Cat. No. D6567).
• the reaction buffer contains the following components: 60mM HEPES (pH 7.2), 75mM NaCl, 75mM KCl, 1mM EDTA, 0.05% TWEEN 20, and 5mM DTT.
• the compound was dissolved and diluted to 100 ⁇ M in DMSO (Sigma, product number D5879), and then serially diluted with DMSO to the lowest concentration of 6.1 nM by 4 times, and then diluted 25 times with reaction buffer at each concentration point.
• DMSO Sigma, product number D5879
• the fluorescence signal value is positively correlated with the degree of dephosphorylation of the substrate, which reflects the catalytic activity of SHP2 phosphatase.
• the experiment not added as 100% inhibition proteome group, but did not increase protein plus compound group group as 0% inhibition, compound using XLfit software drawing inhibition curves and calculate their IC 50 inhibition, the experimental results shown in Table.
• the example compounds of the present invention have an inhibitory effect on the activity of SHP2, and preferably IC 50 is less than 50 nM.
• the luminescent cell viability test was used to evaluate the effects of the compounds of the present invention on the proliferation of NCI-H358 human non-small cell lung cancer cells.
• the compound was dissolved and diluted to 5mM in DMSO (Sigma, catalog number D5879), and then a 4-fold serial dilution was performed with DMSO to the lowest concentration of 0.31 ⁇ M, and RPMI 1640 medium (Thermo Fisher Scientific, catalog number) was used for each concentration point. 11995073) diluted 50 times. If the compound IC 50 value is low, the initial concentration of the compound can be reduced.
• NCI-H358 ATCC, catalog number CRL-5807 cells are cultured in RPMI 1640 complete medium [RPMI 1640 medium contains 10% FBS (GBICO, catalog number 10099-141) and 100 units/mL penicillin streptomycin mixture (Thermo Fisher Scientific, catalog number 15140122)].
• the compounds of the examples of the present invention have an inhibitory effect on cell proliferation, and preferably IC 50 is less than 1000 nM.
• the effect of the compounds of the present invention on possible arrhythmias was evaluated by measuring the blocking effect on the hERG potassium ion channel.
• Compound solution Dissolve the test compound in DMSO and make a 10 mM stock solution, then dilute it to 3 mM with DMSO, and then dilute it to a 3 ⁇ M solution with extracellular fluid for subsequent use.
• HEK293 cell line (Creacell, product number A-0320) stably overexpressing hERG potassium channels contains 10% fetal bovine serum (Gibco, product number 1428478) and 0.8 mg/mL G418 (Amresco, product number E859-5G).
• DMEM medium Gibco, catalog number 1009-141
• PBS Gibco, catalog number 1009-141
• TrypLE TM Express solution (Gibco, catalog number 12604021), and incubate at 37°C for 30 seconds.
• Whole-cell patch clamp voltage stimulation scheme for recording the whole-cell hERG potassium current when the whole-cell seal is formed, the cell membrane voltage is clamped to -80mV.
• the clamping voltage is depolarized from -80mV to -50mV and maintained for 0.5 seconds (as a leakage current detection), then stepped to 30mV and maintained for 2.5 seconds, and then quickly restored to -50mV and maintained for 4 seconds to excite the tail current of the hERG channel ( Peak tail current), the hERG potassium current is recorded every 10 seconds.
• the experimental data is collected by EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA v2x73) software.
• Sutter Instruments is used to draw a capillary glass tube (Sutter Instruments) into a recording electrode.
• the coverslip with the cells is removed from the 24-well plate placed in the incubator, and then placed under an inverted microscope.
• the whole-cell recording mode perform slow capacitance compensation and record the membrane capacitance and series resistance, during which no leakage compensation is given.

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