WO2021057796A1 - 取代的稠合三环衍生物及其组合物及用途 - Google Patents
取代的稠合三环衍生物及其组合物及用途 Download PDFInfo
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- WO2021057796A1 WO2021057796A1 PCT/CN2020/117154 CN2020117154W WO2021057796A1 WO 2021057796 A1 WO2021057796 A1 WO 2021057796A1 CN 2020117154 W CN2020117154 W CN 2020117154W WO 2021057796 A1 WO2021057796 A1 WO 2021057796A1
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- 0 *CC=C(*)c(c(-c1cc2ccccc2nc1)c1C(N)=NC=C)c(*)[n]1N Chemical compound *CC=C(*)c(c(-c1cc2ccccc2nc1)c1C(N)=NC=C)c(*)[n]1N 0.000 description 2
- ZBOJERDRVSBCCB-OAHLLOKOSA-N CC1=C[C@@H](CNC(C=C)=O)Cc2c1c(-c1cnc(cccc3)c3c1)c1[n]2ncnc1N Chemical compound CC1=C[C@@H](CNC(C=C)=O)Cc2c1c(-c1cnc(cccc3)c3c1)c1[n]2ncnc1N ZBOJERDRVSBCCB-OAHLLOKOSA-N 0.000 description 1
- PCBLVUSXBDUGKV-JBZHPUCOSA-N C[C@H](CC(C1)NC(C=C)=O)c(c(-c2cnc(cccc3)c3c2)c23)c1[n]2ncnc3N Chemical compound C[C@H](CC(C1)NC(C=C)=O)c(c(-c2cnc(cccc3)c3c2)c23)c1[n]2ncnc3N PCBLVUSXBDUGKV-JBZHPUCOSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention belongs to the technical field of medicine, and particularly relates to substituted fused tricyclic derivatives with inhibitory effects on mutant epidermal growth factor receptor (EGFR), wild and/or mutant HER2, pharmaceutical compositions containing them, and Their preparation methods and uses.
- EGFR epidermal growth factor receptor
- HER2 mutant epidermal growth factor receptor
- EGFR is a receptor tyrosine kinase that binds to epidermal growth factor (hereinafter also referred to as EGF) as a ligand to exert its physiological functions in normal tissues, and contributes to the inhibition of epithelial tissue growth and apoptosis .
- EGF epidermal growth factor
- somatic mutations of the EGFR gene are oncogenes: for example, EGFR and exons deleted from amino acids 746 to 750 in the region of exon 19 (hereinafter also referred to as "exon 19 deletion mutations”)
- exon 19 deletion mutations The EGFR whose amino acid at position 858 in the 21 region is mutated from leucine to arginine (hereinafter also referred to as "L858R mutation”) continuously induces EGF-independent kinase activity and leads to the growth and survival of cancer cells.
- these mutations are observed in about 30%-50% of non-small cell lung cancers in East Asia, and these mutations are also observed in about 10% of non-small cell lung cancers in Europe and the United States, so they are considered to be one of the causes of cancer. .
- EGFR inhibitors as antitumor agents have been actively carried out and used in the treatment of EGFR mutation-positive lung cancer.
- gefitinib, erlotinib and afatinib exon 19 deletion mutant and L858R mutant EGFR-positive lung cancer have high anti-tumor effects, but their administration at their therapeutic doses can cause digestive tract Side effects such as diseases and skin diseases are generally believed to be attributable to wild-type EGFR.
- point mutations or deletion mutations in exon 18 and point mutations in exon 21 are several rarer EGFR mutations.
- a new EGFR point mutation in lung cancer has been discovered, in which the glycine encoded by codon 719 in exon 18 has been replaced by any amino acid (hereinafter referred to as the G719X mutation), and codon 861 in exon 21 has been Leucine has been replaced by glutamine (hereinafter referred to as the L861Q mutation).
- HER2 (also known as ErbB2) is a receptor tyrosine kinase belonging to the ErbB2 family.
- HER2 is considered to be a proto-oncogene, and gene amplification, mutation, and overexpression of HER2 have been reported in various cancers. It is reported that in these cancer cells with HER2 gene abnormality and overexpression, the signal activation of HER2 and downstream pathways enhances the survival and proliferation signals of cancer cells.
- an inhibitor capable of controlling the kinase activity of HER2 exerts an anti-tumor effect by inhibiting the signal transduction of HER2 and downstream pathways in cancer cells, and therefore, it can be considered that it can be effectively used as a cancer therapeutic agent.
- the present invention provides a new condensed tricyclic derivative and a composition containing the compound and uses thereof, which include exon 20 insertion (exon 20ins) mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19del mutant EGFR, L858R mutant EGFR, exon 19 deletion/T790M mutant EGFR, L858R/T790M mutant EGFR have better inhibitory activity and high It is selective, has no or little inhibitory activity against wild-type EGFR, and has inhibitory activity against wild-type HER2 and/or mutant HER2, thereby providing an anti-tumor inhibitor with low toxic and side effects.
- the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
- Ring A is selected from C 6-14 aryl or 5 to 10 membered heteroaryl
- R is each independently selected from H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
- p is selected from 0, 1, 2, 3, 4 or 5;
- R 1 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group, wherein the C 1 -6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl and 3 to 7 membered heterocyclic group are each independently optionally selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R 2 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl or 5 to 10 membered heteroaryl , Wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group, 3 to 7 membered heterocyclic group, C 6-10 aryl group and 5 to 10 membered heteroaryl group are each independently optionally substituted by one Or more groups selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy; or R 2 and the attached double bond together form a triple bond ;
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl or 5 to 10 membered heteroaryl , Wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group are each independently optionally substituted by one Or more than one group selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy;
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently and optionally one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- X is C(R 4 )(R 4 ');
- Y is C(R 5 )(R 5 ');
- n 0, 1 or 2;
- n 1, 2 or 3;
- R 4 and R 4 ' are each independently selected from H, D, halogen, -CN or C 1-6 alkyl; or R 4 and R 4 ' and the carbon atom to which they are attached form a carbonyl group, C 3-7 cycloalkane Group or 3 to 7 membered heterocyclic group; wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group and 3 to 7 membered heterocyclic group are each independently optionally selected from one or more D , Halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R 5 and R 5 ' are each independently selected from H, D, halogen, -CN or C 1-6 alkyl; or R 5 and R 5 ' and the carbon atom to which they are attached form a carbonyl group, C 3-7 cycloalkane Group or 3 to 7 membered heterocyclic group; wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group and 3 to 7 membered heterocyclic group are each independently optionally selected from one or more D , Halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R a and R b are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7-membered heterocyclic group; or R a , R b and the nitrogen atom to which they are attached form 3 To 7-membered heterocyclic group; wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group and 3 to 7-membered heterocyclic group are each independently optionally selected from D, halogen, -OH, C 1-6 alkyl or C 1-6 alkoxy group substitution;
- the present invention provides a pharmaceutical composition containing the compound of the present invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent Compound, and pharmaceutically acceptable excipients.
- the compound of the invention is provided in a therapeutically effective amount.
- the compound of the present invention is provided in a prophylactically effective amount.
- the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention
- the pharmaceutical composition is used in the preparation of a medicament for the treatment and/or prevention of tumors mediated by mutant EGFR kinase.
- the present invention provides a method for treating and/or preventing a disease in a subject, such as a tumor mediated by a mutant EGFR kinase, comprising administering to the subject a compound of the present invention or its interaction Tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention.
- the mutant EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR.
- the exon 20 insertion mutation is a mutation in which one or more amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is a mutation in which 1 to 7 amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is a mutation in which 1 to 4 amino acids are inserted into the exon 20 region.
- the exon 20 insertion mutation is A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, D770>GY, N771_P772insN, P772_R773insPR, H773_V774ins_V774ins, H773insPR, H773_V774ins_V774ins, H773_H773_H773HinsPR, H773_V774ins_V774ins, H773_VH774ins, H773_VH774ins, H773_H773_H774ins, H773_H773_H774ins_V774ins, H773_H774ins, H773_H774ins, H773_H774ins, H773_
- the exon 18 point mutation is selected from the G719X mutation of exon 18 or the E790X mutation of exon 18.
- the G719X mutation is selected from at least one mutation of G719A, G719S and G719C.
- the E790X mutation is selected from at least one mutation of E790K and E790A.
- the exon 21 point mutation is selected from the L861X mutation of exon 21.
- the L861X mutation is a L861Q mutation.
- the mutated EGFR has a T790M mutation and is selected from the group consisting of exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation, or L858R mutation. At least one mutation.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 20 Tumor patients with inserted mutated EGFR.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with exon 20 insertion mutation of EGFR.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 18 Tumor patients with point mutant EGFR.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with exon 18 point mutation EGFR.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 21 Tumor patients with point mutant EGFR.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Cancer patients with exon 21 point mutant EGFR.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 19 Tumor patients with missing mutant EGFR.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Cancer patients with exon 19 deletion mutant EGFR.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used to treat the expression of L858R mutant EGFR Of cancer patients.
- the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with L858R mutant EGFR.
- the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention
- the use of the pharmaceutical composition of the invention in the preparation of a medicament for the treatment and/or prevention of the following tumors, or the invention provides a method for the treatment and/or prevention of the following tumors in a subject, comprising providing the subject Administration of the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention: lung cancer, breast cancer, Head and neck cancer, brain tumor, uterine cancer, hematopoietic tumor or skin cancer.
- the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention
- the pharmaceutical composition is used in the preparation of a medicament for the treatment and/or prevention of wild and/or mutant HER2 kinase-mediated tumors.
- the present invention provides a method of treating and/or preventing a disease in a subject, such as a wild and/or mutant HER2 kinase-mediated tumor, comprising administering to the subject
- a disease in a subject such as a wild and/or mutant HER2 kinase-mediated tumor
- administering comprising administering to the subject
- the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C Mutant HER2, L755S mutant HER2 or ex20insYVMA mutant HER2.
- the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
- the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention
- the use of the pharmaceutical composition of the invention in the preparation of a medicament for the treatment and/or prevention of the following tumors, or the invention provides a method for the treatment and/or prevention of the following tumors in a subject, comprising providing the subject Administration of the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention: lung cancer, gastric cancer or breast cancer.
- C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
- C 1-6 alkyl group refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and is also referred to herein as a "lower alkyl group”. In some embodiments, C 1-4 alkyl is particularly preferred.
- alkyl group examples include but are not limited to: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert Butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
- each of the alkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
- the appropriate substituents are as follows definition.
- C 1-6 alkoxy refers to the group -OR, where R is a substituted or unsubstituted C 1-6 alkyl group. In some embodiments, C 1-4 alkoxy is particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, N-hexyloxy and 1,2-dimethylbutoxy.
- Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
- the halogen group is F, Cl, or Br.
- the halogen group is F or Cl.
- the halogen group is F.
- C 1-6 haloalkyl and “C 1-6 haloalkoxy” refer to the above-mentioned “C 1-6 alkyl” and “C 1-6 alkoxy", which are substituted by one or more halogen groups. ⁇ Replacement.
- C 1-4 haloalkyl is particularly preferred, and C 1-2 haloalkyl is more preferred.
- C 1-4 haloalkoxy is particularly preferred, and C 1-2 haloalkoxy is more preferred.
- haloalkyl groups include, but the are not limited to: -CF 3, -CH 2 F, -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.
- exemplary halogenated alkoxy groups include, but are not limited to: -OCH 2 F, -OCHF 2 , -OCF 3 , and the like.
- C 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 cycloalkyl is preferred, C 3-6 cycloalkyl is particularly preferred, and C 5-6 cycloalkyl is more preferred. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to indicate The number of carbons in the cycloalkyl system.
- Exemplary cycloalkyl groups include but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene Group (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1] Heptyl (C 7 ), bicyclo[2.2.2]octyl (C 8 ), cyclononyl (C 9 ), cyclononeny
- each of the cycloalkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate.
- the basis is defined as follows.
- heterocyclic group or a group of 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen and oxygen , Sulfur, boron, phosphorus and silicon.
- the point of attachment may be a carbon or nitrogen atom.
- a 3 to 7 membered heterocyclic group is preferred, which is a 3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3 to 6
- the membered heterocyclic group is particularly preferred, which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5 to 6 membered heterocyclic group, which is a ring system having ring carbon atoms and A 5- to 6-membered non-aromatic ring system with 1 to 3 ring heteroatoms.
- Heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl ring is fused with one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in this case, the ring The number of members continues to indicate the number of ring members in the heterocyclyl ring system.
- each of the heterocyclic groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitably substituted
- the basis is defined as follows.
- Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, and thiorenyl.
- Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietane.
- Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
- Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxasulfuranyl. Oxazolidin-2-one.
- Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl.
- Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
- Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiacyclohexyl, dioxanyl.
- Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl.
- Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl, and thieppanyl.
- Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azacyclooctyl, oxetanyl, and thietane.
- Exemplary 5-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to: indolinyl, isoindolinyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc.
- Exemplary 6-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and so on.
- C 6-14 aryl refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6-14 ring carbon atoms and zero heteroatoms)
- the shared 6, 10, or 14 ⁇ electrons) groups are arranged in a ring.
- an aryl group having six ring carbon atoms ( “C 6 aryl”; e.g., phenyl).
- an aryl group has ten ring carbon atoms ("C 10 aryl”; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl).
- an aryl group has fourteen ring carbon atoms (" C14 aryl"; for example, anthryl). In some embodiments, C 6-10 aryl groups are particularly preferred, and C 6 aryl groups are more preferred.
- the aryl group also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring. In this case, the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
- each of the aryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
- the appropriate substituents are as follows definition.
- 5 to 10 membered heteroaryl refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (for example, having a shared ring arrangement 6 or 10 ⁇ electrons), where each heteroatom is independently selected from nitrogen, oxygen and sulfur.
- the point of attachment may be a carbon or nitrogen atom.
- Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
- Heteroaryl groups also include ring systems in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case, the carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system.
- a 5- to 6-membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
- each of the heteroaryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitably substituted
- the basis is defined as follows.
- Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl.
- Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
- Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl.
- Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl.
- Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl.
- Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl.
- Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
- Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl.
- Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , Benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indenazinyl and purinyl.
- Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pterridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
- Carbonyl refers to the -C(O)- group.
- Each of Raa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl, or two Raa groups are combined to form a heterocyclic group or Heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R dd groups Group replacement
- Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R cc groups are combined to form a heterocyclic ring Group or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R dd group substitution;
- R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon Cyclic, heterocyclic, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;
- Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ff groups are combined to form a heterocyclic group Or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R gg Group substitution
- Deuteration or “D” means that one or more hydrogens in a compound or group are replaced by deuterium; deuteration can be mono-, di-, poly, or full-substitution.
- deuteration can be mono-, di-, poly, or full-substitution.
- Non-deuterated compound refers to a compound that contains a proportion of deuterium atoms not higher than the natural deuterium isotope content (0.015%).
- the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably Greater than 99%.
- pharmaceutically acceptable salt means that within the scope of reliable medical judgment, it is suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and is compatible with reasonable benefits/risks. The salt in proportion.
- Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe the pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
- Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
- non-toxic acid addition salts examples include salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. It also includes salts formed using conventional methods in the art, for example, ion exchange methods.
- salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , Malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, pectinate, pers
- Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, Nitrate, lower alkyl sulfonate and aryl sulfonate.
- Subjects to be administered include, but are not limited to: humans (ie, men or women of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults)) and/or non-human animals, for example, mammals, for example, primates (for example, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , Goats, rodents, cats and/or dogs.
- the subject is a human.
- the subject is a non-human animal.
- the terms "human", “patient” and “subject” are used interchangeably herein.
- treatment includes the effect that occurs when a subject suffers from a specific disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder Or the development of a condition ("therapeutic treatment"), and also includes effects that occur before the subject begins to suffer from a specific disease, disorder, or condition ("prophylactic treatment").
- Combination and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention.
- the compound of the present invention may be administered simultaneously or sequentially in separate unit dosage forms with another therapeutic agent, or simultaneously administered in a single unit dosage form with another therapeutic agent.
- the compound of the present invention refers to the following compound of formula (I) (including a subset of each formula), or a pharmaceutically acceptable salt, hydrate or solvate thereof.
- the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
- Ring A is selected from C 6-14 aryl or 5 to 10 membered heteroaryl
- R is each independently selected from H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
- p is selected from 0, 1, 2, 3, 4 or 5;
- R 1 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group, wherein the C 1 -6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl and 3 to 7 membered heterocyclic group are each independently optionally selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R 2 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl or 5 to 10 membered heteroaryl , Wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group, 3 to 7 membered heterocyclic group, C 6-10 aryl group and 5 to 10 membered heteroaryl group are each independently optionally substituted by one Or more groups selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy; or R 2 and the attached double bond together form a triple bond ;
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl or 5 to 10 membered heteroaryl , Wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group are each independently optionally substituted by one Or more than one group selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy;
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently and optionally one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- X is C(R 4 )(R 4 ');
- Y is C(R 5 )(R 5 ');
- n 0, 1 or 2;
- n 1, 2 or 3;
- R 4 and R 4 ' are each independently selected from H, D, halogen, -CN or C 1-6 alkyl; or R 4 and R 4 ' and the carbon atom to which they are attached form a carbonyl group, C 3-7 cycloalkane Group or 3 to 7 membered heterocyclic group; wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group and 3 to 7 membered heterocyclic group are each independently optionally selected from one or more D , Halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R 5 and R 5 ' are each independently selected from H, D, halogen, -CN or C 1-6 alkyl; or R 5 and R 5 ' and the carbon atom to which they are attached form a carbonyl group, C 3-7 cycloalkane Group or 3 to 7 membered heterocyclic group; wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group and 3 to 7 membered heterocyclic group are each independently optionally selected from one or more D , Halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R a and R b are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7-membered heterocyclic group; or R a , R b and the nitrogen atom to which they are attached form 3 To 7-membered heterocyclic group; wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group and 3 to 7-membered heterocyclic group are each independently optionally selected from D, halogen, -OH, C 1-6 alkyl or C 1-6 alkoxy group substitution;
- ring A is selected from C 6-14 aryl or 5 to 10 membered heteroaryl; in another embodiment, ring A is C 6-14 aryl; in another embodiment, ring A is a 5- to 10-membered heteroaryl group; in another embodiment, ring A is selected from phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl , Furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, quinolinyl or isoquinolinyl; in another embodiment, ring A is selected from phenyl, naphthyl, pyridine Azolyl, imidazolyl, oxazolyl, isoxazolyl, quinolinyl or isoquinolinyl; in another embodiment, ring A is selected from phen
- each R is independently selected from H, D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 Haloalkoxy; in another embodiment, each R is independently H; in another embodiment, each R is independently D; in another embodiment, each R is independently halogen; in another embodiment In another embodiment, each R is independently -OH; in another embodiment, each R is independently -CN; in another embodiment, each R is independently C 1-6 alkyl; in another embodiment In another embodiment, each R is independently C 1-6 haloalkyl; in another embodiment, each R is independently C 1-6 alkoxy; in another embodiment, each R is independently C 1-6 Haloalkoxy.
- each R is independently selected from D, halogen, -OH, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkyl
- R is each independently selected from D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy
- each R is independently selected from D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl
- each R is independently selected from D, halogen, or C 1 -6 alkyl
- R is each independently selected from D, F, Cl, Br, -CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -OCH 3 , -CH ( CH 3 ) 2 or -OCH(CH 3 ) 2 ; in another embodiment, each R is independently selected from D, F, , halogen, -OH, -CN, C
- p is selected from 0, 1, 2, 3, 4, or 5; in another embodiment, p is 0; in another embodiment, p is 1; in another embodiment, p is 2; in another embodiment, p is 3; in another embodiment, p is 4; in another embodiment, p is 5.
- R 1 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, Wherein said C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected from D, halogen , -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group; in another embodiment, R 1 is H; in another embodiment, R 1 Is D; in another embodiment, R 1 is halogen; in another embodiment, R 1 is -CN; in another embodiment, R 1 is C 1-6 alkyl; in another embodiment In another embodiment, R 1 is a C 1-6 alkoxy group; in another embodiment, R 1 is a C 3-7 cycloalkyl group; in another embodiment, R 1 is a 3- to 7-membered heterocyclic
- R 1 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclyl, wherein said C 1- 6 alkyl, C 3-7 cycloalkyl, and 3 to 7 membered heterocyclic group are each independently optionally selected by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkane Group or C 1-6 alkoxy group; in another embodiment, R 1 is selected from H, D, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered The heterocyclic group, wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group and 3 to 7 membered heterocyclic group are each independently optionally selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group; in another embodiment, R 1 is
- R 1 is selected from halogen, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, wherein The C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group and 3- to 7-membered heterocyclic group are each independently optionally selected by one or more selected from D, halogen, -OH , -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group; in another embodiment, R 1 is selected from C 1-6 alkyl, C 1-6 alkoxy Group, C 3-7 cycloalkyl group or 3 to 7 membered heterocyclic group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-7 cycloalkyl group and 3 to 7 membered heterocyclic group
- the cyclic groups are each independently optionally substituted with one or more groups selected from D, halogen, -
- R 2 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl or 5 To 10-membered heteroaryl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl are each independently Is optionally substituted with one or more groups selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy; or R 2 and the attached
- R 2 is independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl Group or 5 to 10 membered heteroaryl group, wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group, 3 to 7 membered heterocyclic group, C 6-10 aryl group and 5 to 10 membered heteroaryl group
- the groups are each independently optionally substituted with one or more groups selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy; in another embodiment
- R 2 is independently selected from H, D, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from D, halogen, -OH,- NR a R b , C 1-6 alkyl or C 1-6 alkoxy group; in another embodiment, R 2 is independently
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl, or 5 To 10-membered heteroaryl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl are each independently Is optionally substituted with one or more groups selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy; in another embodiment, R 3 is H; in another embodiment, R 3 is D; in another embodiment, R 3 is halogen; in another embodiment, R 3 is -CN; in another embodiment, R 3 is C 1-6 alkyl; in another embodiment, R 3 is C 3-7 cycloalkyl; in another embodiment, R 3 is 3 to 7 membered heterocyclyl; in
- R 3 is selected from H, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl, or 5 to 10-membered heteroaryl group, wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group, 3- to 7-membered heterocyclic group, C 6-10 aryl group or 5- to 10-membered heteroaryl group are each independently Optionally substituted with one or more groups selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy; in another embodiment, R 3 is selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the C 1- 6 alkyl group, C 3-7 cycloalkyl group, 3 to 7 membered heterocyclic group,
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently optionally One or more groups selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy; in another embodiment, R'is H; In another embodiment, R'is C 1-6 alkyl; in another embodiment, R'is C 1-6 haloalkyl; in another embodiment, C 1-6 alkane in R' And C 1-6 haloalkyl groups are each independently optionally substituted by one or more groups selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl, or C 1-6 alkoxy. ⁇ Replacement.
- R' is selected from H or C 1-6 alkyl; in another embodiment, R'is selected from H, methyl, ethyl, or isopropyl; in another embodiment, R'is selected from H or methyl.
- n is 0, 1, or 2; in another embodiment, m is 0; in another embodiment, m is 1; in another embodiment, m is 2.
- n is 1, 2, or 3; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3.
- any technical solution or any combination of any of the above specific embodiments can be combined with any technical solution or any combination of other specific embodiments.
- any technical solution or any combination of ring A can be combined with any technical solution or any combination of R, R 1 to R 3 , R′, X, Y, m, n, and p.
- the present invention is intended to include all the combinations of these technical solutions, limited to space, and will not be listed one by one.
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- R 1 is selected from H, D, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently and optionally one or more selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R 2 is selected from H, D, halogen, or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution; or R 2 and the attached double bond together form a triple bond;
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group, wherein said C 1-6 alkyl, C 3-
- the 7 cycloalkyl group and the 3 to 7 member heterocyclic group are each independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkane Substitution of oxy groups;
- R a and R b are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7-membered heterocyclic group; or R a , R b and the nitrogen atom to which they are attached form 3 To 7-membered heterocyclic group;
- R 1 is C 1-6 alkyl, preferably methyl
- R’ is H
- R 2 is H
- R 3 is H.
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- R 1 is selected from H, D, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently and optionally one or more selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy group substitution; preferably, R'is selected from C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1 -6 alkyl and C 1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy;
- R 2 is selected from H, D, halogen, or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution; or R 2 and the attached double bond together form a triple bond;
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group, wherein said C 1-6 alkyl, C 3-
- the 7 cycloalkyl group and the 3 to 7 member heterocyclic group are each independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkane Substitution of oxy groups;
- R a and R b are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7-membered heterocyclic group; or R a , R b and the nitrogen atom to which they are attached form 3 To 7-membered heterocyclic group;
- R 1 is C 1-6 alkyl, preferably methyl
- R' is H; or R'is selected from C 1-6 alkyl or C 1-6 haloalkyl;
- R 2 is H
- R 3 is H.
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- R 1 is selected from D, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from D, halogen, -OH, -NR a R b , C 1 -6 alkyl or C 1-6 alkoxy group substitution; preferably, R 1 is in the S configuration; preferably, R 1 is in the R configuration;
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently and optionally one or more selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R 2 is selected from H, D, halogen, or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution; or R 2 and the attached double bond together form a triple bond;
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group, wherein said C 1-6 alkyl, C 3-
- the 7 cycloalkyl group and the 3 to 7 member heterocyclic group are each independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkane Substitution of oxy groups;
- R a and R b are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7-membered heterocyclic group; or R a , R b and the nitrogen atom to which they are attached form 3 To 7-membered heterocyclic group;
- R 1 is a C 1-6 alkyl group, preferably a methyl group; preferably, R 1 is in the S configuration; preferably, R 1 is in the R configuration;
- R’ is H
- R 2 is H
- R 3 is H.
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- R 1 is selected from D, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from D, halogen, -OH, -NR a R b , C 1 -6 alkyl or C 1-6 alkoxy group substitution;
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently and optionally one or more selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy group substitution; preferably, R'is selected from C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1 -6 alkyl and C 1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy;
- R 2 is selected from H, D, halogen, or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution; or R 2 and the attached double bond together form a triple bond;
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group, wherein said C 1-6 alkyl, C 3-
- the 7 cycloalkyl group and the 3 to 7 member heterocyclic group are each independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkane Substitution of oxy groups;
- R a and R b are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7-membered heterocyclic group; or R a , R b and the nitrogen atom to which they are attached form 3 To 7-membered heterocyclic group;
- R 1 is C 1-6 alkyl, preferably methyl
- R' is H; or R'is selected from C 1-6 alkyl or C 1-6 haloalkyl;
- R 2 is H
- R 3 is H.
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- R 1 is selected from H, D, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently and optionally one or more selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R 2 is selected from H, D, halogen, or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution; or R 2 and the attached double bond together form a triple bond;
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group, wherein said C 1-6 alkyl, C 3-
- the 7- cycloalkyl group and the 3- to 7-membered heterocyclic group are each independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkane Substitution of oxy groups;
- R a and R b are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7-membered heterocyclic group; or R a , R b and the nitrogen atom to which they are attached form 3 To 7-membered heterocyclic group;
- R 1 is C 1-6 alkyl, preferably methyl
- R’ is H
- R 2 is H
- R 3 is H.
- the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of the following general formula:
- R 1 is selected from H, D, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution;
- R' is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl and C 1-6 haloalkyl are each independently and optionally one or more selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy group substitution; preferably, R'is selected from C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1 -6 alkyl and C 1-6 haloalkyl are each independently optionally substituted with one or more groups selected from D, halogen, C 1-6 alkyl or C 1-6 alkoxy;
- R 2 is selected from H, D, halogen, or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkoxy group substitution; or R 2 and the attached double bond together form a triple bond;
- R 3 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group, wherein said C 1-6 alkyl, C 3-
- the 7 cycloalkyl group and the 3 to 7 member heterocyclic group are each independently optionally substituted by one or more selected from D, halogen, -OH, -NR a R b , C 1-6 alkyl or C 1-6 alkane Substitution of oxy groups;
- R a and R b are each independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7-membered heterocyclic group; or R a , R b and the nitrogen atom to which they are attached form 3 To 7-membered heterocyclic group;
- R 1 is C 1-6 alkyl, preferably methyl
- R' is H; or R'is selected from C 1-6 alkyl or C 1-6 haloalkyl;
- R 2 is H
- R 3 is H.
- the present invention relates to the following compounds or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, the compounds selected from :
- the compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
- the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, Including racemate mixtures and mixtures rich in one or more stereoisomers.
- the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be separated by Prepared by asymmetric synthesis.
- HPLC high pressure liquid chromatography
- Tautomers means that a functional group in some compounds changes its structure to become another functional group isomer, and can quickly convert between each other, and the two isomers are in dynamic equilibrium, and the two isomers are in dynamic equilibrium. This kind of isomer is called tautomer.
- an organic compound can form a complex with a solvent, which reacts in the solvent or precipitates or crystallizes out of the solvent. These complexes are called “solvates”. When the solvent is water, the complex is called “hydrate”. The present invention covers all solvates of the compounds of the present invention.
- solvate refers to a compound or a salt form thereof combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
- solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like.
- Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
- “Solvate” includes a solvate in a solution state and an isolable solvate. Representative solvates include hydrates, ethanolates, and methanolates.
- hydrate refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, a hydrate of a compound can be represented by, for example, the general formula R ⁇ x H 2 O, where R is the compound, and x is a number greater than zero.
- a given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
- monohydrate x is 1
- lower hydrate x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5H 2 O)
- polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
- the compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic).
- the compounds of the present invention may exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope.
- the term "polymorph” refers to a crystalline form (or a salt, hydrate or solvate thereof) of a compound in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to dominate.
- Various polymorphs of the compound can be prepared by crystallization under different conditions.
- the present invention also includes isotopically-labeled compounds, which are equivalent to those described in formula (I), but one or more atoms are replaced by atoms having an atomic mass or mass number different from those commonly found in nature.
- isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
- Tritium, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. Further, substituted with heavier isotopes such as deuterium, i.e.
- Isotopically-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in this way.
- readily available isotope-labeled reagents are used instead of non-isotopes. Labeled reagents.
- prodrugs are also included in the context of the present invention.
- the term "prodrug” as used herein refers to a compound that is converted into its active form with a medical effect by, for example, hydrolysis in the blood in the body.
- Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ASSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limits overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduced This article serves as a reference.
- a prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in the body.
- Prodrugs are usually prepared by modifying functional groups, and the modification is carried out in such a way that the modification can be performed by conventional operations or cleavage in vivo to produce the parent compound.
- Prodrugs include, for example, the compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group, which can be cleaved to form a hydroxyl, amino, or sulfhydryl group when administered to a patient.
- prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of the compound of formula (I).
- esters such as methyl esters, ethyl esters, and the like can be used.
- the ester itself can be active and/or can be hydrolyzed under human body conditions.
- Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or salt thereof.
- the present invention provides a method for treating and/or preventing a disease in a subject, such as a cancer mediated by a mutant EGFR kinase, comprising administering to the subject a compound of the present invention or a tautomer, Stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or pharmaceutical compositions of the present invention.
- the mutant EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR.
- the mutated EGFR has a T790M mutation and is selected from the group consisting of exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation, or L858R mutation. At least one mutation.
- EGFR refers to human epidermal growth factor receptor protein, and is referred to as ErbB-1 or HER1.
- wild-type EGFR refers to EGFR without somatic mutations.
- exon 20 insertion mutation means that one or more amino acids (preferably 1 to 7, more preferably 1 to 4) are inserted into the exon 20 region of EGFR (such as amino acid 761 to 823).
- Sequence preferably, the mutation is in which the amino acid sequence FQEA (in the order of phenylalanine, glutamine, glutamate and alanine from the N-terminus) is inserted at position 763 in the exon 20 region A mutation between alanine and tyrosine at position 764 (A763_Y764insFQEA); preferably, the mutation is in which the amino acid sequence ASV (in the order of alanine, serine and valine from the N-terminus) is inserted into the exon The mutation between the 769th valine and the 770th aspartic acid in the 20 region (V769_D770insASV); preferably, the mutation is wherein the amino acid sequence SVD (from the N-terminus with serine, valine
- the mutation is in which the amino acid sequence ASV (in the order of alanine, serine and valine from the N-terminus) is inserted into the 769th valine and the 770th aspartic acid in the exon 20 region (V769_D770insASV); More preferably, the mutation is in which the amino acid sequence SVD (in the order of serine, valine and aspartic acid from the N-terminus) is inserted into the aspartic acid at position 770 in the exon 20 region Mutation between amino acid and asparagine at position 771 (D770_N771insSVD); more preferably, the mutation is where the amino acid G (glycine) is inserted into the asparagine at position 770 and asparagine at position 771 in the exon 20 region (D770_N771insG); more preferably, the mutation is in which the amino acid sequence NPH (from the N-terminus in the order of asparagine, proline and histidine) is inserted into
- cancer patients expressing EGFR with exon 20 insertion mutation refers to cancer patients who express EGFR with exon 20 insertion mutation in at least a part of the exon 20 region of EGFR.
- EGFR may have exon 20 insertion mutations in two or more different parts, but one part is preferred.
- EGFR may also have other mutations (such as exon 19 deletion mutation, L858R mutation, or T790M mutation) other than the insertion mutation in exon 20.
- the method for detecting insertion mutations expressing EGFR exon 20 in cancer patients is not particularly limited, as long as the method can detect mutations, and any known detection method can be used.
- the detection target for detecting the insertion mutation of exon 20 can be any one of the gene sequence of the EGFR gene, the transcription product of the EGFR gene, and the EGFR protein.
- the sample for detecting the insertion mutation of exon 20 is not particularly limited, as long as the sample is a biological sample isolated from a cancer patient, especially a sample obtained from a cancer patient and containing malignant tumor cells.
- biological samples include body fluids (for example, blood, urine, etc.), tissues, extracts thereof, and cultures obtained from tissues.
- the method of separating the biological sample can be appropriately selected according to the type of the biological sample.
- Biological samples are prepared by appropriate treatment according to the detection method.
- reagents for detection for example, reagents containing primers or probes
- reagents containing primers or probes can be prepared by conventional methods according to the detection method.
- the step of detecting the presence of insertion mutations in exon 20 of EGFR expressed in patients with malignant tumors may be performed before administering anti-tumor agents to patients with cancer.
- exon 18 point mutation means a point mutation in an amino acid in the exon 18 region of wild-type EGFR.
- the mutation is a point mutation or a deletion mutation in which one amino acid in the exon 18 region is replaced; more preferably, the mutation is a point where the histidine encoded by codon 709 in exon 18 has been replaced by any amino acid Mutations (ie E790X), and point mutations in which the glutamate encoded by codon 719 in exon 18 has been replaced by any amino acid (ie G719X).
- E790X can be, for example, a point mutation in which the glutamic acid encoded by codon 709 in the region of exon 18 has been replaced by lysine (ie E709K), and the point mutation encoded by codon 709 in the region of exon 18 A point mutation in which glutamic acid has been replaced by alanine (ie E709A).
- G719X can be, for example, a point mutation in which the glycine encoded by codon 719 in the exon 18 region has been replaced by alanine (ie G719A), and the point where the glycine encoded by codon 719 in the exon 18 region has been replaced by serine Mutations (namely G719S), and point mutations in which the glycine encoded by codon 719 in the region of exon 18 has been replaced by cysteine (namely G719C), of which G719A is the most common.
- exon 21 represents the region 824-875 in the amino acid sequence of wild-type EGFR.
- exon 21 point mutation means a point mutation in an amino acid in the exon 21 region of wild-type EGFR.
- the 21 point mutation of exon is a point mutation in which one amino acid in the region of exon 21 is replaced; more preferably, the 21 point mutation of exon is a leucine encoded by codon 861 in the region of exon 21.
- a point mutation in which an acid has been replaced by any amino acid ie L861X
- a point mutation in which the leucine encoded by codon 861 in the exon 21 region has been replaced by glutamine ie, L861Q).
- exon 18 point mutant EGFR means EGFR with at least one exon 18 point mutation; preferably, the EGFR means having more than 2 related exon 18 point mutations; more preferably, the EGFR indicates that it has an 18-point mutation in one exon.
- the EGFR may also have mutations other than exon 18 point mutations (for example, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).
- exon 21 point mutant EGFR means EGFR with at least one exon 21 point mutation; preferably, the EGFR means having more than 2 related exon 21 point mutations; more preferably, the EGFR indicates that it has a 21-point mutation in one exon.
- the EGFR may also have mutations other than exon 21 point mutations (for example, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).
- the mutant EGFR has a T790M mutation and is selected from the group consisting of exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation, or L858R mutation. At least one mutation in.
- the present invention has a T790M mutation and is selected from exon 18 point mutant EGFR, exon 21 point mutant EGFR is any one of the following: has T790M mutation and has exon 18 region E709X and / Or G719X mutant EGFR; L861X mutant EGFR with T790M mutation and exon 21 region.
- T790M mutation and E709K or E709A mutant EGFR is any one of the following: T790M mutation and E709K or E709A mutant EGFR; T790M mutation and G719A, G719S, or G719C mutant EGFR; T790M mutation and L861Q mutant EGFR; among them, T790M Mutations with G719A and T790M mutations with L861Q mutant EGFR are more common.
- the detection method for the EGFR expressed by cancer patients with exon 18 and/or exon 21 point mutations is sufficient as long as the above mutations can be detected, and known detection methods can be used.
- the sample used for detecting exon 18 and/or exon 21 point mutations is not particularly limited, as long as the sample is a biological sample isolated from a cancer patient, especially a sample obtained from a cancer patient and containing malignant tumor cells.
- biological samples include body fluids (for example, blood, urine, etc.), tissues, extracts thereof, and cultures obtained from tissues.
- the method of separating the biological sample can be appropriately selected according to the type of the biological sample.
- Biological samples are prepared by appropriate treatment according to the detection method.
- reagents for detection for example, reagents containing primers or probes
- reagents containing primers or probes can be prepared by conventional methods according to the detection method.
- the step of detecting the presence of exon 18 and/or exon 21 point mutations expressed in patients with malignant tumors may be performed before administering anti-tumor agents to cancer patients.
- tumors mediated by mutant EGFR kinase in the present invention include, but are not limited to: head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, cholangiocarcinoma (eg, gallbladder and bile duct cancer), pancreas Cancer, colorectal cancer (for example, colon cancer and rectal cancer), lung cancer (for example, non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (for example, child Cervical cancer and endometrial cancer), urinary tract cancer (for example, kidney cancer, bladder cancer, prostate cancer, and testicular cancer), hematopoietic tumors (for example, leukemia, malignant lymphoma and multiple myeloma), osteosarcoma , Soft tissue sarcoma, skin cancer, brain tumor, etc.
- Preferred examples include lung cancer, breast cancer, head and neck
- the mutant EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR.
- the mutant EGFR has a T790M mutation and is selected from the group consisting of exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR .
- the present invention also provides a method for treating tumor patients, including expressing a mutant EGFR selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, and exon 19 deletion mutant type.
- the present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof, which is used for therapeutic expression of a compound selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, and exon 21 point mutant EGFR , Tumor patients with exon 19 deletion mutant EGFR or L858R mutant EGFR.
- the present invention also provides that the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 Use in tumor patients with deletion of mutant EGFR or L858R mutant EGFR.
- the present invention also provides a method for predicting the therapeutic effect of using an antitumor agent in a tumor patient, the antitumor agent being the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, the method comprising the following steps (1) and ( 2):
- step (1) finds that the EGFR gene has a mutation selected from exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation or L858R mutation, A step that predicts that chemotherapy is highly likely to show a sufficient therapeutic effect on the patient.
- the present invention also provides a method for treating tumor patients, the method comprising the following steps (1) to (2):
- step (1) finds that the EGFR gene has a mutation selected from exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation or L858R mutation.
- the present invention provides a method of treating and/or preventing a disease in a subject, such as a wild and/or mutant HER2 kinase-mediated tumor, comprising administering to the subject
- a disease in a subject such as a wild and/or mutant HER2 kinase-mediated tumor
- administering comprising administering to the subject
- the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C Mutant HER2, L755S mutant HER2 or ex20insYVMA mutant HER2.
- the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
- HER2 includes HER2 of human or non-human mammals. Also, the term “HER2” includes subtypes.
- HER2 kinase-mediated tumors are preferably tumors with HER2 overexpression, HER2 gene amplification or HER2 mutation.
- the above-mentioned “tumor” is not particularly limited, and may be, for example, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder-biliary duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer , Uterine cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone-soft tissue sarcoma, blood cancer, multiple myeloma, skin cancer, brain tumor, mesothelial cancer, etc.
- breast cancer gastric cancer, esophageal cancer, ovarian cancer, lung cancer, esophageal cancer, gallbladder-cholangiocarcinoma, biliary tract cancer, bladder cancer, colon cancer, more preferably breast cancer, stomach cancer, esophageal cancer, biliary cancer, ovarian cancer, lung cancer, esophagus Cancer, breast cancer, stomach cancer, and lung cancer are more preferable.
- effective amount refers to an amount or dose sufficient to produce the desired therapeutic benefit in the individual in need of the treatment.
- the effective amount or dosage of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation or clinical trials) and conventional factors (e.g., the mode or route of drug delivery, the pharmacokinetics of the agent, the severity and course of infection, and the individual Health status and weight, and the judgment of the treating physician) to determine.
- Exemplary dosages are in the range of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day.
- the total dose can be administered in a single dose or in divided dose units (e.g., BID, TID, QID).
- the dosage can be adjusted for preventive or maintenance treatment.
- the dosage or frequency of administration or both can be reduced to an amount that maintains the desired therapeutic or preventive effect based on symptoms.
- treatment can be stopped.
- the patient may require long-term intermittent treatment. Patients may also require long-term slow treatment.
- compositions preparations and kits
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
- the pharmaceutical composition contains an effective amount of active ingredient.
- the pharmaceutical composition includes a therapeutically effective amount of the active ingredient.
- the pharmaceutical composition includes a prophylactically effective amount of the active ingredient.
- the pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that will not destroy the pharmacological activity of the compound formulated together.
- Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-inlay Segment polymers, poly
- kits e.g., pharmaceutical packaging.
- the kit provided may include the compound of the present invention, other therapeutic agents, and first and second containers (for example, vials, ampoules, bottles, syringes, and/or dispersible packages or other containers) containing the compound of the present invention and other therapeutic agents. Suitable container).
- the provided kit may also optionally include a third container, which contains pharmaceutical excipients for diluting or suspending the compound of the present invention and/or other therapeutic agents.
- the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.
- parenteral administration includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , Intracerebrospinal membrane administration, intralesional administration, and intracranial injection or infusion technology.
- an effective amount of the compound provided herein is administered.
- the doctor can determine the amount of the compound actually administered .
- the compound provided herein is administered to a subject at risk of developing the condition, typically based on the doctor's recommendation and under the supervision of the doctor, and the dosage level is as described above.
- Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those subjects who are particularly sensitive to developing the condition as determined by genetic testing or screening.
- long-term administration refers to the administration of the compound or its pharmaceutical composition over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the rest of the subject's life.
- long-term administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.
- the pharmaceutical composition may be administered as a bolus, for example, in order to rapidly increase the concentration of the compound in the blood to an effective level.
- the bolus dose depends on the target systemic level of the active ingredient. For example, an intramuscular or subcutaneous bolus dose releases the active ingredient slowly, while a bolus injection delivered directly to a vein (for example, via IV infusion) can be more effective. The rapid delivery allows the concentration of the active ingredient in the blood to rise rapidly to an effective level.
- the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV infusion, so as to provide a steady-state concentration of the active ingredient in the subject's body.
- a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
- Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate precise dosing, the composition is provided in unit dosage form.
- unit dosage form refers to physically discrete units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined number of active substances suitable for producing the desired therapeutic effect and suitable pharmaceutical excipients.
- Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
- the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remaining part is useful for forming the desired administration form.
- Kinds of carriers or excipients and processing aids are used for forming the desired administration form.
- the representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
- each dose provides about 0.01 to about 20 mg/kg of the compound of the present invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
- the transdermal dose is usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, and preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.
- the injection dose level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour.
- a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be given.
- the maximum total dose cannot exceed approximately 2 g/day.
- Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
- the solid form may include, for example, any of the following components, or compounds with similar properties: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, mint, water Methyl salicylate or orange flavoring agent.
- binders for example, microcrystalline cellulose, tragacanth, or gelatin
- excipients for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch
- Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
- the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
- the transdermal composition is typically formulated as a topical ointment or cream containing the active ingredients.
- the active ingredient When formulated as an ointment, the active ingredient is typically combined with paraffin wax or an ointment base that is miscible with water.
- the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
- Such transdermal formulations are well known in the art, and usually include other components for enhancing the active ingredient or stable skin penetration of the formulation. All such known transdermal preparations and components are included within the scope provided by the present invention.
- transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
- compositions for oral administration, injection or topical administration are only representative.
- Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania in Part 8, which is incorporated herein by reference.
- the compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system.
- sustained-release materials can be found in Remington's Pharmaceutical Sciences.
- the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
- the formulation contains water.
- the formulation comprises a cyclodextrin derivative.
- the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins composed of 6, 7 and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or multiple substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitution.
- the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, for example, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
- the formulation includes hexapropyl- ⁇ -cyclodextrin (e.g., 10-50% in water).
- the compounds of the invention described herein can be used in pharmaceutical compositions or methods in combination with one or more other active ingredients to treat the diseases and conditions described herein.
- additional active ingredients include other therapeutic agents or agents that mitigate the adverse effects of the treatment on the intended disease target.
- the combination can be used to increase efficacy, improve symptoms of other diseases, reduce one or more side effects, or reduce the required dosage of the compound of the present invention.
- the additional active ingredient may be formulated into a pharmaceutical composition separate from the compound of the present invention or may be included in a single pharmaceutical composition with the compound of the present invention.
- the additional active ingredient may be administered at the same time, before or after the administration of the compound of the invention.
- Combination agents include those active ingredients that are known or observed to be effective in the treatment of the diseases and conditions described herein, including those that are effective against another target associated with the disease.
- the compositions and preparations and treatment methods of the present invention may further include other drugs, such as other drugs that can be used to treat or alleviate the target disease or related symptoms or conditions.
- the other agents include (but are not limited to) kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib); Raf inhibitors (e.g., Vero Vemurafenib), VEGFR inhibitors (for example, sunitinib); standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs , Mitosis inhibitors, antibodies, hormone therapy or corticosteroids.
- suitable combination agents include anti-inflammatory agents, such as NSAIDs.
- the pharmaceutical composition of the present invention may additionally include one or more of the active agents, and the treatment method may additionally include administering an effective amount of one or more of the active agents.
- each reaction is carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 100°C, preferably 0°C to 80°C).
- the reaction time is usually 0.1-60 hours, preferably 0.5-24 hours.
- NBS N-bromosuccinimide
- reaction solution was cooled to room temperature, diluted with 100 mL of water, adjusted to pH 8-9 with 2N NaOH solution, extracted with ethyl acetate (60 mL*3), the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, The silica gel column separated 3.64 g of light yellow solid with a yield of 76%.
- reaction solution was moved to an ice bath, 3-bromopropene (3.23 g, 26.7 mmol) was slowly added dropwise, the ice bath was removed after the dropwise addition, and the reaction was carried out at 60° C. overnight.
- TLC detected the completion of the reaction, the reaction solution was diluted with 120mL water and 50mL ethyl acetate, filtered through Celite, the aqueous phase was extracted with ethyl acetate (30mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate , Concentrated, and separated by silica gel column to obtain 1.61 g of light yellow solid with a yield of 30%.
- Step 8 Compound (1-(4-amino-6-bromo-5-(quinolin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pentan Synthesis of tert-butyl 4-en-2-yl) carbamate
- Step 9 Compound (4-amino-6-methylene-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1, Synthesis of 6-a]indol-8-yl) tert-butyl carbamate
- 6-Methyl-5-(quinolin-3-yl)-8,9-dihydro-[1,2,4]triazino[1,6-a]indole-4,8-diamine 152mg, 0.44mmol
- triethylamine 114mg, 0.88mmol
- acryloyl chloride 40mg, 0.44mmol
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- Step 1 Compound (4-amino-6-methyl-5-(quinolin-3-yl)-6,7,8,9-tetrahydro-[1,2,4]triazino[1,6 -a] Synthesis of indole-8-yl) tert-butyl carbamate
- TLC detects the completion of the reaction, removes the solvent by rotary evaporation, dilutes with 20mL of water, adjusts the pH to 8-9 with saturated sodium carbonate solution, extracts with dichloromethane (10mL*3), and washes the organic phase with saturated brine and anhydrous sodium sulfate After drying and concentrating, 134 mg of pale yellow solid was obtained with a yield of 70%.
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- racemate compound T-2 100mg was dissolved in methanol solution, and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain the target product T-2-d (retention time: 39.140min, relative content: 20.1%).
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- reaction solution was diluted with 100mL water and 100mL ethyl acetate, filtered through Celite, and the aqueous phase was extracted with ethyl acetate (40mL*3).
- the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. , Concentrated, and separated by silica gel column to obtain 1.45 g of pale yellow solid, with a yield of 35%.
- N-(1-(4-amino-5-(quinolin-3-yl))pyrrolo[2,1-f][1,2,4]triazin-7-yl)but-3-ene -2-yl)-2-methylpropane-2-sulfinamide (1.01g, 2.33mmol) was dissolved in 15mL methanol, and 7M methanolic hydrogen chloride solution (1.7mL, 11.9mmol) was added dropwise slowly at 0°C.
- TLC detects the completion of the reaction, removes the solvent by rotary evaporation, dilutes with 20mL of water, adjusts the pH to 8-9 with saturated sodium carbonate solution, extracts with dichloromethane (10mL*3), and washes the organic phase with saturated brine and anhydrous sodium sulfate After drying and concentrating, 205 mg of pale yellow solid was obtained with a yield of 74%.
- ESI-MS: m/z 331 [M + +2].
- Triazine-4,7-diamine (205mg, 0.62mmol) and triethylamine (125mg, 1.24mmol) were dissolved in 10mL of dichloromethane, cooled to -20°C in an ice bath, and acryloyl chloride (56mg, 0.62 mmol), after dropping, continue to react at -20°C for 1 hour, add 20mL of water to dilute, extract with dichloromethane (10mL*3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate on a silica gel column 150 mg of light yellow solid was obtained, with a yield of 63%.
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- reaction solution was moved to an ice bath, 3-bromopropene (6.46 g, 52.4 mmol) was slowly added dropwise, the ice bath was removed after the dropwise addition, and the reaction was carried out at 60° C. overnight.
- the reaction was completed by TLC detection, the reaction solution was diluted with 200mL water and 150mL ethyl acetate, filtered through Celite, the aqueous phase was extracted with ethyl acetate (50mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate , Concentrated, separated by silica gel column to obtain 3.25 g of pale yellow solid, with a yield of 29.6%.
- Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- Chiral separation conditions Chiral preparative column: CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
- reaction was completed by TLC detection, the reaction solution was diluted with 150mL water and 150mL ethyl acetate, filtered through Celite, the aqueous phase was extracted with ethyl acetate (80mL*3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate , Concentrated and separated by silica gel column to obtain a light yellow solid 3.0g with a yield of 36.1%.
- reaction solution was diluted with 50 mL of water, extracted with ethyl acetate (40 mL*3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 1.3 g of light yellow solid with a yield of 73.5%.
- ADP-GloTM Kinase Assay kit Promega, V9102 kit to determine the drug to be tested against EGFR (L858R/T790M) (SignalChem, E10-122DG-10) and EGFR (D770_N771insNPG) (SignalChem, E-10-132GG) Inhibit activity.
- the highest concentration of the drug to be tested is 1 ⁇ M, 3 times dilution, 12 concentrations.
- the final reaction concentration in the system is: 0.5nM EGFR, 10 ⁇ M ATP, 0.03mg/mL Poly(4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl 2 10mM, Brij35 0.01%. Then add 10 ⁇ L ADP Glo reagent and incubate at 25°C for 40 minutes. Then add 20 ⁇ L of detection reagent, incubate at 25°C for 40min, read on Envision microplate reader (Perkin Elmer, 2104), and calculate the inhibitory rate of different concentrations of compounds on the enzyme. GraphPad Prism 6.0 software was used to analyze the data, and nonlinear curve regression was used to fit the data to obtain a dose-response curve, and from this, the IC 50 value was calculated.
- the ADP-Glo Kinase Assay kit (Promega, V9102) was used to determine the inhibitory activity of the drug to be tested against HER2 (A775_G776insYVMA) (SignalChem, E27-13BG).
- the highest concentration of the drug to be tested is 1 ⁇ M, 3 times dilution, 12 concentrations.
- the final reaction concentration in the system is: 20nM HER2, 5 ⁇ M ATP, 0.03mg/mL Poly(4:1 Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl 2 10mM, Brij35 0.01%.
- the compounds of the present invention were tested in the above kinase inhibition experiments, and it was found that the compounds of the present invention have potent activity on EGFR (L858R/T790M), EGFR (D770_N771insNPG) and HER2 (A775_G776insYVMA) kinases.
- A431 cells and A549 cells are wild-type EGFR cells; HCC827 cells are mutant EGFR cells with exon 19 deletion; H1975 cells are EGFR cells with L858R point mutation and T790M point mutation.
- CTG Promega, G7573
- the compound of the present invention was tested in the above cytotoxicity experiment, and it was found that the compound of the present invention has no inhibitory activity against wild-type EGFR A431 cells and A549 cells, but has strong activity and high selection against H1975 cells and HCC827 cells of mutant EGFR. Therefore, it can be seen that the compound of the present invention can highly specifically inhibit the mutant EGFR with deletion of exon 19 and the L858R/T790M mutant EGFR.
- Table 1 The results of representative example compounds are summarized in Table 1 below.
- TAS6417 The structure of TAS6417 is as follows:
- the compound of the present invention also has potent activity and high selectivity for Ba/F3EGFR-D770-N771ins_SVD and Ba/F 3 HER2-A775_G776insYVMA cells. It can be seen that the compound of the present invention can highly specifically inhibit the mutation of exon 20 insertion. Type EGFR.
- the rats were fed with standard feed and given water. Fasting was started 16 hours before the test.
- the drug is dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit. The time points of blood collection were 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration.
- the rats were briefly anesthetized after inhaling ether, and a blood sample of 300 ⁇ L was collected from the orbit in a test tube. There is 30 ⁇ L of 1% heparin sodium solution in the test tube. Before use, the test tube was dried overnight at 60°C. After the blood sample was collected at the last time point, the rats were anesthetized with ether and sacrificed.
- the blood sample was centrifuged at 5000 rpm at 4°C for 5 minutes to separate the plasma from the red blood cells. Use a pipette to aspirate 100 ⁇ L of plasma into a clean plastic centrifuge tube, and indicate the name and time point of the compound.
- the plasma is stored at -80°C before analysis.
- the concentration of the compound of the present invention in plasma was determined by LC-MS/MS. The pharmacokinetic parameters are calculated based on the blood drug concentration of each animal at different time points.
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Abstract
Description
Claims (19)
- 式(I)化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物:其中,环A选自C 6-14芳基或5至10元杂芳基;R各自独立地选自H、D、卤素、-OH、-CN、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基;p选自0、1、2、3、4或5;R 1选自H、D、卤素、-CN、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或3至7元杂环基,其中所述的C 1-6烷基、C 1-6烷氧基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R 2选自H、D、卤素、-CN、C 1-6烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基,其中所述的C 1-6烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基和5至10元杂芳基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;或者R 2与所连接的双键一起形成叁键;R 3选自H、D、卤素、-CN、C 1-6烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基,其中所述的C 1-6烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R’选自H、C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;X为C(R 4)(R 4’);Y为C(R 5)(R 5’);m为0、1或2;n为1、2或3;当m为0时,R 1所连接的碳原子与酰胺N原子所连接的碳原子直接形成化学键;R 4和R 4’各自独立地选自H、D、卤素、-CN或C 1-6烷基;或者R 4和R 4’与它们所连接的碳原子形成羰基、C 3-7环烷基或3至7元杂环基;其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R 5和R 5’各自独立地选自H、D、卤素、-CN或C 1-6烷基;或者R 5和R 5’与它们所连接的碳原子形成羰基、C 3-7环烷基或3至7元杂环基;其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R a和R b各自独立地选自H、C 1-6烷基、C 3-7环烷基或3至7元杂环基;或者R a、R b与它们所连接的氮原子形成3至7元杂环基;其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、C 1-6烷基或C 1-6烷氧基的基团取代;
- 根据权利要求1所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其中,环A选自任选地被p个R基团取代的萘基、喹啉基或异喹啉基。
- 根据权利要求1或2所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其中,R 1为C 1-6烷基,优选为甲基。
- 根据权利要求1-3中任一项所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其中,R 3选自H、卤素或C 1-6烷基,其中所述的C 1-6烷基可任选地被一个-NR aR b基团取代;其中,R a和R b各自独立地选自H或C 1-6烷基;或者R a、R b与它们所连接的氮原子形成3至7元杂环基;其中所述的C 1-6烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素或-OH基团取代。
- 根据权利要求1-4中任一项所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其为以下通式的化合物:其中,各基团定义如权利要求1-4中任一项所定义;优选地,R 1选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R’选自H、C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;R 2选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;或者R 2与所连接的双键一起形成叁键;R 3选自H、D、卤素、-CN、C 1-6烷基、C 3-7环烷基或3至7元杂环基,其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R a和R b各自独立地选自H、C 1-6烷基、C 3-7环烷基或3至7元杂环基;或者R a、R b与它们所连接的氮原子形成3至7元杂环基;优选地,R 1为C 1-6烷基,优选为甲基;R’为H;R 2为H;R 3为H。
- 根据权利要求1-4中任一项所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其为以下通式的化合物:其中,各基团定义如权利要求1-4中任一项所定义;优选地,R 1选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R’选自H、C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;优选地,R’选自C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;R 2选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;或者R 2与所连接的双键一起形成叁键;R 3选自H、D、卤素、-CN、C 1-6烷基、C 3-7环烷基或3至7元杂环基,其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R a和R b各自独立地选自H、C 1-6烷基、C 3-7环烷基或3至7元杂环基;或者R a、R b与它们所连接的氮原子形成3至7元杂环基;优选地,R 1为C 1-6烷基,优选为甲基;R’为H;或者R’选自C 1-6烷基或C 1-6卤代烷基;R 2为H;R 3为H。
- 根据权利要求1-4中任一项所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其为以下通式的化合物:其中,各基团定义如权利要求1-4中任一项所定义;优选地,R 1选自D、卤素或C 1-6烷基,其中所述的C 1-6烷基任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;优选地,R 1为S构型;优选地,R 1为R构型;R’选自H、C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;R 2选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;或者R 2与所连接的双键一起形成叁键;R 3选自H、D、卤素、-CN、C 1-6烷基、C 3-7环烷基或3至7元杂环基,其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R a和R b各自独立地选自H、C 1-6烷基、C 3-7环烷基或3至7元杂环基;或者R a、R b与它们所连接的氮原子形成3至7元杂环基;优选地,R 1为C 1-6烷基,优选为甲基;优选地,R 1为S构型;优选地,R 1为R构型;R’为H;R 2为H;R 3为H。
- 根据权利要求1-4中任一项所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其为以下通式的化合物:其中,各基团定义如权利要求1-4中任一项所定义;优选地,R 1选自D、卤素或C 1-6烷基,其中所述的C 1-6烷基任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R’选自H、C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;优选地,R’选自C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;R 2选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;或者R 2与所连接的双键一起形成叁键;R 3选自H、D、卤素、-CN、C 1-6烷基、C 3-7环烷基或3至7元杂环基,其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R a和R b各自独立地选自H、C 1-6烷基、C 3-7环烷基或3至7元杂环基;或者R a、R b与它们所连接的氮原子形成3至7元杂环基;优选地,R 1为C 1-6烷基,优选为甲基;R’为H;或者R’选自C 1-6烷基或C 1-6卤代烷基;R 2为H;R 3为H。
- 根据权利要求1-4中任一项所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其为以下通式的化合物:其中,各基团定义如权利要求1-4中任一项所定义;优选地,R 1选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R’选自H、C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;R 2选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;或者R 2与所连接的双键一起形成叁键;R 3选自H、D、卤素、-CN、C 1-6烷基、C 3-7环烷基或3至7元杂环基,其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R a和R b各自独立地选自H、C 1-6烷基、C 3-7环烷基或3至7元杂环基;或者R a、R b与它们所连接的氮原子形成3至7元杂环基;优选地,R 1为C 1-6烷基,优选为甲基;R’为H;R 2为H;R 3为H。
- 根据权利要求1-4中任一项所述的化合物,或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,其为以下通式的化合物:其中,各基团定义如权利要求1-4中任一项所定义;优选地,R 1选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R’选自H、C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;优选地,R’选自C 1-6烷基或C 1-6卤代烷基,其中所述的C 1-6烷基和C 1-6卤代烷基各自独立地任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6烷氧基的基团取代;R 2选自H、D、卤素或C 1-6烷基,其中所述的C 1-6烷基独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;或者R 2与所连接的双键一起形成叁键;R 3选自H、D、卤素、-CN、C 1-6烷基、C 3-7环烷基或3至7元杂环基,其中所述的C 1-6烷基、C 3-7环烷基和3至7元杂环基各自独立地任选地被一个或多个选自D、卤素、-OH、-NR aR b、C 1-6烷基或C 1-6烷氧基的基团取代;R a和R b各自独立地选自H、C 1-6烷基、C 3-7环烷基或3至7元杂环基;或者R a、R b与它们所连接的氮原子形成3至7元杂环基;条件是,R 1不为H;优选地,R 1为C 1-6烷基,优选为甲基;R’为H;或R’选自C 1-6烷基或C 1-6卤代烷基;R 2为H;R 3为H。
- 药物组合物,其含有权利要求1-14中任一项的化合物其互变异构体、立体异构体、前药、晶 型、药学上可接受的盐、水合物或溶剂合物,和药学上可接受的赋形剂。
- 权利要求1-14中任一项的化合物其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,或权利要求15的药物组合物在制备用于治疗和/或预防突变的EGFR激酶介导的肿瘤的药物中的用途;优选地,其中,突变的EGFR选自外显子20插入突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR;优选地,其中,外显子20插入突变选自V769_D770insASV、D770_N771insSVD、D770_N771insG、H773_V774insNPH或H773_V774insPH;优选地,其中,外显子18点突变选自G719A、G719S、G719C、E790K和E790A中的至少一种突变;优选地,其中,外显子21点突变选自L861Q突变;优选地,其中,突变的EGFR还同时具有T790M突变。
- 权利要求1-14中任一项的化合物其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,或权利要求15的药物组合物在制备用于治疗和/或预防以下肿瘤的药物中的用途:肺癌、乳腺癌、头颈癌、脑肿瘤、子宫癌、造血系统肿瘤或皮肤癌。
- 权利要求1-14中任一项的化合物其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,或权利要求15的药物组合物在制备用于治疗和/或预防野生的和/或突变的HER2激酶介导的肿瘤的药物中的用途;优选地,其中,所述突变的HER2选自G309A突变型HER2、S310F突变型HER2、R678Q突变型HER2、L775_T759缺失突变型HER2、D769H突变型HER2、V777L突变型HER2、V842I突变型HER2、R869C突变型HER2、L755S突变型HER2或ex20insYVMA突变型HER2;优选地,其中,所述ex20insYVMA突变型HER2选自A775_G776insYVMA突变型HER2突变。
- 权利要求1-14中任一项的化合物其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物,或权利要求15的药物组合物在制备用于治疗和/或预防以下肿瘤的药物中的用途:肺癌、胃癌或乳腺癌。
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