WO2023011513A1 - Shp2抑制剂、包含其的药物组合物及其用途 - Google Patents
Shp2抑制剂、包含其的药物组合物及其用途 Download PDFInfo
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- WO2023011513A1 WO2023011513A1 PCT/CN2022/109904 CN2022109904W WO2023011513A1 WO 2023011513 A1 WO2023011513 A1 WO 2023011513A1 CN 2022109904 W CN2022109904 W CN 2022109904W WO 2023011513 A1 WO2023011513 A1 WO 2023011513A1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
Definitions
- the invention belongs to the field of medicinal chemistry, and more specifically, relates to a SHP2 inhibitor, a pharmaceutical composition containing it and a medical application thereof.
- SHP2 (Src homology domain, The Src homology-2 domain) is a non-receptor tyrosine phosphatase encoded by the PTPN11 gene. It is ubiquitously expressed in various tissues and cell types, and contains a conserved tyrosine phosphatase domain, two N-terminal SH2 domains, and a C-terminal tail. Two SH2 domains determine the subcellular localization and functional regulation of SHP2. In the inactive state, the N-terminal SH2 domain binds to and inactivates the PTP domain. When the SH2 domain binds to the receptor or to specific tyrosine residues on the adapter protein, the PTP domain is released.
- SHP2 plays an important role in regulating various signal transduction pathways of cell biological processes, and is involved in the signal transduction pathways of various growth factors and cytokines. Within a single signaling pathway, SHP2 can play both active (signal enhancement) and negative (signal attenuation) roles in intracellular signaling. SHP2 is believed to function by dephosphorylating its associated signaling molecules, thereby attenuating local signaling flow. However, the primary role of SHP2 activity in most signaling pathways (eg, growth factors, interkines, and extracellular matrix receptors) is to enhance signal transduction.
- signaling pathways eg, growth factors, interkines, and extracellular matrix receptors
- SHP2 is a positive regulator of the ERK/MAPK signaling pathway, which plays a key role in regulating cell proliferation and survival.
- SHP2 phosphatases see, eg, K.S. Grossman et al., Adv. Cancer Res. 2010, 106, 53-89; and references cited therein).
- SHP2 is normally autoinhibited due to intramolecular interactions between its N-terminal SH2 (N-SH2) domain and its catalytic (PTP) domain, thereby blocking access to the catalytic site.
- N-SH2 N-terminal SH2
- PTP catalytic
- Activation of proteins that interact with the SH2 domain induces a conformational change that reverses this inhibition and allows substrate access to the catalytic site.
- Mutations in the PTPN11 gene that affect N-SH2 or PTP domain residues involved in the basal repression of SHP2 produce a more activatable form of the SHP2 protein that results in unregulated or increased SHP2 activity.
- SHP2 is widely expressed and involved in multiple cell signaling processes, such as Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR, insulin receptor and NF-kB pathways, in cell proliferation, differentiation, cell important role in cycle and migration.
- Hyperactivation of SHP2 caused by germline or somatic mutations has been described in Noonan Syndrome, Leopard Syndrome, Juvenile myelomonocytic leukemia, myelodysplastic syndrome ), B cell acute lymphoblastic leukemia (B cell acute lymphoblastic leukemia) and acute myelogenous leukemia. Additionally, activating mutations in PTPN11 have also been found in solid tumors such as lung, colon, melanoma, neuroblastoma, and liver cancer. Therefore, activated SHP2 or upregulated SHP2 protein in human tumors or other diseases has become a new therapeutic target, and there is an urgent need to develop SHP2 inhibitors.
- the diarylpropenone compound represented by the following formula (1) has SHP2 inhibitory activity, so a small molecule inhibitor of SHP2 can be provided, which shows the activity of targeting and degrading SHP2.
- the present invention provides the compound represented by formula I or its pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope labeling Compounds, metabolites, chelates, complexes, clathrates or prodrugs of
- X is halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably halogen, methyl, ethyl, isopropyl, cyclopropyl group, more preferably halogen,
- X 1 is NR 4 , O or S, preferably O or S, more preferably O, wherein,
- X 2 , X 3 , X 4 , X 5 and X 6 are each independently CR 6 or N, preferably CR 6 ,
- R 1 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably C1-6 alkyl, more preferably selected from methyl , one of ethyl, isopropyl, cyclopropyl,
- R 2 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably H, C1-6 alkyl, more preferably selected from One of H, methyl, and ethyl, particularly preferably H,
- R 3 is CR 4 R 5 , NR 4 , O or S, preferably NR 4 , O or S, more preferably NR 4 , or O,
- R 4 and R 5 are each independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, saturated or partially unsaturated 3-10 Membered heterocyclyl, C6-10 aryl, 5-14 membered heteroaryl or C6-12 aralkyl,
- R 6 is H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group , C6-10 aryl, 5-14 membered heteroaryl or C6-12 aralkyl,
- R is H, halogen, NH 2 , OH, SH, amino, substituted or unsubstituted C2-10 aliphatic hydrocarbon group, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclic group, substituted or unsubstituted Substituted C6-10 aryl, or substituted or unsubstituted 5-14 membered heteroaryl;
- R is preferably halogen, OH, SH, haloalkyl, amino, saturated C3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C1-6 alkyl substituted amino, or
- R7 is selected from H, halogen, cyano, nitro, hydroxymethyl, hydroxyl, amido, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 alkoxy-C1 ⁇ C6 alkylene ,or one of
- R 8 is H, C1 ⁇ C6 alkyl, saturated or partially unsaturated C 3-6 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-10 aryl, "—" is drawn through
- the expression of the ring structure means that the connection site is at any position on the ring structure that can form a bond;
- E 3 is the following group
- Z 2 is N or CH
- Z 3 is N or CH
- Z 4 is N or CH, and Z 4 is connected to any linkable position among Z 1 , Z 2 , and Z 3 ;
- Z 5 is N or CH, preferably N
- E3 is further preferably
- Z 10 is selected from chemical bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, saturated or partially unsaturated C3-10 cycloalkylene, preferably chemical bond, C1-6 alkylene ;
- Rc is halogen, cyano, nitro, hydroxyl, amido, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, substituted C1 ⁇ C6 alkyl, saturated or partially unsaturated C3-10 cycloalkyl, saturated or partially Unsaturated 3-10 membered heterocyclic group, C6-10 aryl group, 5-14 membered heteroaryl group or C6-12 aralkyl group, preferably C1 ⁇ C6 alkyl, saturated or partially unsaturated C3-10 ring Hydrocarbyl, C6-10 aryl, C6-12 aralkyl,
- the compound designed and synthesized in the present invention can effectively inhibit the function of SHP2, and at the same time reduce the content of SHP2 in cells, has good anti-solid tumor and blood tumor activity in vivo and in vitro, and has low toxicity to normal cells.
- the compounds of the present invention are structurally original.
- This type of compound can inhibit the phosphatase activity of SHP2, inhibit the transmission of SHP2 phosphatase-dependent signaling pathways, inhibit the activity of downstream proteins such as ERK, STAT3, STAT5, c-SRC and JAK2, and inhibit the malignant proliferation and distant
- it can block the important phosphatase-independent downstream signal transmission of SHP2, inhibit the activity of proto-oncogenes such as KRAS and NRAS, and stabilize the tumor suppressor gene TP53, so as to inhibit tumor growth, invasion and metastasis;
- These compounds can also effectively increase the activity of T cells in the tumor microenvironment, and prevent tumor cells from escaping immune surveillance to a certain extent.
- the compound of the present application can affect the function of SHP2 from the two ways of SHP2 phospholipase-dependent and phospholipase-independent, and achieve the purpose of anti-tumor. Therefore, it can be interpreted as specifically inhibiting the two functions of SHP2, and can obtain high-efficiency and low-toxicity. compound.
- alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
- alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
- the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
- C1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally replaced by 1 or more (such as 1 to 3) suitable substituents such as Halogen substitution (in which case the group is referred to as "haloalkyl”) (for example CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5 , CH
- C1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl or tert-butyl).
- alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2-6 carbon atoms (“ C2-6 alkenyl”).
- the alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-butenyl, -hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
- the compound of the present invention contains an alkenyl group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
- alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl or propynyl.
- cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.)), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
- monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl,
- the cycloalkyl has 3 to 15 carbon atoms.
- C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclopropyl) of 3 to 6 ring-forming carbon atoms. hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
- cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, which Including but not limited to (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), ((ylidene)cyclopentyl (ring), ((ylidene)cyclohexyl (ring), (ylidene)cycloheptyl ( (ring), (sub)cyclooctyl (ring), (sub)cyclononyl (ring), (sub)cyclohexenyl (ring), etc.
- heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean having, for example, 3-10 (suitably having 3-8, more suitably having 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., with one or more double bond and/or triple bond) cyclic group.
- a "3-10 membered (sub)heterocyclic (group)” has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated (sub)heterocyclic ring (group) of one or more (for example, 1, 2, 3 or 4) heteroatoms of , O and S.
- heterocyclylene and heterocycle include, but are not limited to: ()oxiranyl, () aziridinyl, (azetidinyl), ()oxy Heterocyclobutyl (oxetanyl), (sub)tetrahydrofuranyl, (sub)dioxolinyl (dioxolinyl), (sub)pyrrolidinyl, (sub)pyrrolidinyl, (sub)imidazolidinyl, (sub) ) pyrazolidinyl, (sub)pyrrolinyl, (sub)tetrahydropyranyl, (sub)piperidinyl, (sub)morpholinyl, (sub)dithianyl (dithianyl), (sub) Thiomorpholinyl, piperazinyl or trithianyl.
- the groups also encompass bicyclic systems, including spiro, fused or bridged systems such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[5.5]undecane, Heterobicyclo[2.2.2]octane, etc.).
- Heterocyclylene and heterocycle(yl) groups may be optionally substituted with one or more (eg 1, 2, 3 or 4) suitable substituents.
- the terms "()arylene” and "aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
- C 6-10 ()arylene” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring).
- ()Arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
- heteroarylene and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom which may be the same or different (the heteroatoms are for example oxygen, nitrogen or sulfur), and, additionally, in each case may be benzo-fused.
- “(y)heteroaryl” or “heteroaromatic ring” is selected from (y)thienyl, (y)furyl, (y)pyrrolyl, (y)oxazolyl, ()thiazolyl, (Yellow) imidazolyl, (lower) pyrazolyl, (lower) isoxazolyl, (lower) isothiazolyl, (lower) oxadiazolyl, (lower) triazolyl, (lower) thiadiazolyl etc., and their benzo derivatives; or (sub)pyridyl, (sub)pyridazinyl, (sub)pyrimidinyl, (sub)pyrazinyl, (sub)triazinyl, etc. derivative.
- aralkyl preferably denotes an aryl or heteroaryl substituted alkyl group, wherein aryl, heteroaryl and alkyl are as defined herein.
- the aryl group can have 6-14 carbon atoms
- the heteroaryl group can have 5-14 ring atoms
- the alkyl group can have 1-6 carbon atoms.
- Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
- halo or halogen group is defined to include F, Cl, Br or I.
- substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
- the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
- each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
- one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
- the point of attachment of a substituent may be from any suitable position of the substituent.
- the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
- isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ).
- isotopes of chlorine such as 36 Cl
- isotopes of fluorine such as 18 F
- isotopes of iodine such as 123 I and 125 I
- isotopes of nitrogen such as 13 N and 15 N); , 17 O and 18 O
- phosphorus isotopes eg 32 P
- sulfur isotopes eg 35 S.
- Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
- are useful in drug and/or substrate tissue distribution studies eg, assays).
- radioisotopes tritium (ie3H ) and carbon-14 (ie14C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
- Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
- Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
- Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone- d6 or DMSO- d6 .
- stereoisomer means isomers formed as a result of at least one asymmetric center.
- compounds with one or more (e.g., one, two, three or four) asymmetric centers which can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers.
- Certain individual molecules may also exist as geometric isomers (cis/trans).
- compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium.
- tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers wait. It is to be understood that the scope of this application encompasses all such ratios in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) %) isomers or mixtures thereof.
- the use of a solid line to delineate a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, specific enantiomers, racemic mixtures, etc.).
- the use of solid or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist.
- solid and imaginary wedges are used to define relative rather than absolute stereochemistry.
- the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
- the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and pairs of diastereoisomers.
- the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
- compositions of the present invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
- pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, chelates, complexes, clathrates or Prodrugs, after their administration to a patient in need thereof, are capable of providing, directly or indirectly, a compound of the invention, or a metabolite or residue thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
- Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, including but not limited to salts containing hydrogen bonds or coordinate bonds.
- Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, seabenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, Pam
- Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium, sodium, tromethamine and zinc salts.
- esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
- the compounds of the invention may also themselves be esters.
- the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as in particular water, methanol or ethanol, as a structural element of the crystal lattice of the compound.
- a polar solvent such as in particular water, methanol or ethanol
- the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
- nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; nitrogen-containing heterocycle.
- tertiary amines are capable of forming N-oxides.
- N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
- MCPBA m-chloroperbenzoic acid
- hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
- sodium perborate and dioxiranes such as dimethyldioxirane
- metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
- the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
- prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (for example as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
- the invention also encompasses compounds of the invention which contain protecting groups.
- protecting groups such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
- Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
- the compound of the present invention has the compound shown in formula 1 or its pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound , metabolite, chelate, complex, clathrate or prodrug,
- X is halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably halogen, methyl, ethyl, isopropyl, cyclopropyl group, more preferably halogen,
- X 1 is NR 4 , O or S, preferably O or S, more preferably O, wherein,
- X 2 , X 3 , X 4 , X 5 and X 6 are each independently CR 6 or N, preferably CR 6 ,
- R 1 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably C1-6 alkyl, more preferably selected from methyl , one of ethyl, isopropyl, cyclopropyl,
- R 2 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably H, C1-6 alkyl, more preferably selected from One of H, methyl, and ethyl, particularly preferably H,
- R 3 is CR 4 R 5 , NR 4 , -N(CH 2 CH 2 ) 2 N-, O or S, preferably NR 4 , O or S, more preferably NR 4 , or O,
- R 4 and R 5 are each independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, saturated or partially unsaturated 3-10 Membered heterocyclyl, C6-10 aryl, 5-14 membered heteroaryl or C6-12 aralkyl,
- R 6 is H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group , C6-10 aryl, 5-14 membered heteroaryl or C6-12 aralkyl,
- R is H, halogen, NH 2 , OH, SH, substituted or unsubstituted C2-10 aliphatic hydrocarbon group, substituted or unsubstituted saturated or partially unsaturated 3-10 membered heterocyclic group, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-14 membered heteroaryl;
- R is preferably halogen, OH, SH, haloalkyl, amino, saturated C3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C1-6 alkyl substituted amino, or
- R7 is selected from H, halogen, cyano, nitro, hydroxymethyl, hydroxyl, amido, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, C1 ⁇ C6 alkoxy-C1 ⁇ C6 alkylene ,or one of
- R 8 is H, C1 ⁇ C6 alkyl, saturated or partially unsaturated C 3-6 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group or C6-10 aryl, "—" is drawn through
- the expression of the ring structure means that the connection site is at any position on the ring structure that can form a bond;
- E 3 is the following group
- Z 2 is N or CH
- Z 3 is N or CH
- Z 4 is N or CH, and Z 4 is connected to any linkable position among Z 1 , Z 2 , and Z 3 ;
- Z 5 is N or CH, preferably N
- E3 is further preferably
- Z 10 is selected from chemical bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, saturated or partially unsaturated C3-10 cycloalkylene, preferably chemical bond, C1-6 alkylene ;
- Rc is halogen, cyano, nitro, hydroxyl, amido, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, substituted C1 ⁇ C6 alkyl, saturated or partially unsaturated C3-10 cycloalkyl, saturated or partially Unsaturated 3-10 membered heterocyclic group, C6-10 aryl group, 5-14 membered heteroaryl group or C6-12 aralkyl group, preferably C1 ⁇ C6 alkyl, saturated or partially unsaturated C3-10 ring Hydrocarbyl, C6-10 aryl, C6-12 aralkyl,
- the compound of the present invention has the structure of the following formula 2,
- X is halogen, C1-6 alkyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably halogen,
- R is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably C1-6 alkyl, more preferably for ethyl,
- R is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably H,
- R 3 is NR 4 , O or S, preferably NR 4 , O or S, more preferably NR 4 , Or O, in formula 2, R 4 is each independently H, C1-6 alkyl, R 4 is preferably H,
- the compound of the present invention has the structure shown in the following formula 3,
- X is halogen, C1-6 alkyl, saturated or partially unsaturated C3-10 cyclic hydrocarbon group, preferably halogen
- R 1 is H, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, preferably C1-6 alkyl, more preferably ethyl,
- the compound of the present invention has the structure shown in the following formula 4,
- R 3 is CR 4 R 5 , NH, O or S, preferably NR 4 , O or S, more preferably NH, Or O, R 4 , R 5 are each independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, saturated or partially unsaturated C3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C6-10 aryl group, 5-14 membered heteroaryl group or C6-12 aralkyl group,
- E3 is one selected from the following groups,
- the above group is connected to L through one of the two positions marked by *— or **—, and the other position is connected to F,
- F is H or one of the following groups
- R 7 is further preferably selected from H, methyl, ethyl, one of
- R is one of the following groups
- L is a divalent group shown in formula 5,
- n 0 is 0 or 1
- L is one of the following divalent groups
- the compound represented by the general formula 1 of the present invention can be obtained by known methods, for example, synthesized by known organic synthesis methods.
- An exemplary synthetic route is given below, but those skilled in the art can also obtain it by other known methods.
- compositions and methods of treatment are provided.
- the present invention provides a pharmaceutical composition, which comprises a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, chelate, complex, clathrate or prodrug, and a pharmaceutically acceptable carrier, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, Liquid or gaseous formulations.
- the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite Use of a compound, a chelate, a complex, a clathrate or a prodrug or a pharmaceutical composition in the preparation of a medicament for treating a disease regulated by SHP2 phosphatase.
- the diseases regulated by SHP2 phosphatase are tumors, such as solid tumors, blood tumors, malignant tumors, refractory tumors, primary or metastatic and recurrent tumors, and the like.
- the SHP2 phosphatase-regulated disease is generally selected from Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal Carcinoma, lung cancer, colon cancer, brain cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large cell lymphoma, and glioblastoma, but are not limited to these.
- the present invention provides a method for treating diseases regulated by SHP2 phosphatase, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer thereof to a human in need of such treatment , polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, chelates, complexes, clathrates or prodrugs or pharmaceutical compositions of the present invention.
- the target disease is selected from advanced solid tumors, including primary or metastatic and recurrent NSCLC, lung squamous cell carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, gastric cancer, colorectal cancer, pancreatic cancer, etc.; Also includes breast cancer, esophageal cancer, lung cancer, colon cancer, brain cancer, neuroblastoma, neuroblastoma, melanoma, squamous cell carcinoma of the head and neck, anaplastic large cell lymphoma, and glioblastoma ; Malignant blood tumor diseases include juvenile myelomonocytic leukemia and acute myeloid leukemia; other diseases related to abnormal expression of SHP2 such as Noonan syndrome, leopard skin syndrome, type 2 diabetes and obesity.
- “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol etc.
- the composition if desired, can also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents.
- Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
- compositions of the invention may act systemically and/or locally.
- they may be administered by a suitable route, for example by injection (e.g. intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasally, transmucosally, topically, in the form of ophthalmic formulations or by inhalation.
- the pharmaceutical composition of the present invention can be administered in an appropriate dosage form.
- the dosage forms include but are not limited to tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , Injectable solutions, elixirs, syrups.
- an effective amount refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
- Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
- the amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
- the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 3500 mg/day, eg about 0.7 mg/day to about 700 mg/day.
- Dosage levels up to the lower limit of the foregoing range may be sufficient in some cases, while in other cases larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first administered.
- the dose is divided into several smaller doses to be administered throughout the day.
- the content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg, 25mg, etc.
- treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
- “Individual” as used herein includes a human or non-human animal.
- Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
- Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
- compositions of the present invention may also comprise one or more additional therapeutic or prophylactic agents.
- Fig. 1 is a graph showing the results of a compound of the present invention degrading SHP2 in vitro.
- Fig. 2 is a statistical chart of the in vitro degradation SHP2 activity of the compounds of the present invention.
- LC-MS was determined on Agilent LC-MS-1110 liquid mass spectrometry instrument, Agilent LC-MS-6110 liquid mass spectrometry instrument, Agilent LC-MS-6120 liquid mass spectrometry instrument (manufacturer: Agilent) or Shimadzu LC - Conducted on MS 2020.
- Preparative high-performance liquid chromatography was performed using MS triggered automatic purification system (Waters), Gilson GX-281 (Gilson) or semi-preparative liquid chromatography (Chuangxin Tongheng LC3000 (Ddlsogel, C18, 30mm x 250mm 10 ⁇ m)).
- Thin-layer chromatography was carried out using Huanghai brand HSGF 254 (5 ⁇ 20 cm) silica gel plates, and preparative thin-layer chromatography was carried out using GF 254 (0.4-0.5 nm) silica gel plates produced in Yantai.
- Adopt thin-layer chromatography (TLC) or LC-MS to detect reaction and the developer system that uses comprises dichloromethane and methanol system, normal hexane and ethyl acetate system and sherwood oil and ethyl acetate system, according to the compound to be separated Adjust the developer system with different polarities (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).
- the microwave reaction was performed using a CEM Discovery Sp (400W, RT ⁇ 300°C) microwave reactor.
- the eluent system includes dichloromethane and methanol system and n-hexane and ethyl acetate system, and the eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc. conduct).
- reaction temperature is room temperature (20° C. to 30° C.).
- the reagents used in the examples were purchased from companies such as Aldrich Chemical Company, Shanghai Bid Pharmaceutical Technology Co., Ltd., Beijing Greenchem Co., Ltd., Shaoyuan Technology (Shanghai) Co., Ltd. or Aibo Technology Co., Ltd.
- Example 1 Referring to the operation of Example 1, the difference is that the starting material compound II monosubstituted or polysubstituted nitrogen alkyl compounds with different structures are reacted with the starting material I to obtain the following compound III.
- Each compound biological activity of the present invention is measured by the following method:
- Reagent complete DMEM medium, product of Gibco Company. Fetal bovine serum, produced by ThermoFisher. trypsin. Produced by Thermo Fisher Corporation. SHP-2 antibody was produced by CST Corporation.
- Measuring method Take the cells growing in the logarithmic phase, collect and suspend them in DMEM containing 10% fetal bovine serum, blow gently with a pipette to form a single-cell suspension, and count live cells under a microscope. 9ml of cultured cell suspension was inoculated in a 10cm culture dish, and the final concentration of cells was 2 ⁇ 10 5 /ml. After pre-cultivation for 24 hours under the culture conditions of 37°C and 5% CO 2 , the compounds of the present invention (TDC.2009 and TDC.2020) DMSO solution (the final concentration of DMSO was not more than 0.5%), and the same volume of DMSO was added to the negative Control group. Another 24 hours of performance training.
- the compound of the present invention inhibits the effective concentration of SHP2 in the cell line
- the compounds of the present invention are less toxic to normal cells.
- the present invention illustrates the detailed methods of the present invention through the above examples, but the present invention is not limited to the above detailed methods, that is, it does not mean that the present invention must rely on the above detailed methods to be implemented.
- Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.
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Abstract
一种以下化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,以及含有化合物的药物组合物。还提供化合物在制备与SHP2磷酸酶相关疾病药物中的应用。还提供与SHP2磷酸酶相关疾病的治疗方法。
Description
本发明属于药物化学领域,更具体而言,涉及SHP2抑制剂、包含其的药物组合物及其医药用途。
SHP2(Src同源结构域,The Src homology-2domain)是一个由PTPN11基因编码的非受体酪氨酸磷酸酶。其遍在表现于各种组织及细胞类型中,包含一个保守的酪氨酸磷酸酶结构域、两个N-端SH2结构域、一个C-端尾巴。两个SH2结构域决定了SHP2的亚细胞定位及功能调节。在非活化状态下,N-端SH2结构域会与PTP结构域结合,并使之失去活性。当SH2结构域与受体或者与接头蛋白上的特定酪氨酸残基结合时,PTP结构域会被释放出来。例如,通过细胞因子和生长因子的刺激导致催化位点的暴露,导致SHP2的活化。SHP2在调控细胞生物过程的各种信号传导路径中起着重要作用,且涉及各种生长因子及细胞介素的信号传导路径。在单个信号传导路径内,SHP2可同时在细胞内信号传导过程中起积极(信号增强)作用及消极(信号衰减)作用。据信,SHP2通过使其相关信号传导分子去磷酸化,从而使局部信号传导流衰减而起作用。然而,SHP2活动在大部分信号传导路径(例如,生长因子、细胞介素及细胞外基质受体)中的主要作用为增强信号转导。举例而言,SHP2为ERK/MAPK信号传导路径的正调控剂,其在调控细胞增殖及存活方面起关键作用。(SHP2磷酸酶的概述参见(例如)K.S.Grossman等人,Adv.Cancer Res.2010,106,53-89;及其中所引用的参考文献)。
在基础状态下,SHP2通常由于其N端SH2(N-SH2)结构域与其催化(PTP)结构域之间的分子内相互作用而自动抑制,从而阻断对催化位点的接近。活化与SH2结构域相互作用的蛋白质诱导使此抑制逆转且允许受质接近催化位点的构形改变。PTPN11基因中影响SHP2的基础抑制所涉及的N-SH2或PTP结构域残基的突变产生SHP2蛋白的更易活化形式,其会引起不受调控或增加的SHP2活性。SHP2表达广泛,且参与到多条细胞信号过程中,比如Ras-Erk、PI3K-Akt、Jak-Stat、Met、FGFR、EGFR,以及胰岛素受体和NF-kB 通路,在细胞增殖、分化、细胞周期和迁移中起重要作用。
由种系或体细胞突变引起的SHP2的超活化已经在努南氏症候群(Noonan Syndrome)、豹皮症候群(Leopard Syndrome)、青少年骨髓单核细胞白血病(Juvenilemyelomonocytic leukemia)、骨髓增生异常症候群(myelodysplastic syndrome)、B细胞急性淋巴细胞白血病(B cell acute lymphoblastic leukemia)和急性骨髓性白血病中发现。另外,PTPN11的活化突变也在实体瘤中发现,如肺癌、结肠癌、黑色素瘤、神经母细胞瘤和肝癌。因此,人类肿瘤中或其它疾病中活化的SHP2或者上调的SHP2蛋白成为新的治疗靶点,迫切需要研发SHP2抑制剂。
发明内容
本发明的发明人发现如下述式(1)所示的二芳基丙烯酮化合物具有SHP2抑制活性,因此可提供一种SHP2小分子抑制剂,其体现了靶向降解SHP2的活性。具体而言,本发明提供式I所示的化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,
式1所示的化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,
式1中,
X为卤素、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为卤素、甲基、乙基、异丙基、环丙基,进一步优选为卤素,
X
1为NR
4、O或S,优选为O或S,更优选为O,其中,
X
7选自化学键、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基、-O-、-CO-、-C(=O)O-、-CONH-、-NHCO-、-NHCONH-、-NH-、-S-、 亚磺酰基、磺酰基中的一种,优选为C1-6亚烷基,进一步优选为亚甲基、亚乙基、亚丙基、O,
X
2、X
3、X
4、X
5和X
6各自独立地为CR
6或N,优选为CR
6,
R
1为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为C1-6烷基,进一步优选为选自甲基、乙基、异丙基、环丙基中的一种,
R
2为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为H、C1-6烷基,进一步优选为选自H、甲基、乙基中的一种,特别优选为H,
R
4、R
5各自独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基,
R
6为H、卤素、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或C6-12芳烷基,
R为H、卤素、NH
2、OH、SH、氨基、取代或未取代的C2-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的3-10元杂环基、取代或未取代的C6-10芳基、或者取代或未取代的5-14元杂芳基;
R优选为卤素、OH、SH、卤代烷基、氨基、饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C1-6烷基取代氨基、
或者
其中,V
1为选自C(R
8)
2、C(R
8)
2-C(R
8)
2、CR
8=CR
8、C=O、C(=O)C(R
8)
2、C(R
8)
2C(=O)、C(=O)O、OC(=O)、C(=O)NR、N=CR
8、CR
8=N、NR
8-C(R
8)
2或C(R
8)
2-NR
8中的一种;
R
9各自独立地选自选自卤素、羟基、氧代、氨基、氰基、硝基、-Si(R
8)
3、C1-6 烷基、C1-6烷氧基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(=O)R
8、-OC(=O)R
8、-C(=O)OR
8、-OR
8、-SR
8、-S(=O)R
8、-S(=O)
2R
8、-S(=O)
2N(R
8)
2、-N(R
8)
2、-C(=O)N(R
8)
2、-NR
8-C(=O)R
8、-NR
8-C(=O)OR
8、-NR
8-S(=O)
2-R
8、-NR
8-C(=O)-N(R
8)
2、-C1-6亚烷基-N(R
8)
2、-C1-6亚烷基-OR
8、-C1-6亚烯基-OR
8和-O-C1-6亚烷基-N(R
8)
2;m为0~4的整数,n为0~3的整数,
R
8为H、C1~C6烷基、饱和或部分不饱和的C
3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基,“—”划过的环结构的表达方式,表示连接位点于该环结构上任意能够成键的位置;
L是连接基团,其表示直链或支链的C3~C29的亚烷基链,其中所述直链或支链的C3~C29的亚烷基链可选地被一或多个选自-O-、-CO-、-C(=O)O-、-CONH-、-NHCO-、-NHCONH-、-NH-、-NR
8-、-C(R
8)
2-、-S-、亚磺酰基、磺酰基、亚磺酰氧基、磺酰氧基、-氨基磺酰基氨基-、亚炔基、亚烯基、亚环烷基、
或它们的任意组合中的二价基团中断一或多次,
E
3为下述基团
Z
1为O、S、NH、CH
2或者C=O,优选为CH
2或者C=O;
Z
4为N或CH,Z
4与Z
1、Z
2、Z
3中任一可相连的位置相连;
Z
5为N或CH,优选为N;
Z
10选自化学键、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基,优选为化学键、C1-6亚烷基;
Rc为卤素、氰基、硝基、羟基、酰胺基、C1~C6烷基、C1~C6烷氧基、取代C1~C6烷基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基,优选为C1~C6烷基、饱和或部分不饱和的C3-10环烃基、C6-10芳基、C6-12芳烷基,
本发明中设计合成的化合物能有效抑制SHP2的功能,同时也能降低细胞内SHP2的含量,具有较好的体内体外抗实体肿瘤和血液肿瘤的活性,对正常细胞毒性较低。
本发明的化合物在结构上具有独创性。该类化合物能够抑制SHP2的磷酸酯酶活性,抑制SHP2磷酸酯酶依赖性的信号通路传达,抑制下游蛋白ERK,STAT3,STAT5,c-SRC和JAK2等蛋白的活性,抑制肿瘤的恶性增殖和远端转移;同时可以阻断SHP2重要的磷酸酯酶非依赖的下游信号传达,抑制KRAS,NRAS等原癌基因活性,亦能稳定抑癌基因TP53,达到抑制肿瘤生长,浸润和转移的目的;该类化合物还可以有效的提高肿瘤微环境中T细胞的活性,一定程度上防止肿瘤细胞逃逸免疫监视。因此,本申请的化合物能够从SHP2磷脂酶依赖和磷脂酶非依赖两个途径影响SHP2的功能,达到抗肿瘤的目的,因此可解释为特异性抑制SHP2两方面功能,能够获得高效低毒的活性化合物。
以下对本发明的各要素进行更加详细的说明。
定义
除非在下文中另有定义,本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术,包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解,但仍然阐述以下定义以更好地解释本 发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的,且不排除其它未列举的元素或方法步骤。
如本文中所使用,术语“亚烷基”表示饱和二价烃基,优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基,例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用,术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中,烷基具有1至12个,例如1至6个碳原子。例如,如本文中所使用,术语“C1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基),其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH
2F、CHF
2、CF
3、CCl
3、C
2F
5、C
2Cl
5、CH
2CF
3、CH
2Cl或-CH
2CH
2CF
3等)。术语“C1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用,术语“烯基”意指线性的或支化的单价烃基,其包含一个双键,且具有2-6个碳原子(“C
2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时,所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用,术语“炔基”表示包含一个或多个三键的单价烃基,其优选具有2、3、4、5或6个碳原子,例如乙炔基或丙炔基。
如本文中所使用,术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环,诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基,或双环,包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)),其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如,术语“C
3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基),其任选地被1或多个(诸如1至3个)适合的取代基取代,例如甲基取代的环丙基。
如本文中所使用,术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个,更适合地具有3-6个)环碳原子的饱和(即,“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环,其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用,术语“杂环基”、“亚杂环基”和“杂环”是指具有例如3-10个(适合地具有3-8个,更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即,杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如,“3-10元(亚)杂环(基)”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环(基)。亚杂环基和杂环(基)的实例包括但不限于:(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯啉基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚)二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。所述基团也涵盖双环系统,包括螺环、稠合或桥连系统(诸如8-氮杂螺[4.5]癸烷、3,9-二氮杂螺[5.5]十一烷、2-氮杂双环[2.2.2]辛烷等)。亚杂环基和杂环(基)可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用,术语“(亚)芳基”和“芳环”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如,如本文中所使用,术语“C
6-10(亚)芳基”和“C
6-10芳环”意指含有6至10个碳原子的芳族基团,诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO
2、C
1-6烷基等)取代。
如本文中所使用,术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系,其具有5、6、8、9、10、11、12、13或14个环原子,特别是1或2或3或4或5或6或9或10个碳原子,且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫),并且,另外在每一种情况下可为苯并稠合的。特别地,“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、 (亚)三唑基、(亚)噻二唑基等,以及它们的苯并衍生物;或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等,以及它们的苯并衍生物。
如本文中所使用,术语“芳烷基”优选表示芳基或杂芳基取代的烷基,其中所述芳基、杂芳基和烷基如本文中所定义。通常,所述芳基可具有6-14个碳原子,所述杂芳基可具有5-14个环原子,并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用,术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用,术语“含氮杂环”指饱和或不饱和的单环或双环基团,其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子,其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C=O、S、S=O和S(=O)
2的环成员,其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接,所述含氮杂环任选地为苯并稠合的,并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替,条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”,则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代,则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代,则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组,则各取代基独立于另一者被选择。因此,各取代基可与另一(其他)取代基相同或不同。
如本文中所使用,术语“一个或多个”意指在合理条件下的1个或超过1个,例如2个、3个、4个、5个或10个。
除非指明,否则如本文中所使用,取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时,则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物,其与本发明的化合物相 同,除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(
2H)、氚(
3H));碳的同位素(例如
11C、
13C及
14C);氯的同位素(例如
36Cl);氟的同位素(例如
18F);碘的同位素(例如
123I及
125I);氮的同位素(例如
13N及
15N);氧的同位素(例如
15O、
17O及
18O);磷的同位素(例如
32P);及硫的同位素(例如
35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即
3H)及碳-14(即14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如
11C、
18F、
15O及
13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些,例如,D
2O、丙酮-d
6或DMSO-d
6。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中,其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地,本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解,本申请的范围涵盖所有这样的以任意比例(例如60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、99%)的异构体或其混合物。
本文中可使用实线(——)、实楔形
或虚楔形
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明,包括该碳原子处的所有可能的立体异构体(例如,特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明,存在所示的立体异构体。当存在于外消旋混合物中时,使用实及虚楔形以定义相对立体化学,而非绝对立体化学。除非另外指明,否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象, 且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物,其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解,本发明的某些化合物可以游离形式存在用于治疗,或适当时,以其药学上可接受的衍生物形式存在。在本发明中,药学上可接受的衍生物包括但不限于,药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物、螯合物、络合物、包合物或前药,在将它们向需要其的患者给药后,能够直接或间接提供本发明的化合物或其代谢物或残余物。因此,当在本文中提及“本发明的化合物”时,也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐,包括但不限于含有氢键或配位键的盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐(xinofoate)。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用,术语“酯”意指衍生自本申请中各个通式化合物的酯,其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在,其中本发明的化合物包 含作为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解,由于氮需要可用的孤对电子来氧化成氧化物,因此并非所有的含氮杂环都能够形成N-氧化物;本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的,包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述,参见例如:T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750;A.R.Katritzky和A.J.Boulton,Eds.,Academic Press;以及G.W.H.Cheeseman和E.S.G.Werstiuk,Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物,即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此,本发明包括本发明的化合物的代谢物,包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药,其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物,其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”,第14卷,ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”,H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中,保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的,由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现,例如,在 T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,JohnWiley&Sons,1991中所述的那些保护基,这些参考文献通过援引加入本文。使用本领域已知的方法,在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10%范围内,优选±5%范围内,更优选±2%范围内。
化合物
本发明的化合物具有式1所示的化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,
式1中,
X为卤素、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、优选为卤素、甲基、乙基、异丙基、环丙基,进一步优选为卤素,
X
1为NR
4、O或S,优选为O或S,更优选为O,其中,
X
7选自化学键、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基、-O-、-CO-、-C(=O)O-、-CONH-、-NHCO-、-NHCONH-、-NH-、-S-、亚磺酰基、磺酰基中的一种,优选为C1-6亚烷基,进一步优选为亚甲基、亚乙基、亚丙基,,
X
2、X
3、X
4、X
5和X
6各自独立地为CR
6或N,优选为CR
6,
R
1为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为C1-6烷基,进一步优选为选自甲基、乙基、异丙基、环丙基中的一种,
R
2为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为H、C1-6烷基,进一步优选为选自H、甲基、乙基中的一种,特别优选为H,
R
4、R
5各自独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基,
R
6为H、卤素、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或C6-12芳烷基,
R为H、卤素、NH
2、OH、SH、取代或未取代的C2-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的3-10元杂环基、取代或未取代的C6-10芳基、或者取代或未取代的5-14元杂芳基;
R优选为卤素、OH、SH、卤代烷基、氨基、饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C1-6烷基取代氨基、
或者
其中,V
1为选自C(R
8)
2、C(R
8)
2-C(R
8)
2、CR
8=CR
8、C=O、C(=O)C(R
8)
2、C(R
8)
2C(=O)、C(=O)O、OC(=O)、C(=O)NR、N=CR
8、CR
8=N、NR
8-C(R
8)
2或C(R
8)
2-NR
8中的一种;
R
9各自独立地选自选自卤素、羟基、氧代、氨基、氰基、硝基、-Si(R)
3、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(=O)R
8、-OC(=O)R
8、-C(=O)OR
8、-OR
8、-SR
8、-S(=O)R
8、-S(=O)
2R
8、-S(=O)
2N(R
8)
2、-N(R
8)
2、-C(=O)N(R
8)
2、-NR
8-C(=O)R
8、-NR
8-C(=O)OR
8、-NR
8-S(=O)
2-R
8、-NR
8-C(=O)-N(R
8)
2、-C1-6亚烷基-N(R
8)
2、-C1-6亚烷基-OR
8、-C1-6亚烯基-OR
8和-O-C1-6亚烷基-N(R
8)
2;m为0~5的整数,n为0~4的整数,
R
8为H、C1~C6烷基、饱和或部分不饱和的C
3-6环烃基、饱和或部分不饱和的 3-10元杂环基或者C6-10芳基,“—”划过的环结构的表达方式,表示连接位点于该环结构上任意能够成键的位置;
L是连接基团,其表示直链或支链的C3~C29的亚烷基链,其中所述直链或支链的C3~C29的亚烷基链可选地被一或多个选自-O-、-CO-、-C(=O)O-、-CONH-、-NHCO-、-NHCONH-、-NH-、-NR
8-、-C(R
8)
2-、-S-、亚磺酰基、磺酰基、亚磺酰氧基、磺酰氧基、-氨基磺酰基氨基-、亚炔基、亚烯基、亚环烷基、
或它们的任意组合中的二价基团中断一或多次,
E
3为下述基团
Z
1为O、S、NH、CH
2或者C=O,优选为CH
2或者C=O;
Z
4为N或CH,Z
4与Z
1、Z
2、Z
3中任一可相连的位置相连;
Z
5为N或CH,优选为N;
Z
10选自化学键、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基,优选为化学键、C1-6亚烷基;
Rc为卤素、氰基、硝基、羟基、酰胺基、C1~C6烷基、C1~C6烷氧基、取代C1~ C6烷基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基,优选为C1~C6烷基、饱和或部分不饱和的C3-10环烃基、C6-10芳基、C6-12芳烷基,
在优选的实施方式中,本发明的化合物具有下述式2的结构,
在式2中,X为卤素、C1-6烷基、饱和或部分不饱和的C3-10环烃基,优选为卤素,
在式2中,R
1为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为C1-6烷基,进一步优选为乙基,
在式2中,R
2为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为H,
在优选的实施方式中,本发明的化合物具有下述式3所示的结构,
在式3中,X为卤素、C1-6烷基、饱和或部分不饱和的C3-10环烃基,优选为卤素,R
1为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为C1-6烷基,进一步优选为乙基,
在优选的实施方式中,本发明的化合物具有下述式4所示的结构,
在式4中,R
3为CR
4R
5、NH、
O或S,优选为NR
4、
O或S,进一步优选为NH、
或O,R
4、R
5各自独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基,
在优选的实施方式中,本发明的化合物通式中,
E
3为选自下述基团中的一种,
以上基团通过*—或**—标记的两个位置之一与L连接,并且另一个位置与F连接,
F为H或下述基团中的一种,
在本发明优选的实施方式中,
R为卤素、OH、或者
其中,V
1为选自CH
2、CH
2—CH
2、CH=CH、NH-CH
2或CH
2-NH中的一种;R
7为选自H、C1~C6烷基、C1~C6烷氧基取代C1~C6亚烷基或者
中的一种,R
9与式1中的定义相同;
在另一优选的实施方式中,本发明的化合物通式中,R为以下基团中的一种,
在优选的实施方式中,本发明的化合物通式中,L为式5所示的二价基团,
n
0为0或1
m为1-5的整数、优选为2或3;n
1为0-3的整数,优选为1;n
2为0-3的整数,优选为1;n
3为0-3的整数,优选为1;n
4为0-3的整数,优选为1;n
5为0-3的整数,优选为1;
在另一优选的实施方式中,L为以下二价基团中的一种,
为了更加详细的说明本发明的化合物,以下例举出的代表性的具体结构,但是本发明并不限定于以下结构,表中还示出相应分子的编号和分子量。
本发明化合物获得的一般方法
本发明通式1所示的化合物可以通过公知方法获得,例如通过公知的有机合成方法进行合成。以下给出了实例性的合成路线,但是本领域人员也可以通过公知的其他方法获得。
在本发明中,对所述化合物的合成方法进行简要说明,通式1化合物的代表性合成路径如下,需要说明的是这里,选取X
1为O,X
2、X
3、X
4和X
5都为CH的式1化合物 的合成路线进行举例,X
1~X
5为其他并列技术方案的化合物的合成可通过替换相应的原料来实现。
代表性技术路线1:
【1】以I和II为起始原料,有机溶剂中,如二氯甲烷,三氯甲烷,乙酸乙酯或DMF等溶剂中,在碱性条件下与不同结构的II在5-100℃的条件下,保温反应1-48小时,制备可得到III;
【2】化合物III和化合物IV在碱性条件下,在5-150℃的条件下反应1-48小时,制备获得V;
【3】化合物V在碱性条件下,于5-100摄氏度条件下反应1-48小时,连接上不同的侧链VI(Linker,相当于是通式1中L的部分的原料),制备得到化合物VII;
【4】化合物VII和E
3在碱性条件下,于1-100℃反应1-48小时,制备得到本发明的化合物代表例A。合成路线图如下:
药物组合物和治疗方法
本发明提供一种药物组合物,其包含预防或治疗有效量的本发明化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,以及药学上可接受的载体,所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明提供一种本发明的化合物或其药学上可接受的盐、酯、光学异构体、立体 异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药或者、药物组合物在制备用于治疗SHP2磷酸酶调节的疾病的药物中的用途。
所述SHP2磷酸酶调节的疾病为肿瘤,例如实体肿瘤、血液肿瘤、恶性肿瘤、难治性肿瘤、原发或转移复发的肿瘤等。
所述SHP2磷酸酶调节的疾病,一般而言选自努南综合征、豹皮综合征、幼年性骨髓单核细胞白血病、成神经细胞瘤、黑素瘤、急性骨髓性白血病、乳腺癌、食管癌、肺癌、结肠癌、脑癌、成神经细胞瘤、头和颈鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤,但是并不限于这些。
本发明提供一种治疗SHP2磷酸酶调节的疾病的方法,该方法包括给予需要此治疗的人有效量的本发明化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药或者本发明药物组合物。
本发明的治疗方法,的目标疾病选自晚期实体肿瘤,包括原发或转移复发的NSCLC,肺鳞癌,肺腺癌,头和颈鳞状细胞癌、胃癌、结直肠癌、胰腺癌等;也包括乳腺癌、食管癌、肺癌、结肠癌、脑癌、成神经细胞瘤、成神经细胞瘤、黑素瘤、头和颈鳞状细胞癌、间变性大细胞淋巴瘤和成胶质细胞瘤;恶行血液肿瘤疾病包括幼年性骨髓单核细胞白血病、急性骨髓性白血病;SHP2异常表达相关的其他疾病如努南综合征、豹皮综合征、Ⅱ型糖尿病和肥胖症等。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物,并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体,例如水和油,包括那些石油、动物、植物或合成来源的油,例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时,水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体,特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还 可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体,如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的,它们可以适合的途径给药,例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射,包括滴注)或经皮给药;或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径,可以适合的剂型给药本发明的药物组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如,可给药单次推注,可随时间给药数个分剂量,或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意,剂量值可随要减轻的病况的类型及严重性而变化,且可包括单次或多次剂量。要进一步理解,对于任何特定个体,具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言,有效剂量在每日每kg体重约0.0001至约50mg,例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言,这会合计为约0.007mg/日至约3500mg/日,例如约0.7mg/日至约700mg/日。在一些情况下,不高于前述范围的下限的剂量水平可以是足够的,而在其它情况下,仍可在不引起任何有害副作用的情况下采用较大剂量,条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg,适合地是0.1-500mg,优选0.5-300mg,更优选1-150mg,特别优选1-50mg,例如1.5mg、2mg、4mg、10mg、25mg等。
除非另外说明,否则如本文中所使用,术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展, 或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物,例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物,例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
在一些实施方案中,本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。
图1是本发明的化合物体外降解SHP2试验结果图。
图2是本发明的化合物的体外降解SHP2活性统计图。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例
提供这些实施例并非意在限制本发明的范围。
化合物的结构通过核磁共振波谱(
1H NMR)和/或质谱(MS)进行确证。
化学位移(δ)以百万分之一(ppm)为单位给出。
1H NMR的测定在Bruker 400或Varian 300核磁仪上进行,测试溶剂为氘代甲醇(CD
3OD)、氘代氯仿(CDCl
3)或六氘代二甲基亚砜(DMSO-d
6),内标为四甲基硅烷(TMS)。
LC-MS的测定在Agilent LC-MS-1110液质联用仪、Agilent LC-MS-6110液质联用仪、Agilent LC-MS-6120液质联用仪(生产商:安捷伦)或者Shimadzu LC-MS 2020上进行。
制备高效液相色谱法使用MS触发自动纯化系统(Waters)、Gilson GX-281(Gilson)或半制备液相色谱仪(创新通恒LC3000(Ddlsogel,C18,30mm x 250mm 10μm))进行。
薄层色谱法(TLC)使用黄海牌HSGF 254(5×20cm)硅胶板进行,制备薄层色谱法采 用规格为烟台产GF 254(0.4~0.5nm)硅胶板进行。
采用薄层色谱法(TLC)或LC-MS检测反应,使用的展开剂体系包括二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系以及石油醚和乙酸乙酯体系,根据要分离的化合物的极性不同对展开剂体系进行调节(通过调节溶剂的体积比或者加入三乙胺等进行)。
微波反应使用CEM Discovery Sp(400W,RT~300℃)微波反应器进行。
柱色谱法一般使用于成化工200~300目硅胶为固定相。洗脱剂的体系包括二氯甲烷和甲醇体系和正己烷和乙酸乙酯体系,根据要分离的化合物的极性不同对洗脱剂体系进行调节(通过调节溶剂的体积比或者加入三乙胺等进行)。
如在实施例中无特殊说明,反应的温度为室温(20℃~30℃)。
实施例中所使用的试剂购自Aldrich Chemical Company、上海毕得医药科技有限公司、北京格林凯默有限公司、韶远科技(上海)有限公司或艾柏科技有限公司等公司。
中间体合成例1
取5g化合物I溶于20ml乙酸乙酯/二氯甲烷中,加入1gK
2CO
3和5.5ml吗啡啉,室温搅拌24小时后,过滤并使用乙酸乙酯/二氯甲烷洗,滤液旋干。加入水和乙酸乙酯/二氯甲烷提取酯层,使用酸洗,再中和调pH值到中性。乙酸乙酯/二氯甲烷萃取。无水氯化钠干燥,旋干得到黄色油状固体。柱层析纯化得到白色固体。1H NMR(CDCl3,300MHz):δ12.35(1H,s,OH),7.64(1H,s),6.42(1H,s),3.85(4H,s),3.65(4H,m),2.52(7H,m).1.52(3H,m).[M+H]
+279
中间体合成例2
取5g化合物I溶于20ml乙酸乙酯/二氯甲烷中,加入1gK
2CO
3和7g化合物II,于5-99℃搅拌0.5-48小时。饱和食盐水清洗三遍,碳酸钠干燥后旋。柱层析得到化合物III。1H NMR(400MHz,DMSO-d6)δ13.34(s,0H),10.97(s,1H),8.02(s,1H),7.33(s,1H),7.00(s,4H),6.73(s,1H),4.17(s,4H),2.61(s,4H),2.23(s,1H),1.84(d,J=39.3Hz,4H),1.39¨C 1.19(m,7H).[M+H]
+409
中间体合成例3
参照实施例1的操作,区别在于用不同结构的起始原料化合物II单取代或多取代氮烷基化合物于起始原料I反应得到下述化合物III。
中间体合成例4
取560mg化合物III,加入360mg化合物IV,800mg KOH,10ml乙醇,室温反应1-16小时,旋干后加入水和乙酸乙酯/二氯甲烷萃取,无水硫酸钠干燥酯层,旋干得到粗品,经过柱层析得到化合物V。[M+H]
+420.4。
中间体合成例5
取400mg化合物III,加入160mg化合物IV,500mg KOH,15ml乙醇,室温反应0.5-16小时,旋干后加入水和二氯甲烷萃取,无水硫酸钠干燥酯层,旋干得到粗品,经过柱层析得到化合物V。
1H NMR(400MHz,Chloroform-d)δ9.18(s,1H),8.16(d,J=15.6Hz,1H),7.85(d,J=9.0Hz,1H),7.75(dd,J=8.8,5.9Hz,1H),7.55(d,J=15.6Hz,1H),7.20(dd,J=8.4,2.6Hz,1H),7.15(s,1H),7.10-7.00(m,5H),6.50(d,J=9.1Hz,1H),6.06(s,1H),4.19-4.06(m,4H),3.58(s,2H),3.01(s,2H),2.55(s,2H),2.10-2.02(m,2H),1.49-1.37(m,4H),1.35-1.22(m,3H),0.92-0.81(m,2H).;(ESI-MS
m/z):[M+H]
+550.2。
化合物合成实施例
实施例1 TDC.2001的合成
取50mg TDP102197-SM1加入5ml超干DMF中,然后加入220mg NaHCO
3、100mg B-2RT搅拌,LC-MS监控直至B-1无剩余。向体系中加适量H
2O,用EA萃取,EA相浓缩至干得粗品,粗品经Per-TLC分离纯化(DCM:MeOH=20:1),得B-3产品120mg(产率:89.74%,纯度:94.32%),MS:307。
取120mg B-3加入1.5ml EtOH中,然后加入88mg KOH、254mg的B-4,RT搅拌,LC-MS监控直至B-3。反应体系用AcOH中和后,经Per-TLC分离纯化(DCM:MeOH=20:1,展开两遍),得产品275mg(产率:91.55%),MS:448。
取95mg B-5加入2ml超干DMF中,然后加入269mg B-7、245mg DIPEA,升温至60℃搅拌,LC-MS监控直至B-5无剩余。反应体系薄层上样,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品30mg(纯度:95.4%),MS:876。1H NMR(400MHz,DMSO-d6)δ11.1047(s,1H),9.0103(m,1H),8.3235(br s,1H),8.1298-8.0989(d,2H),7.9523-7.8647(t,1H),7.8320-7.7925(t,1H),7.5516-7.5302(d,1H),7.4647-7.4466(d,1H),6.9990(s,1H),6.7225-6.6998(d,1H),5.1063-5.0741(d,1H),4.3647-4.3417(t,2H),4.2337-4.1998(t,2H),3.8350-3.8121(t,2H),3.7441(s,1H),3.6772-3.6358(t,H),3.5610-3.5372(m,2H),3.3262(s,2H),2.9270-2.8351(q,2H),2.7759-2.7316(d,2H),2.5601-2.5255(t,4H),2.0461-1.9713(m,2H),1.6777(br s,2H),1.3899-1.3553(t,2H)。
实施例2 TDC.2002的合成
取100mg B-14加入2ml DMF中,然后加入210mg NaHCO
3、106mg B-2,加毕RT搅拌,平行投三批。LC-MS监控直至TDP102101-3无剩余。抽滤,ACN淋洗滤饼,滤液浓缩后经Per-TLC分离纯化(DCM:MeOH=20:1),得产品333mg(产率:58.65%,纯度:93%),MS:278。
1H NMR(400MHz,CDCl3-d)δ7.70(t,1H),6.48(s,1H),4.08 (q,2H),3.75(d,2H),2.84-2.78(m,4H),2.78-2.71(m,4H),2.63(p,1H),1.43(t,3H).
取160mg B-15加入2ml EtOH中,然后加入90mg KOH、280mg B4,RT搅拌,LC-MS监控直至B-15无剩余。反应体系用AcOH中和后,经Per-TLC分离纯化(DCM:MeOH=20:1,),得产品136mg(纯度:90%,产率:64.72%),MS:419。
取55mg B-17加入2ml超干DMF中,然后加入200mg B-7、145mg DIPEA,升温至60℃搅拌,LC-MS监控直至B-17无剩余。反应体系薄层上样,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品13mg(纯度:93.6%),MS:802
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.00(m,1H),7.97(d,1H),7.80(m,1H),7.58(dd,1H),7.53(dd,1H),7.44(m,1H),7.37(m,1H),6.99(m,1H),6.90(m,1H),6.69(m,1H),6.56(s,1H),4.63(tm,1H),4.56(dd,1H),4.08(m,2H),3.75(d,2H),3.65(s,4H),3.64(m,4H),3.60-3.49(m,2H),3.50(s,1H),3.49(m,1H),3.42(m,2H),2.84-2.78(m,4H),2.78-2.71(m,4H),2.63(m,1H),2.60-2.48(m,2H),2.16-2.00(m,2H),1.43mm,3H).
实施例3 TDC.2003的合成
取100mg B-8加入2ml DMF中,然后加入210mg NaHCO
3、106mg B-2,加毕RT搅拌,平行投三批。LC-MS监控直至B-8无剩余。抽滤,ACN淋洗滤饼,滤液浓缩后经 Per-TLC分离纯化(DCM:MeOH=20:1),得产品333mg(产率:58.65%,纯度:93%),MS:408。
1H NMR(400MHz,CDCl3)δ12.88(s,1H),9.74(s,1H),7.69(d,1H),7.13-6.94(m,3H),6.98-6.89(m,1H),6.54(s,1H),6.46(d,1H),4.20(s,2H),4.10(q,2H),3.13(t,H),2.58(s,3H),2.25(t,2H),2.03-1.97(m,2H),1.34(t,3H).
取200mg B-9加入2ml EtOH中,然后加入110mg KOH、319mg B-10,RT搅拌,LC-MS监控直至B-9无剩余。反应体系用AcOH中和后,经Per-TLC分离纯化(DCM:MeOH=20:1,),得产品296mg(纯度:90%,产率:84.72%),MS:714。
1H NMR(400MHz,CDCL3)δ9.05(s,1H),8.20(d,1H),7.86(d,1H),7.68(d,H),7.47(d,1H),7.15(s,1H),7.05(d,3H),6.89(d,1H),6.80(dd,1H),6.48(d,H),6.04(s,1H),5.30(s,1H),4.23-3.91(m,5H),3.58(t,7H),3.29(t,4H),3.13(s,1H),2.95(s,2H),2.51(s,2H),2.08(s,2H),1.49(s,9H),1.42(t,3H).
取290mg B-11加入3ml DCM中,然后加入1ml TFA,RT搅拌,LC-MS监控直至B-11无剩余。反应体系浓缩至干,用TEA中和后,经Per-TLC分离纯化(DCM:MeOH=20:1,展开两遍),得产品150mg(产率:58.94%,纯度:98%),MS:614。
取200mg B-13加入2ml DMF中,然后加入4eq DIPEA、122mg B-19,RT搅拌,LC-MS监控直至B-13无剩余.Pre-TLC纯化,DCM:MeOH=10:1得产品180mg(纯度:92%)MS:1025;
1H NMR(400MHz,CDCl3)δ9.51(s,1H),8.11(m,1H),7.97(d,1H),7.80(m,1H),7.72-7.60(m,3H),7.58-7.49(m,2H),7.42(m,1H),7.27(m,1H),7.16(m,1H),6.97(d,1H),6.80(m,1H),6.56(s,1H),5.50(m,1H),5.41(m,1H),4.08(m,2H),3.85(d,2H),3.55-3.48(m,4H),3.45(m,2H),3.33-3.26(m,4H),2.94-2.81(m,3H),2.64-2.49(m,2H),2.41(m,2H),2.31(m,2H),2.15-2.03(m,3H),1.71-1.56(m,4H),1.43(mm,3H),1.41-1.27(m,4H).
实施例4 TDC.2004的合成
称取B41 125mg,碳酸氢钠200mg,DMF 5ml加入到单口瓶中,加入130mg的B-2,室温下搅拌3小时,LC-MS监控反应进程,结束后将反应液过滤,收集的滤液经过薄层制备分离,展开剂DCM:MeOH(20:1),MS:.410.20
取100mg B-42加入2ml EtOH中,然后加入110mg KOH、110mg B-10,RT搅拌,LC-MS监控直至B-42无剩余。Per-TLC分离纯化(DCM:MeOH=20:1,展开两遍),得产品296mg(纯度:90%,产率:84.72%),MS:716。MS:716.34
取100mg B-43加入1ml DCM中,然后加入1ml TFA,RT搅拌,LC-MS监控直至B-43无剩余。反应体系浓缩至干,用TEA中和后,经Per-TLC分离纯化(DCM:MeOH=20:1,展开两遍),得产品52mg(产率:58.94%,纯度:98%),MS:616。
取200mg B-43加入2ml DMF中,然后加入110mg DIPEA、319mg B-10,RT搅拌,LC-MS监控直至B-43无剩余.Pre-TLC纯化,DCM:MeOH=10:1得产品180mg(纯度:92%)MS:1013.5;
1H NMR(400MHz,CDCl3)δ9.51(s,1H),8.11(m,1H),7.97(d,1H),7.80(m,1H),7.70-7.60(m,2H),7.58-7.49(m,2H),7.46-7.39(m,1H),7.42-7.32(m,1H),7.21-7.08(m,2H),6.97(d,1H),6.80(m,1H),6.56(s,1H),5.41(m,1H),4.50(m,1H),4.08(m,2H),3.85m,1H),3.76(m,1H),3.55-3.48(m,4H),3.33-3.26(m,4H),3.13(m,1H),3.02(m,1H),2.92-2.81(m,1H),2.77-2.49(m,4H),2.41(m,2H),2.31(m,2H),2.15-2.03(m,1H),1.96-1.83(m,2H),1.77-1.46(m,9H),1.43(m,3H).
实施例5 TDC.2005的合成
取45mg B-51加入2ml超干DMF中,然后加入100mg B-7、145mg DIPEA,升温至60℃搅拌,LC-MS监控直至B-51无剩余。反应体系薄层上样,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品34mg(纯度:92.1%),MS:816
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.00(d,1H),7.97(m,1H),7.80(m,1H),7.58(d,1H),7.53(d,1H),7.44(m,1H),7.37(m,1H),6.99(m,1H),6.90(dd,1H),6.69(m,1H),6.56(s,1H),4.63(m,1H),4.56(d,1H),4.08(m,2H),3.75(d,2H),3.65(s,4H),3.64(m,4H),3.60-3.49(m,2H),3.50(s,1H),3.49d,0H),3.42(m,2H),2.61-2.47(m,6H),2.50-2.41(m,4H),2.16-2.00(m,2H),1.43(m,3H).
实施例6 TDC.2006的合成
取B-61 75mg,B-62 156mg和碳酸氢钠200mg,DMF 5ml加入到单口瓶中,反应2小时后柱层析处理得到产物20mg(纯度:88%)。MS:=803。
1H NMR(400MHz,CDCl3)δ9.51(s,1H),7.97(d,1H),7.80(m,1H),7.71(m,1H),7.61-7.49(m,3H),7.45(m,1H),7.09(m,1H),6.90(d,1H),6.69(m,1H),6.56(s,1H),5.41(m,1H),4.63(mm,1H),4.08(m,2H),3.75(d,2H),3.70(s,1H),3.72-3.66(m,3H),3.65(s,4H),3.64(m,4H),3.50(m,2H),3.42(m,2H),2.92-2.81(m,1H),2.67-2.59(m,4H),2.63-2.49(m,2H),2.15-2.03(m,1H),1.43(m,3H).
实施例7 TDC.2007的合成
称取咪唑1.4g,B-71 1g,DCM12ml加入到50ml单口瓶中,降温到0℃以下,开启搅拌,称取TBDPS-Cl 3.3g滴加到反应体系中,滴加完毕后保温搅拌3小时,LC-MS监控,反应结束后加入10ml饱和碳酸氢钠溶液洗涤,收集有机相加入4.0g硅胶拌样,柱层析纯化,得无色油状物,收率55.9%。MS:340.2
称取220mg B-72,440mg B-2,300mg碳酸氢钠,6ml DMF加入到单口瓶中,室温下搅拌过夜,反应结束后减压过滤,收集的有机相经过中压制备纯化,收集90%乙腈洗脱部分,减压蒸干,液质确认,得黄色油状物,收率63.6%。MS:532.29
称取300mgB-73,366mg的B-10,127mgKOH和5mlEtOH,加入到25ml单口瓶中,室温下搅拌过夜,LC-MS监控反应进程。反应结束后减压蒸干反应体系,加入EA,水各15ml分液,并加入几滴醋酸,水相pH调整至6左右,分液收集有机相,上薄层制备分离,展开剂PE;EA=1:1,收集Rf值约为0.5的黄色色带。浓缩至干得黄色油状物,收率72.9% MS:672
称取200mg B-77,5ml 1MTBAF的四氢呋喃溶液,室温下搅拌2小时,反应液直接经过中压制备分离,乙腈/水(含0.1%甲酸)梯度洗脱,得到产物93mg MS:818.3HNMR:
1H NMR(400MHz,CDCl3)δ9.51(s,1H),7.97(d,1H),7.80(m,1H),7.71(m,1H),7.61-7.49(m,3H),7.45(m,1H),7.09(m,1H),6.90(d,1H),6.69(m,1H),6.56(s,1H),5.41(m,1H),4.63(m,1H),4.08(m,2H),3.79(m,1H),3.70(m,1H),3.70-3.58(m,10H),3.50(m,2H),3.48-3.41(m,1H),3.45-3.38(m,2H),2.92-2.81(m,2H),2.77(m,1H),2.74-2.66(m,1H),2.64-2.49(m,2H),2.15-2.03(m,1H),1.82-1.60(m,4H),1.43(m,3H).
实施例8 TDC2008的合成
取200mg B-81加入4ml DMF中,然后加入880mg NaHCO
3、400mg B-2,加毕RT搅拌。LC-MS监控直至B-81无剩余。抽滤,ACN淋洗滤饼,滤液浓缩后经Per-TLC分离纯化(DCM:MeOH=20:1),得产品334mg(纯度:82%),MS:308。
取303mg B-82加入4ml EtOH中,然后加入221mg KOH、640mg B-10,RT搅拌,LC-MS监控直至B-82无剩余。反应体系用AcOH中和后,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品446mg(纯度:90%,产率:73.79%),MS:554。
取446mg B-83加入4ml DCM中,然后加入2ml TFA,RT搅拌,LC-MS监控直至B-83无剩余。反应体系浓缩至干,用TEA中和后,经Per-TLC分离纯化(DCM:MeOH=20:1),得油状物(纯度:90%),按0.726mmol投下一步,MS:445。
将0.726mmol B-84中加入3ml DMF中,然后加入1055mg B-61、938mg DIPEA升温至80℃搅拌,LC-MS监控直至TDP102215-3无剩余。将体系经Per-TLC分离纯化(DCM:MeOH=20:1,展开两遍),得产物粗品,粗品经半制备反相分离纯化后又经Per-TLC分离纯化(DCM:MeOH=20:1)得24mg(纯度:89.07%),MS:832。
1H NMR(400MHz,Chloroform-d)δ9.51(s,1H),7.97(dd,1H),7.80(m,1H),7.71(m,1H),7.61-7.49(m,3H),7.45(m,1H),7.09(m,1H),6.90(d,1H),6.69(m,1H),6.56(s,1H),5.41(m,1H),4.63(mm,1H),4.08(m,2H),3.81(mm,1H),3.70(m,1H),3.65(s,4H),3.67-3.60(m,4H),3.50(m,2H),3.42(m,2H),3.39-3.27(m,2H),3.31(s,3H),2.92-2.79(m,3H),2.69(m,1H),2.64-2.49(m,2H),2.15-2.03(m,1H),1.82-1.73(m,1H),1.77-1.69(m,2H),1.73-1.62(m,1H),1.43(m,3H).
实施例9 TDC2009的合成
称取140mg B-43和330mg B-61,300mg DIPEA在3ml DMF加入到单口圆底烧瓶中,80℃保温搅拌5-6小时,反应结束后,加入EA和水各15ml分液,并用水洗涤2次,有机相经过无水硫酸钠干燥,减压浓缩得到的粗品经过中压制备分离,反相条件乙腈/水梯度洗脱,得到产物。MS:1003,HNMR:
1H NMR(400MHz,CDCl3)δ9.51(s,1H),7.97(d,1H),7.80(m,1H),7.71(tm,1H),7.58-7.49(m,3H),7.45(mm 1H),7.09(m,1H),6.97(m,1H),6.80(m,1.9Hz,1H),6.56(s,1H),5.41(m,1H),4.08(m,2H),3.81(m,1H),3.70m,1H),3.70-3.60(m,6H),3.58-3.46(m,4H),3.39-3.23(m,9H),2.92-2.74(m,7H),2.73-2.64(m,3H),2.64-2.49(m,2H),2.15-2.03(m,1H),1.81-1.73(m,1H),1.77-1.69(m,2H),1.73-1.62(m,1H),1.43(m,3H).
实施例10 TDC2010的合成
取57mg B-13加入2ml DMF中,然后加入133mg的B-76、119mg DIPEA、温至80℃搅拌,LC-MS监控直至B-13无剩余。将体系40℃减压浓缩至干,用适量DCM溶解后薄层上样,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品42mg,又经半制备反相分离纯化得8mg(纯度:92.9%),MS:1002。
1H NMR(400MHz,DMSO-d
6)δ11.10(s,1H),10.93(s,1H),8.34(s,1H),8.26(d,1H),8.13-8.03(m,2H),7.91-7.73(m,2H), 7.54(d,H),7.45(m,1H),6.98(s,6H),6.67(d,H),5.89(s,1H),5.08(m,2H),4.35(m,2H),4.16(m,2H),3.82(m,3H),3.77-3.61(m,5H),3.60-3.50(m,5H),2.88(s,1H),2.71(d,2H),2.64-2.50(m,2H),2.29(s,3H),2.11-1.95(m,2H),1.38-1.26(m,4H),1.23(s,5H).
实施例11 TDC2011的合成
取100mg B-5加入3ml DMF中,然后加入1.5ml DIPEA,60度搅拌,LC-MS监控直至B-55无剩余。反应体系浓缩至干,用TEA中和后,经Per-TLC分离纯化(DCM:MeOH=10:1),得产品46mg(产率:40.12%,纯度:77%)
取275mg B-112加入3ml DCM中,然后加入1.5ml CF
3COOH,RT搅拌,LC-MS监控直至B-112无剩余。反应体系浓缩至干,用TEA中和后,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品144mg(产率:62.69%,纯度:93%),MS:513。
1H NMR(400MHz,DMSO-d6)δ14.0677(br s,1H),8.9402(br s,2H),8.3977-8.3751(d,1H),8.2115-8.1890(d,1H),8.1500-8.1118(d,H),7.9709-7.9329(d,1H),7.1450-7.1388(d,1H),7.0978-7.0755(d,1H),6.7485-6.7257(d,1H),4.2445-4.2081(m,2H),3.9016(br s,2H),3.7234(s, 1H),3.6013-3.5757(m,4H),3.4525(s,1H),3.2387-3.2123(m,4H),3.12-3.0698(m,4H),1.7394(br s,2H),1.4043-1.3697(m,3H)。
取95mg B-113加入2ml DMF中,然后加入269mg B-76、239mg DIPEA、升温至80℃搅拌,LC-MS监控直至B-113无剩余。反应体系薄层上样,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品30mg(纯度:12.8%+85%),MS:901。1H NMR(400MHz,DMSO-d6)δ11.1047(s,1H),8.3235(br s,1H),8.1298-8.0989(d,2H),7.9523-7.8647(m,1H),7.8320-7.7925(m,1H),7.5516-7.5302(d,1H),7.4647-7.4466(d,1H),6.9990(s,1H),6.7225-6.6998(d,1H),5.1063-5.0741(d,1H),4.3647-4.3417(m,2H),4.2337-4.1998(m,2H),3.8350-3.8121(m,2H),3.7441(s,1H),3.6772-3.6358(m,2H),3.5610-3.5372(m,2H),3.3262(s,10H),2.9270-2.8351(m,2H),2.7759-2.7316(d,2H),2.5601-2.5255(m,4H),2.0461-1.9713(m,2H),1.6777(br s,2H),1.3899-1.3553(m,2H)。
实施例12 TDC2012的合成
称取咪唑1.4g,B-71 1g,DCM12ml加入到50ml单口瓶中,降温到0℃以下,开启搅拌,称取TBDPS-Cl 3.3g滴加到反应体系中,滴加完毕后保温搅拌3小时,LC-MS监控,反应结束后加入10ml饱和碳酸氢钠溶液洗涤,收集有机相加入4.0g硅胶拌样,柱层析纯化,得无色油状物,收率55.9%。MS:340.2
称取220mg B-72,440mg B-2,300mg碳酸氢钠,6ml DMF加入到单口瓶中,室温下搅拌过夜,反应结束后减压过滤,收集的有机相经过中压制备纯化,收集90%乙腈洗脱部分,减压蒸干,液质确认,得黄色油状物,收率63.6%。MS:532.29
称取300mgB-73,366mgB-10,127mgKOH和5mlEtOH,加入到25ml单口瓶中,室温下搅拌过夜,LC-MS监控反应进程。反应结束后减压蒸干反应体系,加入EA,水各15ml分液,并加入几滴醋酸,水相pH调整至6左右,分液收集有机相,上薄层制备分离,展开剂PE;EA=1:1,收集Rf值约为0.5的黄色色带。浓缩至干得黄色油状物,收率72.9% MS:838.2
称取340mg B-74,2ml TFA,6ml DCM,加入到单口瓶中,室温下开启搅拌3h,反应结束后减压蒸干,剩余物用少量DCM稀释,加入TEA中和剩余三氟乙酸,直接上薄层制备分离,DCM/MeOH30:1展开,收集Rf值为0.1的橙黄色色带,LC-MS确认,减压浓缩得黄色油状物,241mg,收率80% MS:.738.3548
称取240mg B-75,230mgB-10,400mgDIPEA,5mlDMF加入到50ml单口瓶中,80℃搅拌过夜,反应液冷却降温后,上薄层制备分离,展开剂DCM/MeOH=15:1,收集Rf值约0.5的黄色色带,过滤浓缩得黄色油状物170mg,收率54.6%。LMS:1126.38
称取200mg B-77,5ml 1MTBAF的四氢呋喃溶液,室温下搅拌2小时,反应液直接经过中压制备分离,乙腈/水(含0.1%甲酸)梯度洗脱,得到产物为棕色油状物100mg纯度95%产率:61% MS:888.36HNMR:1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.30(s,2H),8.15(d,H),8.10-7.99(m,1H),7.82(dd,8.7Hz,2H),7.54(d,1H),7.45(d,1H),7.05-6.93(m,2H),6.64(d,1H),5.08(dd,1H),4.39-4.31(m,2H),4.15(s,2H),3.92(d,1H),3.82(d,1H),3.82(s,2H),3.70-3.60(m,3H),3.59-3.50(m,5H),3.30(s,5H),3.16(s,2H),3.16(d,1H),2.96-2.76(m,1H),2.63-2.50(m,3H),2.06-1.96(m,2H),1.81(s,1H),1.57(s,4H),1.34(dt,3H),1.24(s,4H),0.94(t,2H).
实施例13 TDC2013
取200mg B-121加入4ml DMF中,然后加入880mg NaHCO
3、400mg B-2,加毕RT 搅拌。LC-MS监控直至B-121无剩余。抽滤,ACN淋洗滤饼,滤液浓缩后经Per-TLC分离纯化(DCM:MeOH=20:1),得产品334mg(产率:62.63%,纯度:82%),MS:308。
取303mg B-122加入4ml EtOH中,然后加入221mg KOH、640mg B-10,RT搅拌,LC-MS监控直至B-122无剩余。反应体系用AcOH中和后,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品446mg(纯度:88%,产率:73.79%),MS:614。
取446mg B-123加入4ml DCM中,然后加入2ml TFA,RT搅拌,LC-MS监控直至B-123无剩余。反应体系浓缩至干,用TEA中和后,经Per-TLC分离纯化(DCM:MeOH=20:1),得油状物(纯度:99%),按0.726mmol投下一步,MS:514。
将0.726mmol B-124中加入3ml DMF中,然后加入1055mg B-76、938mg DIPEA,升温至770℃搅拌,LC-MS监控直至B-124无剩余。将体系经Per-TLC分离纯化 (DCM:MeOH=20:1,展开两遍),得产物粗品,粗品经半制备反相分离纯化后又经Per-TLC分离纯化(DCM:MeOH=20:1)得342mg(纯度:547.07%),MS:902。
1H NMR(400MHz,DMSO-d
6)δ11.11(s,1H),8.41(s,1H),8.17(d,1H),8.10-8.00(m,2H),7.89-7.76(m,2H),7.54(d,1H),7.45(d,1H),6.97(d,2H),6.64(d,1H),5.08(m,1H),4.35(m,2H),4.15(m,2H),3.94(d,1H),3.82(mm,2H),3.70-3.57(m,3H),3.59-3.44(m,6H),3.26(s,3H),3.18(m,1H),2.96-2.75(m,1H),2.80(s,1H),2.71(s,1H),2.63-2.50(m,2H),2.37-2.27(m,1H),2.10-1.96(m,2H),1.81(d,1H),1.62-1.49(m,4H),1.38(m,3H),1.33-1.20(m,5H),0.85(m,1H)
实施例14 TDC2014的合成
称取140mgB-43,350mg B-141,300mg DIPEA,10mlDMF加入到单口圆底烧瓶中,80℃保温搅拌5-6小时,反应结束后,加入EA和水各15ml分液,并用水洗涤2次,有机相经过无水硫酸钠干燥,减压浓缩得到的粗品经过中压制备分离,反相条件乙腈/水梯度洗脱,得到产物155mg纯度91.1%产率:64%。MS:1047.HNMR:
1H NMR(400MHz,CDCl3)δ9.51(s,1H),7.97(d,1H),7.80(m,1H),7.71(m,1H),7.58-7.49(m,3H),7.49-7.39(m,2H),7.39-7.32(m,1H),7.21-7.06(m,3H),6.97(d,1H),6.80(m 1H),6.56(s,1H),5.41(m,1H),4.50(m,1H),4.08(m,2H),3.85(mm,1H),3.76(m,1H),3.71-3.61(m,10H),3.58-3.46(m,4H),3.30-3.23(m,4H),3.13(m,1H),3.02(m,1H),2.92-2.81(m,1H),2.81-2.71(m,4H),2.76-2.63(m,4H),2.63-2.49(m,2H),2.15-2.03(m,1H),1.96-1.83(m,2H),1.77-1.62(m,2H),1.43m,3H).
实施例15 TDC2015的合成
取Compound1加入70ml SM2和8g NaHCO
3,加热到120度继续反应36h,加水终止反应,全部反应Ar保护。乙酸乙酯萃取,NaSO4干燥,旋干。正相柱层析,EA:PE=1:1;得到产品16g纯度95%,产率:76%,MS:333.
1H NMR(400MHz,CDCl3)10.32(s,1H),9.51(s,1H),7.88(d,1H),6.97(d,1H),6.92(m,1H),4.21(m,2H),3.90-3.85(m,2H),3.74-3.65(m,19H),3.61(m,5H),3.26(s,3H).
取4.2g SM2加入100ml THF和20mL甲醇,0度缓慢加入3.4g t-BuOK,0度继续反应30分钟,继续加入5.5g Compound2,全部反应Ar气保护,缓慢升到室温反应24h。液质监控原料反应完全,产物生成,加水淬灭反应,乙酸乙酯萃取,NaSO4干燥,旋干。粗产品直接投下步反应18g。MS:639,
取SM4 94mg加入5ml DMSO和1ml THF,-10度,Ar气保护,加入叔丁醇钾62mg,0度继续搅拌60min。然后加入Compound3(135mg,1.0eq),自然升至室温,搅拌过夜。LCMS监控无原料剩余。将反应液缓慢滴加到1SM HCl水溶液中进行淬灭,淬灭后体系pH在6~7之间。DCM:MeOH=10:1混合溶剂进行萃取,无水硫酸钠干燥,浓缩旋干。Prep-TLC纯化,DCM:MeOH=10:1,得到淡黄色固体产品90mg产率:39.4% MS:[M-H]1008。
取Compound4 51mg加入10mlDMF,然后加入无水对甲苯磺酸28.5mg,升温至110度,搅拌6小时。LCMS监控无原料剩余。反向柱纯化,ACN:H2O(FA)=3:2,得到白色固体状产品5mg(产率:10.7%)MS:990。HNMR:
1H NMR(400MHz,CDCl3)δ9.51(s,1H),7.97(d,1H),7.82-7.74(m,2H),7.72-7.65(m,1H),7.58(d,1H),7.53(d,1H),7.45-7.38(m,1H),7.36(d,1H),7.27(m,1H),7.16(m,1H),6.94(mm,1H),6.90(d 1H),6.69(m,1H),6.56(s,1H),5.50(m,1H),5.24(m,1H),5.09(m,1H),4.66(m,1H),4.08(m,2H),3.83(d,2H),3.67-3.62(m,6H),3.59(m,2H),3.52(m,4H),3.47-3.38(m,6H),2.94-2.87(m,2H),2.90-2.81(m,1H),2.64-2.49(m,2H),2.15-2.03(m,2H),1.85(m,2H),1.43m,3H).
实施例16 TDC2016的合成
取82mg TDC.2006溶于10ml DMF终加入,15mg B-181,80度反应16小时,柱层析纯化,EA正己烷,1~20%。得到产品20mg产率:25%纯度:92%.MS:916.NMR:
1H NMR(400MHz,CDCl3)δ8.00(m,1H),7.97(d,1H),7.80(m,1H),7.58(d,1H),7.53(d,1H),7.44(m,1H),7.37m,1H),7.06-6.96(m,2H),6.90(ddd,1H),6.69(m,1H),6.56(s,1H),4.76(d,1H),4.63(m,1H),4.08(m,2H),3.80-3.70(m,3H),3.65(s,4H),3.64(m,4H),3.50(m,2H),3.42(m,2H),2.67-2.54(m,2H),2.54-2.47(m,4H),2.47-2.41(m,4H),2.34(m,2H),2.25(m,1H),2.11(m,1H),1.58(dd,3H),1.43(m,3H),1.13(m,3H).
实施例17 TDC2017的合成
将0.726mmol B-84中加入3ml DMF中,然后加入1055mg B-76、938mg DIPEA、,升温至50℃搅拌,LC-MS监控直至B-84无剩余。将体系经Per-TLC分离纯化(DCM:MeOH=20:1),得产物粗品,粗品经半制备反相分离纯化后又经Per-TLC分离纯化(DCM:MeOH=20:1)得24mg纯度:85.07%,MS:833。
1H NMR(400MHz,CDCL3)δ9.51(s,1H),7.97(d,1H),7.80(m,1H),7.74(m,1H),7.61-7.44(m,3H),7.05(m,1H),6.90(d,1H),6.69(m,1H),6.56(s,1H),5.41(mm,1H),4.63(m,1H),4.18(m,2H),4.08(mm,2H),3.85-3.75(m,3H),3.70(m,1H),3.67(dd,2H),3.67-3.60(m,4H),3.42(m,2H),3.39-3.27(m,2H),3.31(s,3H),2.92-2.79(m,3H),2.73-2.64(m,1H),2.64-2.49(m,2H),2.15-2.03(m,1H),1.82-1.73(m,1H),1.77-1.69(m,2H),1.73-1.62(m,1H),1.43(m,3H).
实施例18 TDC2018的合成
44.6mg B-5加入100ml THF和20mL甲醇,0度缓慢加入34mg t-BuOK,60度继续反应30分钟,继续加入80mg B-181,全部反应Ar气保护,缓慢升到室温反应24h。液质监控原料反应完全,产物生成,加水淬灭反应,乙酸乙酯萃取,NaSO
4干燥,旋干。粗产品直接投下步反应18mg。MS:876。
1H NMR(400MHz,CDCl3)δ9.51(s,1H),7.95(d,1H),7.78-7.69(m,2H),7.61-7.44(m,3H),7.05(m,1H),6.90(d,1H),6.72-6.64(m,2H),6.54(s,2H),5.41(m,1H),4.63(m,1H),4.18(m,2H),4.08(m,2H),3.92(d,1H),3.82-3.73(m,3H),3.73-3.66(m,2H),3.70-3.60(m,8H),3.46-3.38(m,3H),2.90(m,2H),2.91-2.81(m,1H),2.64-2.49(m,2H),2.15-2.04(m,1H),2.04-1.87(m,2H),1.87-1.74(m,2H),1.43(m,3H).
实施例19 TDC2019的合成
取95mg B-5加入2ml超干DMF中,然后加入269mg B-7、245mg DIPEA,升温至60℃搅拌,LC-MS监控直至B-5无剩余。反应体系薄层上样,经Per-TLC分离纯化(DCM:MeOH=20:1),得产品30mg(纯度:95.4%),MS:876。1H NMR(400MHz,DMSO-d6)δ11.1047(s,1H),9.0103(m,1H),8.3235(br s,1H),8.1298-8.0989(d,2H),7.9523-7.8647(t,1H),7.8320-7.7925(t,1H),7.5516-7.5302(d,1H),7.4647-7.4466(d,1H),6.9990(s,1H),6.7225-6.6998(d,1H),5.1063-5.0741(d,1H),4.3647-4.3417(t,2H),4.2337-4.1998(t,2H),3.8350-3.8121(t,2H),3.7441(s,1H),3.6772-3.6358(t,H),3.5610-3.5372(m,2H),3.3262(s,2H),2.9270-2.8351(q,2H),2.7759-2.7316(d,2H),2.5601-2.5255(t,4H),2.0461-1.9713(m,2H),1.6777(br s,2H),1.3899-1.3553(t,2H)。
取83mg B-191溶于10ml DMF终加入,25mg B-181,80度反应16小时,柱层析纯化,EA正己烷,1~20%。得到产品9mg产率:12%纯度:92%.
1H NMR(400MHz,CDCl3)δ7.97(d,1H),7.79(mm,1H),7.71(m,1H),7.61-7.49(m,3H),7.45(m,1H),7.09(m,1H),6.90(d,1H),6.69(m,1H),6.55(d,3H),5.82(m,1H),5.79(s,2H),4.63(m,1H),4.08(m,2H),3.89(m,1H),3.73(m,1H),3.68-3.60(m,8H),3.50(m,2H),3.42(m,2H),3.36(m,1H),2.93-2.78(m,2H),2.68-2.55(m,2H),2.29-2.11(m,2H),2.04-1.87(m,2H),1.87-1.75(m,2H),1.43(m,3H),1.19(s,7H).
实施例20 TDC2020的合成
方法同前,MS:1118.68NMR:1H NMR(400MHz,CDCl3)δ7.97(dd,1H),7.87(m,1H),7.80(m,1H),7.58-7.50(m,2H),7.50-7.42(m,1H),7.46-7.39(m,1H),7.39-7.32(m,1H),7.26(dm,1H),7.21-7.08(m,2H),6.97(dd,1H),6.80(m,1H),6.56(s,1H),5.84(s,2H),4.56-4.45(m,2H),4.19(mm,2H),4.12-4.00(m,3H),3.85(dm,1H),3.82-3.72(m,3H),3.71-3.61(m,4H),3.55(m,2H),3.30-3.23(m,4H),3.13(m,1H),3.02(m,1H),2.81-2.71(m,4H),2.75-2.62(m,4H),2.65-2.54(m,2H),2.24(m,1H),2.17-2.04(m,1H),1.89(mm,2H),1.77-1.62(m,2H),1.43(mm,3H),1.19(s,7H).
药理活性测试
本发明的各化合物生物活性通过以下方法测定:
试剂:完全DMEM培养基,Gibco公司产品。胎牛血清,ThermoFisher出品。胰蛋白酶。ThermoFisher公司生产。SHP-2抗体由CST公司生产。
细胞株,MV411,双表型B-粒单核细胞白血病患者的母细胞,由Rovera建立。
测定方法:取对数期生长的细胞,收集悬浮于含10%胎牛血清的DMEM中,用移液管轻轻吹打成单细胞悬液,显微镜下计算活细胞。10cm培养皿中接种培养细胞悬液9ml,细胞终浓度为2X10
5/ml,在37℃、5%CO
2的培养条件下预培养24小时后,加入不同浓度的本发明的化合物(TDC.2009和TDC.2020)的DMSO溶液(DMSO的终浓度不超过0.5%),阴性Control组加入相同体积的DMSO。再绩效培养24小时。收集所有细胞并使用PBS清洗,使用RIPA裂解液裂解细胞,收集到1.7mltube中。95%金属浴5分钟,充分变性蛋白。Western凝聚上样后100V恒压电泳,溴酚蓝条带到终点是停止。采用湿法转醋酸纤维素膜,恒流300-500mA45分钟,使用5%BSA进行封闭室温1-2小时。使用1:500-1:8000的一抗进行孵育,25℃40分钟,后清洗三遍。采用二抗进孵育室温15-40分钟。使用Enlight等超敏ECL发光液来检测蛋白,用X光片自动洗片机。试验结果 参见以下统计表、以及图1和图2。
本发明化合物在所述细胞株中抑制SHP2的有效浓度
MV411 DC50 | |
TDC.2001 | 128nM |
TDC.2002 | 336nM |
TDC.2003 | 52nM |
TDC.2004 | 120nM |
TDC.2005 | 321nM |
TDC.2006 | 445nM |
TDC.2007 | 125nM |
TDC.2008 | 215nM |
TDC.2009 | 16nM |
TDC.2010 | 81nM |
TDC.2011 | 138nM |
TDC.2012 | 10nM |
TDC.2013 | 203nM |
TDC.2014 | 102nM |
TDC.2015 | 97nM |
TDC.2016 | 356nM |
TDC.2017 | 183nM |
TDC.2018 | 142nM |
TDC.2020 | 13nM |
结果表明,本发明的化合物具有较好的体内体外抗肿瘤活性。本发明化合物对正常细胞毒性较低。
本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (17)
- 式1所示的化合物或者其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,式1中,X为卤素、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为卤素、甲基、乙基、异丙基、环丙基,进一步优选为卤素,X 1为NR 4、O或S,优选为O或S,更优选为O,X 7选自化学键、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基、-O-、-CO-、-C(=O)O-、-CONH-、-NHCO-、-NHCONH-、-NH-、-S-、亚磺酰基、磺酰基中的一种,优选为C1-6亚烷基,进一步优选为亚甲基、亚乙基、亚丙基、-O-,X 2、X 3、X 4、X 5和X 6各自独立地为CR 6或N,优选为CR 6,R 1为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为C1-6烷基,进一步优选为选自甲基、乙基、异丙基、环丙基中的一种,R 2为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为H、C1-6烷基,进一步优选为选自H、甲基、乙基中的一种,特别优选为H,R 4、R 5各自独立地为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基,R 6为H、卤素、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或C6-12芳烷基,R为H、卤素、NH 2、OH、SH、氨基、取代或未取代的C2-10的脂肪族烃基、取代或未取代的饱和或部分不饱和的3-10元杂环基、取代或未取代的C6-10芳基、或者取代或未取代的5-14元杂芳基;R优选为卤素、OH、SH、卤代烷基、氨基、饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C1-6烷基取代氨基、 或者 其中,V 1为选自C(R 8) 2、C(R 8) 2-C(R 8) 2、CR 8=CR 8、C=O、C(=O)C(R 8) 2、C(R 8) 2C(=O)、C(=O)O、OC(=O)、C(=O)NR、N=CR 8、CR 8=N、NR 8-C(R 8) 2或C(R 8) 2-NR 8中的一种;R 9各自独立地选自卤素、羟基、氧代、氨基、氰基、硝基、-Si(R 8) 3、C1-6烷基、C1-6烷氧基、饱和或部分不饱和的C3-6环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(=O)R 8、-OC(=O)R 8、-C(=O)OR 8、-OR 8、-SR 8、-S(=O)R 8、-S(=O) 2R 8、-S(=O) 2N(R 8) 2、-N(R 8) 2、-C(=O)N(R 8) 2、-NR 8-C(=O)R 8、-NR 8-C(=O)OR 8、-NR 8-S(=O) 2-R 8、-NR 8-C(=O)-N(R 8) 2、-C1-6亚烷基-N(R 8) 2、-C1-6亚烷基-OR 8、-C1-6亚烯基-OR 8和-O-C1-6亚烷基-N(R 8) 2;m为0~5的整数,n为0~4的整数,R 8为H、C1~C6烷基、饱和或部分不饱和的C 3-6环烃基、饱和或部分不饱和的3-10元杂环基或者C6-10芳基,“—”划过的环结构的表达方式,表示连接位点于该环结构上任意能够成键的位置;L是连接基团,其表示直链或支链的C3~C29的亚烷基链,其中所述直链或支链的C3~C29的亚烷基链可选地被一或多个选自-O-、-CO-、-C(=O)O-、-CONH-、-NHCO-、-NHCONH-、-NH-、-NR 8-、-C(R 8) 2-、-S-、亚磺酰基、磺酰基、亚磺酰氧基、磺酰氧基、-氨基磺酰基氨基-、亚炔基、亚烯基、亚环烷基、 或它们的任意组合中的 二价基团中断一或多次,E 3为下述基团Z 1为O、S、NH、CH 2或者C=O,优选为CH 2或者C=O;Z 4为N或CH,Z 4与Z 1、Z 2、Z 3中任一可相连的位置相连;Z 5为N或CH,优选为N;Z 10选自化学键、C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、饱和或部分不饱和的C3-10亚环烃基,优选为化学键、C1-6亚烷基;Rc为卤素、氰基、硝基、羟基、酰胺基、C1~C6烷基、C1~C6烷氧基、取代C1~C6烷基、饱和或部分不饱和的C3-10环烃基、饱和或部分不饱和的3-10元杂环基、C6-10芳基、5-14元杂芳基或者C6-12芳烷基,优选为C1~C6烷基、饱和或部分不饱和的C3-10环烃基、C6-10芳基、C6-12芳烷基,
- 权利要求1所述的化合物或其药学上可接受的盐、酯、光学异构体、立体异 构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,所述化合物具有下述式2的结构,在式2中,X为卤素、C1-6烷基、饱和或部分不饱和的C3-10环烃基,优选为卤素,在式2中,R 1为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为C1-6烷基,进一步优选为乙基,在式2中,R 2为H、C1-6烷基、C2-6烯基、C2-6炔基、饱和或部分不饱和的C3-10环烃基,优选为H,
- 权利要求1~5中任一项所述的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,其中,L为式5所示的二价基团,n 0为0或1m为1-5的整数、优选为2或3;n 1为0-3的整数,优选为1;n 2为0-3的整数,优选为1;n 3为0-3的整数,优选为1;n 4为0-3的整数,优选为1;n 5为0-3的整数,优选为1;
- 药物组合物,其包含预防或治疗有效量的权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,以及药学上可接受的载体,所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
- 权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药,或者权利要求10的药物组合物在制备用于治疗SHP2磷酸酶调节的疾病的药物中的用途。
- 权利要求12的用途,其中,所述疾病为肿瘤,例如为实体肿瘤、血液肿瘤、恶性肿瘤、难治性肿瘤、原发或转移复发的肿瘤等。
- 权利要求12的用途,其中所述疾病选自原发或转移复发的NSCLC、肺鳞癌、肺腺癌、头和颈鳞状细胞癌、胃癌、结直肠癌、胰腺癌等;也包括乳腺癌、食管癌、肺癌、结肠癌、脑癌、成神经细胞瘤、成神经细胞瘤、黑素瘤、头和颈鳞状细胞癌、间变性大细胞淋巴瘤和成胶质细胞瘤、恶行血液肿瘤疾病包括幼年性骨髓单核细胞白血病、急性骨髓性白血病、努南综合征、豹皮综合征、Ⅱ型糖尿病和肥胖症。
- 治疗SHP2磷酸酶调节的疾病的方法,该方法包括给予需要此治疗的人有效量的权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、光学异构体、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、螯合物、络合物、包合物或前药或者权利要求10的药物组合物。
- 权利要求15的治疗方法,所述疾病为肿瘤,例如为实体肿瘤、血液肿瘤、恶性肿瘤、难治性肿瘤、原发或转移复发的肿瘤等。
- 权利要求15的治疗方法,所述疾病选自原发或转移复发的NSCLC、肺鳞癌、肺腺癌、头和颈鳞状细胞癌、胃癌、结直肠癌、胰腺癌等;也包括乳腺癌、食管癌、肺癌、结肠癌、脑癌、成神经细胞瘤、成神经细胞瘤、黑素瘤、头和颈鳞状细胞癌、间变性大细胞淋巴瘤和成胶质细胞瘤、恶行血液肿瘤疾病包括幼年性骨髓单核细胞白血病、急性骨髓性白血病、努南综合征、豹皮综合征、Ⅱ型糖尿病和肥胖症。
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