WO2020259679A1 - 嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用 - Google Patents

嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2020259679A1
WO2020259679A1 PCT/CN2020/098474 CN2020098474W WO2020259679A1 WO 2020259679 A1 WO2020259679 A1 WO 2020259679A1 CN 2020098474 W CN2020098474 W CN 2020098474W WO 2020259679 A1 WO2020259679 A1 WO 2020259679A1
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group
ring
alkyl
compound represented
pharmaceutically acceptable
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PCT/CN2020/098474
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English (en)
French (fr)
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邹昊
李正涛
王元昊
余健
祝伟
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上海拓界生物医药科技有限公司
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Priority to BR112021024674A priority Critical patent/BR112021024674A2/pt
Priority to AU2020306124A priority patent/AU2020306124A1/en
Priority to CA3144284A priority patent/CA3144284A1/en
Priority to CN202080036459.0A priority patent/CN113840603A/zh
Priority to US17/619,759 priority patent/US20220380385A1/en
Priority to EP20832137.2A priority patent/EP3991731A4/en
Priority to KR1020227001970A priority patent/KR20220054285A/ko
Priority to JP2021575968A priority patent/JP2022538548A/ja
Publication of WO2020259679A1 publication Critical patent/WO2020259679A1/zh

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present disclosure belongs to the field of medicine, and relates to pyrimido five-membered nitrogen heterocyclic derivatives, preparation methods thereof, and applications in medicine.
  • the present disclosure relates to a pyrimido five-membered nitrogen heterocyclic derivative represented by the general formula (I), a preparation method thereof, and a composition containing the derivative, as an SHP2 inhibitor and its use in prevention and/or treatment Tumor or cancer drug use.
  • Src homologous 2 protein tyrosine phosphatase 2 (Src homology domain 2 containing tyrosine phosphatase-2, SHP2) is an evolutionarily conserved non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. Composed of two SH2 domains (N-SH2, C-SH2) and one PTP catalytic domain, it is widely expressed in various human tissues and plays an important role in maintaining tissue development and cell homeostasis. SHP2 is related to signals through the Ras-mitogen-activated protein kinase, JAK-STAT or phosphoinositide 3-kinase AKT pathway.
  • SHP2 represents a highly attractive target for the development of new therapies for the treatment of various diseases.
  • the present disclosure provides a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, atropisomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized by
  • R 1 is selected from hydrogen atom, deuterium atom, hydroxyl group, cyano group, nitro group, halogen, carboxyl group, alkyl group, alkoxy group, halogenated alkyl group, halogenated alkoxy group, amino group, alkenyl group, hydroxyalkyl group;
  • Ring A is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are monocyclic or polycyclic with 5-12 members;
  • R 3 is each independently selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, carboxyl, hydroxyl, hydroxyalkyl, C 3-8 cycloalkyl, C 3-10 heterocyclic group, aryl group, heteroaryl, C 2 - 6 alkenyl, C 4 - 8 cycloalkenyl, C 2-6 alkynyl, -NR a R b, - alkenyl group -NR a R b, - alkenyl group -OR a, - ene -C(O) 2 R a , -alkenyl -R a , -alkenyl -CO-NR a R b , -alkenyl -NR a -CO-NR a R b , -alkenyl -NR a -CO-NR a R b , -alkenyl -NR a -C (O)R
  • the R a and R b are each independently selected from hydrogen, deuterium atom, halogen, amino, hydroxyl, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, haloalkoxy, C 5-10 heteroaryl Group, aryl group, the aryl group or heteroaryl group is optionally further selected by one or more selected from halogen, hydrogen atom, deuterium atom, cyano group, amino group, nitro group, carboxyl group, hydroxyl group, hydroxyalkyl group, alkyl group, Substituent substitution of alkoxy, halogenated alkyl, and halogenated alkoxy;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 1 , X 2 , and X 3 are each independently selected from CR c , N, and at least one of them is N; the R c is selected from hydrogen atom, deuterium atom, C 1-6 alkyl group, C 1-6 alkane Oxy, C 1-6 alkylthio, amino, nitro, hydroxy, carbonyl, carboxy, halogen, cyano, preferably X 1 is CR c ;;
  • R 4 is selected from hydrogen, C 1 - 6 -alkyl, 3-12 membered mono- or polycyclic heterocycle heterocycle, C 3-8 cycloalkyl, each of said alkyl, heterocyclyl, cycloalkyl group Optionally substituted by one or more groups selected from halogen, hydroxy, C 1-3 alkyl, amino, alkylamino, hydroxyalkyl, alkoxy;
  • R 5 is selected from hydrogen, hydroxy, C 1-6 alkyl, C 3-8 cycloalkyl, said alkyl or cycloalkyl is optionally substituted by one or more amino groups; or
  • each of the monocyclic or polycyclic heterocyclic ring is optionally selected from halogen, Hydroxy, halogen-substituted or unsubstituted C 1-6 alkyl, amino, alkylamino, hydroxyalkyl, heteroaryl, heterocyclyl, alkylamino, halogen-substituted or unsubstituted alkoxy groups are substituted by
  • the polycyclic heterocycles include but are not limited to bridged heterocycles and spirocyclic heterocycles;
  • Exemplary rings formed by R 4 and R 5 and the nitrogen atom to which they are commonly connected include but are not limited to:
  • R 4 and R 5 are composed of the nitrogen atom to which they are connected together
  • p is selected from 0, 1, 2, 3 or 4;
  • Each R 7a and R 7b is independently selected from hydrogen atom, deuterium atom, fluorine atom, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, fluorine-substituted or unsubstituted alkyl group, fluorine-substituted or unsubstituted alkoxy group ⁇ ,-NR a S(O)NR a R b ;
  • q is selected from 0, 1, 2, 3 or 4;
  • W is not present or is selected from -O, -S or -NR w , said R w is selected from hydrogen atom, halogen, amino, hydroxyl, cyano, nitro, carboxyl, -C(O)C 1-6 alkyl , -C(O) 2 C 1-6 alkyl, C 1-6 alkyl ether, halogen-substituted or unsubstituted C 1-6 alkyl, halogen-substituted or unsubstituted C 1-6 alkoxy;
  • Ring B does not exist or is a 3-10 membered ring
  • Y 2 is CR 2a R 2b , NR 2a or O
  • Y 3 is CR 3a R 3b , NR 3a or O
  • ring B is a 3-10 membered ring
  • Y 2 is CR 2a or N
  • Y 3 is CR 3a or N, Is a single key
  • Each R 2a , R 2b , R 3a , R 3b is independently selected from hydrogen atom, deuterium atom, halogen, amino, hydroxyl, cyano, nitro, carboxyl, halogen substituted or unsubstituted alkyl, halogen substituted or Unsubstituted alkoxy;
  • Each R 8 is independently selected from hydrogen atom, deuterium atom, halogen, cyano, amino, nitro, carboxy, hydroxy, hydroxyalkyl, C 3-8 cycloalkyl, C 3-10 heterocyclic group, aryl group, a heteroaryl group, C 2 - 6 alkenyl, C 4 - 8 cycloalkenyl, C 2-6 alkynyl, -NR a R b, - alkenyl group -NR a R b, - alkenyl group -OR a, -Alkenyl-C(O) 2 R a , -alkenyl- Ra , -alkenyl-CO-NR a R b , -alkenyl-NR a -CO-NR a R b , -alkenyl-NR a -C(O)R b , -C(O)NR a R b , -C(O)R a
  • the R a and R b are each independently selected from hydrogen, deuterium atom, halogen, amino, hydroxyl, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, haloalkoxy, C 5-10 heteroaryl Group, aryl group, the aryl group or heteroaryl group is optionally further selected by one or more selected from halogen, hydrogen atom, deuterium atom, cyano group, amino group, nitro group, carboxyl group, hydroxyl group, hydroxyalkyl group, alkyl group, Substituent substitution of alkoxy, halogenated alkyl, and halogenated alkoxy;
  • n is selected from 0, 1, 2, 3, 4;
  • R 8 can form a 6-membered aromatic ring, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a C 3-6 heterocyclic group, each of the rings is optionally substituted or unsubstituted,
  • the substituent is selected from halogen, amino, hydroxyl, cyano, nitro, and C 1-6 alkyl.
  • Y 1 is selected from -S- or direct bond
  • Ring A is selected from aryl or heteroaryl
  • R 3 is each independently selected from hydrogen atom, deuterium atom, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkoxy, cyano Group, amino group, nitro group, carboxyl group, hydroxy group, phenyl group, the phenyl group is optionally further selected from halogen, hydrogen atom, deuterium atom, cyano group, amino group, nitro group, carboxyl group, hydroxyl group, hydroxyalkyl group.
  • substituents of group, alkyl group, alkoxy group, halogenated alkyl group, halogenated alkoxy group preferably hydrogen atom, deuterium atom, halogen, halogenated C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkane
  • An oxy group, a halogenated C 1-6 alkoxy group, a phenyl group, and the phenyl group is optionally further selected from halogen, hydrogen atom, deuterium atom, cyano group, amino group, nitro group, carboxyl group, hydroxyl group, Substituent substitution of hydroxyalkyl, alkyl, alkoxy, halogenated alkyl, and halogenated alkoxy;
  • n is selected from 0, 1, 2, 3, 4, 5.
  • the X 1 is CR c
  • the R c is a hydrogen atom
  • R 9 and R 10 are each independently selected from hydrogen atom, deuterium atom, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 hydroxyalkyl, aryl, heteroaryl , Heterocyclyl, amino, C 1-6 alkylamino, -NR a S(O)NR a R b ; or
  • R a and R b are as defined in the general formula (I) according to the claims.
  • R 9 and R 10 are each independently selected from a hydrogen atom, a deuterium atom, C 1-6 alkyl, amino, -NR a S (O) NR a R b, R a, R b As described in claim 1.
  • R 6a and R 6b are each independently selected from hydrogen atom, deuterium atom, C 1-6 alkyl group, C 1-6 alkoxy group, or R 6a , R 6b and the carbon atom to which they are connected together form a 3-12 membered Heterocyclyl or C 3-8 cycloalkyl;
  • p is selected from 0, 1, 2;
  • R 7a, R 7b are each independently selected from a hydrogen atom, a deuterium atom, an amino group, C 1-6 alkyl, -NR a S (O) NR a R b, R a, R b as claimed in claim 1;
  • q 1 or 2;
  • Ring B does not exist or is a 3-10 membered ring
  • Y 2 is CR 2a R 2b or O
  • Y 3 is CR 3a R 3b ;
  • ring B is a 3-10 membered ring
  • Y 2 is CR 2a or N
  • Y 3 is CR 3a or N, Is a single key
  • Each R 2a , R 2b , R 3a is independently selected from a hydrogen atom, a deuterium atom, and a C 1-6 alkyl group;
  • Each R 8 is independently selected from hydrogen atom, deuterium atom, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4; or two R 8 connected to form a 6-membered aromatic ring, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a C 3-6 heterocyclic group, each of said The ring is optionally substituted or unsubstituted, and the substituent is selected from halogen, amino, hydroxyl, cyano, nitro, and C 1-6 alkyl.
  • R 1 is selected from hydrogen atom, deuterium atom, methyl group, amino group
  • Y 1 is selected from -S- or direct bond
  • Ring A is selected from aryl and heteroaryl
  • R 3 is each independently selected from hydrogen atom, deuterium atom, halogen, halogenated C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, substituted Phenyl;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 1 , X 2 , and X 3 are each independently selected from CR c and N, and at least one of them is N, said X 1 is CR c , and said R c is a hydrogen atom;
  • R 9 and R 10 are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, an amino group, -NR a S(O)NR a R b , and R a and R b are as defined in the general formula (I) definition.
  • R 1 is selected from hydrogen atom, deuterium atom, methyl group, amino group
  • Y 1 is selected from -S- or direct bond
  • Ring A is selected from aryl and heteroaryl
  • R 3 is each independently selected from hydrogen atom, deuterium atom, halogen, halogenated C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, substituted Phenyl;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 1 , X 2 , and X 3 are each independently selected from CR c and N, and at least one of them is N, said X 1 is CR c , and said R c is a hydrogen atom;
  • R 6a and R 6b are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, or R 6a , R 6b and the carbon atom to which they are connected together form a 3-12 member ⁇ heterocyclyl or C 3-8 cycloalkyl;
  • p 1 or 2;
  • R 7a and R 7b are each independently selected from hydrogen atom, deuterium atom, amino group, C 1-6 alkyl group, -NR a S(O)NR a R b , R a , R b are as in the general formula (I) Defined
  • q 1 or 2;
  • Ring B does not exist, Y 2 is CR 2a R 2b or O, and Y 3 is CR 3a R 3b ;
  • Each of R 2a , R 2b , R 3a , and R 3b is independently selected from a hydrogen atom, a deuterium atom, and a C 1-6 alkyl group.
  • R 1 is selected from hydrogen atom, deuterium atom, methyl group, amino group
  • Y 1 is selected from -S- or direct bond
  • Ring A is selected from aryl and heteroaryl
  • R 3 is each independently selected from hydrogen atom, deuterium atom, halogen, halogenated C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, substituted Phenyl;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 1 , X 2 , and X 3 are each independently selected from CR c and N, and at least one of them is N, said X 1 is CR c , and said R c is a hydrogen atom;
  • R 6a and R 6b are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, and a C 1-6 alkoxy group;
  • p 1 or 2;
  • R 7a, R 7b are each independently selected from a hydrogen atom, a deuterium atom, an amino group, C 1-6 alkyl, -NR a S (O) NR a R b, R a, R b of general formula (I) as definition;
  • q 1 or 2;
  • Ring B is a 6-membered aryl ring, a 5-membered heteroaryl group, and a 6-membered heteroaryl group;
  • Each R 8 is independently selected from hydrogen atom, deuterium atom, halogen, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, C 1-6 alkyl group, C 1-6 alkoxy group;
  • n is selected from 0,1,2,3,4.
  • R 1 is selected from a hydrogen atom or a methyl group
  • Y 1 is -S-
  • Ring A is selected from aryl and heteroaryl
  • R 3 is each independently selected from hydrogen atom, deuterium atom, halogen, amino, halogenated C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, and halogenated C 1-6 alkoxy , C 1-6 alkylamino;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 3 is N, said X 1 and X 2 are CR c , and said R c is a hydrogen atom;
  • s and t are selected from 0, 1;
  • R 6a and R 6b are each independently selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, and a C 1-6 alkoxy group;
  • p 1;
  • R 7a and R 7b are each independently selected from a hydrogen atom, a deuterium atom, an amino group, and a C 1-6 alkyl group;
  • Ring B is a 6-membered aromatic ring, a 5-membered heteroaromatic ring, and a 6-membered heteroaromatic ring;
  • Each R 8 is independently selected from hydrogen atom, deuterium atom, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy;
  • n is selected from 0,1,2,3,4.
  • the present disclosure provides a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, atropisomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is selected from a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group or an amino group, the alkyl group and the halogenated alkyl group are each independently optionally further substituted with one or more deuterium atom substituents;
  • Y 1 is -S- or direct bond
  • Ring A is selected from aryl and heteroaryl, preferably phenyl or pyridyl;
  • R 3 is independently selected from a hydrogen atom, a deuterium atom, a halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halogenated C 1-6 alkoxy Group, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, -OR a , -CHR a R b , -NR a R b ;
  • the Ra and R b are each independently selected from hydrogen, deuterium atom, hydroxyl, C 1-6 alkyl, 3-12 membered heterocyclic group or C 3-8 cycloalkyl, wherein said alkyl, heterocyclic
  • the group or cycloalkyl group is optionally further substituted with one or more substituents selected from halogen, deuterium, cyano, amino, and hydroxyl;
  • R a, R b atom to which they are attached form a 3-12 membered heterocyclyl or C 3-8 cycloalkyl, said alkyl, cycloalkyl, or heterocyclyl optionally further substituted with one or more Substituent substitution selected from halogen, deuterium atom, cyano group, amino group, and hydroxyl group;
  • Ring B is a 6-membered aromatic ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, and is preferably a benzene ring or a pyridine ring;
  • R 8 is independently selected from a hydrogen atom, a deuterium atom, a halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3, 4;
  • n is selected from 1, 2, 3, 4.
  • the -6 alkyl group is optionally substituted with one or more deuterium atoms.
  • the compound represented by the general formula (II) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, atropisomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the A ring is selected from phenyl or pyridyl.
  • ring B is a benzene ring or a pyridine ring.
  • R 1 is selected from a methyl group, and the methyl group is optionally substituted by one or more deuterium atoms;
  • Y 1 is -S-
  • Ring A is selected from phenyl or pyridyl
  • R 3 is each independently selected from hydrogen atom, deuterium atom, halogen, -NR a R b ;
  • the Ra and R b are each independently selected from hydrogen, deuterium atoms, and C 1-6 alkyl groups, and the alkyl groups are substituted by one or more deuterium atoms;
  • Ring B is a benzene ring or a pyridine ring
  • n is selected from 0;
  • n is selected from 1, 2, 3, 4.
  • R1 is selected from methyl
  • Y1 is -S-
  • Ring A is selected from pyridyl
  • R3 is each independently selected from hydrogen atom, deuterium atom, halogen, -NRaRb;
  • the Ra and Rb are each independently selected from hydrogen, deuterium atoms, and C1-6 alkyl groups, and the alkyl groups are substituted by one or more deuterium atoms;
  • Ring B is a pyridine ring
  • n is selected from 0;
  • n is selected from 1, 2, 3, 4.
  • R 1 is selected from methyl
  • Y 1 is -S-
  • Ring A is selected from pyridyl
  • R 3 is each independently selected from a hydrogen atom, a deuterium atom, a chlorine atom, -NH-CH 3 or N-(CH 3 ) 2 ; the methyl group in the -NH-CH 3 or N-(CH 3 ) 2
  • the hydrogen atom is replaced by one or more deuterium atoms
  • Ring B is a pyridine ring
  • n is selected from 0;
  • n is selected from 1, 2, 3, 4.
  • the compound provided in the present disclosure may exist as a mixture of atropisomers, and the enantiomeric excess is between 0-98% .
  • the stereochemistry of each chiral center can be specified by aR or aS, and these names can also be used for a mixture rich in one atropisomer.
  • the aR and aS atropisomers can be separated by chiral chromatography.
  • Typical compounds of general formula (I) and general formula (II) in the present disclosure include but are not limited to:
  • the present disclosure provides a compound represented by (II-1) or its tautomer, meso, racemate, enantiomer, diastereomer, atropisomer or Its mixture form, or its pharmaceutically acceptable salt method
  • the compound represented by formula (II-6) is C-S coupled under basic conditions to obtain the compound represented by formula (II-5);
  • the reagents that provide alkaline conditions include organic bases and inorganic bases.
  • the organic bases are selected from triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and two Lithium trimethylsilylamine, potassium acetate, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic base is selected from sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, tert-butanol Sodium, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide;
  • Z and Z' are selected from halogen, sulfonyl and sulfinyl;
  • p is selected from 1, 2, 3;
  • q is selected from 1, 2;
  • Ring A, ring B, R 1 , R 3 , R 8 , B, and m are as defined above.
  • p is selected from 1, 2, 3;
  • q is selected from 1, 2;
  • Ring A, ring B, R 1 , R 8 , B, and m are as defined above.
  • Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a therapeutically effective dose of the compound represented by the general formula (II) or its tautomers, mesosomes, racemates, enantiomers Isomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients, the treatment in the present disclosure
  • the effective dose can be 0.1-2000mg.
  • the present disclosure also relates to a method for preparing the pharmaceutical composition, which comprises combining the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer , Diastereomers, atropisomers or their mixtures, or their pharmaceutically acceptable salts, or compounds represented by the general formula (II), or their tautomers, meso, Racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient mixing.
  • a pharmaceutically acceptable carrier diluent or excipient mixing.
  • the present disclosure further relates to compounds represented by general formula (II) or tautomers, mesoisomers, racemates, enantiomers, diastereomers, atropisomers or Use of its mixture in the form of its mixture, or its pharmaceutically acceptable salt or pharmaceutical composition containing it in the preparation of an SHP2 inhibitor.
  • the present disclosure further relates to compounds represented by general formula (II), or tautomers, mesoisomers, racemates, enantiomers, diastereomers, atropisomers thereof Or its mixture form, or its pharmaceutically acceptable salt, or the pharmaceutical composition containing it for preparing diseases or disorders mediated by SHP2 activity.
  • general formula (II) or tautomers, mesoisomers, racemates, enantiomers, diastereomers, atropisomers thereof Or its mixture form, or its pharmaceutically acceptable salt, or the pharmaceutical composition containing it for preparing diseases or disorders mediated by SHP2 activity.
  • the present disclosure further relates to compounds represented by general formula (II), or tautomers, mesoisomers, racemates, enantiomers, diastereomers, atropisomers thereof
  • the present disclosure further relates to compounds represented by general formula (II), or tautomers, mesoisomers, racemates, enantiomers, diastereomers, atropisomers thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of prevention or treatment of Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma Tumor, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, gastric cancer, liver cancer, anaplastic large cell lymphoma and glioblastoma drugs the use of. .
  • Noonan syndrome leopard skin syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma Tumor, acute myelogenous leukemia, breast cancer, esophageal cancer
  • the present disclosure further relates to compounds represented by general formula (II), or tautomers, mesoisomers, racemates, enantiomers, diastereomers, atropisomers thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine.
  • general formula (II) or tautomers, mesoisomers, racemates, enantiomers, diastereomers, atropisomers thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine.
  • the present disclosure also relates to compounds represented by the general formula (II), or tautomers, mesoisomers, racemates, enantiomers, diastereomers, atropisomers thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which acts as an SHP2 inhibitor.
  • the present disclosure also relates to a compound represented by the general formula (general formula (II), or its tautomer, meso, racemate, enantiomer, diastereomer, atrope Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as SHP2 inhibitors for the prevention and/or treatment of tumors or cancers.
  • general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, atrope Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as SHP2 inhibitors for the prevention and/or treatment of tumors or cancers.
  • the present disclosure also relates to a method for the treatment, prevention and/or treatment of tumors or cancers, which comprises administering to a patient in need thereof a therapeutically effective dose of a compound represented by general formula (II) as an SHP2 inhibitor, or a mutual variation thereof Conformer, meso, racemate, enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination containing the same Things.
  • a compound represented by general formula (II) as an SHP2 inhibitor or a mutual variation thereof Conformer, meso, racemate, enantiomer, diastereomer, atropisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination containing the same Things.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickening agents.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure.
  • a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of the compound (II) or the amount of pharmaceutically acceptable salt
  • the type can be verified according to the traditional treatment plan.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbons Atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • a lower alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, and carboxylate.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 3 to 6 ring atoms, of which 1 to 2 Are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably piperidinyl, piperazinyl or morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl , Thiazolyl; more preferably pyridyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl and carboxylate.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • alkylamino refers to an amino group substituted with one or two alkyl groups, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in the body of a mammal, and has due biological activity.
  • One or more refers to one, two, three, four, five, six.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • MS measurement use Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
  • HPLC determination uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).
  • Chiralpak IC-3 100 ⁇ 4.6mm ID, 3um, Chiralpak AD-3 150 ⁇ 4.6mm ID, 3um, Chiralpak AD-3 50 ⁇ 4.6mm ID, 3um, Chiralpak AS-3 150 ⁇ 4.6mm ID, 3um, Chiralpak AS-3 100 ⁇ 4.6mm ID, 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm ID, 3um, Chiralcel OD-3 100 ⁇ 4.6mm ID, 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm ID, 5um, Chiralcel OJ-3 150 ⁇ 4.6mm ID, 3um chromatographic column;
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the chiral preparation column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol, the volume ratio of the solvent depends on the polarity of the compound Adjust, you can also add a small amount of triethylamine and acetic acid and other alkaline or acidic reagents to adjust.
  • compound 1c (9.97 g, 38.7 mmol) was dissolved in tetrahydrofuran (80 mL), and LDA (13.5 mL, 2M tetrahydrofuran and n-hexane solution) was added dropwise at -78°C. After the dropwise addition, it was stirred at -78°C for 1 hour.
  • Compound 1d (8.8 g, 35.07 mmol) was added dropwise at -78°C, and stirring was continued at -78°C for 9 hours.
  • intermediate 4a For the synthesis steps of intermediate 4a, refer to intermediate 3e, wherein the compound dimethyl-d 6 -amine hydrochloride is substituted for methyl-d 3 -amine hydrochloride to prepare the aforementioned intermediate 4a.
  • compound 2b (153mg, 0.30mmol) intermediate 5f (188mg, 0.59mmol) was dissolved in 1,4-dioxane (5mL), and cuprous iodide (56mg, 0.30mmol) was added, N, N'-Dimethylethylenediamine (52mg, 0.59mmol) and potassium phosphate (188mg, 0.89mmol) were heated to react at 130°C under nitrogen atmosphere for 15 hours.
  • reaction stop solution 60 mM HEPES, pH 7.5, 0.2% SDS was used to stop the phosphatase reaction. Read the fluorescence value of Ex358nm/Em455 on the fluorescence plate reader MD SpectraMax.
  • the IC 50 value of the compound is calculated by the four-parameter logit method.
  • x represents the logarithmic form of the compound concentration
  • F(x) represents the effect value (the inhibition rate of cell proliferation at this concentration):
  • F(x) (( AD)/(1+((x/C) ⁇ B))+D.
  • A, B, C and D are four parameters. Different concentrations correspond to different inhibition rates of phosphatase activity, make a reverse curve, and calculate the IC 50 of the inhibitor from the curve. Calculate the IC 50 of the compound with Primer premier 6.0.
  • the in vitro activity of the compound of the present disclosure on SHP2 was determined by the above test, and the oral active SHP2 inhibitor SHP099 was selected as the positive drug.
  • the structure of the compound is disclosed in the document J.Med.Chem.2016,59,7773-7782, specifically The compound was purchased from Shanghai Haoyuan Biomedical Technology Co., Ltd. (Medchemexpress.cn).
  • the measured IC 50 value is shown in Table 1.
  • the compounds of the present disclosure have an IC 50 for SHP2 phosphatase
  • Example number IC 50 (nM) Example number IC 50 (nM) SHP099 79 1 1.7 2 2.1 3 4.5 5 4.8 6 4.7
  • Test Example 2 In vitro metabolic stability experiment of rat liver microsomes
  • LC/MS/MS was used to determine the concentration of the compound in the reaction system to calculate the intrinsic clearance of the test compound and to evaluate the in vitro metabolic stability in rat liver microsomes.
  • the stop plate was centrifuged at 4000 rpm for 20 minutes, then allowed to stand at 4°C for 30 minutes, and then centrifuged at 4000 rpm for 20 minutes. Transfer 40 ⁇ L of each compound supernatant to a 96-well injection plate, and add 160 ⁇ L of pure water to dilute the sample.
  • the obtained sample is quantified by ion chromatogram, and the residual rate is calculated according to the peak area of the test compound or positive control.
  • the slope k was determined using Microsoft Excel from the linear regression of the natural logarithm of the remaining rate to the incubation time.
  • the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the rats were given the compound of the invention by intragastric administration. To study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.
  • Test animals 3 male SD rats healthy for 6-8 weeks per group
  • Rats were intragastrically administered the compound of the present invention. 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2 at 4°C, 4000 revolutions per hour. Centrifuge for 5 minutes to separate plasma and store at -75°C.
  • the rat pharmacokinetic parameters of the compound of the present invention are shown in Table 3 below.
  • the LC/MS/MS method was used to determine the drug concentration in plasma of cynomolgus monkeys at different times after intragastric administration of the compound of the invention. To study the pharmacokinetic behavior of the compound of the invention in cynomolgus monkeys and evaluate its pharmacokinetic characteristics.
  • Test animals 3 healthy male cynomolgus monkeys aged 2-5 years in each group;
  • Gavage Weigh a certain amount of medicine, add 0.5% by mass of hypromellose, 0.1% by volume of Tween 80 and 99.4% by volume of water to prepare a white suspension of 1 mg/mL.
  • the cynomolgus monkeys were fasted overnight and then administered by gavage, with a dose of 5 mg/kg.
  • Cynomolgus monkeys were administered the compound of the present invention by gavage. 0.2 mL of blood was collected from the peripheral vein at 0.25, 0.5, 1, 2, 4, 8, 24 hours after administration, and placed in a test tube containing EDTA-K2 at 2-8°C, The plasma was separated by centrifugation at 2000 rpm for 10 minutes and stored at -75°C.
  • the cynomolgus monkey pharmacokinetic parameters of the compounds of the present invention are shown in Table 4 below.
  • LC/MS/MS Liquid chromatography tandem mass spectrometry
  • HBSS 25 mM HEPES, pH 7.4, 50 ⁇ M quinidine, 30 ⁇ M benzbromarone
  • C R is the concentration of the compound to be tested at the base end (the superscript "120” or “45” is the sampling time, unit: minute), and C D is the concentration of the compound to be tested at the top (the superscript "120” or “45” is the sampling time, Unit: minutes), Area is the surface area of the membrane (0.33cm 2 ), and time is the total transit time (75 ⁇ 60 seconds).
  • test compounds concentration of 0.1, 0.3, 1, 3. 10, 30 ⁇ mol/L or positive compound or blank control and mixed human liver microsomes (0.2mg/mL) reaction system 200 ⁇ L (100mmol/L phosphate buffer, pH 7.4, containing 0.3% by volume respectively DMSO, 0.6% acetonitrile, 0.1% methanol) were incubated at 37°C for 5 minutes.
  • the peak area is calculated from the chromatogram.
  • the residual activity ratio (%) is calculated with the following formula:
  • Peak area ratio metabolic product peak area/internal standard peak area
  • Residual activity ratio (%) peak area ratio of the test compound group/peak area ratio of the blank group
  • CYP half inhibitory concentration (IC 50 ) was calculated by Excel XLfit 5.3.1.3.

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Abstract

嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用。具体为通式(II)所示的嘧啶并五元氮杂环类衍生物、其制备方法、含有该衍生物的组合物，其作为SHP2抑制剂及其用于制备预防和/或治疗肿瘤或者癌症的药物中的用途。

Description

嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及嘧啶并五元氮杂环类衍生物、其制备方法及其在医药上的应用。特别的本公开涉及通式(I)所示的嘧啶并五元氮杂环类衍生物、其制备方法、含有该衍生物的组合物，其作为SHP2抑制剂及其用于预防和/或治疗肿瘤或者癌症的药物中的用途。
背景技术
含Src同源2蛋白质酪氨酸磷酸酶2(Src homology domain 2containing tyrosine phosphatase-2，SHP2)是由PTPN11基因编码的一种进化保守的非受体型蛋白酪氨酸磷酸酶(PTP)，主要由两个SH2结构域(N-SH2、C-SH2)和一个PTP催化域组成，广泛表达于人类各个组织，在维持组织发育和细胞稳态等方面发挥了重要作用。SHP2与通过Ras-有丝分裂原-活化的蛋白激酶、JAK-STAT或磷酸肌醇3-激酶AKT通路的信号有关。PTPN11基因的突变以及随后SHP2的突变已经在多种人类疾病中获得识别，例如努南综合征(Noonan Syndrome)、豹皮综合征(Leopard Syndrome)、幼年性骨髓单核细胞白血病、成神经细胞瘤、黑素瘤、急性骨髓性白血病以及乳腺癌、肺癌和结肠癌(与Claim19相同)。因此，对于治疗各种疾病的新疗法的发展而言，SHP2代表可具有高吸引力的靶点。
已公开的SHP2靶点的相关研究的专利申请有WO2018136264A、WO2015003094A、WO2018160731A、WO2018130928A1、WO2018136265A、WO2018172984A、WO2018081091、WO2016203405、WO2017211303A、WO2018013597A等；目前诺华的SHP2抑制剂TNO155及JACOBIO的SHP2抑制剂JAB-3068均在处于I期临床阶段，尚无已上市的该靶点的产品，因此仍需要继续开发更高效的新的SHP2抑制剂，以期为患者提供新的有效的抗癌药物。
发明内容
本公开提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，其特征在于
Figure PCTCN2020098474-appb-000001
R 1选自氢原子、氘原子、羟基、氰基、硝基、卤素、羧基、烷基、烷氧基、 卤代烷基、卤代烷氧基、氨基、烯基、羟烷基；
R 2自
Figure PCTCN2020098474-appb-000002
其中Y 1选自-S-、-NH-、-S(O) 2-、-S(O) 2-NH-、-C(＝CH 2)-、-S(O)-、或者直接键；
A环选自环烷基、杂环烷基、芳基、杂芳基，所述环烷基、杂环烷基、芳基、杂芳基为5-12元的单环或多环；
R 3各自独立的选自氢原子、氘原子、卤素、氰基、氨基、硝基、羧基、羟基、羟烷基、C 3-8环烷基、C 3-10杂环基、芳基、杂芳基、C 2- 6烯基、C 4- 8环烯基、C 2-6炔基、-NR aR b、-烯基-NR aR b、-烯基-O-R a、-烯基-C(O) 2R a、-烯基-R a、-烯基-CO-NR aR b、-烯基-NR a-CO-NR aR b、-烯基-NR a-C(O)R b、-C(O)NR aR b、-C(O)R a、-CO-烯基-NR aR b、-NR aC(O)R b、-C(O) 2R a、-O-烯基-CO-OR a、-O-烯基-CO-NR aR b、-O-烯基-NR aR b、-OR a、-SR a、-NR a-CO-NR aR b、-NR a-烯基-NR aR b、-NR a-烯基-R b、-NR aS(O) 2R b、-NR aS(O)R b、-NR aS(O) 2NR aR b、-NR aS(O)NR aR b、-S(O) 2NR aR b、-S(O)NR aR b、-S(O)R a、-S(O) 2R a、-P(O)R aR b、-N(S(O)R aR b)、-S(O)(NR a)R b，所述芳基或杂芳基任选进一步被一个或多个选自卤素、氢原子、氘原子、氰基、氨基、硝基、羧基、羟基、羟烷基、烷基、烷氧基、卤代烷基、卤代烷氧基的取代；
所述R a、R b各自独立选自氢、氘原子、卤素、氨基、羟基、氰基、硝基、羧基、烷基、烷氧基、卤代烷基、卤代烷氧基、C 5-10杂芳基、芳基，所述芳基或杂芳基任选进一步被一个或多个选自卤素、氢原子、氘原子、氰基、氨基、硝基、羧基、羟基、羟烷基、烷基、烷氧基、卤代烷基、卤代烷氧基的取代基取代；
n选自0、1、2、3、4、5；
X 1、X 2、X 3各自独立选自CR c、N，且其中至少一个为N；所述R c选自选自氢原子、氘原子、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、氨基、硝基、羟基、羰基、羧基、卤素、氰基，优选X 1为CR c；；
R 4选自氢、C 1- 6烷基、3-12元的单杂环或者多环杂环、C 3-8环烷基，所述每个烷基、杂环基、环烷基任选被一个或多个选自卤素、羟基、C 1-3烷基、氨基、烷氨基、羟烷基、烷氧基的基团取代；
R 5选自氢、羟基、C 1-6烷基、C 3-8环烷基，所述的烷基或者环烷基任选被一个或者多个氨基取代；或者
R 4和R 5与它们共同连接的氮原子组成3-12元的单杂环、多环杂环，所述每个单杂环、多环杂环任选被一个或多个选自卤素、羟基、卤素取代或未取代的C 1-6烷基、氨基、烷氨基、羟烷基、杂芳基、杂环基、烷氨基、卤素取代或未取代的烷氧基的基团取代，所述的多环杂环包括但不限于桥环杂环、螺环杂环；
R 4和R 5与它们共同连接的氮原子组成的示例性的环包括但不限于：
Figure PCTCN2020098474-appb-000003
或者R 4和R 5与它们共同连接的氮原子组成
Figure PCTCN2020098474-appb-000004
其中s和t任选自0、1；
每个R 6a、R 6b、各自独立的选自氢原子、氘原子、氟原子、氨基、羟基、氰基、硝基、羧基、氟取代或者未取代的烷基、氟取代或者未取代的烷氧基；或者R 6a、R 6b与它们共同连接的碳原子形成CO、C＝NH、C＝N-OH、3-12元的杂环基或者C 3-8环烷基；
p选自0、1、2、3或4；
每个R 7a、R 7b各自独立的选自氢原子、氘原子、氟原子、氨基、羟基、氰基、硝基、羧基、氟取代或者未取代的烷基、氟取代或者未取代的烷氧基、-NR aS(O)NR aR b；
或者R 7a、R 7b与它们共同连接的碳原子形成3-10元的杂环基、5-10元的杂芳基、C 3-8环烷基或者C＝NR 7c，所述的R 7c选自氢原子、氘原子、C 1-6烷基，所述环任选被取代；
q选自0、1、2、3或4；
W没有或者选自-O、-S或者-NR w，所述的R w选自氢原子、卤素、氨基、羟基、氰基、硝基、羧基、-C(O)C 1-6烷基、-C(O) 2C 1-6烷基、C 1-6烷基醚、卤素取代或者未取代的C 1-6烷基、卤素取代或者未取代的C 1-6烷氧基；
环B不存在或者为3-10元环；
Figure PCTCN2020098474-appb-000005
为单键或者双键；
当环B不存在时Y 2是CR 2aR 2b、NR 2a或者O,Y 3是CR 3aR 3b、NR 3a或者O；
当环B是3-10元环时；
1)Y 2是CR 2a或者N，Y 3是CR 3a或者N，
Figure PCTCN2020098474-appb-000006
为单键；或者
2)Y 2是C且Y 3是C，
Figure PCTCN2020098474-appb-000007
为双键；
每个R 2a、R 2b、R 3a、R 3b各自独立的选自氢原子、氘原子、卤素、氨基、羟基、氰基、硝基、羧基、卤素取代或者未取代的烷基、卤素取代或者未取代的烷氧基；
每个R 8各自独立的选自氢原子、氘原子、卤素、氰基、氨基、硝基、羧基、 羟基、羟烷基、C 3-8环烷基、C 3-10杂环基、芳基、杂芳基、C 2- 6烯基、C 4- 8环烯基、C 2-6炔基、-NR aR b、-烯基-NR aR b、-烯基-O-R a、-烯基-C(O) 2R a、-烯基-R a、-烯基-CO-NR aR b、-烯基-NR a-CO-NR aR b、-烯基-NR a-C(O)R b、-C(O)NR aR b、-C(O)R a、-CO-烯基-NR aR b、-NR aC(O)R b、-C(O) 2R a、-O-烯基-CO-OR a、-O-烯基-CO-NR aR b、-O-烯基-NR aR b、-OR a、-SR a、-NR a-CO-NR aR b、-NR a-烯基-NR aR b、-NR a-烯基-R b、-NR aS(O) 2R b、-NR aS(O)R b、-NR aS(O) 2NR aR b、-NR aS(O)NR aR b、-S(O) 2NR aR b、-S(O)NR aR b、-S(O)R a、-S(O) 2R a、-P(O)R aR b、-N(S(O)R aR b)、-S(O)(NR a)R b，所述芳基或杂芳基任选进一步被一个或多个选自卤素、氢原子、氘原子、氰基、氨基、硝基、羧基、羟基、羟烷基、烷基、烷氧基、卤代烷基、卤代烷氧基的取代基取代；
所述R a、R b各自独立选自氢、氘原子、卤素、氨基、羟基、氰基、硝基、羧基、烷基、烷氧基、卤代烷基、卤代烷氧基、C 5-10杂芳基、芳基，所述芳基或杂芳基任选进一步被一个或多个选自卤素、氢原子、氘原子、氰基、氨基、硝基、羧基、羟基、羟烷基、烷基、烷氧基、卤代烷基、卤代烷氧基的取代基取代；
m选自0、1、2、3、4；
或者两个相连的R 8可以一起形成6元芳环、5元杂芳基、6元杂芳基、C 3-6杂环基，所述的每一个环任选被取代或者未被取代，所述取代基选自卤素、氨基、羟基、氰基、硝基、C 1-6的烷基。
在一些实施方案中，本公开所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其特征在于所述R 1选自氢原子、氘原子、C 1-6烷基、C 1-6烷氧基、氨基、羟基。
在一些实施方案中，本公开所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其特征在于：
Y 1选自-S-或者直接键；
A环选自芳基或杂芳基；
R 3各自独立的选自氢原子、氘原子、卤素、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、氰基、氨基、硝基、羧基、羟基、苯基，所述苯基任选进一步被一个或多个选自卤素、氢原子、氘原子、氰基、氨基、硝基、羧基、羟基、羟烷基、烷基、烷氧基、卤代烷基、卤代烷氧基的取代基取代；优选氢原子、氘原子、卤素、卤代C 1-6烷基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、苯基，所述苯基任选进一步被一个或多个选自卤素、氢原子、氘原子、氰基、氨基、硝基、羧基、羟基、羟烷基、烷基、烷氧基、卤代烷基、卤代烷氧基的取代基取代；
n选自0、1、2、3、4、5。
在一些实施方案中，本公开所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其特征在于所述X 1、X 2、X 3各自独立选自CR c、N，且其中至少一个为N，所述R c为氢原子。
在一些优选的实施方案中所述X 1为CR c，所述R c为氢原子。
在一些实施方案中，本公开所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其特征在于所述R 4和R 5与它们共同连接的氮原子组成
Figure PCTCN2020098474-appb-000008
其中R 9和R 10各自独立的选自氢原子、氘原子、羟基、C 1-6烷基、C 1-6烷氧基、卤素、C 1-6羟烷基、芳基、杂芳基、杂环基、氨基、C 1-6烷氨基、-NR aS(O)NR aR b；或者
R a、R b如权利要求如通式(I)中所定义。
在一些优选的实施方案中，R 9和R 10各自独立的选自氢原子、氘原子、C 1-6烷基、氨基、-NR aS(O)NR aR b，R a、R b如权利要求1所述。
在本公开的一些实施方案中，通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，其特征在于R 4和R 5与它们共同连接的氮原子组成
Figure PCTCN2020098474-appb-000009
其中s和t任选自0、1；
R 6a、R 6b各自独立的选自氢原子、氘原子、C 1-6烷基、C 1-6烷氧基，或者R 6a、R 6b与它们共同连接的碳原子形成3-12元的杂环基或C 3-8环烷基；
p选自0、1、2；
R 7a、R 7b各自独立的选自氢原子、氘原子、氨基、C 1-6烷基、-NR aS(O)NR aR b，R a、R b如权利要求1所述；
q为1或2；
W没有；
环B不存在或者为3-10元环；
Figure PCTCN2020098474-appb-000010
为单键或者双键；
当环B不存在时，Y 2是CR 2aR 2b或者O,Y 3是CR 3aR 3b；或者
当环B是3-10元环时；
Y 2是CR 2a或者N，Y 3是CR 3a或者N，
Figure PCTCN2020098474-appb-000011
为单键；或者
Y 2是C且Y 3是C，
Figure PCTCN2020098474-appb-000012
为双键；
每个R 2a、R 2b、R 3a各自独立的选自氢原子、氘原子、C 1-6烷基；
每个R 8独立的选自氢原子、氘原子、卤素、氨基、羟基、氰基、硝基、羧基、C 1-6烷基、C 1-6烷氧基；
m选自0、1、2、3、4；或者两个相连R 8形成6元芳环、5元杂芳基、6元杂芳基、C 3-6杂环基，所述的每一个环任选被取代或者未被取代，所述取代基选自卤素、氨基、羟基、氰基、硝基、C 1-6的烷基。
在本公开的一些实施方案中所述的
R 1选自氢原子、氘原子、甲基、氨基；
Y 1选自-S-或者直接键；
A环选自芳基、杂芳基；
R 3各自独立的选自氢原子、氘原子、卤素、卤代C 1-6烷基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、取代苯基；
n选自0、1、2、3、4、5；
X 1、X 2、X 3各自独立选自CR c、N，且其中至少一个为N，所述X 1为CR c，所述R c为氢原子；
R 4和R 5与它们共同连接的氮原子组成
Figure PCTCN2020098474-appb-000013
R 9和R 10各自独立的选自氢原子、氘原子、C 1-6烷基、氨基、-NR aS(O)NR aR b，R a、R b如通式(I)中所定义。
在本公开的一些优选的实施方案中所述的
R 1选自氢原子、氘原子、甲基、氨基；
Y 1选自-S-或者直接键；
A环选自芳基、杂芳基；
R 3各自独立的选自氢原子、氘原子、卤素、卤代C 1-6烷基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、取代苯基；
n选自0、1、2、3、4、5；
X 1、X 2、X 3各自独立选自CR c、N，且其中至少一个为N，所述X 1为CR c，所述R c为氢原子；
R 6a、R 6b各自独立的选自氢原子、氘原子、C 1-6的烷基、C 1-6烷氧基，或者R 6a、R 6b与它们共同连接的碳原子形成3-12元的杂环基或C 3-8环烷基；
p为1或2；
R 7a、R 7b各自独立的选自氢原子、氘原子、氨基、C 1-6的烷基、-NR aS(O)NR aR b， R a、R b如通式(I)中所定义；
q为1或2；
W没有；
环B不存在，Y 2是CR 2aR 2b或者O，Y 3是CR 3aR 3b；
每个R 2a、R 2b、R 3a、R 3b各自独立的选自氢原子、氘原子、C 1-6的烷基。
在本公开的一些优选的实施方案中所述的
R 1选自氢原子、氘原子、甲基、氨基；
Y 1选自-S-或者直接键；
A环选自芳基、杂芳基；
R 3各自独立的选自氢原子、氘原子、卤素、卤代C 1-6烷基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、取代苯基；
n选自0、1、2、3、4、5；
X 1、X 2、X 3各自独立选自CR c、N，且其中至少一个为N，所述X 1为CR c，所述R c为氢原子；
R 6a、R 6b各自独立的选自氢原子、氘原子、C 1-6的烷基、C 1-6烷氧基；
p为1或2；
R 7a、R 7b各自独立的选自氢原子、氘原子、氨基、C 1-6的烷基、-NR aS(O)NR aR b，R a、R b通式(I)中所定义；
q为1或2；
W没有；
环B是6元芳基环、5元杂芳基、6元杂芳基；
Y 2是C且Y 3是C，
Figure PCTCN2020098474-appb-000014
为双键；
每个R 8独立的选自氢原子、氘原子、卤素、氨基、羟基、氰基、硝基、羧基、C 1-6的烷基、C 1-6烷氧基；
m选自0、1、2、3、4。
本公开可选的实施方案中，
R 4和R 5与它们共同连接的氮原子组成
Figure PCTCN2020098474-appb-000015
R 1选自氢原子或甲基；
Y 1为-S-；
A环选自芳基、杂芳基；
R 3各自独立的选自氢原子、氘原子、卤素、氨基、卤代C 1-6烷基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基；
n选自0、1、2、3、4、5；
X 3为N，所述X 1、X 2为CR c，所述R c为氢原子；
s和t任选自0、1；
R 6a、R 6b各自独立的选自氢原子、氘原子、C 1-6烷基、C 1-6烷氧基；
p为1；
R 7a、R 7b各自独立的选自氢原子、氘原子、氨基、C 1-6烷基；
q为1；
W没有；
环B是6元芳环、5元杂芳环、6元杂芳环；
Y 2是C且Y 3是C，
Figure PCTCN2020098474-appb-000016
为双键；
每个R 8独立的选自氢原子、氘原子、卤素、氨基、羟基、氰基、硝基、羧基、C 1-6烷基、C 1-6烷氧基；
m选自0、1、2、3、4。
本公开提供一种通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，其中
Figure PCTCN2020098474-appb-000017
R 1选自氢原子、C 1-6烷基、卤代C 1-6烷基或氨基，所述烷基和卤代烷基各自独立地任选进一步被一个或多个氘原子的取代基取代；
Y 1为-S-或者直接键；
A环选自芳基、杂芳基，优选苯基或吡啶基；
R 3各自独立的选自氢原子、氘原子、卤素、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-OR a、-CHR aR b、-NR aR b；
所述R a、R b各自独立选自氢、氘原子、羟基、C 1-6烷基、3-12元的杂环基或C 3-8环烷基，其中所述烷基、杂环基或环烷基任选进一步被一个或多个选自卤素、氘原子、氰基、氨基、羟基的取代基取代；
或R a、R b与它们共同连接的原子形成3-12元的杂环基或C 3-8环烷基，所述烷基、杂环基或环烷基任选进一步被一个或多个选自卤素、氘原子、氰基、氨基、羟基的取代基取代；
环B是6元芳环、5元杂芳环、6元杂芳环，优选自苯环或吡啶环；
R 8各自独立的选自氢原子、氘原子、卤素、氰基、C 1-6烷基、C 1-6烷氧基；
m选自0，1，2，3，4；
n选自1，2，3，4。
可选的实施方案中，通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其中R 1选自C 1-6烷基或卤代C 1-6烷基，所述C 1-6烷基或卤代C 1-6烷基任选被一个或者多个氘原子取代。
可选的实施方案中，通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其中Y 1为-S-。
可选的实施方案中，通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其中A环选自苯基或吡啶基。
可选的实施方案中，通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其中R 3各自独立的选自氢原子、氘原子、卤素、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-NR aR b；所述R a、R b各自独立选自氢、氘原子、羟基、C 1-6烷基，所述烷基被一个或多个氘原子取代。
可选的实施方案中，通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，环B是苯环或吡啶环。
可选的实施方案中，通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，其中
R 1选自甲基，所述甲基任选被一个或者多个氘原子取代；
Y 1为-S-；
A环选自苯基或吡啶基；
R 3各自独立的选自氢原子、氘原子、卤素、-NR aR b；
所述R a、R b各自独立选自氢、氘原子、C 1-6烷基，所述烷基被一个或多个氘原子取代；
环B为苯环或吡啶环；
m选自0；
n选自1，2，3，4。
可选的实施方案中，通式(II)所示的化合物或其互变异构体、内消旋体、 外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，
其中R1选自甲基；
Y1为-S-；
A环选自吡啶基；
R3各自独立的选自氢原子、氘原子、卤素、-NRaRb；
所述Ra、Rb各自独立选自氢、氘原子、C1-6烷基，所述烷基被一个或多个氘原子取代；
环B为吡啶环；
m选自0；
n选自1，2，3，4。
可选的实施方案中，通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、或其混合物形式，或其可药用的盐，
其中R 1选自甲基，
Y 1为-S-；
A环选自吡啶基；
R 3各自独立的选自氢原子、氘原子、氯原子、-NH-CH 3或者N-(CH 3) 2；所述-NH-CH 3或者N-(CH 3) 2中甲基上的氢原子被一个或多个氘原子取代；
环B为吡啶环；
m选自0；
n选自1，2，3，4。
本公开中，当Y 1为直接键时，由于围绕该键的旋转受到限制，因此本公开提供的化合物可为阻转异构体的混合物存在，其对映体过量在0-98％之间。当化合物是纯的阻转异构体时，每个手性中心的立体化学可以由aR或aS指定，这些名称也可用于富含一种阻转异构体的混合物。可以通过手性色谱法分离出aR和aS阻转异构体。
在Eliel,E.L.&Wilen,S.H.'Stereochemistry of Organic Compounds'John Wiley and Sons,Inc.1994中可以找到对阻转异构和轴向手性的进一步描述。
本公开典型的通式(I)及通式(II)的化合物，包括但不限于：
Figure PCTCN2020098474-appb-000018
Figure PCTCN2020098474-appb-000019
Figure PCTCN2020098474-appb-000020
Figure PCTCN2020098474-appb-000021
Figure PCTCN2020098474-appb-000022
其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐。
本公开提供一种(II-1)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐的方法
Figure PCTCN2020098474-appb-000023
式(II-7)所示的化合物与氘代甲胺或氘代二甲胺在碱性条件下，经取代反应化得到式(II-6)所示化合物；
式(II-6)所示化合物在碱性条件下经C-S偶联，得到式(II-5)所示化合物；
式(II-5)所示化合物在碱性条件下脱去保护基得到式(II-4)所示化合物；
式(II-4)所示化合物和式(II-3)所示化合物在碱性条件下经C-S偶联，得到式(II-2)所示化合物；
式(II-2)所示化合物脱去保护基团PG得到式(II-5)所示化合物；
其中提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱选自三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠和叔丁醇钾，所述的无机碱选自氢化钠、磷酸钾、碳酸钠、碳酸钾、甲醇钠、乙醇钠、叔丁醇钠、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；
Z、Z’选自卤素、磺酰基和亚磺酰基；
PG选自保护基Boc,PMB,S(＝O) tBu，Cbz；
p选自1，2，3；
q选自1，2；
环A、环B、R 1、R 3、R 8、B、m如上定义。
本公开要求保护一种式(II-2)所示的化合物或其药学上可接受的盐，
Figure PCTCN2020098474-appb-000024
其中PG选自保护基Boc,PMB,S(＝O) tBu，Cbz；
p选自1，2，3；
q选自1，2；
环A、环B、R 1、R 8、B、m如上定义。
本公开的另一方面涉及一种药物组合物，其含有治疗有效剂量的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式、或可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂，本公开中治疗有效量的剂量可选0.1-2000mg。
本公开还涉及一种制备所述药物组合物的方法，其包括将通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式、或其可药用的盐，或通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。
本公开进一步涉及通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用盐或包含其的药物组合物在制备SHP2抑制剂中的用途。
本公开进一步涉及通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或包含其的药物组合物在制备由SHP2活性介导的疾病或病症的用途。
本公开进一步涉及通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或包含其的药物组合物在作为SHP2抑制剂在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
本公开进一步涉及通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用 的盐，或包含其的药物组合物在制备预防或者治疗努南综合征、豹皮综合征、幼年性骨髓单核细胞白血病、神经母细胞瘤、黑素瘤、急性骨髓性白血病、乳腺癌、食管癌、肺癌、结肠癌、头癌、胰腺癌、头和颈鳞状细胞癌、胃癌、肝癌、间变性大细胞淋巴瘤和成胶质细胞瘤药物中的用途。。
本公开进一步涉及通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或包含其的药物组合物，其用作药物。
本公开还涉及通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或包含其的药物组合物，其作为SHP2抑制剂。
本公开还涉及通式(通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或包含其的药物组合物，其作为SHP2抑制剂用于预防和/或治疗肿瘤或癌症。
本公开还涉及一种治疗预防和/或治疗肿瘤或癌症的方法，其包括向需要其的患者施用治疗有效剂量的作为SHP2抑制剂的通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或包含其的药物组合物。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，造粒剂、崩解剂，粘合剂，和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(II)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4- 二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2020098474-appb-000025
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3是杂原子；最优选包含3至6个环原子，其中1～2是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗 啉基、高哌嗪基、吡喃基等，优选哌啶基、哌嗪基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2020098474-appb-000026
等。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2020098474-appb-000027
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、四唑基、吡啶基、噻吩基、吡唑基或嘧啶基、噻唑基；更有选吡啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2020098474-appb-000028
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基和羧酸酯基。
术语“卤素”指氟、氯、溴或碘。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“烷氨基”指被一个或两个烷基取代的氨基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“硫基”指-S-
术语“巯基”指-SH
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
“一个或多个”是指任选自1，2，3，4，5，6个。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Shimadzu 2010 Mass Spectrometer或Agilent 6110A MSD质谱仪。
HPLC的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远 化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，D：石油醚/乙酸乙酯/甲醇，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
(S)-1'-(8-((2-氨基-3-氯吡啶-4-基)硫基)咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺
Figure PCTCN2020098474-appb-000029
Figure PCTCN2020098474-appb-000030
第一步
(3-溴吡啶-2-基)甲醇1b
将化合物1a(17.2g，79.6mmol)溶于甲醇(50mL)，在0℃下加入硼氢化钠(15.1g，398mmol)。反应体系于室温条件下搅拌12小时。反应结束后加入饱和氯化铵水溶液(600mL)，乙酸乙酯(200mL×3)萃取。合并有机相，饱和氯化钠(200mL×2)洗涤，无水硫酸钠干燥，减压浓缩得到白色固体化合物1b(9.7g，产率：64.8％)。
MS(ESI)m/z 187.8[M+H] +
1H NMR:(400MHz,MeOD-d 4)δ＝8.52(d,J＝4.8Hz,1H),8.01(dd,J＝1.2,8.0Hz,1H),7.26(dd,J＝4.4,6.4Hz,1H),4.77(s,2H).
第二步
3-溴-2-(氯甲基)吡啶1c
将化合物1b(9.70g，51.6mmol)溶于二氯甲烷(20mL)，室温下加入二氯亚砜(7.48mL，103mmol)。室温条件下搅拌3小时。反应完成后在0℃下加入饱和碳酸氢钠水溶液(300mL)，二氯甲烷萃取(80mL×3)。合并有机相，饱和氯化钠(100mL)洗涤，无水硫酸钠干燥。减压浓缩得到粉红油状物化合物1c(10.3g，产率：96.9％)。
MS(ESI)m/z 207.7[M+H] +
1H NMR(400MHz,Methanol-d4)δ＝8.55-8.45(m,1H),8.12-7.99(m,1H),7.37-7.21(m,1H),4.84-4.80(m,2H).
第三步
1-(叔丁基)4-乙基4-((3-溴吡啶-2-基)甲基)哌啶-1,4-二羧酸酯1e
氮气氛下，将化合物1c(9.97g，38.7mmol)溶于四氢呋喃(80mL)中，-78℃条件下逐滴滴加LDA(13.5mL,2M四氢呋喃和正己烷溶液)。滴加完毕后在-78℃下搅拌1小时。再在-78℃下逐滴滴加化合物1d(8.8g,35.07mmol)，并继续在-78℃条件下搅拌9小时。反应完成后加入饱和氯化铵水溶液(400mL)，乙酸乙酯萃取(100mL×3)，合并有机相，饱和氯化钠溶液洗涤(100mL×2)，无水硫酸钠干燥。真空浓缩得到粗产品，用硅胶色谱法以石油醚、乙酸乙酯洗脱纯化，得到黄色油状物化合物1e(14.8g，产率：89.4％)。
MS(ESI)m/z 429.0[M+H] +
第四步
4-((3-溴吡啶-2-基)甲基)-1-(叔丁氧羰基)哌啶-4-羧酸1f
将化合物1e(14.8g，34.6mmol)溶于甲醇(3mL)，0℃条件下加入氢氧化钠水溶液(13.8g,346mmol,溶于40mL水)，80℃条件下搅拌12小时。反应完成后将反应液浓缩，再向其中加入乙酸乙酯(300mL)和水(300mL)。加入饱和氢氧化钠水溶液(10mL)调节pH至12，分离水相，并用乙酸乙酯洗涤(80mL×2)。向所得水相中加入2N盐酸(25mL)调节pH至3，乙酸乙酯萃取(100mL×3)。合并有机相，饱和氯化钠溶液洗涤(150mL)，无水硫酸钠干燥，减压浓缩得到白色固体化合物1f(11.4g，产率：82.4％)
MS(ESI)m/z 344.0[M-56+H] +
第五步
叔丁基5-羰基-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯1g
氮气氛下，在-15℃条件下将氢化钠(60％煤油混合物，1.32g，33.1mmol)加入到化合物1f(11.0g，27.6mmol)的四氢呋喃(100mL)中。在-15℃条件下搅拌1小时。再将反应液冷却到-78℃，逐滴滴加2.5M正丁基锂的正己烷溶液(16.5mL，41.3mmol)，在-78℃条件下搅拌1小时。反应完成后在0℃下加入饱和氯化铵水溶液(400mL)，乙酸乙酯萃取(100mL×3)。合并有机相，饱和氯化钠(100mL×2)洗涤，无水硫酸钠干燥。真空浓缩得到粗产品，用硅胶色谱法以二氯甲烷、甲醇洗脱纯化，得到白色固体化合物1g(4.60g，产率：55.2％)。
MS(ESI)m/z 246.9[M-56+H] +.
1H NMR(400MHz,Methanol-d4)δ＝8.82(dd,J＝1.6,4.8Hz,1H),8.12(dd,J＝1.6,7.6Hz,1H),7.50(dd,J＝4.8,7.6Hz,1H),4.08(td,J＝3.6,13.6Hz,2H),3.25(s,2H),3.12(br s,2H),1.88-1.77(m,2H),1.51(br s,2H),1.49(s,9H).
第六步
叔丁基(S)-5-((S)-叔丁基亚磺酰氨基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-1'-羧酸酯1i
氮气氛下，将钛酸四乙酯(9.4mL,44.6mmol)加入到化合物1g(4.50g，14.9mmol)的无水甲苯(80mL)中，室温条件下搅拌10分钟。再将化合物1h (5.4g，44.6mmol)加入反应液中，120℃条件下反应5小时。冷却至0℃并加入硼氢化锂(1.58g，89.2mmol)继续反应30分钟后，升温至室温搅拌1小时。反应完成后在0℃下逐滴滴加甲醇(20mL)。再加入水(100mL)和乙酸乙酯(100mL)并搅拌5分钟。硅藻土滤去悬浮物并用乙酸乙酯(300mL)和水(300mL)洗涤。合并有机相，饱和氯化钠(500mL)洗涤，无水硫酸钠干燥。减压浓缩得到粗产品，用硅胶色谱法以石油醚、乙酸乙酯洗脱纯化，得到黄色固体化合物1i(4.40g，产率：72.6％)
MS(ESI)m/z 408.1[M+H] +
第七步
(S)-N-((S)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺1j
将化合物1i(4.40g，10.8mmol)溶于二氯甲烷(15mL)，0℃条件下加入三氟乙酸(5mL)，0℃条件下搅拌1小时。减压浓缩得到粗产品，加入4M氢氧化钠水溶液至pH＝11。氯仿和异丙醇(体积比3:1)萃取(30mL×3)，合并有机相，无水硫酸钠干燥。减压浓缩得到黄色油状产物1j(3.32g，产率：100％)。MS(ESI)m/z 307.9[M+H] +
第八步
(S)-N-((S)-1'-(8-溴咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺1l
氮气氛下，将化合物1j(3.30mg，10.7mmol)和化合物1k(2.50g，10.7mmol)溶于二甲基亚砜(40mL)，加入二异丙基乙基胺(7.7g，59.8mmol)，90℃条件下搅拌2小时。加入乙酸乙酯(50mL)和水(100mL)，乙酸乙酯萃取(50mL×2)，合并有机相，饱和氯化钠溶液洗涤(50mL×3)，无水硫酸钠干燥。减压浓缩得到粗产物，用硅胶色谱法以二氯甲烷、甲醇洗脱纯化得到化合物1l(2.96g，产率：54.6％)
MS(ESI)m/z 503.1[M+H] +
1H NMR(400MHz,METHANOL-d4)δ＝8.41(d,J＝4.8Hz,1H),7.97(s,1H),7.92(d,J＝1.5Hz,1H),7.81(d,J＝7.5Hz,1H),7.66(d,J＝1.5Hz,1H),7.32(dd,J＝5.0,7.5Hz,1H),4.61(br s,2H),3.95-3.83(m,2H),3.30-3.21(m,2H),2.99(d,J＝16.6Hz,1H),2.40(dt,J＝4.0,12.7Hz,1H),2.14(dt,J＝3.6,12.4Hz,1H),1.82(br d,J＝13.3Hz,1H),1.54(br d,J＝12.3Hz,1H),1.36(s,9H).
第九步
(S)-N-((S)-1'-(8-((2-氨基-3-氯吡啶-4-基)硫基)咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺1n
氮气氛下，将化合物1l(70mg，0.14mmol)和化合物1m(33mg，0.21mmol，采用专利申请“WO2015107495A1”公开的方法制备而得)溶于1,4-二氧六环(1mL)，室温条件下加入二异丙基乙胺(54mg，0.42mmol)。加入三(二亚苄基丙酮)二钯(13mg，0.014mmol)和2-二环己基膦-2’,6’-二甲氧基联苯(14mg，0.028mmol)，110℃条件下加热搅拌12小时。反应完成后将反应液过滤，所得滤液浓缩，残余物用C-18反相色谱法以水、甲醇洗脱纯化得到棕色油状化合物1n(45mg，产率：55.1％)。
MS(ESI)m/z 583.1[M+H] +
第十步
(S)-1'-(8-((2-氨基-3-氯吡啶-4-基)硫基)咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺1
将化合物1n(25mg，0.035mmol)溶于1，4-二氧六环中，0℃条件下加入氯化氢的1，4-二氧六环溶液(0.2mL，4N)，2-7℃下反应1小时。反应完成后加入水(30mL)，乙酸乙酯萃取(15mL×2)。合并有机相，饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，减压浓缩后残余物用C-18反相色谱法纯化得到化合物1(3.9mg，产率：19.0％)。
MS(ESI)m/z 479.1[M+H] +
1H NMR:(400MHz,MeOD-d 4)δ＝8.38(d,J＝4.8Hz,1H),8.06(s,1H),7.90-7.84(m,2H),7.57(s,1H),7.50(d,J＝5.2Hz,1H),7.30(dd,J＝5.6,7.6Hz,1H),5.90(d,J＝6.0Hz,1H),4.16(s,1H),4.06(br d,J＝13.6Hz,2H),3.48-3.36(m,2H),3.30-3.24(m,1H),3.01(br d,J＝16.4Hz,1H),2.20-2.01(m,2H),1.80-1.71(m,1H),1.61-1.53(m,1H).
实施例2
(S)-1'-(8-((3-氯-2-(甲基氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺
Figure PCTCN2020098474-appb-000031
Figure PCTCN2020098474-appb-000032
第一步
(S)-N-((S)-1'-(8-溴-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺2b
将化合物1j(260mg，0.85mmol)和化合物2a(271mg,1.10mmol)溶于二甲基亚砜(3mL)，加入二异丙基乙基胺(547mg，4.23mmol)，90℃条件下搅拌1小时。向反应液中加入水(30mL)，乙酸乙酯萃取(30mL×3).合并有机相，再用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤。滤液通过减压浓缩得到粗产物，用硅胶色谱法以甲醇、二氯甲烷洗脱纯化得到化合物2b(370mg，产率：84.5％)
MS(ESI)m/z 518.8[M+H] +
1H NMR(400MHz,Methanol-d4)δ＝8.39(d,J＝4.8Hz,1H),7.82(d,J＝1.2Hz,1H),7.79(d,J＝8.0Hz,1H),7.55(d,J＝1.6Hz,1H),7.30(dd,J＝4.8Hz,7.6Hz,1H),3.90-3.81(m,2H),3.37-3.32(m,1H),3.29-3.17(m,3H),3.00-2.92(m,1H),2.57(s,3H),2.37(td,J＝4.4Hz,12.8Hz,1H),2.13(td,J＝4.4Hz,13.2Hz,1H),1.83-1.75(m,1H),1.56-1.49(m,1H),1.34(s,9H).
第二步
(S)-N-((S)-1'-(8-((3-氯-2-(甲基氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺2d
将化合物2b(50mg，0.10mmol)，化合物2c(77mg，0.39mmol)和磷酸钾(41mg,0.19mmol)溶于1,4-二氧六环(1mL)中，在搅拌的情况下，氮气置换三次。氮气气氛下，快速的加入1,10-菲罗啉(3.5mg,0.02mmol)和碘化亚铜(1.8mg,0.01mmol),再氮气置换三次，并在130℃条件下加热搅拌10小时。向反应液加入水(50mL)并用乙酸乙酯萃取(40mL×3)，合并有机相，饱和氯化钠溶液洗涤(70mL×2)，无水硫酸钠干燥，过滤。滤液通过减压浓缩得到 粗产物，用硅胶板层析分离技术，用二氯甲烷、甲醇层析纯化得到化合物2d(36mg，产率：58.5％)。
MS(ESI)m/z 611.1[M+H] +
第三步
(S)-1'-(8-((3-氯-2-(甲基氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺2
将化合物2d(36mg，0.059mmol)溶于干燥的二氧六环(1mL)，10℃条件下滴加氯化氢的1，4-二氧六环溶液(1mL，4N)，10℃反应15分钟。向悬浊的反应液中加入水(30mL)，并用乙酸乙酯萃取(30×3)。将水相用饱和碳酸氢钠水溶液调节pH＝8，再用氯仿萃取(40mL×4)。将所有有机相合并，无水硫酸钠干燥，过滤，滤液进行减压浓缩得到粗产物。粗产物通过高效液相色谱法制备纯化并冻干得到化合物2(2.3mg，产率：7.7％)。
MS(ESI)m/z 507.3[M+H] +
1H NMR(400MHz,Methanol-d4)δ＝8.35(d,J＝4.4Hz,1H),7.85(d,J＝7.6Hz,1H),7.76(d,J＝1.6Hz,1H),7.58(d,J＝5.6Hz,1H),7.48(d,J＝1.6Hz,1H),7.29(dd,J＝5.2Hz,7.6Hz,1H),5.75(d,J＝6.0Hz,1H),4.12-4.00(m,3H),3.46-3.34(m,2H),3.29-3.23(m,1H),3.01-2.92(m,4H),2.55(s,3H),2.17-2.01(m,2H),1.74(d,J＝13.6Hz,1H),1.53(d,J＝13.6Hz,1H).
实施例3
(S)-1'-(8-((3-氯-2-((甲基-d3)氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺
Figure PCTCN2020098474-appb-000033
中间体3e
2-((甲基-d 3)氨基)-3-氯吡啶-4-硫醇钠
Figure PCTCN2020098474-appb-000034
Figure PCTCN2020098474-appb-000035
第一步
3-氯-4-碘-N-(甲基-d 3)吡啶-2-胺3b
将化合物3a(3.0g，12mmol)和甲基-d 3-胺盐酸盐(1.2g,16mmol)溶于DMSO(50mL)，加入DIEA(5.8mL,35mmol)。70℃下反应12小时。反应结束后加入冰水混合物(50mL)，过滤，冰水洗涤(50mL×3)。所得固体减压干燥得到化合物3b(2.8g，产率：83％)。
MS(ESI)m/z 272.0[M+H] +
1H NMR:(400MHz,CDCl 3)δ＝7.67(d,J＝5.2Hz,1H),7.02(d,J＝5.2Hz,1H),5.14(br s,1H)。
第二步
3-((3-氯-2-((甲基-d 3)氨基)吡啶-4-基)硫基)丙酸乙酯3d
将化合物3b(2.7g，10mmol)溶于二氯甲烷(30mL)，加入3-硫基丙酸乙酯3c(2.0g，15mmol)，三(二亚苄基丙酮)(0.46g，0.50mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.58g，0.99mmol)和N,N-二异丙基乙基胺(4.9mL,30mmol)。氮气氛下100℃条件下反应3小时。反应完成后过滤，滤液减压浓缩，所得残留物用硅胶色谱法以乙酸乙酯、石油醚洗脱纯化得到化合物3d(2.5g，产率：90％)。
MS(ESI)m/z 278.1[M+H] +
1H NMR(400MHz,CDCl 3)δ＝7.96(d,J＝5.6Hz,1H),6.45(d,J＝5.6Hz,1H),5.00(br s,1H),4.19(q,J＝7.2Hz,2H),3.23(t,J＝7.6Hz,2H),2.72(t,J＝7.6Hz,2H),1.28(t,J＝7.2Hz,3H)。
第三步
2-((甲基-d 3)氨基)-3-氯吡啶-4-硫醇钠中间体3e
将化合物3d(2.4g，8.6mmol)溶于四氢呋喃(25mL)中，0℃条件下加入乙醇钠乙醇溶液(3.5g,10mmol,20％w/w,)，0℃下反应1小时。反应完成后，将反应液浓缩，加入50:1甲基叔丁基醚和二氯甲烷的混合溶液(20mL)，过滤，50:1甲基叔丁基醚和二氯甲烷洗涤(10mL×3)。所得固体真减压干燥得到中间体3e(2.0g，产率：99％)。
MS(ESI)m/z 178.0[M+H] +
1H NMR(400MHz,DMSO_d 6)δ＝7.12(d,J＝5.6Hz,1H),6.43(d,J＝5.2Hz,1H),5.29(s,1H)。
第四步
(S)-N-((S)-1'-(8-((3-氯-2-((甲基-d 3)氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺3f
氮气氛下，将化合物2b(200mg，0.39mmol)中间体3e(156mg，0.77mmol)溶于1,4-二氧六环(5mL)，加入碘化亚铜(74mg，0.39mmol)，N,N'-二甲基乙二胺(34mg，0.39mmol)和磷酸钾(246mg，1.2mmol)，130℃氮气氛下加热反应15小时。反应完成后加入氨水(30mL)和乙酸乙酯(15mL)，水相以乙酸乙酯萃取(25mL×3)，合并所有有机相，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩。所得残余物用硅胶色谱法以二氯甲烷、甲醇洗脱纯化得到化合物3f(130mg，产率：55％)。
MS(ESI)m/z 614.3[M+H] +
1H NMR(400MHz,CDCl 3)δ＝8.47(d,J＝4.4Hz,1H),7.68(d,J＝5.6Hz,1H),7.64(d,J＝7.2Hz,1H),7.48(dd,J＝1.2,9.2Hz,2H),7.17(dd,J＝4.8,7.6Hz,1H),5.73(d,J＝5.6Hz,1H),5.28(s,1H),5.03(s,1H),4.64(d,J＝10.0Hz,1H),4.05-3.93(m,2H),3.73(d,J＝10.0Hz,1H),3.33-3.16(m,3H),2.94(d,J＝16.4Hz,1H),2.54(s,3H),2.52-2.44(m,1H),2.13(dt,J＝4.0,12.4Hz,1H),1.82-1.74(m,1H),1.52-1.44(m,1H),1.30(s,9H)。
第五步
(S)-1'-(8-((3-氯-2-((甲基-d 3)氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺3
将化合物3f(130mg，0.21mmol)溶于干燥的二氯甲烷(4.5mL)，0℃条件下滴加氯化氢的1，4-二氧六环溶液(1.5mL，4N)，20℃下反应1小时。向反应液中加入0.1M氢氧化钠水溶液(30mL)调节pH＝14，再用二氯甲烷萃取(30mL×2)。合并有机相，无水硫酸钠干燥，过滤，滤液进行减压浓缩得到粗产物。粗产物通过反相色谱法以0.1％氨水、乙腈洗脱纯化得到化合物3(65mg，产率：41％)。
MS(ESI)m/z 510.2[M+H] +
1H NMR(400MHz,MeOD_d4)δ＝8.36(d,J＝4.4Hz,1H),7.86(d,J＝7.6Hz,1H),7.76(d,J＝1.6Hz,1H),7.57(d,J＝5.6Hz,1H),7.47(d,J＝1.6Hz,1H),7.29(dd,J＝4.8,7.6Hz,1H),5.75(d,J＝6.0Hz,1H),4.11(s,1H),4.05(br d,J＝13.6Hz,2H),3.45-3.35(m,2H),3.27(d,J＝16.8Hz,1H),2.97(d,J＝16.4Hz,1H),2.55(s,3H),2.17-2.03(m,2H),1.74(br d,J＝14.0Hz,1H),1.53(br d,J＝13.6Hz,1H)。
实施例4
(S)-1'-(8-((2-(二(甲基-d3)氨基)-3-氯吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺
Figure PCTCN2020098474-appb-000036
中间体4a
2-(二(甲基-d 3)氨基)-3-氯吡啶-4-硫醇钠
Figure PCTCN2020098474-appb-000037
中间体4a的合成步骤参见中间体3e，其中以化合物二甲基-d 6-胺盐酸盐替换甲基-d 3-胺盐酸盐制备获得前述中间体4a。
MS(ESI)m/z 195.1[M+H] +
1H NMR(400MHz,DMSO_d 6)δ＝7.24(d,J＝5.2Hz,1H),6.79(d,J＝5.2Hz,1H)。
化合物4的合成步骤参见实施例3，其中以中间体4a替换中间体3e制备获得化合物4。
MS(ESI)m/z 527.2[M+H] +
1H NMR(400MHz,MeOD_d 4)δ＝8.36(d,J＝4.4Hz,1H),7.86(d,J＝7.6Hz,1H),7.77(d,J＝1.6Hz,1H),7.72(d,J＝5.2Hz,1H),7.47(d,J＝1.6Hz,1H),7.29(dd,J＝5.2,7.6Hz,1H),6.06(d,J＝5.6Hz,1H),4.11(s,1H),4.06(br d,J＝13.6Hz,2H),3.44-3.37(m,2H),3.25(s,1H),2.97(d,J＝16.8Hz,1H),2.56(s,3H),2.14-2.03(m,2H),1.75(br d,J＝13.2Hz,1H),1.54(br d,J＝13.6Hz,1H)。
实施例5
(S)-1'-(8-((3-氯-2-((甲基-d2)氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺
Figure PCTCN2020098474-appb-000038
中间体5f
Figure PCTCN2020098474-appb-000039
第一步
N,N-双(4-甲氧基苄基)甲胺-d 2 5b
将化合物5a(4.0g，16mmol)溶于甲醇(50mL)，室温下加入氘代甲醛的氘水溶液(3.7g,23mmol,20％w/w)和醋酸(0.93g，16mmol)。再加入氰基硼氢化钠(2.9g，47mmol)，室温下反应15小时。反应完成后，将反应液浓缩，加入2M氢氧化钠溶液调节pH至9～10，乙酸乙酯萃取(30mL×3)。合并有机相，无水硫酸钠干燥，减压浓缩，所得残余物用硅胶色谱法以石油醚、乙酸乙酯洗脱纯化得到化合物5b(4.0g，产率：95％)。
MS(ESI)m/z 274.3[M+H] +
1H NMR:(400MHz,CDCl 3)δ＝7.28-7.25(m,4H),6.89-6.84(m,4H),3.88-3.74(m,7H),3.45(s,4H)。
第二步
N-(4-甲氧基苄基)甲烷-d 2-胺盐酸盐5c
将化合物5b(1.0g，3.7mmol)溶于甲醇(20mL)，加入10％钯碳(含水量1％，100mg)，20％氢氧化钯(100mg)和浓盐酸(0.5mL)。50psi氢气氛下，80℃反应12小时。过滤，甲醇(30mL×3)洗涤，滤液减压浓缩干燥得到化合物5c(0.69g，产率：99％)。
MS(ESI)m/z 153.8[M+H] +
1H NMR(400MHz,DMSO-d 6)δ＝9.18(br s,2H),7.45(d,J＝8.4Hz,2H),6.97(d,J＝8.4Hz,2H),4.01(t,J＝5.6Hz,2H),3.76(s,3H),2.44(br s,1H)。
第三步
3-氯-4-碘-N-(4-甲氧基苄基)-N-(甲基-d 2)吡啶-2-胺5d
将化合物5c(638mg，3.4mmol)和化合物3a(787mg,3.1mmol)溶于DMSO(10mL)，加入DIEA(2.0g,15mmol)。60℃下反应15小时。反应结束后加入冰水混合物(100mL)，乙酸乙酯萃取(30mL×3)。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶色谱法以石油醚、乙酸乙酯洗脱纯化得到化合物5d(590mg，产率：49％)。
MS(ESI)m/z 391.0[M+H] +
1H NMR:(400MHz,CDCl 3)δ＝7.76(d,J＝5.2Hz,1H),7.35(d,J＝5.2Hz,1H),7.32-7.27(m,2H),6.95-6.81(m,2H),4.45(s,2H),3.82(s,3H),2.80(s,1H)。
第四步
3-((3-氯-2-((4-甲氧基苄基)(甲基-d 2)氨基)吡啶-4-基)硫基)丙酸乙酯5e
将化合物5d(590mg，1.5mmol)溶于1,4-二氧六环(8mL)，加入3-硫基丙酸乙酯3c(304mg，2.3mmol)，三(二亚苄基丙酮)二钯(69mg，0.076mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(87mg，0.15mmol)和N,N-二异丙基乙胺(586mg,4.5mmol)。氮气氛下100℃条件下反应5小时。反应完成后过滤，滤液减压浓缩，所得残留物用硅胶色谱法以乙酸乙酯、石油醚洗脱纯化得到化合物5e(614mg，产率：94％)。
MS(ESI)m/z 397.1[M+H] +
1H NMR(400MHz,CDCl 3)δ＝8.07(d,J＝5.6Hz,1H),7.34-7.29(m,2H),6.93-6.83(m,2H),6.71(d,J＝5.2Hz,1H),4.43(s,2H),4.20(q,J＝7.2Hz,2H),3.81(s,3H),3.24(t,J＝7.6Hz,2H),2.80(s,1H),2.75(t,J＝7.6Hz,2H),1.29(t,J＝7.2Hz,3H)。
第五步
3-氯-2-((4-甲氧基苄基)(甲基-d 2)氨基)吡啶-4-硫醇钠中间体5f
将化合5e(614mg，1.4mmol)溶于四氢呋喃(8mL)中，0℃条件下加入乙醇钠乙醇溶液(582mg,1.7mmol,20％w/w,)，0℃下反应1小时。反应完成后，将反应液浓缩，加入甲基叔丁基醚和二氯甲烷的混合溶液(6mL,v/v＝50/2)，过滤，甲基叔丁基醚洗涤(10mL×3)。所得固体真减压干燥得到中间体5f(445mg，产率：98％)。
MS(ESI)m/z 297.1[M+H] +
1H NMR(400MHz,Methanol_d 4)δ＝7.46(d,J＝5.4Hz,1H),7.32-7.22(m,2H),7.17(d,J＝5.6Hz,1H),6.92-6.76(m,2H),4.25(s,2H),3.77(s,3H),2.61(s,1H)。
第六步
(S)-N-((S)-1'-(8-((3-氯-2-((4-甲氧苄基)(甲基-d 2)氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-基)-2-甲基丙烷-2-亚磺酰胺5g
氮气氛下，将化合物2b(153mg，0.30mmol)中间体5f(188mg，0.59mmol)溶于1,4-二氧六环(5mL)，加入碘化亚铜(56mg，0.30mmol)，N,N'-二甲基乙 二胺(52mg，0.59mmol)和磷酸钾(188mg，0.89mmol)，130℃氮气氛下加热反应15小时。反应完成后加入氨水(20mL)和乙酸乙酯(10mL)，水相以乙酸乙酯萃取(20mL×3)，合并所有有机相，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩。所得残余物用硅胶色谱法以二氯甲烷、甲醇洗脱纯化得到化合物5g(190mg，产率：45％)。
MS(ESI)m/z 733.3[M+H] +
第七步
(S)-1'-(8-((3-氯-2-((甲基-d 2)氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺5
将化合物5g(160mg，0.22mmol)溶于TFA中(3mL)，室温条件下反应4小时。再在0℃下滴加氯化氢的1，4-二氧六环溶液(1mL，4N)，室温反应1小时。向反应液中加入0.1M氢氧化钠水溶液(30mL)调节pH＝14，再用二氯甲烷萃取(30mL×2)。合并有机相，无水硫酸钠干燥，过滤，滤液进行减压浓缩得到粗产物。粗产物通过硅胶色谱法以二氯甲烷、甲醇洗脱纯化得到化合物5(51mg，产率：46％)。
MS(ESI)m/z 509.2[M+H] +
1H NMR(400MHz,CDCl 3)δ＝8.45(d,J＝4.4Hz,1H),7.71(d,J＝5.2Hz,1H),7.67(d,J＝7.2Hz,1H),7.56(d,J＝1.2Hz,1H),7.44(d,J＝1.6Hz,1H),7.18(dd,J＝5.2,7.6Hz,1H),5.78(d,J＝5.6Hz,1H),5.03(d,J＝4.4Hz,1H),4.11(s,1H),4.04-3.93(m,2H),3.33(q,J＝11.6Hz,2H),3.25(d,J＝16.8Hz,1H),3.00(br s,1H),2.93(d,J＝16.8Hz,1H),2.58(s,3H),2.11(dt,J＝4.0,12.8Hz,1H),2.02(dt,J＝4.4,12.4Hz,1H),1.81-1.73(m,1H),1.52-1.47(m,1H)。
实施例6
(S)-1'-(8-((3-氯-2-((甲基-d)氨基)吡啶-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-5,7-二氢螺[环戊二烯并[b]吡啶-6,4'-哌啶]-5-胺
Figure PCTCN2020098474-appb-000040
中间体6f
Figure PCTCN2020098474-appb-000041
中间体6f
N,N-双(4-甲氧基苄基)甲胺-d 6a
将化合物5a(3.0g，12mmol)溶于无水甲醇(30mL)，室温下加入甲醛水溶液(2.6mL,37％w/w)和醋酸(0.67mL,12mmol)。室温下反应2小时，再在0℃下加入硼氘化钠(0.97g，23mmol)，室温下再反应1.5小时。反应完成后，将反应液浓缩，加入水(50mL)，乙酸乙酯萃取(30mL×3)。合并有机相，无水硫酸钠干燥，减压浓缩得到化合物6a(3.3g，产率：94％)。
1H NMR:(400MHz,CDCl 3)δ＝7.30-7.25(m,4H),6.91-6.84(m,4H),3.81(s,6H),3.45(s,4H),2.13(s,2H)。
第二步
(4-甲氧基苄基)(甲基-d)氨基甲酸苄酯6b
将化合物6a(3.3g，12mmol)溶于甲苯(30mL)，加入氯甲酸苄酯(4.1mL,29mmol)，氮气氛下120℃反应14小时。反应完成后将反应液减压浓缩，加入乙酸乙酯(50mL)，水(20mL)、饱和食盐水(20mL×2)洗涤，有机相无水硫酸钠干燥，减压浓缩。残余物用硅胶色谱法以石油醚、乙酸乙酯洗脱纯化得到化合物6b(3.8g粗品)。
1H NMR(400MHz,CDCl 3)δ＝7.43-7.31(m,5H),7.21(d,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,1H),6.91-6.82(m,2H),5.20(s,2H),4.45(s,2H),3.82(s,3H),2.86(d,J＝10.8Hz,2H)。
第三步
N-(4-甲氧基苄基)甲烷-d-胺盐酸盐6c
将化合物6b(3.8g，12mmol)溶于甲醇(40mL)，加入10％钯碳(1.0g)。氢气氛下40℃反应16小时。过滤，甲醇(80mL)洗涤，滤液减压浓缩干燥得到化合物6c(2g，产率：99％)。
MS(ESI)m/z 152.9[M+H] +
第四步
3-氯-4-碘-N-(4-甲氧基苄基)-N-(甲基-d)吡啶-2-胺6d
将化合物6c(2g，12mmol)和化合物3a(2.3g,8.8mmol)溶于DMSO(4mL)，加入DIEA(4.3mL,26mmol)。60℃下反应5小时。反应结束后加入水 (50mL)，乙酸乙酯萃取(30mL×3)。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩。所得残余物用硅胶色谱法以石油醚、乙酸乙酯洗脱纯化得到化合物6d(2.6g，产率：76％)。
MS(ESI)m/z 390.0[M+H] +
1H NMR:(400MHz,CDCl 3)δ＝7.76(d,J＝4.8Hz,1H),7.35(d,J＝5.2Hz,1H),7.32-7.27(m,2H),6.92-6.83(m,2H),4.45(s,2H),3.81(s,3H),2.82(s,2H)。
第五步
3-((3-氯-2-((4-甲氧基苄基)(甲基-d)氨基)吡啶-4-基)硫基)丙酸乙酯6e
将化合物6d(2.6g，6.7mmol)溶于1,4-二氧六环(30mL)，加入3-硫基丙酸乙酯3c(1.3g，10mmol)，三(二亚苄基丙酮)二钯(310mg，0.34mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(390mg，0.67mmol)和N,N-二异丙基乙胺(3.3mL,20mmol)。氮气氛下100℃条件下反应6小时。反应完成后过滤，滤液减压浓缩，所得残留物用硅胶色谱法以乙酸乙酯、石油醚洗脱纯化得到化合物6e(2.3g，产率：88％)。
MS(ESI)m/z 396.1[M+H] +
1H NMR(400MHz,CDCl 3)δ＝8.07(d,J＝5.2Hz,1H),7.34-7.28(m,2H),6.93-6.82(m,2H),6.72(d,J＝5.2Hz,1H),4.43(s,2H),4.20(q,J＝7.2Hz,2H),3.81(s,3H),3.24(t,J＝7.6Hz,2H),2.81(s,2H),2.75(t,J＝7.6Hz,2H),1.29(t,J＝6.8Hz,3H)。
第六步
3-氯-2-((4-甲氧基苄基)(甲基-d)氨基)吡啶-4-硫醇钠中间体6f
将化合物6e(2.3g，5.9mmol)溶于四氢呋喃(25mL)中，0℃条件下加入乙醇钠乙醇溶液(2.4g,7.1mmol,20％w/w,)，0℃下反应1小时。反应完成后，将反应液浓缩，加入甲基叔丁基醚和二氯甲烷的混合溶液(40mL,v/v＝50/2)，过滤，甲基叔丁基醚洗涤(15mL×3)。所得固体真减压干燥得到中间体6f(1.7g，产率：91％)。
1H NMR(400MHz,DMSO-d6)δ＝7.29-7.23(m,3H),6.89-6.79(m,3H),4.12(s,2H),3.72(s,3H),3.34(s,2H)。
化合物6的合成步骤参见实施例5，其中以中间体6f替换中间体5f制备获得前述化合物6。
MS(ESI)m/z 508.2[M+H] +
1H NMR(400MHz,CDCl 3)δ＝8.47(d,J＝4.4Hz,1H),7.68(d,J＝5.6Hz,1H),7.64(d,J＝7.2Hz,1H),7.48(dd,J＝1.2,9.2Hz,2H),7.17(dd,J＝4.8,7.6Hz,1H),5.73(d,J＝5.6Hz,1H),5.28(s,1H),5.03(s,1H),4.64(d,J＝10.0Hz,1H),4.05-3.93(m,2H),3.73(d,J＝10.0Hz,1H),3.33-3.16(m,3H),2.94(d,J＝16.4Hz,1H),2.54(s,3H),2.52-2.44(m,1H),2.13(dt,J＝4.0,12.4Hz,1H),1.82-1.74(m,1H),1.52-1.44(m,1H),1.30(s,9H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
测试例1、本公开化合物对SHP2磷酸酶活性检测
1、实验材料及仪器
仪器名称 设备厂家 型号
恒温恒温振荡器 IMB MB-1002A
微孔板读板仪 MDSpectraMax M5
试剂名称 厂商 货号
Shp2 金斯瑞 N/A
激活型多肽 金斯瑞 N/A
DMSO Sigma C34557
1M HEPES Thermofisher 15630080
5M NaCl Thermofisher AM9760G
2M KCl Thermofisher AM9640G
1M DTT Thermofisher P2325
10％SDS Thermofisher AM9822
30％Brij TM-35 Thermofisher 20150
EDTA Sigma EDS-500G
Difmup Invitrogen TM 6567
2、实验步骤
将0.2nM重组表达的全长SHP2(aa 1-593)，0.5nM带有双磷酸化位点的激活型多肽IRS1(sequence:H2N-LN(pY)IDLDLY(dPEG8)LST(pY)ASINFQK-amide)以及一系列浓度的测试化合物(终浓度为1μM，0.3μM，0.1μM，0.03μM，0.01μM，0.003μM，0.001μM，0.0003μM，0.0001μM，0.00003μM)加入磷酸酶反应液(60mM HEPES,PH 7.5 0.005％Brij-35,75mM NaCl,75mM KCl,1mM EDTA,5mM DTT)中，室温震荡(350rpm)30分钟。再加入终浓度为30μM反应底物DiFMUP室温反应30分钟后，用5μL反应终止液(60mM HEPES,pH 7.5，0.2％SDS)终止磷酸酶反应。在荧光读板仪MD SpectraMax上读取Ex358nm/Em455荧光值。
化合物的IC 50值用四参数logit方法计算.下列公式中x代表化合物浓度的对数形式；F(x)代表效应值(该浓度条件下细胞增殖的抑制率):F(x)＝((A-D)/(1+((x/C)^B)))+D。A,B,C和D为四个参数。不同的浓度对应不同的磷酸酶活抑制率，做出一条反曲线，从曲线上算出抑制剂的IC 50。用Primer premier 6.0计算化合物的IC 50。
本公开化合物对SHP2体外活性通过以上的试验进行测定，选取有口服活性 的SHP2抑制剂SHP099做为阳性药，该化合物结构公开于文献J.Med.Chem.2016,59,7773-7782中，具体化合物购买自上海皓元生物医药科技有限公司(Medchemexpress.cn)。
测得的IC 50值见表1。
表1.本公开化合物对SHP2磷酸酶IC 50
实施例编号 IC 50(nM) 实施例编号 IC 50(nM)
SHP099 79 1 1.7
2 2.1 3 4.5
5 4.8 6 4.7
测试例2、大鼠肝微粒体体外代谢稳定性实验
利用LC/MS/MS测定反应体系中的化合物浓度，以此来计算待测化合物的固有清除率，并评估在大鼠肝微粒体中的体外代谢稳定性。
将222.5μL，1.1236mg/mL的大鼠肝微粒体(雄性Wistar Han品系,购自Corning公司，货号452511)混合液和25μL，10mM的NADPH加入孵育板中。用涡旋混匀10秒。在37℃水浴中孵育8分钟。将2.5μL，100μM的待测化合物或阳性对照加入孵育板起始反应。在涡旋上混匀12秒后在37℃水浴中继续孵育。分别在0.5、5、10、15、20和30分钟时将20μL孵育体系转移到含有100μL冷终止液的终止板上来终止反应，用涡旋混匀2分钟。将终止板以4000rpm离心20分钟，然后4℃下静置30分钟，再以4000rpm离心20分钟。转移40μL每个化合物上清液至96孔进样板中，加入160μL纯水稀释样品。
所得样品由离子色谱图定量，根据待测化合物或阳性对照的峰面积来计算残余率。斜率k使用Microsoft Excel由剩余率的自然对数值对孵育时间的线性回归测定。
体外半衰期(in vitro t1/2)由斜率计算：in vitro t1/2＝-(0.693/k)
用以下等式将体外半衰期转化为固有清除率(in vitro CLint，μL/min/mg蛋白)：
in vitro CLint＝(0.693/t1/2)×(孵育体积(μL)/蛋白量(mg))
测得的大鼠肝微粒体固有清除率值见表2。
表2.本发明化合物大鼠肝微粒体固有清除率
Figure PCTCN2020098474-appb-000042
Figure PCTCN2020098474-appb-000043
测试例3、大鼠体内药代动力学实验
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予本发明化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
试验动物：每组健康6-8周雄性SD大鼠3只
药物配制
称取一定量药物，加0.5％质量的羟丙甲纤维素、0.1％体积的吐温80和99.4％体积的水配制成1mg/mL的白色悬浊液。
给药
SD大鼠禁食过夜后灌胃给药，参照物1给药剂量为7.5mg/kg，实施例1给药剂量为5mg/kg。
操作
大鼠灌胃给药本发明化合物，给药后0.25、0.5、1、2、4、8、24小时由颈静脉采血0.2mL，置于含EDTA-K2的试管中，4℃、4000转/分钟离心5分钟分离血浆，于-75℃保存。
测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆50μL，加入内标地塞米松(50ng/mL)的乙腈溶液200μL，涡旋混合30秒，4℃、4700转/分钟离心15分钟，血浆样品取上清液加水稀释三倍，取2.0μL进行LC/MS/MS分析。
药代动力学参数结果
本发明化合物的大鼠药代动力学参数如下表3。
表3.本发明化合物的大鼠药代动力学参数
Figure PCTCN2020098474-appb-000044
测试例4、食蟹猴体内药代动力学实验
以食蟹猴为受试动物，应用LC/MS/MS法测定了食蟹猴灌胃给予本发明化合物后不同时刻血浆中的药物浓度。研究本发明化合物在食蟹猴体内的药代动力学行为，评价其药动学特征。
试验动物：每组健康2-5岁雄性食蟹猴3只；
药物配制
灌胃给药：称取一定量药物，加0.5％质量的羟丙甲纤维素、0.1％体积的吐温80和99.4％体积的水配制成1mg/mL的白色悬浊液。
给药
食蟹猴禁食过夜后灌胃给药，给药剂量为5mg/kg。
操作
食蟹猴灌胃给药本发明化合物，给药后0.25、0.5、1、2、4、8、24小时由外周静脉采血0.2mL，置于含EDTA-K2的试管中，2～8℃、2000转/分钟离心10分钟分离血浆，于-75℃保存。
测定不同浓度的药物灌胃给药后食蟹猴血浆中的待测化合物含量：取给药后各时刻的食蟹猴血浆55μL，加入内标维拉帕米或地塞米松的乙腈溶液200μL，涡旋混合30秒，4℃、3900转/分钟离心15分钟，血浆样品取上清液加水稀释三倍，取15μL进行LC/MS/MS分析。
药代动力学参数结果
本发明化合物的食蟹猴药代动力学参数如下表4。
表4.本发明化合物的食蟹猴药代动力学参数
Figure PCTCN2020098474-appb-000045
测试例5、Caco-2渗透性实验
通过Caco-2细胞模型利用液相色谱串联质谱(LC/MS/MS)测定分析药物的表观渗透系数(P app)。
在Caco-2细胞(购自ATCC)密度为7.92×10cells/cm 2的Transwell(购自康 宁公司)小室顶端加入210μL含10μM待测化合物的HBSS(25mM HEPES，pH 7.4，含50μM quinidine,30μM benzbromarone,20μM sulfasalazine)，同时立即取出10μL样品到已加有90μL HBSS(25mM HEPES，pH 7.4，含50μM quinidine,30μM benzbromarone,20μM sulfasalazine)的96深孔板中作为初始加药端样品，基底端加入800μL HBSS(25mM HEPES，pH 7.4，含50μM quinidine,30μM benzbromarone,20μM sulfasalazine)。37℃孵育2小时。在45分钟和2小时时间点分别从顶端吸取10μL样品到含有90μL HBSS(25mM HEPES，pH 7.4，含50μM quinidine,30μM benzbromarone,20μM sulfasalazine)的96孔深孔板中。在45分钟和2小时时间点分别从基底端吸取100μL样品到96孔深孔板中。然后每孔加入3倍体积的预冷内标。1000rmp涡旋10分钟，4000rpm离心20分钟。每孔取出100μL样品，3个样品一起与100μL纯水混合进行LC/MS/MS分析。
使用Microsoft Excel计算数据，峰面积根据色谱图计算。表观渗透系数(Papp)的单位是cm/s，用如下公式进行计算：
Figure PCTCN2020098474-appb-000046
C R为基底端待测化合物浓度(上标“120”或“45”为取样时间，单位：分钟)，C D为顶端待测化合物浓度(上标“120”或“45”为取样时间，单位：分钟)，Area为膜表面积(0.33cm 2)，时间为总的转运时间(75×60秒)。
测得的Caco-2细胞表观渗透系数值见表5。
表5.本发明化合物Caco-2细胞表观渗透系数
实施例编号 Papp (A-B)(10 -6,cm/s)
1 2.71
2 12.05
3 17.22
测试例6、CYP抑制实验
使用150个供体混合人肝微粒体(购自Corning,货号452117)评估人主要5个CYP亚型(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4/5)的代表性底物代谢反应。通过液相色谱串联质谱(LC/MS/MS)测定不同浓度待测化合物对非那西丁(CYP1A2)、双氯芬酸钠(CYP2C9)、S-美芬妥英(CYP2C19)、丁呋洛尔盐酸盐(2D6)、咪达唑仑(CYP3A4/5)代谢反应的影响。
将30μM非那西丁、10μM双氯芬酸钠、35μM S-美芬妥英、5μM丁呋洛尔盐酸盐、3μM咪达唑仑、1mM NADPH、待测化合物(浓度分别为0.1、0.3、1、3、10、30μmol/L)或阳性化合物或空白对照与混合人肝微粒体(0.2mg/mL)的反应体系200μL(100mmol/L磷酸盐缓冲液，pH 7.4，含体积比分别为0.3％的 DMSO、0.6％的乙腈、0.1％的甲醇)在37℃孵育5分钟。然后加入200μL含3％甲酸及40nM内标维拉帕米的乙腈溶液，4000rpm离心50分钟。置于冰上冷却20分钟，再4000rpm离心20分钟析出蛋白。取200μL上清液进行LC/MS/MS分析。
峰面积根据色谱图计算。残余活性比例(％)用如下公式进行计算：
峰面积比例＝代谢产物峰面积/内标峰面积
残余活性比例(％)＝待测化合物组的峰面积比例/空白组的峰面积比例
CYP半数抑制浓度(IC 50)通过Excel XLfit 5.3.1.3计算得到。
测得的CYP半数抑制浓度(IC 50)数值见表6。
表6.本发明化合物对CYP的半数抑制浓度(IC 50)
Figure PCTCN2020098474-appb-000047

Claims (16)

  1. 一种通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，其中
    Figure PCTCN2020098474-appb-100001
    R 1选自氢原子、C 1-6烷基、卤代C 1-6烷基或氨基，所述烷基和卤代烷基各自独立地任选进一步被一个或多个氘原子的取代基取代；
    Y 1为-S-或者直接键；
    A环选自芳基、杂芳基，优选苯基或吡啶基；
    R 3各自独立的选自氢原子、氘原子、卤素、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-OR a、-CHR aR b、-NR aR b；
    所述R a、R b各自独立选自氢、氘原子、羟基、C 1-6烷基、3-12元的杂环基或C 3-8环烷基，其中所述烷基、杂环基或环烷基进一步被一个或多个选自卤素、氘原子、氰基、氨基、羟基的取代基取代；
    或R a、R b与它们共同连接的原子形成3-12元的杂环基或C 3-8环烷基，所述烷基、杂环基或环烷基任选进一步被一个或多个选自卤素、氘原子、氰基、氨基、羟基的取代基取代；
    环B是6元芳环、5元杂芳环、6元杂芳环，优选自苯环或吡啶环；
    R 8各自独立的选自氢原子、氘原子、卤素、氰基、C 1-6烷基、C 1-6烷氧基；
    m选自0，1，2，3，4；
    n选自1，2，3，4。
  2. 根据权利要求1所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，其中R 1选自C 1-6烷基或卤代C 1-6烷基，所述C 1-6烷基或卤代C 1-6烷基任选被一个或者多个氘原子取代。
  3. 根据权利要求2所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其 可药用的盐，其中Y 1为-S-。
  4. 根据权利要求3所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，其中A环选自苯基或吡啶基。
  5. 根据权利要求4所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，所述R 3各自独立的选自氢原子、氘原子、卤素、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-NR aR b；所述R a、R b各自独立选自氢、氘原子、羟基、C 1-6烷基，所述烷基被一个或多个氘原子取代。
  6. 根据权利要求5所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，环B是苯环或吡啶环。
  7. 根据权利要求1-6任一项所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，其中
    R 1选自甲基，所述甲基任选被一个或者多个氘原子取代；
    Y 1为-S-；
    A环选自苯基或吡啶基；
    R 3各自独立的选自氢原子、氘原子、卤素、-NR aR b；
    所述R a、R b各自独立选自氢、氘原子、C 1-6烷基，所述烷基被一个或多个氘原子取代；
    环B为苯环或吡啶环；
    m选自0；
    n选自1，2，3，4。
  8. 根据权利要求7所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，
    其中R 1选自甲基；
    Y 1为-S-；
    A环选自吡啶基；
    R 3各自独立的选自氢原子、氘原子、卤素、-NR aR b；
    所述R a、R b各自独立选自氢、氘原子、C 1-6烷基，所述烷基被一个或多个氘原子取代；
    环B为吡啶环；
    m选自0；
    n选自1，2，3，4。
  9. 根据权利要求7所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，
    其中R 1选自甲基；
    Y 1为-S-；
    A环选自吡啶基；
    R 3各自独立的选自氢原子、氘原子、氯原子、-NH-CH 3或者N-(CH 3) 2；所述-NH-CH 3或者N-(CH 3) 2中甲基上的氢原子被一个或多个氘原子取代；
    环B为吡啶环；
    m选自0；
    n选自1，2，3，4。
  10. 根据权利要求1-9任一项所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，其为
    Figure PCTCN2020098474-appb-100002
  11. 根据权利要求1-10任一项所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤，式(II-2)所示化合物脱去保护基团PG得到式(II-1)所示化合物，
    Figure PCTCN2020098474-appb-100003
    PG为氨基保护基团，选自Boc,PMB,S(＝O) tBu，Cbz；
    P选自1，2，3；
    q选自1，2；
    其中，环A、环B、R 1、R 8、B、m如权利要求1-10中定义。
  12. 根据权利要求11所述的制备方法，进一步包括以下步骤，
    Figure PCTCN2020098474-appb-100004
    式(II-3)所示化合物与式(II-4)所示化合物在碱性条件下，经C-S偶联，得到式(II-2)所示化合物。
  13. 一种药物组合物，其含有0.1-2000mg的根据权利要求1-10任一项所述的通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  14. 根据权利要求1-10任一项所述的通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或根据权利要求13所述的药物组合物在制备预防或者治疗由SHP2活性介导的疾病或病症的药物中的用途。
  15. 根据权利要求1-10任一项所述的通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或根据权利要求13所述的药物组合物做为SHP2抑制剂在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
  16. 根据权利要求1-10任一项所述的通式(II)所示的化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其可药用的盐，或根据权利要求13所述的药物组合物在制备预防或者治疗努南综合征、豹皮综合征、幼年性骨髓单核细胞白血病、神经母细胞瘤、黑素瘤、急性骨髓性白血病、乳腺癌、食管癌、肺癌、结肠癌、头癌、胰腺癌、头和颈鳞状细胞癌、胃癌、肝癌、间变性大细胞淋巴瘤和成胶质细胞瘤药物中的用途。
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AU2020306124A1 (en) 2022-02-03
KR20220054285A (ko) 2022-05-02
BR112021024674A2 (pt) 2022-05-31
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