WO2021121397A1 - 取代的炔基杂环化合物 - Google Patents

取代的炔基杂环化合物 Download PDF

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WO2021121397A1
WO2021121397A1 PCT/CN2020/137662 CN2020137662W WO2021121397A1 WO 2021121397 A1 WO2021121397 A1 WO 2021121397A1 CN 2020137662 W CN2020137662 W CN 2020137662W WO 2021121397 A1 WO2021121397 A1 WO 2021121397A1
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alkyl
group
methyl
substituted
pyrazolo
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PCT/CN2020/137662
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English (en)
French (fr)
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张晓军
闵汪洋
段小伟
陈曦
许新合
刘希杰
张凯
孙小亮
孙颖慧
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首药控股(北京)股份有限公司
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Priority claimed from CN201911314609.5A external-priority patent/CN113004282A/zh
Priority claimed from CN202010638837.4A external-priority patent/CN113880842A/zh
Application filed by 首药控股(北京)股份有限公司 filed Critical 首药控股(北京)股份有限公司
Publication of WO2021121397A1 publication Critical patent/WO2021121397A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present invention generally relates to a new substituted alkynyl heterocyclic compound with SHP2 inhibitory activity, its preparation method, and its pharmaceutical composition, as well as the use of such compound and its pharmaceutical composition to treat diseases that benefit from SHP2 enzyme inhibition. Such as treating cancer.
  • Cancer is a major disease that seriously threatens human health and life.
  • the incidence and mortality of cancer have been rising rapidly in recent years, and it has surpassed cardiovascular disease to become the number one killer of human health.
  • Tumor proliferation, apoptosis, metastasis, etc. are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside the cell.
  • protein phosphorylation and dephosphorylation are crucial, and this reversible process is jointly regulated by kinases and phosphatases.
  • the phosphorylation of protein tyrosine kinase (PTK) and the dephosphorylation of protein tyrosine phosphatase (PTP) are such a pair of reversible processes. They maintain a dynamic balance to maintain the normal physiological functions of cells. On the contrary, abnormal phosphorylation can lead to cancer, inflammation, diabetes and other diseases.
  • SHP2 protein is a non-receptor protein tyrosine phosphatase encoded by the ptpn11 gene. It is widely expressed in various tissues and participates in important physiological and pathological processes such as embryonic development, metabolism, immune response, and tumorigenesis.
  • the SHP2 protein consists of two N-terminal SH2 domains (N-SH2 and C-SH2) in tandem, a PTP catalytic domain and a C-terminal tail with a regulatory effect.
  • the SH2 domain is a conformational switch that can mediate the interaction between the SHP2 protein and phosphotyrosine-containing activators (such as the insulin receptor substrate 1-IRS1 and GRB2-related binding protein 1-GAB1), as well as the SH2 domain and PTP Intramolecular interaction of the catalytic domain. Under unstimulated conditions, the SHP2 domain binds to the PTP domain to block the catalytically active site, making the SHP2 phosphatase activity in a self-inhibited state.
  • phosphotyrosine-containing activators such as the insulin receptor substrate 1-IRS1 and GRB2-related binding protein 1-GAB1
  • SHP2 is involved in the regulation of cell signal transduction pathways activated by cytokines, growth factors and hormones, including RAS/ERK, JAK/STAT, PI3K/AKT and NF- ⁇ B signaling pathways, thereby regulating cell proliferation, differentiation, cell cycle maintenance and migration And other physiological functions. At the same time, SHP2 also mediates the compensatory activation pathway after MEK and other kinases are inhibited, thereby promoting the occurrence of tumor resistance. As a downstream molecule of the PD-1 receptor, SHP2 is also involved in T cell inhibitory signal transduction. Studies have shown that SHP2 is a downstream molecule of PD-1 signal transduction, which not only inhibits T cell activation but also promotes T cell disability. Therefore, targeting SHP2 can restore or enhance T cell-mediated anti-tumor immune function. In addition, SHP2 can inhibit the immune response mediated by IFN- ⁇ through the inactivation of signal transducer and transcriptional activator STAT1.
  • SHP2 activating mutations and high expression have been successively discovered in leukemia, solid tumors, melanoma, malignant glioma, lung cancer, breast cancer and Numan syndrome, which are closely related to the occurrence, development and prognosis of tumors.
  • SHP2 has been studied as a target molecule for clinical tumors.
  • Traditional SHP2 inhibitors (such as II-B08, PHPS1) have a mechanism of binding to the PTP catalytic domain of SHP2 to prevent tyrosine phosphorylated substrates from entering the catalytic site, thereby inhibiting the phosphatase activity of SHP2.
  • SHP2 inhibitors due to the highly conserved, polar and charged environment of the PTP catalytic domains of various phosphatases, traditional SHP2 inhibitors have relatively large defects in terms of specificity and bioavailability, limiting their clinical applications. Therefore, the development of SHP2 inhibitors with high specificity, high safety, and strong cell membrane permeability is the key to determining whether SHP2 can become a new tumor intervention target. SHP2 protein allosteric inhibitors have become the main direction of current research.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • A is selected from the following two or three heterocyclic heterocycles
  • R 1 is selected from hydrogen, halogen, C 1-6 alkyl and C 3-6 cycloalkyl.
  • the C 1-6 alkyl and C 3-6 cycloalkyl may be optionally substituted by halogen, -OH, or -OC 1-6 alkyl substitution,
  • R 2 is selected from hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl
  • X is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 heteroalicyclic, C 6-10 aryl and 5-10 membered heteroaryl ,
  • the C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group and C 3-8 heteroalicyclic group may optionally be substituted by one or more halogen, -OH, -OC 1 -6 alkyl, -CF 3 , -NH 2 , C 1-6 alkyl, or phenyl substituted, the C 6-10 aryl group and 5-10 membered heteroaryl group can be combined with unsaturated alicyclic and heteroaliphatic
  • the ring or spiro ring is fused, and may optionally be fused with one or more halogens, -CF 3 , -OH, -CN, R, -OR, -NR 3 R 4 , -OC(O)NR 3 R
  • R is selected from C 1-6 alkyl and C 3-6 cycloalkyl, and the alkyl and cycloalkyl may be optionally substituted by halogen, -CF 3 , -OH, -C 1-6 alkyl, -OC 1-6 alkyl or C 3-6 cycloalkyl substituted,
  • R 3 and R 4 are each independently selected from hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl,
  • Y is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 heteroalicyclic group and 5-15 membered spirocyclic group, the aryl, heteroaryl, heteroalicyclic and
  • the spirocyclic group may be optionally substituted by one or more halogens, -OH, -OC 1-6 alkyl, -NH 2 , C 1-6 alkyl, or C 3-6 cycloalkyl, the alkyl Or cycloalkyl can be optionally substituted by halogen, -OH, -OC 1-6 alkyl, or -NH 2 , the heteroalicyclic group and spirocyclic group can be optionally combined with 6-10 membered aryl or 5-10 membered heteroaryl group fused, aryl group or heteroaryl group fused with heteroalicyclic group and spirocyclic group may optionally be substituted by one or more halogen, -OH, -OC 1-6 alkyl,
  • Z is selected from single bond, -S- and -C ⁇ C-.
  • the compound of formula (I) of the present invention has the following formulas II to XIII:
  • R 1 is selected from hydrogen, halogen, C 1-6 alkyl and C 3-6 cycloalkyl.
  • the C 1-6 alkyl and C 3-6 cycloalkyl may be optionally substituted by halogen, -OH, or -OC 1-6 alkyl substitution,
  • R 2 is selected from hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl
  • X is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, C 3-8 heteroalicyclic, C 6-10 aryl and 5-10 membered heteroaryl ,
  • the C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group and C 3-8 heteroalicyclic group may optionally be substituted by one or more halogen, -OH, -OC 1 -6 alkyl, -CF 3 , -NH 2 , C 1-6 alkyl, or phenyl substituted, the C 6-10 aryl group and 5-10 membered heteroaryl group can be substituted with unsaturated alicyclic and heteroaliphatic
  • the ring or spiro ring is fused, and may optionally be fused with one or more halogens, -CF 3 , -OH, -CN, R, -OR, -NR 3 R 4 , -OC(O)NR 3
  • R is selected from C 1-6 alkyl and C 3-6 cycloalkyl, and the alkyl and cycloalkyl may be optionally substituted by halogen, -CF 3 , -OH, -C 1-6 alkyl, -OC 1-6 alkyl or C 3-6 cycloalkyl substituted,
  • R 3 and R 4 are each independently selected from hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl,
  • Y is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 heteroalicyclic group and 5-15 membered spirocyclic group, the aryl, heteroaryl, heteroalicyclic and
  • the spirocyclic group may be optionally substituted by one or more halogens, -OH, -OC 1-6 alkyl, -NH 2 , C 1-6 alkyl, or C 3-6 cycloalkyl, the alkyl Or cycloalkyl can be optionally substituted by halogen, -OH, -OC 1-6 alkyl, or -NH 2 , the heteroalicyclic group and spirocyclic group can be optionally combined with 6-10 membered aryl or 5-10 membered heteroaryl group fused, aryl group or heteroaryl group fused with heteroalicyclic group and spirocyclic group may optionally be substituted by one or more halogen, -OH, -OC 1-6 alkyl,
  • R 1 is selected from hydrogen, halogen, and C 1-6 alkyl, and the C 1-6 alkyl may be optionally substituted by halogen, -OH, or -OC 1-6 alkyl, R 2 is selected from hydrogen and C 1-6 alkyl. ;
  • X is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, the C 1-6 alkyl and The C 3-8 cycloalkyl group may be optionally substituted with one or more halogen, -OH, -OC 1-6 alkyl, -NH 2 , or C 1-6 alkyl, the C 6-10 aryl group And 5-10 membered heteroaryl groups can optionally be substituted by one or more halogen, -CF 3 , -OH, -CN, -OC 1-6 alkyl, -NR 3 R 4 , -OC(O)NR 3 R 4 , -NH-(CO)-C 1-6 alkyl, -S-CH 2 -CONH 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, or C 5-10 heteroaryl substitution,
  • R 3 and R 4 are each independently selected from hydrogen and C 1-6 alkyl
  • Y is selected from C 6-10 aryl, 5-10 membered heteroaryl and C 3-12 heteroalicyclic group, the aryl, heteroaryl and heteroalicyclic group may optionally Substituted by one or more -OH, -NH 2 , or C 1-6 alkyl;
  • the 5-10 membered heteroaryl group is a C 5-10 heteroaryl group.
  • Y is selected from C 3-12 heteroalicyclic groups, which may be optionally substituted with one or more -OH, -NH 2 , or C 1-6 alkyl groups;
  • Y is selected from C 3-12 heteroalicyclic groups, which may be optionally substituted with one or more -NH 2 or C 1-6 alkyl groups;
  • the 5-15 membered spirocyclic group is a 5-15 membered spiroheterocyclic group
  • the spiroheterocyclic group may be optionally substituted by one or more halogen, -OH, -OC 1-6 Alkyl, -NH 2 , C 1-6 alkyl, or C 3-6 cycloalkyl substituted
  • the alkyl or cycloalkyl may be optionally substituted by halogen, -OH, -OC 1-6 alkyl, Or -NH 2 substitution
  • the spiro heterocyclic group may be optionally fused with 6-10 membered aryl or 5-10 membered heteroaryl
  • the aryl or heteroaryl fused with spiro heterocyclic group may be any Optionally substituted by one or more halogen, -OH, -OC 1-6 alkyl, -NH 2 , C 1-6 alkyl, or C 3-6 cycloalkyl;
  • the 5-10 membered heteroaryl group is a C 5-10 heteroaryl group
  • Y is selected from the following structures:
  • X 1 , X 2 and X 2 are each independently selected from bond, O, CR a R b or NR c ,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, -OH, halogen, substituted or unsubstituted amino, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 1-6 alkoxy; and cannot be -OH or -NH 2 at the same time,
  • R a , R b and R c are each independently selected from H, -OH, halogen, substituted or unsubstituted amino, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy base,
  • Ring A is selected from substituted or unsubstituted C 4-8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5-10 membered Heteroaryl, the heterocyclic group or heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O, S or P,
  • R 13 and R 14 are selected from H, -OH, halogen, cyano, substituted or unsubstituted amino, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy,
  • n is any integer from 0 to 3;
  • the substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of halogen, -OH, -NO 2 , -NH 2 , and -CN.
  • one of X 1 and X 2 is O, and X 3 is a bond.
  • one of X 1 and X 2 is CH 2 and the other is a bond.
  • the present invention provides the following compounds:
  • Another embodiment of the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • A is selected from the following two or three heterocyclic heterocycles
  • R 1 and R 2 are each independently selected from hydrogen, halogen and C 1-6 alkyl
  • X is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, the C 1-6 alkyl and C 3-8 cycloalkane
  • the group may be optionally substituted with one or more halogen, -OH, -OC 1-6 alkyl, -NH 2 or C 1-6 alkyl, the C 6-10 aryl and 5-10 membered hetero
  • the aryl group can be fused with unsaturated alicyclic, heteroalicyclic, spiro ring, and can be optionally fused with one or more halogens, -CF 3 , -OH, -CN, -OC 1-6 alkyl,- NR 3 R 4 , -OC(O)NR 3 R 4 , -NH-(CO)-C 1-6 alkyl, -S-CH 2 -CONH 2 , C 1-6 alkyl, C 3-6 ring Alkyl, C 6-10 ary
  • R 3 and R 4 are each independently selected from hydrogen and C 1-6 alkyl
  • Y is selected from C 6-10 aryl groups, 5-10 membered heteroaryl groups and C 3-12 heteroalicyclic groups.
  • the aryl groups, heteroaryl groups and heteroalicyclic groups may optionally be substituted by one or more halogens. , -OH, -OC 1-6 alkyl, -NH 2 , C 1-6 alkyl, or C 3-6 cycloalkyl substituted, the alkyl or cycloalkyl may be optionally substituted by halogen, -OH , -OC 1-6 alkyl, or -NH 2 substitution;
  • Z is selected from single bond, -S- and -C ⁇ C-.
  • the compound of formula (I) of the present invention has the following formulas II to X:
  • R 1 and R 2 are each independently selected from hydrogen, halogen and C 1-6 alkyl;
  • X is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, the C 1-6 alkyl and C 3-8 cycloalkane
  • the group may be optionally substituted with one or more halogen, -OH, -OC 1-6 alkyl, -NH 2 or C 1-6 alkyl, the C 6-10 aryl and 5-10 membered hetero
  • the aryl group can be fused with unsaturated alicyclic, heteroalicyclic, spiro ring, and can be optionally fused with one or more halogens, -CF 3 , -OH, -CN, -OC 1-6 alkyl,- NR 3 R 4 , -OC(O)NR 3 R 4 , -NH-(CO)-C 1-6 alkyl, -S-CH 2 -CONH 2 , C 1-6 alkyl, C 3-6 ring Alkyl, C 6-10 ary
  • R 3 and R 4 are each independently selected from hydrogen and C 1-6 alkyl
  • Y is selected from C 6-10 aryl groups, 5-10 membered heteroaryl groups and C 3-12 heteroalicyclic groups.
  • the aryl groups, heteroaryl groups and heteroalicyclic groups may optionally be substituted by one or more halogens.
  • halogens , -OH, -OC 1-6 alkyl, -NH 2 , C 1-6 alkyl, or C 3-6 cycloalkyl substituted, the alkyl or cycloalkyl may be optionally substituted by halogen, -OH , -OC 1-6 alkyl, or -NH 2 substitution.
  • R 1 and R 2 are each independently selected from hydrogen and C 1-6 alkyl
  • X is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, the C 1-6 alkyl and The C 3-8 cycloalkyl group may be optionally substituted with one or more halogen, -OH, -OC 1-6 alkyl, -NH 2 , or C 1-6 alkyl, the C 6-10 aryl group And 5-10 membered heteroaryl groups can optionally be substituted by one or more halogen, -CF 3 , -OH, -CN, -OC 1-6 alkyl, -NR 3 R 4 , -OC(O)NR 3 R 4 , -NH-(CO)-C 1-6 alkyl, -S-CH 2 -CONH 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, or C 5-10 heteroaryl substitution,
  • R 3 and R 4 are each independently selected from hydrogen and C 1-6 alkyl
  • Y is selected from C 6-10 aryl, 5-10 membered heteroaryl and C 3-12 heteroalicyclic group, the aryl, heteroaryl and heteroalicyclic group may optionally Substituted by one or more -OH, -NH 2 , or C 1-6 alkyl;
  • the 5-10 membered heteroaryl group is a C 5-10 heteroaryl group.
  • Y is selected from C 3-12 heteroalicyclic groups, which may be optionally substituted with one or more -OH, -NH 2 , or C 1-6 alkyl groups;
  • Y is selected from C 3-12 heteroalicyclic groups, which may be optionally substituted with one or more -NH 2 or C 1-6 alkyl groups;
  • the present invention provides the following compounds:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.
  • the pharmaceutical composition of the present invention further includes pharmaceutically acceptable excipients.
  • the present invention provides a method for treating diseases related to SHP2, which comprises administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, solvate, or polysaccharide thereof to a mammal in need of such treatment, preferably a human. Crystal form, or tautomer, or pharmaceutical composition thereof.
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer, or pharmaceutical composition thereof, or any one of the foregoing and SHP2 inhibitor or The use of a KRAS inhibitor or an EGFR inhibitor combination in the preparation of a medicine for treating diseases related to SHP2.
  • the disease associated with SHP2 is leukemia, melanoma, malignant glioma, lung cancer, breast cancer, or Numan syndrome.
  • SHP2 plays a role upstream of KRAS.
  • Hana Algul's team (Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase, Nature Medicine2018) confirmed that SHP2 small molecule inhibitors are effective against aggressive KRAS tumors such as pancreatic ductal adenocarcinoma (PDAC). ) And non-small cell lung cancer (NSCLC). Protein tyrosine phosphatase SHP2 has become a key drug target for aggressive KRAS tumors.
  • bioisostere The structure that plays the same biological role in a drug molecule is called a bioisostere.
  • the isostere structure uses another functional group to replace the original functional group in the drug without affecting the main biological activity of the drug.
  • the replacement of monovalent atoms or groups such as OH, NH2, F, SH, etc., the carboxyl group can be substituted by phosphate, tetrazole, and so on.
  • the "compound” in the present invention includes all stereoisomers, geometric isomers, tautomers and isotopes.
  • the compounds of the invention may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing asymmetric carbon atoms of the present invention can be isolated in an optically pure form or a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • the compounds of the present invention also include tautomeric forms.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.
  • the present invention also includes all isotopic atoms, whether in intermediates or final compounds.
  • Isotopic atoms include atoms that have the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • alkyl refers to a linear or branched saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, such as a C 1-20 alkyl group, preferably a C 1-6 alkyl group, such as methyl, ethyl, propyl Group (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (e.g. n-pentyl, isopentyl, neopentyl), N-hexyl, 2-methylhexyl, etc.
  • the alkyl group may be unsubstituted or substituted.
  • the substituents include but are not limited to alkyl, alkyloxy, cyano, carboxy, aryl, heteroaryl, amino, halogen, sulfonyl, Sulfinyl, phosphoryl and hydroxyl.
  • C 1-6 alkyl refers to a linear or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond, and has 1-6 carbon atoms .
  • the alkyl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, amino, halogen, and hydroxy.
  • Non-limiting examples of unsubstituted alkyl groups include, but are not limited to, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methyl Butyl, neopentyl, n-hexyl, 2-methylhexyl, etc.
  • cycloalkyl refers to an all-carbon monocyclic saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, such as a C 3-20 cycloalkyl group, preferably a C 3-6 cycloalkyl group, such as cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, etc.
  • the cycloalkyl group may be unsubstituted or substituted.
  • the substituents include but are not limited to alkyl, alkyloxy, cyano, carboxy, aryl, heteroaryl, amino, halogen, sulfonyl , Sulfinyl, phosphoryl and hydroxyl.
  • aryl refers to an all-carbon monocyclic or fused ring with a fully conjugated ⁇ -electron system, which has 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms .
  • the aryl group may be unsubstituted or substituted by one or more substituents. Examples of the substituents include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , Sulfinyl, phosphoryl and heteroalicyclic groups.
  • substituents include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , Sulfinyl, phosphoryl and heteroalicyclic groups.
  • Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl,
  • heteroaryl refers to a monocyclic or condensed ring of 5-12 ring atoms, with 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, including 1, 2, 3, or 4 ring atoms selected from N, O, S, the remaining ring atoms are C, and have a fully conjugated ⁇ -electron system. Heteroaryl groups can be unsubstituted or substituted. The substituents include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and hetero Alicyclic group.
  • Non-limiting examples of non-substituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, iso Quinolinyl, tetrazolyl, triazinyl.
  • alicyclic refers to a monocyclic, fused ring or spirocyclic carbocyclic ring with 3-12 ring atoms, with 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms Such rings may be saturated or unsaturated (for example, with one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • alicyclic group refers to the group remaining after one hydrogen atom has been removed from the "alicyclic" molecule.
  • the heteroalicyclic group may be unsubstituted or the hydrogen atom in it may be optionally substituted by a substituent.
  • heteroalicyclic refers to a monocyclic, fused ring or spiro ring with 3-12 ring atoms, with 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, Wherein 1 or 2 ring atoms are heteroatoms selected from N, O, S(O) n (wherein n is 0, 1 or 2), and the remaining ring atoms are C.
  • Such rings may be saturated or unsaturated (e.g., have one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • Examples of 3-membered saturated heteroalicyclic rings include, but are not limited to Examples of 4-membered saturated heteroalicyclic rings include, but are not limited to Examples of 5-membered saturated heteroalicyclic rings include but are not limited to Examples of 6-membered saturated heteroalicyclic rings include but are not limited to Examples of 7-membered saturated heteroalicyclic rings include but are not limited to Examples of 5-membered unsaturated heteroalicyclic rings include but are not limited to Examples of 6-membered unsaturated heteroalicyclic rings include but are not limited to
  • heteroalicyclic refers to the group remaining after one hydrogen atom has been removed from the "heteroalicyclic” molecule.
  • the heteroalicyclic group may be unsubstituted or the hydrogen atom in it may be optionally substituted by a substituent.
  • the present invention also provides a method for preparing the compound of the above formula, including the following synthetic scheme:
  • Compound formula 1-6 can be synthesized using synthesis scheme 1. 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine is reacted with an appropriate protective agent to obtain Intermediate 1-1. Intermediate 1-1 is reacted with sodium hydroxide solution to obtain Intermediate 1-2. Intermediate 1-2 is reacted with methyl iodide and a base to obtain Intermediate 1-3. Intermediate 1-3 is reacted with a compound containing NH or borate to obtain Intermediate 1-4. Intermediate 1-4 is deprotected to obtain Intermediate 1-5. Intermediate 1-5 is reacted with N-iodosuccinimide to obtain compound 1-6.
  • Compound formula 2-5 can be synthesized using synthesis scheme 2.
  • 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine reacts with N-iodosuccinimide to obtain iodo intermediate 2-1.
  • Intermediate 2-1 and ammonia are reacted to intermediate 2-2.
  • Intermediate 2-2 is reacted with an appropriate protective agent to obtain Intermediate 2-3.
  • Intermediate 2-3 is ring-closed with chloroacetaldehyde to obtain intermediate 2-4.
  • Intermediate 2-4 is reacted with a compound containing NH or borate to obtain compound 2-5.
  • Compound formula 3-3 can be synthesized through synthesis scheme 3.
  • the reaction of 6-chloro-1H-pyrazolo[3,4-b]pyrazine with N-iodosuccinimide gives the iodo intermediate 3-1.
  • Intermediate 3-1 is reacted with an appropriate protective agent to obtain Intermediate 3-2.
  • Intermediate 3-2 is reacted with a compound containing NH or borate to obtain compound 3-3.
  • the final compound 4-1 can be synthesized by synthesis scheme 4.
  • R 1 represents terminal acetylene, boric acid or boric acid ester, mercapto group, and R 2 represents iodine or bromine.
  • the two raw materials react in the presence of a palladium catalyst and a base to obtain product 4-1. If the group on 4-1 has a protecting group, use the corresponding method to remove the protecting group.
  • the compound of the present invention or its salt can be administered alone as an active substance, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention provides a pharmaceutical composition containing a compound of general formula I, II, III, IV or V or a pharmaceutically acceptable salt, solvate, polymorph, or metabolite thereof as an active ingredient, and One or more pharmaceutically acceptable carriers.
  • “Pharmaceutical composition” refers to a formulation of one or more compounds of the present invention or salts thereof and a carrier generally accepted in the art for delivering biologically active compounds to an organism (such as a human).
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the invention to an organism.
  • pharmaceutically acceptable carrier refers to those carriers that have no obvious stimulating effect on organisms and do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable carrier” refers to an inert substance that is administered with the active ingredient to facilitate the administration of the active ingredient, including but not limited to those approved by the U.S. Food and Drug Administration as acceptable for use in humans or animals (such as Livestock) any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, Isotonic agent, solvent or emulsifier.
  • Non-limiting examples of the carrier include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the administration of the compound of the present invention or a pharmaceutically acceptable salt thereof in pure form or in the form of a suitable pharmaceutical composition can be carried out by any acceptable mode of administration that provides a medicament for similar purposes.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, Gels, microspheres and aerosols, etc.
  • Typical routes for administering the compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, Intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
  • the preferred route of administration is oral administration.
  • the pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compound of the present invention to be formulated into tablets, pills, lozenges, sugar coatings, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral pharmaceutical composition can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules to obtain The core of the tablet or dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the core of the sugar coating agent can be optionally coated according to a method well known in general pharmaceutical practice, especially an enteric coating is used.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • Suitable excipients such as fillers, buffers or surfactants can be used.
  • Another aspect of the present invention relates to the use of compounds of Formula I to Formula VI or pharmaceutically acceptable salts, solvates, polymorphs, metabolites, etc., in drugs for treating diseases that benefit from SHP2 inhibition.
  • the diseases that benefit from SHP2 inhibition are selected from cancer.
  • the substituted alkynyl heterocyclic compounds provided by the present invention have very good SHP2 inhibitory activity and are expected to become highly effective SHP2 inhibitor drugs.
  • Nuclear magnetic resonance chromatography was measured by Varian VNMRS-400 nuclear magnetic resonance instrument; liquid-mass spectrometry (LC/MS) was measured by FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200series (column: Waters Symmetry C18, Mm, 5 microns, 35°C), using ESI (+) ion mode.
  • 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyrazine is the same as in Example 29 on page 83 of patent WO2018057884 The method of intermediate synthesis.
  • Step 1 4-Methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[ 3,4-d)pyrimidin-6-yl)piperidin-4-yl carbamate
  • Step 2 4-Methyl-1-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidine-4 -Tert-butyl carbamate
  • Step 1 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl-1-( Tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • Step 2 ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro -1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)tert-butyl carbamate
  • Step 3 ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6 -Yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)tert-butyl carbamate
  • Step 4 ((3S,4S)-8-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6- Yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)tert-butyl carbamate
  • step 3 in intermediate 5 using ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3 ,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate tert-butyl ester instead of 4-methyl-1-(5-methyl -4-oxo-4,5-dihydro-1H-pyrazole[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate tert-butyl ester, to give ((3S,4S)- 8-(3-Iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2- Tert-butyl oxa-8-azaspiro[4.5]decan-4-yl)carbamate.
  • Step 1 (3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine -5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • Step 2 ((3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e] (Pyrimidine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)tert-butyl carbamate
  • Step 2 ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6- Yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)tert-butyl carbamate
  • Step 4 ((3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-aza Spiro[4.5]decane-4-yl)tert-butyl carbamate
  • Step 2 (2-(2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethynyl) Trimethylsilane
  • Step 1 6-Chloro-3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolo[4,3-b]pyrazine
  • Step 2 (3S,4S)-8-(3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy )Methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • Step 3 ((3S,4S)-8-(3-iodo-5-(((triisopropylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy (Yl)methyl)-1H-pyrazolo[4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl ) Tert-butyl carbamate
  • Step 1 ((3S,4S)-8-(5-(hydroxymethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole And [4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)tert-butyl carbamate
  • Step 2 ((3S,4S)-8-(5-(fluoromethyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole And [4,3-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)tert-butyl carbamate
  • Step 1 1-(3-(2-((2-chlorophenyl)ethynyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4- d)Pyrimidine-6-yl)-4-methylpiperidin-4-yl)tert-butyl carbamate
  • Step 2 6-(4-Amino-4-methylpiperidin-1-yl)-3-(2-(2-chlorophenyl)ethynyl)-5-methyl-1H-pyrazolo[3 ,4-d)pyrimidin-4(5H)-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 3 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2-chloro (Phenyl) ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • Example 4 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((3-chloro (Phenyl) ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 7 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2-fluoro (Phenyl) ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 8 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((3-amino phenyl) ethynyl) -5-methyl-1,5-dihydro--4H- pyrazolo [3,4-d] pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 11 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((3,5 - dimethoxyphenyl) ethynyl) -5-methyl-1,5-dihydro--4H- pyrazolo [3,4-d] pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 12 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(3-hydroxy- 3 -methylbut-1-yn-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 13 4-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl 4,5-dihydro-4-oxo -1H- pyrazolo [3,4-d] pyrimidin-3-yl) ethynyl) benzonitrile
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 14 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((4-chloro phenyl) ethynyl) -5-methyl-1,5-dihydro--4H- pyrazolo [3,4-d] pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 16 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(3-amino- 3 -methylbut-1-yn-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 17 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl- 3- ((Thien-2-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 18 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2-amino (Phenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 20 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((3-amino -4-fluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 23 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2,6 - difluoro phenyl) ethynyl) -5-methyl-1,5-dihydro--4H- pyrazolo [3,4-d] pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 25 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(imidazo [1 ,2-b]pyridazin-3-ylethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Step 1 ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-3-((trimethylsilyl)ethynyl)-4,5-dihydro-1H -Pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)tert-butyl carbamate
  • Step 2 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-ethynyl-5-methyl Yl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 36 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro- 3- ethynylphenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • Step 1 ((3S,4S)-8-(3-(2-chloro-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-4-oxo-4,5 -Dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid Tert-butyl ester
  • Step 2 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(2-chloro-3 -Ethynylphenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • Example 37 6- (4-amino-4-methyl-piperidin-1-yl) -3 - ((2-fluoro-3,5-dimethoxyphenyl) ethynyl) -5-yl -1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 38 6-(4-Amino-4-methylpiperidin-1-yl)-3-((2,5-difluorophenyl)ethynyl)-5-methyl-1,5-di Hydrogen -4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 13.63-13.90 (1H, brs), 8.13 (2H, s), 7.47-7.51 (1H, m), 7.34-7.44 (2H, m), 3.41- 3.44 (2H, m), 3.37 (3H, s), 3.08-3.14 (2H, m), 1.85-1.92 (2H, m), 1.73-1.79 (2H, m), 1.35 (3H, s).
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 13.19-13.86 (1H, brs), 8.23 (2H, s), 7.94 (2H, s), 3.37-3.44 (2H, m), 3.35 (3H, s), 3.05-3.13 (2H, m), 1.86-1.94 (2H, m), 1.72-7.8 (2H, m), 1.34 (3H, s).
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 13.61-13.94 (1H, brs), 9.22 (1H, s), 8.99 (2H, s), 7.78-8.22 (2H, brs), 3.39-3.46 ( 2H, m), 3.38 (3H, s), 3.08-3.15 (2H, m), 1.83-1.91 (2H, m), 1.72-1.79 (2H, m), 1.34 (3H, s).
  • Example 42 6- (4-amino-4-methyl-piperidin-1-yl) -3 - ((3,5-bis (trifluoromethyl) phenyl) ethynyl) -5-methyl - 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 8.17-8.21 (3H, m), 3.37 (3H, s), 3.12-3.28 (4H, m), 1.54-1.61 (2H, m), 1.46- 1.52 (2H, m), 1.10 (3H, s).
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 12.74-13.90 (1H, brs), 7.70-8.90 (2H, brs), 7.46-7.51 (1H, m), 7.36-7.40 (2H, m), 7.28-7.33 (1H, m), 3.38-3.46 (2H, m), 3.37 (3H, s), 3.07-3.14 (2H, m), 1.91-1.98 (2H, m), 1.75-1.80 (2H, m) ), 1.35(3H,s).
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, CD 3 OD): ⁇ 7.43-7.47 (1H, m), 7.30-7.37 (1H, m), 7.17-7.23 (1H, m), 3.51-3.59 (5H, m), 3.21 -3.29 (2H, m), 1.99-2.06 (2H, m), 1.88-1.94 (2H, m), 1.48 (3H, s).
  • Example 47 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2,3 - difluoro phenyl) ethynyl) -5-methyl-1,5-dihydro--4H- pyrazolo [3,4-d] pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 48 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2-fluoro phenyl) ethynyl) -1,5-dihydro--4H- pyrazolo [3,4-d] pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 56 3- (5 - (( 3S, 4S) -4- amino-3-methyl-2-oxa-8-aza-spiro [4.5] decan-8-yl) -7H- imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-2-chlorophenyl dimethyl carbamate
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 61 5- (5 - (( 3S, 4S) -4- amino-3-methyl-2-oxa-8-aza-spiro [4.5] decan-8-yl) -7H- imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-3H-spiro[benzofuran-2,1'-cyclopropane]-3-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 65 2-((3-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)- 7H- imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-2-chlorophenyl)thio)acetamide
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Embodiment 70 cases: (3S, 4S) -8- ( 9 - ((3- ( difluoromethoxy) -2-fluorophenyl) ethynyl) -7H- imidazo [1,2-c] pyrazole And [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 72 (3S,4S)-3-methyl-8-(9-((2,3,4-trifluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole And [4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 74 (3S,4S)-8-(9-((2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)ethynyl)-7H-imidazo[1, 2-c] pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 78 (3S,4S)-3-methyl-8-(9-((1-methylcyclopropyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4 ,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 80 (3S,4S)-8-(9-((3-(cyclopropylmethoxy)-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c] pyridine Azolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 84 (3S,4S)-8-(9-((2,4-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e ] Pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 86 (3S, 4S) -8- (9 - ((2- fluoro-3- (difluoromethoxy) phenyl) ethynyl) -7H- imidazo [1,2-c] pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 92 4- (5 - (( 3S, 4S) -4- amino-3-methyl-2-oxa-8-aza-spiro [4.5] decan-8-yl) -7H- imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-2-methylbut-3-yn-2-ol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 96 (3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-7H- imidazo [1,2-c] pyrazolo [4,3-e] pyrimidin-9-yl) ethynyl) -2-fluorophenyl) methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 100 (3S,4S)-8-(9-((2-fluoro-3-isobutoxyphenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4 ,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 102 (3S, 4S) -8- (9 - ((3- ( dimethylamino) -2-fluorophenyl) ethynyl) -7H- imidazo [1,2-c] pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 104 (3S,4S)-8-(9-((2,6-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrrolo[3,2-e] Pyrimidine-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 105 (3S,4S)-8-(9-((4-chloro-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3- e] pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 106 (3S,4S)-3-methyl-8-(9-((1-(trifluoromethyl)cyclopropyl)ethynyl)-7H-imidazo[1,2-c] pyridine Azolo[4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 108 (3S,4S)-8-(9-((3,5-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e ] Pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 109 (3S,4S)-8-(9-((2-chloro-3,6-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4 ,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 110 (3S,4S)-3-methyl-8-(9-((pentafluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4,3- e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 111 (3S,4S)-3-methyl-8-(9-((2,4,6-trifluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole And [4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 112 (3S,4S)-3-methyl-8-(9-((2,3,4,5-tetrafluorophenyl)ethynyl)-7H-imidazo[1,2-c] pyrazolo [4,3-e] pyrimidin-5-yl) -2-aza-spiro [4.5] decan-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 113 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2-fluoro -3 -Methoxyphenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 120 (3S,4S)-8-(9-((1H-indol-7-yl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e ] Pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 122 (3S,4S)-8-(9-((3-chloro-2-(cyclopropylamino)pyridin-4-yl)ethynyl)-7H-imidazo[1,2-c] pyridine Azolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 126 (3S,4S)-8-(9-((2,2-difluorocyclopropyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3- e] pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, DMSO-d 6 ): ⁇ .
  • Example 128 (3S,4S)-3-methyl-8-(9-((1-phenylcyclopropyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4 ,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 131 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((5- Chloro-2- fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 132 (3S,4S)-8-(9-((5-chloro-2,4-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4 ,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 133 (3S, 4S) -8- (9 - ((2- fluoro-4- (trifluoromethyl) phenyl) ethynyl) -7H- imidazo [1,2-c] pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 135 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2, 3-fluorophenyl) ethynyl) lH-pyrazolo [3,4-b] pyrazin-5-yl) methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 136 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((6- Chloro-2- fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 137 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((4- Chloro-2- fluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 7.59-7.80 (m, 2H), 7.35-7.48 (m, 1H), 5.50-5.62 (brs, 1H), 4.50-4.64 (m, 2H), 4.04-4.16 (m, 1H), 3.50-3.78 (m, 4H), 2.98-3.18 (m, 3H), 1.75-2.03 (m, 2H), 1.50-1.72 (m, 2H), 1.06-1.15 (m ,3H).
  • Example 138 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2, 3,6- Trifluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 139 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-(3,3 - dimethyl-1-yn-1-yl) lH-pyrazolo [3,4-b] pyrazin-5-yl) methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 140 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((3, 3,5-difluorophenyl) ethynyl) lH-pyrazolo [3,4-b] pyrazin-5-yl) methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 141 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((4- Chloro- 2,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 142 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2, 3,5,6- Tetrafluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 143 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2- Fluoro-3 -methoxyphenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 144 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2, 6-difluorophenyl) ethynyl) lH-pyrazolo [3,4-b] pyrazin-5-yl) methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 145 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2, 4-fluorophenyl) ethynyl) lH-pyrazolo [3,4-b] pyrazin-5-yl) methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 146 (3S,4S)-8-(3-((5-chloro-2-fluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3,4-b ] Pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 148 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2- Chloro -3,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 149 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2- Fluoro-4 -methylphenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 150 (3S,4S)-8-(3-((4-chloro-2,6-dimethoxyphenyl)ethynyl)-5-(methoxymethyl)-1H- pyrazole And [3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 151 (3S,4S)-8-(3-((4-chloro-2,6-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo [3, 4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 152 (3S,4S)-8-(3-((4-chloro-2-fluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3,4-b ] Pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 154 (3S,4S)-8-(3-((2-chloro-3,6-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo [3, 4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 156 (3S,4S)-8-(3-((2-chloro-6-fluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3,4-b ] Pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 160 (3S,4S)-8-(3-((2-fluoro-4-methylphenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3,4- b] Pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 161 (3S,4S)-8-(3-((2,6-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3,4-b] pyrazol-6-yl) -3-methyl-2-oxa-8-aza-spiro [4.5] decan-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 162 (3S,4S)-8-(5-(fluoromethyl)-3-((2,3,5,6-tetrafluorophenyl)ethynyl)-1H-pyrazolo[3, 4-b] pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 164 (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-3-((2- Chloro -4,6-difluorophenyl)ethynyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 165 (3S,4S)-8-(3-((2,3-difluorophenyl)ethynyl)-5-(fluoromethyl)-1H-pyrazolo[3,4-b] pyrazol-6-yl) -3-methyl-2-oxa-8-aza-spiro [4.5] decan-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • 1 H NMR (400MHz, CD 3 OD): ⁇ 8.36 (m, 1H), 7.71 (m, 1H), 7.27 (m, 2H), 7.13 (m, 1H), 4.79 (s, 2H), 4.07 ( m,1H),3.77(m,2H),3.06-3.16(m,3H),2.90-2.95(m,1H),1.95-2.10(m,2H),1.63-1.77(m,1H),1.42- 1.57 (m, 1H).
  • Example 168 (3-((2-Amino-3-chloropyridin-4-yl)thio)-6-((3S,4S)-4-amino-3-methyl-2-oxa-8 - azaspiro [4.5] decan-8-yl) lH-pyrazolo [3,4-b] pyrazin-5-yl) methanol
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 169 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-((2-chloro -4,6-Difluorophenyl)ethynyl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 170 (3S,4S)-8-(7-((2-chloro-4,6-difluorophenyl)ethynyl)-5H-pyrrolo[2,3-b]pyrazine-3- Yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 171 (3S,4S)-8-(8-((2-chloro4,6-difluorophenyl)ethynyl)-6H-dipyrazolo[1,5-a:3',4 '-e] pyrazin-4-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • Example 172 (3S,4S)-8-(8-((2-chloro4,6-difluorophenyl)ethynyl)-1,6-dihydroimidazo[4,5-d]pyrazole And [3,4-b]pyridin-4-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the target compound can be synthesized using appropriate starting materials and intermediates.
  • the enzymatic activity detection of SHP2 in this patent adopts a fast fluorescence method, uses DiFMUP as an alternative substrate for reaction and optimizes the establishment of a high-throughput screening platform.
  • the detection of the compound's inhibitory activity on SHP2 is performed on this platform.
  • the specific method is as follows: pre-incubate the mixture of SHP2 with a final concentration of 1nM and 2.5 ⁇ M of diphosphorylated IRS1 peptide (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) at 23°C for 30 minutes .
  • the compound was diluted 5-fold with 100% DMSO starting from 0.2mM (7 concentrations in total), and 2 ⁇ L of each concentration was added to 48 ⁇ L of reaction buffer (60mM HEPES, pH7.2, 75mM NaCl, 75mM KCl, Dilute and mix in 1mM EDTA, 0.05% Tween 20, 5mM DTT). Take 5 ⁇ L of the diluted compound into a black 384-well plate (OptiPlate-384, catalog number 6007270, purchased from PerkinElmer), then add 10 ⁇ L of pre-incubated SHP2 and IRS1 peptide mixture, centrifuge to mix, and incubate at 23°C for 30 minutes.
  • reaction buffer 60mM HEPES, pH7.2, 75mM NaCl, 75mM KCl, Dilute and mix in 1mM EDTA, 0.05% Tween 20, 5mM DTT.
  • Example IC 50 (nM) 3 6.73 7 2.35 17 2.18 26 1.23 49 3.24 50 3.64 51 3.22 58 8.62 60 0.712 61 2.22 63 0.871 64 2.18 75 3.43 82 2.99 90 1.00 106 3.95 139 4.44 144 2.34 149 1.38 161 5.07 164 1.29 165 5.47 166 4.77 167 10.4 168 3.16 169 8.54 170 10.2 171 2.25 172 3.16 173 5.18
  • NCI-H358 cells use RPMI-1640 medium (Cat. No. C11875500BT, purchased from Biological Industries) plus 10% fetal bovine serum (FBS, Catalog No. 04-001-1ACS, purchased from Biological Industries, BI) It was cultured with 1% penicillin/streptomycin double antibody (P/S, catalog number 15070-063, purchased from Gibco) at 37°C and 5% CO2. The day before the compound detection, NCI-H358 cells were plated in a 196-well plate (Cat. No. 3917, purchased from Corning) at a concentration of 2000 cells/195 ⁇ L/well.
  • RPMI-1640 medium Cat. No. C11875500BT, purchased from Biological Industries
  • FBS fetal bovine serum
  • FBS fetal bovine serum
  • P/S penicillin/streptomycin double antibody
  • the compound was diluted 3-fold with 100% DMSO from 10 mM (10 concentrations in total), and then 2 ⁇ L of each concentration was added to 48 ⁇ L of serum- and double-antibody-free medium for dilution. Add 5 ⁇ L of each diluted compound to the paved cell suspension. Incubate the compound and cells in a cell incubator for 72 hours (3 days). After exhausting the medium, add 25 ⁇ L of Cell-Titer Glo (G7570, (Buy from Promega) reagent and incubate again for 5-10 minutes. Then the fluorescence value was read on Envision, and the data was calculated using GraphPad Prism software to calculate the IC 50 value of the compound's inhibition of cell proliferation.
  • Kasumi-1 cells use RPMI-1640 medium (Cat. No. C11875500BT, purchased from Biological Industries) plus 20% fetal bovine serum (FBS, Catalog No. 04-001-1ACS, purchased from Biological Industries, BI ) And 1% penicillin/streptomycin double antibody (P/S, catalog number 15070-063, purchased from Gibco) for cultivation under 37°C and 5% CO2.
  • FBS fetal bovine serum
  • P/S penicillin/streptomycin double antibody
  • Kasumi-1 cells were plated in a 196-well plate (Cat. No. 3599, purchased from Corning) at a concentration of 3000 cells/195 ⁇ L/well.
  • the compound was diluted 3-fold with 100% DMSO from 10 mM (10 concentrations in total), and then 2 ⁇ L of each concentration was added to 48 ⁇ L of serum and double antibody-free medium for dilution. Add 5 ⁇ L of each concentration of the diluted compound to the paved cell suspension. Incubate the compound and cells in a cell incubator for 72 hours (3 days). Add 35 ⁇ L of Cell-Titer Blue (G8082, purchased from Promega) reagent Incubate again for 4 hours. After reading the fluorescence (excitation of 560 nm, 590nm detection) on Flexstation III, data calculated using GraphPad Prism software to obtain the IC 50 values of the compounds on inhibiting cell proliferation. The test results of some compounds are shown in Table 2.
  • test data in Table 1-2 show that the compound provided by the present invention has a good SHP2 kinase inhibitory activity, and at the same time has a good inhibitory activity on the proliferation of SHP2-positive cells.
  • the present invention provides a substituted alkynyl heterocyclic compound represented by formula I.
  • the present invention provides substituted alkynyl heterocyclic compounds with SHP2 inhibitory activity, preparation methods thereof, and pharmaceutical compositions thereof, as well as uses of such compounds and pharmaceutical compositions to treat diseases that benefit from SHP2 enzyme inhibition, such as the treatment of cancer .
  • the compound of formula I is prepared through reactions such as iodination, amination, up-protection, coupling, deprotection, and ring-closure reaction.
  • the alkynyl heterocyclic compounds provided by the present invention have very good SHP2 inhibitory activity, are expected to become highly effective SHP2 inhibitor drugs, and have good economic value and application prospects.

Abstract

本发明涉及式I所示取代的炔基杂环化合物。本发明涉及具有SHP2抑制活性的取代的炔基杂环化合物、其制备方法、其药物组合物，还涉及这类化合物及其药物组合物治疗受益于SHP2酶抑制的疾病的用途，例如治疗癌症。在制备过程中，通过碘代、胺化、上保护、偶联、脱保护、闭环反应等反应，得到式I化合物。

Description

取代的炔基杂环化合物
交叉引用
本申请要求2020年7月2日提交的专利名称为“取代的炔基杂环化合物”的第202010638837.4号中国专利申请和2019年12月19日提交的专利名称为“取代的炔基杂环化合物”的第201911314609.5号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本发明一般性涉及新的具有SHP2抑制活性的取代的炔基杂环化合物、其制备方法、其药物组合物，还涉及这类化合物及其药物组合物治疗受益于SHP2酶抑制的疾病的用途，例如治疗癌症。
背景技术
癌症是严重威胁人类健康及生命一类疾重大疾病，尤其是癌症近几年的发病率及死亡率呈快速上升趋势，己超越心血管疾病成为人类健康的头号杀手。肿瘤的增殖、凋亡、转移等与细胞内外的一系列信号传导通路中某个环节的异常密切相关。在这些信号传导途径中，蛋白的磷酸化和去磷酸化至关重要，这个可逆的过程受到激酶和磷酸酶的共同调控。蛋白质酪氨酸激酶(PTK)的磷酸化和蛋白质酪氨酸磷酸酶(PTP)的去磷酸化即是这样一对可逆过程，它们之间保持动态平衡以维持细胞的正常生理功能。反之异常的磷酸化能导致癌症、炎症、糖尿病和其它疾病的产生。
SHP2蛋白是由ptpn11基因编码的一种非受体型蛋白质酪氨酸磷酸酶，广泛表达于各组织，参与胚胎发育、新陈代谢、免疫反应以及肿瘤发生等重要的生理病理过程。
SHP2蛋白由N末端的两个串联SH2结构域(N-SH2和C-SH2)，PTP催化结构域和具有调节作用的C末端尾部组成。SH2结构域是一个构象开关，可以介导SHP2蛋白与含磷酸酪氨酸的激活剂(例如胰岛素受体底物1-IRS1和GRB2相关结合蛋白1-GAB1)的相互作用以及SH2结构域与PTP催化结构域的分子内相互作用。在未受刺激的情况下，SHP2结构域与PTP结构域结合，封闭催化活性位点，使SHP2磷酸酶活性处于自抑制状态。当SH2结构域结合激活剂，抑制性分子内相互作用解除，SHP2磷酸酶处于开放构象，允许SHP2底物定位至催化活性位点并发挥磷酸酶功能。SHP2的这种活性转换的特性，使得各种关于SHP2的突变都有可能破坏SHP2自抑制状态，导致SHP2蛋白磷酸酶活性过度激活，进而引发癌变。实验和临床数据均证实，SHP2在大多数癌症中起到了促进作用，作为第一个被发现的促进癌症发展的酪氨酸磷酸酶，其在癌症领域得到了极大地关注，它的磷酸酶活性在细胞内信号调控中起到了重要作用。
SHP2参与调控由细胞因子、生长因子和激素激活的细胞信号转导途径，包括RAS/ERK，JAK/STAT，PI3K/AKT与NF-κB信号通路，进而调控细胞增殖、分化、细胞周期维持和迁移等生理功能。同时，SHP2还介导了MEK等激酶被抑制之后的代偿性激活途径，从而促进肿瘤耐药的发生。作为PD-1受体的下游分子，SHP2还参与T细胞抑制性信号的传导。已有研究表明，SHP2是PD-1信号传导的下游分子， 它不仅抑制T细胞活化而且促进T细胞的失能。因此，靶向SHP2可恢复或增强T细胞介导的抗肿瘤免疫功能。另外SHP2可以通过失活信号转导及转录激活因子STAT1抑制IFN-γ介导的免疫反应。
近年来，SHP2激活突变和高表达在白血病、实体瘤、黑色素瘤、恶性胶质瘤、肺癌、乳腺癌和努男综合症中陆续被发现，与肿瘤的发生、发展和预后密切相关。目前，SHP2已被研究用作临床肿瘤的靶分子。传统SHP2抑制剂(例如II-B08、PHPS1)作用机制均为与SHP2的PTP催化结构域结合，阻止酪氨酸磷酸化的底物进入催化位点，从而抑制SHP2的磷酸酶活性。然而，由于各种磷酸酶PTP催化结构域高度保守、极性和带电环境，使得SHP2传统抑制剂在特异性与生物利用度方面具有较大的缺陷，限制了其临床应用。因此，开发具有高特异性、高安全性、细胞膜渗透性强的SHP2抑制剂是决定SHP2是否可以成为新型肿瘤干预靶点的关键，SHP2蛋白变构抑制剂成为目前研究的主要方向。
发明内容
本发明提供一种式(I)表示的化合物或其药学上可接受的盐、溶剂化物、多晶型物、互变异构体、代谢物或前药，
Figure PCTCN2020137662-appb-000001
其中，
A选自如下两并杂环或三并杂环；
Figure PCTCN2020137662-appb-000002
R 1选自氢、卤素、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基可任选地被卤素、-OH、或-O-C 1-6烷基取代，
R 2选自氢、C 1-6烷基和C 3-6环烷基，
X选自氢、C 1-6烷基、C 2-6烯基、C 3-8环烷基、C 3-8杂脂环基、C 6-10芳基和5-10 元杂芳基，所述C 1-6烷基、C 2-6烯基、C 3-8环烷基和C 3-8杂脂环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-CF 3、-NH 2、C 1-6烷基、或者苯基取代，所述C 6-10芳基和5-10元杂芳基可与不饱和脂环、杂脂环、或螺环稠合，并且可任选地被一个或多个卤素、-CF 3、-OH、-CN、R、-OR、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-(CO)NH 2、C 6-10芳基、-O-C 6-10芳基、或者C 5-10杂芳基取代，所述不饱和脂环、杂脂环、或者螺环可任选地被一个或多个卤素、-CF 3、-OH、-CN、R、-OR、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-(CO)NH 2、C 6-10芳基、-O-C 6-10芳基、C 5-10杂芳基、或＝O取代，
R选自C 1-6烷基和C 3-6环烷基，所述烷基和环烷基可任选地被卤素、-CF 3、-OH、-C 1-6烷基、-O-C 1-6烷基、或者C 3-6环烷基取代，
R 3和R 4各自独立地选自氢、C 1-6烷基和C 3-6环烷基，
Y选自C 6-10芳基、5-10元杂芳基、C 3-12杂脂环基和5-15元的螺环基，所述芳基、杂芳基、杂脂环基和螺环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C 1-6烷基、或-NH 2取代，所述杂脂环基和螺环基可任选地与6-10元芳基或者5-10元杂芳基稠和，与杂脂环基和螺环基稠和的芳基或者杂芳基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，
Z选自单键、-S-和-C≡C-。
根据本发明的一些实施方式，本发明的式(I)化合物中，具有下式II～XIII：
Figure PCTCN2020137662-appb-000003
其中，
R 1选自氢、卤素、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基可任选地被卤素、-OH、或-O-C 1-6烷基取代，
R 2选自氢、C 1-6烷基和C 3-6环烷基，
X选自氢、C 1-6烷基、C 2-6烯基、C 3-8环烷基、C 3-8杂脂环基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 3-8环烷基和C 3-8杂脂环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-CF 3、-NH 2、C 1-6烷基、或者苯基取代，所述C 6-10芳基和5-10元杂芳基可与不饱和脂环、杂脂环、或螺环稠合，并且可任选地被一个或多个卤素、-CF 3、-OH、-CN、R、-OR、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-(CO)NH 2、C 6-10芳基、-O-C 6-10芳基、或者C 5-10杂芳基取代，所述不饱和脂环、杂脂环、或者螺环可任选地被一个或多个卤素、-CF 3、-OH、-CN、R、-OR、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-(CO)NH 2、C 6-10芳基、-O-C 6-10芳基、C 5-10杂芳基、或＝O取代，
R选自C 1-6烷基和C 3-6环烷基，所述烷基和环烷基可任选地被卤素、-CF 3、-OH、-C 1-6烷基、-O-C 1-6烷基、或者C 3-6环烷基取代，
R 3和R 4各自独立地选自氢、C 1-6烷基和C 3-6环烷基，
Y选自C 6-10芳基、5-10元杂芳基、C 3-12杂脂环基和5-15元的螺环基，所述芳基、杂芳基、杂脂环基和螺环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C 1-6烷基、或-NH 2取代，所述杂脂环基和螺环基可任选地与6-10元芳基或者5-10元杂芳基稠和，与杂脂环基和螺环基稠和的芳基或者杂芳基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代。
在一些实施方式中，R 1选自氢、卤素和C 1-6烷基，所述C 1-6烷基可任选地被卤素、-OH、或-O-C 1-6烷基取代，R 2选自氢和C 1-6烷基。；
在一些实施方式中，X选自氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基和C 3-8环烷基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、或C 1-6烷基取代，所述C 6-10芳基和5-10元杂芳基可任选地被一个或多个卤素、-CF 3、-OH、-CN、-O-C 1-6烷基、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-CONH 2、C 1-6烷基、C 3-6环烷基、C 6-10芳基、或C 5-10杂芳基取代，
R 3和R 4各自独立地选自氢和C 1-6烷基；
在一些实施方式中，Y选自C 6-10芳基、5-10元杂芳基和C 3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个-OH、-NH 2、或C 1-6烷基取代；
在一些实施方式中，所述5-10元杂芳基为C 5-10杂芳基。
在一些实施方式中，Y选自C 3-12杂脂环基，所述杂脂环基可任选地被一个或多个-OH、-NH 2、或C 1-6烷基取代；
在一些实施方式中，Y选自C 3-12杂脂环基，所述杂脂环基可任选地被一个或多个-NH 2或C 1-6烷基取代；
在一些实施方式中，所述5-15元螺环基为5-15元螺杂环基，所述螺杂环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C 1-6烷基、或-NH 2取代，所述螺杂环基可任选地与6-10元芳基或者5-10元杂芳基稠和，与螺杂环基稠和的芳基或者杂芳基 可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代；
在一些实施方式中，所述5-10元杂芳基为C 5-10杂芳基；
在一些实施方式中，Y选自如下结构：
Figure PCTCN2020137662-appb-000004
X 1、X 2和X 2各自独立地选自键、O、CR aR b或NR c，
R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、-OH、卤素、取代或未取代的氨基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基；且不能同时为-OH或-NH 2，
R a、R b和R c各自独立地选自H、-OH、卤素、取代或未取代的氨基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基，
环A选自取代或未取代的C 4-8环烃基、取代或未取代的4-8元杂环基、取代或未取代的C 5-10芳基、取代或未取代的5-10元杂芳基，所述杂环基或杂芳基包含1-3个选自下组的杂原子：N、O、S或P，
R 13和R 14选自H、-OH、卤素、氰基、取代或未取代的氨基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基，
n为0至3中的任一整数；
所述取代是指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、-OH、-NO 2、-NH 2、-CN。
优选地，X 1和X 2中的一个为O，X 3为键。
优选地，X 1和X 2中的一个为CH 2，另一个为键。根据本发明的一些实施方式，本发明提供以下化合物：
Figure PCTCN2020137662-appb-000005
Figure PCTCN2020137662-appb-000006
Figure PCTCN2020137662-appb-000007
Figure PCTCN2020137662-appb-000008
Figure PCTCN2020137662-appb-000009
Figure PCTCN2020137662-appb-000010
本发明的另一个实施方案提供了一种式(I)表示的化合物或其药学上可接受的盐、溶剂化物、多晶型物、互变异构体、代谢物或前药，
Figure PCTCN2020137662-appb-000011
其中，
A选自如下两并杂环或三并杂环；
Figure PCTCN2020137662-appb-000012
R 1和R 2各自独立地选自氢、卤素和C 1-6烷基；
X选自氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基和C 3-8环烷基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、或C 1-6烷基取代，所述C 6-10芳基和5-10元杂芳基可与不饱和的脂环、杂脂环、螺环稠合，并且可任选地被一个或多个卤素、-CF 3、-OH、-CN、-O-C 1-6烷基、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-CONH 2、C 1-6烷基、C 3-6环烷基、C 6-10芳基、或C 6-10杂芳基取代；
R 3和R 4各自独立地选自氢和C 1-6烷基；
Y选自C 6-10芳基、5-10元杂芳基和C 3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C 1-6烷基、或-NH 2取代；
Z选自单键、-S-和-C≡C-。
根据本发明的一些实施方式，本发明的式(I)化合物中，具有下式II～X：
Figure PCTCN2020137662-appb-000013
其中，R 1和R 2各自独立地选自氢、卤素和C 1-6烷基；
X选自氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基和C 3-8环烷基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、或C 1-6烷基取代，所述C 6-10芳基和5-10元杂芳基可与不饱和的脂环、杂脂环、螺环稠合，并且可任选地被一个或多个卤素、-CF 3、-OH、-CN、-O-C 1-6烷基、-NR 3R 4、-O-C(O)NR 3R 4、 -NH-(CO)-C 1-6烷基、-S-CH 2-CONH 2、C 1-6烷基、C 3-6环烷基、C 6-10芳基、或C 6-10杂芳基取代；
R 3和R 4各自独立地选自氢和C 1-6烷基；
Y选自C 6-10芳基、5-10元杂芳基和C 3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C 1-6烷基、或-NH 2取代。
在一些实施方式中，R 1和R 2各自独立地选自氢和C 1-6烷基；
在一些实施方式中，X选自氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基和C 3-8环烷基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、或C 1-6烷基取代，所述C 6-10芳基和5-10元杂芳基可任选地被一个或多个卤素、-CF 3、-OH、-CN、-O-C 1-6烷基、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-CONH 2、C 1-6烷基、C 3-6环烷基、C 6-10芳基、或C 5-10杂芳基取代，
R 3和R 4各自独立地选自氢和C 1-6烷基；
在一些实施方式中，Y选自C 6-10芳基、5-10元杂芳基和C 3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个-OH、-NH 2、或C 1-6烷基取代；
在一些实施方式中，所述5-10元杂芳基为C 5-10杂芳基。
在一些实施方式中，Y选自C 3-12杂脂环基，所述杂脂环基可任选地被一个或多个-OH、-NH 2、或C 1-6烷基取代；
在一些实施方式中，Y选自C 3-12杂脂环基，所述杂脂环基可任选地被一个或多个-NH 2或C 1-6烷基取代；
根据本发明的一些实施方式，本发明提供以下化合物：
Figure PCTCN2020137662-appb-000014
Figure PCTCN2020137662-appb-000015
Figure PCTCN2020137662-appb-000016
另一方面，本发明提供一种药物组合物，其包含本发明的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体。在一些实施方案中，本发明的药物组合物还包括药学上可接受的辅料。
另一方面，本发明提供治疗与SHP2相关的疾病的方法，其包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体、或其药物组合物。
另一方面，本发明提供本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体、或其药物组合物、或者上述任其一与SHP2抑制剂或KRAS抑制剂或EGFR抑制剂联合在制备治疗与SHP2相关的疾病的药物中的用途。
在本发明的部分实施方式中，所述与SHP2相关的疾病为白血病、黑色素瘤、恶性胶质瘤、肺癌、乳腺癌或努男综合症。
另一方面，SHP2在KRAS的上游起作用，Hana Algul团队(Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase，Nature Medicine2018)证实了SHP2小分子抑制剂对侵袭性KRAS肿瘤如胰腺导管腺癌(PDAC)和非小细胞肺癌(NSCLC)有显著疗效，蛋白酪氨酸磷酸酶SHP2已成为侵袭性KRAS肿瘤的关键药物靶标，此外，Schneeberger,V.E.团队(Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma.Onco target 2015)证实了在EGFR突变的非小细胞肺癌中，SHP2可促进RAS-RAF-MEK-ERK信号传导。因此，单独使用本发明的SHP2小分子抑制剂、或者与现有技术中KRAS抑制剂(AMG510等)、EGFR抑制剂(Iressa、Tarceva等)进行联用，均能够有效抑制肿瘤的发生和进展。
另一方面，在具有类似空间或电子性质的官能团中经常发现生物活性相似性。在药物分子中起相同生物学作用的结构称为生物电子等排体，电子等排体结构通过使用另一种官能团替代药物中原有的官能团，而不影响药物的主要生物活性。例如OH、NH2、F、SH等一价原子或基团的替换，羧基可以被磷酸酯、四唑取代等等。
某些化学术语
本发明所述的“化合物”包括所有立体异构体、几何异构体、互变异构体和同位素。本发明化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本发明化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
本发明还包括所有同位素的原子，无论是在中间体或最后的化合物。同位素的原子包括具有相同的原子数，但不同质量数。例如，氢的同位素包括氚和氘。
在通式I-Ⅴ化合物的上述定义中，本文中所用的术语具有如下含义：
术语“卤素”是指氟、氯、溴或碘，优选氟、氯或溴。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和烃基团，如C 1-20烷 基，优选为C 1-6烷基，例如甲基、乙基、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、仲丁基或叔丁基)、戊基(例如正戊基、异戊基、新戊基)、正己基、2-甲基己基等。所述烷基可以是非取代的或是被取代的，所述的取代基包括但不限于烷基、烷基氧基、氰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基和羟基。
术语“C 1-6烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接，其具有1-6个碳原子。所述烷基可以是非取代的或是被一个或多个选自烷基、烷氧基、氨基、卤素和羟基的取代基所取代。非取代的烷基的非限制性实例包括但不限于诸如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔-丁基、正-戊基、2-甲基丁基、新戊基、正己基、2-甲基己基等。
术语“环烷基”是指由碳原子和氢原子组成的全碳单环的饱和烃基团，如C 3-20环烷基，优选为C 3-6环烷基，例如环丙基、环丁基、环戊基、环己基等。所述环烷基可以是非取代的或是被取代的，所述的取代基包括但不限于烷基、烷基氧基、氰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基和羟基。
术语“芳基”是指具有完全共轭的π电子体系的全碳单环或稠合环，其具有6-14个碳原子，优选具有6-12个碳原子，最优选具有6个碳原子。芳基可以是非取代的或被一个或多个取代基所取代，所述取代基的实例包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、磺酰基、亚磺酰基、磷酰基和杂脂环基。非取代的芳基的非限制性实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”是指5-12个环原子的单环或稠合环，具有5、6、7、8、9、10、11或12个环原子，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。杂芳基可以是非取代的或取代的，所述的取代基包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。非取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三嗪基。
术语“脂环”是指具有3-12个环原子的单环、稠合环或螺环碳环，具有3、4、5、6、7、8、9、10、11或12个环原子，这样的环可以是饱和的或不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。
术语“脂环基”是指“脂环”分子去掉1个氢原子后余下的基团。杂脂环基可以是非取代的或者其中的氢原子任选地被取代基取代，所述的取代基包括但不限于烷基、烷氧基、＝O、芳基、芳烷基、-COOH、-CN、氨基、卤素和羟基。
术语“杂脂环”是指具有3-12个环原子的单环、稠合环或螺环，具有3、4、5、6、7、8、9、10、11或12个环原子，其中1或2个环原子是选自N、O、S(O) n(其中n为0、1或2)的杂原子，其余环原子为C。这样的环可以是饱和的或不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。3元饱和杂脂环的实例包括但不限于
Figure PCTCN2020137662-appb-000017
4元饱和杂脂环的实例包括但不限于
Figure PCTCN2020137662-appb-000018
5元饱和杂脂环的实例包括但不限于
Figure PCTCN2020137662-appb-000019
6元饱和杂脂环的实例包括但不限于
Figure PCTCN2020137662-appb-000020
7元饱和杂脂环的实例包括但不限于
Figure PCTCN2020137662-appb-000021
5元不饱和杂脂环的实例包括但不限于
Figure PCTCN2020137662-appb-000022
6元不饱和杂脂环的实例包括但不限于
Figure PCTCN2020137662-appb-000023
术语“杂脂环基”是指“杂脂环”分子去掉1个氢原子后余下的基团。杂脂环基可以是非取代的或者其中的氢原子任选地被取代基取代，所述的取代基包括但不限于烷基、烷氧基、＝O、芳基、芳烷基、-COOH、-CN、氨基、卤素和羟基。
本发明还提供了制备上述式化合物的方法，包括以下合成方案：
合成方案1：
Figure PCTCN2020137662-appb-000024
化合物式1-6可以使用合成方案1合成。4,6-二氯-1H-吡唑并[3,4-d]嘧啶与适当的保护剂反应得到中间体1-1。中间体1-1与氢氧化钠溶液反应，得到中间体1-2。中间体1-2与碘甲烷和碱反应得到中间体1-3。中间体1-3与含NH或硼酸酯的化合物反应得到中间体1-4。中间体1-4脱去保护基得到中间体1-5。中间体1-5与N-碘代丁二酰亚胺反应得到化合物1-6。
合成方案2：
Figure PCTCN2020137662-appb-000025
化合物式2-5可以使用合成方案2合成。4,6-二氯-1H-吡唑并[3,4-d]嘧啶与N-碘代丁二酰亚胺反应得碘代中间体2-1。中间体2-1和氨水反应到中间体2-2。中间体2-2和适当的保护剂反应得到中间体2-3。中间体2-3用氯乙醛闭环得中间体2-4。中间体2-4与含NH或硼酸酯的化合物反应得到化合物2-5。
合成方案3：
Figure PCTCN2020137662-appb-000026
化合物式3-3可以通过合成方案3合成。6-氯-1H-吡唑并[3,4-b]吡嗪与N-碘代丁二酰亚胺反应得到碘代中间体3-1。中间体3-1和适当的保护剂反应得到中间体3-2。中间体3-2与含NH或硼酸酯的化合物反应得到化合物3-3。
合成方案4：
Figure PCTCN2020137662-appb-000027
最终化合物4-1可以通过合成方案4合成。R 1代表端基乙炔、硼酸或硼酸酯、巯基，R 2代表碘或溴，两个原料在钯催化剂和碱存在下反应得到产物4-1。若4-1上的基团带有保护基则采用相应的方法脱除保护基。
上述合成方案只是列举了本发明中部分化合物的制备方法，按照本领域的公知技术，技术人员在上述合成方案的基础上，采用类似的方法也可合成本发明中的化合物。
本发明的化合物或其盐可以作为活性物质单独给药，优选以其药物组合物的形式给药。
本发明另一方面提供一种药物组合物，其含有通式Ⅰ、Ⅱ、Ⅲ、Ⅳ或Ⅴ的化合物或其药学上可接受的盐、溶剂化物、多晶型、代谢物作为活性成份，以及一种或多种 药学上可接受的载体。
“药物组合物”是指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有机体给予本发明的化合物。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于被美国食品药品管理局许可为可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
以纯的形式或以适宜的药物组合物形式的本发明化合物或其药物可接受的盐的给药可通过提供类似用途的药剂的任何可接受的给药模式来进行。本发明的药物组合物可通过将本发明的化合物与适宜的药物可接受的载剂、稀释剂或赋形剂组合而制备。本发明的药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
给予本发明化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
本发明的药物组合物可以采用本领域周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在优选的实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合，来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服药物组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本发明再一方面涉及通式I至通式VI的化合物或其药学上可接受的盐、溶剂化物、多晶型、代谢物等在治疗受益于SHP2抑制的疾病的药物中的用途。所述的受益于SHP2抑制的疾病选自癌症。
本发明提供的取代的炔基杂环类化合物具有非常好的SHP2抑制活性，有望成为高效的SHP2抑制剂类药物。
具体实施方式
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。本领域技术人员应该理解：还有形成本发明化合物的其它合成途径，下面提供的是非限制性的实施例。
凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本发明使用的原料都是市场上直接买到未经进一步纯化直接使用的。
柱层析色谱采用青岛化工有限公司生产的硅胶(200-300目)。薄层色谱采用E.Merck公司生产的预制板(硅胶60PF 254,0.25毫米)。手性化合物分离和对映体过量值(ee)测定使用Agilent LC 1200series(柱子：CHIRALPAK AD-H,
Figure PCTCN2020137662-appb-000028
毫米，5微米，30℃)。核磁共振色谱(NMR)使用Varian VNMRS-400核磁共振仪测定；液质联用(LC/MS)使用FINNIGAN Thermo LCQ Advantage MAX，Agilent LC 1200series(柱子：Waters Symmetry C18,
Figure PCTCN2020137662-appb-000029
毫米，5微米，35℃)，采用ESI(+)离子模式。
实验部分
中间体1： (3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺二盐酸盐
Figure PCTCN2020137662-appb-000030
(3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺二盐酸盐按照专利WO2017216706中中间体14的方法合成。
中间体2： 6-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮
Figure PCTCN2020137662-appb-000031
步骤1：4,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶
将4,6-二氯-1H-吡唑并[3,4-d]嘧啶(2.7g)、3,4-二氢-2H-吡喃(2.4g)、对甲苯磺酸(0.25g)加入四氢呋喃(25mL)中，回流8小时，降至室温后，减压浓缩并用硅胶柱色谱分离(石油醚：乙酸乙酯，10:1)得4,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶(3.0g)。MS m/z[LC-MS]:273.03[M+1]。
步骤2：6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮
将4,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶(3.0g)和20％氢氧化钠溶液(4mL)加入乙腈(40mL)中，室温搅拌过夜，减压浓缩后用硅胶柱色谱分离(石油醚：乙酸乙酯，6:1)得6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(2.4g)。MS m/z[LC-MS]:255.07[M+1]。 1HNMR(400MHz,DMSO-d 6):δ＝13.300(1H,brs),8.113(1H,s),5.693(1H,m),3.908(1H,m),3.645(1H,m),2.286(1H,m),1.967(1H,m),1.820(1H,m),1.708(1H,m),1.523(2H,m)。
步骤3：6-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮
将6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(2.4g)、碳酸钾(3.8g)加入N,N-二甲基甲酰胺(40mL)中，然后滴加碘甲烷(1.0mL)，室温搅拌4小时。反应液倒入200mL水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱分离(石油醚：乙酸乙酯，8:1)得6-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(1.8g)。MS m/z[LC-MS]:269.08[M+1]。 1HNMR(400MHz,DMSO-d 6):δ＝8.150(1H,s),5.710(1H,m),3.911(1H,m),3.659(1H,m),3.567(3H,s),2.310(1H,m),1.974(1H,m),1.822(1H,m),1.708(1H,m),1.530(2H,m)。
中间体3： 9-碘-5-氯-7-(4-甲氧基苄基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶
Figure PCTCN2020137662-appb-000032
步骤1：3-碘-4,6-二氯-1H-吡唑并[3,4-d]嘧啶
将4,6-二氯-1H-吡唑并[3,4-d]嘧啶(4.0g)、N-碘代丁二酰亚胺(5.72g)加入乙腈(25mL)中，加热至100℃微波反应25分钟，降至室温后，减压浓缩并用硅胶柱色谱分离(石油醚：乙酸乙酯，8:1)得3-碘-4,6-二氯-1H-吡唑并[3,4-d]嘧啶(5.4g)。MS m/z[LC-MS]:314.87[M+1]。
步骤2：3-碘-6-氯-1H-吡唑并[3,4-d]嘧啶-4-胺
将3-碘-4,6-二氯-1H-吡唑并[3,4-d]嘧啶(1.2g)和浓氨水(25％-28％，2mL)加入乙腈(20mL)中，室温搅拌过夜，减压浓缩后用硅胶柱色谱分离(石油醚：乙酸乙酯，3:1)得3-碘-6-氯-1H-吡唑并[3,4-d]嘧啶-4-胺(1.1g)。MS m/z[LC-MS]:295.92[M+1]。
步骤3：3-碘-6-氯-1-(4-甲氧基苄基)-1H-吡唑并[3,4-d]嘧啶-4-胺
将3-碘-6-氯-1H-吡唑并[3,4-d]嘧啶-4-胺(1.1g)、碳酸钾(1.3g)加入N,N-二甲基甲酰胺(20mL)中，然后滴加4-甲氧基苄氯(0.5mL)，室温搅拌2小时。反应液倒入150mL水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱分离(石油醚：乙酸乙酯，4:1)得3-碘-6-氯-1-(4-甲氧基苄基)-1H-吡唑并[3,4-d]嘧啶-4-胺(0.90g)。MS m/z[LC-MS]:415.98[M+1]。
步骤4：9-碘-5-氯-7-(4-甲氧基苄基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶
将3-碘-6-氯-1-(4-甲氧基苄基)-1H-吡唑并[3,4-d]嘧啶-4-胺(700mg)和氯乙醛(2mL)加入乙腈(20mL)中，加热至100℃封管反应5小时，倒入水中，用饱和碳酸钠水溶液调pH值到9～10，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱分离(石油醚：乙酸乙酯，8:1)得9-碘-5-氯-7-(4-甲氧基苄基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶(460mg)。MS m/z[LC-MS]:439.98[M+1]。 1HNMR(400MHz,DMSO-d 6):δ＝8.097(1H,d,J＝1.6Hz),7.629(1H,d,J＝1.6Hz),7.261(2H,d,J＝8.4Hz),6.898(2H,d,J＝8.4Hz),5.381(2H,s),3.72(3H,s)。
中间体4： 6-氯-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[4,3-b]吡嗪
Figure PCTCN2020137662-appb-000033
6-氯-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[4,3-b]吡嗪按照专利WO2018057884中第83页实施例29中相同中间体的方法合成。
中间体5： 1-(3-碘-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基哌 啶-4-基氨基甲酸叔丁酯
Figure PCTCN2020137662-appb-000034
步骤1：4-甲基-1-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯
将中间体2(538mg)、4-甲基哌啶-4-基氨基甲酸叔丁酯(514mg)、二异丙基乙基胺(1mL)加入四氢呋喃(20mL)中，加热至120℃搅拌2小时，减压旋蒸除去溶剂，用硅胶柱色谱分离(石油醚：乙酸乙酯，5:1)得4-甲基-1-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯(800mg)。MS m/z[LC-MS]:447.27[M+1]。
步骤2：4-甲基-1-(5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯
将4-甲基-1-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯(445mg)加入甲醇(10mL)中，再加入1M盐酸溶液(2mL)，室温搅拌过夜，用饱和碳酸氢钠水溶液调pH值到8～9，旋蒸除去有机溶剂，再用乙酸乙酯萃取，萃取液干燥浓缩后用硅胶柱色谱分离(石油醚：乙酸乙酯， 4:1)得4-甲基-1-(5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯(305mg)。MS m/z[LC-MS]:363.22[M+1]。
步骤3：1-(3-碘-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基哌啶-4-基氨基甲酸叔丁酯
将4-甲基-1-(5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯(300mg)、N-碘代丁二酰亚胺(177mg)加入乙腈(5mL)中，加热至100℃微波反应25分钟，降至室温，减压浓缩后用硅胶柱色谱分离(石油醚：乙酸乙酯，4:1)得1-(3-碘-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基哌啶-4-基氨基甲酸叔丁酯(320mg)。MS m/z[LC-MS]:489.11[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.545(1H,s),6.583(1H,s),3.317(3H,s),3.168(2H,m),2.994(2H,m),2.102(1H,m),1.529(2H,m),1.356(9H,s),1.230(3H,s)。
中间体6： ((3S,4S)-8-(3-碘-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-3- 甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
Figure PCTCN2020137662-appb-000035
步骤1：6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
参照中间体5中步骤1的方法，用中间体1替代4-甲基哌啶-4-基氨基甲酸叔丁酯，得6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮。MS m/z[LC-MS]:403.25[M+1]。
步骤2：((3S,4S)-3-甲基-8-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
将6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮(400mg)、三乙胺(500mg)加入二氯甲烷(10mL)中，冰水浴冷却下滴加二碳酸二叔丁酯(260mg)，滴加完后升至室温搅拌4小时，依次用水和饱和食盐水洗，有机相干燥浓缩后用硅胶柱色谱(石油醚：乙酸乙酯，4:1)分离得((3S,4S)-3-甲基-8-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯 (420mg)。MS m/z[LC-MS]:503.3[M+1]。
步骤3：((3S,4S)-3-甲基-8-(5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
参照中间体5中步骤2的方法，用((3S,4S)-3-甲基-8-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯替代4-甲基-1-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4,5-二氢-1H-吡唑[3,4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯，得((3S,4S)-3-甲基-8-(5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]:419.24[M+1]。
步骤4：((3S,4S)-8-(3-碘-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
参照中间体5中步骤3的方法，用((3S,4S)-3-甲基-8-(5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯替代4-甲基-1-(5-甲基-4-氧代-4,5-二氢-1H-吡唑[3,4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯，得((3S,4S)-8-(3-碘-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]:545.14[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.562(1H,s),6.988(1H,s),4.134(1H,m),3.848(1H,m),3.638(1H,d,J＝8.4Hz),3.487(1H,d,J＝8.4Hz),3.328(3H,s),3.184(1H,m),3.092(2H,m),1.62-1.76(3H,m),1.50-1.60(1H,m),1.37(9H,s),0.994(3H,d,J＝6.0Hz)。
中间体7： ((3S,4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶 -5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
Figure PCTCN2020137662-appb-000036
步骤1：(3S,4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
参照中间体5中步骤1的方法，用中间体3替代中间体2，用中间体1替代4-甲基哌啶-4-基氨基甲酸叔丁酯，得(3S,4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺。MS m/z[LC-MS]:574.14[M+1]。
步骤2：((3S,4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
参照中间体6中步骤2的方法，用(3S,4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺替代6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮，得((3S,4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑 并[1,2-c]吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]:674.2[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.707(1H,d,J＝1.2Hz),7.437(1H,d,J＝1.2Hz),7.251(2H,d,J＝8.4Hz),6.850(2H,d,J＝8.4Hz),5.391(2H,s),4.163(1H,m),3.913(1H,m),3.673(3H,s),3.35-3.55(6H,m),1.72-1.90(3H,m),1.60-1.72(1H,m),1.352(9H,s),1.007(3H,d,J＝6.4Hz)。
中间体8： ((3S,4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3- 甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
Figure PCTCN2020137662-appb-000037
步骤1：(3S,4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
参照中间体5中步骤1的方法，用中间体4替代中间体2，用中间体1替代4-甲基哌啶-4-基氨基甲酸叔丁酯，得(3S,4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺。MS m/z[LC-MS]:499.13[M+1]。
步骤2：((3S,4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
参照中间体6中步骤2的方法，用(3S,4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺替代6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮，得((3S,4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]:599.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.410(1H,s),6.988(1H,s),5.71(1H,m),4.14(1H,m),3.84-3.92(2H,m),3.65(2H,m),3.472(1H,d,J＝8.4Hz),3.18(1H,m),3.09(2H,m),2.31(1H,m),1.98(1H,m),1.62-1.83(5H,m),1.49-1.60(3H,m),1.38(9H,s),1.004(3H,d,J＝6.0Hz)。
中间体9： ((3S,4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡嗪-6-基)-3- 甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
Figure PCTCN2020137662-appb-000038
步骤1：8-溴-7-氯-5-(甲硫基)咪唑并[1,2-c]嘧啶
5-溴-6-氯-2-(甲硫基)嘧啶-4-胺(1.0g)和40％氯乙醛水溶液(1.2mL)溶于二氧六环(6mL)中，氮气保护下回流14小时，冷却至室温后过滤，得8-溴-7-氯-5-(甲硫基)咪唑并[1,2-c]嘧啶(900mg)。MS m/z[LC-MS]:277.92[M+1]。
步骤2：8-溴-7-氯-5-(甲基亚磺酰基)咪唑并[1,2-c]嘧啶
8-溴-7-氯-5-(甲硫基)咪唑并[1,2-c]嘧啶(557mg)溶于二氯甲烷(20mL)中，加入间氯过氧化苯甲酸(85％，487mg)，室温搅拌6小时，反应液依次用饱和碳酸氢钠水溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液旋蒸浓缩，硅胶柱色谱分离纯化(石油醚：乙酸乙酯，5:1)得8-溴-7-氯-5-(甲基亚磺酰基)咪唑并[1,2-c]嘧啶(420mg)。MS m/z[LC-MS]:293.91[M+1]。
步骤3：(3S,4S)-8-(8-溴-7-氯咪唑并[1,2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
参照中间体5中步骤1的方法，用8-溴-7-氯-5-(甲基亚磺酰基)咪唑并[1,2-c]嘧啶替代中间体2，用中间体1替代4-甲基哌啶-4-基氨基甲酸叔丁酯，得(3S,4S)-8-(8-溴-7-氯咪唑并[1,2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺。MS m/z[LC-MS]:400.06[M+1]。
步骤4：((3S,4S)-8-(8-溴-7-氯咪唑并[1,2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
参照中间体6中步骤2的方法，用(3S,4S)-8-(8-溴-7-氯咪唑并[1,2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺替代6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮，得((3S,4S)-8-(8-溴-7-氯咪唑并[1,2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]:500.11[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.79(1H,d,J＝1.6Hz),7.62(1H,d,J＝1.6Hz),
中间体10： 2-乙炔基-1,1-二氟环丙烷
Figure PCTCN2020137662-appb-000039
2-乙炔基-1,1-二氟环丙烷按照专利WO2015066413中中间体3.1.35d的方法合成。
中间体11： 1-乙炔基-1-甲基环丙烷
Figure PCTCN2020137662-appb-000040
1-乙炔基-1-甲基环丙烷按照专利WO2011059784中实施例4的方法合成。
中间体12： (2-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)乙炔基) 三甲基硅烷
Figure PCTCN2020137662-appb-000041
步骤1：(2-(3-溴-2-氯苯基)乙炔基)三甲基硅烷
将1-溴-2-氯-3-碘苯(560mg)、乙炔基三甲基硅烷(196mg)、碘化亚铜(34mg)、二(三苯基膦)二氯化钯(121mg)和三乙胺(533mg)加入四氢呋喃(10mL)中，用高纯氮气置换反应体系中的空气三次，回流12小时，降至室温后，减压浓缩并用硅胶柱色谱分离(以正己烷为洗脱液)得(2-(3-溴-2-氯苯基)乙炔基)三甲基硅烷(424mg)。 1HNMR(400MHz,CDCl 3):δ＝7.55(1H,m),7.43(1H,m),7.03(1H,m),0.25(9H,m)。
步骤2：(2-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)乙炔基)三甲基硅烷
将(2-(3-溴-2-氯苯基)乙炔基)三甲基硅烷(232mg)、联硼酸频哪醇酯(244mg)、(1,1'-双(二苯膦基)二茂铁)二氯化钯(56mg)和无水乙酸钾(157mg)加入二氧六环(2mL)中，用高纯氮气置换反应体系中的空气三次，加热至90℃反应12小时，反应混合物不经处理可直接进行下步偶联反应。MS m/z[LC-MS]:335.14[M+1]。
中间体13： 5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3H-螺[苯并呋喃-2,1'- 环丙烷]-3-酮
Figure PCTCN2020137662-appb-000042
原料5-溴-3H-螺[苯并呋喃-2,1'-环丙烷]-3-酮参照文献Chemical and Pharmaceutical Bulletin；vol.32；nb.9；(1984)；p.3532-3550合成。
将5-溴-3H-螺[苯并呋喃-2,1'-环丙烷]-3-酮按照中间体12步骤2的方法进行反应得到相应硼酸酯，反应混合物不经处理可直接进行下步偶联反应。MS m/z[LC-MS]:287.15[M+1]。
中间体14： 2-(3-氯-[1,1'-联苯]-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷
Figure PCTCN2020137662-appb-000043
原料4-溴-3-氯-1,1'-联苯按照文献Journal of the Chemical Society；(1964)；p.3786-3790合成。
将4-溴-3-氯-1,1'-联苯按照中间体12步骤2的方法进行反应得到相应硼酸酯，反应混合物不经处理可直接进行下步偶联反应。MS m/z[LC-MS]:315.13[M+1]。
中间体15：( (3S,4S)-8-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧 基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
Figure PCTCN2020137662-appb-000044
起始中间体(6-氯-3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-5-基)甲醇按照专利WO2019167000中第237页制备179中相同的方法合成。
步骤1：6-氯-3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪
将中间体(6-氯-3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-5-基)甲醇(2.28g)、三异丙基氯化硅(1.49g)、咪唑(693mg)加入二氯甲烷(40mL)中，室温搅拌过夜，反应液用水洗涤，有机相用无水硫酸钠干燥后减压旋蒸除去溶剂，用硅胶柱色谱分离(石油醚：乙酸乙酯，5:1)得6-氯-3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪(2.75g)。MS m/z[LC-MS]:597.14[M+1]。
步骤2：(3S,4S)-8-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
将6-氯-3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪(2.70g)加入正丁醇(30mL)中，再加入中间体1(1.32g)和二异丙基乙基胺(5mL)，加热至120℃搅拌2小时，冷却至室温，旋蒸除去有机溶剂，用硅胶柱色谱分离(二氯甲烷：甲醇，10:1)得(3S,4S)-8-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺(2.82g)。MS m/z[LC-MS]:731.3[M+1]。
步骤3：((3S,4S)-8-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
将(3S,4S)-8-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺(2.80g)加入二氯甲烷(30mL)中，再加入二异丙基乙基胺(2mL)，冰水浴冷却下滴加二碳酸二叔丁酯(1.25g)，滴加完毕后升至室温搅拌4小时，旋蒸除去有机溶剂，用硅胶柱色谱分离(石油醚：乙酸乙酯，8:1)得((3S,4S)-8-(3-碘-5-(((三异丙基硅基)氧)甲 基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(3.05g)。MS m/z[LC-MS]:831.35[M+1]。
中间体16：((3S,4S)-8-(5-(氟甲基)-3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
Figure PCTCN2020137662-appb-000045
步骤1：((3S,4S)-8-(5-(羟甲基)-3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
将中间体15(1.66g)、四丁基氟化铵(670mg)加入四氢呋喃(20mL)中，室温搅拌2小时，旋蒸除去有机溶剂，剩余物分配于水和乙酸乙酯中，有机相分离，水相用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥后减压旋蒸除去溶剂，用硅胶柱色谱分离(石油醚：乙酸乙酯，5:1)得((3S,4S)-8-(5-(羟甲基)-3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(1.25g)。MS m/z[LC-MS]:675.22[M+1]。
步骤2：((3S,4S)-8-(5-(氟甲基)-3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
将((3S,4S)-8-(5-(羟甲基)-3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(1.25g)加入二氯甲烷(15mL)中，冰水浴冷却下滴加二乙胺基三氟化硫(358mg)，滴加完毕后升至室温搅拌1小时，旋蒸除去有机溶剂，用硅胶柱色谱分离(石油醚：乙酸乙酯，8:1)得((3S,4S)-8-(5-(氟甲基)-3-碘-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(1.06g)。MS m/z[LC-MS]:677.22[M+1]。
中间体17：(S)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺二盐酸盐
Figure PCTCN2020137662-appb-000046
(S)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺二盐酸盐按照专利WO2017216706实施例26中的方法合成。
中间体18：(S)-5,7-二氢螺[环戊烷[b]吡啶-6,4'-哌啶]-7-胺二盐酸盐
Figure PCTCN2020137662-appb-000047
(S)-5,7-二氢螺[环戊烷[b]吡啶-6,4'-哌啶]-7-胺二盐酸盐按照专利WO2018172984实施例82中的方法合成。
中间体19：(S)-(8-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
Figure PCTCN2020137662-appb-000048
(S)-(8-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯按照上述中间体15的方法合成。MS m/z[LC-MS]:817.34[M+1]。
中间体20：( S)-(1'-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基) 甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-5,7-二氢螺[环戊烷[b]吡啶-6,4'-哌啶]-7-基)氨基甲 酸叔丁酯
Figure PCTCN2020137662-appb-000049
(S)-(1'-(3-碘-5-(((三异丙基硅基)氧)甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-b]吡嗪-6-基)-5,7-二氢螺[环戊烷[b]吡啶-6,4'-哌啶]-7-基)氨基甲酸叔丁酯按照上述中间体15的方法合成。MS m/z[LC-MS]:864.35[M+1]。
中间体21： 2-氨基-3-氯吡啶-4-硫酚
Figure PCTCN2020137662-appb-000050
2-氨基-3-氯吡啶-4-硫酚按照专利WO2018013597实施例6中的方法合成。
中间体22： 5-溴-3-甲基-2-(甲磺酰基)-7-((2-(三甲基硅基)乙氧基)甲基)-3H-吡咯并 [2,3-d]嘧啶-4(7H)-酮
Figure PCTCN2020137662-appb-000051
5-溴-3-甲基-2-(甲磺酰基)-7-((2-(三甲基硅基)乙氧基)甲基)-3H-吡咯并[2,3-d]嘧啶-4(7H)-酮按照专利WO2016203404实施例5中的方法合成。
中间体23： 7-溴-3-氯-5H-吡咯并[3,2-b]吡嗪
Figure PCTCN2020137662-appb-000052
7-溴-3-氯-5H-吡咯并[3,2-b]吡嗪按照专利WO2016203404实施例12中的方法合成。
实施例1： 6-(4-氨基-4-甲基哌啶-1-基)-3-(2-(2-氯苯基)乙炔基)-5-甲基-1H-吡唑并 [3,4-d]嘧啶-4(5H)-酮
Figure PCTCN2020137662-appb-000053
步骤1：1-(3-(2-((2-氯苯基)乙炔基)-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯
将中间体5(150mg)、1-氯-2-乙炔基苯(50mg)、碘化亚铜(12mg)、三乙胺(100mg)、二(三苯基膦)二氯化钯(21mg)和四氢呋喃(10mL)加入封管中，氮气置换，加热至80℃搅拌过夜。冷却到室温，倒入水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱分离(石油醚：乙酸乙酯，6:1)得1-(3-((2-(2-氯苯基)乙炔基)-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(75mg)。MS m/z[LC-MS]:498.0[M+1]。
步骤2：6-(4-氨基-4-甲基哌啶-1-基)-3-(2-(2-氯苯基)乙炔基)-5-甲基-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮
将1-(3-(2-((2-氯苯基)乙炔基)-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(70mg)加入4M氯化氢的二氧六环溶液(3mL)中，室温搅拌1小时，旋干，加入10％碳酸钠水溶液(10mL)，用二氯甲烷萃取，萃取液用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层硅胶色谱分离(二氯甲烷：甲醇，10:1)得6-(4-氨基-4-甲基哌啶-1-基)-3-(2-(2-氯苯基)乙炔基)-5-甲基-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮(35mg)。MS m/z[LC-MS]:397.16[M+1]。 1HNMR(400MHz,DMSO-d 6):δ＝7.70-8.40(3H,brs),7.66(1H,dd,J＝8.0Hz,1.6Hz),7.59(1H,d,J＝8.0Hz),7.46(1H,td,J＝8.0Hz,1.6Hz),7.41(1H,t,J＝8.0Hz),3.36-3.46(5H,m),3.08-3.16(2H,m),1.83-1.91(2H,m),1.72-1.80(2H,m),1.34(3H,s)。
实施例2： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,4-二氟 苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000054
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:455.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.2-13.9(1H,brs),7.69(1H,td,J＝8.4Hz,6.4Hz),7.45(1H,td,J＝9.6Hz,2.8Hz),7.19(1H,td,J＝8.4Hz,2.8Hz),6.71-6.84(2H,brs),4.13-4.17(1H,m),3.79(1H,d,J＝8.8Hz),3.59(1H,d,J＝8.8Hz),3.34-3.48(6H,m),2.85-2.96(2H,m),1.82-1.91(2H,m),1.66-1.73(1H,m),1.56-1.62(1H,m),1.17(3H,d,J＝6.4Hz)。
实施例3： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氯苯基) 乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000055
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:453.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.66(1H,dd,J＝7.6Hz,2.0Hz),7.59(1H,dd,J＝8.0Hz,1.6Hz),7.46(1H,td,J＝7.6Hz,1.6Hz),7.41(1H,td,J＝7.6Hz,1.6Hz),6.71-6.84(3H,brs),4.01-4.08(1H,m),3.64(1H,d,J＝8.8Hz),3.47(1H,d,J＝8.8Hz),3.39(3H,s),3.22-3.34(2H,m),2.90-3.07(3H,m),1.79-1.87(1H,m),1.69-1.78(1H,m),1.50-1.63(2H,m),1.06(3H,d,J＝6.0Hz)。
实施例4： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3-氯苯基) 乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000056
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:453.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.60(1H,t,J＝2.0Hz),7.45-7.54(3H,m),4.01-4.06(1H,m),3.63(1H,d,J＝8.4Hz),3.46(1H,d,J＝8.4Hz),3.39(3H,s),3.26-3.34(2H,m),2.89-3.07(3H,m),1.80-1.86(1H,m),1.69-1.77(1H,m),1.51-1.61(2H,m),1.06(3H,d,J＝6.4Hz)。
实施例5： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-甲氧基 苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000057
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:449.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝12.80-13.80(1H,brs),7.46(1H,dd,J＝7.6Hz,1.6Hz),7.41(1H,td,J＝7.6Hz,1.6Hz),7.09(1H,d,J＝8.4Hz),6.98(1H,t,J＝7.6Hz),4.01-4.08(1H,m),3.84(3H,s),3.64(1H,d,J＝8.8Hz),3.47(1H,d,J＝8.8Hz),3.38(3H,s),3.26-3.34(2H,m),2.88-3.05(3H,m),1.79-1.88(1H,m),1.69-1.76(1H,m),1.50-1.62(2H,m),1.07(3H,d,J＝6.0Hz)。
实施例6： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(苯 基乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000058
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:419.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.54-7.57(2H,m),7.42-7.47(3H,m),4.03-4.09(1H,m),3.66(1H,d,J＝8.4Hz),3.49(1H,d,J＝8.4Hz),3.39(3H,s),3.26-3.35(2H,m),2.90-3.04(3H,m),1.82-1.88(1H,m),1.72-1.78(1H,m),1.52-1.64(2H,m),1.08(3H,d,J＝6.8Hz)。
实施例7： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氟苯基) 乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000059
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:437.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.62(1H,td,J＝7.6Hz,1.6Hz),7.47-7.53(1H,m),7.35(1H,t,J＝8.8Hz),7.28(1H,t,J＝8.0Hz),4.01-4.07(1H,m),3.63(1H,d,J＝8.4Hz),3.46(1H,d,J＝8.4Hz),3.39(3H,s),3.25-3.34(2H,m),2.88-3.07(3H,m),1.80-1.87(1H,m),1.68-1.76(1H,m),1.50-1.62(2H,m),1.06(3H,d,J＝6.0Hz)。
实施例8： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3-氨基苯 基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000060
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:434.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.3-13.8(1H,brs),7.05(1H,t,J＝8.0Hz),6.73(1H,s),6.65(1H,d,J＝7.6Hz),6.61(1H,d,J＝7.6Hz),5.30(2H,s),4.08-4.16(1H,m),3.75(1H,d,J＝8.8Hz),3.54(1H,d,J＝8.8Hz),3.39(3H,s),3.26-3.37(3H,m),2.88-2.98(2H,m),1.80-1.90(2H,m),1.56-1.70(2H,m),1.14(3H,5.6Hz)。
实施例9： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(吡 啶-3-基乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000061
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:420.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.71(1H,s),8.74(1H,s),8.62(1H,d,J＝4.8Hz),7.96-8.04(3H,m),7.49(1H,dd,J＝8.0hz,4.8Hz),4.16-4.22(1H,m),3.83(1H,d,J＝9.2Hz),3.64(1H,d,J＝9.2Hz),3.40-3.50(3H,m),3.39(3H,s),2.84-2.94(2H,m),1.82-1.92(2H,m),1.70-1.76(1H,m),1.58-1.64(1H,m),1.20(3H,d,J＝6.0Hz)。
实施例10： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(吡 啶-4-基乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000062
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:420.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.65(2H,d,J＝5.6Hz),7.51(2H,d,J＝5.6Hz),4.10-4.16(1H,m),3.77(1H,d,J＝8.8Hz),3.56(1H,d,J＝8.8Hz),3.40(3H,s),3.22-3.32(3H,m),2.87-2.99(2H,m),1.80-1.90(2H,m),1.65-1.70(1H,m),1.55-1.61(1H,m),1.15(3H,d,J＝6.4Hz)。
实施例11： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3,5-二甲 氧基苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000063
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:479.24[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.48-13.80(1H,brs),6.68(2H,s),6.58(1H,s),4.08-4.16(1H,m),3.76(6H,s),3.74(1H,d,J＝8.8Hz),3.56(1H,d,J＝8.8Hz),3.35-3.43(5H,m),3.16-3.22(1H,m),2.86-2.99(2H,m),1.78-1.88(2H,m),1.64-1.69(1H,m),1.54-1.61(1H,m),1.14(3H,d,J＝6.4Hz)。
实施例12： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(3-羟基-3- 甲基丁-1-炔-1-基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000064
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:401.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.36-13.48(1H,brs),5.52(1H,s),4.08-4.14(1H,m),3.73(1H,d,J＝8.8Hz),3.55(1H,d,J＝8.8Hz),3.37(3H,s),3.11-3.21(2H,m),2.84-2.96(3H,m),1.77-1.86(2H,m),1.63-1.67(1H,m),1.54-1.58(1H,m),1.45(6H,s),1.13(3H,d,J＝6.4Hz)。
实施例13： 4-((6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基 -4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-3-基)乙炔基)苯甲腈
Figure PCTCN2020137662-appb-000065
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:444.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.91(2H,d,J＝8.0Hz),7.73(2H,d,J＝8.0Hz),4.06-4.13(1H,m),3.72(1H,d,J＝8.8Hz),3.53(1H,d,J＝8.8Hz),3.40(3H,s),3.34-3.38(2H,m),3.09-3.13(1H,m),2.89-3.01(2H,m),1.77-1.88(2H,m),1.62-1.66(1H,m),1.54-1.58(1H,m),1.12(3H,d,J＝6.8Hz)。
实施例14： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((4-氯苯 基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000066
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:453.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.57(2H,d,J＝8.0Hz),7.51(2H,d,J＝8.0Hz),4.08-4.14(1H,m),3.74(1H,d,J＝8.8Hz),3.54(1H,d,J＝8.8Hz),3.39(3H,s),3.34-3.38(2H,m),3.15-3.18(1H,m),2.87-2.99(2H,m),1.79-1.89(2H,m),1.63-1.67(1H,m),1.55-1.59(1H,m),1.14(3H,d,J＝6.0Hz)。
实施例15： (3S,4S)-8-(3-((2-氯苯基)乙炔基)-1H-吡唑并[4,3-b]吡嗪-6基)-3-甲基-2- 氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000067
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:423.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.30(1H,s),7.68(1H,dd,J＝7.2Hz,2.0Hz),7.43(1H,d,J＝8.0Hz),7.23-7.32(2H,m),4.17-4.22(1H,m),3.96-4.06(2H,m),3.82(1H,d,J＝8.4Hz),3.70(1H,d,J＝8.4Hz),3.52-3.59(1H,m),3.42-3.49(1H,m),3.01(1H,d,J＝4.0Hz),1.88-2.03(2H,m),1.67-1.79(2H,m),1.24(3H,d,J＝6.8Hz)。
实施例16： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(3-氨基-3- 甲基丁-1-炔-1-基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000068
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:400.25[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.33-13.46(1H,brs),4.08-4.14(1H,m),3.73(1H,d,J＝8.8Hz),3.55(1H,d,J＝8.8Hz),3.37(3H,s),3.11-3.21(2H,m),2.85-2.96(3H,m),1.76-1.86(2H,m),1.63-1.67(1H,m),1.54-1.59(1H,m),1.43(6H,s),1.14(3H,d,J＝6.4Hz)。
实施例17： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基 -3-((噻吩-2-基)乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000069
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:425.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71(1H,dd,J＝5.2Hz,0.8Hz),7.45(1H,dd,J＝3.6Hz,0.8Hz),7.14(1H,dd,J＝5.2Hz,3.6Hz),4.07-4.13(1H,m),3.72(1H,d,J＝8.8Hz),3.53(1H,d,J＝8.8Hz),3.39(3H,s),3.32-3.38(2H,m),3.11(1H,d,J＝5.2Hz),2.88-2.99(2H,m),1.77-1.88(2H,m),1.61-1.66(1H,m),1.53-1.58(1H,m),1.12(3H,d,J＝6.8Hz)。
实施例18： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氨基 苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000070
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:434.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.21(1H,d,J＝8.0Hz),7.09(1H,t,J＝8.0Hz),6.71(1H,d,J＝8.4Hz),6.51(1H,t,J＝7.2Hz),6.01(2H,s),4.41-4.46(1H,m),4.12-4.20(1H,m),3.82(1H,d,J＝8.4Hz),3.58(1H,d,J＝8.4Hz),3.45-3.49(1H,m),3.42(3H,s),3.13-3.15(1H,m),2.85-2.95(2H,m),1.84-1.98(2H,m),1.66-1.72(2H,m),1.58-1.63(2H,m),1.19(3H,d,J＝6.4Hz)。
实施例19： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(环丙基乙 炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000071
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:383.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.20-13.58(1H,brs),4.02-4.08(1H,m),3.90-4.00(1H,m),3.65(1H,d,J＝8.4Hz),3.47(1H,d,J＝8.4Hz),3.35(3H,s),3.24-3.30(1H,m),3.11-3.15(1H,m),2.86-2.99(3H,m),1.70-1.85(2H,m),1.50-1.62(2H,m),1.08(3H,d,J＝6.4Hz),0.91-0.94(2H,m),0.75-0.83(2H,m)。
实施例20： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3-氨基 -4-氟苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000072
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:452.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.07(1H,d,J＝8.0Hz),6.94-6.99(1H,m),6.87-6.91(1H,m),4.26-4.32(1H,m),3.93(1H,d,J＝8.0Hz),3.82(1H,d,J＝8.4Hz),3.47-3.58(5H,m),3.39-3.42(1H,m),2.96-3.08(2H,m),1.86-2.02(3H,m),1.71-1.75(1H,m),1.30(3H,d,J＝7.2Hz)。
实施例21： 2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氰基 苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000073
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:444.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.75(1H,d,J＝8.0Hz),7.63-7.68(1H,m),7.51-7.58(1H,m),7.45(1H,m),4.14-4.20(1H,m),3.81(1H,d,J＝8.8Hz),3.68(1H,d,J＝8.8Hz),3.53(3H,s),3.30-3.43(2H,m),2.94-3.16(3H,m),1.52-1.86(4H,m),0.86(3H,d,J＝6.4Hz)。
实施例22： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基 -3-((2-(三氟甲基)苯基)乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000074
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:487.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.82(1H,d,J＝7.6Hz),7.68(1H,d,J＝8.4Hz),7.52(1H,m),7.44(1H,m),4.13-4.19(1H,m),3.79(1H,d,J＝8.8Hz),3.67(1H,d,J＝8.8Hz),3.53(3H,s),3.31-3.41(2H,m),2.98-3.16(3H,m),1.46-1.90(4H,m),0.95(3H,d,J＝6.8Hz)。
实施例23： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,6-二氟 苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000075
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:455.2[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.51-7.59(1H,m),7.22-7.27(2H,m),4.04-4.11(1H,m),3.69(1H,d,J＝8.4Hz),3.51(1H,d,J＝8.8Hz),3.38(3H,s),3.32-3.6(1H,m),3.11-3.15(1H,m),3.05-3.08(1H,m),2.88-3.01(2H,m),1.73-1.86(2H,m),1.60-1.66(1H,m),1.52-1.58(1H,m),1.10(3H,d,J＝6.4Hz)。
实施例24： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(丙 -1-炔-1-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000076
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:357.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.12-13.58(1H,brs),4.02-4.08(1H,m),3.65(1H,d,J＝8.4Hz),3.47(1H,d,J＝8.4Hz),3.35(3H,s),3.24-3.30(1H,m),3.11-3.15(1H,m),2.86-2.99(3H,m),2.05(3H,s),1.70-1.85(2H,m),1.50-1.62(2H,m),1.07(3H,d,J＝6.4Hz)。
实施例25： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(咪唑并 [1,2-b]哒嗪-3-基乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000077
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:460.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.66-1.84(1H,brs),8.67(1H,dd,J＝4.8Hz,2.4Hz),8.24(1H,dd,J＝8.8Hz,1.6Hz),8.19(1H,s),7.37(1H,dd,J＝8.8Hz,4.8Hz),4.40-4.43(1H,m),4.16-4.20(1H,m),3.83(1H,d,J＝8.8Hz),3.62(1H,d,J＝8.8Hz),3.43-3.50(1H,m),3.39(3H,s),3.34-3.36(1H,m),2.85-2.94(2H,m),1.85-1.94(2H,m),1.70-1.73(1H,m),1.58-1.62(1H,m),1.19(3H,d,J＝6.4Hz)。
实施例26： (3S,4S)-8-(9-((2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-5- 基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000078
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:446.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71(1H,m),7.68(1H,t,J＝8.0Hz),7.50-7.55(2H,m),7.37(1H,t,J＝8.0Hz),7.31(1H,t,J＝8.0Hz),4.11-4.16(1H,m),3.76(1H,d,J＝8.0Hz),3.58-3.64(2H,m),3.14-3.32(4H,m),1.89-1.99(2H,m),1.72-1.77(1H,m),1.62-1.68(1H,m),1.14(3H,d,J＝6.8Hz)。
实施例27： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-乙炔基-5- 甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000079
步骤1：((3S,4S)-3-甲基-8-(5-甲基-4-氧代-3-((三甲基硅基)乙炔基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
参照实施例1中步骤1的方法，用中间体6代替中间体5，三甲基硅基乙炔代替1-氯-2-乙炔基苯，得到目标化合物。MS m/z[LC-MS]:515.28[M+1]。
步骤2：6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-乙炔基-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
将((3S,4S)-3-甲基-8-(5-甲基-4-氧代-3-((三甲基硅基)乙炔基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(40mg)溶于二氯甲烷(1mL)，加入1M四丁基氟化铵的四氢呋喃溶液(0.5mL)，室温搅拌0.5小时。再加入4M氯化氢的二氧六环溶液(3mL)，室温搅拌1小时，旋干，加入10％碳酸钠水溶液(10mL)，用二氯甲烷萃取，萃取液用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层硅胶色谱分离得，得到目标化合物(15mg)。MS m/z[LC-MS]:343.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.29-13.74(1H,brs),4.35(1H,s),4.05-4.12(1H,m),3.70(1H,d,J＝8.8Hz),3.52(1H,d,J＝8.8Hz),3.36(3H,s),3.22-3.35(2H,m),3.08-3.12(1H,m),2.86-2.98(2H,m),1.74-1.88(2H,m),1.60-1.64(1H,m),1.52-1.56(1H,m),1.11(3H,d,J＝6.0Hz)。
实施例28： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基 -3-(3,3,3-三氟丙-1-炔-1-基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000080
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:452.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝4.06-4.12(1H,m),3.71(1H,d,J＝8.8Hz),3.52(1H,d,J＝8.8Hz),3.38(3H,s),3.24-3.36(2H,m),3.10-3.14(1H,m),2.89-3.01(2H,m),1.76-1.86(2H,m),1.61-1.65(1H,m),1.53-1.57(1H,m),1.11(3H,d,J＝6.4Hz)。
实施例29： (3S,4S)-8-(8-((3-氨基苯基)乙炔基)-7-氯咪唑并[1,2-c]嘧啶-5-基)-3-甲 基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000081
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:437.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.75(1H,d,J＝1.6Hz),7.59(1H,d,J＝1.6Hz),7.10(1H,t,J＝8.0Hz),6.98(1H,t,J＝1.6Hz),6.95(1H,d,J＝7.6Hz),6.73(1H,dd,J＝8.0Hz,1.6Hz),4.56(1H,s),4.23-4.29(1H,m),3.84-3.93(3H,m),3.79(1H,d,J＝9.2Hz),3.35-3.39(1H,m),3.23(1H,d,J＝4.8Hz),1.94-2.05(2H,m),1.83-1.87(1H,m),1.74-1.78(1H,m),1.26(3H,d,J＝6.4Hz)。
实施例30： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氨基 吡啶-3-基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000082
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:435.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.97(1H,d,J＝5.2Hz),7.60(1H,dd,J＝7.6Hz,2.0Hz),6.73(2H,s),6.55(1H,dd,J＝7.6Hz,5.2Hz),4.09-4.16(1H,m),3.77(1H,d,J＝8.8Hz),3.55(1H,d,J＝8.8Hz),3.41(3H,s),3.22-3.39(2H,m),2.86-2.97(3H,m),1.82-1.92(2H,m),1.65-1.68(1H,m),1.56-1.61(1H,m),1.15(3H,d,J＝6.8Hz)。
实施例31： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((1-羟基 环丙基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000083
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:399.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.38-13.54(1H,brs),6.35(1H,s),4.05-4.11(1H,m),3.68(1H,d,J＝9.2Hz),3.51(1H,d,J＝8.4Hz),3.35(3H,s),3.17-3.32(2H,m),3.02-3.08(1H,m),2.84-2.98(2H,m),1.72-1.84(2H,m),1.59-1.64(1H,m),1.51-1.56(1H,m),1.09(3H,d,J＝6.0Hz),0.97-0.99(2H,m),0.85-0.93(2H,m)。
实施例32： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基 -3-((1-甲基-1H-咪唑-4-基)乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000084
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:423.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.54(1H,s),7.69(1H,s),7.58(1H,s),4.15-4.20(1H,m),3.82(1H,d,J＝8.8Hz),3.66(3H,s),3.63(1H,d,J＝8.8Hz),3.36-3.47(5H,m),2.82-2.93(3H,m),1.82-1.92(2H,m),1.70-1.74(1H,m),1.57-1.60(1H,m),1.19(3H,d,J＝6.8Hz)。
实施例33： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(吡 啶-2-基乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000085
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:420.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝12.92-13.88(1H,brs),8.61(1H,d,J＝5.2Hz),7.86(1H,td,J＝8.0Hz,1.6Hz),7.62(1H,d,J＝7.6Hz),7.43(1H,dd,J＝7.6Hz,5.2Hz),4.04-4.10(1H,m),3.68(1H,d,J＝8.8Hz),3.51(1H,d,J＝8.8Hz),3.36-3.42(5H,m),2.89-3.06(3H,m),1.72-1.84(2H,m),1.60-1.64(1H,m),1.52-1.56(1H,m),1.09(3H,d,J＝6.4Hz)。
实施例34： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基 -3-((1-甲基-1H-吡唑-4-基)乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000086
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:423.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.22-1.82(1H,brs),7.85(1H,s),7.70(1H,s),4.04-4.10(1H,m),3.85(3H,s),3.68(1H,d,J＝8.8Hz),3.51(1H,d,J＝8.8Hz),3.32-3.42(5H,m),2.88-3.04(3H,m),1.72-1.86(2H,m),1.60-1.64(1H,m),1.52-1.56(1H,m),1.09(3H,d,J＝6.4Hz)。
实施例35： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基 -3-((1-甲基-1H-吡唑-3-基)乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000087
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:423.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.22-1.82(1H,brs),7.78(1H,d,J＝2.4Hz),6.52(1H,d,J＝2.4Hz),4.04-4.10(1H,m),3.85(3H,s),3.68(1H,d,J＝8.8Hz),3.51(1H,d,J＝8.8Hz),3.32-3.42(5H,m),2.88-3.04(3H,m),1.72-1.86(2H,m),1.60-1.64(1H,m),1.52-1.56(1H,m),1.09(3H,d,J＝6.4Hz)。
实施例36： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(2-氯-3- 乙炔基苯基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000088
步骤1：((3S,4S)-8-(3-(2-氯-3-((三甲基硅基)乙炔基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯
将中间体6(160mg)、含中间体12的反应液(0.8mL)、四(三苯基膦)钯(18mg)、磷酸钾(185mg)加入二氧六环和水的混合溶剂(10:1，5mL)中，用氮气置换反应体系中的空气三次，加热至80℃搅拌过夜。冷却到室温，倒入水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱分离(石油醚：乙酸乙酯，3:1)得((3S,4S)-8-(3-(2-氯-3-((三甲基硅基)乙炔基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(80mg)。MS m/z[LC-MS]:625.27[M+1]。
步骤2：6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(2-氯-3-乙炔基苯基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
将((3S,4S)-8-(3-(2-氯-3-((三甲基硅基)乙炔基)苯基)-5-甲基-4-氧代-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(80mg)加入4M氯化氢的二氧六环溶液(3mL)中，室温搅拌1小时，旋干，加入10％碳酸钠水溶液(10mL)，用二氯甲烷萃取，萃取液用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层硅胶色谱分离(二氯甲烷：甲醇，10:1)得6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(2-氯-3-乙炔基苯基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮(38mg)。MS m/z[LC-MS]:453.18[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.70(1H,d,J＝8.0Hz),7.49(1H,d,J＝7.6Hz),7.34-7.40(1H,m),4.25-4.32(1H,m),3.94(1H,d,J＝10.4Hz),3.83(1H,d,J＝10.4Hz),3.71-3.73(1H,m),3.46-3.68(6H,m),2.94-3.09(2H,m),1.87-2.05(2H,m),1.70-1.77(1H,m),1.56-1.62(1H,m),1.29(3H,d,J＝7.6Hz)。
实施例37： 6-(4-氨基-4-甲基哌啶-1-基)-3-((2-氟-3,5-二甲氧基苯基)乙炔基)-5-甲 基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000089
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:441.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.21-13.90(1H,brs),8.22(2H,s),6.81(1H,dd,J＝7.2Hz,2.8Hz),6.60(1H,dd,J＝4.4Hz,2.8Hz),3.84(3H,s),3.76(3H,s),3.38-3.46(2H,m),3.37(3H,s),3.07-3.14(2H,m),1.86-1.95(2H,m),1.73-1.82(2H,m),1.35(3H,s)。
实施例38： 6-(4-氨基-4-甲基哌啶-1-基)-3-((2,5-二氟苯基)乙炔基)-5-甲基-1,5-二氢 -4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000090
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:399.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.63-13.90(1H,brs),8.13(2H,s),7.47-7.51(1H,m),7.34-7.44(2H,m),3.41-3.44(2H,m),3.37(3H,s),3.08-3.14(2H,m),1.85-1.92(2H,m),1.73-1.79(2H,m),1.35(3H,s)。
实施例39： (S)-1-(4-(9-(2,3-二氯苯基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-5- 基)-1H-吡唑-1-基)丙烷-2-胺
Figure PCTCN2020137662-appb-000091
参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:427.10[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.78-8.92(1H,brs),8.28-8.42(1H,brs),8.24(1H,s),7.77(1H,dd,J＝8.0Hz,1.6Hz),7.69(1H,dd,J＝7.6Hz,1.6Hz),7.48-7.51(2H,m),4.22-4.54(2H,m),3.50-3.85(1H,m),1.02-1.32(3H,m)。
实施例40： 3-((1H-吡唑-4-基)乙炔基)-6-(4-氨基-4-甲基哌啶-1-基)-5-甲基-1,5-二 氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000092
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:353.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.19-13.86(1H,brs),8.23(2H,s),7.94(2H,s),3.37-3.44(2H,m),3.35(3H,s),3.05-3.13(2H,m),1.86-1.94(2H,m),1.72-7.8(2H,m),1.34(3H,s)。
实施例41： 6-(4-氨基-4-甲基哌啶-1-基)-5-甲基-3-(嘧啶-5-基乙炔基)-1,5-二氢-4H- 吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000093
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:365.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.61-13.94(1H,brs),9.22(1H,s),8.99(2H,s),7.78-8.22(2H,brs),3.39-3.46(2H,m),3.38(3H,s),3.08-3.15(2H,m),1.83-1.91(2H,m),1.72-1.79(2H,m),1.34(3H,s)。
实施例42： 6-(4-氨基-4-甲基哌啶-1-基)-3-((3,5-二(三氟甲基)苯基)乙炔基)-5-甲基 -1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000094
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。 MS m/z[LC-MS]:499.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.17-8.21(3H,m),3.37(3H,s),3.12-3.28(4H,m),1.54-1.61(2H,m),1.46-1.52(2H,m),1.10(3H,s)。
实施例43： 6-(4-氨基-4-甲基哌啶-1-基)-5-甲基-3-((3-(三氟甲基)苯基)乙炔基)-1,5- 二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000095
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:431.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.58-13.86(1H,brs),8.08-8.18(2H,brs),7.85-7.87(2H,m),7.81(1H,d,J＝7.6Hz),7.69(1H,t,J＝7.6Hz),3.40-3.46(2H,m),3.38(3H,s),3.08-3.14(2H,m),1.86-1.93(2H,m),1.73-1.80(2H,m),1.35(3H,s)。
实施例44： 6-(4-氨基-4-甲基哌啶-1-基)-5-甲基-3-(噻吩-3-基乙炔基)-1,5-二氢-4H- 吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000096
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:369.14[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.21(2H,s),7.95(1H,d,J＝1.6Hz),7.69(1H,dd,J＝4.8Hz,2.8Hz),7.27(1H,d,J＝4.8Hz),3.65-3.73(2H,m),3.39(3H,s),3.01-3.06(2H,m),1.89-1.97(2H,m),1.76-1.84(2H,m),1.38(3H,s)。
实施例45： 6-(4-氨基-4-甲基哌啶-1-基)-3-((3-氟苯基)乙炔基)-5-甲基-1,5-二氢-4H- 吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000097
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:381.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝12.74-13.90(1H,brs),7.70-8.90(2H,brs),7.46-7.51(1H,m),7.36-7.40(2H,m),7.28-7.33(1H,m),3.38-3.46(2H,m),3.37(3H,s),3.07-3.14(2H,m),1.91-1.98(2H,m),1.75-1.80(2H,m),1.35(3H,s)。
实施例46： 6-(4-氨基-4-甲基哌啶-1-基)-3-((2,3-二氟苯基)乙炔基)-5-甲基-1,5-二氢 -4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000098
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:399.18[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.43-7.47(1H,m),7.30-7.37(1H,m),7.17-7.23(1H,m),3.51-3.59(5H,m),3.21-3.29(2H,m),1.99-2.06(2H,m),1.88-1.94(2H,m),1.48(3H,s)。
实施例47： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,3-二氟 苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000099
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:455.20[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.43-7.47(1H,m),7.30-7.37(1H,m),7.17-7.22(1H,m),4.22-4.28(1H,m),3.89(1H,d,J＝8.8Hz),3.76(1H,d,J＝8.8Hz),3.46-3.54(5H,m),3.24-3.29(1H,m),3.97-3.12(2H,m),1.91-2.02(2H,m),1.80-1.86(1H,m),1.68-1.74(1H,m),1.40(3H,s)。
实施例48： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氟苯 基)乙炔基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000100
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:423.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.19-13.37(1H,brs),7.61(1H,td,J＝7.2Hz,1.6Hz),7.46-7.52(1H,m),7.34(1H,t,J＝8.4Hz),7.27(1H,td,J＝8.4Hz,0.8Hz),3.96-4.19(3H,m),3.77(1H,d,J＝8.8Hz),3.54(1H,d,J＝8.8Hz),3.13-3.25(m,3H),1.64-1.75(2H,m),1.53-1.62(1H,m),1.43-1.50(1H,m),1.14(3H,d,J＝6.0Hz)。
实施例49： (3S,4S)-8-(9-((2,3-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000101
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:464.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70(1H,m),7.48-7.59(3H,m),7.28-7.33(1H,m),4.13-4.21(1H,m),3.81(1H,d,J＝8.4Hz),3.60-3.72(3H,m),3.13-3.25(3H,m),1.90-2.01(2H,m),1.62-1.80(2H,m),1.17(3H,d,J＝5.6Hz)。
实施例50： (3S,4S)-8-(9-((3-氯-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000102
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:480.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.62-7.72(3H,m),7.52(1H,d,J＝1.6Hz),7.33(1H,t,J＝7.6Hz),4.14-4.20(1H,m),3.82(1H,d,J＝8.8Hz),3.62-3.72(3H,m),3.12-3.24(3H,m),1.91-1.99(2H,m),1.74-1.81(1H,m),1.64-1.71(1H,m),1.17(3H,d,J＝6.0Hz)。
实施例51： (3S,4S)-8-(9-((2-氟-3,5-二甲氧基苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000103
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:506.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.69(1H,s),7.50(1H,s),6.84(1H,dd,J＝6.8Hz,2.8Hz),6.70-6.69(1H,m),4.14-4.19(1H,m),3.85(3H,s),3.77-3.81(4H,m),3.60-3.69(3H,m),3.12-3.22(4H,m),1.89-1.99(2H,m),1.63-1.68(1H,m),1.64-1.68(1H,m),1.16(3H,d,J＝6.8Hz)。
实施例52： (3S,4S)-8-(9-((2-氟-5-(三氟甲基)苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000104
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。 MS m/z[LC-MS]:514.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.04-8.07(1H,m),7.89-7.94(1H,m),7.70(1H,s),7.64(1H,t,J＝8.8Hz),7.52(1H,s),4.15-4.21(1H,m),3.81(1H,d,J＝8.0Hz),3.61-3.70(3H,m),3.13-3.23(3H,m),1.90-2.01(2H,m),1.73-1.80(1H,m),1.62-1.70(1H,m),1.17(3H,d,J＝6.4Hz)。
实施例53： (3S,4S)-3-甲基-8-(9-((3-(三氟甲基)苯基)乙炔基)-7H-咪唑并[1,2-c]吡 唑并[4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000105
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:496.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.90-7.93(2H,m),7.83(1H,d,J＝7.6Hz),7.69-7.74(2H,m),7.53(1H,s),4.15-4.21(1H,m),3.83(1H,d,J＝9.2Hz),3.63-3.71(3H,m),3.34(1H,d,J＝5.2Hz),3.10-3.19(2H,m),1.92-2.01(2H,m),1.75-1.79(1H,m),1.65-1.70(1H,m),1.18(3H,d,J＝6.4Hz)。
实施例54： (3S,4S)-8-(9-((2,5-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000106
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:464.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70(1H,m),7.48-7.59(2H,m),7.35-7.44(2H,m),4.13-4.21(1H,m),3.82(1H,d,J＝8.4Hz),3.61-3.72(3H,m),3.13-3.25(3H,m),1.91-2.01(2H,m),1.62-1.81(2H,m),1.17(3H,d,J＝5.6Hz)。。
实施例55： (3S,4S)-8-(9-((2-氟-3-(三氟甲基)苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000107
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:514.20[M+1]。 1H NMR(400MHz,CD 3OD):δ＝8.11(1H,t,J＝6.8Hz),7.72-7.77(2H,m),7.52(1H,d,J＝1.2Hz),7.42(1H,t,J＝8.0Hz),4.27-4.32(1H,m), 3.96(1H,d,J＝8.8Hz),3.79-3.89(3H,m),3.41(1H,d,J＝4.0Hz),3.17-3.28(2H,m),1.95-2.09(3H,m),1.78-1.82(1H,m),1.30(3H,d,J＝6.8Hz)。
实施例56： 3-(5-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑 并[1,2-c]吡唑并[4,3-e]嘧啶-9-基)-2-氯苯基二甲基氨基甲酸酯
Figure PCTCN2020137662-appb-000108
参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:525.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.85(1H,s),7.64(1H,d,J＝1.6Hz),7.60(1H,dd,J＝7.2Hz,1.6Hz),7.45(1H,t,J＝7.6Hz),7.36-7.39(2H,m),4.15-4.21(1H,m),3.84(1H,d,J＝9.2Hz),3.60-3.72(3H,m),3.06-3.20(6H,m),2.91(3H,s),1.90-1.99(2H,m),1.74-1.81(1H,m),1.64-1.70(1H,m),1.19(3H,d,J＝6.4Hz)。
实施例57： 3-((5-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑 并[1,2-c]吡唑并[4,3-e]嘧啶-9-基)乙炔基)-2-氟苯腈
Figure PCTCN2020137662-appb-000109
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:471.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.99-8.06(2H,m),7.72(1H,s),7.48-7.52(2H,m),4.09-4.15(1H,m),3.46(1H,d,J＝8.4Hz),3.55-3.66(3H,m),3.12-3.25(3H,m),1.87-1.99(2H,m),1.62-1.74(2H,m),1.13(3H,d,J＝6.4Hz)。
实施例58： (3S,4S)-8-(9-(环丙基乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-5- 基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000110
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:392.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.56-13.84(1H,brs),7.65(1H,d,J＝0.8Hz),7.45(1H,d,J＝0.8Hz),4.05-4.13(1H,m),3.94-4.02(1H,m),3.71(1H,d,J＝8.4Hz),3.46-3.60(3H,m),3.02-3.23(3H,m),1.80-1.99(3H,m), 1.64-1.74(1H,m),1.10(3H,d,J＝6.4Hz),0.90-0.94(2H,m),0.75-0.82(2H,m)。
实施例59： N-(3-((5-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H- 咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-9-基)乙炔基)-2-氟苯基)乙酰胺
Figure PCTCN2020137662-appb-000111
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:503.23[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.98(1H,t,J＝7.6Hz),7.75(1H,d,J＝1.6Hz),7.59(1H,t,J＝7.2Hz),7.50(1H,d,J＝1.6Hz),7.19(1H,t,J＝8.0Hz),4.26-4.32(1H,m),3.95(1H,d,J＝9.2Hz),3.77-3.85(3H,m),3.33-3.36(1H,m),3.14-3.24(2H,m),2.18(3H,s),1.99-2.10(2H,m),1.89-1.95(1H,m),1.76-1.83(1H,m),1.29(3H,d,J＝6.4Hz)。
实施例60： (3S,4S)-8-(9-((3-氨基-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000112
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:461.22[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.73(1H,d,J＝2.0Hz),7.49(1H,d,J＝2.0Hz),7.03-7.07(1H,m),6.93(1H,t,J＝7.6Hz),6.88(1H,td,J＝8.0Hz,2.0Hz),4.26-4.32(1H,m),3.95(1H,d,J＝9.2Hz),3.76-3.85(3H,m),3.35(1H,d,J＝4.4Hz),3.17-3.25(2H,m),1.99-2.10(2H,m),1.88-1.96(1H,m),1.76-1.83(1H,m),1.29(3H,d,J＝6.4Hz)。
实施例61： 5-(5-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑 并[1,2-c]吡唑并[4,3-e]嘧啶-9-基)-3H-螺[苯并呋喃-2,1'-环丙烷]-3-酮
Figure PCTCN2020137662-appb-000113
参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:486.23[M+1]。 1H NMR(400MHz,CD 3OD):δ＝8.93(1H,s),7.87(1H,d,J＝8.8Hz),7.73(1H,s),7.49(1H,s),7.38(1H,d,J＝8.4Hz),4.25-4.32(1H,m), 3.98(1H,d,J＝9.2Hz),3.76-3.88(3H,m),3.44(1H,d,J＝4.4Hz),3.11-3.29(2H,m),2.04-2.11(2H,m),1.93-1.98(1H,m),1.74-1.84(3H,m),1.55-1.58(2H,m),1.31(3H,d,J＝6.4Hz)。
实施例62： (3S,4S)-8-(9-((2,3-二氯苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000114
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:496.14[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.61-7.74(3H,m),7.51(1H,d,J＝1.6Hz),7.31(1H,t,J＝7.6Hz),4.11-4.20(1H,m),3.78(1H,d,J＝8.4Hz),3.61-3.74(3H,m),3.10-3.24(3H,m),1.89-1.99(2H,m),1.73-1.85(1H,m),1.64-1.72(1H,m),1.16(3H,d,J＝6.4Hz)。
实施例63： (3S,4S)-8-(9-((2-氟-3-甲氧基苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000115
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:476.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70(1H,m),7.50(1H,m),7.16-7.32(3H,m),4.10-4.22(1H,m),3.87(3H,s),3.78(1H,d,J＝8.4Hz),3.57-3.69(3H,m),3.12-3.26(3H,m),1.87-2.01(2H,m),1.71-1.79(1H,m),1.62-1.69(1H,m),1.15(3H,d,J＝5.6Hz)。
实施例64： (3S,4S)-8-(9-(3-氯-[1,1'-联苯基]-4-基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000116
参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:514.21[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.84(1H,s), 7.70-7.72(5H,m),7.49(2H,t,J＝7.6Hz),7.38-7.42(1H,m),7.35(1H,d,J＝1.6Hz),4.26-4.32(1H,m),3.97(1H,d,J＝8.8Hz),3.78-3.87(3H,m),3.39(1H,d,J＝3.6Hz),3.17-3.27(2H,m),1.99-2.12(2H,m),1.91-1.98(1H,m),1.78-1.84(1H,m),1.30(3H,d,J＝6.8Hz)。
实施例65： 2-((3-(5-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H- 咪唑并[1,2-c]吡唑并[4,3-e]嘧啶-9-基)-2-氯苯基)硫基)乙酰胺
Figure PCTCN2020137662-appb-000117
参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:527.18[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.71-7.77(1H,m),7.53(1H,d,J＝6.8Hz),7.36-7.46(3H,m),4.29-4.35(1H,m),4.01(1H,d,J＝10.0Hz),3.81-3.91(3H,m),3.76(2H,s),3.52-3.54(1H,m),3.17-3.24(2H,m),2.03-2.22(2H,m),1.95-2.04(1H,m),1.80-1.86(1H,m),1.33(3H,d,J＝6.4Hz)。
实施例66： 3-((5-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑 并[1,2-c]吡唑并[4,3-e]嘧啶-9-基)乙炔基)-2-氟苯酚
Figure PCTCN2020137662-appb-000118
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:462.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝10.14-10.29(1H,brs),7.68(1H,d,J＝1.2Hz),7.50(1H,d,J＝1.2Hz),7.01-7.08(3H,m),4.16-4.23(1H,m),3.84(1H,d,J＝9.2Hz),3.63-3.73(3H,m),3.40(1H,d,J＝4.4Hz),3.08-3.19(2H,m),1.89-2.01(2H,m),1.76-1.82(1H,m),1.64-1.72(1H,m),1.19(3H,d,J＝6.8Hz)。
实施例67： (3S,4S)-8-(9-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-4-基)乙炔基)-7H-咪 唑并[1,2-c]吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000119
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:508.19[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.74(1H,d,J＝1.6Hz),7.55(1H,d,J＝8.0Hz),7.51(1H,d,J＝1.6Hz),7.26(1H,d,J＝8.0Hz),7.20(1H,t,J＝8.0Hz),4.26-4.32(1H,m),3.95(1H,d,J＝8.8Hz),3.77-3.88(3H,m),3.39(1H,d,J＝4.4Hz),3.16-3.25(2H,m),2.01-2.02(2H,m),1.89-1.96(1H,m),1.76-1.83(1H,m),1.29(3H,d,J＝6.4Hz)。
实施例68： (3S,4S)-8-(9-((2-氟-3-甲基苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000120
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:460.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.80(1H,m),7.62-7.70(2H,m),7.52(1H,d,J＝1.6Hz),7.41-7.20(1H,m),4.13-4.20(1H,m),3.81(1H,d,J＝8.8Hz),3.60-3.72(3H,m),3.27-3.29(1H,m),3.12-3.21(2H,m),2.35(3H,s),1.89-1.97(2H,m),1.61-1.79(2H,m),1.18(3H,d,J＝6.4Hz)。
实施例69： (3S,4S)-8-(9-((2-氟-3-异丙基苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000121
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:504.25[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70(1H,d,J＝1.4Hz),7.51(1H,d,J＝1.4Hz),7.18-7.32(3H,m),4.55(1H,m),4.10-4.21(1H,m),3.77(1H,d,J＝8.4Hz),3.57-3.68(3H,m),3.10-3.25(3H,m),1.87-2.02(2H,m),1.70-1.79(1H,m),1.60-1.70(1H,m),1.32(6H,d,J＝6.8Hz),1.16(3H,d,J＝5.6Hz)。
实施例70： (3S,4S)-8-(9-((3-(二氟甲氧基)-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡 唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000122
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:512.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.76(1H,d,J＝1.6Hz),7.51(1H,d,J＝1.6Hz),7.38(1H,t,J＝56.0Hz),7.21-7.35(3H,m),4.12-4.22(1H,m),3.79(1H,d,J＝8.4Hz),3.58-3.68(3H,m),3.12-3.26(3H,m),1.88-2.01(2H,m),1.70-1.80(1H,m),1.61-1.70(1H,m),1.18(3H,d,J＝5.6Hz)。
实施例71： (3S,4S)-8-(9-((3-(二氟甲基)-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000123
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:496.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.84-7.88(1H,m),7.70-7.74(2H,m),7.51(1H,d,J＝1.6Hz),7.41-7.18(1H,m),7.28(1H,t,J＝54.0Hz),4.13-4.19(1H,m),3.80(1H,d,J＝8.8Hz),3.60-3.71(3H,m),3.27-3.28(1H,m),3.12-3.21(2H,m),1.90-1.99(2H,m),1.61-1.78(2H,m),1.17(3H,d,J＝6.8Hz)。
实施例72： (3S,4S)-3-甲基-8-(9-((2,3,4-三氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000124
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:482.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70(1H,d,J＝1.2Hz),7.52-7.59(1H,m),7.51(1H,d,J＝1.2Hz),7.40-7.47(1H,m),4.13-4.19(1H,m),3.80(1H,d,J＝8.8Hz),3.60-3.71(3H,m),3.28-3.29(1H,m),3.12-3.21(2H,m),1.90-1.99(2H,m),1.72-1.79(1H,m),1.64-1.70(1H,m),1.16(3H,d,J＝6.8Hz)。
实施例73： (3S,4S)-8-(9-((3-氯-2,5-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000125
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:498.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.85-8.11(1H,brs),7.77-7.83(1H,m),7.74(0.5H,d,J＝1.6Hz),7.70(0.5H,d,J＝1.6Hz),7.59-7.63(1H,m),7.52(0.5H,d,J＝1.6Hz),7.49(0.5H,d,J＝1.6Hz),4.18-4.28(1H,m),3.66-3.88(4H,m),3.43(1H,d,J＝4.4Hz),3.11-3.21(2H,m),1.91-2.02(2H,m),1.66-1.86(2H,m),1.14-1.28(3H,m)。
实施例74： (3S,4S)-8-(9-((2-氟-3-(2,2,2-三氟乙氧基)苯基)乙炔基)-7H-咪唑并[1,2-c] 吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000126
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:544.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.73(1H,d,J＝1.6Hz),7.50(1H,d,J＝1.6Hz),7.20-7.34(3H,m),4.46(2H,m),4.10-4.22(1H,m),3.78(1H,d,J＝8.4Hz),3.57-3.68(3H,m),3.12-3.25(3H,m),1.87-2.01(2H,m),1.70-1.79(1H,m),1.62-1.70(1H,m),1.17(3H,d,J＝5.6Hz)。
实施例75： (3S,4S)-8-(9-(3,3-二甲基丁-1-炔-1-基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000127
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:408.25[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.65(1H,d,J＝1.2Hz),7.45(1H,d,J＝1.2Hz),4.04-4.16(1H,m),3.70(1H,d,J＝8.6Hz),3.40-3.60(3H,m),3.00-3.24(3H,m),1.81-1.99(3H,m),1.64-1.75(1H,d,J＝6.8Hz),1.27(9H,s),1.08(3H,d,J＝6.4Hz)。
实施例76： (3S,4S)-8-(9-(3-氯-3-甲基丁-1-炔-1-基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000128
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:428.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.46-13.81(1H,brs),7.68(1H,d,J＝1.2Hz),7.50(1H,d,J＝1.2Hz),4.02-4.17(1H,m),3.71(1H,m),3.42-3.61(3H,m),2.99-3.25(3H,m),1.80-2.00(9H,m),1.64-1.79(1H,d,J＝6.8Hz),1.10(3H,d,J＝6.8Hz)。
实施例77： (3S,4S)-3-甲基-8-(9-(3-甲基丁-1-炔-1-基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000129
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:394.24[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.65(1H,d,J＝1.2Hz),7.45(1H,d,J＝1.2Hz),4.04-4.16(1H,m),3.70(1H,d,J＝8.6Hz),3.40-3.60(3H,m),2.98-3.24(4H,m),1.81-1.99(3H,m),1.64-1.75(1H,m),1.28(6H,d,J＝6.8Hz),1.07(3H,d,J＝6.4Hz)。
实施例78： (3S,4S)-3-甲基-8-(9-((1-甲基环丙基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000130
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:406.24[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.58-13.84(1H,brs),7.63(1H,d,J＝0.8Hz),7.43(1H,d,J＝0.8Hz),4.05-4.14(1H,m),3.72(1H,d,J＝8.6Hz),3.46-3.60(3H,m),3.02-3.23(3H,m),1.80-1.99(3H,m),1.64-1.74(1H,m),1.26(3H,s),1.10(3H,d,J＝6.4Hz),0.92-0.95(2H,m),0.72-0.80(2H,m)。
实施例79： (3S,4S)-8-(9-((2,2-二氟环丙基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000131
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:428.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.68(1H,d,J＝1.2Hz),7.48(1H,d,J＝1.2Hz),4.05-4.17(2H,m),3.71(1H,d,J＝8.6Hz),3.46-3.60(3H,m),3.02-3.23(3H,m),1.80-1.99(3H,m),1.64-1.78(2H,m),1.52(1H,m),1.12(3H,d,J＝6.4Hz)。
实施例80： (3S,4S)-8-(9-((3-(环丙基甲氧基)-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c] 吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000132
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:516.25[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.75(1H,d,J＝1.6Hz),7.49(1H,d,J＝1.6Hz),7.32-7.36(1H,m),7.07-7.16(2H,m),4.23-4.28(1H,m),3.89-3.92(3H,m),3.71-3.79(3H,m),3.16-3.26(3H,m),1.97-2.05(2H,m),1.75-1.88(2H,m),1.24(3H,d,J＝6.4Hz),0.84-0.91(1H,m),0.61-0.65(2H,m),0.35-0.39(2H,m)。
实施例81： (3S,4S)-8-(9-((3-乙氧基-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000133
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:490.24[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71(1H,d,J＝1.6Hz),7.48(1H,d,J＝1.6Hz),7.24-7.29(1H,m),7.16-7.21(2H,m),4.13(2H,q,J＝6.8Hz),4.04-4.11(1H,m),3.68(1H,d,J＝8.4Hz),3.50-3.61(3H,m),3.17-3.26(2H,m),2.98(1H,d,J＝5.2Hz),1.81-1.96(2H,m),1.57-1.72(2H,m),1.34(3H,t,J＝6.8Hz),1.08(3H,d,J＝6.8Hz)。
实施例82： (3S,4S)-3-甲基-8-(9-(3-甲基丁-3-烯-1-炔-1-基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000134
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:392.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.69(1H,d,J＝1.6Hz),7.48(1H,d,J＝1.6Hz),5.46-5.48(2H,m),4.05-4.11(1H,m),3.69(1H,d,J＝8.4Hz),3.51-3.60(3H,m),3.12-3.26(2H,m),3.04(1H,d,J＝4.0Hz),1.98(3H,s),1.82-1.95(2H,m),1.59-1.70(m,2H),1.09(3H,d,J＝6.4Hz)。
实施例83： (3S,4S)-8-(9-((2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)乙炔基)-7H-咪 唑并[1,2-c]吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000135
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:508.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.67-7.73(2H,m),7.45-7.53(3H,m),4.09-4.16(1H,m),3.75(1H,d,J＝8.8Hz),3.51-3.66(3H,m),3.11-3.25(3H,m),1.87-1.98(2H,m),1.61-1.76(2H,m),1.13(3H,d,J＝6.4Hz)。
实施例84： (3S,4S)-8-(9-((2,4-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000136
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:464.20[M+1]。 1H NMR(400MHz,DMSO-d6):δ＝7.74(1H,td,J＝8.4Hz,6.4Hz),7.70(1H,d,J＝1.6Hz),7.49(1H,d,J＝1.6Hz),7.46(1H,td,J＝9.6Hz,2.4Hz),7.21(1H,td,J＝8.4Hz,2.0Hz),4.09-4.16(1H,m),3.75(1H,d,J＝8.8Hz),3.50-3.61(3H,m),3.13-3.24(3H,m),1.87-1.99(2H,m),1.71-1.75(1H,m),1.63-1.67(1H,m),1.13(3H,d,J＝6.0Hz)。
实施例85： (3S,4S)-8-(9-((3-氯-2,4-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000137
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:498.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71-7.77(2H,m),7.51(1H,d,J＝1.6Hz),7.44(1H,td,J＝8.8Hz,1.6Hz),4.10-4.16(1H,m),3.76(1H,d,J＝8.8Hz),3.56-3.66(3H,m),3.13-3.24(3H,m),1.88-1.97(2H,m),1.71-1.75(1H,m),1.62-1.68(1H,m),1.14(3H,d,J＝6.0Hz)。
实施例86： (3S,4S)-8-(9-((2-氟-3-(氟甲氧基)苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000138
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:494.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71(1H,d,J＝1.6Hz),7.50(1H,d,J＝1.6Hz),7.38-7.46(2H,m),7.28(1H,t,J＝8.0Hz),5.92(2H,d,J＝53.6Hz),4.09-4.15(1H,m),3.75(1H,d,J＝8.8Hz),3.55-3.67(3H,m),3.14-3.26(3H,m),1.87-1.98(2H,m),1.70-1.76(1H,m),1.60-1.67(1H,m),1.13(3H,d,J＝6.4Hz)。
实施例87： (3S,4S)-8-(9-((4-苯氧苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e]嘧啶 -5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000139
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:520.25[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.66(1H,d,J＝1.6Hz),7.57(1H,d,J＝1.6Hz),7.30-7.41(4H,m),7.10(1H,t,J＝7.2Hz),6.93(2H,d,J＝8.0Hz),6.78(2H,.d,J＝8.4Hz),4.21-4.29(1H,m),3.89(1H,d,J＝8.8Hz),3.63-3.82(3H,m),3.10-3.26(3H,m),1.96-2.07(2H,m),1.82-1.88(1H,m),1.73-1.79(1H,m),1.25(3H,d,J＝6.0Hz)。
实施例88： (3S,4S)-8-(9-((2,4,5-三氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000140
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:482.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.83-7.90(1H,m), 7.73-7.80(1H,m),7.70(1H,d,J＝1.6Hz),7.51(1H,d,J＝1.6Hz),4.14-4.20(1H,m),3.80(1H,d,J＝9.2Hz),3.61-3.69(3H,m),3.11-3.24(3H,m),1.90-1.98(2H,m),1.74-1.78(1H,m),1.64-1.68(1H,m),1.16(3H,d,J＝6.8Hz)。
实施例89： (3S,4S)-8-(9-((2-氟-3-(氟甲基)苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000141
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:478.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.68-7.74(2H,m),7.60-7.66(1H,m),7.52(1H,d,J＝1.6Hz),7.35(1H,t,J＝7.6Hz),5.53(2H,d,J＝47.6Hz),4.17-4.23(1H,m),3.84(1H,d,J＝8.8Hz),3.63-3.74(3H,m),3.41(1H,d,J＝4.8Hz),3.09-3.19(2H,m),1.91-1.99(2H,m),1.77-1.81(1H,m),1.66-1.70(1H,m),1.19(3H,d,J＝6.8Hz)。
实施例90： (3S,4S)-3-甲基-8-(9-(噻吩-2-基乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000142
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:434.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70-7.73(2H,m),7.48-7.50(2H,m),7.15(1H,t,J＝4.0Hz),4.08-4.15(1H,m),3.73(1H,d,J＝8.0Hz),3.50-3.64(3H,m),3.10-3.24(3H,m),1.85-1.99(2H,m),1.69-1.74(1H,m),1.61-1.67(1H,m),1.12(3H,d,J＝6.4Hz)。
实施例91： (3S,4S)-8-(9-((2,3,5-三氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000143
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:482.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.68-7.76(2H,m),7.52(1H,d,J＝1.6Hz),7.43-7.48(1H,m),4.12-4.18(1H,m),3.78(1H,d,J＝8.8Hz),3.59-3.68(3H,m),3.13-3.28(3H,m),1.88-1.99(2H,m),1.72-1.78(1H,m),1.62-1.69(1H, m),1.15(3H,d,J＝6.4Hz)。
实施例92： 4-(5-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑 并[1,2-c]吡唑并[4,3-e]嘧啶-9-基)-2-甲基丁-3-炔-2-醇
Figure PCTCN2020137662-appb-000144
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:410.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.72-13.94(1H,brs),7.65(1H,d,J＝1.6Hz),7.49(1H,d,J＝1.6Hz),5.57(1H,s),4.12-4.18(1H,m),3.79(1H,d,J＝9.2Hz),3.55-3.64(3H,m),3.26(1H,d,J＝3.6Hz),3.08-3.16(2H,m),1.90-1.98(2H,m),1.71-1.78(1H,m),1.61-1.68(1H,m),1.49(6H,s),1.16(3H,d,J＝6.4Hz)。
实施例93： (3S,4S)-8-(9-(3,3-二甲基丁-1-炔-1-基)-7H-咪唑并[1,2-c]吡咯并[3,2-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000145
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:407.26[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝11.92(1H,d,J＝2.4Hz),7.55(1H,d,J＝1.6Hz),7.47(1H,d,J＝1.6Hz),7.25(1H,d,J＝2.4Hz),4.14-4.20(1H,m),3.80(1H,d,J＝8.8Hz),3.62(1H,d,J＝8.8Hz),3.45-3.54(2H,m),3.27-3.29(1H,m),2.96-3.04(2H,m),1.89-1.99(2H,m),1.64-1.80(2H,m),1.28(9H,s),1.17(3H,d,J＝6.8Hz)。
实施例94： (3S,4S)-8-(9-((2,3,4,5-四氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000146
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:500.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71-7.79(2H,m),7.52(1H,d,J＝1.6Hz),4.26-4.32(1H,m),3.95(1H,d,J＝9.2Hz),3.76-3.88(3H,m),3.40(1H,d,J＝4.0Hz),3.15-3.25(2H,m),2.01-2.11(2H,m),1.90-1.94(1H,m),1.78-1.82(1H,m),1.29(3H,d,J＝6.8Hz)。
实施例95： (3S,4S)-8-(9-((2-氟-3-(甲氧甲基)苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000147
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:490.24[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.74-7.79(2H,m),7.48-7.52(2H,m),7.23(1H,t,J＝8.0Hz),4.55(2H,s),4.27-4.33(1H,m),3.97(1H,d,J＝9.2Hz),3.78-3.87(3H,m),3.42(1H,d,J＝4.0Hz),3.41(3H,s),3.16-3.25(2H,m),1.99-2.12(2H,m),1.92-1.97(1H,m),1.78-1.83(1H,m),1.30(3H,d,J＝6.8Hz)。
实施例96： (3-((5-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪 唑并[1,2-c]吡唑并[4,3-e]嘧啶-9-基)乙炔基)-2-氟苯基)甲醇
Figure PCTCN2020137662-appb-000148
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:476.22[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.72-7.76(2H,m),7.50-7.56(2H,m),7.23(1H,t,J＝8.0Hz),4.70(2H,s),4.28-4.34(1H,m),3.98(1H,d,J＝9.6Hz),3.80-3.91(3H,m),3.50(1H,d,J＝4.0Hz),3.11-3.27(2H,m),1.95-2.14(3H,m),1.78-1.84(1H,m),1.32(3H,d,J＝6.4Hz)。
实施例97： (3S,4S)-8-(9-((2,6-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000149
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:494.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71(1H,d,J＝1.6Hz),7.53-7.61(1H,m),7.49(1H,d,J＝1.6Hz),7.24-7.30(2H,m),4.08-4.13(1H,m),3.73(1H,d,J＝8.4Hz),3.53-3.64(3H,m),3.11-3.25(3H,m),1.85-1.97(2H,m),1.60-1.75(2H,m),1.11(3H,d,J＝6.4Hz)。
实施例98： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(3,3-二甲 基丁-1-炔-1-基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000150
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:399.25[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.14-13.55(1H,brs),4.04-4.10(1H,m),3.68(1H,d,J＝8.8Hz),3.50(1H,d,J＝8.8Hz),3.35(3H,s),3.23-3.34(2H,m),3.04-3.08(1H,m),2.83-2.97(2H,m),1.71-1.84(2H,m),1.50-1.64(2H,m),1.26(9H,s),1.09(3H,d,J＝6.0Hz)。
实施例99： (3S,4S)-8-(9-((2,4-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡咯并[3,2-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000151
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:463.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝12.23(1H,s),7.58-7.65(2H,m),7.56(1H,s),7.48(1H,s),7.36-7.42(1H,m),7.12-7.18(1H,m),4.15-4.22(1H,m),3.82(1H,d,J＝8.4Hz),3.64(1H,d,J＝8.4Hz),3.50-3.60(2H,m),3.35-3.38(1H,m),2.99-3.07(2H,m),1.88-2.01(2H,m),1.76-1.82(1H,m),1.64-1.72(1H,m),1.18(3H,d,J＝6.8Hz)。
实施例100： (3S,4S)-8-(9-((2-氟-3-异丁氧基苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000152
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:518.27[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.69(1H,d,J＝1.6Hz),7.51(1H,d,J＝1.6Hz),7.24-7.29(1H,m),7.15-7.20(2H,m),4.15-4.21(1H,m),3.82-3.83(3H,m),3.62-3.70(3H,m),3.33(1H,d,J＝4.8Hz),3.10-3.20(2H,m),1.92-2.08(3H,m),1.64-1.80(2H,m),1.18(3H,d,J＝6.4Hz),0.97(6H,d,J＝7.2Hz)。
实施例101： (3S,4S)-8-(9-((3,4-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000153
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:464.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.68-7.74(2H,m), 7.46-7.58(3H,m),4.10-4.16(1H,m),3.76(1H,d,J＝9.2Hz),3.57-3.67(3H,m),3.13-3.22(3H,m),1.87-1.98(2H,m),1.71-1.75(1H,m),1.62-1.68(1H,m),1.13(3H,d,J＝6.4Hz)。
实施例102： (3S,4S)-8-(9-((3-(二甲胺基)-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000154
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:489.25[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.69(1H,d,J＝1.2Hz),7.50(1H,d,J＝1.2Hz),7.02-7.14(3H,m),4.11-4.17(1H,m),3.77(1H,d,J＝8.4Hz),3.57-3.66(3H,m),3.13-3.24(3H,m),2.80(6H,s),1.88-1.99(2H,m),1.71-1.77(1H,m),1.62-1.68(1H,m),1.14(3H,d,J＝6.4Hz)。
实施例103： (3S,4S)-8-(9-((2,3-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡咯并[3,2-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000155
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:463.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝12.31(1H,s),7.58-7.62(2H,m),7.48(1H,d,J＝1.2Hz),7.37-7.46(2H,m),7.21-7.27(1H,m),4.12-4.18(1H,m),3.78(1H,d,J＝8.4Hz),3.59(1H,d,J＝8.4Hz),3.47-3.56(2H,m),3.22-3.25(1H,m),3.01-3.10(2H,m),1.89-1.99(2H,m),1.73-1.77(1H,m),1.64-1.69(1H,m),1.15(3H,d,J＝6.8Hz)。
实施例104： (3S,4S)-8-(9-((2,6-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡咯并[3,2-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000156
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:463.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝12.31(1H,s),7.58-7.62(2H,m),7.43-7.50(2H,m),7.18-7.24(2H,m),4.11-4.17(1H,m),3.76(1H,d,J＝8.8Hz),3.58(1H,d,J＝8.4Hz),3.46-3.55(2H,m),3.19-3.22(1H,m),3.01-3.10(2H,m),1.89-1.99(2H,m),1.72-1.76(1H,m),1.64-1.68(1H,m),1.14(3H,d,J＝6.4Hz)。
实施例105： (3S,4S)-8-(9-((4-氯-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000157
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:480.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.67-7.72(2H,m),7.65(1H,dd,J＝9.2Hz,2.0Hz),7.51(1H,d,J＝1.6Hz),7.40(1H,dd,J＝8.4Hz,2.0Hz),4.12-4.18(1H,m),3.79(1H,d,J＝8.8Hz),3.59-3.70(3H,m),3.25(1H,d,J＝4.8Hz),3.11-3.21(2H,m),1.89-1.98(2H,m),1.72-1.78(1H,m),1.63-1.68(1H,m),1.15(3H,d,J＝6.4Hz)。
实施例106： (3S,4S)-3-甲基-8-(9-((1-(三氟甲基)环丙基)乙炔基)-7H-咪唑并[1,2-c] 吡唑并[4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000158
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:460.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.66(1H,d,J＝1.2Hz),7.50(1H,d,J＝1.2Hz),4.14-4.20(1H,m),3.82(1H,d,J＝8.8Hz),3.59-3.70(3H,m),3.35(1H,d,J＝4.0Hz),3.07-3.16(2H,m),1.90-1.99(2H,m),1.74-1.78(1H,m),1.64-1.68(1H,m),1.48-1.52(2H,m),1.38-1.43(2H,m),1.18(3H,d,J＝6.0Hz)。
实施例107： (3S,4S)-3-甲基-8-(9-((2,3,6-三氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000159
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:482.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71(1H,d,J＝1.6Hz),7.62-7.69(1H,m),7.51(1H,d,J＝1.6Hz),7.29-7.35(1H,m),4.13-4.19(1H,m),3.80(1H,d,J＝9.2Hz),3.60-3.71(3H,m),3.33(1H,d,J＝4.0Hz),3.11-3.21(2H,m),1.89-1.97(2H,m),1.74-1.78(1H,m),1.64-1.68(1H,m),1.16(3H,d,J＝6.4Hz)。
实施例108： (3S,4S)-8-(9-((3,5-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000160
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:464.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.72(1H,d,J＝1.4Hz),7.51(1H,d,J＝1.4Hz),7.33-7.44(3H,m),4.06-4.12(1H,m),3.70(1H,d,J＝8.4Hz),3.51-3.62(3H,m),3.13-3.24(2H,m),3.03(1H,d,J＝4.8Hz),1.82-1.96(2H,m),1.60-1.72(2H,m),1.09(3H,d,J＝6.4Hz)。
实施例109： (3S,4S)-8-(9-((2-氯-3,6-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000161
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:498.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70(1H,d,J＝1.6Hz),7.59-7.64(1H,m),7.51(1H,d,J＝1.6Hz),7.44-7.50(1H,m),4.16-4.21(1H,m),3.82(1H,d,J＝9.2Hz),3.64-3.71(3H,m),3.37(1H,d,J＝4.4Hz),3.11-3.20(2H,m),1.89-1.99(2H,m),1.76-1.80(1H,m),1.66-1.69(1H,m),1.18(3H,d,J＝6.4Hz)。
实施例110： (3S,4S)-3-甲基-8-(9-((五氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000162
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:518.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.72(1H,d,J＝1.6Hz),7.51(1H,d,J＝1.6Hz),4.10-4.16(1H,m),3.76(1H,d,J＝9.2Hz),3.55-3.67(3H,m),3.12-3.25(3H,m),1.88-1.99(2H,m),1.71-1.75(1H,m),1.62-1.67(1H,m),1.13(3H,d,J＝6.0Hz)。
实施例111： (3S,4S)-3-甲基-8-(9-((2,4,6-三氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000163
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:482.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70(1H,d,J＝1.6Hz),7.51(1H,d,J＝1.6Hz),7.41-7.45(2H,m),4.16-4.20(1H,m),3.81(1H,d,J＝9.2Hz),3.62-3.71(3H,m),3.33-3.35(1H,m),3.10-3.20(2H,m),1.90-1.99(2H,m),1.75-1.79(1H,m),1.64-1.69(1H,m),1.17(3H,d,J＝6.4Hz)。
实施例112： (3S,4S)-3-甲基-8-(9-((2,3,4,5-四氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡 唑并[4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000164
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:500.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.03-8.12(1H,m),7.72(1H,d,J＝1.6Hz),7.52(1H,d,J＝1.6Hz),4.12-4.19(1H,m),3.78(1H,d,J＝8.4Hz),3.59-3.70(3H,m),3.12-3.26(3H,m),1.88-1.99(2H,m),1.72-1.78(1H,m),1.62-1.68(1H,m),1.15(3H,d,J＝6.8Hz)。
实施例113： 6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氟-3- 甲氧基苯基)乙炔基)-5-甲基-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000165
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:467.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.26(J H,td,J＝8.0Hz,1.6Hz),7.19(1H,t,J＝8.0Hz),7.10-7.14(1H,m),4.07-4.12(1H,m),3.85(3H,s),3.72(1H,d,J＝8.8Hz),3.53(1H,d,J＝8.8Hz),3.38(3H,s),3.22-3.36(3H,m),2.87-2.99(2H,m),1.76-1.87(2H,m),1.62-1.66(1H,m),1.54-1.58(1H,m),1.11(3H,d,J＝6.8Hz)。
实施例114： (3S,4S)-8-(9-((3-甲氧基吡啶-4-基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000166
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:459.23[M+1]。 1H NMR(400MHz,CD 3OD):δ＝8.78(1H,s),8.43(1H,d,J＝6.0Hz),7.75(1H,d,J＝1.6Hz),7.52(1H,d,J＝1.6Hz),7.16(1H,d,J＝6.0Hz),4.27-4.33(1H,m),4.02(3H,s),3.98(1H,d,J＝9.6Hz),3.80-3.89(3H,m),3.50(1H,d,J＝3.6Hz),3.15-3.24(2H,m),1.94-2.11(3H,m),1.78-1.83(1H,m),1.32(3H,d,J＝6.4Hz)。
实施例115： (3S,4S)-8-(9-((3-氟吡啶-4-基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000167
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:447.21[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.33(1H,d,J＝5.2Hz),7.72(1H,d,J＝1.6Hz),7.52-7.54(2H,m),7.40-7.41(1H,m),4.13-4.19(1H,m),3.80(1H,d,J＝8.8Hz),3.60-3.71(3H,m),3.14-3.27(3H,m),1.90-1.99(2H,m),1.73-1.78(1H,m),1.64-1.68(1H,m),1.16(3H,d,J＝6.4Hz)。
实施例116： (3S,4S)-3-甲基-8-(9-(螺[色烷-2,1'-环丁烷]-6-基)-7H-咪唑并[1,2-c]吡 唑并[4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000168
参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:500.28[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.51-13.77(1H,brs),8.52(1H,d,J＝8.8Hz),8.35(1H,d,J＝1.6Hz),7.67(1H,d,J＝1.6Hz),7.51(1H,d,J＝1.2Hz),6.83(1H,d,J＝8.4Hz),4.13-4.19(1H,m),3.81(1H,d,J＝8.8Hz),3.56-3.66(3H,m),3.28(1H,d,J＝5.2Hz),3.07-3.16(2H,m),2.82(2H,t,J＝6.8Hz),2.13-2.21(2H,m),2.03-2.10(2H,m),191-2.01(4H,m),1.72-1.83(2H,m),1.62-1.71(2H,m),1.17(3H,d,J＝6.0Hz)。
实施例117： (3S,4S)-3-甲基-8-(9-(螺[色烷-2,1'-环丁烷]-7-基)-7H-咪唑并[1,2-c]吡 唑并[4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000169
参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:500.28[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.58-13.82(1H,brs),8.20-8.25(1H,m),8.13(1H,d,J＝7.6Hz),7.69(1H,d,J＝1.4Hz),7.55(1H,d,J＝1.4Hz),7.14(1H,d,J＝7.6Hz),4.16-4.22(1H,m),3.83(1H,d,J＝9.6Hz),3.59-3.70(3H,m),3.06-3.18(3H,m),2.77(2H,t,J＝6.4Hz),2.14-2.23(2H,m),2.02-2.10(2H,m),1.90-1.98(4H,m),1.76-1.83(2H,m),1.64-1.70(2H,m),1.18(3H,d,J＝6.0Hz)。
实施例118： (3S,4S)-8-(9-((5-氯-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000170
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:480.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70-7.75(2H,m),7.56-7.60(1H,m),7.50(1H,d,J＝1.6Hz),7.43(1H,t,J＝9.2Hz),4.08-4.14(1H,m),3.73(1H,d,J＝8.0Hz),3.54-3.64(3H,m),3.10-3.26(3H,m),1.85-1.97(2H,m),1.69-1.74(1H,m),1.62-1.66(1H,m),1.11(3H,d,J＝6.4Hz)。
实施例119： (3S,4S)-8-(9-(苯并呋喃-7-基乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000171
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:468.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.76(1H,d,J＝6.8Hz),7.68(1H,d,J＝1.6Hz),7.56(1H,d,J＝7.2Hz),7.51(1H,d,J＝1.6Hz),7.31-7.36(2H,m),7.06(1H,d,J＝6.8Hz),4.18-4.25(1H,m),3.90(1H,d,J＝8.4Hz),3.63-3.76(3H,m),3.41-3.46(1H,m),3.07-3.17(2H,m),1.92-2.08(2H,m),1.77-1.82(1H,m),1.68-1.72(1H,m),1.23(3H,d,J＝6.0Hz)。
实施例120： (3S,4S)-8-(9-((1H-吲哚-7-基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000172
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:467.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.98(1H,d,J＝8.0Hz),7.87(1H,d,J＝6.4Hz),7.68(1H,d,J＝1.6Hz),7.65(1H,d,J＝6.8Hz),7.55(1H,d,J＝5.6Hz),7.52(1H,d,J＝1.6Hz),7.48(1H,t,J＝8.0Hz),4.18-4.25(1H,m),3.89(1H,d,J＝8.4Hz),3.63-3.76(3H,m),3.42-3.45(1H,m),3.08-3.17(2H,m),1.93-2.06(2H,m),1.78-1.82(1H,m),1.69-1.72(1H,m),1.22(3H,d,J＝6.4Hz)。
实施例121： (3S,4S)-8-(9-((2-氟-4-甲基苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000173
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:460.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.69(1H,d,J＝1.2Hz),7.54(1H,t,J＝8.0Hz),7.49(1H,d,J＝1.2Hz),7.20(1H,d,J＝10.8Hz),7.11(1H,d,J＝7.6Hz),4.12-4.18(1H,m),3.78(1H,d,J＝8.8Hz),3.59-3.69(3H,m),3.24(1H,d,J＝4.8Hz),3.12-3.20(2H,m),2.36(3H,s),1.90-1.97(2H,m),1.72-1.76(1H,m),1.64-1.68(1H,m),1.15(3H,d,J＝6.8Hz)。
实施例122： (3S,4S)-8-(9-((3-氯-2-(环丙胺基)吡啶-4-基)乙炔基)-7H-咪唑并[1,2-c] 吡唑并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000174
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:518.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.08(1H,d,J＝4.8Hz),7.71(1H,d,J＝1.6Hz),7.50(1H,d,J＝1.6Hz),6.84(1H,d,J＝4.8Hz),4.08-4.13(1H,m),3.73(1H,d,J＝8.4Hz),3.53-3.64(3H,m),3.13-3.25(2H,m),3.10(1H,d,J＝4.8Hz),2.71-2.77(1H,m),1.85-1.97(2H,m),1.69-1.73(1H,m),1.62-1.66(1H,m),1.11(3H,d,J＝6.4Hz),0.65-0.70(2H,m),0.52-0.56(2H,m)。
实施例123： (3S,4S)-8-(9-((4-氯-2,6-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000175
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:498.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.70(1H,d,J＝1.6Hz),7.58(2H,d,J＝7.2Hz),7.50(1H,d,J＝1.6Hz),4.12-4.18(1H,m),3.77(1H,d,J＝8.0Hz),3.58-3.69(3H,m),3.12-3.25(3H,m),1.87-1.97(2H,m),1.72-1.78(1H,m),1.62-1.67(1H,m),1.14(3H,d,J＝6.8Hz)。
实施例124： (3S,4S)-8-(9-((6-氯-2-氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000176
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:480.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.71(1H,d,J＝1.6Hz),7.48-7.55(3H,m),7.37-7.42(1H,m),4.08-4.14(1H,m),3.73(1H,d,J＝8.0Hz),3.54-3.64(3H,m),3.10-3.24(3H,m),1.85-1.97(2H,m),1.69-1.75(1H,m),1.61-1.67(1H,m),1.11(3H,d,J＝6.4Hz)。
实施例125： (3S,4S)-8-(9-(螺[色烷-2,1'-环丁烷]-8-基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000177
参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:500.28[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.20-13.48(1H,brs),8.10-8.30(1H,m),7.64(1H,d,J＝1.6Hz),7.36(1H,d,J＝1.6Hz),7.13(1H,d,J＝7.6Hz),6.83-6.98(1H,m),4.12-4.18(1H,m),3.78(1H,d,J＝9.2Hz),3.50-3.62(3H,m),3.23(1H,d,J＝4.4Hz),3.07-3.17(2H,m),2.81(2H,t,J＝6.0Hz),1.86-2.01(7H,m),1.73-1.77(1H,m),1.52-1.68(4H,m),1.15(3H,d,J＝6.4Hz)。
实施例126： (3S,4S)-8-(9-((2,2-二氟环丙基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000178
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:506.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.19(1H,d,J＝5.2Hz),7.70(1H,d,J＝1.2Hz),7.52(1H,d,J＝1.2Hz),7.14(1H,d,J＝5.2Hz),4.12-4.19(1H,m),3.80(1H,d,J＝8.8Hz),3.60-3.70(3H,m),3.12-3.28(3H,m),2.94(6H,s),1.90-1.99(2H,m),1.73-1.77(1H,m),1.65-1.68(1H,m),1.16(3H,d,J＝6.8Hz)。
实施例127： (3S,4S)-8-(9-((3,5-二氯-2,6-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000179
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:532.13[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝。
实施例128： (3S,4S)-3-甲基-8-(9-((1-苯基环丙基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000180
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:468.25[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝13.64-13.90(brs,1H),7.68(d,J＝1.6Hz,1H),7.54(d,J＝8.4Hz,2H),7.50(d,J＝1.6Hz,1H),7.33(t,J＝8.0Hz,2H),7.21(t,J＝7.2Hz,1H),4.08-4.14(m,1H),3.73(d,J＝8.8Hz,1H),3.50-3.63(m,3H),3.08-3.23(m,3H),1.84-1.99(m,2H),1.60-1.76(m,2H),1.56-1.59(m,2H),1.44-1.47(m,2H),1.12(d,J＝6.4Hz,3H)。
实施例129： (3S,4S)-8-(9-((3,5-二氯苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并[4,3-e] 嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000181
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:496.14[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.75(t,J＝2.0Hz,1H),7.70(d,J＝1.6Hz,1H),7.66(d,J＝2.0Hz,2H),7.55(d,J＝1.6Hz,1H),4.14-4.21(m,1H),3.82(d,J＝9.6Hz,1H),3.58-3.74(m,4H),3.34-3.40(m,1H),3.08-3.21(m,1H),1.86-1.99(m,2H),1.74-1.83(m,1H),1.62-1.71(m,1H),1.18(d,J＝6.0Hz,3H)。
实施例130： (3S,4S)-8-(9-((3-氯2,6-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000182
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:498.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.75-7.81(m,1H),7.70(d,J＝1.6Hz,1H),7.52(d,J＝1.6Hz,1H),7.36(td,J＝8.8Hz,1.6Hz,1H),4.16-4.22(m,1H),3.83(d,J＝9.2Hz,1H),3.62-3.76(m,4H),3.36-3.41(m,1H),3.12-3.20(m,1H),1.86-2.01(m,2H),1.74-1.82(m,1H),1.62-1.71(m,1H),1.18(d,J＝6.8Hz,3H)。
实施例131： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((5-氯-2- 氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000183
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:471.17[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.69(dd,J＝6.0Hz,2.8Hz,1H),7.43-7.47(m,1H),7.23(t,J＝9.2Hz,1H),4.79(s,2H),4.25-4.32(m,1H),3.96(d,J＝9.2Hz,1H),3.68-3.86(m,3H),3.46-3.48(m,1H),3.01-3.16(m,2H),1.96-2.07(m,2H),1.88-1.95(m,1H),1.72-1.79(m,1H),1.31(d,J＝6.4Hz,3H)。
实施例132： (3S,4S)-8-(9-((5-氯-2,4-二氟苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000184
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。 MS m/z[LC-MS]:498.16[M+1]。 1H NMR(400MHz,CD 3OD):δ＝8.07(t,J＝7.6Hz,1H),7.73(d,J＝1.6Hz,1H),7.50(d,J＝1.6Hz,1H),7.27(t,J＝9.2Hz,1H),4.24-4.30(m,1H),3.92(d,J＝8.8Hz,1H),3.74-3.84(m,3H),3.14-3.32(m,3H),1.99-2.10(m,2H),1.86-1.93(m,1H),1.76-1.82(m,1H),1.27(d,J＝6.4Hz,3H)。
实施例133： (3S,4S)-8-(9-((2-氟-4-(三氟甲基)苯基)乙炔基)-7H-咪唑并[1,2-c]吡唑 并[4,3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000185
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:514.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.86-7.92(m.2H),7.71(d,J＝1.6Hz,1H),7.69(d,J＝8.4Hz,1H),7.52(d,J＝1.6Hz,1H),4.10-4.17(m,1H),3.87(d,J＝8.4Hz,1H),3.57-3.70(m,3H),3.12-3.24(m,3H),1.87-1.98(m,2H),1.70-1.79(m,1H),1.62-1.69(m,1H),1.14(d,J＝6.8Hz,3H)。
实施例134： (3S,4S)-3-甲基-8-(9-(3-苯基丙-1-炔-1-基)-7H-咪唑并[1,2-c]吡唑并 [4,3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000186
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:442.24[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.77(d,J＝1.6Hz,1H),7.58(d,J＝1.6Hz,1H),7.21-7.36(m,5H),4.13-4.22(m,1H),4.80(d,J＝6.4Hz,1H),3.58-3.72(m,3H),3.06-3.35(m,5H),1.85-2.01(m,2H),1.73-1.82(m,1H),1.62-1.71(m,1H),1.16(d,J＝6.8Hz,3H)。
实施例135： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,3-二 氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000187
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:455.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.46-7.60(m,2H),7.24-7.34(m,1H),5.58(t,J＝4.8Hz,1H),4.59(d,J＝4.8Hz,2H),4.07-4.16(m,1H), 3.49-3.78(m,4H),2.99-3.36(m,3H),1.77-2.01(m,2H),1.54-1.72(m,2H),1.13(d,J＝6.8Hz,3H)。
实施例136： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((6-氯-2- 氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000188
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:471.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.48-7.56(m,2H),7.37-7.42(m,1H),5.56(t,J＝5.2Hz,1H),4.59(d,J＝5.2Hz,2H),4.11-4.18(m,1H),3.59-3.80(m,4H),3.24-3.26(m,1H),3.01-3.14(m,2H),1.80-1.93(m,2H),1.66-1.75(m,1H),1.55-1.65(m,1H),1.15(d,J＝6.4Hz,3H)。
实施例137： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((4-氯-2- 氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000189
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:471.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.59-7.80(m,2H),7.35-7.48(m,1H),5.50-5.62(brs,1H),4.50-4.64(m,2H),4.04-4.16(m,1H),3.50-3.78(m,4H),2.98-3.18(m,3H),1.75-2.03(m,2H),1.50-1.72(m,2H),1.06-1.15(m,3H)。
实施例138： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,3,6- 三氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000190
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:473.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.61-7.70(m,1H),7.29-7.35(m,1H),5.57(t,J＝5.6Hz,1H),4.58(d,J＝4.2Hz,2H),4.05-4.11(m,1H),3.57-3.72(m,3H),3.53(d,J＝12.8Hz,1H),3.37-3.44(m,1H),3.01-3.21(m,2H), 1.72-1.90(m,2H),1.51-1.68(m,2H),1.09(d,J＝6.0Hz,3H)。
实施例139： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(3,3-二 甲基丁-1-炔-1-基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000191
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:399.25[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝4.85-4.93(m,1H),4.56(d,J＝5.6Hz,2H),4.11-4.20(m,1H),3.57-3.83(m,4H),3.36-3.44(m,1H),3.16-3.22(m,2H),1.78-1.92(m,2H),1.52-1.66(m,2H),1.32(s,9H),1.15(d,J＝6.4Hz,3H)。
实施例140： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3,5-二 氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000192
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:455.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.36-7.44(m,3H),5.56(t,J＝6.0Hz,1H),4.59(d,J＝4.2Hz,2H),4.06-4.16(m,1H),3.75(d,J＝8.8Hz,1H),3.50-3.72(m,3H),3.02-3.18(m,3H),1.77-1.92(m,2H),1.64-1.72(m,1H),1.55-1.62(m,1H),1.13(d,J＝6.0Hz,3H)。
实施例141： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((4-氯 -2,6-二氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000193
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:488.15[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.57-7.61(m,2H),5.62(t,J＝5.6Hz,1H),4.58(d,J＝5.6Hz,2H),4.13-4.20(m,1H),3.68-3.84(m,2H),3.64(d,J＝9.2Hz,1H),3.34-3.38(m,1H),3.28-3.30(m,1H),2.97-3.11(m,2H), 1.83-1.92(m,2H),1.70-1.78(m,1H),1.57-1.65(m,1H),1.18(d,J＝6.8Hz,3H)。
实施例142： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,3,5,6- 四氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000194
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:491.18[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.51-7.60(m,1H),4.78(s,2H),4.23-4.29(m,1H),3.90(d,J＝9.2Hz,1H),3.68-3.80(m,3H),3.06-3.26(m,3H),1.92-2.04(m,2H),1.80-1.88(m,1H),1.70-1.77(m,1H),1.26(d,J＝7.2Hz,3H)。
实施例143： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氟-3- 甲氧基苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000195
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:467.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.26-7.30(m,1H),7.18-7.22(m,2H),5.59(t,J＝5.6Hz,1H),4.58(d,J＝5.6Hz,2H),4.12-4.18(m,1H),3.86(s,3H),3.64-3.81(m,3H),3.60(d,J＝8.8Hz,1H),3.23-3.27(m,1H),2.99-3.11(m,2H),1.82-1.92(m,2H),1.66-1.74(m,1H),1.57-1.63(m,1H),1.16(d,J＝6.0Hz,3H)。
实施例144： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,6-二 氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000196
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:455.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.53-7.61(m,1H),7.25-7.30(m,2H),5.61(t,J＝5.6Hz,1H),4.58(d,J＝5.6Hz,2H),4.12-4.18(m,1H), 3.65-3.82(m,3H),3.60(d,J＝8.8Hz,1H),3.27(d,J＝4.4Hz,1H),3.01-3.14(m,2H),1.84-1.94(m,2H),1.68-1.74(m,1H),1.58-1.64(m,1H),1.17(d,J＝6.0Hz,3H)。
实施例145： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,4-二 氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000197
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:455.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.73-7.79(m,1H),7.47(td,J＝9.6Hz,2.4Hz,1H),7.18-7.22(m,1H),5.58(t,J＝5.6Hz,1H),4.58(d,J＝5.6Hz,2H),4.10-4.16(m,1H),3.77(d,J＝8.8Hz,1H),3.62-3.75(m,2H),3.58(d,J＝8.8Hz,1H),3.20(d,J＝4.8Hz,1H),3.01-3.14(m,2H),1.80-1.92(m,2H),1.64-1.72(m,1H),1.55-1.63(m,1H),1.14(d,J＝6.4Hz,3H)。
实施例146： (3S,4S)-8-(3-((5-氯-2-氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并[3,4-b] 吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000198
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:473.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.81(dd,J＝6.4Hz,2.8Hz,1H),7.57-7.61(m,1H),7.44(t,J＝8.8Hz,1H),5.54(d,J＝48.0Hz,2H),4.12-4.18(m,1H),3.80(d,J＝8.8Hz,1H),3.48-3.62(m,3H),3.26(d,J＝4.4Hz,1H),3.02-3.14(m,2H),1.84-1.96(m,2H),1.68-1.74(m,1H),1.58-1.65(m,1H),1.16(d,J＝6.0Hz,3H)。
实施例147： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2,4,5- 三氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000199
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:473.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.89-7.96(m,1H),7.74-7.81(m,1H),5.58(t,J＝6.0Hz,1H),4.58(d,J＝5.6Hz,2H),4.10-4.16(m,1H),3.62-3.79(m,3H),3.58(d,J＝8.8Hz,1H),3.21(d,J＝4.8Hz,1H),3.01-3.12(m,2H),1.80-1.92(m,2H),1.65-1.72(m,1H),1.56-1.63(m,1H),1.14(d,J＝6.8Hz,3H)。
实施例148： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氯 -3,6-二氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000200
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:489.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.59-7.65(m,1H),7.45-7.50(m,1H),5.60(t,J＝6.0Hz,1H),4.59(d,J＝6.0Hz,2H),4.15-4.21(m,1H),3.70-3.85(m,3H),3.66(d,J＝8.8Hz,1H),3.39(d,J＝4.8Hz,1H),2.98-3.10(m,2H),1.84-1.92(m,2H),1.72-1.78(m,1H),1.57-1.64(m,1H),1.18(d,J＝6.8Hz,3H)。
实施例149： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氟-4- 甲基苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000201
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:451.23[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.55(t,J＝7.6Hz,1H),7.21(d,J＝7.2Hz,1H),7.10(d,J＝7.2Hz,1H),5.60(t,J＝5.6Hz,1H),4.58(d,J＝5.6Hz,2H),4.10-4.16(m,1H),3.64-3.81(m,3H),3.61(d,J＝8.4Hz,1H),3.26-3.30(m,1H),2.98-3.01(m,2H),2.35(s,3H),1.82-1.92(m,2H),1.68-1.75(m,1H),1.57-1.62(m,1H),1.16(d,J＝6.4Hz,3H)。
实施例150： (3S,4S)-8-(3-((4-氯-2,6-二甲氧基苯基)乙炔基)-5-(甲氧基甲基)-1H- 吡唑并[3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000202
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:527.22[M+1]。 1H NMR(400MHz,CD 3OD):δ＝6.72(s,2H),4.62(s,2H),4.19-4.25(m,1H),3.88(s,6H),3.84(d,J＝8.4Hz,1H),3.64-3.72(m,3H),3.49(s,3H),3.09-3.27(m,2H),3.02(d,J＝5.2Hz,1H),1.87-2.04(m,2H),1.68-1.79(m,2H),1.20(d,J＝6.0Hz,3H)。
实施例151： (3S,4S)-8-(3-((4-氯-2,6-二氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并 [3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000203
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:491.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.57-7.61(m,2H),5.54(d,J＝47.6Hz,2H),4.07-4.13(m,1H),3.72(d,J＝8.4Hz,1H),3.45-3.58(m,3H),3.04-3.08(m,3H),1.78-1.94(m,2H),1.64-1.72(m,1H),1.55-1.63(m,1H),1.11(d,J＝6.4Hz,3H)。
实施例152： (3S,4S)-8-(3-((4-氯-2-氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并[3,4-b] 吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000204
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:473.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.73(t,J＝8.0Hz,1H),7.65(dd,J＝9.6Hz,2.0Hz,1H),7.38(dd,J＝8.0Hz,2.0Hz,1H),5.54(d,J＝48.0Hz,2H),4.08-4.14(m,1H),3.73(d,J＝8.4Hz,1H),3.46-3.58(m,3H),3.04-3.18(m,3H),1.79-1.93(m,2H),1.64-1.73(m,1H),1.55-1.63(m,1H),1.12(d,J＝6.4Hz,3H)。
实施例153： (3S,4S)-8-(3-((2-氟-3-甲氧基苯基)乙炔基)-5-(氟甲基)-1H-吡唑并 [3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000205
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:469.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.24-7.32(m,1H),7.17-7.23(m,2H),5.54(d,J＝48.0Hz,2H),4.09-4.15(m,1H),3.86(s,3H),3.74(d,J＝8.8Hz,1H),3.46-3.60(m,3H),3.02-3.19(m,3H),1.76-1.94(m,2H),1.65-1.73(m,1H),1.55-1.64(m,1H),1.12(d,J＝6.4Hz,3H)。
实施例154： (3S,4S)-8-(3-((2-氯-3,6-二氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并 [3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000206
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:491.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.59-7.65(m,1H),7.45-7.51(m,1H),5.55(d,J＝47.6Hz,2H),4.13-4.19(m,1H),3.81(d,J＝9.2Hz,1H),3.50-3.65(m,3H),2.98-3.14(m,3H),1.84-1.95(m,2H),1.70-1.77(m,1H),1.58-1.66(m,1H),1.17(d,J＝6.4Hz,3H)。
实施例155： (3S,4S)-8-(3-((3,5-二氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并[3,4-b]吡 嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000207
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:457.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.38-7.44(m,3H),5.54(d,J＝47.6Hz,2H),4.08-4.15(m,1H),3.74(d,J＝9.2Hz,1H),3.46-3.60(m,3H),3.02-3.20(m,3H),1.79-1.93(m,2H),1.66-1.74(m,1H),1.55-1.64(m,1H),1.13(d,J＝ 6.4Hz,3H)。
实施例156： (3S,4S)-8-(3-((2-氯-6-氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并[3,4-b] 吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000208
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:473.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.48-7.56(m,2H),7.38-7.43(m,1H),5.54(d,J＝47.6Hz,2H),4.11-4.18(m,1H),3.79(d,J＝8.8Hz,1H),3.49-3.63(m,3H),3.02-3.15(m,3H),1.83-1.95(m,2H),1.69-1.76(m,1H),1.57-1.65(m,1H),1.16(d,J＝6.4Hz,3H)。
实施例157： (3S,4S)-8-(3-((2,4-二氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并[3,4-b]吡 嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000209
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:457.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.75-7.81(m,1H),7.44-7.50(m,1H),7.18-7.22(m,1H),5.54(d,J＝48.0Hz,2H),4.06-4.12(m,1H),3.70(d,J＝8.4Hz,1H),3.44-3.56(m,3H),3.02-3.20(m,3H),1.76-1.92(m,2H),1.54-1.70(m,2H),1.10(d,J＝6.0Hz,3H)。
实施例158： (3S,4S)-8-(5-(氟甲基)-3-((2,4,5-三氟苯基)乙炔基)-1H-吡唑并[3,4-b] 吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000210
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:475.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.92-7.98(m,1H),7.74-7.80(m,1H),5.54(d,J＝47.6Hz,2H),4.10-4.16(m,1H),3.76(d,J＝8.8Hz,1H), 3.48-3.60(m,3H),3.02-3.16(m,2H),3.18(d,J＝5.2Hz,1H),1.80-1.94(m,2H),1.65-1.73(m,1H),1.56-1.64(m,1H),1.14(d,J＝6.4Hz,3H)。
实施例159： (3S,4S)-8-(5-(氟甲基)-3-((2,3,6-三氟苯基)乙炔基)-1H-吡唑并[3,4-b] 吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000211
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:475.19[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.62-7.71(m,1H),7.29-7.35(m,1H),5.54(d,J＝48.0Hz,2H),4.08-4.15(m,1H),3.74(d,J＝8.8Hz,1H),3.48-3.60(m,3H),3.04-3.18(m,3H),1.79-1.94(m,2H),1.66-1.73(m,1H),1.56-1.64(m,1H),1.13(d,J＝6.8Hz,3H)。
实施例160： (3S,4S)-8-(3-((2-氟-4-甲基苯基)乙炔基)-5-(氟甲基)-1H-吡唑并[3,4-b] 吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000212
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:453.22[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.56(t,J＝7.6Hz,1H),7.21(d,J＝7.2Hz,1H),7.10(d,J＝7.6Hz,1H),5.54(d,J＝48.0Hz,2H),4.09-4.15(m,1H),3.75(d,J＝9.2Hz,1H),3.46-3.60(m,3H),3.02-3.19(m,3H),2.35(s,3H),1.81-1.85(m,2H),1.66-1.72(m,1H),1.57-1.64(m,1H),1.13(d,J＝6.4Hz,3H)。
实施例161： (3S,4S)-8-(3-((2,6-二氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并[3,4-b]吡 嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000213
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。 MS m/z[LC-MS]:457.20[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.54-7.63(m,1H),7.25-7.32(m,2H),5.55(d,J＝47.6Hz,2H),4.13-4.19(m,1H),3.81(d,J＝8.8Hz,1H),3.50-3.64(m,3H),3.26-3.32(m,1H),3.02-3.12(m,2H),1.85-1.98(m,2H),1.69-1.76(m,1H),1.59-1.66(m,1H),1.18(d,J＝6.0Hz,3H)。
实施例162： (3S,4S)-8-(5-(氟甲基)-3-((2,3,5,6-四氟苯基)乙炔基)-1H-吡唑并[3,4-b] 吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000214
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:493.18[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.03-8.12(m,1H),5.54(d,J＝47.6Hz,2H),4.09-4.15(m,1H),3.76(d,J＝8.8Hz,1H),3.47-3.60(m,3H),3.04-3.21(m,3H),1.80-1..94(m,2H),1.66-1.73(m,1H),1.56-1.64(m,1H),1.13(d,J＝6.4Hz,3H)。
实施例163： (3S,4S)-8-(3-((2-氯-4,6-二氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并 [3,4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000215
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:491.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.54-7.63(m,2H),5.54(d,J＝47.6Hz,2H),4.08-4.14(m,1H),3.73(d,J＝8.4Hz,1H),3.46-3.58(m,3H),3.03-3.18(m,3H),1.78-1.92(m,2H),1.65-1.72(m,1H),1.55-1.63(m,1H),1.12(d,J＝6.8Hz,3H)。
实施例164： (6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氯 -4,6-二氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000216
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:489.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.53-7.62(m,2H),5.52(t,J＝5.4Hz,1H),4.58(d,J＝5.4Hz,2H),4.06-4.12(m,1H),3.57-3.72(m,3H),3.53(d,J＝8.4Hz,1H),3.04-3.19(m,3H),1.75-1.90(m,2H),1.53-1.68(m,2H),1.10(d,J＝6.4Hz,3H)。
实施例165： (3S,4S)-8-(3-((2,3-二氟苯基)乙炔基)-5-(氟甲基)-1H-吡唑并[3,4-b]吡 嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000217
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:457.48[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.48-7.60(m,2H),7.27-7.32(m,1H),5.54(d,J＝48.0Hz,2H),4.06-4.13(m,1H),3.72(d,J＝9.2Hz,1H),3.45-3.56(m,3H),3.04-3.20(m,3H),1.76-1.94(m,2H),1.54-1.71(m,2H),1.11(d,J＝6.4Hz,3H)。
实施例167： (S)-(6-(7-氨基-5,7-二氢螺[环戊烷[b]吡啶-6,4'-哌啶]-1'-基)-3-((2-氯 -4,6-二氟苯基)乙炔基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000218
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:522.16[M+1]。 1H NMR(400MHz,CD 3OD):δ＝8.36(m,1H),7.71(m,1H),7.27(m,2H),7.13(m,1H),4.79(s,2H),4.07(m,1H),3.77(m,2H),3.06-3.16(m,3H),2.90-2.95(m,1H),1.95-2.10(m,2H),1.63-1.77(m,1H),1.42-1.57 (m,1H)。
实施例168： (3-((2-氨基-3-氯吡啶-4-基)硫代)-6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8- 氮杂螺[4.5]癸烷-8-基)-1H-吡唑并[3,4-b]吡嗪-5-基)甲醇
Figure PCTCN2020137662-appb-000219
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:477.16[M+1]。 1H NMR(400MHz,CDCl 3):δ＝7.60(d,J＝5.4Hz,2H),5.86(d,J＝5.4Hz,2H),5.52(t,J＝5.4Hz,1H),5.20(brs,2H),4.60(d,J＝5.4Hz,2H),4.08-4.14(m,1H),3.57-3.72(m,3H),3.52(m,1H),3.05-3.19(m,3H),1.75-1.91(m,2H),1.52-1.68(m,2H),1.12(d,J＝6.4Hz,3H)。
实施例169： 2-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-((2-氯 -4,6-二氟苯基)乙炔基)-3-甲基-3,7-二氢-4H-吡咯并[2,3-d]嘧啶-4-酮
Figure PCTCN2020137662-appb-000220
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:488.17[M+1]。 1H NMR(400MHz,CD 3OD):δ＝7.25-7.7.30(1H,m),7.10-7.14(1H,m),6.93(1H,s),4.05-4.12(1H,m),3.70(1H,d,J＝8.4Hz),3.50(1H,d,J＝8.8Hz),3.32-3.61(1H,m),3.18(3H,s),3.10-3.14(1H,m),3.04-3.08(1H,m),2.88-3.00(2H,m),1.73-1.86(2H,m),1.60-1.65(1H,m),1.51-1.58(1H,m),1.09(3H,d,J＝6.4Hz)。
实施例170： (3S,4S)-8-(7-((2-氯-4,6-二氟苯基)乙炔基)-5H-吡咯并[2,3-b]吡嗪-3- 基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000221
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:458.17[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝8.24(1H,s),7.24-7.30(1H,m),7.09-7.13(1H,m),6.88(1H,s),4.17-4.23(1H,m),3.95-4.06(2H,m),3.81(1H,d,J＝8.4Hz),3.71(1H,d,J＝8.4Hz),3.52-3.60(1H,m),3.41-3.49(1H,m),3.02(1H,d,J＝4.0Hz),1.89-2.02(2H,m),1.66-1.77(2H,m),1.22(3H,d,J＝6.8Hz)。
实施例171： (3S,4S)-8-(8-((2-氯4,6-二氟苯基)乙炔基)-6H-二吡唑并[1,5-a:3',4'-e] 吡嗪-4-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000222
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:498.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.60(1H,J＝1.6Hz,d),7.30-7.36(1H,m),7.14-7.19(1H,m),7.06(1H,J＝1.6Hz,d),4.17-4.24(1H,m),3.84(1H,J＝9.2Hz,d),3.61-3.77(4H,m),3.35-3.40(1H,m),3.12-3.29(1H,m),1.86-2.01(2H,m),1.73-1.82(1H,m),1.62-1.70(1H,m),1.19(3H,J＝6.8Hz,d)。
实施例172： (3S,4S)-8-(8-((2-氯4,6-二氟苯基)乙炔基)-1,6-二氢咪唑并[4,5-d]吡唑 并[3,4-b]吡啶-4-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000223
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:498.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝7.44(1H,s),7.31(1H,m),7.13-7.18(1H,m),4.15-4.22(1H,m),3.82(1H,J＝9.4Hz,d),3.61-3.76(4H,m),3.34-3.40(1H,m),3.10-3.20(1H,m),1.85-2.00(2H,m),1.72-1.81(1H,m),1.61-1.70(1H,m),1.18(3H,J＝6.8Hz,d)。
实施例173： (3S,4S)-8-(9-((2-氯4,6-二氟苯基)乙炔基)-7H-吡唑并[4',3':5,6]吡啶并 [4,3-d]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
Figure PCTCN2020137662-appb-000224
参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]:510.16[M+1]。 1H NMR(400MHz,DMSO-d 6):δ＝9.13(1H,s),8.44(1H,s),7.35(1H,m),7.15-7.20(1H,m),4.17-4.23(1H,m),3.84(1H,J＝9.2Hz,d),3.64-3.78(4H,m),3.15-3.42(2H,m),1.89-2.04(2H,m),1.64-1.83(2H,m),1.19(3H,J＝6.8Hz,d)。
化合物对SHP2的体外酶学活性抑制作用的测定
本专利中SHP2的酶学活性检测采用快速荧光法进行，使用DiFMUP作为替代底物进行反应并且优化建立了高通量的筛选平台。化合物对SHP2的抑制活性的检测在此平台进行操作。具体方法如下：将终浓度1nM的SHP2与2.5μM的二磷酸化的IRS1肽段(序列:H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide)混合物在23℃预孵育30分钟。将化合物从0.2mM开始用100％DMSO进行5倍的梯度稀释(共7个浓度)，每个浓度取2μL的化合物加入48μL的反应缓冲液(60mM HEPES，pH7.2,75mM NaCl，75mM KCl，1mM EDTA，0.05％Tween 20,5mM DTT)中进行稀释 混匀。取5μL稀释后的化合物加入黑色384孔板中(OptiPlate-384,货号6007270，购买于PerkinElmer)，然后加入10μL的预孵育的SHP2和IRS1肽段混合液，离心混匀,23℃孵育30分钟。加入5μL替代底物DiFMUP(终浓度50μM,货号D6567，购买于Invitrogen)加入反应中并在23℃下孵育60分钟。然后通过加入5μL 160μMbpV(Phen)溶液(SC-22137,购买于Santa)终止反应。反应终止后立即使用酶标仪(Perkin-Elmer)分别在340nm和450nm的激发和发射波长检测测荧光信号，数据使用GraphPad Prism软件计算得到该化合物的IC 50值。经检测发现，本发明实施例中的具体化合物均具备SHP2体外酶学抑制活性，IC 50值位于0.1nM至1uM的区间，例举部分化合物的活性见表1：
表1 实施例中部分化合物对SHP2酶抑制活性
实施例 IC 50(nM)
3 6.73
7 2.35
17 2.18
26 1.23
49 3.24
50 3.64
51 3.22
58 8.62
60 0.712
61 2.22
63 0.871
64 2.18
75 3.43
82 2.99
90 1.00
106 3.95
139 4.44
144 2.34
149 1.38
161 5.07
164 1.29
165 5.47
166 4.77
167 10.4
168 3.16
169 8.54
170 10.2
171 2.25
172 3.16
173 5.18
化合物对SHP2阳性细胞增殖抑制作用的测定
人非小细胞肺癌细胞系NCI-H358细胞使用RPMI-1640培养基(货号C11875500BT，购买于Biological Industries)加10％的胎牛血清(FBS，货号04-001-1ACS，购买于Biological Industries，BI)和1％青霉素/链霉素双抗(P/S，货号15070-063，购买于Gibco)进行培养，培养条件为37℃，5％CO2。进行化合物检测的前一天，将NCI-H358细胞以2000个细胞/195μL/孔的浓度铺于196孔板(货号3917，购买于Corning)中。24小时后将化合物从10mM开始用100％DMSO进行3倍的梯度稀释(共10个浓度)，然后每个浓度取2μL的化合物加入48μL的不含血清和双抗的培养基中进行稀释。稀释后的化合物每个浓度取5μL加入铺好的细胞悬液中，将化合物与细胞在细胞培养箱中共孵育72小时(3天)，吸尽培养基后加入25μL的Cell-Titer Glo(G7570，购买于Promega)试剂再次孵育5-10分钟。之后在Envision上读取荧光值，数据使用GraphPad Prism软件计算得到该化合物对细胞增殖的抑制的IC 50值。人急性成髓细胞白血病细胞系Kasumi-1细胞使用RPMI-1640培养基(货号C11875500BT，购买于Biological Industries)加20％的胎牛血清(FBS，货号04-001-1ACS，购买于Biological Industries，BI)和1％青霉素/链霉素双抗(P/S，货号15070-063，购买于Gibco)进行培养，培养条件为37℃，5％CO2。进行化合物检测的前一天，将Kasumi-1细胞以3000个细胞/195μL/孔的浓度铺于196孔板(货号3599，购买于Corning)中。24小时后将化合物从10mM开始用100％DMSO进行3倍的梯度稀释(共10个浓度)，然后每个浓度取2μL的化合物加入48μL的不含血清和双抗的培养基中进行稀释。稀释后的化合物每个浓度取5μL加入铺好的细胞悬液中，将化合物与细胞在细胞培养箱中共孵育72小时(3天)，加入35μL的Cell-Titer Blue(G8082，购买于Promega)试剂再次孵育4小时。之后在Flexstation III上读取荧光值(560nm激发，590nm检测)，数据使用GraphPad Prism软件计算得到该化合物对细胞增殖的抑制的IC 50值。部分化合物检测结果见表2。
表2 实施例化合物对细胞(NCI-H358)增殖抑制活性
实施例 IC 50(nM)
3 374
7 315
17 389
26 178
49 310
50 382
51 376
58 236
60 370
61 366
63 359
64 251
75 77.8
82 85
90 101
106 77
139 26.5
144 84
149 126
161 82.3
164 59
165 103
166 258
167 261
168 150
表1-2的试验数据表明，本发明提供的化合物具有很好的SHP2激酶抑制活性，同时对SHP2阳性表达细胞的增殖也有很好的抑制活性。
工业实用性
本发明提供一种式I所示取代的炔基杂环化合物。本发明提供了具有SHP2抑制活性的取代的炔基杂环化合物、其制备方法、其药物组合物，还提供这类化合物及其药物组合物治疗受益于SHP2酶抑制的疾病的用途，例如治疗癌症。所述式I化合物通过碘代、胺化、上保护、偶联、脱保护、闭环反应等反应制备得到。本发明提供的炔基杂环类化合物具有非常好的SHP2抑制活性，有望成为高效的SHP2抑制剂类药物，具有较好的经济价值和应用前景。

Claims (13)

  1. 式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，
    Figure PCTCN2020137662-appb-100001
    A选自如下两并杂环或三并杂环：
    Figure PCTCN2020137662-appb-100002
    R 1选自氢、卤素、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基可任选地被卤素、-OH、或-O-C 1-6烷基取代，
    R 2选自氢、C 1-6烷基和C 3-6环烷基，
    X选自氢、C 1-6烷基、C 2-6烯基、C 3-8环烷基、C 3-8杂脂环基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 3-8环烷基和C 3-8杂脂环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-CF 3、-NH 2、C 1-6烷基、或者苯基取代，所述C 6-10芳基和5-10元杂芳基可与不饱和脂环、杂脂环、或螺环稠合，并且可任选地被一个或多个卤素、-CF 3、-OH、-CN、R、-OR、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-(CO)NH 2、C 6-10芳基、-O-C 6-10芳基、或者C 5-10杂芳基取代，所述不饱和脂环、杂脂环、或者螺环可任选地被一个或多个卤素、-CF 3、-OH、-CN、R、-OR、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-(CO)NH 2、C 6-10芳基、-O-C 6-10芳基、C 5-10杂芳基、或＝O取代，
    R选自C 1-6烷基和C 3-6环烷基，所述烷基和环烷基可任选地被卤素、-CF 3、-OH、-C 1-6烷基、-O-C 1-6烷基、或者C 3-6环烷基取代，
    R 3和R 4各自独立地选自氢、C 1-6烷基和C 3-6环烷基，
    Y选自C 6-10芳基、5-10元杂芳基、C 3-12杂脂环基和5-15元螺环基，所述芳基、杂芳基、杂脂环基和螺环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C 1-6烷 基、或-NH 2取代，所述杂脂环基和螺环基可任选地与6-10元芳基或者5-10元杂芳基稠和，与杂脂环基和螺环基稠和的芳基或者杂芳基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，
    Z选自单键、-S-和-C≡C-。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其具有下式II～XIII：
    Figure PCTCN2020137662-appb-100003
    其中，
    R 1选自氢、卤素、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基和C 3-6环烷基可任选地被卤素、-OH、或-O-C 1-6烷基取代，
    R 2选自氢、C 1-6烷基和C 3-6环烷基，
    X选自氢、C 1-6烷基、C 2-6烯基、C 3-8环烷基、C 3-8杂脂环基、C 6-10芳基和5-10元杂芳基，所述C 1-6烷基、C 2-6烯基、C 3-8环烷基和C 3-8杂脂环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-CF 3、-NH 2、C 1-6烷基、或者苯基取代，所述C 6-10芳基和5-10元杂芳基可与不饱和脂环、杂脂环、或螺环稠合，并且可任选地被一个或多个卤素、-CF 3、-OH、-CN、R、-OR、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-(CO)NH 2、C 6-10芳基、-O-C 6-10芳基、或者C 5-10杂芳基取代，所述不饱和脂环、杂脂环、或者螺环可任选地被一个或多个卤素、-CF 3、-OH、-CN、R、-OR、-NR 3R 4、-O-C(O)NR 3R 4、-NH-(CO)-C 1-6烷基、-S-CH 2-(CO)NH 2、C 6-10芳基、-O-C 6-10芳基、C 5-10杂芳基、或＝O取代，
    R选自C 1-6烷基和C 3-6环烷基，所述烷基和环烷基可任选地被卤素、-CF 3、-OH、-C 1-6烷基、-O-C 1-6烷基、或者C 3-6环烷基取代，
    R 3和R 4各自独立地选自氢、C 1-6烷基和C 3-6环烷基，
    Y选自C 6-10芳基、5-10元杂芳基、C 3-12杂脂环基和5-15元螺环基，所述芳基、杂芳基、杂脂环基和螺环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C 1-6烷基、或-NH 2取代，所述杂脂环基和螺环基可任选地与6-10元芳基或者5-10元杂芳基稠和，与杂脂环基和螺环基稠和的芳基或者杂芳基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其特征在于，所述5-15元螺环基为5-15元螺杂环基，所述螺杂环基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C 1-6烷基、或-NH 2取代，所述螺杂环基可任选地与6-10元芳基或者5-10元杂芳基稠和，与螺杂环基稠和的芳基或者杂芳基可任选地被一个或多个卤素、-OH、-O-C 1-6烷基、-NH 2、C 1-6烷基、或C 3-6环烷基取代。
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其特征在于，所述5-10元杂芳基为C 5-10杂芳基。
  5. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其特征在于，所述Y选自如下结构：
    Figure PCTCN2020137662-appb-100004
    X 1、X 2和X 2各自独立地选自键、O、CR aR b或NR c；
    R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、-OH、卤素、取代或未取代的氨基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基；且不能同时为-OH或-NH 2；
    R a、R b和R c各自独立地选自H、-OH、卤素、取代或未取代的氨基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基；
    环A选自取代或未取代的C 4-8环烃基、取代或未取代的4-8元杂环基、取代或未取代的C 5-10芳基、取代或未取代的5-10元杂芳基，所述杂环基或杂芳基包含1-3个选自下组的杂原子：N、O、S或P；
    R 13和R 14选自H、-OH、卤素、氰基、取代或未取代的氨基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基；
    n为0至3中的任一整数；
    所述取代是指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、-OH、-NO 2、-NH 2、-CN。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其特征在于，X 1和X 2中的一个为O，X 3为键。
  7. 根据权利要求5所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其特征在于，X 1和X 2中的一个为CH 2，另一个为键。
  8. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其中Y选自C 6-10芳基、5-10元杂芳基和C 3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个-OH、-NH 2、或C 1-6烷基取代；
    优选地，所述5-10元杂芳基为C 5-10杂芳基。
  9. 根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其中Y选自C 3-12杂脂环基，所述杂脂环基可任选地被一个或多个-OH、-NH 2、或C 1-6烷基取代。
  10. 以下化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体：
    Figure PCTCN2020137662-appb-100005
    Figure PCTCN2020137662-appb-100006
    Figure PCTCN2020137662-appb-100007
    Figure PCTCN2020137662-appb-100008
    Figure PCTCN2020137662-appb-100009
    Figure PCTCN2020137662-appb-100010
    Figure PCTCN2020137662-appb-100011
  11. 一种药物组合物，其包含根据权利要求1-10中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，并任选地包含药学上可接受的辅料。
  12. 权利要求1-10中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、互变异构体、权利要求11所述的药物组合物、或者权利要求1-10中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、互变异构体或权利要求11所述的药物组合物与SHP2抑制剂或KRAS抑制剂或EGFR抑制剂联合在制备治疗与SHP2和/或KRAS和/或EGFR相关的疾病的药物中的用途。
  13. 根据权利要求12所述的用途，其中所述与SHP2和/或KRAS和/或EGFR相关的疾病为白血病、黑色素瘤、恶性胶质瘤、肺癌、乳腺癌或努男综合症。
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