WO2024041519A1 - Morpholinyl quinazoline compound, and pharmaceutical composition and use thereof - Google Patents

Morpholinyl quinazoline compound, and pharmaceutical composition and use thereof Download PDF

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Publication number
WO2024041519A1
WO2024041519A1 PCT/CN2023/114208 CN2023114208W WO2024041519A1 WO 2024041519 A1 WO2024041519 A1 WO 2024041519A1 CN 2023114208 W CN2023114208 W CN 2023114208W WO 2024041519 A1 WO2024041519 A1 WO 2024041519A1
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heteroatoms
compound
alkylene
group
substituted
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PCT/CN2023/114208
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French (fr)
Chinese (zh)
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许祖盛
楼杨通
谢铁刚
许林林
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上海璎黎药业有限公司
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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to a morpholinoquinazoline compound, its pharmaceutical composition and application
  • PI3K Phosphatidylinositol 3-kinase (phosphatidylinositol 3-kinase), which is involved in the regulation of various cell functions such as cell proliferation, differentiation, apoptosis and glucose transport.
  • PI3K can be divided into class I, class II and class III kinases, and the most widely studied is class I PI3K that can be activated by cell surface receptors.
  • Class I PI3K in mammalian cells is further divided into class Ia and class Ib based on structure and receptor, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors respectively.
  • Class Ia PI3K includes PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ subtypes
  • class Ib PI3K includes PI3K ⁇ subtype (Trends. Biochem. Sci., 1997, 22, 267-272).
  • Class Ia PI3K is a dimer protein composed of the catalytic subunit p110 and the regulatory subunit p85. It has dual activities of lipid kinase and protein kinase (Nat.Rev.Cancer 2002, 2, 489-501), and is considered to be related to cell proliferation. Associated with cancer development, immune disorders and diseases involving inflammation.
  • Linperlisib (YY-20394), chemical name is N-(5-(6-fluoro-8-((4-(2-hydroxypropyl-2-yl)piperidin-1-yl)methyl)-2- Morphinolquinazolin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide is a new type of PI3K ⁇ inhibitor.
  • Clinical studies have shown that in patients with relapsed and/or refractory B-cell hematological malignancies, Linperlisib showed good safety and clinical benefits when administered orally at 80 mg once daily for 4 weeks.
  • Histone deacetylases are an important class of epigenetic enzymes that regulate gene expression by removing acetyl groups from N-terminal lysine residues on histones. HDACs are closely related to the occurrence and development of tumors. Inhibiting HDACs can inhibit the proliferation of tumor cells and induce cell differentiation and/or apoptosis by increasing the acetylation degree of intracellular histones and increasing the expression levels of p21 and other genes. . Currently, multiple histone deacetylase inhibitors have been approved for marketing, such as Vorinostat, Panobinostat, etc.
  • the present invention provides a morpholinoquinazoline compound, its pharmaceutical composition and application.
  • the morpholinoquinazoline compound of the present invention has dual inhibitory activities of PI3K ⁇ inhibitor and HDAC, and is expected to achieve better curative effect and wider application.
  • the invention provides a morpholinoquinazoline compound shown in formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug,
  • R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
  • R 2 is hydrogen or -OC 1-4 alkyl
  • A, C and E are independently connecting bonds, or, -(U 1 ) n1 -(R L-1 ) n2 -(U 2 ) n3 -(R L-2 ) n4 -(U 3 ) n5 -(R L-3 ) n6 -;
  • U 1 , U 2 and U 3 are independently -O-, -S-, -NH- or -NR 3 -, and R 3 is C 1-6 alkyl;
  • R L-1 , R L-2 and R L-3 are independently C 1-6 alkylene, C 2-6 alkenyl or C 2-6 alkynyl;
  • n1, n3 and n5 are independently 0 or 1;
  • n2, n4 and n6 are independently 0, 1, 2, 3 or 4;
  • B and D are independently a connecting bond, C 3-10 cycloalkyl, C 3-10 cycloalkyl substituted by one or more R 1-1 , "containing "4-10 membered heterocycloalkyl” containing 1 to 3 heteroatoms, the heteroatoms are selected from O and N, "containing 1 to 3 heteroatoms, substituted by one or more R 1-2 , the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl", C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from "Heteroaryl group consisting of 5 to 12 members from O, S and N," substituted by one or more R 1-4 "contains 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12 members of O, S and N.
  • Heteroaryl "8-12 membered benzoheterocyclenyl containing 1 to 3 heteroatoms independently selected from O, S and N", "substituted by one or more R 1-5 Containing 1 to 3 heteroatoms, the heteroatoms are independently selected from O, S and N 8-12-membered benzoheterocyclenyl", 5-7-membered cycloalkenyl, or, by one or more R 1- 6- substituted 5-7 membered cycloalkenyl; when there are multiple substituents, they may be the same or different;
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently halogen or C 1-6 alkyl.
  • U1 is O
  • n1 is 1
  • n2, n3, n4, n5 and n6 are all 0.
  • A is -O-.
  • A is -O-, C 1-6 alkylene, -OC 1-6 alkylene, or C 1-6 alkylene-NH-.
  • B is a connecting bond, C 3-10 cycloalkyl group, containing 1-3 heteroatoms, and the heteroatoms are selected from 4-10 membered heterocycloalkyl groups of O and N, surrounded by one or more R 1-2 substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from O and N", C 6-20 aryl substituted by one or more R 1-3 , 5-12 membered heteroaryl containing 1 to 4 heteroatoms selected from O, S and N, "containing 1 to 4 heteroatoms selected from one or more R 1-4 ""5-12 membered heteroaryl group of O, S and N", or "heteroaryl group substituted by one or more R 1-5 " contains 1 to 3 heteroatoms, and the heteroatoms are independently selected from 8 of O, S and N ⁇ 12-membered benzoheterocyclenyl”.
  • C is a bond, C 1-6 alkylene, C 2-6 alkenyl, -OC 1-6 alkylene, -OC 1-6 alkylene -OC 1-6 alkylene base, -C 1-6 alkylene -OC 1-6 alkylene or C 1-6 alkylene -NH-.
  • D is a linkage, C 6-20 aryl, C 6-20 aryl substituted by one or more R 1-3 , C 3-10 cycloalkyl, substituted by one or more R 1-4 substituted 5- to 12-membered heteroaryl containing 1 to 4 heteroatoms, the heteroatoms being selected from O, S and N, "containing 1 to 4 heteroatoms substituted by one or more R 1-4 , a 5- to 12-membered heteroaryl group with heteroatoms selected from O, S and N, or a 4- to 10-membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N.
  • the morpholinoquinazoline compound represented by formula I has dual inhibitory activities of PI3K ⁇ inhibitor and HDAC.
  • E is the connecting key.
  • E is a linkage or a C 1-6 alkylene group.
  • R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
  • R 2 is hydrogen or -OC 1-4 alkyl
  • A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
  • B is a connecting bond, C 3-10 cycloalkyl group, containing 1-3 heteroatoms, the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl groups, substituted by one or more R 1-2 "4-10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from O and N, C 6-20 aryl group substituted by one or more R 1-3 , containing 1 to 4 heteroatoms" Atoms, heteroatoms selected from O, S and N 5 to 12-membered heteroaryl, substituted by one or more R 1-4 "containing 1 to 4 heteroatoms, heteroatoms selected from O, S and N 5-12-membered heteroaryl" or "8-12-membered benzoheterogeneous group containing 1-3 heteroatoms independently selected from O, S and N substituted by one or more R 1-5 cycloalkenyl”;
  • C is a connecting bond, C 1-6 alkylene group, C 2-6 alkenyl group, -OC 1-6 alkylene group, -OC 1-6 alkylene group -OC 1-6 alkylene group, -C 1- 6 alkylene-OC 1-6 alkylene or C 1-6 alkylene-NH-;
  • D is a connecting bond, C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5 ⁇ 12-membered heteroaryl", C 3-10 cycloalkyl, substituted by one or more R 1-4 " contains 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12 members of O, S and N "Heteroaryl", or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N;
  • E is a connecting bond or C 1-6 alkylene group.
  • R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
  • R 2 is hydrogen or -OC 1-4 alkyl
  • A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
  • B is a connecting bond, C 3-10 cycloalkyl group, containing 1-3 heteroatoms, the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl groups, substituted by one or more R 1-2 Containing 1 to 3 heteroatoms, the heteroatoms are selected from O and N, 4 to 10-membered heterocycloalkyl", C 6-20 aryl group substituted by one or more R 1-3 , or, substituted by one or more R 1-3 Each R 1-4 substituted "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N";
  • C is a connecting bond or C 1-6 alkylene group
  • D is a connecting bond, C 6-20 aryl group, C 6-20 arylene group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5-12-membered heteroaryl", or "5-12-membered heteroaryl containing 1-4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
  • E is a connecting bond or C 1-6 alkylene group.
  • R 1 is a C 1-4 alkyl group or a C 1-4 alkyl group substituted by one or more halogens
  • the C 1-4 alkyl group is methyl, ethyl, n- Propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.
  • R 1 is a C 3-8 cycloalkyl group
  • the C 3-8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, for example , cyclopropyl.
  • R 2 is hydrogen or -OC 1-4 alkyl
  • the -OC 1-4 alkyl is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, iso-butoxy or tert-butoxy, for example methoxy.
  • R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently halogen
  • the halogen is fluorine, chlorine , bromine or iodine.
  • R 1 is C 1-4 alkyl substituted by one or more halogens
  • the halogens are fluorine, chlorine, bromine or iodine.
  • R 1 is a C 1-4 alkyl group substituted by one or more halogens
  • the plurality is two or three.
  • R 1 when R 1 is a C 1-4 alkyl group substituted by one or more halogens, said R 1 is a C 1-2 alkyl group substituted by two or three fluorine, for example, three Fluoromethyl.
  • R 3 , R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently C 1-6 alkyl
  • the C 1-6 alkyl group is a C 1-4 alkyl group, and further is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • the C 1-6 alkylene is - CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - or -C(CH 3 ) 2 CH 2 -, for example, -CH 2 -.
  • the C 3-10 cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclohexyl (
  • B is C 3-10 cycloalkyl
  • the C 3-10 cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclohexyl (
  • its relationship with the groups on both sides is ).
  • B is "a 4- to 10-membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N" or “containing 1" substituted by one or more -3 heteroatoms
  • the heteroatoms are independently selected from O, S and N 4-10 membered heterocycloalkyl
  • the heteroatoms are independently selected from O, S and N 4-10 membered heterocycloalkyl” means "containing 1-2 heteroatoms
  • the heteroatoms are independently selected from N 3-6 membered heterocycloalkyl", for example like, Further, its position a is connected to A.
  • B is "a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N" substituted by one or more R 1-2
  • R 1-2 is halogen
  • the C 6-20 aryl group is phenyl, for example,
  • R 1-3 is halogen
  • B is an 8- to 12-membered benzoheterocyclen containing 1 to 3 heteroatoms substituted by one or more R 1-5
  • the heteroatoms are independently selected from O, S and N.
  • base the "8-12-membered benzoheterocyclenyl group containing 1 to 3 heteroatoms independently selected from O, S and N” is "9-10 membered benzoheterocyclenyl group containing 1 N atom""benzoheterocyclenyl", for example, Further, its position a is connected to A.
  • B is an 8- to 12-membered benzoheterocyclen containing 1 to 3 heteroatoms substituted by one or more R 1-5 , the heteroatoms are independently selected from O, S and N.
  • base the B is Further, its position a is connected to A.
  • C is C 1-6 alkylene, -OC 1-6 alkylene-OC 1-6 alkylene , -C 1-6 alkylene - OC 1-6 alkylene Or -C 1-6 alkylene -NH-
  • the C 1-6 alkylene is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - or -C(CH 3 ) 2 CH 2 -.
  • C when C is C 1-6 alkylene-NH-, the C 1-6 alkylene end is attached to B.
  • the C 2-6 alkenyl is vinyl, propenyl or allyl; further, when the C 2-6 alkenyl When it is vinyl, the vinyl is
  • the C 6-20 aryl group is phenyl or naphthyl ,For example,
  • D is "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms
  • the heteroatoms are selected from O, S and N" or a "containing heteroaryl group” substituted by one or more R 1-4 1 to 4 heteroatoms, 5 to 12-membered heteroaryl group selected from O, S and N.”
  • the "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N” is "containing 1 to 2 heteroatoms selected from O and N 5-6 membered heteroaryl", for example, Further, its position a is connected to C.
  • R 1-4 are halogen.
  • D when D is a 4-10-membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N, the D is a 4-10-membered heterocycloalkyl group containing 1-2 heteroatoms, and the heteroatoms are 5-6 membered heterocycloalkyl group selected from O and N, for example, Further, its position a is connected to C.
  • the C 1-6 alkylene group is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 ) CH 2 - or -C(CH 3 ) 2 CH 2 -, for example, -CH 2 -.
  • A is -O-, -CH 2 -, Further, its position a is connected to B.
  • B is the connecting key, Further, its position a is connected to A.
  • C is the connecting bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, a -OCH 2 CH 2 OCH 2 -, Or a -C(CH 3 ) 2 OCH 2 -, further, its position a is connected to B.
  • D is the connection key, Further, its position a is connected to C.
  • E is a linkage or -CH2- .
  • -EDCBA- is Furthermore, its position a is the same as connected.
  • the morpholinoquinazoline compound shown in formula I as mentioned above, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug is a scheme One or option two:
  • R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
  • R 2 is hydrogen or -OC 1-4 alkyl
  • A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
  • B is a connecting bond, C 3-10 cycloalkylene group, containing 1-3 heteroatoms
  • the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl groups, substituted by one or more R 1-3 C 6-20 aryl, 5-12 membered heteroaryl containing 1 to 4 heteroatoms, heteroatoms selected from O, S and N, "containing 1 to 4" substituted by one or more R 1-4 Heteroatom, the heteroatom is selected from O, S and N 5-12 membered heteroaryl" or "containing 1-3 heteroatoms substituted by one or more R 1-5 , the heteroatom is independently selected from O, S and N 8-12 membered benzoheterocyclenyl";
  • C is a connecting bond, C 1-6 alkylene group, C 2-6 alkenyl group, -OC 1-6 alkylene group, -OC 1-6 alkylene group -OC 1-6 alkylene group, -C 1- 6 alkylene-OC 1-6 alkylene or C 1-6 alkylene-NH-;
  • D is a connecting bond, C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5 ⁇ 12-membered heteroaryl", C 3-10 cycloalkyl, substituted by one or more R 1-4 " contains 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12 members of O, S and N "Heteroaryl", or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N;
  • R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
  • R 2 is hydrogen or -OC 1-4 alkyl
  • A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
  • B is a connecting bond, C 3-10 cycloalkyl group, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from O and N, C substituted by one or more R 1-3 6-20 aryl, or "5-12 membered heteroaryl containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
  • C is a connecting bond or C 1-6 alkylene group
  • D is a connecting bond, C 6-20 aryl group, C 6-20 arylene group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5-12-membered heteroaryl", or "5-12-membered heteroaryl containing 1-4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
  • the morpholinoquinazoline compound shown in Formula I can be any of the following structures:
  • the present invention also provides a method for preparing the above-mentioned nitrogen-containing heterocyclic compound represented by Formula I.
  • R 1 , R 2 , A, B, C, D or E are all as defined above;
  • MET is independently a metal group, such as BF 3 K, B(OH) 2 ;
  • PG is a protecting group, so The protective group is, for example, THP;
  • ALK is a C 1-6 alkyl group, such as methyl, ethyl; the steps of the route one are as follows: Compounds A1 and A2 generate A3 through a coupling reaction, A3 is hydrolyzed to obtain A4, and A4 is condensed It is converted into A5, and A5 is removed from the protecting group to obtain compound I.
  • R 1 , R 2 , A, B, C, D or E are as mentioned above;
  • MET is independently a metal group, such as BF 3 K, B(OH) 2 ;
  • PG is a protecting group, so The protecting group is, for example, Boc;
  • ALK is a C 1-6 alkyl group, such as methyl, ethyl; the steps of route two are as follows: Compound A1 and B1 generate B2 through a coupling reaction, and B2 removes the protecting group and converts into Compound B3, B3 is converted to A4 through coupling, etc., and A4 is further converted to obtain compound I.
  • R 1 , R 2 , A, B, C, D or E are as mentioned above;
  • ALK is a C 1-6 alkyl group, such as methyl, ethyl;
  • Q is independently a leaving group, For example, OTs and Br;
  • the steps of Route 3 are as follows: Compounds C1 and C2 generate A4 through nucleophilic substitution reaction, and A4 is further converted to obtain compound Ia.
  • R 1 , R 2 , B, C, D or E are as mentioned above;
  • PG is a protecting group, and the protecting group is such as THP;
  • the steps of route 4 are as follows: Compounds D1 and D2 pass through Reductive amination reaction generates D3, which is deprotected and converted into compound Ib.
  • R 1 , R 2 , B, C, D or E are as mentioned above;
  • PG is a protecting group, such as THP;
  • the steps of route five are as follows: Compounds E1 and E2 pass through Reductive amination reaction generates E3, which is deprotected and converted into compound Ic.
  • the invention also provides a compound:
  • the present invention also provides a pharmaceutical composition, which contains substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of the above-mentioned morpholinylquinazoline compound represented by formula I, and its pharmaceutical Acceptable salts, solvates, polymorphs or prodrugs thereof.
  • the present invention also provides the application of substance A in the manufacture of medicines for preventing or treating diseases involving abnormal cell proliferation, differentiation or survival.
  • the substance A is a therapeutically effective amount of the above-mentioned morpholine represented by formula I.
  • the disease is cancer.
  • the cancer is caused by the proliferation of malignant new cells, such as tumors, neoplasms, sarcomas, leukemias, lymphomas, etc.
  • the drug has dual inhibitory activities of PI3K ⁇ inhibitor and HDAC.
  • the present invention also provides an application of substance A in the manufacture of a drug for reducing the number of lymphocytes circulating in a subject; the substance A is a therapeutically effective amount of the above-mentioned morpholino group represented by formula I.
  • the subject includes a subject suffering from a hematological disease, such as a hematological cancer, a subject suffering from an autoimmune disease, and a subject needing to modulate the immune response, such as a patient suffering from Diabetic subjects or organ transplant recipients.
  • a hematological disease such as a hematological cancer
  • a subject suffering from an autoimmune disease such as a hematological cancer
  • a subject needing to modulate the immune response such as a patient suffering from Diabetic subjects or organ transplant recipients.
  • R L-1 , R L-2 and R L-3 are independently C 2-6 alkenyl or C 2-6 alkynyl
  • the alkenyl or alkynyl group is an alkene or alkyne A hydrocarbon group with one or more hydrogen atoms missing.
  • an alkene or alkyne has one or two hydrogen atoms missing to form an alkenyl or alkynyl group.
  • the definition of other groups refers to alkyl, alkenyl or aryl groups.
  • pharmaceutically acceptable salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
  • base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts.
  • acid addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in pure solution or a suitable inert solvent.
  • a salt included in The pharmaceutically acceptable acid, and the inorganic acid includes but is not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc.
  • the pharmaceutically acceptable acids include organic acids, and the organic acids include but are not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartaric acid, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the specified number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It is similar to an alkyl group.
  • alkylene is meant as a linking group between two other species, it can also be straight chain or branched, examples Including but not limited to -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH(CH 2 CH 3 )CH 2 -.
  • alkoxy refers to the group -ORX , where RX is alkyl as defined above.
  • cycloalkyl refers to a saturated cyclic group having a specified number of carbon atoms (eg, C 3 to C 6 ), consisting only of carbon atoms, and is a monocyclic, bridged or spirocyclic group.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • aryl refers to an aromatic group composed of carbon atoms, with each ring possessing aromatic properties. For example phenyl or naphthyl.
  • heteroaryl refers to a specified number of heteroatoms (such as 1, 2 or 3) and a specified heteroatom species (among N, O and S) with a specified number of ring atoms (e.g., 5 to 12 members).
  • one or more) cyclic groups which are monocyclic or polycyclic, and at least one ring is aromatic (in compliance with Huckel's rule).
  • the heteroaryl group is connected to other segments in the molecule through an aromatic ring or a non-aromatic ring.
  • Heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.
  • heterocyclyl refers to a group having a specified number of ring atoms (eg, 3 to 8 members), a specified number of heteroatoms (eg, 1, 2, or 3), A cyclic group specifying a heteroatom species (one or more of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated.
  • Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidinyl, and the like.
  • hydroxy refers to a -OH group.
  • cyano refers to a -CN group.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the present invention provides morpholinoquinazoline compounds, pharmaceutical compositions and applications thereof.
  • the morpholinoquinazoline compound of the present invention has dual inhibitory activities of PI3K ⁇ inhibitor and HDAC, and is expected to achieve better curative effect and wider application.
  • room temperature refers to the ambient temperature, which is 10°C-35°C. Overnight refers to 8-15 hours. Reflux refers to the solvent reflux temperature under normal pressure.
  • the compound piperidine-4-carboxylic acid methyl ester (3.15g, 22.00mmoL) was dissolved in 50 mL of acetonitrile, potassium iodide (199 mg, 1.20mmoL) and potassium bromomethylfluoroborate (4g, 19.92mmoL) were added successively at room temperature. Stir under nitrogen conditions at 80°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (10 mL), and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was dissolved in 5 mL of acetonitrile, and methyl tert-butyl ether (100 mL) was added dropwise with stirring.
  • Dissolve compound 1-b (59 mg, 0.10 mmoL) in 5 mL of DMF at room temperature, add HATU (70 mg, 0.18 mmoL) and DIPEA (101 ⁇ L, 0.61 mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (29 mg, 0.24 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours.
  • Dissolve compound 6-d 400mg, about 0.40mmoL) in 20mL of DMF, add DIPEA (660 ⁇ L, 4mmoL) and 2-chloro-pyrimidine-4-carboxylic acid ethyl ester (82mg, 0.44mmoL) in sequence, and the reaction mixture is at room temperature. Stir under nitrogen for 16 hours. Add 30mL of water, extract with ethyl acetate (100mL*2), and use saturated salt for the organic phase.
  • DIPEA 660 ⁇ L, 4mmoL
  • 2-chloro-pyrimidine-4-carboxylic acid ethyl ester 82mg, 0.44mmoL
  • Dissolve compound 8-b (153mg, 0.27mmoL) in 10mL of DMF at room temperature, add HATU (154mg, 0.41mmoL) and DIPEA (224uL, 1.36mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (64 mg, 0.54 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours.
  • HATU 154mg, 0.41mmoL
  • DIPEA 224uL, 1.36mmoL
  • Dissolve compound 16-a (36 mg, 0.05 mmoL) in 5 mL of DCM, cool to 0°C, and slowly add hydrogen chloride in 1,4-dioxane solution (4 M, 0.25 mL) dropwise. After the addition is completed, the mixture is After stirring at 0°C for 20 minutes, the reaction was quenched with saturated sodium bicarbonate solution (1 mL), DCM (20 mL) was added, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 16 (33 mg, 100%) .
  • Dissolve compound 21-b (10 mg, 0.015mmoL) in 1 mL of DMF at room temperature, add HATU (9 mg, 0.023mmoL) and DIPEA (13 ⁇ L, 0.077mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (10 mg, 0.085 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with 10 mL of water, and then extracted with ethyl acetate (20 mL*2).
  • Dissolve compound 24-f (438 mg, 1 mmoL) in 30 mL of toluene at room temperature, and add water (10 mL), isopropyl alcohol (10 mL), and 3-amino-2-methoxypyridine-5-boronic acid pinacol in sequence.
  • Ester 300 mg, 1.2 mmoL
  • tetraphenylphosphorus palladium 58 mg, 0.05 mmoL
  • sodium carbonate (636 mg, 6 mmoL). The reaction mixture was stirred under nitrogen at 30°C for 16 hours.
  • Dissolve compound 1-e (763 mg, 1.63 mmoL) in 50 mL of THF at room temperature, and add water (5 mL), 28-d (1.12 g, 3.26 mmoL), palladium acetate (37 mg, 0.16 mmoL), and x-Phos in sequence. (155 mg, 0.33 mmoL), cesium carbonate (1.59 g, 4.89 mmoL), and the reaction mixture was stirred under nitrogen at 80°C for 36 hours.
  • Dissolve compound 1-e (2.0g, 4.27mmoL) in 30mL of DMF, then add zinc cyanide (999mg, 8.54mmoL), X-Phos (407mg, 0.85mmoL), Pd 2 (dba) 3 (391mg) ,0.43mmoL), zinc powder (200mg, 3.08mmoL), and the mixture was stirred under nitrogen at 100°C for 18 hours.
  • reaction solution was diluted with ethyl acetate, washed with water, washed with saturated NaCl, dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness and purified through column (mobile phase: petroleum ether/ethyl acetate 100/0 to 100/80) to obtain crude product Dissolve in ethyl acetate, wash three times with citric acid aqueous solution (3%), and evaporate to dryness to obtain compound 36-b (350 mg, 100%).
  • reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness and purified by column (mobile Phase: petroleum ether/ethyl acetate, dichloromethane/methanol, 100/0 to 100/100, 100/4) to obtain compound 39-e (550 mg, 78%).
  • reaction solution was added to ice water, extracted twice with ethyl acetate, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column (mobile phase: dichloromethane/acetic acid Ethyl ester, 100/0 to 60/40), giving 46-c (300 mg, 51%).
  • the experiment used the ADP-Glo Kinase Assay kit and followed the instructions.
  • the test compound sample is dissolved in DMSO, diluted 3 times at a certain starting concentration such as 10 ⁇ M, and added to the screening system.
  • DMSO controls and no-kinase controls are set at the same time.
  • Use buffer to prepare optimal concentrations of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and PI3K ⁇ enzymes, substrate (PIP2) and ATP.
  • the enzyme reaction system includes: buffer, ATP 25 ⁇ M, kinase substrate (PIP2, 50 ⁇ g/mL), kinase [PI3K ⁇ (0.15 ⁇ g/mL), PI3K ⁇ (1.2 ⁇ g/mL), PI3K ⁇ (0.3 ⁇ g/mL) and PI3K ⁇ ( 2.5 ⁇ g/mL)] etc.
  • the reaction system was allowed to react at room temperature for 1 hour. Add the stop reagent (ADP-Glo reagent, 5 ⁇ L) to stop the reaction, and use the detection reagent (Kinase Detection Reagent, 10 ⁇ L) to detect the ADP content in the system. Signal data were collected with Envision instruments.
  • % inhibition rate (DMSO control Signal value-sample signal value)/(DMSO control signal value-no kinase control signal value).
  • Y Bottom+(Top-Bottom)/(1+(IC50/X) ⁇ HillSlope) formula to fit a curve and obtain the IC 50 value.
  • test compound sample is dissolved in DMSO, diluted 3 times at a certain starting concentration such as 10 ⁇ M, and added to the screening system.
  • DMSO controls and no-enzyme controls are set at the same time.
  • the enzyme and compound react at room temperature for 15 minutes.
  • HDAC8 50mM Tris 8.0, 2.7mM KCl, 137mM NaCl, 1mM MgCl 2 , 1mg/ML BSA
  • HDAC10 50mM Tris 7.5, 0.01% Tween-20, 50mM NaCl, 0.05mg/ML BSA
  • enzyme solution and substrate solution acetylated polypeptide
  • the test compound sample is dissolved in DMSO, diluted 3 times at a certain starting concentration such as 10 ⁇ M, and added to the screening system.
  • DMSO controls and no-enzyme controls are set at the same time.
  • the enzyme and compound react at room temperature for 15 minutes.
  • Use Envision instrument to read fluorescence signal data (excitation wavelength 355nM/emission wavelength 460nm). The inhibition rate at this concentration was calculated based on relative fluorescence units (RFU).
  • IC 50 >10 ⁇ M is represented by “*”
  • 10 ⁇ M ⁇ IC 50 >1 ⁇ M is represented by “**”
  • 1 ⁇ M ⁇ IC 50 >100nM is represented by "***”
  • 100nM ⁇ IC 50 >10nM is represented by “****”
  • IC 50 ⁇ 10nM is represented by “*****”.

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Abstract

Provided is a morpholinyl quinazoline compound represented by formula I, or a pharmaceutically acceptable salt, a solvate, a polymorph or a prodrug thereof. The morpholinyl quinazoline compound has a dual inhibitory activity against PI3Kδ and HDAC, and is prospective for better therapeutic effects and broader applications.

Description

一种吗啉基喹唑啉类化合物、其药物组合物及应用A kind of morpholinoquinazoline compound, its pharmaceutical composition and application
本申请要求申请日为2022年8月24日的中国专利申请202211018096.5的优先权。本申请引用上述中国专利申请的全文。This application claims priority from Chinese patent application 202211018096.5 with a filing date of August 24, 2022. This application cites the full text of the above-mentioned Chinese patent application.
技术领域Technical field
本发明涉及一种吗啉基喹唑啉类化合物、其药物组合物及应用The invention relates to a morpholinoquinazoline compound, its pharmaceutical composition and application
背景技术Background technique
PI3K全称为Phosphatidylinositol 3-kinase(磷脂酰肌醇3-激酶)，其参与细胞增殖、分化、凋亡和葡萄糖转运等多种细胞功能的调节。PI3K可分为Ⅰ类、Ⅱ类和Ⅲ类激酶，而研究最广泛的是能被细胞表面受体所激活的Ⅰ类PI3K。哺乳动物细胞中Ⅰ类PI3K根据结构和受体又分为Ⅰa类和Ⅰb类，它们分别传递来自酪氨酸激酶-偶联受体和G蛋白-偶联受体的信号。Ⅰa类PI3K包括PI3Kα、PI3Kβ、PI3Kδ亚型，Ⅰb类PI3K包括PI3Kγ亚型(Trends.Biochem.Sci.,1997,22,267-272)。Ⅰa类PI3K是由催化亚单位p110和调节亚单位p85所组成的二聚体蛋白，具有类脂激酶和蛋白激酶的双重活性(Nat.Rev.Cancer 2002,2,489-501)，被认为与细胞增殖和癌症发生，免疫疾病和涉及炎症的疾病相关。The full name of PI3K is Phosphatidylinositol 3-kinase (phosphatidylinositol 3-kinase), which is involved in the regulation of various cell functions such as cell proliferation, differentiation, apoptosis and glucose transport. PI3K can be divided into class I, class II and class III kinases, and the most widely studied is class I PI3K that can be activated by cell surface receptors. Class I PI3K in mammalian cells is further divided into class Ia and class Ib based on structure and receptor, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors respectively. Class Ia PI3K includes PI3Kα, PI3Kβ, and PI3Kδ subtypes, and class Ib PI3K includes PI3Kγ subtype (Trends. Biochem. Sci., 1997, 22, 267-272). Class Ia PI3K is a dimer protein composed of the catalytic subunit p110 and the regulatory subunit p85. It has dual activities of lipid kinase and protein kinase (Nat.Rev.Cancer 2002, 2, 489-501), and is considered to be related to cell proliferation. Associated with cancer development, immune disorders and diseases involving inflammation.
目前全球已有多款PI3Kδ抑制剂药物成功上市，如Idelalisib、Copanlisib、Duvelisb，均用于治疗血液循环系统癌症。Linperlisib(YY-20394)，化学名称为N-(5-(6-氟-8-((4-(2-羟基丙基-2-基)哌啶-1-基)甲基)-2-吗啡啉喹唑啉-4-基)-2-甲氧基吡啶-3-基)甲磺酰胺，为一类新型的PI3Kδ抑制剂。临床研究表明，对于复发和/或难治B细胞恶性血液肿瘤患者，每日一次口服80mg，持续4周，Linperlisib显示出良好的安全性和临床获益。At present, a number of PI3Kδ inhibitor drugs have been successfully launched around the world, such as Idelalisib, Copanlisib, and Duvelisb, all of which are used to treat blood circulation system cancers. Linperlisib (YY-20394), chemical name is N-(5-(6-fluoro-8-((4-(2-hydroxypropyl-2-yl)piperidin-1-yl)methyl)-2- Morphinolquinazolin-4-yl)-2-methoxypyridin-3-yl)methanesulfonamide is a new type of PI3Kδ inhibitor. Clinical studies have shown that in patients with relapsed and/or refractory B-cell hematological malignancies, Linperlisib showed good safety and clinical benefits when administered orally at 80 mg once daily for 4 weeks.
组蛋白去乙酰化酶(HDACs)是一类重要的表观遗传酶，通过从组蛋白上的N-端赖氨酸残基中去除乙酰基来调节基因表达。HDACs与肿瘤的发生和发展密切相关，抑制HDACs，可以通过增加细胞内组蛋白的乙酰化程度，提高p21等基因的表达水平等途径，抑制肿瘤细胞的增殖，诱导细胞分化和(或)凋亡。目前，已经多个组蛋白去乙酰化酶抑制剂获批上市，如Vorinostat、Panobinostat等。
Histone deacetylases (HDACs) are an important class of epigenetic enzymes that regulate gene expression by removing acetyl groups from N-terminal lysine residues on histones. HDACs are closely related to the occurrence and development of tumors. Inhibiting HDACs can inhibit the proliferation of tumor cells and induce cell differentiation and/or apoptosis by increasing the acetylation degree of intracellular histones and increasing the expression levels of p21 and other genes. . Currently, multiple histone deacetylase inhibitors have been approved for marketing, such as Vorinostat, Panobinostat, etc.
尽管PI3Kδ抑制剂和HDAC抑制剂都已有药物获批上市，然而，单药的使用往往存在适应症范围有限，容易耐药等缺陷。如果利用两类抑制剂的结构特点，研究具有PI3Kδ和HDAC双重抑制作用的药物，有望实现更好的疗效，更广的应用。Although both PI3Kδ inhibitors and HDAC inhibitors have been approved for marketing, the use of single drugs often has shortcomings such as limited indications and easy drug resistance. If the structural characteristics of the two types of inhibitors are used to study drugs with dual inhibitory effects on PI3Kδ and HDAC, it is expected to achieve better efficacy and wider applications.
发明内容Contents of the invention
本发明针对现有技术中缺乏具有PI3Kδ和HDAC双重抑制作用药物等缺陷，提供了一种吗啉基喹唑啉类化合物、其药物组合物及应用。本发明的吗啉基喹唑啉类化合物具有PI3Kδ抑制剂和HDAC双重抑制活性，有望实现更好的疗效，更广的应用。In view of the lack of drugs with dual inhibitory effects on PI3Kδ and HDAC in the prior art, the present invention provides a morpholinoquinazoline compound, its pharmaceutical composition and application. The morpholinoquinazoline compound of the present invention has dual inhibitory activities of PI3Kδ inhibitor and HDAC, and is expected to achieve better curative effect and wider application.
本发明是通过以下技术方案来解决上述技术问题的：The present invention solves the above technical problems through the following technical solutions:
本发明提供了一种如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，
The invention provides a morpholinoquinazoline compound shown in formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug,
其中，R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或C3-8环烷基；Wherein, R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
A、C和E独立地为连接键、或、-(U1)n1-(RL-1)n2-(U2)n3-(RL-2)n4-(U3)n5-(RL-3)n6-；A, C and E are independently connecting bonds, or, -(U 1 ) n1 -(R L-1 ) n2 -(U 2 ) n3 -(R L-2 ) n4 -(U 3 ) n5 -(R L-3 ) n6 -;
U1、U2和U3独立地为-O-、-S-、-NH-或-NR3-，R3为C1-6烷基；U 1 , U 2 and U 3 are independently -O-, -S-, -NH- or -NR 3 -, and R 3 is C 1-6 alkyl;
RL-1、RL-2和RL-3独立地为C1-6亚烷基、C2-6烯基或C2-6炔基；R L-1 , R L-2 and R L-3 are independently C 1-6 alkylene, C 2-6 alkenyl or C 2-6 alkynyl;
n1、n3和n5独立地为0或1；n1, n3 and n5 are independently 0 or 1;
n2、n4和n6独立地为0、1、2、3或4；n2, n4 and n6 are independently 0, 1, 2, 3 or 4;
B和D独立地为连接键、C3-10环烷基、被一个或多个R1-1取代的C3-10环烷基、“含 1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、被一个或多个R1-2取代的“含1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、C6-20芳基、被一个或多个R1-3取代的C6-20芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”、被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”、5～7元环烯基、或、被一个或多个R1-6取代的5～7元环烯基；当取代基为多个时，相同或不同；B and D are independently a connecting bond, C 3-10 cycloalkyl, C 3-10 cycloalkyl substituted by one or more R 1-1 , "containing "4-10 membered heterocycloalkyl" containing 1 to 3 heteroatoms, the heteroatoms are selected from O and N, "containing 1 to 3 heteroatoms, substituted by one or more R 1-2 , the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl", C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from "Heteroaryl group consisting of 5 to 12 members from O, S and N," substituted by one or more R 1-4 "contains 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12 members of O, S and N. "Heteroaryl", "8-12 membered benzoheterocyclenyl containing 1 to 3 heteroatoms independently selected from O, S and N", "substituted by one or more R 1-5 Containing 1 to 3 heteroatoms, the heteroatoms are independently selected from O, S and N 8-12-membered benzoheterocyclenyl", 5-7-membered cycloalkenyl, or, by one or more R 1- 6- substituted 5-7 membered cycloalkenyl; when there are multiple substituents, they may be the same or different;
R1-1、R1-2、R1-3、R1-4、R1-5和R1-6独立地为卤素或C1-6烷基。R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently halogen or C 1-6 alkyl.
在某一方案中，如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药里，某些基团具有如下定义，未提及的基团的定义如本发明中任一方案所述(本段内容以下简称为“在某一方案中”)，如式I所示的吗啉基喹唑啉类化合物，In a certain scheme, in the morpholinoquinazoline compounds represented by Formula I, their pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof, certain groups have the following definitions , the definition of the unmentioned group is as described in any scheme of the present invention (the content of this paragraph is hereinafter referred to as "in a certain scheme"), such as the morpholinylquinazoline compound shown in formula I,
在某一方案中，U1为O，n1为1，n2、n3、n4、n5和n6均为0，此时，A为-O-。In a certain scheme, U1 is O, n1 is 1, n2, n3, n4, n5 and n6 are all 0. At this time, A is -O-.
在某一方案中，A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-。In one embodiment, A is -O-, C 1-6 alkylene, -OC 1-6 alkylene, or C 1-6 alkylene-NH-.
在某一方案中，B为连接键、C3-10环烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-2取代的“含1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、被一个或多个R1-3取代的C6-20芳基、含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”。In a certain scheme, B is a connecting bond, C 3-10 cycloalkyl group, containing 1-3 heteroatoms, and the heteroatoms are selected from 4-10 membered heterocycloalkyl groups of O and N, surrounded by one or more R 1-2 substituted "4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from O and N", C 6-20 aryl substituted by one or more R 1-3 , 5-12 membered heteroaryl containing 1 to 4 heteroatoms selected from O, S and N, "containing 1 to 4 heteroatoms selected from one or more R 1-4 ""5-12 membered heteroaryl group of O, S and N", or "heteroaryl group substituted by one or more R 1-5 " contains 1 to 3 heteroatoms, and the heteroatoms are independently selected from 8 of O, S and N ~12-membered benzoheterocyclenyl”.
在某一方案中，C为连接键、C1-6亚烷基、C2-6烯基、-OC1-6亚烷基、-OC1-6亚烷基-OC1-6亚烷基、-C1-6亚烷基-O-C1-6亚烷基或C1-6亚烷基-NH-。In a certain embodiment, C is a bond, C 1-6 alkylene, C 2-6 alkenyl, -OC 1-6 alkylene, -OC 1-6 alkylene -OC 1-6 alkylene base, -C 1-6 alkylene -OC 1-6 alkylene or C 1-6 alkylene -NH-.
在某一方案中，D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20芳基、C3-10环烷基、被一个或多个R1-4取代的含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基。In a certain embodiment, D is a linkage, C 6-20 aryl, C 6-20 aryl substituted by one or more R 1-3 , C 3-10 cycloalkyl, substituted by one or more R 1-4 substituted 5- to 12-membered heteroaryl containing 1 to 4 heteroatoms, the heteroatoms being selected from O, S and N, "containing 1 to 4 heteroatoms substituted by one or more R 1-4 , a 5- to 12-membered heteroaryl group with heteroatoms selected from O, S and N, or a 4- to 10-membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N.
在某一方案中，无论E为连接键或者任意基团，所述的如式I所示的吗啉基喹唑啉类化合物均具有PI3Kδ抑制剂和HDAC双重抑制活性。In a certain scheme, regardless of whether E is a connecting bond or any group, the morpholinoquinazoline compound represented by formula I has dual inhibitory activities of PI3Kδ inhibitor and HDAC.
在某一方案中，E为连接键。In a certain scheme, E is the connecting key.
在某一方案中，E为连接键或C1-6亚烷基。 In one embodiment, E is a linkage or a C 1-6 alkylene group.
在某一方案中，所述的如式I所示的吗啉基喹唑啉类化合物中，In a certain scheme, in the morpholinoquinazoline compound shown in Formula I,
R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或C3-8环烷基；R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
B为连接键、C3-10环烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-2取代的“含1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、被一个或多个R1-3取代的C6-20芳基、含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”；B is a connecting bond, C 3-10 cycloalkyl group, containing 1-3 heteroatoms, the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl groups, substituted by one or more R 1-2 "4-10 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from O and N, C 6-20 aryl group substituted by one or more R 1-3 , containing 1 to 4 heteroatoms" Atoms, heteroatoms selected from O, S and N 5 to 12-membered heteroaryl, substituted by one or more R 1-4 "containing 1 to 4 heteroatoms, heteroatoms selected from O, S and N 5-12-membered heteroaryl" or "8-12-membered benzoheterogeneous group containing 1-3 heteroatoms independently selected from O, S and N substituted by one or more R 1-5 cycloalkenyl”;
C为连接键、C1-6亚烷基、C2-6烯基、-OC1-6亚烷基、-OC1-6亚烷基-OC1-6亚烷基、-C1-6亚烷基-O-C1-6亚烷基或C1-6亚烷基-NH-；C is a connecting bond, C 1-6 alkylene group, C 2-6 alkenyl group, -OC 1-6 alkylene group, -OC 1-6 alkylene group -OC 1-6 alkylene group, -C 1- 6 alkylene-OC 1-6 alkylene or C 1-6 alkylene-NH-;
D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、C3-10环烷基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基；D is a connecting bond, C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5 ~12-membered heteroaryl", C 3-10 cycloalkyl, substituted by one or more R 1-4 " contains 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12 members of O, S and N "Heteroaryl", or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N;
E为连接键或C1-6亚烷基。E is a connecting bond or C 1-6 alkylene group.
在某一方案中，所述的如式I所示的吗啉基喹唑啉类化合物中，In a certain scheme, in the morpholinoquinazoline compound shown in Formula I,
R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或C3-8环烷基；R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
B为连接键、C3-10环烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-2取代的“含1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、被一个或多个R1-3取代的C6-20芳基、或、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”；B is a connecting bond, C 3-10 cycloalkyl group, containing 1-3 heteroatoms, the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl groups, substituted by one or more R 1-2 Containing 1 to 3 heteroatoms, the heteroatoms are selected from O and N, 4 to 10-membered heterocycloalkyl", C 6-20 aryl group substituted by one or more R 1-3 , or, substituted by one or more R 1-3 Each R 1-4 substituted "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N";
C为连接键或C1-6亚烷基；C is a connecting bond or C 1-6 alkylene group;
D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20亚芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”；D is a connecting bond, C 6-20 aryl group, C 6-20 arylene group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5-12-membered heteroaryl", or "5-12-membered heteroaryl containing 1-4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
E为连接键或C1-6亚烷基。 E is a connecting bond or C 1-6 alkylene group.
在某一方案中，当R1为C1-4烷基或被一个或多个卤素取代的C1-4烷基时，所述的C1- 4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，例如甲基。In a certain scheme, when R 1 is a C 1-4 alkyl group or a C 1-4 alkyl group substituted by one or more halogens, the C 1-4 alkyl group is methyl, ethyl, n- Propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.
在某一方案中，当R1为C3-8环烷基时，所述的C3-8环烷基为环丙基、环丁基、环戊基、环己基或环庚基，例如，环丙基。In a certain embodiment, when R 1 is a C 3-8 cycloalkyl group, the C 3-8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, for example , cyclopropyl.
在某一方案中，当R2为氢或-OC1-4烷基时，所述的-OC1-4烷基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基，例如甲氧基。In a certain scheme, when R 2 is hydrogen or -OC 1-4 alkyl, the -OC 1-4 alkyl is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, iso-butoxy or tert-butoxy, for example methoxy.
在某一方案中，当R1-1、R1-2、R1-3、R1-4、R1-5和R1-6独立地为卤素时，所述的卤素为氟、氯、溴或碘。In a certain solution, when R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently halogen, the halogen is fluorine, chlorine , bromine or iodine.
在某一方案中，当R1为被一个或多个卤素取代的C1-4烷基时，所述的卤素为氟、氯、溴或碘。In a certain embodiment, when R 1 is C 1-4 alkyl substituted by one or more halogens, the halogens are fluorine, chlorine, bromine or iodine.
在某一方案中，当R1为被一个或多个卤素取代的C1-4烷基时，所述的多个为两个或三个。In a certain aspect, when R 1 is a C 1-4 alkyl group substituted by one or more halogens, the plurality is two or three.
在某一方案中，当R1为被一个或多个卤素取代的C1-4烷基时，所述的R1为两个或三个氟取代的C1-2烷基，例如，三氟甲基。In a certain aspect, when R 1 is a C 1-4 alkyl group substituted by one or more halogens, said R 1 is a C 1-2 alkyl group substituted by two or three fluorine, for example, three Fluoromethyl.
在某一方案中，当R3、R1-1、R1-2、R1-3、R1-4、R1-5和R1-6独立地为C1-6烷基时，所述的C1-6烷基为C1-4烷基，进一步为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。In a certain embodiment, when R 3 , R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently C 1-6 alkyl, The C 1-6 alkyl group is a C 1-4 alkyl group, and further is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
在某一方案中，当A为C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-时，所述的C1- 6亚烷基为-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH(CH3)2-、-CH2CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-或-C(CH3)2CH2-，例如，-CH2-。In a certain scheme, when A is C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-, the C 1-6 alkylene is - CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - or -C(CH 3 ) 2 CH 2 -, for example, -CH 2 -.
在某一方案中，当A为-OC1-6亚烷基时，C1-6亚烷基端与B相连。In one embodiment, when A is -OC 1-6 alkylene, the C 1-6 alkylene end is attached to B.
在某一方案中，当B为C3-10环烷基时，所述的C3-10环亚烷基为环丙基、环丁基、环戊基或环己基，例如，环己基(例如，进一步地，更进一步，其与两边基团的关系为)。In a certain scheme, when B is C 3-10 cycloalkyl, the C 3-10 cycloalkylene is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclohexyl ( For example, further, Furthermore, its relationship with the groups on both sides is ).
在某一方案中，当B为“含有1-3个杂原子，杂原子独立地选自O，S和N的4～10元杂环烷基”或被一个或多个取代的“含有1-3个杂原子，杂原子独立地选自O，S和N的4～10元杂环烷基”时，所述的“含有1-3个杂原子，杂原子独立地选自O，S和N的4～10元杂环烷基”为“含有1-2个杂原子，杂原子独立地选自N的3-6元杂环烷基”，例 如，进一步地，其位置a处与A相连。In a certain scheme, when B is "a 4- to 10-membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N" or "containing 1" substituted by one or more -3 heteroatoms, the heteroatoms are independently selected from O, S and N 4-10 membered heterocycloalkyl", the "contains 1-3 heteroatoms, the heteroatoms are independently selected from O, S and N 4-10 membered heterocycloalkyl" means "containing 1-2 heteroatoms, and the heteroatoms are independently selected from N 3-6 membered heterocycloalkyl", for example like, Further, its position a is connected to A.
在某一方案中，当B为被一个或多个R1-2取代的“含有1-3个杂原子，杂原子独立地选自O，S和N的4～10元杂环烷基”时，所述的R1-2为卤素。In a certain scheme, when B is "a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N" substituted by one or more R 1-2 When, the R 1-2 is halogen.
在某一方案中，当B为被一个或多个R1-3取代的C6-20芳基时，所述的C6-20芳基为苯基，例如， In a certain embodiment, when B is a C 6-20 aryl group substituted by one or more R 1-3 , the C 6-20 aryl group is phenyl, for example,
在某一方案中，当B为被一个或多个R1-3取代的C6-20芳基时，所述的R1-3为卤素。In a certain embodiment, when B is a C 6-20 aryl group substituted by one or more R 1-3 , said R 1-3 is halogen.
在某一方案中，当B为“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，所述的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”为“含有1-2个N的5-6元杂芳基”，例如，进一步地，其位置a处与A相连。In a certain scheme, when B is "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, the heteroatoms are selected from O, S and N", or "substituted by one or more R 1-4 " When "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S, and N", the "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S, and N "5-12-membered heteroaryl" means "5-6-membered heteroaryl containing 1-2 N", for example, Further, its position a is connected to A.
在某一方案中，当B为被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，所述的R1-4为卤素。In a certain scheme, when B is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 , the R 1-4 mentioned above are halogen.
在某一方案中，当B为被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，所述的B为进一步地，其位置a处与A相连。In a certain scheme, when B is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 , the The B mentioned above is Further, its position a is connected to A.
在某一方案中，当B为被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”时，所述的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”为“含1个N原子的9～10元苯并杂环烯基”，例如，进一步地，其位置a处与A相连。In a certain scheme, when B is an 8- to 12-membered benzoheterocyclen containing 1 to 3 heteroatoms substituted by one or more R 1-5 , the heteroatoms are independently selected from O, S and N. "base", the "8-12-membered benzoheterocyclenyl group containing 1 to 3 heteroatoms independently selected from O, S and N" is "9-10 membered benzoheterocyclenyl group containing 1 N atom""benzoheterocyclenyl", for example, Further, its position a is connected to A.
在某一方案中，当B为被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选 自O、S和N的8～12元苯并杂环烯基”时，所述的R1-5为卤素。In a certain scheme, when B is "containing 1 to 3 heteroatoms substituted by one or more R 1-5 , the heteroatoms are independently selected In the case of "8-12 membered benzoheterocyclenyl group consisting of O, S and N", the R 1-5 is halogen.
在某一方案中，当B为被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”时，所述的B为进一步地，其位置a处与A相连。In a certain scheme, when B is an 8- to 12-membered benzoheterocyclen containing 1 to 3 heteroatoms substituted by one or more R 1-5 , the heteroatoms are independently selected from O, S and N. When "base", the B is Further, its position a is connected to A.
在某一方案中，当C为C1-6亚烷基、-OC1-6亚烷基-OC1-6亚烷基、-C1-6亚烷基-O-C1- 6亚烷基或-C1-6亚烷基-NH-时，所述的C1-6亚烷基为-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH(CH3)2-、-CH2CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-或-C(CH3)2CH2-。In a certain embodiment, when C is C 1-6 alkylene, -OC 1-6 alkylene-OC 1-6 alkylene , -C 1-6 alkylene - OC 1-6 alkylene Or -C 1-6 alkylene -NH-, the C 1-6 alkylene is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - or -C(CH 3 ) 2 CH 2 -.
在某一方案中，当C为-OC1-6亚烷基或-OC1-6亚烷基-OC1-6亚烷基时，-O端与B相连。In a certain embodiment, when C is -OC 1-6 alkylene or -OC 1-6 alkylene-OC 1-6 alkylene, the -O end is connected to B.
在某一方案中，当C为C1-6亚烷基-NH-时，C1-6亚烷基端与B相连。In one embodiment, when C is C 1-6 alkylene-NH-, the C 1-6 alkylene end is attached to B.
在某一方案中，当C为C2-6烯基时，所述的C2-6烯基为乙烯基、丙烯基或烯丙基；进一步地，当所述的C2-6烯基为乙烯基时，所述的乙烯基为 In a certain solution, when C is C 2-6 alkenyl, the C 2-6 alkenyl is vinyl, propenyl or allyl; further, when the C 2-6 alkenyl When it is vinyl, the vinyl is
在某一方案中，当D为C6-20芳基或被一个或多个R1-3取代的C6-20芳基时，所述的C6-20芳基为苯基或萘基，例如， In a certain scheme, when D is a C 6-20 aryl group or a C 6-20 aryl group substituted by one or more R 1-3 , the C 6-20 aryl group is phenyl or naphthyl ,For example,
在某一方案中，当D为C6-20芳基或被一个或多个R1-3取代的C6-20芳基时，所述的R1-3为卤素。In a certain embodiment, when D is a C 6-20 aryl group or a C 6-20 aryl group substituted by one or more R 1-3 , said R 1-3 is halogen.
在某一方案中，当D为被一个或多个R1-3取代的C6-20芳基时，所述的D为 进一步地，其位置a处与C相连。In a certain scheme, when D is a C 6-20 aryl group substituted by one or more R 1-3 , the D is Further, its position a is connected to C.
在某一方案中，当D为“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”或被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基” 时，所述的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”为“含1～2个杂原子，杂原子选自O和N的5～6元杂芳基”，例如，进一步地，其位置a处与C相连。In a certain scheme, when D is "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, the heteroatoms are selected from O, S and N" or a "containing heteroaryl group" substituted by one or more R 1-4 1 to 4 heteroatoms, 5 to 12-membered heteroaryl group selected from O, S and N." When, the "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" is "containing 1 to 2 heteroatoms selected from O and N 5-6 membered heteroaryl", for example, Further, its position a is connected to C.
在某一方案中，当D为被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，R1-4为卤素。In a certain scheme, when D is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 , R 1-4 are halogen.
在某一方案中，当D为被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，所述的D为进一步地，其位置a处与C相连。In a certain scheme, when D is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 , the The D mentioned above is Further, its position a is connected to C.
在某一方案中，当D为含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基时，所述的D为含有1-2个杂原子，杂原子选自O和N的5～6元杂环烷基，例如，进一步地，其位置a处与C相连。In a certain scheme, when D is a 4-10-membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N, the D is a 4-10-membered heterocycloalkyl group containing 1-2 heteroatoms, and the heteroatoms are 5-6 membered heterocycloalkyl group selected from O and N, for example, Further, its position a is connected to C.
在某一方案中，当E为C1-6亚烷基时，所述的C1-6亚烷基为-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH(CH3)2-、-CH2CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-或-C(CH3)2CH2-，例如，-CH2-。In a certain solution, when E is a C 1-6 alkylene group, the C 1-6 alkylene group is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 ) CH 2 - or -C(CH 3 ) 2 CH 2 -, for example, -CH 2 -.
在某一方案中，A为-O-、-CH2-、 进一步地，其位置a处与B相连。In a certain scheme, A is -O-, -CH 2 -, Further, its position a is connected to B.
在某一方案中，B为连接键、 进一步地，其位置a处与A相连。In a certain scheme, B is the connecting key, Further, its position a is connected to A.
在某一方案中，C为连接键、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、a-OCH2CH2OCH2-、或a-C(CH3)2OCH2-，进一步地，其位置a处与B相连。In a certain scheme, C is the connecting bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, a -OCH 2 CH 2 OCH 2 -, Or a -C(CH 3 ) 2 OCH 2 -, further, its position a is connected to B.
在某一方案中，D为连接键、 进一步地，其位置a处与C相连。In a certain scheme, D is the connection key, Further, its position a is connected to C.
在某一方案中，E为连接键或-CH2-。In one embodiment, E is a linkage or -CH2- .
某一方案中，-D-C-B-A-为 进一步地，其位置a处与E相连。 In a certain scheme, -DCBA- is Further, its position a is connected to E.
在某一方案中，-E-D-C-B-A-为 进一步地，其位置a处与相连。In a certain scenario, -EDCBA- is Furthermore, its position a is the same as connected.
在某一方案中，如前所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其为方案一或方案二：In a certain scheme, the morpholinoquinazoline compound shown in formula I as mentioned above, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug, is a scheme One or option two:
方案一：R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或，C3-8环烷基；Option 1: R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
B为连接键、C3-10环亚烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-3取代的C6-20芳基、含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”；B is a connecting bond, C 3-10 cycloalkylene group, containing 1-3 heteroatoms, the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl groups, substituted by one or more R 1-3 C 6-20 aryl, 5-12 membered heteroaryl containing 1 to 4 heteroatoms, heteroatoms selected from O, S and N, "containing 1 to 4" substituted by one or more R 1-4 Heteroatom, the heteroatom is selected from O, S and N 5-12 membered heteroaryl" or "containing 1-3 heteroatoms substituted by one or more R 1-5 , the heteroatom is independently selected from O, S and N 8-12 membered benzoheterocyclenyl";
C为连接键、C1-6亚烷基、C2-6烯基、-OC1-6亚烷基、-OC1-6亚烷基-OC1-6亚烷基、-C1-6亚烷基-O-C1-6亚烷基或C1-6亚烷基-NH-； C is a connecting bond, C 1-6 alkylene group, C 2-6 alkenyl group, -OC 1-6 alkylene group, -OC 1-6 alkylene group -OC 1-6 alkylene group, -C 1- 6 alkylene-OC 1-6 alkylene or C 1-6 alkylene-NH-;
D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、C3-10环烷基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基；D is a connecting bond, C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5 ~12-membered heteroaryl", C 3-10 cycloalkyl, substituted by one or more R 1-4 " contains 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12 members of O, S and N "Heteroaryl", or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N;
E为连接键；E is the connection key;
方案二：R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或C3-8环烷基；Option 2: R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
B为连接键、C3-10环烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-3取代的C6-20芳基、或、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”；B is a connecting bond, C 3-10 cycloalkyl group, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from O and N, C substituted by one or more R 1-3 6-20 aryl, or "5-12 membered heteroaryl containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
C为连接键或C1-6亚烷基；C is a connecting bond or C 1-6 alkylene group;
D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20亚芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”；D is a connecting bond, C 6-20 aryl group, C 6-20 arylene group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5-12-membered heteroaryl", or "5-12-membered heteroaryl containing 1-4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
E为连接键；E is the connection key;
其它基团的定义如前所述。Other groups are as defined previously.
在某一方案中，所述的如式I所示的吗啉基喹唑啉类化合物可为下述任一结构：


In a certain solution, the morpholinoquinazoline compound shown in Formula I can be any of the following structures:


本发明还提供了上述的如式I所示的含氮杂环化合物的制备方法。The present invention also provides a method for preparing the above-mentioned nitrogen-containing heterocyclic compound represented by Formula I.
路线一、合成路线如下：
Route 1. The synthesis route is as follows:
其中，R1、R2、A、B、C、D或E的定义均如前所述；MET独立地为金属基团，例如BF3K、B(OH)2；PG为保护基，所述保护基例如THP；ALK为C1-6烷基，例如甲基、乙基；所述路线一的步骤如下所述：化合物A1与A2通过偶联反应生成A3，A3水解得到A4，A4缩合转化为A5，A5脱除保护基得到化合物I。Among them, R 1 , R 2 , A, B, C, D or E are all as defined above; MET is independently a metal group, such as BF 3 K, B(OH) 2 ; PG is a protecting group, so The protective group is, for example, THP; ALK is a C 1-6 alkyl group, such as methyl, ethyl; the steps of the route one are as follows: Compounds A1 and A2 generate A3 through a coupling reaction, A3 is hydrolyzed to obtain A4, and A4 is condensed It is converted into A5, and A5 is removed from the protecting group to obtain compound I.
路线二、合成路线如下：
Route 2. The synthesis route is as follows:
其中，R1、R2、A、B、C、D或E的定义均同前所述；MET独立地为金属基团，例如BF3K、B(OH)2；PG为保护基，所述保护基例如Boc；ALK为C1-6烷基，例如甲基、乙基；所述路线二的步骤如下所述：化合物A1与B1通过偶联反应生成B2，B2脱除保护基转化为化合物B3，B3通过偶联等方式转化为A4，A4进一步转化得到化合物I。Among them, the definitions of R 1 , R 2 , A, B, C, D or E are as mentioned above; MET is independently a metal group, such as BF 3 K, B(OH) 2 ; PG is a protecting group, so The protecting group is, for example, Boc; ALK is a C 1-6 alkyl group, such as methyl, ethyl; the steps of route two are as follows: Compound A1 and B1 generate B2 through a coupling reaction, and B2 removes the protecting group and converts into Compound B3, B3 is converted to A4 through coupling, etc., and A4 is further converted to obtain compound I.
路线三、合成路线如下：
Route 3. The synthesis route is as follows:
其中，R1、R2、A、B、C、D或E的定义均同前所述；ALK为C1-6烷基，例如甲基、乙基；Q独立地为离去基团，例如OTs、Br；所述路线三的步骤如下所述：化合物C1与C2通过亲核取代反应生成A4，A4进一步转化得到化合物Ia。Among them, the definitions of R 1 , R 2 , A, B, C, D or E are as mentioned above; ALK is a C 1-6 alkyl group, such as methyl, ethyl; Q is independently a leaving group, For example, OTs and Br; the steps of Route 3 are as follows: Compounds C1 and C2 generate A4 through nucleophilic substitution reaction, and A4 is further converted to obtain compound Ia.
路线四、合成路线如下：
Route 4. The synthesis route is as follows:
其中，R1、R2、B、C、D或E的定义均同前所述；PG为保护基，所述保护基例如THP；所述路线四的步骤如下所述：化合物D1与D2通过还原胺化反应生成D3，D3脱保护转化为化合物Ib。Among them, the definitions of R 1 , R 2 , B, C, D or E are as mentioned above; PG is a protecting group, and the protecting group is such as THP; the steps of route 4 are as follows: Compounds D1 and D2 pass through Reductive amination reaction generates D3, which is deprotected and converted into compound Ib.
路线五、合成路线如下：
Route 5. The synthesis route is as follows:
其中，R1、R2、B、C、D或E的定义均同前所述；PG为保护基，所述保护基例如THP；所述路线五的步骤如下所述：化合物E1与E2通过还原胺化反应生成E3，E3脱保护转化为化合物Ic。Among them, the definitions of R 1 , R 2 , B, C, D or E are as mentioned above; PG is a protecting group, such as THP; the steps of route five are as follows: Compounds E1 and E2 pass through Reductive amination reaction generates E3, which is deprotected and converted into compound Ic.
本发明还提供了一种化合物：








The invention also provides a compound:








本发明还提供了一种药物组合物，其包含物质A和药用辅料；所述的物质A为治疗有效量的上述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药。The present invention also provides a pharmaceutical composition, which contains substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of the above-mentioned morpholinylquinazoline compound represented by formula I, and its pharmaceutical Acceptable salts, solvates, polymorphs or prodrugs thereof.
本发明还提供了一种物质A在制造预防或治疗涉及细胞异常增殖、分化或存活的疾病的药物中的应用，所述的物质A为治疗有效量的上述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药。The present invention also provides the application of substance A in the manufacture of medicines for preventing or treating diseases involving abnormal cell proliferation, differentiation or survival. The substance A is a therapeutically effective amount of the above-mentioned morpholine represented by formula I. Quinazoline compounds, their pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof.
在某一方案中，所述的疾病为癌症。In one embodiment, the disease is cancer.
在某一方案中，所述癌症为由恶性新生细胞的增殖而引发的，如肿瘤、赘生物、肉瘤、白血病、淋巴瘤等。In a certain scheme, the cancer is caused by the proliferation of malignant new cells, such as tumors, neoplasms, sarcomas, leukemias, lymphomas, etc.
在某一方案中，所述药物具有PI3Kδ抑制剂和HDAC双重抑制活性。 In a certain regimen, the drug has dual inhibitory activities of PI3Kδ inhibitor and HDAC.
本发明还提供了一种物质A在制造用于减少受试者体内循环的淋巴细胞数目的药物中的应用；所述的物质A为治疗有效量的上述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药。The present invention also provides an application of substance A in the manufacture of a drug for reducing the number of lymphocytes circulating in a subject; the substance A is a therapeutically effective amount of the above-mentioned morpholino group represented by formula I. Quinazoline compounds, their pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof.
在某一方案中，所述受试者包括患血液性疾病的受试者，例如血液性癌症，患有自身免疫性疾病的受试者，和需要调节免疫反应的受试者，如患有糖尿病的受试者或器官移植的接受者。In a certain aspect, the subject includes a subject suffering from a hematological disease, such as a hematological cancer, a subject suffering from an autoimmune disease, and a subject needing to modulate the immune response, such as a patient suffering from Diabetic subjects or organ transplant recipients.
本发明中，当RL-1、RL-2和RL-3独立地为C2-6烯基或C2-6炔基时，所述的烯基或炔基为烯烃或炔烃少一个或几个氢原子而成的烃基，比如，烯烃或炔烃少一个或两个氢原子而成烯基或炔基。同理，当其它基团的定义涉及到烷基、烯基或芳基时也是如此。In the present invention, when R L-1 , R L-2 and R L-3 are independently C 2-6 alkenyl or C 2-6 alkynyl, the alkenyl or alkynyl group is an alkene or alkyne A hydrocarbon group with one or more hydrogen atoms missing. For example, an alkene or alkyne has one or two hydrogen atoms missing to form an alkenyl or alkynyl group. The same applies when the definition of other groups refers to alkyl, alkenyl or aryl groups.
术语“多个”是指2个、3个、4个或5个。The term "plurality" means 2, 3, 4 or 5.
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When compounds of the present invention contain relatively basic functional groups, acid addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in pure solution or a suitable inert solvent. A salt. The pharmaceutically acceptable acid includes inorganic acid, and the inorganic acid includes but is not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acids include organic acids, and the organic acids include but are not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartaric acid, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4'-methylene-bis( 3-Hydroxy-2-naphthoic acid)), amino acids (such as glutamic acid, arginine), etc. When the compound of the present invention contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camille G.Wermuth, ed., Wiley-VCH, 2002).
术语“卤素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基及其类似烷基。The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It is similar to an alkyl group.
术语“亚烷基”是指作为两个其它类之间的连接基团，它也可以是直链或支链，例子 包括但不限于-CH2-，-CH2CH2-，-CH2CH2CH2CH(CH3)-，-CH2CH(CH2CH3)CH2-。The term "alkylene" is meant as a linking group between two other species, it can also be straight chain or branched, examples Including but not limited to -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH(CH 2 CH 3 )CH 2 -.
术语“烷氧基”是指基团-O-RX，其中，RX为如上文所定义的烷基。The term "alkoxy" refers to the group -ORX , where RX is alkyl as defined above.
术语“环烷基”是指具有指定的碳原子数(例如C3～C6)的、仅由碳原子组成的、饱和的环状基团，其为单环、桥环或螺环。环烷基包括但不限于环丙基、环丁基、环戊基、环己基等。The term "cycloalkyl" refers to a saturated cyclic group having a specified number of carbon atoms (eg, C 3 to C 6 ), consisting only of carbon atoms, and is a monocyclic, bridged or spirocyclic group. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
术语“芳基”是指由碳原子组成的芳香基团，每个环均具有芳香性。例如苯基或萘基。The term "aryl" refers to an aromatic group composed of carbon atoms, with each ring possessing aromatic properties. For example phenyl or naphthyl.
术语“杂芳基”是指具有指定环原子数(例如5～12元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团，其为单环或多环，且至少一个环具有芳香性(符合休克尔规则)。杂芳基通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。杂芳基包括但不限于呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、噁唑基、噻唑基、吡啶基、嘧啶基、吲哚基等。The term "heteroaryl" refers to a specified number of heteroatoms (such as 1, 2 or 3) and a specified heteroatom species (among N, O and S) with a specified number of ring atoms (e.g., 5 to 12 members). one or more) cyclic groups, which are monocyclic or polycyclic, and at least one ring is aromatic (in compliance with Huckel's rule). The heteroaryl group is connected to other segments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.
术语“杂环基”、“杂环”或“杂环烷基”指具有指定环原子数(例如3～8元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团，其为单环、桥环或螺环，且每一个环均为饱和的。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基、哌啶基等。The term "heterocyclyl", "heterocycle" or "heterocycloalkyl" refers to a group having a specified number of ring atoms (eg, 3 to 8 members), a specified number of heteroatoms (eg, 1, 2, or 3), A cyclic group specifying a heteroatom species (one or more of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidinyl, and the like.
术语“羟基”指一个-OH基团。The term "hydroxy" refers to a -OH group.
术语“氰基”指一个-CN基团。The term "cyano" refers to a -CN group.
术语“氧代”指一个＝O基团。The term "oxo" refers to an =O group.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common sense in the field, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本发明提供了吗啉基喹唑啉类化合物、其药物组合物及应用。本发明的吗啉基喹唑啉类化合物具有PI3Kδ抑制剂和HDAC双重抑制活性，有望实现更好的疗效，更广的应用。The positive and progressive effect of the present invention is that the present invention provides morpholinoquinazoline compounds, pharmaceutical compositions and applications thereof. The morpholinoquinazoline compound of the present invention has dual inhibitory activities of PI3Kδ inhibitor and HDAC, and is expected to achieve better curative effect and wider application.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by means of examples, but the present invention is not limited to the scope of the described examples. Experimental methods that do not indicate specific conditions in the following examples should be selected according to conventional methods and conditions, or according to product specifications.
本发明中，室温指环境温度，为10℃-35℃。过夜是指8-15小时。回流是指常压下溶剂回流温度。In the present invention, room temperature refers to the ambient temperature, which is 10°C-35°C. Overnight refers to 8-15 hours. Reflux refers to the solvent reflux temperature under normal pressure.
以下为实施例中使用到的缩写列表： The following is a list of abbreviations used in the examples:
PE             石油醚PE Petroleum Ether
EA             乙酸乙酯EA Ethyl acetate
DCM            二氯甲烷DCM Dichloromethane
THF            四氢呋喃THF Tetrahydrofuran
DMF            N,N-二甲基甲酰胺DMF N,N-dimethylformamide
DIPEA          二异丙基乙基胺DIPEA Diisopropylethylamine
DABCO          二氮杂二环辛烷DABCO         Diazabicyclooctane
TFA            三氟乙酸TFA trifluoroacetic acid
Tf             三氟甲磺酰基Tf trifluoromethanesulfonyl
Tf2O           三氟甲磺酸酐Tf 2 O trifluoromethanesulfonic anhydride
TsCl           对甲苯磺酰氯TsCl p-toluenesulfonyl chloride
Cbz-Cl         氯甲酸苄酯Cbz-Cl Benzyl chloroformate
Boc2O          二碳酸二叔丁酯Boc 2 O di-tert-butyl dicarbonate
Pd(PPh3)4      四三苯基膦钯Pd(PPh 3 ) 4 tetrakis triphenylphosphine palladium
Pd2(dba)3      二亚苄基丙酮二钯Pd 2 (dba) 3 dibenzylideneacetone dipalladium
Pd(dppf)Cl2    [1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物Pd(dppf)Cl 2 [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex
X-Phos         2-二环己基磷-2',4',6'-三异丙基联苯X-Phos 2-Dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl
HATU           2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯HATU 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate
PCC            氯铬酸吡啶PCC Pyridinium Chlorochromate
DMAP           对二甲氨基吡啶DMAP p-dimethylaminopyridine
CDI            N,N-碳酰二咪唑CDI N,N-carbonyldiimidazole
t-Butyl-x-Phos 2-二-叔丁膦基-2',4',6'-三异丙基联苯t-Butyl-x-Phos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl
化合物1的合成路线
Synthetic route of compound 1
化合物1-e的合成Synthesis of compound 1-e
根据专利CN104557872A路线和操作合成。It is synthesized according to the route and operation of patent CN104557872A.
化合物1-d的合成Synthesis of Compound 1-d
将化合物哌啶-4-甲酸甲酯(3.15g,22.00mmoL)溶解在50mL的乙腈中，室温下依次加入碘化钾(199mg,1.20mmoL)，溴甲基氟硼酸钾(4g,19.92mmoL)，在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后滤液减压浓缩，得到粗品。粗品溶解在5mL的乙腈，搅拌下滴加甲基叔丁基醚(100mL)，固体析出，过滤，滤饼用甲基叔丁基醚(20mL)洗涤，收集固体，真空干燥，得到化合物1-d(4.5g，100％)。LC-MS(ESI):m/z＝243.1[M+18]+.The compound piperidine-4-carboxylic acid methyl ester (3.15g, 22.00mmoL) was dissolved in 50 mL of acetonitrile, potassium iodide (199 mg, 1.20mmoL) and potassium bromomethylfluoroborate (4g, 19.92mmoL) were added successively at room temperature. Stir under nitrogen conditions at 80°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (10 mL), and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was dissolved in 5 mL of acetonitrile, and methyl tert-butyl ether (100 mL) was added dropwise with stirring. The solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (20 mL). The solid was collected and dried under vacuum to obtain compound 1- d(4.5g, 100%). LC-MS(ESI):m/z＝243.1[M+18] + .
化合物1-c的合成Synthesis of compound 1-c
室温下将化合物1-e(600mg,1.28mmoL)溶解在50mL的THF中，依次加入水(5mL)、1-d(1.0g,4.48mmoL)、醋酸钯(29mg,0.13mmoL)、X-Phos(122mg,0.26mmoL)、碳酸铯(1.25g,3.84mmoL)，反应混合物在80℃氮气条件下搅拌36小时。向反应体系中加入50mL水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝1:1)，得到化合物1-c(60mg,8％)。LC-MS(ESI):m/z＝589.2[M+1]+.Dissolve compound 1-e (600mg, 1.28mmoL) in 50mL of THF at room temperature, and add water (5mL), 1-d (1.0g, 4.48mmoL), palladium acetate (29mg, 0.13mmoL), and X-Phos in sequence. (122mg, 0.26mmoL), cesium carbonate (1.25g, 3.84mmoL), the reaction mixture was stirred under nitrogen at 80°C for 36 hours. Add 50 mL of water to the reaction system, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified through a fast separation column (PE/EA=1:1) to obtain compound 1-c (60 mg, 8%). LC-MS(ESI): m/z＝589.2[M+1] + .
化合物1-b的合成Synthesis of compound 1-b
将化合物1-c(60mg,0.10mmoL)溶解在5mL的甲醇中，室温下依次加入THF(5mL)、水(2.5mL)、氢氧化钠(41mg,1.02mmoL)，反应混合物室温下搅拌2小时。减压浓缩，残留物溶解在水(10mL)中，用1M HCl水溶液调节pH值到3，用混合溶剂 (DCM/MeOH＝10:1,100mL*2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩的粗品化合物1-b(58mg,100％)。LC-MS(ESI):m/z＝575.2[M+1]+.Compound 1-c (60 mg, 0.10 mmoL) was dissolved in 5 mL of methanol, THF (5 mL), water (2.5 mL), and sodium hydroxide (41 mg, 1.02 mmoL) were added successively at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. . Concentrate under reduced pressure, dissolve the residue in water (10 mL), adjust the pH value to 3 with 1M HCl aqueous solution, and use mixed solvents (DCM/MeOH=10:1, 100mL*2) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 1-b (58 mg, 100%). LC-MS(ESI): m/z＝575.2[M+1] + .
化合物1-a的合成Synthesis of Compound 1-a
室温下将化合物1-b(59mg,0.10mmoL)溶解在5mL的DMF中，冰浴下依次加入HATU(70mg,0.18mmoL)、DIPEA(101μL,0.61mmoL)，反应混合物在0℃下搅拌10分钟，然后加入O-(四氢-2H-吡喃)-2-羟胺(29mg，0.24mmoL)，反应混合物升到室温并搅拌16小时。反应用20mL水淬灭，用乙酸乙酯(80mL*2)萃取，有机相用饱和食盐水(100mL*3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品。粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物1-a(40mg,58％)。LC-MS(ESI):m/z＝674.2[M+1]+.Dissolve compound 1-b (59 mg, 0.10 mmoL) in 5 mL of DMF at room temperature, add HATU (70 mg, 0.18 mmoL) and DIPEA (101 μL, 0.61 mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (29 mg, 0.24 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with 20 mL of water, extracted with ethyl acetate (80 mL*2), the organic phase was washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified through a fast separation column (DCM/MeOH=10:1) to obtain compound 1-a (40 mg, 58%). LC-MS(ESI): m/z＝674.2[M+1] + .
化合物1的合成Synthesis of Compound 1
将化合物1-a(40mg,0.059mmoL)溶解在10mL的DCM中，冷却到0℃，慢慢滴加氯化氢的1,4-二氧六环溶液(4M,0.5mL)，加毕，混合物在0℃下搅拌10分钟后，用饱和碳酸氢钠溶液(10mL)淬灭反应，用混合溶剂(DCM/MeOH＝10:1,100mL*2)，有机相用无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过PREP-HPLC纯化(DCM/MeOH＝6:1)，得到化合物1(6mg,17％)。LC-MS(ESI):m/z＝590.2[M+1]+；1H NMR(400MHz,CDCl3):δ8.25(1H,d,J＝2.0Hz),8.09(1H,s),8.05-8.00(2H,m),7.61-7.57(1H,m),7.32-7.28(1H,m),4.67-4.58(1H,m),4.12-4.01(1H,m),4.04(3H,s),4.00-3.93(2H,m),3.91-3.81(4H,m),3.80-3.70(4H,m),3.37(1H,s),3.05-2.91(1H,m),2.99(3H,s),2.31-2.04(5H,m),1.58-1.49(2H,m).Dissolve compound 1-a (40 mg, 0.059 mmoL) in 10 mL of DCM, cool to 0°C, and slowly add hydrogen chloride in 1,4-dioxane solution (4 M, 0.5 mL) dropwise. After the addition is completed, the mixture is After stirring at 0°C for 10 minutes, the reaction was quenched with saturated sodium bicarbonate solution (10 mL), and mixed solvent (DCM/MeOH=10:1, 100 mL*2) was used. The organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure. Concentrate to obtain a crude product, which is purified by PREP-HPLC (DCM/MeOH=6:1) to obtain compound 1 (6 mg, 17%). LC-MS (ESI): m/z=590.2[M+1] + ; 1 H NMR (400MHz, CDCl 3 ): δ8.25 (1H, d, J=2.0Hz), 8.09 (1H, s), 8.05-8.00(2H,m),7.61-7.57(1H,m),7.32-7.28(1H,m),4.67-4.58(1H,m),4.12-4.01(1H,m),4.04(3H,s ),4.00-3.93(2H,m),3.91-3.81(4H,m),3.80-3.70(4H,m),3.37(1H,s),3.05-2.91(1H,m),2.99(3H,s ),2.31-2.04(5H,m),1.58-1.49(2H,m).
化合物2的合成路线
Synthetic route of compound 2
化合物2-d的合成Synthesis of Compound 2-d
将化合物哌啶-4-乙酸乙酯(2.50g，14.60mmoL)溶解在50mL的乙腈中，室温下依次加入碘化钾(132mg，0.80mmoL)，溴甲基氟硼酸钾(2.67g，13.28mmoL)，在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后滤液减压浓缩，得到粗品。粗品溶解在3mL的乙腈，搅拌下滴加甲基叔丁基醚(30mL)， 固体析出，过滤，滤饼用甲基叔丁基醚(10mL)洗涤，收集固体，真空干燥，得到化合物2-d(3.3g，100％)。LC-MS(ESI):m/z＝271.2[M+18]+.Dissolve the compound piperidine-4-acetate ethyl ester (2.50g, 14.60mmoL) in 50mL acetonitrile, and add potassium iodide (132mg, 0.80mmoL) and potassium bromomethylfluoroborate (2.67g, 13.28mmoL) in sequence at room temperature. Stir under nitrogen at 80°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (10 mL), and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was dissolved in 3 mL of acetonitrile, and methyl tert-butyl ether (30 mL) was added dropwise while stirring. The solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (10 mL). The solid was collected and dried under vacuum to obtain compound 2-d (3.3 g, 100%). LC-MS(ESI): m/z＝271.2[M+18] + .
化合物2的合成Synthesis of Compound 2
参照化合物1的合成路线和操作，使用化合物2-d替代化合物1-d，得到化合物2(82mg)。LC-MS(ESI):m/z＝604.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.42(1H,s),9.59(1H,brs),8.72(1H,s),8.42(1H,d,J＝1.2Hz),8.01(1H,d,J＝1.2Hz),7.59(1H,brs),4.67-4.63(1H,m),4.03(3H,s),3.96-3.81(4H,m),3.79-3.64(4H,m),3.56(4H,s),3.11(3H,s),1.96-1.83(2H,m),1.79-1.64(2H,m),1.63-1.53(1H,m),1.52-1.28(3H,m).Referring to the synthetic route and operation of compound 1, compound 2-d was used instead of compound 1-d to obtain compound 2 (82 mg). LC-MS (ESI): m/z=604.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.42 (1H, s), 9.59 (1H, brs), 8.72 (1H ,s),8.42(1H,d,J＝1.2Hz),8.01(1H,d,J＝1.2Hz),7.59(1H,brs),4.67-4.63(1H,m),4.03(3H,s) ,3.96-3.81(4H,m),3.79-3.64(4H,m),3.56(4H,s),3.11(3H,s),1.96-1.83(2H,m),1.79-1.64(2H,m) ,1.63-1.53(1H,m),1.52-1.28(3H,m).
化合物3的合成路线
Synthetic route of compound 3
化合物3-g的合成Synthesis of compound 3-g
将化合物1-Boc-4-甲酰基哌啶(3.5g，16.40mmoL)溶解在50mL的氯仿中，加入甲氧甲酰基亚甲基三苯基膦(5.5g，16.45mmoL)，反应混合物回流16小时。冷到室温，减压浓缩，残余物悬浮在50mL的乙醚中，过滤，滤饼用乙醚(10mL)淋洗，将滤液减压浓缩，得到粗品，粗品通过快速分离柱分离纯化(PE/EA＝5:1)，得到化合物3-g(4.4g，100％)。LC-MS(ESI):m/z＝292.1[M+Na]+.Compound 1-Boc-4-formylpiperidine (3.5g, 16.40mmoL) was dissolved in 50 mL of chloroform, methoxyformylmethylenetriphenylphosphine (5.5g, 16.45mmoL) was added, and the reaction mixture was refluxed for 16 Hour. Cool to room temperature, concentrate under reduced pressure, suspend the residue in 50 mL of diethyl ether, filter, rinse the filter cake with diethyl ether (10 mL), and concentrate the filtrate under reduced pressure to obtain a crude product, which is separated and purified through a rapid separation column (PE/EA= 5:1), obtaining compound 3-g (4.4g, 100%). LC-MS(ESI): m/z=292.1[M+Na] + .
化合物3-f的合成Synthesis of compound 3-f
将化合物3-g(3g，11.14mmoL)溶解在100mL的甲醇中，加入Pd/C(50％wet，10％，0.6g)，反应体系先用氮气置换3次，再用氢气置换3次，然后反应混合物在室温氢气条件下搅拌16小时。过滤，滤饼用甲醇(20mL)淋洗，将滤液减压浓缩，得到化合物3-f(2.56g，85％)。LC-MS(ESI):m/z＝294.1[M+Na]+.Dissolve compound 3-g (3g, 11.14mmoL) in 100 mL of methanol, add Pd/C (50% wet, 10%, 0.6g), and replace the reaction system with nitrogen three times and then with hydrogen three times. The reaction mixture was then stirred under hydrogen at room temperature for 16 hours. Filter, rinse the filter cake with methanol (20 mL), and concentrate the filtrate under reduced pressure to obtain compound 3-f (2.56 g, 85%). LC-MS(ESI): m/z=294.1[M+Na] + .
化合物3-e的合成Synthesis of compound 3-e
将化合物3-f(2.56g，9.43mmoL)溶解在10mL的甲醇中，室温条件下加入氯化氢的甲醇溶液(4M，30mL)，反应混合物在室温下搅拌2天。减压浓缩后，将粗产物悬浮在30mL的饱和碳酸氢钠溶液中，减压浓缩，真空干燥1小时后，将粗产物悬浮在50mL 的THF中，过滤，滤饼用THF(10mL)淋洗，将滤液减压浓缩，得到化合物3-e(520mg，32％)。LC-MS(ESI):m/z＝172.2[M+H]+.Compound 3-f (2.56g, 9.43mmoL) was dissolved in 10 mL of methanol, a methanol solution of hydrogen chloride (4M, 30 mL) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 days. After concentration under reduced pressure, the crude product was suspended in 30 mL of saturated sodium bicarbonate solution, concentrated under reduced pressure, and dried under vacuum for 1 hour. The crude product was suspended in 50 mL of saturated sodium bicarbonate solution. in THF, filtered, the filter cake was rinsed with THF (10 mL), and the filtrate was concentrated under reduced pressure to obtain compound 3-e (520 mg, 32%). LC-MS(ESI): m/z=172.2[M+H] + .
化合物3-d的合成Synthesis of Compound 3-d
将化合物3-e(520mg，3.04mmoL)溶解在20mL的乙腈中，室温下依次加入碘化钾(27mg，0.17mmoL)，溴甲基氟硼酸钾(554mg，2.76mmoL)，然后在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(5mL)洗涤，然后将滤液减压浓缩，得到粗品。粗品溶解在2mL的乙腈，搅拌下滴加甲基叔丁基醚(50mL)，固体析出，过滤，滤饼用甲基叔丁基醚(10mL)洗涤，收集固体，真空干燥，得到化合物3-d(635mg，91％)。LC-MS(ESI):m/z＝271.2[M+18]+.Compound 3-e (520 mg, 3.04 mmoL) was dissolved in 20 mL of acetonitrile, potassium iodide (27 mg, 0.17 mmoL) and potassium bromomethylfluoroborate (554 mg, 2.76 mmoL) were added successively at room temperature, and then incubated under nitrogen at 80°C. Stir for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (5 mL), and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was dissolved in 2 mL of acetonitrile, and methyl tert-butyl ether (50 mL) was added dropwise with stirring. The solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (10 mL). The solid was collected and dried under vacuum to obtain compound 3- d (635 mg, 91%). LC-MS(ESI):m/z＝271.2[M+18] + .
化合物3的合成Synthesis of Compound 3
参照化合物1的合成路线和操作，使用化合物3-d替代化合物1-d，得到化合物3(120mg)。LC-MS(ESI):m/z＝618.3[M+1]+；1H NMR(400MHz,CDCl3):δ8.32(1H,d,J＝1.2Hz),8.15(1H,s),7.68(1H,brs),7.42-7.31(1H,m),5.02-4.87(1H,m),4.11(2H,s),4.11-4.05(2H,m),3.93(4H,s),3.82(4H,s),3.70(3H,s),3.07(3H,s),3.11-2.95(2H,m),2.36-2.08(4H,m),1.90-1.46(7H,m).Referring to the synthetic route and operation of compound 1, compound 3-d was used instead of compound 1-d to obtain compound 3 (120 mg). LC-MS (ESI): m/z=618.3[M+1] + ; 1 H NMR (400MHz, CDCl 3 ): δ8.32 (1H, d, J=1.2Hz), 8.15 (1H, s), 7.68(1H,brs),7.42-7.31(1H,m),5.02-4.87(1H,m),4.11(2H,s),4.11-4.05(2H,m),3.93(4H,s),3.82( 4H,s),3.70(3H,s),3.07(3H,s),3.11-2.95(2H,m),2.36-2.08(4H,m),1.90-1.46(7H,m).
化合物4的合成路线
Synthetic route of compound 4
化合物4-e的合成Synthesis of compound 4-e
将化合物1-Boc-4-哌啶-丁酸(1g,3.68mmoL)溶解在10mL的甲醇中，冷却到0℃，滴加氯化亚砜(1mL)，反应混合物升到室温并搅拌5小时。减压浓缩，得到化合物4-e(816mg,100％)。LC-MS(ESI):m/z＝186.2[M+H]+.Compound 1-Boc-4-piperidine-butyric acid (1g, 3.68mmoL) was dissolved in 10mL of methanol, cooled to 0°C, thionyl chloride (1mL) was added dropwise, and the reaction mixture was raised to room temperature and stirred for 5 hours. . Concentrate under reduced pressure to obtain compound 4-e (816 mg, 100%). LC-MS(ESI): m/z=186.2[M+H] + .
化合物4-d的合成Synthesis of Compound 4-d
将化合物4-e(816mg,3.68mmoL)溶解在20mL的乙腈中，室温下依次加入碘化钾(33mg,0.20mmoL)，碳酸钾(693mg,5.02mmoL)，溴甲基氟硼酸钾(673mg,3.35mmoL)， 然后在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后将滤液减压浓缩，得到粗品。粗品溶解在2mL的乙腈，搅拌下滴加甲基叔丁基醚(80mL)，固体析出，过滤，滤饼用甲基叔丁基醚(10mL)洗涤，收集固体，真空干燥，得到化合物4-d(838mg,94％)。LC-MS(ESI):m/z＝285.2[M+18]+.Dissolve compound 4-e (816 mg, 3.68 mmoL) in 20 mL of acetonitrile, and add potassium iodide (33 mg, 0.20 mmoL), potassium carbonate (693 mg, 5.02 mmoL), and potassium bromomethylfluoroborate (673 mg, 3.35 mmoL) in sequence at room temperature. ), Then stir at 80°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (10 mL), and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was dissolved in 2 mL of acetonitrile, and methyl tert-butyl ether (80 mL) was added dropwise with stirring. The solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (10 mL). The solid was collected and dried under vacuum to obtain compound 4- d(838mg,94%). LC-MS(ESI): m/z＝285.2[M+18] + .
化合物4的合成Synthesis of compound 4
参照化合物1的合成路线和操作，使用化合物4-d替代化合物1-d，得到化合物4(50mg)。LC-MS(ESI):m/z＝632.2[M+1]+；1H NMR(400MHz,CD3OD):δ8.29(1H,d,J＝2.0Hz),8.04(1H,d,J＝2.4Hz),7.78(1H,d,J＝6.4Hz),7.65(1H,dd,J1＝8.8Hz,J2＝2.4Hz),4.68(2H,s),4.02(3H,s),3.88(4H,t,J＝4Hz),3.72(4H,t,J＝5.2Hz),3.59-3.45(2H,m),3.09(2H,t,J＝12.4Hz),2.95(3H,s),1.98(1H,t,J＝7.6Hz),1.94-1.64(3H,m),1.60-1.46(3H,m),1.44-1.20(4H,m).Referring to the synthetic route and operation of compound 1, compound 4-d was used instead of compound 1-d to obtain compound 4 (50 mg). LC-MS (ESI): m/z=632.2[M+1] + ; 1 H NMR (400MHz, CD 3 OD): δ8.29 (1H, d, J=2.0Hz), 8.04 (1H, d, J＝2.4Hz),7.78(1H,d,J＝6.4Hz),7.65(1H,dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz),4.68(2H,s),4.02(3H,s) ,3.88(4H,t,J＝4Hz),3.72(4H,t,J＝5.2Hz),3.59-3.45(2H,m),3.09(2H,t,J＝12.4Hz),2.95(3H,s ),1.98(1H,t,J＝7.6Hz),1.94-1.64(3H,m),1.60-1.46(3H,m),1.44-1.20(4H,m).
化合物5的合成路线
Synthetic route of compound 5
化合物5-e的合成Synthesis of compound 5-e
将化合物3-g(1.7g,6.31mmoL)溶解在20mL的DCM中，冰浴下，加入TFA(4mL)，然后反应混合物在室温下搅拌5小时。减压浓缩，得到化合物5-e(1.78g,100％)。LC-MS(ESI):m/z＝170.2[M+H]+.Compound 3-g (1.7g, 6.31mmoL) was dissolved in 20 mL of DCM, TFA (4 mL) was added under ice bath, and then the reaction mixture was stirred at room temperature for 5 hours. Concentrate under reduced pressure to obtain compound 5-e (1.78g, 100%). LC-MS(ESI): m/z=170.2[M+H] + .
化合物5-d的合成Synthesis of compound 5-d
将化合物5-e(1.78g,6.28mmoL)溶解在40mL的乙腈中，室温下依次加入碘化钾(56.9mg,0.34mmoL)，碳酸钾(1.18g,8.56mmoL)，溴甲基氟硼酸钾(1.15g,5.71mmoL)，然后在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后将滤液减压浓缩，得到粗品。粗品溶解在5mL的乙腈，搅拌下滴加甲基叔丁 基醚(100mL)，固体析出，过滤，滤饼用甲基叔丁基醚(10mL)洗涤，收集固体，真空干燥，得到粗品化合物5-d(1.58g,100％)。LC-MS(ESI):m/z＝269.2[M+18]+.Dissolve compound 5-e (1.78g, 6.28mmoL) in 40 mL of acetonitrile, and add potassium iodide (56.9 mg, 0.34mmoL), potassium carbonate (1.18g, 8.56mmoL), and potassium bromomethylfluoroborate (1.15 g, 5.71mmoL), and then stirred at 80°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (10 mL), and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was dissolved in 5 mL of acetonitrile, and methyl tert-butyl was added dropwise while stirring. methyl ether (100 mL), a solid precipitated, filtered, and the filter cake was washed with methyl tert-butyl ether (10 mL). The solid was collected and dried under vacuum to obtain crude compound 5-d (1.58 g, 100%). LC-MS(ESI): m/z＝269.2[M+18] + .
化合物5的合成Synthesis of compound 5
参照化合物1的合成路线和操作，使用化合物5-d替代化合物1-d，得到化合物5(50mg,88％)。LC-MS(ESI):m/z＝616.2[M+1]+；1H NMR(400MHz,CD3OD):δ8.38(1H,d,J＝2.4Hz),8.15(1H,d,J＝2.0Hz),7.77(1H,d,J＝7.6Hz),7.62(1H,d,J＝10.0Hz),6.77(1H,dd,J1＝15.6Hz,J2＝6.8Hz),5.84(1H,d,J＝15.2Hz),4.52-4.28(2H,m),4.13(3H,s),4.04-3.89(4H,m),3.89-3.77(4H,m),3.41-3.35(1H,m),3.07(3H,s),2.99-2.86(1H,m),2.86-2.32(3H,m),1.92(2H,d,J＝13.2Hz),1.75-1.53(2H,m).Referring to the synthetic route and operation of compound 1, compound 5-d was used instead of compound 1-d to obtain compound 5 (50 mg, 88%). LC-MS (ESI): m/z=616.2[M+1] + ; 1 H NMR (400MHz, CD 3 OD): δ8.38 (1H, d, J=2.4Hz), 8.15 (1H, d, J＝2.0Hz),7.77(1H,d,J＝7.6Hz),7.62(1H,d,J＝10.0Hz),6.77(1H,dd,J 1 ＝15.6Hz,J 2 ＝6.8Hz),5.84 (1H,d,J＝15.2Hz),4.52-4.28(2H,m),4.13(3H,s),4.04-3.89(4H,m),3.89-3.77(4H,m),3.41-3.35(1H ,m),3.07(3H,s),2.99-2.86(1H,m),2.86-2.32(3H,m),1.92(2H,d,J＝13.2Hz),1.75-1.53(2H,m).
化合物6的合成路线
Synthetic route of compound 6
化合物6-f的合成Synthesis of compound 6-f
将化合物1-Boc-哌嗪(2g,10.74mmoL)溶解在50mL的乙腈中，室温下依次加入碘化钾(97mg,0.58mmoL)，溴甲基氟硼酸钾(1.95g,9.71mmoL)，然后在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后将滤液减压浓缩，得到粗品。粗品溶解在3mL的乙腈，搅拌下滴加甲基叔丁基醚(100mL)，固体析出，过滤，滤饼用甲基叔丁基醚(10mL)洗涤，收集固体，真空干燥，得到化合物6-f(1.9g,73％)。LC-MS(ESI):m/z＝286.2[M+18]+.Compound 1-Boc-piperazine (2g, 10.74mmoL) was dissolved in 50 mL of acetonitrile, potassium iodide (97 mg, 0.58mmoL) and potassium bromomethylfluoroborate (1.95g, 9.71mmoL) were added successively at room temperature, and then incubated at 80 ° C under nitrogen conditions for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (10 mL), and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was dissolved in 3 mL of acetonitrile, and methyl tert-butyl ether (100 mL) was added dropwise with stirring. The solid precipitated and was filtered. The filter cake was washed with methyl tert-butyl ether (10 mL). The solid was collected and dried under vacuum to obtain compound 6- f(1.9g,73%). LC-MS(ESI): m/z＝286.2[M+18] + .
化合物6-e的合成Synthesis of compound 6-e
室温下将化合物1-e(600mg,1.28mmoL)溶解在100mL的THF中，依次加入水 (10mL)、6-f(1.03g,3.84mmoL)、醋酸钯(29mg,0.13mmoL)、x-Phos(122mg,0.26mmoL)、碳酸铯(1.25g,3.85mmoL)，反应混合物在80℃氮气条件下搅拌36小时。向反应体系中加入100mL水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝1:1～EA)，得到化合物6-e(810mg,100％)。LC-MS(ESI):m/z＝632.2[M+1]+.Dissolve compound 1-e (600mg, 1.28mmoL) in 100mL THF at room temperature, and add water in sequence (10mL), 6-f (1.03g, 3.84mmoL), palladium acetate (29mg, 0.13mmoL), x-Phos (122mg, 0.26mmoL), cesium carbonate (1.25g, 3.85mmoL), the reaction mixture was heated at 80°C under nitrogen Stir under these conditions for 36 hours. Add 100 mL of water to the reaction system, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified through a fast separation column (PE/EA=1:1~EA) to obtain compound 6-e (810 mg, 100%). LC-MS(ESI): m/z=632.2[M+1] + .
化合物6-d的合成Synthesis of compound 6-d
将化合物6-e(810mg,1.28mmoL)，溶解在36mL的DCM中，并冷却到0℃，加入TFA(9mL)，反应混合物升到室温，搅拌3小时，减压浓缩，真空干燥1小时，得到粗品化合物6-d(1.3g,100％)。LC-MS(ESI):m/z＝532.2[M+1]+.Dissolve compound 6-e (810 mg, 1.28 mmoL) in 36 mL of DCM, cool to 0°C, add TFA (9 mL), raise the reaction mixture to room temperature, stir for 3 hours, concentrate under reduced pressure, and dry under vacuum for 1 hour. Crude compound 6-d (1.3 g, 100%) was obtained. LC-MS(ESI): m/z＝532.2[M+1] + .
化合物6-c的合成Synthesis of compound 6-c
将化合物6-d(400mg,0.40mmoL)溶解在20mL的DMF中，依次加入碳酸钾(386mg,2.80mmoL)，5-溴-戊酸甲酯(63μL,0.44mmoL)，反应混合物在室温氮气条件下搅拌2天。加入30mL的水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物6-c(240mg,93％)。LC-MS(ESI):m/z＝646.2[M+1]+.Dissolve compound 6-d (400 mg, 0.40 mmoL) in 20 mL of DMF, add potassium carbonate (386 mg, 2.80 mmoL) and 5-bromo-pentanoic acid methyl ester (63 μL, 0.44 mmoL) in sequence, and the reaction mixture is maintained under nitrogen at room temperature. Stir for 2 days. Add 30 mL of water, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is passed through a rapid separation column After separation and purification (DCM/MeOH=10:1), compound 6-c (240 mg, 93%) was obtained. LC-MS(ESI): m/z＝646.2[M+1] + .
化合物6的合成Synthesis of compound 6
参照化合物1的合成路线和操作，使用化合物6-c替代化合物1-c，得到化合物6(46mg)。LC-MS(ESI):m/z＝647.1[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.40(1H,s),8.71(1H,s),8.39(1H,d,J＝2Hz),7.98(1H,d,J＝2.0Hz),7.71(1H,d,J＝8.4Hz),7.47(1H,d,J＝8.8Hz),4.04(2H,s),4.02(3H,s),3.91-3.79(4H,m),3.78-3.67(4H,m),3.09(3H,s),3.02-2.55(7H,m),2.04-1.88(2H,m),1.64-1.37(4H,m),1.37-1.07(4H,m).Referring to the synthetic route and operation of compound 1, compound 6-c was used instead of compound 1-c to obtain compound 6 (46 mg). LC-MS(ESI): m/z=647.1[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.40(1H,s),8.71(1H,s),8.39(1H ,d,J＝2Hz),7.98(1H,d,J＝2.0Hz),7.71(1H,d,J＝8.4Hz),7.47(1H,d,J＝8.8Hz),4.04(2H,s) ,4.02(3H,s),3.91-3.79(4H,m),3.78-3.67(4H,m),3.09(3H,s),3.02-2.55(7H,m),2.04-1.88(2H,m) ,1.64-1.37(4H,m),1.37-1.07(4H,m).
化合物7的合成路线
Synthetic route of compound 7
化合物7-c的合成Synthesis of compound 7-c
将化合物6-d(400mg,约0.40mmoL)溶解在20mL的DMF中，依次加入DIPEA(660μL,4mmoL)，2-氯-嘧啶-4-甲酸乙酯(82mg,0.44mmoL)，反应混合物在室温氮气条件下搅拌16小时。加入30mL的水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐 水(100mL*3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物7-c(200mg,73％)。LC-MS(ESI):m/z＝682.2[M+1]+.Dissolve compound 6-d (400mg, about 0.40mmoL) in 20mL of DMF, add DIPEA (660μL, 4mmoL) and 2-chloro-pyrimidine-4-carboxylic acid ethyl ester (82mg, 0.44mmoL) in sequence, and the reaction mixture is at room temperature. Stir under nitrogen for 16 hours. Add 30mL of water, extract with ethyl acetate (100mL*2), and use saturated salt for the organic phase. Wash with water (100mL*3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is separated and purified by a rapid separation column (DCM/MeOH=10:1) to obtain compound 7-c (200 mg, 73 %). LC-MS(ESI): m/z＝682.2[M+1] + .
化合物7的合成Synthesis of Compound 7
参照化合物1的合成路线和操作，使用化合物7-c替代化合物1-c，得到化合物7(130mg)。LC-MS(ESI):m/z＝669.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ11.07(1H,s),9.51(1H,s),9.00(1H,s),8.67(2H,d,J＝5.2Hz),8.41(1H,d,J＝2.4Hz),8.01(1H,d,J＝2.0Hz),7.77(1H,dd,J1＝2.8Hz,J2＝8.8Hz),7.47(1H,dd,J1＝3.2Hz,J2＝9.6Hz),4.04(2H,s),4.03(3H,s),3.93-3.78(8H,m),3.77-3.63(4H,m),3.10(3H,s),2.62-2.54(4H,m).Referring to the synthetic route and operation of compound 1, compound 7-c was used instead of compound 1-c to obtain compound 7 (130 mg). LC-MS(ESI): m/z=669.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ11.07(1H,s),9.51(1H,s),9.00(1H ,s),8.67(2H,d,J＝5.2Hz),8.41(1H,d,J＝2.4Hz),8.01(1H,d,J＝2.0Hz),7.77(1H,dd,J 1 ＝2.8 Hz,J 2 =8.8Hz),7.47(1H,dd,J 1 =3.2Hz,J 2 =9.6Hz),4.04(2H,s),4.03(3H,s),3.93-3.78(8H,m) ,3.77-3.63(4H,m),3.10(3H,s),2.62-2.54(4H,m).
化合物8的合成路线
Synthetic route of compound 8
化合物8-d的合成Synthesis of compound 8-d
将化合物1-e(600mg,1.28mmoL)溶解在25mL的1,4-二氧六环中，室温下依次加入水(15mL)、Pd2(dba)3(117mg,0.13mmoL)、t-Butyl-x-Phos(217mg,0.51mmoL)、KOH(3.1g,55.04mmoL)。反应混合物在100℃氮气条件下搅拌16小时。将反应混合物冷却到0℃，慢慢滴加1N的盐酸(约55mL,pH＝4～5)，用DCM萃取(200mL*2)，有机相用无水硫酸钠干燥、过滤，滤液减压浓缩，得到粗品。粗品通过快速分离柱分离纯化(二氯甲烷：甲醇＝10:1)，得到化合物8-d(575mg,100％)。LC-MS(ESI):m/z＝450.1[M+1]+. Compound 1-e (600mg, 1.28mmoL) was dissolved in 25mL of 1,4-dioxane, and water (15mL), Pd 2 (dba) 3 (117mg, 0.13mmoL), and t-Butyl were added in sequence at room temperature. -x-Phos (217mg, 0.51mmoL), KOH (3.1g, 55.04mmoL). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. Cool the reaction mixture to 0°C, slowly add 1N hydrochloric acid (about 55mL, pH=4~5) dropwise, extract with DCM (200mL*2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , get crude product. The crude product was separated and purified through a fast separation column (dichloromethane: methanol = 10:1) to obtain compound 8-d (575 mg, 100%). LC-MS(ESI): m/z＝450.1[M+1] + .
化合物8-c的合成Synthesis of compound 8-c
室温条件下，将化合物6-溴-己酸甲酯(92mg,0.44mmoL)溶解在10mL的DMF中，加入碳酸铯(217mg,0.67mmoL)。反应混合物在80℃氮气条件下搅拌10分钟后，将化合物8-d(200mg,0.44mmoL)加入上述反应体系中，并且在80℃氮气条件下搅拌16小时。将反应混合物冷却到室温，加入50mL水，用乙酸乙酯萃取(100mL*2)，有机相用无水硫酸钠干燥、过滤，滤液加压浓缩，得到粗品，粗品通过快速分离柱分离纯化(石油醚：乙酸乙酯＝1:1)，得到化合物8-c(157mg,62％)。LC-MS(ESI):m/z＝578.2[M+1]+.At room temperature, compound 6-bromo-hexanoic acid methyl ester (92 mg, 0.44 mmoL) was dissolved in 10 mL of DMF, and cesium carbonate (217 mg, 0.67 mmoL) was added. After the reaction mixture was stirred at 80°C under nitrogen for 10 minutes, compound 8-d (200 mg, 0.44mmoL) was added to the above reaction system, and stirred at 80°C under nitrogen for 16 hours. Cool the reaction mixture to room temperature, add 50 mL of water, and extract with ethyl acetate (100 mL*2). The organic phase is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated under pressure to obtain a crude product. The crude product is separated and purified through a rapid separation column (petroleum Ether: ethyl acetate = 1:1) to obtain compound 8-c (157 mg, 62%). LC-MS(ESI):m/z＝578.2[M+1] + .
化合物8-b的合成Synthesis of compound 8-b
将化合物8-c(157mg,0.27mmoL)溶解在10mL的甲醇中，室温下依次加入THF(10mL)、水(5mL)、氢氧化钠(54mg,1.36mmoL)，反应混合物室温下搅拌2小时。减压浓缩，残留物溶解在水(20mL)中，用1N HCl水溶液调节pH值到4～5，用DCM萃取(100mL*2)，有机相用无水硫酸钠干燥、过滤，减压浓缩，得到化合物8-b(153mg,100％)。LC-MS(ESI):m/z＝564.2[M+1]+.Compound 8-c (157 mg, 0.27 mmoL) was dissolved in 10 mL of methanol, THF (10 mL), water (5 mL), and sodium hydroxide (54 mg, 1.36 mmoL) were added in sequence at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. Concentrate under reduced pressure, dissolve the residue in water (20mL), adjust the pH value to 4~5 with 1N HCl aqueous solution, extract with DCM (100mL*2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Compound 8-b (153 mg, 100%) was obtained. LC-MS(ESI): m/z＝564.2[M+1] + .
化合物8-a的合成Synthesis of compound 8-a
室温下将化合物8-b(153mg,0.27mmoL)溶解在10mL的DMF中，冰浴下依次加入HATU(154mg,0.41mmoL)、DIPEA(224uL,1.36mmoL)，反应混合物在0℃下搅拌10分钟，然后加入O-(四氢-2H-吡喃)-2-羟胺(64mg,0.54mmoL)，将反应混合物升到室温并搅拌16小时。反应用30mL水淬灭，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品。粗品通过PREP-HPLC分离纯化，得到化合物8-a(125mg,70％)。LC-MS(ESI):m/z＝663.2[M+1]+.Dissolve compound 8-b (153mg, 0.27mmoL) in 10mL of DMF at room temperature, add HATU (154mg, 0.41mmoL) and DIPEA (224uL, 1.36mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (64 mg, 0.54 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with 30 mL of water, extracted with ethyl acetate (100 mL*2), the organic phase was washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by PREP-HPLC to obtain compound 8-a (125 mg, 70%). LC-MS(ESI): m/z=663.2[M+1] + .
化合物8的合成Synthesis of compound 8
将化合物8-a(125mg,0.19mmoL)溶解在20mL的DCM中，冷却到0℃，慢慢滴加氯化氢的1,4-二氧六环溶液(4M,1mL)，加毕，混合物在0℃下搅拌10分钟后，用饱和碳酸氢钠溶液(30mL)淬灭反应，用混合溶剂(DCM/MeOH＝10:1,100mL*5)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩，得到化合物8(85mg,78％)。LC-MS(ESI):m/z＝579.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.36(1H,s),9.51(1H,s),8.39(1H,dd,J＝2.4Hz),7.99(1H,dd,J＝1.6Hz),7.22(1H,dd,J1＝2.4Hz,J2＝10.8Hz),7.07(1H,dd,J1＝2.4Hz,J2＝9.6Hz),4.14(2H,t,J＝6.4Hz),4.03(3H,s),3.89-3.76(4H,m),3.76-3.62(4H,m),3.62-3.53(1H,m),3.10(3H,s),1.99(2H,t,J＝7.2Hz),1.90-1.75(2H,m),1.68-1.56(2H,m),1.54-1.39(2H,m).Dissolve compound 8-a (125 mg, 0.19 mmoL) in 20 mL of DCM, cool to 0°C, and slowly add hydrogen chloride in 1,4-dioxane solution (4 M, 1 mL) dropwise. After the addition is completed, the mixture is at 0 After stirring for 10 minutes at ℃, the reaction was quenched with saturated sodium bicarbonate solution (30mL), extracted with a mixed solvent (DCM/MeOH=10:1, 100mL*5), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentration gave compound 8 (85 mg, 78%). LC-MS(ESI): m/z=579.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.36(1H,s),9.51(1H,s),8.39(1H ,dd,J＝2.4Hz),7.99(1H,dd,J＝1.6Hz),7.22(1H,dd,J 1 ＝2.4Hz,J 2 ＝10.8Hz),7.07(1H,dd,J 1 ＝2.4 Hz,J 2 =9.6Hz),4.14(2H,t,J＝6.4Hz),4.03(3H,s),3.89-3.76(4H,m),3.76-3.62(4H,m),3.62-3.53( 1H,m),3.10(3H,s),1.99(2H,t,J＝7.2Hz),1.90-1.75(2H,m),1.68-1.56(2H,m),1.54-1.39(2H,m) .
化合物9的合成路线
Synthetic route of compound 9
化合物9的合成Synthesis of Compound 9
参照化合物8的合成路线和操作，使用化合物7-溴-庚酸甲酯替代化合物6-溴-己酸甲酯，得到化合物9(118mg)。LC-MS(ESI):m/z＝593.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.35(1H,s),9.51(1H,s),8.67(1H,d,J＝1.2Hz),8.40(1H,d,J＝2.4Hz),7.99(1H,d,J＝2Hz),7.20(1H,dd,J1＝2Hz,J2＝10.4Hz),7.07(1H,dd,J1＝2.4Hz,J2＝9.6Hz),4.13(2H,t,J＝6Hz),4.03(3H,s),3.93-3.78(4H,m),3.78-3.63(4H,m),3.11(3H,s),1.96(2H,t,J＝7.2Hz),1.89-1.73(2H,m),1.62-1.43(4H,m),1.43-1.27(2H,m).Referring to the synthetic route and operation of compound 8, compound 7-bromo-heptanoic acid methyl ester was used instead of compound 6-bromo-hexanoic acid methyl ester to obtain compound 9 (118 mg). LC-MS(ESI): m/z=593.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.35(1H,s),9.51(1H,s),8.67(1H ,d,J＝1.2Hz),8.40(1H,d,J＝2.4Hz),7.99(1H,d,J＝2Hz),7.20(1H,dd,J 1 ＝2Hz,J 2 ＝10.4Hz), 7.07(1H,dd,J 1 =2.4Hz,J 2 =9.6Hz),4.13(2H,t,J＝6Hz),4.03(3H,s),3.93-3.78(4H,m),3.78-3.63( 4H,m),3.11(3H,s),1.96(2H,t,J＝7.2Hz),1.89-1.73(2H,m),1.62-1.43(4H,m),1.43-1.27(2H,m) .
化合物10的合成路线
Synthetic route of compound 10
化合物10-c的合成Synthesis of compound 10-c
将化合物6-d(290mg,0.29mmoL)溶解在10mL的DMF中，依次加入DIPEA(485μL,2.94mmoL)，4-溴甲基苯甲酸甲酯(74mg,0.32mmoL)，反应混合物在室温氮气条件下搅拌16小时。加入30mL的水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过快速分离柱分离纯化(PE/EA＝1:1,EA)，得到化合物10-c(160mg,80％)。LC-MS(ESI):m/z＝680.4[M+1]+.Compound 6-d (290mg, 0.29mmoL) was dissolved in 10mL of DMF, and DIPEA (485μL, 2.94mmoL) and 4-bromomethylbenzoic acid methyl ester (74mg, 0.32mmoL) were added in sequence. The reaction mixture was incubated under nitrogen at room temperature. Stir for 16 hours. Add 30 mL of water, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is passed through a rapid separation column After isolation and purification (PE/EA=1:1, EA), compound 10-c (160 mg, 80%) was obtained. LC-MS(ESI): m/z＝680.4[M+1] + .
化合物10的合成Synthesis of compound 10
参照化合物1的合成路线和操作，使用化合物10-c替代化合物1-c，得到化合物10(100mg)。LC-MS(ESI):m/z＝681.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ11.17(1H,s),9.53(1H,s),9.00(1H,s),8.40(1H,d,J＝2.4Hz),8.00(1H,d,J＝2.4Hz),7.74-7.62(3H,m),7.51-7.41(1H,m),7.37(2H,d,J＝8.0Hz),4.03(3H,s),3.99(2H,s),3.90-3.79(4H,m),3.78- 3.65(4H,m),3.53(2H,s),3.10(3H,s),2.64-2.27(8H,m).Referring to the synthetic route and operation of compound 1, compound 10-c was used instead of compound 1-c to obtain compound 10 (100 mg). LC-MS(ESI): m/z=681.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ11.17(1H,s),9.53(1H,s),9.00(1H ,s),8.40(1H,d,J＝2.4Hz),8.00(1H,d,J＝2.4Hz),7.74-7.62(3H,m),7.51-7.41(1H,m),7.37(2H, d,J＝8.0Hz),4.03(3H,s),3.99(2H,s),3.90-3.79(4H,m),3.78- 3.65(4H,m),3.53(2H,s),3.10(3H,s),2.64-2.27(8H,m).
化合物11的合成路线
Synthetic route of compound 11
化合物11-f的合成Synthesis of Compound 11-f
将化合物N-Cbz-4-羟基哌啶(2.35g,10mmoL)溶解在50mL的1,4-二氧六环中，室温下依次加入叔丁醇钾(60mg,0.54mmoL)，丙烯酸叔丁酯(3.7mL,25mmoL)，反应混合物在室温氮气条件下搅拌30分钟，然后在110℃氮气条件下搅拌16小时。反应混合物冷却到室温，减压浓缩，得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝2:1)，得到化合物11-f(1.58g,44％)。LC-MS(ESI):m/z＝386.2[M+23]+.Dissolve compound N-Cbz-4-hydroxypiperidine (2.35g, 10mmoL) in 50mL of 1,4-dioxane, and add potassium tert-butoxide (60mg, 0.54mmoL) and tert-butyl acrylate in sequence at room temperature. (3.7 mL, 25 mmoL), the reaction mixture was stirred at room temperature under nitrogen for 30 minutes, and then at 110°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a fast separation column (PE/EA=2:1) to obtain compound 11-f (1.58g, 44%). LC-MS(ESI): m/z＝386.2[M+23] + .
化合物11-e的合成Synthesis of Compound 11-e
将化合物11-f(1.58g,4.35mmoL)溶解在100mL的甲醇中，室温氮气下加入Pd/C(0.5g)，反应混合物在室温氢气条件下搅拌16小时。过滤，减压浓缩，得到化合物11-e(875mg,88％)。LC-MS(ESI):m/z＝230.3[M+1]+.Compound 11-f (1.58g, 4.35mmoL) was dissolved in 100 mL of methanol, Pd/C (0.5g) was added under nitrogen at room temperature, and the reaction mixture was stirred under hydrogen at room temperature for 16 hours. Filter and concentrate under reduced pressure to obtain compound 11-e (875 mg, 88%). LC-MS(ESI):m/z＝230.3[M+1] + .
化合物11-d的合成Synthesis of Compound 11-d
将化合物11-e(875mg,3.82mmoL)溶解在50mL的乙腈中，室温下依次加入碘化钾(35mg,0.21mmoL)，溴甲基氟硼酸钾(697mg,3.47mmoL)，在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后滤液减压浓缩，得到粗品化合物11-d(1.25g)。粗品未经纯化直接用于下一步反应。LC-MS(ESI):m/z＝329.1[M+18]+. Dissolve compound 11-e (875 mg, 3.82 mmoL) in 50 mL of acetonitrile, add potassium iodide (35 mg, 0.21 mmoL) and potassium bromomethylfluoroborate (697 mg, 3.47 mmoL) at room temperature, and stir under nitrogen at 80°C. 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (10 mL). The filtrate was then concentrated under reduced pressure to obtain crude compound 11-d (1.25 g). The crude product was used directly in the next reaction without purification. LC-MS(ESI): m/z＝329.1[M+18] + .
化合物11-c的合成Synthesis of compound 11-c
室温下将化合物1-e(200mg,0.43mmoL)溶解在30mL的THF中，依次加入水(3mL)、11-d(399mg,1.28mmoL)、醋酸钯(10mg,0.043mmoL)、x-Phos(41mg,0.085mmoL)、碳酸铯(417mg,1.28mmoL)，反应混合物在80℃氮气条件下搅拌36小时。向反应体系中加入50mL水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物11-c(290mg,100％)。LC-MS(ESI):m/z＝675.2[M+1]+.Compound 1-e (200mg, 0.43mmoL) was dissolved in 30mL of THF at room temperature, and water (3mL), 11-d (399mg, 1.28mmoL), palladium acetate (10mg, 0.043mmoL), x-Phos ( 41 mg, 0.085 mmoL), cesium carbonate (417 mg, 1.28 mmoL), and the reaction mixture was stirred under nitrogen at 80°C for 36 hours. Add 50 mL of water to the reaction system, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by a fast separation column (DCM/MeOH=10:1) to obtain compound 11-c (290 mg, 100%). LC-MS(ESI):m/z＝675.2[M+1] + .
化合物11-b的合成Synthesis of compound 11-b
将化合物11-c(100mg,0.15mmoL)溶解在5mL的DCM中，冰浴条件下加入TFA(2.5mL)，反应混合物升到室温搅拌2小时，得到粗品化合物11-b(92mg)。粗品未经纯化，直接用于下一步反应。LC-MS(ESI):m/z＝619.2[M+1]+.Compound 11-c (100 mg, 0.15 mmoL) was dissolved in 5 mL of DCM, TFA (2.5 mL) was added under ice bath conditions, and the reaction mixture was raised to room temperature and stirred for 2 hours to obtain crude compound 11-b (92 mg). The crude product was used directly in the next reaction without purification. LC-MS(ESI): m/z＝619.2[M+1] + .
化合物11-a的合成Synthesis of Compound 11-a
室温下将化合物11-b(92mg,0.15mmoL)溶解在10mL的DMF中，冰浴下依次加入HATU(84mg,0.22mmoL)、DIPEA(244μL,1.48mmoL)，反应混合物在0℃下搅拌10分钟，然后加入O-(四氢-2H-吡喃)-2-羟胺(35mg,0.30mmoL)，反应混合物升到室温并搅拌16小时。反应用20mL水淬灭，用乙酸乙酯(80mL*2)萃取，有机相用饱和食盐水(100mL*3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品。粗品通过PREP-HPLC分离纯化，得到化合物11-a(52mg,49％)。LC-MS(ESI):m/z＝718.2[M+1]+.Dissolve compound 11-b (92 mg, 0.15 mmoL) in 10 mL of DMF at room temperature, add HATU (84 mg, 0.22 mmoL) and DIPEA (244 μL, 1.48 mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (35 mg, 0.30 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with 20 mL of water, extracted with ethyl acetate (80 mL*2), the organic phase was washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by PREP-HPLC to obtain compound 11-a (52 mg, 49%). LC-MS(ESI): m/z=718.2[M+1] + .
化合物11的合成Synthesis of Compound 11
将化合物11-a(52mg,0.072mmoL)溶解在20mL的DCM中，冷却到0℃，慢慢滴加氯化氢的1,4-二氧六环溶液(4M,1mL)，加毕，混合物在0℃下搅拌10分钟后，用饱和碳酸氢钠溶液(30mL)淬灭反应，用混合溶剂DCM(100mL*2)，有机相用无水硫酸钠干燥，过滤，减压浓缩，得到化合物11(40mg,87％)。LC-MS(ESI):m/z＝634.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.39(1H,s),9.56(1H,brs),8.75(1H,s),8.40(1H,d,J＝2.0Hz),8.00(1H,d,J＝2.0Hz),7.75(1H,brs),7.48(1H,brs),4.13-3.97(4H,m),3.91-3.78(4H,m),3.79-3.65(5H,m),3.60(2H,t,J＝8.0Hz),3.58-3.49(1H,m),3.10(3H,s),3.02-2.70(2H,m),2.17(2H,t,J＝6.4Hz),1.94-1.72(2H,m),1.64-1.32(4H,m).Dissolve compound 11-a (52 mg, 0.072 mmoL) in 20 mL of DCM, cool to 0°C, and slowly add hydrogen chloride in 1,4-dioxane solution (4 M, 1 mL) dropwise. After the addition is completed, the mixture is at 0 After stirring for 10 minutes at ℃, the reaction was quenched with saturated sodium bicarbonate solution (30 mL), and the mixed solvent DCM (100 mL*2) was used. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11 (40 mg ,87%). LC-MS (ESI): m/z=634.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.39 (1H, s), 9.56 (1H, brs), 8.75 (1H ,s),8.40(1H,d,J＝2.0Hz),8.00(1H,d,J＝2.0Hz),7.75(1H,brs),7.48(1H,brs),4.13-3.97(4H,m) ,3.91-3.78(4H,m),3.79-3.65(5H,m),3.60(2H,t,J＝8.0Hz),3.58-3.49(1H,m),3.10(3H,s),3.02-2.70 (2H,m),2.17(2H,t,J＝6.4Hz),1.94-1.72(2H,m),1.64-1.32(4H,m).
化合物12的合成路线
Synthetic route of compound 12
化合物12-d的合成Synthesis of Compound 12-d
将化合物2-甲基嘧啶-5-羧酸乙酯(1g，6.02mmoL)，溶解在10mL的四氯化碳中，依次加入NBS(1.07g，6.02mmoL)，AIBN(49mg，0.3mmoL)，反应混合物在80℃氮气条件下搅拌16小时。减压浓缩，粗品悬浮在100mL的乙酸乙酯，过滤，滤液依次用饱和碳酸氢钠(100mL*2)，饱和食盐水(100mL)洗涤，有机相用无水硫酸钠干燥、过滤，加压浓缩，得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝3:1)，得到化合物12-d(320mg，22％)。LC-MS(ESI):m/z＝245.1[M+1]+.Dissolve the compound 2-methylpyrimidine-5-carboxylic acid ethyl ester (1g, 6.02mmoL) in 10mL of carbon tetrachloride, and add NBS (1.07g, 6.02mmoL) and AIBN (49mg, 0.3mmoL) in sequence. The reaction mixture was stirred at 80°C under nitrogen for 16 hours. Concentrate under reduced pressure, suspend the crude product in 100 mL of ethyl acetate, filter, and wash the filtrate with saturated sodium bicarbonate (100 mL*2) and saturated brine (100 mL). The organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under pressure. , get crude product. The crude product was separated and purified through a fast separation column (PE/EA=3:1) to obtain compound 12-d (320 mg, 22%). LC-MS(ESI): m/z＝245.1[M+1] + .
化合物12-c的合成Synthesis of compound 12-c
将化合物6-d(290mg，0.29mmoL)溶解在10mL的DMF中，依次加入DIPEA(485μL，2.94mmoL)，12-d(79mg，0.32mmoL)，反应混合物在室温氮气条件下搅拌16小时。加入30mL的水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物12-c(170mg，83％)。LC-MS(ESI):m/z＝696.3[M+1]+.Compound 6-d (290 mg, 0.29 mmoL) was dissolved in 10 mL of DMF, and DIPEA (485 μL, 2.94 mmoL) and 12-d (79 mg, 0.32 mmoL) were added successively. The reaction mixture was stirred under nitrogen at room temperature for 16 hours. Add 30 mL of water, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*3), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is passed through a rapid separation column After isolation and purification (DCM/MeOH=10:1), compound 12-c (170 mg, 83%) was obtained. LC-MS(ESI): m/z＝696.3[M+1] + .
化合物12的合成Synthesis of compound 12
参照化合物1的合成路线和操作，使用化合物12-c替代化合物1-c，得到化合物12(70mg)。LC-MS(ESI):m/z＝683.4[M+1]+；1H NMR(400MHz,DMSO-d6):δ11.46(1H,brs),9.61(1H,brs),9.36(1H,s),9.03(2H,s),8.39(1H,d,J＝2.0Hz),7.99(1H,d,J＝2.0Hz),7.65(1H,dd,J1＝9.2Hz,J2＝2.0Hz),7.43(1H,dd,J1＝9.2Hz,J2＝2.4Hz),4.02(3H,s),3.95(2H,s),3.90-3.79(4H,m),3.76(2H,s),3.74-3.64(4H,m),3.09(3H,s),2.65-2.51(8H,m).Referring to the synthetic route and operation of compound 1, compound 12-c was used instead of compound 1-c to obtain compound 12 (70 mg). LC-MS (ESI): m/z=683.4[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ11.46 (1H, brs), 9.61 (1H, brs), 9.36 (1H ,s),9.03(2H,s),8.39(1H,d,J＝2.0Hz),7.99(1H,d,J＝2.0Hz),7.65(1H,dd,J 1 ＝9.2Hz,J 2 ＝ 2.0Hz),7.43(1H,dd,J 1 =9.2Hz,J 2 =2.4Hz),4.02(3H,s),3.95(2H,s),3.90-3.79(4H,m),3.76(2H, s),3.74-3.64(4H,m),3.09(3H,s),2.65-2.51(8H,m).
化合物13的合成路线
Synthetic route of compound 13
化合物13-f的合成Synthesis of compound 13-f
将化合物N-Cbz-4-羟基哌啶(791mg，3.36mmoL)与4-碘-丁酸乙酯(977mg，4.03mmoL)混合，室温下加入氧化银(1.56g，6.72mmoL)，反应混合物在60℃氮气条件下搅拌5天，冷却到室温，100mL的DCM加入，过滤，减压浓缩，得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝2:1)，得到化合物13-f(100mg，8.5％)。LC-MS(ESI):m/z＝350.2[M+1]+.Compound N-Cbz-4-hydroxypiperidine (791mg, 3.36mmoL) and 4-iodo-butyric acid ethyl ester (977mg, 4.03mmoL) were mixed, silver oxide (1.56g, 6.72mmoL) was added at room temperature, and the reaction mixture was Stir under nitrogen conditions at 60°C for 5 days, cool to room temperature, add 100 mL of DCM, filter, and concentrate under reduced pressure to obtain crude product. The crude product was separated and purified by a fast separation column (PE/EA=2:1) to obtain compound 13-f (100 mg, 8.5%). LC-MS(ESI): m/z＝350.2[M+1] + .
化合物13-e的合成Synthesis of compound 13-e
将化合物13-f(100mg，0.29mmoL)溶解在50mL的甲醇中，室温氮气下加入Pd/C(50mg)，反应混合物在室温氢气条件下搅拌16小时。过滤，减压浓缩，得到粗品化合物13-e(40mg)。LC-MS(ESI):m/z＝216.2[M+1]+.Compound 13-f (100 mg, 0.29 mmoL) was dissolved in 50 mL of methanol, Pd/C (50 mg) was added under nitrogen at room temperature, and the reaction mixture was stirred under hydrogen at room temperature for 16 hours. Filter and concentrate under reduced pressure to obtain crude compound 13-e (40 mg). LC-MS(ESI): m/z＝216.2[M+1] + .
化合物13-d的合成Synthesis of Compound 13-d
将化合物13-e(40mg，0.19mmoL)溶解在6mL的乙腈中，室温下依次加入碘化钾(2mg，0.011mmoL)，溴甲基氟硼酸钾(34mg，0.17mmoL)，在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后滤液减压浓缩，得到粗品化合物13-d(60mg)。粗品未经纯化直接用于下一步反应。Compound 13-e (40 mg, 0.19 mmoL) was dissolved in 6 mL of acetonitrile, potassium iodide (2 mg, 0.011 mmoL) and potassium bromomethylfluoroborate (34 mg, 0.17 mmoL) were added successively at room temperature, and stirred under nitrogen at 80°C. 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (10 mL). The filtrate was then concentrated under reduced pressure to obtain crude compound 13-d (60 mg). The crude product was used directly in the next reaction without purification.
化合物13的合成Synthesis of Compound 13
参照化合物1的合成路线和操作，使用化合物13-d替代化合物1-d，得到化合物13(4mg)。LC-MS(ESI):m/z＝648.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.38(1H,s),9.56(1H,s),8.69(1H,s),8.43(1H,d,J＝2.0Hz),8.08(1H,brs),8.01(1H,d,J＝2.4Hz),7.68(1H,brs),4.03(3H,s),3.96-3.83(4H,m),3.79-3.72(4H,m),3.72-3.64(1H,m),3.59(2H,s),3.43-3.39(2H,m),3.10(3H,s),2.04-1.95(4H,m),1.78-1.59(4H,m),1.53-1.39(4H,m).Referring to the synthetic route and operation of compound 1, compound 13-d was used instead of compound 1-d to obtain compound 13 (4 mg). LC-MS(ESI): m/z=648.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.38(1H,s),9.56(1H,s),8.69(1H ,s),8.43(1H,d,J＝2.0Hz),8.08(1H,brs),8.01(1H,d,J＝2.4Hz),7.68(1H,brs),4.03(3H,s),3.96 -3.83(4H,m),3.79-3.72(4H,m),3.72-3.64(1H,m),3.59(2H,s),3.43-3.39(2H,m),3.10(3H,s),2.04 -1.95(4H,m),1.78-1.59(4H,m),1.53-1.39(4H,m).
化合物14的合成路线
Synthetic route of compound 14
化合物14-f的合成Synthesis of Compound 14-f
将化合物N-Cbz-4-哌啶酮(2g，8.57mmoL)溶解在20mL的DCM中，依次加入4-哌啶甲酸甲酯(1.23g，8.57mmoL)，醋酸(491μL，8.57mmoL)，反应混合物在室温氮气条件下搅拌30分钟，加入醋酸硼氢化钠(3.63g，17.14mmoL)，反应混合物在室温氮气条件下搅拌5天。加入100mL水，用DCM(100mL*2)萃取，有机相用无水硫酸钠干燥、过滤，减压浓缩，粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物14-f(600mg，19％)。LC-MS(ESI):m/z＝361.2[M+1]+.Dissolve compound N-Cbz-4-piperidone (2g, 8.57mmoL) in 20 mL of DCM, add methyl 4-piperidinecarboxylate (1.23g, 8.57mmoL) and acetic acid (491 μL, 8.57mmoL) in sequence, and react The mixture was stirred under nitrogen at room temperature for 30 minutes, sodium acetate borohydride (3.63g, 17.14mmoL) was added, and the reaction mixture was stirred under nitrogen at room temperature for 5 days. Add 100 mL of water and extract with DCM (100 mL*2). The organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is separated and purified through a rapid separation column (DCM/MeOH=10:1) to obtain compound 14-f. (600mg, 19%). LC-MS(ESI): m/z＝361.2[M+1] + .
化合物14-e的合成Synthesis of Compound 14-e
将化合物14-f(600mg，1.66mmoL)溶解在50mL的甲醇中，室温氮气下加入Pd/C(100mg)，反应混合物在室温氢气条件下搅拌16小时。过滤，减压浓缩，得到粗品化合物14-e(370mg)。LC-MS(ESI):m/z＝227.2[M+1]+.Compound 14-f (600 mg, 1.66 mmoL) was dissolved in 50 mL of methanol, Pd/C (100 mg) was added under nitrogen at room temperature, and the reaction mixture was stirred under hydrogen at room temperature for 16 hours. Filter and concentrate under reduced pressure to obtain crude compound 14-e (370 mg). LC-MS(ESI): m/z＝227.2[M+1] + .
化合物14-d的合成Synthesis of Compound 14-d
将化合物14-e(370mg，1.63mmoL)溶解在20mL的乙腈中，室温下依次加入碘化钾(15mg，0.09mmoL)，溴甲基氟硼酸钾(297mg，1.48mmoL)，在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后滤液减压浓缩，得到粗品化合物14-d(456mg)。粗品未经纯化直接用于下一步反应。LC-MS(ESI):m/z＝309.1[M+1]+.Dissolve compound 14-e (370 mg, 1.63 mmoL) in 20 mL of acetonitrile, add potassium iodide (15 mg, 0.09 mmoL) and potassium bromomethylfluoroborate (297 mg, 1.48 mmoL) in sequence at room temperature, and stir under nitrogen at 80°C. 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (10 mL). The filtrate was then concentrated under reduced pressure to obtain crude compound 14-d (456 mg). The crude product was used directly in the next reaction without purification. LC-MS(ESI): m/z＝309.1[M+1] + .
化合物14的合成Synthesis of compound 14
参照化合物1的合成路线和操作，使用化合物14-d替代化合物1-d，得到化合物14(10mg)。LC-MS(ESI):m/z＝673.3[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.59(1H,s),9.57(1H,s),8.82(1H,s),8.43(1H,d,J＝2.0Hz),8.13(1H,brs),8.01(1H,d,J＝2.0Hz),7.71 (1H,brs),4.74(2H,s),4.04(3H,s),3.98-3.81(4H,m),3.79-3.68(4H,m),3.66-3.43(4H,m),3.11(3H,s),3.06-2.83(4H,m),2.71-2.64(1H,m),2.36-2.30(1H,m),2.30-2.15(2H,m),2.14-1.98(2H,m),1.97-1.80(4H,m).Referring to the synthetic route and operation of compound 1, compound 14-d was used instead of compound 1-d to obtain compound 14 (10 mg). LC-MS(ESI): m/z=673.3[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.59(1H,s),9.57(1H,s),8.82(1H ,s),8.43(1H,d,J＝2.0Hz),8.13(1H,brs),8.01(1H,d,J＝2.0Hz),7.71 (1H,brs),4.74(2H,s),4.04(3H,s),3.98-3.81(4H,m),3.79-3.68(4H,m),3.66-3.43(4H,m),3.11(3H ,s),3.06-2.83(4H,m),2.71-2.64(1H,m),2.36-2.30(1H,m),2.30-2.15(2H,m),2.14-1.98(2H,m),1.97 -1.80(4H,m).
化合物15的合成路线
Synthetic route of compound 15
化合物15-h的合成Synthesis of compound 15-h
往反应瓶中加入3-(1-Boc-4-哌啶基)-1-丙醇(2.43g，10.00mmol)，二氯甲烷(100mL)，PCC(4.30g，20.00mmol)，室温搅拌过夜24小时。饱和碳酸氢钠(200mL)淬灭，二氯甲烷(200mL*3)萃取。合并有机相，用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物15-h(1.93g，80％)。LC-MS(ESI):m/z 186.3(M-56+H)+.Add 3-(1-Boc-4-piperidyl)-1-propanol (2.43g, 10.00mmol), dichloromethane (100mL), PCC (4.30g, 20.00mmol) into the reaction flask, and stir at room temperature overnight. 24 hours. Quench with saturated sodium bicarbonate (200mL) and extract with dichloromethane (200mL*3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 15-h (1.93 g, 80%). LC-MS(ESI):m/z 186.3(M-56+H) + .
化合物15-g的合成Synthesis of compound 15-g
往反应瓶中加入15-h(1.93g，8.01mmol)，甲氧甲酰基亚甲基三苯基膦(2.67g，8.01mmol)，甲苯(100mL)。反应液用N2置换，在120℃下搅拌12小时。浓缩过柱纯化(流动相：石油醚/乙酸乙酯10/1到3/1)，得到化合物15-g(1.76g，74％)。LC-MS(ESI):m/z 320.4(M+Na)+.Add 15-h (1.93g, 8.01mmol), methoxyformylmethylenetriphenylphosphine (2.67g, 8.01mmol) and toluene (100mL) into the reaction flask. The reaction solution was replaced with N2 and stirred at 120°C for 12 hours. Concentrate and purify through column (mobile phase: petroleum ether/ethyl acetate 10/1 to 3/1) to obtain compound 15-g (1.76g, 74%). LC-MS(ESI):m/z 320.4(M+Na) + .
化合物15-f的合成Synthesis of compound 15-f
往反应瓶中加入15-g(1.76g，5.93mmol)，钯碳(0.35g，10％pd，50％wet)，甲醇(150mL)。反应在氢气(1000mL)条件下，室温搅拌12小时。过滤浓缩得到化合物15-f(1.46g，83％)。LC-MS(ESI):m/z 200.3(M-100+H)+.Add 15-g (1.76g, 5.93mmol), palladium on carbon (0.35g, 10% pd, 50% wet), and methanol (150 mL) into the reaction flask. The reaction was stirred at room temperature for 12 hours under hydrogen gas (1000 mL). Filtration and concentration gave compound 15-f (1.46g, 83%). LC-MS(ESI):m/z 200.3(M-100+H) + .
化合物15-e的合成Synthesis of Compound 15-e
往反应瓶中加入15-f(1.46g，4.88mmol)，盐酸1,4-二氧六环(50mL，200.00mmol)。氮气保护下室温搅拌24小时。过滤浓缩得到化合物15-e(0.97g)。LC-MS(ESI):m/z 200.4(M+H)+.Add 15-f (1.46g, 4.88mmol) and 1,4-dioxane hydrochloride (50mL, 200.00mmol) into the reaction flask. Stir at room temperature under nitrogen protection for 24 hours. Filtration and concentration gave compound 15-e (0.97g). LC-MS(ESI):m/z 200.4(M+H) + .
化合物15-d的合成Synthesis of Compound 15-d
将15-e(0.76g，3.23mmol)，碘化钾(0.03g，0.18mmol)，溴甲基氟硼酸钾(0.58g， 2.91mmol)，碳酸钾(0.58g，4.20mmol)溶解在乙腈(60mL)中。氮气保护下在80℃搅拌12小时。将反应液冷却至室温，过滤浓缩，得到粗产品。后将粗产物用甲基叔丁醚洗涤，过滤。浓缩有机相得到化合物15-d(0.91g，100％)。LC-MS(ESI):m/z 299.2(M+NH4)+.Mix 15-e (0.76g, 3.23mmol), potassium iodide (0.03g, 0.18mmol), potassium bromomethylfluoroborate (0.58g, 2.91 mmol), potassium carbonate (0.58 g, 4.20 mmol) was dissolved in acetonitrile (60 mL). Stir at 80°C for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered and concentrated to obtain a crude product. The crude product was washed with methyl tert-butyl ether and filtered. The organic phase was concentrated to obtain compound 15-d (0.91 g, 100%). LC-MS(ESI): m/z 299.2(M+NH 4 ) + .
化合物15的合成Synthesis of compound 15
参照化合物1的合成路线和操作，使用化合物15-d替代化合物1-d，得到化合物15(30mg)。LC-MS(ESI):m/z 646.3(M+H)+；1H NMR(400MHz,DMSO-d6):δ10.35(1H,s),9.57(1H,s),8.66(1H,s),8.43(1H,d,J＝2.0Hz),8.11(1H,s),8.01(1H,d,J＝1.6Hz),7.66(1H,s),4.64(1H,s),4.04(3H,s),3.84-3.95(4H,m),3.68-3.76(4H,m),3.57(1H,s),3.11(3H,s),1.90-1.96(2H,m),1.70-1.83(3H,m),1.36-1.52(6H,s),1.10-1.34(6H,m).Referring to the synthetic route and operation of compound 1, compound 15-d was used instead of compound 1-d to obtain compound 15 (30 mg). LC-MS(ESI): m/z 646.3(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ10.35(1H,s),9.57(1H,s),8.66(1H, s),8.43(1H,d,J＝2.0Hz),8.11(1H,s),8.01(1H,d,J＝1.6Hz),7.66(1H,s),4.64(1H,s),4.04( 3H,s),3.84-3.95(4H,m),3.68-3.76(4H,m),3.57(1H,s),3.11(3H,s),1.90-1.96(2H,m),1.70-1.83( 3H,m),1.36-1.52(6H,s),1.10-1.34(6H,m).
化合物16的合成路线
Synthetic route of compound 16
化合物16-g的合成Synthesis of compound 16-g
将化合物N-Boc-3-羟基氮杂环丁烷(1.73g，10mmoL)溶解在20mL的DMF中，冷却到0℃，氮气条件下加入NaH(800mg，20mmoL，60％)，将反应混合物升温到60℃，然后滴加苄基2-溴乙基醚(2.37mL，15mmoL)，反应混合物在同样的条件下搅拌16小 时。将反应混合物冷却到0℃，用20mL的饱和氯化铵溶液淬灭，并加水50mL，用乙酸乙酯(100ml*2)萃取，有机相用饱和食盐水(100mL*5)洗涤，无水硫酸钠干燥、过滤，减压浓缩，粗品通过快速分离柱分离纯化(PE/EA＝1:1)，得到化合物16-g(2.58g，84％)。LC-MS(ESI):m/z＝252.1[M-56+1]+.Dissolve compound N-Boc-3-hydroxyazetidine (1.73g, 10mmoL) in 20mL of DMF, cool to 0°C, add NaH (800mg, 20mmoL, 60%) under nitrogen, and heat the reaction mixture to 60°C, then benzyl 2-bromoethyl ether (2.37mL, 15mmoL) was added dropwise, and the reaction mixture was stirred under the same conditions for 16 hours. hour. Cool the reaction mixture to 0°C, quench with 20 mL of saturated ammonium chloride solution, add 50 mL of water, extract with ethyl acetate (100 ml*2), wash the organic phase with saturated brine (100 mL*5), and anhydrous sulfuric acid It was dried over sodium, filtered, and concentrated under reduced pressure. The crude product was separated and purified through a rapid separation column (PE/EA=1:1) to obtain compound 16-g (2.58g, 84%). LC-MS(ESI): m/z＝252.1[M-56+1] + .
化合物16-f的合成Synthesis of Compound 16-f
将化合物16-g(2.58g，8.39mmoL)溶解在100mL的甲醇中，室温氮气下加入Pd/C(10％Pd，50％wet，0.5g)，反应混合物在室温氢气条件下搅拌16小时。过滤，减压浓缩，得到化合物16-f(1.86g,100％)。LC-MS(ESI):m/z＝162.1[M-56+1]+.Compound 16-g (2.58g, 8.39mmoL) was dissolved in 100 mL of methanol, Pd/C (10% Pd, 50% wet, 0.5g) was added under nitrogen at room temperature, and the reaction mixture was stirred under hydrogen at room temperature for 16 hours. Filter and concentrate under reduced pressure to obtain compound 16-f (1.86g, 100%). LC-MS(ESI): m/z＝162.1[M-56+1] + .
化合物16-e的合成Synthesis of Compound 16-e
室温氮气下，将NaH(177mg，4.42mmoL，60％)溶解在10mL的THF中，然后慢慢加入化合物16-f(800mg，3.68mmoL)的THF(5mL)溶液，反应混合物在室温搅拌1小时后，冷却到0℃，滴加溴乙酸乙酯(490μL，4.42mmoL)，加毕，升到室温，搅拌16小时。0℃下，用饱和氯化铵溶液(30ml)淬灭反应，加水50mL，混合物用乙酸乙酯(100mL*2)萃取，有机相用饱和碳酸氢钠溶液(100mL)洗涤，用无水硫酸钠干燥、过滤，减压浓缩，粗品通过快速分离柱分离纯化(PE/EA＝1:1)，得到化合物16-e(518mg，46％)。LC-MS(ESI):m/z＝248.1[M-56+1]+.Under nitrogen at room temperature, NaH (177 mg, 4.42 mmoL, 60%) was dissolved in 10 mL of THF, and then a solution of compound 16-f (800 mg, 3.68 mmoL) in THF (5 mL) was slowly added, and the reaction mixture was stirred at room temperature for 1 hour. Afterwards, cool to 0°C, add ethyl bromoacetate (490 μL, 4.42 mmoL) dropwise, complete the addition, raise to room temperature, and stir for 16 hours. At 0°C, quench the reaction with saturated ammonium chloride solution (30ml), add 50mL of water, extract the mixture with ethyl acetate (100mL*2), wash the organic phase with saturated sodium bicarbonate solution (100mL), and use anhydrous sodium sulfate. Dry, filter, and concentrate under reduced pressure. The crude product is separated and purified through a rapid separation column (PE/EA=1:1) to obtain compound 16-e (518 mg, 46%). LC-MS(ESI): m/z＝248.1[M-56+1] + .
化合物16-d的合成Synthesis of Compound 16-d
室温下将化合物16-e(518mg，1.71mmoL)溶解在10mL的DCM中，冷却到0℃，加入TFA(2mL)，反应混合物升到室温搅拌2.5小时后，减压浓缩，粗品溶解在DCM(20mL)，减压浓缩，重复上述操作3次，得到粗品化合物16-d(542mg)，粗品直接用于下一步反应。LC-MS(ESI):m/z＝204.1[M+1]+.Compound 16-e (518 mg, 1.71 mmoL) was dissolved in 10 mL of DCM at room temperature, cooled to 0°C, TFA (2 mL) was added, the reaction mixture was raised to room temperature and stirred for 2.5 hours, then concentrated under reduced pressure, and the crude product was dissolved in DCM ( 20 mL), concentrated under reduced pressure, and repeated the above operation three times to obtain crude compound 16-d (542 mg), which was directly used in the next reaction. LC-MS(ESI): m/z＝204.1[M+1] + .
化合物16-c的合成Synthesis of compound 16-c
将化合物16-d(542mg，1.71mmoL)溶解在20mL的乙腈中，室温下依次加入碘化钾(15mg，0.093mmoL)，溴甲基氟硼酸钾(311mg，1.55mmoL)，碳酸钾(321mg，2.32mmoL)，然后混合物在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后滤液减压浓缩，得到粗品化合物16-c(1g，按理论值计算约44％的纯度)。粗品未经纯化直接用于下一步反应。LC-MS(ESI):m/z＝303.1[M+18]+.Compound 16-d (542 mg, 1.71 mmoL) was dissolved in 20 mL of acetonitrile, and potassium iodide (15 mg, 0.093 mmoL), potassium bromomethylfluoroborate (311 mg, 1.55 mmoL), and potassium carbonate (321 mg, 2.32 mmoL) were added successively at room temperature. ), and then the mixture was stirred at 80°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (10 mL), and then the filtrate was concentrated under reduced pressure to obtain crude compound 16-c (1 g, about 44% purity based on theoretical value). The crude product was used directly in the next reaction without purification. LC-MS(ESI): m/z＝303.1[M+18] + .
化合物16-b的合成Synthesis of compound 16-b
室温下将化合物1-e(482mg，1.03mmoL)溶解在60mL的THF中，依次加入水(6mL)、16-c(1g，44％，1.54mmoL)、醋酸钯(23mg，0.10mmoL)、x-Phos(98mg，0.21mmoL)、碳酸铯(1.01g，3.1mmoL)，反应混合物在80℃氮气条件下搅拌36小时。将反应液冷却至室温，并加入50mL水，用乙酸乙酯(100mL)萃取，水相用1N稀盐酸调pH的5， 将水相减压浓缩，粗品悬浮在混合溶剂中(DCM/MeOH＝10:1，20mL)，过滤，滤饼用混合物溶剂(DCM/MeOH＝10:1，20mL*2)洗涤，合并有机相，减压浓缩，粗品通过PREP-HPLC分离纯化，得到化合物16-b(136mg，21％)。LC-MS(ESI):m/z＝621.2[M+1]+.Compound 1-e (482 mg, 1.03 mmoL) was dissolved in 60 mL of THF at room temperature, and water (6 mL), 16-c (1 g, 44%, 1.54 mmoL), palladium acetate (23 mg, 0.10 mmoL), x -Phos (98mg, 0.21mmoL), cesium carbonate (1.01g, 3.1mmoL), the reaction mixture was stirred under nitrogen at 80°C for 36 hours. Cool the reaction solution to room temperature, add 50 mL of water, extract with ethyl acetate (100 mL), and adjust the aqueous phase to pH 5 with 1N dilute hydrochloric acid. The aqueous phase was concentrated under reduced pressure, the crude product was suspended in a mixed solvent (DCM/MeOH=10:1, 20mL), filtered, the filter cake was washed with a mixed solvent (DCM/MeOH=10:1, 20mL*2), and the organic phases were combined , concentrated under reduced pressure, and the crude product was separated and purified by PREP-HPLC to obtain compound 16-b (136 mg, 21%). LC-MS(ESI): m/z＝621.2[M+1] + .
化合物16-a的合成Synthesis of compound 16-a
室温下将化合物16-b(50mg，0.08mmoL)溶解在3mL的DMF中，冰浴下依次加入HATU(46mg，0.12mmoL)、DIPEA(66uL，0.40mmoL)，反应混合物在0℃下搅拌10分钟，然后加入O-(四氢-2H-吡喃)-2-羟胺(19mg，0.16mmoL)，反应混合物升到室温并搅拌16小时。用20mL水淬灭反应，然后用乙酸乙酯(50mL*2)萃取，有机相用饱和食盐水(100mL*3)洗涤，无水硫酸钠干燥、过滤，减压浓缩，粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物16-a(36mg，63％)。LC-MS(ESI):m/z＝720.2[M+1]+.Dissolve compound 16-b (50mg, 0.08mmoL) in 3mL of DMF at room temperature, add HATU (46mg, 0.12mmoL) and DIPEA (66uL, 0.40mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (19 mg, 0.16 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with 20 mL of water, and then extracted with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by a rapid separation column. Purification (DCM/MeOH=10:1) gave compound 16-a (36 mg, 63%). LC-MS(ESI): m/z=720.2[M+1] + .
化合物16的合成Synthesis of compound 16
将化合物16-a(36mg，0.05mmoL)溶解在5mL的DCM中，冷却到0℃，慢慢滴加氯化氢的1,4-二氧六环溶液(4M，0.25mL)，加毕，混合物在0℃下搅拌20分钟后，用饱和碳酸氢钠溶液(1mL)淬灭反应，加入DCM(20mL)，混合物用无水硫酸钠干燥，过滤，减压浓缩，得到化合物16(33mg，100％)。LC-MS(ESI):m/z＝636.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.48(1H,s),9.52(1H,brs),8.87(1H,s),8.39(1H,d,J＝2.4Hz),8.00(1H,d,J＝1.6Hz),7.61-7.53(1H,m),7.47-7.37(1H,m),4.17(1H,t,J＝5.6Hz),4.08(2H,s),4.03(3H,s),3.91-3.79(6H,m),3.77-3.70(4H,m),3.70-3.62(2H,m),3.59-3.51(2H,m),3.51-3.46(2H,m),3.10(3H,s),3.07-2.96(2H,m).Dissolve compound 16-a (36 mg, 0.05 mmoL) in 5 mL of DCM, cool to 0°C, and slowly add hydrogen chloride in 1,4-dioxane solution (4 M, 0.25 mL) dropwise. After the addition is completed, the mixture is After stirring at 0°C for 20 minutes, the reaction was quenched with saturated sodium bicarbonate solution (1 mL), DCM (20 mL) was added, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 16 (33 mg, 100%) . LC-MS (ESI): m/z=636.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.48 (1H, s), 9.52 (1H, brs), 8.87 (1H ,s),8.39(1H,d,J＝2.4Hz),8.00(1H,d,J＝1.6Hz),7.61-7.53(1H,m),7.47-7.37(1H,m),4.17(1H, t,J＝5.6Hz),4.08(2H,s),4.03(3H,s),3.91-3.79(6H,m),3.77-3.70(4H,m),3.70-3.62(2H,m),3.59 -3.51(2H,m),3.51-3.46(2H,m),3.10(3H,s),3.07-2.96(2H,m).
化合物17的合成路线
Synthetic route of compound 17
化合物17-g的合成Synthesis of compound 17-g
将化合物3-氟-4-溴苯甲酸乙酯(1g，4.00mmoL)溶解在20mL的1,4-二氧六环中， 室温条件下依次加入N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(1.40g，4.40mmoL)，四三苯基膦钯(462mg，0.40mmoL)，碳酸铯(2.60g，8.00mmoL)，水(4mL)，反应混合物在100℃氮气条件下搅拌5小时。反应混合物冷却至室温，加水，用乙酸乙酯萃取。合并有机相，用水洗，饱和NaCl洗，无水Na2SO4干燥，过滤，蒸干，过柱纯化(流动相：DCM/MeOH 10/0到10/1)，得到化合物17-g(1.1g，79％)。LC-MS(ESI):m/z＝294.2[M-56+H]+.Dissolve compound 3-fluoro-4-bromobenzoic acid ethyl ester (1g, 4.00mmoL) in 20mL of 1,4-dioxane, Add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.40g, 4.40mmoL), tetrakistriphenylphosphine palladium (462mg, 0.40mmoL), and carbonic acid in sequence at room temperature. Cesium (2.60g, 8.00mmoL), water (4mL), the reaction mixture was stirred at 100°C under nitrogen for 5 hours. The reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. Combine the organic phases, wash with water and saturated NaCl, dry over anhydrous Na 2 SO 4 , filter, evaporate to dryness, and purify through column (mobile phase: DCM/MeOH 10/0 to 10/1) to obtain compound 17-g (1.1 g, 79%). LC-MS(ESI): m/z=294.2[M-56+H] + .
化合物17-f的合成Synthesis of compound 17-f
将化合物17-g(1.1g，3.15mmoL)溶解在50mL的甲醇中，室温下加入Pd/C(10％Pd，50％wet，1g)，反应混合物在室温氢气条件下搅拌过夜。将反应混合物过滤，浓缩，得到粗品化合物17-f(980mg，88％)。LC-MS(ESI):m/z＝296.1[M-56+H]+.Compound 17-g (1.1g, 3.15mmoL) was dissolved in 50 mL of methanol, Pd/C (10% Pd, 50% wet, 1g) was added at room temperature, and the reaction mixture was stirred under hydrogen at room temperature overnight. The reaction mixture was filtered and concentrated to obtain crude compound 17-f (980 mg, 88%). LC-MS(ESI): m/z=296.1[M-56+H] + .
化合物17-e的合成Synthesis of compound 17-e
将化合物17-f(980mg，2.79mmoL)加入氯化氢的甲醇溶液(M,10mL)，混合物室温搅拌过夜。将反应混合物浓缩至干，得到粗品化合物17-e(870mg)。将粗产品直接用于下一步。LC-MS(ESI):m/z＝252.2[M+1]+.Compound 17-f (980 mg, 2.79 mmoL) was added to a methanol solution of hydrogen chloride (M, 10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to obtain crude compound 17-e (870 mg). The crude product is used directly in the next step. LC-MS(ESI): m/z＝252.2[M+1] + .
化合物17-d的合成Synthesis of Compound 17-d
将化合物17-e(870mg，2.79mmoL)溶解在10mL的乙腈中，室温下依次加入KI(52mg，0.30mmoL)，溴甲基氟硼酸钾(632mg，3.14mmoL)，K2CO3(652mg，4.72moL)，将反应混合物在80℃氮气条件下搅拌过夜。将反应混合物冷却到室温，过滤，滤液浓缩至干，得到粗品。将粗品溶解在5mL的乙腈中，冷却到0℃，慢慢加入乙醚(50mL)，固体析出，过滤，收集固体，固体真空干燥1小时，得到粗品化合物17-d(900mg)。Compound 17-e (870 mg, 2.79 mmoL) was dissolved in 10 mL of acetonitrile, and KI (52 mg, 0.30 mmoL), potassium bromomethylfluoroborate (632 mg, 3.14 mmoL), and K 2 CO 3 (652 mg, 4.72moL), and the reaction mixture was stirred overnight at 80°C under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to obtain crude product. The crude product was dissolved in 5 mL of acetonitrile, cooled to 0°C, diethyl ether (50 mL) was slowly added, the solid precipitated, filtered, collected the solid, and dried the solid in vacuum for 1 hour to obtain crude compound 17-d (900 mg).
化合物17的合成Synthesis of compound 17
参照化合物1的合成路线和操作，使用化合物17-d替代化合物1-d，得到化合物17(28mg)。LC-MS(ESI):m/z＝684.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ11.38(1H,s),9.56(1H,s),9.13(1H,s),8.44(1H,d,J＝2Hz),8.27(1H,d,J＝8.0Hz),8.02(1H,d,J＝2.0Hz),7.71(1H,d,J＝9.2Hz),7.61(1H,d,J＝7.2Hz),7.54(1H,d,J＝11.2Hz),7.34(1H,t,J＝6.8Hz),4.78(2H,d,J＝3.2Hz),4.03(3H,s),3.92(4H,m),3.75(4H,m),3.67(1H,s),3.56-3.48(2H,m),3.28-3.25(2H,m),3.10(3H,s),2.19-2.09(2H,m),1.93-1.86(2H,m).Referring to the synthetic route and operation of compound 1, compound 17-d was used instead of compound 1-d to obtain compound 17 (28 mg). LC-MS(ESI): m/z=684.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ11.38(1H,s),9.56(1H,s),9.13(1H ,s),8.44(1H,d,J＝2Hz),8.27(1H,d,J＝8.0Hz),8.02(1H,d,J＝2.0Hz),7.71(1H,d,J＝9.2Hz) ,7.61(1H,d,J＝7.2Hz),7.54(1H,d,J＝11.2Hz),7.34(1H,t,J＝6.8Hz),4.78(2H,d,J＝3.2Hz),4.03 (3H,s),3.92(4H,m),3.75(4H,m),3.67(1H,s),3.56-3.48(2H,m),3.28-3.25(2H,m),3.10(3H,s ),2.19-2.09(2H,m),1.93-1.86(2H,m).
化合物18的合成路线
Synthetic route of compound 18
化合物18的合成Synthesis of compound 18
参照化合物17的合成路线和操作，使用化合物2-氟-4-溴苯甲酸甲酯替代化合物3-氟-4-溴苯甲酸乙酯，得到化合物18(81mg)。LC-MS(ESI):m/z＝684.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ11.16(1H,s),10.93(1H,s),9.56(1H,s),8.43(1H,d,J＝2.0Hz),8.33-8.28(1H,m),8.02(1H,d,J＝2.0Hz),7.69(1H,m),7.50(1H,t,J＝7.6Hz),7.12(2H,t,J＝9.2Hz),4.78(2H,d,J＝3.2Hz),4.03(3H,s),3.92(4H,m),3.75(4H,m),3.67(1H,s),3.52-3.50(2H,m),3.21-3.18(2H,m),3.10(3H,s),2.22-2.11(2H,m),1.96-1.93(2H,m).Referring to the synthetic route and operation of compound 17, compound 2-fluoro-4-bromobenzoic acid methyl ester was used instead of compound 3-fluoro-4-bromobenzoic acid ethyl ester to obtain compound 18 (81 mg). LC-MS (ESI): m/z=684.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ11.16 (1H, s), 10.93 (1H, s), 9.56 (1H ,s),8.43(1H,d,J＝2.0Hz),8.33-8.28(1H,m),8.02(1H,d,J＝2.0Hz),7.69(1H,m),7.50(1H,t, J＝7.6Hz),7.12(2H,t,J＝9.2Hz),4.78(2H,d,J＝3.2Hz),4.03(3H,s),3.92(4H,m),3.75(4H,m) ,3.67(1H,s),3.52-3.50(2H,m),3.21-3.18(2H,m),3.10(3H,s),2.22-2.11(2H,m),1.96-1.93(2H,m) .
化合物19的合成路线
Synthetic route of compound 19
化合物19的合成Synthesis of compound 19
参照化合物17的合成路线和操作，使用化合物4-溴-3,5-二氟苯甲酸乙酯替代化合物3-氟-4-溴苯甲酸乙酯，得到化合物19(2mg)。LC-MS(ESI):m/z＝702.1[M+1]+.Referring to the synthetic route and operation of compound 17, compound 4-bromo-3,5-difluorobenzoic acid ethyl ester was used instead of compound 3-fluoro-4-bromobenzoic acid ethyl ester to obtain compound 19 (2 mg). LC-MS(ESI): m/z＝702.1[M+1] + .
化合物20的合成路线
Synthetic route of compound 20
化合物20的合成 Synthesis of compound 20
参照化合物17的合成路线和操作，使用化合物4-溴-2,5-二氟苯甲酸甲酯替代化合物3-氟-4-溴苯甲酸乙酯，得到化合物20(85mg)。LC-MS(ESI):m/z＝702.2[M+1]+.Referring to the synthetic route and operation of compound 17, compound 4-bromo-2,5-difluorobenzoic acid methyl ester was used instead of compound 3-fluoro-4-bromobenzoic acid ethyl ester to obtain compound 20 (85 mg). LC-MS(ESI):m/z＝702.2[M+1] + .
化合物21的合成路线
Synthetic route of compound 21
化合物21-g的合成Synthesis of compound 21-g
将化合物N-Boc-4-羟基哌啶(2.01g，10mmoL)溶解在20mL的DMF中，冷却到0℃，氮气条件下加入NaH(800mg，20mmoL，60％)，将反应混合物升温到60℃，搅拌30分钟，然后滴加苄基2-溴乙基醚(2.37mL，15mmoL)，反应混合物在同样的条件下搅拌16小时。将反应混合物冷却到0℃，用50mL的饱和氯化铵溶液淬灭，并加水50mL，用乙酸乙酯(100ml*2)萃取，有机相用饱和食盐水(100mL*3)洗涤，无水硫酸钠干燥、过滤，减压浓缩，粗品通过快速分离柱分离纯化(PE/EA＝2:1)，得到化合物21-g(1g，30％)。LC-MS(ESI):m/z＝280.2[M-56+1]+.Dissolve compound N-Boc-4-hydroxypiperidine (2.01g, 10mmoL) in 20mL of DMF, cool to 0°C, add NaH (800mg, 20mmoL, 60%) under nitrogen conditions, and heat the reaction mixture to 60°C , stir for 30 minutes, then benzyl 2-bromoethyl ether (2.37mL, 15mmoL) was added dropwise, and the reaction mixture was stirred under the same conditions for 16 hours. Cool the reaction mixture to 0°C, quench with 50 mL of saturated ammonium chloride solution, add 50 mL of water, extract with ethyl acetate (100 ml*2), wash the organic phase with saturated brine (100 mL*3), and anhydrous sulfuric acid It was dried over sodium, filtered, and concentrated under reduced pressure. The crude product was separated and purified through a rapid separation column (PE/EA=2:1) to obtain compound 21-g (1g, 30%). LC-MS(ESI): m/z＝280.2[M-56+1] + .
化合物21-f的合成Synthesis of Compound 21-f
将化合物21-g(1g，2.98mmoL)溶解在100mL的甲醇中，室温氮气下加入Pd/C(10％Pd，50％wet，0.5g)，反应混合物在室温氢气条件下搅拌16小时。过滤，减压浓缩，得到化合物21-f(736mg，100％)。LC-MS(ESI):m/z＝190.2[M-56+1]+.Compound 21-g (1g, 2.98mmoL) was dissolved in 100 mL of methanol, Pd/C (10% Pd, 50% wet, 0.5g) was added under nitrogen at room temperature, and the reaction mixture was stirred under hydrogen at room temperature for 16 hours. Filter and concentrate under reduced pressure to obtain compound 21-f (736 mg, 100%). LC-MS(ESI): m/z＝190.2[M-56+1] + .
化合物21-e的合成Synthesis of Compound 21-e
室温氮气下，将NaH(156mg，3.9mmoL，60％)溶解在10mL的THF中，然后慢慢加入化合物21-f(736mg，3.0mmoL)的THF(5mL)溶液，反应混合物在室温搅拌2小时后，冷却到0℃，滴加溴乙酸乙酯(432uL，3.9mmoL)，加毕，升到室温，搅拌16小时。0℃下，用饱和氯化铵溶液(50ml)淬灭反应，混合物用乙酸乙酯(100mL*2)萃取， 有机相用无水硫酸钠干燥、过滤，减压浓缩，粗品通过快速分离柱分离纯化(PE/EA＝1:1到EA)，得到化合物21-e(313mg，32％)。LC-MS(ESI):m/z＝276.1[M-56+1]+.Under nitrogen at room temperature, NaH (156 mg, 3.9 mmoL, 60%) was dissolved in 10 mL of THF, and then a solution of compound 21-f (736 mg, 3.0 mmoL) in THF (5 mL) was slowly added, and the reaction mixture was stirred at room temperature for 2 hours. Afterwards, cool to 0°C, add ethyl bromoacetate (432uL, 3.9mmoL) dropwise, complete the addition, raise to room temperature, and stir for 16 hours. At 0°C, the reaction was quenched with saturated ammonium chloride solution (50ml), and the mixture was extracted with ethyl acetate (100mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified through a rapid separation column (PE/EA=1:1 to EA) to obtain compound 21-e (313 mg, 32%). LC-MS(ESI): m/z＝276.1[M-56+1] + .
化合物21-d的合成Synthesis of Compound 21-d
室温下将化合物21-e(313mg，0.94mmoL)溶解在10mL的DCM中，冷却到0℃，加入氯化氢的1,4-二氧六环溶液(5mL)，反应混合物升到室温搅拌16小时后，减压浓缩，得到粗品化合物21-d(252mg)，粗品直接用于下一步反应。LC-MS(ESI):m/z＝232.2[M+1]+.Dissolve compound 21-e (313 mg, 0.94 mmoL) in 10 mL of DCM at room temperature, cool to 0°C, add hydrogen chloride in 1,4-dioxane solution (5 mL), and raise the reaction mixture to room temperature and stir for 16 hours. , concentrated under reduced pressure to obtain crude compound 21-d (252 mg), which was directly used in the next step of reaction. LC-MS(ESI): m/z＝232.2[M+1] + .
化合物21-c的合成Synthesis of compound 21-c
将化合物21-d(252mg，0.94mmoL)溶解在20mL的乙腈中，室温下依次加入碘化钾(9mg，0.054mmoL)，溴甲基氟硼酸钾(180mg，0.90mmoL)，碳酸钾(185mg，1.34mmoL)，然后混合物在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后滤液减压浓缩，粗品溶解在5mL的乙腈中，加入50mL的乙醚，固体析出，过滤，滤饼用乙醚(10mL)洗涤，收集固体，得到化合物21-c(216mg，77％)。LC-MS(ESI):m/z＝331.2[M+18]+.Compound 21-d (252 mg, 0.94mmoL) was dissolved in 20 mL of acetonitrile, and potassium iodide (9 mg, 0.054mmoL), potassium bromomethylfluoroborate (180 mg, 0.90mmoL), and potassium carbonate (185 mg, 1.34mmoL) were added successively at room temperature. ), and then the mixture was stirred at 80°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with acetonitrile (10 mL), and then the filtrate was concentrated under reduced pressure. The crude product was dissolved in 5 mL of acetonitrile, 50 mL of diethyl ether was added, the solid precipitated, filtered, and the filter cake was washed with diethyl ether (10 mL). The solid was collected to give compound 21-c (216 mg, 77%). LC-MS(ESI): m/z＝331.2[M+18] + .
化合物21-b的合成Synthesis of compound 21-b
室温下将化合物1-e(215mg，0.46mmoL)溶解在20mL的THF中，依次加入水(2mL)、21-c(216mg，0.69mmoL)、醋酸钯(10mg，0.046mmoL)、x-Phos(44mg，0.092mmoL)、碳酸铯(450mg，1.38mmoL)，反应混合物在80℃氮气条件下搅拌48小时。将反应液冷却至室温，并加入30mL水，用乙酸乙酯(100mL)萃取，水相用1N稀盐酸调pH的5，将水相减压浓缩，粗品悬浮在混合溶剂中(DCM/MeOH＝10:1，20mL)，过滤，滤饼用混合物溶剂(DCM/MeOH＝10:1，20mL*2)洗涤，合并有机相，减压浓缩，粗品通过PREP-HPLC分离纯化，得到化合物21-b(10mg，3.3％)。LC-MS(ESI):m/z＝649.2[M+1]+.Compound 1-e (215mg, 0.46mmoL) was dissolved in 20mL of THF at room temperature, and water (2mL), 21-c (216mg, 0.69mmoL), palladium acetate (10mg, 0.046mmoL), x-Phos ( 44 mg, 0.092 mmoL), cesium carbonate (450 mg, 1.38 mmoL), and the reaction mixture was stirred under nitrogen at 80°C for 48 hours. The reaction solution was cooled to room temperature, 30 mL of water was added, extracted with ethyl acetate (100 mL), the aqueous phase was adjusted to pH 5 with 1N dilute hydrochloric acid, the aqueous phase was concentrated under reduced pressure, and the crude product was suspended in a mixed solvent (DCM/MeOH = 10:1, 20mL), filtered, and the filter cake was washed with a mixture solvent (DCM/MeOH=10:1, 20mL*2). The organic phases were combined and concentrated under reduced pressure. The crude product was separated and purified by PREP-HPLC to obtain compound 21-b. (10 mg, 3.3%). LC-MS(ESI): m/z＝649.2[M+1] + .
化合物21-a的合成Synthesis of compound 21-a
室温下将化合物21-b(10mg，0.015mmoL)溶解在1mL的DMF中，冰浴下依次加入HATU(9mg，0.023mmoL)、DIPEA(13μL，0.077mmoL)，反应混合物在0℃下搅拌10分钟，然后加入O-(四氢-2H-吡喃)-2-羟胺(10mg，0.085mmoL)，反应混合物升到室温并搅拌16小时。用10mL水淬灭反应，然后用乙酸乙酯(20mL*2)萃取，有机相用饱和食盐水(30mL*3)洗涤，无水硫酸钠干燥、过滤，减压浓缩，粗品通过PREP-HPLC分离纯化，得到化合物21-a(12mg，100％)。LC-MS(ESI):m/z＝748.3[M+1]+.Dissolve compound 21-b (10 mg, 0.015mmoL) in 1 mL of DMF at room temperature, add HATU (9 mg, 0.023mmoL) and DIPEA (13 μL, 0.077mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (10 mg, 0.085 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with 10 mL of water, and then extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated brine (30 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by PREP-HPLC. Purification gave compound 21-a (12 mg, 100%). LC-MS(ESI): m/z=748.3[M+1] + .
化合物21的合成Synthesis of Compound 21
将化合物21-a(12mg，0.016mmoL)溶解在5mL的DCM中，冷却到0℃，慢慢滴加氯化氢的1,4-二氧六环溶液(4M，0.3mL)，加毕，混合物在0℃下搅拌20分钟后，用 饱和碳酸氢钠溶液(2mL)淬灭反应，加入DCM(20mL)，混合物用无水硫酸钠干燥，过滤，减压浓缩，得到化合物21(6mg，54％)。LC-MS(ESI):m/z＝664.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.45(1H,s),9.53(1H,brs),8.88(1H,s),8.41(1H,d,J＝1.2Hz),8.05(1H,s),8.00(1H,d,J＝2.4Hz),4.64(1H,s),4.02(3H,s),3.93-3.79(4H,m),3.79-3.65(4H,m),3.55(2H,s),3.52-3.19(10H,m),3.09(3H,s),2.00-1.83(3H,m),1.59-1.38(2H,m).Dissolve compound 21-a (12 mg, 0.016 mmoL) in 5 mL of DCM, cool to 0°C, and slowly add hydrogen chloride in 1,4-dioxane solution (4 M, 0.3 mL) dropwise. After the addition is completed, the mixture is After stirring for 20 minutes at 0°C, use The reaction was quenched with saturated sodium bicarbonate solution (2 mL), DCM (20 mL) was added, and the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 21 (6 mg, 54%). LC-MS (ESI): m/z=664.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.45 (1H, s), 9.53 (1H, brs), 8.88 (1H ,s),8.41(1H,d,J＝1.2Hz),8.05(1H,s),8.00(1H,d,J＝2.4Hz),4.64(1H,s),4.02(3H,s),3.93 -3.79(4H,m),3.79-3.65(4H,m),3.55(2H,s),3.52-3.19(10H,m),3.09(3H,s),2.00-1.83(3H,m),1.59 -1.38(2H,m).
化合物22的合成路线
Synthetic route of compound 22
化合物22-e的合成Synthesis of compound 22-e
将化合物Linperlisib(3g，5.1mmoL)溶解在30mL的DCM中，室温氮气下加入DMAP(716mg，5.86mmoL)、BOC2O(1.17g，5.35mmoL)，然后搅拌16小时。减压浓缩，粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物22-e(3g，86％)。LC-MS(ESI):m/z＝689.2[M+1]+.Compound Linperlisib (3g, 5.1mmoL) was dissolved in 30 mL of DCM, and DMAP (716 mg, 5.86mmoL) and BOC 2 O (1.17g, 5.35mmoL) were added under nitrogen at room temperature, and then stirred for 16 hours. The mixture was concentrated under reduced pressure, and the crude product was separated and purified through a fast separation column (DCM/MeOH=10:1) to obtain compound 22-e (3g, 86%). LC-MS(ESI): m/z＝689.2[M+1] + .
化合物22-d的合成Synthesis of Compound 22-d
将化合物22-e(200mg，0.29mmoL)溶解在20mL的DCM中，室温氮气下加入Rh2(OAc)4(65mg，0.15mmoL)、重氮乙酸乙酯(99mg，0.87mmoL)，然后混合物在室温氮气下搅拌2天。补加500μL的重氮乙酸乙酯，并在30℃氮气下搅拌16小时。冷到室温，过滤，滤液减压浓缩，粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到粗品化合物22-d(约100mg)，粗品直接用于下一步。LC-MS(ESI):m/z＝775.3[M+1]+.Compound 22-e (200 mg, 0.29 mmoL) was dissolved in 20 mL of DCM, Rh 2 (OAc) 4 (65 mg, 0.15 mmoL) and ethyl diazoacetate (99 mg, 0.87 mmoL) were added under nitrogen at room temperature, and then the mixture was added Stir under nitrogen at room temperature for 2 days. Add 500 μL of ethyl diazoacetate and stir at 30°C under nitrogen for 16 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified through a rapid separation column (DCM/MeOH = 10:1) to obtain crude compound 22-d (about 100 mg). The crude product is directly used in the next step. LC-MS(ESI): m/z=775.3[M+1] + .
化合物22-c的合成Synthesis of compound 22-c
将粗品化合物22-d(200mg，0.26mmoL)溶解在20mL的DCM中，0℃氮气下加入TFA(7mL)，并在0℃氮气下搅拌5小时。减压浓缩，粗品悬浮在50mL的饱和碳酸氢钠溶液中，用DCM(100mL*2)萃取，有机相用无水硫酸钠干燥、过滤，减压浓缩，粗 品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物22-c(115mg，66％)，为黄色固体。LC-MS(ESI):m/z＝675.3[M+1]+.Crude compound 22-d (200 mg, 0.26 mmoL) was dissolved in 20 mL of DCM, TFA (7 mL) was added under nitrogen at 0°C, and stirred at 0°C under nitrogen for 5 hours. Concentrate under reduced pressure, suspend the crude product in 50 mL of saturated sodium bicarbonate solution, extract with DCM (100 mL*2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain the crude product. The product was separated and purified through a fast separation column (DCM/MeOH=10:1) to obtain compound 22-c (115 mg, 66%) as a yellow solid. LC-MS(ESI): m/z＝675.3[M+1] + .
化合物22的合成Synthesis of compound 22
参照化合物1的合成路线和操作，使用化合物22-c替代化合物1-c，得到化合物22(18mg)。LC-MS(ESI):m/z＝662.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.21(1H,s),9.49(1H,brs),8.75(1H,s),8.41(1H,d,J＝2.0Hz),8.00(1H,d,J＝2.0Hz),7.72(1H,brs),7.47(1H,brs),4.03(3H,s),3.90-3.78(4H,m),3.80-3.61(6H,m),3.24-3.20(1H,m),3.10(3H,s),3.10-2.89(2H,m),2.22-1.89(2H,m),1.72-1.55(2H,m),1.55-1.26(4H,m),1.07(6H,s).Referring to the synthetic route and operation of compound 1, compound 22-c was used instead of compound 1-c to obtain compound 22 (18 mg). LC-MS (ESI): m/z=662.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.21 (1H, s), 9.49 (1H, brs), 8.75 (1H ,s),8.41(1H,d,J＝2.0Hz),8.00(1H,d,J＝2.0Hz),7.72(1H,brs),7.47(1H,brs),4.03(3H,s),3.90 -3.78(4H,m),3.80-3.61(6H,m),3.24-3.20(1H,m),3.10(3H,s),3.10-2.89(2H,m),2.22-1.89(2H,m) ,1.72-1.55(2H,m),1.55-1.26(4H,m),1.07(6H,s).
化合物23的合成路线
Synthetic route of compound 23
化合物23的合成Synthesis of compound 23
参照化合物17的合成路线和操作，使用化合物4-溴-苯甲酸乙酯替代化合物3-氟-4-溴苯甲酸乙酯，得到化合物23(40mg)。LC-MS(ESI):m/z＝666.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ11.13(1H,s),8.98(1H,s),8.39(1H,d,J＝1.6Hz),7.99(1H,d,J＝2Hz),7.75(1H,d,J＝7.6Hz),7.67(2H,d,J＝8.0Hz),7.45(1H,d,J＝7.6Hz),7.33(2H,d,J＝8.0Hz),4.14-3.95(1H,m),4.01(3H,s),3.93-3.78(4H,m),3.77-3.65(4H,m),3.14-2.97(2H,m),3.09(3H,s),2.88(2H,s),2.66-2.54(1H,m),2.40-2.14(2H,m),1.86-1.63(4H,m).Referring to the synthetic route and operation of compound 17, compound 4-bromo-ethyl benzoate was used instead of compound 3-fluoro-4-bromoethyl benzoate to obtain compound 23 (40 mg). LC-MS(ESI): m/z=666.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ11.13(1H,s),8.98(1H,s),8.39(1H ,d,J＝1.6Hz),7.99(1H,d,J＝2Hz),7.75(1H,d,J＝7.6Hz),7.67(2H,d,J＝8.0Hz),7.45(1H,d, J＝7.6Hz),7.33(2H,d,J＝8.0Hz),4.14-3.95(1H,m),4.01(3H,s),3.93-3.78(4H,m),3.77-3.65(4H,m ),3.14-2.97(2H,m),3.09(3H,s),2.88(2H,s),2.66-2.54(1H,m),2.40-2.14(2H,m),1.86-1.63(4H,m ).
化合物24的合成路线
Synthetic route of compound 24
化合物24-f的合成Synthesis of compound 24-f
根据专利CN111440142A的路线和操作合成。It is synthesized according to the route and operation of patent CN111440142A.
化合物24-e的合成Synthesis of Compound 24-e
往反应瓶中加入化合物24-f(2g，4.56mmol)，5-氨基吡啶-3-硼酸频哪醇酯(1.2g，5.48mmol)，甲苯(30mL)，异丙醇(10mL)，水(10mL)，碳酸钠(3.8g，27.4mmol)和四三苯基膦钯(264mg，0.23mmol)，用氮气置换三次，氮气中100℃搅拌过夜。反应结束后，反应液旋干，过柱纯化(流动相：甲醇/二氯甲烷0/100到5/95)，得到化合物24-e(400mg，24％)。LC-MS(ESI):m/z＝360.0(M+H)+.Add compound 24-f (2g, 4.56mmol), 5-aminopyridine-3-boronic acid pinacol ester (1.2g, 5.48mmol), toluene (30mL), isopropanol (10mL), water ( 10 mL), sodium carbonate (3.8 g, 27.4 mmol) and tetrakis triphenylphosphine palladium (264 mg, 0.23 mmol), replaced with nitrogen three times, and stirred at 100°C overnight in nitrogen. After the reaction was completed, the reaction solution was spin-dried and purified through column (mobile phase: methanol/dichloromethane 0/100 to 5/95) to obtain compound 24-e (400 mg, 24%). LC-MS(ESI): m/z=360.0(M+H) + .
化合物24-d的合成Synthesis of Compound 24-d
往反应瓶中加入24-e(400mg，1.11mmol)，吡啶(5mL)，然后在冰浴下滴加甲磺酰氯(191mg，1.66mmol)，室温搅拌过夜。次日，反应用水淬灭，乙酸乙酯萃取(50mL*2)，饱和食盐水洗涤，无水硫酸钠干燥，旋干，过柱纯化(流动相：乙酸乙酯/石油醚0/100到100/0)，得到化合物24-d(350mg，72％)。LC-MS(ESI):m/z＝438.0(M+H)+；Add 24-e (400 mg, 1.11 mmol) and pyridine (5 mL) to the reaction flask, then add methanesulfonyl chloride (191 mg, 1.66 mmol) dropwise in an ice bath, and stir at room temperature overnight. The next day, the reaction was quenched with water, extracted with ethyl acetate (50mL*2), washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified through column (mobile phase: ethyl acetate/petroleum ether 0/100 to 100 /0) to obtain compound 24-d (350 mg, 72%). LC-MS(ESI): m/z=438.0(M+H) + ;
化合物24-c的合成Synthesis of compound 24-c
往反应瓶中加入24-d(350mg，0.80mmol)，四氢呋喃(20mL)，4-d(641mg，2.40mmol)， 水(2mL)，X-Phos(76mg，0.16mmol)，碳酸铯(781mg，2.40mmol)，醋酸钯(18mg，0.08mmol)，氮气置换三次，氮气中80℃搅拌36小时，反应液旋干，过柱纯化(流动相：甲醇/二氯甲烷0/100到5/95)，得到化合物24-c(300mg，62％)。LC-MS(ESI):m/z＝601.2(M+H)+.Add 24-d (350mg, 0.80mmol), tetrahydrofuran (20mL), 4-d (641mg, 2.40mmol) to the reaction flask, Water (2mL), X-Phos (76mg, 0.16mmol), cesium carbonate (781mg, 2.40mmol), palladium acetate (18mg, 0.08mmol), replace with nitrogen three times, stir at 80°C for 36 hours in nitrogen, spin the reaction liquid to dryness, After column purification (mobile phase: methanol/dichloromethane 0/100 to 5/95), compound 24-c (300 mg, 62%) was obtained. LC-MS(ESI):m/z＝601.2(M+H) + .
化合物24-b的合成Synthesis of compound 24-b
往反应瓶中加入24-c(300mg，0.50mmol)，四氢呋喃(10mL)，甲醇(10mL)，水(5mL)和氢氧化钠(80mg，2mmol)，氮气中室温搅拌过夜，次日，旋掉四氢呋喃和甲醇，用1N盐酸调节pH到4，二氯甲烷/甲醇10/1萃取(15mL*6)，无水硫酸钠干燥，旋干，得到化合物24-b(200mg，68％)，该化合物未经纯化直接用于下一步反应。LC-MS(ESI):m/z＝587.2(M+H)+.Add 24-c (300 mg, 0.50 mmol), tetrahydrofuran (10 mL), methanol (10 mL), water (5 mL) and sodium hydroxide (80 mg, 2 mmol) to the reaction flask, stir under nitrogen at room temperature overnight, and spin off the next day. Tetrahydrofuran and methanol, adjust the pH to 4 with 1N hydrochloric acid, extract with dichloromethane/methanol 10/1 (15mL*6), dry over anhydrous sodium sulfate, and spin to dryness to obtain compound 24-b (200 mg, 68%). This compound It was used directly in the next reaction without purification. LC-MS(ESI): m/z=587.2(M+H) + .
化合物24-a的合成Synthesis of compound 24-a
往反应瓶中加入24-b(200mg，0.34mmol)，DMF(5mL)，O-(四氢-2H-吡喃-2-基)羟基胺(60mg，0.51mmol)，HATU(260mg，0.68mmol)和DIPEA(132mg，1.02mmol)，氮气中室温搅拌过夜。次日，反应液直接HPLC制备(碳酸氢铵)，冻干，得到化合物24-a(120mg，51％)。LC-MS(ESI):m/z＝686.2(M+H)+；Add 24-b (200mg, 0.34mmol), DMF (5mL), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (60mg, 0.51mmol), HATU (260mg, 0.68mmol) to the reaction flask. ) and DIPEA (132 mg, 1.02 mmol), stirred at room temperature under nitrogen overnight. The next day, the reaction solution was directly prepared by HPLC (ammonium bicarbonate) and lyophilized to obtain compound 24-a (120 mg, 51%). LC-MS(ESI): m/z=686.2(M+H) + ;
化合物24的合成Synthesis of compound 24
将24-a(120mg，0.17mmol)溶于二氯甲烷(20mL)，冰浴下滴加4M盐酸1,4-二氧六环(1.0mL)，并在该温度下搅拌50分钟，先用1mL饱和碳酸氢钠溶液淬灭，再补加1g固体碳酸氢钠和100mL二氯甲烷/甲醇(10/1)溶液，该溶液用无水硫酸钠干燥，过滤，滤液旋干，再用乙腈水冻干，得到24(70mg，66％)。LC-MS(ESI):m/z＝602.3(M+H)+；1H NMR(400MHz,DMSO-d6):δ10.32-10.65(2H,m),8.65-8.69(3H,m),8.20-8.32(1H,m),7.97-7.98(1H,m),7.62-7.64(1H,m),4.64-4.77(2H,m),3.87-4.02(4H,m),3.69-3.79(4H,m),3.58(2H,s),3.30-3.50(2H,m),3.16(3H,s),2.91-3.11(2H,m),1.88-1.99(2H,m),1.73-1.84(2H,m),1.39-1.60(5H,m).Dissolve 24-a (120 mg, 0.17 mmol) in dichloromethane (20 mL), add 4M 1,4-dioxane hydrochloride (1.0 mL) dropwise in an ice bath, and stir at this temperature for 50 minutes. Quench 1 mL of saturated sodium bicarbonate solution, then add 1 g of solid sodium bicarbonate and 100 mL of methylene chloride/methanol (10/1) solution. The solution is dried with anhydrous sodium sulfate, filtered, and the filtrate is spun to dryness, and then washed with acetonitrile water. Lyophilization afforded 24 (70 mg, 66%). LC-MS (ESI): m/z=602.3(M+H) + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.32-10.65(2H,m),8.65-8.69(3H,m) ,8.20-8.32(1H,m),7.97-7.98(1H,m),7.62-7.64(1H,m),4.64-4.77(2H,m),3.87-4.02(4H,m),3.69-3.79( 4H,m),3.58(2H,s),3.30-3.50(2H,m),3.16(3H,s),2.91-3.11(2H,m),1.88-1.99(2H,m),1.73-1.84( 2H,m),1.39-1.60(5H,m).
化合物25的合成路线
Synthetic route of compound 25
化合物25-e的合成Synthesis of compound 25-e
室温下将化合物24-f(438mg，1mmoL)溶解在30mL的甲苯中，依次加入水(10mL)、异丙醇(10mL)、3-氨基-2-甲氧基吡啶-5-硼酸频哪醇酯(300mg，1.2mmoL)、四三苯基磷钯(58mg，0.05mmoL)、碳酸钠(636mg，6mmoL)，反应混合物在30℃氮气条件下搅拌16小时。减压浓缩后，向反应体系中加入50mL水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝1:1)，得到化合物25-e(381mg，98％)。LC-MS(ESI):m/z＝390.1[M+1]+.Dissolve compound 24-f (438 mg, 1 mmoL) in 30 mL of toluene at room temperature, and add water (10 mL), isopropyl alcohol (10 mL), and 3-amino-2-methoxypyridine-5-boronic acid pinacol in sequence. Ester (300 mg, 1.2 mmoL), tetraphenylphosphorus palladium (58 mg, 0.05 mmoL), and sodium carbonate (636 mg, 6 mmoL). The reaction mixture was stirred under nitrogen at 30°C for 16 hours. After concentration under reduced pressure, 50mL of water was added to the reaction system, extracted with ethyl acetate (100mL*2), the organic phase was washed with saturated brine (100mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Crude. The crude product was separated and purified through a fast separation column (PE/EA=1:1) to obtain compound 25-e (381 mg, 98%). LC-MS(ESI): m/z＝390.1[M+1] + .
化合物25-d的合成Synthesis of Compound 25-d
冰浴下将化合物25-e(381mg，0.98mmoL)溶解在6mL的吡啶中，滴加环丙基磺酰氯(276mg，1.96mmoL)，加毕，反应混合物升到40度搅拌16小时。反应混合物冷到室温，加入100mL水，用DCM(100mL*2)萃取，有机相用无水硫酸钠干燥、过滤，减压浓缩，得到粗品，粗品通过快速分离柱分离纯化(PE/EA＝1:1)，得到化合物25-d(400mg，83％)。LC-MS(ESI):m/z＝494.1[M+1]+.Dissolve compound 25-e (381 mg, 0.98 mmoL) in 6 mL of pyridine under an ice bath, and add cyclopropylsulfonyl chloride (276 mg, 1.96 mmoL) dropwise. After the addition is completed, the reaction mixture is raised to 40 degrees and stirred for 16 hours. The reaction mixture was cooled to room temperature, 100mL of water was added, and extracted with DCM (100mL*2). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified through a rapid separation column (PE/EA=1 :1), compound 25-d (400 mg, 83%) was obtained. LC-MS(ESI):m/z＝494.1[M+1] + .
化合物25-c的合成 Synthesis of compound 25-c
室温下将化合物25-d(200mg，0.41mmoL)溶解在20mL的THF中，依次加入水(2mL)、4-d(325mg，1.22mmoL)、醋酸钯(10mg，0.041mmoL)、x-Phos(39mg，0.081mmoL)、碳酸铯(396mg，1.22mmoL)，反应混合物在80℃氮气条件下搅拌48小时。向反应体系中加入50mL水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝1:1，DCM/MeOH＝10:1)，得到化合物25-c(135mg，51％)。LC-MS(ESI):m/z＝657.2[M+1]+.Compound 25-d (200 mg, 0.41 mmoL) was dissolved in 20 mL of THF at room temperature, and water (2 mL), 4-d (325 mg, 1.22 mmoL), palladium acetate (10 mg, 0.041 mmoL), x-Phos ( 39 mg, 0.081 mmoL), cesium carbonate (396 mg, 1.22 mmoL), and the reaction mixture was stirred under nitrogen at 80°C for 48 hours. Add 50 mL of water to the reaction system, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified through a fast separation column (PE/EA=1:1, DCM/MeOH=10:1) to obtain compound 25-c (135 mg, 51%). LC-MS(ESI): m/z＝657.2[M+1] + .
化合物25-b的合成Synthesis of compound 25-b
将化合物25-c(135mg，0.21mmoL)溶解在10mL的甲醇中，室温下依次加入THF(10mL)、水(5mL)、氢氧化钠(82mg，2.06mmoL)，反应混合物室温下搅拌12小时。减压浓缩，残留物溶解在水(20mL)中，用1N HCl水溶液调节pH值到4～5，用混合溶剂(DCM/MeOH＝10:1，100mL*3)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩的粗品化合物25-b(127mg，96％)。LC-MS(ESI):m/z＝643.2[M+1]+.Compound 25-c (135 mg, 0.21 mmoL) was dissolved in 10 mL of methanol, THF (10 mL), water (5 mL), and sodium hydroxide (82 mg, 2.06 mmoL) were added successively at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. Concentrate under reduced pressure, dissolve the residue in water (20mL), adjust the pH value to 4-5 with 1N HCl aqueous solution, extract with mixed solvent (DCM/MeOH=10:1, 100mL*3), and use anhydrous sulfuric acid for the organic phase The crude compound 25-b (127 mg, 96%) was dried over sodium, filtered, and concentrated under reduced pressure. LC-MS(ESI):m/z＝643.2[M+1] + .
化合物25-a的合成Synthesis of compound 25-a
室温下将化合物25-b(127mg，0.20mmoL)溶解在3mL的DMF中，冰浴下依次加入HATU(113mg，0.30mmoL)、DIPEA(163uL，0.99mmoL)，反应混合物在0℃下搅拌10分钟，然后加入O-(四氢-2H-吡喃)-2-羟胺(46mg，0.40mmoL)，将反应混合物升到室温并搅拌16小时。反应液通过PREP-HPLC分离纯化，得到化合物25-a(98mg，67％)。LC-MS(ESI):m/z＝742.1[M+1]+.Dissolve compound 25-b (127mg, 0.20mmoL) in 3mL of DMF at room temperature, add HATU (113mg, 0.30mmoL) and DIPEA (163uL, 0.99mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C for 10 minutes. , then O-(tetrahydro-2H-pyran)-2-hydroxylamine (46 mg, 0.40 mmoL) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction solution was separated and purified by PREP-HPLC to obtain compound 25-a (98 mg, 67%). LC-MS(ESI):m/z＝742.1[M+1] + .
化合物25的合成Synthesis of compound 25
将化合物25-a(98mg，0.13mmoL)溶解在5mL的DCM中，冷却到0℃，慢慢滴加氯化氢的1,4-二氧六环溶液(4M，0.25mL)，加毕，混合物在0℃下搅拌20分钟后，用饱和碳酸氢钠溶液(1mL)淬灭反应，加入混合溶剂(DCM/MeOH＝10:1，50mL)，体系用无水硫酸钠干燥，过滤，减压浓缩，得到化合物25(80mg，92％)。LC-MS(ESI):m/z＝658.3[M+1]+；1H NMR(400MHz,DMSO-d6):δ10.33(1H,s),9.52(1H,brs),8.66(1H,s),8.39(1H,d,J＝2.4Hz),7.99(1H,d,J＝2.0Hz),7.67(1H,d,J＝9.6Hz),7.42(1H,dd,J1＝2.0Hz,J2＝8.8Hz),4.01(3H,s),3.96(2H,s),3.89-3.77(4H,m),3.77-3.63(4H,m),2.96-2.82(2H,m),2.82-2.69(1H,m),2.16-2.01(2H,m),1.94-1.85(2H,m),1.67-1.55(2H,m),1.52-1.41(2H,m),1.24-1.11(5H,m),0.99-0.88(4H,m).Dissolve compound 25-a (98 mg, 0.13 mmoL) in 5 mL of DCM, cool to 0°C, and slowly add hydrogen chloride in 1,4-dioxane solution (4 M, 0.25 mL) dropwise. After the addition is completed, the mixture is After stirring at 0°C for 20 minutes, the reaction was quenched with saturated sodium bicarbonate solution (1 mL), a mixed solvent (DCM/MeOH=10:1, 50 mL) was added, the system was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 25 was obtained (80 mg, 92%). LC-MS (ESI): m/z=658.3[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.33 (1H, s), 9.52 (1H, brs), 8.66 (1H ,s),8.39(1H,d,J＝2.4Hz),7.99(1H,d,J＝2.0Hz),7.67(1H,d,J＝9.6Hz),7.42(1H,dd,J 1 ＝2.0 Hz,J 2 =8.8Hz),4.01(3H,s),3.96(2H,s),3.89-3.77(4H,m),3.77-3.63(4H,m),2.96-2.82(2H,m), 2.82-2.69(1H,m),2.16-2.01(2H,m),1.94-1.85(2H,m),1.67-1.55(2H,m),1.52-1.41(2H,m),1.24-1.11(5H ,m),0.99-0.88(4H,m).
化合物26的合成路线
Synthetic route of compound 26
化合物26-d的合成Synthesis of Compound 26-d
将化合物25-e(200mg，0.51mmoL)溶解在10mL的DCM中，0℃氮气条件下，滴加三氟甲磺酸酐(255μL，1.54mmoL)，反应混合物在0℃氮气条件下搅拌30分钟。0℃条件下，用饱和碳酸氢钠(50mL)淬灭反应，混合物用DCM(100mL*5)萃取，有机相用无水硫酸钠干燥、过滤、浓缩至干，得到粗品。粗品通过快速分离柱分离纯化(二氯甲烷：甲醇＝10:1)，得到化合物26-d(260mg，97％)。LC-MS(ESI):m/z＝522.0[M+1]+.Compound 25-e (200 mg, 0.51 mmoL) was dissolved in 10 mL of DCM, trifluoromethanesulfonic anhydride (255 μL, 1.54 mmoL) was added dropwise under nitrogen at 0°C, and the reaction mixture was stirred for 30 minutes under nitrogen at 0°C. At 0°C, the reaction was quenched with saturated sodium bicarbonate (50 mL), the mixture was extracted with DCM (100 mL*5), and the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product. The crude product was separated and purified through a fast separation column (dichloromethane: methanol = 10:1) to obtain compound 26-d (260 mg, 97%). LC-MS(ESI):m/z＝522.0[M+1] + .
化合物26-c的合成Synthesis of compound 26-c
室温下将化合物26-d(260mg，0.50mmoL)溶解在50mL的THF中，依次加入水(5mL)、4-d(399mg，1.49mmoL)、醋酸钯(11mg，0.5mmoL)、x-Phos(48mg，0.10mmoL)、碳酸铯(487mg，1.49mmoL)，反应混合物在80℃氮气条件下搅拌36小时。向反应体系中加入50mL水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物26-c(290mg，85％)。LC-MS(ESI):m/z＝685.2[M+1]+.Compound 26-d (260 mg, 0.50 mmoL) was dissolved in 50 mL of THF at room temperature, and water (5 mL), 4-d (399 mg, 1.49 mmoL), palladium acetate (11 mg, 0.5 mmoL), x-Phos ( 48 mg, 0.10 mmoL), cesium carbonate (487 mg, 1.49 mmoL), and the reaction mixture was stirred under nitrogen at 80°C for 36 hours. Add 50 mL of water to the reaction system, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified through a fast separation column (DCM/MeOH=10:1) to obtain compound 26-c (290 mg, 85%). LC-MS(ESI): m/z＝685.2[M+1] + .
化合物26-b的合成Synthesis of compound 26-b
将化合物26-c(290mg，0.42mmoL)溶解在10mL的甲醇中，室温下依次加入THF(10mL)、水(5mL)、氢氧化钠(170mg，4.24mmoL)，反应混合物室温下搅拌16小时。减压浓缩，残留物溶解在水(20mL)中，用1N HCl水溶液调节pH值到3～4，用DCM/MeOH(10:1)的混合溶剂(100mL*5)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩的粗品化合物26-b(270mg，95％)。LC-MS(ESI):m/z＝671.2[M+1]+.Compound 26-c (290 mg, 0.42 mmoL) was dissolved in 10 mL of methanol, THF (10 mL), water (5 mL), and sodium hydroxide (170 mg, 4.24 mmoL) were added successively at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. Concentrate under reduced pressure, dissolve the residue in water (20mL), adjust the pH value to 3~4 with 1N HCl aqueous solution, extract with a mixed solvent (100mL*5) of DCM/MeOH (10:1), and use anhydrous for the organic phase The crude compound 26-b (270 mg, 95%) was dried over sodium sulfate, filtered, and concentrated under reduced pressure. LC-MS(ESI): m/z＝671.2[M+1] + .
化合物26-a的合成Synthesis of compound 26-a
室温下将化合物26-b(100mg，0.15mmoL)溶解在3mL的DMF中，冰浴下依次加入HATU(86mg，0.23mmoL)、DIPEA(124uL，0.75mmoL)，反应混合物在0℃下搅拌 10分钟，然后加入O-(四氢-2H-吡喃)-2-羟胺(35mg，0.3mmoL)，将反应混合物升到室温并搅拌16小时。反应液通过PREP-HPLC分离纯化，得到化合物26-a(85mg，74％)。LC-MS(ESI):m/z＝770.2[M+1]+.Dissolve compound 26-b (100mg, 0.15mmoL) in 3mL of DMF at room temperature, add HATU (86mg, 0.23mmoL) and DIPEA (124uL, 0.75mmoL) in sequence under ice bath, and stir the reaction mixture at 0°C. 10 minutes, then O-(tetrahydro-2H-pyran)-2-hydroxylamine (35 mg, 0.3 mmoL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction solution was separated and purified by PREP-HPLC to obtain compound 26-a (85 mg, 74%). LC-MS(ESI): m/z=770.2[M+1] + .
化合物26的合成Synthesis of compound 26
将化合物26-a(85mg，0.11mmoL)溶解在DCM/MeOH的混合溶剂(10mL，10:1)中，冷却到0℃，慢慢滴加氯化氢的甲醇溶液(4M，1mL)，加毕，混合物在0℃下搅拌20分钟后，在0℃下用饱和碳酸氢钠溶液(约10mL)淬灭反应(pH＝8)，50℃减压浓缩，残余物悬浮在50mL乙醇中，浓缩至干，重复上述操作3次，得到干燥的粗品。将上述粗品悬浮在DCM/MeOH的混合溶剂(100mL，约4:1)中，过滤，将滤液减压浓缩至干，得到粗品。将粗品悬浮在DCM/MeOH(50mL，8:1)混合溶剂中，用微孔滤膜过滤，将滤液减压浓缩，粗品通过PREP-HPLC(酸法)分离纯化，得到化合物26(6.7mg，8.9％)。LC-MS(ESI):m/z＝686.1[M+1]+.Compound 26-a (85 mg, 0.11 mmoL) was dissolved in a mixed solvent of DCM/MeOH (10 mL, 10:1), cooled to 0°C, and a methanol solution of hydrogen chloride (4 M, 1 mL) was slowly added dropwise. After the addition, After the mixture was stirred at 0°C for 20 minutes, the reaction was quenched with saturated sodium bicarbonate solution (about 10 mL) at 0°C (pH=8), and concentrated under reduced pressure at 50°C. The residue was suspended in 50 mL of ethanol and concentrated to dryness. , repeat the above operation 3 times to obtain dry crude product. The above crude product was suspended in a mixed solvent of DCM/MeOH (100 mL, about 4:1), filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was suspended in a mixed solvent of DCM/MeOH (50 mL, 8:1), filtered with a microporous membrane, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by PREP-HPLC (acid method) to obtain compound 26 (6.7 mg, 8.9%). LC-MS(ESI): m/z＝686.1[M+1] + .
化合物27的合成路线
Synthetic route of compound 27
化合物27的合成Synthesis of compound 27
参照化合物24的合成路线和操作，使用化合物环丙基磺酰氯替代化合物甲磺酰氯，得到27(53mg)。LC-MS(ESI):m/z＝628.1(M+H)+；1H NMR(400MHz,DMSO-d6):δ10.34(1H,bs),8.66(1H,m),8.22-8.15(1H,m),8.05-7.98(1H,m),7.70-7.58(2H,m),7.40-7.33(1H,m),3.94(2H,s),3.90-3.81(4H,m),3.77-3.67(4H,m),2.90(1H,d,J＝10.0Hz),2.41-2.30(1H,m),2.07(2H,t,J＝10.0Hz),1.93(2H,t,J＝7.2Hz),1.69-1.58(2H,m),1.56-1.44(2H,m),1.30-1.09(6H,m),0.83-0.64(4H,m).Referring to the synthetic route and operation of compound 24, compound cyclopropylsulfonyl chloride was used instead of compound methanesulfonyl chloride to obtain 27 (53 mg). LC-MS (ESI): m/z=628.1 (M+H) + ; 1 H NMR (400MHz, DMSO-d 6 ): δ10.34 (1H, bs), 8.66 (1H, m), 8.22-8.15 (1H,m),8.05-7.98(1H,m),7.70-7.58(2H,m),7.40-7.33(1H,m),3.94(2H,s),3.90-3.81(4H,m),3.77 -3.67(4H,m),2.90(1H,d,J＝10.0Hz),2.41-2.30(1H,m),2.07(2H,t,J＝10.0Hz),1.93(2H,t,J＝7.2 Hz),1.69-1.58(2H,m),1.56-1.44(2H,m),1.30-1.09(6H,m),0.83-0.64(4H,m).
化合物28的合成路线
Synthetic route of compound 28
化合物28-f的合成Synthesis of compound 28-f
将化合物N-Boc-4-氨基乙基哌啶(2g，8.76mmoL)溶解在40mL的THF中，在冰水浴下，加入5mL水，NaHCO3(2.2g，26.28mmoL)，滴加氯甲酸苄酯(1.85mL，13.14mmoL)，反应混合物升到室温，搅拌16小时。用50ml水淬灭反应，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥、过滤，减压浓缩，得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝1:1)，得到粗品化合物28-f(3.81g)。LC-MS(ESI):m/z＝263.1[M+1]+.Dissolve compound N-Boc-4-aminoethylpiperidine (2g, 8.76mmoL) in 40mL of THF, add 5mL of water and NaHCO 3 (2.2g, 26.28mmoL) under an ice-water bath, and add benzyl chloroformate dropwise ester (1.85 mL, 13.14 mmoL), the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with 50 ml of water, extracted with ethyl acetate (100 mL*2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through a rapid separation column (PE/EA=1:1) to obtain crude compound 28-f (3.81g). LC-MS(ESI):m/z＝263.1[M+1] + .
化合物28-e的合成Synthesis of compound 28-e
将化合物28-f(1.9g，80％，4.19mmoL)溶解在10mL的DCM中，冰水浴条件下加入氯化氢的甲醇溶液(4M，10mL)，反应混合物升到室温，搅拌2天。减压浓缩，粗品悬浮在1,4-二氧六环(50mL)中，减压浓缩，粗品悬浮在乙酸乙酯(50mL)中，将混合物过滤，滤饼用乙酸乙酯(10mL)洗涤，收集固体，真空干燥1小时，得到化合物28-e(1.16g，93％)。LC-MS(ESI):m/z＝263.2[M+1]+.Compound 28-f (1.9g, 80%, 4.19mmoL) was dissolved in 10 mL of DCM, and a methanol solution of hydrogen chloride (4M, 10 mL) was added in an ice-water bath. The reaction mixture was raised to room temperature and stirred for 2 days. Concentrate under reduced pressure. The crude product is suspended in 1,4-dioxane (50 mL). Concentrate under reduced pressure. The crude product is suspended in ethyl acetate (50 mL). The mixture is filtered. The filter cake is washed with ethyl acetate (10 mL). The solid was collected and dried under vacuum for 1 hour to obtain compound 28-e (1.16 g, 93%). LC-MS(ESI): m/z＝263.2[M+1] + .
化合物28-d的合成Synthesis of Compound 28-d
将化合物28-e(1.16g，3.88mmoL)溶解在5mL的乙腈中，室温下依次加入碘化钾 (37mg，0.22mmoL)，溴甲基氟硼酸钾(743mg，3.70mmoL)，碳酸钾(766mg，5.55mmoL)，在80℃氮气条件下搅拌16小时。反应混合物冷却到室温，过滤，滤饼用乙腈(10mL)洗涤，然后滤液减压浓缩，得到粗品，粗品溶解在5mL的乙腈中，加入50mL的乙醚，析出大量固体，过滤，收集固体，真空干燥，得到化合物28-d(1.12g，88％)。LC-MS(ESI):m/z＝362.2[M+18]+.Compound 28-e (1.16g, 3.88mmoL) was dissolved in 5 mL of acetonitrile, and potassium iodide was added successively at room temperature. (37mg, 0.22mmoL), potassium bromomethylfluoroborate (743mg, 3.70mmoL), potassium carbonate (766mg, 5.55mmoL), stir at 80°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (10 mL). The filtrate was then concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 5 mL of acetonitrile, and 50 mL of diethyl ether was added to precipitate a large amount of solid. Filter, collect the solid, and dry under vacuum. , compound 28-d (1.12g, 88%) was obtained. LC-MS(ESI): m/z＝362.2[M+18] + .
化合物28-c的合成Synthesis of compound 28-c
室温下将化合物1-e(763mg，1.63mmoL)溶解在50mL的THF中，依次加入水(5mL)、28-d(1.12g，3.26mmoL)、醋酸钯(37mg，0.16mmoL)、x-Phos(155mg，0.33mmoL)、碳酸铯(1.59g，4.89mmoL)，反应混合物在80℃氮气条件下搅拌36小时。向反应体系中加入50mL水，用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL*2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到化合物28-c(1.1g，96％)。LC-MS(ESI):m/z＝708.3[M+1]+.Dissolve compound 1-e (763 mg, 1.63 mmoL) in 50 mL of THF at room temperature, and add water (5 mL), 28-d (1.12 g, 3.26 mmoL), palladium acetate (37 mg, 0.16 mmoL), and x-Phos in sequence. (155 mg, 0.33 mmoL), cesium carbonate (1.59 g, 4.89 mmoL), and the reaction mixture was stirred under nitrogen at 80°C for 36 hours. Add 50 mL of water to the reaction system, extract with ethyl acetate (100 mL*2), wash the organic phase with saturated brine (100 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified through a fast separation column (DCM/MeOH=10:1) to obtain compound 28-c (1.1 g, 96%). LC-MS(ESI):m/z＝708.3[M+1] + .
化合物28-b的合成Synthesis of compound 28-b
将化合物28-c(1.1g，1.55mmoL)溶解在100mL的甲醇中，室温氮气条件下，加入钯碳(0.5g，10％Pd，50％wet)，反应混合物在室温氢气条件下，搅拌16小时。将反应混合物过滤，用混合溶剂(DCM/MeOH(NH3)＝10:1，500mL)洗涤，得到粗品化合物28-b(1.0g)，粗品直接用于下一步。LC-MS(ESI):m/z＝574.2[M+1]+.Compound 28-c (1.1g, 1.55mmoL) was dissolved in 100 mL of methanol. Palladium on carbon (0.5g, 10% Pd, 50% wet) was added under nitrogen at room temperature. The reaction mixture was stirred for 16 under hydrogen at room temperature. Hour. The reaction mixture was filtered and washed with a mixed solvent (DCM/MeOH(NH 3 )=10:1, 500 mL) to obtain crude compound 28-b (1.0 g), which was directly used in the next step. LC-MS(ESI):m/z＝574.2[M+1] + .
化合物28-a的合成Synthesis of compound 28-a
将化合物28-b(100mg，0.17mmoL)溶解在3mL的DMF中，0℃氮气条件下依次加入CDI(62mg，0.38mmoL)、TEA(53μL，0.38mmoL)，反应混合物在室温氮气条件下，搅拌30分钟后，加入O-(四氢-2H-吡喃-2-基)羟基胺(22mg，0.19mmoL)的DMF(2mL)溶液，然后室温氮气下搅拌16小时。反应液通过PREP-HPLC分离纯化，得到化合物28-a(60mg，48％)。LC-MS(ESI):m/z＝717.3[M+1]+.Compound 28-b (100 mg, 0.17 mmoL) was dissolved in 3 mL of DMF, CDI (62 mg, 0.38 mmoL) and TEA (53 μL, 0.38 mmoL) were added in sequence under nitrogen at 0°C, and the reaction mixture was stirred under nitrogen at room temperature. After 30 minutes, a solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (22 mg, 0.19 mmoL) in DMF (2 mL) was added, and then stirred under nitrogen at room temperature for 16 hours. The reaction solution was separated and purified by PREP-HPLC to obtain compound 28-a (60 mg, 48%). LC-MS(ESI): m/z=717.3[M+1] + .
化合物28的合成Synthesis of compound 28
将化合物28-a(60mg，0.084mmoL)溶解在DCM(5mL)中，冷却到0℃，慢慢滴加氯化氢的1,4-二氧六环溶液(4M，0.3mL)，加毕，混合物在0℃下搅拌15分钟后，在0℃下用饱和碳酸氢钠溶液(约2mL)淬灭反应(pH＝8)后，加入混合溶剂(DCM/MeOH＝10:1，100mL)，将混合物用无水硫酸钠干燥、过滤，滤液减压浓缩，得到化合物28(20mg，38％)。LC-MS(ESI):m/z＝633.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ9.42(1H,brs),8.50(1H,s),8.38(1H,d,J＝2.0Hz),8.20(1H,s),7.98(1H,d,J＝2.0Hz),7.66(1H,dd,J1＝9.2Hz,J2＝2.0Hz),7.42(1H,dd,J1＝8.8Hz,J2＝2.4Hz),6.63(1H,t,J＝5.6Hz),4.02(3H,s),3.94(2H,s),3.89-3.78(4H,m),3.78-3.65(4H,m),3.09(3H,s),3.13-3.00(2H,m),2.88(2H,d,J＝10.4Hz), 2.07(2H,t,J＝10.8Hz),1.66(2H,d,J＝11.6Hz),1.41-1.31(2H,m),1.31-1.09(3H,m).Dissolve compound 28-a (60 mg, 0.084 mmoL) in DCM (5 mL), cool to 0°C, and slowly add hydrogen chloride in 1,4-dioxane solution (4 M, 0.3 mL) dropwise. After addition, the mixture After stirring at 0°C for 15 minutes, the reaction (pH=8) was quenched with saturated sodium bicarbonate solution (about 2mL) at 0°C, and a mixed solvent (DCM/MeOH=10:1, 100mL) was added, and the mixture was Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 28 (20 mg, 38%). LC-MS (ESI): m/z=633.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ9.42 (1H, brs), 8.50 (1H, s), 8.38 (1H ,d,J＝2.0Hz),8.20(1H,s),7.98(1H,d,J＝2.0Hz),7.66(1H,dd,J 1 ＝9.2Hz,J 2 ＝2.0Hz),7.42(1H ,dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz),6.63(1H,t,J＝5.6Hz),4.02(3H,s),3.94(2H,s),3.89-3.78(4H,m) ,3.78-3.65(4H,m),3.09(3H,s),3.13-3.00(2H,m),2.88(2H,d,J＝10.4Hz), 2.07(2H,t,J＝10.8Hz),1.66(2H,d,J＝11.6Hz),1.41-1.31(2H,m),1.31-1.09(3H,m).
化合物29的合成路线
Synthetic route of compound 29
化合物29的合成Synthesis of compound 29
参照化合物26的合成路线和操作，使用化合物17-d替代化合物4-d，得到化合物29(76mg)。LC-MS(ESI):m/z＝738.2[M+1]+；1H NMR(400MHz,DMSO-d6):δ7.96(1H,d,J＝1.6Hz),7.78(1H,d,J＝1.6Hz),7.70(1H,dd,J1＝2.0Hz,J2＝9.2Hz),7.49(1H,d,J＝7.6Hz),7.44(1H,dd,J1＝2.4Hz,J2＝9.2Hz),7.36(1H,d,J＝12.0Hz),7.24(1H,t,J＝8.0Hz),4.11(1H,brs),4.00(2H,s),3.88-3.79(7H,m),3.79-3.65(4H,m),3.03(2H,d,J＝10.8Hz),2.85-2.71(1H,m),2.23(2H,t,J＝11.2Hz),2.04-1.90(1H,m),1.86-1.64(4H,m),1.52-1.30(1H,m).Referring to the synthetic route and operation of compound 26, compound 17-d was used instead of compound 4-d to obtain compound 29 (76 mg). LC-MS (ESI): m/z=738.2[M+1] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ7.96 (1H, d, J=1.6Hz), 7.78 (1H, d ,J＝1.6Hz),7.70(1H,dd,J 1 ＝2.0Hz,J 2 ＝9.2Hz),7.49(1H,d,J＝7.6Hz),7.44(1H,dd,J 1 ＝2.4Hz, J 2 ＝9.2Hz),7.36(1H,d,J＝12.0Hz),7.24(1H,t,J＝8.0Hz),4.11(1H,brs),4.00(2H,s),3.88-3.79(7H ,m),3.79-3.65(4H,m),3.03(2H,d,J＝10.8Hz),2.85-2.71(1H,m),2.23(2H,t,J＝11.2Hz),2.04-1.90( 1H,m),1.86-1.64(4H,m),1.52-1.30(1H,m).
化合物30的合成路线
Synthetic route of compound 30
化合物30-e的合成Synthesis of compound 30-e
冰浴冷却下，往反应瓶中加入6-溴-5-氟烟酸甲酯(234mg，1.00mmol)，4-羟基哌啶(101mg，1.00mmol)，DMAP(122mg，1.00mmol)和DMF(4mL)。混合物在80℃搅拌4.5小时。向反应液中加入冰水。水相用乙酸乙酯萃取。合并有机相，用饱和NaCl洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：石油醚/乙酸乙酯，100/0到100/40)，得到化合物30-e(200mg，79％)。LC-MS(ESI):m/z 255.0(M+H)+.Under ice bath cooling, add 6-bromo-5-fluoronicotinic acid methyl ester (234mg, 1.00mmol), 4-hydroxypiperidine (101mg, 1.00mmol), DMAP (122mg, 1.00mmol) and DMF ( 4mL). The mixture was stirred at 80°C for 4.5 hours. Add ice water to the reaction solution. The aqueous phase was extracted with ethyl acetate. Combine the organic phases, wash with saturated NaCl, dry over anhydrous Na 2 SO 4 , filter, evaporate to dryness and purify through column (mobile phase: petroleum ether/ethyl acetate, 100/0 to 100/40) to obtain compound 30-e ( 200mg, 79%). LC-MS(ESI):m/z 255.0(M+H) + .
化合物30-c的合成Synthesis of compound 30-c
往反应瓶中加入30-e(100mg，0.39mmol)，DABCO(88mg，0.79mmol)和二氯甲烷(4mL)，然后冰浴下加入TsCl(112mg，0.59mmol)。混合物在0～25℃氮气保护下搅拌18小时。反应液蒸干过柱纯化(流动相：石油醚/乙酸乙酯，100/0到100/50)，得到化合物30-d(70mg，44％)。LC-MS(ESI):m/z 409.1(M+H)+.Add 30-e (100 mg, 0.39 mmol), DABCO (88 mg, 0.79 mmol) and dichloromethane (4 mL) to the reaction flask, and then add TsCl (112 mg, 0.59 mmol) under ice bath. The mixture was stirred under nitrogen protection at 0-25°C for 18 hours. The reaction solution was evaporated to dryness and subjected to column purification (mobile phase: petroleum ether/ethyl acetate, 100/0 to 100/50) to obtain compound 30-d (70 mg, 44%). LC-MS(ESI):m/z 409.1(M+H) + .
往反应瓶中加入30-d(70mg，0.17mmol)，碳酸铯(70mg，0.21mmol)和DMF(2.5mL)。混合物在80℃氮气保护下搅拌2分钟。加入8-d(64mg，0.14mmol)，混合物在80℃氮气保护下搅拌18小时。反应液冷却至室温，乙酸乙酯稀释，用水洗，饱和食盐水洗，无 水Na2SO4干燥，过滤，蒸干得到化合物30-c(150mg，100％)。LC-MS(ESI):m/z 686.1(M+H)+.Add 30-d (70 mg, 0.17 mmol), cesium carbonate (70 mg, 0.21 mmol) and DMF (2.5 mL) to the reaction flask. The mixture was stirred at 80°C under nitrogen protection for 2 minutes. 8-d (64 mg, 0.14 mmol) was added, and the mixture was stirred under nitrogen protection at 80°C for 18 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water, and washed with saturated brine. Dry over Na 2 SO 4 , filter, and evaporate to dryness to obtain compound 30-c (150 mg, 100%). LC-MS(ESI):m/z 686.1(M+H) + .
化合物30-b的合成Synthesis of compound 30-b
往反应瓶中加入30-c(150mg，0.14mmol)，THF(2mL)，甲醇(1.5mL)和水(0.5mL)。反应液0℃加入氢氧化锂(20mg，0.83mmol)，然后0～25℃搅拌18小时。蒸干，粗品用乙酸乙酯、水稀释，加入少量柠檬酸和无水硫酸钠，分液，水相用THF萃取两次，合并有机相，蒸干得到化合物30-b(120mg，100％)。LC-MS(ESI):m/z 672.1(M+H)+.Add 30-c (150 mg, 0.14 mmol), THF (2 mL), methanol (1.5 mL) and water (0.5 mL) to the reaction flask. Lithium hydroxide (20 mg, 0.83 mmol) was added to the reaction solution at 0°C, and then stirred at 0 to 25°C for 18 hours. Evaporate to dryness, dilute the crude product with ethyl acetate and water, add a small amount of citric acid and anhydrous sodium sulfate, separate the liquids, extract the aqueous phase twice with THF, combine the organic phases, and evaporate to dryness to obtain compound 30-b (120 mg, 100%) . LC-MS(ESI):m/z 672.1(M+H) + .
化合物30-a的合成Synthesis of compound 30-a
往反应瓶中加入30-b(120mg，0.14mmol)，O-(四氢-2H-吡喃-2-基)羟基胺(70mg，0.61mmol)，DIPEA(70mg，0.54mmol)和DMF(2mL)。冰浴冷却下加入HATU(117mg，0.33mmol)。反应液5～25℃搅拌2小时。乙酸乙酯稀释，用水洗，饱和NaCl洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：二氯甲烷/甲醇100/0到100/5)，得到化合物30-a(120mg，100％)。LC-MS(ESI):m/z 771.2(M+H)+.Add 30-b (120mg, 0.14mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (70mg, 0.61mmol), DIPEA (70mg, 0.54mmol) and DMF (2mL) to the reaction flask. ). HATU (117 mg, 0.33 mmol) was added while cooling in an ice bath. The reaction solution was stirred at 5-25°C for 2 hours. Dilute with ethyl acetate, wash with water, wash with saturated NaCl, dry over anhydrous Na 2 SO 4 , filter, evaporate to dryness and purify through column (mobile phase: dichloromethane/methanol 100/0 to 100/5) to obtain compound 30-a (120mg, 100%). LC-MS(ESI):m/z 771.2(M+H) + .
化合物30的合成Synthesis of compound 30
往反应瓶中加入30-a(120mg，0.14mmol)和二氯甲烷(3mL)，冰浴下加入4M盐酸/1.4-二氧六环溶液(0.4mL)。反应液0℃搅拌1.5h。浓氨水(0.2mL)淬灭反应。反应液蒸干制备柱分离(0.1％氨水水溶液、乙腈)得到化合物30(22mg，23％)。LC-MS(ESI):m/z 687.0(M+H)+；1H NMR(400MHz,DMSO-d6):δ11.16(1H,s),9.52(1H,s),9.08(1H,s),8.41(1H,t,J＝1.7Hz),8.39(1H,d,J＝2.3Hz),7.99(1H,d,J＝2.3Hz),7.76(1H,dd,J＝14.6,1.9Hz),7.44(1H,dd,J＝10.8,2.6Hz),7.16(1H,dd,J＝9.4,2.6Hz),5.04–4.92(1H,m),4.03(3H,s),3.98–3.87(2H,m),3.85–3.81(4H,m),3.71–3.67(4H,m),3.62–3.50(2H,m),3.09(3H,s),2.12–2.04(2H,m),1.89–1.80(2H,m).Add 30-a (120 mg, 0.14 mmol) and dichloromethane (3 mL) to the reaction flask, and add 4M hydrochloric acid/1.4-dioxane solution (0.4 mL) under ice bath. The reaction solution was stirred at 0°C for 1.5h. Concentrated ammonia (0.2 mL) quenched the reaction. The reaction solution was evaporated to dryness and subjected to preparative column separation (0.1% ammonia aqueous solution, acetonitrile) to obtain compound 30 (22 mg, 23%). LC-MS(ESI): m/z 687.0(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ11.16(1H,s),9.52(1H,s),9.08(1H, s),8.41(1H,t,J＝1.7Hz),8.39(1H,d,J＝2.3Hz),7.99(1H,d,J＝2.3Hz),7.76(1H,dd,J＝14.6,1.9 Hz),7.44(1H,dd,J＝10.8,2.6Hz),7.16(1H,dd,J＝9.4,2.6Hz),5.04–4.92(1H,m),4.03(3H,s),3.98–3.87 (2H,m),3.85–3.81(4H,m),3.71–3.67(4H,m),3.62–3.50(2H,m),3.09(3H,s),2.12–2.04(2H,m),1.89 –1.80(2H,m).
化合物31合成路线
Synthetic route of compound 31
化合物31-e的合成Synthesis of Compound 31-e
将3,4-二氟苯甲酸甲酯(200mg，1.16mmol)，4-羟基哌啶(117mg，1.16mmol)，DIPEA(0.6mL)加入DMSO(5mL)中，在120℃条件下搅拌过夜。反应液冷却至室温，向反 应液中加入饱和氯化铵(50mL)，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到化合物31-e(130mg，44％)。Add 3,4-difluorobenzoic acid methyl ester (200 mg, 1.16 mmol), 4-hydroxypiperidine (117 mg, 1.16 mmol), and DIPEA (0.6 mL) to DMSO (5 mL), and stir at 120°C overnight. The reaction solution was cooled to room temperature and reversed Saturated ammonium chloride (50mL) was added to the reaction solution, extracted with ethyl acetate (50mLx3), the organic phase was washed with saturated brine (100mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 31-e ( 130 mg, 44%).
化合物31-d的合成Synthesis of Compound 31-d
将化合物31-e(113mg，0.45mmol)加入DCM(5mL)中，0℃下依次加入TEA(0.12mL)，DMAP(3mg，0.022mmol)，TsCl(93mg，0.49mmol)，在室温下搅拌过夜。反应液减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝20:1)，得到化合物31-d(180mg，98％)。LC-MS(ESI):m/z＝408.1[M+H]+.Add compound 31-e (113 mg, 0.45 mmol) to DCM (5 mL), add TEA (0.12 mL), DMAP (3 mg, 0.022 mmol), and TsCl (93 mg, 0.49 mmol) in sequence at 0°C, and stir at room temperature overnight. . The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a fast separation column (PE/EA=20:1) to obtain compound 31-d (180 mg, 98%). LC-MS(ESI): m/z=408.1[M+H] + .
化合物31的合成Synthesis of Compound 31
参照化合物30的合成路线和操作，使用化合物31-d替代化合物30-d，得到化合物31(13mg，72％)。LC-MS(ESI):m/z＝685.8[M+H]+；1H NMR(400MHz,DMSO-d6):δ11.14(1H,s),9.51(1H,s),9.00(1H,s),8.39(1H,d,J＝2.0Hz),7.99(1H,d,J＝2.0Hz),7.66-7.38(3H,m),7.21-7.07(2H,m),5.03-4.86(1H,m),4.02(3H,s),3.88-3.78(4H,m),3.74-3.61(4H,m),3.50-3.39(2H,m),3.17-3.04(5H,m),2.17-2.04(2H,m),1.99-1.84(2H,m).Referring to the synthetic route and operation of compound 30, compound 31-d was used instead of compound 30-d to obtain compound 31 (13 mg, 72%). LC-MS(ESI): m/z=685.8[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ11.14(1H,s),9.51(1H,s),9.00(1H ,s),8.39(1H,d,J＝2.0Hz),7.99(1H,d,J＝2.0Hz),7.66-7.38(3H,m),7.21-7.07(2H,m),5.03-4.86( 1H,m),4.02(3H,s),3.88-3.78(4H,m),3.74-3.61(4H,m),3.50-3.39(2H,m),3.17-3.04(5H,m),2.17- 2.04(2H,m),1.99-1.84(2H,m).
化合物32的合成路线
Synthetic route of compound 32
化合物32-e的合成Synthesis of compound 32-e
冰浴冷却下，往反应瓶中加入4-哌啶甲酸乙酯(700mg，4.45mmol)，4-羟基环己酮(1.02g，8.94mmol)，醋酸(100mg，1.67mmol)和二氯甲烷(30mL)。2小时内分批加入三乙酰氧基硼氢化钠(3.8g，17.8mmol)。混合物在0～25℃搅拌18小时。向反应液中加入冰水。水相用碳酸氢钠和无水硫酸钠饱和，二氯甲烷萃取。合并有机相，无水Na2SO4干燥，过滤，蒸干得到化合物32-e(粗品2.0g，100％)。LC-MS(ESI):m/z 256.1(M+H)+.Under ice bath cooling, add ethyl 4-piperidinecarboxylate (700mg, 4.45mmol), 4-hydroxycyclohexanone (1.02g, 8.94mmol), acetic acid (100mg, 1.67mmol) and dichloromethane ( 30mL). Sodium triacetoxyborohydride (3.8g, 17.8mmol) was added portionwise within 2 hours. The mixture was stirred at 0-25°C for 18 hours. Add ice water to the reaction solution. The aqueous phase was saturated with sodium bicarbonate and anhydrous sodium sulfate, and extracted with dichloromethane. The organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness to obtain compound 32-e (crude product 2.0 g, 100%). LC-MS(ESI):m/z 256.1(M+H) + .
化合物32-d的合成Synthesis of Compound 32-d
往反应瓶中加入32-e(粗品2.0g，4.46mmol)，DABCO(1.5g，13.2mmol)和二氯甲烷(20mL)，然后冰浴下加入TsCl(1.65g，8.66mmol)。混合物在0～25℃氮气保护下搅拌18小时。反应液蒸干过柱纯化(流动相：二氯甲烷/甲醇，100/0到100/5)，得到化合物32-d(900mg，48％)。LC-MS(ESI):m/z 410.1(M+H)+.Add 32-e (crude product 2.0g, 4.46mmol), DABCO (1.5g, 13.2mmol) and dichloromethane (20mL) into the reaction flask, then add TsCl (1.65g, 8.66mmol) under ice bath. The mixture was stirred under nitrogen protection at 0-25°C for 18 hours. The reaction solution was evaporated to dryness and subjected to column purification (mobile phase: dichloromethane/methanol, 100/0 to 100/5) to obtain compound 32-d (900 mg, 48%). LC-MS(ESI):m/z 410.1(M+H) + .
化合物32-c的合成Synthesis of compound 32-c
往反应瓶中加入32-d(80mg，0.20mmol)，碳酸铯(106mg，0.33mmol)和DMF(2.5mL)。混合物在80℃氮气保护下搅拌3分钟。加入中间体1(74mg，0.16mmol)，混合物在80℃氮气保护下搅拌18小时。反应液冷却至室温，乙酸乙酯稀释，用水洗，饱和食盐水洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：二氯甲烷/甲醇，100/0到100/10)，得到化合物32-c(120mg，100％)。LC-MS(ESI):m/z 687.1(M+H)+.Add 32-d (80 mg, 0.20 mmol), cesium carbonate (106 mg, 0.33 mmol) and DMF (2.5 mL) to the reaction flask. The mixture was stirred at 80°C under nitrogen protection for 3 minutes. Intermediate 1 (74 mg, 0.16 mmol) was added, and the mixture was stirred under nitrogen protection at 80°C for 18 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness and purified through column (mobile phase: dichloromethane/methanol, 100/0 to 100/10 ) to obtain compound 32-c (120 mg, 100%). LC-MS(ESI):m/z 687.1(M+H) + .
化合物32-b的合成Synthesis of compound 32-b
往反应瓶中加入32-c(120mg，0.17mmol)，THF(3mL)，甲醇(1.5mL)和水(0.5mL)。反应液0℃加入氢氧化锂(24mg，1.0mmol)，然后0～25℃搅拌23小时。蒸干，粗品加入少量柠檬酸，用乙酸乙酯萃取1次，DMF萃取(1.5mLx3)。合并有机相，蒸干得到化合物32-b的DMF溶液(4.5mL)。LC-MS(ESI):m/z 659.2(M+H)+.Add 32-c (120 mg, 0.17 mmol), THF (3 mL), methanol (1.5 mL) and water (0.5 mL) to the reaction flask. Lithium hydroxide (24 mg, 1.0 mmol) was added to the reaction solution at 0°C, and then stirred at 0-25°C for 23 hours. Evaporate to dryness, add a small amount of citric acid to the crude product, extract once with ethyl acetate, and extract with DMF (1.5mLx3). The organic phases were combined and evaporated to dryness to obtain a DMF solution of compound 32-b (4.5 mL). LC-MS(ESI):m/z 659.2(M+H) + .
化合物32-a的合成Synthesis of compound 32-a
往反应瓶中加入32-b(4.5mL DMF溶液)，O-(四氢-2H-吡喃-2-基)羟基胺(80mg，0.68mmol)，DIPEA(100mg，0.78mmol)。冰浴冷却下加入HATU(160mg，0.42mmol)。反应液5～25℃搅拌2小时。乙酸乙酯稀释，用水洗，饱和NaCl洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：二氯甲烷/甲醇/5％氨100/0到100/10)，得到化合物32-a(60mg，45％)。LC-MS(ESI):m/z 758.0(M+H)+.Add 32-b (4.5 mL DMF solution), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (80 mg, 0.68 mmol), and DIPEA (100 mg, 0.78 mmol) into the reaction bottle. HATU (160 mg, 0.42 mmol) was added while cooling in an ice bath. The reaction solution was stirred at 5-25°C for 2 hours. Dilute with ethyl acetate, wash with water, wash with saturated NaCl, dry with anhydrous Na 2 SO 4 , filter, evaporate to dryness and purify through column (mobile phase: dichloromethane/methanol/5% ammonia 100/0 to 100/10) to obtain Compound 32-a (60 mg, 45%). LC-MS(ESI):m/z 758.0(M+H) + .
化合物32的合成Synthesis of compound 32
往反应瓶中加入32-a(60mg，0.052mmol)和二氯甲烷(4mL)，冰浴下加入4M盐酸/1,4-二氧六环溶液(0.4mL)。反应液0℃搅拌1.5h。浓氨水(0.3mL)淬灭反应。反应 液蒸干制备柱分离(0.1％甲酸水溶液、乙腈)得到化合物32(10mg，18％)。LC-MS(ESI):m/z 674.0(M+H)+；1H NMR(400MHz,DMSO-d6):δ10.36(1H,s),8.64(1H,bs),8.31(1H,s),8.27(1H,d,J＝2.0Hz),7.92(1H,d,J＝2.4Hz),7.29(1H,dd,J＝10.9,2.7Hz),7.11(1H,dd,J＝9.4,2.6Hz),4.57–4.44(1H,m),4.00(3H,s),3.83(4H,t,J＝4.7Hz),3.71(4H,t,J＝4.8Hz),3.02(3H,s),2.90–2.82(2H,m),2.44–2.31(2H,m),2.20–2.09(4H,m),1.98–1.89(1H,m),1.86–1.77(2H,m),1.60–1.39(8H,m).Add 32-a (60 mg, 0.052 mmol) and dichloromethane (4 mL) to the reaction flask, and add 4M hydrochloric acid/1,4-dioxane solution (0.4 mL) under ice bath. The reaction solution was stirred at 0°C for 1.5h. Concentrated ammonia (0.3 mL) quenched the reaction. reaction The liquid was evaporated to dryness and subjected to preparative column separation (0.1% formic acid aqueous solution, acetonitrile) to obtain compound 32 (10 mg, 18%). LC-MS(ESI): m/z 674.0(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ10.36(1H,s),8.64(1H,bs),8.31(1H, s),8.27(1H,d,J＝2.0Hz),7.92(1H,d,J＝2.4Hz),7.29(1H,dd,J＝10.9,2.7Hz),7.11(1H,dd,J＝9.4 ,2.6Hz),4.57–4.44(1H,m),4.00(3H,s),3.83(4H,t,J＝4.7Hz),3.71(4H,t,J＝4.8Hz),3.02(3H,s ),2.90–2.82(2H,m),2.44–2.31(2H,m),2.20–2.09(4H,m),1.98–1.89(1H,m),1.86–1.77(2H,m),1.60–1.39 (8H,m).
化合物33合成路线
Synthetic route of compound 33
化合物33-e的合成Synthesis of compound 33-e
将3-氟-4-(溴甲基)苯甲酸甲酯(733mg，2.97mmol)，4-羟基哌啶(300mg，2.97mmol)，K2CO3(1.23g，8.91mmol)加入DMF(10mL)中，在室温条件下搅拌过夜。向反应液中加入饱和氯化钠(80mL)，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx6)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物33-e(500mg，63％)。3-Fluoro-4-(bromomethyl)benzoic acid methyl ester (733 mg, 2.97 mmol), 4-hydroxypiperidine (300 mg, 2.97 mmol), K 2 CO 3 (1.23 g, 8.91 mmol) were added to DMF (10 mL ), stir at room temperature overnight. Saturated sodium chloride (80mL) was added to the reaction solution, extracted with ethyl acetate (50mLx3), the organic phase was washed with saturated brine (100mLx6), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 33-e ( 500mg, 63%).
化合物33-d的合成Synthesis of Compound 33-d
将化合物33-e(200mg，0.75mmol)加入DCM(5mL)中，0℃下依次加入TEA(0.21mL)，DMAP(5mg，0.037mmol)，TsCl(156mg，0.82mmol)，在室温下搅拌过夜。反应液减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝20:1)，得到化合物33-d(188mg，59％)。Add compound 33-e (200 mg, 0.75 mmol) to DCM (5 mL), add TEA (0.21 mL), DMAP (5 mg, 0.037 mmol), and TsCl (156 mg, 0.82 mmol) in sequence at 0°C, and stir at room temperature overnight. . The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by a fast separation column (PE/EA=20:1) to obtain compound 33-d (188 mg, 59%).
化合物33的合成Synthesis of compound 33
参照化合物30的合成路线和操作，使用化合物33-d替代化合物30-d，得到化合物33(5mg)。LC-MS(ESI):m/z＝699.8[M+H]+.Referring to the synthetic route and operation of compound 30, compound 33-d was used instead of compound 30-d to obtain compound 33 (5 mg). LC-MS(ESI):m/z＝699.8[M+H] + .
化合物34合成路线
Synthetic route of compound 34
化合物34-c的合成Synthesis of compound 34-c
将化合物6-d(164mg,0.17mmoL)溶解在5mL的DMF中，室温下加入3,4-二氟苯甲酸甲酯(162mg,0.94mmoL)，碳酸钾(80mg,0.58mmoL)，然后将混合物在100℃氮气条件下搅拌16小时。反应混合物冷却到室温，加入饱和食盐水(50mL)，用乙酸乙酯(50mL*3)，有机相用无水硫酸钠干燥，过滤、浓缩，得到粗品化合物，粗品通过快速分离柱分离纯化(DCM/MeOH＝10:1)，得到粗品化合物34-c(116mg,100％)。LC-MS(ESI):m/z＝683.8[M+1]+.Dissolve compound 6-d (164mg, 0.17mmoL) in 5mL of DMF, add methyl 3,4-difluorobenzoate (162mg, 0.94mmoL) and potassium carbonate (80mg, 0.58mmoL) at room temperature, and then add the mixture Stir under nitrogen at 100°C for 16 hours. The reaction mixture was cooled to room temperature, saturated brine (50mL) was added, and ethyl acetate (50mL*3) was used. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude compound, which was separated and purified through a rapid separation column (DCM /MeOH=10:1) to obtain crude compound 34-c (116 mg, 100%). LC-MS(ESI): m/z＝683.8[M+1] + .
化合物34的合成Synthesis of compound 34
参照化合物1的合成路线和操作，使用化合物34-c替代化合物1-c，得到化合物34(5mg)。LC-MS(ESI):m/z＝684.9[M+H]+.Referring to the synthetic route and operation of compound 1, compound 34-c was used instead of compound 1-c to obtain compound 34 (5 mg). LC-MS(ESI): m/z=684.9[M+H] + .
化合物35的合成路线
Synthetic route of compound 35
化合物35-e的合成Synthesis of compound 35-e
将化合物1-e(2.0g,4.27mmoL)，溶解在30mL的DMF中，依次加入氰化锌(999mg,8.54mmoL)，X-Phos(407mg,0.85mmoL)，Pd2(dba)3(391mg,0.43mmoL)，锌粉(200mg,3.08mmoL)，混合物在100℃氮气下搅拌18小时。将混合物冷却到室温，用100mL水淬灭，用乙酸乙酯(100mL*2)，有机相用饱和食盐水(100mL*3)洗涤，无水硫酸钠干燥、过滤、减压浓缩，得到粗品，粗品通过快速分离柱分离纯化(EA/PE＝0～80％)，得到化合物35-e(1.2g,61％)。LC-MS(ESI):m/z＝459.1[M+1]+.Dissolve compound 1-e (2.0g, 4.27mmoL) in 30mL of DMF, then add zinc cyanide (999mg, 8.54mmoL), X-Phos (407mg, 0.85mmoL), Pd 2 (dba) 3 (391mg) ,0.43mmoL), zinc powder (200mg, 3.08mmoL), and the mixture was stirred under nitrogen at 100°C for 18 hours. The mixture was cooled to room temperature, quenched with 100 mL of water, washed with ethyl acetate (100 mL*2), and the organic phase was washed with saturated brine (100 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by a fast separation column (EA/PE=0-80%) to obtain compound 35-e (1.2g, 61%). LC-MS(ESI): m/z＝459.1[M+1] + .
化合物35-d的合成Synthesis of Compound 35-d
往反应瓶中加入35-e(140mg，0.31mmol)，雷尼镍(200mg)和四氢呋喃(20mL)。混合物在25℃氢气环境下搅拌40小时。过滤，蒸干过柱纯化(流动相：二氯甲烷/甲醇/氨，100/0/0到100/10/5)，得到化合物35-d(62mg，44％)。LC-MS(ESI):m/z 463.1(M+H) +.Add 35-e (140 mg, 0.31 mmol), Raney Nickel (200 mg) and tetrahydrofuran (20 mL) to the reaction flask. The mixture was stirred at 25°C under hydrogen atmosphere for 40 hours. Filter, evaporate to dryness and perform column purification (mobile phase: dichloromethane/methanol/ammonia, 100/0/0 to 100/10/5) to obtain compound 35-d (62 mg, 44%). LC-MS(ESI):m/z 463.1(M+H) + .
化合物35-c的合成Synthesis of compound 35-c
往反应瓶中加入6-溴-5-氟烟酸甲酯(350mg，1.50mmol)，THF(4mL)，甲醇(3.2mL)和水(0.8mL)。反应液0℃加入氢氧化锂(72mg，3.0mmol)，然后0℃搅拌2小时。少量柠檬酸淬灭反应，蒸干，粗品加入水，用乙酸乙酯萃取2次。合并有机相，饱和食盐水洗，无水Na2SO4干燥，过滤，蒸干得到化合物35-c(320mg，97％)。LC-MS(ESI):m/z 220.0(M+H)+.Add 6-bromo-5-fluoronicotinic acid methyl ester (350 mg, 1.50 mmol), THF (4 mL), methanol (3.2 mL) and water (0.8 mL) to the reaction flask. Lithium hydroxide (72 mg, 3.0 mmol) was added to the reaction solution at 0°C, and then stirred at 0°C for 2 hours. The reaction was quenched with a small amount of citric acid, evaporated to dryness, water was added to the crude product, and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness to obtain compound 35-c (320 mg, 97%). LC-MS(ESI):m/z 220.0(M+H) + .
化合物35-b的合成Synthesis of compound 35-b
冰浴冷却下，往反应瓶中加入35-c(320mg，1.45mmol)，O-(四氢-2H-吡喃-2-基)羟基胺(185mg，1.60mmol)，DMF(4mL)，HATU(1.10g，2.90mmol)和DIPEA(561mg，4.35mmol)。反应液0～25℃搅拌2小时。加入少量柠檬酸，乙酸乙酯稀释，用水洗，饱和NaCl洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：石油醚/乙酸乙酯100/0到100/80)，得到化合物35-b(350mg，64％)。LC-MS(ESI):m/z 375.1(M+H)+.While cooling in an ice bath, add 35-c (320 mg, 1.45 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (185 mg, 1.60 mmol), DMF (4 mL), and HATU into the reaction flask. (1.10 g, 2.90 mmol) and DIPEA (561 mg, 4.35 mmol). The reaction solution was stirred at 0-25°C for 2 hours. Add a small amount of citric acid, dilute with ethyl acetate, wash with water, wash with saturated NaCl, dry with anhydrous Na 2 SO 4 , filter, evaporate to dryness and purify through column (mobile phase: petroleum ether/ethyl acetate 100/0 to 100/80) , compound 35-b (350 mg, 64%) was obtained. LC-MS(ESI):m/z 375.1(M+H) + .
化合物35-a的合成Synthesis of compound 35-a
往反应瓶中加入35-d(58mg，0.13mmol)，35-b(94mg，0.25mmol)，DIPEA(65mg，0.50mmol)和DMF(2.5mL)。混合物在80℃氮气保护下搅拌6小时。反应液冷却至室温，乙酸乙酯稀释，用水洗，饱和食盐水洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：0.1％甲酸/水、乙腈)，得到化合物35-a(30mg，34％)。LC-MS(ESI):m/z 701.1(M+H)+.Add 35-d (58 mg, 0.13 mmol), 35-b (94 mg, 0.25 mmol), DIPEA (65 mg, 0.50 mmol) and DMF (2.5 mL) into the reaction flask. The mixture was stirred at 80°C under nitrogen protection for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness and purified through column (mobile phase: 0.1% formic acid/water, acetonitrile) to obtain compound 35- a(30mg, 34%). LC-MS(ESI):m/z 701.1(M+H) + .
化合物35的合成Synthesis of compound 35
往反应瓶中加入35-a(30mg，0.043mmol)和二氯甲烷(3mL)，冰浴下加入4M盐酸/1,4-二氧六环溶液(0.3mL)。反应液0℃搅拌40分钟。浓氨水(0.2mL)淬灭反应。反应液蒸干制备柱分离(0.1％氨水水溶液、乙腈)得到化合物35(8mg，30％)。LC-MS(ESI):m/z 617.0(M+H)+；1H NMR(400MHz,DMSO-d6):δ11.02(1H,s),9.51(1H,bs),8.98(1H,s),8.42(1H,d,J＝2.2Hz),8.21(1H,d,J＝1.5Hz),8.01(1H,d,J＝2.2Hz),7.78(1H,t,J＝6.5Hz),7.68(1H,dd,J＝12.2,1.8Hz),7.51–7.38(2H,m),5.06(2H,d,J＝5.9Hz),4.03(3H,s),3.93–3.82(4H,m),3.71(4H,t,J＝4.7Hz),3.10(3H,s).Add 35-a (30 mg, 0.043 mmol) and dichloromethane (3 mL) to the reaction flask, and add 4M hydrochloric acid/1,4-dioxane solution (0.3 mL) under ice bath. The reaction solution was stirred at 0°C for 40 minutes. Concentrated ammonia (0.2 mL) quenched the reaction. The reaction solution was evaporated to dryness and subjected to preparative column separation (0.1% ammonia aqueous solution, acetonitrile) to obtain compound 35 (8 mg, 30%). LC-MS(ESI): m/z 617.0(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ11.02(1H,s),9.51(1H,bs),8.98(1H, s),8.42(1H,d,J＝2.2Hz),8.21(1H,d,J＝1.5Hz),8.01(1H,d,J＝2.2Hz),7.78(1H,t,J＝6.5Hz) ,7.68(1H,dd,J＝12.2,1.8Hz),7.51–7.38(2H,m),5.06(2H,d,J＝5.9Hz),4.03(3H,s),3.93–3.82(4H,m ),3.71(4H,t,J＝4.7Hz),3.10(3H,s).
化合物36的合成路线
Synthetic route of compound 36
化合物36-d的合成Synthesis of Compound 36-d
将化合物35-e(160mg,0.35mmoL)溶解在15mL的DCM中，冷却到-78℃，滴加DIBAL-H(1.05mL,1.05mmoL,1M甲苯溶液)，反应混合物升到室温并搅拌2.5小时，然后冷却到0℃，用50％的酒石酸钾钠溶液(30mL)淬灭，加入100mL乙酸乙酯，室温下搅拌1.5小时，有机相分离，水相用100mL乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤(100mL*2)，无水硫酸钠干燥、过滤、减压浓缩，得到粗品，粗品通过快速分离柱分离纯化(EA/PE＝0～100％)，得到化合物36-d(41mg,25％)。LC-MS(ESI):m/z＝462.1[M+1]+.Dissolve compound 35-e (160 mg, 0.35 mmoL) in 15 mL of DCM, cool to -78°C, add DIBAL-H (1.05 mL, 1.05 mmoL, 1 M toluene solution) dropwise, and the reaction mixture rises to room temperature and stirs for 2.5 hours. , then cooled to 0°C, quenched with 50% potassium sodium tartrate solution (30mL), added 100mL ethyl acetate, stirred at room temperature for 1.5 hours, the organic phase was separated, the aqueous phase was extracted with 100mL ethyl acetate, and the organic phases were combined. Wash with saturated brine (100mL*2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is separated and purified through a rapid separation column (EA/PE=0~100%) to obtain compound 36-d ( 41 mg, 25%). LC-MS(ESI): m/z＝462.1[M+1] + .
化合物36-c的合成Synthesis of compound 36-c
往反应瓶中加入3-氟-4-硝基苯甲酸(1.0g，5.4mmol)，钯碳(200mg)甲醇(5mL)和四氢呋喃(5mL)。混合物在25℃氢气环境下搅拌18小时。过滤，蒸干得到化合物36-c(750mg，89％)。LC-MS(ESI):m/z 156.0(M+H)+.Add 3-fluoro-4-nitrobenzoic acid (1.0g, 5.4mmol), palladium on carbon (200mg), methanol (5mL) and tetrahydrofuran (5mL) to the reaction flask. The mixture was stirred at 25°C under hydrogen atmosphere for 18 hours. Filter and evaporate to dryness to obtain compound 36-c (750 mg, 89%). LC-MS(ESI):m/z 156.0(M+H) + .
化合物36-b的合成Synthesis of compound 36-b
冰浴冷却下，往反应瓶中加入36-c(200mg，1.29mmol)，O-(四氢-2H-吡喃-2-基)羟 基胺(453mg，3.87mmol)，DMF(4mL)，DIEA(500mg，3.87mmol)和HATU(640mg，1.68mmol)。反应液0℃搅拌1小时。反应液乙酸乙酯稀释，用水洗，饱和NaCl洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：石油醚/乙酸乙酯100/0到100/80)，得到粗品用乙酸乙酯溶解，柠檬酸水溶液(3％)洗涤三次，蒸干得到化合物36-b(350mg，100％)。LC-MS(ESI):m/z 255.1(M+H)+.While cooling in an ice bath, add 36-c (200 mg, 1.29 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxy to the reaction flask. amine (453 mg, 3.87 mmol), DMF (4 mL), DIEA (500 mg, 3.87 mmol) and HATU (640 mg, 1.68 mmol). The reaction solution was stirred at 0°C for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, washed with saturated NaCl, dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness and purified through column (mobile phase: petroleum ether/ethyl acetate 100/0 to 100/80) to obtain crude product Dissolve in ethyl acetate, wash three times with citric acid aqueous solution (3%), and evaporate to dryness to obtain compound 36-b (350 mg, 100%). LC-MS(ESI):m/z 255.1(M+H) + .
化合物36-a的合成Synthesis of compound 36-a
往反应瓶中加入36-d(60mg，0.13mmol)，36-b(66mg，0.26mmol)和甲醇(3mL)。反应液室温搅拌2小时。加入2-甲基吡啶硼烷络合物(21mg，0.195mmol)混合物在25℃氮气保护下搅拌18小时。加入丙酮(0.2mL)，室温搅拌10分钟，蒸干过柱纯化(流动相：0.1％FA/水、乙腈)，得到化合物36-a(40mg，44％)。LC-MS(ESI):m/z 700.2(M+H)+.Add 36-d (60 mg, 0.13 mmol), 36-b (66 mg, 0.26 mmol) and methanol (3 mL) to the reaction flask. The reaction solution was stirred at room temperature for 2 hours. 2-methylpyridineborane complex (21 mg, 0.195 mmol) was added and the mixture was stirred under nitrogen protection at 25°C for 18 hours. Acetone (0.2 mL) was added, stirred at room temperature for 10 minutes, evaporated to dryness and subjected to column purification (mobile phase: 0.1% FA/water, acetonitrile) to obtain compound 36-a (40 mg, 44%). LC-MS(ESI):m/z 700.2(M+H) + .
化合物36的合成Synthesis of compound 36
往反应瓶中加入36-a(40mg，0.057mmol)和二氯甲烷(4mL)，冰浴下加入4M盐酸/1,4-二氧六环溶液(0.4mL)。反应液0℃搅拌40分钟。浓氨水(0.3mL)淬灭反应。反应液蒸干制备柱分离(0.1％氨水水溶液、乙腈)得到化合物36(5mg，14％)。LC-MS(ESI):m/z 616.0(M+H)+；1H NMR(400MHz,DMSO-d6):δ10.89(1H,s),9.50(1H,bs),8.83(1H,s),8.42(1H,d,J＝2.0Hz),8.02(1H,d,J＝2.3Hz),7.53(1H,dd,J＝9.4,2.9Hz),7.50–7.42(2H,m),7.36(1H,dd,J＝8.5,2.0Hz),6.77(1H,s),6.63(1H,t,J＝8.7Hz),4.85(2H,d,J＝6.2Hz),4.03(3H,s),3.90(4H,t,J＝4.9Hz),3.74(4H,t,J＝4.9Hz),3.10(3H,s).Add 36-a (40 mg, 0.057 mmol) and dichloromethane (4 mL) to the reaction flask, and add 4M hydrochloric acid/1,4-dioxane solution (0.4 mL) under ice bath. The reaction solution was stirred at 0°C for 40 minutes. Concentrated ammonia (0.3 mL) quenched the reaction. The reaction solution was evaporated to dryness and subjected to preparative column separation (0.1% ammonia aqueous solution, acetonitrile) to obtain compound 36 (5 mg, 14%). LC-MS(ESI): m/z 616.0(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ10.89(1H,s),9.50(1H,bs),8.83(1H, s),8.42(1H,d,J＝2.0Hz),8.02(1H,d,J＝2.3Hz),7.53(1H,dd,J＝9.4,2.9Hz),7.50–7.42(2H,m), 7.36(1H,dd,J＝8.5,2.0Hz),6.77(1H,s),6.63(1H,t,J＝8.7Hz),4.85(2H,d,J＝6.2Hz),4.03(3H,s ), 3.90(4H,t,J＝4.9Hz), 3.74(4H,t,J＝4.9Hz), 3.10(3H,s).
化合物37的合成路线
Synthetic route of compound 37
化合物37-d的合成Synthesis of Compound 37-d
冰浴冷却下，往反应瓶中加入甲氧基甲基三苯基氯化膦(989mg，2.88mmol)和四氢 呋喃(10mL)。加入叔丁醇钾(308mg，2.75mmol)。混合物在0℃搅拌5分钟，加入3-氟-4-甲酰基苯甲酸甲酯(250mg，1.37mmol)。反应液在0℃搅拌4小时。旋去溶剂，残余物用乙酸乙酯/石油醚混合物洗涤，洗涤液蒸干过柱纯化(流动相：石油醚/乙酸乙酯，100/0到100/15)，得到化合物37-d(200mg，69％)。Under ice bath cooling, add methoxymethyltriphenylphosphine chloride (989mg, 2.88mmol) and tetrahydrogen to the reaction flask. Furan (10 mL). Potassium tert-butoxide (308 mg, 2.75 mmol) was added. The mixture was stirred at 0°C for 5 minutes and methyl 3-fluoro-4-formylbenzoate (250 mg, 1.37 mmol) was added. The reaction solution was stirred at 0°C for 4 hours. The solvent was spun off, and the residue was washed with an ethyl acetate/petroleum ether mixture. The washing liquid was evaporated to dryness and subjected to column purification (mobile phase: petroleum ether/ethyl acetate, 100/0 to 100/15) to obtain compound 37-d (200 mg). , 69%).
化合物37-c的合成Synthesis of compound 37-c
往反应瓶中加入37-d(200mg，0.95mmol)，THF(5mL)和盐酸水溶液(6M，0.5mL)。混合物在60℃搅拌4小时。旋去溶剂，残余物用乙酸乙酯稀释，水洗，饱和食盐水洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：石油醚/乙酸乙酯，100/0到100/30)，得到化合物37-c(160mg，85％)。Add 37-d (200 mg, 0.95 mmol), THF (5 mL) and aqueous hydrochloric acid solution (6 M, 0.5 mL) to the reaction flask. The mixture was stirred at 60°C for 4 hours. The solvent was spun off, and the residue was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness and purified through column (mobile phase: petroleum ether/ethyl acetate, 100/0 to 100/ 30) to obtain compound 37-c (160 mg, 85%).
化合物37-b的合成Synthesis of compound 37-b
冰浴冷却下，往反应瓶中加入37-c(160mg，0.82mmol)和甲醇(5mL)。10分钟内分批加入硼氢化钠(61mg，1.62mmol)。混合物在0℃搅拌2小时。向反应液中加入丙酮(0.5mL)，在0℃继续搅拌0.5小时。反应液蒸干过柱纯化(流动相：石油醚/乙酸乙酯，100/0到100/60)，得到化合物37-b(140mg，87％)。While cooling in an ice bath, add 37-c (160 mg, 0.82 mmol) and methanol (5 mL) into the reaction flask. Sodium borohydride (61 mg, 1.62 mmol) was added portionwise over 10 minutes. The mixture was stirred at 0°C for 2 hours. Acetone (0.5 mL) was added to the reaction solution, and stirring was continued at 0°C for 0.5 hours. The reaction solution was evaporated to dryness and subjected to column purification (mobile phase: petroleum ether/ethyl acetate, 100/0 to 100/60) to obtain compound 37-b (140 mg, 87%).
化合物37-a的合成Synthesis of compound 37-a
往反应瓶中加入37-b(140mg，0.71mmol)，DABCO(246mg，2.12mmol)和二氯甲烷(5mL)，然后冰浴下加入TsCl(200mg，1.06mmol)。混合物在0℃氮气保护下搅拌1小时。反应液水洗，饱和食盐水洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动相：石油醚/乙酸乙酯，100/0到100/20)，得到化合物37-a(225mg，90％)。Add 37-b (140 mg, 0.71 mmol), DABCO (246 mg, 2.12 mmol) and dichloromethane (5 mL) to the reaction flask, and then add TsCl (200 mg, 1.06 mmol) under ice bath. The mixture was stirred at 0°C under nitrogen protection for 1 hour. The reaction solution was washed with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness and purified through column (mobile phase: petroleum ether/ethyl acetate, 100/0 to 100/20) to obtain compound 37-a (225 mg , 90%).
化合物37的合成Synthesis of compound 37
参照化合物8的合成路线和操作，使用化合物37-a替代化合物6-溴-己酸甲酯，得到化合物37(11.3mg，28％)。LC-MS(ESI):m/z 631.0(M+H)+；1H NMR(400MHz,DMSO-d6):δ11.30(1H,s),9.49(1H,bs),9.14(1H,s),8.32(1H,s),7.94(1H,d,J＝2.2Hz),7.67(1H,t,J＝7.8Hz),7.59–7.50(2H,m),7.25(1H,dd,J＝10.9,2.6Hz),7.08(1H,dd,J＝9.5,2.5Hz),4.38(2H,t,J＝6.2Hz),4.01(3H,s),3.87–3.81(4H,m),3.72(4H,t,J＝4.7Hz),3.23(2H,t,J＝6.2Hz),3.05(3H,s).Referring to the synthetic route and operation of compound 8, compound 37-a was used instead of compound 6-bromo-hexanoic acid methyl ester to obtain compound 37 (11.3 mg, 28%). LC-MS(ESI): m/z 631.0(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ11.30(1H,s),9.49(1H,bs),9.14(1H, s),8.32(1H,s),7.94(1H,d,J＝2.2Hz),7.67(1H,t,J＝7.8Hz),7.59–7.50(2H,m),7.25(1H,dd,J ＝10.9,2.6Hz),7.08(1H,dd,J＝9.5,2.5Hz),4.38(2H,t,J＝6.2Hz),4.01(3H,s),3.87–3.81(4H,m),3.72 (4H,t,J＝4.7Hz), 3.23(2H,t,J＝6.2Hz), 3.05(3H,s).
化合物38合成路线
Synthetic route of compound 38
化合物38-a的合成Synthesis of compound 38-a
将化合物3-氟-4-羟甲基苯甲酸甲酯(300mg，1.63mmol)加入DCM(5mL)中，0℃下依次加入TEA(0.45mL)，DMAP(10mg，0.082mmol)，TsCl(341mg，1.79mmol)，在室温下搅拌过夜。反应液减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝20:1)，得到化合物38-a(150mg，27％)。The compound 3-fluoro-4-hydroxymethylbenzoic acid methyl ester (300 mg, 1.63 mmol) was added to DCM (5 mL), and TEA (0.45 mL), DMAP (10 mg, 0.082 mmol), and TsCl (341 mg) were added successively at 0°C. , 1.79mmol), stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a fast separation column (PE/EA=20:1) to obtain compound 38-a (150 mg, 27%).
化合物38的合成Synthesis of compound 38
参照化合物8的合成路线和操作，使用化合物38-a替代化合物6-溴-己酸甲酯，得到化合物38(2mg)。LC-MS(ESI):m/z＝617.0[M+H]+.Referring to the synthetic route and operation of compound 8, compound 38-a was used instead of compound 6-bromo-hexanoic acid methyl ester to obtain compound 38 (2 mg). LC-MS(ESI): m/z=617.0[M+H] + .
化合物39的合成路线
Synthetic route of compound 39
化合物39-e的合成Synthesis of compound 39-e
往反应瓶中加入1-叔丁氧羰基-4-(对甲苯磺酰氧基)哌啶(500mg，1.41mmol)，碳酸铯(1.02g，3.14mmol)和DMF(8mL)。混合物在80℃氮气保护下搅拌5分钟。加入中间体1(500mg，1.11mmol)，混合物在80℃氮气保护下搅拌4小时。反应液冷却至室温，乙酸乙酯稀释，用水洗，饱和食盐水洗，无水Na2SO4干燥，过滤，蒸干过柱纯化(流动 相：石油醚/乙酸乙酯、二氯甲烷/甲醇，100/0到100/100，100/4)，得到化合物39-e(550mg，78％)。LC-MS(ESI):m/z 633.2(M+H)+.1-tert-butoxycarbonyl-4-(p-toluenesulfonyloxy)piperidine (500 mg, 1.41 mmol), cesium carbonate (1.02 g, 3.14 mmol) and DMF (8 mL) were added to the reaction flask. The mixture was stirred at 80°C under nitrogen protection for 5 minutes. Intermediate 1 (500 mg, 1.11 mmol) was added, and the mixture was stirred under nitrogen protection at 80°C for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness and purified by column (mobile Phase: petroleum ether/ethyl acetate, dichloromethane/methanol, 100/0 to 100/100, 100/4) to obtain compound 39-e (550 mg, 78%). LC-MS(ESI):m/z 633.2(M+H) + .
化合物39-d的合成Synthesis of Compound 39-d
冰浴冷却下，往反应瓶中加入39-e(550mg，0.87mmol)，二氯甲烷(15mL)和三氟乙酸(1mL)。混合物在0℃搅拌3小时。反应液蒸干，残余物用甲基叔丁基醚洗涤，真空干燥得到化合物39-d(600mg，95％)。LC-MS(ESI):m/z 533.2(M+H)+.While cooling in an ice bath, add 39-e (550 mg, 0.87 mmol), dichloromethane (15 mL) and trifluoroacetic acid (1 mL) into the reaction flask. The mixture was stirred at 0°C for 3 hours. The reaction solution was evaporated to dryness, and the residue was washed with methyl tert-butyl ether and dried under vacuum to obtain compound 39-d (600 mg, 95%). LC-MS(ESI):m/z 533.2(M+H) + .
化合物39-c的合成Synthesis of compound 39-c
冰浴冷却下，往反应瓶中加入39-d(120mg，0.17mmol)，2-氯嘧啶-5-甲酸乙酯(44mg，0.24mmol)，碳酸钾(109mg，0.79mmol)和乙腈(5mL)。混合物在70℃搅拌6小时。反应液蒸干，残余物中加入冰水。水相用乙酸乙酯萃取。合并有机相，用饱和NaCl洗，无水Na2SO4干燥，过滤，蒸干得到化合物39-c(150mg，100％)。LC-MS(ESI):m/z 683.2(M+H)+.Under ice bath cooling, add 39-d (120 mg, 0.17 mmol), 2-chloropyrimidine-5-carboxylic acid ethyl ester (44 mg, 0.24 mmol), potassium carbonate (109 mg, 0.79 mmol) and acetonitrile (5 mL) into the reaction flask. . The mixture was stirred at 70°C for 6 hours. The reaction solution was evaporated to dryness, and ice water was added to the residue. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated NaCl, dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness to obtain compound 39-c (150 mg, 100%). LC-MS(ESI):m/z 683.2(M+H) + .
化合物39的合成Synthesis of compound 39
参照化合物30的合成路线和操作，使用化合物39-c替代化合物30-c，得到化合物39(24mg)。LC-MS(ESI):m/z 670.0(M+H)+；1H NMR(400MHz,DMSO-d6):δ11.10(1H,s),9.53(1H,s),9.04(1H,s),8.69(2H,s),8.39(1H,d,J＝2.1Hz),7.99(1H,d,J＝2.3Hz),7.45(1H,dd,J＝10.8,2.5Hz),7.16(1H,dd,J＝9.5,2.6Hz),5.01(1H,s),4.21–4.08(2H,m),4.03(3H,s),3.93–3.77(6H,m),3.72–3.67(4H,m),3.10(3H,s),2.10–1.94(2H,m),1.88–1.73(2H,m).Referring to the synthetic route and operation of compound 30, compound 39-c was used instead of compound 30-c to obtain compound 39 (24 mg). LC-MS(ESI): m/z 670.0(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ11.10(1H,s),9.53(1H,s),9.04(1H, s),8.69(2H,s),8.39(1H,d,J＝2.1Hz),7.99(1H,d,J＝2.3Hz),7.45(1H,dd,J＝10.8,2.5Hz),7.16( 1H,dd,J＝9.5,2.6Hz),5.01(1H,s),4.21–4.08(2H,m),4.03(3H,s),3.93–3.77(6H,m),3.72–3.67(4H, m),3.10(3H,s),2.10–1.94(2H,m),1.88–1.73(2H,m).
化合物40的合成路线
Synthetic route of compound 40
化合物40-c的合成Synthesis of compound 40-c
冰浴冷却下，往反应瓶中加入39-d(120mg，0.17mmol)，6-氯烟酸甲酯(44mg，0.26mmol)，碳酸钾(109mg，0.79mmol)和乙腈(2mL)。混合物在80℃搅拌22小时。加入DMF(2mL)。混合物在80℃搅拌20小时。反应液蒸干，残余物中加入冰水。水相用乙酸乙酯萃取。合并有机相，用饱和NaCl洗，无水Na2SO4干燥，过滤，蒸干得到化合物40-c(150mg，100％)。LC-MS(ESI):m/z 668.3(M+H)+. Under ice bath cooling, add 39-d (120 mg, 0.17 mmol), methyl 6-chloronicotinate (44 mg, 0.26 mmol), potassium carbonate (109 mg, 0.79 mmol) and acetonitrile (2 mL) into the reaction flask. The mixture was stirred at 80°C for 22 hours. DMF (2 mL) was added. The mixture was stirred at 80°C for 20 hours. The reaction solution was evaporated to dryness, and ice water was added to the residue. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated NaCl, dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness to obtain compound 40-c (150 mg, 100%). LC-MS(ESI):m/z 668.3(M+H) + .
化合物40的合成Synthesis of compound 40
参照化合物30的合成路线和操作，使用化合物40-c替代化合物30-c，得到化合物40(28mg)。LC-MS(ESI):m/z 669.0(M+H)+；1H NMR(400MHz,DMSO-d6):δ11.00(1H,s),9.51(1H,bs),8.90(1H,s),8.52(1H,d,J＝2.4Hz),8.39(1H,d,J＝2.2Hz),7.99(1H,d,J＝2.2Hz),7.87(1H,dd,J＝9.0,2.5Hz),7.44(1H,dd,J＝10.8,2.7Hz),7.15(1H,dd,J＝9.5,2.7Hz),6.92(1H,d,J＝9.0Hz),4.98(1H,dt,J＝7.5,3.8Hz),4.03(3H,s),3.98(2H,td,J＝8.2,7.3,3.6Hz),3.82(4H,t,J＝4.7Hz),3.67(4H,t,J＝4.8Hz),3.62(2H,td,J＝7.6,6.9,3.6Hz),3.10(3H,s),2.07–1.93(2H,m),1.86–1.72(2H,m).Referring to the synthetic route and operation of compound 30, compound 40-c was used instead of compound 30-c to obtain compound 40 (28 mg). LC-MS(ESI): m/z 669.0(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ11.00(1H,s),9.51(1H,bs),8.90(1H, s),8.52(1H,d,J＝2.4Hz),8.39(1H,d,J＝2.2Hz),7.99(1H,d,J＝2.2Hz),7.87(1H,dd,J＝9.0,2.5 Hz),7.44(1H,dd,J＝10.8,2.7Hz),7.15(1H,dd,J＝9.5,2.7Hz),6.92(1H,d,J＝9.0Hz),4.98(1H,dt,J ＝7.5,3.8Hz),4.03(3H,s),3.98(2H,td,J＝8.2,7.3,3.6Hz),3.82(4H,t,J＝4.7Hz),3.67(4H,t,J＝ 4.8Hz),3.62(2H,td,J=7.6,6.9,3.6Hz),3.10(3H,s),2.07–1.93(2H,m),1.86–1.72(2H,m).
化合物41合成路线
Synthetic route of compound 41
化合物41-h的合成Synthesis of Compound 41-h
室温下将化合物4-溴-3-氟苯甲酸甲酯(3.00g，12.87mmol)，1,4-二氧杂-螺[4,5]癸-7-烯-8-硼酸频哪醇酯(3.77g，14.16mmol)，Pd(PPh3)4(1.49g，1.29mmol)，Cs2CO3(8.39g，25.74mmol)加入混合溶剂1,4-二氧六环(60mL)和水(12mL)中，反应混合物在100℃氮气条件下搅拌过夜。冷至室温，向反应液中加入饱和食盐水(50mL)，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝10:1)，得到化合物41-h(3.74g，99％)。The compound 4-bromo-3-fluorobenzoic acid methyl ester (3.00g, 12.87mmol), 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester was mixed at room temperature. (3.77g, 14.16mmol), Pd(PPh 3 ) 4 (1.49g, 1.29mmol), Cs 2 CO 3 (8.39g, 25.74mmol) were added to the mixed solvent 1,4-dioxane (60mL) and water ( 12 mL), the reaction mixture was stirred overnight at 100°C under nitrogen. Cool to room temperature, add saturated brine (50mL) to the reaction solution, extract with ethyl acetate (50mLx3), wash the organic phase with saturated brine (100mLx3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure Get crude product. The crude product was separated and purified through a fast separation column (PE/EA=10:1) to obtain compound 41-h (3.74g, 99%).
化合物41-g的合成Synthesis of Compound 41-g
将化合物41-h(1.50g,5.13mmol)加入乙酸乙酯(30mL)中，冷却至0℃，HCl的1,4-二氧六环溶液(4M,15mL)加入乙酸乙酯溶液中，室温搅拌1hrs,重新冷却至0℃，向反应 液中加入水(50mL),用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，得到化合物41-g(1.4g)。Compound 41-h (1.50g, 5.13mmol) was added to ethyl acetate (30mL), cooled to 0°C, HCl 1,4-dioxane solution (4M, 15mL) was added to the ethyl acetate solution, room temperature Stir for 1hrs, re-cool to 0°C, and add to the reaction Water (50mL) was added to the solution, extracted with ethyl acetate (50mLx3), the organic phase was washed with saturated brine (100mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 41-g (1.4g) .
化合物41-f的合成Synthesis of Compound 41-f
将化合物41-g(1.40g)加入甲醇(30mL)中，然后Pd/C(140mg)加入，反应混合物在室温，氢气条件下搅拌过夜。过滤掉反应液中的Pd/C，滤液减压浓缩得到化合物41-f(1.10g)。LC-MS(ESI):m/z＝251.1[M+H]+.Compound 41-g (1.40 g) was added to methanol (30 mL), then Pd/C (140 mg) was added, and the reaction mixture was stirred overnight at room temperature under hydrogen. The Pd/C in the reaction solution was filtered off, and the filtrate was concentrated under reduced pressure to obtain compound 41-f (1.10 g). LC-MS(ESI): m/z＝251.1[M+H] + .
化合物41-e的合成Synthesis of Compound 41-e
将化合物41-f(530mg,2.12mmol)加入THF(15mL)中，冷却至0℃，NaBH4(160mg,4.24mmol)分三批加入THF溶液中，室温搅拌2hrs,重新冷却至0℃，向反应液中加入饱和氯化铵淬灭反应，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到产物。得到化合物41-e(530mg,99％)。Add compound 41-f (530 mg, 2.12 mmol) to THF (15 mL), cool to 0°C, add NaBH 4 (160 mg, 4.24 mmol) to the THF solution in three batches, stir at room temperature for 2 hrs, cool to 0°C again, and add to Saturated ammonium chloride was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mLx3). The organic phase was washed with saturated brine (100 mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product. Compound 41-e (530 mg, 99%) was obtained.
化合物41-d的合成Synthesis of Compound 41-d
将化合物41-e(530mg，2.10mmol)加入DCM(10mL)中，0℃下依次加入TEA(0.584mL)，DMAP(13mg，0.11mmol)，TsCl(440mg，2.31mmol)，在室温下搅拌过夜。反应液减压浓缩得到粗品。粗品通过快速分离柱分离纯化(DCM/MeOH＝20:1,10:1)，得到化合物41-d(354mg，41％)。Add compound 41-e (530 mg, 2.10 mmol) to DCM (10 mL), add TEA (0.584 mL), DMAP (13 mg, 0.11 mmol), and TsCl (440 mg, 2.31 mmol) in sequence at 0°C, and stir at room temperature overnight. . The reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a fast separation column (DCM/MeOH = 20:1, 10:1) to obtain compound 41-d (354 mg, 41%).
化合物41-c的合成Synthesis of compound 41-c
将化合物41-d(150mg，0.37mmol)，Cs2CO3(98mg，0.30mmol)加入DMF(5mL)中，在80℃氮气条件下搅拌15min，然后将8-d(166mg，0.37mmol)溶解在DMF(1mL)的溶液加入反应液中，在80℃氮气条件下继续搅拌过夜,反应液冷却至室温，向反应液中加入饱和氯化钠(50mL)，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品通过快速分离柱分离纯化(DCM/MeOH＝20:1)得到化合物41-c(144mg，57％)。Compound 41-d (150 mg, 0.37 mmol) and Cs 2 CO 3 (98 mg, 0.30 mmol) were added to DMF (5 mL), stirred for 15 min under nitrogen at 80°C, and then 8-d (166 mg, 0.37 mmol) was dissolved. A solution of DMF (1mL) was added to the reaction solution, and stirring was continued overnight at 80°C under nitrogen. The reaction solution was cooled to room temperature, saturated sodium chloride (50mL) was added to the reaction solution, and extracted with ethyl acetate (50mLx3). The organic phase was washed with saturated brine (100 mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified through a rapid separation column (DCM/MeOH=20:1) to obtain compound 41-c (144 mg, 57%).
化合物41-b的合成Synthesis of Compound 41-b
将化合物41-c(144mg，0.21mmol)，LiOH·H2O(26mg，0.62mmol)加入混合溶剂甲醇(2mL)，1,4-二氧六环(2mL)和水(0.5mL)中，反应混合物室温下搅拌过夜。反应液用HCl(1M)溶液调节pH值到7，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到化合物41-b(117mg，83％)。Compound 41-c (144 mg, 0.21 mmol), LiOH·H 2 O (26 mg, 0.62 mmol) were added to the mixed solvent methanol (2 mL), 1,4-dioxane (2 mL) and water (0.5 mL), The reaction mixture was stirred at room temperature overnight. The reaction solution was adjusted to pH 7 with HCl (1M) solution, extracted with ethyl acetate (50mLx3), the organic phase was washed with saturated brine (100mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 41- b(117mg, 83%).
化合物41-a的合成Synthesis of Compound 41-a
室温下将化合物41-b(117mg，0.17mmol)，O-(四氢-2H-吡喃)-2-羟胺(40mg，0.34mmol)，HATU(99mg，0.26mmol)，DIPEA(0.091mL)加入DMF中(5mL)，室温 搅拌过夜。向反应液中加入饱和食盐水(50mL)，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到粗品,粗品通过制备HPLC(酸法HCOOH)纯化，得到化合物41-a(28mg，22％)。Compound 41-b (117 mg, 0.17 mmol), O-(tetrahydro-2H-pyran)-2-hydroxylamine (40 mg, 0.34 mmol), HATU (99 mg, 0.26 mmol), and DIPEA (0.091 mL) were added at room temperature. In DMF (5mL), room temperature Stir overnight. Saturated brine (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mLx3), the organic phase was washed with saturated brine (100 mLx3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was prepared by HPLC (acid HCOOH) purification gave compound 41-a (28 mg, 22%).
化合物41的合成Synthesis of Compound 41
将化合物41-a(28mg，0.037mmol)加入DCM(5mL)中，冷却到0℃，慢慢滴加氯化氢的1,4-二氧六环溶液(4M，0.5mL)，加毕，混合物在0℃下搅拌30分钟后，反应液在0℃下用饱和碳酸氢钠溶液淬灭反应，淬灭后pH＝8，DCM(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到化合物41(18mg，72％)。LC-MS(ESI):m/z＝684.9[M+H]+；1H NMR(400MHz,DMSO-d6):δ11.34(1H,s),9.52(1H,s),9.13(1H,s)，8.41(1H,d,J＝2.0Hz),8.00(1H,d,J＝2.4Hz),7.63(1H,dd,J＝8.0Hz,J＝1.2Hz),7.54(1H,dd,J＝11.2Hz,J＝1.6Hz),7.47-7.34(2H,m),7.12(1H,d,J＝9.2Hz,J＝2.4Hz)，5.11-4.98(1H,m)，4.03(3H,s)，3.89(4H,t,J＝4.8Hz),3.72(4H,t,J＝4.4Hz),3.10(3H,s),3.01(1H,t,J＝12.4Hz),2.20-1.96(4H,m),1.86-1.53(4H,m).Compound 41-a (28 mg, 0.037 mmol) was added to DCM (5 mL), cooled to 0°C, and a 1,4-dioxane solution of hydrogen chloride (4 M, 0.5 mL) was slowly added dropwise. After the addition, the mixture was After stirring for 30 minutes at 0°C, the reaction solution was quenched with saturated sodium bicarbonate solution at 0°C. After quenching, the pH=8, and extracted with DCM (50mLx3). The organic phase was washed with saturated brine (100mLx3), and washed with Dry over aqueous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 41 (18 mg, 72%). LC-MS (ESI): m/z=684.9[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ11.34(1H,s),9.52(1H,s),9.13(1H ,s), 8.41 (1H, d, J = 2.0Hz), 8.00 (1H, d, J = 2.4Hz), 7.63 (1H, dd, J = 8.0Hz, J = 1.2Hz), 7.54 (1H, dd ,J＝11.2Hz,J＝1.6Hz),7.47-7.34(2H,m),7.12(1H,d,J＝9.2Hz,J＝2.4Hz),5.11-4.98(1H,m),4.03(3H ,s), 3.89(4H,t,J＝4.8Hz), 3.72(4H,t,J＝4.4Hz), 3.10(3H,s), 3.01(1H,t,J＝12.4Hz), 2.20-1.96 (4H,m),1.86-1.53(4H,m).
化合物42的合成路线
Synthetic route of compound 42
化合物42-c的合成Synthesis of compound 42-c
微波管中加入39-d(150mg,0.21mmol)，3,4,5-三氟苯甲酸甲酯(126mg,0.66mmol)，碳酸钾(142mg 1.00mmol)和DMF(1.5mL)。氮气吹1分钟。反应液80℃加热2.5小时。反应液冷却至室温，加入冰水中，乙酸乙酯萃取，柠檬酸水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干得到42-c(180mg，粗品)直接用于下一步反应。LC-MS(ESI):m/z 703.2(M+H)+.Add 39-d (150 mg, 0.21 mmol), methyl 3,4,5-trifluorobenzoate (126 mg, 0.66 mmol), potassium carbonate (142 mg 1.00 mmol) and DMF (1.5 mL) into the microwave tube. Blow nitrogen for 1 minute. The reaction solution was heated at 80°C for 2.5 hours. The reaction solution was cooled to room temperature, added with ice water, extracted with ethyl acetate, washed with citric acid, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 42-c (180 mg, crude product), which was directly used in the next reaction. LC-MS(ESI):m/z 703.2(M+H) + .
化合物42的合成Synthesis of compound 42
参照化合物30的合成路线和操作，使用化合物42-c替代化合物30-c，得到42(35mg)。LC-MS(ESI):m/z 704.3(M+H)+；1H NMR(400MHz,DMSO-d6):δ11.26(1H,bs),9.49(1H,bs),9.16(1H,s),8.39(1H,d,J＝2.2Hz),7.99(1H,d,J＝2.2Hz),7.50–7.38(3H,m),7.15(1H,dd,J＝9.5,2.7Hz),4.97–4.91(1H,m),4.03(3H,s),3.87(4H,t,J＝4.7Hz),3.72(4H,t,J＝4.7Hz),3.58–3.47(2H,m),3.20–3.10(2H,m),3.10(3H,s),2.12–2.01(2H,m),1.95–1.84 (2H,m).Referring to the synthetic route and operation of compound 30, compound 42-c was used instead of compound 30-c to obtain 42 (35 mg). LC-MS(ESI): m/z 704.3(M+H) + ; 1 H NMR(400MHz, DMSO-d 6 ): δ11.26(1H,bs),9.49(1H,bs),9.16(1H, s),8.39(1H,d,J＝2.2Hz),7.99(1H,d,J＝2.2Hz),7.50–7.38(3H,m),7.15(1H,dd,J＝9.5,2.7Hz), 4.97–4.91(1H,m),4.03(3H,s),3.87(4H,t,J＝4.7Hz),3.72(4H,t,J＝4.7Hz),3.58–3.47(2H,m),3.20 –3.10(2H,m),3.10(3H,s),2.12–2.01(2H,m),1.95–1.84 (2H,m).
化合物43合成路线
Synthetic route of compound 43
化合物43-h的合成Synthesis of Compound 43-h
6-溴-8-氟异喹啉(900mg,3.98mmol)加入乙酸(10mL)中，冷却至0℃，NaBH4(527mg,13.93mol)分三批加入乙酸溶液中，室温搅拌过夜，重新冷却至0℃，反应液用饱和碳酸氢钠淬灭反应，淬灭后pH＝7-8，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx3)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到产物。得到化合物43-h(760mg,83％)。6-Bromo-8-fluoroisoquinoline (900mg, 3.98mmol) was added to acetic acid (10mL), cooled to 0°C, NaBH 4 (527mg, 13.93mol) was added to the acetic acid solution in three batches, stirred at room temperature overnight, and cooled again to 0°C, quench the reaction solution with saturated sodium bicarbonate. After quenching, the pH=7-8. Extract with ethyl acetate (50mLx3). Wash the organic phase with saturated brine (100mLx3) and dry with anhydrous sodium sulfate. , filtered, and concentrated under reduced pressure to obtain the product. Compound 43-h (760 mg, 83%) was obtained.
化合物43-g的合成Synthesis of Compound 43-g
将化合物43-h(760mg,3.30mmol)，Boc2O(2.16g,9.90mmol)，TEA(1.38mL，9.90mmol)加入DCM(20mL)中，室温搅拌过夜，向反应液中加入2g硅胶，减压浓缩，粗品通过快速分离柱分离纯化(PE/EA＝20:1)，得到化合物43-g(913mg,84％)。Add compound 43-h (760 mg, 3.30 mmol), Boc 2 O (2.16 g, 9.90 mmol), and TEA (1.38 mL, 9.90 mmol) into DCM (20 mL), stir at room temperature overnight, and add 2 g of silica gel to the reaction solution. It was concentrated under reduced pressure, and the crude product was separated and purified through a rapid separation column (PE/EA=20:1) to obtain compound 43-g (913 mg, 84%).
化合物43-f的合成Synthesis of Compound 43-f
将43-g(813mg,2.46mmol)，Pd(dppf)Cl2(183mg,0.25mmol)，三乙胺(1.03mL,7.39mmol)加入MeOH(10mL)中，在CO条件下，100℃搅拌过夜，冷至室温，向反应液中加入2g硅胶，减压浓缩得到粗品，粗品通过快速分离柱分离纯化(PE/EA＝20:1)，得到化合物43-f(430mg,57％)。Add 43-g (813 mg, 2.46 mmol), Pd(dppf)Cl 2 (183 mg, 0.25 mmol), and triethylamine (1.03 mL, 7.39 mmol) into MeOH (10 mL), and stir at 100°C overnight under CO conditions. , cool to room temperature, add 2g of silica gel to the reaction solution, and concentrate under reduced pressure to obtain a crude product. The crude product is separated and purified through a rapid separation column (PE/EA=20:1) to obtain compound 43-f (430 mg, 57%).
化合物43-e的合成Synthesis of Compound 43-e
将化合物43-f(430mg,1.39mmol)加入氯化氢的1,4-二氧六环溶液(4M,8mL)溶液中，室温搅拌1hrs，反应液减压浓缩得到化合物43-e(319mg,94％)。Compound 43-f (430 mg, 1.39 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4M, 8 mL), stirred at room temperature for 1 hrs, and the reaction solution was concentrated under reduced pressure to obtain compound 43-e (319 mg, 94% ).
化合物43-d的合成Synthesis of Compound 43-d
将化合物43-e(319mg，1.30mmol)加入乙腈(20mL)中，室温下依次加入碘化钾 (13mg，0.078mmol)，溴甲基氟硼酸钾(783mg，3.90mmol)，碳酸钾(539mg，3.90mmol)，在80℃氮气条件下搅拌过夜。反应液冷却到室温，过滤，减压浓缩得到化合物43-d(120mg，32％)。Compound 43-e (319 mg, 1.30 mmol) was added to acetonitrile (20 mL), and potassium iodide was added successively at room temperature. (13 mg, 0.078 mmol), potassium bromomethylfluoroborate (783 mg, 3.90 mmol), potassium carbonate (539 mg, 3.90 mmol), stirred overnight at 80°C under nitrogen. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain compound 43-d (120 mg, 32%).
化合物43的合成Synthesis of compound 43
参照化合物1的合成路线和操作，使用化合物43-d替代化合物1-d，得到化合物43(8mg)。LC-MS(ESI):m/z＝656.3[M+H]+.Referring to the synthetic route and operation of compound 1, compound 43-d was used instead of compound 1-d to obtain compound 43 (8 mg). LC-MS(ESI): m/z=656.3[M+H] + .
化合物44的合成路线
Synthetic route of compound 44
化合物44-d的合成Synthesis of Compound 44-d
反应瓶中加入氯代肟基乙酸乙酯(5.5g,36.29mmol)和1,1-二氯乙烯(50mL)，10℃氮气保护下在2小时内滴加三乙胺(13.5mL,95.18mmol)的1,1-二氯乙烯(50mL)溶液。1小时时撤去水浴。室温继续反应30分钟。倒入二氯甲烷和水的混合物中，分液，二氯甲烷相用1N盐酸洗，饱和氯化钠洗，无水硫酸钠干燥，过滤，旋干，粗品硅胶柱纯化(流动相：石油醚/乙酸乙酯100/0到80/20)得到44-d(1.00g，16％)。Add ethyl chlorooximeacetate (5.5g, 36.29mmol) and 1,1-dichloroethylene (50mL) to the reaction bottle, and add triethylamine (13.5mL, 95.18mmol) dropwise within 2 hours under nitrogen protection at 10°C. ) in 1,1-dichloroethylene (50 mL). Remove the water bath after 1 hour. Continue the reaction at room temperature for 30 minutes. Pour into a mixture of dichloromethane and water, separate the layers, wash the dichloromethane phase with 1N hydrochloric acid, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, spin dry, and purify the crude product on a silica gel column (mobile phase: petroleum ether) /ethyl acetate 100/0 to 80/20) gave 44-d (1.00 g, 16%).
化合物44-c的合成Synthesis of compound 44-c
微波管中加入39-d(150mg,0.21mmol)，44-d(150mg,0.85mmol)，碳酸钾(145mg,1.02mmol)和DMF(1.5mL)。氮气吹1分钟。反应液80℃加热3.5小时。反应液冷却至室温，加入冰水中，乙酸乙酯萃取，柠檬酸水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干过柱纯化(流动相：二氯甲烷/甲醇，100/0到96/4)，得到44-c(67mg，47％)直接用于下一步反应。LC-MS(ESI):m/z 672.4(M+H)+.Add 39-d (150mg, 0.21mmol), 44-d (150mg, 0.85mmol), potassium carbonate (145mg, 1.02mmol) and DMF (1.5mL) into the microwave tube. Blow nitrogen for 1 minute. The reaction solution was heated at 80°C for 3.5 hours. The reaction solution was cooled to room temperature, added with ice water, extracted with ethyl acetate, washed with citric acid, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified through column (mobile phase: dichloromethane/methanol, 100/0 to 96/4), and 44-c (67 mg, 47%) was obtained and used directly for the next reaction. LC-MS(ESI):m/z 672.4(M+H) + .
化合物44的合成Synthesis of compound 44
参照化合物30的合成路线和操作，使用化合物44-c替代化合物30-c，得到44(12mg)。LC-MS(ESI):m/z 659.3(M+H)+；1H NMR(DMSO-d6,400MHz):δ11.29(1H,s),9.52(1H,s),9.26(1H,s),8.39(1H,d,J＝2.2Hz),7.99(1H,d,J＝2.3Hz),7.47(1H,dd,J＝10.7, 2.6Hz),7.17(1H,dd,J＝9.4,2.6Hz),5.63(1H,s),5.00–4.93(1H,m),4.03(3H,s),3.88–3.75(4H,m),3.71–3.61(6H,m),3.44–3.33(2H,m),3.10(3H,s),2.11–1.95(2H,m),1.92–1.79(2H,m).Referring to the synthetic route and operation of compound 30, compound 44-c was used instead of compound 30-c to obtain 44 (12 mg). LC-MS(ESI): m/z 659.3(M+H) + ; 1 H NMR(DMSO-d 6 ,400MHz): δ11.29(1H,s),9.52(1H,s),9.26(1H, s),8.39(1H,d,J＝2.2Hz),7.99(1H,d,J＝2.3Hz),7.47(1H,dd,J＝10.7, 2.6Hz),7.17(1H,dd,J＝9.4,2.6Hz),5.63(1H,s),5.00–4.93(1H,m),4.03(3H,s),3.88–3.75(4H,m), 3.71–3.61(6H,m),3.44–3.33(2H,m),3.10(3H,s),2.11–1.95(2H,m),1.92–1.79(2H,m).
化合物45合成路线
Synthetic route of compound 45
化合物45-d的合成Synthesis of Compound 45-d
将化合物5-氟-6-甲基烟酸甲酯(140mg，0.83mmol)，NBS(148mg，0.83mmol)，AIBN(14mg，0.083mmol)加入)中，氮气保护下，回流搅拌过夜。反应液降至室温，反应液减压浓缩得到粗品。粗品通过快速分离柱分离纯化(PE/EA＝10:1),得到化合物45-d(128mg，62％)。LC-MS(ESI):m/z＝249.7[M+H]+.Add the compound 5-fluoro-6-methylnicotinic acid methyl ester (140 mg, 0.83 mmol), NBS (148 mg, 0.83 mmol), and AIBN (14 mg, 0.083 mmol) to the mixture, and stir under reflux overnight under nitrogen protection. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified through a fast separation column (PE/EA=10:1) to obtain compound 45-d (128 mg, 62%). LC-MS(ESI): m/z=249.7[M+H] + .
化合物45-c的合成Synthesis of compound 45-c
将化合物45-d(128mg，0.52mmol)，8-d(126mg，0.28mmol)，K2CO3(79mg，0.57mmol)加入DMF(5mL)中，在室温条件下搅拌过夜。向反应液中加入饱和氯化钠(80mL)，用乙酸乙酯(50mLx3)萃取，有机相用饱和食盐水(100mLx6)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物45-c(170mg，98％)。Compound 45-d (128 mg, 0.52 mmol), 8-d (126 mg, 0.28 mmol), K 2 CO 3 (79 mg, 0.57 mmol) were added to DMF (5 mL), and stirred at room temperature overnight. Saturated sodium chloride (80mL) was added to the reaction solution, extracted with ethyl acetate (50mLx3), the organic phase was washed with saturated brine (100mLx6), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 45-c. (170mg, 98%).
化合物45的合成Synthesis of Compound 45
参照化合物30的合成路线和操作，使用化合物39-c替代化合物30-c，得到化合物45(1mg)。LC-MS(ESI):m/z＝618.0[M+H]+.Referring to the synthetic route and operation of compound 30, compound 39-c was used instead of compound 30-c to obtain compound 45 (1 mg). LC-MS(ESI): m/z=618.0[M+H] + .
化合物46的合成路线
Synthetic route of compound 46
化合物46-f的合成Synthesis of Compound 46-f
在反应瓶中加入3,3-二氟-4-羟基-1-哌啶羧酸叔丁酯(1.0g,4.22mmol)，DCM(20mL)和吡啶(1.02mL,12.65mmol)。-78℃缓慢滴加三氟甲磺酸酐(1.06mL,6.32mmol)。加毕，反应液室温搅拌2小时。往反应液中加入冰水淬灭反应，分液，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干得到46-f(1.55g，100％)。3,3-Difluoro-4-hydroxy-1-piperidinecarboxylic acid tert-butyl ester (1.0g, 4.22mmol), DCM (20mL) and pyridine (1.02mL, 12.65mmol) were added to the reaction bottle. Trifluoromethanesulfonic anhydride (1.06 mL, 6.32 mmol) was slowly added dropwise at -78°C. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. Ice water was added to the reaction solution to quench the reaction, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 46-f (1.55 g, 100%).
化合物46-e的合成Synthesis of Compound 46-e
往反应瓶中加入8-d(0.82g,1.82mmol)和NMP(8mL)，氮气保护下加入碳酸铯(1.66g,5.11mmol)。混合物升温到60℃，氮气保护下滴加46-f(1.05g,2.84mmol)的NMP(5mL)溶液，大概1.5小时内递交完毕，反应液60℃氮气保护下继续搅拌0.5小时。反应液冷却至室温，加入冰水，用乙酸乙酯萃取两次，旋去溶剂。往剩余物中再次加入冰水，用乙酸乙酯萃取两次。有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干，石油醚洗两次，干燥，得到46-e(560mg，46％)。LC-MS(ESI):m/z 669.6(M+H)+.Add 8-d (0.82g, 1.82mmol) and NMP (8mL) to the reaction flask, and add cesium carbonate (1.66g, 5.11mmol) under nitrogen protection. The mixture was heated to 60°C, and the NMP (5mL) solution of 46-f (1.05g, 2.84mmol) was added dropwise under nitrogen protection. The solution was completed within about 1.5 hours. The reaction solution was stirred at 60°C under nitrogen protection for 0.5 hours. The reaction solution was cooled to room temperature, ice water was added, extracted twice with ethyl acetate, and the solvent was evaporated. Ice water was added to the residue again, and the mixture was extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, washed twice with petroleum ether and dried to obtain 46-e (560 mg, 46%). LC-MS(ESI):m/z 669.6(M+H) + .
化合物46-d的合成Synthesis of Compound 46-d
在反应瓶中加入46-e(560mg,0.84mmol)和二氯甲烷(6mL)，室温下滴加三氟乙酸(3mL)。加毕，反应液室温搅拌2小时。旋去溶剂，油泵干燥。加入甲基叔丁基醚和石油醚，析出固体，弃去液体，残余物用石油醚洗1次，旋干得到46-d(560mg，98％)。LC-MS(ESI):m/z 569.6(M+H)+.Add 46-e (560 mg, 0.84 mmol) and dichloromethane (6 mL) to the reaction bottle, and add trifluoroacetic acid (3 mL) dropwise at room temperature. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. Spin off the solvent and dry the oil pump. Methyl tert-butyl ether and petroleum ether were added to precipitate a solid, and the liquid was discarded. The residue was washed once with petroleum ether and spun to dryness to obtain 46-d (560 mg, 98%). LC-MS(ESI):m/z 569.6(M+H) + .
化合物46-c的合成Synthesis of compound 46-c
在反应瓶中加入46-d(560mg,0.82mmol)，6-溴-5-氟吡啶-3-甲酸甲酯(530mg,2.27mmol)，碳酸钾(750mg,5.43mmol)和DMF(10mL)。混合物在氮气保护下80℃加热搅拌22小时。反应液加入到冰水中，用乙酸乙酯萃取两次，合并有机相，有机相水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干，过柱纯化(流动相：二氯甲烷/乙酸乙酯， 100/0到60/40)，得到46-c(300mg，51％)。LC-MS(ESI):m/z 722.7(M+H)+.46-d (560 mg, 0.82 mmol), 6-bromo-5-fluoropyridine-3-carboxylic acid methyl ester (530 mg, 2.27 mmol), potassium carbonate (750 mg, 5.43 mmol) and DMF (10 mL) were added to the reaction bottle. The mixture was heated and stirred at 80°C for 22 hours under nitrogen protection. The reaction solution was added to ice water, extracted twice with ethyl acetate, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column (mobile phase: dichloromethane/acetic acid Ethyl ester, 100/0 to 60/40), giving 46-c (300 mg, 51%). LC-MS(ESI):m/z 722.7(M+H) + .
化合物46-b的合成Synthesis of compound 46-b
在反应瓶中加入46-c(300mg,0.42mmol)，四氢呋喃(5mL)，甲醇(4mL)和水(1mL)。冰浴下加入一水合氢氧化锂(38mg,0.91mmol)。反应液从冰浴自然升温到室温，搅拌2小时。补加一水合氢氧化锂(30mg,0.72mmol)，反应液室温搅拌8小时。往反应液中加入硫酸氢钠固体(230mg)，室温搅拌5分钟，旋去溶剂，剩余物用乙酸乙酯萃取。有机相用无水硫酸钠干燥，过滤，蒸干得到46-b(280mg，95％)。LC-MS(ESI):m/z 708.7(M+H)+.Add 46-c (300 mg, 0.42 mmol), tetrahydrofuran (5 mL), methanol (4 mL) and water (1 mL) to the reaction flask. Lithium hydroxide monohydrate (38 mg, 0.91 mmol) was added under ice bath. The reaction solution was naturally warmed from the ice bath to room temperature and stirred for 2 hours. Lithium hydroxide monohydrate (30 mg, 0.72 mmol) was added, and the reaction solution was stirred at room temperature for 8 hours. Sodium bisulfate solid (230 mg) was added to the reaction solution, stirred at room temperature for 5 minutes, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 46-b (280 mg, 95%). LC-MS(ESI):m/z 708.7(M+H) + .
化合物46-a的合成Synthesis of compound 46-a
在反应瓶中加入46-b(280mg,0.40mmol)，HOBt(130mg,0.96mmol)，二氯甲烷(10mL)和四氢呋喃(1mL)。室温加入EDCI(190mg,0.99mmol)，混合物在室温搅拌10分钟后加入O-(四氢-2H-吡喃)-2-羟胺(120mg,1.02mmol)。反应液室温搅拌3小时。旋去溶剂。过柱纯化(C8柱，流动相：水(10mM碳酸氢铵)/乙腈，95/5到5/95)得到消旋体46-a(150mg，47％)。LC-MS(ESI):m/z 807.8(M+H)+.Add 46-b (280 mg, 0.40 mmol), HOBt (130 mg, 0.96 mmol), dichloromethane (10 mL) and tetrahydrofuran (1 mL) into the reaction bottle. EDCI (190 mg, 0.99 mmol) was added at room temperature, and the mixture was stirred at room temperature for 10 minutes, and then O-(tetrahydro-2H-pyran)-2-hydroxylamine (120 mg, 1.02 mmol) was added. The reaction solution was stirred at room temperature for 3 hours. Spin off the solvent. Column purification (C8 column, mobile phase: water (10mM ammonium bicarbonate)/acetonitrile, 95/5 to 5/95) gave racemate 46-a (150 mg, 47%). LC-MS(ESI):m/z 807.8(M+H) + .
化合物46的合成Synthesis of compound 46
在反应瓶中加入46-a(150mg,0.19mmol)和二氯甲烷(6mL)。原料溶解后冰浴冷却下滴加盐酸甲醇溶液(4M，0.47mL)。反应液冰浴搅拌3小时后，加入饱和碳酸氢钠水溶液和饱和食盐水，调节pH～7。用乙酸乙酯萃取2次，合并有机相，无水硫酸钠干燥，过滤，蒸干。粗品过柱纯化(流动相：二氯甲烷/甲醇，100/0到94/6)，得到化合物46(80mg，收率60％)。LC-MS(ESI):m/z 723.2(M+H)+；1H NMR(DMSO-d6,400MHz)δ11.22(1H,s),9.52(1H,s),9.13(1H,s),8.48–8.38(2H,m),8.00(1H,d,J＝2.0Hz),7.84(1H,dd,J＝14.4,1.6Hz),7.59(1H,dd,J＝10.4,2.4Hz),7.27(1H,dd,J＝9.2,2.4Hz),5.38–5.26(1H,m),4.29–4.13(1H,m),4.06–4.00(4H,m),3.93–3.80(5H,m),3.76–3.64(5H,m),3.11(3H,s),2.32–2.07(2H,m).Add 46-a (150 mg, 0.19 mmol) and dichloromethane (6 mL) to the reaction bottle. After the raw materials were dissolved, hydrochloric acid methanol solution (4M, 0.47mL) was added dropwise while cooling in an ice bath. After the reaction solution was stirred in an ice bath for 3 hours, saturated sodium bicarbonate aqueous solution and saturated brine were added to adjust the pH to ~7. Extract twice with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and evaporate to dryness. The crude product was purified by column (mobile phase: dichloromethane/methanol, 100/0 to 94/6) to obtain compound 46 (80 mg, yield 60%). LC-MS(ESI): m/z 723.2(M+H) + ; 1 H NMR(DMSO-d 6 ,400MHz) δ11.22(1H,s),9.52(1H,s),9.13(1H,s ),8.48–8.38(2H,m),8.00(1H,d,J＝2.0Hz),7.84(1H,dd,J＝14.4,1.6Hz),7.59(1H,dd,J＝10.4,2.4Hz) ,7.27(1H,dd,J＝9.2,2.4Hz),5.38–5.26(1H,m),4.29–4.13(1H,m),4.06–4.00(4H,m),3.93–3.80(5H,m) ,3.76–3.64(5H,m),3.11(3H,s),2.32–2.07(2H,m).
化合物47的合成路线
Synthetic route of compound 47
化合物47-e的合成Synthesis of Compound 47-e
往微波管中加入2-氯-5-吡啶乙酸甲酯(980mg,5.28mmol)，4-羟基哌啶(680mg,6.72mmol)，RuPhos(50mg,0.11mmol)，Pd-PEPPSI-IHEPT-Cl(60mg,0.070mmol)(cas：1435347-24-2)和碳酸铯(2100mg,6.45mmol)。加入无水1,4-二氧六环(10mL)。氮气置换3次，封好盖子，反应液80℃加热搅拌18小时。反应液冷却至室温，用乙酸乙酯稀释，过滤，滤渣用乙酸乙酯洗涤3次，合并有机相，蒸干得到化合物47-e(1.32g，100％)。LC-MS(ESI):m/z 251.2(M+H)+.Add 2-chloro-5-pyridineacetic acid methyl ester (980mg, 5.28mmol), 4-hydroxypiperidine (680mg, 6.72mmol), RuPhos (50mg, 0.11mmol), Pd-PEPPSI-IHEPT-Cl ( 60 mg, 0.070 mmol) (cas: 1435347-24-2) and cesium carbonate (2100 mg, 6.45 mmol). Anhydrous 1,4-dioxane (10 mL) was added. Nitrogen was replaced three times, the lid was sealed, and the reaction solution was heated and stirred at 80°C for 18 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and filtered. The filter residue was washed three times with ethyl acetate. The organic phases were combined and evaporated to dryness to obtain compound 47-e (1.32g, 100%). LC-MS(ESI):m/z 251.2(M+H) + .
化合物47-d的合成Synthesis of Compound 47-d
在反应瓶中加入47-e(1.32g,5.27mmol)，DABCO(1.92g,17.12mmol)和二氯甲烷(20mL)。冰浴下加入TsCl(1.68g,8.81mmol)。反应液从冰浴缓慢升到室温，搅拌3小时。往反应液中加入水，有机相分开，无水硫酸钠干燥，过滤，蒸干，过柱纯化(流动相：石油醚/乙酸乙酯，100/0到60/40)得到47-d(1.6g，75％)，放置冰箱固化。LC-MS(ESI):m/z 405.6(M+H)+.Add 47-e (1.32g, 5.27mmol), DABCO (1.92g, 17.12mmol) and dichloromethane (20mL) into the reaction bottle. TsCl (1.68g, 8.81mmol) was added under ice bath. The reaction solution was slowly raised from the ice bath to room temperature and stirred for 3 hours. Add water to the reaction solution, separate the organic phase, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and purify through column (mobile phase: petroleum ether/ethyl acetate, 100/0 to 60/40) to obtain 47-d (1.6 g, 75%), placed in the refrigerator to solidify. LC-MS(ESI):m/z 405.6(M+H) + .
化合物47-c的合成Synthesis of compound 47-c
在微波管中加入47-d(126mg,0.31mmol)，8-d(90mg,0.20mmol)，碳酸铯(185mg,0.57mmol)和NMP(1mL)。氮气置换后密闭。反应混合物在65℃搅拌8小时。反应液冷却至室温，用乙酸乙酯稀释，加入水和硫酸氢钠固体。分液，水相用乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，蒸干得到47-c(120mg，88％)。LC-MS(ESI):m/z 682.8(M+H)+.Add 47-d (126 mg, 0.31 mmol), 8-d (90 mg, 0.20 mmol), cesium carbonate (185 mg, 0.57 mmol) and NMP (1 mL) into the microwave tube. Sealed after nitrogen replacement. The reaction mixture was stirred at 65°C for 8 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and water and sodium bisulfate solid were added. The liquids were separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 47-c (120 mg, 88%). LC-MS(ESI):m/z 682.8(M+H) + .
化合物47-b的合成Synthesis of compound 47-b
在反应瓶中加入47-c(120mg,0.18mmol)，四氢呋喃(4mL)，无水甲醇(3mL)和水(1mL)。冰浴下加入一水合氢氧化锂(48mg,1.14mmol)。反应液从冰浴到室温搅拌3 小时。旋去溶剂，冰浴下加入硫酸氢钠固体(160mg)，搅拌5分钟后加入乙酸乙酯和四氢呋喃，旋干。粗品用四氢呋喃洗涤3次，合并有机相，旋干得到47-b(110mg，94％)。LC-MS(ESI):m/z 668.3(M+H)+.Add 47-c (120 mg, 0.18 mmol), tetrahydrofuran (4 mL), anhydrous methanol (3 mL) and water (1 mL) to the reaction flask. Lithium hydroxide monohydrate (48 mg, 1.14 mmol) was added under ice bath. The reaction solution was stirred from ice bath to room temperature for 3 Hour. Spin off the solvent, add solid sodium bisulfate (160 mg) in an ice bath, stir for 5 minutes, add ethyl acetate and tetrahydrofuran, and spin to dryness. The crude product was washed three times with tetrahydrofuran, the organic phases were combined, and spin-dried to obtain 47-b (110 mg, 94%). LC-MS(ESI):m/z 668.3(M+H) + .
化合物47-a的合成Synthesis of compound 47-a
在反应瓶中加入47-b(110mg,0.17mmol)，HOBt(80mg,0.59mmol)和二氯甲烷(6mL)。室温搅拌下加入EDCI(115mg,0.60mmol)。反应液室温搅拌15分钟后，加入O-(四氢-2H-吡喃)-2-羟胺(70mg,0.60mmol)。反应液室温搅拌1小时。旋去溶剂，粗品过柱纯化(流动相：二氯甲烷/甲醇，100/0到98/2)得到47-a(120mg，95％)。LC-MS(ESI):m/z 767.8(M+H)+.47-b (110 mg, 0.17 mmol), HOBt (80 mg, 0.59 mmol) and dichloromethane (6 mL) were added to the reaction bottle. EDCI (115 mg, 0.60 mmol) was added with stirring at room temperature. After the reaction solution was stirred at room temperature for 15 minutes, O-(tetrahydro-2H-pyran)-2-hydroxylamine (70 mg, 0.60 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The solvent was removed, and the crude product was purified by column (mobile phase: dichloromethane/methanol, 100/0 to 98/2) to obtain 47-a (120 mg, 95%). LC-MS(ESI):m/z 767.8(M+H) + .
化合物47的合成Synthesis of compound 47
在反应瓶中加入47-a(120mg,0.16mmol)和二氯甲烷(5mL)。冰浴冷却下滴加盐酸甲醇溶液(4M，0.4mL)。反应液从冰浴自然升到室温，搅拌3小时。加入乙酸乙酯稀释，加入饱和碳酸氢钠溶液调节pH～8。分液，水相用二氯甲烷萃取1次。合并有机相，蒸干，用四氢呋喃溶解。水相过滤，滤饼用水洗1次后用四氢呋喃溶解。合并四氢呋喃溶液，蒸干得到粗品。粗品过柱纯化(流动相：二氯甲烷/甲醇，100/0到90/10)，得到化合物47(38mg，36％)。LC-MS(ESI):m/z 683.5(M+H)+；1H NMR(DMSO-d6,400MHz)δ10.61(1H,s),9.51(1H,s),8.81(1H,s),8.40(1H,d,J＝2.0Hz),8.00(1H,d,J＝2.0Hz),7.98(1H,d,J＝2.0Hz),7.47(1H,d,J＝8.8Hz),7.43(1H,dd,J＝11.2,2.4Hz),7.15(1H,dd,J＝9.2,2.4Hz),6.89(1H,d,J＝7.6Hz),4.98–4.90(1H,m),4.03(3H,s),3.96–3.85(2H,m),3.87–3.76(4H,m),3.74–3.64(4H,m),3.54–3.42(2H,m),3.16(2H,s),3.11(3H,s),2.08–1.95(2H,m),1.83–1.69(2H,m).Add 47-a (120 mg, 0.16 mmol) and dichloromethane (5 mL) to the reaction bottle. Hydrochloric acid methanol solution (4M, 0.4mL) was added dropwise while cooling in an ice bath. The reaction solution was naturally raised from the ice bath to room temperature and stirred for 3 hours. Add ethyl acetate to dilute, and add saturated sodium bicarbonate solution to adjust pH to 8. The liquids were separated, and the aqueous phase was extracted once with dichloromethane. The organic phases were combined, evaporated to dryness, and dissolved in tetrahydrofuran. The aqueous phase was filtered, and the filter cake was washed once with water and dissolved in tetrahydrofuran. Combine the tetrahydrofuran solutions and evaporate to dryness to obtain crude product. The crude product was purified by column (mobile phase: dichloromethane/methanol, 100/0 to 90/10) to obtain compound 47 (38 mg, 36%). LC-MS(ESI): m/z 683.5(M+H) + ; 1 H NMR(DMSO-d 6 ,400MHz) δ10.61(1H,s),9.51(1H,s),8.81(1H,s ),8.40(1H,d,J＝2.0Hz),8.00(1H,d,J＝2.0Hz),7.98(1H,d,J＝2.0Hz),7.47(1H,d,J＝8.8Hz), 7.43(1H,dd,J＝11.2,2.4Hz),7.15(1H,dd,J＝9.2,2.4Hz),6.89(1H,d,J＝7.6Hz),4.98–4.90(1H,m),4.03 (3H,s),3.96–3.85(2H,m),3.87–3.76(4H,m),3.74–3.64(4H,m),3.54–3.42(2H,m),3.16(2H,s),3.11 (3H,s),2.08–1.95(2H,m),1.83–1.69(2H,m).
效果实施例1 PI3Kα、PI3Kδ、PI3Kβ和PI3Kγ酶活性抑制IC50评价实验Effect Example 1 PI3Kα, PI3Kδ, PI3Kβ and PI3Kγ enzyme activity inhibition IC 50 evaluation experiment
实验使用ADP-Glo Kinase Assay试剂盒，按照说明书操作。配制以下缓冲溶液：50mM HEPES,pH 7.5,3mM MgCl2,1mM EGTA,100mM NaCl,0.03％CHAPS,2mM DTT。测试化合物样品用DMSO溶解，按照一定的起始浓度比如10μM，3倍稀释，加入到筛选体系中，同时设置DMSO对照和未加激酶对照。用缓冲液配制PI3Kα、PI3Kδ、PI3Kβ和PI3Kγ酶、底物(PIP2)和ATP的最佳浓度。酶反应体系包括：缓冲液，ATP 25μM，激酶底物(PIP2,50μg/mL)，激酶【PI3Kα(0.15μg/mL)、PI3Kδ(1.2μg/mL)、PI3Kβ(0.3μg/mL)和PI3Kγ(2.5μg/mL)】等。反应体系在室温下反应1小时。加入终止试剂(ADP-Glo reagent,5μL)终止反应，使用检测试剂(Kinase Detection Reagent,10μL)检测体系内的ADP含量。用Envision仪器收集信号数据。按照以下公式计算抑制率：％抑制率＝(DMSO对照 信号值-样品信号值)/(DMSO对照信号值-未加激酶对照信号值)。使用Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)公式拟合成曲线，获得IC50值。The experiment used the ADP-Glo Kinase Assay kit and followed the instructions. Prepare the following buffer solution: 50mM HEPES, pH 7.5, 3mM MgCl2, 1mM EGTA, 100mM NaCl, 0.03% CHAPS, 2mM DTT. The test compound sample is dissolved in DMSO, diluted 3 times at a certain starting concentration such as 10 μM, and added to the screening system. DMSO controls and no-kinase controls are set at the same time. Use buffer to prepare optimal concentrations of PI3Kα, PI3Kδ, PI3Kβ and PI3Kγ enzymes, substrate (PIP2) and ATP. The enzyme reaction system includes: buffer, ATP 25μM, kinase substrate (PIP2, 50μg/mL), kinase [PI3Kα (0.15μg/mL), PI3Kδ (1.2μg/mL), PI3Kβ (0.3μg/mL) and PI3Kγ ( 2.5μg/mL)] etc. The reaction system was allowed to react at room temperature for 1 hour. Add the stop reagent (ADP-Glo reagent, 5 μL) to stop the reaction, and use the detection reagent (Kinase Detection Reagent, 10 μL) to detect the ADP content in the system. Signal data were collected with Envision instruments. Calculate the inhibition rate according to the following formula: % inhibition rate = (DMSO control Signal value-sample signal value)/(DMSO control signal value-no kinase control signal value). Use the Y=Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope) formula to fit a curve and obtain the IC 50 value.
效果实施例2 HDAC1、HDAC2、HDAC3、HDAC6酶活性抑制IC50评价实验Effect Example 2 HDAC1, HDAC2, HDAC3, HDAC6 enzyme activity inhibition IC 50 evaluation experiment
按照试剂盒说明配制缓冲液(50mM Tris 7.5，0.01％Tween-20，50mM NaCl)，使用缓冲液配制酶溶液、底物溶液(乙酰化多肽，同时加入胰蛋白酶)。测试化合物样品用DMSO溶解，按照一定的起始浓度比如10μM，3倍稀释，加入到筛选体系中，同时设置DMSO对照和未加酶对照。酶反应体系包括：缓冲液，酶【终浓度：HDAC1＝10nM，HDAC2＝4nM，HDAC3＝7nM，HDAC6＝5nM】、底物(乙酰化多肽)【终浓度：Peptide(HDAC1)＝8μM，Peptide(HDAC2)＝10μM，Peptide(HDAC3)＝5μM，Peptide(HDAC6)＝11μM】、胰蛋白酶【终浓度：Trypsin(HDAC1，2，3)＝0.05μM，Trypsin(HDAC6)＝0.1μM】等。酶和化合物在室温下反应15分钟。加入底物和Trypsin后，离心1min，用Envision连续读取60min荧光信号数据(激发波长355nM/发射波长460nm)，并选取线性反应段得到斜率，进而计算该浓度下的抑制率。使用Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)公式拟合成曲线，获得IC50值。Prepare buffer (50mM Tris 7.5, 0.01% Tween-20, 50mM NaCl) according to the instructions of the kit, and use the buffer to prepare enzyme solution and substrate solution (acetylated polypeptide, while adding trypsin). The test compound sample is dissolved in DMSO, diluted 3 times at a certain starting concentration such as 10 μM, and added to the screening system. DMSO controls and no-enzyme controls are set at the same time. The enzyme reaction system includes: buffer, enzyme [final concentration: HDAC1=10nM, HDAC2=4nM, HDAC3=7nM, HDAC6=5nM], substrate (acetylated peptide) [final concentration: Peptide (HDAC1)=8μM, Peptide ( HDAC2) = 10 μM, Peptide (HDAC3) = 5 μM, Peptide (HDAC6) = 11 μM], trypsin [final concentration: Trypsin (HDAC1, 2, 3) = 0.05 μM, Trypsin (HDAC6) = 0.1 μM], etc. The enzyme and compound react at room temperature for 15 minutes. After adding the substrate and Trypsin, centrifuge for 1 minute, use Envision to continuously read the fluorescence signal data for 60 minutes (excitation wavelength 355nM/emission wavelength 460nm), and select the linear reaction section to obtain the slope, and then calculate the inhibition rate at this concentration. Use the Y=Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope) formula to fit a curve and obtain the IC 50 value.
效果实施例3 HDAC8、HDAC10酶活性抑制IC50评价实验Effect Example 3 HDAC8, HDAC10 enzyme activity inhibition IC50 evaluation experiment
按照试剂盒说明配制缓冲液(HDAC8：50mM Tris 8.0，2.7mM KCl，137mM NaCl，1mM MgCl2，1mg/ML BSA；HDAC10：50mM Tris 7.5，0.01％Tween-20，50mM NaCl，0.05mg/ML BSA)，使用缓冲液配制酶溶液、底物溶液(乙酰化多肽)。测试化合物样品用DMSO溶解，按照一定的起始浓度比如10μM，3倍稀释，加入到筛选体系中，同时设置DMSO对照和未加酶对照。酶反应体系包括：缓冲液，酶【终浓度：HDAC8＝10nM，HDAC10＝10nM】、底物(乙酰化多肽)【终浓度：Peptide(HDAC8)＝20μM，Peptide(HDAC10)＝4μM】等。酶和化合物在室温下反应15分钟。加入底物多肽后反应体系在室温下反应240分钟，加入胰蛋白酶溶液【终浓度：Trypsin＝50μM】，继续孵育120分钟。用Envision仪器读取荧光信号数据(激发波长355nM/发射波长460nm)。根据相对荧光单位(RFU)计算该浓度下的抑制率。使用Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)公式拟合成曲线，获得IC50值。代表性化合物的活性结果见下表1。其中，“IC50>10μM”用“*”表示，“10μM≥IC50>1μM”用“**”表示，“1μM≥IC50>100nM”用“***”表示，“100nM≥IC50>10nM”用“****”表示，“IC50≤10nM”用“*****”表示。Prepare the buffer according to the instructions of the kit (HDAC8: 50mM Tris 8.0, 2.7mM KCl, 137mM NaCl, 1mM MgCl 2 , 1mg/ML BSA; HDAC10: 50mM Tris 7.5, 0.01% Tween-20, 50mM NaCl, 0.05mg/ML BSA ), use buffer to prepare enzyme solution and substrate solution (acetylated polypeptide). The test compound sample is dissolved in DMSO, diluted 3 times at a certain starting concentration such as 10 μM, and added to the screening system. DMSO controls and no-enzyme controls are set at the same time. The enzyme reaction system includes: buffer, enzyme [final concentration: HDAC8=10nM, HDAC10=10nM], substrate (acetylated peptide) [final concentration: Peptide (HDAC8)=20μM, Peptide (HDAC10)=4μM], etc. The enzyme and compound react at room temperature for 15 minutes. After adding the substrate peptide, the reaction system reacted at room temperature for 240 minutes, then added trypsin solution [final concentration: Trypsin = 50 μM], and continued incubation for 120 minutes. Use Envision instrument to read fluorescence signal data (excitation wavelength 355nM/emission wavelength 460nm). The inhibition rate at this concentration was calculated based on relative fluorescence units (RFU). Use the Y=Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope) formula to fit a curve and obtain the IC 50 value. Activity results for representative compounds are shown in Table 1 below. Among them, "IC 50 >10μM" is represented by "*", "10μM≥IC 50 >1μM" is represented by "**", "1μM≥IC 50 >100nM" is represented by "***", "100nM≥IC 50 >10nM” is represented by “****”, and “IC 50 ≤10nM” is represented by “*****”.
表1本发明代表性化合物活性数据


Table 1 Activity data of representative compounds of the present invention


应当理解的是，本发明中所述的实施例和实施方案仅用于解释说明目的，有鉴于此的各种改进或变化会提示给本领域技术人员，它们包括在本申请的主旨和范围以及所附权利要求的范围内。通过引用的方式将本发明所引用的所有出版物、专利和专利申请合并入本发明并用于所有目的。 It should be understood that the examples and implementations described in the present invention are for illustrative purposes only, and various modifications or changes in view of this will be suggested to those skilled in the art, and they are included in the spirit and scope of the present application and within the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference and used for all purposes.

Claims (14)

  1. 一种如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，
    A morpholinoquinazoline compound represented by formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug,
    其中，R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或C3-8环烷基；Wherein, R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
    R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
    A、C和E独立地为连接键、或、-(U1)n1-(RL-1)n2-(U2)n3-(RL-2)n4-(U3)n5-(RL-3)n6-；A, C and E are independently connecting bonds, or, -(U 1 ) n1 -(R L-1 ) n2 -(U 2 ) n3 -(R L-2 ) n4 -(U 3 ) n5 -(R L-3 ) n6 -;
    U1、U2和U3独立地为-O-、-S-、-NH-或-NR3-，R3为C1-6烷基；U 1 , U 2 and U 3 are independently -O-, -S-, -NH- or -NR 3 -, and R 3 is C 1-6 alkyl;
    RL-1、RL-2和RL-3独立地为C1-6亚烷基、C2-6烯基或C2-6炔基；R L-1 , R L-2 and R L-3 are independently C 1-6 alkylene, C 2-6 alkenyl or C 2-6 alkynyl;
    n1、n3和n5独立地为0或1；n1, n3 and n5 are independently 0 or 1;
    n2、n4和n6独立地为0、1、2、3或4；n2, n4 and n6 are independently 0, 1, 2, 3 or 4;
    B和D独立地为连接键、C3-10环烷基、被一个或多个R1-1取代的C3-10环烷基、“含1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、被一个或多个R1-2取代的“含1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、C6-20芳基、被一个或多个R1-3取代的C6-20芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”、被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”、5～7元环烯基、或、被一个或多个R1-6取代的5～7元环烯基；当取代基为多个时，相同或不同；B and D are independently connecting bonds, C 3-10 cycloalkyl, C 3-10 cycloalkyl substituted by one or more R 1-1 , "containing 1 to 3 heteroatoms, and the heteroatoms are selected from O and N "4-10-membered heterocycloalkyl", "4-10-membered heterocycloalkyl containing 1-3 heteroatoms selected from O and N" substituted by one or more R 1-2 , C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "Containing 1 to 4 heteroatoms, the heteroatoms are selected from 5 to 12-membered heteroatoms of O, S and N Aryl", "5-12 membered heteroaryl containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 , "5-12 membered heteroaryl containing 1 to 3 heteroatoms" Atoms, heteroatoms independently selected from O, S and N 8-12 membered benzoheterocyclenyl", "containing 1-3 heteroatoms, substituted by one or more R 1-5 "8-12-membered benzoheterocyclealkenyl" selected from O, S and N, 5-7-membered cycloalkenyl, or 5-7-membered cycloalkenyl substituted by one or more R 1-6 ; when When there are multiple substituents, they may be the same or different;
    R1-1、R1-2、R1-3、R1-4、R1-5和R1-6独立地为卤素或C1-6烷基。R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently halogen or C 1-6 alkyl.
  2. 如权利要求1所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，The morpholinoquinazoline compound represented by formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug as claimed in claim 1, characterized in that,
    R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或C3-8环烷基；R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
    R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
    A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
    B为连接键、C3-10环烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环 烷基、被一个或多个R1-2取代的“含1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、被一个或多个R1-3取代的C6-20芳基、含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”；B is a connecting bond, C 3-10 cycloalkyl group, containing 1-3 heteroatoms, and the heteroatoms are selected from O and N 4-10 membered heterocyclic rings Alkyl, "4-10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from O and N" substituted by one or more R 1-2 , substituted by one or more R 1-3 Substituted C 6-20 aryl, containing 1 to 4 heteroatoms, 5 to 12-membered heteroaryl selected from O, S and N, "containing 1 to 1" substituted by one or more R 1-4 4 heteroatoms, the heteroatoms are selected from O, S and N 5-12 membered heteroaryl" or "containing 1-3 heteroatoms substituted by one or more R 1-5 , the heteroatoms are independently 8-12 membered benzoheterocyclenyl group selected from O, S and N;
    C为连接键、C1-6亚烷基、C2-6烯基、-OC1-6亚烷基、-OC1-6亚烷基-OC1-6亚烷基、-C1-6亚烷基-O-C1-6亚烷基或C1-6亚烷基-NH-；C is a connecting bond, C 1-6 alkylene group, C 2-6 alkenyl group, -OC 1-6 alkylene group, -OC 1-6 alkylene group -OC 1-6 alkylene group, -C 1- 6 alkylene-OC 1-6 alkylene or C 1-6 alkylene-NH-;
    D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、C3-10环烷基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基；D is a connecting bond, C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5 ~12-membered heteroaryl", C 3-10 cycloalkyl, substituted by one or more R 1-4 " contains 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12 members of O, S and N "Heteroaryl", or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N;
    E为连接键或C1-6亚烷基。E is a connecting bond or C 1-6 alkylene group.
  3. 如权利要求1所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，The morpholinoquinazoline compound represented by formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug as claimed in claim 1, characterized in that,
    R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或C3-8环烷基；R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
    R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
    A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
    B为连接键、C3-10环烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-2取代的“含1～3个杂原子，杂原子选自O和N的4～10元杂环烷基”、被一个或多个R1-3取代的C6-20芳基、或、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”；B is a connecting bond, C 3-10 cycloalkyl group, containing 1-3 heteroatoms, the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl groups, substituted by one or more R 1-2 Containing 1 to 3 heteroatoms, the heteroatoms are selected from O and N, 4 to 10-membered heterocycloalkyl", C 6-20 aryl group substituted by one or more R 1-3 , or, substituted by one or more R 1-3 Each R 1-4 substituted "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N";
    C为连接键或C1-6亚烷基；C is a connecting bond or C 1-6 alkylene group;
    D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20亚芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”；D is a connecting bond, C 6-20 aryl group, C 6-20 arylene group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5-12-membered heteroaryl", or "5-12-membered heteroaryl containing 1-4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
    E为连接键或C1-6亚烷基。E is a connecting bond or C 1-6 alkylene group.
  4. 如权利要求1-3任一项所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，The morpholinoquinazoline compound represented by formula I according to any one of claims 1 to 3, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug, characterized by lies in,
    A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
    和/或，B为连接键、C3-10环烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-2取代的“含1～3个杂原子，杂原子选自O和N的4～10元 杂环烷基”、被一个或多个R1-3取代的C6-20芳基、含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”；And/or, B is a connecting bond, C 3-10 cycloalkyl, containing 1-3 heteroatoms, the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl, surrounded by one or more R 1- 2- substituted "contains 1 to 3 heteroatoms, and the heteroatoms are selected from 4 to 10 elements of O and N "Heterocycloalkyl", a C 6-20 aryl group substituted by one or more R 1-3 , containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N. " 5-12 membered heteroaryl containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4, or, by one or more R 1-5 Substituted "8-12-membered benzoheterocyclenyl group containing 1-3 heteroatoms independently selected from O, S and N";
    和/或，C为连接键、C1-6亚烷基、C2-6烯基、-OC1-6亚烷基、-OC1-6亚烷基-OC1-6亚烷基、-C1-6亚烷基-O-C1-6亚烷基或C1-6亚烷基-NH-；And/or, C is a connecting bond, C 1-6 alkylene group, C 2-6 alkenyl group, -OC 1-6 alkylene group, -OC 1-6 alkylene group -OC 1-6 alkylene group, -C 1-6 alkylene-OC 1-6 alkylene or C 1-6 alkylene-NH-;
    和/或，D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20芳基、C3-10环烷基、被一个或多个R1-4取代的含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基；And/or, D is a connecting bond, C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , C 3-10 cycloalkyl group, substituted by one or more R 1- 4- substituted 5- to 12-membered heteroaryl groups containing 1 to 4 heteroatoms, the heteroatoms being selected from O, S and N, and "containing 1 to 4 heteroatoms, substituted by one or more R 1-4 " 5-12-membered heteroaryl with atoms selected from O, S and N, or 4-10-membered heterocycloalkyl containing 1-3 heteroatoms, and the heteroatoms are selected from O and N;
    和/或，E为连接键或C1-6亚烷基。And/or, E is a connecting bond or C 1-6 alkylene group.
  5. 如权利要求4所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，The morpholinoquinazoline compound represented by formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug as claimed in claim 4, characterized in that,
    当R1为C1-4烷基或被一个或多个卤素取代的C1-4烷基时，所述的C1-4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基；When R 1 is a C 1-4 alkyl group or a C 1-4 alkyl group substituted by one or more halogens, the C 1-4 alkyl group is methyl, ethyl, n-propyl, or isopropyl , n-butyl, sec-butyl, isobutyl or tert-butyl;
    和/或，当R1为C3-8环烷基时，所述的C3-8环烷基为环丙基、环丁基、环戊基、环己基或环庚基；And/or, when R 1 is a C 3-8 cycloalkyl group, the C 3-8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
    和/或，当R2为氢或-OC1-4烷基时，所述的-OC1-4烷基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基或叔丁氧基；And/or, when R 2 is hydrogen or -OC 1-4 alkyl, the -OC 1-4 alkyl is methoxy, ethoxy, n-propoxy, isopropoxy, n-butyl Oxygen, sec-butoxy, isobutoxy or tert-butoxy;
    和/或，当R1-1、R1-2、R1-3、R1-4、R1-5和R1-6独立地为卤素时，所述的卤素为氟、氯、溴或碘；And/or, when R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R1为被一个或多个卤素取代的C1-4烷基时，所述的卤素为氟、氯、溴或碘；And/or, when R 1 is a C 1-4 alkyl group substituted by one or more halogens, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，当R1为被一个或多个卤素取代的C1-4烷基时，所述的多个为两个或三个；And/or, when R 1 is a C 1-4 alkyl group substituted by one or more halogens, the plurality is two or three;
    和/或，当R3、R1-1、R1-2、R1-3、R1-4、R1-5和R1-6独立地为C1-6烷基时，所述的C1-6烷基为C1-4烷基；And/or, when R 3 , R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 and R 1-6 are independently C 1-6 alkyl, the The C 1-6 alkyl group is C 1-4 alkyl;
    和/或，当A为C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-时，所述的C1-6亚烷基为-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH(CH3)2-、-CH2CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-或-C(CH3)2CH2-；And/or, when A is C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-, the C 1-6 alkylene is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH (CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 - or -C(CH 3 ) 2 CH 2 -;
    和/或，当A为-OC1-6亚烷基时，C1-6亚烷基端与B相连；And/or, when A is -OC 1-6 alkylene, the C 1-6 alkylene end is connected to B;
    和/或，当B为C3-10环烷基时，所述的C3-10环烷基为环丙基、环丁基、环戊基或环己基； And/or, when B is a C 3-10 cycloalkyl group, the C 3-10 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
    和/或，当B为“含有1-3个杂原子，杂原子独立地选自O，S和N的4～10元杂环烷基”或被一个或多个取代的“含有1-3个杂原子，杂原子独立地选自O，S和N的4～10元杂环烷基”时，所述的“含有1-3个杂原子，杂原子独立地选自O，S和N的4～10元杂环烷基”为“含有1-2个杂原子，杂原子独立地选自N的3-6元杂环烷基”；And/or, when B is "4-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from O, S and N" or "containing 1-3" substituted by one or more When "a 4-10-membered heterocycloalkyl group with heteroatoms independently selected from O, S and N", the "contains 1-3 heteroatoms, and the heteroatoms are independently selected from O, S and N" "4-10-membered heterocycloalkyl" is "3-6-membered heterocycloalkyl containing 1-2 heteroatoms, and the heteroatoms are independently selected from N";
    和/或，当B为被一个或多个R1-2取代的“含有1-3个杂原子，杂原子独立地选自O，S和N的4～10元杂环烷基”时，所述的R1-2为卤素；And/or, when B is "a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from O, S and N" substituted by one or more R 1-2 , The R 1-2 is halogen;
    和/或，当B为被一个或多个R1-3取代的C6-20芳基时，所述的C6-20芳基为苯基；And/or, when B is a C 6-20 aryl group substituted by one or more R 1-3 , the C 6-20 aryl group is phenyl;
    和/或，当B为被一个或多个R1-3取代的C6-20芳基时，所述的R1-3为卤素；And/or, when B is a C 6-20 aryl group substituted by one or more R 1-3 , said R 1-3 is halogen;
    和/或，当B为“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，所述的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”为“含有1-2个N的5-6元杂芳基”；And/or, when B is "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N", or a "containing 1" substituted by one or more R 1-4 When the "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S, and N," the "containing 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12-membered heteroaryls of O, S, and N. "12-membered heteroaryl" means "5-6-membered heteroaryl containing 1-2 N's";
    和/或，当B为被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，所述的R1-4为卤素；And/or, when B is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 , the described R 1-4 is halogen;
    和/或，当B为被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，所述的B为 And/or, when B is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 , the described B is
    和/或，当B为被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”时，所述的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”为“含1个N原子的9～10元苯并杂环烯基”；And/or, when B is "8-12 membered benzoheterocyclenyl group containing 1-3 heteroatoms independently selected from O, S and N" substituted by one or more R 1-5 When, the "8- to 12-membered benzoheterocyclenyl group containing 1 to 3 heteroatoms, and the heteroatoms are independently selected from O, S and N" is "9- to 10-membered benzene group containing 1 N atom and heterocycloalkenyl”;
    和/或，当B为被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”时，所述的R1-5为卤素；And/or, when B is "8-12 membered benzoheterocyclenyl group containing 1-3 heteroatoms independently selected from O, S and N" substituted by one or more R 1-5 When, the R 1-5 is halogen;
    和/或，当B为被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”时，所述的B为 And/or, when B is "8-12 membered benzoheterocyclenyl group containing 1-3 heteroatoms independently selected from O, S and N" substituted by one or more R 1-5 When, the B is
    和/或，当C为C1-6亚烷基、-OC1-6亚烷基-OC1-6亚烷基、C1-6亚烷基-O-C1-6亚烷基或C1-6亚烷基-NH-时，所述的C1-6亚烷基为-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH(CH3)2-、-CH2CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-或-C(CH3)2CH2-；and/or, when C is C 1-6 alkylene, -OC 1-6 alkylene-OC 1-6 alkylene, C 1-6 alkylene-OC 1-6 alkylene or C 1 When -6 alkylene group -NH-, the C 1-6 alkylene group is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -or -C(CH 3 ) 2 CH 2 -;
    和/或，当C为-OC1-6亚烷基或-OC1-6亚烷基-OC1-6亚烷基时，-O端与B相连； And/or, when C is -OC 1-6 alkylene or -OC 1-6 alkylene-OC 1-6 alkylene, the -O end is connected to B;
    和/或，当C为C1-6亚烷基-NH-时，C1-6亚烷基端与B相连；And/or, when C is C 1-6 alkylene-NH-, the C 1-6 alkylene end is connected to B;
    和/或，当C为C2-6烯基时，所述的C2-6烯基为乙烯基、丙烯基或烯丙基；And/or, when C is C 2-6 alkenyl, the C 2-6 alkenyl is vinyl, propenyl or allyl;
    和/或，当D为C6-20芳基或被一个或多个R1-3取代的C6-20芳基时，所述的C6-20芳基为苯基或萘基；And/or, when D is a C 6-20 aryl group or a C 6-20 aryl group substituted by one or more R 1-3 , the C 6-20 aryl group is phenyl or naphthyl;
    当D为C6-20芳基或被一个或多个R1-3取代的C6-20芳基时，所述的R1-3为卤素；When D is a C 6-20 aryl group or a C 6-20 aryl group substituted by one or more R 1-3 , the R 1-3 is halogen;
    和/或，当D为“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”或被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，所述的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”为“含1～2个杂原子，杂原子选自O和N的5～6元杂芳基”；And/or, when D is "a 5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" or a "containing 1 to 12-membered heteroaryl group" substituted by one or more R 1-4 When "4 heteroatoms are selected from 5 to 12-membered heteroaryl groups of O, S and N", the "contains 1 to 4 heteroatoms, and the heteroatoms are selected from 5 to 12 members of O, S and N""One-memberedheteroaryl" is "5-6 membered heteroaryl containing 1 to 2 heteroatoms, and the heteroatoms are selected from O and N";
    和/或，当D为被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”时，R1-4为卤素；And/or, when D is a "5- to 12-membered heteroaryl group containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 , R 1- 4 is halogen;
    和/或，当D为“含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基”时，所述的D为“含有1-2个杂原子，杂原子选自O和N的5～6元杂环烷基”；And/or, when D is "a 4-10-membered heterocycloalkyl group containing 1-3 heteroatoms, and the heteroatoms are selected from O and N", the D is "containing 1-2 heteroatoms, and the heteroatoms are selected from O and N." 5-6 membered heterocycloalkyl with atoms selected from O and N";
    和/或，当E为C1-6亚烷基时，所述的C1-6亚烷基为-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(CH3)CH2-、-CH(CH3)2-、-CH2CH2CH2CH2-、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-或-C(CH3)2CH2-。And/or, when E is a C 1-6 alkylene group, the C 1-6 alkylene group is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH (CH 3 )CH 2 -, -CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -or-C(CH 3 ) 2 CH 2 -.
  6. 如权利要求1所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，The morpholinoquinazoline compound represented by formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug as claimed in claim 1, characterized in that,
    A为-O-、-CH2-、-CH2NH-、-OCH2-、-OCH2CH2-、 A is -O-, -CH 2 -, -CH 2 NH-, -OCH 2 -, -OCH 2 CH 2 -,
    和/或，B为连接键、 and/or, B is the connection key,
    和/或，C为连接键、-CH2-、-OCH2CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-OCH2CH2OCH2-、-CH2CH2NH-或-C(CH3)2OCH2-；and/or, C is a connecting bond, -CH 2 -, -OCH 2 CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -OCH 2 CH 2 OCH 2 -, -CH 2 CH 2 NH- or -C(CH 3 ) 2 OCH 2 -;
    和/或，D为连接键、 and/or, D is the connection key,
    和/或，E为连接键或-CH2-。and/or, E is a connecting bond or -CH 2 -.
  7. 如权利要求6所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，The morpholinoquinazoline compound represented by formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug as claimed in claim 6, characterized in that,
    -D-C-B-A-为 -DCBA-for
  8. 如权利要求6所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，The morpholinoquinazoline compound represented by formula I, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug as claimed in claim 6, characterized in that,
    -E-D-C-B-A-为 -edcba-for
  9. 如权利要求1-8任一项所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，所述的如式I所示的吗啉基喹唑啉类化合物为下述任一结构：


    The morpholinoquinazoline compound represented by formula I according to any one of claims 1 to 8, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug, characterized by The morpholinoquinazoline compound represented by Formula I has any of the following structures:


  10. 一种化合物：








    A compound:








  11. 一种药物组合物，其包含物质A和药用辅料；所述的物质A为治疗有效量的如权利要求1-9任一项所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药。A pharmaceutical composition, which includes substance A and pharmaceutical excipients; the substance A is a therapeutically effective amount of the morpholinoquinazolines shown in Formula I as described in any one of claims 1-9 Compounds, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof.
  12. 一种物质A在制造预防或治疗涉及细胞异常增殖、分化或存活的疾病的药物中的应用；所述的物质A为治疗有效量的如权利要求1-9任一项所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药；所述的疾病为癌症；所述癌症为由恶性新生细胞的增殖而引发的肿瘤、赘生物、肉瘤、白血病或淋巴瘤。An application of substance A in the manufacture of drugs for the prevention or treatment of diseases involving abnormal cell proliferation, differentiation or survival; the substance A is a therapeutically effective amount of formula I as described in any one of claims 1-9 The indicated morpholinoquinazoline compounds, their pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof; the disease is cancer; the cancer is caused by the proliferation of malignant neoblasts tumors, tumors, sarcomas, leukemias, or lymphomas.
  13. 一种物质A在制造用于减少受试者体内循环的淋巴细胞数目的药物中的应用；所述的物质A为治疗有效量的如权利要求1-9任一项所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药；所述受试者优选包括患血液性疾病的受试者，患有自身免疫性疾病的受试者，和需要调节免疫反应的受试者。An application of substance A in the manufacture of a medicament for reducing the number of lymphocytes circulating in a subject; the substance A is a therapeutically effective amount of formula I as described in any one of claims 1-9 The morpholinoquinazoline compounds shown, their pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof; the subjects preferably include subjects suffering from hematological diseases, patients with Subjects with autoimmune diseases, and subjects who need to modulate their immune response.
  14. 如权利要求1所述的如式I所示的吗啉基喹唑啉类化合物、其药学上可接受的盐、溶剂合物、多晶型物或其前药，其特征在于，其为方案一或方案二：The morpholinoquinazoline compound represented by formula I as claimed in claim 1, its pharmaceutically acceptable salt, solvate, polymorph or its prodrug, characterized in that it is a scheme One or option two:
    方案一：R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或，C3-8环烷基；Option 1: R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
    R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
    A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
    B为连接键、C3-10环亚烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-3取代的C6-20芳基、含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-5取代的“含1～3个杂原子，杂原子独立地选自O、S和N的8～12元苯并杂环烯基”；B is a connecting bond, C 3-10 cycloalkylene group, containing 1-3 heteroatoms, the heteroatoms are selected from O and N 4-10 membered heterocycloalkyl groups, substituted by one or more R 1-3 C 6-20 aryl, 5-12 membered heteroaryl containing 1 to 4 heteroatoms, heteroatoms selected from O, S and N, "containing 1 to 4" substituted by one or more R 1-4 Heteroatom, the heteroatom is selected from O, S and N 5-12 membered heteroaryl" or "containing 1-3 heteroatoms substituted by one or more R 1-5 , the heteroatom is independently selected from O, S and N 8-12 membered benzoheterocyclenyl";
    C为连接键、C1-6亚烷基、C2-6烯基、-OC1-6亚烷基、-OC1-6亚烷基-OC1-6亚烷基、-C1-6亚烷基-O-C1-6亚烷基或C1-6亚烷基-NH-；C is a connecting bond, C 1-6 alkylene group, C 2-6 alkenyl group, -OC 1-6 alkylene group, -OC 1-6 alkylene group -OC 1-6 alkylene group, -C 1- 6 alkylene-OC 1-6 alkylene or C 1-6 alkylene-NH-;
    D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、C3-10环烷基、被一个或多个R1-4取代的“含1～4 个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基；D is a connecting bond, C 6-20 aryl group, C 6-20 aryl group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5 ~12-membered heteroaryl", C 3-10 cycloalkyl, "containing 1 to 4 substituted by one or more R 1-4 heteroatoms, the heteroatoms are selected from 5-12-membered heteroaryl groups of O, S and N, or "containing 1-3 heteroatoms, and the heteroatoms are selected from 4-10-membered heterocycloalkyl groups of O and N;
    E为连接键；E is the connection key;
    方案二：R1为C1-4烷基、被一个或多个卤素取代的C1-4烷基、或C3-8环烷基；Option 2: R 1 is C 1-4 alkyl, C 1-4 alkyl substituted by one or more halogens, or C 3-8 cycloalkyl;
    R2为氢或-OC1-4烷基；R 2 is hydrogen or -OC 1-4 alkyl;
    A为-O-、C1-6亚烷基、-OC1-6亚烷基或C1-6亚烷基-NH-；A is -O-, C 1-6 alkylene, -OC 1-6 alkylene or C 1-6 alkylene -NH-;
    B为连接键、C3-10环烷基、含有1-3个杂原子，杂原子选自O和N的4～10元杂环烷基、被一个或多个R1-3取代的C6-20芳基、或、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”；B is a connecting bond, C 3-10 cycloalkyl group, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from O and N, C substituted by one or more R 1-3 6-20 aryl, or "5-12 membered heteroaryl containing 1 to 4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
    C为连接键或C1-6亚烷基；C is a connecting bond or C 1-6 alkylene group;
    D为连接键、C6-20芳基、被一个或多个R1-3取代的C6-20亚芳基、“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”、或、被一个或多个R1-4取代的“含1～4个杂原子，杂原子选自O、S和N的5～12元杂芳基”；D is a connecting bond, C 6-20 aryl group, C 6-20 arylene group substituted by one or more R 1-3 , "containing 1 to 4 heteroatoms, and the heteroatoms are selected from O, S and N 5-12-membered heteroaryl", or "5-12-membered heteroaryl containing 1-4 heteroatoms selected from O, S and N" substituted by one or more R 1-4 ;
    E为连接键；E is the connection key;
    其它基团的定义如权利要求1-8任一项所述。 Other groups are as defined in any one of claims 1-8.
PCT/CN2023/114208 2022-08-24 2023-08-22 Morpholinyl quinazoline compound, and pharmaceutical composition and use thereof WO2024041519A1 (en)

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CN102970868A (en) * 2010-04-16 2013-03-13 柯瑞斯公司 Treatment of cancers having K-RAS mutations
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