WO2024041519A1 - Composé morpholinyl quinazoline, composition pharmaceutique et utilisation associée - Google Patents

Composé morpholinyl quinazoline, composition pharmaceutique et utilisation associée Download PDF

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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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English (en)
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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Priority to CN202380016569.4A priority Critical patent/CN118525011A/zh
Publication of WO2024041519A1 publication Critical patent/WO2024041519A1/fr

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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

L'invention concerne un composé morpholinyl quinazoline représenté par la formule I, ou un sel pharmaceutiquement acceptable, un solvate, un polymorphe ou un promédicament de celui-ci. Le composé morpholinyl quinazoline a une double activité inhibitrice contre PI3Kδ et HDAC, et est prospectif pour de meilleurs effets thérapeutiques et des applications plus larges.
PCT/CN2023/114208 2022-08-24 2023-08-22 Composé morpholinyl quinazoline, composition pharmaceutique et utilisation associée WO2024041519A1 (fr)

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WO2018237007A1 (fr) * 2017-06-22 2018-12-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de la phosphoinositide 3-kinase et de l'histone désacétylase pour le traitement du cancer
CN110950844A (zh) * 2018-09-27 2020-04-03 上海璎黎药业有限公司 吗啉基喹唑啉类化合物的晶型、其制备方法及应用
CN111646973A (zh) * 2019-03-04 2020-09-11 中国医学科学院药物研究所 多取代的喹唑啉类衍生物及其制备方法、药物组合物和用途
CN113444073A (zh) * 2020-03-26 2021-09-28 上海璎黎药业有限公司 吗啉基喹唑啉类化合物的晶型ⅲ、其制备方法及应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101889015A (zh) * 2007-10-05 2010-11-17 S*Bio私人有限公司 嘧啶取代的嘌呤衍生物
CN102970868A (zh) * 2010-04-16 2013-03-13 柯瑞斯公司 具有k-ras突变的癌症的治疗
CN103374021A (zh) * 2012-04-21 2013-10-30 通化济达医药有限公司 含有锌结合基的吡啶并嘧啶类HDAC和mTOR抑制剂
CN104557872A (zh) * 2013-10-16 2015-04-29 上海璎黎药业有限公司 稠合杂环化合物、其制备方法、药物组合物和用途
WO2018237007A1 (fr) * 2017-06-22 2018-12-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de la phosphoinositide 3-kinase et de l'histone désacétylase pour le traitement du cancer
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CN111646973A (zh) * 2019-03-04 2020-09-11 中国医学科学院药物研究所 多取代的喹唑啉类衍生物及其制备方法、药物组合物和用途
CN113444073A (zh) * 2020-03-26 2021-09-28 上海璎黎药业有限公司 吗啉基喹唑啉类化合物的晶型ⅲ、其制备方法及应用

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