WO2023143482A1 - Composé ou sel de 2-aminopyrimidine, son procédé de préparation et son utilisation - Google Patents

Composé ou sel de 2-aminopyrimidine, son procédé de préparation et son utilisation Download PDF

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WO2023143482A1
WO2023143482A1 PCT/CN2023/073500 CN2023073500W WO2023143482A1 WO 2023143482 A1 WO2023143482 A1 WO 2023143482A1 CN 2023073500 W CN2023073500 W CN 2023073500W WO 2023143482 A1 WO2023143482 A1 WO 2023143482A1
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alkyl
halogen
cycloalkyl
membered
amino
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PCT/CN2023/073500
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Chinese (zh)
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王永辉
余发志
程耀邦
陈伟
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上海辉启生物医药科技有限公司
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to 2-aminopyrimidine compounds and their pharmaceutically acceptable salts, tautomers, stereoisomers, solvates or prodrugs, their preparation methods, and their pharmaceutical compositions.
  • the present invention also relates to methods for treating or preventing cyclin-dependent kinase 12 (CDK12)-related diseases or disorders, and the use of the compound in the preparation of medicaments for treating or preventing CDK12-related diseases or disorders.
  • CDK12 cyclin-dependent kinase 12
  • CDKs Cyclin-dependent kinases
  • CDK12 cyclin-dependent kinase 12
  • the gene encoding cyclin-dependent kinase 12 is located on autosome 17, encoding 1490 amino acids, and the protein molecular weight is 164kDa.
  • the main structure includes proline-rich anchor structures (proline-rich motifs, PRM), Arginine/serine rich motifs (RS) and a catalytic kinase domain.
  • CDK12 is currently known to have three main functions: (1) CDK12 phosphorylates RNA polymerase PoL II to promote transcription elongation; (2) CDK12 interacts with RNA processing factors to regulate splicing; (3) CDK12 mediates transcriptional RNA Polyadenylation of introns by polymerase II phosphorylation and mRNA 3'-end processing.
  • CDK12 regulates splicing of exons by localizing in nuclear speckles and pre-mRNA splice bodies. Overall, CDK12 is mainly involved in DNA damage response or stress response by regulating genome transcription and expression.
  • CDK12 is considered to be involved in the transcription elongation response of genes with long gene length, and affects the expression of genes such as BRCA1, ATR, FANCD2 (Blazek D. et al., Genes Dev., 2011, 25, 2158-2172). All these genes are a group of genes involved in DNA damage response (DDR), mainly involved in maintaining the stability of genomic DNA through DNA repair mechanism. Inhibition of CDK12 reduces the expression of DDR-related genes, thereby inhibiting DNA repair responses. As a result, the damaged DNA of cancer cells cannot be repaired, and the growth and survival of cancer cells are inhibited.
  • DDR DNA damage response
  • CDK12 has specific contextual roles in tumor and cancer development, providing effective therapeutic approaches.
  • THZ531 is a covalent inhibitor selective for CDK12/13 (European Journal of Medicinal Chemistry 221(2021) 113481).
  • WO2019193509A1, EP3782986A1, Bioorg.Med.Chem.Lett.25(17), 3420-3435(2015)) etc. reported other types of CDK12 inhibitors respectively.
  • the small molecule inhibitors of CDK12 reported so far have many hidden dangers of druggability: for example, the metabolic stability of mouse liver microsomes is poor, the exposure in vivo is low, and the metabolic half-life is short.
  • the current small-molecule inhibitors of CDK12 basically show a considerable inhibitory effect on CDK13, and there are potential safety issues. Moreover, studies have shown that the existing small molecule inhibitors of CDK12 induce the generation of drug-resistant cell lines soon after administration (Jiang B. et al., Nat. Chem. Bio. 2021, 17, 675-683.).
  • PROTACs Proteolysis-targeting chimeras
  • PROTACs consist of three functional structures: (1) a part that can bind to a target protein; (2) a part that can bind to E3 ubiquitin ligase; and (3) a connecting chain between the first two parts.
  • PROTACs can simultaneously bind the target protein and E3 ubiquitin ligase, so that the target protein that could not bind to E3 can bind to E3 and be ubiquitinated, and then be recognized and degraded by the proteasome (Angew.Chem.Int.Ed.Engl. , 2016, 55(6), 1996-1973).
  • the bifunctional compound that binds both the target protein CDK12 and E3 ubiquitin ligase, so as to target and ubiquitinate CDK12, induce proteasome degradation of CDK12, and be used for treating related diseases or conditions. More advantageously, the bifunctional compound has good CDK12 specificity, improved physical and chemical properties and/or improved pharmacokinetic properties. Moreover, through the development of CDK12 degradation agents, problems such as drug resistance mutations of existing CDK12 small molecule inhibitors have been overcome.
  • the present inventors unexpectedly found that the compound of the present invention can bind to both the target protein CDK12 and E3 ubiquitin ligase, thereby targeting and ubiquitinating CDK12, inducing proteasomal degradation of CDK12, and having good CDK12 degradation activity And good activity of inhibiting the proliferation of cancer cells.
  • the inventors also unexpectedly found that the compounds of the present invention have good CDK12 specificity, improved physical and chemical stability and/or improved pharmacokinetic properties such as improved metabolic stability, and can be well formulated into medicines.
  • the compound of the present invention is not easy to cause drug resistance mutations, and overcomes the defects of known small molecule inhibitors of CDK12.
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug is provided.
  • a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier, diluent or excipient.
  • a compound of the invention for use in the treatment or prevention of a CDK12-associated disease or disorder.
  • a method of treating or preventing a CDK12-associated disease or condition in an individual comprising administering to the individual an effective amount of a compound of the invention.
  • the use of the compound of the present invention in the preparation of a medicament for treating or preventing CDK12-related diseases or disorders is provided.
  • a compound of the invention in combination with another active agent.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof,
  • X is N, C or CR x1 ;
  • Y is each independently O, N, CR y1 , CR y1 R y2 or NR y3 ;
  • Z is each independently O, N, CR z1 , CR z1 R z2 or NR z3 ;
  • n and n are each independently 0, 1 or 2, and m+n ⁇ 2;
  • the two Zs can be the same or different; when n is 2, the two Ys can be the same or different;
  • R x1 is selected from H, hydroxyl, halogen, CN or C 1-6 alkyl;
  • R y1 , R y2 , R z1 , R z2 and R 4 are each independently selected from H, halogen, CN, NR 6 R 7 , oxo, C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl, -C 1-3 alkylene-C 3-8 cycloalkyl, or -OC 1-3 alkylene-C 3-8 cycloalkyl , each of the C 1-6 alkyl, C 1-3 alkylene and C 3-8 cycloalkyl is optionally substituted by a group selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl ;
  • Ry3 and Rz3 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, -CO-C 1-6 alkyl, nitrogen protecting group;
  • the ring may be saturated, partially unsaturated, or aromatic
  • R 2 is selected from hydrogen, halogen, CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl and cyclopropyl;
  • R is selected from H; C 1-6 alkyl optionally substituted by halogen, hydroxyl, CN and/or C 3-8 cycloalkyl; optionally substituted by halogen, CN and/or C 3-8 cycloalkyl C 3-8 cycloalkyl; optionally one or more R 8 substituted 3-10 membered heterocyclic hydrocarbon group, one or more R 9 substituted C 6-10 aryl, optionally one Or multiple R 9 substituted 5-10 membered heteroaryls;
  • R 6 and R 7 are each independently selected from H; C 1-6 alkyl, C 3-8 cycloalkyl or 3-10 membered heterocyclic hydrocarbon group, each of which is optionally replaced by one or more selected from halogen, CN, Substituents of OH, C 1-6 alkyl and/or C 3-8 cycloalkyl; C 6-10 aryl or 5-7 membered heteroaryl, each of which is optionally selected from one or more halogen , CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-3 alkylene-C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OC 1-3 alkylene-C 3-8 cycloalkyl, -SO-C 1-6 alkyl, -SO 2 -C 1-6 alkyl, -SO-C 3-8 cycloalkyl, -SO 2 -C 3-8
  • R 8 is selected from halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy;
  • R 10a , R 10b , R 10c , R 10d , R 10e are each independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic hydrocarbon group, C 6-10 aryl and 5 -10 membered heteroaryl;
  • R 11 and R 12 are each independently selected from C 1-6 alkyl or C 3-8 cycloalkyl
  • L is an absent or saturated or partially unsaturated divalent C 1-24 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently selected from the group consisting of -O-, -CO-, - NR L3 -, -SO-, -SO 2 - and/or units of 3-12 membered cyclic groups are replaced, and L is optionally replaced by one or more independently selected from deuterium, halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 4-8 membered heterocyclic hydrocarbon groups containing oxygen atoms or nitrogen atoms, and C 3-8 cycloalkyl substituents, Wherein R L3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or nitrogen protecting group; And wherein, when the two cyclic groups in the linking base L are adjacent , which optionally together form a fuse
  • E is the E3 ubiquitin ligase binding moiety.
  • X is N, C or CH.
  • each Y is independently O, N, CH or CH2 , preferably N, CH or CH2 .
  • each Z is independently O, N, CH or CH2 , preferably N, CH or CH2 .
  • m is 1 and n is 0. In other embodiments, m is 1 and n is 1. In other embodiments, m is 0 and n is 1. In other embodiments, m is 0 and n is 2. In other embodiments, m is 2 and n is 0.
  • compounds of Formula (I) of the present invention have the structure of Formula (Ia):
  • each variable is as defined herein.
  • Each may be saturated, partially unsaturated, or aromatic.
  • the selection of X, Y, Z and substituents on the ring should conform to the rules of valence and be chemically feasible, which can be routinely determined by those skilled in the art. When vacant valences are shown on a ring member, it indicates that an unmarked hydrogen atom is attached to the ring member.
  • Moieties are subunit moieties derived from the following: cyclobutane, azetidine, oxetane, cyclopentane, azacyclopentane, oxolane, diazolane, cyclo Pentene, cyclopentadiene, pyrrole, pyrazole, imidazole, triazole, furan or oxazole.
  • said moiety is a subunit moiety derived from: azacyclopentane, pyrrole, pyrazole, triazole.
  • Sections can be selected from:
  • Sections can be selected from:
  • R 4 is selected from H, halogen, CN, oxo, C 1-6 alkyl, or C 3-8 cycloalkyl.
  • R 4 is selected from H, halogen, CN, oxo or C 1-3 alkyl. More preferably, R4 is hydrogen.
  • R is selected from H, halogen, CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, and C 1-3 haloalkyl.
  • R 2 is H, halogen, CN or C 1-3 haloalkyl. More preferably, R2 is H, halogen, CN or CF3 , most preferably halogen. In some preferred embodiments, R 2 is halogen or C 1-3 haloalkyl, preferably Cl or CF 3 .
  • R 1 and R 3 are each independently selected from H; halogen; CN; OH; NR 6 R 7 ; C 1-6 alkyl , optionally substituted by one or more R 8 ; -10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by one or more R 9 .
  • R 6 is H.
  • each R 8 is independently selected from halogen, CN, OH, C 1-6 alkyl, and C 1-6 alkoxy.
  • each R 8 is independently selected from halogen, CN, OH, C 1-3 alkyl and C 1-3 alkoxy. More preferably, each R8 is independently selected from halogen and OH.
  • one of R and R is H, and the other is selected from H, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, phenyl, halophenyl,
  • one of R and R is H, and the other is selected from H, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, phenyl, halophenyl,
  • the formula (I) has the structure of formula (Ib):
  • each variable is as defined herein.
  • the linker L is absent or is a saturated or partially unsaturated divalent C 1-24 hydrocarbon chain, preferably a C 1-18 hydrocarbon chain, more preferably a C 1-12 hydrocarbon chain, wherein the hydrocarbon chain One or more hydrocarbon chain units of are optionally independently replaced by -O-, -CO-, -NH-, -SO-, -SO 2 - and/or 3-10 membered cyclic groups, and wherein L is any One or more are independently selected from deuterium, halogen, CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, 4- Substituents of 6-membered heterocyclic hydrocarbon group and C 3-6 cycloalkyl group; and wherein, when the two cyclic groups in the linker L are adjacent, they optionally form a condensed ring, a spiro ring or a bridged ring together form.
  • the cyclic groups that are part of L are each independently selected from divalent groups derived from: C 3-8 cycloalkane; 3-8 membered nitrogen-containing heterocyclic hydrocarbon; C 6-10 aromatic ring; 5 -7-membered nitrogen-containing heteroaromatic ring; wherein when two cyclic groups are adjacent, they optionally form a condensed ring, a spiro ring or a bridged ring together; and the cyclic group is optionally surrounded by one or more Substituents independently selected from deuterium, halogen, OH, NH 2 are substituted.
  • the cyclic groups that are part of L are each independently selected from divalent groups derived from: C 3-8 cycloalkane; 3-8 membered nitrogen-containing heterocyclic hydrocarbon; C 6-10 aromatic ring; 5 - a 7-membered nitrogen-containing heteroaryl ring; wherein when two cyclic groups are adjacent, they optionally together form a condensed ring, a spiro ring or a bridged ring.
  • the cyclic groups that are part of L are each independently selected from divalent groups selected from the group consisting of: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclohexane, azepine Cyclopropane, azetidine, pyrrole, dihydropyrrole, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, triazolidine, tetrazole, tetrazolidine , pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyridazine, dihydropyridazine, tetrahydropyridazine, hexahydropyridazine, pyrimidine, dihydropyrimidine, tetrahydropyrimidine,
  • L is a saturated or partially unsaturated divalent C 1-18 hydrocarbon chain, preferably a C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of said hydrocarbon chain are optionally independently represented by - O-, -CO-, -NH-, -SO-, -SO 2 -, 3-8 membered nitrogen-containing heterocycloalkanes and/or 5-7 membered nitrogen-containing heteroaromatic rings, and wherein, when the linker L When two cyclic groups in are adjacent to each other, they optionally form a condensed ring, a spiro ring or a bridged ring together.
  • L is a saturated or partially unsaturated divalent C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently represented by -O-, -CO-, -NH- and/or 4-7 membered nitrogen-containing heterocycloalkanes (such as piperidine ring, piperazine ring, tetrahydropyrrole, azetidine, etc.) are replaced, and wherein, when the two rings in the linker L When the like groups are adjacent, they optionally together form a fused ring, a spiro ring or a bridged ring.
  • nitrogen-containing heterocycloalkanes such as piperidine ring, piperazine ring, tetrahydropyrrole, azetidine, etc.
  • the units used to replace the hydrocarbon chain units may or may not be adjacent when there is more than one.
  • a cyclic group that is part of L may be attached to the rest of the linker L via any available ring member on the ring, as chemically feasible.
  • two cyclic groups in the linker L are adjacent, they together form a condensed ring, a spiro ring or a bridged ring, such as 7 containing one or more heteroatoms independently selected from N, O and/or S -10-membered bridge ring, spiro ring or condensed ring form, for example with form.
  • linker L may be on any chain unit, including on hydrocarbon chain units and/or on replacement units for hydrocarbon chain units.
  • L is selected from:
  • L is selected from:
  • L is selected from:
  • L is selected from:
  • L is selected from:
  • L is selected from:
  • L is selected from:
  • the 4-7 membered nitrogen-containing heterocycloalkane is piperazine ring, piperidine ring, tetrahydropyrrole or azetidine.
  • L is selected from:
  • the 4-7 membered nitrogen-containing heterocycloalkane is optionally substituted by OH;
  • the 4-7 membered nitrogen-containing heterocycloalkane is piperazine ring, piperidine ring, tetrahydropyrrole or azetidine.
  • L moiety can be attached to the remaining two moieties of the molecule in any direction, for example, from left to right, or from right to left.
  • E is an E3 ubiquitin ligase binding moiety. It can specifically bind E3 ubiquitin ligase in vivo. In some embodiments, E is a moiety of formula (Ea):
  • V is N or CR v , wherein R v is hydrogen or C 1-6 alkyl optionally substituted by one or more halogen, hydroxyl and/or CN; preferably, V is N, CH, -C(C 1 -6 alkyl)-; More preferably, V is N or CH;
  • W is a single bond, -NH-, -NH-CO-, -NH- Rw- , or Rw , wherein Rw is C 1-6 optionally substituted by one or more halogen, hydroxyl and/or CN Alkylene; preferably, W is a single bond, -NH-, -NH-CO-, -NH-C 1-6 alkylene-, or -C 1-6 alkylene-; more preferably, W is a single bond, -NH-, -NH-CO-, -NH-C 1-3 alkylene-, or -C 1-3 alkylene-;
  • R is selected from H, halogen, CN or C 1-6 alkyl; preferably, R is selected from H, halogen, CN or C 1-3 alkyl; and
  • B is a 3-10 membered cyclic group, preferably a C3-8 cycloalkyl group, a 3-10 membered heterocyclic hydrocarbon group (such as a 3-8 membered monocyclic heterocyclic hydrocarbon group or a 7-10 membered bicyclic heterocyclic hydrocarbon group) , C 6-10 aryl (for example phenyl) or 5-10 membered heteroaryl (for example 5-8 membered monocyclic heteroaryl or 7-10 membered bicyclic heteroaryl), any of the cyclic groups Optionally replaced by one or more R s2 ;
  • R s2 are each independently selected from halogen, CN, OH, oxo, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyloxy base, -C(O)-C 1-6 alkyl, -C(O)-C 3-6 cycloalkyl, -SO-C 1-6 alkyl, -SO-C 3-6 cycloalkyl, -SO 2 -C 1-6 alkyl, -SO 2 -C 3-6 cycloalkyl, C 6-10 aryl and halogenated C 6-10 aryl; preferably, each R s2 is independently selected from halogen , CN, OH, oxo,
  • V is N, CH, -C(C 1-6 alkyl)-, preferably N or CH.
  • W is a single bond, -NH-, -NH-CO-, -NH-C 1-6 alkylene-, or -C 1-6 alkylene-.
  • W is a single bond, -NH-, -NH-CO-, -NH-C 1-3 alkylene-, or -C 1-3 alkylene-.
  • B is C 3-8 cycloalkyl, 3-10 membered heterocycloalkyl (such as 3-8 membered monocyclic heterocycloalkyl or 7-10 membered bicyclic heterocycloalkyl), C 6-10 Aryl (eg phenyl) or 5-10 membered heteroaryl (eg 5-8 membered monocyclic heteroaryl or 7-10 membered bicyclic heteroaryl), each optionally substituted by one or more R s2 .
  • 3-10 membered heterocycloalkyl such as 3-8 membered monocyclic heterocycloalkyl or 7-10 membered bicyclic heterocycloalkyl
  • C 6-10 Aryl eg phenyl
  • 5-10 membered heteroaryl eg 5-8 membered monocyclic heteroaryl or 7-10 membered bicyclic heteroaryl
  • each R s2 is independently selected from halogen, CN, OH, oxo, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, and C 1 -6 alkoxy.
  • each R s2 is independently selected from halogen, CN, OH, NH 2 and C 1-6 alkyl.
  • the moiety of formula (Ea) has the structure of formula (Ea1):
  • V is N or CH; W is a single bond, -NH-, -NH-C 1-6 alkylene-, or -C 1-6 alkylene-; Ra is H; and q is 0. It will be appreciated that the moiety of formula (Ea1) is attached to the rest of the molecule through any available position on the right-hand phenyl ring.
  • the structure of formula (Ea1) is:
  • E has the structure of formula (Ea2):
  • R a is H, halogen, CN or C 1-6 alkyl; preferably H or C 1-3 alkyl;
  • U is -CO-, -CR u1 R u1 - or -CO-CR u1 R u1 -, wherein CR u1 and R u1 are each independently H or C 1-6 alkyl; preferably, U is -CO- or -CH2- ;
  • R s2 are each independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and C 1-6 alkoxy; preferably, R s2 are each independently selected from halogen, CN, OH, C 1-3 alkyl or C 1-3 haloalkyl; and
  • r 0, 1, 2, 3 or 4.
  • R a is H or C 1-3 alkyl.
  • U is -CO- or -CH 2 -.
  • R s2 is halogen, CN, OH, C 1-6 alkyl or C 1-6 haloalkyl, preferably halogen, CN, OH, C 1-3 alkyl or C 1-3 haloalkyl, more Halogen is preferred.
  • the structure of formula (Ea2) is:
  • the moiety of formula (Ea) has the structure of formula (Ea3):
  • P is N, C or CH
  • Q is N, NH, -CO-, -CR q1 R q1 - or -CO- CR q1 R q1 -, wherein CR q1 and R q1 are each independently H or C 1-6 alkyl such as C 1-3 alkane group; preferably, Q is N, NH, -CO- or -CH 2 -; and
  • R s2 is H or C 1-6 alkyl such as C 1-3 alkyl
  • V, W and Ra are as defined herein.
  • the structure of formula (Ea3) is:
  • E is a moiety of formula (Eb):
  • R S3 and R S4 are each independently selected from H; C 1-6 alkyl, C 3-8 cycloalkyl or 3-10 membered heterocyclic hydrocarbon group, each of which is optionally substituted by halogen or hydroxyl; C 6-10 aromatic or 5-10 membered heteroaryl, each of which is optionally substituted by one or more R 9 ; or R S3 , R S4 and the carbon atom to which they are attached together form C optionally substituted by one or more R 8 3-8 cycloalkyl;
  • R S5 is O, -NH-, C 3-8 cycloalkylene optionally substituted by one or more R 8 , C 6-10 arylene optionally substituted by one or more R 9 , optionally A 5-10 membered heteroarylene group substituted by one or more R 9 ;
  • R S6 and R S7 are each independently selected from H and C 1-6 alkyl optionally substituted by one or more R 8 ;
  • R S8 is H; Halogen ; CN; OH ; NO 2 ; -NR S9 R S10 ; -OR S11 ; -CONR S9 R S10 ; S10 ; C 1-6 alkyl, C 3-8 cycloalkyl or 3-10 membered heterocyclic hydrocarbon group, each of which is optionally substituted by one or more R 8 ; C 6-10 aryl or 5-10 membered heterocyclic Aryl, each of which is optionally substituted by one or more R 9 ;
  • R S9 and R S10 is independently hydrogen or C 1-6 alkyl optionally substituted by one or more R 8 .
  • Part E is selected from:
  • X is N, C or CH
  • Y is each independently N, CH or CH2 ;
  • Z is each independently N, CH or CH2 ;
  • n and n are each independently 0, 1 or 2, and m+n ⁇ 2;
  • the two Zs can be the same or different; when n is 2, the two Ys can be the same or different;
  • R is selected from H, halogen, CN and OH, more preferably H;
  • the ring may be saturated, partially unsaturated, or aromatic
  • R 2 is H, halogen, CN or C 1-3 haloalkyl
  • R 1 and R 3 are each independently selected from H; -NHR 7 ; C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl; phenyl optionally substituted by halogen; or 5- 10-membered heteroaryl, which is optionally substituted by one or more R 9 ;
  • L is an absent or saturated or partially unsaturated divalent C 1-18 hydrocarbon chain, preferably a C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently replaced by -O- , -CO-, -NH-, -SO-, -SO 2 - and/or 3-10 membered cyclic groups (for example derived from C 3-8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, C 6- 10 aryl or a divalent group of a 5-7 membered heteroaryl ring), and wherein L is optionally replaced by one or more independently selected from deuterium, halogen, CN, OH, NH 2 , C 1-3 alkyl , C 1-3 haloalkyl, C 1-3 hydroxyalkyl, a 4-6 membered heterocyclic hydrocarbon group containing an oxygen atom, and a C 3-6 cycloalkyl substituent; and wherein, when the linking group L When two cyclic groups
  • E is an E3 ubiquitin ligase binding moiety, preferably a moiety of formula (Ea), more preferably a moiety of formula (Ea1), (Ea2) or (Ea3).
  • X is N, C or CH
  • Y is each independently N, CH or CH2 ;
  • Z is each independently N, CH or CH2 ;
  • n and n are each independently 0, 1 or 2, and m+n ⁇ 2;
  • the two Zs can be the same or different; when n is 2, the two Ys can be the same or different;
  • R is selected from H, halogen, CN and OH, more preferably H;
  • the ring may be saturated, partially unsaturated, or aromatic
  • R 2 is H, halogen, CN or C 1-3 haloalkyl
  • R 1 and R 3 is H, and the other is H; -NHR 7 ; 5-10 yuan nitrogen-containing heteroaryl, such as 7-10 yuan nitrogen-containing heteroaryl, such as indolyl;
  • L is a saturated or partially unsaturated divalent C 1-18 hydrocarbon chain, preferably a C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently represented by -O-, -CO- , -NH-, -SO-, -SO 2 -, 3-8 membered nitrogen-containing heterocycloalkane and/or 5-7 membered nitrogen-containing heteroaromatic rings, and wherein, when the two rings in the linker L When the groups are adjacent, they optionally together form a fused ring, a spiro ring or a bridged ring; and
  • R a is H or C 1-3 alkyl, and U is -CO- or -CH 2 -.
  • X is N, C or CH
  • Y is each independently N, CH or CH2 ;
  • Z is each independently N, CH or CH2 ;
  • n and n are each independently 0, 1 or 2, and m+n ⁇ 2;
  • the two Zs can be the same or different; when n is 2, the two Ys can be the same or different;
  • R is selected from H, halogen, CN and OH, more preferably H;
  • the ring may be saturated, partially unsaturated, or aromatic
  • R 2 is H, halogen, CN or C 1-3 haloalkyl
  • R 1 and R 3 is H, and the other is H; -NHR 7 ; 5-10 yuan nitrogen-containing heteroaryl, such as 7-10 yuan nitrogen-containing heteroaryl, such as indolyl;
  • L is a saturated or partially unsaturated divalent C 1-18 hydrocarbon chain, preferably a C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently represented by -O-, -CO- , -NH-, -SO-, -SO 2 -, 3-8 membered nitrogen-containing heterocycloalkane and/or 5-7 membered nitrogen-containing heteroaromatic rings, and wherein, when the two rings in the linker L When the groups are adjacent, they optionally together form a fused ring, a spiro ring or a bridged ring; and
  • R a is H or C 1-3 alkyl, and U is -CO- or -CH 2 - ;
  • R s2 are each independently selected from halogen, CN, or C 1-3 alkyl, preferably halogen; and r is 0 or 1;
  • each R s2 is independently selected from halogen, and r is 0 or 1; more preferably, each R s2 is independently selected from F, and r is 0 or 1.
  • R 2 is H, halogen, CN or C 1-3 haloalkyl, preferably H, halogen, CN, CF 3 ; more preferably halogen;
  • R 1 and R 3 is H, and the other is H; -NHR 7 ; 5-10 yuan nitrogen-containing heteroaryl, such as 7-10 yuan nitrogen-containing heteroaryl, such as indolyl;
  • L is a saturated or partially unsaturated divalent C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently replaced by -O-, -CO-, -NH- and/or 4 -7-membered nitrogen-containing heterocycloalkane (such as piperidine ring, piperazine ring, tetrahydropyrrole, azetidine) replacement, and wherein, when the two cyclic groups in the linker L are adjacent, they Optionally together form a condensed ring, a spiro ring or a bridged ring (for example with in the form of ); and
  • R a is H or C 1-3 alkyl, and U is -CO- or -CH 2 -.
  • R 2 is H, halogen, CN or C 1-3 haloalkyl, preferably H, halogen, CN, CF 3 ; more preferably halogen;
  • R 1 and R 3 is H, and the other is H; -NHR 7 ; 5-10 yuan nitrogen-containing heteroaryl, for example 7-10 yuan nitrogen-containing heteroaryl, such as indolyl or 1H-pyrrole [ 2,3-[2,3-b]pyridine (1H-pyrrolo[2,3-b]pyridine);
  • L is a saturated or partially unsaturated divalent C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently replaced by -O-, -CO-, -NH- and/or 4 -7-membered nitrogen-containing heterocycloalkane (such as piperidine ring, piperazine ring, tetrahydropyrrole, azetidine) replacement, and wherein, when the two cyclic groups in the linker L are adjacent, they Optionally together form a condensed ring, a spiro ring or a bridged ring (for example with in the form of ); and
  • R a is H or C 1-3 alkyl, and U is -CO- or -CH 2 - ;
  • R s2 are each independently selected from halogen, CN, or C 1-3 alkyl, preferably halogen; and r is 0 or 1;
  • each R s2 is independently selected from halogen, and r is 0 or 1; more preferably, each R s2 is independently selected from F, and r is 0 or 1.
  • the compound of the invention is selected from the compounds of the Examples, such as:
  • a dash (“-") not between two letters or symbols indicates the point of attachment of a substituent.
  • -NR 6 R 7 means that the group is attached to the rest of the molecule through a nitrogen atom.
  • "-" can be omitted when the point of attachment of the substituent is obvious to those skilled in the art (eg, for halogen, hydroxyl, NR6R7 , etc.).
  • a dashed ring when used in a ring structure, it means that the ring structure may be saturated, partially unsaturated, or aromatic.
  • a valence bond passes through a ring, such as in In , it means that the ring is connected to other moieties through any available position on the ring.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Preferred halogens are fluorine and chlorine.
  • alkyl alone or as part of another group denotes a fully saturated straight or branched chain hydrocarbon group consisting of carbon and hydrogen atoms.
  • the alkyl group preferably has 1-12 carbon atoms (i.e. C 1-12 alkyl), more preferably 1-8 carbon atoms (i.e. C 1-8 alkyl), 1-6 carbon atoms (i.e. C 1-6 Alkyl), 1-4 carbon atoms (ie C 1-4 alkyl) or 1-3 carbon atoms (ie C 1-3 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (Pr) (including n-propyl and isopropyl), butyl (Bu) (including n-butyl, isopropyl butyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl, etc.), hexyl, heptyl, octyl, nonyl, decyl, dodecyl, etc.
  • alkylene denotes a fully saturated straight or branched chain divalent hydrocarbon group composed of carbon and hydrogen atoms.
  • the alkylene group preferably has 1-12 carbon atoms (i.e. C 1-12 alkylene), more preferably 1-8 carbon atoms (i.e. C 1-8 alkylene), 1-6 carbon atoms (i.e. C 1-6 alkylene), 1-4 carbon atoms (ie C 1-4 alkylene) or 1-3 carbon atoms (ie C 1-3 alkylene).
  • Representative examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.
  • alkenyl alone or as part of another group denotes a straight or branched chain hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one double bond.
  • Alkenyl preferably has 2-12 carbon atoms (ie C 2-12 alkenyl ) , more preferably 2-8 carbon atoms (ie C 2-8 alkenyl), 2-6 carbon atoms (ie C 2-6 alkenyl), 2-4 carbon atoms (i.e. C 2-4 alkenyl) or 2-3 carbon atoms (i.e. C 2-3 alkenyl).
  • alkenyl include, but are not limited to, vinyl, propenyl, allyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, and the like.
  • alkenylene alone or as part of another group denotes a straight or branched divalent hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one double bond.
  • Alkenylene preferably has 2-12 carbon atoms (ie C 2-12 alkenylene), more preferably 2-8 carbon atoms (ie C 2-8 alkenylene), 2-6 carbon atoms (ie C 2-6 alkenylene), 2-4 carbon atoms (ie C 2-4 alkenylene) or 2-3 carbon atoms (ie C 2-3 alkenylene).
  • Representative examples of alkenylene include, but are not limited to, ethenylene, propenylene, allylylene, butenylene, and the like.
  • alkynyl alone or as part of another group denotes a straight or branched chain hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one triple bond.
  • the alkynyl preferably contains 2-12 carbon atoms (ie C 2-12 alkynyl), more preferably 2-8 carbon atoms (ie C 2-8 alkynyl ), 2-6 carbon atoms (ie C 2-6 alkynyl), 2-4 carbon atoms (ie C 2-4 alkynyl) or 2-3 carbon atoms (ie C 2-3 alkynyl).
  • alkynyl include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentynyl, hexynyl, heptynyl, and the like.
  • alkynylene alone or as part of another group denotes a straight or branched divalent hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one triple bond.
  • Alkynylene preferably has 2-12 carbon atoms (i.e. C 2-12 alkynylene), more preferably 2-8 carbon atoms (i.e. C 2-8 alkynylene), 2-6 carbon atoms (i.e. C 2-6 alkynylene), 2-4 carbon atoms (ie C 2-4 alkynylene), or 2-3 carbon atoms (ie C 2-3 alkynylene).
  • Representative examples of alkynylene include, but are not limited to, ethynylene, propynylene, butynylene, and the like.
  • haloalkyl refers to a group as defined herein wherein one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by a halogen alkyl. It is understood that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different carbon atoms.
  • Haloalkyl is preferably C 1-12 haloalkyl, More preferably, it is C 1-8 haloalkyl, C 1-6 haloalkyl, C 1-4 haloalkyl or C 1-3 haloalkyl.
  • haloalkyl include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, dichlorofluoromethyl, 2 , 2-difluoroethyl, trifluoroethyl, trichloroethyl, difluorochloroethyl, difluoropropyl and trifluoropropyl, etc.
  • haloalkenyl and “haloalkynyl” refer to one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 7 hydrogen atoms, respectively.
  • hydroxyalkyl refers to a group as defined herein wherein one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by a hydroxyl group of alkyl.
  • the hydroxyalkyl group is preferably a C 1-12 hydroxyalkyl group, more preferably a C 1-8 hydroxyalkyl group, a C 1-6 hydroxyalkyl group, a C 1-4 hydroxyalkyl group or a C 1-3 hydroxyalkyl group.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.
  • alkoxy or "alkyloxy” are used interchangeably to denote an alkyl group as defined above attached through an oxygen bridge.
  • Alkoxy preferably has 1-12 carbon atoms (ie C 1-12 alkoxy), more preferably 1-8 carbon atoms (ie C 1-8 alkoxy), 1-6 carbon atoms (ie C 1-6 alkoxy), 1-4 carbon atoms (ie C 1-4 alkoxy) or 1-3 carbon atoms (ie C 1-3 alkoxy).
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, etc.), pentyloxy (including n-pentyloxy, isopentyloxy, neopentyloxy, etc.), hexyloxy, heptyloxy, octyloxy, nonyloxy, Decyloxy, etc.
  • haloalkoxy or "haloalkyloxy” are used interchangeably to denote a haloalkyl group as defined above attached through an oxygen bridge.
  • the haloalkoxy is preferably C 1-12 haloalkoxy, more preferably C 1-8 haloalkoxy, C 1-6 haloalkoxy, C 1-4 haloalkoxy or C 1-3 haloalkoxy.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or bicyclic hydrocarbon group. When a “cycloalkyl” is fully saturated, it may be referred to as a "cycloalkyl”.
  • Cycloalkyl or cycloalkyl preferably has 3-12 ring carbon atoms (ie C 3-12 cycloalkyl or C 3-12 cycloalkyl), more preferably 3-8 ring carbon atoms (ie C 3-8 cycloalkyl or C 3-8 cycloalkyl), most preferably 4-7 ring carbon atoms (ie C 4-7 cycloalkyl or C 4-7 cycloalkyl) or 3-6 ring carbon atoms (ie C 3-6 cycloalkyl or C 3-6 cycloalkyl).
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, base, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1.1]heptyl or bicyclo[3.2.1]octyl, etc.
  • cycloalkylene and cycloalkylene refer to cycloalkylene and cycloalkylene, respectively, as defined herein, except that they are divalent.
  • Cycloalkylene or cycloalkylene preferably has 3-12 ring carbon atoms (ie C 3-12 cycloalkylene or C 3-12 cycloalkylene), more preferably 3-8 ring carbon atoms (ie C 3 -8 cycloalkylene or C 3-8 cycloalkylene), most preferably 4-7 ring carbon atoms (i.e. C 4-7 cycloalkylene or C 4-7 cycloalkylene) or 3-6 ring carbon atom (ie C 3-6 cycloalkylene or C 3-6 cycloalkylene).
  • Cycloalkoxy or "cycloalkyloxy” are used interchangeably to denote a cycloalkyl group as defined above attached through an oxygen bridge.
  • Cycloalkoxy preferably has 3-12 ring carbon atoms (i.e. C 3-12 cycloalkoxy), more preferably 3-8 ring carbon atoms (i.e. C 3-8 cycloalkoxy), most preferably 3- 6 ring carbon atoms (ie C 3-6 cycloalkoxy).
  • cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopentenyloxy, cyclohexyloxy, cyclohexenyloxy, and the like.
  • cycloalkylalkyl or "cycloalkylalkyl-” denotes an alkyl group substituted by a cycloalkyl group, wherein cycloalkyl and alkyl are respectively as defined herein, with the point of attachment at the alkyl group.
  • the term may also be denoted “cycloalkyl-alkylene-", ie a cycloalkyl group attached through an alkylene group.
  • cycloalkylalkyl means substituted by C 3-12 cycloalkyl, preferably C 3-8 cycloalkyl, more preferably C 3-6 cycloalkyl C 1-12 alkyl, preferably C 1-8 alkyl, more preferably C 1-6 alkyl, C 1-4 alkyl or C 1-3 alkyl.
  • "cycloalkylalkyl” is C 3-6 cycloalkyl-C 1-6 alkyl-, ie, C 3-6 cycloalkyl-C 1-6 alkylene-.
  • alkoxyalkyl or "alkoxyalkyl-” denotes an alkyl group substituted by an alkoxy group, wherein alkoxy and alkyl are respectively as defined herein, and the point of attachment is at the alkyl group.
  • alkoxy-alkylene- ie, an alkoxy group attached through an alkylene group.
  • alkoxyalkyl represents C 1-12 alkoxy, preferably C 1-8 alkoxy , more preferably C 1-6 alkoxy, C 1-4 alkoxy or C 1-3 alkoxy C 1-12 alkyl group substituted, preferably C 1-8 alkyl group, more preferably C 1-6 alkyl group, C 1-4 alkyl group or C 1-3 alkyl group.
  • "alkoxyalkyl” is C 1-6 alkoxy-C 1-6 alkyl- or C 1-6 alkoxy-C 1-6 alkylene-.
  • alkylcycloalkyl or "alkylcycloalkyl-” denotes a cycloalkyl group substituted by an alkyl group, wherein alkyl and cycloalkyl are respectively as defined herein, with the point of attachment being the cycloalkyl group.
  • alkyl-cycloalkylene- ie, an alkyl group attached through a cycloalkylene.
  • alkylcycloalkyl means C 3 alkyl substituted by C 1-12 alkyl, preferably C 1-8 alkyl, more preferably C 1-6 alkyl, C 1-4 alkyl or C 1-3 -12 cycloalkyl, preferably C 3-8 cycloalkyl, more preferably C 3-6 cycloalkyl.
  • "alkylcycloalkyl” is C 1-6 alkyl-C 3-6 cycloalkyl- or C 1-6 alkyl-C 3-6 cycloalkylene-.
  • aryl refers to a monovalent carbocyclic ring having one or more rings, for example 1, 2 or 3 rings, of which at least one ring is aromatic and the other rings, if present, may be aromatic or non-aromatic of.
  • Aryl preferably has 6-14 (i.e. C 6-14 aryl), more preferably 6-10 (i.e. C 6-10 aryl), most preferably 6 ring carbon atoms (i.e. C aryl or phenyl ).
  • aryl include, but are not limited to, phenyl (ie, C aryl ), naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, or anthracenyl, and the like.
  • arylene refers to an aryl group as defined herein except that it is divalent.
  • the arylene group preferably has 6-14 ring carbon atoms (i.e. C 6-14 arylene), more preferably 6-10 ring carbon atoms (i.e. C 6-10 arylene), most preferably 6 ring carbon atoms (i.e. C 6 arylene or phenylene).
  • heterocycle refers to having one or more, such as 1-6, more preferably 1, 2, 3 or A fully saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic ring group having 4 heteroatoms independently selected from N, O or S and the remaining ring members being carbon.
  • the carbon members of the heterocycle can be replaced by -CO-, and the arbitrary N and S heteroatoms can be optionally oxidized (for example in NO, SO, SO 2 ) and the arbitrary N heteroatoms can be optionally quaternized (for example in [NR] + Cl - , [NR] + OH - ).
  • heterocycloalkyl fully saturated or partially unsaturated “heterocycloalkyl", aromatic "heteroaryl” and the like.
  • the heterocycle has 3-20 ring members, more preferably 3-12 ring members, for example 3 to 10, 5 to 10, 3 to 8, 5 to 7, 7 to 10, 4 to 6, or 5 to 6 ring members.
  • nitrogen-containing means that the associated heterocyclic group (including heterocycloalkyl, heterocycloalkyl, heteroaryl, etc.) contains only nitrogen atoms as ring heteroatoms and other ring members are carbon, such as in nitrogen-containing heterocyclic hydrocarbons , nitrogen-containing heterocycloalkanes, nitrogen-containing heteroaryl groups, nitrogen-containing heteroaromatic rings, etc.
  • heterocyclic hydrocarbon and “heterocycloalkyl” are used interchangeably and refer to having one or more, such as 1-6, more preferably 1, 2, 3 or 4, independently selected from N, O or S A saturated or partially unsaturated non-aromatic monocyclic, bicyclic or tricyclic cyclic group with heteroatoms and the remaining ring members being carbon.
  • heterocycloalkyl When a “heterocycloalkyl” is fully saturated, it may be referred to as a “heterocycloalkyl”.
  • the carbon members of the heterocyclic hydrocarbon can be replaced by -CO-, and the arbitrary N and S heteroatoms can be optionally oxidized (for example in NO, SO, SO 2 ) and the arbitrary N heteroatoms can be optionally quaternized Ammonification (eg in [NR] + Cl ⁇ , [NR] + OH ⁇ ).
  • the heterocycloalkyl group may have 3-20 ring members, such as 3-12 ring members, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring members or combinations thereof Ring members in any numerical range, such as 3-10, 3-8, 4-7 ring members, such as 3-8 membered monocyclic heterocycloalkyl or 7-10 membered Bicyclic heterocycloalkyl.
  • Representative examples thereof include, but are not limited to: aziridinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, dihydropyrrolyl, pyrrolidinyl , pyrrolidonyl, dihydrofuranyl, tetrahydrofuryl, dihydrothienyl, tetrahydrothienyl, tetrahydrothienyl 1-oxide, tetrahydrothienyl 1,1-dioxide, dihydropyrazolyl, pyr Oxazolidinyl, imidazolinyl, imidazolidinyl, imidazolone, dihydroimidazolone, tetrahydroimidazolidinyl, dihydrooxazolyl, oxazolidinyl, dihydroisoxazolyl, isoxazolidine Dihydrothiazolyl, thiazolidinyl, dihydro
  • heterocycloalkyloxy refers to a heterocycloalkyl attached through an oxygen bridge, wherein the heterocycloalkyl is as defined herein.
  • heteroaryl refers to a monocyclic ring having one or more, preferably 1-6, more preferably 1, 2, 3 or 4 heteroatoms independently selected from N, O or S and the remaining ring members being carbon , a bicyclic or tricyclic cyclic group wherein at least one ring is aromatic and the other rings, if present, may be aromatic or non-aromatic.
  • Any N and S heteroatoms of the heteroaryl group may be optionally oxidized (eg in NO, SO, SO 2 ) and said arbitrary N heteroatoms may be optionally quaternized (eg in [NR] + Cl ⁇ , [NR] + OH - medium).
  • Heteroaryl is preferably 5-14 membered, more preferably 5-10 membered heteroaryl, for example 5-7 membered heteroaryl (e.g. monocyclic, e.g. nitrogen-containing) or 7-10 membered heteroaryl (e.g. bicyclic, such as nitrogenous).
  • 5-7 membered heteroaryl e.g. monocyclic, e.g. nitrogen-containing
  • 7-10 membered heteroaryl e.g. bicyclic, such as nitrogenous
  • heteroaryl include, but are not limited to: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, Pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl, oxazinyl, oxadiazinyl, indolyl, isoindolyl, azaindolyl (e.g.
  • heteroarylene refers to a heteroaryl group as defined herein except that it is divalent.
  • cyclic group refers herein to a functional group derived by removal of one or two hydrogen atoms from a ring system such as a cyclohydrocarbon, cycloalkane, heterocyclohydrocarbon, heterocycloalkane, aromatic ring or heteroaryl ring , which may be monovalent or divalent as appropriate, preferably having 3-20 ring members, more preferably 3-14 ring members, for example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring members or any combination of ring members, such as 3-12, 6-14, 3-10, 3-8, 5-10 or 5-8 ring members.
  • the cyclic group that is part of the linker L is divalent.
  • cyclic group includes C 3-8 cycloalkane, 3-10 membered heterocyclic hydrocarbon (such as 3-8 membered heterocyclic hydrocarbon or 4-7 membered heterocyclic hydrocarbon), C 6- 14 aromatic rings or 5-10 membered heteroaromatic rings (such as 5-7 membered heteroaromatic rings or 7-10 membered heteroaromatic rings), wherein the meanings of cycloalkane, heterocyclic hydrocarbon, aromatic ring and heteroaromatic ring are similar respectively Cycloalkyl, heterocycloalkyl, aryl and heteroaryl as defined herein, except for valence.
  • subunit means a divalent group derived by removing two hydrogen atoms from a molecule.
  • CN means cyano
  • OH means hydroxyl
  • NH2 denotes an amino group
  • hydrocarbon chain denotes a saturated or unsaturated linear or branched hydrocarbon chain composed of carbon and hydrogen atoms, which may optionally contain one or more double or triple bonds.
  • E3 ubiquitin ligase binding moiety refers to a group or moiety that specifically binds to an E3 ubiquitin ligase.
  • nitrogen protecting group refers to a group that protects nitrogen from undesired chemical reactions when chemically reacted and is easily removed after the reaction. Examples include, but are not limited to, carbamates, amides, alkyls, aryls, imines, and the like.
  • nitrogen protecting groups include, but are not limited to, benzyloxycarbonyl (Cbz), p-methoxybenzyl (Pmb), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzene Formyl, benzyl, p-methoxyphenyl, 3,4-dimethoxybenzyl, etc.
  • each of the R 8 may be the same or different.
  • ring structure When a dotted ring is used in a ring structure, this means that the ring structure may be saturated, partially saturated or unsaturated.
  • divalent groups are described generically without specifying bonding arrangements. It is understood that this description is intended to include both bonding arrangements unless otherwise indicated.
  • R'-R"-R"' if the group R" is described as -CH2C (O)-, it is understood that the group can be bonded as R'- CH2C (O )-R" and R'-C(O)CH2 - R"', unless otherwise indicated.
  • compound of the present invention refers to a compound or a salt thereof, particularly a pharmaceutically acceptable salt and a stereoisomer thereof, according to formula (I) or a subform thereof such as formula (Ia) or (Ib) (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotamers and atropisomers), tautomers, Metabolites, Prodrugs, and Isotopes Labeled compounds, including deuterium substitutions, include polymorphs, solvates and/or hydrates.
  • “compounds of the present invention” specifically refer to the compounds of the examples or their salts, especially pharmaceutically acceptable salts and stereoisomers, geometric isomers, conformational isomers, tautomers, Metabolites, prodrugs, and isotopically labeled compounds, including polymorphs, solvates, and/or hydrates. In some embodiments, solvates, metabolites, isotopes or prodrugs or any combination thereof are excluded.
  • references to formula (I) also include subforms thereof, eg formula (Ia) or (Ib).
  • phrases "pharmaceutically acceptable” or “pharmaceutically acceptable” are used interchangeably to refer to a substance or composition that does not produce adverse, allergic or other undesired reactions when administered to an animal, such as a human.
  • the compounds of the invention may be in the form of salts, eg pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salt” includes acid addition salts and base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the biological effectiveness and properties of the free bases and are not biologically or otherwise undesirable.
  • Acid addition salts may be formed with inorganic or organic acids such as hydrochloride, hydrobromide, sulfate, hydrogensulfate, nitrate, carbonate, phosphate, etc., and organic acid salts such as Formate, Acetate, Trifluoroacetate, Propionate, Glycolate, Gluconate, Lactate, Pyruvate, Oxalate, Malate, Malonate, Pentadiol adipate, succinate, fumarate, maleate, tartrate, citrate, aspartate, xinafoate, ascorbate, glutamate, o-amino Benzoate, benzoate, cinnamate, mandelate, pamoate, phenylacetate, methanesulfonate, ethanesulfonate, edisylate, benzenesulfonate, p-toluenesulfonate, xylenesulfonate, mes
  • Salts also include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like; and those derived from nontoxic organic bases: primary amines, secondary amines and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylamine aminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, Glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. Salts can be synth
  • the compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, compounds may exist as diastereomers, enantiomers or mixtures thereof. The synthesis of compounds may employ racemates, diastereomers or isomers as starting materials or as intermediates. A mixture of particular diastereomeric compounds may be separated or enriched in one or more particular diastereoisomers by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated or enantiomerically enriched using the same technique or other techniques known in the art. The asymmetric carbon or nitrogen atoms may each be in the R or S configuration, both configurations being within the scope of this invention. In the structures shown herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers are included as compounds of the invention. The stereochemical definitions and conventions used herein follow the usual conventions in the art.
  • diastereomer refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and biological activities. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • enantiomer refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
  • tautomer refers to structural isomers of different energies that are interconvertible through a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Bonded tautomers include interconversions by recombination of some of the bonding electrons.
  • metabolite refers to the product produced by the metabolism of a specific compound or its salt in the body. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound. Metabolite structures are determined in a conventional manner, eg by MS, LC/MS or NMR analysis. In general, metabolite analysis is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites are useful in diagnostic assays for therapeutic doses of the compounds of the invention, provided they are not found in vivo.
  • prodrug refers to a chemically modified active or inactive compound that is converted to a compound of the present invention by in vivo physiological effects (eg, hydrolysis, metabolism, etc.) after administration to an individual. Techniques for making and using prodrugs are well known to those skilled in the art.
  • polymorph refers to crystalline forms that have the same chemical structure/composition but differ in the spatial arrangement of the molecules and/or ions forming the crystals.
  • the compounds of the invention may be provided as amorphous solids or crystalline solids. The scope of the present invention is intended to encompass all such physical forms.
  • solvate refers to an association or complex of one or more solvent molecules with a compound of the invention.
  • solvents that form solvates include water, isopropanol, EtOH, MeOH, DMSO, EA, AcOH, and ethanolamine.
  • hydrate refers to a complex in which the solvent molecule is water. Methods of solvation are well known in the art.
  • the term "individual” or “patient” refers to an animal, preferably a mammal.
  • subjects include, but are not limited to, primates (eg, humans and non-human primates such as monkeys), horses, cows, sheep, cats, dogs, rabbits, rabbits, and rodents (eg, mice and rats).
  • primates eg, humans and non-human primates such as monkeys
  • horses cows, sheep, cats, dogs, rabbits, rabbits, and rodents (eg, mice and rats).
  • rodents eg, mice and rats.
  • the individual is a human, including a child, adolescent, or adult.
  • treating refers to (i) treating or preventing a particular disease, condition or disorder, (ii) attenuating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder and optionally (iii) preventing or delaying the The onset of one or more symptoms of the specified disease, condition or disorder.
  • “treating” refers to improving at least one physical parameter, which may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both.
  • prevention refers to the administration of one or more pharmaceutical substances, especially the compounds of the present invention and/or pharmaceutically acceptable salts thereof, to an individual having a predisposing predisposition to the disease or condition in order to prevent the individual from suffering from the disease.
  • inhibitor and “alleviate” and the like refer to the alleviation or inhibition of a particular condition, symptom or disorder or disease, or to a significant reduction in the baseline activity of a biological activity or process.
  • an effective amount refers to an amount effective, at dosages required and for periods of time required, to achieve the desired therapeutic or prophylactic effect. It can be determined by the participating physician or veterinary practitioner and will vary with the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the attending physician or veterinary practitioner Depending on factors such as the judgment of the examiner. Typically, a “prophylactically effective amount” will be less than a "therapeutically effective amount”.
  • degradation of CDK12 refers to the use of ubiquitin-proteasome pathway, which leads to the degradation of CDK12 protein under the action of ubiquitin ligase White matter is ubiquitinated and degraded.
  • formulation refers to a composition comprising at least one active ingredient and at least one inactive ingredient, such as a pharmaceutically acceptable excipient, suitable for administration to animals, preferably mammals, including humans.
  • the preparation of the present invention may be any preparation suitable in the art, such as tablet, capsule, liquid preparation and the like.
  • pharmaceutically acceptable excipient refers to an ingredient of a pharmaceutical formulation other than the active ingredient, which is non-toxic to the individual.
  • pharmaceutically acceptable carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.
  • Treating when referring to a chemical reaction mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It is to be understood that the reaction leading to the shown and/or desired product may not necessarily result directly from the combination of the two reagents originally added, i.e. there may be one or more intermediates formed in the mixture which eventually lead to formation of the indicated and/or desired products.
  • a "and/or" B includes A alone, B alone and A+B.
  • the term "about” when used in conjunction with a numerical value indicates a range of ⁇ 20%, preferably ⁇ 10%, more preferably ⁇ 5% of the numerical value.
  • the compound of the present invention has cell cyclin-dependent kinase 12 (CDK12) degrading activity and has good selectivity to CDK12.
  • CDK12 cell cyclin-dependent kinase 12
  • the compounds of the present invention show good activity of inhibiting the proliferation of cancer cells.
  • the compounds of the present invention have improved physical and chemical properties and good pharmacokinetic properties (such as good metabolic stability), good druggability, few side effects, and high resistance to drug resistance.
  • the compounds of the invention are useful in a variety of applications where inhibition or degradation of CDK12 is desired.
  • the compound of the present invention can effectively degrade CDK12 and/or effectively inhibit the activity of tumor cell lines, and can achieve one or more of the following technical effects:
  • CDK12 protein degradation experiment (Western Blot) results show that at 200nM concentration, the compounds of the present invention can degrade CDK12 protein to varying degrees;
  • High tumor cell line proliferation inhibitory activity for example: high HCC70 cell line proliferation inhibitory activity, the IC50 of HCC70 cell proliferation inhibition is 50-3000nM, preferably 50-2500nM, more preferably 50-2000nM, and preferably 50-1500nM, Most preferably the scope of 50 ⁇ 1000nM, as verified by activity example A; On JurKat cell, also show the advantage of obvious proliferation inhibitory activity; To HT-29 cell (human colon cancer cell) and A-673 cell (human striated muscle sarcoma cells) also exhibit significant proliferation inhibitory activity; and/or
  • Good pharmacokinetic properties such as longer t 1/2 , so that, for example, the dosing interval can be increased, and the half-life can be longer, so that patients have better compliance, as verified by active example C ;and / or
  • CDK12-associated diseases or conditions are, for example, abnormal cell proliferative diseases, myotonic dystrophy type 1 (DM1), infections (such as viruses such as herpes, HIV infection, fungal infections, etc.), inflammatory conditions (such as rheumatoid arthritis , osteoarthritis, etc.), autoimmune diseases (such as psoriasis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular diseases (such as myocardial infarction, stroke, atherosclerosis sclerosis, postoperative vascular stenosis, etc.), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.) and hematopoietic toxic diseases caused by radiation (such as bone marrow suppression, neutropenia, leukopenia, anemia, etc.).
  • DM1 myotonic dystrophy type 1
  • infections such as viruses such as herpes, HIV infection, fungal
  • the abnormal cell proliferation disease is tumor and/or cancer; optionally, the cancer is selected from CDK12-related diseases or disorders are tumor and/or cancer, such as breast cancer, ovarian cancer , prostate cancer, central nervous system tumors (eg, spinal tumors, brainstem gliomas, glioblastoma multiforme, astrocytoma), esophageal cancer, bowel cancer, gastric cancer, liver cancer, pancreatic cancer (eg, pancreatic Ductal carcinoma, pancreatic endocrine tumors), colorectal cancer (e.g. colon, rectal), lung (e.g. non-small cell lung, small cell lung, bronchoalveolar cell carcinoma), kidney cancer, skin cancer (e.g.
  • CDK12-related diseases or disorders are tumor and/or cancer, such as breast cancer, ovarian cancer , prostate cancer, central nervous system tumors (eg, spinal tumors, brainstem gliomas, glioblastoma multiforme, astrocytoma),
  • sarcomas e.g. Ewing sarcoma, angiosarcoma, liposarcoma, myoma
  • osteochondroma osteoma
  • osteosarcoma seminoma
  • testicular tumor uterine cancer (e.g. cervical cancer, endometrial cancer), head and neck tumor (e.g.
  • maxillary bone tumor pharyngeal cancer, laryngeal, tongue, intraoral
  • multiple myeloma benign and malignant lymphomas (e.g. reticulocyte sarcoma, lymphosarcoma, Hodgkin lymphoma, mantle cell lymphoma), polycythemia vera, leukemia (e.g.
  • the cancer is selected from breast cancer, ovarian cancer, prostate cancer, gastric cancer, esophageal cancer, endometrial cancer, uterine cancer, bladder cancer, colorectal cancer, pancreatic ductal carcinoma, neuroblastoma tumor and Ewing's sarcoma.
  • the disease is selected from myotonic dystrophy type I (DM1).
  • compounds of the invention are useful for treating or preventing CDK12-associated diseases or disorders, such as tumors or cancers.
  • the compounds of the present invention are useful for the treatment or prevention of lung cancer, non-small cell lung cancer, bronchoalveolar cell lung cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, esophageal cancer, endometrial cancer, uterine cancer, Bladder cancer, colorectal cancer, pancreatic ductal carcinoma, neuroblastoma, Ewing's sarcoma and other tumors or cancers.
  • the compounds of the present invention may be administered in the form of pharmaceutical compositions by any suitable route, such as but not limited to oral administration (in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions or suspensions). form), inhalation (for example, in the form of a spray), rectally (for example, in the form of a suppository), or parenterally (for example, in the form of an injection, such as intravenous, intramuscular, subcutaneous, intraperitoneal, intracranial, etc.). Oral, intranasal and parenteral administration are particularly preferred.
  • oral administration in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions or suspensions. form
  • inhalation for example, in the form of a spray
  • rectally for example, in the form of a suppository
  • parenterally for example, in the form of an injection, such as intravenous, intramuscular, subcutaneous, intraperi
  • the compounds of the present invention can be processed into the form of pharmaceutical compositions, such as tablets, coated tablets, capsules, liquid preparations (such as injections) using one or more pharmaceutically acceptable carriers, diluents or excipients.
  • pharmaceutically acceptable carriers such as injections
  • liquid, infusion, syrup, emulsion, suspension, etc. powder, powder injection, dispersion, spray, suppository, liposome, etc.
  • Pharmaceutically acceptable carriers, diluents or excipients are well known in the art, such as fillers, disintegrants, solvents, solubilizers, stabilizers, wetting agents, emulsifiers, preservatives, sweeteners, colorants, corrective agents, Flavoring agents, salts for changing osmotic pressure, buffers, masking agents or antioxidants, etc.
  • the dosage may vary widely and, of course, must be adjusted to the individual needs in each particular case.
  • the appropriate dose can be determined by the attending physician as appropriate based on the type and severity of the disease to be treated, the individual's health status and previous medical history, shared drugs, the specific compound administered and the route of administration, etc.
  • a daily dosage for oral administration to a 70 kg human adult is typically from about 0.01 mg to about 1000 mg of a compound of the invention or a corresponding amount of a pharmaceutically acceptable salt.
  • the compound of the present invention may be used in an amount outside this dosage range as required.
  • the daily dose can be administered as a single dose or in divided doses.
  • the compounds of the present invention may be used alone or in combination with one or more other active agents or therapies, which may have the same or different pharmacological efficacy as the compounds of the present invention.
  • the compounds of the invention may be administered simultaneously with, prior to, or subsequent to the other active agent or therapy.
  • the dosage of the active agents administered in combination will of course vary depending on such factors as the co-medicaments, the condition being treated, the general health of the individual, the judgment of the physician or veterinarian, and the like.
  • the compounds of the present invention may be administered simultaneously, separately or sequentially with other co-active agents by the same or different routes of administration. They can be contained in the same pharmaceutical composition (fixed composition), or they can be combined in separate form, eg in the form of a kit. They may be formulated and/or supplied by the same or different manufacturers.
  • the compounds of the invention and other active agents may be obtained (i) (i) prior to sending the combination product to a physician (for example, in the case of a kit comprising the compounds of the invention and other active agents); (ii) immediately prior to administration.
  • a physician for example, in the case of a kit comprising the compounds of the invention and other active agents
  • immediately prior to administration The physician himself (or under the direction of the physician); or (iii) by the patient himself, for example during the sequential administration of the compound of the invention and the other active agent together in the combination therapy.
  • the application provides pharmaceutical compositions comprising a compound of the invention and one or more other active agents.
  • the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the application provides pharmaceutical combination products, such as kits, comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention.
  • the kit includes means for containing the compositions separately, such as containers, divided bottles, or divided foil pouches.
  • kits of the present application can be used for administering different dosage forms, such as oral and parenteral dosage forms, for administering individual compositions at different dosage intervals, or for stepping up individual compositions relative to one another.
  • the kits of the present application will generally contain instructions for administration.
  • the compounds of the present invention can be prepared by a variety of methods, including methods known in the art, methods in the schemes below, methods given in the examples, or methods analogous thereto. Suitable reaction conditions for the individual reaction steps are known to or can be readily determined by the person skilled in the art. Starting materials are generally commercially available or can be readily prepared using methods known in the art or described herein. Each variable in the general formula has the meaning defined herein, unless otherwise stated.
  • Synthetic Scheme 1 of the present invention provides a method for the synthesis of compounds of formula (I), wherein R', R", R"' and R"" are terminal functional groups, and other variables are as defined herein for compounds of formula (I), which Include the following steps:
  • Step a reacting the compound of formula (I-1) with compound R"-LR"' to obtain the compound of formula (I-2).
  • Such reactions include, but are not limited to, nucleophilic substitution reactions, condensation reactions, reductive amination reactions, etc., depending on the nature of the terminal functional groups of groups X and L.
  • the nucleophilic substitution reaction can be carried out in the presence of a base, which includes but not limited to sodium carbonate, K 2 CO 3 , cesium carbonate, N,N-diisopropylethylamine (DIPEA), triethylamine (Et 3 One or more of N), HOBt, pyridine, and KI; preferably, the base is used in conjunction with DIPEA and KI.
  • DIPEA N,N-diisopropylethylamine
  • Et 3 triethylamine
  • the condensation reaction can be performed in the presence of condensing agents well known in the art for coupling carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride ( T3P ), EDC, DCC , HATU, EDCI, etc.
  • the reductive amination reaction can be carried out in the presence of a reducing agent, which is a condensing agent well known in the art for reductive amination, including but not limited to sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride (NaBH(AcO) 3 ), etc.
  • these reactions are preferably carried out in a suitable organic solvent, which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane), dimethyl sulfoxide (DMSO) and any combination thereof.
  • a suitable organic solvent which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane
  • Step b reacting the compound of formula (I-2) with compound ER"" to obtain the compound of formula (I).
  • Such reactions include, but are not limited to, nucleophilic substitution reactions, condensation reactions, reductive amination reactions, Suzuki coupling reactions, Chan-Lam reactions, Sonogashira coupling reactions, depending on the group E and the terminal functional group of (I-2) nature. Nucleophilic substitution reaction, condensation reaction, and reductive amination reaction are the same as step a.
  • Pd(PPh 3 ) 4 , PdCl 2 (Amphos) 2 , Cu(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppp)Cl can be used for Suzuki coupling reaction, Chan-Lam reaction, and Sonogashira coupling reaction 2 and so on as a catalyst.
  • these reactions are preferably carried out in a suitable organic solvent, which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane), dimethyl sulfoxide (DMSO), toluene and any combination thereof.
  • a suitable organic solvent which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (d
  • Synthetic Scheme 2 of the present invention provides another method for the synthesis of compounds of formula (I), wherein R', R", R"' and R"" are terminal functional groups, and other variables are as described herein for compounds of formula (I) definition, which includes the following steps:
  • Step a react the compound of formula (In-1) with the compound R"-LR"' to obtain the compound of formula (In-2).
  • Such reactions include, but are not limited to, nucleophilic substitution reactions, condensation reactions, reductive amination reactions, Suzuki coupling reactions, Chan-Lam reactions, Sonogashira coupling reactions, depending on the nature of the terminal functionality of groups E and L.
  • the nucleophilic substitution reaction, condensation reaction, and reductive amination reaction are the same as those described above.
  • Pd(PPh 3 ) 4 , PdCl 2 (Amphos) 2 , Cu(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppp)Cl can be used for Suzuki coupling reaction, Chan-Lam reaction, and Sonogashira coupling reaction 2 and so on as a catalyst.
  • these reactions are preferably carried out in a suitable organic solvent, which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane), dimethyl sulfoxide (DMSO), toluene and any combination thereof.
  • a suitable organic solvent which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (d
  • Step b reacting the compound of formula (In-2) with the compound of formula (I-1) to obtain the compound of formula (I).
  • Such reactions include, but are not limited to, nucleophilic substitution reactions, condensation reactions, reductive amination reactions, etc., depending on the nature of the terminal functional groups of groups X and L.
  • the nucleophilic substitution reaction can be carried out in the presence of a base, which includes but not limited to sodium carbonate, K 2 CO 3 , cesium carbonate, N,N-diisopropylethylamine (DIPEA), triethylamine (Et 3 One or more of N), HOBt, pyridine, and KI; preferably, the base is used in conjunction with DIPEA and KI.
  • DIPEA N,N-diisopropylethylamine
  • Et 3 triethylamine
  • the condensation reaction can be performed in the presence of condensing agents well known in the art for coupling carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride ( T3P ), EDC, DCC , HATU, EDCI, etc.
  • the reductive amination reaction can be carried out in the presence of a reducing agent, which is a condensing agent well known in the art for reductive amination, including but not limited to sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride (NaBH(AcO) 3 ), etc.
  • these reactions are preferably carried out in a suitable organic solvent, which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane), dimethyl sulfoxide (DMSO) and any combination thereof.
  • a suitable organic solvent which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane
  • Figure 1 shows the dose-response curves of the inhibitory activity of compound BSJ-04-023 and the compound of Example 20 on the proliferation of Jurkat cells.
  • Figure 2 shows the Western Blot diagram of the degradation activity of compound BSJ-04-023 on CDK12 protein (Example B).
  • Figure 3 shows the Western Blot diagram of the degrading activity of the compound of Example 27 on CDK12 protein (Example B).
  • Figure 4 shows the Western Blot graph of the degrading activity of the compounds of Examples 19 and 20 on CDK12 protein (Example B).
  • Figure 5 shows the time dependence of the degradation of CDK12 by Example 111.
  • Figure 6 shows the time dependence of the degradation of CDK12 by Example 112.
  • reagents used in the examples are either commercially available or readily prepared by methods known in the art or as described herein.
  • column chromatography adopts silica gel (100-200 order and 200-300 order) produced by Shanghai Titan Technology Co., Ltd.; thin-layer chromatography adopts GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR ) was determined using a Bruker Avance III 400MHz nuclear magnetic resonance instrument.
  • the liquid mass spectrometry (LC/MS) method used in the embodiment of the present application has:
  • Method A SHIMADZU LC-20AD-PDA; Column: sunfire C18 4.6*50mm; Mobile phase A: 0.1% FA in H 2 O (V/V), Mobile phase B: 0.1% FA in ACN (V/V); Flow rate 2mL/min; injection volume (2 ⁇ L); 2.6min; 254nm; column temperature 40°C.
  • Method B Agilent 1260 DAD-6120-ELSD; Column: Xbridge C18 5 ⁇ m 4.6*50mm; Mobile phase A: 0.1% NH 3 .H 2 O in H 2 O (V/V), Mobile phase B: 0.1% NH 3 .H 2 O in ACN (V/V); flow rate 2mL/min; injection volume (2 ⁇ L); 2.6min; 254nm, column temperature 40°C.
  • Method C Waters ACQUITY UPLC Hclass-QDa LCMS; Column: ACQUITY UPLC BEH C18 2.1*50mm 1.7 ⁇ m; Mobile phase A: 0.1% FA in H 2 O (V/V), Mobile phase B: 0.1% FA in ACN ( V/V); flow rate 2mL/min; injection volume (2 ⁇ L); 2.0min; 254nm; column temperature 40°C.
  • Method D ACQUITY UPLC BEH 1.7um 2.1*50mm 2.0min 0.6mL/min; Column temperature: 40°C; Gradient: 10%B increase to 30%B for 0.10min,increase to 95%B within 1.20min,95%B hold for 0.80min.
  • Method E SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Column temperature: 40°C; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B for 0.90min, back to 10% B within 0.01min.
  • the raw materials used in the present invention are all commercially available raw materials, which can be used directly without further purification, and the temperatures used in the present invention are all degrees Celsius (° C.).
  • the ratio of liquids is by volume, eg in PE:EA.
  • Methylmagnesium bromide (6.50 g, 10.8 mmol) was added dropwise to a nitrogen-protected solution of indole (6.39 g, 54.5 mmol) in THF (50.0 mL) at 0° C. within 10 minutes. The solution was then stirred at 0-2°C for 0.5 hr. Then add 2,4,5-trichloropyrim Pyridine (5.00 g, 27.3 mmol) gave a yellow solution. The ice bath was removed, followed by stirring at room temperature for 1 hr, resulting in a red solution. The reaction solution was heated to 60°C, and then stirred at 60°C for 1.5 hrs. The reaction solution was then cooled to room temperature.
  • Step 2 Synthesis of (R)-tert-butyl 3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate
  • Step 4 (R)-(7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-7-oxo Synthesis of tert-butyl carbamate
  • Step 6 N-(7-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-7 -Oxoheptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide Synthesis
  • Step 1 Synthesis of tert-butyl (7-bromoheptyl)carbamate
  • Step 2 (R)-(7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptyl)amino Synthesis of tert-butyl formate
  • Step 3 Synthesis of (R)-N-(1-(7-aminoheptyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine
  • Step 4 N-(7-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptyl Synthesis of )-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  • Example 3 N-(6-(((1S,3S)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino )hexyl)-2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide
  • Step 1 Synthesis of tert-butyl ((1S,3S)-3–((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)carbamate
  • Step 2 Synthesis of (1S,3S)-N 1 -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1,3-diamine
  • Step 3 (6-(((1S,3S)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino)hexyl) Synthesis of tert-butyl carbamate
  • Step 4 (1S,3S) -N1- (6-aminohexyl) -N3- (5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1 , Synthesis of 3-diamine
  • Step 5 N-(6-(((1S,3S)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino) Synthesis of Hexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  • Step 1 Synthesis of tert-butyl 3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidine-1-carboxylate
  • Step 3 (7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidin-1-yl)heptyl)carbamate Synthesis of tert-butyl ester
  • Step 4 Synthesis of N-(1-(7-aminoheptyl)azetidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine
  • Step 5 N-(7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidin-1-yl)heptyl) Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  • Step 1 Synthesis of 5-chloro-4-(1H-indol-3-yl)-N-(1H-pyrazol-4-yl)pyrimidin-2-amine
  • Step 2 (7-(4-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl)carbamate Synthesis of tert-butyl ester
  • Step 3 Synthesis of N-(1-(7-aminoheptyl)-1H-pyrazol-4-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine
  • Step 4 N-(7-(4-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl) Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  • Example 8 N-(7-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl )-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide
  • Step 1 Synthesis of tert-butyl (7-(5-nitro-2-oxopyridin-1(2H)-yl)heptyl)carbamate
  • Step 2 Synthesis of tert-butyl (7-(5-amino-2-oxopiperidin-1-yl)heptyl)carbamate
  • Step 3 (7-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopiperidin-1-yl)heptyl) Synthesis of tert-butyl carbamate
  • reaction solution was diluted with EA (50.0mL), washed with water (50.0mL) and saturated brine (50.0mL ⁇ 2) successively, the organic phase was dried with anhydrous Na 2 SO 4 , filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was passed through Purified by silica gel chromatography to obtain the target compound (40.0 mg, yield 9.20%, yellow solid).
  • Step 4 Synthesis of 1-(7-aminoheptyl)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-2-one
  • Step 5 N-(7-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopiperidin-1-yl)heptan Synthesis of yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  • Step 1 Synthesis of tert-butyl (7-(5-nitro-2-oxopyridin-1(2H)-yl)heptyl)carbamate
  • Step 2 Synthesis of tert-butyl (7-(5-amino-2-oxopyridin-1(2H)-yl)heptyl)carbamate
  • Step 3 (7-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopyridin-1(2H)-yl)heptan base) synthesis of tert-butyl carbamate
  • Step 4 1-(7-Aminoheptyl)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-2(1H)-one synthesis
  • Step 5 N-(-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopyridin-1(2H)-yl) Synthesis of Heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  • Example 11 N-(7-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl )-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide
  • Example 12 4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)- 2-oxoethoxy) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 1 4-(2-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2 Synthesis of -oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 13 N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptan Base)-2-((2-(1-methyl -2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)ethyl Amide, trifluoroacetate
  • Step 1 2-((2-(1-Methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid Synthesis of tert-butyl ester
  • Step 3 N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptyl )-2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide synthesis
  • Example 14 4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl Oxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt
  • Step 1 (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethane-1- Alcohol synthesis
  • Step 3 4-(2-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethoxy Synthesis of 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 3 4-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propoxy Synthesis of 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formate
  • Example 16 4-(2-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiper Pyridine-3-yl)isoindoline-1,3-dione, FA salt
  • Step 1 Synthesis of (R)-methyl 2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetate
  • Step 2 Synthesis of (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid
  • Step 3 (R)-4-(1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl )Synthesis of acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 4 (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-(4 Synthesis of -(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one
  • Step 5 4-(2-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine Synthesis of -3-yl)isoindoline-1,3-dione
  • Example 17 4-(2-(4-((1-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkane-1-carbonyl)piperidin-4- yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione, FA salt
  • Step 1 Synthesis of tert-butyl 4-(1-((4-nitrophenoxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
  • Step 2 (R)-4-((1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)piper Synthesis of pyridin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 3 (R)-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)(4-(piperazine- Synthesis of 1-ylmethyl)piperidin-1-yl)methanone
  • Step 4 4-(2-(4-((1-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)iso Synthesis of Indoline-1,3-dione
  • Example 18 4-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-diketone
  • Step 1 4-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones
  • Example 19 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-diketone
  • Step 1 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones
  • Example 20 5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)piperidin- 1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 - diketone, FA salt
  • Step 3 (R)-4-((4-((3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Synthesis of tert-butyl methyl)piperidine-1-yl)methyl)piperidine-1-carboxylate
  • Step 4 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-((1-(piperidin-4-ylmethyl)piperidin-4-yl) Synthesis of Methyl)pyrrolidin-3-yl)pyrimidin-2-amine
  • Step 5 5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Synthesis of diketones
  • Example 21 5-(4-((4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -yl)piperidin-1-yl)methyl )piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 2 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine synthesis
  • Step 3 (R)-4-((4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Synthesis of pyridine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester
  • Step 4 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(1-(piperidin-4-ylmethyl)piperidin-4-yl)pyrrole Synthesis of alk-3-yl)pyrimidin-2-amine (HQ-0012-149)
  • Step 5 5-(4-((4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 22 4-(2-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)-2-oxoethyl) piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 1 Synthesis of tert-butyl 4-((1-(2-methoxy-2-oxoethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
  • Step 2 Synthesis of 2-(4-((4-(tert-butyloxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid
  • tert-butyl 4-((1-(2-methoxy-2-oxoethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (689 mg, 1.94 mmol) was dissolved in MeOH /water (4/1, 10.0 mL), and LiOH (93.0 mg, 3.88 mmol) was added. The resulting reaction solution was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, dilute hydrochloric acid was added to adjust the pH to 2-3. Then it was extracted with EA, and the organic phase was distilled off under reduced pressure to obtain the target compound (550 mg, yield 83.1%, yellow solid). LC-MS (ESI) m/z: 342.4 [M+H] + .
  • Step 3 (R)-4-((1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-)amino)pyrrolidin-1-yl Synthesis of )-2-oxoethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 4 (R)-1-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2-(4 Synthesis of -(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one
  • Step 5 4-(2-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyridin-2-yl)amino )pyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6- Synthesis of dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 23 4-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)-2-oxoethyl )piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione
  • Step 1 4-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindo Synthesis of Indoline-1,3-dione
  • Example 24 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)-2-oxyethyl) piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol Indoline-1,3-dione
  • Step 1 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of Phenyl-1,3-Diones
  • Example 25 N-(6-(((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino )hexyl)-2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide
  • Step 1 Synthesis of tert-butyl ((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)carbamate
  • Step 2 Synthesis of (1R,3S)-N 1 -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1,3-diamine
  • Step 3 (6-(((1S,3R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino)hexyl) Synthesis of tert-butyl carbamate
  • Step 4 (1S,3R)-N 1 -(6-aminohexyl)-N 3 -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1 , Synthesis of 3-diamine
  • Step 5 N-(6-(((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino) Synthesis of Hexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide
  • Example 26 5-(4-((4-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)propyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone,FA salt
  • Step 1 Synthesis of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate
  • Step 4 (R)-4-((4-(3-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl (yl)propyl)piperidin-1-yl)methyl)piperidine-1-carboxylate
  • Step 5 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(3-(1-(piperidin-4-ylmethyl)piperidine-4- Synthesis of yl)propyl)pyrrolidin-3-yl)pyrimidin-2-amine
  • Step 6 5-(4-((4-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)propyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones
  • Example 27 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone,FA salt
  • Step 2 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl) Synthesis of pyrimidin-2-amine
  • Step 4 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(2-(1-(1-(piperidin-4-ylmethyl)piperidine Synthesis of -4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine
  • Step 5 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-diketone
  • Example 28 4-(2-(4-((1-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)propionyl) piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiper Pyridine-3-yl)isoindoline-1,3-dione
  • Step 1 (R)-3-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propanoic acid methyl ester synthesis
  • Step 2 Synthesis of (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propanoic acid
  • Step 3 (R)-4-(1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl )propionyl)piperidin-4-yl)methyl)piperazine-1-formic acid tert-butyl ester
  • Step 4 (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-(4 Synthesis of -(piperazin-1-ylmethyl)piperidin-1-yl)propan-1-one
  • Step 5 4-(2-(4-((1-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)propionyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine Synthesis of -3-yl)isoindoline-1,3-dione
  • Example 29 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione
  • Step 1 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindol Synthesis of Indoline-1,3-dione
  • Step 1 5-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2-(2 ,Synthesis of 6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 31 5-(1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base) acetyl) piperidin- 4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 1 5-(1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )acetyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 32 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base)ethyl)piperidin-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt
  • Step 1 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 2 5-(4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methanol Synthesis of yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 1 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine synthesis
  • Step 2 5-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine Synthesis of -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 2 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperazin-1-yl)ethyl)pyrrolidin-3-yl) Synthesis of pyrimidin-2-amine
  • Step 3 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • the reaction solution was cooled to room temperature, diluted with EA (10.0 mL), washed successively with saturated saline solution (10.0 mL), water (10.0 mL), and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated under reduced pressure, and the residue
  • Example 36 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- yl)acetyl)piperazin- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt
  • Step 1 (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid methyl ester synthesis
  • Step 2 Synthesis of (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid
  • Step 4 (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-(piper Synthesis of oxin-1-yl)ethan-1-one
  • Step 5 5-(4-(2-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 37 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piper Pyridin-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone,FA salt
  • Step 1 Synthesis of (R)-methyl 2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)acetate
  • Step 2 Synthesis of (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)acetic acid
  • Step 4 (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)-1-(4 Synthesis of -(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one
  • Step 5 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine -1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones
  • Example 38 5-(4-((1-(2-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin- 1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione
  • Step 2 Synthesis of (R)-5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(pyrrolidin-3-yl)pyrimidine-2,4-diamine
  • Step 3 (R)-2-(3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl ) Synthesis of methyl acetate
  • Step 4 (R)-2-(3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl ) Synthesis of acetic acid
  • Step 5 (R)-4-((1-(2-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino Synthesis of )pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 6 (R)-2-(3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )-1-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one
  • Step 7 5-(4-((1-(2-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2- Base)amino)pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Synthesis of Indoline-1,3-dione
  • Example 39 5-(4-((1-(2-((R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin- 1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione, FA salt
  • Step 2 Synthesis of (R)-(2-((5-chloro-2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
  • Step 4 (R)-2-(3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl ) Synthesis of acetic acid
  • Step 5 (R)-4-((1-(2-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino Synthesis of )pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester
  • the reaction solution was diluted with water (10.0 mL), extracted with EA (10.0 mL ⁇ 2), and the organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product.
  • Step 6 (R)-2-(3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )-1-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one
  • Step 7 5-(4-((1-(2-((R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-2- Base)amino)pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Synthesis of Indoline-1,3-dione
  • Example 40 5-(4-((4-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1- yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Phenyl-1,3-dione
  • Step 1 Synthesis of (R)-5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(pyrrolidin-3-yl)pyrimidine-2,4-diamine
  • Step 2 (R)-4-((3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl)methyl)piperidine-1-carboxylate
  • Step 3 (R)-5-Chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl ) Synthesis of pyrimidine-2,4-diamine
  • Step 4 (R)-4-((4-((3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrole Synthesis of tert-butyl (alk-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate
  • Step 5 (R)-5-Chloro- N4- (2-(isopropylsulfonyl)phenyl) -N2- (1-((1-(piperidin-4-ylmethyl)piperidine Synthesis of -4-yl)methyl)pyrrolidin-3-yl)pyrimidine-2,4-diamine
  • Step 6 5-(4-((4-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino )pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline Synthesis of -1,3-diketones
  • Example 41 5-(4-((4-(((R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl )amino)pyrrolidin-1- yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol Indoline-1,3-dione, FA salt
  • Step 3 (R)-4-((4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrole Synthesis of tert-butyl (alk-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate
  • Step 4 (R)-(2-((5-Chloro-2-((1-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrrolidine-3 Synthesis of -yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
  • Step 5 5-(4-((4-(((R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of Phenyl-1,3-Diones
  • Example 42 2-(((3R)-1-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindoline-5-yl)piperidin-4- yl)methyl)piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile,diformate
  • Step 2 (R)-tert-butyl 4-(2-(3-((5-cyanopyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylate synthesis
  • Step 3 Synthesis of (R)-2-((1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile.
  • Step 4 4-((3-(2-((R)-3-((5-cyanopyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl) Synthesis of tert-butyl methyl)piperidine-1-carboxylate
  • Step 5 2-(((3R)-1-(2-(1-(piperidin-4-ylmethyl)piperidin-3-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine- Synthesis of 5-carbonitrile
  • Step 6 2-(((3R)-1-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Synthesis of Indoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile
  • Example 43 2-(((3R)-1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol Indoline-5-yl)piperidin-4-yl) methyl(piperidin-4-yl)methyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile, FA salt
  • Step 1 2-(((3R)-1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole Lin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile
  • Step 1 Synthesis of (R)-tert-butyl 3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate
  • Step 4 Synthesis of (R)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine
  • Step 6 (R)-N-(1-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)-5-(trifluoromethane base) synthesis of pyrimidin-2-amine
  • Step 7 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(((R)-3-((5-(trifluoromethyl)pyrimidine- Synthesis of 2-yl)amino)pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione
  • Example 45 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3 -yl) isoindoline-1,3-dione, trifluoroacetate
  • Step 1 (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethane-1- Alcohol synthesis
  • Step 3 (R)-N-(1-(2-azidoethyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine synthesis
  • Step 4 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3- base) synthesis of isoindoline-1,3-dione
  • Example 46 5-(1-(1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)piperidin- 4-yl)-1H-1,2,3-triazol-4-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione
  • Example 47 5-(1-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin -4-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-(2,6-dioxopiperidine- 3-yl)isoindoline-1,3-dione
  • Example 48 5-(4-((4-(((R)-3-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazole- 4-yl)pyrimidin-2-yl)amino)pyrrolidin -1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione
  • Step 1 Synthesis of cyclopropyl(1-methyl-1H-pyrazol-5-yl)methanol
  • n-butyllithium 2.5N, 60.0mL, 150mmol
  • 1-methyl-1H-pyrazole 8.20g, 100mmol
  • cyclopropanaldehyde 8.20g, 100mmol was added dropwise solution in THF (80.0 mL), then stirred at room temperature for 16 hrs.
  • Step 4 5-(cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -Synthesis of 1H-pyrazole
  • n-butyllithium (1.6N, 4.20mL, 5.60mmol) was slowly added dropwise to 4-bromo-5-(cyclopropyl)-1-methyl-1H-pyrazole (600mg, 2.80 mmol) in anhydrous THF (15.0 mL), stirred at this temperature for 0.5 hr, then added dropwise 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dihe Oxaborane (1.00 g, 5.60 mmol) in THF (2.00 mL) was then stirred at room temperature for 0.5 hr.
  • Step 6 (R)-3-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino) Synthesis of tert-butyl pyrrolidine-1-carboxylate
  • Step 7 (R)-5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-N-(pyrrolidin-3-yl)pyrimidine Synthesis of -2-amine
  • Step 8 5-(4-((4-(((R)-3-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-4 -yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiper Synthesis of pyridin-3-yl)isoindoline-1,3-dione
  • Example 49 5-(4-((4-(((R)-3-((5-chloro-4-(4-(cyclopropylmethyl)-1H-pyrazol-3-yl)pyrimidine -2-yl)amino)pyrrolidin- 1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine-3- base) isoindoline-1,3-dione
  • Example 50 (E)-N-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -Carbonyl)phenyl)-4- (4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine- 1-yl)butyl-2-enamide
  • Example 51 (E)-N-(4-((R)-3-((5-chloro-4-(4-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl)amino )pyrrolidine-1-carbonyl)phenyl )-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) piperazin-1-yl) butyl-2-enamide
  • Example 52 (E)-N-(4-((R)-3-((5-chloro-4-(4,5-dimethyl-1H-pyrazol-3-yl)pyrimidine-2- Base)amino)pyrrolidine-1-carbonyl )phenyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole Lin-5-yl)piperazin-1-yl)butyl-2-enamide
  • Example 53 5-(4-((4-(((R)-3-((5-chloro-4-(6-methylpyridin-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)methyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-diketone
  • Example 54 5-(4-((4-(((R)-3-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Methyl)piperidin-1-yl) methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 55 5-(4-((4-(((R)-3-((5-chloro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 - dione
  • Example 56 5-(4-((4-(2-((R)-3-((5-chloro-4-(4-methyl-1H-pyrazol-3-yl)pyrimidine-2- Base)amino)pyrrolidin-1-yl)ethyl) piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione
  • Example 57 5-(4-((4-(2-((R)-3-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1- Base) ethyl) piperidin-1- yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-di ketone
  • Example 58 5-(4-((4-(2-((R)-3-((5-chloro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-diketone
  • Example 59 5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)piperidin- 1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline -1,3-dione
  • Example 60 3-(5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin -1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2, 6-diketone
  • Example 61 3-(6-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin -1-yl)methyl)piperidin-1-yl)-5-fluoro-1-oxoisoindoline-2-yl)piperidine-2, 6-diketone
  • Example 62 3-((4-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)methyl)piperidin-1 -yl)methyl)piperidin-1-yl)benzyl)amino)piperidine-2,6-dione
  • Example 63 3-((4-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)methyl)piperidin-1 -yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione
  • Example 64 (R)-1-(4-(4-((4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin-1 -yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example 65 (R)-1-(6-(4-((4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin-1 -yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4( 1H,3H)-Diketone
  • Example 66 (R)-1-(4-(1-((1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin- 4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example 68 (R)-1-(4-(1-(1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)ethyl)piperidin- 4-yl)azetidin-3-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example 70 4-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Pyridin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt
  • Step 1 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine synthesis
  • Step 2 4-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine Synthesis of -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 71 4-(4-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Methyl)piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt
  • Step 2 4-(4-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methanol Synthesis of yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 72 4-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Pyridin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt
  • Step 1 3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1- tert-butyl formate
  • Step 2 5-Chloro-4-(1H-indol-3-yl)-N-((3R)-1-(piperidin-3-yl)pyrrolidin-3-yl)pyrimidin-2-amine
  • Step 3 4-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • the reaction solution was cooled to room temperature, diluted with DCM (50.0 mL), and the organic phase was washed with water (40.0 mL ⁇ 2) and saturated brine (40.0 mL) successively, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain
  • Step 1 3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1- Synthesis of tert-butyl formate
  • Step 2 5-Chloro-4-(1H-indol-3-yl)-N-((3R)-1-(piperidin-3-yl)pyrrolidin-3-yl)pyrimidin-2-amine
  • Step 3 5-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • reaction solution was cooled to room temperature, diluted with DCM (50.0 mL), and the organic phase was washed with water (40.0 mL ⁇ 2) and saturated brine (40.0 mL) successively, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure.
  • Example 74 5-(3-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Methyl)piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 1 3-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piper Synthesis of tert-butyl pyridine-1-carboxylate
  • Step 3 5-(3-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methanol Synthesis of yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Example 75 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin- 1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione, FA salt
  • Step 1 (R)-3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester Synthesis
  • Step 2 Synthesis of (R)-5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(pyrrolidin-3-yl)pyrimidine-2,4-diamine
  • Step 3 (R)-4-(2-(3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine- Synthesis of tert-butyl 1-yl)ethyl)piperidine-1-carboxylate
  • Step 4 (R)-5-Chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(1-(2-(piperidin-4-yl)ethyl)pyrrolidine Synthesis of -3-yl)pyrimidine-2,4-diamine
  • Step 5 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2- Base) amino) pyrrolidin-1-yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) iso Synthesis of indoline-1,3-dione formate
  • Example 76 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidine-2- Base) amino) pyrrolidin-1- yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) iso Indoline-1,3-dione, FA salt
  • Step 1 Synthesis of (R)-3-((5-chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 2 Synthesis of (R)-5-chloro-N 4 -(2-(ethylsulfonyl)phenyl)-N 2 -(pyrrolidin-3-yl)pyrimidine-2,4-diamine
  • Step 3 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of Phenyl-1,3-Diketone Formate
  • Example 77 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(methylsulfonyl)phenyl)amino)pyrimidine-2- Base) amino) pyrrolidin-1- yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) iso Indoline-1,3-dione, TFA salt
  • Step 1 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(thysulfonyl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of Phenyl-1,3-dione Trifluoroacetate
  • Example 78 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin- 1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione, TFA salt
  • DIPEA (1.04 mg, 8.00 mmol) was added to (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg, 1.60 mmol) and (R)-3 -Aminopyrrolidine-1-carboxylic acid tert-butyl ester (596 mg, 3.20 mmol) in NMP (7.00 mL), then stirred at 120° C. overnight.
  • Step 2 Synthesis of (R)-(2-((5-chloro-2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
  • Step 3 (R)-4-(2-(3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine- Synthesis of tert-butyl 1-yl)ethyl)piperidine-1-carboxylate
  • Step 4 (R)-(2-((5-Chloro-2-((1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl ) amino) phenyl) dimethyl phosphine oxide synthesis
  • Step 5 5-(4-((4-(2-((R)-3-)((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Synthesis of Isoindoline-1,3-dione Trifluoroacetate
  • Example 79 3-((4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl )amino)pyrrolidin-1-yl)ethyl)piperidin- 1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione
  • Step 4 (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(2-(1-((1-(4-nitrophenyl)piperidine- Synthesis of 4-yl)methyl)piperidin-4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine
  • Step 5 (R)-N-(1-(2-(1-((1-(4-aminophenyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)pyrrole Synthesis of alk-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine
  • Step 6 3-((4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Synthesis of amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione
  • Example 80 (R)-1-(4-(4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin -1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 1 Synthesis of ethyl 3-((4-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)amino)propanoate (1.12g, 12.5mmol) was added to DBU (1.90g, 12.5mmol), and after stirring for 2hrs, the mixture was added to 4-(4-((tert-butyldimethylsilyloxy)methyl)piperidine -1-yl)aniline (2.00g, 6.24mmol), after stirring for 5 minutes, ethyl acrylate (6.25g, 62.4mmol) was added, and then stirred overnight at 80°C.
  • Step 2 Synthesis of ethyl 3-(N-(4-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)cyanamido)propionate

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Abstract

La présente invention concerne un composé de 2-aminopyrimidine tel que représenté dans la formule (I), un sel pharmaceutiquement acceptable, un tautomère, un stéréoisomère, un solvate ou un promédicament de celui-ci, son procédé de préparation, et une composition pharmaceutique le comprenant. La présente invention concerne également une méthode de traitement ou de prévention de maladies ou de troubles liés à la kinase 12 dépendante des cyclines (CDK12), et une utilisation du composé dans la préparation d'un médicament pour le traitement ou la prévention de maladies ou de troubles liés à la CDK12.
PCT/CN2023/073500 2022-01-29 2023-01-28 Composé ou sel de 2-aminopyrimidine, son procédé de préparation et son utilisation WO2023143482A1 (fr)

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WO2024102849A1 (fr) * 2022-11-11 2024-05-16 Nikang Therapeutics, Inc. Composés bifonctionnels contenant des dérivés de pyrimidine 2,5-substitués pour dégrader la kinase 2 dépendante des cyclines par l'intermédiaire d'une voie ubiquitine-protéasome
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2024102849A1 (fr) * 2022-11-11 2024-05-16 Nikang Therapeutics, Inc. Composés bifonctionnels contenant des dérivés de pyrimidine 2,5-substitués pour dégrader la kinase 2 dépendante des cyclines par l'intermédiaire d'une voie ubiquitine-protéasome

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