WO2022214044A1 - Composés cycliques condensés de pyridine à substitution amine, leur procédé de préparation et leur utilisation - Google Patents

Composés cycliques condensés de pyridine à substitution amine, leur procédé de préparation et leur utilisation Download PDF

Info

Publication number
WO2022214044A1
WO2022214044A1 PCT/CN2022/085658 CN2022085658W WO2022214044A1 WO 2022214044 A1 WO2022214044 A1 WO 2022214044A1 CN 2022085658 W CN2022085658 W CN 2022085658W WO 2022214044 A1 WO2022214044 A1 WO 2022214044A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
membered
group
heteroaryl
cycloalkyl
Prior art date
Application number
PCT/CN2022/085658
Other languages
English (en)
Chinese (zh)
Inventor
赵吉辰
周福生
林崇懒
张涛
杨华彬
李震
兰炯
Original Assignee
劲方医药科技(上海)有限公司
浙江劲方药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 劲方医药科技(上海)有限公司, 浙江劲方药业有限公司 filed Critical 劲方医药科技(上海)有限公司
Priority to CN202280033521.XA priority Critical patent/CN117279896A/zh
Publication of WO2022214044A1 publication Critical patent/WO2022214044A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Hematopoietic progenitor kinase 1 is a hematopoietic system-specific serine/threonine protein kinase that belongs to the MAP4K family of mammalian ste20-related protein kinases. HPK1 is mainly expressed in hematopoietic tissues and cells. There are three activation modes of HPK1, namely serine phosphorylation, threonine phosphorylation or tyrosine phosphorylation. Previous studies have shown that in vitro HPK1-/- T cells have a lower TCR activation threshold, proliferate robustly, and produce more Th1 cytokines.
  • HPK1-/- mice develop more severe self when immunized with peptides derived from myelin oligodendrocyte glycoprotein (MOG) immune symptoms. Furthermore, in the PGE2-producing Lewis lung cancer tumor model, tumor development was significantly slower in HPK1-knockout mice compared with wild-type mice.
  • HPK1 can interact with many adaptor proteins, such as SLP-76 family, CARD11, HIS, HIP-55, GRB2 family, LAT, CRK family, etc., and activate the JNK/SAPK signaling pathway of hematopoietic stem cells, thereby Negative regulation of the TCR pathway.
  • the present invention provides an efficient HPK1 inhibitor with novel structure, which has the advantages of high activity, good selectivity, low toxicity and side effects, and has good physicochemical properties and drug-forming properties.
  • the first aspect of the present invention provides a compound represented by formula (A) or formula (D) or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • Cy1 ring is C 3-20 cycloalkyl, 3 to 20 membered heterocyclyl, C6-14 aryl or 5 to 20 membered heteroaryl; the 3 to 20 membered heterocyclyl, the 5 to 20 membered heterocyclyl Heteroaryl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
  • R x is a substituent at a position on the Cy2 ring
  • R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl);
  • R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl);
  • the bond between R 2a and the carbon atom is a single bond ;
  • R 2c and R 2d are each independently hydrogen, C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclic group;
  • the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms;
  • the 3- to 20-membered heterocyclic group is substituted with 1, 2, 3 or 4 groups selected from group S1; or
  • R 2a is hydrogen, deuterium or C when R 2c and R 2d together with the atoms to which they are attached form a 3- to 20-membered heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl group 1-6 alkyl (eg methyl),
  • R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); and the bond between R 2a and the carbon atom is a single bond;
  • the 3 to 20-membered Heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, or the 8- to 10-membered bicyclic heteroaryl each independently contains one nitrogen atom and optionally 1 or 2 independently selected from N, O, S and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally replaced by 1, 2 , 3 or 4 groups selected
  • Rx is in
  • Rx is in
  • R 2 is a substituent at any other position on the Cy2 ring; m is 0, 1, 2 or 3;
  • p1 is 0, 1 or 2;
  • R 7 is H, C 1-6 alkyl or deuterated C 1-6 alkyl
  • each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
  • a compound of formula (A) or a pharmaceutically acceptable salt, solvate or prodrug thereof is prepared by a method comprising the steps of:
  • Rm and Rm' are selected from reactive groups known in the art.
  • R x is a substituent at a position on the Cy2 ring
  • Ry and Ry' are selected from reactive groups known in the art.
  • the boronic acid group or boronic acid ester group is selected from or -B(OH) 2 .
  • the third aspect of the present invention provides a compound represented by formula (C) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 is a substituent at any position on the Cy1 ring; n is 0, 1, 2 or 3;
  • Rx is wherein, when R 2a and R 2d together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, R 2c is hydrogen; R 2b is hydrogen and the bond between R 2a and the carbon atom is a single bond or R 2b is absent and the bond between R 2a and the carbon atom is a double bond; the 3- to 20-membered heterocyclic group, the 5- or 6-membered The monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl groups each independently contain one nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the said The 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally surrounded by 1, 2,
  • Rx is wherein R 2e and R 2f together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group each independently contains a nitrogen atom and optionally 1 or 2 heterocyclic heteroaryl groups independently selected from N, O, S and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, and the 8- to 10-membered bicyclic heteroaryl are each independently optionally Or 4 groups selected from S1 group are substituted;
  • R 2 is a substituent at any other position on the Cy2 ring; m is 1 or 2; R 2 is selected from the group consisting of 3- to 20-membered heterocyclyl, -OC 3-20 cycloalkyl, -O-3 to 20-membered Heterocyclyl, -OC 6-14 aryl, -NH-C 3-20 cycloalkyl, -NH-3 to 20 membered heterocyclyl, N-5 to 20 membered heteroaryl, -NH-C 6- 14 Aryl; wherein, the 3- to 20-membered heterocyclic group, C 3-20 cycloalkyl, 5- to 20-membered heteroaryl, C 6-14 aryl are optionally replaced by 1, 2, 3 or 4 substituted with a group selected from the S3 group; the 3- to 20-membered heterocyclic group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, S as ring atoms;
  • Rx is in
  • R 2a is hydrogen, deuterium or C 1-6 alkyl (eg methyl); R 2b is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the bond between R 2a and the carbon atom is a single bond ; R 2c and R 2d are each independently C 1-6 alkyl, C 3-20 cycloalkyl or 3- to 20-membered heterocyclyl; and when R 2c is C 1-6 alkyl, R 2d is not 3 to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O, S as ring atoms; the 3- to 20-membered heterocyclic group is replaced by 1 , 2, 3 or 4 groups selected from group S1; or
  • R 2c and R 2d together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group
  • R 2a is deuterium
  • R 2b is hydrogen, Deuterium or C 1-6 alkyl (eg methyl) and the bond between R 2a and the carbon atom is a single bond
  • the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms
  • the 3- to 20-membered heterocyclic groups , the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted with 1, 2, 3 or 4 groups selected
  • R 2g , R 2h , R 2h' , R 2g' is hydrogen or deuterium or C 1-6 alkyl (eg methyl), at least one of R 2g , R 2h , R 2h' and R 2g' is deuterium;
  • the 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as a ring and the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally surrounded by 1, 2, 3, or 4 Replaced by
  • R 2d and R 2g together with the atoms connected to them form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group;
  • R 2c , R 2h , R 2h' , R 2g' is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heterocyclic group
  • the aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered
  • the monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
  • R 2d and R 2g' together with the atoms to which they are attached form a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group;
  • R 2c , R 2h , R 2h' , R 2g is hydrogen, deuterium or C 1-6 alkyl (eg methyl); the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl or the 8- to 10-membered bicyclic heterocyclic group
  • the aryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms; and the 3- to 20-membered heterocyclyl, the 5- or 6-membered
  • the monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
  • R x is a substituent at a position on the Cy2 ring
  • R 2e and R 2f together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group, the 3- to 20-membered heterocyclic group,
  • the 5- or 6-membered monocyclic heteroaryl groups or the 8- to 10-membered bicyclic heteroaryl groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as and the 3- to 20-membered heterocyclyl, the 5- or 6-membered monocyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted by 1, 2, 3, or 4 substituted with a group selected from group S1;
  • R 2c and R 2d together with the atoms to which they are attached constitute a 3- to 20-membered heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group
  • R 2a is deuterium
  • R 2b is hydrogen, deuterium or methyl
  • the bond between R 2a and the carbon atom is a single bond
  • the 3- to 20-membered heterocyclic group, the 5- or 6-membered monocyclic heteroaryl group, or the 8- to 10-membered bicyclic heteroaryl group groups each independently contain a nitrogen atom and optionally 1 or 2 heteroatoms independently selected from N, O, S as ring atoms
  • the cyclic heteroaryl, the 8- to 10-membered bicyclic heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 groups selected from group S1;
  • R x is a substituent at a position on the Cy2 ring
  • each R a , each R b , each R a1 , and each R b1 are independently H, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl base, -C 1-4 alkyl-hydroxyl, -C 1-4 alkyl-cyano, -C 1-4 alkyl-halogenated C 1-6 alkyl, -C 1-4 alkyl-deuterated C 1-6 alkyl, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halogenated C 1-6 alkoxy, -C 1-4 alkyl-deuterium Substituted C 1-6 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-4 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group,
  • each R d and each R d1 are independently H, C 1-6 alkyl or deuterated C 1-6 alkyl;
  • n hydrogen atoms on each of the above groups can be optionally substituted by R 1 ; n is 0, 1, 2 or 3; each R 1 is independently defined as before.
  • the Cy2 ring is selected from the group consisting of:
  • each R 2 is independently defined as above.
  • each of R x and R 2 is independently defined as above.
  • each of R x and R 2 is independently defined as above.
  • the hydrogen atoms on the ring in each of the above groups can be independently optionally substituted by 1, 2, 3 or 4 groups selected from the S1 group;
  • Rx is selected from the group consisting of: In each formula, each n1 and each n2 are independently 0, 1, 2 or 3; the hydrogen atoms in each of the above groups can be independently optionally replaced by 1, 2, 3 or 4 selected from the S1 group. group substituted.
  • Rx is selected from the group consisting of: In each formula, each n1 and each n2 are independently 0, 1, 2 or 3; the hydrogen atoms in each of the above groups can be independently optionally replaced by 1, 2, 3 or 4 selected from the S1 group. group substituted.
  • Rx is Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d are each independently H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl or 3 to 6 Monocyclic heterocyclyl.
  • Rx is Wherein, R 2a is H or deuterium; R 2b is H, deuterium or methyl; R 2c and R 2d are each independently H, C 1-6 alkyl, C 3-6 monocyclic cycloalkyl or 3 to 6 and when R 2c is C 1-6 alkyl, R 2d is not a 3- to 6-membered monocyclic heterocyclyl.
  • the boronic acid group or boronic acid ester group is selected from or -B(OH) 2 .
  • the compound of the present invention is selected from Table (I):
  • the 3- to 20-membered heterocyclic group is selected from the group consisting of: 3- to 6-membered monocyclic heterocyclic group, 7- to 11-membered spiro heterocyclic group, 6- to 10-membered condensed heterocyclic group Heterocyclyl, 6- to 14-membered bridged heterocyclyl.
  • each R a , each R b , each R a1 , each R b1 is each independently hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl base, -C 1-2 alkyl-hydroxyl, -C 1-2 alkyl-cyano, -C 1-2 alkyl-halogenated C 1-4 alkyl, -C 1-2 alkyl-deuterated C 1-4 alkyl, -C 1-2 alkyl-C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkoxy, -C 1-2 alkyl-deuterium Substituted C 1-4 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-OC 3-6 mono Cyclocycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -C
  • each R d , each R d1 is each independently hydrogen, C 1-4 alkyl, or deuterated C 1-4 alkyl.
  • each R c , each R c1 is each independently hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy base, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkyl, -C 1-2 alkyl-deuterated C 1-4 alkyl, -C 1-2 alkyl-C 1-4 alkoxy, -C 1-2 alkyl-halogenated C 1-4 alkoxy, -C 1-2 alkyl-deuterated C 1-4 alkoxy, C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-C 3-6 monocyclic cycloalkyl, -C 1-2 alkyl-OC 3-6 monocyclic Cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, -C 1-2 alkyl-3 to 6-membered monocyclic
  • the -C 1-2 alkyl- is unsubstituted; or the hydrogen atoms on the -C 1-2 alkyl- are each independently selected from halogen, cyano, hydroxyl, C 1- 4 alkyl group, halogenated C 1-4 alkyl group, deuterated C 1-4 alkyl group, -CH 2 -hydroxyl group, -CH 2 -cyano group, phenyl group substituted or C 1-2 alkyl group Two hydrogen atoms of the same carbon atom are simultaneously substituted with -(CH 2 ) j - to form a cycloalkyl group, where j is 2, 3, 4, 5 or 6.
  • any 3 to 6 membered monocyclic heterocyclyl is selected from the group consisting of: aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole , piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran; the 3- to 6-membered monocyclic heterocyclic group is optionally replaced by 1, substituted with 2, 3 or 4 groups selected from group S1.
  • any one 5 or 6 membered monocyclic heteroaryl is selected from the group consisting of thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2 ,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine ;
  • the 5- or 6-membered monocyclic heteroaryl group is optionally substituted by 1, 2, 3 or 4 groups selected from the S1 group.
  • Cy2 ring As described in this article, may be referred to as the Cy2 ring. may be referred to as the Cy1 ring.
  • a fourth aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising the compound described in the first, second or third aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be administered orally, by inhalation, rectally, nasally, bucally, topically, parenterally, such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
  • parenterally such as subcutaneously, intravenously, intramuscularly , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the present invention may be formulated in any orally acceptable formulation, including but not limited to tablets, capsules, aqueous solutions or suspensions. Carriers for tablets typically include lactose and cornstarch, although lubricants such as magnesium stearate may also be added.
  • Diluents used in capsule formulations typically include lactose and dried cornstarch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral formulations.
  • the compounds of the present invention can be prepared into different topical formulations according to different affected surfaces or organs
  • the compounds of the present invention when administered topically to the eye, may be formulated as a micronized suspension or solution in the form of an isotonic, pH, sterile, isotonic carrier, with or without the addition of a preservative such as Benzyl alkoxide chloride.
  • the compounds can also be formulated in the form of an ointment such as petrolatum ointment.
  • the compounds of the present invention may be formulated in a suitable ointment, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions.
  • Useful vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils can also be employed as a solvent or suspending medium such as mono- or diglycerides.
  • Another aspect of the present invention provides the compound of the above-mentioned first, second or third aspect or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof or the pharmaceutical composition of the above-mentioned fourth aspect in the preparation of prophylaxis and/or use in a medicament for the treatment of a disease or condition; a disease or condition associated with HPK1 activity.
  • the disease or disorder is cancer.
  • Another aspect of the present invention provides the compound described in the first, second or third aspect above, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or the pharmaceutical composition described in the fourth aspect above. Use in HPK1 inhibitors.
  • Another aspect of the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described in the first, second or third aspect or a pharmaceutically acceptable salt thereof, A stereoisomer, solvate or prodrug, or any combination of the above, or the step of administering the pharmaceutical composition of the fourth aspect above.
  • the term "subject” refers to an animal, particularly a mammal. People are preferred.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of a drug or agent to achieve the desired effect.
  • the amount of a given drug depends on factors such as the particular dosing regimen, the type of disease or condition and its severity, the subject in need of treatment or the uniqueness of the host (e.g. body weight), however, the dose to be administered may be known in the art depending on the particular surrounding circumstances, including, for example, the particular drug that has been employed, the route of administration, the condition being treated, and the subject or host being treated method is routinely determined.
  • the administered dose is typically in the range of 0.02-5000 mg/day, eg, about 1-1500 mg/day.
  • the desired dose may conveniently be presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, eg, two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound.
  • Such salts include: acid addition salts with inorganic acids or organic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, caproic acid, cyclopentanoic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases Formed coordination compounds, the organic bases such as ethanolamine and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • solvate and “solvate” refer to substances formed by combining a compound of the present invention with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include acetic acid and the like.
  • Solvates include stoichiometric amounts and non-stoichiometric amounts of solvates. Certain compounds of the present invention may exist in unsolvated as well as solvated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds described in the present invention may exist in stereoisomeric forms, and therefore all possible stereoisomeric forms are encompassed, including but not limited to cis-trans isomers, tautomers, enantiomers, non-isomers Enantiomers, atropisomers, etc.
  • the compounds of the present invention can also be in any combination or any mixture of the aforementioned stereoisomers, such as meso, racemate, atropisomer exist in the form of an equivalent mixture.
  • a single enantiomer, a single diastereomer or a mixture of the above, or a single atropisomer or a mixture thereof When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, they include cis isomers and trans isomers, and any combination thereof.
  • Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation. And as a drug, a stereoisomer having excellent activity is preferable.
  • the compounds of the present invention have optical isomers derived from asymmetric carbons and the like, and if necessary, single isomers can be obtained by separation by methods known in the art, such as crystallization or chiral chromatography.
  • halophenyl refers to a phenyl group having only halogen as a substituent; excluding one substituent on the phenyl group which is a halogen and the other substituents being substituents other than halogen.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbyl group.
  • C 1-20 alkyl refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms. Preferably it is a C 1-10 alkyl group. More preferred are C1-6 alkyl groups (ie straight or branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms). More preferred is C 1-4 alkyl. More preferred is C 1-3 alkyl.
  • Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various Branched chain isomers, etc.
  • alkoxy refers to a group having the structure -O-alkyl, wherein alkyl is as defined above.
  • C 1-10 alkoxy refers to an alkoxy group having 1 to 10 carbon atoms. Preferred is C 1-6 alkoxy. More preferred is C 1-4 alkoxy. More preferred is C 1-3 alkoxy. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkoxy refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by halogen, wherein alkoxy is as defined above.
  • haloC 1-10 alkoxy refers to a haloalkoxy having 1 to 10 carbon atoms.
  • Preferred is halogenated C 1-6 alkoxy. More preferred is a halogenated C 1-4 alkoxy group. More preferred is a halogenated C 1-3 alkoxy group. Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • deuterated alkyl refers to an alkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by deuterium atoms, wherein alkyl is as defined above.
  • deuterated C 1-10 alkyl refers to a deuterated alkyl group having 1 to 10 carbon atoms. Deuterated C 1-6 alkyl is preferred. More preferred is deuterated C 1-4 alkyl. More preferred is deuterated C 1-3 alkyl. Specific examples include, but are not limited to, deuteromethyl, dideuteromethyl, trideuteromethyl, monodeuteroethyl, 1,2-dideuteroethyl, trideuteroethyl, and the like.
  • deuterated alkoxy refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by deuterium atoms, wherein alkoxy is as defined above .
  • deuterated C 1-10 alkoxy refers to a deuterated alkoxy group having 1 to 10 carbon atoms. Preferred is deuterated C 1-6 alkoxy. More preferred is deuterated C 1-4 alkoxy. More preferred is deuterated C 1-3 alkoxy.
  • Specific examples include, but are not limited to, tri-deuteriomethoxy, tri-deuteroethoxy, mono-deuteromethoxy, mono-deuteroethoxy, dideuteromethoxy, dideuteroethoxy, and the like.
  • cycloalkyl and “cycloalkyl ring” are used interchangeably and refer to saturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic cycloalkyls, spirocycloalkyls, fused cycloalkanes and bridged cycloalkyl groups.
  • the ring carbon atoms of the cycloalkyl group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure.
  • 3 to 20 membered cycloalkyl or "C 3-20 cycloalkyl” refers to a cycloalkyl group having 3 to 20 ring carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. Preferably it is C 3-12 cycloalkyl, C 5-20 spirocycloalkyl, C 5-20 fused cycloalkyl or C 5-20 bridged cycloalkyl. More preferred is C 3-8 monocyclic cycloalkyl.
  • C 3-8 monocyclic cycloalkyl and “3- to 8-membered monocyclic cycloalkyl” refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 ring carbon atoms.
  • it is a C 3-6 monocyclic cycloalkyl group (ie, a 3- to 6-membered monocyclic cycloalkyl group) or a C 4-6 monocyclic cycloalkyl group (ie, a 4- to 6-membered monocyclic cycloalkyl group). More preferred is a C3, C4 , C5 or C6 monocyclic cycloalkyl.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • spirocycloalkyl and “spirocycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by two or more monocyclic rings sharing one carbon atom (referred to as a spiro atom). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl groups, double-spirocycloalkyl groups and poly-spirocycloalkyl groups.
  • 5- to 20-membered spirocycloalkyl or "C 5-20 spirocycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the single ring sharing the spiro atoms is 3 to 8 membered Monocyclic cycloalkyl ring.
  • Preferred are 6 to 14 membered (ie C6-14 ) spirocycloalkyl. More preferred is a 6- to 14-membered monospirocycloalkyl. More preferred is a 7- to 11-membered (ie C7-11 ) spirocycloalkyl.
  • fused cycloalkyl and “fused cycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group in which two or more monocyclic rings are formed by sharing an adjacent pair of carbon atoms. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl.
  • the term “5 to 20 membered fused cycloalkyl” or " C5-20 fused cycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic rings sharing adjacent pairs of carbon atoms are 3 to 20 ring carbon atoms.
  • 8-membered monocyclic cycloalkyl ring Preferably it is a 6- to 14-membered (ie C 6-14 ) fused cycloalkyl group. More preferred is a 6- to 14-membered di-fused cycloalkyl group. More preferred is a 7- to 10-membered (ie C 7-10 ) fused cycloalkyl group. More preferred is a 7- to 10-membered di-fused cycloalkyl group.
  • fused cycloalkyl include, but are not limited to:
  • fused cycloalkyl groups can be attached to the rest of the molecule through any one of the ring atoms.
  • bridged cycloalkyl groups include, but are not limited to:
  • bridged cycloalkyl groups can be attached to the remainder of the molecule through any one of the ring atoms.
  • halocycloalkyl refers to a cycloalkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms have been replaced by halogen, wherein cycloalkyl is as defined above.
  • haloC 3-8 monocyclic cycloalkyl refers to a halogenated monocyclic cycloalkyl having 3 to 8 ring carbon atoms. Preferably it is a halogenated C 3-6 monocyclic cycloalkyl. More preferred is a haloC3 , haloC4 , haloC5 or haloC6 monocyclic cycloalkyl. Specific examples include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • heterocyclyl and “heterocyclyl ring” are used interchangeably and refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclyl, spiroheterocyclyl , fused heterocyclyl and bridged heterocyclyl.
  • the ring carbon atoms of the heterocyclic group in the present invention can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • the 3- to 20-membered heterocyclyl groups of the present invention include monocyclic heterocyclyl groups (eg, 3- to 8-membered monocyclic heterocyclyl groups), 5- to 20-membered spiro heterocyclyl groups, 5- to 20-membered fused heterocyclyl groups, and 5- to 20-membered fused heterocyclyl groups. to 20-membered bridged heterocyclyl.
  • a 4- to 6-membered monocyclic heterocyclyl group having 4 to 6 ring atoms, of which 1 or 2 are heteroatoms. More preferred is a 5- or 6-membered monocyclic heterocyclyl having 5 or 6 ring atoms, of which 1 or 2 are heteroatoms.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • the heteroatom is a sulfur atom
  • the ring carbon atoms of the monocyclic heterocyclyl may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • monocyclic heterocyclyl groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2 -one, oxazolidine, pyrrolidin-2-one, pyrrolidin-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3
  • azetidinyl ie, tetrahydropyrrole
  • azepinyl ie, hexahydropyridine
  • morpholinyl morpholinyl
  • piperazinyl oxazolidine
  • 3 to 8 membered monocyclic heterocycloalkyl refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms.
  • it is a 3- to 6-membered monocyclic heterocycloalkyl, ie a saturated monocyclic cyclic hydrocarbon group having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms.
  • heterocycloalkyl examples include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolanyl, Dioxane, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1- Dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazepanyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1 ,4-dioxanyl.
  • spiroheterocyclyl and “spiroheterocyclyl ring” refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (referred to as a spiro atom).
  • the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
  • 5- to 20-membered spiroheterocyclyl refers to a spiroheterocyclyl having 5 to 20 ring atoms, wherein one of the monocycles sharing the spiro atoms is a 3- to 8-membered monocyclic heterocyclyl ring and the other
  • the monocycle is a 3- to 8-membered monocyclic heterocyclyl ring or a 3- to 8-membered monocyclic cycloalkyl ring.
  • 7 to 11 membered spiroheterocyclyl groups having 7 to 11 ring atoms, of which 1 or 2 are heteroatoms.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • Each single ring may contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Shared pairs of adjacent ring atoms can be CC or NC. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups.
  • the term "5- to 20-membered fused heterocyclyl” refers to a fused heterocyclyl group having 5 to 20 ring atoms, wherein the monocycles sharing adjacent pairs of ring atoms are 3- to 8-membered monocyclic heterocyclyl rings.
  • Preferred is a 6- to 14-membered fused heterocyclic group having 6 to 14 ring atoms, of which 1 or 2 are heteroatoms.
  • fused heterocyclic groups include, but are not limited to:
  • fused heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
  • 5- to 20-membered bridged heterocyclyl refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms, wherein any two rings share two non-directly connected ring atoms, each monocyclic Rings can contain one or more double bonds, but no ring has a fully conjugated pi electron system.
  • Preferred is a 6- to 14-membered bridged heterocyclyl group. More preferred is a 7- to 10-membered bridged heterocyclyl group.
  • Specific examples of bridged heterocyclyl groups include, but are not limited to:
  • bridged heterocyclyl groups can be attached to the remainder of the molecule through any suitable ring atom.
  • the above various types of heterocyclic groups may be optionally substituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
  • aryl As used herein, the terms “aryl”, “aryl ring” and “aromatic ring” are used interchangeably and refer to an all-carbon monocyclic, all-carbon non-fused polycyclic ring (rings connected to rings by covalent bonds, non-fused group) or all-carbon fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups in which at least one ring is aromatic, ie, has a conjugated pi-electron system.
  • C 6-14 aryl refers to an aryl group having 6 to 14 ring atoms. Preferably it is a C 6-10 aryl group.
  • the C 6-14 aryl group in the present invention includes a monocyclic aryl group, a non-fused polycyclic aryl group and an aromatic fused polycyclic group, wherein examples of the monocyclic aryl group include phenyl, and examples of the non-fused polycyclic aryl group include Biphenyl, etc.
  • the aromatic condensed polycyclic ring may be a polycyclic group formed by condensing a single aryl ring with one or more single aryl rings , non-limiting examples of which include naphthyl, anthracenyl, and the like.
  • the above-mentioned various aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in this application.
  • heteroaryl As used herein, the terms “heteroaryl”, “heteroaryl ring” and “heteroaromatic ring” are used interchangeably to refer to a monocyclic or fused ring having ring atoms substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur.
  • the heteroaryl group has 6, 10 or 14 pi electrons shared and at least one ring in the group is aromatic.
  • the fused bicyclic heteroaryl group can be either a bicyclic group formed by condensing a single aryl ring (such as phenyl) with a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).
  • the 2 ring atoms connected arbitrarily on the above-mentioned monocyclic heteroaryl ring, including C-C, N-C, N-N, can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monoaryl ring, 5 Or 6-membered monocyclic heteroaryl ring and other cycloalkyl, heterocyclyl, aryl or heteroaryl are fused to form a fused polycyclic ring.
  • the 2 ring atoms attached to the monocyclic heteroaryl ring forming a fused ring with other rings are preferably C-C, including without limitation the following forms:
  • Non-limiting examples of 8- to 10-membered bicyclic heteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, iso Quinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[ 4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-nap
  • the fused bicyclic heteroaryl or fused tricyclic heteroaryl may be a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a A polycyclic group formed by condensing multiple non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.
  • the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the Ring carbon atoms can be substituted with 1 or 2 oxo groups to form a cyclic ketone structure) and the like.
  • a 3- to 6-membered monocyclic heterocyclyl ring preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be replaced by 1 to 2 oxo group substitution to form a cycl
  • the non-aromatic heterocycle includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be 2 oxo groups are substituted to form a cyclic lactam or cyclic lactone structure), etc.
  • the polycyclic group formed by condensing the above-mentioned monocyclic aryl ring and one or more non-aromatic heterocycles can be connected with other groups or parent structures through nitrogen atoms or carbon atoms, and the ring connected with the parent structure is a monocyclic aryl group Ring or non-aromatic heterocycle.
  • heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in the present application.
  • hydroxy refers to -OH.
  • hydroxymethyl refers to -CH2OH and "hydroxyethyl” refers to -CH2CH2OH or -CH(OH ) CH3 .
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • benzyl refers to -CH2 -benzene.
  • acetyl refers to -COCH3 .
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, which may include deuterium and hydrogen variants, so long as the valence of the specified atom is normal and the substituted compound is stable.
  • optionally substituted or “optionally substituted” means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any group if If the label is on a bond (not the bond itself), it means that the bond labeled by the group is attached to the rest of the molecule.
  • any group or compound structural formula if a chemical bond connected to a double bond is drawn as It means that the group or compound can be a mixture of cis-isomer and trans-isomer.
  • Step 2 Add 7-bromoisoquinolin-1-amine (500mg, 2.24mmol), bis(pinacol)diboron (683mg, 2.69mmol), [1,1'-bis(2.69mmol) to a 50mL round-bottomed flask (diphenylphosphino)ferrocene]palladium dichloride (161 mg, 0.22 mmol), potassium acetate (658 mg, 6.72 mmol), 1,4-dioxane (15 mL), nitrogen replaced three times, the reaction was carried out at 95°C Reaction for 16h.
  • Step 3 Add 7-fluoro-3-iodoimidazo[1,2-a]pyridine (500 mg, 1.91 mmol), isoquinolin-1-amine-7-boronic acid (1.0 g, 3.82 mmol) to a 50 mL round-bottomed flask mmol), potassium carbonate (791 mg, 5.73 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (139 mg, 0.19 mmol), 1,4-dioxane (20 mL ) and water (5 mL), nitrogen was replaced three times, and the reaction was carried out at 100° C. for 4 hours.
  • Step four 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (294 mg, 1.06 mmol) was dissolved in N,N-dimethylformamide (8 mL) ) N-iodosuccinimide (262 mg, 1.17 mmol) was added in an ice bath, and the reaction was stirred at room temperature for 4 h. Water (30 mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried under vacuum.
  • Step six 2-(6-(1-(1-amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl]isoquinolin-4-yl)isochroman-8 -yl) tert-butyl pyrrolidine-1-carboxylate (50mg, 0.086mmol) was dissolved in methanol (1ml), 4M hydrochloric acid dioxane solution (3ml) was added, and the reaction was stirred at room temperature for 1 hour.
  • reaction solution was concentrated, 7.0M ammonia methanol solution (4 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate method) to obtain 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4- (8-(pyrrolidin-2yl)isochroman-6-yl)isoquinolin-1-amine (Z1, 20 mg, 78% yield), white solid.
  • Step 1 Add 1-(5-bromo-2-(tetrahydro-2H-pyran-4-yl)phenyl)-N,N-dimethylmethylamine (90mg, 0.30mmol) to a 5mL microwave tube , bispinacol borate (91mg, 0.36mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (22mg, 0.03mmol), potassium acetate (88mg, 0.90 mmol), 1,4-dioxane (2 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 120 °C for 30 min.
  • bispinacol borate 9mg, 0.36mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium 22mg, 0.03mmol
  • potassium acetate 88mg, 0.90 mmol
  • 1,4-dioxane (2
  • Step 2 Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (60mg, 0.15mmol) to a 5mL microwave tube, N, N-Dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroyl) Alk-2-yl)phenyl)methanamine (185 mg, crude), potassium carbonate (62 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2 mL) and water (0.4 mL), purged with nitrogen for 1 min, and reacted at 100 °C for 1 h in a microwave reactor.
  • N N-Dimethyl-1-(2-(tetrahydro-2H-pyr
  • Step 1 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (160mg, 0.396mmol) and di-tert-butyl dicarbonate (305mg , 1.40mmol) was suspended in dichloromethane (10mL) at room temperature, added N,N-diisopropylethylamine (206mg, 1.60mmol) and 4-dimethylaminopyridine (8mg, 0.06mmol), the reaction was stirred at room temperature 18h. The reaction solution was concentrated, and water (10 mL) was added, followed by extraction with ethyl acetate (50 mL).
  • Step 2 Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo-1-(bis(tert-butyloxycarbonyl)amino)iso to a 50mL round-bottomed flask Quinoline (150 mg, 0.25 mmol), bispinacol borate (126 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (27 mg, 0.038 mmol) ), potassium acetate (74 mg, 0.75 mmol), N,N-dimethylformamide (4 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 3 hours.
  • Step 3 1-(6-Chloro-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-N,N-dimethylmethylamine (65mg, 0.25mmol), 7- (7-Fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl )-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (280mg, crude), potassium carbonate (103mg, 0.75mmol), 2-dicyclohexylphosphine-2',6'-dimethoxy - Biphenyl (10 mg, 0.025 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1' - Biphenyl-2-yl)palladium(II
  • Step 1 Dissolve tert-butyl 4-(5-bromothiazol-2-yl)piperidine-1-carboxylate (35 mg, 0.1 mmol) in dichloromethane (0.2 mL), add trifluoroacetic acid dropwise with stirring (0.2 mL). The reaction was completed at room temperature for 2 hours. After the reaction solution was concentrated, it was dissolved in dichloromethane (1 mL), and 3 drops of aqueous formaldehyde solution were added to the system. After the reaction was stirred for 15 minutes, sodium triacetylborohydride (64 mg, 0.3 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction was completely converted.
  • Step 2 In a 10 mL sealed tube, 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (60 mg, 0.1 mmol), 5-bromo-2-(1-methylpiperidine) -4-yl)thiazole (30 mg, crude product) was dissolved in 1,4-dioxane (0.8 mL), an aqueous solution of potassium carbonate (41 mg, 0.3 mmol) (0.2 mL) and [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (7 mg, 0.01 mmol).
  • Step three 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(2-(1-methylpiperidin-4-yl)thiazol-5-yl)- 1-(Bis(tert-butyloxycarbonyl)amino)isoquinoline (70 mg, crude) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added with stirring. The reaction was stirred at room temperature for 4 hours.
  • Step 2 3-(3,6-Dihydro-2H-pyran-4-yl)thiophene-2-carbaldehyde (1.7g, 8.76mmol) and methylamine hydrochloride (2.96g, 43.80mmol) were suspended in acetonitrile (40 mL), sodium cyanoborohydride (1.1 g, 17.52 mmol) was added, and the reaction was allowed to react at room temperature for 24 hours. Adjust the pH of the reaction solution to 10 with 1M sodium hydroxide solution, spin off most of the acetonitrile, and extract with dichloromethane (40 mL ⁇ 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step six ((5-bromo-3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)methyl)(methyl)carbamate (1.25g, 3.20mmol) was dissolved in To formic acid (10 mL), 37% aqueous formaldehyde solution (4 mL) was added, and the reaction was stirred at 80° C. for 3 hours. The reaction solution was concentrated, saturated sodium bicarbonate (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 7 Add 1-(5-bromo-3-(tetrahydro-2H-pyran-4-yl)thiophen-2-yl)-N,N-dimethylmethylamine (61mg, 0.20 mmol), bispinacol borate (76 mg, 0.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), potassium acetate ( 59 mg, 0.60 mmol), N,N-dimethylformamide (1.5 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 100 °C for 1 h.
  • Step 8 7-Fluoroimidazo[1,2-a]pyridine (3.0g, 22.06mmol) was suspended in acetonitrile (50mL), and N-bromosuccinimide (4.12g, 23.16mmol) was added under ice bath , and the reaction was stirred under ice bath for 1 h.
  • the reaction solution was added with saturated sodium thiosulfate (30 mL), saturated sodium bicarbonate (30 mL) and water (30 mL), and extracted with dichloromethane (50 mL ⁇ 2). The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step 9 3-Bromo-7-fluoroimidazo[1,2-a]pyridine (3.0 g, 13.95 mmol) and isopropanol pinacol boronate (7.78 g, 41.85 mmol) were dissolved in tetrahydrofuran (60 mL) , isopropylmagnesium chloride lithium chloride tetrahydrofuran solution (21.50mL, 27.90mmol, 1.3M) was added dropwise at 0°C under nitrogen protection, and the reaction was stirred at 0°C for 2h.
  • Step ten add 3-bromo-1,6-naphthyridine (700mg, 3.13mmol), 7-fluoro-3-(4,4,5,5-tetramethyl-1,3, 2-Dioxaboran-2-yl)imidazo[1,2-a]pyridine (4.0 g, crude), sodium carbonate (1.33 g, 12.52 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (227 mg, 0.31 mmol), 1,4-dioxane (50 mL) and water (10 mL), replaced with nitrogen three times, and reacted at 100° C. for 4 hours.
  • Step eleven 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1,6-naphthyridin-5-amine (685 mg, 2.45 mmol) was dissolved in N,N-dimethyl N-iodosuccinimide (606 mg, 2.70 mmol) was added to N-iodosuccinimide (20 mL) in an ice bath, and the reaction was stirred at room temperature for 24 hours.
  • Step 12 add 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-8-iodo-1,6-naphthyridin-5-amine (40 mg, 0.10 mmol), N,N-dimethyl-1-(3-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaboran-2-yl)thiophen-2-yl)methanamine (130 mg, crude), potassium carbonate (41 mg, 0.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (7 mg, 0.01 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 110° C.
  • Step 2 Dissolve 2-(2-chloroacetyl)pyrrolidine-1-carboxylate tert-butyl ester (10g, 40.4mmol) in ethanol (200mL), add thiourea (3.07g, 40.4mmol) at room temperature, heat to The reaction was stirred at 90°C for 3 hours.
  • Step 4 Dissolve tert-butyl 2-(2-bromothiazol-4-yl)pyrrolidine-1-carboxylate (66.2 mg, 0.20 mmol) in dioxane (10 mL) and water (2 mL) at room temperature Add 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1, 1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol), under nitrogen The reaction was stirred at 100°C for 2 hours.
  • Step 2 2-Bromo-6,7-dihydro-benzo[d]thiazol-4(5H)-one (320 mg, 1.38 mmol) was dissolved in dichloromethane (10 mL), and methylamine hydrochloride was added at room temperature (138.7 mg, 2.07 mmol), N,N-diisopropylethylamine (3 mL), stirred for 20 minutes, added acetic acid (5 mL), stirred at room temperature for 16 hours, and added sodium cyanoborohydride ( 260.8 mg, 4.14 mmol).
  • Step 3 2-Bromo-N-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (49.4 mg, 0.20 mmol) was dissolved in dioxane (10 mL) and water (2 mL), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-di Methoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol), the reaction was stirred at 100 °C for 2 hours under nitrogen protection.
  • Step 4 2-(1-(bis(tert-butyloxycarbonyl)amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-N -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (56mg, 0.09mmol) was dissolved in dichloromethane (4mL), trifluoroacetic acid (2mL) was added, and the reaction was carried out at room temperature for 1 The reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (trifluoroacetic acid method) to obtain 2-(1-amino-7-(7-fluoroimidazo[1, 2-a]pyridin-3-yl)isoquinolin-4-yl)-N-methyl-4,5,6,7-tetrahydrobenzo[d]thia
  • Step 1 Methyl 2-((tert-butoxycarbonyl)amino)-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (900mg, 2.63mmol) was dissolved in dichloromethane ( 5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated, adjusted to pH 8 with saturated sodium bicarbonate (30 mL), a solid was precipitated, filtered, the filter cake was washed with water (10 mL), and dried in vacuo to obtain 2-amino-5-(tetrahydro-2H-pyran-4- (395 mg, yield: 62%), white solid.
  • ES-API: [M+H] + 243.1.
  • Step 2 copper bromide (950mg, 4.26mmol) was dissolved in acetonitrile (6mL), tert-butyl nitrite (219mg, 2.13mmol) was added dropwise at room temperature, the reaction was heated to 60°C, 2-amino-5-( A suspension (7 mL) of methyl tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (345 mg, 1.42 mmol) in acetonitrile was stirred at 60°C for 2 hours. The reaction solution was poured into 1M aqueous sodium hydroxide solution (20 mL), and extracted with ethyl acetate (30 mL ⁇ 2).
  • Step 3 Methyl 2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carboxylate (285 mg, 0.93 mmol) was dissolved in tetrahydrofuran (5 mL), and hydroboration was added dropwise under ice bath A solution of lithium in tetrahydrofuran (0.93 mL, 1.86 mmol, 2.0 M), the reaction was stirred under an ice bath for 30 minutes and at room temperature for an additional 2 hours. The reaction was quenched with water (8 mL) and 1.0 M dilute hydrochloric acid (4 mL) under ice bath, and extracted with ethyl acetate (30 mL ⁇ 2).
  • Step 4 (2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (230 mg, 0.83 mmol) and triethylamine (210 mg, 2.08 mmol) were dissolved in dichloro Methane (10 mL) was added dropwise with methanesulfonyl chloride (142 mg, 1.24 mmol) under an ice bath, and the reaction was stirred under an ice bath for 2 hours.
  • Step 5 Methyl (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methylmethanesulfonate (295 mg, 0.83 mmol) was dissolved in tetrahydrofuran (5 mL), room temperature A 2.0M solution of dimethylaminetetrahydrofuran (10 mL, 20.0 mmol) was added under it, and the reaction was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (40 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 6 Add 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N,N-dimethylmethanamine (45mg, 0.15mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (200 mg, crude), potassium carbonate (62 mg, 0.45 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2 mL) and water (0.5 mL), purged with nitrogen for 1 min, at 110 °C in a microwave reactor The reaction was carried out for 45 minutes.
  • Step 7 4-(4-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1 ,2-a]pyridin-3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (35 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added , at room temperature for 1 hour.
  • Step 1 copper bromide (637.1 mg, 2.85 mmol) was dissolved in anhydrous acetonitrile (5 mL), tert-butyl nitrite (392.4 mg, 3.81 mmol) was added, 2-amino-6 was added after stirring at room temperature for 2 minutes, 7-Dihydrobenzo[d]thiazol-4(5H)-one (400 mg, 2.38 mmol), the reaction solution was stirred at room temperature for 2 hours.
  • Step 2 2-Bromo-6,7-dihydro-benzo[d]thiazol-4(5H)-one (320 mg, 1.38 mmol) was dissolved in dichloromethane (10 mL) and methylamine hydrochloride was added at room temperature (138.7 mg, 2.07 mmol), N,N-diisopropylethylamine (3 mL), after stirring for 20 minutes, acetic acid (5 mL) was added, and after stirring at room temperature for 16 hours, sodium cyanoborohydride ( 260.8 mg, 4.14 mmol).
  • Step 4 2-Bromo-N,N-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-4-amine (52.2mg, 0.20mmol) was dissolved in dioxane (10.0 mL) and water (2.0 mL), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2 ',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), phosphoric acid Potassium (127.2 mg, 0.60 mmol), and the reaction was stirred at 100 °C
  • Step 1 (2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methanol (300 mg, 1.08 mmol) was dissolved in dichloromethane (25 mL), added under ice bath Dess-Martin oxidizer (572 mg, 1.35 mmol) and the reaction was stirred at room temperature for 3 hours. Dichloromethane (25 mL) was added to the reaction solution, washed with saturated sodium bicarbonate solution (25 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 4 Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 55mg, 0.14mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (147 mg, crude), potassium carbonate (58 mg, 0.42 mmol), [1,1'-bis(bis(bis)) Phenylphosphine)ferrocene]palladium dichloride (10 mg, 0.014 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, in a microwave reactor for 110 The reaction was carried out at
  • Step five (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7- Di-tert-butyl (7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate (27 mg, 0.034 mmol) was dissolved in methanol (1 mL) and 4.0 M was added A solution of hydrogen chloride in dioxane (4 mL, 16.0 mmol) was allowed to react at room temperature for 18 hours.
  • Step 2 Into a 5mL microwave tube, add: 1-(2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)-N,N-dimethylmethanamine (50mg, 0.17mmol), 7 -(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (128 mg, crude), potassium carbonate (71 mg, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (13 mg, 0.017 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, and reacted in a microwave reactor at 110° C.
  • Step 3 4-(4-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)-7-(7-fluoroimidazo[1,2-a]pyridine -3-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (37 mg, 0.05 mmol) was dissolved in methanol (1 mL) and 4.0 M hydrogen chloride solution in dioxane (5 mL, 20.0 mmol) was added, The reaction was carried out at room temperature for 18 hours.
  • Step 1 2-Bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole-4-carbaldehyde (500mg, 1.81mmol) and (S)-2-methylpropane-2-sulfinamide ( 439 mg, 3.62 mmol) was dissolved in dichloromethane (25 mL), titanium tetraethoxide (1.03 g, 4.53 mmol) was added, and the reaction was stirred at room temperature for 18 hours. Saturated brine (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL ⁇ 2).
  • Step 2 (S,E)-N-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methylene)-2-methylpropane-2- Sulfonamide (570 mg, 1.50 mmol) was dissolved in tetrahydrofuran (15 mL), and 0.5 M (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide tetrahydrofuran solution was added dropwise at -78°C under nitrogen protection (1.05 mL, 0.53 mmol) and the reaction was stirred at -78 °C for 30 minutes.
  • Step 4 (S)--2-Bromo-4-(pyrrolidin-2-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole trifluoroacetate (2.5g, crude product) Dissolved in dichloromethane (15 mL), triethylamine (800 mg, 7.91 mmol) and di-tert-butyl dicarbonate (650 mg, 7.91 mmol) were added at 0°C, and the reaction was stirred at room temperature for 1 hour. Dichloromethane (25 mL) was added to the reaction solution, washed successively with water (10 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 Add (S)-2-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)pyrrolidine-1-carboxylic acid tert-butyl into a 5mL microwave tube Ester (60 mg, 0.14 mmol), 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (130 mg, crude), potassium carbonate (60 mg, 0.43 mmol), [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.014 mmol), 1,4-dioxane (1.5 mL) and water (0.3 mL), purged with nitrogen for 1 min, in a microwave reactor The reaction was carried out at 110
  • Step 1 1-benzyl 2-methylpiperidine-1,2-dicarboxylate (5.0 g, 18.1 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), chloroiodomethane (15.9 g, 90.5 mmol) was added, Stir at room temperature for 2 minutes, cool down to -78 ° C and stir for 10 minutes, slowly add lithium diisopropylamide solution (45.3 mL, 2 M, 90.5 mmol) dropwise within 1.5 hours, keep the temperature below -70 ° C during the period, and drop after dropping in React at -78°C for 1 hour, then add acetic acid/tetrahydrofuran mixed solution (1:3, 80mL), stir at -78°C for 10 minutes, warm to room temperature, pour the reaction solution into water (50mL), add acetic acid Extracted with ethyl ester (200 mL ⁇ 2), dried over anhydrous sodium sulfate, concentrated by filtration and purified by si
  • Step 2 Benzyl 2-(2-chloroacetyl)piperidine-1-carboxylate (3.0g, 10.1mmol) was dissolved in ethanol (50mL), thiourea (1.5g, 20.2mmol) was added at room temperature, and the reaction Heat to 90°C and stir for 3 hours.
  • Step 3 Cuprous bromide (607.1 mg, 4.25 mmol) was dissolved in acetonitrile (5 mL), tert-butyl nitrite (583.0 mg, 5.66 mmol) was added at room temperature, and the mixture was stirred for 5 minutes and then added with 2-(2-amino) Thiazol-4-yl)piperidine-1-carboxylate benzyl ester (900 mg, 2.83 mmol), the reaction solution was stirred at room temperature for 3 hours.
  • Step 4 Benzyl 2-(2-bromothiazol-4-yl)piperidine-1-carboxylate (137.5 mg, 0.36 mmol) was dissolved in dioxane (10.0 mL) and water (2.0 mL) at room temperature 7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane -2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (150 mg, crude), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.4 mg, 0.02 mmol), potassium phosphate (127.2 mg, 0.60 mmol) under nitrogen The reaction was stirred at 100°C for 2 hours under
  • Step 1 7-Chloroisoquinolin-1-amine (1.0g, 5.60mmol) was dissolved in acetonitrile (20mL), N-bromosuccinimide (1.0g, 5.60mmol) was added under ice bath, and the reaction Stir under ice bath for 2 hours. Water (30 mL) was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried under vacuum. The crude product was purified by flash silica gel column (methanol/dichloromethane: 0-5%) to obtain the target product 4-bromo-7-chloroisoquinolin-1-amine (1.3 g, yield 90.2%) as pale yellow solid.
  • ES-API: [M+H] + 257.0, 259.0.
  • Step 2 4-Bromo-7-chloroisoquinolin-1-amine (1.3g, 5.05mmol) and di-tert-butyl dicarbonate (4.41g, 20.19mmol) were suspended in dichloromethane (25mL), added at room temperature Triethylamine (2.55 g, 25.24 mmol) and 4-dimethylaminopyridine (62 mg, 0.51 mmol), and the reaction was stirred at room temperature for 18 hours. Dichloromethane (30 mL) and water (15 mL) were added to the reaction solution, the organic layer was separated, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 3 Add (4-bromo-7-chloroisoquinolin-1-yl) di-tert-butyl iminodicarbonate (350 mg, 0.77 mmol), bis(pinacol) diboron to a 50 mL round-bottomed flask (388 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (56 mg, 0.076 mmol), potassium acetate (225 mg, 2.29 mmol), 1,4-dioxo Hexacyclic (15 mL) was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 2 hours.
  • Step 4 tert-butyl (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (170 mg, 0.43 mmol), (4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-7-chloroisoquinolin-1-yl)di-tert-butyl iminodicarbonate (720 mg, crude), potassium carbonate (180 mg, 1.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.043 mmol), 1,4-dioxane
  • the ring (16 mL) and water (4 mL) were replaced with nitrogen three times, and the reaction was carried out at 110°C for 2 hours.
  • Step 5 Add (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazole-2 to a 5mL microwave tube -yl)-7-chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (30 mg, 0.044 mmol), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboran-2-yl)-1H-pyrrolo[2,3-b]pyridine (23 mg, 0.087 mmol), potassium carbonate (18 mg, 0.13 mmol), 2-dicyclohexyl Phosphine-2',6'-dimethoxy-biphenyl (5mg, 0.007mmol), Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl yl)(2'-a
  • reaction solution was concentrated, 7.0M ammonia methanol solution (5mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-( 1-Methyl-1H-pyrro[2,3-b]pyridin-4-yl)-4-(4-((methylamino)methyl)-5-(tetrahydro-2H-pyran-4- yl)thiazol-2-yl)isoquinolin-1-amine (Z161, 11 mg, yield 58.2%), pale yellow solid.
  • Step 1 Add 3-bromo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (250mg, 1.06mmol), 1,5-dimethyl-1H- Pyrazole-4-boronic acid pinacol ester (553g, 2.66mmol), potassium carbonate (406mg, 2.94mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (78mg, 0.11 mmol), 1,4-dioxane (15 mL) and water (3 mL), nitrogen was replaced three times, and the reaction was carried out at 100° C. for 4 hours.
  • Step 2 Dissolve 3-(1,5-dimethyl-1H-pyrazol-4-yl)-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (185mg, 0.70mmol) To N,N-dimethylformamide (6 mL) was added N-iodosuccinimide (173 mg, 0.77 mmol) under an ice bath, and the reaction was stirred at 0° C. for 15 minutes. Water was added to the reaction solution, the precipitated solid was filtered, and the filter cake was washed with water and dried in vacuo.
  • Step 3 3-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-iodo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (120mg, 0.32 mmol) and di- tert- butyl dicarbonate (209 mg, 0.96 mmol) were suspended in dichloromethane (6 mL), triethylamine (97 mg, 0.96 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) were added at room temperature , the reaction was stirred at room temperature for 18 hours. The reaction solution was concentrated.
  • Step 4 Add 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-iodopyrrole[4,3,2-ij]isoquinoline-1(2H to a 5mL microwave tube )-carboxylate tert-butyl ester (40mg, 0.084mmol), bis(pinacol)diboron (43mg, 0.17mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (9 mg, 0.013 mmol), potassium acetate (25 mg, 0.25 mmol), N,N-dimethylformamide (1 mL), purged with nitrogen for 1 minute, reacted at 110° C.
  • Step 5 Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (50mg) to a 5mL microwave tube , 0.13mmol), 3-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (60 mg, crude), potassium carbonate (53 mg, 0.38 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]palladium dichloride (9 mg, 0.013 mmol), 1,4-dioxane (2 mL) and water (0.5 mL), purged with nitrogen for 1 min, placed in a microwave The reaction was carried out in the reactor at 110°C for 1 hour.
  • Step six 6-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-3-( 1,5-Dimethyl-1H-pyrazol-4-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (9 mg, 0.014 mmol) in methanol (1 mL) was added 4.0 M hydrogen chloride dioxane solution (5 mL, 20.0 mmol), and the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 Take 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-iodopyrrolo[4,3,2-ij]isoquinoline-1(2H)-carboxyl tert-butyl acid (0.06g, 0.116mmol), pinacol diboronate (0.055g, 0.22mmol), potassium acetate (21mg g, 0.22mmol), [1,1'-bis(diphenylphosphine)di Ferrocene]palladium(II) dichloride (10 mg) was dissolved in 1,4-dioxane (5 mL) and stirred at 110°C for 2 hours.
  • Step 2 Take (1-(tert-butoxycarbonyl)-3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1,2-dihydropyrrolo[4,3, 2-ij]isoquinolin-6-yl)boronic acid (38 mg, 0.08 mmol), 1-(2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-N , N-dimethylmethylamine (42 mg, 0.14 mmol), potassium carbonate (22 mg, 0.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5 mg ) was dissolved in 1,4-dioxane/water (2.5 ml) and stirred at 110°C for 2 hours.
  • Step 3 Take 6-(4-((dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-3-(7-fluoroimidazolium [1,2-a]pyridin-3-yl)pyrrolo[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (10 mg, 0.016 mmol) was dissolved in anhydrous dichloride Methane (0.5 mL), trifluoroacetic acid (0.2 mL) was added, and the reaction was carried out at room temperature for 2 hours.
  • Step 1 2,2-Dimethoxyethane-1-amine (4.75g, 45.22mmol) was dissolved in methanol (90mL) and 3-bromo-2-methylbenzaldehyde (9.0g, 45.22mmol) was added at room temperature , the reaction was stirred at 70 °C for 2 hours. The reaction was cooled to 0°C, sodium borohydride (1.71 g, 45.22 mmol) was added in portions, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated to remove the solvent, ice water (200 mL) was added, and the mixture was extracted with dichloromethane (100 mL ⁇ 2).
  • Step 2 Cool chlorosulfonic acid (28.5 mL, 433.74 mmol) to 0 °C, slowly add N-(3-bromo-2-methylbenzyl)-2,2-dimethoxyethane-1- Amine (12.5 g, 43.37 mmol) over 30 minutes. The reaction was stirred at 100°C for 2 hours, then cooled and poured into ice (250 g), filtered, and the filtrate was cooled in an ice bath and adjusted to pH 14 with 50% sodium hydroxide solution. Extracted with dichloromethane (150 mL ⁇ 2), the combined organic layers were dried over anhydrous sodium sulfate and concentrated.
  • Step 3 7-Bromo-8-methylisoquinoline (4.8g, 21.61mmol) was dissolved in dichloromethane (150mL), 85% m-chloroperoxybenzoic acid (7.90g, 38.90mmol) was added under ice bath, The reaction was stirred at room temperature for 18 hours. The reaction was cooled to 0°C, saturated sodium bicarbonate solution (250 mL), and extracted with 10% methanol/dichloromethane (100 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 4 Phosphorus oxychloride (41.0 mL, 441.03 mmol) was cooled to 0° C., 7-bromo-8-methylisoquinoline 2-oxide (4.2 g, 17.64 mmol) was added in batches, and the reaction was carried out at room temperature. The reaction was stirred for 15 minutes and then at 105°C for 4 hours. The reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL ⁇ 3), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 7-Bromo-1-chloro-8-methylisoquinoline (1.1 g, 4.29 mmol) was suspended in carbon tetrachloride (70 mL), and N-bromosuccinimide (840 mg, 4.72 mmol) was added. ), benzoyl peroxide (277 mg, 0.86 mmol), and the reaction was refluxed for 6 hours. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL), washed with 1M sodium hydroxide solution (30 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 6 (2,4-Dimethoxyphenyl)methanamine (1.50g, 8.94mmol) and potassium carbonate (0.74g, 5.37mmol) were dissolved in N,N-dimethylformamide (25mL), in A solution of 7-bromo-8-(bromomethyl)-1-chloroisoquinoline in N,N-dimethylformamide (1.5 mL) was added dropwise under an ice bath, and the reaction was stirred at 0°C for 2 hours. The reaction solution was added with water (60 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step 7 3-Bromo-1-(3,4-dimethylbenzyl)-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (1.1 g, 2.855 mmol) was added with trifluoro Acetic acid (30 mL), and the reaction solution was stirred at 80°C for 3 hours. The reaction solution was concentrated, 7M ammonia methanol (30 mL) was added, and it was concentrated again. The obtained crude product was purified by flash silica gel column (methanol solution/dichloromethane: 0-7%) to obtain the target product 3-bromo-1,2-dihydropyrro[4,3,2-ij]isoquinoline (620 mg, produced rate 92.4%), light brown solid.
  • ES-API: [M+H] + 235.0, 237.0.
  • Step 8 Add 3-bromo-1,2-dihydropyrrole[4,3,2-ij]isoquinoline (320mg, 2.86mmol), 7-fluoro-3-(4,4 to a 250mL round-bottomed flask , 5,5-tetramethyl-1,3,2-dioxaboran-2-yl)imidazo[1,2-a]pyridine (3.2g, crude), sodium carbonate (433mg, 4.08mmol), [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (100 mg, 0.14 mmol), 1,4-dioxane (50 mL) and water (10 mL), replaced with nitrogen three times, the reaction The reaction was carried out at 100°C for 4 hours.
  • Step 9 3-(7-Fluoroimidazo[1,2-a]pyridin-3-yl)-1,2-dihydropyrro[4,3,2-ij]isoquinoline (175mg, 0.60mmol) Dissolved in N,N-dimethylformamide (6 mL), N-iodosuccinimide (149 mg, 0.66 mmol) was added under an ice bath, and the reaction was stirred at 0°C for 30 minutes.
  • Step 11 Add 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-iodopyrrole[4,3,2-ij]isoquinoline-1 to a 5mL microwave tube (2H)-tert-butyl carboxylate (100 mg, 0.19 mmol), bis(pinacol)diboron (98 mg, 0.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]di Palladium chloride (21 mg, 0.03 mmol), potassium acetate (57 mg, 0.58 mmol), N,N-dimethylformamide (2 mL), purged with nitrogen for 1 minute, and reacted at 110° C. for 1 hour in a microwave reactor.
  • 2H 2-tert-butyl carboxylate
  • bis(pinacol)diboron 98 mg, 0.39 mmol
  • Step 12 Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 60mg, 0.15mmol), 3-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-di Oxaboran-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (120 mg, crude), potassium carbonate (64 mg, 0.46 mmol), [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min , in a microwave reactor at 110 °C for 1 hour.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (400 mg, 1.66 mmol) was dissolved in dry dioxane (4 mL), and bis-borate pinacol ester (505.9 mg, 1.99 mg) was added at room temperature mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (122.4 mg, 0.17 mmol) and potassium acetate (325.4 mg, 3.32 mmol), oil bath 100°C under nitrogen protection The reaction was stirred for 18 hours.
  • ES-API: [M+H] + 207.2.
  • Step 2 (1-Amino-8-fluoroisoquinolin-7-yl)boronic acid (153.2 mg, 0.74 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and 5- Bromo-1,2-dimethyl-1H-imidazole (155.4 mg, 0.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50.4 mg, 0.07 mmol), Potassium carbonate (204.2 mg, 1.48 mmol) was stirred in an oil bath at 100° C. for 18 hours under nitrogen protection.
  • Step 4 7-(1,2-Dimethyl-1H-imidazol-5-yl)-8-fluoro-4-iodo-isoquinolin-1-amine (90.5mg, 0.24mmol) was dissolved in dichloromethane (2.0 mL), di-tert-butyl dicarbonate (209.3 mg, 0.96 mmol), triethylamine (121.2 mg, 1.20 mmol) and 4-dimethylaminopyridine (5.8 mg, 0.12 mmol) were added, and the reaction was carried out at room temperature React for 2 hours.
  • Step 5 tert-butyl (7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoro-4-iodo-isoquinolin-1-yl)carbamic acid tert-butyl ester (75.3 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), and bis(pinacol borate) (66.0 mg, 0.26 mmol), [1,1'-bis(diphenylphosphine) was added at room temperature ) ferrocene] palladium dichloride (14.4 mg, 0.02 mmol), potassium acetate (25.5 mg, 0.26 mmol), nitrogen was replaced, and the reaction was stirred at 90° C.
  • Step seven ((2-(1-amino-7-(1,2-dimethyl-1H-imidazol-5-yl)-8-fluoroisoquinolin-4-yl)-5-(tetrahydro- 2H-Pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (35.3 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL) and trifluoroacetic acid (1.0 mL), the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (400 mg, 1.66 mmol) was dissolved in dioxane (4.0 mL) and water (1.0 mL), and (1,5-dioxane) was added at room temperature Methyl-1H-pyrazol-4-yl)boronic acid (278.6 mg, 1.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (122.4 mg, 0.17 mmol), Potassium carbonate (458.2 mg, 3.32 mmol) was stirred in an oil bath at 100° C. for 18 hours under nitrogen protection.
  • ES-API: [M+H] + 257.2.
  • Step 3 7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (231.2 mg, 0.60 mmol) was dissolved in dichloromethane (6.0 mL), di-tert-butyl dicarbonate (523.2 mg, 2.40 mmol), triethylamine (303.0 mg, 3.00 mmol) and 4-dimethylaminopyridine (14.6 mg, 0.12 mmol) were added, and the reaction was carried out at room temperature The reaction was carried out for 5 hours.
  • Step 4 (7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-yl)-carbamic acid tert-butyl ester (265.7 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), bis(pinacol borate) (137.2 mg, 0.54 mmol), [1,1'-bis(diphenylene) were added at room temperature phosphine) ferrocene] palladium dichloride (36.0 mg, 0.05 mmol), potassium acetate (441.0 mg, 4.50 mmol), nitrogen was replaced, and the reaction was stirred at 90° C. in a microwave for 2 hours under nitrogen protection.
  • N,N-dimethylformamide 2.0 mL
  • bis(pinacol borate) 137.2 mg, 0.54 mmol
  • [1,1'-bis(diphenylene) were added at room temperature phosphine) ferrocen
  • Step 5 (7-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborol-2-yl))isoquinolin-1-yl)-carbamic acid tert-butyl ester (195.3 mg, 0.33 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL) ), tert-butyl((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (97.5 mg) was added at room temperature , 0.25mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21.6mg, 0.03mmol), potassium carbonate (69.0mg, 0.50mmol), microwave 110 under nitrogen protection The reaction was stirred for 2 hours.
  • Step six tert-butyl ((2-(1-amino-7-(1,5-dimethyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-4-yl)-5- (Tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (97.6 mg, 0.17 mmol) was dissolved in dichloromethane (4.0 mL) and trifluoromethane was added Acetic acid (2.0 mL), the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 Under nitrogen protection, (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamic acid tert-butyl ester (50 mg, 0.07 mmol), (2,3-lutidine-4-yl)boronic acid ( 22mg, 0.15mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- A mixed solution of 2-yl)palladium(II) (5 mg, 0.01 mmol) and potassium carbonate (30 mg, 0.22 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 110 °C
  • reaction solution was poured into ethyl acetate (10 mL), and washed with saturated brine (5 mL) and water (5 mL) in this order.
  • the organic phase was dried over anhydrous sodium sulfate, concentrated by filtration and purified with a flash silica gel column (0-100% ethyl acetate/petroleum ether) to give (tert-butoxycarbonyl) (4-(4-(((tert-butoxycarbonyl) as a yellow oily liquid.
  • Step 2 Under ice bath conditions, trifluoroacetic acid (0.5 mL) was added dropwise to (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl) -5-(Tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-7-(2,3-lutidine-4-yl)isoquinolin-1-yl)carbamic acid tert. A solution of butyl ester (40 mg, 53 ⁇ mol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour.
  • Step 1 ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamic acid tert-butyl ester (40.0 mg, 0.06 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and (4,5- Lutidine-3-yl)boronic acid (10.5 mg, 0.07 mmol), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl) (2 '-Amino-1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (16.6 mg, 0.12 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours.
  • ES-API: [M+H] + 560.2.
  • Step 1 ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamic acid tert-butyl ester (45.3 mg, 0.08 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), (4-methyl) was added at room temperature Pyridin-3-yl)boronic acid (13.2 mg, 0.10 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (22.1 mg, 0.16 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours.
  • ES-API: [M+H] + 546.2.
  • Step 2 (2-(1-Amino-7-(4-methylpyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamate tert-butyl ester (35.2 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (2.0 mL) was added, and the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 ((2-(1-((tert-butoxycarbonyl)amino)-7-chloroisoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole- tert-Butyl 4-yl)methyl)(methyl)carbamate (45.3 mg, 0.08 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and (5-methyl) was added at room temperature Pyridin-3-yl)boronic acid (13.2 mg, 0.10 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II) (7.2 mg, 0.01 mmol), potassium carbonate (22.1 mg, 0.16 mmol), and the reaction was stirred at 110°C under nitrogen protection for 2 hours.
  • ES-API: [M+H] + 546.2.
  • Step 2 ((2-(1-Amino-7-(5-methylpyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)thiazole -4-yl)methyl)(methyl)carbamate tert-butyl ester (35.2 mg, 0.06 mmol) was dissolved in dichloromethane (4.0 mL), trifluoroacetic acid (2.0 mL) was added, and the reaction was allowed to react at room temperature for 2 hours .
  • Step 1 take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamate (68 mg, 0.1 mmol), 1-methyl-4-(4,4,5,5-tetrakis Methyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (40 mg, 0.2 mmol), potassium carbonate (27 mg, 0.2 mmol), [1,1'-bis( Diphenylphosphine)ferrocene]palladium(II) dichloride (10 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110°C for 2 hours.
  • Step 2 take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-(1-methyl-1H-pyrazol-5-yl)isoquinolin-1-yl)carbamate (40 mg, 0.054 mmol) was dissolved in anhydrous Dichloromethane (0.5 mL) was added with trifluoroacetic acid (0.2 mL), and the mixture was reacted at room temperature for 2 hours.
  • Step 2 Take 1,3-bis(1,1-dimethylethyl)2-(7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo) Boran-2-yl)isoquinolinyl)iminodicarbonate (400 mg, 0.8 mmol), tert-butyl ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazole- 4-yl)methyl)(methyl)carbamate (310 mg, 0.8 mmol), potassium carbonate (0.22 g, 1.6 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (50 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110°C for 2 hours.
  • Step 3 take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamate (68 mg, 0.1 mmol), 1-methyl-4-(4,4,5,5-tetrakis Methyl-1,3,2-dioxaborol-2-yl)pyrazole tert-butyl (40 mg, 0.2 mmol), carbonic acid and (27 mg, 0.2 mmol), 1,1-bis(diphenyl) Phosphino)ferrocene palladium dichloride (10 mg) was dissolved in 1,4-dioxane/water (2.5 mL) and stirred at 110° C.
  • Step 4 take tert-butyl(tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran- 4-yl)thiazol-2-yl)-7-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1-yl)carbamate (40 mg, 0.054 mmol) was dissolved in anhydrous Dichloromethane (0.5 mL) was added with trifluoroacetic acid (0.2 mL), and the mixture was reacted at room temperature for 2 hours.
  • Step 1 4-Bromopyridin-3-ol (500mg, 2.874mmol), bromocyclopropane (1.151mL, 14.368mmol), potassium carbonate (1189.66mg, 8.621mmol), potassium iodide (95.40mg, 0.575mmol) were added into N-methylpyrrolidone (8mL), the microwave reaction was stirred at 180°C for 5 hours, after the reaction was completed, water (30mL), ethyl acetate (30mLx3) were added, the organic phases were combined, washed with saturated brine (30mLx1), and anhydrous sodium sulfate Dry, filter and concentrate to obtain crude product.
  • Step 2 Dissolve 4-bromo-3-(cyclopropoxy)pyridine (80mg, 0.374mmol) and pinacol biboronate (189.81mg, 0.747mmol) in 1,4-dioxane (8mL) ), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (30.52 mg, 0.037 mmol) and potassium acetate (73.36 mg, 0.747 mmol) were added. Under nitrogen, stir at 90°C for 3 hours.
  • Step 3 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) -7-Chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (60 mg, 0.087 mmol) and 3-cyclopropoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborol-2-yl)pyridine (120 mg, crude) was dissolved in a solution of 1,4-dioxane (8 mL) and water (2 mL), chlorine (2- Dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) catalyst ( 12.55 mg, 0.017 mmol) and potassium carbonate (36.09
  • Step 4 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(3-cyclopropoxypyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (20 mg, 0.025 mmol) was dissolved in dichloromethane (2 mL) and then added Trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour.
  • the system was replaced with nitrogen three times and then protected with a nitrogen balloon.
  • the reaction was carried out at 100°C for 2 hours, the reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified with a flash silica gel column (ethyl acetate: petroleum ether).
  • Step 2 Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-neck round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-(3-methoxypyridin-4-yl)isoquinolin-1-yl)carbamic acid tert-butyl ester (30 mg, 0.05 mmol), tris Fluoroacetic acid (3 mL) and dichloromethane (6 mL) were stirred at room temperature for 30 minutes.
  • Step 1 Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 25mL three-necked round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-chloroisoquinolin-1-yl)carbamic acid tert-butyl ester (50 mg, 0.073 mmol), 3-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (31.79mg, 0.145mmol), chloro(2-dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (10.45mg, 0.015mmol), potassium carbonate (30.08mg
  • Step 2 Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-neck round-bottomed flask -pyran-4-yl)thiazol-2-yl)-7-(3-methylpyridin-4-yl)isoquinolin-1-yl)carbamic acid tert-butyl ester (30 mg, 0.05 mmol), trifluoro Acetic acid (3 mL) and 6 mL of dichloromethane (6 mL) were stirred at room temperature for 30 minutes.
  • Step 2 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(2-methylpyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (30 mg, 0.040 mmol) was dissolved in dichloromethane (2 mL) followed by the addition of trifluoro Acetic acid (1 mL), stirred at room temperature for 1 hour.
  • Step 1 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) -7-Chloroisoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (60 mg, 0.087 mmol) and 1,5-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborol-2-yl)pyrazole (38.64 mg, 0.174 mmol) was dissolved in a solution of 1,4-dioxane (8 mL) and water (2 mL), added Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium ( II) (12.55 mg, 0.017 mmol) and
  • Step 2 (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl) - Di-tert-butyl 7-(1,5-dimethyl-1H-pyrazol-4-yl)isoquinolin-1-yl)iminodicarbonate (40 mg, 0.053 mmol) was dissolved in dichloromethane (5 mL) ), then trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (300mg, 1.25mmol) and 1-methylimidazole-5-boronic acid pinacol ester (1.04g, 4.98mmol) were dissolved in 1,4- Dioxane (20 mL) and water (4 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (137 mg, 0.19 mmol), potassium carbonate (516 mg, 3.73 mmol) , nitrogen was replaced three times, and the reaction was stirred at 100 °C for 18 h.
  • Step 2 8-Fluoro-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-amine (190mg, 0.78mmol) was dissolved in N,N-dimethylformamide (6mL) , N-iodosuccinimide (229 mg, 1.02 mmol) was added under an ice bath, and the reaction was stirred at room temperature for 18 hours.
  • Step 3 8-Fluoro-4-iodo-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-amine (260mg, 0.71mmol) and di-tert-butyl dicarbonate (616mg, 2.82 mmol) was suspended in dichloromethane (15 mL), triethylamine (357 mg, 4.07 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added at room temperature, and the reaction was stirred at room temperature for 18 hours.
  • Step 5 Add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (60mg) to a 5mL microwave tube , 0.15 mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(1-methyl- 1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (180 mg, crude), potassium carbonate (64 mg, 0.46 mmol), [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, in a microwave reactor at 110 °C The reaction was carried out for 45 minutes.
  • Step six (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(1-methyl-1H-imidazol-5-yl)isoquinolin-1-yl)iminodicarbonate (30 mg, 0.04 mmol) was dissolved in methanol (1 mL), 4.0 M was added A solution of hydrogen chloride in dioxane (4 mL, 20.0 mmol) was reacted at room temperature for 18 hours.
  • Step 1 Add 7-bromoisoquinolin-1-amine (510mg, 2.28mmol), pyridin-4-ylboronic acid (562mg, 4.57mmol), 1-bis(diphenylphosphino) to a 25mL three-necked round bottom flask ) ferrocene palladium dichloride (167 mg, 0.22 mmol), potassium carbonate (948 mg, 6.85 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, then protected with a nitrogen balloon, and reacted at 100°C for 2 hours.
  • Step 2 Add 7-(pyridin-4-yl)isoquinolin-1-amine (500mg, 2.26mmol), N-iodosuccinimide (661mg, 2.94mmol) and Dimethylformamide (10 mL) was reacted at 100°C for 1 hour under nitrogen protection. The reaction solution was filtered with water, and the solid was spin-dried to obtain the target product 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (500 mg, yield: 63.7%).
  • ES-API: [M+H] + 348.0
  • Step 3 add 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (500mg, 1.44mmol), di-tert-butyl dicarbonate (1.26g, 5.76mmol) to a 25mL three-necked round bottom flask ), triethylamine (728 mg, 7.2 mmol), 4-dimethylaminopyridine (17.6 mg, 0.144 mmol), dichloromethane (10 mL), the system was replaced with nitrogen three times, then protected with a nitrogen balloon, and reacted overnight at room temperature .
  • Step 4 Add ⁇ [4-iodo-7-(pyridin-4-yl)isoquinolin-1-yl] ⁇ [(2-methylpropan-2-yl)oxy] to a 25mL three-necked round bottom flask Carbonyl ⁇ amino ⁇ carboxylate tert-butyl ester (150 mg, 0.274 mmol), pinacol diboronate (139.2 mg, 0.545 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (30 mg, 0.04 mmol), potassium acetate (80.68 mg, 0.82 mmol), dioxane (10 mL), the system was replaced with nitrogen three times, and then reacted for 3 hours under the protection of a nitrogen balloon at 90 degrees.
  • Step 6 Add (4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl) to a 5mL single-necked round-bottomed flask ) thiazol-2-yl)-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl (100 mg, 0.15 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL), and the reaction was stirred at room temperature for 30 minutes.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (200 mg, 0.83 mmol) and 4-pyridineboronic acid (204 mg, 1.66 mmol) were dissolved in 1,4-dioxane (10 mL) and water ( 2.5 mL) was added with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (61 mg, 0.08 mmol), potassium carbonate (344 mg, 2.49 mmol), nitrogen was replaced three times, and the reaction was carried out at 100 °C Stir for 2 hours. The reaction solution was concentrated.
  • Step 4 Add (8-fluoro-4-iodo-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (150mg, 0.27mmol) to a 50mL round bottom flask , bis(pinacol)diboron (135mg, 0.53mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29mg, 0.04mmol), potassium acetate (78mg, 0.80 mmol), N,N-dimethylformamide (3 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 2 hours.
  • Step 5 Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 60mg, 0.15mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(pyridine-4- (1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (11 mg, 0.015 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 minute, were reacted in a microwave reactor at 110° C.
  • Step six (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(pyridin-4-yl)isoquinolin-1-yl)iminodicarbonate (75 mg, 0.12 mmol) was dissolved in methanol (1 mL) and 4.0 M hydrogen chloride solution in dioxane (5 mL) was added , 20.0 mmol), the reaction was reacted at room temperature for 18 hours.
  • Step 1 7-Bromo-8-fluoroisoquinolin-1-amine (300 mg, 1.25 mmol) and 3-pyridineboronic acid (306 mg, 2.49 mmol) were dissolved in 1,4-dioxane (12 mL) and water ( 3 mL) was added with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (91 mg, 0.12 mmol), potassium carbonate (516 mg, 3.73 mmol), nitrogen was replaced three times, and the reaction was stirred at 100 °C 2 hours. The reaction solution was concentrated.
  • Step 2 8-Fluoro-7-(pyridin-3-yl)isoquinolin-1-amine (265mg, 1.11mmol) was dissolved in N,N-dimethylformamide (12mL) and N- Iodosuccinimide (324 mg, 1.44 mmol) and the reaction was stirred at room temperature for 3 hours. Ice water was added to the reaction solution, the precipitated solid was filtered, the filter cake was washed with water, and dried in vacuo to obtain the target product 8-fluoro-4-iodo-7-(pyridin-3-yl)isoquinolin-1-amine (400 mg, yield 98.9%), light brown solid.
  • ES-API: [M+H] + 356.0.
  • Step 3 8-Fluoro-4-iodo-7-(pyridin-3-yl)isoquinolin-1-amine (400 mg, 1.10 mmol) and di-tert-butyl dicarbonate (956 mg, 4.38 mmol) were suspended in dichloro Methane (25 mL), triethylamine (554 mg, 5.48 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) were added at room temperature, and the reaction was stirred at room temperature for 18 hours.
  • Step 5 Into a 5mL microwave tube, add: ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester ( 70 mg, 0.18 mmol), (8-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-7-(pyridine-3- (1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (13 mg, 0.018 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, reacted in a microwave reactor at 110° C.
  • Step six (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-8- Di-tert-butyl fluoro-7-(pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate (90 mg, 0.12 mmol) was dissolved in methanol (1 mL), and a 4.0 M solution of hydrogen chloride in dioxane was added ( 5 mL, 20.0 mmol), the reaction was allowed to react at room temperature for 18 hours.
  • Step 1 Methyl 5-bromo-2-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate (1.5g, 4.45mmol) and 2-(2,5-dihydrofuran-3-yl)- 4,4,5,5-Tetramethyl-1,3,2-dioxaborane (0.96 g, 4.89 mmol) was dissolved in 2-methyltetrahydrofuran (8 mL) and water (2 mL), [1,1 '-Bis(diphenylphosphino)ferrocene]palladium dichloride (0.33 g, 0.45 mmol), potassium carbonate (1.84 g, 13.35 mmol), nitrogen purged three times, and the reaction was stirred at 85°C for 3 hours.
  • Step 3 Methyl 2-((tert-butoxycarbonyl)amino)-5-(tetrahydrofuran-3-yl)thiazole-4-carboxylate (1.25g, 3.81mmol) was dissolved in dichloromethane (10mL), added with trichloromethane Fluoroacetic acid (10 mL), the reaction was allowed to react at room temperature for 3 hours.
  • Step 4 copper bromide (2.28g, 10.18mmol) was dissolved in acetonitrile (15mL), tert-butyl nitrite (525mg, 5.09mmol) was added dropwise at room temperature, the reaction was heated to 60°C, 2-amino-5 was added dropwise - A suspension of methyl (tetrahydrofuran-3-yl)thiazole-4-carboxylate (775 mg, 3.40 mmol) in acetonitrile (20 mL), the reaction was stirred at 60°C for 2 hours.
  • Step 5 Methyl 2-bromo-5-(tetrahydrofuran-3-yl)thiazole-4-carboxylate (300 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL), and 2.0 M lithium borohydride solution in tetrahydrofuran was added dropwise under ice bath (1.0 mL, 2.0 mmol) and methanol (66 mg, 2.06 mmol), the reaction was stirred under an ice bath for 30 minutes, then at room temperature for 2 hours. The reaction solution was quenched with water (6 mL) and 1.0 M dilute hydrochloric acid (3 mL) under ice bath, and extracted with ethyl acetate (30 mL ⁇ 2).
  • Step 6 2-Bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methanol (470mg, 1.78mmol) was dissolved in dichloromethane (25mL), Dess-Martin oxidant (906mg) was added under ice bath , 2.14 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction solution was added with dichloromethane (40 mL), washed successively with saturated sodium bicarbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 7 2-Bromo-5-(tetrahydrofuran-3-yl)thiazole-4-carbaldehyde (200 mg, 0.76 mmol) and methylamine hydrochloride (258 mg, 3.82 mmol) were suspended in 1,2-dichloromethane (12 mL) ) and methanol (4 mL), sodium triacetylborohydride (322 mg, 1.53 mmol) was added, and the reaction was allowed to react at room temperature for 18 hours. The reaction solution was adjusted to pH 10 with 1M sodium hydroxide solution, and extracted with dichloromethane (50 mL).
  • Step 8 1-(2-Bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)-N-methylmethanamine (205mg, crude) and triethylamine (112mg, 1.11mmol) were dissolved in two Chloromethane (10 mL) was added with di-tert-butyl dicarbonate (210 mg, 0.96 mmol) under an ice bath, and the reaction was stirred at room temperature for 1 hour.
  • Step 9 Add ((2-bromo-5-(tetrahydrofuran-3-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (150 mg, 0.40 mmol), 7 -(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2- yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (450 mg, crude), potassium carbonate (165 mg, 1.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene ] Palladium dichloride (29 mg, 0.04 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 minute, and reacted in a microwave reactor at 110° C.
  • Step ten (4-(4-((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)-7-(7-fluoroimidazole[ 1,2-a]Pyridin-3-yl)isoquinolin-1-yl)iminodicarbonate di-tert-butyl ester (130 mg, 0.17 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride solution in dioxane was added (4 mL, 16.0 mmol) and the reaction was allowed to react for 2 hours at room temperature.
  • reaction solution was concentrated, 7.0M ammonia methanol solution (5 mL) was added, the solvent was spin-dried, and the crude product was purified by preparative HPLC (ammonium bicarbonate) to obtain the target product 7-(7-fluoroimidazo[1,2-a]pyridine-3- yl)-4-(4-(methylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazol-2-yl)isoquinolin-1-amine (Z160, 45 mg, 54.8% yield), Pale yellow solid.
  • Step eleven 7-(7-Fluorimidazo[1,2-a]pyridin-3-yl)-4-(4-(methylamino)methyl)-5-(tetrahydrofuran-3-yl)thiazole -2-yl)isoquinolin-1-amine (Z160, 40 mg, 0.084 mmol) was suspended in dichloromethane (5 mL), triethylamine (26 mg, 0.25 mmol) and di- tert- butyl dicarbonate (28 mg) were added at room temperature , 0.13 mmol), and the reaction was stirred at room temperature for 1 hour.
  • Step 12 (R)-(2-(1-Amino-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)-5-(tetrahydrofuran -3-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (12 mg, 0.02 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride solution in dioxane (5 mL, 20.0 mmol) was added ), the reaction was allowed to react at room temperature for 18 hours.
  • Step 1 2,2-Dimethoxyethane-1-amine (5.18g, 49.26mmol) was dissolved in methanol (100mL), 3-bromo-2-fluorobenzaldehyde (10g, 49.26mmol) was added at room temperature, The reaction was stirred at 70°C for 2 hours. The reaction was cooled to 0°C, sodium borohydride (1.86 g, 49.26 mmol) was added portionwise, and the reaction was stirred at room temperature for 16 hours. Concentrate to remove the solvent, add ice water (300 mL), and extract with dichloromethane (100 mL ⁇ 3).
  • Step 2 Cool chlorosulfonic acid (31.8 mL, 482.63 mmol) to 0 °C, slowly add N-(3-bromo-2-fluorobenzyl)-2,2-dimethoxyethane-1-amine dropwise (14.1 g, 48.26 mmol) over 30 minutes.
  • the reactant was stirred at 100°C for 45 minutes, then cooled and poured into ice (300 g), filtered, the filtrate was cooled in an ice bath, and the pH was adjusted to 14 with 50% sodium hydroxide solution, and dichloromethane (150 mL ⁇ 2 ) extraction, the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 3 7-Bromo-8-fluoroisoquinoline (5.5g, 24.33mmol) was dissolved in dichloromethane (150mL), 85% m-chloroperoxybenzoic acid (9.88g, 48.66mmol) was added under ice bath, and the reaction The reaction was stirred at room temperature for 18 hours. The reaction was cooled to 0°C, added to saturated sodium bicarbonate solution (200 mL), and extracted with 10% methanol/dichloromethane (100 mL ⁇ 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 Add 7-bromo-8-fluoroisoquinolin-1-amine (1.0 g, 4.15 mmol), bis(pinacol)diboron (1.58 g, 6.22 mmol) to a 50 mL round-bottomed flask, [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.30 g, 0.42 mmol), potassium acetate (1.22 g, 12.45 mmol), 1,4-dioxane (25 mL), The nitrogen was replaced three times, and the reaction was carried out at 95°C for 18 hours.
  • Step 6 Add 7-fluoro-3-iodoimidazo[1,2-a]pyridine (1.0 g, 3.82 mmol), (1-amino-8-fluoroisoquinolin-7-yl) to a 100 mL round-bottomed flask ) boric acid (2.65g, crude product), potassium carbonate (1.58g, 11.45mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (0.28g, 0.38mmol), 1,1'-bis(diphenylphosphino)ferrocene] 4-Dioxane (40 mL) and water (10 mL) were replaced with nitrogen three times, and the reaction was carried out at 100° C.
  • Step 7 8-Fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoquinolin-1-amine (730mg, 2.46mmol) was dissolved in N,N-dimethyl Formamide (20 mL), N-iodosuccinimide (720 mg, 3.20 mmol) was added under an ice bath, and the reaction was stirred at room temperature for 3 hours.
  • Step 8 8-Fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodoisoquinolin-1-amine (980 mg, 2.32 mmol) and di-tert-dicarbonate Butyl ester (2.03g, 9.28mmol) was suspended in dichloromethane (25mL), triethylamine (1.17g, 11.61mmol) and 4-dimethylaminopyridine (28mg, 0.23mmol) were added at room temperature, and the reaction was stirred at room temperature 18 hours.
  • Step 9 Add 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-iodo-1-(bis(tert-butyloxycarbonyl) to a 50 mL round bottom flask ) amino) isoquinoline (150 mg, 0.24 mmol), bis(pinacol)diboron (122 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26 mg, 0.036 mmol), potassium acetate (71 mg, 0.72 mmol), N,N-dimethylformamide (3 mL), nitrogen was replaced three times, and the reaction was carried out at 90° C. for 2 hours.
  • Step ten add ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate (80mg) to a 5mL microwave tube , 0.20 mmol), 8-fluoro-7-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)-1-(bis(tert-butyloxycarbonyl)amino)isoquinoline (230 mg, crude), potassium carbonate (85 mg, 0.61 mmol), [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), 1,4-dioxane (2.5 mL) and water (0.6 mL), purged with nitrogen for 1 min, react in microwave The reaction was carried out at 110°C for 45 minutes in a vessel.
  • Step 2 3-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-(4-(dimethylamino)methyl)-5-(tetrahydro-2H-pyran-4 -yl)thiazol-2-yl)pyrro[4,3,2-ij]isoquinoline-1(2H)-carboxylate tert-butyl ester (45 mg, 0.08 mmol) was dissolved in methanol (1 mL), 4.0 M hydrogen chloride was added Dioxane solution (5 mL, 20.0 mmol), the reaction was allowed to react at room temperature for 18 hours.
  • Step 1 N,N-diisopropylethylamine (6.48mL, 37.17mmol) and 50% ethyl acetate solution of 1-propylphosphoric anhydride (11.82g, 18.57mmol) were added to 3-bromo-6 -Chloro-2-picolinic acid (2.93 g, 12.39 mmol), tert-butylamine (1.56 g, 14.87 mmol) in dichloromethane (30 mL) solution, stirred at room temperature for 1 hour. After the reaction, it was quenched by adding saturated sodium carbonate solution (50 mL), and extracted with dichloromethane (30 mL ⁇ 3).
  • 1-propylphosphoric anhydride 11.82g, 18.57mmol
  • Step 2 Under nitrogen protection, 3-bromo-N-(tert-butyl)-6-chloropyridine amide (2.1 g, 7.02 mmol), (E)-1-ethoxyethylene-2-boronic acid pinacol ester (1.85g, 9.36mmol), tris(dibenzylideneacetone)dipalladium (0.33g, 0.36mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (0.30g, 0.72mmol) ) and potassium carbonate (2.99 g, 21.61 mmol) in 1,4-dioxane (30 mL) and water (7 mL) were stirred at 80°C for 1 hour.
  • Step 3 Add (E)-N-(tert-butyl)-6-chloro-3-(2-ethoxyvinyl)pyridineamide (700 mg, 2.48 mmol) to concentrated sulfuric acid (2 mL) under ice bath conditions. ), the temperature was raised to 110°C and stirred for 2 hours. Cool to room temperature and pour slowly into potassium hydroxide (4.23 g, 75.27 mmol) in ice water. Concentration gave 2-chloro-1,7-naphthyridin-8(7H)-one (450 mg, crude) as a yellow solid containing potassium sulfate.
  • ES-API: [M+H] + 181.1.
  • Step 4 Under nitrogen protection, 2-chloro-1,7-naphthyridin-8(7H)-one (450mg, 2.49mmol), 1,5-dimethyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (1.11 g, 4.98 mmol), chloro(2-dicyclohexylphosphino-2',6'-Dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (26 mg, 0.04 mmol) and potassium carbonate (344 mg, 2.49 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 100°C for 2 hours.
  • Step 5 Add phosphorus oxychloride (5 mL) to crude 2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine-8(7H) under ice bath condition )-one (300 mg, 1.25 mmol), the temperature was raised to 100° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step 6 Ammonia (8 mL, 122 mmol) was added to compound 8-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine (150 mg, 0.58 mmol) sulfolane (4 mL) solution, microwave reaction at 150 °C for 10 hours. After the reaction, the reaction solution was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL ⁇ 3) and washed with water (20 mL) successively.
  • Step 7 Add N-iodosuccinimide (226 mg, 1 mmol) to 2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthyridin-8-amine (200 mg, 0.84 mmol) of a mixed solution of acetonitrile (4 mL) and N,N-dimethylformamide (0.4 mL), and stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with sodium thiosulfate (20 mL) solution, and extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 8 2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-iodo-1,7-naphthyridin-8-amine (270mg, 0.74mmol), di-tert-butyl dicarbonate A solution of ester (645 mg, 2.96 mmol), triethylamine (0.514 mL, 3.70 mmol) and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight.
  • reaction solution was concentrated and purified by flash silica gel column (0-80% ethyl acetate/petroleum ether) to obtain 2-methylpropan-2-yl((2-(1,5-dimethylpyrazole-4) as a white solid -yl)-5-iodopyrido[3,4-b]pyridin-8-yl)(((2-methylprop-2-yl)oxy)carbonyl)amino)carboxylate (170 mg, yield 41%).
  • ES-API: [M+H] + 566.2.
  • Step 10 Under nitrogen protection, add (2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)(methyl)carbamic acid tert-butyl ester (111mg) to the above reaction solution , 0.28 mmol), potassium carbonate (59 mg, 0.42 mmol) and water (0.4 mL), stirred at 100 °C for 2 hours. After completion of the reaction, the reaction solution was dissolved in ethyl acetate (20 mL), and washed with saturated brine (10 mL) and water (10 mL).
  • Step 11 Under ice bath conditions, add trifluoroacetic acid (0.5 mL) dropwise to (tert-butoxycarbonyl)(5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl )-5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-1,7-naphthalene A solution of tert-butyl pyridin-8-yl)carbamate (60 mg, 80 ⁇ mol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour.
  • Step 1 Add 7-bromo-8-fluoroquinolin-1-amine (300mg, 1.24mmol), 4-methoxy-3-(4,4,4,5,5 to a 25mL three-necked round bottom flask) -Tetramethyl-1,3,2-boron-2-yl)pyridine (586mg, 2.49mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (91mg, 0.12 mmol), potassium carbonate (516 mg, 3.73 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, and then reacted for 2 hours under the protection of nitrogen balloon at 100°C.
  • Step 2 Add 8-fluoro-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (260mg crude product), N-iodosuccinimide to a 25mL single-neck round bottom flask (651 mg, 2.89 mmol) and dimethylformamide (10 mL), reacted at 100° C. for 1 hour. The reaction solution was filtered with water, and the solid was spin-dried to obtain the target product 8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (880 mg, 2-step yield: 53%) ).
  • ES-API: [M+H] + 396.0.
  • Step 3 Add 8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-amine (200mg 0.5mmol), di-tertiary dicarbonate to a 25mL three-necked round-bottomed flask Butyl ester (441 mg, 2.02 mmol), triethylamine (256 mg, 2.53 mmol), 4-dimethylaminopyridine (6.1 mg, 0.05 mmol), dichloromethane (10 mL). The system was replaced with nitrogen three times, and then reacted overnight at room temperature under nitrogen balloon protection.
  • Step 4 Add ⁇ [8-fluoro-4-iodo-7-(4-methoxypyridin-3-yl)isoquinolin-1-yl] ⁇ [tert-butoxycarbonyl ⁇ to a 25mL three-necked round-bottomed flask tert-Butyl amino ⁇ carboxylate (130 mg, 0.21 mmol), pinacol diboronate (110 mg, 0.43 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (24 mg, 0.03 mmol) , potassium acetate (64 mg, 0.65 mmol), dioxane (10 mL).
  • Step 1 Add 7-bromo-8-fluoroquinolin-1-amine (300mg, 1.24mmol), 2-methyl-5-(4,4,5,5-tetramethyl) into a 25mL three-necked round bottom flask base-1,3,2-dioxaborol-2-yl)pyridine 818mg, 3.73mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (91mg, 0.12mmol) ), potassium carbonate (516 mg, 3.73 mmol), dioxane (10 mL) and water (1 mL). The system was replaced with nitrogen three times, and then reacted for 2 hours under the protection of nitrogen balloon at 100°C.
  • Step 3 add 4-iodo-7-(pyridin-4-yl)isoquinolin-1-amine (170mg 0.45mmol), di-tert-butyl dicarbonate (391mg, 1.79mmol) to a 25mL three-necked round bottom flask, Triethylamine (227 mg, 2.24 mmol), 4-dimethylaminopyridine (5.5 mg, 0.04 mmol), dichloromethane (10 mL). The system was replaced with nitrogen three times, and the reaction was carried out overnight under nitrogen balloon protection at room temperature.
  • Step 5 Add ⁇ [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-8-fluoro into a 25mL three-necked round bottom flask -7-(6-Methylpyridin-3-yl)isoquinolin-1-yl] ⁇ [(2-methylpyridin-2-yl)oxy]carbonyl ⁇ amino ⁇ carboxylic acid tert-butyl ester (300 mg, crude ), ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (50 mg, 0.153 mmol), 1, 1-Bis(diphenylphosphino)ferrocene palladium dichloride (9.4 mg, 0.01 mmol), potassium carbonate (53 mg, 0.38 mmol), dioxane (10 mL) and water (1 mL).
  • reaction solution was added with ethyl acetate (30 mL), washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was used in a flash silica column.
  • Step 6 Add (tert-butoxycarbonyl)(4-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-(tetrahydro-2H to a 5mL single-necked round-bottomed flask -pyran-4-yl)thiazol-2-yl)-8-fluoro-7-(6-methylpyridin-3-yl)isoquinolin-1-yl)carboxylate tert-butyl ester (90 mg, 0.12 mmol), trifluoroacetic acid (3 mL) and dichloromethane (6 mL), and the reaction was stirred at room temperature for 30 minutes.
  • Step 2 (1-Amino-8-fluoroisoquinolin-7-yl)boronic acid (340 mg, 1.65 mmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and 4-bromo was added at room temperature -1-ethyl-5-methyl-1H-pyrazole (300 mg, 1.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (121 mg, 0.17 mmol), Potassium carbonate (684 mg, 4.95 mmol) was stirred in an oil bath at 100° C. for 5 hours under nitrogen protection.
  • Step 3 7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoroisoquinolin-1-amine (180 mg, 0.67 mmol) was dissolved in acetonitrile (5 mL), added N-Iodosuccinimide (180 mg, 0.80 mmol) and the reaction was allowed to react at room temperature for 2 hours.
  • Step 5 tert-butyl (7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodo-isoquinolin-1-yl)carbamate ( 120mg, 0.20mmol) was dissolved in N,N-dimethylformamide (2.0mL), at room temperature was added pinacol bis-boronate (77mg, 0.30mmol), [1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride (15 mg, 0.02 mmol), potassium acetate (59 mg, 0.60 mmol), nitrogen was replaced, and the reaction was stirred at 100° C. for 2 hours under nitrogen protection.
  • Step six (7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborol-2-yl))isoquinolin-1-yl)carbamic acid tert-butyl ester (115 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (2.0 mL) and water (0.5 mL), and tert-butyl ((2-bromo-5-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate was added at room temperature (151 mg, 0.39 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl) -2-yl)palladium(II) (14 mg, 0.02
  • Step 7 ((2-(1-Amino-7-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-8-fluoro-isoquinolin-4-yl)-5- (Tetrahydro-2H-pyran-4-)yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (60 mg, 0.08 mmol) was dissolved in dichloromethane (2.0 mL) and trichloromethane was added. Fluoroacetic acid (0.5 mL), and the reaction was allowed to react at room temperature for 2 hours.
  • Step 1 get 5-bromo-1-methyl-1H-pyrazole (1.6g, 10mmol), cyclopropylboronic acid (2.58g, 30mmol), 1,1-bis(diphenylphosphino)ferrocene Palladium chloride (160 mg, 0.24 mmol), potassium carbonate (4.14 g, 30 mmol) were dissolved in 1,4-dioxane (50 ml) and water (10 ml), and stirred at 110° C. for 2 hours.
  • Step 2 get 5-cyclopropyl-1-methyl-1H-pyrazole (244mg, 2mmol) and dissolve it in acetonitrile, add N-bromosuccinimide (430mg, 2.4mmol) under ice bath, react at room temperature 2 hours. After the reaction, water (10ml) was added, extracted with ethyl acetate (10mL ⁇ 3), the organic phase was washed with saturated sodium bicarbonate solution (10ml), washed with saturated brine (10ml), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure 4-Bromo-5-cyclopropyl-1-methyl-1H-pyrazole (340 mg, 85% yield) was obtained.
  • ES-API: [M+H]+ 201.1.
  • Step 3 get 4-bromo-5-cyclopropyl-1-methyl-1H-pyrazole (200mg, 1mmol), biboronic acid pinacol ester (510mg, 2mmol), 1,1-bis(diphenylphosphine) base) ferrocene palladium dichloride (24 mg, 0.036 mmol), potassium acetate (196 mg, 2 mmol) was dissolved in 1,4-dioxane (5 mL), and stirred at 110° C. for 2 hours.
  • Step five get 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoroisoquinoline-1-amine (85mg g, 0.3mmol) is dissolved in N,N -Dimethylformamide (1 mL), N-iodosuccinimide (68 mg g, 0.3 mmol) was added under an ice bath, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added to precipitate a solid, and suction filtration to obtain 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinoline -1-amine (105 mg, 85% yield).
  • ES-API: [M+H]+ 409.0.
  • Step six get 7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-8-fluoro-4-iodoisoquinolin-1-amine (105mg, 0.25mmol) dissolved in Dichloromethane (5 ml), triethylamine (50 mg, 0.5 mmol), DMAP (4 mg, 0.025 mmol), di-tert-butyl dicarbonate (110 mg, 0.5 mmol) were added under ice bath, and the reaction was carried out at room temperature for 2 hours.
  • Step eight take 2-methylpropan-2-yl ⁇ [7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)isoquinolin-1-yl] ⁇ [(2-methylpropan-2-yl)oxy]carbonyl ⁇ amino ⁇ carboxylate tert-butyl ester (73 mg, 0.12 mmol), ((2-bromo-5-( Tetrahydro-2H-pyran-4-yl)thiazol-4-yl)methyl)(methyl)carbamate tert-butyl ester (46 mg, 0.12 mmol), 1,1-bis(diphenylphosphino)diocene Iron palladium dichloride (8 mg g, 0.012 mmol), potassium carbonate (48 mg, 0.34 mmol) were dissolved in 1,4-dioxane (2 ml) and water (0.5 ml), and stirred at 110° C.
  • Step 2 get (7-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-4-(4-((dimethylamino)methyl)-5-(tetrahydro Di-tert-butyl -2H-pyran-4-yl)thiazol-2-yl)-8-fluoroisoquinolin-1-yl)carbamate (40 mg, 0.05 mmol) was dissolved in anhydrous dichloromethane (0.5 mL) ), trifluoroacetic acid (0.2 mL) was added, and the mixture was reacted at room temperature for 2 hours.
  • Buffer preparation Use sterile water to prepare 1 ⁇ reaction buffer: 40 mM Tris-HCl, 20 mM MgCl 2 , 0.01% Brij35, 50 ⁇ M DTT, 0.1 mg/ml BSA, and use it on the day of the experiment.
  • 1000 ⁇ stocking drug plate preparation prepare 1000 ⁇ compound stocking plate, dilute 10 mM compound stock solution with DMSO, the initial concentration is 1 mM, 10 concentration gradients, 3.162 times dilution.
  • the compound storage plate was sealed with sealing film and stored in a -20°C refrigerator for later use.
  • Compound preparation and dosing Take out the 1000 ⁇ storage plate and thaw at room temperature in the dark. Then prepare a 5X intermediate plate with reaction buffer and mix thoroughly. Transfer 2 ⁇ L from the 5 ⁇ intermediate plate to a 384-well plate, set up negative control wells and positive control wells (add 2 ⁇ L of reaction buffer containing 0.5% DMSO), and repeat each point twice.
  • reaction solution preparation and incubation use reaction buffer to dilute HPK1 protein into 2.5 ⁇ working solution, add 4 ⁇ L of 2.5 ⁇ HPK1 protein to each well containing the test compound and the positive control well, and add 4 ⁇ L of HPK1 protein-free protein to the negative control well.
  • reaction buffer Centrifuge at 1000 rpm for 1 minute, then incubate in a 20°C incubator for 15 minutes.
  • Use reaction buffer to prepare 2.5 ⁇ MBP protein and ATP mixed working solution the concentrations are 0.5 ⁇ g/ ⁇ L and 50 ⁇ M, respectively, add 4 ⁇ L MBP and ATP mixed working solution to each well, centrifuge at 1000 rpm for 1 minute, and then incubator at 20 °C Incubate for 90 minutes.
  • ADP-Glo detection and plate reading Add 10 ⁇ L of ADP-Glo to each well of the experimental plate, centrifuge at 1000 rpm for 1 minute, and incubate in a 20°C incubator for 60 minutes. Then transfer 10 ⁇ L of the incubation solution from the experimental plate to a new 384-well plate, add 10 ⁇ L of kinase detection reagent to each well, centrifuge at 400g for 1 minute, incubate in a 20°C incubator for 60 minutes, and read with a microplate reader Chemiluminescence signal.
  • Inhibition rate% (1-(experimental well-negative control well)/(positive control well-negative control well))*100%; negative control well: 10 ⁇ M ATP+0.1 ⁇ g/ ⁇ L MBP+DMSO; positive Control wells: 1nM HPK1+10 ⁇ M ATP+0.1 ⁇ g/ ⁇ L MBP+DMSO; experimental wells: 1nM HPK1+10 ⁇ M ATP+0.1 ⁇ g/ ⁇ L MBP+compound; use Graphpad Prism 8.0.1 to analyze data, and use four-parameter method to fit drug effects Inhibition rate curves and IC50 values of the drugs were calculated.
  • the compounds of the present invention have high inhibitory activity on HPK1 kinase, and the IC50 value is less than 10 ⁇ M (for example, 0.1 nM to 10 ⁇ M); the IC50 value of some compounds is even less than 1 ⁇ M (for example, 0.1 nM to 1 ⁇ M) or less than 500 nM (for example, 0.1 nM to 1 ⁇ M). 0.1 nM to 500 nM).
  • Table 1 The experimental results of some of the compounds are shown in Table 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Sont divulgués des composés représentés par les formules (A) à (D) ou leurs sels, stéréoisomères, solvates ou promédicaments pharmaceutiquement acceptables, les définitions des groupes dans les formules étant détaillées dans la description. Sont divulguées en outre des compositions pharmaceutiques contenant les composés décrits et leur utilisation dans la préparation de médicaments pour la prévention et/ou le traitement de maladies ou de troubles associés à l'activité de HPK 1.
PCT/CN2022/085658 2021-04-07 2022-04-07 Composés cycliques condensés de pyridine à substitution amine, leur procédé de préparation et leur utilisation WO2022214044A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280033521.XA CN117279896A (zh) 2021-04-07 2022-04-07 氨基取代的吡啶并环类化合物及其制法和用途

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202110373644 2021-04-07
CN202110373644.5 2021-04-07
CN202111101177.7 2021-09-18
CN202111101177 2021-09-18

Publications (1)

Publication Number Publication Date
WO2022214044A1 true WO2022214044A1 (fr) 2022-10-13

Family

ID=83545118

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/085658 WO2022214044A1 (fr) 2021-04-07 2022-04-07 Composés cycliques condensés de pyridine à substitution amine, leur procédé de préparation et leur utilisation

Country Status (2)

Country Link
CN (1) CN117279896A (fr)
WO (1) WO2022214044A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143344A1 (fr) * 2022-01-30 2023-08-03 微境生物医药科技(上海)有限公司 Nouvel inhibiteur d'egfr

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104334532A (zh) * 2012-01-30 2015-02-04 霍夫曼-拉罗奇有限公司 异喹啉和二氮杂萘衍生物
CN109721620A (zh) * 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 Hpk1抑制剂及其用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104334532A (zh) * 2012-01-30 2015-02-04 霍夫曼-拉罗奇有限公司 异喹啉和二氮杂萘衍生物
CN109721620A (zh) * 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 Hpk1抑制剂及其用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 8 July 2021 (2021-07-08), ANONYMOUS : "-1-Isoquinolinamine, 7-(4-methoxyphenyl)-4-[3-(methylsulfonyl)phenyl]- (CA INDEX NAME) ", XP055975813, retrieved from STN Database accession no. 2650657-18-2 *
GAMO, F. J. ET AL.: "Thousands of chemical starting points for antimalarial lead identification", NATURE, vol. 465, 20 May 2010 (2010-05-20), XP002698188, DOI: 10.1038/NATURE09107 *
TRICIA L. MAY-DRACKA, ROBERT ARDUINI, ANDREA BERTOLOTTI-CIARLET, GOVINDA BHISETTI, MARGOT BRICKELMAIER, ELLEN CAHIR-MCFARLAND, IST: "Investigating small molecules to inhibit germinal center kinase-like kinase (GLK/MAP4K3) upstream of PKCθ phosphorylation: Potential therapy to modulate T cell dependent immunity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 28, no. 10, 1 June 2018 (2018-06-01), Amsterdam NL , pages 1964 - 1971, XP055644699, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2018.03.032 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143344A1 (fr) * 2022-01-30 2023-08-03 微境生物医药科技(上海)有限公司 Nouvel inhibiteur d'egfr

Also Published As

Publication number Publication date
CN117279896A (zh) 2023-12-22

Similar Documents

Publication Publication Date Title
TWI754438B (zh) 取代的雜環并環類化合物，其製法與醫藥上的用途
WO2022228568A1 (fr) Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale
WO2020177629A1 (fr) Composé cyclique fusionné à une pyrimidine spiro-substitué, son procédé de préparation et son utilisation médicale
WO2021031952A1 (fr) Composé de pyrimidine cyclique à six chaînons substitué par oxygène, son procédé de préparation et son utilisation médicale
TWI747846B (zh) 苯內醯胺化合物
CN112110918A (zh) 螺环取代的嘧啶并环类化合物，其制法与医药上的用途
WO2020221239A1 (fr) Composé oxaazaquinazoline-7(8h)-cétone, son procédé de préparation et son application pharmaceutique
WO2019174533A1 (fr) Inhibiteur de pd-1/pd-l1 à petites molécules et son utilisation dans des médicaments
WO2021143680A1 (fr) Dérivé hétéroaryle, son procédé de préparation et son utilisation
TW201605866A (zh) 可用作ｐｉｍ激酶抑制劑之呋喃并－及噻吩并－吡啶甲醯胺化合物
WO2015101293A1 (fr) Inhibiteur kinase et son utilisation
CN114096536A (zh) 作为HPK1抑制剂的吡咯并[2,3-b]吡嗪及其用途
JP2014528482A (ja) Ｉｉｉ型受容体チロシンキナーゼの調節因子としての複素環式化合物及びその使用
WO2022184152A1 (fr) Composé hétérocyclique à six chaînons substitué par un cycle condensé, son procédé de préparation et son utilisation
WO2021190417A1 (fr) Nouvel inhibiteur aminopyrimidine d'egfr
JP2020537692A (ja) ヘテロ環式化合物、ヘテロ環式化合物を含む組成物、及びその使用方法
WO2022166920A1 (fr) Composé de pyrrolopyridazine, son procédé de préparation et son utilisation
WO2022214044A1 (fr) Composés cycliques condensés de pyridine à substitution amine, leur procédé de préparation et leur utilisation
TW201927787A (zh) 吡咯並三嗪化合物及抑制ｔａｍ激酶之方法
CN115667273A (zh) 毒蕈碱型乙酰胆碱受体m5的竞争性和非竞争性抑制剂
TWI838644B (zh) 芳甲醯取代的三環化合物及其製法和用途
TW202342010A (zh) 治療神經疾病之方法(二)
TWI779487B (zh) 二氫萘啶酮類化合物，其製法與醫藥上的用途
WO2023131122A1 (fr) Composé hétérocyclique à six chaînons substitué par un cycle fusionné, son procédé de préparation et son utilisation
TWI707853B (zh) 1,2-二氫-1,6-萘啶類衍生物、其製備方法、其藥物組合物及其在醫藥上的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22784110

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280033521.X

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22784110

Country of ref document: EP

Kind code of ref document: A1