Tricyclic compounds and their uses

Abstract

The present invention relates to a compound of formula (I): [Formula 1] JPEG2024506886000271.jpg44153 With respect to the tricyclic compounds of formula (I), pharmaceutical compositions comprising same, processes for preparing same, and uses thereof, each variable is as defined in the specification.

Description

[Technical Field]

[0001] This invention relates to a tricyclic compound, a pharmaceutical composition containing the same, a method for preparing the same, and the use of the same. [Background technology]

[0002] SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) is a non-receptor protein tyrosine phosphohydrolase encoded by the PTPN11 gene. SHP2 contains two SH2 domains (N-terminal SH2 domain and C-terminal SH2 domain), a catalytic domain, and a C-terminal sequence containing two tyrosine phosphorylation sites. The non-receptor protein tyrosine phosphohydrolase subfamily includes two members, SHP1 and SHP2. SHP1 and SHP2 proteins share 61% similarity in their amino acid sequences and less than 75% amino acid identity in their catalytic domains (PTP). SHP1 is mainly expressed in hematopoietic cells and some epithelial cells and is primarily involved in the negative regulation of intracellular signaling. SHP2 is widely expressed in various organs in the human body and plays an important physiological role in human growth and development and homeostasis. After stimulation by growth factors or hormones, SHP2 is involved in signal modulation and transmission of many signaling pathways, including RAS-ERK, JAK-STAT, PI3K-AKT, and PD1-PD-L1, thereby promoting many biological functions such as cell proliferation, cell differentiation, and cell migration.

[0003] Mutations or overexpression of SHP2 can lead to hereditary developmental diseases and tumors. In hereditary developmental diseases, it has been reported that 90% of Leopard syndrome cases and 50% of Noonan syndrome cases have gain-of-function (GOF) mutations in the PTPN11 gene. Mutations in the PTPN11 gene have also been reported in hematological malignancies, including myelodysplastic syndrome (10%), B-cell acute lymphoblastic leukemia (7%), and juvenile acute myeloid leukemia (5%). While SHP2 mutations are rare in solid tumors, SHP2 overexpression / activation is closely associated with the development of various tumors. SHP2 expression is increased by 70% in invasive ductal breast cancer; overexpression of the SHP2-binding protein GAB2 is detected in 10%–15% of breast cancers; and SHP2 overexpression in melanoma is often closely associated with a poor prognosis.

[0004] SHP2 is closely associated with tumors and is an attractive target for antitumor drugs. Several selective SHP2 inhibitors, such as TNO155 (Novartis), RMC-4630 (Revolution Medicines / Sanofi), JAB-3068 (Jacobio), and RLY-1971 (Relay Therapeutics), are currently in clinical trials; however, SHP2 inhibitors are not yet approved for commercial use.

[0005] Therefore, SHP2 inhibitors are attractive candidates for the development of treatments for related diseases, particularly cancer, Noonan syndrome, and Leopard syndrome. [Overview of the project]

[0006] The present invention relates to formula (I):

[0007] [ka]

[0008] The compound or its pharmaceutically acceptable salt, or its solvate, racemic mixture, enantiomer, diastereomer or tautomer, wherein in the above formula (I), Ring A is a benzene ring or a pyridine ring; Z is CH2, O, S or NH; R1 is C 1~6 , 3~8 , 1~6 , 1~6 , 1~6 , 1~6 , 1~6 , 1~6 selected from alkynyl, -NR3R4, -SR5 and -SR6, and the said C 2~6 alkynyl is; halogen, -CN, -OH, -NH2, C 3~8 cycloalkyl, 4- to 8-membered heterocyclyl, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -O(C 3~8 cycloalkyl), -O(4- to 8-membered heterocyclyl), -S(C 1~6 alkyl), -S(C 3~8 cycloalkyl), -S(4- to 8-membered heterocyclyl), -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, -NH-CN, -NHCONH2, -NHCO(C 1~6 alkyl), -CONR a R b , -COOR c and -COR d may each independently be substituted with one or more groups selected from, and R a , R b , R c and R <​​​​​​​​​​​​​​​​​​​​​​​​​1~6 Independently selected from alkyl)-CN; R4 and R5 are C 3~8 R6 is independently selected from cycloalkyl, phenyl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R6 is -CO(C 1~6 Alkyl), -CO(C 3~8 Cycloalkyl), -CO (4-membered to 8-membered heterocyclyl), -CONH2, -CONH(C 1~6 Alkyl), -CONH(C 3~8 Cycloalkyl), -CONH (4-membered to 8-membered heterocyclyl), -CON (C 1~6 Alkyl)2,-(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-NH(C 1~6 Alkyl), -(C 1~6 Alkyl)-N(C 1~6 Alkyl)2 and -(C 1~6 Alkyl)-NHCO(C 1~6 Selected from alkyl; the C of R6 1~6 Alkyls are: halogens, -CN, -OH and -O(C 1~6 The above C may be substituted with one or more groups independently selected from alkyl; 3~8 Cycloalkyl, phenyl, 4- to 8-membered heterocyclyl and 5- to 12-membered heteroaryl are: halogen, -CN, -CONH2, -OH, oxo, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -S(C 1~6 Alkyl), -NH(C 1~6 Alkyl) and -N(C 1~6may each be substituted by one or more groups independently selected from (alkyl)2; R1’ is halogen, -CN, -CONH2, -OH, -NH2, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, 4- to 8-membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 alkyl)-O-(C 1~6 alkyl), -(C 1~6 alkyl)-CN, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -O(C 3~8 cycloalkyl), -O(4- to 8-membered heterocyclyl), -S(C 1~6 alkyl), -NH(C 1~6 alkyl) and -N(C 1~6 alkyl)2, independently selected, wherein the C 3~8 cycloalkyl and 4- to 8-membered heterocyclyl may each be independently substituted by one or more halogens; n is 0, 1, 2 or 3;[[ID=3D]] R2 is -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, oxo and -OH; Cy1 is 5- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, each of which is: halogen, -CN, -CONH2, -OH, oxo, -NH2, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, 4- to 8-membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 alkyl)-O-(C 1~6 alkyl), -(C 1~6 alkyl)-CN, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -O(C 3~8(cycloalkyl), -O(4- to 8-membered heterocyclyl), -S(C 1~6 alkyl), -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, -NHCO(C 1~6 alkyl), -CONH(C 1~6 alkyl) and -CON(C 1~6 alkyl)2, and may be substituted by one or more groups independently selected from, the C 3~8 cycloalkyl and 4- to 8-membered heterocyclyl may each independently be substituted by one or more halogens; Cy2 is phenyl or 5- to 14-membered heteroaryl, each of which: halogen, -CN, -CONH2, -OH, oxo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 alkyl)-O-(C 1~6 alkyl), -(C 1~6 alkyl)-CN, -O(C 1~6 alkyl), -O(C 1~6 haloalkyl), -O(C 3~8 cycloalkyl), -O(4- to 8-membered heterocyclyl), -S(C 1~6 alkyl), -NR7R8, -NHCO(C 1~6 alkyl), -CONH(C 1~6 alkyl) and CON(C 1~6 alkyl)2, and may be substituted by one or more groups independently selected from, R7 and R8 are hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 alkyl)-O-(C 1~6 alkyl), -(C 1~6 alkyl)-CN, C 3~8 cycloalkyl, phenyl, 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl, each independently selected; and L does not exist, or L is S, O, NH, C 1~6 Alkyl, C 2~6 Alkenil or C 2~6 Alkinyl is The present invention provides compounds or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof.

[0009] The compounds and active compounds (including compounds of general formulas and specific compounds) disclosed in connection with the present invention, as well as their pharmaceutically acceptable salts, solvates, racemic mixtures, enantiomers, diastereomers, or tautomers, are collectively referred to herein as "compounds of the present invention."

[0010] The present invention also provides pharmaceutical compositions comprising the compound of the present invention and optionally comprising pharmaceutically acceptable excipients.

[0011] The present invention also provides a method for inhibiting the activity of SHP2 in vivo or in vitro, the method comprising contacting SHP2 with an effective amount of the compound of the present invention.

[0012] The present invention also provides a method for treating or preventing a disease mediated by SHP2 or at least partially by SHP2, the method comprising administering an effective amount of the compound of the present invention to a subject in need of treatment or prevention.

[0013] The present invention also provides a method for treating or preventing cancer, Noonan syndrome, or Leopard syndrome, wherein the method comprises administering an effective amount of the compound of the present invention to a subject in need of treatment or prevention.

[0014] The present invention also provides the use of the compounds of the present invention in the treatment or prevention of diseases mediated by SHP2 or at least partially by SHP2.

[0015] The present invention also provides the use of the compounds of the present invention in the treatment or prevention of cancer, Noonan syndrome, or Leopard syndrome.

[0016] The present invention also provides the use of the compounds of the present invention in the manufacture of pharmaceuticals for the treatment or prevention of diseases mediated by SHP2 or at least partially by SHP2.

[0017] The present invention also provides for the use of the compounds of the present invention in the manufacture of pharmaceuticals for the treatment or prevention of cancer, Noonan syndrome, or Leopard syndrome.

[0018] The present invention also provides compounds for inhibiting SHP2 activity in vivo or in vitro.

[0019] The present invention also provides compounds of the present invention for use as pharmaceuticals.

[0020] The present invention also provides compounds for use as pharmaceuticals for the treatment or prevention of diseases mediated by SHP2 or at least partially by SHP2, particularly for the treatment or prevention of cancer, Noonan syndrome, or Leopard syndrome.

[0021] The present invention also provides a pharmaceutical combination comprising the compound of the present invention and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably selected from: an antitumor agent, an anti-inflammatory agent, or an immunomodulator, and the antitumor agent includes a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0022] The present invention also provides a kit for the treatment or prevention of diseases mediated by SHP2 or at least partially by SHP2. The kit may comprise a pharmaceutical composition of the present invention and instructions for use, the pharmaceutical composition comprising a compound of the present invention. [Modes for carrying out the invention]

[0023] definition When used in this application, the following words, phrases, and symbols are intended to have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0024] A dash ("-") between two letters or symbols is used to indicate a substituent bond point. For example, -OR6 represents the bond of R6 to the rest of the molecule by an oxygen atom.

[0025] As used herein, the term "alkyl" refers to a group of 1 to 18 carbon atoms (C) 1~18 ), preferably 1 to 10 carbon atoms (C 1~10 ), more preferably 1 to 6 carbon atoms (C 1~6 ), more preferably 1 to 4 carbon atoms (C 1~4 ) or 1-3 carbon atoms (C 1~3 Represents a linear or branched saturated hydrocarbon radical containing ). The term "alkyl" is a prefix of "C". a~b If it has ", it means the number of carbon atoms in this alkyl, where a is the minimum number of carbon atoms in this alkyl and b is the maximum number of carbon atoms in this alkyl. For example, "C 1~6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms. 1~3 "Alkyl" refers to an alkyl group containing 1 to 3 carbon atoms. 1~6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (e.g., n-butyl, i-butyl, s-butyl, and t-butyl), pentyl (e.g., n-pentyl, i-pentyl, neopentyl), hexyl, and similar groups. They can also be used as linkers (e.g., in the definition of L) or between two dashes ("-") (e.g., -(C)). 1~6 When used in alkyl)-OH), alkyl represents alkylene.

[0026] As used herein, the term “alkenyl” means one or more, for example, 1, 2, or 3 carbon-carbon double bonds (C=C) and 2 to 18 carbon atoms (C=C). 2~18 ), preferably 2 to 10 carbon atoms (C 2~10 ), more preferably 2-6 carbon atoms (C 2~6 ), more preferably 2 to 4 carbon atoms (C 2~4 The term "alkenyl" is a linear or branched unsaturated hydrocarbon radical containing "C". a~b If it has ", it means the number of carbon atoms in this alkenyl, where a is the minimum number of carbon atoms in this alkenyl and b is the maximum number of carbon atoms in this alkenyl. For example, "C 2~6 "Alkenyl" refers to an alkenyl containing 2 to 6 carbon atoms. 2~4 "Alkenyl" refers to an alkenyl containing 2 to 4 carbon atoms. 2~6 Examples of alkenyls include, but are not limited to, vinyl, propenyl (e.g., 2-propenyl), and butenyl (e.g., 2-butenyl), and similar compounds. The alkenyl bond may or may not be on a double bond. When used as a linker (e.g., in the definition of L), alkenyl represents alkenylene.

[0027] As used herein, the term "alkynyl" means one or more carbon-carbon triple bonds (C≡C) and 2 to 18 carbon atoms (C≡C). 2~18 ), preferably 2 to 10 carbon atoms (C 2~10 ), more preferably 2-6 carbon atoms (C 2~6 ), more preferably 2 to 4 carbon atoms (C 2~4 The term "alkynyl" is a linear or branched unsaturated hydrocarbon radical containing "C". a~b If it has ", it means the number of carbon atoms in this alkynyl, where a is the minimum number of carbon atoms in this alkynyl and b is the maximum number of carbon atoms in this alkynyl. For example, "C 2~6 "Alkynyl" refers to an alkynyl compound containing 2 to 6 carbon atoms. 2~4"Alkykenyl" refers to an alkynyl compound containing 2 to 4 carbon atoms. 2~6 Examples of alkenyls include, but are not limited to, ethynyl, propynyl (e.g., 2-propynyl), and butynyl (e.g., 2-butynyl), and similar ones. The alkynyl bond may or may not be on a triple bond. When used as a linker (e.g., in the definition of L), alkynyl represents alkynylene.

[0028] As used herein, the term "halogen" or "halo" means fluoro, chloro, bromo, and iodine, preferably fluoro, chloro, and bromo, more preferably fluoro and chloro.

[0029] As used herein, the term “haloalkyl” refers to an alkyl radical as defined herein in which one or more, for example, 1, 2, 3, 4, or 5, or all of the hydrogen atoms are substituted by halogen atoms, and if multiple hydrogen atoms are substituted by halogen atoms, these halogen atoms may be the same or different from each other. In one embodiment, as used herein, the term “haloalkyl” refers to an alkyl radical as defined herein in which two or more, such as 2, 3, 4, or 5, or all of the hydrogen atoms are substituted by halogen atoms, and these halogen atoms are the same from each other. In another embodiment, as used herein, the term “haloalkyl” refers to an alkyl radical as defined herein in which two or more, such as 2, 3, 4, or 5, or all of the hydrogen atoms are substituted by halogen atoms, and these halogen atoms are different from each other. a~b If it has ", it means the number of carbon atoms in this haloalkyl, where a is the minimum number of carbon atoms in this haloalkyl and b is the maximum number of carbon atoms in this haloalkyl. For example, "C 1~6 "Haloalkyl" refers to a haloalkyl as defined herein, containing 1 to 6 carbon atoms. 1~4"Haloalkyl" refers to a haloalkyl as defined herein, containing 1 to 4 carbon atoms. 1~6 Examples of haloalkyls include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH(CF3)2, and similar ones.

[0030] As used herein, the term "cycloalkyl" refers to a ring of 3-8 carbon atoms (C) 3~8 ), 5-7 ring carbon atoms (C 5~7 ), 4-7 ring carbon atoms (C 4~7 ), or 3-6 ring carbon atoms (C 3~6 ) and other 3-12 ring carbon atoms (C 3~12 The term "cycloalkyl" represents a saturated or partially unsaturated cyclic hydrocarbon radical having 1, 2, or 3 rings, preferably 1 or 2 rings. a~b If "C" is present, it means the number of carbon atoms in this cycloalkyl group, where a is the minimum number of carbon atoms in this cycloalkyl group and b is the maximum number of carbon atoms in this cycloalkyl group. For example, "C 3~8 "Cycloalkyl" or "3-membered to 8-membered cycloalkyl" refers to a cycloalkyl group containing 3 to 8 ring carbon atoms; "C 3~6 "Cycloalkyl" or "3- to 6-membered cycloalkyl" refers to a cycloalkyl group containing 3 to 6 ring carbon atoms. A cycloalkyl group may include a fused ring, a bridging ring, or a spirocyclic ring. The rings of a cycloalkyl group may be saturated and may have one or more double bonds (e.g., one or two double bonds, i.e., partially unsaturated), but not fully conjugated and not aryl as defined herein. 3~8 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2,2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl.

[0031] As used herein, the terms “heterocyclyl” and “heterocycle” may be used interchangeably, each representing a saturated or partially unsaturated cyclic radical having 3 to 12 ring atoms, such as 5 to 12 ring atoms (5- to 12-membered heterocyclyl), 3 to 8 ring atoms (3- to 8-membered heterocyclyl), 4 to 8 ring atoms (4- to 8-membered heterocyclyl), 4 to 6 ring atoms (4- to 6-membered heterocyclyl), or 4 to 5 ring atoms (4- to 5-membered heterocyclyl), where the ring contains one or more heteroatoms independently selected from N, O, and S, e.g., 1, 2, or 3, preferably 1 or 2, and the remaining ring atoms are carbon; a heterocyclyl or heterocycle may have one or more rings, e.g., 1, 2, or 3, preferably 1 or 2. A heterocyclyl also includes those in which the N or S heteroatom is oxidized to various oxidation states as desired. The bonding sites of heterocyclines can be on N heteroatoms or carbon atoms. For example, a "4- to 8-membered heterocycline" is a heterocycline having 4-8 (4, 5, 6, 7, or 8) ring atoms comprising at least one, preferably 1 or 2 heteroatoms, independently selected from N, O, and S; a "4- to 6-membered heterocycline" is a heterocycline having 4-6 (4, 5, or 6) ring atoms comprising at least one, preferably 1 or 2 heteroatoms, independently selected from N, O, and S (preferably N and O), and is preferably a monocyclic ring; and a "4- to 5-membered heterocycline" is a heterocycline having 4-5 ring atoms comprising at least one, preferably 1 or 2 heteroatoms, independently selected from N, O, and S (preferably N and O), and is a monocyclic ring. Heterocyclines also include fused rings, bridging rings, or spirocyclic rings. The heterocyclyl ring may be saturated and may have one or more double bonds, for example, one or two (i.e., partially unsaturated), but not fully conjugated and is not a heteroaryl as defined herein.Examples of heterocyclyl include 3- to 8-membered heterocyclyl such as oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, tetrahydropyridyl, dihydropyrimidyl, dihydropyrazinyl, pyrazolidinyl, and oxaspiro[3.3]heptyl, 4- to 8-membered heterocyclyl, 4- to 6-membered heterocyclyl, and 4- to 5-membered heterocyclyl, but are not limited thereto. Preferably, oxetanyl (oxetan-3-yl), azetidinyl, tetrahydropyranyl, morpholinyl (such as morpholino), piperazinyl (piperazin-1-yl), tetrahydropyridyl (such as 1,2,3,6-tetrahydropyridyl), dihydropyrimidyl (such as 1,6-dihydropyrimidyl) are included.

[0032] As used herein, the terms "aryl" or "aromatic ring" can be used interchangeably, and each represents a carbocyclic hydrocarbon of 6 to 14 carbon atoms consisting of one ring or one or more fused rings in which at least one ring is an aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, phenanthryl, indenyl, indanyl, azulenyl. Preferably, phenyl and naphthalenyl are included.

[0033] As used herein, the terms "heteroaryl" or "heteroaromatic ring" can be used interchangeably, and each refers to: a monocyclic, bicyclic, or tricyclic system having 5 to 15 ring atoms, preferably 5 to 14 ring atoms, more preferably 5 to 12 ring atoms, still more preferably 5 to 10 ring atoms, most preferably 5 to 6 ring atoms or 8 to 10 ring atoms, with at least one ring being a 5- or 6-membered aromatic ring containing one or more, such as 1 to 4, heteroatoms independently selected from N, O, and S, and S and N may optionally be oxidized to various oxidation states. When the total number of S and O atoms in the heteroaryl group exceeds 1, the S and O heteroatoms are not adjacent to each other. Preferably, the heteroaryl is a 5- to 12-membered heteroaryl. For example, heteroaryls include the following:

[0034] A 5- to 6-membered monocyclic heteroaryl, i.e., a monocyclic ring aromatic hydrocarbon having 5 or 6 ring atoms, where the ring atoms include one or more heteroatoms such as 1, 2, or 3 independently selected from N, O, and S (preferably N), and the remaining ring atoms are carbon atoms; this heteroaryl is preferably triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyrazolyl, imidazolyl, isoxazolyl, triazinyl, oxazolyl, thiadiazolyl, and pyridazinyl, more preferably pyridyl (such as pyridin-4-yl, pyridin-3-yl, etc.), pyrazinyl, pyrimidyl, and triazinyl (such as 1,2,4-triazinyl, etc.), and

[0035] 8- to 10-membered bicyclic heteroaryls, i.e., bicyclic aromatic hydrocarbyls having 8, 9, or 10 ring atoms, where the ring atoms include one or more heteroatoms such as 1, 2, 3, or 4, preferably 1, 2, or 3, independently selected from N, O, and S (preferably N), and the remaining ring atoms are carbon atoms, and at least one ring is an aromatic ring; these are preferably imidazo[1,2-c]pyrimidyl, 1H-pyrrolo[ These include [2,3-b]pyridyl, indazolyl, imidazo[1,2-a]pyradinyl, imidazo[1,5-a]pyradinyl, pyrrolo[1,2-a]pyradinyl, pyrazolo[1,5-a]pyradinyl, [1,2,4]triazolo[1,5-a]pyradinyl, [1,2,4]triazolo[4,3-c]pyrimidyl, [1,2,4]triazolo[1,5-c]pyrimidyl, and 1,2,3,4-tetrahydro-1,5-naphthilidinyl.

[0036] Examples of heteroaryls include: pyridyl, N-oxidepyridyl, pyrazinyl, pyrimidyl, triazinyl (1,2,4-triazinyl, 1,3,5-triazinyl, etc.), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, and 1,3,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furanyl, pyranyl, pyrrolyl, and pyridazinyl, which are 5- to 6-membered monocyclic compounds. Heteroaryl compounds; as well as benzoxazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyrimidyl (imidazo[1,2-c]pyrimidyl, etc.), imidazopyradinyl (imidazo[1,2-a]pyradinyl and imidazo[1,5-a]pyradinyl, etc.), imidazopyridyl (imidazo[1,2-a]pyridyl, etc.), imidazopyridazinyl (imidazo[1,2-b]pyridazinyl, etc.), pyrrolopyrazinyl (pyroro[1,2-a]pyradinyl, etc.), pyrrolopyrazinyl (1 (e.g., H-pyrrolo[2,3-b]pyridyl), pyrrolopyrimidyl (e.g., pyrrolo[3,4-d]pyrimidyl), pyrazolopyrazine (e.g., pyrazolo[1,5-a]pyridinyl), pyrazolopyrimidyl (e.g., 1H-pyrazolo[3,4-b]pyridyl), pyrazolopyrimidyl (e.g., pyrazolo[1,5-a]pyrimidyl), triazolopyrimidyl (e.g., [1,2,4]triazolo[4,3-c]pyrimidyl and [1,2,4]triazolo[1,5-c]pyrimidyl), triazolopyrazine (e.g., [1,2,4]triazolo[1,5-a]pyridinyl) Examples include, but are not limited to, 8- to 10-membered bicyclic heteroaryls such as triazolopyridyl (e.g., [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl), tetrazolopyridyl (e.g., tetrazolo[1,5-a]pyridyl), benzofuranil, indolyl, indazolyl, prinyl, quinolinil, isoquinolinil, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, and 1,2,3,4-tetrahydro-1,5-naphthilidinyl.

[0037] As used herein, the term "-OH" represents a hydroxyl radical.

[0038] As used herein, the term "-CN" represents a cyanoradical.

[0039] As used herein, the term "oxo" represents = O.

[0040] When used herein, the terms “optional” or “optionally” mean that the event or environment described thereafter may or may not occur, and such description includes both the cases in which such event or environment occurs and the cases in which such event or environment does not occur. For example, “may be substituted by one or more” includes being unsubstituted and being substituted by one, two, three or more substituents described. With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such group is not intended to introduce any substitution or substitution pattern that is sterically impractical, chemically incorrect, synthetically unfeasible and / or inherently unstable.

[0041] As used herein, the terms “substituted” or “substituted by” means that one or more (1, 2, 3, or 4) hydrogens on a given atom or group are substituted by one or more (1, 2, 3, or 4) substituents, preferably substituents selected from the designated group of the substituent or radical, provided that the hydrogens on the given atom or group do not exceed the normal valence of the given atom. The substituents may be the same or different from each other. As used herein, the terms “substituted by one or more groups selected from” or “substituted by one or more” means that one or more hydrogens on a given atom or group are independently substituted by one or more radicals from the designated group of the substituent or radical, and the radicals may be the same or different from each other. Preferably, “substituted by one or more groups selected from” or “substituted by one or more” means that the given atom or group is substituted by one, two, three, or four radicals independently selected from the designated group of the substituent or radical, and the radicals may be the same or different from each other. In some embodiments, when the substituent is oxo (i.e., =O), two hydrogens on a single atom are substituted by the oxo. Optional substituents can be any radical, provided that the combination of substituents and / or variables results in a chemically valid and stable compound. A chemically valid and stable compound is intended to mean a compound that is robust enough to be sufficiently isolated and remain in the reaction mixture, allowing the chemical structure of the compound to be identified. Preferably, the substituents are those exemplified in the compounds of the complementary examples.

[0042] Unless otherwise specified, substituents are classified as part of the core structure. For example, if (cycloalkyl)alkyl is listed as a possible substituent, it should be understood that the bonding site of this substituent to the core structure is within the alkyl portion.

[0043] In this specification, where a structural formula contains an asterisk "*", the chiral center (or chiral axis) at the "*" mark in the compound is a single structure of either an (R) or (S) structure; and the content of single-structure compounds marked with "*" is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between these enumerated values). For example, some compounds of the present invention are axial chiral compounds, such as the compound of formula (a) below, whose structural formula contains an asterisk "*", where the asterisk "*" means that the compound is a single structure of the compound of formula (b) or the compound of formula (c).

[0044] [ka]

[0045] Those skilled in the art will understand that some compounds of formula (I) contain one or more chiral centers (or chiral axes) and therefore may exist in two or more stereoisomers. Racemates of these isomers, mixtures rich in individual isomers and one enantiomer, as well as diastereomers in the case of two chiral centers (or chiral axes), and mixtures partially rich in a particular diastereomer are within the scope of the present invention. Those skilled in the art will further understand that the present invention includes all individual stereoisomers (e.g., enantiomers, diastereomers), racemic mixtures, or partially separated mixtures of compounds of formula (I) and, where appropriate, their individual tautomers.

[0046] As used herein, the term “axial chirality” refers to a specific case of chirality. A molecule has a chiral axis, and multiple groups are arranged around this axis, resulting in a molecule that cannot be superimposed on its mirror image. Axial chirality is most widely observed in asymmetric diaromatic ring (e.g., biphenyl) compounds with limited rotation, such as 1,1'-bi-(2-naphthol).

[0047] As used herein, the term “stereoisomer” refers to a compound that has the same chemical structure but differs in the spatial arrangement of its atoms or groups. Examples of stereoisomers include enantiomers, diastereomers, and similar compounds.

[0048] As used herein, the terms “enantiomers” and “enantiomeric forms” are interchangeable and refer to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed.

[0049] As used herein, the terms “diastereomers” and “diastereomeric forms” are interchangeable and refer to stereoisomers having two or more chiral centers (or chiral axes) whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral characteristics, or biological activity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0050] In some embodiments, the present invention provides compounds with various stereoisomer purities, i.e., enantiomer or diastereomer purities expressed by different "ee" or "de" values. In some embodiments, the compounds of formula (I) described herein have an enantiomer purity of at least 60%ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%ee, or any value between these enumerated values). In some embodiments, the compounds of formula (I) described herein have an enantiomer purity higher than 99.9%ee. In some embodiments, the compounds of formula (I) described herein have a diastereomer purity of at least 60%de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%de, or any value between these enumerated values). In some embodiments, the compounds of formula (I) described herein have a diastereomer purity higher than 99.9%de.

[0051] The term “enantiomer excess” or “ee” represents the amount of one enantiomer relative to the other. For a mixture of R and S enantiomers, the percentage of enantiomer excess is defined as |RS| × 100, where R and S are the mole fraction or weight fraction of each enantiomer in the mixture, and R + S = 1. If the optical rotation of a chiral substance is known, the percentage of enantiomer excess is defined as ([a]obs / [a]max) × 100, where [a]obs is the optical rotation of the enantiomer mixture and [a]max is the optical rotation of the pure enantiomer.

[0052] The term "diastereomeric excess" or "de" represents the amount of one diastereomer relative to the other and is analogously defined for enantiomeric excess. Thus, for a mixture of diastereomers D1 and D2, the percentage of diastereomeric excess is defined as |D1 - D2|×100, where D1 and D2 in the formula are the mole fractions or weight fractions of the respective diastereomers in the mixture and D1 + D2 = 1.

[0053] Diastereomeric excess and enantiomeric excess can be measured by several analytical techniques (including nuclear magnetic resonance spectroscopy, chiral column chromatography, and / or polarimetry) according to conventional protocols well known to those skilled in the art.

[0054] A racemic mixture can be used as such, or it can be separated into its individual isomers. Separation can yield a stereochemically pure compound or a mixture rich in one or more isomers. Methods for isomer separation are well known (see Allinger NL and Eliel EL in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography with chiral adsorbents. Individual isomers can be prepared into chiral forms from chiral precursors. Alternatively, individual isomers can be chemically separated from a mixture by forming diastereomer salts with chiral acids (such as 10-camphorsulfonic acid, camphor acid, α-bromosodium, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and their individual enantiomers), fractionally crystallizing these salts, and then, if desired, repeating this process to liberate one or both of the separated bases and obtain one or both of the forms that are substantially free of the others, i.e., have an optical purity of >95%. Alternatively, the racemic mixture can be covalently bonded with a chiral compound (auxiliary agent) to produce diastereomers, which can then be separated by chromatography or fractional crystallization. The chiral auxiliary agent can then be chemically removed to obtain pure enantiomers.

[0055] As used herein, the term “tautomer” refers to a structural isomer of a compound produced by the rapid movement of atoms at two positions in the molecule. Tautomers rapidly interconvert, and enol and ketone bodies are typical examples.

[0056] "Pharmacopoeially acceptable salts" are intended to mean salts of free acids or free bases of compounds of formula (I) that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the target of treatment or prevention. For example, acid addition salts include salts derived from inorganic and organic acids. See, for example, SM Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.

[0057] In addition, when obtaining the compounds described herein as acid addition salts, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, when the product is a free base, the acid addition salt, more specifically a pharmaceutically acceptable acid addition salt, may be prepared by dissolving the free base in a suitable solvent and treating the solution with acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used without unnecessary experimentation to prepare non-toxic, pharmaceutically acceptable acid addition salts or base addition salts.

[0058] The term "solvate" refers to a solvation form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture a certain molar ratio of solvent molecules in the solid state, and thus form solvates. When the solvent is water, the resulting solvate is a hydrate; when the solvent is an alcohol, the resulting solvate is an alcoholate. Hydrates are formed by a combination of one or more molecules of water, or less than one molecule of water, and one molecule of another substance, where the water retains its molecular state as H2O. Such combinations can produce one or more hydrates, such as hemihydrates, monohydrates, and dihydrates.

[0059] As used herein, the terms “group” and “radical” are synonymous and are intended to refer to a functional group or fragment of a molecule that can bind to other fragments of the molecule.

[0060] The term "active ingredient" is used to refer to a chemical substance that has biological activity. In some embodiments, the "active ingredient" is a chemical substance that has medicinal properties.

[0061] As used herein, the term “combination drug” means a product obtained by mixing or combining two or more active ingredients, including fixed and unfixed combinations of active ingredients such as kits and pharmaceutical compositions. The term “fixed combination” means administering two or more active ingredients (such as the compound of the present invention and an additional therapeutic agent) to a patient simultaneously in single or dose form. The term “unfixed combination” means administering two or more active ingredients (such as the compound of the present invention and an additional therapeutic agent) to a patient simultaneously, in parallel or sequentially in separate entities, and that administration provides the patient with a therapeutic efficacy level of the compound.

[0062] In relation to obtaining a therapeutic effect, the terms “to treat” or “to cure” or “to prevent” a disease or disorder mean administering one or more pharmaceutical substances, particularly the compounds of the present invention, to a subject having a disease or disorder, having symptoms of a disease or disorder, or having a tendency to develop a disease or disorder, for the purpose of curing, healing, relieving, alleviating, altering, resolving, restoring, improving, or influencing a disease or disorder, symptoms of a disease or disorder, or a tendency to develop a disease or disorder. In some embodiments, the disease or disorder is a solid tumor or cancer such as a hematological malignancy including leukemia, lymphoma, and myeloma. In other embodiments, the disease or disorder is Noonan syndrome or Leopard syndrome.

[0063] In relation to chemical reactions, the terms “processing,” “contacting,” and “reacting” mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. The reaction that produces the indicated and / or desired product may not necessarily be obtained directly from the combination of the two reagents initially added; that is, there may be one or more intermediates produced in the mixture that ultimately leads to the production of the indicated and / or desired product.

[0064] As used herein, the term “effective dose” refers to the amount or dosage of an SHP2 inhibitor sufficient to produce an overall therapeutic effect in a patient who needs to treat or prevent a disease or disorder mediated by SHP2 or at least partially by SHP2. The effective dose or dosage of the active ingredients of this disclosure may be determined by methods such as modeling, dose escalation studies or clinical trials, and by taking into account factors such as administration or drug delivery, pharmacokinetics of the drug, severity and course of the disease or disorder, the patient’s treatment history or ongoing treatment, the patient’s health status and response to the drug, and the judgment of the attending physician.

[0065] Exemplary doses range from approximately 0.0001 to 200 mg of the active agent per kg of body weight per day, such as approximately 0.001 to 100 mg / kg / day, or approximately 0.01 to 35 mg / kg / day, or approximately 0.1 to 10 mg / kg / day, in single or divided dose units (e.g., twice daily (BID), three times daily (TID), or four times daily (QID)). For a 70 kg person, the exemplary range of appropriate doses is approximately 0.05 to 7 g / day, or approximately 0.2 to 5 g / day. Once the patient's disease or disability has improved, the dose may be adjusted for maintenance therapy. For example, the dose, frequency, or both of the administration may be reduced according to the symptoms to a level that maintains the desired therapeutic effect. Of course, treatment may be discontinued when symptoms have been adequately relieved. However, the patient may require long-term intermittent treatment in the event of relapse of any of the symptoms.

[0066] The term “inhibition” or “inhibiting” refers to a reduction in the fundamental activity of a biological activity or biological process. The term “inhibition of SHP2 activity” is a practical pharmaceutically active term for the purposes of this disclosure and represents a reduction in SHP2 activity as a direct or indirect response to the presence of the compound of the present invention compared to the activity of SHP2 in the absence of the compound of the present invention. The reduction in activity may be due to a direct interaction between the compound of the present invention and SHP2, or to an interaction between the compound of the present invention and one or more other factors that subsequently affect SHP2 activity. For example, the presence of the compound of the present invention may reduce SHP2 activity by directly binding to SHP2, (directly or indirectly) inducing another factor that reduces SHP2 activity, or (directly or indirectly) reducing the amount of SHP2 present in a cell or organism.

[0067] As used herein, the terms “subject” or “patient” mean mammals and non-mammals. Mammals mean any member of the class Mammalia, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkey species; domesticated animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; laboratory animals including rodents such as rats, mice, and guinea pigs; and similar animals. Examples of non-mammals include but not limited to birds and similar animals. The terms “subject” or “patient” do not represent a specific age or sex. In some embodiments, the subject or patient is human.

[0068] In general, the term "approximately" is used herein to adjust for values ​​above or below a specified value by a 20% variance.

[0069] Technical and scientific terms used herein, and not specifically defined, have meanings that are more broadly understood by those skilled in the art to which this disclosure belongs.

[0070] In this specification, all numerical ranges should be construed as disclosing each numerical value and a subset of numerical values ​​within that range, regardless of whether they are specifically disclosed elsewhere. For example, when referring to any range of values, it should be considered to represent all values ​​within that range, e.g., all integers within that range. For example, when used herein, C 1~6 This indicates that it includes 1C, 2C, 3C, 4C, 5C, or 6C. The present invention relates to all values ​​within a range, all smaller ranges, and upper or lower limits of numerical ranges.

[0071] Detailed description of the embodiment Embodiment 1. Equation (I):

[0072] [ka]

[0073] A compound of or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer or tautomer thereof, wherein in formula (I), Ring A is either a benzene ring or a pyridine ring; Z is CH2, O, S, or NH; R1 is C 2~6 Selected from alkynyl, -NR3R4, -SR5 and -SR6, and the C 2~6 Alkynnyl is a halogen, -CN, -OH, -NH2, C 3~8 Cycloalkyl, 4-membered to 8-membered heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -S(C 3~8 Cycloalkyl), -S (4-membered to 8-membered heterocyclyl), -NH (C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NH-CN,-NHCONH2,-NHCO(C 1~6 Alkyl), -CONRa R b ,-COOR c and -COR d It may be substituted by one or more groups independently selected from R a , R b , R c and R d is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN, C 3~8 Cycloalkyl and 4- to 8-membered heterocyclines are independently selected; R3 is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and -(C 1~6 Independently selected from alkyl)-CN; R4 and R5 are C 3~8 R6 is independently selected from cycloalkyl, phenyl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl; R6 is -CO(C 1~6 Alkyl), -CO(C 3~8 Cycloalkyl), -CO (4-membered to 8-membered heterocyclyl), -CONH2, -CONH(C 1~6 Alkyl), -CONH(C 3~8 Cycloalkyl), -CONH (4-membered to 8-membered heterocyclyl), -CON (C 1~6 Alkyl)2,-(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-NH(C 1~6 Alkyl), -(C 1~6 Alkyl)-N(C 1~6 Alkyl)2 and -(C 1~6 Alkyl)-NHCO(C 1~6 Selected from alkyl; the C of R6 1~6Alkyls are: halogens, -CN, -OH and -O(C 1~6 The above C may be substituted with one or more groups independently selected from alkyl; 3~8 Cycloalkyl, phenyl, 4- to 8-membered heterocyclyl and 5- to 12-membered heteroaryl are: halogen, -CN, -CONH2, -OH, oxo, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -S(C 1~6 Alkyl), -NH(C 1~6 Alkyl) and -N(C 1~6 Each of the alkyl)2 groups may be substituted with one or more groups independently selected from the alkyl group; R1' is halogen, -CN, -CONH2, -OH, -NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 4-membered to 8-membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -NH(C 1~6 Alkyl) and -N(C 1~6 A C is independently selected from alkyl)2. 3~8 Cycloalkyl and 4- to 8-membered heterocyclyls may each be independently substituted with one or more halogens; n is 0, 1, 2, or 3; R2 is -NH2, -NH(C 1~6 Alkyl), -N(C 1~6 Selected from alkyl)2, oxo, and -OH; Cy1 is a 5- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, each of which is: halogen, -CN, -CONH2, -OH, oxo, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, 4-membered to 8-membered heterocyclyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NHCO(C 1~6 Alkyl), -CONH(C 1~6 Alkyl) and -CON(C 1~6 The alkyl)2 may be substituted with one or more groups independently selected from the C 3~8 Cycloalkyl and 4- to 8-membered heterocyclyls may each be independently substituted with one or more halogens; Cy2 is a phenyl or 5- to 14-membered heteroaryl, each of which is: halogen, -CN, -CONH2, -OH, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN,-O(C 1~6 Alkyl), -O(C 1~6Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -NR7R8, -NHCO(C 1~6 Alkyl), -CONH(C 1~6 Alkyl) and CON(C 1~6 It may be substituted with one or more groups independently selected from alkyl)2, where R7 and R8 are hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN, C 3~8 They are independently selected from cycloalkyl, phenyl, 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl; and L does not exist, or L is S, O, NH, C 1~6 Alkyl, C 2~6 Alkenil or C 2~6 Alkinyl is A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, racemic mixture, enantiomer, diastereomer, or tautomer.

[0074] Embodiment 2. The aforementioned compound is given by formula (IA):

[0075] [ka]

[0076] A compound of the compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0077] Embodiment 3. Z is CH2 or O; preferably, Z is CH2, the compound or a pharmaceutically acceptable salt thereof according to Embodiment 1 or 2, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof.

[0078] Embodiment 4. R1 is C 2~6 Selected from alkynyl, -NR3R4 and -SR5, and the C 2~6 Alkynnyls are: halogens, -CN, -OH, -NH2, C 3~8 Cycloalkyl, 4-membered to 8-membered heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -S(C 3~8 Cycloalkyl), -S (4-membered to 8-membered heterocyclyl), -NH (C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NHCONH2,-NHCO(C 1~6 Alkyl), -CONR a R b ,-COOR c and -COR d It may be substituted by one or more groups independently selected from R a , R b , R c and R d is hydrogen, C 1~6 Alkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-OH, C 3~8 Cycloalkyls and 4- to 8-membered heterocyclines are independently selected; R3 consists of hydrogen and C 1~6 Selected independently from alkyl; R4 and R5 are C 3~8 A cycloalkyl group is independently selected from 4- to 8-membered heterocyclines and 5- to 12-membered heteroaryl groups; and the above C 3~8Cycloalkyl, 4- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl are: halogen, -CN, -CONH2, -OH, oxo, -NH2, C 1~6 Alkyl and -O(C 1~6 The compounds described in any one of Embodiments 1 to 3, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof, which may each be substituted with one or more groups independently selected from alkyl groups.

[0079] Embodiment 5. R1 is C 2~6 It is an alkynyl, and the C 2~6 Alkinyl is -OH, -O(C) 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NHCONH2,-CONRaR b ,-COOR c and -COR d It may be substituted by one or more groups independently selected from R a , R b , R c and R d is hydrogen, C 1~6 Alkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), C 3~8 The C is independently selected from cycloalkyl and 4- to 8-membered heterocyclines; 3~8 Cycloalkyl and 4- to 8-membered heterocyclyls are:C 1~6 Alkyl and -O(C 1~6 Each of the alkyl groups may be substituted with one or more groups independently selected from the alkyl group; preferably, R1 is C 2~6 It is an alkynyl, and the C 2~6 Alkinyl is -OH, -CONH2, -O(C 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NHCONH2,-CONH(C 1~6 Alkyl), -CONH(C 1~6Alkyl)-O-(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2,-CON(C 1~6 Alkyl)(C 1~6 Alkyl-OC 1~6 Alkyl), -CONH(C 3~8 Cycloalkyl), -COOH, -COO(C 1~6 Alkyl), -CO(C 1~6 Alkyl), -CO (4- to 8-membered heterocyclyl) and -CO (4- to 8-membered heterocyclyl)-O-(C 1~6 R1 may be substituted with one or more groups independently selected from alkyl groups; more preferably, R1 is ethynyl, propynyl or butynyl, each of which may be unsubstituted or -OH, -CONH2, -OCH3, -NH(CH3), -N(CH3)2, -NHCONH2, -CONH(C 1~3 Substituted with alkyl, -CONH(CH2CH2)-O-(CH3), -CON(CH3)2, -CON(CH3)(CH2CH2-O-CH3), -CONH(cyclopropyl), -COOH, -COO(CH3), -CO(CH3), -CO(azetidinyl), or -CO(azetidinyl)-O-(CH3); most preferably, R1 is ethynyl, or -CONH(C 1~3 The compound described in Embodiment 4, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, which is an ethynyl substituted with an alkyl group.

[0080] Embodiment 6. R1 is selected from -NR3R4 and -SR5, and R3 is hydrogen and C 1~6 Selected independently from alkyl; R4 and R5 are C 3~8 The following are independently selected from cycloalkyl, 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl, and the C 3~8 Cycloalkyls, 4- to 8-membered heterocyclines, and 5- to 6-membered heteroaryls are:C 1~6The compounds described in Embodiment 4, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, which may each be substituted with one or more groups independently selected from alkyl groups.

[0081] Embodiment 7. R1' is halogen, -CN, -O(C 1~6 Alkyl) and -S(C 1~6 A compound or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, selected from alkyl, and n is 0 or 1; preferably, R1' is a halogen and n is 0 or 1; more preferably, n is 0, as described in any one of Embodiments 1 to 6.

[0082] Embodiment 8. R2 is selected from -NH2 and oxo; preferably, R2 is -NH2, the compound or pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, as described in any one of Embodiments 1 to 7.

[0083] Embodiment 9. Cy1 is a 5- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, preferably a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heterocyclyl or 5- to 9-membered heteroaryl, and these are: oxo, -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and -(C) 1~6 A compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, which may be substituted with one or more groups independently selected from alkyl)-OH.

[0084] Embodiment 10. Cy1 is selected from 1,6-dihydropyrimidyl, pyrazinyl, pyrimidyl, 1,2,4-triazinyl, imidazopyrimidyl, triazolopyrimidyl, imidazopyrazinyl, pyrrolopyrazinyl, pyrazolopyrazinyl and triazolopyrazinyl, each of which is: oxo, -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and -(C) 1~6 The compounds described in Embodiment 9, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, which may be substituted with one or more groups independently selected from alkyl)-OH.

[0085] Embodiment 11. Cy1 is

[0086] [ka]

[0087] Selected from, Each of these is: -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and -(C) 1~6 Independently selected from alkyl)-OH; preferably, Cy1 is

[0088] [ka]

[0089] It may be replaced by one or more groups selected from, Each of these is: -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and -(C) 1~6 It may be substituted with one or more groups independently selected from alkyl)-OH; More preferably, Cy1 is

[0090] [ka]

[0091] Selected from, Each of these is: -NH2, C 1~6 Alkyl and -(C 1~6 It may be substituted with one or more groups independently selected from alkyl)-OH; More preferably, Cy1 is

[0092] [ka]

[0093] And, These are: -NH2 and C 1~6 It may be substituted with one or more groups independently selected from alkyl; or Cy1 is

[0094] [ka]

[0095] And, These are:C 1~6 It may be substituted with one or more groups independently selected from alkyl; or Cy1 is

[0096] [ka]

[0097] And, These are: -NH2, C 1~6 Alkyl and -(C 1~6 It may be substituted with one or more groups independently selected from alkyl)-OH; or Cy1 is

[0098] [ka]

[0099] And, These are: -NH2 and C 1~6 It may be substituted with one or more groups independently selected from alkyl groups. The compounds described in Embodiment 10, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof.

[0100] Embodiment 12. Cy2 is phenyl or a 5- to 14-membered heteroaryl, preferably phenyl or a 5- to 10-membered heteroaryl, more preferably phenyl, a 5- to 6-membered heteroaryl, or a 9- to 10-membered heteroaryl, each of which is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-CN and C 3~8 Compounds described in any one of Embodiments 1 to 11, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, each independently selected from cycloalkyl groups.

[0101] Embodiment 13. The aforementioned compound is given by formula (II):

[0102] [ka]

[0103] A compound of the above formula (II), Z is CH2 or O; preferably, Z is CH2; R1 is C 2~6 Selected from alkynyl, -NR3R4 and -SR5, and the C 2~6 Alkynnyls are: halogens, -CN, -OH, -NH2, C 3~8 Cycloalkyl, 4-membered to 8-membered heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -S(C 3~8 Cycloalkyl), -S (4-membered to 8-membered heterocyclyl), -NH (C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NH-CN,-NHCONH2,-NHCO(C 1~6 Alkyl), -CONR a R b ,-COOR c and -COR d It may be substituted by one or more groups independently selected from R a , R b , R c and R d is hydrogen, C 1~6 Alkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-OH, C 3~8 Cycloalkyls and 4- to 8-membered heterocyclines are independently selected; R3 consists of hydrogen and C 1~6 Selected independently of alkyl, R4 and R5 are C 3~8 Each is independently selected from cycloalkyl, 4- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl; and the above C 3~8 Cycloalkyls, 4- to 8-membered heterocyclines, and 5- to 6-membered heteroaryls are:C 1~6 Alkyl and -O(C 1~6 Each of the alkyl groups may be substituted with one or more groups independently selected from the alkyl group, preferably R1 is C 2~6 It is an alkynyl, and the C2~6 Alkinyl is -OH, -CONH2, -O(C 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CONH(C 1~6 Alkyl) and -CON(C 1~6 R1 may be substituted with one or more groups independently selected from alkyl)2; more preferably, R1 is ethynyl, propynyl or butynyl, each of which is unsubstituted or substituted with -OH, -CONH2, -OCH3, -NH(CH3), -N(CH3)2, -CONH(CH3), or -CON(CH3)2; more preferably, R1 is ethynyl; R1' is halogen, -CN, -O(C 1~6 Alkyl) and -S(C 1~6 Selected from alkyl, and n is 0 or 1; preferably, R1' is a halogen, and n is 0 or 1; more preferably, n is 0; R2 is -NH2; R9 and R 10 It is hydrogen, -NH2, halogen, C 1~6 Alkyl and C 1~6 Each is independently selected from haloalkyl groups; preferably, R9 and R 10 is hydrogen and C 1~6 Each alkyl group is independently selected; Cy2 is phenyl or a 5- to 14-membered heteroaryl, preferably phenyl or a 5- to 10-membered heteroaryl, more preferably phenyl, each of which is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and C 3~8Each is independently selected from cycloalkyl groups; and L does not exist. A compound, such as the compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0104] Embodiment 14. The aforementioned compound is given by formula (III):

[0105] [ka]

[0106] A compound of the above formula (III), Z is CH2; R1 is C 2~6 Selected from alkynyl, -NR3R4 and -SR5, and the C 2~6 Alkynnyls are: halogens, -CN, -OH, -NH2, C 3~8 Cycloalkyl, 4-membered to 8-membered heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -S(C 3~8 Cycloalkyl), -S (4-membered to 8-membered heterocyclyl), -NH (C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NH-CN,-NHCONH2,-NHCO(C 1~6 Alkyl), -CONR a R b ,-COOR c and -COR d It may be substituted by one or more groups independently selected from R a , R b , R c and R d is hydrogen, C 1~6 Alkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C1~6 Alkyl)-OH, C 3~8 Cycloalkyls and 4- to 8-membered heterocyclines are independently selected; R3 consists of hydrogen and C 1~6 Selected independently of alkyl, R4 and R5 are C 3~8 Each is independently selected from cycloalkyl, 4- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl; and the above C 3~8 Cycloalkyls, 4- to 8-membered heterocyclines, and 5- to 6-membered heteroaryls are:C 1~6 Alkyl and -O(C 1~6 Each of the alkyl groups may be substituted with one or more groups independently selected from the alkyl group, preferably R1 is C 2~6 And the above C 2~6 Alkinyl is -OH, -CONH2, -O(C 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CONH(C 1~6 Alkyl) and -CON(C 1~6 R1 may be substituted with one or more groups independently selected from alkyl)2; more preferably, R1 is ethynyl, propynyl or butynyl, each of which is unsubstituted or substituted with -OH, -CONH2, -OCH3, -NH(CH3), -N(CH3)2 or -CONH(CH3); more preferably, R1 is ethynyl; R1' is halogen, -CN, -O(C 1~6 Alkyl) and -S(C 1~6 Selected from alkyl, and n is 0 or 1; preferably, R1' is a halogen, and n is 0 or 1; more preferably, n is 0; R2 is selected from -NH2 and oxo; preferably, R2 is -NH2; R 11 , R 12 and R 13 These are hydrogen, -NH2, -CN, and C 1~6 Alkyl and C 1~6 Each is independently selected from haloalkyl groups; preferably, R 11 , R12 and R 13 is hydrogen and C 1~6 Each is independently selected from alkyl groups; more preferably, R 11 , R 12 and R 13 It is all hydrogen; Cy2 is a phenyl or 5- to 14-membered heteroaryl, preferably a phenyl or 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl, each of which is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and C 3~8 Each is independently selected from cycloalkyl groups; and L is either nonexistent or L is S; preferably, L is S. A compound, such as the compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0107] Embodiment 15. The aforementioned compound is of formula (IV):

[0108] [ka]

[0109] A compound of the above formula (IV), Z is CH2 or O; preferably, Z is CH2; R1 is C 2~6 It is an alkynyl, and the C 2~6 Alkynnyls are: halogens, -CN, -OH, -NH2, C 3~8Cycloalkyl, 4-membered to 8-membered heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -S(C 3~8 Cycloalkyl), -S (4-membered to 8-membered heterocyclyl), -NH (C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NH-CN,-NHCONH2,-NHCO(C 1~6 Alkyl), -CONR a R b ,-COOR c and -COR d It may be substituted by one or more groups independently selected from R a , R b , R c and R d is hydrogen, C 1~6 Alkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 Alkyl)-OH, C 3~8 The above C is independently selected from cycloalkyl and 4- to 8-membered heterocyclines; 3~8 Cycloalkyl and 4- to 8-membered heterocyclyls are:C 1~6 Alkyl and -O(C 1~6 Each of the alkyl groups may be substituted with one or more groups independently selected from the alkyl group; preferably, R1 is C 2~6 It is an alkynyl, and the C 2~6 Alkinyl is -OH, -O(C) 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-CONH(C 1~6 Alkyl) and -CON(C 1~6R1 may be substituted with one or more groups independently selected from alkyl)2; more preferably, R1 is ethynyl, propynyl, or butynyl, each of which is unsubstituted or substituted with -OH, -OCH3, -NH(CH3), or -N(CH3)2; more preferably, R1 is ethynyl; R1' is halogen, -O(C 1~6 Alkyl) and -S(C 1~6 Selected from alkyl, and n is 0 or 1; preferably, R1' is a halogen, and n is 0 or 1; more preferably, n is 0; R2 is -NH2; R 14 It consists of hydrogen, -NH2, and C 1~6 Selected from alkyl groups; preferably, R 14 is hydrogen or -NH2; more preferably, R 14 It is hydrogen. R 14 ' is C 1~6 It is alkyl; Cy2 is a phenyl or 5- to 14-membered heteroaryl, preferably a phenyl or 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl or a 9- to 10-membered heteroaryl, each of which is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH and -(C 1~6 Alkyl)-O-(C 1~6 Each is independently selected from alkyl; and L is either nonexistent or L is S; preferably, L is S. A compound, such as the compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0110] Embodiment 16. The aforementioned compound is of formula (V):

[0111] [ka]

[0112] A compound of the above formula (V), Z is CH2 or O; preferably, Z is CH2; R1 is C 2~6 It is an alkynyl, and the C 2~6 Alkynnyls are: halogens, -CN, -OH, -NH2, C 3~8 Cycloalkyl, 4-membered to 8-membered heterocyclyl, -O(C 1~6 Alkyl), -O(C 1~6 Haloalkyl), -O(C 3~8 Cycloalkyl), -O (4-membered to 8-membered heterocyclyl), -S (C 1~6 Alkyl), -S(C 3~8 Cycloalkyl), -S (4-membered to 8-membered heterocyclyl), -NH (C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NH-CN,-NHCONH2,-NHCO(C 1~6 Alkyl), -CONR a R b ,-COOR c and -COR d It may be substituted by one or more groups independently selected from R a , R b , R c and R d is hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-CN, C 3~8 The above C is independently selected from cycloalkyl and 4- to 8-membered heterocyclines; 3~8Cycloalkyl and 4- to 8-membered heterocyclyls are:C 1~6 Alkyl and -O(C 1~6 Each of the alkyl groups may be substituted with one or more groups independently selected from the alkyl group; preferably, R1 is C 2~6 It is an alkynyl, and the C 2~6 Alkinyl is -OH, -O(C) 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NHCONH2,-CONR a R b ,-COOR c and -COR d It may be substituted by one or more groups independently selected from R a , R b , R c and R d is hydrogen, C 1~6 Alkyl, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl), C 3~8 A cycloalkyl and a 4- to 8-membered heterocycline are independently selected, and the C 3~8 Cycloalkyl and 4- to 8-membered heterocyclyls are:C 1~6 Alkyl and -O(C 1~6 Each of the alkyl groups may be substituted with one or more groups independently selected from the alkyl group; more preferably, R1 is C 2~6 It is an alkynyl, and the C 2~6 Alkinyl is -OH, -CONH2, -O(C 1~6 Alkyl), -NH(C 1~6 Alkyl), -N(C 1~6 Alkyl)2,-NHCONH2,-CONH(C 1~6 Alkyl), -CONH(C 1~6 Alkyl)-O-(C 1~6 Alkyl), -CON(C 1~6 Alkyl)2,-CON(C 1~6 Alkyl)(C 1~6 Alkyl-OC 1~6 Alkyl), -CONH(C 3~8 Cycloalkyl), -COOH, -COO(C1~6 Alki), -CO(C 1~6 Alky), -CO (4- to 8-membered heterocyclyl) and -CO (4- to 8-membered heterocyclyl)-O-(C 1~6 R1 may be substituted with one or more groups independently selected from alkyl groups; more preferably, R1 is ethynyl, propynyl or butynyl, each of which may be unsubstituted or -OH, -CONH2, -OCH3, -NH(CH3), -N(CH3)2, -NHCONH2, -CONH(C 1~3 It is substituted with alkyl, -CONH(CH2CH2)-O-(CH3), -CON(CH3)2, -CON(CH3)(CH2CH2-O-CH3), -CONH(cyclopropyl), -COOH, -COO(CH3), -CO(CH3), -CO(azetidinyl), or -CO(azetidinyl)-O-(CH3); most preferably, R1 is ethynyl substituted with -CONH(CH3), -CONH(CH2CH3), or -CONH(CH2CH2)-O-(CH3); R1' is halogen, -O(C 1~6 Alkyl) and -S(C 1~6 Selected from alkyl, and n is 0 or 1; preferably, R1' is a halogen, and n is 0 or 1; more preferably, n is 0; R2 is -NH2; R 15 and R 15 ' is hydrogen, -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and -(C) 1~6 Each is independently selected from alkyl)-OH; preferably, R 15 and R 15 ' is hydrogen, -NH2, C 1~6 Alkyl and -(C 1~6 Each is independently selected from alkyl)-OH; more preferably, R 15 and R 15 ' is both hydrogen; Cy2 is a phenyl or 5- to 14-membered heteroaryl, preferably a phenyl or 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl or a 9- to 10-membered heteroaryl, each of which is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and C 3~8 Each is independently selected from cycloalkyl groups; and L is either nonexistent or L is S; preferably, L is S. A compound, such as the compound described in Embodiment 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0113] Embodiment 17. Cy2 is phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolopyridyl, or 1,2,3,4-tetrahydro-1,5-naphthilidinyl, each of which is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and C 3~8 Compounds described in any one of Embodiments 1 to 16, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof, each independently selected from cycloalkyl groups.

[0114] Embodiment 18. Cy2 is

[0115] [ka]

[0116] Selected from, Each of these is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and C 3~8 Each is independently selected from cycloalkyl groups; Preferably, Cy2 is

[0117] [ka]

[0118] Selected from, Each of these is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and C 3~8 Each is independently selected from cycloalkyl groups; and More preferably, Cy2 is

[0119] [ka]

[0120] Selected from, Each of these is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl), -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and C 3~8 Each is independently selected from cycloalkyl groups. The compounds described in Embodiment 17, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof.

[0121] Embodiment 19. Cy2 is

[0122] [ka]

[0123] And, This is: halogen, -CN, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, -O(C) 1~6 Alkyl) and -S(C 1~6 It may be substituted with one or more groups independently selected from alkyl groups; or

[0124] Cy2 is

[0125] [ka]

[0126] And, This is: halogen, C 1~6Alkyl, -O(C 1~6 It may be substituted with one or more groups independently selected from alkyl) and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH, -(C 1~6 Alkyl)-O-(C 1~6 Alkyl) and C 3~8 Each is independently selected from cycloalkyl groups; preferably, both R7 and R8 are hydrogen; or Cy2 is

[0127] [ka]

[0128] And, This is :C 1~6 It may be substituted with one or more groups independently selected from alkyl and -NR7R8, where R7 and R8 are hydrogen, -(C 1~6 alkyl)-OH and -(C 1~6 Alkyl)-O-(C 1~6 Each is independently selected from alkyl groups; preferably, R7 and R8 are both hydrogen. The compounds described in Embodiment 18, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers, or tautomers thereof.

[0129] Embodiment 20. The aforementioned compound,

[0130] [Table 1] JPEG0007856666000023.jpg231170JPEG0007856666000024.jpg226170JPEG0007856666000025.j pg242170JPEG0007856666000026.jpg237170JPEG0007856666000027.jpg230170JPEG00078566660 00028.jpg186170JPEG0007856666000029.jpg214170JPEG0007856666000030.jpg216170JPEG000 7856666000031.jpg226170JPEG0007856666000032.jpg240170JPEG0007856666000033.jpg215170 JPEG0007856666000034.jpg208170JPEG0007856666000035.jpg247170JPEG0007856666000036.j pg228170JPEG0007856666000037.jpg240170JPEG0007856666000038.jpg229170JPEG00078566660 00039.jpg242170JPEG0007856666000040.jpg222170JPEG0007856666000041.jpg230170JPEG000 7856666000042.jpg237170JPEG0007856666000043.jpg242170JPEG0007856666000044.jpg180170

[0131] A compound selected from Embodiment 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0132] Embodiment 21. A pharmaceutical composition comprising a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 20, and optionally comprising a pharmaceutically acceptable excipient.

[0133] Embodiment 22. A method for inhibiting the activity of SHP2 in vivo or in vitro, the method comprising contacting SHP2 with an effective amount of a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 20.

[0134] Embodiment 23. Use of compounds and / or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment or prevention of diseases mediated by or at least partially mediated by SHP2, preferably for the treatment or prevention of cancer, Noonan syndrome and Leopard syndrome, wherein the cancer is preferably a solid tumor or hematological malignancy including leukemia, lymphoma and myeloma; more preferably breast cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, head and neck cancer (squamous cell carcinoma of the head and neck), liver cancer, Use is selected from the following: kidney cancer, ovarian cancer, cervical cancer, prostate cancer, endometrial cancer, thyroid cancer, sarcoma, adrenal cancer, acute myeloid leukemia (AML), juvenile acute myeloid leukemia, chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, and myeloma (such as multiple myeloma).

[0135] Embodiment 24. A method for treating or preventing a disease in a subject, comprising administering an effective amount of a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 20 to the subject in need of such treatment or prevention, wherein the disease is mediated by or at least partially mediated by SHP2, the disease is preferably cancer, Noonan syndrome and Leopard syndrome, the cancer is preferably a solid tumor or hematological malignancy including leukemia, lymphoma and myeloma; the cancer is more preferably breast cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, A method selected from head and neck cancer (squamous cell carcinoma of the head and neck), liver cancer, kidney cancer, ovarian cancer, cervical cancer, prostate cancer, endometrial cancer, thyroid cancer, sarcoma, adrenal cancer, acute myeloid leukemia (AML), juvenile acute myeloid leukemia, chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, and myeloma (such as multiple myeloma).

[0136] Embodiment 25. A compound and / or a pharmaceutically acceptable salt thereof, as described in any one of Embodiments 1 to 20, for use as a pharmaceutical.

[0137] Embodiment 26. The compounds and / or pharmaceutically acceptable salts thereof are for use in the treatment or prevention of diseases mediated by or at least partially mediated by SHP2, preferably compounds and / or pharmaceutically acceptable salts thereof for use in the treatment or prevention of cancer, Noonan syndrome and Leopard syndrome, wherein the cancer is preferably a solid tumor or hematological malignancy including leukemia, lymphoma and myeloma; more preferably breast cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, head and neck cancer (squamous cell carcinoma of the head and neck), liver cancer, kidney cancer, ovarian cancer, cervical cancer, Compounds and / or pharmaceutically acceptable salts thereof described in any one of Embodiments 1 to 20, selected from prostate cancer, endometrial cancer, thyroid cancer, sarcoma, adrenal cancer, acute myeloid leukemia (AML), juvenile acute myeloid leukemia, chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, and myeloma (such as multiple myeloma).

[0138] Embodiment 27. A combination pharmaceutical comprising a compound and / or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 20 and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably selected from: an antitumor agent, an anti-inflammatory agent or an immunomodulator, and the antitumor agent comprises a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0139] Various embodiments of the present invention (including the following embodiments) and features of various embodiments should be interpreted as being interchangeable with each other, and unless otherwise specified in the context, all various solutions obtained from such combinations are included within the scope of the present invention, as are the solutions obtained from combinations specifically and individually described herein.

[0140] General synthesis method Compounds of formula (I) and / or pharmaceutically acceptable salts thereof described herein can be synthesized using commercially available starting materials by methods known in the art or by methods disclosed in this patent application. The synthesis routes shown in Schemes 1 to 4 illustrate general methods for synthesizing the compounds of the present invention.

[0141] [ka]

[0142] The rings A, Z, R1, R1', n, L and Cy2 are as defined in formula (I); Pg is an amino protecting group; and R9 and R 10 It is hydrogen, -NH2, halogen, C 1~6 Alkyl and C 1~6 Each is independently selected from the haloalkyl groups.

[0143] As shown in Scheme 1, the compound of formula II-A is reacted with acetonitrile under the catalysis of hydrogen chloride to obtain the compound of formula II-B. The compound of formula II-B is reacted with the corresponding malonic acid ester under alkaline conditions (sodium ethoxide / ethanol) to obtain the compound of formula II-C. The compound of formula II-C is reacted with 2,4,6-triisopropylbenzenesulfonyl chloride to obtain the compound of formula II-D. The compound of formula II-D is reacted with the compound of formula II-E under alkaline conditions (Et3N or DIEA) to obtain the compound of formula II-F. The compound of formula II-F is deprotected with an acid to obtain the compound of formula II-G.

[0144] [ka]

[0145] The rings A, Z, R1, R1', n, L and Cy2 are as defined in formula (I); Pg is an amino protecting group; and R 11 , R 12 and R 13 These are hydrogen, -NH2, -CN, and C 1~6 Alkyl and C 1~6 Each is independently selected from the haloalkyl groups.

[0146] As shown in Scheme 2, the compounds of formula III-A and III-B are subjected to a nucleophilic substitution reaction under alkaline conditions (Et3N or DIEA) to obtain the compound of formula III-C. The compound of formula III-C and a sulfur-containing sodium salt or boronic acid ester are subjected to a coupling reaction under palladium catalysis to obtain the compound of formula III-D. The palladium-catalyzed coupling reaction is carried out under appropriate conditions. The base used can be selected from Cs2CO3, K2CO3, DIEA, etc., and the catalyst used can be selected from Pd2(dba)3, Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2, etc. The compound of formula III-D is deprotected with an acid to obtain the compound of formula III-E.

[0147] [ka]

[0148] The rings A, Z, R1, R1', n, L and Cy2 are as defined in formula (I); Pg is an amino protecting group; R 14 It consists of hydrogen, -NH2, and C 1~6 Selected from alkyl; and R 14 ' is C 1~6 It is alkyl.

[0149] As shown in Scheme 3, the compound of formula IV-A is reacted with the compound of formula IV-B under BOP and DBU conditions to obtain the compound of formula IV-C. The compound of formula IV-C is reacted with NIS to obtain the compound of formula IV-D. The compound of formula IV-D and a sulfur-containing sodium salt or boronic acid ester are coupled under palladium catalysis to obtain the compound of formula IV-E. The palladium-catalyzed coupling reaction is carried out under appropriate conditions. The base used can be selected from Cs2CO3, K2CO3, DIEA, etc., and the catalyst used can be selected from Pd2(dba)3, Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2, etc. The compound of formula IV-E is deprotected with an acid to obtain the compound of formula IV-F.

[0150] [ka]

[0151] The rings A, R1, R1', n, L and Cy2 are as defined in formula (I); Pg is an amino protecting group; and R 15 Hydrogen, -NH2, -CN, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and -(C) 1~6 Selected from alkyl)-OH.

[0152] As shown in Scheme 4, the compound of formula VA is reacted with the compound of formula VB under alkaline conditions (Et3N or DIEA) to obtain the compound of formula VC. The compounds of formula IV-C are reacted with DIBAL-H to obtain the compound of formula VD. The compound of formula VD and a sulfur-containing sodium salt or boronic acid ester are coupled under palladium catalyst and deprotected with an acid to obtain the compound of formula VE. The palladium-catalyzed coupling reaction is carried out under appropriate conditions. The base used can be selected from Cs2CO3, K2CO3, DIEA, etc., and the catalyst used can be selected from Pd2(dba)3, Pd(PPh3)4, Pd(dppf)Cl2·CH2Cl2, etc.

[0153] The substituents of the compounds obtained in this way can be further modified to obtain other desired compounds. Synthetic chemical transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0154] Before use, the compounds of the present invention can be purified by column chromatography, high-performance liquid chromatography, crystallization, or other suitable methods.

[0155] Pharmaceutical composition and utility The compounds of the present invention (for example, any of the compounds in the examples described herein) are used alone or in combination with one or more additional therapeutic agents to formulate pharmaceutical compositions. A pharmaceutical composition comprises: (a) an effective amount of the compound of the present invention; (b) a pharmaceutically acceptable excipient (for example, one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional therapeutic agent.

[0156] A pharmaceutically acceptable excipient is an excipient that is compatible with the active ingredient of the composition (and in some embodiments can stabilize the active ingredient) and is not harmful to the subject being treated. For example, a solubilizer such as cyclodextrin (which is specific to the compounds of the present invention and forms a more soluble complex) can be used as a pharmaceutical excipient for the delivery of the active ingredient. Examples of other excipients include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable salt excipients are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference in the art.

[0157] Pharmaceutical compositions comprising the compounds of the present invention can be administered by various known methods, such as orally, topically, rectally, parenterally, by inhalation spray, or by implanted reservoir. As used herein, the term "parenterally" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-bursal, intrasternal, subarachnoid, intrafocal, and intracranial injection or infusion techniques.

[0158] The pharmaceutical compositions described herein may be formulated in the form of tablets, capsules, sachets, sugars, powders, granules, lozenges, powders for re-preparation, liquid formulations, or suppositories. In some embodiments, pharmaceutical compositions comprising the compounds of the present invention are formulated for intravenous infusion, topical administration, or oral administration.

[0159] Oral compositions may be, but are not limited to, tablets, capsules, emulsions, and any orally acceptable dosage form including aqueous suspensions, dispersants, and liquids. Lactose and corn starch are commonly used carriers for tablets. Lubricants such as magnesium stearate are usually added to tablets. For oral administration in capsule form, lactose and dried corn starch are useful diluents. When administering aqueous suspensions or emulsions orally, the active ingredient may be suspended or dissolved in an oil phase mixed with an emulsifier or suspending agent. Specific sweeteners, flavorings, or colorings may be added as desired.

[0160] In some embodiments, the compounds of the present invention may be present in tablets in amounts of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg. In some embodiments, the compounds of the present invention may be present in capsules in amounts of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg.

[0161] Sterile injectable compositions (e.g., aqueous or oily suspensions) can be formulated by techniques known in the art using appropriate dispersing or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable compositions may also be sterile injectable liquids or suspensions in a non-toxic, parenterally acceptable diluent or solvent, for example, as a 1,3-butanediol solution. Among the pharmaceutically acceptable media and solvents that can be used are mannitol, water, Ringer's solution, and sodium chloride isotonic solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media (e.g., synthetic monoglycerides or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives, as well as naturally pharmaceutically acceptable oils such as olive oil or castor oil, particularly their polyoxyethylated versions, can be used as sterile injectable media. These oily liquids or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersing agents.

[0162] The inhalation composition can be formulated by techniques well known in the art of pharmaceutical formulations, and can be formulated as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, and / or other solubilizers or dispersants known in the art.

[0163] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, and the like. Suitable carriers for the compositions include vegetable oils or mineral oils, white petrolatum (white soft paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (greater than C12). In some embodiments, a pharmaceutically acceptable carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, hydraters, and antioxidants may be included as desired, as well as agents that impart color or fragrance. In addition, transdermal absorption enhancers may be used in these topical formulations. Examples of such enhancers can be found in U.S. Patent No. 3,989,816 and U.S. Patent No. 4,444,762.

[0164] A cream may be prepared from a mixture of mineral oil, self-emulsifying beeswax, and a small amount of oil, such as almond oil, containing an active ingredient dissolved in it. An example of such a cream contains about 40 parts by weight of water, about 20 parts by weight of beeswax, about 40 parts by weight of mineral oil, and about 1 part by weight of almond oil. An ointment may be prepared by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warmed soft paraffin, and then allowing the mixture to cool. An example of such an ointment contains about 30% by weight of almond oil and about 70% by weight of white soft paraffin.

[0165] The effect of the compounds of the present invention on inhibiting SHP2 activity can be evaluated using appropriate in vitro assays. Further investigation of the compounds of the present invention's effects in cancer prevention or treatment can be conducted using in vivo assays. For example, the compounds of the present invention can be administered to animals with cancer (e.g., mouse models) and their therapeutic effects can be evaluated. If preclinical results are favorable, dosage ranges and routes of administration for animals such as humans can be planned.

[0166] The compounds of the present invention are found to possess sufficient preclinical practical utility to warrant clinical trials where they are expected to demonstrate beneficial therapeutic or preventive effects in subjects suffering from cancer.

[0167] As used herein, the term “cancer” refers to a cellular disease characterized by uncontrolled or unregulated cell proliferation, impaired cell differentiation, inadequate ability to invade surrounding tissues, and / or ability to establish new growth in ectopic locations. Examples of “cancer” include, but are not limited to, solid tumors and hematological malignancies such as leukemia, lymphoma, or myeloma. The term “cancer” encompasses diseases of the skin, tissues, organs, bone, cartilage, blood, and blood vessels. The term “cancer” further includes primary cancer, and metastatic cancer, recurrent cancer, and refractory cancer.

[0168] Non-limiting examples of solid tumors include: pancreatic cancer; bladder cancer; colorectal cancer; colon cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; renal cancer, including metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular carcinoma; lung cancer, including non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including advanced epithelial carcinoma or primary peritoneal carcinoma; and children. Examples include cervical cancer; endometrial cancer; gastric cancer; esophageal cancer; head and neck cancers, such as squamous cell carcinoma of the head and neck; skin cancers, such as melanoma and basal cell carcinoma; neuroendocrine cancers, such as metastatic neuroendocrine tumors; brain tumors, such as glioma, anaplastic oligodendroglioma, pleoplastic gliablastoma, and adult anaplastic astrocytoma; bone cancer; sarcomas, such as Kaposi's sarcoma; adrenal cancer; mesothelioma; mesothelial carcinoma; choriocarcinoma; muscle cancer; connective tissue cancer; and thyroid cancer.

[0169] Non-limiting examples of hematological malignancies include: acute myeloid leukemia (AML); juvenile acute myeloid leukemia; chronic myeloid leukemia (CML), including accelerated CML and acute transformation CML (CML-BP); acute lymphoblastic leukemia (ALL); B-cell acute lymphoblastic leukemia (B-ALL); chronic lymphocytic leukemia (CLL), including high-risk CLL; human acute monocytic leukemia (M(5)); hair cell leukemia; lymphocytic leukemia; chronic lymphocytic leukemia; myeloid leukemia; acute lymphoblastic leukemia; small lymphocytic lymphoma (SLL); lymphoblastic lymphoma; Hodgkin lymphoma; non-Hodgkin lymphoma (NHL); mantle cell lymphoma These include lymphoma (MCL); B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL); large B-cell lymphoma (LBCL); follicular lymphoma; marginal zone lymphoma; Burkitt lymphoma; non-Burkitt high-grade B-cell lymphoma; extranodal marginal zone B-cell lymphoma; multiple myeloma (MM); Waldenström macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with blast plaque (RAEB), and refractory anemia with blast plaque in the transitional phase (RAEB-T); and myeloproliferative syndromes.

[0170] In some embodiments, solid tumors include breast cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, head and neck cancer (such as squamous cell carcinoma of the head and neck); liver cancer, kidney cancer, ovarian cancer, cervical cancer, prostate cancer, endometrial cancer, thyroid cancer, sarcoma, and adrenal cancer.

[0171] In some embodiments, hematological malignancies include acute myeloid leukemia (AML), juvenile acute myeloid leukemia, chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, and myeloma (such as multiple myeloma).

[0172] The compounds of the present invention can be used, for example, to obtain beneficial therapeutic or preventive effects in subjects suffering from cancer.

[0173] In addition, the compounds of the present invention (for example, any of the compounds in the examples described herein) may be administered in combination with additional therapeutic agents for the treatment of diseases or disorders described herein, such as cancer. The additional therapeutic agents may be administered separately from the compounds of the present invention, or they may be included together with the components in a pharmaceutical composition according to this disclosure, such as a fixed-dose combination product. In some embodiments, the additional therapeutic agents are known or discovered to be effective in the treatment of SHP2 or diseases mediated by SHP2, such as another SHP2 inhibitor or a compound active against another target associated with a particular disease. The combinations may help to increase efficacy (for example, by including a compound that enhances the potency or efficacy of the compounds of the present invention in the combination), reduce one or more side effects, or reduce the required dose of the compounds of the present invention.

[0174] In some embodiments, the compounds of the present invention (for example, any of the compounds in the examples described herein) may be administered in combination with additional therapeutic agents such as antitumor agents, anti-inflammatory agents, or immunomodulators, the antitumor agents including chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapies. As used herein, the term “antitumor agent” refers to any agent administered to a cancer-affected subject for the purpose of treating cancer, such as chemotherapeutic agents, immune checkpoint inhibitors or agonists, and targeted therapies.

[0175] Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogs or metabolites, as well as doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin C, and cyclophosph Examples include: amides; DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); free radical generators such as bleomycin; nucleoside mimetic compounds (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, docetaxel, and related analogues; vincristine, vinblastine, and related analogues; thalidomide and related analogues (e.g., CC-5013 and CC-4047).

[0176] Non-limiting examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors, such as pembrolizumab, nivolumab, and anti-PD-1 antibodies such as PDR001 (spartalizumab); PD-L1 inhibitors, such as atezolizumab, durvalumab, and avelumab; anti-CTLA-4 antibodies, such as ipilimumab; as well as BTLA inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors, OX-40 agonists, and similar agents.

[0177] Targeted therapies include a variety of small molecule or macromolecule targeted therapies, and non-limiting examples include: protein tyrosine kinase inhibitors (such as imatinib mesylate and gefitinib); proteasome inhibitors (such as bortezomib); NF-κB inhibitors including IκB kinase inhibitors; KRAS G12C inhibitors; ERK inhibitors; CDK4 / 6 inhibitors; PI3Kδ inhibitors; SYK inhibitors; Bcl2 inhibitors; IDO inhibitors; A2AR inhibitors; BRAF inhibitors (such as dabrafenib); MEK inhibitors (such as trametinib); mTOR inhibitors (such as rapamycin); anti-CD40 antibodies (such as APX005M, RO7009789); anti-CD20 antibodies (such as rituximab, ibritumomab tiuxetan, and tositumomab); anti-Her2 monoclonal antibodies (tras) Examples include antibodies that bind to proteins overexpressed in cancer and downregulate cell replication, such as tuzumab, anti-EGFR antibodies (such as cetuximab), and anti-VEGF antibodies (such as bevacizumab); anti-angiogenic drugs such as lenalidomide; and other protein inhibitors or enzyme inhibitors. These proteins or enzymes are known to be upregulated, overexpressed, or activated in cancer, and these inhibitors can downregulate cell replication. [Examples]

[0178] The following examples are for illustrative purposes only and should not be considered limiting. While efforts have been made to ensure accuracy regarding the numerical values ​​used (e.g., quantities, temperatures, etc.), those skilled in the art should understand that some experimental error and deviation should be taken into account. Unless otherwise specified, parts are in parts by weight, temperatures are in Celsius, and pressures are atmospheric pressure or near atmospheric pressure. All MS data were determined using Agilent 6120 or Agilent 1100. All NMR data were prepared using a Varian 400 MR instrument. All reagents and substances used in this invention, with the exception of synthetic intermediates, are commercially available. All compound names, with the exception of reagents, were prepared using Chemdraw 16.0.

[0179] If any atom having an empty valence exists in any of the structures disclosed herein, this empty valence is a hydrogen atom, which is omitted for convenience.

[0180] In this application, if the name and structure of a compound do not match, and both are assigned to this compound, the structure of the compound shall apply unless the context indicates that the structure of the compound is incorrect and the name is correct.

[0181] List of abbreviations used in the following examples:

[0182] [Table 2] JPEG0007856666000050.jpg207170

[0183] Example 1 Compound Synthesis Intermediate I-A1 Sodium 2-amino-3-chloropyridine-4-thiolate

[0184] [ka]

[0185] Step 1: 3-((2-amino-3-chloropyridine-4-yl)thio)methyl propanoate Under nitrogen, 3-chloro-4-iodopyridine-2-amine (10.0 g, 39.3 mmol), methyl 3-mercaptopropanoate (5.20 g, 42.8 mmol), palladium acetate (0.44 g, 1.97 mmol), xanthophos (2.27 g, 3.93 mmol), and DIEA (10.2 g, 78.6 mmol) were added to 1,4-dioxane (160 mL). The reaction solution was refluxed, stirred for 2 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (9.70 g, 100% yield). [M+H] + 201.1

[0186] Step 2: Sodium 2-amino-3-chloropyridine-4-thiolate Under nitrogen, a solution of methyl 3-((2-amino-3-chloropyridine-4-yl)thio)propanoate (9.70 g, 39.3 mmol) in tetrahydrofuran was mixed with 2M sodium ethoxide / ethanol solution (20 mL, 40 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Dichloromethane was added to the resulting residue, and the mixture was stirred. Solid matter precipitated, and the mixture was filtered. The filtered cake was collected to obtain the target product (7.18 g, 100% yield). [M+2H-Na] + 161.0

[0187] The intermediates listed in the table below were prepared according to the steps for preparing intermediate I-A1 from the corresponding starting materials and reagents:

[0188] [Table 3]

[0189] Intermediate I-A2 3-((2-amino-3-chloropyridine-4-yl)thio)-6-chloropyrazine-2-amine

[0190] [ka]

[0191] Step 1: 3-((3-amino-5-chloropyrazine-2-yl)thio)methyl propanoate Under nitrogen, 3-bromo-6-chloropyrazine-2-amine (500 mg, 2.4 mmol), methyl 3-mercaptopropanoate (317 mg, 2.6 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), xanthophos (138 mg, 0.24 mmol), and DIEA (620 mg, 4.8 mmol) were added to 1,4-dioxane (20 mL). The reaction solution was refluxed, stirred for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (460 mg, yield 78%). [M+H] + 248.0

[0192] Step 2: Sodium 3-amino-5-chloropyrazine-2-thiolate Under nitrogen, a solution of methyl 3-((3-amino-5-chloropyrazine-2-yl)thio)propanoate (460 mg, 1.87 mmol) in tetrahydrofuran was mixed with a 2 M sodium ethoxide / ethanol solution. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Dichloromethane was added to the resulting residue, and the mixture was stirred. Solid matter precipitated, and the mixture was filtered. The filtered cake was collected to obtain the target product (400 mg, yield 118%). [M+2H-Na] + 162.0

[0193] Step 3: 3-((2-amino-3-chloropyridine-4-yl)thio)-6-chloropyrazine-2-amine Under nitrogen, sodium 3-amino-5-chloropyrazine-2-thiolate (300 mg, 1.63 mmol), 3-chloro-4-iodopyridine-2-amine (414 mg, 1.63 mmol), Pd2(dba)3 (75 mg, 0.08 mmol), xanthophos (93 mg, 0.16 mmol), and DIEA (0.55 mg, 3.26 mmol) were added to 1,4-dioxane (20 mL). The reaction solution was refluxed and stirred for 4 hours, then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product (300 mg, yield 65%). [M+H] + 288.0

[0194] The intermediates listed in the table below were prepared according to the steps for preparing intermediates I-A2 from the corresponding starting materials and reagents:

[0195] [Table 4] JPEG0007856666000055.jpg116170

[0196] Intermediate I-A4 6-amino-2-hydroxy-5-iodo-3-methylpyrimidine-4(3H)-one

[0197] [ka]

[0198] Under nitrogen, 6-amino-2-hydroxy-3-methylpyrimidine-4(3H)-one (1.41 g, 10 mmol) and NIS (2.47 g, 11 mmol) were placed in tetrahydrofuran (20 mL) and stirred at room temperature for 16 hours. The mixture was filtered, and the filter cake was collected to obtain the target product (2.40 g, 90% yield). [M+H] + 267.9

[0199] Intermediate I-A8 (8-bromo-5-(methylsulfinyl)imidazo[1,2-c]pyrimidine-7-yl)(tert-butoxycarbonyl)carbamate tert-butyl

[0200] [ka]

[0201] Step 1: 5-Bromo-2-(methylthio)pyrimidine-4,6-diamine At 0°C, NBS (6.2 g, 35 mmol) was added to a solution of 2-(methylthio)pyrimidine-4,6-diamine (5 g, 32 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was stirred at room temperature for 12 hours, the reaction solution was poured into water (200 mL), filtered, and dried to obtain the target product (5.7 g, yield 76%) as a yellow solid. [M+H] + 234.9, 236.9

[0202] Step 2: 8-bromo-5-(methylthio)imidazo[1,2-c]pyrimidine-7-amine To a solution of 5-bromo-2-(methylthio)pyrimidine-4,6-diamine (5.7 g, 24.2 mmol) in N,N-dimethylformamide (70 mL), a 40% aqueous solution of 2-chloroacetaldehyde (7.1 g, 36 mmol) was added. The reaction mixture was stirred at 80°C for 2 hours, and the reaction solution was poured into water (500 mL). The pH was adjusted to 10 using solid sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic phases were collected and combined, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (3.0 g, yield 48%). [M+H] + 258.9, 260.9

[0203] Step 3: (8-bromo-5-(methylthio)imidazo[1,2-c]pyrimidine-7-yl)(tert-butoxycarbonyl)carbamate tert-butyl To a solution of 8-bromo-5-(methylthio)imidazo[1,2-c]pyrimidine-7-amine (3.0 g, 11.6 mmol) in tetrahydrofuran (40 mL), (Boc)2O (7.6 g, 24.8 mmol) and DMAP (283 mg, 2.3 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours, and the reaction solution was poured into water (200 mL) and extracted with ethyl acetate. The organic phases were collected and combined, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (3.6 g, yield 68%). [M+H] + 459.2, 461.2. 1 H NMR (400MHz, CDCl3): δ 7.71 (d, J = 1.4 Hz, 1H), 7.57 (d, J = 1.4 Hz, 1H), 2.72 (s, 3H), 1.42 (s, 18H).

[0204] Step 4: (8-bromo-5-(methylsulfinyl)imidazo[1,2-c]pyrimidine-7-yl)(tert-butoxycarbonyl)carbamate tert-butyl At 0°C, m-chloroperoxybenzoic acid (530 mg, 2.6 mmol) was added to a solution of (8-bromo-5-(methylthio)imidazo[1,2-c]pyrimidine-7-yl)(tert-butoxycarbonyl)carbamate tert-butyl (400 mg, 0.87 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 0°C for 2 hours, and a saturated aqueous solution of sodium bisulfite (2 mL) was added. The reaction solution was adjusted to a pH of 8 using a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (500 mg, yield 120%), which was used directly in the next step of the reaction. [M+H] + 475.0

[0205] Intermediates I-B1 and I-B2 Enantiomer of 1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl triisopropylbenzenesulfonic acid

[0206] [ka]

[0207] Step 1: N-(2,3-dichlorophenyl)acetimamide 2,3-Dichloroaniline (13.0 g, 80.0 mmol) was added to 1 M hydrochloric acid / acetonitrile (160 mL, 160 mmol). The reaction mixture was stirred at 120°C for 16 hours, and then concentrated under reduced pressure to obtain the target product (19.5 g, yield 120%), which was used directly in the next step of the reaction.

[0208] Step 2: 1-(2,3-dichlorophenyl)-2-methylpyrimidine-4,6(1H,5H)-dione N-(2,3-dichlorophenyl)acetimidoamide (19.5 g, 80 mmol) and diethyl malonate (25.6 g, 160 mmol) were added to ethanol (80 mL). To this solution, 2 M sodium ethoxide / ethanol solution (120 mL, 240 mmol) was added. The reaction mixture was stirred at 120 °C for 16 hours and then concentrated under reduced pressure. The resulting residue was dissolved in water (100 mL), and the pH of this solution was adjusted to 2 using 6 M hydrochloric acid to precipitate the solids. The mixture was filtered, the filter cake was collected, and dried under reduced pressure to obtain the target product (10.5 g, yield 49%). [M+H] + 271.0

[0209] Step 3: 1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl 2,4,6-triisopropylbenzenesulfonic acid To a solution of 3-(2,3-dichlorophenyl)-6-hydroxy-2-methylpyrimidine-4(3H)-one (10.5 g, 38.7 mmol) and 2,4,6-triisopropylbenzenesulfonic acid (17.7 g, 58.5 mmol) in dichloromethane (50 mL), DMAP (240 mg, 1.9 mmol) and triethylamine (9.9 g, 97.4 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain the target product (18.0 g, yield 87%). [M+H] + 537.2

[0210] Step 4: Enantiomer of 1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl triisopropylbenzenesulfonic acid 19.0 g of 1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl triisopropylbenzenesulfonic acid was separated by chiral HPLC to obtain enantiomer pairs. Chiral HPLC separation conditions: Column: IG-H (inner diameter 0.46 cm × length 15 cm); Mobile phase: Carbon dioxide / ethanol = 60:40; Flow rate: 2.5 mL / min; Detector: UV 254 nm. First eluate (intermediate I-B2, 8.66 g, RT = 0.808 min), ee% = 100%. Second eluate (intermediate I-B1, 9.66 g, RT = 1.236 min), ee% = 99.94%.

[0211] The intermediates listed in the table below were prepared according to steps 1-3 for preparing intermediates I-B1 and I-B2 from the corresponding starting materials and reagents:

[0212] [Table 5] JPEG0007856666000060.jpg140170

[0213] The intermediates listed in the table below were prepared according to steps 1-3 for preparing intermediates I-B1 and I-B2 from the corresponding substituted aniline, diethyl 2-methylmalonate, or diethyl 2-fluoromalonate, and reagents:

[0214] [Table 6]

[0215] The intermediates listed in the table below were prepared from intermediate I-B13 by chiral separation according to step 4 for preparing intermediates I-B1 and I-B2:

[0216] Chiral HPLC separation conditions: Column: IG-H (inner diameter 0.46 cm × length 15 cm); Mobile phase: Carbon dioxide / ethanol = 80:20; Flow rate: 2.5 mL / min; Detector: UV 254 nm. First eluate (intermediate I-B21, RT = 2.784 min), ee% = 100%. Second eluate (intermediate I-B22, RT = 3.119 min), ee% = 99.92%.

[0217] [Table 7]

[0218] Intermediate I-B26 2,4,6-Triisopropylbenzenesulfonic acid 1-(2-chloropyridine-4-yl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl

[0219] [ka]

[0220] Step 1: N-(2-chloropyridine-4-yl)acetimamide 2-Chloro-4-iodopyridine (3.78 g, 15.8 mmol), acetimidohydrochloride (1.92 g, 20.3 mmol), cuprous iodide (301 mg, 1.58 mmol), cesium carbonate (13.2 g, 40.6 mmol), and N,N-dimethylformamide (22 mL) were placed in a sealed tube. The reaction mixture was stirred at 90°C for 12 hours, cooled to room temperature, and acetonitrile (200 mL) was added. The mixture was filtered, and the filtrate was concentrated under reduced pressure and vacuum to obtain the target product (1.75 g, 70% yield), which was used directly in the next step of the reaction. [M+H] + 170.0

[0221] Step 2: 3-(2-chloropyridine-4-yl)-6-hydroxy-2-methylpyrimidine-4(3H)-one N-(2-chloropyridine-4-yl)acetimidoamide (1.70 g, 10.0 mmol), bis(2,4,6-trichlorophenyl) malonate (5.55 g, 12 mmol), and tetrahydrofuran (20 mL) were placed in a sealed tube. The reaction mixture was stirred at 90°C for 16 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product (1.19 g, 50% yield). [M+H] + 238.0

[0222] Step 3: 1-(2-chloropyridine-4-yl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl triisopropylbenzenesulfonic acid The target product was prepared according to step 3 for preparing intermediates I-B1 and I-B2 from the corresponding starting materials and reagents. [M+H] + 504.2 The intermediates listed in the table below were prepared according to the steps for preparing intermediates I-B26 from the corresponding starting materials and reagents:

[0223] [Table 8]

[0224] Intermediate I-B48 2,4,6-Triisopropylbenzenesulfonic acid 2-amino-1-(2,3-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-4-yl

[0225] [ka]

[0226] Step 1: 1-(2,3-dichlorophenyl)thiourea A solution of 2,3-dichloroaniline (6.48 g, 40 mmol) and benzoyl isothiocyanate (9.79 g, 60 mmol) in acetone (20 mL) was stirred under reflux for 30 minutes. The reaction solution was poured into ice water and filtered. The filtered cake was washed with cold acetone, collected, and mixed with 1 M NaOH aqueous solution (50 mL). The mixture was stirred at 80°C for 3 hours. After cooling to room temperature, the mixture was extracted by DCM. The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with PE / EA) to obtain the target product (8.2 g, yield 93%) as a white solid.

[0227] Step 2: 3-(2,3-dichlorophenyl)-6-hydroxy-2-mercaptopyrimidine-4(3H)-one A solution of 1-(2,3-dichlorophenyl)thiourea (1.1 g, 5.0 mmol), diethyl malonate (1.6 g, 10.0 mmol), 18-crown-6 (661 mg, 2.5 mmol), and 2M NaOMe / MeOH (5.0 mL, 10.0 mmol) in 1,4-dioxane (15 mL) was stirred at 70°C for 3 hours. The reaction solution was purified by silica gel column chromatography (elution with DCM / MeOH) to obtain the target product (1.8 g, 99% yield) as a yellow solid. [M+H] + 289.0

[0228] Step 3: 3-(2,3-dichlorophenyl)-6-hydroxy-2-(methylthio)pyrimidine-4(3H)-one At 0°C, a solution of 3-(2,3-dichlorophenyl)-6-hydroxy-2-mercaptopyrimidine-4(3H)-one (1.45 g, 5.0 mmol) in THF (10 mL) was mixed with MeI (1.42 g, 10.0 mmol) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with DCM / MeOH) to obtain the target product (1.18 g, yield 78%) as a yellow oily substance.

[0229] Step 4: 1-(2,3-dichlorophenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-yl triisopropylbenzenesulfonic acid A solution of 3-(2,3-dichlorophenyl)-6-hydroxy-2-(methylthio)pyrimidine-4(3H)-one (1.18 g, 3.9 mmol), bis(2,4,6-trichlorophenyl) malonate (1.77 g, 5.9 mmol), DMAP (24 mg, 0.20 mmol), and Et3N (790 mg, 7.8 mmol) in DCM (25 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with PE / EA) to obtain the target product (500 mg, yield 22%) as a white solid. [M+H] + 568.4

[0230] Step 5: 1-(2,3-dichlorophenyl)-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-yl triisopropylbenzenesulfonic acid At 0°C, a solution of 1-(2,3-dichlorophenyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-yl (2,4,6-triisopropylbenzenesulfonic acid) in 30 mL of DCM was mixed dropwise with a solution of m-CPBA (757 mg, 4.4 mmol) in DCM, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with PE / EA) to obtain the target product (420 mg, yield 80%).

[0231] Step 6: 2,4,6-triisopropylbenzenesulfonic acid 2-amino-1-(2,3-dichlorophenyl)-6-oxo-1,6-dihydropyrimidine-4-yl 2,4,6-triisopropylbenzenesulfonic acid 1-(2,3-dichlorophenyl)-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-yl (420 mg, 0.70 mmol) was dissolved in 0.5 M NH3 / THF solution (7.0 mL, 3.5 mmol) and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with PE / EA) to obtain the target product (120 mg, yield 48%) as a yellow oily substance. [M+H] + 538.2.

[0232] Intermediate I-C3 (R)-2-methyl-N-((S)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)propan-2-sulfinamide

[0233] [ka]

[0234] Step 1: 4-(4-bromobenzyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl At -78°C under nitrogen, a solution of 1-tert-butyl-4-ethylpiperidine-1,4-dicarboxylic acid (20.6 g, 80 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise to a solution of 2 M LDA / tetrahydrofuran (52 mL, 104 mmol). The reaction mixture was stirred at -78°C for 2 hours, and a solution of 1-bromo-4-(bromomethyl)benzene (19.4 g, 80 mmol) in anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78°C for 3 hours, warmed to room temperature, and the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product as a white solid, which was used directly in the next step of the reaction.

[0235] Step 2: 4-(4-bromobenzyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 4-(4-bromobenzyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl (80 mmol) and lithium hydroxide (18.7 g, 780 mmol) were added to ethanol (200 mL) and water (100 mL). The reaction mixture was stirred at 90°C for 16 hours and then concentrated under reduced pressure. The residue was dissolved in water and washed with ethyl acetate / petroleum ether (volume ratio 1:1). The aqueous phase was collected, adjusted to pH 3 with 6 M hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product (34.0 g, 2-step yield 107%) as a white solid, which was used directly in the next step of the reaction. [M+H-56] + 342.2

[0236] Step 3: 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl 4-(4-bromobenzyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (34.0 g, 85 mmol) was added to polyphosphate (200 mL). The reaction mixture was stirred at 120 °C for 16 hours, cooled to room temperature, dissolved with additional water, and the mixture was adjusted to pH 9 using sodium hydroxide. (Boc)2O was added to the solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was extracted with ethyl acetate, the organic phase was collected, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (23.4 g, yield 72%) as a yellow solid. [M+H-56] + 324.0

[0237] Step 4: (R,E)-6-bromo-1-((tert-butylsulfinyl)imino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl Under nitrogen, 6-bromo-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl (23.4 g, 62 mmol) and (R)-2-methylpropane-2-sulfinamide (28.7 g, 237 mmol) were added to Ti(OEt)4 (200 mL). The reaction mixture was stirred at 80°C for 16 hours, and the reaction solution was poured into water / ethyl acetate and filtered. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, which was used directly in the next step of the reaction.

[0238] Step 5: (S)-6-bromo-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl Under nitrogen, (R,E)-6-bromo-1-((tert-butylsulfinyl)imino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl (62 mmol) was added to anhydrous tetrahydrofuran (200 mL). Sodium borohydride (9.07 g, 240 mmol) was added to the mixture at -78 °C, and the resulting solution was stirred at this temperature for 30 minutes. After warming to room temperature, it was poured into water and extracted with ethyl acetate. The organic phase was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (14.5 g, yield 48%) as a yellow solid. [M+H] + 485.2

[0239] Step 6: (S)-1-(((R)-tert-butylsulfinyl)amino)-6-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl Under nitrogen, (S)-6-bromo-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl (6.0 g, 12.4 mmol), ethynyltrimethylsilane (20 ml), Pd(PPh3)2Cl2 (0.87 g, 1.2 mmol), cuprous iodide (0.24 g, 1.2 mmol), triethylamine (40 mL), and N,N-dimethylformamide (40 mL) were placed in a sealed tube. The reaction mixture was stirred at 90°C for 16 hours, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product.

[0240] Step 7: (R)-2-methyl-N-((S)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)propan-2-sulfinamide To a solution of (S)-1-(((R)-tert-butylsulfinyl)amino)-6-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl (12.4 mmol) in dichloromethane (60 mL), methanesulfonic acid (3.6 g, 37.1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, and the reaction solution was cooled in an ice bath while adjusting the pH to 8 with aqueous ammonia. The organic phase was collected and concentrated under reduced pressure to obtain the target product (3.9 g, 78% yield in two steps) as a brown solid. [M+H] + 403.2

[0241] The intermediates listed in the table below were prepared according to the steps for preparing intermediates I-C3 from the corresponding starting materials and reagents:

[0242] [Table 9] JPEG0007856666000068.jpg65170

[0243] Intermediate I-C20 3-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-methylpropioamide

[0244] [ka]

[0245] Step 1: (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(3-methylamino)-3-oxopropa-1-in-1-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl Under N2 conditions, (S)-6-bromo-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl (4.85 g, 10.0 mmol), Pd(PPh3)2Cl2 (701 mg, 0.1 mmol), CuI (380 mg, 0.2 mmol), KOAc (2.94 g, 30.0 mmol), and DMSO (100 mL) were placed in a three-necked flask. At 90°C, the mixture was stirred, and a solution of N-methylpropioamide (2.49 g, 30.0 mmol) in DMSO (50 mL) was added dropwise over 2 hours, followed by stirring for a further 3 hours. The reaction solution was poured into water and filtered. The solid was collected and purified by silica gel column chromatography (elution with DCM / EA) to obtain the target product.

[0246] Step 2: 3-((S)-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-methylpropioamide In an ice bath, a solution of (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(3-methylamino)-3-oxopropa-1-in-1-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl was added dropwise to a solution of (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(3-methylamino)-3-oxopropa-1-in-1-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl in DCM (15 mL). The reaction solution was stirred at room temperature for 30 minutes and adjusted to pH 8 in an ice bath using aqueous ammonia solution. The organic layer was collected and concentrated under reduced pressure to obtain the target product (2.2 g, 57% yield in two steps) as a yellow solid. [M+H] + 388.2 The intermediates listed in the table below were prepared according to the steps for preparing intermediate I-C20 from the corresponding starting materials and reagents:

[0247] [Table 10]

[0248] Intermediate I-C35 3-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-(2-methoxyethyl)-N-methylpropioamide

[0249] [ka]

[0250] Step 1: 3-((S)-1'-(tert-butoxycarbonyl)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)propiolic acid To a solution of (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(3-methoxy-3-oxopropa-1-in-1-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl (1.0 g, 2.05 mmol; prepared according to steps 1-6 for preparing intermediates I-C3) in EtOH / water (10 mL / 2 mL), LiOH (245 mg, 10.23 mmol) was added, and the mixture was stirred at 85°C for 1 hour and then concentrated under reduced pressure. The residue was dissolved in water and extracted with EA. The aqueous layer was collected, adjusted to pH 6 with AcOH, and extracted with DCM. The organic layer was collected, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the target product (920 mg, yield 95%) as a white solid. [M+H] + 475.2.

[0251] Step 2: (S)-1-(((R)-tert-butylsulfinyl)amino)-6-(3-((2-methoxyethyl)(methyl)amino)-3-oxopropa-1-in-1-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl Et3N (202 mg, 2.0 mmol) was added dropwise to a solution of 3-((S)-1'-(tert-butoxycarbonyl)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)propiolic acid (477 mg, 1.0 mmol), 2-methoxy-N-methylethane-1-amine (178 mg, 2.0 mmol), and HATU (760 mg, 2.0 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 1 hour, poured into water, and filtered. The solid was collected to obtain the target product.

[0252] Step 3: 3-((S)-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-(2-methoxyethyl)-N-methylpropioamide The target product was prepared according to step 7 for preparing intermediate I-C3 from the corresponding starting materials and reagents (380 mg, 2 steps, 85% yield). [M+H] + 446.2

[0253] Intermediate I-C1 (R)-N-((S)-5-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0254] [ka]

[0255] To a solution of (S)-1-(((R)-tert-butylsulfinyl)amino)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl (1.08 g, 2.2 mmol) in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 minutes, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product (0.25 g, yield 35%). [M+H] + 331.2 The intermediates listed in the table below were prepared according to the steps for preparing intermediates I-C1 from the corresponding starting materials and reagents:

[0256] [Table 11]

[0257] Intermediate I-C5 (R)-2-methyl-N-((R)-6-((trimethylsilyl)ethynyl)-3H-spiro[benzofuran-2,4'-piperidine]-3-yl)propan-2-sulfinamide

[0258] [ka]

[0259] Step 1: 2-(4-bromo-2-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile Under nitrogen, TMSCN (3.78 g, 38.0 mmol) was added dropwise to a solution of 4-bromo-2-fluorobenzaldehyde (6.84 g, 33.7 mmol) and DMAP (50 mg) in acetonitrile (50 mL). The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure and the residue was used directly in the next step of the reaction.

[0260] Step 2: 4-(4-bromo-2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate tert-butyl At -78°C under nitrogen, 2-(4-bromo-2-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile was dissolved in 150 mL of anhydrous tetrahydrofuran, and 37.1 mL of 1 M LiHMDS / tetrahydrofuran solution (37.1 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1.5 hours, and a solution of 7.39 g of tert-butyl 4-oxopiperidine-1-carboxylate in 30 mL of anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78°C for 3 hours, and 200 mL of 1 M hydrochloric acid was added. The reaction solution was warmed to room temperature, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate. The organic phases were washed together with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was used directly in the next step of the reaction.

[0261] Step 3: 6-bromo-3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate tert-butyl 4-(4-bromo-2-fluorobenzoyl)-4-hydroxypiperidine-1-carboxylate tert-butyl (13.56 g, 33.7 mmol) was dissolved in 1,4-dioxane, and potassium t-butoxide (4.16 g, 37.1 mmol) was added. The reaction mixture was stirred at 85°C for 3 hours, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the target product (6.6 g, yield 51.2%). [M+H-56] + 326.0

[0262] Step 4: (R)-2-methyl-N-((R)-6-((trimethylsilyl)ethynyl)-3H-spiro[benzofuran-2,4'-piperidine]-3-yl)propan-2-sulfinamide The target product was prepared according to steps 4-7 for preparing intermediates I-C3 from the corresponding starting materials and reagents. [M+H] + 405.2 The intermediates listed in the table below were prepared according to the steps for preparing intermediates I-C5 from the corresponding starting materials and reagents:

[0263] [Table 12]

[0264] Intermediates I-C8 and I-C8' (R)-N-((S)-5-(3-hydroxypropa-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide and (R)-N-((S)-5-(3-(tert-butoxy)propa-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide

[0265] [ka]

[0266] Step 1: (S)-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-in-1-yl)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl The target product was prepared according to step 6 for preparing intermediate I-C3 from the corresponding starting materials and reagents. [M+H] + 575.2

[0267] Step 2: (R)-N-((S)-5-(3-hydroxypropa-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide and (R)-N-((S)-5-(3-(tert-butoxy)propa-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide A mixture of the target products I-C8 and I-C8' was prepared according to step 7 for preparing intermediate I-C3 from the corresponding starting materials and reagents. [M+H] + 361.2, 417.2

[0268] Step 3: (R)-N-((S)-5-(3-hydroxypropane-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide The target product was prepared according to the procedure for preparing intermediate I-C1 from the corresponding starting materials and reagents. [M+H] + 361.2

[0269] Intermediate I-C11 (R)-2-methyl-N-((S)-5-((1-methyl-1H-pyrazole-4-yl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)propan-2-sulfinamide

[0270] [ka]

[0271] Step 1: (S)-1-(((R)-tert-butylsulfinyl)amino)-6-((1-methyl-1H-pyrazole-4-yl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl Under nitrogen, (S)-6-bromo-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate tert-butyl (485 mg, 1.0 mmol), 1-methyl-1H-pyrazole-4-amine (135 mg, 1.4 mmol), xanthophos (35 mg, 0.06 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), and CsCO3 (650 mg, 2.0 mmol) were added to 1,4-dioxane (15 mL). The reaction mixture was stirred at 110 °C for 16 hours, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product. [M+H] + 502.3

[0272] Step 2: (R)-2-methyl-N-((S)-5-((1-methyl-1H-pyrazole-4-yl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)propan-2-sulfinamide The target product was prepared according to the procedure for preparing intermediate I-C1 from the corresponding starting materials and reagents. [M+H] + 402.2

[0273] compound 1 (S)-1'-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-5-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1-amine

[0274] [ka]

[0275] Step 1: (R)-N-((S)-5-ethynyl-1'-(8-iodoimidazo[1,2-c]pyrimidine-5-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide Intermediate I-C1 (149 mg, 0.45 mmol), 5-chloro-8-iodoimidazo[1,2-c]pyrimidine (126 mg, 0.45 mmol), and diisopropylethylamine (116 mg, 0.90 mmol) were added to N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by silica gel column chromatography (water / methanol) to obtain the target product (132 mg, 51% yield). [M+H] + 574.1

[0276] Step 2: (R)-N-((S)-1'-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-5-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide

[0277] Under nitrogen, (R)-N-((S)-5-ethynyl-1'-(8-iodoimidazo[1,2-c]pyrimidine-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (132 mg, 0.23 mmol), intermediate I-A1 (42 mg, 0.23 mmol), xanthophos (13.3 mg, 0.023 mmol), Pd2(dba)3 (10.5 mg, 0.012 mmol), and diisopropylethylamine (59 mg, 0.46 mmol) were added to 1,4-dioxane (4 mL). The reaction mixture was stirred at 100 °C for 3 hours, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (water / methanol) to obtain the target product (101 mg, yield 72%). [M+H] + 606.2

[0278] Step 3: (S)-1'-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-5-ethynyl-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (R)-N-((S)-1'-(8-((2-amino-3-chloropyridine-4-yl)thio)imidazo[1,2-c]pyrimidine-5-yl)-5-ethynyl-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (101 mg, 0.17 mmol) was dissolved in 2 M hydrochloric acid / methanol solution. The reaction mixture was stirred at room temperature for 3 minutes. While cooling in an ice bath, the reaction solution was diluted with dichloromethane (15 mL) and the pH was adjusted to 8 using aqueous ammonia solution. The organic phase was collected and concentrated under reduced pressure and the resulting residue was purified by thin-layer chromatography (dichloromethane / methanol = 12 / 1) to obtain the target product (76 mg, 91% yield in two steps). [M+H] + 502.1. 1 H NMR(400MHz,CD3OD):δ 8.08~7.97(m,1H),7.85~7.79(m,1H),7.57~7.5(m,1H),7.51~7.45(m,1H),7.39~7.28(m,3H),5.93~5.82(m,1H),4.06~3.96(m,3H), 3.43~3.33(m,3H)3.20~3.13(m,1H),2.86~2.74(m,1H),2.14~2.05(m,1H),2.04~1.95(m,1H),1.76~1.65(m,1H),1.53~1.42(m,1H). The compounds listed in the table below were prepared according to the steps for preparing compound 1 from the corresponding intermediates and reagents:

[0279] [Table 13] JPEG0007856666000080.jpg234136JPEG0007856666000081.jpg231149JPEG0007856666000082.jpg239147JPEG00078566660 00083.jpg236132JPEG0007856666000084.jpg231151JPEG0007856666000085.jpg231145JPEG0007856666000086.jpg231147 JPEG0007856666000087.jpg234130JPEG0007856666000088.jpg236142JPEG0007856666000089.jpg231147JPEG00078566660 00090.jpg236145JPEG0007856666000091.jpg228147JPEG0007856666000092.jpg226138JPEG0007856666000093.jpg236147

[0280] The compounds listed in the table below were prepared according to steps 1 and 3 for preparing compound 1 from the corresponding intermediates and reagents:

[0281] [Table 14] JPEG0007856666000095.jpg236138JPEG0007856666000096.jpg234142JPEG0007856666000097.jpg234136JPEG000 7856666000098.jpg231140JPEG0007856666000099.jpg236138JPEG0007856666000100.jpg231147JPEG00078566660 00101.jpg228151JPEG0007856666000102.jpg234136JPEG0007856666000103.jpg236142JPEG0007856666000104.j pg230147JPEG0007856666000105.jpg233138JPEG0007856666000106.jpg238136JPEG0007856666000107.jpg238130 JPEG0007856666000108.jpg238140JPEG0007856666000109.jpg236142JPEG0007856666000110.jpg233134JPEG000 7856666000111.jpg238138JPEG0007856666000112.jpg236138JPEG0007856666000113.jpg236145JPEG00078566660 00114.jpg233138JPEG0007856666000115.jpg236142JPEG0007856666000116.jpg238153JPEG0007856666000117.j pg236132JPEG0007856666000118.jpg233132JPEG0007856666000119.jpg228130JPEG0007856666000120.jpg236136

[0282] compound 4 (S)-6-amino-2-(1-amino-5-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-methyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-4(3H)-one

[0283] [ka]

[0284] Step 1: (R)-N-((S)-1'-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide 6-amino-2-hydroxy-3-methylpyrimidine-4(3H)-one (170 mg, 1.20 mmol), BOP (1.06 g, 2.40 mmol), and DBU (366 mg, 2.40 mmol) were added to anhydrous acetonitrile (10 mL), and the reaction mixture was stirred at room temperature for 30 minutes. Intermediate I-C6 (242 mg, 0.60 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was purified by silica gel column chromatography (water / methanol) to obtain the target product (95 mg, yield 15%). [M+H] + 526.3

[0285] Step 2: (R)-N-((S)-1'-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethinyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide Under nitrogen, (R)-N-((S)-1'-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (95 mg, 0.18 mmol) and NIS (45 mg, 0.20 mmol) were added to N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction solution was purified by silica gel column chromatography (water / methanol) to obtain the target product (70 mg, yield 60%). [M+H] + 652.3

[0286] Step 3: (R)-N-((S)-1'-(4-amino-1-methyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethinyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide Under nitrogen, (R)-N-((S)-1'-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethinyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (70 mg, 0.11 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (36 mg, 0.14 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), and potassium carbonate (45 mg, 0.32 mmol) were placed in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction mixture was stirred at 100°C for 1 hour, and the reaction solution was purified by silica gel column chromatography (water / methanol) to obtain the target product (10 mg, yield 14%). [M+H] + 656.3

[0287] Step 4: (S)-6-amino-2-(1-amino-5-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-methyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-4(3H)-one (R)-N-((S)-1'-(4-amino-1-methyl-5-(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (10 mg, 0.015 mmol) was dissolved in 2 M hydrochloric acid / methanol solution. The reaction mixture was stirred at room temperature for 3 minutes. While cooling in an ice bath, the reaction solution was diluted with dichloromethane (15 mL) and adjusted to pH 8 using aqueous ammonia solution. The organic phase was collected and concentrated under reduced pressure. The resulting residue and potassium carbonate (10 mg, 0.072 mmol) were added to methanol (0.5 mL). The mixture was stirred at room temperature for 10 minutes and purified by thin-layer chromatography (dichloromethane / methanol = 15 / 1) to obtain the target product (5.5 mg, 75% yield). [M+H] + 480.2. 1 H NMR(400MHz,CD3OD):δ 8.26~8.20(m,1H),7.82~7.75(m,1H),7.37~7.30(m,4H),7.11~7.07(m,1H),3.99~3.96(m,1H),3.90(s,3H),3.54~3.49(m,2H),3.47(s,3 H),3.41~3.39(m,1H),3.16~3.07(m,3H),2.78~2.72(m,1H),2.05~1.98(m,1H),1.96~1.86(m,1H),1.65~1.59(m,1H),1.44~1.37(m,1H). The compounds listed in the table below were prepared according to the steps for preparing compound 4 from the corresponding intermediates and reagents:

[0288] [Table 15] JPEG0007856666000123.jpg236151JPEG0007856666000124.jpg241136JPEG0007856666000125.jpg236132

[0289] compound 299 (S)-5-((2-amino-3-chloropyridine-4-yl)thio)-2-(1-amino-6-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-methylpyrimidine-4(3H)-one

[0290] [ka]

[0291] Step 1: (R)-N-((S)-1'-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide Intermediate I-C3 (0.88 g, 2.19 mmol), 2-chloro-5-iodo-3-methylpyrimidine-4(3H)-one (0.59 g, 2.19 mmol), and DIEA (0.57 g, 4.38 mmol) were placed in DMA (5 mL) and stirred at 90°C for 3 hours. The reaction solution was purified by silica gel column chromatography (elution with water / MeOH) to obtain the target product (0.82 g, yield 59%). [M+H] + 637.2

[0292] Step 2: (R)-N-((S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethinyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide Under N2 conditions, (R)-N-((S)-1'-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethinyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide (637 mg, 1.0 mmol), intermediate I-A1 (337 mg, 1.85 mmol), 4,7-dimethoxy-1,10-phenanthroline (156 mg, 0.65 mmol), CuI (43 mg, 0.23 mmol), and anhydrous K3PO4 (420 mg, 1.98 mmol) were added to 1,4-dioxane (10 mL). The reaction solution was stirred at 100 °C for 3 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with water / MeOH) to obtain the target product (506 mg, 76% yield). [M+H] + 669.2

[0293] Step 3: (S)-5-((2-amino-3-chloropyridine-4-yl)thio)-2-(1-amino-6-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-methylpyrimidine-4(3H)-one (R)-N-((S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-yl)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide (506 mg, 0.76 mmol) was dissolved in 2 M HCl / MeOH solution (6 mL). The reaction solution was stirred at room temperature for 5 minutes, diluted with DCM (15 mL), and adjusted to pH 8 in an ice bath using aqueous ammonia solution. The organic layer was collected and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL), K2CO3 powder (522 mg, 3.78 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was purified by thin-layer chromatography (elution with DCM / MeOH = 12 / 1) to obtain the target product (96 mg, yield 26%). [M+H] + 493.2. 11H NMR (400 MHz, CD3OD): δ 8.16~8.11(m,1H),7.62~7.56(m,1H),7.51~7.48(m,1H),7.35~7.30(m,1H), 7.24~7.19(m,1H),6.17~6.10(m,1H),3.99(s,1H),3.77~3.69(m,2H),3.53( s,3H),3.42(s,1H),3.29~3.19(m,2H),3.18~3.12(m,1H),2.85~2.76(m,1H) ,2.05~1.96(m,1H),1.94~1.86(m,1H),1.68~1.60(m,1H),1.46~1.38(m,1H). The compounds listed in the table below were prepared according to the steps for preparing compound 299 from the corresponding intermediates and reagents:

[0294] [Table 16] JPEG0007856666000128.jpg236147

[0295] compound 12 (S)-6-(1-amino-6-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one

[0296] [ka]

[0297] Step 1: (R)-N-((S)-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide Intermediate I-B1 (2.0 g, 3.73 mmol), intermediate I-C3 (1.5 g, 3.73 mmol), and DIEA (1.9 g, 14.9 mmol) were placed in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 100 °C for 3 hours, and the reaction solution was purified by silica gel column chromatography (water / methanol) to obtain the target product.

[0298] Step 2: (R)-N-((S)-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-5-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide (R)-N-((S)-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-5-((trimethylsilyl)ethynyl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide was dissolved in 2M hydrochloric acid / methanol solution (5 mL, 10 mmol). The reaction mixture was stirred at room temperature for 10 minutes, and while cooling in an ice bath, aqueous ammonia solution (3 mL) and water (30 mL) were added. The mixture was extracted with dichloromethane. The organic phases were collected and combined, and concentrated under reduced pressure and vacuum to obtain the crude product. [M+H] + 551.2

[0299] Step 3: (S)-6-(1-amino-6-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one Crude (R)-N-((S)-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-5-ethynyl-1,3-dihydrospiro[indene-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide and potassium carbonate (2.1 g, 14.9 mmol) were placed in methanol (15 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added, and the mixture was extracted with dichloromethane. The organic phases were collected and combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (490 mg, 3-step yield 27%). [M+H] + 479.2. 1 H NMR(400MHz,CD3OD):δ 7.70(dd,J=8.2,1.5Hz,1H),7.52~7.45(m,2H),7.38(dd,J=7.9,1.5Hz, 1H),7.33~7.27(m,1H),7.19(d,J=7.7Hz,1H),5.48(s,1H),4.51~4.05(m ,2H),3.92(s,1H),3.39(s,1H),3.26~3.12(m,3H),2.77(d,J=16.1Hz,1H ),2.06(s,3H),1.89~1.67(m,2H),1.63~1.54(m,1H),1.39~1.31(m,1H). The compounds listed in the table below were prepared according to the steps for preparing compound 12 from the corresponding intermediates and reagents:

[0300] [Table 17] JPEG0007856666000131.jpg238147JPEG0007856666000132.jpg241134JPEG0007856666000133.jpg252163JPEG0007856666000134.jpg252151JPEG0007856666000135.jpg250164JPEG0007856666000136.jpg252146JPEG0007856666000137.jpg252147JPEG0007856666000138.jpg252164JPEG0007856666000139.jpg252141JPEG0007856666000140.jpg252149JPEG0007856666000141.jpg252163JPEG0007856666000142.jpg252152JPEG0007856666000143.jpg252149JPEG0007856666000144.jpg252146JPEG0007856666000145.jpg252160JPEG0007856666000146.jpg252141JPEG0007856666000147.jpg252152JPEG0007856666000148.jpg252149JPEG0007856666000149.jpg252135JPEG0007856666000150.jpg252132JPEG0007856666000151.jpg252144JPEG0007856666000152.jpg252146JPEG0007856666000153.jpg252148JPEG0007856666000154.jpg252149JPEG0007856666000155.jpg252128JPEG0007856666000156.jpg252150JPEG0007856666000157.jpg252141JPEG0007856666000158.jpg252150JPEG0007856666000159.jpg252153JPEG0007856666000160.jpg252144JPEG0007856666000161.jpg252145JPEG0007856666000162.jpg252142JPEG0007856666000163.jpg252146JPEG0007856666000164.jpg252148JPEG0007856666000165.jpg252154JPEG000785666600 0166.jpg252148JPEG0007856666000167.jpg252147JPEG0007856666000168.jpg252150JPEG0007856 666000169.jpg252145JPEG0007856666000170.jpg252137JPEG0007856666000171.jpg252142JPEG00 07856666000172.jpg252148JPEG0007856666000173.jpg252149JPEG0007856666000174.jpg252131.

[0301] The optically pure diastereomers listed in the table are subjected to chiral HPLC under the following conditions (flow rate: 15 mL / min; detector: UV 254 nm):

[0302] [Table 18]

[0303] compound 81 (S)-6-(1-amino-6-(oxetane-3-ylthio)-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one

[0304] [ka]

[0305] Step 1: (R)-N-((S)-5-bromo-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide The target product was prepared according to step 1 for preparing compound 12 from the corresponding starting materials and reagents. [M+H] + 639.1

[0306] Step 2: 3-(((S)-1-(((R)-tert-butylsulfinyl)amino)-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)thio)propanoate ethyl The target product was prepared according to step 1 for preparing intermediate I-A1 from the corresponding starting materials and reagents. [M+H] + 691.1

[0307] Step 3: (S)-3-((1-amino-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-yl)thio)propanoate ethyl The target product was prepared according to step 2 for preparing compound 12 from the corresponding starting materials and reagents. [M+H] + 587.2

[0308] Step 4: (S)-1-amino-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-thiolate sodium The target product was prepared according to step 2 for preparing intermediate I-A1 from the corresponding starting materials and reagents.

[0309] Step 5: (S)-6-(1-amino-6-(oxetane-3-ylthio)-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidine-4(3H)-one (S)-1-amino-1'-(1-(2,3-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-thiolate sodium was dissolved in N,N-dimethylformamide (3 mL), and 3-bromooxetane (93 mg, 0.68 mmol) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes, and water (10 mL) was added thereto. The mixture was extracted with dichloromethane. The organic phases were collected and combined, concentrated under reduced pressure and vacuum, and the residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the target product (13 mg, yield 7.0%). [M+H] + 543.2. 1 H NMR(400MHz,CD3OD):δ 7.71(dd,J=8.1,1.4Hz,1H),7.48(t,J=8.0Hz1H),7.38(dd,J=7.9,1.4Hz,1H),7.29(s,1 H),7.21~7.10(m,2H),5.48(s,1H),5.04(t,J=6.8Hz,2H),4.58~4.47(m,3H),4.44~4.10 (m,2H),3.91(s,1H),3.25~3.20(m,2H),3.13(d,J=15.9Hz,1H),2.75(d,J=15.9Hz,1H), 2.06(s,3H),1.90~1.79(m,1H),1.77~1.67(m,1H),1.62~1.54(m,1H),1.39~1.32(m,1H). The compounds listed in the table below were prepared according to the steps for preparing compound 81 from the corresponding intermediates and reagents:

[0310] [Table 19] JPEG0007856666000178.jpg252147JPEG0007856666000179.jpg252145JPEG0007856666000180.jpg252143

[0311] compound 87 (S)-(3-(1-amino-6-(3-methoxypropane-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-6-((2-aminopyrimidine-4-yl)thio)pyrazine-2-yl)methanol

[0312] [ka]

[0313] Step 1: 6-bromo-3-((S)-1-(((R)-tert-butylsulfinyl)amino)-6-(3-methoxypropa-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate methyl The target product was prepared according to step 1 for preparing compound 1 from the corresponding starting materials and reagents. [M+H] + 589.1

[0314] Step 2: (R)-N-((S)-1'-(5-bromo-3-(hydroxymethyl)pyrazine-2-yl)-5-(3-methoxypropa-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide Under nitrogen at -78°C, a solution of methyl 6-bromo-3-((S)-1-(((R)-tert-butylsulfinyl)amino)-6-(3-methoxypropa-1-in-1-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate methyl (380 mg, 0.64 mmol) in anhydrous THF (15 mL) was added dropwise with 1.0 M DIBAL-H solution (3.2 mL, 3.2 mmol). The reaction mixture was stirred at -78°C for 2 hours, then warmed to room temperature and stirred for 20 minutes. Na2SO4·10H2O and water (20 mL) were added, and the mixture was filtered. The aqueous phase was extracted with dichloromethane. The organic phases were collected and combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (water / methanol) to obtain the target product (186 mg, 52% yield). [M+H] + 561.2

[0315] Step 3: (S)-(3-(1-amino-6-(3-methoxypropane-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-6-((2-aminopyrimidine-4-yl)thio)pyrazine-2-yl)methanol The target product was prepared according to steps 2-3 for preparing compound 1 from the corresponding starting materials and reagents. [M+H] + 504.2. 1 1H NMR (400 MHz, CD3OD): δ 8.31(s,1H),7.90(d,J=5.5Hz,1H),7.45(s,1H),7.27(d,J=7.7Hz,1H),7.19(d, J=7.8Hz,1H),6.28(d,J=5.5,1H),4.66(s,2H),4.30(s,2H),3.93(s,1H),3.84~ 3.75(m,2H),3.41(s,3H),3.26~3.17(m,2H),3.13(d,J=16.0Hz,1H),2.76(d,J= 16.1Hz, 1H), 2.03~1.83 (m, 2H), 1.61 (d, J=12.2Hz, 1H), 1.39 (d, J=12.6Hz, 1H). The compounds listed in the table below were prepared according to the steps for preparing compound 87 from the corresponding intermediates and reagents:

[0316] [Table 20] JPEG0007856666000183.jpg252146

[0317] compound 159 (S)-1-(3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)propa-2-in-1-yl)urea

[0318] [ka]

[0319] Step 1: N,N-bis(4-methoxybenzyl)propa-2-in-1-amine To a solution of propagylamine (550 mg, 10 mmol) in MeCN (30 mL), p-methoxybenzyl chloride (3.4 g, 22 mmol) and K2CO3 (4.1 g, 30 mmol) were added. The reaction solution was heated to 60°C and stirred for 16 hours. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with EA (100 mL x 2). The organic layers were collected and combined, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with PE / EA) to obtain the target product (2.1 g, yield 71%). [M+H] + 296.1

[0320] Step 2: N-(4-methoxybenzyl)-N-(propa-2-in-1-yl)cyanamide N,N-bis(4-methoxybenzyl)propa-2-in-1-amine (2.1 g, 7.1 mmol), BrCN (1.5 g, 14.2 mmol), and K2CO3 (2.2 g, 16.3 mmol) were placed in 1,4-dioxane (70 mL), stirred at room temperature for 20 hours, water (50 mL) was added, and the mixture was extracted with EA (50 mL x 2). The organic layers were collected and combined, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with PE / EA) to obtain the target product (750 mg, yield 50%). [M+Na] + 223.2

[0321] Step 3: (R)-N-((S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-5-(3-(N-(4-methoxybenzyl)cyanamide)propa-1-in-1-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide Under N2 conditions, (R)-N-((S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-5-bromo-1,3-dihydrospiro[inden-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide (424 mg, 0.67 mmol; prepared according to step 1 for preparing compound 1 from intermediates I-A2 and I-C4), N-(4-methoxybenzyl)-N-(propa-2-in-1-yl)cyanamide (200 mg, 1 mmol), Pd(PPh3)2Cl2 (94 mg, 0.13 mmol), CuI (25 mg, 0.13 mmol), and DIEA (1 mL) were placed in DMF (3 mL). The reaction solution was heated to 90°C and stirred for 20 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with water / MeOH) to obtain the target product (70 mg, yield 14%). [M+H] + 756.3

[0322] Step 4: (S)-N-(3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)propa-2-in-1-yl)-N-(4-methoxybenzyl)cyanamide (R)-N-((S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-5-(3-(N-(4-methoxybenzyl)cyanamide)propa-1-in-1-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide (70 mg, 0.09 mmol) was dissolved in 2 M HCl / MeOH solution (1 mL) and stirred at room temperature for 10 minutes. The mixture was adjusted to pH=9 with aqueous ammonia solution, water (10 mL) was added, and the mixture was extracted with DCM (10 mL x 2). The organic layers were collected and combined, and concentrated under reduced pressure and vacuum to obtain the target product (50 mg, yield 85%). [M+H] + 652.2

[0323] Step 5: (S)-1-(3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)propa-2-in-1-yl)urea (S)-N-(3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)propa-2-in-1-yl)-N-(4-methoxybenzyl)cyanamide (50 mg, 0.07 mmol) was mixed with TFA (2 mL) and stirred at 50°C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure, saturated NaHCO3 aqueous solution (10 mL) was added, and extraction was performed with DCM (10 mL x 2). The organic layers were collected and combined, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (elution with DCM / MeOH) to obtain the target product (10 mg, yield 25%). [M+H] + 550.2. 1H NMR(400MHz,CD3OD):δ 7.59~7.56(m,2H),7.42(s,1H),7.30~7.25(m,1H),7.22~7.18(m,1H),5.94~5.86(m,1H),4.33~4.24(m,2H),4.09( s,2H),3.96(s,1H),3.25~3.13(m,3H),2.84~2.80(m,1H),1.88~1.67(m,2H),1.58~1.56(m,1H),1.40~1.38(m,1H).

[0324] compound 222 (S)-3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)-3-chloropyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-methylpropioamide

[0325] [ka]

[0326] Step 1: 3-((S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)-3-chloropyrazine-2-yl)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-methylpropioamide To a solution of 3-((S)-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-yl)-N-methylpropioamide (96 mg, 0.15 mmol; prepared according to step 1 for preparing compound 1 from intermediates I-A2 and I-C20) in DMF (3 mL), NCS (40 mg, 0.30 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by silica gel column chromatography (eluted with water / MeOH) to obtain the target product.

[0327] Step 2: (S)-3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)-3-chloropyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-methylpropioamide The target product was prepared according to step 3 for preparing compound 1 from the corresponding starting materials and reagents (26 mg, 2-step yield 31%). [M+H] + 569.2. 1 H NMR(400MHz,CD3OD):δ 7.60(d,J=5.5Hz,1H),7.55(s,1H),7.40(d,J=7.7Hz,1H),7.26(d,J=7.8Hz,1H),5.94(d,J=5.5Hz,1H),4.08~4.01(m,2H) ),3.94(s,1H),3.22~3.12(m,3H),2.81~2.74(m,4H),1.99~1.82(m,2H),1.58(d,J=13.4Hz,1H),1.36(d,J=13.2Hz,1H). The compounds listed in the table below were prepared according to the steps for preparing compound 222 from the corresponding intermediates and reagents:

[0328] [Table 21] JPEG0007856666000187.jpg252139

[0329] compound 239 (S)-3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)-3-fluoropyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-methylpropioamide

[0330] [ka]

[0331] At 0°C, NFSI (97 mg, 0.31 mmol) was added to a solution of (S)-3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-yl)-N-methylpropioamide (compound 229; 165 mg, 0.31 mmol) in DMF (2 mL) and MeCN (3 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified by silica gel column chromatography (elution with water / MeOH) and thin-layer chromatography (elution with DCM / MeOH) to obtain the target product (28 mg, yield 16%). [M+H] + 553.2. 1 H NMR(400MHz,CD3OD):δ 7.63~7.57(m,1H),7.54(s,1H),7.42~7.38(m,1H),7.26(d,J=7.7Hz,1H),5.99(d,J=5.5Hz,1H),4.30~4.26(m,2H),3.94( s,1H),3.34-3.32(m,1H),3.26~3.01(m,2H),2.82~2.78(m,4H),1.95~1.72(m,2H),1.59~1.55(m,1H),1.35~1.31(m,1H).

[0332] compound 240 (S)-3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)-3-bromopyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-methylpropioamide

[0333] [ka]

[0334] To a solution of (S)-3-(1-amino-1'-(6-amino-5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-yl)-N-methylpropioamide (compound 229; 60 mg, 0.093 mmol) in DMF (1.5 mL), NBS (33 mg, 0.188 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography (elution with water / MeOH) and thin-layer chromatography (elution with DCM / MeOH) to obtain the target product (15 mg, yield 26%). [M+H] + 613.1. 1 H NMR(400MHz,CD3OD):δ 7.62(d,J=5.5Hz,1H),7.57(s,1H),7.41(d,J=7.7Hz,1H),7.27(d,J=7.8Hz,1H),5.96(d,J=5.6Hz,1H),4.09 ~3.91(m,3H),3.24~3.09(m,3H),2.87~2.73(m,4H),2.04~1.80(m,2H),1.62~1.58(m,1H),1.41~1.37(m,1H).

[0335] compound 243 (S)-3-(1-amino-1'-(5-(3,4-dihydro-1,5-naphthyridine-1(2H)-yl)pyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-ethylpropioamide

[0336] [ka]

[0337] Step 1: 3-((S)-1-(((R)-tert-butylsulfinyl)amino)-1'-(5-(3,4-dihydro-1,5-naphthyridine-1(2H)-yl)pyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-ethylpropioamide Under N2 conditions, 3-((S)-1'-(5-bromopyrazine-2-yl)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-yl)-N-ethylpropioamide (80 mg, 0.14 mmol); prepared according to step 1 for preparing compound 1 from 2,5-dibromopyrazine and intermediate I-C23), 1,2,3,4-tetrahydro-1,5-naphthiridine (37 mg, 0.28 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xanthophos (12 mg, 0.02 mmol), and Cs2CO3 (91 mg, 0.28 mmol) were added to 1,4-dioxane (10 mL). The reaction mixture was heated to 100°C and stirred for 16 hours. After vacuum concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution with water / MeOH and 0.05% formic acid) to obtain the target product.

[0338] Step 2: (S)-3-(1-amino-1'-(5-(3,4-dihydro-1,5-naphthyridine-1(2H)-yl)pyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)-N-ethylpropioamide The target product was prepared according to step 3 for preparing compound 1 from the corresponding starting materials and reagents (25 mg, 35% yield). [M+H] + 508.3. 1 H NMR(400MHz,CD3OD):δ 8.06(d,J=2.4Hz,2H),7.83(dd,J=4.7,1.3Hz,1H),7.56(s,1H),7.42(d,J=7.6Hz,1H),7.28(d, J=7.8Hz,1H),7.08(dd,J=8.4,1.2Hz,1H),7.03~6.95(m,1H),4.25~4.12(m,2H),3.95(s,1H),3 .72~3.65(m,2H),3.29~3.14(m,5H),2.99(t,J=6.5Hz,2H),2.81(d,J=16.3Hz,1H),2.18~2.09( m,2H),1.96~1.75(m,2H),1.60(d,J=12.5Hz,1H),1.37(d,J=12.7Hz,1H),1.16(t,J=7.3Hz,3H). The compounds listed in the table below were prepared according to the steps for preparing compound 243 from the corresponding intermediates and reagents:

[0339] [Table 22] JPEG0007856666000192.jpg252148JPEG0007856666000193.jpg252147

[0340] compound 279 (S)-3-(1-amino-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)propiolic acid

[0341] [ka]

[0342] Step 1: 3-((S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[inden-2,4'-piperidine]-6-yl)propiolic acid LiOH (120 mg, 5.0 mmol) was added to a solution of 3-((S)-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-yl)propiolate ethyl (320 mg, 0.5 mmol; prepared according to step 1 for preparing compound 1 from intermediates I-A15 and I-C30) in EtOH / water. The reaction solution was stirred at 70°C for 1 hour and adjusted to pH 5 using MeSO3H. After vacuum concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution with DCM / MeOH) to obtain the target product (80 mg, yield 26%).

[0343] Step 2: (S)-3-(1-amino-1'-(5-((2-amino-3-chloropyridine-4-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-6-yl)propiolic acid The target product was prepared according to step 3 for preparing compound 1 from the corresponding starting materials and reagents (30 mg, 45% yield). [M+H] + 507.2. 1 H NMR(400MHz,CD3OD):δ 8.45-8.30(m,2H),7.73-7.54(m,3H),7.49-7.38(m,1H),6.00-5.91(m,1H),4.55-4.4 6(m,2H),4.41~4.34(m,1H),3.46~3.38(m,2H),3.27~3.21(m,2H),1.91~1.67(m,4H). The compounds listed in the table below were prepared according to the steps for preparing compound 279 from the corresponding intermediates and reagents:

[0344] [Table 23]

[0345] Compounds 56 and 57 (S)-6-(1-amino-6-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-(2-chlorophenyl)-2-methylpyrimidine-4(3H)-one diastereomer

[0346] [ka]

[0347] Compound 42 of (S)-6-(1-amino-6-ethynyl-1,3-dihydrospiro[inden-2,4'-piperidine]-1'-yl)-3-(2-chlorophenyl)-2-methylpyrimidine-4(3H)-one was separated by chiral HPLC to obtain a diastereomer pair. Chiral HPLC conditions: Column: inner diameter (2 × 25 cm); Mobile phase: acetonitrile / ethanol = 10:90; Flow rate: 15 mL / min; Detector: UV 254 nm.

[0348] First eluate (compound 56, RT=6.942 min), de%=100%, [M+H] + 445.2. 1 H NMR(400MHz,CD3OD):δ 7.65~7.59(m,1H),7.53~7.46(m,3H),7.41~7.36(m,1H),7.33~7.28(m,1H),7.22~7.17(m,1H),5.48(s,1H),4.27(br,2H),3.92(s,1H),3. 39(s,1H),3.27~3.13(m,3H),2.82~2.74(m,1H),2.04(s,3H),1.88~1 .79(m,1H),1.77~1.67(m,1H),1.61~1.54(m,1H),1.39~1.32(m,1H).

[0349] Second eluate (compound 57, RT=9.352 min), de%=100%, [M+H] + 445.2. 1 H NMR(400MHz,CD3OD):δ 7.66~7.60(m,1H),7.54~7.45(m,3H),7.41~7.36(m,1H),7.33~7.27(m,1H),7.22~7.17(m,1H),5.48(s,1H),4.27(br,2H),3.93(s,1H),3. 39(s,1H),3.27~3.12(m,3H),2.83~2.74(m,1H),2.04(s,3H),1.88~1 .78(m,1H),1.77~1.68(m,1H),1.61~1.54(m,1H),1.40~1.33(m,1H). The compounds listed in the table below were prepared according to the chiral separation conditions for compounds 56 and 57:

[0350] [Table 24] JPEG0007856666000198.jpg252143JPEG0007856666000199.jpg252141JPEG000 7856666000200.jpg252151JPEG0007856666000201.jpg252128JPEG00078566660 00202.jpg252140JPEG0007856666000203.jpg252143JPEG0007856666000204.j pg252143JPEG0007856666000205.jpg252149JPEG0007856666000206.jpg252147 JPEG0007856666000207.jpg249161JPEG0007856666000208.jpg252150JPEG000 7856666000209.jpg252148JPEG0007856666000210.jpg252155JPEG00078566660 00211.jpg245161JPEG0007856666000212.jpg252154JPEG0007856666000213.j pg252150JPEG0007856666000214.jpg252151JPEG0007856666000215.jpg252161

[0351] The diastereomers listed in the table are subjected to chiral HPLC under the following conditions (flow rate: 15 mL / min; detector: UV254 nm):

[0352] [Table 25] JPEG0007856666000217.jpg176170

[0353] The compounds listed in the table below were prepared according to the steps for preparing the above compounds from the corresponding intermediates and reagents:

[0354] [Table 26] JPEG0007856666000219.jpg254170JPEG0007856666000220.jpg248170

[0355] Example 2 Assay of full-length SHP2 phosphatase activity 1. Reagents and Substances • Human full-length SHP2 recombinant protein: BPS Bioscience, Cat#79018; ·SHP2 substrate DiFMUP (1mM): BPS Bioscience, Cat#79769; • SHP2 active peptide (100 μM): BPS Bioscience, Cat#79319-2; DTT:Merck, Cat#DTT-RO; 384-well plate: Corning, Cat#3575; 96-well plate: Thermo Fisher Scientific, Cat#249952; Equipment: EnVision2104, PerkinElmer.

[0356] 2. Preparation of reaction solution The test compound was dissolved in DMSO and diluted to 100.0 μM with DMSO. This compound was then further diluted threefold with DMSO to 100.00, 33.33, 11.11, 3.70, 1.23, 0.41, 0.14, and 0.05 μM. Next, 4 μL of the compound at different dilution concentrations was added to 96 μL of enzyme reaction buffer to prepare the 4X test compound, with a DMSO concentration of 4% (the final DMSO concentration was 1%). Preparation of 1X enzyme reaction buffer: 5X reaction buffer (250 mM HEPES, 500 mM NaCl, 2.5 mM EDTA, 0.005% Brij-35 and 0.01% BSA, pH 7.2) was diluted 5-fold with deionized water, and then DTT was added to it so that the 1X enzyme reaction buffer contained 5 mM DTT. Preparation of a 4X mixed solution of SHP2 enzyme / active peptide: A 4X mixed solution of SHP2 enzyme / active peptide (0.12 nM SHP2 and 2 μM active peptide) was prepared by diluting SHP2 enzyme (75.5 nM) and active peptide (100 μM) using enzyme reaction buffer. The final concentrations of SHP2 enzyme and active peptide in the enzyme reaction system were 0.03 nM and 0.5 μM, respectively. Preparation of 2X DiFMUP substrate: 1 mM DiFMUP was diluted 100-fold using enzyme reaction buffer to prepare a 2X substrate (10 μM). The final concentration of the DiFMUP substrate in the enzyme reaction system was 5 μM.

[0357] 3. Experimental Procedure • 2.5 μL of the 4X test compound or 2.5 μL of 4% DMSO solution was added to the corresponding well of a 384-well plate, and the mixture was centrifuged at 1000 rpm for 30 seconds. 2.5 μL of SHP2 enzyme / active peptide 4X mixed solution was added to the test compound well and the positive control well, while 2.5 μL of 1X enzyme reaction buffer was added to the negative control well; centrifugation was performed at 1000 rpm for 30 seconds, and incubation was performed at room temperature for 30 minutes. • 5 μL of 2X DiFMUP substrate was added to each well to initiate the enzymatic reaction. The plate was then briefly vibrated, centrifuged at 1000 rpm for 30 seconds, the 384-well plate was sealed with a sealing membrane, and incubated in the dark at 25°C for 60 minutes using a low-speed shaker (100 rpm). The fluorescence values ​​(relative fluorescence units, RFU) of each well were detected using EnVision2104 (excitation: 355 nm, emission: 460 nm).

[0358] 4. Data Analysis

[0359] Inhibition rate (%) = 100 - [(RFU in compound well - RFU in negative control well) / (RFU in positive control well - RFU in negative control well)] × 100

[0360] During the ceremony, • The RFU of a compound well represents the fluorescence reading at 460 nm of the well containing the test compound; • The RFU of the negative control well represents the fluorescence reading at 460 nm in the background well containing 1% DMSO and enzyme reaction buffer; • The RFU of the positive control well represents the fluorescence reading at 460 nm of the well containing a mixed solution of 1% DMSO and SHP2 enzyme / active peptide.

[0361] I C 50 The value was calculated using the XL-Fit 5.0 software with the following equation 205: y = A + ((BA) / (1 + ((C / X)) D ))).

[0362] 5. Test Results

[0363] [Table 27] JPEG0007856666000222.jpg239170JPEG0007856666000223.jpg122170

[0364] Example 3 Assay of intracellular pERK1 / 2(Thr202 / Tyr204) phosphorylation 1. Reagents and Substances • pERK1 / 2 (Thr202 / Tyr204) HTRF kit: Cisbio, Cat#64ERKPEH; ·Cell line: Miapaca2, ATCC, CRL-1420; • OptiPlate (trademark) - 384-well plate: PerkinElmer, Cat#6007299; • 96-well plate: Corning, Cat#353072; • Equipment: EnVision2104, PerkinElmer

[0365] 2. Preparation of reaction solution The test compound was dissolved in DMSO and diluted to 600.0 μM using DMSO. This compound was then further diluted threefold using DMSO to 600.0, 200.0, 66.7, 22.2, 7.4, 2.5, 0.82, and 0.27 μM. Next, 10 μL of the compound at different dilution concentrations was added to 190 μL of DMEM medium to prepare the 10X test compound, with a DMSO concentration of 5% (the final DMSO concentration was 0.5%). • 1X cell lysis buffer: The 4X cell lysis stock solution (provided in the kit) was diluted four-fold with desalted water, and then the 1% 100X blockage stock solution (provided in the kit) was added to it. • pERK1 / 2 detection solution (to be prepared immediately before use): pERK1 / 2 d2 antibody (provided by the kit) and pERK1 / 2 cryptotate antibody (provided by the kit) were diluted in a ratio of 1:1:38 with the detection solution (provided by the kit).

[0366] 3. Experimental Procedure Miapaca2 cells were seeded in 96-well plates at a density of 10,000 cells / well with 90 μL / well, and cultured overnight in a cell incubator at 5% CO2 and 37°C. 10 μL of the 10X test compound was added to a 90 μL 96-well cell culture plate; 10 μL of 5% DMSO culture medium was added to the cell-positive control well; and the plate was cultured in a cell incubator at 5% CO2 and 37°C for 2 hours. Remove the culture medium from the 96-well plate; add 50 μL of 1X cell lysis buffer to each well; place the plate in a microplate shaker; and lyse at 900 rpm for 1 hour at room temperature while shaking. • 16 μL of lysis buffer was taken from a 96-well plate and transferred to a 384-well plate, and centrifuged at 1000 rpm for 30 seconds; then, 4 μL of pERK1 / 2 detection solution was added to each well; centrifuged at 1000 rpm for 30 seconds; the 384-well plate was sealed with a sealing membrane and incubated in the dark at 25°C for 2 hours using a low-speed shaker (100 rpm). The fluorescence values ​​(relative fluorescence units, RFU) of each well were detected using EnVision2104 (excitation 1: 665 nm, excitation 2: 615 nm).

[0367] 4. Data Analysis

[0368] Fluorescence ratio = RFU 665nm / RFU 615nm Inhibition rate (%) = 100 - [(fluorescence ratio of compound well - fluorescence ratio of negative control well) / (fluorescence ratio of positive control well - fluorescence ratio of negative control well)] × 100

[0369] During the ceremony, The fluorescence ratio of the compound wells represents the fluorescence ratio of the wells containing the test compound; • The fluorescence ratio of the negative control well represents the background fluorescence ratio, which includes cell lysis buffer but does not include Miapaca2 cells; • The fluorescence ratio of the positive control well represents the fluorescence ratio of a well containing 0.5% DMSO but without Miapaca2 cells.

[0370] I C 50 The value was calculated using the XL-Fit 5.0 software with the following equation 205: y = A + ((BA) / (1 + ((C / X)) D ))).

[0371] 5. Test Results

[0372] [Table 28] JPEG0007856666000225.jpg239170

[0373] Example 4: Assay of cell proliferation on Miapaca2 3D spheroids 1. Reagents and Substances • CellTiter-Glo® 3D Cell Survival Assay Kit: Promega, Cat#G9683; CellCarrier Spheroid ULA 96-well plate: Corning, Cat#4515; • Equipment: EnVision, PerkinElmer; ·Cell line: Miapaca2, ATCC, Cat#CRL-1420.

[0374] 2. Preparation of reaction solution The test compound was dissolved in DMSO and diluted to 3000.0 μM with DMSO. This compound was then further diluted threefold with DMSO to 1000.0, 333.3, 111.1, 37.0, 12.3, 4.1, and 1.4 μM. Next, 2 μL of the compound at different dilution concentrations was added to 198 μL of 1640 medium to prepare the 10X test compound, with a DMSO concentration of 1% (the final DMSO concentration was 0.1%).

[0375] 3. Experimental Method Day 0: Digestion of cells and counting of cell counts. Miapaca2 cells were seeded at a density of 300 cells / well in 100 μL / well of spheroid ULA 96-well plates and cultured in a cell incubator at 5% CO2 and 37°C. Day 2: Cell spheroids formed on day 2. 10 μL of the 10X test compound was added to a 96-well plate. 10 μL of 1% DMSO1640 medium was added to the cell-positive control well. Cell spheroids were further incubated in a cell incubator at 5% CO2 and 37°C for 5 days. • Cell viability assay: Add 50 μL of CellTiter-Glo reagent to each well, place the plate in a microplate shaker, and dissolve while shaking at 900 rpm for 5 minutes at room temperature. Then, incubate the plate in the dark at room temperature for 30 minutes. • The luminescence from each well was detected using Envision2104.

[0376] 4. Data Analysis Cell viability % = (Luminescence (d7 treatment) - Luminescence (d2 cells)) / (Luminescence (d7 cells) - Luminescence (d2 cells)) × 100 During the ceremony: • Luminescence (d7 treatment) refers to the luminescence of cells treated with the test compound on day 7; • Luminescence (d2 cells) represents luminescence in 0.1% DMSO-treated Miapaca2 cells on day 2; • Luminescence (d7 cells) represents luminescence in 0.1% DMSO-treated Miapaca2 cells on day 7;

[0377] I C 50 The value was calculated using the XL-Fit 5.0 software with the following equation 205: y = A + ((BA) / (1 + ((C / X)) D ))).

[0378] 5. Test Results

[0379] [Table 29]

Claims

1. Equation (I): 【Chemistry 1】 A compound of the above formula (I), Ring A is a benzene ring; Z is CH ２ , or O; R １ is alkynyl, and said C ２～６ alkynyl is; halogen, -CN, -OH, -NH ２～６ , C ２ cycloalkyl, 4- to 8-membered heterocyclyl, -O(C ３～８ alkyl), -O(C １～６ haloalkyl), -O(C １～６ cycloalkyl), -O(4- to 8-membered heterocyclyl), -S(C ３～８ alkyl), -S(C １～６ cycloalkyl), -S(4- to 8-membered heterocyclyl), -NH(C ３～８ alkyl), -N(C １～６ alkyl) １～６ and is optionally substituted by one or more groups independently selected from -NH-CN, -NHCONH ２ , -NHCO(C ２ alkyl), -CONR １～６ R ａ R ｂ , -COOR ｃ and -COR ｄ ; R ａ , R ｂ , R ｃ and R ｄ are each independently selected from hydrogen, C １～６ alkyl, C １～６ haloalkyl, -(C １～６ alkyl)-O-(C １～６ alkyl), -(C １～６ alkyl)-OH, -(C １～６ alkyl)-CN, C ３～８ cycloalkyl and 4- to 8-membered heterocyclyl; said C ３～８ cycloalkyl, and 4- to 8-membered heterocyclyl are: halogen, -CN, -CONH ２ , -OH, oxo, -NH ２ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C[[ID=7\3]] １～６ haloalkyl, -(C １～６ alkyl)-OH, -(C １～６ alkyl)-O-(C １～６ alkyl), -(C １～６ Alkyl)-CN,-O(C １～６ Alkyl), -O (C １～６ Haloalkyl), -S (C １～６ Alkyl), -NH(C １～６ Alkyl) and -N(C) １～６ Alkyl) ２ Each of them may be substituted by one or more elements selected independently of each other; R １ ' is halogen, -CN, -CONH ２ -OH, -NH ２ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, 4-membered to 8-membered heterocyclyl, -(C １～６ Alkyl)-OH,-(C １～６ Alkyl)-O-(C １～６ Alkyl), -(C １～６ Alkyl)-CN,-O(C １～６ Alkyl), -O (C １～６ Haloalkyl), -O(C) ３～８ Cycloalkyl), -O (4- to 8-membered heterocyclyl), -S (C １～６ Alkyl), -NH(C １～６ Alkyl) and -N(C) １～６ Alkyl) ２ Selected independently from, C ３～８ Cycloalkyls and 4- to 8-membered heterocyclines may each be substituted with one or more halogens; n is 0, 1, 2, or 3; R ２ is, -NH ２ And, Cy １ teeth, 【Chemistry 2】 Selected from, each of these is: -NH ２ -CN, halogen, C １～６ Alkyl, C １～６ Haloalkyl and -(C １～６ It may be substituted with one or more groups independently selected from alkyl)-OH, Cy ２ is phenyl or 5- to 14-membered heteroaryl, each of which is: halogen, -CN, -CONH ２ , -OH, oxo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, -(C １～６ alkyl)-OH, -(C １～６ alkyl)-O-(C １～６ alkyl), -(C １～６ alkyl)-CN, -O(C １～６ alkyl), -O(C<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ L does not exist, or L is S. A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, racemic mixture, enantiomer, diastereomer, or tautomer.

2. Z is CH2, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof.

3. R １ C ２～６ It is an alkynyl, and the C ２～６ Alkynnyls are: halogen, -CN, -OH, -NH ２ , C ３～８ Cycloalkyl, 4- to 8-membered heterocyclyl, -O(C) １～６ Alkyl), -O (C １～６ Haloalkyl), -O(C) ３～８ Cycloalkyl), -O (4- to 8-membered heterocyclyl), -S (C １～６ Alkyl), -S (C ３～８ Cycloalkyl), -S (4- to 8-membered heterocyclyl), -NH (C １～６ Alkyl), -N(C １～６ Alkyl) ２ , -NHCONH ２ , - NHCO (C １～６ Alkyl), -CONR ａ R ｂ , -COOR ｃ and -COR ｄ It may be substituted by one or more groups independently selected from R ａ , R ｂ , R ｃ and R ｄ is hydrogen, C １～６ Alkyl, -(C １～６ Alkyl)-O-(C １～６ Alkyl), -(C １～６ Alkyl)-OH, C ３～８ A cycloalkyl group and a 4- to 8-membered heterocycline group are independently selected from each other; and the above C ３～８ Cycloalkyls and 4- to 8-membered heterocyclines include: halogens, -CN, -CONH ２ -OH, oxo, -NH ２ , C １～６ Alkyl and -O(C) １～６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, which may each be substituted with one or more groups independently selected from alkyl groups.

4. R １ C ２～６ It is an alkynyl, and the C ２～６ Alkinyl is: -OH, -CONH ２ , -O(C １～６ Alkyl), -NH(C １～６ Alkyl), -N(C １～６ Alkyl) ２ , -NHCONH ２ , -CONH(C １～６ Alkyl), -CONH(C １～６ Alkyl)-O-(C １～６ Alkyl), -CON(C １～６ Alkyl) ２ , -CON(C １～６ (Alkyl) (C １～６ Alkyl-O-C １～６ Alkyl), -CONH(C ３～８ Cycloalkyl), -COOH, -COO(C １～６ Alkyl), -CO(C １～６ Alkyl), -CO (4- to 8-membered heterocyclyl) and -CO (4- to 8-membered heterocyclyl)-O-(C １～６ The compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, which may be substituted with one or more groups independently selected from alkyl groups.

5. R1 is ethinyl, propynyl or butynyl, each of which is unsubstituted or -OH, -CONH2, -OCH3, -NH(CH3), -N(CH3)2, -NHCONH2, -CONH(C1-3 alkyl), -CONH(CH2CH2)-O-(CH3), -CON(CH3)2, -CON(CH3)(CH2CH2-O-CH3), -CONH(cyclopropyl), -COOH, -COO(CH3), -CO(CH3), -CO(azetidinyl) or -CO(azetidinyl)-O-(CH3 The compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, which is substituted with ).

6. R １ ' is halogen, -CN, -O(C １～６ Alkyl) and -S (C １～６ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, selected from alkyl, and where n is 0 or 1.

7. The compound according to Claim 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein n is 0.

8. Cy １ teeth, 【Transformation 3】 Selected from, each of these is: -NH ２ -CN, halogen, C １～６ Alkyl, C １～６ Haloalkyl and -(C) １～６ It may be substituted with one or more groups independently selected from alkyl)-OH, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer thereof.

9. Cy 1 is, 【Chemistry 4】 These may be substituted with one or more groups independently selected from -NH2 and C1-6 alkyl groups; Or Cy 1 is, 【Transformation 5】 These may be substituted with one or more groups independently selected from C1-6 alkyl groups; Or Cy 1 is, 【Transformation 6】 These may be substituted with one or more groups independently selected from: -NH₂, C1-6 alkyl, and -(C1-6 alkyl)-OH; Or Cy 1 is, 【Transformation 7】 The compounds described in claim 1, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof, which may be substituted with one or more groups independently selected from -NH2 and C1-6 alkyl groups.

10. Cy ２ These are phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl, each of which is: halogen, -CN, -OH, C １～６ Alkyl, C １～６ Haloalkyl, -O(C) １～６ Alkyl), -S (C １～６ Alkyl) and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-OH,-(C １～６ Alkyl)-O-(C １～６ Alkyl), -(C １～６ Alkyl)-CN and C ３～８ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, each independently selected from cycloalkyl groups.

11. The aforementioned compound is given by formula (II): 【Transformation 8】 A compound of the above formula (II), Z is CH ２ or O; R １ C ２～６ It is an alkynyl, and the C ２～６ Alkynnyls are: halogen, -CN, -OH, -NH ２ , C ３～８ Cycloalkyl, 4- to 8-membered heterocyclyl, -O(C) １～６ Alkyl), -O (C １～６ Haloalkyl), -O(C) ３～８ Cycloalkyl), -O (4- to 8-membered heterocyclyl), -S (C １～６ Alkyl), -S (C ３～８ Cycloalkyl), -S (4- to 8-membered heterocyclyl), -NH (C １～６ Alkyl), -N(C １～６ Alkyl) ２ , -NH-CN, -NHCONH ２ , - NHCO (C １～６ Alkyl), -CONR ａ R ｂ , -COOR ｃ and -COR ｄ It may be substituted by one or more groups independently selected from R ａ , R ｂ , R ｃ and R ｄ is hydrogen, C １～６ Alkyl, -(C １～６ Alkyl)-O-(C １～６ Alkyl), -(C １～６ Alkyl)-OH, C ３～８ A cycloalkyl group and a 4- to 8-membered heterocycline group are independently selected from each other; and the above C ３～８ Cycloalkyls and 4- to 8-membered heterocyclines are: C １～６ Alkyl and -O(C) １～６ Each of the alkyl groups may be substituted with one or more groups independently selected; R １ ' is halogen, -CN, -O(C １～６ Alkyl) and -S (C １～６ Selected from alkyl, and n is 0 or 1; R ２ is, -NH ２ And; R ９ and R １０ is hydrogen, -NH ２ , halogen, C １～６ Alkyl and C １～６ Each is independently selected from the haloalkyl groups; Cy ２ These are phenyl or 5- to 10-membered heteroaryl compounds, each of which is: halogen, -CN, -OH, C １～６ Alkyl, C １～６ Haloalkyl, -O(C) １～６ Alkyl), -S (C １～６ Alkyl) and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, -(C １～６ Alkyl)-OH,-(C １～６ Alkyl)-O-(C １～６ Alkyl) and C ３～８ Each is independently selected from cycloalkyl groups; and L does not exist. It is a compound, The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer thereof.

12. R1 is a C2-6 alkynyl, and the C2-6 alkynyl may be substituted with one or more groups independently selected from: -OH, -CONH2, -O(C1-6 alkyl), -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -CONH(C1-6 alkyl), and -CON(C1-6 alkyl)2; R1' is a halogen, and n is 0 or 1; R9 and R10 are independently selected from hydrogen and C1-6 alkyl groups, respectively. The compound described in claim 11, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.

13. The aforementioned compound is of formula (III): 【Chemistry 9】 A compound of the above formula (III), Z is CH ２ And; R １ C ２～６ It is an alkynyl, and the C ２～６ Alkynnyls are: halogen, -CN, -OH, -NH ２ , C ３～８ Cycloalkyl, 4- to 8-membered heterocyclyl, -O(C) １～６ Alkyl), -O (C １～６ Haloalkyl), -O(C) ３～８ Cycloalkyl), -O (4- to 8-membered heterocyclyl), -S (C １～６ Alkyl), -S (C ３～８ Cycloalkyl), -S (4- to 8-membered heterocyclyl), -NH (C １～６ Alkyl), -N(C １～６ Alkyl) ２ , -NH-CN, -NHCONH ２ , - NHCO (C １～６ Alkyl), -CONR ａ R ｂ , -COOR ｃ and -COR ｄ It may be substituted by one or more groups independently selected from R ａ , R ｂ , R ｃ and R ｄ is hydrogen, C １～６ Alkyl, -(C １～６ Alkyl)-O-(C １～６ Alkyl), -(C １～６ Alkyl)-OH, C ３～８ A cycloalkyl group and a 4- to 8-membered heterocycline group are independently selected from each other; and the above C ３～８ Cycloalkyls and 4- to 8-membered heterocyclines are: C １～６ Alkyl and -O(C) １～６ Each of the alkyl groups may be substituted with one or more groups independently selected; R １ ' is halogen, -CN, -O(C １～６ Alkyl) and -S (C １～６ Selected from alkyl, and n is 0 or 1; R ２ is, -NH ２ And; R １１ , R １２ and R １３ is hydrogen, -NH ２ ,-CN,C １～６ Alkyl and C １～６ Each is independently selected from the haloalkyl groups; Cy ２ These are phenyl or 5- to 10-membered heteroaryl compounds, each of which is: halogen, -CN, -OH, C １～６ Alkyl, C １～６ Haloalkyl, -O(C) １～６ Alkyl), -S (C １～６ Alkyl) and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, -(C １～６ Alkyl)-OH,-(C １～６ Alkyl)-O-(C １～６ Alkyl) and C ３～８ Each is independently selected from cycloalkyl groups; and L either does not exist, or L is a compound that is S. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer thereof.

14. R1 is a C2-6 alkynyl, and the C2-6 alkynyl may be substituted with one or more groups independently selected from: -OH, -CONH2, -O(C1-6 alkyl), -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -CONH(C1-6 alkyl), and -CON(C1-6 alkyl)2; R1' is a halogen, and n is 0 or 1; R11, R12, and R13 are independently selected from hydrogen and C1-6 alkyl groups; Cy2 is a phenyl or a 5- to 6-membered heteroaryl, each of which may be substituted with one or more groups independently selected from: halogen, -CN, -OH, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), -S(C1-6 alkyl) and -NR7 R8, where R7 and R8 are independently selected from hydrogen, -(C1-6 alkyl)-OH, -(C1-6 alkyl)-O-(C1-6 alkyl) and C3-8 cycloalkyl; and L is S. The compound described in claim 13, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.

15. The aforementioned compound is of formula (IV): 【Chemistry 10】 A compound of the above formula (IV), Z is CH ２ or O; R １ C ２～６ It is an alkynyl, and the C ２～６ Alkynnyls are: halogen, -CN, -OH, -NH ２ , C ３～８ Cycloalkyl, 4- to 8-membered heterocyclyl, -O(C) １～６ Alkyl), -O (C １～６ Haloalkyl), -O(C) ３～８ Cycloalkyl), -O (4- to 8-membered heterocyclyl), -S (C １～６ Alkyl), -S (C ３～８ Cycloalkyl), -S (4- to 8-membered heterocyclyl), -NH (C １～６ Alkyl), -N(C １～６ Alkyl) ２ , -NH-CN, -NHCONH ２ , - NHCO (C １～６ Alkyl), -CONR ａ R ｂ , -COOR ｃ and -COR ｄ It may be substituted by one or more groups independently selected from R ａ , R ｂ , R ｃ and R ｄ is hydrogen, C １～６ Alkyl, -(C １～６ Alkyl)-O-(C １～６ Alkyl), -(C １～６ Alkyl)-OH, C ３～８ The above C is independently selected from cycloalkyl and 4- to 8-membered heterocyclines; ３～８ Cycloalkyl and 4- to 8-membered heterocyclyls are: C １～６ Alkyl and -O(C) １～６ Each of the alkyl groups may be substituted with one or more groups independently selected; R １ ' is halogen, -O(C １～６ Alkyl) and -S (C １～６ Selected from alkyl, and n is 0 or 1; R ２ is, -NH ２ And; R １４ is hydrogen, -NH ２ and C １～６ Selected from alkyl groups; R １４ ' is C １～６ It is alkyl; Cy ２ These are phenyl or 5- to 10-membered heteroaryl compounds, each of which is: halogen, -CN, -OH, C １～６ Alkyl, C １～６ Haloalkyl, -O(C) １～６ Alkyl), -S (C １～６ Alkyl) and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, -(C １～６ Alkyl)-OH and -(C １～６ Alkyl)-O-(C １～６ Each is independently selected from alkyl; and L either does not exist, or L is a compound that is S. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer thereof.

16. The aforementioned compound is of formula (V): 【Chemistry 11】 A compound of the above formula (V), Z is CH ２ or O; R １ C ２～６ It is an alkynyl, and the C ２～６ Alkynnyls are: halogen, -CN, -OH, -NH ２ , C ３～８ Cycloalkyl, 4- to 8-membered heterocyclyl, -O(C) １～６ Alkyl), -O (C １～６ Haloalkyl), -O(C) ３～８ Cycloalkyl), -O (4- to 8-membered heterocyclyl), -S (C １～６ Alkyl), -S (C ３～８ Cycloalkyl), -S (4- to 8-membered heterocyclyl), -NH (C １～６ Alkyl), -N(C １～６ Alkyl) ２ , -NH-CN, -NHCONH ２ , - NHCO (C １～６ Alkyl), -CONR ａ R ｂ , -COOR ｃ and -COR ｄ It may be substituted by one or more groups independently selected from R ａ , R ｂ , R ｃ and R ｄ is hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, -(C) １～６ Alkyl)-O-(C １～６ Alkyl), -(C １～６ Alkyl)-OH,-(C １～６ Alkyl)-CN,C ３～８ The above C is independently selected from cycloalkyl and 4- to 8-membered heterocyclines; ３～８ Cycloalkyl and 4- to 8-membered heterocyclyls are: C １～６ Alkyl and -O(C) １～６ Each of the alkyl groups may be substituted with one or more groups independently selected; R １ ' is halogen, -O(C １～６ Alkyl) and -S (C １～６ Selected from alkyl, and n is 0 or 1; R ２ is, -NH ２ And; R １５ and R １５ ' is hydrogen, -NH ２ -CN, halogen, C １～６ Alkyl, C １～６ Haloalkyl and -(C) １～６ Each is independently selected from alkyl)-OH; Cy ２ These are phenyl or 5- to 10-membered heteroaryl compounds, each of which is: halogen, -CN, -OH, C １～６ Alkyl, C １～６ Haloalkyl, -O(C) １～６ Alkyl), -S (C １～６ Alkyl) and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, -(C １～６ Alkyl)-OH,-(C １～６ Alkyl)-O-(C １～６ Alkyl) and C ３～８ Each is independently selected from cycloalkyl groups; and L either does not exist, or L is a compound that is S. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer thereof.

17. R1 is a C2-6 alkynyl, and the C2-6 alkynyl is: -OH, -CONH2, -O(C1-6 alkyl), -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NHCONH2, -CONH(C1-6 alkyl), -CONH(C1-6 alkyl)-O-(C1-6 alkyl), -CON(C1-6 alkyl)2, -CON(C1-6 alkyl)(C1-6 alkyl-O-C1-6 alkyl), -CONH(C3-8 cycloalkyl), -COOH, -COO(C1-6 alkyl), -CO(C1-6 It may be substituted with one or more groups independently selected from alkyl), -CO (4- to 8-membered heterocycline) and -CO (4- to 8-membered heterocycline)-O-(C1-6 alkyl), The compound described in claim 16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.

18. R1 is ethynyl substituted with -CONH(CH3), -CONH(CH2CH3), or -CONH(CH2CH2)-O-(CH3); R1' is a halogen, and n is 0 or 1; R15 and R15' are independently selected from hydrogen, -NH2, C1-6 alkyl, and -(C1-6 alkyl)-OH, The compound described in claim 16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.

19. R15 and R15' are both hydrogen, The compound described in claim 16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.

20. Cy ２ These are phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolopyridyl, or 1,2,3,4-tetrahydro-1,5-naphthilidinyl, each of which is: halogen, -CN, -OH, C １～６ Alkyl, C １～６ Haloalkyl, -O(C) １～６ Alkyl), -S (C １～６ Alkyl) and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, -(C １～６ Alkyl)-OH,-(C １～６ Alkyl)-O-(C １～６ Alkyl) and C ３～８ Compounds according to any one of claims 1 to 13 and 15 to 19, each independently selected from cycloalkyl groups, or pharmaceutically acceptable salts thereof, or solvates, racemic mixtures, enantiomers, diastereomers or tautomers thereof.

21. Cy ２ teeth, 【Chemistry 12】 Selected from, each of these is: halogen, -CN, -OH, C １～６ Alkyl, C １～６ Haloalkyl, -O(C) １～６ Alkyl), -S (C １～６ Alkyl) and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, -(C １～６ Alkyl)-OH,-(C １～６ Alkyl)-O-(C １～６ Alkyl) and C ３～８ Each is independently selected from cycloalkyl groups. The compound described in claim 20, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.

22. Cy ２ teeth, 【Chemistry 13】 This is: halogen, -CN, -OH, C １～６ Alkyl, C １～６ Haloalkyl, -O(C) １～６ Alkyl) and -S (C １～６ It may be substituted with one or more groups independently selected from alkyl; Or, Cy ２ teeth, 【Chemistry 14】 And this is: halogen, C １～６ Alkyl, -O(C) １～６ Alkyl) and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, -(C １～６ Alkyl)-OH,-(C １～６ Alkyl)-O-(C １～６ Alkyl) and C ３～８ Each is independently selected from cycloalkyl groups; Or, Cy ２ teeth, 【Chemistry 15】 And this is: C １～６ Alkyl and -NR ７ R ８ It may be substituted by one or more groups independently selected from R ７ and R ８ is hydrogen, -(C １～６ Alkyl)-OH and -(C １～６ Alkyl)-O-(C １～６ Each of the alkyl elements is independently selected. The compound described in claim 21, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.

23. Both R7 and R8 are hydrogen, The compound described in claim 22, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.

24. The aforementioned compound, Table 1 Table 2 A compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, racemic mixture, enantiomer, diastereomer, or tautomer selected from the above.

25. A pharmaceutical composition comprising a compound and / or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 24, and optionally comprising a pharmaceutically acceptable excipient.

26. A method for in vitro inhibition of the activity of SHP2, the method comprising contacting SHP2 with an effective amount of a compound and / or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 24.

27. Use of a compound and / or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 in the manufacture of a pharmaceutical product for the treatment or prevention of a disease mediated by or at least partially mediated by SHP2.

28. A pharmaceutical composition for the treatment or prevention of a disease in a subject, comprising a compound and / or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 24, wherein the disease is mediated by or at least partially mediated by SHP2.

29. The pharmaceutical composition according to claim 28, wherein the disease is cancer, Noonan syndrome, or Leopard syndrome.

30. The pharmaceutical composition according to claim 29, wherein the cancer is a solid tumor or a hematological malignancy.

31. The cancer is breast cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, head and neck cancer, liver cancer, kidney cancer, ovarian cancer, cervical cancer, prostate cancer, endometrial cancer, thyroid cancer, sarcoma, adrenal cancer, acute myeloid leukemia (AML), juvenile acute myeloid leukemia, chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia The pharmaceutical composition according to claim 29, selected from B-ALL, acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), large B-cell lymphoma (LBCL), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, and myeloma.

32. A pharmaceutical combination comprising a compound and / or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 and at least one additional therapeutic agent, wherein the additional therapeutic agent is selected from an antitumor agent, an anti-inflammatory agent, or an immunomodulator.

33. The combination drug according to claim 32, wherein the antitumor active agent is selected from a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

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