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JP-7856666-B2 - Tricyclic compounds and their uses

JP7856666B2JP 7856666 B2JP7856666 B2JP 7856666B2JP-7856666-B2

Inventors

  • タイ、コアンシウ
  • シアオ、クン
  • デン、ウェイ

Assignees

  • ハチメド リミテッド

Dates

Publication Date
20260511
Application Date
20220128
Priority Date
20210205

Claims (20)

  1. Equation (I): A compound of the above formula (I), Ring A is a benzene ring ; Z is CH₂ or O ; R1 is a C2-6 alkynyl, and the C2-6 alkynyl may be substituted with one or more groups independently selected from : halogen, -CN, -OH, -NH2 , C3-8 cycloalkyl, 4- to 8-membered heterocyclyl, -O( C1-6 alkyl), -O( C1-6 haloalkyl), -O( C3-8 cycloalkyl), -O(4- to 8-membered heterocyclyl), -S( C1-6 alkyl), -S( C3-8 cycloalkyl), -S(4- to 8-membered heterocyclyl), -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , -NH-CN, -NHCONH2 , -NHCO( C1-6 alkyl), -CONR a R b , -COOR c and -COR d , and R a , R b , R c and R d is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -( C1-6 alkyl)-O-(C1-6 alkyl), -( C1-6 alkyl)-OH, -( C1-6 alkyl)-CN, C3-8 cycloalkyl and 4-8 membered heterocyclyl ; the above C3-8 cycloalkyl and 4-8 membered heterocyclyl are : halogen, -CN, -CONH2 , -OH, oxo, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -( C1-6 alkyl)-OH, -( C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-CN, -O( C1-6 alkyl), -O (C1-6 haloalkyl ), -S(C Each of these groups may be substituted with one or more groups independently selected from 1-6 alkyl, -NH( C1-6 alkyl), and -N( C1-6 alkyl) 2 ; R1 ' is independently selected from halogens, -CN, -CONH2 , -OH, -NH2 , C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, 4- to 8-membered heterocyclil, -( C1-6 alkyl)-OH, -(C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-CN, -O( C1-6 alkyl), -O( C1-6 haloalkyl), -O( C3-8 cycloalkyl), -O(4- to 8-membered heterocyclil), -S( C1-6 alkyl), -NH( C1-6 alkyl), and -N( C1-6 alkyl) 2 , wherein the C3-8 cycloalkyl and 4- to 8-membered heterocyclil may each be substituted with one or more halogens; n is 0, 1, 2, or 3; R2 is -NH2 , C y 1 is, Selected from , each of these may be substituted with one or more groups independently selected from : -NH₂ , -CN, halogen, C1-6 alkyl , C1-6 haloalkyl , and -( C1-6 alkyl)-OH . C y 2 is a phenyl or a 5- to 14-membered heteroaryl, each of which may be substituted with one or more groups independently selected from: halogen, -CN, -CONH 2 , -OH, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -( C1-6 alkyl)-OH, -( C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-CN, -O( C1-6 alkyl), -O( C1-6 haloalkyl), -O(C3-8 cycloalkyl), -O(4- to 8-membered heterocyclyl), -S( C1-6 alkyl), -NR 7 R 8 , -NHCO( C1-6 alkyl), -CONH( C1-6 alkyl) and CON( C1-6 alkyl) 2 , and R 7 and R8 are independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -( C1-6 alkyl)-OH, -(C1-6 alkyl)-O-(C1-6 alkyl ), -( C1-6 alkyl)-CN, C3-8 cycloalkyl, phenyl, 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; and L is either absent 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. R1 is a C2-6 alkynyl, and the C2-6 alkynyl may be substituted with one or more groups independently selected from : halogen, -CN, -OH, -NH2 , C3-8 cycloalkyl, 4-8 membered heterocyclyl, -O( C1-6 alkyl), -O( C1-6 haloalkyl), -O(C3-8 cycloalkyl), -O( 4-8 membered heterocyclyl), -S( C1-6 alkyl), -S( C3-8 cycloalkyl), -S(4-8 membered heterocyclyl), -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , -NHCONH2 , -NHCO( C1-6 alkyl), -CONR a R b , -COOR c and -COR d , where R a , R b , R c and R d are hydrogen, C Each of the following is independently selected from 1-6 alkyl groups, -( C1-6 alkyl)-O-( C1-6 alkyl groups), -( C1-6 alkyl)-OH groups, C3-8 cycloalkyl groups, and 4-8 membered heterocyclines ; and each of the above C3-8 cycloalkyl groups and 4-8 membered heterocyclines may be substituted with one or more groups independently selected from: halogen, -CN , -CONH2, -OH, oxo, -NH2 , C1-6 alkyl groups, and -O( C1-6 alkyl groups), the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer or tautomer thereof.
  4. R1 is a C2-6 alkynyl, and the C2-6 alkynyls are: -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 alkyl), -CO( 4- to 8 -membered heterocyclyl), and -CO(4- to 8-membered heterocyclyl)-O-(C 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 1 to 6 alkyl groups.
  5. R 1 These are ethynyl, propynyl, or butynyl, each of which is unsubstituted or -OH, -CONH 2 , -OCH 3 ,-NH(CH 3 ), -N(CH 3 ) 2 , -NHCONH 2 , -CONH(C 1-3 Alkyl), -CONH(CH 2 CH 2 )-O-(CH 3 ), -CON(CH 3 ) 2 , -CON(CH 3 ) (CH 2 CH 2 -O-CH 3 ), -CONH(cyclopropyl), -COOH, -COO(CH 3 ), -CO(CH 3 ), -CO (azetidinyl) or -CO (azetidinyl)-O-(CH 3 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. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer or tautomer thereof, wherein R1 ' is selected from halogen, -CN, -O ( C1-6 alkyl), and -S ( C1-6 alkyl), and n is 0 or 1.
  7. n is 0, the compound or a pharmaceutically acceptable salt thereof according to claim 1, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof.
  8. C y 1 is, Selected from, each of these may be substituted with one or more groups independently selected from: -NH₂ , -CN, halogen, C1-6 alkyl, C1-6 haloalkyl and -( C1-6 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 teeth, These are: -NH 2 and C 1-6 It may be substituted with one or more groups independently selected from alkyl groups; or Cy 1 teeth, These are C 1-6 It may be substituted with one or more groups independently selected from alkyl groups; or Cy 1 teeth, These are: -NH 2 , C 1-6 Alkyl and -(C 1-6 It may be substituted with one or more groups independently selected from alkyl)-OH; or Cy 1 teeth, These are: -NH 2 and 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 be substituted with one or more groups independently selected from alkyl.
  10. Cy2 is a phenyl , a 5- to 6-membered heteroaryl, or a 9- to 10-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, C1-6 haloalkyl, -( C1-6 alkyl)-OH, -( C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-CN, and C3-8 cycloalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.
  11. The aforementioned compound is given by formula (II): A compound of the above formula (II), Z is CH₂ or O ; R1 is a C2-6 alkynyl, and the C2-6 alkynyl may be substituted with one or more groups independently selected from : halogen, -CN, -OH, -NH2 , C3-8 cycloalkyl, 4-8 membered heterocyclyl, -O( C1-6 alkyl), -O( C1-6 haloalkyl), -O(C3-8 cycloalkyl), -O( 4-8 membered heterocyclyl), -S( C1-6 alkyl), -S( C3-8 cycloalkyl), -S(4-8 membered heterocyclyl), -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , -NH-CN, -NHCONH2 , -NHCO( C1-6 alkyl), -CONR a R b , -COOR c and -COR d , and R a , R b , R c and R d is independently selected from hydrogen, C1-6 alkyl, -( C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-OH, C3-8 cycloalkyl and 4-8 membered heterocyclines ; and the above C3-8 cycloalkyl and 4-8 membered heterocyclines may each be substituted with one or more groups independently selected from C1-6 alkyl and -O( C1-6 alkyl) ; R1 ' is selected from halogen, -CN, -O ( C1-6 alkyl), and -S ( C1-6 alkyl), and n is 0 or 1 ; R2 is -NH2 ; R9 and R10 are independently selected from hydrogen, -NH2 , halogens, C1-6 alkyls, and C1-6 haloalkyls ; C y 2 is phenyl or 5-membered to 10-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 -NR 7 R 8 , where R 7 and R 8 are independently selected from hydrogen, -( C1-6 alkyl)-OH, -( C1-6 alkyl)-O-( C1-6 alkyl) and C3-8 cycloalkyl ; and L is absent. 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. R 1 is 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 , -CONH(C 1-6 Alkyl) and -CON(C 1-6 Alkyl) 2 It may be substituted by one or more groups independently selected from; R 1 ' is a halogen, and n is 0 or 1; R 9 and R 10 is hydrogen and C 1-6 Each alkyl group is independently selected. 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): A compound of the above formula (III), Z is CH 2 ; R1 is a C2-6 alkynyl, and the C2-6 alkynyl may be substituted with one or more groups independently selected from : halogen, -CN, -OH, -NH2 , C3-8 cycloalkyl, 4-8 membered heterocyclyl, -O( C1-6 alkyl), -O( C1-6 haloalkyl), -O(C3-8 cycloalkyl), -O( 4-8 membered heterocyclyl), -S( C1-6 alkyl), -S( C3-8 cycloalkyl), -S(4-8 membered heterocyclyl), -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , -NH-CN, -NHCONH2 , -NHCO( C1-6 alkyl), -CONR a R b , -COOR c and -COR d , and R a , R b , R c and R d is independently selected from hydrogen, C1-6 alkyl, -( C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-OH, C3-8 cycloalkyl and 4-8 membered heterocyclines ; and the above C3-8 cycloalkyl and 4-8 membered heterocyclines may each be substituted with one or more groups independently selected from C1-6 alkyl and -O( C1-6 alkyl) ; R1 ' is selected from halogen, -CN, -O ( C1-6 alkyl), and -S ( C1-6 alkyl), and n is 0 or 1 ; R2 is -NH2 ; R11 , R12 , and R13 are independently selected from hydrogen, -NH2 , -CN, C1-6 alkyl, and C1-6 haloalkyl ; C y 2 is phenyl or 5- to 10-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 -NR 7 R 8 , where R 7 and R 8 are independently selected from hydrogen, -( C1-6 alkyl)-OH, -( C1-6 alkyl)-O-( C1-6 alkyl) and C3-8 cycloalkyl; and L is absent or L is S, in the compound. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer thereof.
  14. 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 , -CONH(C 1-6 Alkyl) and -CON(C 1-6 Alkyl) 2 It may be substituted by one or more groups independently selected from; R 1 ' is a halogen, and n is 0 or 1; R 11 , R 12 and R 13 is hydrogen and C 1-6 Each alkyl group is independently selected; Cy 2 These are phenyl or 5- to 6-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 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): A compound of the above formula (IV), Z is CH₂ or O ; R1 is a C2-6 alkynyl, and the C2-6 alkynyl may be substituted with one or more groups independently selected from: halogen, -CN, -OH, -NH2 , C3-8 cycloalkyl, 4-8 membered heterocyclyl, -O( C1-6 alkyl), -O( C1-6 haloalkyl), -O(C3-8 cycloalkyl), -O( 4-8 membered heterocyclyl), -S( C1-6 alkyl), -S( C3-8 cycloalkyl), -S(4-8 membered heterocyclyl), -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , -NH-CN, -NHCONH2 , -NHCO( C1-6 alkyl), -CONR a R b , -COOR c and -COR d , and R a , R b , R c and R d is independently selected from hydrogen, C1-6 alkyl, -( C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-OH, C3-8 cycloalkyl and 4-8 membered heterocyclines; the above C3-8 cycloalkyl and 4-8 membered heterocyclines may each be substituted with one or more groups independently selected from C1-6 alkyl and -O( C1-6 alkyl) ; R1 ' is selected from halogen, -O ( C1-6 alkyl), and -S ( C1-6 alkyl), and n is 0 or 1 ; R2 is -NH2 ; R 14 is selected from hydrogen, -NH2 , and C1-6 alkyl groups ; R14 ' is a C1-6 alkyl group; Cy2 is a phenyl or a 5- to 10-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 and -( C1-6 alkyl)-O-( C1-6 alkyl); and L is absent or L is S in the compound. 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): A compound of the above formula (V), Z is CH₂ or O ; R1 is a C2-6 alkynyl, and the C2-6 alkynyl may be substituted with one or more groups independently selected from: halogen, -CN, -OH, -NH2 , C3-8 cycloalkyl, 4-8 membered heterocyclyl, -O( C1-6 alkyl), -O( C1-6 haloalkyl), -O(C3-8 cycloalkyl), -O( 4-8 membered heterocyclyl), -S( C1-6 alkyl), -S( C3-8 cycloalkyl), -S(4-8 membered heterocyclyl), -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , -NH-CN, -NHCONH2 , -NHCO( C1-6 alkyl), -CONR a R b , -COOR c and -COR d , and R a , R b , R c and R d is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -( C1-6 alkyl)-O-(C1-6 alkyl), -( C1-6 alkyl)-OH, - (C1-6 alkyl)-CN, C3-8 cycloalkyl and 4-8 membered heterocyclils; the above C3-8 cycloalkyl and 4-8 membered heterocyclils may each be substituted with one or more groups independently selected from C1-6 alkyl and -O( C1-6 alkyl) ; R1 ' is selected from halogen, -O ( C1-6 alkyl), and -S ( C1-6 alkyl), and n is 0 or 1 ; R2 is -NH2 ; R15 and R15 ' are independently selected from hydrogen, -NH2 , -CN, halogen, C1-6 alkyl, C1-6 haloalkyl, and -( C1-6 alkyl)-OH ; C y 2 is a phenyl or a 5- to 10-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 -NR 7 R 8 , where R 7 and R 8 are independently selected from hydrogen, -( C1-6 alkyl)-OH, -( C1-6 alkyl)-O-( C1-6 alkyl) and C3-8 cycloalkyl; and L is absent or L is S in the compound. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer thereof.
  17. 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 Alky), -CO(C 1-6 Alkyl), -CO (4- to 8-membered heterocyclyl) and -CO (4- to 8-membered heterocyclyl)-O-(C 1-6 It may be substituted with one or more groups independently selected from alkyl groups. The compound described in claim 16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.
  18. R 1 is -CONH(CH 3 ), -CONH(CH 2 CH 3 ) or -CONH(CH 2 CH 2 )-O-(CH 3 It is an ethynyl substituted with; R 1 ' is a halogen, and n is 0 or 1; R 15 and R 15 ' is hydrogen, -NH 2 , C 1-6 Alkyl and -(C 1-6 Each of the alkyl)-OH groups is independently selected. The compound described in claim 16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.
  19. R 15 and R 15 Both are hydrogen. The compound described in claim 16, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture thereof, enantiomer, diastereomer, or tautomer.
  20. Cy2 is phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolopyridyl or 1,2,3,4-tetrahydro-1,5-naphthilidinyl, 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, the compound according to any one of claims 1 to 13 and 15 to 19 , or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof.

Description

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. 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 (PTPs). SHP1 is primarily expressed in hematopoietic cells and some epithelial cells and is mainly 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 regulation and the transmission of numerous 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. 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. SHP2 is closely associated with tumors and is an attractive target for antitumor drugs. Currently, several selective SHP2 inhibitors, such as TNO155 (Novartis), RMC-4630 (Revolution Medicines/Sanofi), JAB-3068 (Jacobio), and RLY-1971 (Relay Therapeutics), are in clinical trials; however, SHP2 inhibitors are not yet approved for commercial use. Therefore, SHP2 inhibitors are attractive candidates for the development of treatments for related diseases, particularly cancer, Noonan syndrome, and Leopard syndrome. This invention relates to formula (I): 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 selected from C2-6 alkynyl, -NR3 , R4 , -SR5 , and -SR6 , where the C2-6 alkynyl is: halogen, -CN, -OH, -NH2, C3-8 cycloalkyl, 4-8 membered heterocyclyl, -O( C1-6 alkyl), -O(C1-6 haloalkyl), -O( C3-8 cycloalkyl), -O(4-8 membered heterocyclyl), -S( C1-6 alkyl), -S( C3-8 cycloalkyl), -S(4-8 membered heterocyclyl), -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , -NH-CN, -NHCONH2 , -NHCO( C1-6 alkyl), -CONR a, R b , -COOR c , and -COR R a , R b , R c and R d are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-OH, -( C1-6 alkyl)-CN, C3-8 cycloalkyl and 4-8 membered heterocyclyl; R 3 is each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -( C1-6 alkyl)-OH, -( C1-6 alkyl)-O-( C1-6 alkyl) and -( C1-6 alkyl)-CN; R 4 and R 5 are each independently selected from C3-8 cycloalkyl , phenyl, 4-8 membered heterocyclyl and 5-12 membered heteroaryl; R 6 is selected from -CO ( C1-6 alkyl), -CO ( C3-8 cycloalkyl), -CO (4- to 8-membered heterocycline), -CONH2 , -CONH ( C1-6 alkyl), -CONH ( C3-8 cycloalkyl), -CONH (4- to 8-membered heterocycline), -CON ( C1-6 alkyl) 2 , -( C1-6 alkyl)-O-( C1-6 alkyl), -( C1-6 alkyl)-OH, -(C1-6 alkyl)-NH ( C1-6 alkyl), -( C1-6 alkyl)-N ( C1-6 alkyl) 2 and -( C1-6 alkyl)-NHCO ( C1-6 alkyl); the C1-6 alkyl of R6 may be substituted with one or more groups independently selected from halogen, -CN, -OH and -O ( C1-6 alkyl); the above C 3- to 8 -cycloalkyl, phenyl, 4- to 8-membered heterocyclyl and 5- to 12-membered heteroaryl may each be substituted with one or more groups independently selected from: halogen, -CN, -CONH2 , -OH, oxo, -NH2 , C1- to 6- alkyl , C2- to 6 -alkenyl, C2- to 6- alkynyl, C1- to 6 - haloalkyl, -(C1- to 6-alkyl)-OH, -(C1- to 6 -alkyl)-O-(C1- to 6 -alkyl), -(C1- to 6-alkyl)-CN, -O(C1- to 6- alkyl), -O( C1- to 6-haloalkyl), -S(C1- to 6- alkyl), -NH(C1- to 6-alkyl), and -N(C1- to 6 -alkyl) 2 ; R1 ' is independently selected from halogens, -C