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CN-122010929-A - Lactam structure CDK inhibitor compound

CN122010929ACN 122010929 ACN122010929 ACN 122010929ACN-122010929-A

Abstract

The invention relates to a compound shown in a formula (I), a pharmaceutical composition containing the compound, and application of the compound shown in the formula (I) in preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune mediated diseases.

Inventors

  • LIU SHUAISHUAI
  • WU PENG
  • FU XIANGYU
  • YU ZHIYONG
  • HE NANHAI

Assignees

  • 杭州阿诺生物医药科技有限公司

Dates

Publication Date
20260512
Application Date
20251111
Priority Date
20241111

Claims (20)

  1. 1. A compound of formula I, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof: Wherein: R 1 represents D, halogen, CN, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 2 alkoxy or 3-6 membered heterocycloalkyl; ar 1 represents a 5-membered heteroaryl group; Cy 1 represents a 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl or 5-8 membered heteroaryl; X 1 and X 2 are bridgehead atoms common to Ar 1 and Cy 1 , X 1 and X 2 each independently represent C or N, and the covalent bond between X 1 and X 2 may be a single bond or a double bond; R 2 each independently represents H, D, halogen 、CN、OR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 0, 1,2, 3, or 4R 22 ; R 3 each independently represents H, D, oxo, halogen 、CN、OR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 0, 1,2,3, or 4R 23 ; 2R 3 attached to the same C or 2R 3 attached to different atoms may form together with the atoms to which they are attached a 3-8 membered ring, which optionally may contain 0, 1,2, 3 heteroatoms selected from N, O or S, which ring may further comprise 0, 1,2 or 3 unsaturated bonds, which ring may further be substituted with 0, 1,2, 3 or 4R 30 ; Y 1 and Y 2 each independently represent CR 4 or N; R 4 each independently represents H, D, halogen, CN, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy optionally may be substituted by 0, 1,2, 3 or 4R 24 ; Each W independently represents CR 5 R 5 '、C(O)、NR 6 、O、S、S(O)、S(O) 2 or S (O) (NR 6 ); R 5 、R 5 ' each independently represents H, D, halogen 、CN、OR a 、SR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、-S(O) 2 R a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by 0,1, 2,3 or 4R 25 ; R 5 、R 5 ' attached to the same C may also form together with the C atom to which it is attached a 3-8 membered ring, which optionally may contain 0,1, 2, 3 heteroatoms selected from N, O or S, which ring may further comprise 0,1, 2 or 3 unsaturated bonds, which ring may further be substituted by 0,1, 2, 3 or 4R 30 ; r 5 and R 5 ' attached to different C atoms may together with the C atom to which they are attached form a 3-8 membered ring, which optionally may contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring may further comprise 0, 1, 2 or 3 unsaturated bonds, which ring may further be substituted with 0, 1, 2, 3 or 4R 30 ; R 6 each independently represents H, D, -S (O) 2 R a 、-S(O)R a 、-C(O)R a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by 0, 1,2, 3 or 4R 26 ; R 5 and R 6 together with the ring atoms to which they are attached may form a 3-8 membered ring, which optionally may contain 0, 1,2,3 heteroatoms selected from N, O or S, which ring may further comprise 0, 1,2 or 3 unsaturated bonds, which ring may further be substituted by 0, 1,2,3 or 4R 30 ; R 22 、R 23 、R 24 、R 25 、R 26 、R 30 each independently represents H, D, oxo, halogen 、CN、OR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、-S(O) 2 R a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl OR 4-8 membered heterocycloalkyl, which C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl optionally may be substituted with 0, 1,2, 3 OR 4 atoms selected from halogen, OR a 、NR a R a '、C 1 -C 2 alkyl OR halo C 1 -C 2 alkyl, two R 22 on the same atom OR different atoms, two R 23 on the same atom OR different atoms, two R 24 on the same atom OR different atoms, two R 25 on the same atom OR different atoms, OR two R 26 on the same atom OR different atoms, OR R 25 and R 26 may form a 3-6 membered ring with the C atom and/OR N atom to which they are attached, which ring may further contain 0, 1,2 OR 3 heteroatoms selected from N, O, S; R a and R a ' each independently represent H, D, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; m represents 0,1 or 2; n represents 0, 1,2, 3 or 4; o is 2,3, 4, 5 or 6.
  2. 2. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein Ar 1 represents pyrazolyl, imidazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, preferably Ar 1 represents pyrazolyl.
  3. 3. A compound as claimed in any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein V represents C (O) or S (O) 2 , preferably V represents C (O).
  4. 4. A compound as claimed in any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein Y 1 and Y 2 each independently represent CR 4 .
  5. 5. A compound as claimed in any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein m represents 0 or 1.
  6. 6. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, having the structure shown in formula II: Wherein: R 1 represents D, halogen, CN, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 2 alkoxy; Cy 1 represents a 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl or 5-8 membered heteroaryl; R 2 each independently represents H, D, halogen, CN, OR a 、NR a R a '、C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl, wherein said C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by 0, 1, 2 OR 3R 22 ; R 3 each independently represents H, D, oxo, halogen 、CN、OR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl optionally may be substituted with 0,1, 2, 3 or 4R 23 , 2R 3 attached to the same C or 2R 3 attached to different C atoms may form together with the atom to which they are attached a 3-8 membered ring, which optionally may contain 0,1, 2 heteroatoms selected from N, O or S, which ring may be further substituted with 0,1 or 2R 30 ; R 4 each independently represents H, D, halogen, CN, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy optionally may be substituted by 0,1, 2,3 or 4R 24 ; R 5 、R 5 ' each independently represents H, D, halogen 、CN、OR a 、SR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、-S(O) 2 R a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by 0,1, 2,3 or 4R 25 ; R 5 、R 5 ' attached to the same C may also form together with the C atom to which it is attached a 3-8 membered ring, which optionally may contain 0,1, 2, 3 heteroatoms selected from N, O or S, which ring may further comprise 0,1, 2 or 3 unsaturated bonds, which ring may further be substituted by 0,1, 2, 3 or 4R 30 ; r 5 and R 5 ' attached to different C atoms may together with the C atom to which they are attached form a 3-8 membered ring, which optionally may contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring may further comprise 0, 1, 2 or 3 unsaturated bonds, which ring may further be substituted with 0, 1, 2, 3 or 4R 30 ; R 6 each independently represents H, D, -S (O) 2 R a 、-S(O)R a 、-C(O)R a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by 0, 1,2, 3 or 4R 26 ; R 5 and R 6 together with the ring atoms to which they are attached may form a 3-8 membered ring, which optionally may contain 0, 1,2,3 heteroatoms selected from N, O or S, which ring may further comprise 0, 1,2 or 3 unsaturated bonds, which ring may further be substituted by 0, 1,2,3 or 4R 30 ; r 22 、R 23 、R 24 、R 25 、R 26 、R 30 each independently represents D, oxo, halogen 、CN、OR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、-S(O) 2 R a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl OR 4-8 membered heterocycloalkyl, which C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl optionally may be substituted with 0, 1,2, 3 OR 4 atoms selected from halogen, OR a 、NR a R a '、C 1 -C 2 alkyl OR halo C 1 -C 2 alkyl, two R 22 on the same atom OR different atoms, two R 23 on the same atom OR different atoms, two R 24 on the same atom OR different atoms, two R 25 on the same atom OR different atoms, OR R 26 on the same atom OR different atoms, OR R 25 and R 26 may form a 3-6 membered ring with the C atom and/OR N atom to which they are attached, which ring may further contain 0, 1,2 OR 3 heteroatoms selected from N, O, S; R a and R a ' each independently represent H, D, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl; n represents 0, 1,2, 3 or 4; o is 2,3, 4, 5 or 6.
  7. 7. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 1 represents D, halogen, CN, C 1 -C 2 alkyl, fluoro C 1 -C 2 alkyl, preferably R 1 represents F, cl, CN, methyl, trifluoromethyl.
  8. 8. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein Cy 1 represents a 4-8 membered heterocycloalkyl or a 5-8 membered heteroaryl.
  9. 9. The compound, OR a pre-isotopic derivative OR stereoisomer, OR a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R 2 each independently represents H, D, halogen, CN, OR a 、NR a R a '、C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl, wherein said C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by 0,1, 2 OR 3R 22 , preferably R 2 each independently represents H, D, halogen, CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl.
  10. 10. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 3 each independently represents H, D, oxo, halogen 、CN、OR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl optionally may be substituted by 0, 1, 2, 3 or 4R 23 , 2R 3 attached to the same C or 2R 3 attached to different atoms may together form a 3-8 membered ring, which optionally may contain 0, 1, 2, 3 heteroatoms selected from N, O or S, which ring may further comprise 0, 1, 2 or 3 unsaturated bonds, which ring may further be substituted by 0, 1, 2, 3 or 4R 30 .
  11. 11. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein 2R 3 attached to the same C or 2R 3 attached to different atoms may form together with the atom to which they are attached a 3-8 membered ring, which optionally may contain 0, 1, 2 heteroatoms selected from N, O or S, which ring may be further substituted with 0, 1 or 2R 30 .
  12. 12. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 4 represents H, D, halogen, CN, C 1 -C 6 alkyl, or R 4 represents H, D, halogen, CN, methyl, methoxy, hydroxymethyl or methoxymethyl, preferably R 4 represents H, D, halogen, CN, methyl.
  13. 13. A compound as claimed in any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein W each independently represents CR 5 R 5 '、C(O)、NR 6 , O or S (O) 2 , preferably W each independently represents CR 5 R 5 '、NR 6 , O.
  14. 14. The compound according to any one of the preceding claims, OR a pre-isotopic derivative OR stereoisomer, OR a pharmaceutically acceptable salt thereof, wherein R 5 、R 5 'each independently represents H, halogen, CN, OR a 、SR a 、NR a R a '、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl OR 4-8 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl optionally may be substituted with 0,1, 2 OR 3R 25 , R 5 、R 5 ' attached to the same C may also form together with the C atom attached thereto a 3-8 membered ring optionally containing 0,1, 2,3 heteroatoms selected from N, O OR S, said ring may further comprise 0,1, 2 OR 3 unsaturated bonds, said ring may further be substituted with 0,1, 2,3 OR 4R 30 , R 5 attached to different C atoms may together with the C atom attached thereto form a 3-8 membered ring, said ring may optionally contain 3 heteroatoms selected from 3, 1,2 OR 3 further substituents selected from the group consisting of 0,1, 2 OR 3 substituents, said ring may further comprise 0,1, 2,3 OR 3 substituents, preferably 3 substituents selected from the group consisting of methyl, 3825, 3 OR 3 substituents, each further comprising 0, 3 substituents, 3 OR 25 .
  15. 15. A compound as claimed in any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 5 、R 5 ' attached to the same C may form, with the C atom to which it is attached, a C 3 -C 6 aliphatic ring or a 4-8 membered heterocyclic ring, which C 3 -C 6 aliphatic ring, 4-8 membered heterocyclic ring may be substituted by 0, 1,2 or 3R 30 , preferably R 30 each independently represents halogen or methyl.
  16. 16. The compound, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R 6 each independently represents H, -S (O) 2 R a 、-C(O)R a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-8 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by 0, 1, 2, or 3R 26 , preferably R 26 each independently represents halogen or methyl, more preferably R 6 each independently represents H or C 1 -C 6 alkyl.
  17. 17. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 5 ' or R 5 and R 6 , which are attached at different atoms, may form together with the atoms on the ring a C 3 -C 6 aliphatic ring or a 4-8 membered heterocyclic ring, which C 3 -C 6 aliphatic ring, 4-8 membered heterocyclic ring may be substituted by 0,1, 2 or 3R 30 .
  18. 18. A compound according to any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 5 ' or R 5 and R 6 attached at different atoms may form together with the atoms on the ring a 3-8 membered ring comprising an unsaturated bond, preferably a 5-6 membered heteroaromatic ring, which 5-6 membered heteroaromatic ring may be substituted by 0, 1, 2 or 3R 30 .
  19. 19. The compound of any of the preceding claims, OR a pre-isotopic derivative OR stereoisomer, OR a pharmaceutically acceptable salt thereof, wherein R 22 、R 23 、R 24 、R 25 、R 26 、R 30 each independently represents H, D, oxo, halogen 、CN、OR a 、NR a R a '、N(R a )COR a '、CON(R a )R a '、COR a 、-S(O) 2 R a 、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl OR 4-8 membered heterocycloalkyl, which C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl optionally may be substituted with 0,1, 2, 3 OR 4 groups selected from halogen, OR a 、NR a R a '、C 1 -C 2 alkyl OR halo C 1 -C 2 alkyl, preferably R 22 、R 23 、R 24 、R 25 、R 26 、R 30 each independently represents H, oxo, halogen, CN, OR a 、NR a R a '、C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl OR 4-8 membered heterocycloalkyl, which C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-8 membered heterocycloalkyl optionally may be substituted with 0,1, 2 OR 3 groups selected from halogen, OH, C 1 -C 2 alkyl, more preferably R 22 、R 23 、R 24 、R 25 、R 26 、R 30 each independently is selected from H, oxo, F, cl, CN, OR a 、NR a R a '.
  20. 20. A compound as claimed in any one of the preceding claims, or a pre-isotopic derivative or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R a and R a ' each independently represent H, D or C 1 -C 3 alkyl.

Description

Lactam structure CDK inhibitor compound Technical Field The present invention relates to a compound, in particular to a high activity CDK inhibitor containing a lactam structure and use thereof. Background Cyclin-dependent kinases (CDKs) are a class of serine (Ser)/threonine (Thr) kinases that can be divided into two broad classes, cell cycle related (e.g., CDK 1/2/4/6) and cell transcription related (e.g., CDK 7/9/12). The most studied at present are CDK4 and CDK6, which play a key regulatory role in the cell division cycle, and are capable of forming a CDK-cyclin complex with cyclin D (cyclin D), involved in cell growth, proliferation, dormancy or apoptosis. CDK4/6-cyclin D is a critical pathway for the passage of the cell cycle from the G1 phase to the S phase, and when overexpressed, results in an uncontrolled cell division cycle and thus in cancer. As represented by the global first CDK4/6 selective inhibitor, palbociclib, by the company Consumer, a number of CDK4/6 selective inhibitors have been approved for the treatment of HR+/HER 2-breast cancer. Although CDK4/6 inhibitors have met with great success, they still present significant side effects in the clinic, particularly myelosuppressive toxicity. CDK6 has been shown to be a key factor in hematopoietic stem cell activation, whereas CDK4 has less effect on the hematopoietic system. Further studies indicate that CDK4 is more highly expressed in tumors, whereas CDK6 is weaker, CDK4 being probably the more important oncogenic factor in breast cancer. Thus, reducing the inhibition of CDK6 while maintaining CDK4 activity would be beneficial to CDK inhibitors in reducing clinical toxicity. CDK2 is another important cell cycle regulatory factor capable of binding to cyclin E or a and playing a role in the progression of G1 into S phase and maintenance of S phase, respectively. When CDK4/6 is inhibited, CDK2-cyclin E is activated, compensating for CDK4/6 function, possibly one of the main causes of CDK4/6 inhibitor resistance. In conclusion, the therapeutic effect and safety of the existing CDK4/6 inhibitor are further improved by optimizing the selectivity, and the method has important social significance. Disclosure of Invention The present invention provides a novel class of CDK inhibitors. The structure is different from the existing CDK4/6 double-target inhibitor, but has optimized activity and selectivity, thereby achieving the purposes of improving the anti-tumor drug effect and reducing the toxic and side effects. Compared with the prior art, the method has great improvement. In one aspect, the invention provides a compound of formula I, an isotopic derivative or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Wherein: R 1 represents D, halogen, CN, C 1-C3 alkyl, halogenated C 1-C3 alkyl, C 3-C6 cycloalkyl, C 1-C2 alkoxy or 3-6 membered heterocycloalkyl; ar 1 represents a 5-membered heteroaryl group; Cy 1 represents a 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl or 5-8 membered heteroaryl; X 1 and X 2 are bridgehead atoms common to Ar 1 and Cy 1, X 1 and X 2 each independently represent C or N, and the covalent bond between X 1 and X 2 may be a single bond or a double bond; R 2 each independently represents H, D, halogen 、CN、ORa、NRaRa'、N(Ra)CORa'、CON(Ra)Ra'、CORa、C1-C6 alkyl, C 3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C 1-C6 alkyl, C 3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 0, 1,2, 3, or 4R 22; R 3 each independently represents H, D, oxo, halogen 、CN、ORa、NRaRa'、N(Ra)CORa'、CON(Ra)Ra'、CORa、C1-C6 alkyl, C 3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said C 1-C6 alkyl, C 3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl is optionally substituted with 0, 1,2,3, or 4R 23; 2R 3 attached to the same C or 2R 3 attached to different atoms may form together with the atoms to which they are attached a 3-8 membered ring, which optionally may contain 0, 1,2, 3 heteroatoms selected from N, O or S, which ring may further comprise 0, 1,2 or 3 unsaturated bonds, which ring may further be substituted with 0, 1,2, 3 or 4R 30; Y 1 and Y 2 each independently represent CR 4 or N; R 4 each independently represents H, D, halogen, CN, C 1-C6 alkyl or C 1-C6 alkoxy, wherein the C 1-C6 alkyl, C 1-C6 alkoxy is optionally substituted with 0,1, 2, 3 or 4R 24; V represents C (O), S (O) 2 or S (O) (NR 6); W each independently represents CR 5R5'、C(O)、NR6、O、S、S(O)、S(O)2 or S (O) (NR 6);R5、R5' each independently represents H, D, halogen 、CN、ORa、SRa、NRaRa'、N(Ra)CORa'、CON(Ra)Ra'、CORa、-S(O)2Ra、C1-C6 alkyl, C 3-C6 cycloalkyl, or 4-8 membered heterocycloalkyl, wherein said C 1-C6 alkyl, C 3-C6 cycloalkyl, 4-8 membered heterocycloalkyl is optionally substituted by 0, 1, 2, 3, or 4R 25; R 5、R5' attached to the same C may also form together with the C ato