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CN-121991094-A - Novel heterocyclic compound

CN121991094ACN 121991094 ACN121991094 ACN 121991094ACN-121991094-A

Abstract

The present invention relates to a novel heterocyclic compound having FGFR protein activity. In particular, the present invention relates to a compound of formula (II), or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and its use in the manufacture of a medicament for the treatment of a disease associated with FGFR.

Inventors

  • LIU ZHIHUA
  • REN REN
  • CHEN KUNCHENG
  • YUAN BAOKUN
  • GAO XING
  • ZHANG KAI
  • CHEN XI

Assignees

  • 首药控股(北京)股份有限公司

Dates

Publication Date
20260508
Application Date
20251030
Priority Date
20241106

Claims (13)

  1. 1. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof: Wherein, the R is Or- (CO) -NH-R 10 , R 10 is C 1-6 alkyl, - (CH 2 ) 0-2 - (3-8 membered cycloalkyl), or- (CH 2 ) 0-2 - (3-8 membered heterocyclyl), said alkyl, cycloalkyl and heterocyclyl being optionally substituted by halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, halo C 2-6 alkenyl, or halo C 2-6 alkynyl, The C and D rings are each independently a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring, The ring A and the ring B are condensed, The A ring is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, The B ring is a benzene ring, a 5-6 membered heteroaromatic ring, a 5-6 membered carbocyclic ring, or a 5-6 membered heterocyclic ring, and the B ring is optionally substituted with halogen, -CN, -OH, -NH 2 、-O-C 1-6 alkyl, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, or 5-6 membered heteroaryl, R 2 and R 3 are each independently halogen, -CN, -OH, -NH 2 , or C 1-6 alkyl, R 4 、R 5 、R 6 and R 7 are each independently H, halogen, -CN, -0H, -NH 2 、-O-C 1-6 alkyl, or C 1-6 alkyl, R 8 and R 9 are each independently H, -OH, -NH 2 , or C 1-6 alkyl, or R 7 and R 8 may optionally be joined together to form a 6-10 membered ring, R 1 is Or alternatively P is 0,1, or 2, Q is 0,1, or 2.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R 4 、R 5 、R 6 and R 7 are each independently H, halogen, -CN, -OH, -NH 2 , or C 1-6 alkyl.
  3. 3. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R 10 is-CH 2 -CF 3 .
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, having a structure of formula (I): Wherein, the The C and D rings are each independently a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring, The ring A and the ring B are condensed, The A ring is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, The B ring is benzene ring, 5-6 membered heteroaromatic ring, 5-6 membered carbocycle, or 5-6 membered heterocycle, R 2 and R 3 are each independently halogen, -CN, -OH, -NH 2 , or C 1-6 alkyl, R 4 、R 5 、R 6 and R 7 are each independently H, halogen, -CN, -OH, -NH 2 , or C 1-6 alkyl, R 8 and R 9 are each independently H, -OH, -NH 2 , or C 1-6 alkyl, or R 7 and R 8 may optionally be joined together to form a 6-10 membered ring, R 1 is Or alternatively P is 0,1, or 2, Q is 0,1, or 2.
  5. 5. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein C-ring is a 5-6 membered heteroaryl ring and D-ring is a benzene ring.
  6. 6. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein ring a is a 5-6 membered heteroaryl ring and ring B is a benzene or pyridine ring.
  7. 7. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R 4 、R 5 、R 6 and R 7 are H and R 8 and R 9 are H.
  8. 8. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein p is 0 and q is 1.
  9. 9. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R 1 is
  10. 10. The following compounds or pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof
  11. 11. A pharmaceutical composition comprising a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.
  12. 12. Use of a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for treatment of a disease associated with FGFR.
  13. 13. The use of claim 12, wherein the FGFR-related disease is cholangiocarcinoma, urothelial carcinoma, lung cancer, bladder cancer, cervical cancer, endometrial cancer, breast cancer, thyroid cancer, intestinal cancer, gastric cancer, liver cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gall bladder cancer, leukemia, multiple myeloma, hodgkin's lymphoma, or melanoma.

Description

Novel heterocyclic compound Technical Field The invention relates to compounds for inhibiting FGFR protein activity, and also relates to a preparation method of the compounds and application of the compounds in pharmaceutical compositions thereof. Background Fibroblast growth factor receptors (fibroblast growth factor receptors, FGFR) belong to transmembrane polypeptide tyrosine kinases, 5 species (FGFR 1-FGFR 5) have been found in total, with FGFR2 being predominantly distributed in tissue originating from endoderm, such as stomach, liver, pancreas, esophagus, bile duct, etc. in the digestive system. Previous studies have shown that FGFR2 is associated with a variety of tumors, FGFR2 gene amplification has been reported in triple negative breast cancer and gastric cancer with poor prognosis, FGFR2 gene mutations have been found in endometrial, lung, gastric and urothelial cancers, and FGFR2 fusion proteins are present in lung adenocarcinoma, squamous cell carcinoma, thyroid, prostate and cholangiocarcinoma. In colorectal cancer FGFR2 can up-regulate apoptosis-ligand 1 (programmed CELL DEATH LIGAND, pd-L1) expression via the JAK/STAT3 pathway, regulate tumor immune evasion, and FGFR2 expression levels are closely related to prognosis. FGFR2 gene fusion was found in 10-20% of intrahepatic cholangiocarcinoma patients. FGFR3 abnormalities include point mutations, fusions, amplifications and overexpression, which may be associated with a variety of tumors, found in about 15% -20% of advanced urothelial carcinomas, 15% of uterine sarcomas, 5% of endometrial carcinomas, and other solid tumors. With the intensive search of the tumorigenesis mechanism by scientists, the FGFR (fibroblast growth factor receptor) family has received extensive attention due to abnormal expression in a variety of tumors. In particular, FGFR2 and FGFR3, both of which find significant variations in many types of cancer, which are closely related to tumor growth, spread, and resistance to traditional therapies. Therefore, the development of drugs capable of effectively inhibiting FGFR2 and FGFR3 has become a serious clinical need. Although the first-generation pan-FGFR inhibitors have a certain curative effect clinically, side effects (hyperphosphatemia and tissue mineralization) caused by the inhibition of FGFR1 severely limit the safety window of the first-generation pan-FGFR inhibitors, so that the clinical application of the medicines is influenced. The invention aims to develop a new generation of small molecule FGFR2/3 inhibitors with oral administration, high activity and high selectivity. While significantly reducing the inhibition effect on FGFR1, while maintaining high activity on FGFR2 and FGFR3, it is expected to solve various drug resistance problems. Disclosure of Invention The invention provides an FGFR inhibitor which is a compound represented by a general formula (I) or pharmaceutically acceptable salt, solvate, polymorph or isomer thereof. The invention also provides a series of compounds represented by the general formula (I), pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, pharmaceutical compositions containing the compounds, and methods of treating diseases associated with FGFR using the compounds. In one aspect, the present invention provides a compound of formula (II): Wherein, the R isOr- (CO) -NH-R 10, R 10 is C 1-6 alkyl, - (CH 2)0-2 - (3-8 membered cycloalkyl), or- (CH 2)0-2 - (3-8 membered heterocyclyl), said alkyl, cycloalkyl and heterocyclyl being optionally substituted by halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, halo C 2-6 alkenyl, or halo C 2-6 alkynyl, The C and D rings are each independently a 6-10 membered aromatic ring or a 5-12 membered heteroaromatic ring, The ring A and the ring B are condensed, The A ring is a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring, The B ring is a benzene ring, a 5-6 membered heteroaromatic ring, a 5-6 membered carbocyclic ring, or a 5-6 membered heterocyclic ring, and the B ring is optionally substituted with halogen, -CN, -OH, -NH 2、-O-C1-6 alkyl, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, or 5-6 membered heteroaryl, R 2 and R 3 are each independently halogen, -CN, -OH, -NH 2, or C 1-6 alkyl, R 4、R5、R6 and R 7 are each independently H, halogen, -CN, -OH, -NH 2、-O-C1-6 alkyl, or C 1-6 alkyl, R 8 and R 9 are each independently H, -OH, -NH 2, or C 1-6 alkyl, or R 7 and R 8 may optionally be joined together to form a 6-10 membered ring, R 1 isOr alternatively P is 0,1, or 2, Q is 0,1, or 2. In some embodiments, R 4、R5、R6 and R 7 are each independently H, halogen, -CN, -OH, -NH 2, or C 1-6 alkyl. In some embodiments, R 10 is-CH 2-CF3. In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof: Wherein, the The C and D rings are each independently a 6-10 membered aromatic ring or a 5-12