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US-20260125359-A1 - HETEROARYL COMPOUNDS AS MULTI-TARGET PROTEIN KINASE INHIBITORS

US20260125359A1US 20260125359 A1US20260125359 A1US 20260125359A1US-20260125359-A1

Abstract

The present disclosure provides compounds of formula (I) having receptor protein tyrosine kinase activity, and a pharmaceutically acceptable salt, stereoisomers, isotopic isomers thereof. The compounds of the present disclosure have high biological activity and can be used to treat diseases or disorders related to the target.

Inventors

  • Ruyong Wang
  • Hongxue SUN
  • Yuxuan ZHANG
  • Lili Qiu
  • Junqing Li
  • Guangming Chen
  • Xinshan Kang
  • Fengsen ZHANG
  • Xin Lian
  • Hengdong LI
  • Xuan Gong
  • Daqiang Lin
  • Zhipeng Zheng
  • Xin Chen
  • Xueyin WU

Assignees

  • FUJIAN HAIXI PHARMACEUTICALS CO., LTD.

Dates

Publication Date
20260507
Application Date
20251226
Priority Date
20231230

Claims (20)

  1. 1 - 29 . (canceled)
  2. 30 . A compound or a pharmaceutically acceptable salt of formula (I) or a stereoisomer or an isotopic isomer thereof, wherein, X 1 represents (CR L R L′ ) m ; wherein, X 2 represents (CR T R T′ ) n ; wherein, W 1 independently represents N; wherein, W 2 independently represents CR W2 or N; wherein, W 3 independently represents CR W3 or N; wherein, W 4 independently represents CR W4 or N; wherein, W 5 independently represents CR 1 or N; wherein, Y 1 independently represents CR Y1 ; wherein, Y 2 independently represents CR Y2 ; wherein, Y 3 independently represents CR Y3 ; wherein, each R W2 , R W3 , R W4 , R Y1 , R Y2 , R Y3 independently represents hydrogen, C 1 -C 6 alkyl, halogen, —OR a , —CN, —NR a R b , —CR a R b NR a R b , C 1 -C 6 haloalkyl; or W 1 and W 2 together with the atom which they are attached to form a 5-6 membered saturated or unsaturated ring fused to ring A, and the said ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from O, N, or S; or W 1 and W 4 together with the atom which they are attached to form a 5-6 membered saturated or unsaturated ring fused to ring A, and the said ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from O, N, or S; wherein, L 1 represents —O—, —NR a —; wherein, L 2 represents —NR a —, —NR a C(O)NR b —, —NR a C(O)—, or —C(O)NR a —; Wherein, R 1 represents hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogen, —OR a , —SR a , —P(O)R a R b , —CN, —S(O) 2 R a , —S(O)R a , —SF 5 , —NR a R b , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkylthio, hydroxy (C 1 -C 6 alkyl); or R 1 represents C 3 -C 10 cycloalkyl, C 6 -C 10 cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, which are substituted by 0-4 substituents that selected from deuterium, halogen, C 1 -C 6 alkyl, C 3 -C 6 heterocycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), NR a R b , —CR a R b NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; and when R 1 is a ring, any two adjacent substituents on the ring may combine to form a ring, and the said ring may optionally contain 0, 1 or 2 heteroatoms selected from O, N, or S; further, the said ring may optionally be substituted by halogen, hydroxy or C 1 -C 6 alkyl; or W 5 and W 2 together with the atom which they are attached to form a 5-6 membered saturated or unsaturated ring fused to ring A, and the said ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from O, N, or S; and further, the said ring may optionally substituted by 0, 1 or 2 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; wherein, R 2 represents C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, —CR a R b C 6 -C 10 aryl, —CR a R b (5-10 membered heteroaryl); which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, —OR a f, oxo, hydroxy (C 1 -C 6 alkyl), —NR a R b , —CR a R b NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 6 halocycloalkyl, C 3 -C 6 haloheterocycloalkyl, C 1 -C 6 alkyl-substituted C 3 -C 6 heterocycloalkyl, —SO 3 R a , —SR a , —S(O) 2 R a , —S(O)R a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; and when R 2 is a ring, any two adjacent substituents on the ring may combine to form a ring, and the said ring may optionally contain 0, 1 or 2 heteroatoms selected from O, N, or S; and further, the said ring may optionally be substituted by halogen, hydroxy or C 1 -C 6 alkyl; wherein, R 3 represents hydrogen, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or hydroxy; or R 3 and W 3 together with the atom which they are attached to form a 5-7 membered saturated or unsaturated ring fused to ring A, and the said ring may optionally contain 0, 1 or 2 heteroatoms selected from O, N, or S; and further, the said ring may optionally be substituted by 0, 1 or 2 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; wherein, each R a and R b independently represents hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy (C 1 -C 6 alkyl), (CH 3 ) 2 N—(C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl; or R a and R b together with the carbon atom which they are attached to form a 3-6 membered ring, and the said ring may optionally contain 0, 1 or 2 heteroatoms selected from O, N, or S; and further, the said ring may optionally be substituted by halogen, hydroxy or C 1 -C 6 alkyl; wherein, each R L and R L′ independently represents hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy (C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl; wherein, each R T and R T′ independently represents hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy (C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl; wherein, o, m, n represents the integer of 1, 2 or 3.
  3. 31 . The compound or the pharmaceutically acceptable salt according to claim 30 , or the stereoisomer or isotopic isomer thereof, wherein, wherein, X 1 represents O, S, NR a , (CR L R L′ ) m , C(O); wherein, X 2 represents O, S, NR a f, (CR T R T′ ) n , C(O); wherein, W 1 independently represents N; wherein, W 2 independently represents CR W2 or N; wherein, W 3 independently represents CR W3 or N; wherein, W 4 independently represents CR W4 or N; wherein, W 5 independently represents CR 1 or N; wherein, Y 1 independently represents CR Y1 ; wherein, Y 2 independently represents CR Y2 ; wherein, Y 3 independently represents CR Y3 ; wherein, each R W2 , R W3 , R W4 , R Y1 , R Y2 , R Y3 independently represents hydrogen, C 1 -C 6 alkyl, halogen, —OR a , —CN, —NR a R b , —CR a R b NR a R b , C 1 -C 6 haloalkyl; or W 1 and W 2 together with the atom which they are attached to form a 5-6 membered saturated or unsaturated ring fused to ring A, and the said ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from O, N, or S; or W 1 and W 4 together with the atom which they are attached to form a 5-6 membered saturated or unsaturated ring fused to ring A, and the said ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from O, N, or S; wherein, L 1 represents —O—, or —NR a ; wherein, L 2 represents —NR a —, —NR a C(O)NR b —, —NR a C(O)—, or —C(O)NR a —; Wherein, R 1 represents hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogen, —OR a , —SR a , —P(O)R a R b , —CN, —S(O) 2 R a , —S(O)R a , —SF 5 , —NR a R b , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkylthio, hydroxy (C 1 -C 6 alkyl); or R 1 represents C 3 -C 10 cycloalkyl, C 6 -C 10 cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, which are substituted by 0-4 substituents that selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; or W 5 and W 2 together with the atom which they are attached to form a 5-6 membered saturated or unsaturated ring fused to ring A, and the said ring may optionally contain 0, 1 or 2 heteroatoms selected from O, N, or S; and further, the said ring may optionally substituted by 0, 1 or 2 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; wherein, R 2 represents C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, —CR a R b C 6 -C 10 aryl, —CR a R b (5-10 membered heteroaryl); which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), —NR a R b , —CR a R b NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —S(O) 2 R a , —S(O)R a , —SF 5 , —C(O)R a , —C(O)OR a f, —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; wherein, R 3 represents hydrogen, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or hydroxy; or R 3 and W 3 together with the atom which they are attached to form a 5-7 membered saturated or unsaturated ring fused to ring A, and the said ring may optionally contain 0, 1 or 2 heteroatoms selected from O, N, or S; and further, the said ring may optionally be substituted by 0, 1 or 2 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; wherein, each R a and R b independently represents hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy (C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl; or R a and R b together with the carbon atom which they are attached to form a 3-6 membered ring, and the said ring may optionally contain 0, 1 or 2 heteroatoms selected from O, N, or S; and further, the said ring may optionally be substituted by halogen, hydroxy or C 1 -C 6 alkyl; wherein, each R L and R L′ independently represents hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy (C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl; wherein, each R T and R T′ independently represents hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy (C 1 -C 6 alkyl), C 3 -C 10 cycloalkyl; wherein, o, m, n represents the integer of 1, 2 or 3.
  4. 32 . The compound or the pharmaceutically acceptable salt according to claim 30 , or the stereoisomer or isotopic isomer thereof, wherein R 1 represents C 1 -C 6 alkyl, halogen, —OH, O(C 1 -C 6 alkyl); or R 1 represents C 3 -C 10 cycloalkyl, C 6 -C 10 cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), NR a R b , —CR a R b NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b .
  5. 33 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 1 represents C 3 -C 10 cycloalkyl, C 6 -C 10 cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b .
  6. 34 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 1 represents C 3 -C 10 cycloalkyl, C 6 -C 10 cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, —OR a , hydroxy (C 1 -C 6 alkyl), —CN or C 1 -C 6 haloalkyl.
  7. 35 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 1 represents 5-10 membered heteroaryl, which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, —OR a f, hydroxy (C 1 -C 6 alkyl), —CN or C 1 -C 6 haloalkyl.
  8. 36 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 1 represents pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, —OR a , hydroxy (C 1 -C 6 alkyl), —CN or C 1 -C 6 haloalkyl.
  9. 37 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 1 represent
  10. 38 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 2 represents C 3 -C 10 cycloalkyl, C 6 -C 10 cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), —NR a R b , —CR a R b NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b .
  11. 39 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein W 5 and W 2 combine to form a ring fused to ring A having the following structure: wherein the said ring may optionally be substituted by 0, 1 or 2 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), NR a R b , —CR a R b NR a R b , —CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —SO 3 R a , —SR a , —SF 5 , —C(O)R a , —C(O)OR a , —OC(O)R a , —OC(O)NR a R b , —NR a COR b or —CONR a R b ; and wherein the wavy line indicates the point of attachment with L 1 .
  12. 40 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein W 5 and W 2 combine to form a ring fused to ring A having the following structure: wherein the wavy line indicates the point of attachment with L 1 .
  13. 41 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 2 represents phenyl, pyridinyl, indazolyl, indolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridazinyl, piperazinyl, pyrazinyl, cyclohexyl, benzothienyl, 1,2-benzoisoxazolyl, benzo[d] isothiazolyl, which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, phenyl, 5-6 membered heteroaryl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), —NR a R b , —CR a R b NR a R b , —CN, or C 1 -C 6 haloalkyl.
  14. 42 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 2 represents which are substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), —NR a R b , —CR a R b NR a R b , —CN or C 1 -C 6 haloalkyl.
  15. 43 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 2 represents: which is substituted by 0-4 substituents selected from deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —OR a , oxo, hydroxy (C 1 -C 6 alkyl), —NR a R b , —CR a R b NR a R b , —CN, or C 1 -C 6 haloalkyl.
  16. 44 . The compound or the pharmaceutically acceptable salt according to claim 31 , or the stereoisomer or isotopic isomer thereof, wherein R 3 represents hydrogen or CH 3 .
  17. 45 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  18. 46 . The compound according to claim 45 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  19. 47 . The compound according to claim 45 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  20. 48 . The compound according to claim 45 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

Description

DECLARATION OF PRIORITY The present application is a continuation application filed under 35 U.S.C. § 111(a) of PCT Application No. PCT/CN2024/143464, filed on Dec. 27, 2024, which claims priority to, and the benefit of, Chinese Application No. 202410788666.1, filed Jun. 18, 2024, Chinese Application No. 202410788320.1, filed Jun. 18, 2024, Chinese Application No. 202311858456.7, filed Dec. 30, 2023, and Chinese Application No. 202410788646.4, filed Jun. 18, 2024, the contents of each of which are hereby incorporated by reference in their entireties. TECHNICAL FIELD The present disclosure relates to a compound having kinase inhibitory activity, and to its application in the field of medicine. More specifically, the present invention provides heteroaryl compounds having protein tyrosine kinase activity. BACKGROUND Clinical and preclinical evidence demonstrates that TAMs, as key regulatory immune cells, can promote tumor development. Macrophages primarily exist in two polarized states. Alternatively activated M2 subtype TAMs promote tumor progression by secreting anti-inflammatory cytokines (e.g., interleukin (IL)-10, transforming growth factor-s), whereas activated M1 subtype TAMs enhance immune-mediated tumor killing by producing pro-inflammatory cytokines. To overcome the immunosuppressive and tumor-promoting functions of TAMs, current therapeutic strategies focus on the depletion of TAMs in the tumor microenvironment and the reprogramming of TAMs to promote anti-tumor functions (shifting M2 polarization to M1). The CSF-1R kinase is a product encoded by the proto-oncogene c-fms and belongs to the class III receptor tyrosine kinase family, which also includes FMS-like tyrosine kinase 3, stem cell factor receptor, FDGFR, and PDGFR. CSF-1R binds to its ligands, CSF-1 and IL-34, to activate CSF-1R, thereby playing a crucial role in the proliferation, differentiation, and growth of mononuclear phagocytes. In the tumor microenvironment, a large number of macrophages (TAMs) are present, expressing the CSF-1R on their cell surface. When CSF-1 binds to this receptor, macrophages are converted to a pro-tumor state, driving immune suppression and promoting tumor cell growth. Furthermore, high expression of CSF-1R on tumor cells is associated with lower survival rates in certain cancer patients, indicating tumor dependency, making it a potential therapeutic target. By targeting CSF-1R, the development of CSF-1R/CSF-1 inhibitors can effectively reduce the number of TAMs in tumor tissues, promote the generation of anti-tumor macrophages, and help relieve immune suppression. Additionally, it facilitates the infiltration of various immune cells, including T cells and lymphocytes, into the tumor tissue. Cancer cell growth and metastasis depend on the formation of neovascularization. Vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic factor because solid tumors depend on angiogenesis to provide oxygen and nutrients to aid in their growth and, in turn, as a pathway for invasion and metastasis. In addition, the VEGFa-VEGFR2 signaling pathway plays an important role in the tumor microenvironment and significantly promotes the proliferation and infiltration of Treg (regulatory T cells) in tumor tissues in animal models. Inhibition of the VEGFa-VEGFR2 signaling pathway can inhibit tumor growth by regulating Tregs, MDSCs, and M2 macrophages. Inhibition of VEGFR2 significantly reduced Treg levels in tumor tissues, further helping to deregulate immunosuppression. PDGFR is a transmembrane glycoprotein with tyrosine kinase activity, primarily expressed on mesenchymal-derived cells such as fibroblasts, pericytes, vascular smooth muscle cells, and stromal stem/progenitor cells. PDGFR consists of a and § subunits. Typically, PDGFRα and PDGFRβ exist as monomers in an autoinhibited state. Upon binding with platelet-derived growth factor (PDGF), PDGFR monomers dimerize, forming isomers PDGFR-αα, PDGFR-αβ, and PDGFR-ββ, which mediate a series of downstream signaling responses. The PDGF/PDGFR primarily promotes angiogenesis and vascular maturation, playing a role in growth and development, and is also closely related to the occurrence and progression of various diseases. Due to the characteristics of tumor microvasculature, such as rapid but immature growth, irregularity, and high permeability, the transport and distribution of chemotherapeutic drugs and oxygen to tumor tissues are hindered, making it easy for tumor cells to metastasize and invade other areas through the leaky vessels. The abnormal vascular system creates a malignant tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure, which interferes with the function of immune cells within the tumor and reduces the efficacy of radiation therapy and chemotherapy. Therefore, the focus of current anti-angiogenic therapy has shifted from simply destroying blood vessels to “normalizing” tumor microvasculature, in order to i