WO2021093817A1 - Composés immunomodulateurs, composition et utilisation associées - Google Patents

Composés immunomodulateurs, composition et utilisation associées Download PDF

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WO2021093817A1
WO2021093817A1 PCT/CN2020/128435 CN2020128435W WO2021093817A1 WO 2021093817 A1 WO2021093817 A1 WO 2021093817A1 CN 2020128435 W CN2020128435 W CN 2020128435W WO 2021093817 A1 WO2021093817 A1 WO 2021093817A1
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substituted
unsubstituted
chloro
pyridine
dihydro
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PCT/CN2020/128435
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Chinese (zh)
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周星露
刘兴国
胡苗
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杭州和正医药有限公司
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions

  • the invention belongs to the field of medicine, and specifically relates to an amide compound, a pharmaceutical composition and an application thereof.
  • the compound can block the interaction of PD1 and PD-L1, and can be used to treat a variety of diseases, disorders or diseases, including infectious diseases, immune diseases, inflammatory diseases and cancer.
  • the human immune system plays an extremely important regulatory role in many disease processes including tumors.
  • a variety of immune escape mechanisms have been developed and evolved. Among them, changing the expression of co-stimulatory or co-suppressive molecules on the surface of tumor cells or immune cells is one of the most critical tumor immune escape mechanisms.
  • blocking the interaction of inhibitory immune checkpoint molecules (such as PD1/PD-L1) has become one of the effective tumor immunotherapy strategies. (Postow et al., J. Clinical Oncology 2015, 1-9).
  • PD-1 is a surface receptor that can be expressed on a variety of immune cells. It plays an extremely important immune negative feedback regulation effect in the body and can effectively prevent autoimmune system diseases caused by excessive activation of T cells (Sharpe et al., Nat. Immunol., 2007, 8, 239-245).
  • the PD-1 receptor has two corresponding endogenous ligands, PD-L1/PD-L2 in the body. PD-L1 and PD-L2 are different in expression.
  • PD-L1 is mostly expressed in dendritic cells, macrophages, B cells and T cells (Greenwald et al., Annu. Rev. Immunol.
  • PD-L2 is usually only expressed on dendritic cells. Drug blocking the interaction of PD-1/PD-L1 is currently the hottest direction in the field of tumor immunotherapy.
  • the purpose of the present invention is to provide a novel amide compound or its stereoisomers or a mixture of stereoisomers or pharmaceutically acceptable salts thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound or its stereoisomer or its mixture of stereoisomers or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound or a stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof for preparing and treating diseases and disorders that benefit from the inhibition of PD1 or PD-L1 activity Or the application of the medicine for the disease.
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • R 1 , R 2 , and R 3 are each independently selected from H, halogen, CN, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl group, substituted or unsubstituted 5-14 membered heteroaryl group, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 2 -C 6 alkenyl group, substituted or Unsubstituted C 2 -C 6 alkynyl, -OR a , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 1 -C 6 haloalkoxy, -NR a R a , -NHOR a , -C(O)R a , -C(O)NR
  • Y 1 and Y 2 are independently selected from N or C, and Y 1 and Y 2 are not N at the same time;
  • the bond between Y 1 , Y 2 , N and Z can be a double bond or a single bond, provided that the electronic pairing rules are met, of course, it can also be a part of a single bond and a part of a double bond.
  • Y 1 , Y 2 , N and Z form a conjugated ring structure
  • Z is O, S, N, NR 4 or CR 4 ; Z is preferably NCH 3 , CCH 3 , S, O;
  • G 1 is NR 6
  • G 2 is CR 7 R 7 ; here, the two R 7 in “CR 7 R 7 " are independent of each other and can be the same or different;
  • G 1 is CR 6 R 6
  • G 2 is NR 7 ; here, the two R 6 in “CR 6 R 6 "are independent of each other and can be the same or different;
  • A is C 6 -C 12 aryl, 5 to 14 heteroaryl, 3 to 14 membered cycloalkyl, 3 to 14 membered heterocyclic group, the aryl, heteroaryl, cycloalkyl, and heterocyclic group are not Condensed or fused by A 1 , the A 1 is 4-8 membered cycloalkane, 4-8 membered heterocycloalkane, 4-8 membered cycloalkene, 4-8 membered heterocycloalkene, 5-8 membered aromatic ring , 5 to 8-membered heteroaromatic ring; each of the above substituents may be 0 to 5 substituents R 8; R 8 is plural, a plurality of R 8 independently of each other, may not be the same, may be the same; the present invention, the The term "fused" includes a spiro ring, fused ring structure, etc. that share one, two or more C or N;
  • R 4, R 5, R 6 , R 7, R 8 is independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, containing one or more deuterium atoms, C 1 -C 6 alkyl group, a substituted Or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl, Substituted or unsubstituted C 1 -C 6 haloalkoxy, substituted or unsubstituted C 1 -C 6 hydroxyalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 5-14 membered heteroaryl, substitute
  • the two adjacent R 8 on A can form a ring with the connected atoms (constitute “M” and “N” structure, or form a spiro ring structure, where "M” and “N” do not have specific Meaning, it only means the structure where two rings share two adjacent carbon/nitrogen atoms),
  • the ring can be a benzene ring, a C 3 -C 6 cycloalkyl group, a 5-6 membered heteroaryl group or a 5-7 membered heterocyclic group.
  • R c is a plurality, the plurality of R c may be the same or different, each R c is independently selected from H, halo, a substituted or unsubstituted C 1- C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted Substituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclic group;
  • R 5 when there are two carbon atoms, while R 5 substituents, two R 5 may be the same or different, R 5 may form C 3 -C 6 cycloalkyl with the carbon atoms are attached, 4-7 membered heterocyclyl , each of which may be substituted with 0-3 R d; wherein, R c is a plurality, the plurality of R c may be the same or different, each R d is independently selected from H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 5-14 membered heteroaryl, substitute
  • R 9 is selected from H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted Substituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 1 -C 6 haloalkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl , Substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclic group, -CN, -NO 2 , -OR e , -SR e , -NR e R e , -N (OH)R e , -C(O)R
  • L 1 is independently selected from bond, O, S, SO, SO 2 , (CR f R f ) n , (NR f ) n , C (O), C (O) NR f , NR f C (O), ( CR f R f ) n CR f R f (CR f R f ) n , (CR f R f ) n O(CR f R f ) n , (CR f R f ) n S(CR f R f ) n , (CR f R f ) n SO 2 (CR f R f ) n , (CR f R f ) n NR f (CR f R f ) n , (CR f R f ) n C(O)(CR f R f ) n , (CR f R f ) n C(O)NR f (CR f R f )
  • R 10 , R 11 , R 13 , and R 14 are independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, containing one or more C 1 -C 6 alkoxy of deuterium atom, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 haloalkyl , Substituted or unsubstituted C 1 -C 6 haloalkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 5-14 Member heteroaryl, substituted or unsubstituted 3-10 membered heterocyclic group, CN, NO 2
  • the R 10 , R 11 , R 13 , and R 14 are each independently preferably F, H, Cl, C 1 to C 3 alkyl (methyl, ethyl, propyl), cyano, substituted or Unsubstituted C 1 ⁇ C 3 alkoxy (methoxy, ethoxy, propoxy; substituents are one or more fluorine, cyclopropyl), deuterated methyl, C3 ⁇ C5 cycloalkyl, benzene Group, substituted and unsubstituted benzyloxy (cyano-substituted, methyl-substituted or hydroxy-substituted, etc.), substituted pyridine methoxy (cyano-substituted, methyl-substituted or hydroxy-substituted, etc.), and pyridine methoxy.
  • R 10 , R 11 , R 13 , R 14 is H, or one of R 10 , R 11 , R 13 , and R 14 is H; or R 10 , R 11 , R 13. Two of R 14 are H at the same time.
  • R 12 is selected from NR i R i , -(C 1 -C 6 alkylene) -NR h R h , -O-(C 1 -C 6 alkylene) -NR h R h , -(C 1- C 6 alkylene) -O-(C 1 -C 6 alkylene) -NR h R h , -NR i -(C 1 -C 6 alkylene) -NR h R h , -(C 1- C 6 alkylene) -N + R h R h R h , -S-(C 1 -C 6 alkylene) -NR h R h , C(O)NR h R h , S(O) 2 R h , -(CH 2 ) o SO 2 NR h R h , -(CH 2 ) o NR h SO 2 NR h R h , -SO 2 NR h -(
  • R C 12 of the above-described 1 -C 6 alkylene group may be substituted with 0 to 3 substituents selected from substituent group NR h R h, halo, cyano, oxo, ORi, substituted and unsubstituted have C 1 - 6 alkyl, substituted and unsubstituted C 1 - 6 haloalkyl, substituted and unsubstituted C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl;
  • V is independently selected from bond, O, C(O), NR h , S, SO, SO 2 , C(O)NR h , NR h C(O), SO 2 NR h or NR h SO 2 ;
  • L 2 is independently selected from bond, O, C(O), NR h , S, SO, SO 2 , C(O)NR h , NR i C(O), SO 2 NR h or NR h SO 2 ;
  • B is selected from substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3- 10-membered heterocyclic group;
  • T is independently selected from H, OR h , (CH 2 ) q NR h R h , (CH 2 ) q NR h C(O)R i , (CH 2 ) q NR h C(O)OR i , (CH 2 ) q C(O)R i or (CH 2 ) q C(O)OR i ;
  • Each R h is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or Unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 1 -C 6 haloalkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl Group, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclic group;
  • Each R i is independently selected from H, OH, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, Substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 1 -C 6 haloalkoxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 12 aryl groups, substituted or unsubstituted 5-14 membered heteroaryl groups, substituted or unsubstituted 3-10 membered heterocyclic groups;
  • o is independently selected from an integer from 0 to 4.
  • p is independently selected from an integer of 0-5;
  • q is independently selected from an integer of 0-5;
  • l is independently selected from an integer of 0-5.
  • each R a is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted C 2 -C 6 alkenyl group, a substituted or unsubstituted C 2 -C 6 alkynyl group, Substituted or unsubstituted C 1 -C 6 alkoxy group, substituted or unsubstituted C 3 -C 10 cycloalkyl group, substituted or unsubstituted C 6 -C 12 aryl group, substituted or unsubstituted 4-14 member Heteroaryl, substituted or unsubstituted 3-10 membered heterocyclic group.
  • R b, R c, R d , R e explains R f, R g, R
  • the preferred compound of the present invention has the structure of the general formula II-A, II-B, II-C, II-D, II-E, II-F or II-G:
  • A is selected from C 6 -C 10 aryl, 5-12 heteroaryl, 5-12 membered cycloalkyl, 5-12 membered heterocyclic group, the aryl, heteroaryl, cycloalkane
  • the group and the heterocyclic group are not fused or fused by A 1
  • the A 1 is a 5- to 6-membered cycloalkane, a 5- to 6-membered heterocycloalkane, a 5- to 6-membered cycloalkene, a 5- to 6-membered heterocycloalkene, 5-6 membered aromatic ring, 5-6 membered heteroaromatic ring; each of the above substituents may be substituted by 0-4 R 8 ;
  • Each R 8 is independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 1 -C 6 haloalkyl Oxy, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3- 10-membered heterocyclic group, cyano group, nitro group, amino group, substituted or unsubstituted C 1 -C 6 alkoxy group, N(CH 3 ) 2 , S(O 2 )CH 3 , SO 2 NH 2 ;
  • the two adjacent R 8 on A can form a ring with the connected atoms, and the ring can be a benzene ring, a C 3 -C 6 cycloalkyl group, a 5-6 membered heteroaryl group or a 5-7 membered heterocyclic ring Groups, each of which can be substituted by 0 to 3 R c;
  • each R c is independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-12 membered heterocyclic aryl, substituted or unsubstituted 3-10 membered heterocyclic group.
  • the preferred compounds of the present invention have the structure of the general formula III-A or III-A', the structure of the general formula III-B or III-B', the structure of the general formula III-C or III-C', The structure of formula III-D or III-D', the structure of general formula III-E or III-E', the structure of general formula III-F or III-F', the structure of general formula III-G or III-G' :
  • J 1 is N, CR';
  • J 2 is CR', CR'R”, N, NR”, O, S, C(O), S(O), S(O) 2 ;
  • J 3 is CR'R”, NR”, O, S, C(O), S(O), S(O) 2 ; J 2 and J 3 are not NR”, O, S, C(O) at the same time , S(O), S(O) 2 ;
  • J 2 and J 3 can be a double bond or a single bond
  • J 1 is N
  • J 2 and J 3 are not NR", O, S, C(O), S(O), S(O) 2 ;
  • R' is independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
  • R" is independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, benzene ring, 5-6 membered Heteroaryl, benzene ring, OR"', NR"'R"', wherein each R"' is independently selected from H, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl;
  • R 8 One H or two H in R'and R" may be substituted by the R 8 ; when there are two or more R 8 substituents on the A ring, each R 8 may be different; one of R'and R" H or multiple H can be replaced by deuterium;
  • r is an integer from 0 to 4.
  • s is an integer of 0-3.
  • J 1 can be further preferably CH, N, when J 1 is CH, it can be R configuration or S configuration or a mixture of the two configurations in any ratio;
  • J 2 can be further preferably CH 2 , Halogen-substituted CH, one or more C1-C3 alkyl-substituted CH/C, C of spirocyclopropyl, or CH that forms a ring with J 3 through CH 2 or multiple CH 2, forms a double with J 3
  • the CH and N at the time of the bond are C (C1 ⁇ C3 alkyl), etc.
  • J 3 when they form a double bond with J 3 and are substituted by a C1-C3 alkyl group; J 3 may be more preferably CH 2 , NH, O, and the like. CH 2 CH 2 or more looped and J 2 CH, CH and J 2 when a double bond, N, and J 2 is a double bond and is substituted at the C1 ⁇ C C3 alkyl group (C1 ⁇ C3 alkoxy Group), N when forming a double bond with J 2, etc.
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3 ;
  • R 1 , R 2 , and R 3 are each selected from H, halogen, CN, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 1 -C 6 haloalkoxy group, a substituted or unsubstituted C 3 -C 10 cycloalkyl, OR a, NR a R a , NHOR a, C (O) R a, C (O) NR a R a, OC ( O) NR a R a, NR a C (O) R a, NR a C (O) OR a, NR a C (O) NR a R a; wherein each R a is independently selected from H, substituted or unsubstituted Substituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C
  • R 1 , R 2 , and R 3 are each independently selected from H, F, C 1 to C 3 alkyl, and C 1 to C 3 alkoxy.
  • X 1 , X 2 , and X 3 are independently selected from CH and CF.
  • the Z is NR 4 , CR 4 , N, S, O;
  • G 1 is NR 6 , and
  • G 2 is CR 7 R 7 ;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 Hydroxyalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclic group, C(O)R b , -C 1 -C 6 alkyl-C(O)R b ; wherein R b is selected from H, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 10 cycloalkyl, 3- 10-membered heterocyclic group;
  • the R 6 is selected from H, methyl, hydroxyethyl, acetyl, hydroxy-substituted isopropyl (3-hydroxy-substituted isopropyl, 2-hydroxy-substituted isopropyl), hydroxy-substituted propyl (3 -Hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl), 3-hydroxyethyloxetane-3-methyl, 2-methyl-2-hydroxypropyl, methylsulfonyl, ring Propanesulfonyl, difluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-trifluoromethylethyl, isopropyloxycarbonyl, methoxyethyl (1-methoxyethyl, 2-methoxyethyl), 1-hydroxymethyl-2-hydroxyethyl, cyclopentyl, oxanyl, carboxylic acid e
  • the R 5 is selected from H, 1 to 3 methyl groups (may be one methyl group substituted on any C atom, two methyl groups substituted on the same C atom or two different C atoms, Substituting three methyl groups on two C atoms, etc.), a combination of deuterated methyl ethyl methyl and deuterated methyl. Or when two R 5 are substituted on one carbon atom, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, etc. are formed. Or, two adjacent R 5 may form a ring with adjacent atoms, and the ring may be a C 3 -C 10 cycloalkyl group or a 3-10 membered heterocyclic group; m is 0, 1, or 2.
  • R 7 is selected from H.
  • R 8 is independently preferably H, methyl (including one methyl substituted on one atom or two methyl substituted on one atom or multiple methyl substituted on different atoms, etc.), ethyl, cyano, F. Hydroxyethyl; or two R 8 are substituted on two adjacent carbon atoms to form a cyclopropyl group; or two R 5 are substituted on one carbon atom to form a cyclopropyl group.
  • R 10 , R 11 , R 13 , and R 14 are each independently selected from F, H, Cl, cyano, C 1 ⁇ C 3 alkoxy, C 1 ⁇ C 3 alkyl, phenyl substituted C 1 ⁇ C 3 alkoxy, substituted phenyl substituted C 1 ⁇ C 3 alkoxy, pyridine substituted C 1 ⁇ C 3 alkoxy, substituted pyridine substituted C 1 ⁇ C 3 alkoxy, 3 ⁇ 5 membered cycloalkyl substituted with C 1 ⁇ C 3 alkoxy group, containing one or more deuterium atoms, C 1 ⁇ C 3 alkoxy, fluoro substituted with one or more of C 1 ⁇ C 3 alkoxy, phenyl, C 3 to C 6 cycloalkyl; more preferably deuterated methyloxy, difluoromethyl, cyclopropyl, cyclobutyl, cyclopropylmethoxy, phenyl, substituted and
  • R 12 is selected from
  • L 1 is selected from O, NH, CH 2 , S, SO 2 , CO, -NHCH(CF 3 )-, -CH(CF 3 )NH-, -NHCF 2 , -OCH(CF 3 )-;
  • A is selected from
  • R 9 is selected from H, from Cl, methyl, ethyl, F, cyano;
  • R 1 , R 2 , and R 3 are each independently selected from H, F, C 1 ⁇ C 3 alkyl, and C 1 ⁇ C 3 alkoxy;
  • R 4 , R 5 , R 6 , and R 7 each independently select H, F, methyl, ethyl, cyano, and hydroxyethyl.
  • the compound or its stereoisomer or its mixture of stereoisomers or its pharmaceutically acceptable salt is selected from the following compounds:
  • the compound is the following compound:
  • aryl used in the present invention refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms (one of the fused rings may be partially saturated).
  • aromatic rings are: benzene ring, naphthalene ring, anthracene ring, indene ring, dihydroindenyl (indanyl). The aromatic ring can be unsubstituted or substituted.
  • the substituent of the aromatic ring is selected from halogen (preferably fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxyl, carboxy, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 Alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.), C 1 -C 6 hydroxyalkyl (preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, etc.), C 1 -C 6 alkoxy (preferably methoxy, ethoxy, propoxy, isopropyl) Propyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halo C 1 -C 6
  • heteroaryl used in the present invention refers to a monocyclic or condensed polycyclic group of 5 to 14 ring atoms (one of the condensed rings may be partially saturated), which corresponds to one or more carbons in the aforementioned "aryl” Replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc.
  • the heteroaromatic ring can be a single ring or a bicyclic ring, that is, it is formed by the fusion of two rings.
  • heteroaryl groups can be: pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, Indoline, benzimidazole, etc.
  • the heterocyclic aryl group may be unsubstituted or substituted.
  • the substituent of the heterocyclic aryl group is selected from halogen, cyano, nitro, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halo C 1 -C 6 hydroxyalkyl, halo C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, halo C 3 -C 6 cycloalkyl, 3 To 10-membered heterocyclic group, C 6 -C 12 aryl group, C 5 -C 14 heteroaryl group.
  • alkyl used in the present invention refers to a linear saturated monovalent hydrocarbon group with one to six carbon atoms or a branched saturated monovalent hydrocarbon group with three to six carbon atoms, preferably methyl, ethyl, propyl , Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.
  • the alkyl group can be unsubstituted or mono-substituted or multi-substituted, and the substituents can be the same or different in the case of multi-substitution; the substituents of the alkyl group are selected from halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, Isopropyl ester, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkyl Amido, hydroxyalkylamido, sulfonamido, 3- to 10-membered heterocyclic group, or amino or mono- or poly-substituted amino, wherein the substituents of the amino group may be the same or different, and are selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • hydroxyalkyl refers to -alkyl-OH, where alkyl is as defined above.
  • alkyl is as defined above.
  • Examples of "hydroxyalkyl” used in the present invention include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and the like.
  • Haldroxyalkyl also includes substituted hydroxyalkyl, the substituents of which can be halogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1- C 6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • alkoxy refers to an -O-alkyl group, where alkyl is as defined above.
  • alkoxy used in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy.
  • Alkoxy also includes substituted alkoxy, and its substituents can be halogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1- C 6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • cycloalkyl used in the present invention refers to a monocyclic or polycyclic ring (two monocyclic rings connected by a chemical bond or bridged ring or spiro ring or condensed) with three to ten carbon atoms and a non-aromatic monovalent
  • the hydrocarbyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., in which one or two carbon atoms can be replaced by an oxo group.
  • the cycloalkyl group may be unsubstituted or substituted, and its substituent is selected from halogen, nitro, hydroxyl, carboxyl, methyl carboxylate, ethyl carboxylate, formamide, C 1 -C 6 alkyl, C 1- C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkoxy, C 3- C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3 to 10 members Heterocyclic group, or amino or mono- or poly-substituted amino, wherein the substituents of the amino group may be the same or different, and are selected
  • heterocyclic group used in the present invention refers to a non-aromatic ring having three to ten ring atoms in a monocyclic or polycyclic ring (two monocyclic rings are connected by a chemical bond or bridged or spiro ring or condensed).
  • the heterocyclic group may be unsubstituted or substituted, and its substituent is selected from halogen, nitro, hydroxyl, carboxy, methyl carboxylate, ethyl carboxylate, formamide, oxo, thio, C 1 -C 6 Alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 hydroxyalkyl, halogenated C 1 -C 6 alkane Oxy, C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide Group, 3- to 10-membered heterocyclic group, or amino or mono- or
  • alkenyl used in the present invention refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, containing at least one double bond and having 2 to 10 carbon atoms (ie C 2 -C 10 alkenyl) , Including but not limited to vinyl, allyl, but-1-enyl, pent-1-enyl, pent-1,4-di-enyl and the like.
  • Alkenyl groups may be substituted by one or more substituents, which are independently alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkane Group, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
  • substituents which are independently alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkane Group, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
  • alkynyl used in the present invention refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, containing at least one triple bond and having 2 to 10 carbon atoms (ie C 2 -C 10 alkynyl) , Including but not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl, etc.
  • the alkynyl group may be substituted by one or more substituents, which are independently alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkane Group, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
  • substituents which are independently alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkane Group, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
  • halogen used in the present invention refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine or bromine.
  • halo used in the present invention refers to the substitution of the same atom or different atoms by halogen, which can be substituted once or multiple times, such as di- or tri-substituted.
  • haloalkyl refers to an alkyl group substituted by halogen (preferably fluorine, chlorine, bromine, or iodine), wherein the alkyl group is as defined above. "Haloalkyl” can be substituted one or more times with halogen.
  • halohydroxyalkyl refers to a hydroxyalkyl group substituted by halogen (preferably fluorine, chlorine, bromine, or iodine), wherein the hydroxyalkyl group is as defined above.
  • halogen preferably fluorine, chlorine, bromine, or iodine
  • the "halohydroxyalkyl” may be substituted one or more times by halogen.
  • haloalkoxy refers to an alkoxy group substituted by halogen (preferably fluorine, chlorine, bromine, or iodine), where alkoxy is as defined above. "Haloalkoxy” may be substituted one or more times with halogen.
  • halocycloalkyl used in the present invention refers to a cycloalkyl group substituted by halogen (preferably fluorine, chlorine, bromine, or iodine), wherein cycloalkyl is as defined above. "Halocycloalkyl” may be substituted one or more times with halogen.
  • m used in the present invention is preferably 0, 1, 2;
  • n used in the present invention is preferably 0, 1, 2.
  • o used in the present invention is preferably 0, 1, 2, 3.
  • p used in the present invention is preferably 0, 1, 2, 3.
  • q used in the present invention is preferably 0, 1, 2, 3.
  • the term "1" used in the present invention is preferably 0, 1, 2, 3.
  • r used in the present invention is preferably 0, 1, 2, 3.
  • s used in the present invention is preferably 0, 1, 2.
  • the present invention adopts methods well known to those skilled in the art to prepare the salt of the compound of the present invention.
  • the salt may be an organic acid salt, an inorganic acid salt, etc.
  • the organic acid salt includes citrate, fumarate, oxalate, malate, lactate, camphorsulfonate, and Toluenesulfonate, methanesulfonate, etc.;
  • the inorganic acid salt includes hydrohalide, sulfate, phosphate, nitrate and the like.
  • lower alkyl sulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, etc.
  • methanesulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid, etc.
  • arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid, etc. It can form p-toluenesulfonate and benzenesulfonate
  • organic carboxylic acid such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid, etc.
  • amino acid can form glutamate or aspartate.
  • inorganic acids such as hydrohalic acid (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid can also form corresponding salts.
  • the compounds of the present invention include compounds in which a certain atom is substituted by an isotope.
  • Isotopes refer to atoms with the same atomic number and different atomic masses.
  • Isotopes such as hydrogen include deuterium and tritium.
  • one or more atoms may be substituted by natural or unnatural isotopes.
  • the hydrogen atom in any embodiment may be replaced by one or more deuterium atoms.
  • the method for synthesizing compounds containing isotopic atoms is known in the art.
  • the second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any one of the above technical solutions.
  • the pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above technical solutions and other compounds, or one or more of the compounds described in any of the above technical solutions composition.
  • the present invention provides the use of the general formula I, the general formulas II-A to II-G, the general formulas III-A to III-H, and the general formulas III-A' to III-G' disclosed herein.
  • the present invention provides a method for blocking the interaction between PD1 and PD-L1 of the subject by administering a composition containing a therapeutically effective amount of at least one compound to a subject in need.
  • the method wherein the structural formula of the compound is general formula I, general formula II-A to II-G, general formula III-A to III-H, general formula III-A' to III-G'.
  • the subject in need suffers from cancer, which includes hematological tumors and solid tumors, such as melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, Lymphocytic lymphoma, primary central nervous system lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic granuloma Cell leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovialoma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, biliary
  • the subject in need suffers from infectious diseases, immune diseases, and inflammatory diseases, such as sepsis, liver infection, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, Herpes virus, papilloma virus, influenza, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory enteritis, Crohn's disease, colitis, autoimmune hemolytic anemia, ankylosing spondylitis, Pemphigus, urticaria, asthma, optic neuritis, psoriasis, chronic obstructive airway disease, dermatitis, alopecia.
  • infectious diseases such as sepsis, liver infection, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, Herpes virus, papilloma virus, influenza, rheumatoid arthritis, systemic lup
  • the present invention also provides the application of the compound of the present invention or the pharmaceutically usable salt thereof in the preparation of blocking the interaction of PD1 and PD-L1, especially the application in the preparation of the treatment of cell proliferation diseases.
  • the cell proliferative diseases include cancer.
  • the present invention also provides compounds of general formula I, general formulas II-A to II-G, general formulas III-A to III-G, general formulas III-A' to III-G' or their pharmaceutically acceptable compounds.
  • the accepted salt is used alone or in combination with other drugs in the treatment of proliferative diseases (such as cancer).
  • the drug used in combination with the compound or composition of the present invention may be selected from antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutic agents, anticancer agents, antiangiogenic agents, and immunotherapeutic agents. (Such as immune checkpoint inhibitors), one or more of anti-fibrotic agents, radiotherapy, radiotherapy agents, anti-tumor agents (such as kinase inhibitors), or anti-proliferative agents.
  • a preparation comprising one or more of the compounds described in any of the above schemes.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc., commonly used in the pharmaceutical field. If necessary, flavors can also be added. Agents, sweeteners, etc.
  • the medicament of the present invention can be made into various forms such as tablets, powders, capsules, injection preparations, granular preparations, sprays, etc.
  • the medicaments of the above-mentioned various dosage forms can be prepared according to conventional methods in the field of pharmacy.
  • the compound or composition of the present invention can be used in combination with one or more other drugs for the treatment of diseases, disorders or conditions that benefit from inhibition of PD1 or PD-L1 activity.
  • the other drugs are selected from antimicrobial agents, antiviral agents, cytotoxic agents, gene expression regulators, chemotherapeutics, anticancer agents, antiangiogenesis agents, immunotherapeutics, antifibrosis agents, radiotherapy agents, and antitumor agents Agent or anti-proliferative agent.
  • the present invention also relates to a method of using the compound or pharmaceutical composition in combination with radiotherapy to treat cell proliferative diseases.
  • the techniques for administering radiotherapy are known in the art, and these techniques can be used in the combination therapy described in this application.
  • the compounds of the present invention can also be used in combination with other methods of treating cancer, such as by chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery.
  • immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, recipient T cell transfer, Toll receptor agonist Drugs, STING agonists, oncolytic virus therapy and immunomodulatory small molecules, including thalidomide or JAK1/2 inhibitors, etc.
  • the inventors of the present invention have confirmed through experiments that the compound of the present invention exhibits strong PD-1/PD-L1 blocking activity and can reverse the T cell function inhibited by PD-L1.
  • the compound of the present invention can activate the NFAT signal pathway caused by the combination of PD-1/PD-L1, and can be absorbed orally, and has good pharmacokinetic properties. Therefore, the compounds of the present invention can be applied in the treatment of diseases, disorders or conditions that benefit from the inhibition of PD1 or PD-L1 activity, including infectious diseases, immune diseases, and inflammations, alone or in combination with other drugs. Sexual diseases and cancer.
  • Figure 1 The results of the in vitro co-incubation experiment of the compound.
  • Figure 2 The results of the NFAT reporter gene experiment of the compound.
  • Example 1 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,3,5,6-tetrafluorobenzyl)pyrrolidine-3- Preparation of formic acid
  • Step 1 Dissolve 2,3,4,5,6-pentafluorobenzaldehyde (2.3mmol) in 10mL DMF solution, add 4-bromo-2,3-dihydro-1H-inden-1-ol (3.0 mmol), cesium carbonate (3.0 mmol), heated to 100°C under the protection of nitrogen, and stirred for about 12 hours.
  • the reaction solution was cooled to room temperature and quenched with water, extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate.
  • Step 2 4-((4-Bromo-2,3-dihydro-1H-inden-1-yl)oxy)-2,3,5,6-tetrafluorobenzaldehyde (2.0mmol) and diboronic acid Naol ester (1.6mmol) was dissolved in 15mL 1,4-dioxane, Pd(dppf)Cl 2 (0.2mmol) and potassium acetate (4.0mmol) were added, and heated to 90°C for about 12 hours under the protection of nitrogen . After stopping the reaction and cooling to room temperature, water and ethyl acetate were added for extraction, and the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 3 Add 2,3,5,6-tetrafluoro-4-((4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl) -2,3-Dihydro-1H-inden-1-yl)oxy)benzaldehyde (1.8mmol) and 3-bromo-2-chloroaniline (2.0mmol) were dissolved in 10mL of 1,4-dioxane, 3.0 mL of purified water was added, Pd(PPh 3 ) 4 (0.2 mmol) and sodium carbonate (4.0 mmol) were added, and the reaction mixture was heated to reflux and reacted for about 24 hours.
  • Step 4 Add 4-((4-(3-amino-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,3,5,6-tetra Fluorobenzaldehyde (1.5mmol) and 1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxylic acid (1.5mmol) were dissolved in Add HATU (3.0 mmol) and DIPEA (4.5 mmol) to 10 mL of anhydrous DMF, and react at room temperature for about 24 hours under the protection of nitrogen.
  • HATU 3.0 mmol
  • DIPEA 4.5 mmol
  • Step 5 Add N-(2-chloro-3-(1-(2,3,5,6-tetrafluoro-4-formylphenoxy)-2,3-dihydro-1H-indene-4- Yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.5mmol) and pyrrolidine- 3-Formic acid (1.0 mmol) was dissolved in a solution of 5 mL methanol and 5 mL dichloromethane, acetic acid (1.2 mmol) was added, the reaction solution was mixed and stirred for about 1 hour, and then sodium triacetate borohydride (2.0 mmol) was added.
  • Example 2 1-(5-Chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine Preparation of -3-carboxylic acid
  • Step 1 Combine 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde (3.5mmol) and 4-bromo-2,3-dihydro-1H-inden-1-ol (5.6mmol) Dissolve in 20 mL of anhydrous tetrahydrofuran solution, add triphenylphosphine (5.6 mmol), then slowly add DIAD (5.6 mmol) dropwise, and react at room temperature for about 12 hours. The reaction was stopped, and most of the reaction solvent was removed by concentration under reduced pressure.
  • Step 2 Add 4-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)-5-chloro-3-fluoro-2-methoxybenzaldehyde (2.0mmol) Pinacol diborate (1.6mmol) was dissolved in 15mL 1,4-dioxane, added Pd(dppf)Cl 2 (0.2mmol) and potassium acetate (4.0mmol), heated to 90°C under nitrogen The reaction takes about 12 hours. After stopping the reaction and cooling to room temperature, water and ethyl acetate were added for extraction, and the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 3 Add 5-chloro-3-fluoro-2-methoxy-4-((4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2 -Yl)-2,3-dihydro-1H-inden-1-yl)oxy)benzaldehyde (1.5mmol) and 3-bromo-2-chloroaniline (2.0mmol) dissolved in 10mL 1,4-diox Six ring, add 3.0mL purified water, then add Pd(PPh3)4 (0.15mmol) and sodium carbonate (3.0mmol), the reaction mixture is heated to reflux and react for about 24 hours.
  • Step 4 Add 4-((4-(3-amino-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chloro-3-fluoro-2 -Methoxybenzaldehyde (1.2mmol) and 1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxylic acid (1.5mmol ) was dissolved in 10 mL of anhydrous DMF, HATU (3.0 mmol) and DIPEA (4.5 mmol) were added, and reacted at room temperature for about 24 hours under the protection of nitrogen.
  • Step 5 Add N-(2-chloro-3-(1-(6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy)-2,3-dihydro-1H-indene -4-yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.4mmol) and Pyrrolidine-3-carboxylic acid (0.8 mmol) was dissolved in a solution of 5 mL methanol and 5 mL dichloromethane, acetic acid (1.0 mmol) was added, the reaction solution was mixed and stirred for about 1 hour, and then sodium triacetate borohydride (1.6 mmol) was added.
  • Step 1 Add 5-chloro-3-fluoro-2-methoxy-4-((4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2 -Yl)-2,3-dihydro-1H-inden-1-yl)oxy)benzaldehyde (1.2mmol, can be prepared according to step 2 in Example 2) and 3-bromo-2-methylaniline (1.5 mmol) was dissolved in 8 mL of 1,4-dioxane, 3.0 mL of purified water was added, Pd(PPh 3 ) 4 (0.12 mmol) and sodium carbonate (2.5 mmol) were added, and the reaction mixture was heated to reflux and reacted for about 24 hours.
  • Step 2 Add 4-((4-(3-amino-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chloro-3-fluoro- 2-methoxybenzaldehyde (1.0mmol) and 1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxylic acid (1.3 mmol) was dissolved in 10 mL of anhydrous DMF, HATU (2.5 mmol) and DIPEA (3.0 mmol) were added, and reacted at room temperature for about 24 hours under nitrogen protection.
  • Step 3 Add N-(3-(1-(6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl )-2-methylphenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.2mmol) And pyrrolidine-3-carboxylic acid (0.4mmol) was dissolved in a solution of 3mL methanol and 3mL dichloromethane, acetic acid (0.5mmol) was added, the reaction solution was mixed and stirred for about 1 hour, then sodium triacetate borohydride (1.6mmol) was added .
  • Example 7 1-(5-Chloro-4-((4-(3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]Pyridine-2-carboxamido)-2,6-difluorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl ) Preparation of pyrrolidine-3-carboxylic acid
  • Example 8 1-(5-Chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl Base) pyrrolidine-3-carboxylic acid preparation
  • Example 2 replace 4-bromo-2,3-dihydro-1H-indene-1-ol with 4-bromo-2-fluoro-2,3-dihydro-1H-indene-1- Alcohol, synthetically prepared to obtain the target compound 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole And [4,5-c]pyridine-2-carboxamido)phenyl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methyl Oxybenzyl)pyrrolidine-3-carboxylic acid (13 mg), LC-MS (ESI-MS): 740 [M+H] + .
  • Example 9 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2- (Methoxybenzyl) pyrrolidine-3-carboxylic acid preparation
  • Example 2 replace 4-bromo-2,3-dihydro-1H-indene-1-ol with 4-bromo-2,2-dimethyl-2,3-dihydro-1H- Indene-1-ol, the target compound 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro -1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)oxy) -3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid (16mg), 1H NMR (500MHz, DMSO-d6) ⁇ 7.98 (brs, 1H), 7.61–7.52 (m, 2H), 7.44–7.36(m,1H), 7.34–7.29(m,2H), 7.23(s,1H), 5.44–
  • Example 10 1-(5-chloro-4-((4'-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine-2-carboxamido)phenyl)-1',3'-dihydrospiro[cyclopropane-1,2'-indene]-1'-yl)oxy)-3- Preparation of fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 2 replace 4-bromo-2,3-dihydro-1H-inden-1-ol with 4'-bromo-1',3'-dihydrospiro[cyclopropane-1,2 '-Indene]-1'-alcohol, synthetically prepared to obtain the target compound 1-(5-chloro-4-((4'-(2-chloro-3-(1,5-dimethyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-1',3'-dihydrospiro[cyclopropane-1,2'-indene]- 1'-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid (8 mg), LC-MS (ESI-MS): 748 [M+H] + .
  • Example 11 1-(5-chloro-4-((2-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c]pyridine-2-carboxamido)phenyl)-1,1a,6,6a-tetrahydrocyclopropyl(a]inden-6-yl)oxy)-3-fluoro-2-methyl (Oxybenzyl) pyrrolidine-3-carboxylic acid preparation
  • Example 2 replace 4-bromo-2,3-dihydro-1H-inden-1-ol with 2-bromo-1,1a,6,6a-tetrahydrocyclopropyl[a] Indene-6-ol, synthetically prepared the target compound 1-(5-chloro-4-((2-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro -1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-1,1a,6,6a-tetrahydrocyclopropyl(a]inden-6-yl)oxy)- 3-Fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid (10 mg), LC-MS (ESI-MS): 734 [M+H] + .
  • Example 12 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-2-methoxybenzyl)pyrrolidine- Preparation of 3-formic acid
  • Example 13 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)thio)-3-fluoro-2-methoxybenzyl)pyrrolidine Preparation of -3-carboxylic acid
  • Example 14 1-(5-Chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)indol-1-yl)methyl)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 16 1-(5-Chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 2 Referring to the synthesis method and steps of Example 2, the 4-bromo-2,3-dihydro-1H-inden-1-ol was replaced with 4-bromo-1H-inden-1-ol, and the target compound 1- (5-Chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine -2-Carboxamido)phenyl)-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid (26mg), LC-MS(ESI -MS):720[M+H] + .
  • Example 17 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-3-methyl-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3 -Preparation of formic acid
  • Example 2 replace 4-bromo-2,3-dihydro-1H-inden-1-ol with 4-bromo-3-methyl-1H-inden-1-ol, and synthetically prepare The target compound 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4, 5-c)pyridine-2-carboxamido)phenyl)-3-methyl-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3- Formic acid (26 mg), LC-MS (ESI-MS): 734 [M+H] + .
  • Example 18 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2-methyl-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3 -Preparation of formic acid
  • Example 2 replace 4-bromo-2,3-dihydro-1H-inden-1-ol with 4-bromo-2-methyl-1H-inden-1-ol, and synthetically prepare The target compound 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4, 5-c)pyridine-2-carboxamido)phenyl)-2-methyl-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3- Formic acid (16 mg), LC-MS (ESI-MS): 734 [M+H] + .
  • Example 19 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-1H-indol-1-yl)methyl)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 20 1-(5-chloro-4-(4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4, Preparation of 5-c)pyridine-2-carboxamido)phenyl)-1H-indole-1-carbonyl)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 21 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-1H-indol-1-yl)sulfonyl)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 22 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,3,5-trifluoro-6-methoxybenzyl)pyrrole
  • Example 2 replace 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 2,3,5-trifluoro-4-hydroxy-6-methoxy Benzaldehyde, synthetically prepared to obtain the target compound 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,3,5-trifluoro-6-methoxy Benzyl)pyrrolidine-3-carboxylic acid (6 mg), LC-MS (ESI-MS): 724 [M+H] + .
  • Example 23 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,3,5-trifluorobenzyl)pyrrolidine-3-carboxylic acid preparation
  • Example 2 replace 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 2,3,5-trifluoro-4-hydroxybenzaldehyde, and synthetically prepare The target compound 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c] (Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,3,5-trifluorobenzyl)pyrrolidine-3-carboxylic acid (12mg ), LC-MS (ESI-MS): 694[M+H] + .
  • Example 24 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3,5-difluoro-2-methoxybenzyl)pyrrolidine- Preparation of 3-formic acid
  • Example 2 replace 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 3,5-difluoro-4-hydroxy-2-methoxybenzene Formaldehyde, synthetically prepared the target compound 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4, 5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3,5-difluoro-2-methoxybenzyl) Pyrrolidine-3-carboxylic acid (22 mg), LC-MS (ESI-MS): 706 [M+H] + .
  • Example 25 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,3-difluorobenzyl)pyrrolidine-3- Preparation of formic acid
  • Example 26 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-cyano-2,3-difluorobenzyl)pyrrolidine-3 -Preparation of formic acid
  • Example 2 replace 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 2,3-difluoro-4-formyl-6-cyanophenol ,
  • the target compound 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5 -c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-cyano-2,3-difluorobenzyl)pyrrolidine -3-carboxylic acid (11 mg), LC-MS (ESI-MS): 701 [M+H] + .
  • Example 27 1-(3-Chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-fluoro-2-methoxybenzyl)pyrrolidine Preparation of -3-carboxylic acid
  • Example 2 replace 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 3-chloro-5-fluoro-4-hydroxy-2-methoxy Benzaldehyde, synthetically prepared to obtain the target compound 1-(3-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H- Imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-fluoro-2-methoxybenzyl Yl)pyrrolidine-3-carboxylic acid (30 mg), LC-MS (ESI-MS): 722 [M+H] + .
  • Example 2 replace 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 3,5-dichloro-4-hydroxy-2-methoxybenzene Formaldehyde, synthetically prepared to obtain the target compound 1-(3,5-dichloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro- 1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxybenzyl) Pyrrolidine-3-carboxylic acid (25 mg), LC-MS (ESI-MS): 738 [M+H] + .
  • Example 29 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((3-cyanobenzyl)oxy) Preparation of -3-fluorobenzyl)pyrrolidine-3-carboxylic acid
  • Step 1 Add N-(2-chloro-3-(1-(6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy)-2,3-dihydro-1H-indene -4-yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (1.0mmol) dissolved In 10 mL of dichloromethane, place in an ice bath at 0°C under the protection of nitrogen, add boron tribromide (5.0 mmol), and react at room temperature for about 4 hours after addition.
  • boron tribromide 5.0 mmol
  • Step 2 Add N-(2-chloro-3-(1-(6-chloro-2-fluoro-4-formyl-3-hydroxyphenoxy)-2,3-dihydro-1H-indene-4 -Yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.8mmol) and 3- Hydroxymethyl benzonitrile (1.6 mmol) was dissolved in 8 mL of anhydrous tetrahydrofuran solution, triphenylphosphine (1.6 mmol) was added, then DIAD (1.6 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for about 12 hours.
  • Step 3 Add N-(2-chloro-3-(1-(6-chloro-3-((3-cyanobenzyl)oxy)-2-fluoro-4-formylphenoxy)-2 ,3-Dihydro-1H-inden-4-yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine -2-carboxamide (0.3mmol) and pyrrolidine-3-carboxylic acid (0.6mmol) were dissolved in a solution of 5mL methanol and 5mL dichloromethane, acetic acid (0.6mmol) was added, the reaction solution was mixed and stirred for about 1 hour, and then added Sodium triacetate borohydride (1.0 mmol).
  • Example 30 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-(pyridin-3-ylmethoxy (4)benzyl)pyrrolidine-3-carboxylic acid preparation
  • Example 31 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-((5-cyanopyridin-3-yl) (Methoxy)-3-fluorobenzyl)pyrrolidine-3-carboxylic acid preparation
  • Example 32 1-(5-chloro-4-((4-(2-chloro-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine -2-Carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Step 1 Add 4-((4-(3-amino-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chloro-3-fluoro-2 -Methoxybenzaldehyde (0.5mmol) and 5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxylic acid (0.5mmol) dissolved in 5mL anhydrous Add HATU (1.5 mmol) and DIPEA (1.5 mmol) to DMF, and react at room temperature for about 24 hours under the protection of nitrogen.
  • HATU 1.5 mmol
  • DIPEA 1.5 mmol
  • Step 2 Add N-(2-chloro-3-(1-(6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy)-2,3-dihydro-1H-indene -4-yl)phenyl)-5-methyl-4,5,6,7-tetrahydro[4,5-c]pyridine-2-carboxamide (0.2mmol) and pyrrolidine-3-carboxylic acid (0.4 mmol) was dissolved in a solution of 3 mL methanol and 3 mL dichloromethane, acetic acid (0.5 mmol) was added, the reaction solution was mixed and stirred for about 1 hour, and then sodium triacetate borohydride (1.0 mmol) was added.
  • Example 33 1-(5-chloro-4-((4-(2-chloro-3-(3,6-dimethyl-4,5,6,7-tetrahydropyrazolo[4,5 -c)pyrimidine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3 -Preparation of formic acid
  • Example 34 1-(5-chloro-4-((4-(2-chloro-3-(3,7-dimethyl-5,6,7,8-tetrahydroimidazo[1,2- a) Pyrazine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3 -Preparation of formic acid
  • Example 35 1-(5-chloro-4-((4-(2-chloro-3-(1,4,4,5 tetramethyl-4,5,6,7-tetrahydro-1H-imidazole And [4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl ) Preparation of pyrrolidine-3-carboxylic acid
  • Example 36 1-(5-chloro-4-((4-(2-chloro-3-(1',5'-dimethyl-1',5',6',7'-tetrahydrospiro [Cyclopropane 1,4'-imidazo[4,5-c]pyridine]-2'-ylcarboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)
  • Example 37 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-1,5,6,7-tetrahydrospiro[imidazo[4, 5-c)pyridine-4,3'-oxetan-2-ylcarboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro -2-Methoxybenzyl)pyrrolidine-3-carboxylic acid preparation
  • Example 38 1-(5-chloro-4-((4-(2-chloro-3-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro -1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methyl (Oxybenzyl) pyrrolidine-3-carboxylic acid preparation
  • Example 39 1-(4-((4-(3-(5-Acetyl-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine -2-Carboxamido)-2-chlorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-5-chloro-3-fluoro-2-methoxybenzyl) Preparation of pyrrolidine-3-carboxylic acid
  • Example 40 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)piperidine Preparation of -3-carboxylic acid
  • Example 41 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)aza
  • Example 42 2-((5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)amino ) Preparation of 3-hydroxy-2-methylpropionic acid
  • Example 44 N-(2-chloro-3-(1-(6-chloro-2-fluoro-3-methoxy-4-((((R)-5-oxopyrrolidine-2- (Yl)methyl)amino)methyl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-1,5-dimethyl-4,5,6,7 -Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide
  • Example 45 N-(2-Chloro-3-(1-(6-chloro-2-fluoro-4-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)-3 -Methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole Preparation of and [4,5-c]pyridine-2-carboxamide
  • Example 46 2-((5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)amino )-2-Methylpropionic acid preparation
  • Step 1 Dissolve 1,2,3,4,5-pentafluoro-6-methoxybenzene (2.0mmol) in 10mL DMF solution, add 4-bromo-2,3-dihydro-1H-indene- 1-alcohol (3.0mmol), cesium carbonate (4.0mmol), heated to 100°C under the protection of nitrogen, and stirred for about 24 hours. After the reaction, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 2 4-Bromo-1-(2,3,5,6-tetrafluoro-4-methoxyphenoxy)-2,3-dihydro-1H-indene (1.5mmol) and pina boronic acid Alcohol ester (1.2mmol) was dissolved in 1,4-dioxane (12mL), Pd(dppf)Cl 2 (0.15mmol) and potassium acetate (3.0mmol) were added, and heated to 90°C under nitrogen to react for about 12 hour. After stopping the reaction and cooling to room temperature, water and ethyl acetate were added for extraction, and the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 3 Add 4,4,5,5-tetramethyl-2-(1-(2,3,5,6-tetrafluoro-4-methoxyphenoxy)-2,3-dihydro- 1H-inden-4-yl)-1,3-dioxaborolane (1.5mmol) and 3-bromo-2-chloroaniline (2.0mmol) were dissolved in 10mL of 1,4-dioxane, and 3.0mL was added Purified water, Pd(PPh 3 ) 4 (0.15 mmol) and sodium carbonate (3.0 mmol) were added, and the reaction mixture was heated to reflux for about 24 hours.
  • Step 4 Add 2-chloro-3-(1-(2,3,5,6-tetrafluoro-4-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl) Aniline (1.5mmol) and 1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxylic acid (1.5mmol) were dissolved in 10mL without Add HATU (3.0 mmol) and DIPEA (4.5 mmol) to water DMF, and react at room temperature for about 24 hours under the protection of nitrogen. Then water was added to quench the reaction, extracted with ethyl acetate, the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 5 The N-(2-chloro-3-(1-(2,3,5,6-tetrafluoro-4-methoxyphenoxy)-2,3-dihydro-1H-indene-4 -Yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.5mmol) dissolved in 5mL Place dichloromethane in an ice bath at 0°C under the protection of nitrogen, add boron tribromide (2.5 mmol), and react at room temperature for about 4 hours after the addition is complete.
  • Step 6 Add N-(2-chloro-3-(1-(2,3,5,6-tetrafluoro-4-hydroxyphenoxy)-2,3-dihydro-1H-inden-4-yl )Phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.3mmol) dissolved in 5mL acetonitrile solution Add 1-bromo-2-chloroethane (0.3 mmol) and potassium carbonate (0.6 mmol), and react at room temperature for about 5 hours.
  • Step 7 Add N-(2-chloro-3-(1-(4-(2-chloroethoxy)-2,3,5,6-tetrafluorophenoxy)-2,3-dihydro- 1H-inden-4-yl)phenyl)-1-,5-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.1 mmol) was dissolved in 3 mL of acetone, pyrrolidin-3-ol (0.2 mmol) and potassium carbonate (0.3 mmol) were added, and the reaction was stirred at room temperature for about 12 hours.
  • Example 48 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzoyl)pyrrole
  • Step 1-4 Referring to the synthesis method of step 1-4 in Example 2, replace 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 5-chloro-3-fluoro-4- Hydroxy-2-methoxybenzoic acid methyl ester can be prepared to obtain the compound 5-chloro-4-(4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetra Hydrogen-1H-imidazo[4,5-c]pyridine-2-carboxamido)yl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro- Methyl 2-methoxybenzoate (0.45 g), LC-MS (ESI-MS): 654 [M+H]+.
  • Step 5 5-Chloro-4-(4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c] (Pyridine-2-carboxamido)yl)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzoic acid methyl ester (0.6mmol) Dissolved in 5mL methanol, added anhydrous LiOH (2.0mmol), reacted at room temperature for 3 hours, and concentrated under reduced pressure.
  • Step 6 Add 5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5- c)Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzoic acid (0.3mmol) and pyrrole Tert-butyl alkane-3-carboxylate (0.6mmol) was dissolved in 5mL of anhydrous DMF, EDCI (1.0mmol), HOBt (1.0mmol) and Et 3 N (1.2mmol) were added, and the reaction was stirred at room temperature for about 20 hours .
  • the reaction was quenched by adding water and extracted with ethyl acetate three times.
  • the organic phase was washed with water and saturated brine.
  • the ethyl acetate layer was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained concentrate was purified by chromatography.
  • Step 7 Add tert-butyl 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole [4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzoyl ) Pyrrolidine-3-carboxylate (0.1 mmol) was dissolved in 5 mL methanol, 4N HCl methanol solution (0.5 mL) was added, and the reaction was carried out at room temperature for 12 hours, and then concentrated under reduced pressure.
  • Example 48 Referring to the synthesis method of Example 48, replacing tert-butyl pyrrolidine-3-carboxylate with 2-aminoethanol, the target compound N-(2-chloro-3-(1-(6-chloro-2-fluoro -4-((2-hydroxyethyl)carbamoyl)-3-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-1,5-di Methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (16mg), LC-MS(ESI-MS): 682[M+H] + .
  • Example 50 N-(2-Chloro-3-(1-(6-chloro-2-fluoro-4-((1-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-3 -Yl)methyl)-3-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-1,5-dimethyl-4,5,6, Preparation of 7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide
  • Example 52 N-(2-chloro-3-(1-(6-chloro-2-fluoro-3-methoxy-4-((6-oxo-5-oxa-2,7-di Azaspiro[3.4]oct-2-yl)methyl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-1,5-dimethyl-4,5 ,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide
  • Example 54 1-(5-Chloro-4-(4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4, Preparation of 5-c]pyridine-2-carboxamido)phenyl)-1H-benzo[d]imidazole-1-carbonyl)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 15 Referring to the synthesis method and reaction steps of Example 15, replacing 4-bromoindoline with 4-bromo-1H-benzo[d]imidazole, the target compound 1-(5-chloro-4-(4 -(2-Chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl) -1H-Benzo[d]imidazole-1-carbonyl)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid (12mg), LC-MS(ESI-MS): 734[M+ H] + .
  • Example 56 1-(5-chloro-4-((7-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-3-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine- Preparation of 3-formic acid
  • Example 2 replace 4-bromo-2,3-dihydro-1H-inden-1-ol with 7-bromo-2,3-dihydrobenzofuran-3-ol,
  • the target compound 1-(5-chloro-4-((7-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydrobenzofuran-3-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine -3-carboxylic acid (22 mg), LC-MS (ESI-MS): 724 [M+H] + .
  • Example 57 1-(5-chloro-4-((1-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethyl)amino)- Preparation of 3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 58 1-(5-chloro-4-(1-((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-2,2,2-trifluoroethyl)- Preparation of 3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Step 1 Combine 3-bromo-2-chloroaniline (3.0mmol) and 1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2 -Carboxylic acid (3.0 mmol) was dissolved in 12 mL of anhydrous DMF, HATU (4.5 mmol) and DIPEA (6.0 mmol) were added, and reacted at room temperature for about 24 hours under the protection of nitrogen. Then water was added to quench the reaction, extracted with dichloromethane, the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 2 Add N-(3-bromo-2-chlorophenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine- 2-formamide (2.0mmol) and pinacol diborate (2.0mmol) were dissolved in 20mL 1,4-dioxane, and Pd(dppf)Cl 2 (0.2mmol) and potassium acetate (4.0mmol) were added, Under the protection of nitrogen, it was heated to 90°C for about 12 hours. After stopping the reaction and cooling to room temperature, water and ethyl acetate were added for extraction, and the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 3 Add N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)phenyl)-1,5- Dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (1.5mmol) and 3-bromo-2-methylaniline (2.0mmol) Dissolved in 10 mL of 1,4-dioxane, added 3.0 mL of purified water, then added Pd(PPh 3 ) 4 (0.15 mmol) and sodium carbonate (3.0 mmol), the reaction mixture was heated to reflux and reacted for about 24 hours.
  • Step 4 Combine 1-(6-chloro-4-(dimethoxymethyl)-2-fluoro-3-methoxyphenyl)-2,2,2-trifluoroethanone (1.0mmol) and N-(3'-Amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetra Hydrogen-1H-imidazo[4,5-c]pyridine-2-carboxamide (1.2mmol) solvent in 10mL 1,2-dichloroethane solution, stir at room temperature for 30 minutes, then add sodium triacetate borohydride (2.0 mmol), the reaction was carried out at room temperature for about 12 hours, and the reaction was completed as detected by TLC.
  • Step 5 Add N-(2-chloro-3'-((1-(6-chloro-2-fluoro-4-formyl-3-methoxyphenyl)-2,2,2-trifluoroethane Yl)amino)-2'-methyl-[11,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine-2-carboxamide (0.2mmol) and pyrrolidine-3-carboxylic acid (0.4mmol) were dissolved in a solution of 5mL methanol and 5mL dichloromethane, acetic acid (1.0mmol) was added, and the reaction mixture was mixed Stir for about 1 hour, then add sodium triacetate borohydride (1.0 mmol).
  • Example 59 1-(5-chloro-4-((1-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)cyclopropyl)amino)-3-fluoro-2-methyl (Oxybenzyl) pyrrolidine-3-carboxylic acid preparation
  • Step 1 Combine 3-bromo-2-chloroaniline (4.0mmol) and 1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2 -The carboxylic acid (4.8 mmol) was dissolved in 20 mL of anhydrous DMF, HATU (6.4 mmol) and DIPEA (8.0 mmol) were added, and the reaction was carried out at room temperature for about 24 hours under the protection of nitrogen. Then add water to quench the reaction, extract twice with dichloromethane, combine the organic phase to wash with water and saturated brine, separate the organic phase and dry with anhydrous sodium sulfate.
  • Step 2 Add N-(3-bromo-2-chlorophenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine- 2-formamide (2.0mmol) and pinacol diborate (1.6mmol) were dissolved in 15mL 1,4-dioxane, and Pd(dppf)Cl 2 (0.2mmol) and potassium acetate (4.0mmol) were added, Under the protection of nitrogen, heat to 90°C and react for about 20 hours. After stopping the reaction and cooling to room temperature, water and ethyl acetate were added for extraction, and the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 3 Combine 1-(3-bromo-2-methylphenyl)cyclopropylamine (1.5mmol) and N-(2-chloro-3-(4,4,5,5-tetramethyl-1,3 -Dioxaborolan-2-yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2 -Formamide (1.2 mmol) was dissolved in 12 mL of toluene solution, copper acetate (0.3 mmol) and potassium carbonate (1.0 mmol) were added, and reacted at 50°C for about 48 hours.
  • Step 4 Combine 6-chloro-2-fluoro-4-formyl-3-methoxyphenyl triflate (1.0 mmol) and N-(3'-(1-aminocyclopropyl)- 2-Chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c]pyridine-2-carboxamide (0.5mmol) was dissolved in 10mL of toluene solution, and cuprous iodide (0.1mmol), cesium carbonate (0.2mmol) and 3,4,7,8-tetramethyl were added -1,10-phenanthroline (0.2mmol), the reaction solution was heated to reflux conditions and reacted for 12 hours.
  • Step 5 Add N-(2-chloro-3'-(1-((6-chloro-2-fluoro-4-formyl-3-methoxyphenyl)amino)cyclopropyl)-2'- Methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine- 2-formamide (0.2mmol) and pyrrolidine-3-carboxylic acid (0.4mmol) were dissolved in a solution of 5mL methanol and 5mL dichloromethane, acetic acid (1.0mmol) was added, the reaction solution was mixed and stirred for about 1 hour, and then three Sodium acetate borohydride (1.0 mmol).
  • Example 60 1-(5-chloro-4-(1-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)cyclopropoxy)-3-fluoro-2-methoxybenzyl Base) pyrrolidine-3-carboxylic acid preparation
  • N-(2-chloro-3'-(1-(((6-chloro-2-fluoro-4-formyl-3-methoxyphenyl)amino )Cyclopropyl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamide is replaced with N-(2-chloro-3'-(1-hydroxycyclopropyl)-2'-methyl-[1,1'-biphenyl]- 3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide, the target compound 1-( 5-chloro-4-(1-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5
  • Example 61 1-(5-chloro-4-((1-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)cyclobutyl)amino)-3-fluoro-2-methoxy Benzyl) pyrrolidine-3-carboxylic acid preparation
  • Example 62 1-(5-chloro-4-((((2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine-2-carboxamido)-2-methyl-[[1,1'-biphenyl]-3-yl)difluoromethyl)amino)-3-fluoro-2-methyl (Oxybenzyl) pyrrolidine-3-carboxylic acid preparation
  • Example 63 1-(5-chloro-4-((3-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)oxetan-3-yl)oxy)-3 -Fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid preparation
  • N-(2-chloro-3'-(1-(((6-chloro-2-fluoro-4-formyl-3-methoxyphenyl)amino )Cyclopropyl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamide is replaced by N-(2-chloro-3'-(3-hydroxyoxetan-3-yl)-2'-methyl-[1,1 '-Biphenyl]-3-yl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide can be prepared
  • Example 64 1-(5-chloro-4-((4-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)oxy) Preparation of -3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 65 1-(5-Chloro-4-(1-(2'-chloro-3'-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine-2-carboxamido-2-methyl-[[1,1'-biphenyl]-3-yl)-2,2,2-trifluoroethoxy)-3- Preparation of fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid
  • Example 66 (R)-1-(5-chloro-4-((((S)-4-(2-chloro-3-(1,5-dimethyl-4,5,6,7- Tetrahydro-1H-imidazole, 5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxy Benzyl) pyrrolidine-3-carboxylic acid preparation
  • Step 1 4-Bromo-1-indanone (5.0mmol) was dissolved in 50mL of dichloromethane solution, and the temperature was reduced to -20°C under nitrogen protection, and then (S)-2-methyl-CBS-oxazole was added Borane (0.5 mmol), toluene solution (2M, 12.5 mL) of borane dimethyl sulfide complex was slowly added dropwise through a dropping funnel, and the reaction was continued for about 3 hours after the addition was completed. Then water was added to quench the reaction, extracted with dichloromethane, the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 2 Combine 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde (3.0mmol) and (R)-4-bromo-2,3-dihydro-1H-inden-1-ol (4.5 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran solution, triphenylphosphine (4.5 mmol) was added, then DIAD (4.5 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for about 12 hours. The reaction was stopped, and most of the reaction solvent was removed by concentration under reduced pressure.
  • Example 66 replacing (R)-pyrrolidine-3-carboxylic acid with (S)-pyrrolidine-3-carboxylic acid, the target compound (S)-1-(5-chloro-4- ((((S)-4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole,5-c)pyridine-2-formyl Amino)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid (11mg), LC-MS (ESI-MS): 722[M+H] + .
  • Example 68 (R)-1-(5-chloro-4-((((R)-4-(2-chloro-3-(1,5-dimethyl-4,5,6,7- Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2 -Methoxybenzyl)pyrrolidine-3-carboxylic acid preparation
  • Step 1 4-Bromo-1-indanone (5.0mmol) was dissolved in 50mL of dichloromethane solution, and the temperature was reduced to -20°C under nitrogen protection, and then (R)-2-methyl-CBS-oxazole was added Borane (0.5 mmol), toluene solution (2M, 12.5 mL) of borane dimethyl sulfide complex was slowly added dropwise through a dropping funnel, and the reaction was continued for about 3 hours after the addition was completed. Then water was added to quench the reaction, extracted with dichloromethane, the organic phase was separated and dried with anhydrous sodium sulfate.
  • Step 2 Combine 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde (3.0mmol) and (S)-4-bromo-2,3-dihydro-1H-inden-1-ol (4.5 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran solution, triphenylphosphine (4.5 mmol) was added, then DIAD (4.5 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for about 12 hours. The reaction was stopped, and most of the reaction solvent was removed by concentration under reduced pressure.
  • Example 69 (S)-1-(5-chloro-4-(((R)-4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetra Hydrogen-1H-imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methyl (Oxybenzyl) pyrrolidine-3-carboxylic acid preparation
  • Example 68 replacing (R)-pyrrolidine-3-carboxylic acid with (S)-pyrrolidine-3-carboxylic acid, the target compound (S)-1-(5-chloro-4- ((((R)-4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole,5-c)pyridine-2-formyl Amino)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine-3-carboxylic acid (11mg), LC-MS (ESI-MS): 722[M+H] + .
  • Example 70 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine
  • 4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)pyrrolidine Preparation of Methyl-3-carboxylate
  • Example 71 1-(4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c ]Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,3,5,6-tetrafluorobenzyl)pyrrolidine-3- Preparation of methyl formate
  • Example 72 N-(2-chloro-3-(1-(6-chloro-4-((dimethylamino)methyl)-2-fluoro-3-methoxyphenoxy)-2, 3-Dihydro-1H-inden-4-yl)phenyl)-1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2 -Formamide preparation
  • Example 73 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)piperidine
  • Example 74 1-(5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)proline Acid preparation
  • the target compound 1-(5-chloro-4-((4-(2-chloro-3-(1,5 -Dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indene- 1-yl)oxy)-3-fluoro-2-methoxybenzyl)proline (7 mg), LC-MS (ESI-MS): 722 [M+H] + .
  • Example 75 (2S)-2-((5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H -Imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl (Yl)amino)-3-hydroxy-2-methylpropionic acid
  • Example 76 (2R)-2-((5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H -Imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl (Yl)amino)-3-hydroxy-2-methylpropionic acid
  • Example 77 2-((5-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluoro-2-methoxybenzyl)serine Preparation
  • Example 2 Referring to the synthesis method of Example 2, replacing pyrrolidine-3-carboxylic acid with serine, the target compound 2-((5-chloro-4-((4-(2-chloro-3-(1,5- Dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indene-1 -Yl)oxy)-3-fluoro-2-methoxybenzyl)serine (6 mg), LC-MS (ESI-MS): 712 [M+H] + .
  • the target compound ((5-chloro-4-((4-(2-chloro-3-(1,5- Dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indene-1 -Yl)oxy)-3-fluoro-2-methoxybenzyl)serine methyl ester (10 mg), LC-MS (ESI-MS): 726 [M+H] + .
  • Example 79 1-(5-chloro-4-((6-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-7-methyl-2,3-dihydro-1H-indan-1-yl)oxy)-3-fluoro-2-methoxy Benzyl) pyrrolidine-3-carboxylic acid preparation
  • Example 2 replace 4-bromo-2,3-dihydro-1H-indane-1-ol with 6-bromo-7-methyl-2,3-dihydro-1H-indan- 1-alcohol, the target compound 1-(5-chloro-4-((6-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H -Imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-7-methyl-2,3-dihydro-1H-indan-1-yl)oxy)-3-fluoro -2-Methoxybenzyl)pyrrolidine-3-carboxylic acid (7 mg), LC-MS (ESI-MS): 736 [M+H] + .
  • Example 80 1-(5-chloro-4-((7-chloro-6-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H- Imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indenyl-1-yl)oxy)-3-fluoro-2-methoxybenzyl Base) pyrrolidine-3-carboxylic acid preparation
  • Example 2 replace 4-bromo-2,3-dihydro-1H-indane-1-ol with 6-bromo-7-chloro-2,3-dihydro-1H-indan-1 -Alcohol, the target compound 1-(5-chloro-4-((7-chloro-6-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetra Hydro-1H-imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indenyl-1-yl)oxy)-3-fluoro-2- Methoxybenzyl)pyrrolidine-3-carboxylic acid (8 mg), LC-MS (ESI-MS): 756 [M+H] + .
  • Example 81 1-(5-chloro-4-((6-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-7-cyano-2,3-dihydro-1H-indan-1-yl)oxy)-3-fluoro-2-methoxy Benzyl) pyrrolidine-3-carboxylic acid preparation
  • Example 2 replace 4-bromo-2,3-dihydro-1H-indane-1-ol with 5-bromo-3-hydroxy-2,3-dihydro-1H-indan-4 -Nitriles, the target compound 1-(5-chloro-4-((6-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H- Imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-7-cyano-2,3-dihydro-1H-indan-1-yl)oxy)-3-fluoro- 2-Methoxybenzyl)pyrrolidine-3-carboxylic acid (8 mg), LC-MS (ESI-MS): 747 [M+H] + .
  • Example 82 1-(5-chloro-4-((5-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[4 ,5-c)pyridine-2-carboxamido)phenyl)-4-methyl-2,3-dihydrobenzofuran-3-yl)oxy)-3-fluoro-2-methoxybenzyl Base) pyrrolidine-3-carboxylic acid preparation
  • Example 083 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2- Preparation of fluoro-6-methoxybenzyl)amino)cyclobutane carboxylic acid
  • Step 1 Add 2-((3-bromo-2-chlorophenyl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5( 4H)-Carboxylic acid tert-butyl ester (prepared with reference to WO2018119224A1 and CN110267953) (4g) was dissolved in 40mL dichloromethane, 4mL trifluoroacetic acid was added, and the reaction was heated to 40°C for 3h. TLC detected that the reaction was complete, and the reaction was evaporated under reduced pressure. Evaporate the solvent; then extract with dichloromethane and water, separate the organic phase and concentrate under reduced pressure.
  • Step 2 Add N-(3-bromo-2-chlorophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-methyl Amide (4g) and ((4-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)-2,3-dihydro-1H-indene-1- (Yl)oxy)tert-butyldimethylsilane (8.1g) dissolved in 20ml 1,4-epoxy hexacyclic ring, add H 2 0 (10mL), Na 2 CO 3 (2.3g), Pd(dppf)Cl 2 (787mg), heated to 90°C and reacted overnight.
  • Step 3 Add N-(3-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-2-chlorophenyl)- 1-Methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (3g) was dissolved in 30mL tetrahydrofuran, and 28mL TBAF (1mol/L in THF), heated to 40°C and reacted overnight. After the completion of the reaction was detected by TLC, the solvent was evaporated under reduced pressure, and then extracted with ethyl acetate EA and water. The organic phase was separated and concentrated under reduced pressure.
  • Step 4 Add N-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)-1-methyl-4,5,6,7- Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (500mg) and propyl 2-carbonylbenzoate (632mg) were dissolved in 10mL of dichloromethane, DIPEA (458mg) was added, and stirred at room temperature After 0.5 hours, sodium acetate borohydride (752 mg) was added, and the reaction was carried out at room temperature overnight. After the completion of the reaction detected by TLC, it was extracted with dichloromethane and water. The organic phase was separated and concentrated under reduced pressure.
  • Step 5 Dissolve 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde (1.02g) and methyl 1-aminocyclobutanoate hydrochloride (1.66g) in 20mL of dichloromethane , Add triethylamine (1.3mL) and sodium acetate borohydride (2.12g), and react at room temperature overnight. After the completion of the reaction detected by TLC, it was extracted with dichloromethane and water. The organic phase was separated and concentrated under reduced pressure.
  • Step 6 Add 2-(2-((2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)carbamoyl)-1-methyl- 6,7-Dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl) propyl benzoate (70mg) and 1-((3-chloro-2-fluoro-4-hydroxyl -6-Methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester (57mg) was dissolved in 2mL 2-methyltetrahydrofuran, triphenylphosphine (78mg) was added, DIAD (60mg) was added dropwise under the protection of nitrogen, The reaction was carried out at room temperature for 30 minutes.
  • Step 7 The 2-(2-((2-chloro-3-(1-(2-chloro-3-fluoro-5-methoxy-4-((1-(methoxycarbonyl)cyclobutyl) (Amino)methyl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazole (4 ,5-c]pyridine-5(4H)-yl)propyl benzoate (45mg) was dissolved in 2mL methanol, lithium hydroxide (24mg) was added, and the reaction was carried out overnight at room temperature.
  • Example 084 1-((3-chloro-4-((4-(2-chloro-3-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetra Hydrogen-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6- (Methoxybenzyl) amino) cyclobutane carboxylic acid preparation
  • Step 1 Add N-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)-1-methyl-4,5,6,7- Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (405mg) and 2-bromoethyl benzoate (286mg) were dissolved in 10mL DMF, DIPEA (269mg) was added and heated to Reacted overnight at 60°C. After TLC detected that the reaction was complete, ethyl acetate and water were added for extraction. The organic phase was separated and concentrated under reduced pressure.
  • Step 2 the 2-(2-((2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)carbamoyl)-1-methyl- 6,7-Dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl) ethyl benzoate (75mg) and 1-((3-chloro-2-fluoro-4-hydroxyl -6-Methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester (60mg) was dissolved in 2mL 2-methyltetrahydrofuran, triphenylphosphine (80mg) was added, DIAD (65mg) was added dropwise under the protection of nitrogen, The reaction was carried out at room temperature for 30 minutes.
  • Step 3 Add 2-(2-((2-chloro-3-(1-(2-chloro-3-fluoro-5-methoxy-4-((1-(methoxycarbonyl)cyclobutyl) (Amino)methyl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazole (4 ,5-c]pyridine-5(4H)-yl)ethyl benzoate (40mg) was dissolved in 2mL methanol, lithium hydroxide (22mg) was added, and the reaction was carried out overnight at room temperature.
  • Example 085 1-((3-chloro-4-((4-(2-chloro-3-(5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetra Hydrogen-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6- (Methoxybenzyl) amino) cyclobutane carboxylic acid preparation
  • Step 1 Add N-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)-1-methyl-4,5,6,7- Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (200mg) was dissolved in 5mL ethanol, 2-methylepoxypropane (82mg) and DIPEA (183mg) were added and heated to 80°C The reaction was carried out overnight; after the completion of the reaction was detected by TLC, the solvent was evaporated under reduced pressure, and then extracted with ethyl acetate and water. The organic phase was separated and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography to obtain the white solid product N-(2-chloro-3- (1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(2-hydroxypropyl)-1-methyl-4,5,6,7-tetrahydro- 1H-imidazole[4,5-c]pyridine-2-carboxamide (170mg), the yield was 75%.
  • Step 3 Add 2-(2-((2-chloro-3-(1-(2-chloro-3-fluoro-5-methoxy-4-((1-(methoxycarbonyl)cyclobutyl) (Amino)methyl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazole (4 ,5-c]pyridine-5(4H)-yl)ethyl benzoate (41mg) was dissolved in 2mL methanol, lithium hydroxide (22mg) was added, and the reaction was carried out overnight at room temperature.
  • Example 086 1-((6-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-methoxy-3-methylbenzyl) (Amino) cyclopropane carboxylic acid preparation
  • Example 083 propyl 2-carbonylbenzoate was replaced with paraformaldehyde, and the 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino) ring was replaced with paraformaldehyde.
  • Methyl butane carboxylate is replaced with 1-((6-chloro-4-hydroxy-2-methoxy-3-methylbenzyl)amino)cyclopropane carboxylate (from 2-chloro-4-hydroxy -5-methyl-6-methoxybenzaldehyde and 1-aminocyclopropanoic acid methyl ester hydrochloride synthesis), synthetically obtain the target compound 1-((6-chloro-4-((4-(2- Chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3- Dihydro-1H-inden-1-yl)oxy)-2-methoxy-3-methylbenzyl)amino)cyclopropanecarboxylic acid (31mg), LC-MS(ESI-MS):704[M +H] + .
  • Example 087 1-((3-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole [4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,6-difluorobenzyl)amino)cyclopropanecarboxy Acid preparation
  • Example 083 propyl 2-carbonylbenzoate was replaced with paraformaldehyde, and the 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino) ring was replaced with paraformaldehyde.
  • Methyl butanecarboxylate is replaced with 1-((3-chloro-2,6-difluoro-4-hydroxybenzyl)amino)cyclopropanemethyl carboxylate (from 2-fluoro-4-hydroxy-5-chloro -6-Fluorobenzaldehyde and 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride were synthesized), and the target compound 1-((3-chloro-4-((4-(2-chloro-3-(1, 5-Dimethyl-4,5,6,7-tetrahydro-1H-imidazole (4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indene- 1-yl)oxy)-2,6-difluorobenzyl)amino)cyclopropanecarboxylic acid (45 mg), LC-MS (ESI-MS): 696 [M+H] + .
  • Example 088 1-((3,5-Dichloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H- Imidazole (4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,6-difluorobenzyl)amino)
  • Example 083 propyl 2-carbonylbenzoate was replaced with paraformaldehyde, and the 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino) ring was replaced with paraformaldehyde.
  • Methyl butanecarboxylate is replaced with 1-((3,5-Dichloro-2,6-difluoro-4-hydroxybenzyl)amino)cyclopropanecarboxylate (from 2-fluoro-3-chloro-4 -Hydroxy-5-chloro-6-fluorobenzaldehyde and 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride were synthesized), and the target compound 1-((3,5-dichloro-4-((4-( 2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2, 3-Dihydro-1H-inden-1-yl)oxy)-2,6-difluorobenzyl)amino)cyclopropanecarboxylic acid (18mg), LC-MS(ESI-MS): 730[M+H
  • Example 089 1-((4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole [4,5-c ]Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-3,5-difluoro-2-methoxybenzyl)amino)ring
  • Example 083 propyl 2-carbonylbenzoate was replaced with paraformaldehyde, and the 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino) ring was replaced with paraformaldehyde.
  • Methyl butanecarboxylate was replaced with 1-((3,5-difluoro-4-hydroxy-2-methoxybenzyl)amino)cyclobutane carboxylate (from 2-methoxy-3- Fluoro-4-hydroxy-5-fluorobenzaldehyde and methyl 1-aminocyclobutanoate hydrochloride were synthesized, and the target compound 1-((4-((4-(2-chloro-3-(1 ,5-Dimethyl-4,5,6,7-tetrahydro-1H-imidazole (4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indene -1-yl)oxy)-3,5-difluoro-2-methoxybenzyl)amino)cyclobutanecarboxylic acid (26mg), LC-MS(ESI-MS): 706[M+H] + .
  • Example 090 1-((3-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole [4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)
  • Example 091 1-((3-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole [4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2,6-dimethoxybenzyl)amino) ring
  • Example 092 1-((3-chloro-4-((4-(2-chloro-3-(5-(2-hydroxy-2-methylpropyl)-1-methyl-4,5, 6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2 -Fluoro-6-methoxybenzyl)amino)cyclobutane carboxylic acid preparation
  • Example 085 With reference to the synthesis method of Example 085, the 2-methyl propylene oxide was replaced with 2,2-dimethyl ethylene oxide to synthesize the target compound 1-((3-chloro-4-((4-(2 -Chloro-3-(5-(2-hydroxy-2-methylpropyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine- 2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)cyclobutanecarboxylic acid (15mg ), LC-MS (ESI-MS): 780[M+H] + .
  • Example 093 1-((3-chloro-4-((4-(2-chloro-3-(5-(2-methoxyethyl)-1-methyl-4,5,6,7 -Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro- Preparation of 6-methoxybenzyl)amino)cyclobutane carboxylic acid
  • Example 084 the 2-bromoethyl benzoate was replaced with 1-bromo-2-methoxyethane to synthesize the target compound 1-((3-chloro-4-((4- (2-Chloro-3-(5-(2-methoxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2 -Carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)cyclobutanecarboxylic acid (20mg) , LC-MS (ESI-MS): 766[M+H] + .
  • Example 094 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2- Preparation of fluoro-6-methoxybenzyl)amino)cyclopropane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclopropane carboxylate (comprised of 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and 1- Methyl aminocyclopropanecarboxylate hydrochloride was prepared according to step 5 of Example 083), and the target compound 1-((3-chloro-4-((4-(2-chloro-3-(5-(1 -Hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2 ,3-Dihydro-1H-inden-1-yl
  • Example 095 2-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2- Preparation of fluoro-6-methoxybenzyl)amino)acetic acid
  • Example 083 the methyl 1-aminocyclobutanoate hydrochloride was replaced with methyl aminoacetate hydrochloride to synthesize the target compound 2-((3-chloro-4-((4-(2 -Chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2 -Carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)acetic acid (16mg), LC-MS (ESI-MS): 726[M+H] + .
  • Example 096 1-((3-chloro-4-((4-(2-chloro-3-(5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetra Hydrogen-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6- (Methoxybenzyl) amino) cyclopropane carboxylic acid preparation
  • Example 084 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 1-((3- Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclopropane carboxylate (comprised of 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and 1- Methyl aminocyclopropanecarboxylate hydrochloride was prepared according to step 5 of Example 083), and the target compound 1-((3-chloro-4-((4-(2-chloro-3-(5-(2 -Hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-di Hydrogen-1H-inden-1-yl)oxy)-2-fluorine
  • Example 097 1-((3-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole [4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)
  • Example 083 propyl 2-carbonylbenzoate was replaced with paraformaldehyde, and the 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino) ring was replaced with paraformaldehyde.
  • Methyl butanecarboxylate was replaced with methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclopropanecarboxylate to synthesize the target compound 1-((3 -Chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2- Carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)cyclopropanecarboxylic acid (31mg), LC -MS (ESI-MS): 708[M+H] + .
  • Example 098 1-((3-chloro-4-((4-(2-chloro-3-(1-methyl-4,5,6,7-tetrahydro-1H-imidazole [4,5- c)Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-index-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)cyclopropanecarboxy Acid preparation
  • Step 1 Add N-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)-1-methyl-4,5,6,7- Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (100mg) was dissolved in 3mL 2-methyltetrahydrofuran, and 1-((3-chloro-2-fluoro-4-hydroxy-6 -Methoxybenzyl)amino)cyclopropanecarboxylic acid methyl ester (86mg) and triphenylphosphine (124mg), DIAD (96mg) was added dropwise under the protection of nitrogen, and reacted at room temperature for 1 hour.
  • Step 2 Add 1-((3-chloro-4-((4-(2-chloro-3-(1-methyl-4,5,6,7-tetrahydro-1H-imidazole [4,5- c)Pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)cyclopropanecarboxy Methyl acid methyl ester (50mg) was dissolved in 2mL methanol, lithium hydroxide (20mg) was added, and the reaction was carried out overnight at room temperature.
  • Example 099 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6- Preparation of fluoro-2-methoxybenzyl)amino)cyclobutane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-6-fluoro-4-hydroxy-2-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester (comprised of 2-methoxy-3-chloro-4-hydroxy-6-fluorobenzaldehyde and 1 -Methyl aminocyclobutanoate hydrochloride was prepared according to step 5 in Example 83), and the target compound 1-((3-chloro-4-((4-(2-chloro-3-(5-( 1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)- 2,3-Dihydro-1H-inden-1-yl)oxy
  • Example 100 N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((3-hydroxyazetidin-1-yl)methyl)-5-methoxy Phenyloxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro Preparation of -1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 084 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 1-(3-chloro -2-fluoro-4-hydroxy-6-methoxybenzyl)azetidine-3-ol (composed of 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and 3- Hydroxyazetidine hydrochloride was prepared according to step 5 of Example 083), and the target compound N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((3- Hydroxyazetidin-1-yl)methyl)-5-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(2-hydroxy Ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2-car
  • Example 084 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 4-((3- Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)isoxazolidin-3-one (comprised of 2-fluoro-3-chloro-4-hydroxy-6-methoxyformaldehyde and 4 -Amino-3-isoxazolidinone was prepared according to step 5 in Example 83), and the target compound N-(2-chloro-3-(1-(2-chloro-3-fluoro-5-methoxy -4-((3-oxazolidin-4-yl)amino)methyl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(2-hydroxy Ethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imi
  • Example 102 N-(2-Chloro-3-(1-(2-chloro-3-fluoro-4-((2-(hydroxymethyl)pyrrolidin-1-yl)methyl)-5-methyl (Oxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(2-hydroxyethyl)-1-methyl-4,5,6,7-tetra Preparation of Hydrogen-1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 084 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with (1-(3- Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)pyrrolidin-2-yl)methyl acetate (3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and pyrrole Alk-2-yl methyl acetate was prepared according to step 5 in Example 83), and the target compound N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((2- (Hydroxymethyl)pyrrolidin-1-yl)methyl)-5-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(2- Hydroxyethyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo
  • Example 103 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6- Preparation of fluoro-2-methoxybenzyl)amino)cyclopropane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-6-fluoro-4-hydroxy-2-methoxybenzyl)amino)cyclopropane carboxylate (comprised of 3-chloro-6-fluoro-4-hydroxy-2-methoxybenzaldehyde and 1- Methyl aminocyclopropanecarboxylate hydrochloride was prepared according to step 5 of Example 083), and the target compound 1-((3-chloro-4-((4-(2-chloro-3-(5-(1 -Hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2 ,3-Dihydro-1H-inden-1-yl
  • Example 104 1-((3-chloro-4-((4-(2-chloro-3-(5-(3-hydroxypropyl)-1-methyl-4,5,6,7-tetra Hydrogen-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6- (Methoxybenzyl) amino) cyclopropane carboxylic acid preparation
  • Example 105 1-((3-chloro-4-((4-(2-chloro-3-(5-((3-(hydroxymethyl)oxytan-3-yl)methyl)-1- Methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indene-1- (Yl)oxy)-2-fluoro-6-methoxybenzyl)amino)cyclopropane carboxylic acid
  • Example 106 4-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2- Preparation of fluoro-6-methoxybenzyl)amino)butyric acid
  • Example 083 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 4-((3- Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino) butyric acid methyl ester was synthesized to obtain the target compound 4-((3-chloro-4-((4-(2-chloro-3- (5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido) (Phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)butanoic acid (22mg), LC-MS (ESI-MS ):754[M+H] + .
  • Example 107 1-((3-chloro-4-((4-(3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole [4,5-c )Pyridine-2-carboxamido)-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino ) Preparation of cyclopropane carboxylic acid
  • Example 108 1-((3-chloro-2-fluoro-4-((4-(3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)-2-methylphenyl)-2,3-dihydro-1H-inden-1-yl)oxy (4)-6-methoxybenzyl)amino)cyclopropane carboxylic acid
  • Example 109 1-((3-Chloro-4-((4-(2-cyano-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl) (Amino) cyclopropane carboxylic acid preparation
  • Example 110 1-((3-chloro-4-((4-(2-cyano-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5, 6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2 -Fluoro-6-methoxybenzyl)amino)cyclopropane carboxylic acid preparation
  • Example 111 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6- Preparation of fluoro-2-methoxybenzyl)amino)cyclobutane carboxylic acid
  • Example 112 1-((3-chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole [4 ,5-c)pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6-fluoro-2-methoxybenzyl)amino)
  • Example 083 propyl 2-carbonylbenzoate was replaced with paraformaldehyde, and the 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino) ring was replaced with paraformaldehyde.
  • Methyl butanecarboxylate was replaced with methyl 1-((3-chloro-6-fluoro-4-hydroxy-2-methoxybenzyl)amino)cyclopropanecarboxylate to synthesize the target compound 1-((3 -Chloro-4-((4-(2-chloro-3-(1,5-dimethyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2- Carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6-fluoro-2-methoxybenzyl)amino)cyclopropanecarboxylic acid (21mg), LC -MS (ESI-MS): 708[M+H] + .
  • Example 113 N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((3-(hydroxymethyl)piperidin-1-yl)methyl)-5-methyl (Oxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6, 7-Tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 083 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with (1-(3- Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) piperidin-3-yl) methyl acetate (comprised of 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and Methyl piperidin-3-yl acetate was prepared according to step 5 of Example 083), and the target compound N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((3- (Hydroxymethyl)piperidin-1-yl)methyl)-5-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1- Hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro
  • Example 114 N-(2-Chloro-3-(1-(2-chloro-3-fluoro-5-methoxy-4-(((5-oxopyrrolidin-2-yl)methyl)amino )Methyl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5, 6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide
  • Example 083 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 5-((3- Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)methylaminomethyl)pyrrolidin-2-one (from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzene Formaldehyde and 3-aminomethylpyrrolidin-2-one were prepared according to step 5 of Example 083), and the target compound N-(2-chloro-3-(1-(2-chloro-3-fluoro-5- Methoxy-4-(((5-oxopyrrolidin-2-yl)methyl)amino)methyl)phenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl )-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydr
  • Example 115 N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((3-hydroxypyrrolidin-1-yl)methyl)-5-methoxyphenoxy Yl)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro -1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 083 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 1-(3-chloro -2-fluoro-4-hydroxy-6-methoxybenzyl)pyrrolidine-3-acetate (from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and pyrrolidine- 3-Acetate was prepared according to step 5 of Example 083), and the target compound N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((3-hydroxypyrrolidine- 1-yl)methyl)-5-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)- 1-Methyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide (
  • Example 116 N-(2-chloro-3-(1-(2-chloro-4-((cyclobutylamino)methyl)-3-fluoro-5-methoxyphenoxy)-2, 3-Dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazole [ 4,5-c)pyridine-2-carboxamide
  • Example 083 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 2-chloro-4- ((Cyclobutylamino)methyl)-3-fluoro-5-methoxyphenol (from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and cyclobutylamine according to Example 083 Prepared in step 5), synthetically obtain the target compound N-(2-chloro-3-(1-(2-chloro-4-((cyclobutylamino)methyl)-3-fluoro-5-methoxybenzene (Oxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetra Hydrogen-1H-imidazole [4,5-c]pyridine-2-carboxamide (11 mg
  • Example 117 N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-(((1-hydroxy-2-methylpropan-2-yl)amino)methyl)- 5-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5 ,6,7-Tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 083 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 2-((3- Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)-2-methylpropyl acetate (from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzene Formaldehyde and 2-amino-2-methylpropyl acetate were prepared according to step 5 of Example 083), and the target compound N-(2-chloro-3-(1-(2-chloro-3-fluoro- 4-(((1-hydroxy-2-methylpropan-2-yl)amino)methyl)-5-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl) Phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro-1
  • Example 118 N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)-5-methyl (Oxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6, 7-Tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 083 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with (1-((3 -Chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclopropyl)methyl acetate (comprised of 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and (1-Aminocyclopropyl-1-)methyl acetate was prepared according to step 5 of Example 083), and the target compound N-(2-chloro-3-(1-(2-chloro-3-fluoro-4 -(((1-(hydroxymethyl)cyclopropyl)amino)methyl)-5-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)- 5-(1-Hydroxypropan-2-yl)-1-methyl-4,5
  • Example 119 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6- Ethoxy-2-fluorobenzyl)amino)cyclopropane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-6-ethoxy-2-fluoro-4-hydroxybenzyl)amino)cyclopropane carboxylate (comprised of 3-chloro-2-fluoro-4-hydroxy-6-ethoxybenzaldehyde and 1- Methyl aminocyclopropanecarboxylate hydrochloride was prepared according to step 5 of Example 083), and the target compound 1-((3-chloro-4-((4-(2-chloro-3-(5-(1 -Hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2 ,3-Dihydro-1H-inden-1-yl
  • Example 120 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6- (Cyclopropylmethoxy)-2-fluorobenzyl)amino)cyclopropane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-6-(cyclopropylmethoxy)-2-fluoro-4-hydroxybenzyl)amino)cyclopropanecarboxylic acid methyl ester (from 3-chloro-2-fluoro-4-hydroxy-6-cyclopropylmethyl Oxybenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride were prepared according to step 5 of Example 083), and the target compound 1-((3-chloro-4-((4-(2-chloro- 3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (Yl)phenyl)-2,3-dihydr
  • Example 121 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6- (Difluoromethoxy)-2-fluorobenzyl)amino)cyclopropane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-6-(difluoromethoxy)-2-fluoro-4-hydroxybenzyl)amino)cyclopropanecarboxylic acid methyl ester (from 3-chloro-2-fluoro-4-hydroxy-6-difluoroethoxy Benzaldehyde and 1-aminocyclopropane carboxylic acid methyl ester hydrochloride were prepared according to step 5 of Example 083), and the target compound 1-((3-chloro-4-((4-(2-chloro-3 -(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide )Phenyl)-2,3-d
  • Example 122 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6- (Cyclobutylmethoxy)-2-fluorobenzyl)amino)cyclobutane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-6-(cyclobutylmethoxy)-2-fluoro-4-hydroxybenzyl)amino)cyclobutanecarboxylic acid methyl ester (from 3-chloro-2-fluoro-4-hydroxy-6-cyclobutylmethoxy Benzaldehyde and methyl 1-aminocyclobutanecarboxylate hydrochloride were prepared according to step 5 of Example 083), and the target compound was synthesized: 1-((3-chloro-4-((4-(2-chloro- 3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (Yl)phenyl)-2
  • Example 123 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2- Fluoro-6-isopropoxybenzyl)amino)cyclobutane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-6-(isopropoxy)-2-fluoro-4-hydroxybenzyl)amino)cyclobutanecarboxylic acid methyl ester (from 3-chloro-2-fluoro-4-hydroxy-6-isopropyloxy Benzaldehyde and methyl 1-aminocyclobutanecarboxylate hydrochloride were prepared according to step 5 in Example 083), and the target compound 1-((3-chloro-4-((4-(2-chloro- 3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (Yl)phenyl)-2,3-dihydro-1H-in
  • Example 124 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6, 7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro -6-(2,2,2-Trifluoroethoxy)benzyl)amino)cyclobutane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-2-fluoro-4-hydroxy-6-(2,2,2-trifluoroethoxy)benzyl)amino)cyclobutanecarboxylic acid methyl ester (from 3-chloro-2-fluoro-4-hydroxy -6-(2,2,2-Trifluoroethoxy)benzaldehyde and 1-aminocyclobutanecarboxylic acid methyl ester hydrochloride were prepared according to step 5 of Example 083), synthesized to obtain the target compound 1-(( 3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazole And [4,5-c]pyridine-2-carboxamid
  • Example 125 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2- Fluoro-6-(pyridin-3-ylmethoxy)benzyl)amino)cyclobutane carboxylic acid
  • Example 083 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylic acid methyl ester was replaced with 1-((3- Chloro-2-fluoro-4-hydroxy-6-(pyridin-3-ylmethoxy)benzyl)amino)cyclobutanecarboxylic acid methyl ester (from 3-chloro-2-fluoro-4-hydroxy-6- (Pyridin-3-ylmethoxy)benzaldehyde and methyl 1-aminocyclobutanecarboxylate hydrochloride were prepared according to step 5 of Example 083), and the target compound 1-((3-chloro-4- ((4-(2-Chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5 -c)pyridine-2-carboxamido)phenyl)
  • Example 126 1-((6-(Benzyloxy)-3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1- Methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indene-1- (Yl)oxy)-2-fluorobenzyl)amino)cyclobutane carboxylic acid
  • Example 083 the methyl 1-((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl)amino)cyclobutanecarboxylate was replaced with 1-((6- (Benzyloxy)-3-chloro-2-fluoro-4-hydroxybenzyl)amino)cyclobutanecarboxylic acid methyl ester (from 3-chloro-2-fluoro-4-hydroxy-6-benzyloxybenzaldehyde And 1-aminocyclobutanecarboxylic acid methyl ester hydrochloride according to Example 083 step 5), synthetically obtain the target compound 1-((6-(benzyloxy)-3-chloro-4-((4- (2-Chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine -2-Carboxamido)phenyl)-2,3-dihydr
  • Example 127 1-((3-chloro-4-((4-(2-chloro-3-(1-methyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro -1H-imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indenyl-1-yl)oxy)-2-fluoro-6-methyl (Oxybenzyl)amino)cyclopropanecarboxylic acid
  • Step 1 Combine 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde (0.51g) and N-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H -Inden-4-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamide (0.85g) dissolved in To 10mL 2-methyltetrahydrofuran, add triphenylphosphine (0.79g), add DIAD (0.59mL) dropwise under the protection of nitrogen, and react at room temperature for 1 hour. After the reaction is detected by HPLC, silica gel is added and the sample is mixed and purified by column chromatography.
  • Step 2 Add N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-formyl-5-methoxyphenoxy)-2,3-dihydro-1H-indene -4-yl)phenyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide (0.61g) dissolved in 5mL dichloride Methanesulfonic acid chloride (171mg) and triethylamine (202mg) were added to the methane. The reaction was stirred at room temperature for 2 hours. After the reaction was detected by TLC, water and dichloromethane were added for extraction. The organic phase was separated and concentrated under reduced pressure.
  • Step 3 Add N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-formyl-5-methoxyphenoxy)-2,3-dihydro-1H-indene -4-yl)phenyl)-1-methyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide (500mg) and methyl 1-aminocyclopropanecarboxylate hydrochloride (220mg) were dissolved in 4mL 1,2-dichloroethane, stirred at room temperature for 30 minutes, then sodium acetate borohydride (464mg) was added, and reacted at room temperature overnight.
  • Step 4 Add methyl 1-((3-chloro-4-((4-(2-chloro-3-(1-methyl-5-(methylsulfonyl)-4,5,6,7- Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6 -Methoxybenzyl)amino)cyclopropane carboxylate (79mg) was dissolved in 3mL of methanol, lithium hydroxide (25mg) was added, and the reaction was left overnight at room temperature. After the reaction was completed by TLC, the column layer was mixed with silica gel.
  • Example 128 1-((3-chloro-4-((4-(2-chloro-3-(5-(cyclopropylsulfonyl)-1-methyl-4,5,6,7-tetra Hydrogen-1H-imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-indenyl-1-yl)oxy)-2-fluoro-6- (Methoxybenzyl)amino)cyclopropanecarboxylic acid
  • Example 127 the methylsulfonic acid chloride was replaced with cyclopropanesulfonic acid chloride to synthesize the target compound 1-((3-chloro-4-((4-(2-chloro-3-(5- (Cyclopropylsulfonyl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamido)phenyl)-2,3- Dihydro-1H-indenyl-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)cyclopropanecarboxylic acid (27mg), LC-MS(ESI-MS):798[M+ H] + .
  • Example 129 (2R)-methyl 2-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl) -4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl) (Oxy)-2-fluoro-6-methoxybenzyl)amino)-3-hydroxypropionate
  • Step 1 Add N-(2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)-1-methyl-4,5,6,7- Tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide (0.85g) and propyl 2-carbonylbenzoate (0.55g) were dissolved in 10mL of dichloromethane, and DIPEA (0.5mL) was added, Stir at room temperature for 0.5 hours, then add sodium acetate borohydride (0.85 mg), and react at room temperature overnight. After the completion of the reaction detected by TLC, it was extracted with dichloromethane and water. The organic phase was separated and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography to obtain the white solid product 2-(2-((2-chloro-3-(1-hydroxy- 2,3-Dihydro-1H-inden-4-yl)phenyl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5( 4H)-yl)propyl benzoate (0.96g), the yield was 82%.
  • Step 2 Add 2-(2-((2-chloro-3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)phenyl)carbamoyl)-1-methyl- 6,7-Dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)propyl benzoate (0.88g) and 3-chloro-2-fluoro-4-hydroxy-6- Methoxybenzaldehyde (0.41g) was dissolved in 10mL 2-methyltetrahydrofuran, triphenylphosphine (0.52g) was added, DIAD (0.4mL) was added dropwise under the protection of nitrogen, and the reaction was carried out at room temperature for 2 hours.
  • Step 3 Add 2-(2-((2-chloro-3-(1-(2-chloro-3-fluoro-4-formyl-5-methoxyphenoxy)-2,3-dihydro -1H-inden-4-yl)phenyl)carbamoyl)-1-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridine-5(4H)-yl)benzene
  • Step 4 Combine D-serine methyl ester hydrochloride (38mg) and N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-formyl-5-methoxyphenoxy )-2,3-Dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro- 1H-imidazo[4,5-c]pyridine-2-carboxamide (80mg) was dissolved in 4mL 1,2-dichloroethane, stirred at room temperature for 30 minutes, then sodium acetate borohydride (71mg) was added, and reacted at room temperature overnight .
  • Example 130 (2R)-2-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl-4, 5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy) -2-fluoro-6-methoxybenzyl)amino)-3-hydroxypropionic acid
  • Example 131 1-((3-chloro-4-((4-(2-chloro-3-(5-(1,3-dihydroxypropyl-2-yl)-1-methyl-4, 5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy) -2-fluoro-6-methoxybenzyl)amino)cyclopropane carboxylic acid
  • Example 129 and Example 130 With reference to the synthesis methods of Example 129 and Example 130, the propyl 2-carbonylbenzoate was replaced by 2-oxopropane-1,3-dibenzoic acid diester, and the D-serine methyl ester hydrochloride was replaced by 1 -Aminocyclopropanecarboxylic acid methyl ester hydrochloride, synthesized to obtain the target compound 1-((3-chloro-4-((4-(2-chloro-3-(5-(1,3-dihydroxypropyl-2 -Yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro- 1H-Inden-1-yl)oxy)-2-fluoro-6-methoxybenzyl)amino)cyclopropanecarboxylic acid (10mg), LC-MS(ESI-MS): 768[M+
  • Example 132 N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5-methyl (Oxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6, 7-Tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 129 D-serine methyl ester hydrochloride was replaced with 1-(aminomethyl)cyclopropanol to synthesize the target compound N-(2-chloro-3-(1-(2-chloro -3-fluoro-4-((((1-hydroxycyclopropyl)methyl)amino)methyl)-5-methoxyphenoxy)-2,3-dihydro-1H-indene-4- Yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-2- Formamide (13 mg), LC-MS (ESI-MS): 738 [M+H] + .
  • Example 133 (2S)-methyl 1-(3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl-4 ,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy )-2-Fluoro-6-methoxybenzyl)piperidine-2-carboxylate
  • Example 134 (2S)-1-(3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4, 5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy) -2-fluoro-6-methoxybenzyl)piperidine-2-carboxylic acid
  • Example 135 (2S)-Methyl 1-(3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl- 4,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy (Yl)-2-fluoro-6-methoxybenzyl)pyrrolidine-2-carboxylate
  • Example 136 (2S)-1-(3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4, 5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy) -2-fluoro-6-methoxybenzyl)pyrrolidine-2-carboxylic acid
  • Example 137 (2R)-Methyl 2-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl- 4,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy (Yl)-6-cyclopropyl-2-fluorobenzyl)amino)-3-hydroxypropionate
  • Example 138 (2R)-2-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl-4, 5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy) -6-Cyclopropyl-2-fluorobenzyl)amino)-3-hydroxypropionic acid
  • Example 139 Methyl 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5 ,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)- 6-Cyclopropyl-2-fluorobenzyl)amino)cyclopropane carboxylate
  • Example 140 1-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropyl-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-6- Cyclopropyl-2-fluorobenzyl)amino)cyclopropane carboxylic acid
  • Example 141 N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((((1r,4r)-4-hydroxycyclohexyl)amino)methyl)-5- Methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6 ,7-Tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 129 D-serine methyl ester hydrochloride was replaced with trans-4aminocyclohexanol to synthesize the target compound N-(2-chloro-3-(1-(2-chloro-3 -Fluoro-4-((((1r,4r)-4-hydroxycyclohexyl)amino)methyl)-5-methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl )Phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide (21 mg), LC-MS (ESI-MS): 766 [M+H] + .
  • Example 142 (2R)-2-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl-4, 5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy) -2-fluoro-6-methoxybenzyl)amino)-4-hydroxybutyric acid
  • Example 129 and Example 130 D-serine methyl ester hydrochloride was replaced with (R)-2-amino-4-hydroxybutyric acid methyl ester hydrochloride to synthesize the target compound (2R)- 2-((3-chloro-4-((4-(2-chloro-3-(5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro -1H-imidazo[4,5-c]pyridine-2-carboxamido)phenyl)-2,3-dihydro-1H-inden-1-yl)oxy)-2-fluoro-6-methyl (Oxybenzyl)amino)-4-hydroxybutyric acid (13 mg), LC-MS (ESI-MS): 770 [M+H] + .
  • Example 143 N-(2-chloro-3-(1-(2-chloro-3-fluoro-4-((((1S,2S)-2-hydroxycyclopentyl)amino)methyl)-5 -Methoxyphenoxy)-2,3-dihydro-1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5, 6,7-Tetrahydro-1H-imidazole[4,5-c]pyridine-2-carboxamide
  • Example 129 D-serine methyl ester hydrochloride was replaced with (1S, 2S)-2-aminocyclopentanol hydrochloride, and the target compound N-(2-chloro-3-(1 -(2-Chloro-3-fluoro-4-((((1S,2S)-2-hydroxycyclopentyl)amino)methyl)-5-methoxyphenoxy)-2,3-dihydro -1H-inden-4-yl)phenyl)-5-(1-hydroxypropan-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-imidazole [4,5- c] Pyridine-2-carboxamide (11 mg), LC-MS (ESI-MS): 752 [M+H] + .

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Abstract

L'invention concerne une classe de composés amides ayant de nouvelles structures ou des stéréoisomère ou des mélanges de stéréoisomères et des sels pharmaceutiquement acceptables de ceux-ci, et leur utilisation dans la préparation de médicaments pour le traitement de maladies, de troubles ou d'états pathologiques qui peuvent bénéficier de l'inhibition de l'activité de PD1 ou de PD-L1. Les composés selon la présente invention présentent une forte activité de blocage PD-1/PD-L1, et peuvent inverser la fonction des lymphocytes T inhibée par PD-L1. De plus, les composés selon la présente invention peuvent activer la voie du signal NFAT provoquée par la liaison de PD-1/PD-L1, et peuvent être absorbés par voie orale, et ont de bonnes propriétés pharmacocinétiques. Par conséquent, les composés selon la présente invention peuvent être utilisés, seuls ou en combinaison avec d'autres médicaments, dans le traitement de maladies, de troubles ou d'états pathologiques qui peuvent bénéficier de l'inhibition de l'activité de PD1 ou de PD-L1, comprenant des maladies infectieuses, des maladies immunitaires, des maladies inflammatoires et le cancer.
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