CN112812113B - Immunomodulatory compounds, compositions and uses thereof - Google Patents

Immunomodulatory compounds, compositions and uses thereof Download PDF

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CN112812113B
CN112812113B CN202011262439.3A CN202011262439A CN112812113B CN 112812113 B CN112812113 B CN 112812113B CN 202011262439 A CN202011262439 A CN 202011262439A CN 112812113 B CN112812113 B CN 112812113B
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chloro
pyridine
imidazo
tetrahydro
dihydro
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CN112812113A (en
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周星露
刘兴国
胡苗
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Hangzhou Hertz Pharmaceutical Co ltd
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Hangzhou Hertz Pharmaceutical Co ltd
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Abstract

The invention discloses an amide compound with a novel structure or a stereoisomer mixture thereof and pharmaceutically acceptable salts thereof, and application thereof in preparing medicaments for treating diseases, disorders or symptoms benefited from the inhibition of PD1 or PD-L1 activity. The compound shows strong PD-1/PD-L1 blocking activity, and can reverse the function of T cells inhibited by PD-L1. Meanwhile, the compound can activate NFAT signal path caused by PD-1/PD-L1 combination, can be orally absorbed and has good pharmacokinetic property. Accordingly, the compounds of the present invention may find application in the treatment of diseases, disorders or conditions that benefit from inhibition of PD1 or PD-L1 activity, including infectious diseases, immune diseases, inflammatory diseases and cancer, alone or in combination with other drugs.

Description

Immunomodulatory compounds, compositions and uses thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to an amide compound, a pharmaceutical composition and application thereof. The compounds can block the interaction of PD1 with PD-L1 and can be used to treat a variety of diseases, disorders, or diseases, including infectious diseases, immune diseases, inflammatory diseases, and cancer.
Background
The human immune system plays an extremely important regulatory role in a wide range of disease processes including tumors. In the course of malignant tumor development, in order to evade the monitoring of the human immune system, various immune escape mechanisms have been developed. Among them, altering the expression of co-stimulatory or co-inhibitory molecules on the surface of tumor cells or immune cells is one of the most critical tumor immune escape mechanisms. Currently, blocking the interaction of inhibitory immune checkpoint molecules (e.g., 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 which can be expressed in various immune cells, plays an extremely important role in regulating the negative immune feedback in vivo, and can effectively prevent autoimmune system diseases caused by over-activation of T cells (Sharpe et al, nat. Immunol.,2007,8, 239-245). The PD-1 receptor has two corresponding endogenous ligands of PD-L1/PD-L2 in vivo. PD-L1 differs in expression from PD-L2, and PD-L1 is expressed more in dendritic cells, macrophages, B cells and T cells (Greenwald et al, Annu. Rev. Immunol.2005,23: 515-548; Okazaki and Honjo, Trends Immunol 2006, (4):195-201), and can also be expressed more in a variety of tumor cells. Whereas PD-L2 is normally expressed only on dendritic cells. The drug blocking the interaction of PD-1/PD-L1 is the most popular direction in the field of tumor immunotherapy at present.
At present, a plurality of PD-1 and PD-L1 monoclonal antibodies are clinically used for treating more than 10 tumor indications. However, the antibody drug has the defects of non-oral administration, too long half life period to be beneficial to the control of adverse reactions, poor tissue permeability, easy generation of anti-drug antibodies and the like. Therefore, the development of a novel small molecule inhibitor aiming at blocking PD1/PD-L1 is expected to overcome the defects of antibody drugs, and becomes a brand-new development direction of immune checkpoint inhibitors.
Disclosure of Invention
The invention aims to provide a novel amide compound or a stereoisomer mixture or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition comprising the compound or a stereoisomer mixture or a pharmaceutically acceptable salt thereof.
The invention also provides the use of a compound as described above, or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease, disorder or condition which benefits from the inhibition of PD1 or PD-L1 activity.
The invention adopts the following technical scheme:
a compound having the structure of formula I:
Figure GDA0003709489340000021
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;
Wherein:
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 、R 3 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, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C 2 -C 6 Alkenyl, 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 a R a 、-C(O)OR a 、-OC(O)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 、-C(＝NR a )R a 、-C(＝NR a )NR a R a 、-NR a C(＝NR a )NR a R a 、 -NR a S(O)R a 、-NR a S(O) 2 R a 、-NR a S(O) 2 NR a R a 、-S(O) 2 R a 、-S(O) 2 NR a R a 、-PR a R a 、-P(O)R a R a -SeRa; wherein one of the above substituents contains two or more R a When two or more than two R a May be different, each for example "R" in the present invention a R a "middle two R a Are independent of each other, can be the same or different; such as "-NR a C(O)NR a R a "includes three R a Three R a Are independent of each other, can be the same or different; and each R a 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, substituted or unsubstituted 3-10 membered heterocyclyl;
Y 1 and Y 2 Is independently selected from N or C, and Y 1 And Y 2 Not N at the same time;
in the above structure, on the premise of satisfying the electronic pairing rule, Y is 1 、Y 2 The bond between N and Z may be a double bond or a single bond, or it may be a partially selected single bond or a partially selected double bond. Preferably, Y is 1 、Y 2 N and Z form a conjugated ring structure;
z is O, S, N, NR 4 Or CR 4 (ii) a Z is preferably NCH 3 、CCH 3 、S、O；
N、Z、Y 1 And Y 2 In the five-membered ring, the chemical bond between two adjacent atoms is a single bond or a double bond; preferably, the five-membered ring has two double bonds, which may be C ═ N or NC ═ C, or may be C ═ C;
when G is 1 Is NR 6 When, G 2 Is CR 7 R 7 (ii) a Here, "CR 7 R 7 "middle two R 7 Are independent of each other, can be the same or different;
when G is 1 Is CR 6 R 6 When, G 2 Is NR 7 (ii) a Here, "CR 6 R 6 "middle two R 6 Are independent of each other, can be the same or different;
a is C 6 -C 12 Aryl, 5-14 heteroaryl, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, said aryl, heteroaryl, cycloalkyl, heterocyclyl being not fused or being substituted by A 1 Thick and solution of A 1 Is 4-to 8-membered cycloalkane, 4-to 8-membered heterocycloalkyl, 4-to 8-membered cycloalkene, 4-to 8-membered heterocycloalkene, 5-to 8-membered aromatic ring, 5-to 8-membered heteroaromatic ring; each of the above substituents may be substituted by 0 to 5R 8 Substitution; r 8 When there are plural, plural R 8 Independent of each other, different or identical; in the present invention, the term "fused" includes spiro rings, fused ring structures, and the like, which share one, two, or more than two C or N;
R 4 、R 5 、R 6 、R 7 、R 8 independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 Alkyl, C containing one or more deuterium atoms 1 -C 6 Alkyl, 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, substituted or unsubstituted 3-10 membered heterocyclyl, cyano, nitro, -CR b R b (CR b R b )CR b R b OH、-OR b 、-NR b R b 、-NHOR b 、-C(O)R b 、-C 1 -C 6 alkyl-C (O) R b 、 -C(O)NR b R b 、-C(O)OR b 、-OC(O)R b 、-OC(O)NR b R b 、-NR b C(O)R b 、-NR b C(O)OR b 、 -NR b C(O)NR b R b 、-C(＝NR b )R b 、-C(＝NR b )NR b R b 、-NR b C(＝NR b )NR b R b 、-NR b S(O)R b 、 -NR b S(O) 2 R b 、-NR b S(O) 2 NR b R b 、-S(O) 2 R b 、-S(O) 2 NR b R b 、-PR b R b 、-P(O)R b R b 、-SeR b (ii) a Wherein each R is b Independently selected from H, OH, substituted or unsubstituted C 1 -C 6 Hydroxyalkyl, 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, substituted or unsubstituted 3-10 membered heterocyclyl; or R b R b Can further form 3-6 membered ring or 3-6 membered heterocycle;
or, 2 adjacent R on A 8 Can form a ring with the atoms connected (forming an "M" and "N" structure, or forming a spiro ring structure, wherein "M" and "N" have no specific meaning and only mean a structure in which two rings share two adjacent carbon/nitrogen atoms), and the ring can be a benzene ring, C 3 -C 6 Cycloalkyl, 5-6 membered heteroaryl or 5-7 membered heterocyclyl, each of which may be substituted with 0-3R c Substitution; wherein R is c When there are plural, plural R c May be the same or different, each R c Independently 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 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, substituted or unsubstituted 3-10 membered heterocyclyl;
or, when the carbon atom has two R at the same time 5 When substituted, two R 5 May be the same or different, R 5 May form C with the carbon atom to which it is attached 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl, each optionally substituted with 0-3R d Substitution; wherein R is c When there are plural, plural R c Which may be the same or different, each R d 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, substituted or unsubstituted 3-10 membered heterocyclyl; m is independently an integer of 0-4;
R 9 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 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 heterocyclyl, -CN, -NO 2 、-OR e 、-SR e 、-NR e R e 、-N (OH)R e 、-C(O)R e 、-C(O)NR e R e 、-C(O)OR e 、-OC(O)R e 、-OC(O)NR e R e 、-NR e C(O)R e 、 -NR e C(O)OR e 、-NR e C(O)NR e R e 、-C(＝NR e )R e 、-C(＝NR e )NR e R e 、-NR e C(＝NR e )NR e R e 、 -NR e S(O)R e 、-NR e S(O) 2 R e 、-NR e S(O) 2 NR e R e 、-S(O) 2 R e 、-S(O) 2 NR e R e 、-PR e R e 、-P(O)R e R e 、 -S e R e (ii) a Wherein, for the purpose of simplifying the structural formula, "R" in the present invention e R e "middle two R e Are independent of each other, can be the same or different; and each R e 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 heterocycloaryl, substituted or unsubstituted 3-10 membered heterocyclyl;
L 1 Independently selected from the group consisting of a bond, O, S, 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 ) n 、(CR f R f ) n NR f C(O) (CR f R f ) n 、C 2 -C 6 Alkenyl radical, C 2 -C 6 An alkynyl group; wherein, for the purpose of simplifying the structural formula, "R" in the present invention f R f "middle two R f Are independent of each other, can be the same or different; and each R f Independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 2 -C 6 Alkenyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl radical, C 6 -C 12 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl; each n is independently selected from an integer of 0-4; two R on the same atom f Can form a ring with an adjacent atom, which is replaced by C 3 -C 6 Cycloalkyl or 3-6 membered heterocycloalkyl.
R 10 、R 11 、R 13 、R 14 Independently selected from H, halogen, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, C containing one or more deuterium atoms 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 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 heterocyclyl, CN, NO 2 、N 3 、OR g 、SR g 、NR g R g 、 NHOR g 、C(O)R g 、C(O)NR g R g 、C(O)OR g 、OC(O)R g 、OC(O)NR g R g 、NR g C(O)R g 、 NR g C(O)OR g 、NR g C(O)NR g R g 、NR g S(O)R g 、NR g S(O) 2 R g 、NR g S(O) 2 NR g R g 、S(O) 2 R g 、 S(O) 2 NR g R g 、PR g R g 、P(O)R g R g 、SeR g (ii) a Wherein each R is g 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, substituted or unsubstituted 3-10 membered heterocyclyl; and, R 10 、R 11 、R 13 、R 14 At least three of which are not simultaneously H (i.e. R) 10 、R 11 、R 13 、R 14 May have no H, may have one H, or may have 2H);
preferably, R is 10 、R 11 、R 13 、R 14 Each independently preferably being F, H, Cl, C 1 ～C 3 Alkyl (methyl, ethyl, propyl), cyano, substituted or unsubstituted C 1 ～C 3 Alkoxy (methoxy, ethoxy, propoxy; the substituent is one or more of fluorine and cyclopropyl), deuterated methyl, C3-C5 cycloalkyl, phenyl, substituted and unsubstituted benzyloxy (cyano-substituted, methyl-substituted or hydroxy-substituted, etc.), substituted pyridylmethoxy (cyano-substituted, methyl-substituted or hydroxy-substituted, etc.), pyridylmethoxy.
Preferably, R is 10 、R 11 、R 13 、R 14 Are not all H, or said R 10 、R 11 、R 13 、R 14 One of which is H; or the said R 10 、R 11 、R 13 、R 14 Two of which are simultaneously H.
R 12 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 -(C 1 -C 6 Alkylene) -NR h R h 、NR h SO 2 -(C 1 -C 6 Alkylene) -NR h R h 、 -(CH 2 ) o C(O)NR h SO 2 NR h R h 、-(CH 2 ) o N + R h R h O - 、-(CH 2 ) o P + R i R i R i 、-(CH 2 ) o P + R i R i O - 、 -(CH 2 ) o P + O(NR h R h )(NR h R h )、-(CH 2 ) o NR h P(O)(OR i )(OR i )、-(CH 2 ) o CH 2 OP(O)(OR i )(OR i )、 (CH 2 ) o OP(O)(OR i )(OR i )、(CH 2 ) o OP(O)(NR h R h )(OR i ) Or
Figure GDA0003709489340000041
Wherein:
r is as defined above 12 C of (A) 1 -C 6 The alkylene group may be substituted with 0 to 3 substituents selected from NR h R h Halogen, cyano, oxo, ORi, substituted and unsubstituted C 1 -C 6 Alkyl, substituted and unsubstituted C 1 -C 6 Haloalkyl, substituted and unsubstituted C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclyl;
v is independently selected from the group consisting of a 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 Independently selected from the group consisting of a 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 heterocyclyl;
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 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, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl;
each R i 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, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl;
o is independently selected from an integer of 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 to 5.
In the present invention, for convenience of expression, the term "C (O)" means "C ═ O".
In the present invention, for the sake of simplicity of representation, in one group (e.g. -NR) a C(＝NR a )NR a R a ”、“-(CH 2 ) o P + O(NR h R h )(NR h R h ) ") or an atom (such as" CR 7 R 7 ”、“CR 6 R 6 "C" in ") or a cyclic group (e.g., R) 5 、R 8 Corresponding rings, A, etc.) two or more letters with the same letter (e.g. R) may appear a 、R b 、R c 、R d 、R e 、R f 、R g 、R h 、R i 、R 5 、R 8 Etc.), which does not require that a plurality of the same letters be the same substituent at the same time, and two or more of the same letters may be different substituents independently of each other. For example, with R a For example, when a group includes two or more R a When two or more R are present a May be the same or different, two or more R a Independently of each other, each R a 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 4-14 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocyclyl. Other R b 、R c 、R d 、R e 、R f 、R g 、R h 、R i Is as defined in R a 。
For the occurrence on the ring in "(R) Subscript ) M "or" M (R) Subscript ) "substituents represented by" (e.g., "(R)") 5 ) M "), wherein M represents the number of substituents; when M is a natural number of 2 or more, it means that a plurality of R's exist on the ring Subscript A substituent, and each substituent R Subscript May be the same or different.
Still further, preferred compounds of the present invention have the structure of formula II-A, II-B, II-C, II-D, II-E, II-F or II-G:
Figure GDA0003709489340000061
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
Preferably, A is selected from C 6 -C 10 Aryl, 5-12 heteroaryl, 5-12 membered cycloalkyl and 5-12 membered heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group are not fused or are A 1 Thick and solution of A 1 5-6 membered cycloalkane, 5-6 membered heterocycloalkyl, 5-6 membered cycloalkene, 5-6 membered heterocycloalkene, 5-6 membered aromatic ring, 5-6 membered heteroaromatic ring; each of the above substituents may be substituted by 0 to 4R 8 Substitution;
each R 8 Each 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 Haloalkoxy, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaryl, or a pharmaceutically acceptable salt thereofSubstituted or unsubstituted 3-to 10-membered heterocyclic group, cyano group, nitro group, amino group, substituted or unsubstituted C 1 -C 6 Alkoxy, N (CH) 3 ) 2 、S(O 2 )CH 3 、SO 2 NH 2 ；
Or, 2 adjacent R on A 8 Can form a ring with the atoms connected, the ring can be a benzene ring or C 3 -C 6 Cycloalkyl, 5-6 membered heteroaryl or 5-7 membered heterocyclyl, each of which may be substituted with 0-3R c Substitution;
wherein each R is c 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.
Further, preferred compounds of the present invention have the structure of the formula III-A or III-A ', the structure of the formula III-B or III-B ', the structure of the formula III-C or III-C ', the structure of the formula III-D or III-D ', the structure of the formula III-E or III-E ', the structure of the formula III-F or III-F ', the structure of the formula III-G or III-G ':
Figure GDA0003709489340000071
Figure GDA0003709489340000081
Or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;
in the above-mentioned structure of the formula III-A or III-A ', the structure of the formula III-B or III-B ', the structure of the formula III-C or III-C ', the structure of the formula III-D or III-D ', the structure of the formula III-E or III-E ', the structure of the formula III-F or III-F ', the structure of the formula III-G or III-G ', J 2 And J 3 The bonds between are dotted and solidA double bond which may be a single bond or a double bond;
wherein:
J 1 n, CR';
J 2 is CR ', CR' R ', N, NR', O, S, C (O), S (O) 2 ；
J 3 Is CR ' R ', NR ', O, S, C (O), S (O) 2 ；J 2 、J 3 Not NR', O, S, C (O), S (O) 2 ；
Wherein J 2 、J 3 Can be a double bond or a single bond;
when J is 1 When is N, J 2 、J 3 Not NR', O, S, C (O), S (O) 2 ；
R' is independently selected from H, halogen and C 1 -C 6 Alkyl radical, C 1 -C 6 A haloalkyl group;
r' is independently selected from H, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl ring, 5-6 membered heteroaryl, phenyl ring, OR '", NR'" R '", wherein each R'" is independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 A haloalkyl group;
one H or two H of R ', R' may be replaced by said R 8 Substituted, with two or more R's on the A ring 8 When a substituent is present, each R 8 May be different; one or more H in R ', R' may be replaced by deuterium;
r is an integer of 0 to 4;
s is an integer of 0 to 3.
Preferably, J is 1 May further preferably be CH, N, when J 1 When the compound is CH, the compound can be in an R configuration or an S configuration or a mixture of the two configurations in any ratio; j. the design is a square 2 May be further preferably CH 2 Halogen substituted CH, one or more C1-C3 alkyl substituted CH/C, spirocyclopropyl C, or through CH 2 Or a plurality of CH 2 And J 3 Form a ringCH and J of 3 CH, N, when forming a double bond, being a radical of formula J 3 C (C1-C3 alkyl) which is a double bond and substituted with C1-C3 alkyl; j. the design is a square 3 May be further preferably CH 2 NH, O, is through CH 2 Or a plurality of CH 2 And J 2 Cyclic CH, and J 2 CH, N, when forming a double bond, being a radical of formula J 2 C (C1-C3 alkyl) which is a double bond and is substituted by C1-C3 alkyl, and J 2 And N in the case of a double bond.
As a preferred embodiment, in said compound or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof:
X 1 is CR 1 ，X 2 Is CR 2 ，X 3 Is CR 3 ；
R 1 、R 2 、R 3 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, 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 (ii) a Wherein each R is a 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 3-10 membered heterocyclyl.
Preferably, R 1 、R 2 、R 3 Each independently selected from H, F, C 1 ～C 3 Alkyl radical, C 1 ～C 3 An alkoxy group. Further preferably, X is 1 、X 2 、X 3 Each independently selected from CH and CF.
As a further preferred embodiment, Z is NR 4 、CR 4 、N、S、O；G 1 Is NR 6 ，G 2 Is CR 7 R 7 ；
R 4 、R 5 、R 6 、R 7 Each independently selected from H, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy, C 1 -C 6 Hydroxyalkyl radical, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl, C (O) R b 、-C 1 -C 6 alkyl-C (O) R b (ii) a Wherein R is b Selected from H, OH, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Hydroxyalkyl radical, C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl;
preferably, R is 6 Selected from the group consisting of 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, cyclopropanesulfonyl, difluoromethyl, 2,2, 2-trifluoroethyl, 2, 2-difluoroethyl, 1-trifluoromethylethyl, isopropyloxycarbonyl, methoxyethyl (1-methoxyethyl, 2-methoxyethyl), 1-hydroxymethyl-2-hydroxyethyl, cyclopentyl, oxacyclohexyl, carboxyethyl, 2-fluoroethyl, oxetanyl, 2-hydroxy-propyl, 2-methyl-2-hydroxyethyl, cyclopentyl, oxacyclohexyl, carboxyethyl, A deuterated methyl group; the R is 7 Selected from H and methyl. R 4 Methyl and ethyl are preferred.
Preferably, said R is 5 Selected from the group consisting of H, 1-3 methyl groups (which may be one methyl group substituted on any one C atom, two methyl groups substituted on the same C atom or two different C atoms, three methyl groups substituted on two C atoms, etc.), deuterated methylethylmethyl groups, and deuterated methyl groups. Or two R 5 When substituted on one carbon atom, there are cyclopropyl, cyclobutyl, oxetanyl, azetidinyl and the like. OrTwo adjacent R 5 May form a ring with an adjacent atom, which ring may be C 3 -C 10 Cycloalkyl, 3-10 membered heterocyclyl; m is 0, 1 or 2.
R 7 Is selected from H.
R 8 Independently preferably H, methyl (including methyl substituted on one atom or 2 methyl substituted on one atom or methyl substituted on different atoms, etc.), ethyl, cyano, F, hydroxyethyl; or two R 8 Form cyclopropyl when substituted on two adjacent carbon atoms; or two R 5 When substituted on one carbon atom, form a cyclopropyl group.
As a preferred embodiment of the present invention,
Figure GDA0003709489340000101
part is selected from
Figure GDA0003709489340000102
Figure GDA0003709489340000103
As a preferred embodiment, R 10 、R 11 、R 13 、R 14 Each independently selected from F, H, Cl, cyano, C 1 ～C 3 Alkoxy radical, 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-to 5-membered cycloalkyl substituted C 1 ～C 3 Alkoxy, C containing one or more deuterium atoms 1 ～C 3 Alkoxy, one or more fluorine substituted C 1 ～C 3 Alkoxy, phenyl, C 3 ～C 6 A cycloalkyl group; further preferred are deuterated methyloxy, difluoromethyl, cyclopropyl, cyclobutyl, cyclopropylmethoxy, phenyl, substituted and unsubstituted benzyloxy, substituted and unsubstituted pyridylmethoxy;
R 12 is selected from
Figure GDA0003709489340000111
Figure GDA0003709489340000112
Figure GDA0003709489340000121
L 1 Selected from O, NH, CH 2 、S、SO 2 、CO、-NHCH(CF 3 )-、-CH(CF 3 )NH-、
Figure GDA0003709489340000122
Figure GDA0003709489340000123
-NHCF 2 、
Figure GDA0003709489340000124
-OCH(CF 3 )-；
A is selected from
Figure GDA0003709489340000125
Figure GDA0003709489340000126
Figure GDA0003709489340000131
R 9 H, selected from Cl, methyl, ethyl, F and cyano;
R 1 、R 2 、R 3 each independently selected from H, F, C 1 ～C 3 Alkyl radical, C 1 ～C 3 An alkoxy group;
R 4 、R 5 、R 6 、R 7 h, F, methyl, ethyl, cyano, hydroxyethyl are each independently selected.
Preferably, said compound, or a stereoisomer or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
Figure GDA0003709489340000132
Figure GDA0003709489340000141
Figure GDA0003709489340000151
Figure GDA0003709489340000161
Figure GDA0003709489340000171
Figure GDA0003709489340000181
Figure GDA0003709489340000191
Figure GDA0003709489340000201
Figure GDA0003709489340000211
Figure GDA0003709489340000221
Figure GDA0003709489340000231
Figure GDA0003709489340000241
Figure GDA0003709489340000251
Figure GDA0003709489340000261
Figure GDA0003709489340000271
Figure GDA0003709489340000281
Figure GDA0003709489340000291
or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof. Preferably, the compound is the following:
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-carboxylic acid 001
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-3-carboxylic acid 002
1- (5-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 003
1- (5-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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 004
1- (5-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-fluorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 005
1- (5-chloro-4- ((4- (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 006
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) pyrrolidine-3-carboxylic acid 007
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) pyrrolidine-3-carboxylic acid 008
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 009
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 010
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,6,6 a-tetrahydrocyclopropyl [ a ] inden-6-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 011
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-3-carboxylic acid 012
013 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-3-carboxylic acid
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) indolin-1-yl) methyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 014
015- (5-chloro-4- (4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) indoline-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
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 016
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-carboxylic acid 017
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-carboxylic acid 018
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 019
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-indole-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 020
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 021
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) pyrrolidine-3-carboxylic acid 022
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 023
024-1- (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
025- (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-carboxylic acid
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 026
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-3-carboxylic acid 027
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 028
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) -3-fluorobenzyl) pyrrolidine-3-carboxylic acid 029
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) phenyl) pyrrolidine-3-carboxylic acid 030
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 031
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 032
1- (5-chloro-4- ((4- (2-chloro-3- (3, 6-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-c ] pyrimidine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 033
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-carboxylic acid 034
1- (5-chloro-4- ((4- (2-chloro-3- (1,4,4, 5-tetramethyl-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 035
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' -carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 036
1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-1, 5,6, 7-tetrahydrospiro [ imidazo [4,5-c ] pyridine-4, 3' -oxetane ] -2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 037
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-methoxybenzyl) pyrrolidine-3-carboxylic acid 038
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) pyrrolidine-3-carboxylic acid 039
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-3-carboxylic acid 040
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) azetidine-3-carboxylic acid 041
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) -3-hydroxy-2-methylpropionic acid 042
N- (2-chloro-3- (1- (6-chloro-2-fluoro-4- ((3-hydroxypyrrolidin-1-yl) methyl) -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-carboxamide 043
N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((((((R) -5-oxopyrrolidin-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 044
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-imidazo [4,5-c ] pyridine-2-carboxamide 045
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-methylpropanoic acid 046
N- (2-chloro-3- (1- (2,3,5, 6-tetrafluoro-4- (2- (3-hydroxypyrrolidin-1-yl) ethoxy) 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 047
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-methoxybenzyloxy) pyrrolidine-3-carboxylic acid 048
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-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 049
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, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 050
N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((3-oxopiperazin-1-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 051
N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((6-oxo-5-oxa-2, 7-diazaspiro [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 052
N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((6-oxo-2, 5, 7-triazaspiro [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 053
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 054
1- (5-chloro-4- (4- (2-chloro-3- (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridine-2-carboxamido) phenyl) -1H-benzo [ d ] imidazole-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 055
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 056
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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 057
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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 058
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-methoxybenzyl) pyrrolidine-3-carboxylic acid 059
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) pyrrolidine-3-carboxylic acid 060
1- (5-chloro-4- ((1- (2' -chloro-3 ' - (1,5-erjiaj-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-methoxybenzyl) pyrrolidine-3-carboxylic acid 061
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-methoxybenzyl) pyrrolidine-3-carboxylic acid 062
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 063
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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 064
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-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 065
(R) -1- (5-chloro-4- (((S) -4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 066
(S) -1- (5-chloro-4- (((S) -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 067
(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 068
(S) -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 069
Methyl 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-3-carboxylate 070
Methyl 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-carboxylate 071
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-carboxamide 072
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-2-carboxylic acid 073
(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 074
(2S) -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) -3-hydroxy-2-methylpropanoic acid 075
(2R) -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) -3-hydroxy-2-methylpropanoic acid 076
(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 077
(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 methyl ester 078
1- (5-chloro-4- ((6- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -7-methyl-2, 3-dihydro-1H-indan-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 079
1- (5-chloro-4- ((7-chloro-6- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 080
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 081
1- (5-chloro-4- ((5- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -4-methyl-2, 3-dihydrobenzofuran-3-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid 082
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) amino) cyclobutanecarboxylic acid 083
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-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid 084
1- ((3-chloro-4- ((4- (2-chloro-3- (5- (2-hydroxypropyl) -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 085
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) cyclopropanecarboxylic acid 086
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) -2, 6-difluorobenzyl) amino) cyclopropanecarboxylic acid 087
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, 6-difluorobenzyl) amino) cyclopropanecarboxylic acid 088
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) amino) cyclobutanecarboxylic acid 089
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) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid 090
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) -2, 6-dimethoxybenzyl) amino) cyclobutanecarboxylic acid 091
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 092
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 093
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) amino) cyclopropanecarboxylic acid 094
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 095
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-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid 096
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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid 097
098- ((3-chloro-4- ((4- (2-chloro-3- (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
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-fluoro-2-methoxybenzyl) amino) cyclobutanecarboxylic acid 099
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-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 100
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-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 101
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 [4,5-c ] pyridine-2-carboxamide 102
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-fluoro-2-methoxybenzyl) amino) cyclopropanecarboxylic acid 103
1- ((3-chloro-4- ((4- (2-chloro-3- (5- (3-hydroxypropyl) -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 104
1- ((3-chloro-4- ((4- (2-chloro-3- (5- ((3- (hydroxymethyl) oxatan-3-yl) methyl) -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 105
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 106
1- ((3-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid 107
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) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid 108
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) cyclopropanecarboxylic acid 109
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) cyclopropanecarboxylic acid 110
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-fluoro-2-methoxybenzyl) amino) cyclobutanecarboxylic acid 111
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) -6-fluoro-2-methoxybenzyl) amino) cyclopropanecarboxylic acid 112
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-1H-imidazo [4,5-c ] pyridine-2-carboxamide 113
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 114
N- (2-chloro-3- (1- (2-chloro-3-fluoro-4- ((3-hydroxypyrrolidin-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-imidazo [4,5-c ] pyridine-2-carboxamide 115
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-imidazo [4,5-c ] pyridine-2-carboxamide 116
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-imidazo [4,5-c ] pyridine-2-carboxamide 117
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, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 118
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) cyclopropanecarboxylic acid 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- (cyclopropylmethoxy) -2-fluorobenzyl) amino) cyclopropanecarboxylic acid 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- (difluoromethoxy) -2-fluorobenzyl) amino) cyclopropanecarboxylic acid 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- (cyclobutylmethoxy) -2-fluorobenzyl) amino) cyclobutanecarboxylic acid 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) -2-fluoro-6-isopropoxybenzyl) amino) cyclobutanecarboxylic acid 123
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) cyclobutanecarboxylic acid 124
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) cyclobutanecarboxylic acid 125
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-inden-1-yl) oxy) -2-fluorobenzyl) amino) cyclobutanecarboxylic acid 126
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-indenyl-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid 127
1- ((3-chloro-4- ((4- (2-chloro-3- (5- (cyclopropylsulfonyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid 128
(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-hydroxypropanoate 129
(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 130
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 131
N- (2-chloro-3- (1- (2-chloro-3-fluoro-4- ((((1-hydroxycyclopropanyl) methyl) 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-imidazo [4,5-c ] pyridine-2-carboxamide 132
(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 133
(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 134
(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) -2-fluoro-6-methoxybenzyl) pyrrolidine-2-carboxylate 135
(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 136
(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) -6-cyclopropyl-2-fluorobenzyl) amino) -3-hydroxypropionate 137
(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 138
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) cyclopropanecarboxylate 139
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) cyclopropanecarboxylic acid 140
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-imidazo [4,5-c ] pyridine-2-carboxamide 141
(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 142
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-imidazo [4,5-c ] pyridine-2-carboxamide 143
(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-methoxypropionic acid 144
3- ((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) benzoic acid 145
4- ((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) benzoic acid 146
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) benzoic acid 147
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) -3-fluorobenzoic acid 148
149- ((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) -3-methoxybenzoic acid
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) amino) cyclobutanecarboxylate 150
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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylate 151
Methyl 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) cyclobutanecarboxylate 152
Methyl 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) cyclopropanecarboxylate 153
(2R) -methyl 2- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) -3-hydroxypropionate 154
(2R) -2- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) -3-hydroxypropionic acid 155
1- ((3-chloro-4- ((4- (3- (5- (2, 2-difluoroethyl) -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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid 156
157- ((3-chloro-4- ((4- (2-chloro-3- (5- (2, 2-difluoroethyl) -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
1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-3- (1-methyl-5- (2,2, 2-trifluoroethyl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid 158
1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-3- (1-methyl-5- (1,1, 1-trifluoropropan-2-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid 159
1- ((3-chloro-4- ((4- (3- (5- (difluoromethyl) -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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid 160
1- ((3-chloro-4- ((4- (2-chloro-3- (5- (isopropoxycarbonyl) -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 161
1- ((3-chloro-6-ethoxy-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) benzyl) amino) cyclopropanecarboxylic acid 162
1- ((3-chloro-6- (difluoromethoxy) -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) benzyl) amino) cyclopropanecarboxylic acid 163
N- (3- (1- (2-chloro-3-fluoro-4- (((1- (hydroxymethyl) cyclopropyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- (1-hydroxypropan-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 164
N- (3- (1- (2-chloro-3-fluoro-4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- (1-hydroxypropan-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 165
1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-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) benzyl) amino) cyclopropanecarboxylic acid 166
1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (isopropoxycarbonyl) -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) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid 167
3- ((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) -6-methoxybenzyl) amino) benzoic acid 168
4- ((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) -6-methoxybenzyl) amino) -3-methoxybenzoic acid 169
1- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxyphenyl) amine) cyclopropyl-1-carboxylic acid 170
1- ((4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) benzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2, 5-dimethylphenyl) amino) cyclopropane-1-carboxylic acid 171
172- ((4- ((4- (3- (5-acetyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) -2-chlorobenzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -5-chloro-2-methoxyphenyl) amino) cyclopropane-1-carboxylic acid
173-1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) benzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxyphenyl) piperidine-2-carboxylic acid
Methyl 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) benzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxyphenyl) piperidine-2-carboxylate 174
2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) benzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxyphenyl) amino) -2-methylpropanoic acid 175
N- (2-chloro-3- (1- (2-chloro-4- ((3-hydroxy-1-azetidinyl) methyl) -5-methoxyphenyl) -2, 3-dihydro-1H-4-indenyl) benzyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 176
1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid 177
N- (2-chloro-3- (1- (2-chloro-4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-4-indenyl) benzyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 178
(5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) serine 179
1- (4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2, 5-dimethylbenzyl) pyrrolidine-3-carboxylic acid 180
1- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclobutane-1-carboxylic acid 181
1- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopentane-1-carboxylic acid 182
(5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) leucine 183
Methyl 2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) -3, 3-dimethylbutyrate 184
2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) -3- (4-fluorobenzene) propanoic acid 185
1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) piperidine-3-carboxylic acid 186
Ethyl 1- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) (methyl) amino) cyclopropane-1-carboxylate 187
(5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) arginate 188
(5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) glycine 189
(5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) proline 190
1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) -2-methylpyrrolidine-2-carboxylic acid 191
N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((((5-pyrrolidin-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 192
N- (2-chloro-3- (1- (2-chloro-4- (((1-cyanocyclopropyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 193
N- (3- (1- (4- (((1-amino-3-methyl-1-oxobutan-2-yl) amino) methyl) -2-chloro-5-methoxyphenyl) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 194
N- (3- (1- (4- (((1-amino-4-methyl-1-oxopentan-2-yl) amino) methyl) -2-chloro-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 195
N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- (((2-oxopiperidin-3-yl) 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 196
197-2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amine) -2- (2-chlorophenyl) acetic acid
1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) -4-fluoropyrrolidine-2-carboxylic acid 198
N- (3- (1- (4- (((1-carbamoylcyclopropyl) amino) methyl) -2-chloro-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 199
N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((((R) -3-oxoisoxazol-4-yl) 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 200
N- (2-chloro-3- (1- (2-chloro-4- (((1- (hydroxycarbamoyl) cyclopropyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 201
N- (3- (1- (4- (((1- (tert-Butylcarbamoyl) cyclopropyl) amino) methyl) -2-chloro-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 202
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-methoxybenzyl) (methyl) amino) cyclopropyl-1-carboxylic acid 203
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) -2-methoxybenzyl) amino) -3-hydroxy-2-methylpropanoic acid 204
1- ((4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2, 6-difluorobenzyl) amino) cyclopropyl-1-carboxylic acid 205
1- ((5-chloro-4- ((4- (2-chloro-3- (5-cyclopentanyl-1-methyl-4, 5,6,7 tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopentane-1-carboxylic acid 206
1- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (tetrahydro-2H-pyran-4-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropyl-1-carboxylic acid 207
1- ((5-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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 208
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) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 209
1- ((4- ((4- (3- (5- (carboxymethyl) -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-2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 210
1- ((5-chloro-4- ((4- (2-chloro-3- (5- (2-fluoroethyl) -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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 211
1- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (oxetan-3-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 212
N- (2-chloro-3- (1- (2, 5-dichloro-4- (2- (3-hydroxypyrrolidin-1-yl) ethoxy) 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 213
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-methoxybenzyl) pyrrolidine-3-carboxylic acid 214
(5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxyphenyl) glycine 215
N- (2-chloro-3- (1- (2-chloro-4- ((1- (hydroxymethyl) -3-azabicyclo [3.1.0] hex-3-yl) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide 216
N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((6-oxo-5-oxa-2, 7-diazaspiro [3.4] oct-2-cyclyl) 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 217
N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((6-oxo-2, 5, 7-triazaspiro [3.4] oct-2-cyclyl) 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 218
1- (5-chloro-4- (4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -1H-indole-1-carbonyl) -2-methoxyphenyl) pyrrolidine-3-carboxylic acid 219
1- (5-chloro-4- (4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) indoline-1-carbonyl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid 220
1- (5-chloro-4- ((7- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydrobenzofuran-3-yl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid 221
1- (5-chloro-4- ((1- (2' -chloro-3 ' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) - [1,1' -biphenyl ] -3-yl) -2,2, 2-trifluoroethyl) amino) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid 222
1- (5-chloro-4- (1- (2' -chloro-3 ' - (1, 5-dimethyl-4, 5,6, 7-t-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) - [1,1' -biphenyl ] -3-yl) cyclopropyl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid 223
1- (5-chloro-4- ((3- (2' -chloro-3 ' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) - [1,1' -biphenyl ] -3-yl) oxetan-3-yl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid 224
(R) -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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 225
(S) -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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 226
227-chloro-1- ((5-chloro-4- ((4- (2-chloro-3- (5-methyl-4, 5,6, 7-tetrahydrooxazolo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
1- ((5-chloro-4- ((4- (2-chloro-3- (5-methyl-4, 5,6, 7-tetrahydrothiazole [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 228
1- ((5-chloro-4- ((4- (2-chloro-3- (6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [1,5-c ] pyrimidine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 229
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) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 230
1- ((5-chloro-4- ((4- (2-chloro-3- (7-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyrazine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 231
1- ((5-chloro-4- ((4- (2-chloro-3- (3, 6-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-c ] pyrimidine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 232
233 of 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) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
1- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 234
N- (3- (1- (4- (((1-carboxamidocyclopropyl) amino) methyl) -2-chloro-5-methoxyphenyl) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1-methyl-5- (methyl-d) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamides 235
(5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) glycine 236
1- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclobutane-1-carboxylic acid 237
2- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-bishydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) -2-methylpropionic acid 238
1- (5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -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 239
(5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) valine 240
2- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) -3-hydroxy-2-methylpropanoic acid 241
(5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) serine 242
N- (2-chloro-3- (1- (2-chloro-4- ((3-hydroxyazetidin-1-yl) methyl) -5-methoxyphenyl) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-5- (methyl-d 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamides 243
N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((6-oxo-2, 5, 7-triazaspiro [3.4 ]]Cycloneoalkan-2-yl) methyl) phenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-5- (methyl-d 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamides 244
1- ((5-chloro-4- ((4- (2-chloro-3- (5-methyl-1- (methyl-d) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid 245
1- ((5-chloro-4- ((4- (2-chloro-3- (5-methyl-1- (methyl-d) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclobutane-1-carboxylic acid 246
1- (5-chloro-4- ((4- (2-chloro-3- (5-methyl-1- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazolesAzole [4,5-c ]]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid 247
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- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid 248
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- (methoxy-d 3 ) Benzyl) pyrrolidine-3-carboxylic acid 249
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) -2- (methoxy-d 3 ) Benzyl) amino) -2-methylpropanoic acid 250
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- (methoxy-d 3 ) Benzyl) amino) cyclobutane-1-carboxylic acid 251
(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- (methoxy-d 3 ) Benzyl) glycine 252
(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- (methoxy-d 3 ) Benzyl) serine 253
(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- (methoxy-d 3 ) Benzyl) leucine 254
1- ((4- ((4- (3- (5-acetyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamido) -2-chlorobenzene) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid 255
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-bishydro-1H-inden-1-yl) oxy) -2- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid 256
1- ((5-chloro-4- ((4- (2-chloro-3- (5- (2-fluoroethyl) -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- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid 257
1- ((4- ((4- (3- (5- (carboxymethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamido) -2-chlorobenzene) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid 258
1- ((5-chloro-4- ((4- (2-chloro-3- (5-cyclopentyl-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- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid 259
1- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (oxocyclobutane-3-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid 260
1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-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 261
1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-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 262
1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-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) cyclopropanecarboxylic acid 263
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) -6-ethoxy-2-fluorobenzyl) amino) cyclopropanecarboxylic acid 264
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) -6-ethoxy-2-fluorobenzyl) amino) cyclobutanecarboxylic acid 265
1- ((3-chloro-2-fluoro-4- ((4- (3- (5-isopropyl-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) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid 266
1- ((3-chloro-2-fluoro-4- ((4- (3- (5-isopropyl-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) -6-methoxybenzyl) amino) cyclobutanecarboxylic acid 267
1- ((3-chloro-6-ethoxy-2-fluoro-4- ((4- (3- (5-isopropyl-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) benzyl) amino) cyclopropanecarboxylic acid 268
1- ((3-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-ethoxy-2-fluorobenzyl) amino) cyclobutanecarboxylic acid 269
1- ((3-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid 270
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) cyclobutanecarboxylic acid 271
1- ((3-chloro-4- ((4- (2-cyano-3- (5-isopropyl-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 272
Or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.
Description of terms:
the term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms in which one fused ring may be partially saturated.Non-limiting examples of aromatic rings are: benzene ring, naphthalene ring, anthracene ring, indene ring, indanyl (indanyl). The aromatic ring may be unsubstituted or substituted. The substituents of the aromatic ring are selected from halogen (preferably fluorine, chlorine, bromine, iodine), cyano, nitro, amino, hydroxyl, carboxyl, carboxylic acid methyl ester, carboxylic acid ethyl ester, 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, isopropyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, etc.), halogeno C 1 -C 6 Alkyl (preferably halomethyl, haloethyl, halopropyl, haloisopropyl, halobutyl, haloisobutyl, halosec-butyl, halotert-butyl, etc.), halogeno-C 1 -C 6 Hydroxyalkyl (preferably halogenated hydroxymethyl, halogenated hydroxyethyl, halogenated hydroxypropyl, halogenated hydroxyisopropyl, etc.), halogenated C 1 -C 6 Alkoxy (preferably halogenomethoxy, halogenoethoxy, halogenopropoxy, halogenoisopropoxy, halogenobutoxy, halogenoisobutoxy, halogenosec-butyloxy, halogenotert-butyloxy, etc.), C 3 -C 6 Cycloalkyl (preferably cyclopropyl, cyclopentyl, cyclohexyl, etc.), halogeno C 3 -C 6 Cycloalkyl (preferably halogenocyclopropyl, halogenocyclopentyl, halogenocyclohexyl, etc.), 3-to 10-membered heterocyclic group (preferably tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.), C 6 -C 12 Aryl radical, C 5 -C 14 A heteroaryl group; the substitution of the aromatic ring can be mono-substitution (such as ortho-substitution, meta-substitution and para-substitution), and can also be di-substitution or tri-substitution, and the like.
The term "heteroaryl" as used herein refers to a monocyclic or fused polycyclic group of 5 to 14 ring atoms (wherein one fused ring may be partially saturated), corresponding to the replacement of one or more carbons in the above-mentioned "aryl" by heteroatoms such as oxygen, nitrogen, sulfur, and the like. The heteroaromatic ring may be monocyclic or may be monocyclicAs a bicyclic ring, i.e., fused through two rings. Specific heteroaryl (heterocycloaryl) groups may be: pyridyl, pyrimidinyl, pyrazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, indole, indoline, benzimidazole and the like. The heterocyclic aryl group may be unsubstituted or substituted. The substituent of the heterocyclic aryl is selected from halogen, cyano, nitro, amino, hydroxyl and C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halo C 1 -C 6 Hydroxyalkyl, halo C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl radical, C 5 -C 14 A heteroaryl group.
The term "alkyl" as used herein means a straight-chain saturated monovalent hydrocarbon group having one to six carbon atoms or a branched-chain saturated monovalent hydrocarbon group having three to six carbon atoms, and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, or the like. The alkyl can be unsubstituted, mono-substituted or multi-substituted, and the substituents can be the same or different when the alkyl is multi-substituted; the substituent of the alkyl group is selected from the group consisting of halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, isopropyl carboxylate, carbamoyl, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 10 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy radical, C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl radical, C 5 -C 14 A heteroaryl group.
The term "hydroxyalkyl" as used herein means-alkyl-OH, whereinAlkyl is as defined above. Examples of "hydroxyalkyl" as used herein include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like. "hydroxyalkyl" also includes substituted hydroxyalkyl groups, the substituents of which may be halogen, amino, hydroxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl radical, C 5 -C 14 A heteroaryl group.
The term "alkoxy" as used herein refers to an-O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy. "alkoxy" also includes substituted alkoxy groups, the substituents of which can be halogen, amino, hydroxy, C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl radical, C 5 -C 14 A heteroaryl group.
The term "cycloalkyl" as used herein refers to a non-aromatic monovalent hydrocarbon group having three to ten carbon atoms of a monocyclic or polycyclic ring (two monocyclic rings are chemically linked or bridged or spiro or fused) ring, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., wherein one or two carbon atoms may be replaced by an oxo group. The cycloalkyl group may be unsubstituted or substituted, and the substituents are selected from the group consisting of halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halo C 1 -C 6 Hydroxyalkyl, halogeno C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamide, sulfonamido, 3-to 10-membered heterocyclyl, or amino or mono-substitutedA polysubstituted amino, wherein the amino substituents may be the same or different and are selected from the group consisting of hydrogen and C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl radical, C 5 -C 14 A heteroaryl group.
The term "heterocyclyl" as used herein refers to a non-aromatic cyclic group having three to ten ring atoms, either monocyclic or polycyclic (two monocyclic rings are chemically linked or bridged or spiro or fused), having one or more heteroatoms selected from N, O, S, including but not limited to
Figure GDA0003709489340000461
Figure GDA0003709489340000462
Figure GDA0003709489340000463
The heterocyclic group may be unsubstituted or substituted, and the substituent is selected from the group consisting of halogen, nitro, hydroxy, carboxy, methyl carboxylate, ethyl carboxylate, carboxamide, oxo, thioxo, C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halo C 1 -C 6 Hydroxyalkyl, halo C 1 -C 6 Alkoxy radical, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamido, hydroxyalkylamido, sulfonamido, 3-to 10-membered heterocyclyl or amino or mono-or polysubstituted amino, wherein the substituents of the amino group may be the same or different and are selected from hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Hydroxyalkyl radical, C 1 -C 6 Alkoxy radical, C 3 -C 10 Cycloalkyl, 3-to 10-membered heterocyclyl, C 6 -C 12 Aryl radical, C 5 -C 14 A heteroaryl group.
The invention isBy the term "alkenyl" is meant a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing at least one double bond and having from 2 to 10 carbon atoms (i.e. C) 2 -C 10 Alkenyl) including, but not limited to, vinyl, allyl, but-1-enyl, pent-1, 4-di-enyl, and the like. The alkenyl group may be substituted with one or more substituents independently being alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
The term "alkynyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing at least one triple bond and having from 2 to 10 carbon atoms (i.e., C) 2 -C 10 Alkynyl) including but not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted with one or more substituents independently being alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro.
The term "halogen" as used herein means fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine or bromine.
The term "halo" as used herein means substituted by halogen, either by the same atom or by a different atom, either once or multiple times, e.g., di-or tri-substituted.
The term "haloalkyl" as used herein refers to an alkyl group substituted with halo, preferably fluoro, chloro, bromo, iodo, wherein alkyl is as defined above. "haloalkyl" may be substituted one or more times with halo.
The term "halohydroxyalkyl" as used herein refers to a hydroxyalkyl group substituted with halogen, preferably fluorine, chlorine, bromine, iodine, wherein hydroxyalkyl is as defined above. "haloalkyl" may be substituted one or more times with halo.
The term "haloalkoxy" as used herein refers to an alkoxy group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein alkoxy is as defined above. "haloalkoxy" may be substituted one or more times by halogen.
The term "halocycloalkyl" as used herein refers to a cycloalkyl group substituted with halogen (preferably fluorine, chlorine, bromine, iodine), wherein cycloalkyl is as defined above. "halocycloalkyl" may be substituted one or more times by halogen.
The term "m" as used herein is preferably 0, 1, 2;
the term "n" as used herein is preferably 0, 1, 2.
The term "o" as used herein is preferably 0, 1, 2, 3.
The term "p" as used herein is preferably 0, 1, 2, 3.
The term "q" as used in the present invention is preferably 0, 1, 2, 3.
The term "l" as used in the present invention is preferably 0, 1, 2, 3.
The term "r" as used herein is preferably 0, 1, 2, 3.
The term "s" as used herein is preferably 0, 1, 2.
The salts of the compounds of the present invention may be prepared by methods well known to those skilled in the art. The salt can be organic acid salt, inorganic acid salt and the like, and the organic acid salt comprises citrate, fumarate, oxalate, malate, lactate, camphorsulfonate, p-toluenesulfonate, methanesulfonate and the like; the inorganic acid salt comprises hydrohalic acid salt, sulfate, phosphate, nitrate and the like. For example, with lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and the like, methanesulfonate, trifluoromethanesulfonate, etc. may be formed; with arylsulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid, etc. to form p-toluenesulfonic acid salts, benzenesulfonic acid salts; corresponding salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; with amino acids, such as glutamic acid or aspartic acid, glutamate or aspartate can be formed. Corresponding salts can also be formed with inorganic acids, such as hydrohalic acids (e.g., hydrofluoric, hydrobromic, hydroiodic, hydrochloric), nitric, carbonic, sulfuric or phosphoric acids, and the like.
The compounds of the present invention include compounds in which an atom is substituted with an isotope. Isotopes refer to atoms having the same atomic number but different atomic masses. Isotopes such as hydrogen include deuterium and tritium. One or more of the atoms of the compounds of the present invention may be replaced by natural or unnatural isotopes. The hydrogen atoms in the embodiments as well may be substituted with one or more deuterium atoms. Methods for the synthesis of compounds containing isotopic atoms are known in the art.
A second object of the invention is to provide a pharmaceutical composition comprising one or more of the compounds according to any of the above-mentioned embodiments. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above embodiments with other compounds, or one or more of the compounds described in any of the above embodiments.
In another aspect, the invention provides the use of a compound of formula I, formula II-a to II-G, formula III-a to III-H, formula III-a 'to III-G', or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein for the treatment of a disease, disorder or condition that would benefit from inhibition of PD1 or PD-L1 activity.
In a further preferred embodiment, the present invention provides a method of blocking the interaction of PD1 and PD-L1 in a subject by administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound having the formula I, formulas II-A-II-G, formulas III-A-III-H, formulas III-A 'to III-G'.
In some embodiments, a subject in need thereof has a cancer, including hematological and solid tumors, such as melanoma, glioblastoma, esophageal tumors, nasopharyngeal carcinomas, 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 myeloid leukemia, kaposi's sarcoma fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, biliary tract tumor, basal cell carcinoma, thymic tumor, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, MeRkel (MeRkel) cell carcinoma, melanoma, sarcoidosis, and combinations thereof, Neurological tumors, follicular central lymphoma, colon cancer, hodgkin's disease, non-hodgkin's lymphoma, leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, mesothelioma, breast cancer, squamous non-small cell lung cancer (SClC), non-squamous non-small cell lung cancer, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, ductal adenocarcinoma of the pancreas, squamous cell carcinoma of the head and neck, gastrointestinal tract, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, esophageal cancer, small bowel cancer, cancer of the endocrine system, cancer of the urethra, urinary tract, cervical cancer, Penile cancer, bladder cancer, kidney cancer, ureter cancer, renal pelvis cancer, Central Nervous System (CNS), tumor angiogenesis, spinal cord axis tumor, brain stem glioma, pituitary adenoma, epidermoid carcinoma, asbestosis, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchopulmonary carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.
In further embodiments, the subject in need thereof is suffering from infectious, immunological, 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.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for blocking the interaction between PD1 and PD-L1, in particular application in preparing medicines for treating cell proliferative diseases. The cell proliferative disease includes cancer. In other words, the invention also provides the application of the compound shown in the general formula I, the general formulas II-A-II-G, the general formulas III-A-III-G and the general formulas III-A 'to III-G' or the pharmaceutically acceptable salt thereof in treating proliferative diseases (such as cancer) singly or in combination with other medicines.
The medicament for use in combination with a compound or composition of the invention may be selected from one or more of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulator, a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent (such as an immune checkpoint inhibitor), an anti-fibrotic agent, radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent (such as a kinase inhibitor) or an antiproliferative agent.
A formulation comprising one or more of the compounds of any of the above schemes.
The carrier includes conventional diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc., and flavoring agent, sweetener, etc. may be added if necessary.
The medicine of the invention can be prepared into various forms such as tablets, powder, capsules, injection preparations, granular preparations, sprays and the like, and the medicines of the various forms can be prepared according to the conventional method in the pharmaceutical field.
In some embodiments, the compounds or compositions of the present invention may be used in combination with one or more other drugs for the treatment of diseases, disorders, or conditions that benefit from the inhibition of PD1 or PD-L1 activity. The additional agent is selected from an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulator, a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent, an anti-fibrotic agent, a radiotherapeutic agent, an antineoplastic agent, or an antiproliferative agent.
The invention also relates to methods of treating cell proliferative diseases using said compounds or pharmaceutical compositions in combination with radiation therapy. Techniques for administering radiation therapy are known in the art and can be used in the combination therapies described herein.
The compounds of the invention may also be used in combination with other methods of treating cancer, for example by chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, tolerizing T cell metastases, Toll receptor agonists, STING agonists, oncolytic viral therapy, and immunomodulatory small molecules, including thalidomide (thalidomide) or JAK1/2 inhibitors, among others.
The inventor of the invention proves through experiments that the compound of the invention shows strong PD-1/PD-L1 blocking activity, and can reverse the function of T cells inhibited by PD-L1. Meanwhile, the compound can activate NFAT signal path caused by PD-1/PD-L1 combination, can be orally absorbed and has good pharmacokinetic property. Accordingly, the compounds of the present invention may find application in the treatment of diseases, disorders or conditions that benefit from inhibition of PD1 or PD-L1 activity, including infectious diseases, immune diseases, inflammatory diseases and cancer, alone or in combination with other drugs.
Drawings
Figure 1 in vitro co-incubation experimental results for compounds.
Figure 2 results of NFAT reporter gene experiments for compounds.
Detailed Description
The implementation of the present invention is illustrated by the following examples, and those skilled in the art should understand that the corresponding technical features can be modified or replaced according to the teaching of the prior art, and still fall into the protection scope of the present invention.
Example 1: preparation of 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-carboxylic acid
Figure GDA0003709489340000491
Step 1: 2,3,4,5, 6-Pentafluorobenzaldehyde (2.3mmol) is dissolved in 10mL DMF solution, 4-bromo-2, 3-dihydro-1H-inden-1-ol (3.0mmol) and cesium carbonate (3.0mmol) are added, and the mixture is heated to 100 ℃ under nitrogen and stirred for reaction for about 12 hours. The reaction solution was cooled to room temperature and quenched with water, extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography to obtain 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde (188mg) with yield of 21%.
Step 2: 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde (2.0mmol) and pinacol diboron (1.6mmol) were dissolved in 15mL of 1, 4-dioxane, Pd (dppf) Cl was added 2 (0.2mmol) and potassium acetate (4.0mmol) were heated to 90 ℃ under nitrogen for about 12 hours. After the reaction was stopped and the temperature was reduced to room temperature, water and ethyl acetate were added to conduct extraction, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography gave the compound 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 (400mg) in a yield of 46%.
And step 3: dissolving 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) in 10mL of 1, 4-dioxane, adding 3.0mL of purified water, and adding Pd (PPh) 3 ) 4 (0.2mmol) and sodium carbonate (4.0mmol), the reaction mixture was heated to reflux for about 24 hours. Then, the temperature was decreased to room temperature, water was added, extraction was performed 3 times with ethyl acetate, organic phases were combined and washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain compound 4- ((4- (3-amino-2-chlorophenyl)) -2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde (336mg), yield 43%.
And 4, step 4: 4- ((4- (3-amino-2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde (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 anhydrous DMF, HATU (3.0mmol) and DIPEA (4.5mmol) were added and the reaction was allowed to react at room temperature under nitrogen for about 24 hours. The reaction was then quenched with water, extracted with ethyl acetate, the organic phase separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound N- (2-chloro-3- (1- (2,3,5, 6-tetrafluoro-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 (349mg) in 38% yield.
And 5: mixing N- (2-chloro-3- (1- (2,3,5, 6-tetrafluoro-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 (0.5mmol) and pyrrolidine-3-carboxylic acid (1.0mmol) were dissolved in a solution of 5mL methanol and 5mL dichloromethane, acetic acid (1.2mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (2.0mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give 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, 6-tetrafluorobenzyl) pyrrolidine-3-carboxylic acid (42mg) in 12% yield. LC-MS (ESI-MS):712[ M + H] + 。
Example 2: preparation of 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-3-carboxylic acid
Figure GDA0003709489340000501
Step 1: 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde (3.5mmol) and 4-bromo-2, 3-dihydro-1H-inden-1-ol (5.6mmol) were dissolved in 20mL of anhydrous tetrahydrofuran solution, triphenylphosphine (5.6mmol) was added, then DIAD (5.6mmol) was slowly added dropwise, and the reaction was carried out at room temperature for about 12 hours. The reaction was stopped, concentrated under reduced pressure to remove most of the reaction solvent, and the resulting concentrate was purified by silica gel column chromatography to give 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.86g) in 62% yield.
Step 2: 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde (2.0mmol) and pinacol diboron (1.6mmol) were dissolved in 15mL of 1, 4-dioxane, Pd (dppf) Cl was added 2 (0.2mmol) and potassium acetate (4.0mmol) were heated to 90 ℃ under nitrogen for about 12 hours. After the reaction was stopped and the temperature was reduced to room temperature, water and ethyl acetate were added to conduct extraction, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography gave compound 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 (0.47g) in 50% yield.
And step 3: 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) were dissolved in 10mL of 1, 4-dioxane, 3.0mL of purified water was added, Pd (PPh3)4(0.15mmol) and sodium carbonate (3.0mmol) were added, and the reaction mixture was heated to reflux for about 24 hours. Then, the temperature was reduced to room temperature, water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave 4- ((4- (3-amino-2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde (274mg) in 41% yield.
And 4, step 4: 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) were dissolved in 10mL anhydrous DMF and HATU (3.0mmol) and DIPEA (4.5mmol) were added and reacted at room temperature under nitrogen for about 24 hours. The reaction was then quenched with water, extracted with ethyl acetate, the organic phase separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-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-carboxamide (320mg) in 43% yield.
And 5: n- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) is reacted with a carboxylic acid to form a mixture]Pyridine-2-carboxamide (0.4mmol) and pyrrolidine-3-carboxylic acid (0.8mmol) were dissolved in a solution of 5mL methanol and 5mL dichloromethane, acetic acid (1.0mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.6mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give 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-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (43mg) in 15% yield. LC-MS (ESI-MS) 722[ M + H ]] + 。
Example 3: preparation of 1- (5-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000511
Step 1: 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, prepared as in step 2 of example 2) and 3-bromo-2-methylaniline (1.5mmol) were dissolved in 8mL of 1, 4-dioxane, 3.0mL of purified water was added, and Pd (PPh) was added 3 ) 4 (0.12mmol) and sodium carbonate (2.5mmol), the reaction mixture was heated to reflux for about 24 hours. Cooling to room temperature, adding water, and extracting with ethyl acetateThe organic phases were taken 3 times, combined and washed with brine, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave compound 4- ((4- (3-amino-2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde (245mg) in 48% yield.
Step 2: 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 (1.3mmol) were dissolved in 10mL anhydrous DMF and HATU (2.5mmol) and DIPEA (3.0mmol) were added and reacted at room temperature under nitrogen for about 24 hours. The reaction was then quenched with water, extracted with ethyl acetate, the organic phase separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound 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 (247mg) in 41% yield.
And step 3: mixing 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) were dissolved in a solution of 3mL methanol and 3mL dichloromethane, acetic acid (0.5mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.6mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give compound 1- (5-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (22mg) in 16% yield. LC-MS (ESI-MS):702[ M + H] + 。
Example 4: preparation of 1- (5-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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000521
With reference to the synthesis procedure of example 3, 1- (5-chloro-4- ((4- (2-cyano-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] -c), a target compound, was synthetically prepared by replacing 3-bromo-2-methylaniline with 2-amino-6-bromobenzonitrile ]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (20mg), LC-MS (ESI-MS):714[ M + H] + 。
Example 5: preparation of 1- (5-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-fluorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000522
With reference to the synthesis method of example 3, 1- (5-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as a target compound was synthetically prepared by replacing 3-bromo-2-methylaniline with 3-bromo-2-fluoroaniline]Pyridine-2-carboxamido) -2-fluorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (26mg), LC-MS (ESI-MS):707[ M + H] + 。
Example 6: preparation of 1- (5-chloro-4- ((4- (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
Figure GDA0003709489340000523
With reference to the synthesis procedure of example 3, 1- (5-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) ] as a target compound was synthetically prepared by replacing 3-bromo-2-methylaniline with 3-bromoaniline ]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxyPhenylbenzyl) pyrrolidine-3-carboxylic acid (30mg), LC-MS (ESI-MS):688[ M + H] + 。
Example 7: preparation of 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) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000531
With reference to the synthesis procedure of example 3, 1- (5-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as a target compound was synthetically prepared by replacing 3-bromo-2-methylaniline with 3-bromo-2, 4-difluoroaniline]Pyridine-2-carboxamido) -2, 6-difluorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (12mg), 1H NMR (500MHz, CD) 3 OD)δ9.37(brs,1H),7.71(s,1H),7.40(s,1H),7.32 –7.28(m,2H),7.24(d,J＝10.0Hz,2H),5.82(brs,1H),4.21(s,1H),4.03(s,1H),3.92(s, 3H),3.76–3.60(m,5H),3.44(s,1H),3.16(d,J＝50.0Hz,2H),2.85(s,3H),2.92–2.59(m, 5H),2.51(s,1H),2.24(d,J＝15.1Hz,4H),2.02(s,1H),1.73(s,1H).LC-MS(ESI-MS):724 [M+H] + 。
Example 8: preparation of 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) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000532
With reference to the synthesis procedure of example 2, the title compound, 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c), was synthetically prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 4-bromo-2-fluoro-2, 3-dihydro-1H-inden-1-ol ]Pyridine-2-carboxamido) phenyl) -2-fluoro-2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (13mg), LC-MS (ESI-MS):740[ M + H] + 。
Example 9: preparation of 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
Figure GDA0003709489340000533
Referring to the synthesis method of example 2, the target compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) was synthetically prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 4-bromo-2, 2-dimethyl-2, 3-dihydro-1H-inden-1-ol]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) δ 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), 5.44-5.40 (m,1H), 4.24-4.03 (m,2H), 3.92-3.76 (m,6H),3.68(d, J ═ 36.3Hz,2H),3.44(dd, J ═ 23.9,17.7Hz,1H),3.00(s,2H), 2.92-2.85H, 2 m-85H, 2H, 1H, 78(m, 73H), 2.71(dd, J ═ 11.7,1.3Hz,2H),2.69 to 2.60(M,1H),2.52(dt, J ═ 24.8,13.8Hz,1H), 2.26(s,3H),2.10 to 1.93(M,1H),1.81 to 1.65(M,1H),1.01(s,6H), LC-MS (ESI-MS):750 [ M + H (M, 1H): 750 ] + 。
Example 10: preparation of 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
Figure GDA0003709489340000541
Referring to the synthesis of example 2, 4-bromo-2, 3-dihydro-1H-inden-1-ol was replaced with 4 '-bromo-1', 3 '-dihydrospiro [ cyclopropane-1, 2' -indene]Synthesizing (1-1 '-alcohol) to obtain a 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 (8mg), LC-MS (ESI-MS):748[ M + H] + 。
Example 11: preparation of 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,6,6 a-tetrahydrocyclopropyl [ a ] inden-6-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000542
Referring to the synthesis of example 2, 4-bromo-2, 3-dihydro-1H-inden-1-ol was replaced with 2-bromo-1, 1a,6,6 a-tetrahydrocyclopropylo [ a]Synthesizing indene-6-alcohol to obtain a 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,6,6 a-tetrahydrocyclopropyl [ a]Inden-6-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (10mg), LC-MS (ESI-MS):734[ M + H] + 。
Example 12: preparation of 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-3-carboxylic acid
Figure GDA0003709489340000543
4-amino-5-chloro-3-fluoro-2-methoxybenzaldehyde (2.0mmol) was dissolved in 10.0mL of anhydrous DMF, and 4-bromo-2, 3-dihydro-1H-indene-1-methylsulfonate (2.6mmol), cesium carbonate (4.0mmol) were added and heated to 60 ℃ under nitrogen for about 12 hours. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate for 3 times, combining organic phases, washing with saturated saline water, and drying with anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave compound 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-chloro-3-fluoro-2-methoxybenzaldehyde (278mg) in 35% yield. Then, referring to the synthesis method and reaction procedure of example 1, 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -The compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)) can be finally prepared by replacing 2,3,5, 6-tetrafluorobenzaldehyde with 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-chloro-3-fluoro-2-methoxybenzaldehyde ]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) amino) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (9mg), LC-MS (ESI-MS):722[ M + H] + 。
Example 13: preparation of 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-3-carboxylic acid
Figure GDA0003709489340000551
5-chloro-3-fluoro-4-mercapto-2-methoxybenzaldehyde (2.0mmol) was dissolved in 20.0mL of anhydrous acetonitrile, and 4-bromo-2, 3-dihydro-1H-indene-1-methylsulfonate (2.8mmol), potassium carbonate (5.0mmol) were added and heated to 60 ℃ under nitrogen for about 12 hours. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate for 3 times, combining organic phases, washing with saturated saline water, and drying with anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) thio) -5-chloro-3-fluoro-2-methoxybenzaldehyde (456mg) in 55% yield. Thereafter, referring to the synthesis method and reaction procedure of example 1, 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde was replaced with 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) thio) -5-chloro-3-fluoro-2-methoxybenzaldehyde to prepare the compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) imidazo ]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) thio) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (22mg), LC-MS (ESI-MS):738[ M + H] + 。
Example 14: preparation of 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) indolin-1-yl) methyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000552
4-Bromoindoline (3.0mmol) and 5-chloro-3-fluoro-4- (hydroxymethyl) -2-methoxybenzaldehyde (4.5mmol) were dissolved in 20mL of anhydrous tetrahydrofuran solution, triphenylphosphine (4.5mmol) was added, DIAD (5.0mmol) was slowly added dropwise, and the reaction was carried out at room temperature for about 12 hours. The reaction was stopped, most of the reaction solvent was removed by concentration under reduced pressure, and the obtained concentrate was purified by silica gel column chromatography to give 4- ((4-bromoindolin-1-yl) methyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.77g) in a yield of 65%. Thereafter, referring to the synthesis method and reaction procedure of example 1, 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde was replaced with 4- ((4-bromoindolin-1-yl) methyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde to prepare the compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] -c) ]Pyridine-2-carboxamido) phenyl) indolin-1-yl) methyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (25mg), LC-MS (ESI-MS) 721[ M + H] + 。
Example 15: preparation of 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) indoline-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000561
6-chloro-2-fluoro-4-formyl-3-methoxybenzoic acid (3.0mmol) and 4-bromoindoline (3.3mmol) were dissolved in 20mL of anhydrous DMF, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.9mmol), 1-hydroxybenzotriazole (3.9mmol) and triethylamine (6.0mmol) were added and the reaction was stirred at room temperature for about 20 hours. Quenched with water, extracted with ethyl acetate, the organic phase washed with water and saturated brine, and the ethyl acetate layer separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying the obtained concentrate by silica gel column chromatography to obtain compound 4- (4-bromoindoline)-1-carbonyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.64g) in 52% yield. Thereafter, referring to the synthesis method and reaction procedure of example 1, 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde was replaced with 4- (4-bromoindoline-1-carbonyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde to prepare the compound 1- (5-chloro-4- (4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] -c ]Pyridine-2-carboxamido) phenyl) indoline-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (11mg), LC-MS (ESI-MS):735[ M + H] + 。
Example 16: preparation of 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
Figure GDA0003709489340000562
Referring to the synthesis method and procedure of example 2, the target compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)) was synthetically prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 4-bromo-1H-inden-1-ol]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: preparation of 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-carboxylic acid
Figure GDA0003709489340000563
Referring to the synthetic method and procedure of example 2, the target compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) was synthetically prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 4-bromo-3-methyl-1H-inden-1-ol ]Pyridine-2-carboxamido) phenyl) -3-methyl-1H-inden-1-yl) oxy) -3-Fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (26mg), LC-MS (ESI-MS):734[ M + H] + 。
Example 18: preparation of 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-carboxylic acid
Figure GDA0003709489340000571
Referring to the synthetic method and procedure of example 2, the target compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) was synthetically prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 4-bromo-2-methyl-1H-inden-1-ol]Pyridine-2-carboxamido) phenyl) -2-methyl-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (16mg), LC-MS (ESI-MS) 734[ M + H] + 。
Example 19: preparation of 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
Figure GDA0003709489340000572
4-bromo-1H-indole (3.0mmol) and 5-chloro-3-fluoro-4- (hydroxymethyl) -2-methoxybenzaldehyde (6.0mmol) were dissolved in 20mL of anhydrous tetrahydrofuran, triphenylphosphine (6.0mmol) was added, DIAD (6.0mmol) was slowly added dropwise, and the reaction was carried out at room temperature for about 12 hours. The reaction was stopped, concentrated under reduced pressure to remove most of the reaction solvent, and the resulting concentrate was purified by silica gel column chromatography to give 4- ((4-bromo-1H-indol-1-yl) methyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.52g) in 44% yield. Thereafter, referring to the synthesis method and reaction procedure of example 1, 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde was replaced with 4- ((4-bromo-1H-indol-1-yl) methyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde, thereby preparing compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-chloro-1) methoxy benzaldehyde -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 (15mg), LC-MS (ESI-MS):721[ M + H] + 。
Example 20: preparation of 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-indole-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000573
6-chloro-2-fluoro-4-formyl-3-methoxybenzoic acid (3.0mmol) and 4-bromo-1H-indole (3.3mmol) were dissolved in 20mL of anhydrous DMF, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.9mmol), 1-hydroxybenzotriazole (3.9mmol) and triethylamine (6.0mmol) were added and the reaction was stirred at room temperature for about 20 hours. Quenching with water, extracting with ethyl acetate, washing the organic phase with water and saturated brine, separating the ethyl acetate layer, and drying over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the compound 4- (4-bromo-1H-indole-1-carbonyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.49g) in 40% yield from the concentrate which was purified by silica gel column chromatography. Thereafter, referring to the synthesis method and reaction procedure of example 1, 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzaldehyde was replaced with 4- (4-bromo-1H-indole-1-carbonyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde to prepare the 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-indole-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (21mg), LC-MS (ESI-MS):733[ M + H] + 。
Example 21: preparation of 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
Figure GDA0003709489340000581
4-bromo-1H-indole (3.0mmol) as a solvent was dissolved in 15mL of methylene chloride, and 6-chloro-2-fluoro-4-formyl-3-methoxybenzene-1-sulfonyl chloride (3.0mmol) and triethylamine (6.0mmol) were added thereto, followed by reflux reaction under heating for 12 hours. Cooling to room temperature, adding water, extracting with dichloromethane for 2 times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the concentrate by silica gel column chromatography to obtain the compound 4- ((4-bromo-1H-indol-1-yl) sulfonyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.83g) in 62% yield. Thereafter, referring to the synthesis method and reaction procedure of example 2, 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde was replaced with 4- ((4-bromo-1H-indol-1-yl) sulfonyl) -5-chloro-3-fluoro-2-methoxybenzaldehyde to prepare the compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] -imidazo ]Pyridine-2-carboxamido) phenyl) -1H-indol-1-yl) sulfonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (28mg), LC-MS (ESI-MS):769[ M + H] + 。
Example 22: preparation of 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) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000582
Referring to the synthesis method and reaction procedure of example 2, 1- (4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)) as a target compound was synthetically prepared by replacing 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 2,3, 5-trifluoro-4-hydroxy-6-methoxybenzaldehyde]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2,3, 5-trifluoro-6-methoxybenzyl) pyrrolidine-3-carboxylic acid (6mg), LC-MS (ESI-MS):724[ M + H] + 。
Example 23: preparation of 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
Figure GDA0003709489340000591
Referring to the synthesis method and reaction procedure of example 2, 1- (4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as a target compound was synthetically prepared by replacing 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 2,3, 5-trifluoro-4-hydroxybenzaldehyde ]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 ] M] + 。
Example 24: preparation of 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
Figure GDA0003709489340000592
Referring to the synthesis method and reaction procedure of example 2, 1- (4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as a target compound was synthetically prepared by replacing 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 3, 5-difluoro-4-hydroxy-2-methoxybenzaldehyde]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3, 5-difluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (22mg), LC-MS (ESI-MS):706[ M + H] + 。
Example 25: preparation of 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-carboxylic acid
Figure GDA0003709489340000593
Referring to the synthesis method and reaction procedure of example 2, 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde was replaced with 5-chloro-2, 3-difluoro Synthesizing 4-hydroxybenzaldehyde 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) -2, 3-dihydro-1H-inden-1-yl) oxy) -2, 3-difluorobenzyl) pyrrolidine-3-carboxylic acid (9mg), LC-MS (ESI-MS):710[ M + H] + 。
Example 26: preparation of 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
Figure GDA0003709489340000594
Referring to the synthesis method and reaction procedure of example 2, 1- (4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as a target compound was synthetically prepared by replacing 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 2, 3-difluoro-4-formyl-6-cyanophenol]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-cyano-2, 3-difluorobenzyl) pyrrolidine-3-carboxylic acid (11mg), LC-MS (ESI-MS):701[ M + H] + 。
Example 27: preparation of 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-3-carboxylic acid
Figure GDA0003709489340000601
Referring to the synthesis method and reaction procedure of example 2, 1- (3-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) as a target compound was synthetically prepared by replacing 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 3-chloro-5-fluoro-4-hydroxy-2-methoxybenzaldehyde]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (30mg), LC-MS (ESI-MS):722[ M + H] + 。
Example 28: preparation of 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
Figure GDA0003709489340000602
Referring to the synthesis method and reaction procedure of example 2, 1- (3, 5-dichloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) was synthetically prepared by replacing 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with 3, 5-dichloro-4-hydroxy-2-methoxybenzaldehyde]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid (25mg), LC-MS (ESI-MS):738[ M + H] + 。
Example 29: preparation of 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) -3-fluorobenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000603
Step 1: n- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-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-carboxamide (1.0mmol) was dissolved in 10mL of dichloromethane, placed in an ice bath at 0 ℃ under nitrogen protection, boron tribromide (5.0mmol) was added, and after the addition was completed, the reaction was carried out at room temperature for about 4 hours. Put in an ice bath at 0 ℃, water is carefully added for quenching, dichloromethane is used for extraction, organic phase is separated, anhydrous sodium sulfate is dried, filtration is carried out, filtrate is decompressed and concentrated, and the obtained concentrate is purified by silica gel column chromatography to obtain the compound N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-hydroxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamide (0.55g) with the yield of 91%.
And 2, step: n- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-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 (0.8mmol) and 3-hydroxymethylbenzonitrile (1.6mmol) were dissolved in 8mL of anhydrous tetrahydrofuran solution, triphenylphosphine (1.6mmol) was added, then DIAD (1.6mmol) was slowly added dropwise, and the reaction was carried out at room temperature for about 12 hours. The reaction was stopped, concentrated under reduced pressure to remove most of the reaction solvent, and the resulting concentrate was purified by silica gel column chromatography to give the compound 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 (0.35g) in 60% yield.
And step 3: reacting 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 was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give 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-inden-1-yl) oxy) -2- ((3-cyanobenzyl) oxy) -3-fluorobenzyl) pyrrolidine-3-carboxylic acid (29mg) in 12% yield. LC-MS (ESI-MS):823[ M + H] + 。
Example 30: preparation of 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) benzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000611
Referring to the synthesis method and reaction procedure of example 29, the target compound, 1- (5-chloro-4- ((4- (2-chloro-3)) was synthesized by replacing 3-hydroxymethylbenzonitrile with 3-hydroxymethylpyridine - (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) benzyl) pyrrolidine-3-carboxylic acid (18mg), LC-MS (ESI-MS):799[ M + H] + 。
Example 31: preparation of 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
Figure GDA0003709489340000612
Referring to the synthesis and reaction procedures in example 29, 3-hydroxymethylbenzonitrile was replaced with 3-hydroxymethyl-5-cyanopyridine, and the title compound, 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c), was synthesized]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2- ((5-cyanopyridin-3-yl) methoxy) -3-fluorobenzyl) pyrrolidine-3-carboxylic acid (20mg), LC-MS (ESI-MS):824[ M + H] + 。
Example 32: preparation of 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
Figure GDA0003709489340000621
Step 1: 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) were dissolved in 5mL of anhydrous DMF, HATU (1.5mmol) and DIPEA (1.5mmol) were added, and the reaction was carried out at room temperature under nitrogen for about 24 hours. The reaction was then quenched with water, extracted with ethyl acetate, the organic phase separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure, followed by purification by silica gel column chromatography gave the compound N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -5-methyl-4, 5,6, 7-tetrahydro [4,5-c ] pyridine-2-carboxamide (0.16g) in 53% yield.
And 2, step: mixing N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -5-methyl-4, 5,6, 7-tetrahydro [4,5-c ] with water]Pyridine-2-carboxamide (0.2mmol) and pyrrolidine-3-carboxylic acid (0.4mmol) were dissolved in a solution of 3mL methanol and 3mL dichloromethane, acetic acid (0.5mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. After about 20 hours of reaction at room temperature, the organic solvent was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give compound 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 (24mg) in 17% yield. LC-MS (ESI-MS): 725[ M + H] + 。
Example 33: preparation of 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-carboxylic acid
Figure GDA0003709489340000622
Referring to the synthesis and reaction procedure of example 32, 5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ]]Replacement of pyridine-2-carboxylic acid with 3, 6-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-c ]Pyrimidine-2-carboxylic acid, and can be used for preparing target compound 1- (5-chloro-4- ((4- (2-chloro-3- (3, 6-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1, 5-c)]Pyrimidine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (21mg), LC-MS (ESI-MS):722[ M + H] + 。
Example 34: preparation of 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-carboxylic acid
Figure GDA0003709489340000631
Referring to the synthesis and reaction procedure of example 32, 5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ]]Replacement of pyridine-2-carboxylic acid with 3, 7-dimethyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyrazine-2-carboxylic acid, and can be used for preparing target compound 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-carboxylic acid (30mg), LC-MS (ESI-MS):722[ M + H] + 。
Example 35: preparation of 1- (5-chloro-4- ((4- (2-chloro-3- (1,4,4, 5-tetramethyl-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
Figure GDA0003709489340000632
Referring to the synthesis and reaction procedure of example 32, 5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ]]Replacement of pyridine-2-carboxylic acid with 1,4,4, 5-tetramethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine-2-carboxylic acid, and can be used for preparing target compound 1- (5-chloro-4- ((4- (2-chloro-3- (1,4,4,5 tetramethyl-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 (15mg), LC-MS (ESI-MS):750[ M + H] + 。
Example 36: preparation of 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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000633
Synthesis method and reaction procedure of reference example 32A step of reacting 5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ]]Replacement of pyridine-2-carboxylic acid with 1',5' -dimethyl-1 ',5',6',7' -tetrahydrospiro [ cyclopropane-1, 4' -imidazo [4,5-c ]]Pyridine compound]The (E) -2 '-carboxylic acid can be used for preparing the target compound 1- (5-chloro-4- ((4- (2-chloro-3- (1',5 '-dimethyl-1', 5',6',7 '-tetrahydrospiro [ cyclopropane 1,4' -imidazo [4,5-c ])]Pyridine compound]-2' -Ylcarbamoylamino) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (10mg), LC-MS (ESI-MS):748[ M + H ] + 。
Example 37: preparation of 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
Figure GDA0003709489340000641
Referring to the synthesis and reaction procedure of example 32, 5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ]]Replacement of pyridine-2-carboxylic acid with 1, 5-dimethyl-1, 5,6, 7-tetrahydrospiro [ imidazo [4,5-c ]]Pyridine-4, 3' -oxetanes]-2-carboxylic acid, to obtain the target compound 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 (11mg), LC-MS (ESI-MS):764[ M + H-MS] + 。
Example 38: preparation of 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-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000642
Referring to the synthesis and reaction procedure of example 32, 5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ]]Replacement of pyridine-2-carboxylic acid with 5- (2-hydroxyethyl) -1-methyl-4, 5,6, 7-tetra-ethyl hydro-1H-imidazo [4,5-c ]]Pyridine-2-carboxylic acid, and can be used for preparing target compound 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-methoxybenzyl) pyrrolidine-3-carboxylic acid (7mg), LC-MS (ESI-MS):752[ M + H] + 。
Example 39: preparation of 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) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000643
Referring to the synthesis and reaction procedure of example 32, 5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ]]Replacement of pyridine-2-carboxylic acid with 5-acetyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxylic acid, and can be used for preparing target compound 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) pyrrolidine-3-carboxylic acid (10mg), LC-MS (ESI-MS):750[ M + H] + 。
Example 40: preparation of 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-3-carboxylic acid
Figure GDA0003709489340000651
Mixing N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-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-carboxamide (0.2mmol) and piperidine-3-carboxylic acid (0.4mmol) were dissolved in a solution of 3mL methanol and 3mL dichloromethane, acetic acid (0.6mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. In the roomAfter about 20 hours of reaction at room temperature, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give 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-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) piperidine-3-carboxylic acid (23mg) in 16% yield. LC-MS (ESI-MS):736[ M + H] + 。
Example 41: preparation of 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) azetidine-3-carboxylic acid
Figure GDA0003709489340000652
Mixing N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-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-carboxamide (0.2mmol) and azetidine-3-carboxylic acid (0.4mmol) were dissolved in a solution of 3mL methanol and 3mL dichloromethane, acetic acid (0.6mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give 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-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) azetidine-3-carboxylic acid (11mg) in 8% yield. LC-MS (ESI-MS):708[ M + H] + 。
Example 42: preparation of 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) -3-hydroxy-2-methylpropionic acid
Figure GDA0003709489340000653
Reacting N- (2-chloro)-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] phenyl]Pyridine-2-carboxamide (0.2mmol) and 2-amino-3-hydroxy-2-methylpropanoic acid (0.4mmol) were dissolved in a solution of 3mL of methanol and 3mL of dichloromethane, acetic acid (0.6mmol) was added, the reaction mixture was mixed and stirred for about 1 hour, and then sodium borohydride triacetate (1.0mmol) was added. After about 20 hours of reaction at room temperature, the organic solvent was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give 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-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) amino) -3-hydroxy-2-methylpropionic acid (13mg) in 9% yield. LC-MS (ESI-MS):726[ M + H [)] + 。
Example 43: preparation of N- (2-chloro-3- (1- (6-chloro-2-fluoro-4- ((3-hydroxypyrrolidin-1-yl) methyl) -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-carboxamide
Figure GDA0003709489340000661
N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) is reacted with a carboxylic acid to form a mixture]Pyridine-2-carboxamide (0.2mmol) and 3-hydroxypyrrole (0.4mmol) were dissolved in a solution of 3mL of methanol and 3mL of dichloromethane, acetic acid (0.6mmol) was added, the reaction mixture was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. After about 20 hours of reaction at room temperature, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give the compound N- (2-chloro-3- (1- (6-chloro-2-fluoro-4- ((3-hydroxypyrrolidin-1-yl) methyl) -3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] imidazo]Pyridine-2-carboxamide (15mg), yield 11%. LC-MS (ESI-MS):694[ M + H ] ] + 。
Example 44: preparation of N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((((((R) -5-oxopyrrolidin-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
Figure GDA0003709489340000662
Mixing N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-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-carboxamide (0.2mmol) and (R) -5- (aminomethyl) pyrrolidin-2-one (0.4mmol) were dissolved in a solution of 3mL methanol and 3mL methylene chloride, acetic acid (0.6mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium borohydride triacetate (1.0mmol) was added. After about 20 hours at room temperature, the organic solvent is concentrated under reduced pressure and the residue is purified by reverse phase preparative HPLC chromatography to give the compound N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- (((((((R) -5-oxopyrrolidin-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 (22mg), yield 16%. LC-MS (ESI-MS) 721[ M + H] + 。
Example 45: preparation of 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-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000671
Mixing N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-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-carboxamide (0.2mmol) and (1S, 2R) -2-aminocyclopentanol (0.4mmol) were dissolved in a solution of 3mL of methanol and 3mL of dichloromethane, acetic acid (0.6mmol) was added, the reaction mixture was stirred with mixing for about 1 hour, and then sodium borohydride triacetate (1.0mmol) was added. After about 20 hours of reaction at room temperature, concentration under reduced pressure will beThe organic solvent was spun dry and the residue was purified by reverse phase preparative HPLC chromatography to give the compound 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-imidazo [4,5-c ] imidazo]Pyridine-2-carboxamide (17mg), yield 12%. LC-MS (ESI-MS):708[ M + H] + 。
Example 46: preparation of 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
Figure GDA0003709489340000672
Mixing N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-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-carboxamide (0.2mmol) and 2-amino-2-methylpropanoic acid (0.4mmol) were dissolved in a solution of 3mL methanol and 3mL dichloromethane, acetic acid (0.6mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give 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 (12mg) in 9% yield. LC-MS (ESI-MS):710[ M + H] + 。
Example 47: preparation of N- (2-chloro-3- (1- (2,3,5, 6-tetrafluoro-4- (2- (3-hydroxypyrrolidin-1-yl) ethoxy) 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
Figure GDA0003709489340000681
Step 1: 1,2,3,4, 5-pentafluoro-6-methoxybenzene (2.0mmol) was dissolved in 10mL of DMF solution, 4-bromo-2, 3-dihydro-1H-inden-1-ol (3.0mmol) and cesium carbonate (4.0mmol) were added, and the mixture was heated to 100 ℃ under nitrogen protection and stirred for about 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification of the concentrate by silica gel column chromatography gave 4-bromo-1- (2,3,5, 6-tetrafluoro-4-methoxyphenoxy) -2, 3-dihydro-1H-indene (0.25g) in 32% yield.
Step 2: 4-bromo-1- (2,3,5, 6-tetrafluoro-4-methoxyphenoxy) -2, 3-dihydro-1H-indene (1.5mmol) and pinacol diboron (1.2mmol) were dissolved in 1, 4-dioxane (12mL), Pd (dppf) Cl was added 2 (0.15mmol) and potassium acetate (3.0mmol) were heated to 90 ℃ under nitrogen for about 12 hours. After the reaction was stopped and the temperature was reduced to room temperature, water and ethyl acetate were added to conduct extraction, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtration was carried out, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 4,4,5, 5-tetramethyl-2- (1- (2,3,5, 6-tetrafluoro-4-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -1, 3-dioxolane (0.33g) as a compound in 50% yield.
And 3, step 3: 4,4,5, 5-tetramethyl-2- (1- (2,3,5, 6-tetrafluoro-4-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -1, 3-dioxolane (1.5mmol) and 3-bromo-2-chloroaniline (2.0mmol) were dissolved in 10mL of 1, 4-dioxane, 3.0mL of purified water was added, and Pd (PPh) was added 3 ) 4 (0.15mmol) and sodium carbonate (3.0mmol), the reaction mixture was heated to reflux for about 24 hours. Then, the temperature was reduced to room temperature, water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound 2-chloro-3- (1- (2,3,5, 6-tetrafluoro-4-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) aniline (0.31g) in 48% yield.
And 4, step 4: 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 anhydrous DMF and HATU (3.0mmol) and DIPEA (4.5mmol) were added and reacted at room temperature under nitrogen for about 24 hours. The reaction was then quenched with water, extracted with ethyl acetate, the organic phase separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound N- (2-chloro-3- (1- (2,3,5, 6-tetrafluoro-4-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (0.32g) in 35% yield.
And 5: n- (2-chloro-3- (1- (2,3,5, 6-tetrafluoro-4-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (0.5mmol) was dissolved in 5mL of dichloromethane, placed in an ice bath at 0 ℃ under nitrogen protection, boron tribromide (2.5mmol) was added, and after the addition was completed, the reaction was carried out at room temperature for about 4 hours. Put in an ice bath at 0 ℃, water is carefully added for quenching, dichloromethane is used for extraction, organic phase is separated, anhydrous sodium sulfate is dried, filtration is carried out, filtrate is decompressed and concentrated, and the obtained concentrate is purified by silica gel column chromatography to obtain the compound 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-formamide (0.27g) with 90 percent yield.
Step 6: 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) was dissolved in 5mL of acetonitrile solution, and 1-bromo-2-chloroethane (0.3mmol) and potassium carbonate (0.6mmol) were added and reacted at room temperature for about 5 hours. Quenching with water, extracting with ethyl acetate, separating the organic phase, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the concentrate by silica gel column chromatography to obtain the compound 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 (125mg), yield 63%.
And 7: mixing 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 (0.1mmol) was dissolved in 3mL of acetone, and pyrrolidin-3-ol (0.2mmol) and potassium carbonate (0.3mmol) were added theretoThe reaction was stirred at room temperature for about 12 hours. Quenching with water, extracting with ethyl acetate, separating organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the concentrate by reversed-phase preparative HPLC chromatography to obtain N- (2-chloro-3- (1- (2,3,5, 6-tetrafluoro-4- (2- (3-hydroxypyrrolidine-1-yl) ethoxy) 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 (25mg), yield 35%. LC-MS (ESI-MS): 714[ M + H] + 。
Example 48: preparation of 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) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000691
Step 1-4: referring to the synthesis method of steps 1 to 4 of example 2, the compound methyl 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-methoxybenzoate (0.45g) was prepared by replacing 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde with methyl 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzoate, LC-MS (ESI-MS):654[ M + H ] +.
And 5: methyl 5-chloro-4- (4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-carboxamido) yl) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzoate (0.6mmol) was dissolved in 5mL of methanol, anhydrous LiOH (2.0mmol) was added, the reaction was carried out at room temperature for 3 hours, concentration under reduced pressure was carried out, and the resulting concentrate was purified by chromatography to give 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 (0.34g) in 88% yield.
Step 6: mixing 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 pyrrolidine-3-carboxylic acid tert-butyl ester (0.6mmol) were dissolved in 5mL anhydrous DMF and EDCI (1.0mmol), HOBt (1.0mmol) and Et were added 3 N (1.2mmol) and the reaction stirred at room temperature for about 20 hours. Quenching reaction with water, extracting with ethyl acetate for 3 times, combining organic phases, washing with water and saturated brine, separating ethyl acetate layer, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the obtained concentrate by chromatography to obtain tert-butyl 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) pyrrolidine-3-carboxylic acid ester (125mg) in 53% yield.
And 7: mixing 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-carboxylic acid ester (0.1mmol) was dissolved in 5mL of methanol, 4N HCl in methanol (0.5mL) was added, the reaction was carried out at room temperature for 12 hours, then, concentration was carried out under reduced pressure, and the obtained concentrate was purified by reversed-phase preparative HPLC chromatography to give the objective compound 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] imidazo [4 ]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzoyl) pyrrolidine-3-carboxylic acid (38mg) in 52% yield. LC-MS (ESI-MS):736[ M + H] + 。
Example 49: preparation of 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-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000701
With reference to the synthesis procedure of example 48, by replacing tert-butyl pyrrolidine-3-carboxylate with 2-aminoethanol, the title 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-dimethyl-4, 5,6, 7-tetrahydro-1H-imid-ol was preparedAzolo [4,5-c]Pyridine-2-carboxamide (16mg), LC-MS (ESI-MS):682[ M + H] + 。
Example 50: preparation of 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, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000702
N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) is reacted with a carboxylic acid to form a mixture ]Pyridine-2-carboxamide (0.2mmol) and 3-azabicyclo [3.1.0]Hex-1-ylcarbinol (0.4mmol) was dissolved in a solution of 3mL of methanol and 3mL of methylene chloride, acetic acid (1.0mmol) was added, the reaction mixture was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give the compound 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, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamide (14mg), yield 10%. LC-MS (ESI-MS) 720[ M + H ]] + 。
Example 51: preparation of N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((3-oxopiperazin-1-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
Figure GDA0003709489340000703
N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) is reacted with a carboxylic acid to form a mixture]Pyridine-2-carboxamide (0.2mmol) and piperazin-2-one (0.4mmol) were dissolved in a solution of 3mL methanol and 3mL methylene chloride, Acetic acid (1.0mmol) was added, the reaction mixture was mixed and stirred for about 1 hour, and then sodium borohydride triacetate (1.0mmol) was added. After about 20 hours of reaction at room temperature, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give the compound N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((3-oxopiperazin-1-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 (11mg), yield 8%. LC-MS (ESI-MS):707[ M + H] + 。
Example 52: preparation of N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((6-oxo-5-oxa-2, 7-diazaspiro [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
Figure GDA0003709489340000711
N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) is reacted with a carboxylic acid to form a mixture]Pyridine-2-carboxamide (0.2mmol) and 5-oxa-2, 7-diazaspiro [3.4]]Oct-6-one (0.3mmol) was dissolved in a solution of 3mL of methanol and 3mL of methylene chloride, acetic acid (0.6mmol) was added, the reaction mixture was mixed and stirred for about 1 hour, and then sodium triacetyl borohydride (1.0mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was spin-dried by concentration under reduced pressure, and the residue was purified by reverse phase preparative HPLC chromatography to give the compound N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((6-oxo-5-oxa-2, 7-diazaspiro [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 (9mg), yield 6%. LC-MS (ESI-MS):735[ M + H] + 。
Example 53: preparation of N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((6-oxo-2, 5, 7-triazaspiro [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
Figure GDA0003709489340000712
N- (2-chloro-3- (1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) is reacted with a carboxylic acid to form a mixture]Pyridine-2-carboxamide (0.2mmol) and 2,5, 7-triazaspiro [3.4]]Octane-6-one (0.3mmol) was dissolved in a solution of 3mL of methanol and 3mL of dichloromethane, acetic acid (0.6mmol) was added, the reaction mixture was stirred for about 1 hour, and then sodium borohydride triacetate (1.0mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give the compound N- (2-chloro-3- (1- (6-chloro-2-fluoro-3-methoxy-4- ((6-oxo-2, 5, 7-triazaspiro [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 (13mg), yield 9%. LC-MS (ESI-MS):734[ M + H] + 。
Example 54: preparation of 1- (5-chloro-4- (4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -1H-benzo [ d ] imidazole-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000721
Referring to the synthetic method and reaction procedure of example 15, 4-bromoindoline was replaced with 4-bromo-1H-benzo [ d ]]Imidazole, and can 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) -1H-benzo [ d]Imidazole-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (12mg), LC-MS (ESI-MS):734[ M + H] + 。
Example 55: preparation of 1- (5-chloro-4- (4- (2-chloro-3- (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ] pyridine-2-carboxamido) phenyl) -1H-benzo [ d ] imidazole-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000722
Reference example 15 Synthesis method and reaction procedure for substituting 4-bromoindoline with 4-bromo-1H-benzo [ d]Imidazole, 1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Replacement of pyridine-2-carboxylic acid with 5-methyl-4, 5,6, 7-tetrahydrothiazolo [4,5-c ]]Pyridine-2-carboxylic acid, can be used for preparing the target compound 1- (5-chloro-4- (4- (2-chloro-3- (5-methyl-4, 5,6, 7-tetrahydrothiazolo [4, 5-c) ]Pyridine-2-carboxamido) phenyl) -1H-benzo [ d]Imidazole-1-carbonyl) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (19mg), LC-MS (ESI-MS):737[ M + H ]] + 。
Example 56: preparation of 1- (5-chloro-4- ((7- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydrobenzofuran-3-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000723
Referring to the synthetic method and reaction procedure of example 2, 1- (5-chloro-4- ((7- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) ] as a target compound can be prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 7-bromo-2, 3-dihydrobenzofuran-3-ol]Pyridine-2-carboxamido) phenyl) -2, 3-dihydrobenzofuran-3-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (22mg), LC-MS (ESI-MS):724[ M + H] + 。
Example 57: preparation of 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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000731
1- (3-bromo-2-methylphenyl) -2,2, 2-trifluoroacetone (3.0mmol) and 6-chloro-4- (dimethyl)The oxymethyl) -2-fluoro-3-methoxyaniline (3.6mmol) was dissolved in 20mL of 1, 2-dichloroethane, stirred at room temperature for 30 minutes, added with sodium borohydride triacetate (6.0mmol), and reacted at room temperature for about 12 hours, followed by completion of the reaction by TLC. 5mL of 6N HCl solution was added and the mixture was heated to 50 ℃ for about 6 hours. The reaction was stopped, and sodium hydrogencarbonate aqueous solution was added to neutralize to basicity, and extraction was performed with dichloromethane, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by chromatography to give compound 4- ((1- (3-bromo-2-methylphenyl) -2,2, 2-trifluoroethyl) amino) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.75g) in 55% yield. Subsequent reaction referring to the reaction procedures of steps 2 to 5 of example 2, 1- (5-chloro-4- ((1- (2 '-chloro-3' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) as a target compound can be prepared ]Pyridine-2-carboxamido) -2-methyl- [1,1' -biphenyl]-3-yl) -2,2, 2-trifluoroethyl) amino) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (18mg), LC-MS (ESI-MS):777[ M + H] + 。
Example 58: preparation of 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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000732
Step 1: 3-bromo-2-chloroaniline (3.0mmol) and 1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxylic acid (3.0mmol) were dissolved in 12mL anhydrous DMF and HATU (4.5mmol) and DIPEA (6.0mmol) were added and reacted at room temperature under nitrogen for about 24 hours. The reaction was then quenched with water, extracted with dichloromethane, the organic phase separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound N- (3-bromo-2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (0.7g) in 61% yield.
And 2, step: mixing N- (3-bromo-2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamides(2.0mmol) and pinacol diboron (2.0mmol) were dissolved in 20mL of 1, 4-dioxane, Pd (dppf) Cl was added 2 (0.2mmol) and potassium acetate (4.0mmol) were heated to 90 ℃ under nitrogen for about 12 hours. After the reaction was stopped and the temperature was reduced to room temperature, water and ethyl acetate were added to conduct extraction, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain compound 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 (0.47g) in 55% yield.
And 3, step 3: mixing 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) were dissolved in 10mL of 1, 4-dioxane, 3.0mL of purified water was added, and Pd (PPh) was added 3 ) 4 (0.15mmol) and sodium carbonate (3.0mmol), the reaction mixture was heated to reflux for about 24 hours. Then, the temperature was reduced to room temperature, water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain compound N- (3' -amino-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 (0.27g), yield 44%.
And 4, step 4: 1- (6-chloro-4- (dimethoxymethyl) -2-fluoro-3-methoxyphenyl) -2,2, 2-trifluoroacetone (1.0mmol) and N- (3' -amino-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 (1.2mmol) in 10mL of 1, 2-dichloroethane solution were stirred at room temperature for 30 minutes, then sodium borohydride triacetate (2.0mmol) was added, the reaction was allowed to proceed at room temperature for about 12 hours, and the reaction was complete by TLC. 5mL of 6N HCl solution was added and the mixture was heated to 50 ℃ for about 6 hours. The reaction was stopped, an aqueous sodium bicarbonate solution was added to neutralize to basicity, extraction was performed with dichloromethane, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by chromatography to give the compound N- (2-chloro-3 ' - ((1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenyl) -2,2, 2-trifluoroethyl) amino) -2' -methyl- [11,1' -biphenyl ] -3-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (0.21g) with a yield of 32%.
And 5: reacting N- (2-chloro-3 ' - ((1- (6-chloro-2-fluoro-4-formyl-3-methoxyphenyl) -2,2, 2-trifluoroethyl) 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, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. After about 20 hours of reaction at room temperature, the organic solvent was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give compound 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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (17mg) in 11% yield. LC-MS (ESI-MS):777[ M + H] + 。
Example 59: preparation of 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-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000741
Step 1: 3-bromo-2-chloroaniline (4.0mmol) and 1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxylic acid (4.8mmol) were dissolved in 20mL anhydrous DMF and HATU (6.4mmol) and DIPEA (8.0mmol) were added and reacted at room temperature under nitrogen for about 24 hours. Then water was added to quench the reaction, dichloromethane was used to extract 2 times, the combined organic phase was washed with water and saturated brine, respectively, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound N- (3-bromo-2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (1.12g), 73% yield.
Step (ii) of2: mixing N- (3-bromo-2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamide (2.0mmol) and pinacol diboron (1.6mmol) were dissolved in 15mL of 1, 4-dioxane, Pd (dppf) Cl was added 2 (0.2mmol) and potassium acetate (4.0mmol) were heated to 90 ℃ under nitrogen for about 20 hours. After the reaction was stopped and the temperature was reduced to room temperature, water and ethyl acetate were added to conduct extraction, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain compound 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 (0.38g), yield 44%.
And step 3: 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-carboxamide (1.2mmol) were dissolved in 12mL of a toluene solution, and copper acetate (0.3mmol) and potassium carbonate (1.0mmol) were added and reacted at 50 ℃ for about 48 hours. After the reaction was completed, water and methylene chloride were added to extract 2 times, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure, followed by purification by silica gel column chromatography gave the compound 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 (220mg), yield 41%.
And 4, step 4: 6-chloro-2-fluoro-4-formyl-3-methoxyphenyl trifluoromethanesulfonate (1.0mmol) 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) were dissolved in 10mL of a toluene solution, and cuprous iodide (0.1mmol), cesium carbonate (0.2mmol) and 3,4,7, 8-tetramethyl-1, 10-phenanthroline (0.2mmol) were added, and the reaction solution was heated to reflux conditions for 12 hours. After the reaction was stopped, water and ethyl acetate were added to extract 3 times, the organic phase was combined, washed with water and saturated brine, respectively, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound 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 (0.16g) in 50% yield.
And 5: reacting 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 (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 was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (1.0mmol) was added. After reaction at room temperature for about 20 hours, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give compound 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-methoxybenzyl) pyrrolidine-3-carboxylic acid (23mg) in 16% yield. LC-MS (ESI-MS):735[ M + H] + 。
Example 60: preparation of 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) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000751
Referring to the synthesis and reaction procedure of example 59, 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]Replacement of pyridine-2-carboxamide by 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-formamide to obtain the target compound 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) pyrrolidine-3-carboxylic acid (10mg), LC-MS (ESI-MS):736[ M + H] + 。
Example 61: preparation of 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-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000761
Referring to the synthesis method and reaction procedure of example 59, 1- (5-chloro-4- ((1- (2 '-chloro-3' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as the target compound can be prepared by replacing 1- (3-bromo-2-methylphenyl) cyclopropylamine with 1- (3-bromo-2-methylphenyl) cyclobutylamine]Pyridine-2-carboxamido) -2-methyl- [1,1' -biphenyl]-3-yl) cyclobutyl) amino) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (12mg), LC-MS (ESI-MS) 750[ M + H] + 。
Example 62: preparation of 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-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000762
Referring to the synthesis and reaction procedure of example 59, 1- (5-chloro-4- (((2 '-chloro-3' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)) was prepared as the target compound by replacing 1- (3-bromo-2-methylphenyl) cyclopropylamine with 1- (3-bromo-2-methylphenyl) -1, 1-difluoromethylamine]Pyridine-2-carboxamido) -2-methyl- [ [1,1' -biphenyl]-3-yl) difluoromethyl) amino) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (8mg), LC-MS (ESI-MS):746[ M + H] + 。
Example 63: preparation of 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
Figure GDA0003709489340000763
Referring to the synthesis and reaction procedure of example 59, 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]Replacement of pyridine-2-carboxamide 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-formamide can be used for preparing a target compound 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 (5mg), LC-MS (ESI-MS):752[ M + H] + 。
Example 64: preparation of 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) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000771
Referring to the synthesis and reaction procedure of example 59, 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 ]Replacement of pyridine-2-carboxamide with N- (2-chloro-3 ' - (4-hydroxytetrahydro-2H-pyran-4-yl) -2' -methyl- [1,1' -biphenyl]-3-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-formamide, and can be used for preparing a 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) -2-methyl- [1,1' -biphenyl]-3-yl) tetrahydro-2H-pyran-4-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (6mg), LC-MS (ESI-MS):780[ M + H] + 。
Example 65: preparation of 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-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000772
Referring to the synthesis and reaction procedure of example 59, 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]Replacement of pyridine-2-carboxamide with N- (2-chloro-2 ' -methyl-3 ' - (2,2, 2-trifluoro-1-hydroxyethyl) - [1,1' -biphenyl]-3-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-formamide to obtain the target compound 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-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (6mg), LC-MS (ESI-MS):778[ M + H] + 。
Example 66: preparation of (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-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000773
Step 1: 4-bromo-1-indanone (5.0mmol) is dissolved in 50mL of dichloromethane solution, cooled to-20 ℃ under nitrogen protection, then (S) -2-methyl-CBS-oxazoleborane (0.5mmol) is added, a toluene solution of borane dimethyl sulfide complex (2M, 12.5mL) is slowly added dropwise through a dropping funnel, and the reaction is continued for about 3 hours after the dropwise addition. The reaction was quenched by addition of water, extracted with dichloromethane, the organic phase separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave compound (R) -4-bromo-2, 3-dihydro-1H-inden-1-ol (0.98g) in 92% yield.
And 2, step: 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde (3.0mmol) and (R) -4-bromo-2, 3-dihydro-1H-inden-1-ol (4.5mmol) were dissolved in 20mL of anhydrous tetrahydrofuran solution, triphenylphosphine (4.5mmol) was added, and DIAD (4.5mmol) was slowly added dropwise and reacted at room temperature for about 12 hours. The reaction was stopped, and most of the reaction solvent was removed by concentration under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography to give compound (S) -4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.78g) in 65% yield.
Then, referring to the reaction scheme and procedure of example 2, 4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde was replaced with (S) -4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde; the target compound (R) -1- (5-chloro-4- (((S) -4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole, 5-c) can be prepared by replacing pyrrolidine-3-carboxylic acid with (R) -pyrrolidine-3-carboxylic acid]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (14mg), LC-MS (ESI-MS):722[ M + H] + 。
Example 67: preparation of (S) -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-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000781
With reference to the procedure for the synthesis of example 66, by substituting (R) -pyrrolidine-3-carboxylic acid with (S) -pyrrolidine-3-carboxylic acid, the objective compound (S) -1- (5-chloro-4- ((((S) -4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole, 5-c) was produced]Pyridine-2-carboxamido) 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 preparation of (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
Figure GDA0003709489340000782
Step 1: 4-bromo-1-indanone (5.0mmol) is dissolved in 50mL of dichloromethane solution and cooled to-20 ℃ under nitrogen protection, then (R) -2-methyl-CBS-oxazoleborane (0.5mmol) is added, a toluene solution of borane dimethyl sulfide complex (2M, 12.5mL) is slowly added dropwise through a dropping funnel, and the reaction is continued for about 3 hours after the dropwise addition. The reaction was quenched by addition of water, extracted with dichloromethane, the organic phase separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure followed by purification by silica gel column chromatography gave the compound (S) -4-bromo-2, 3-dihydro-1H-inden-1-ol (0.96g) in 90% yield.
Step 2: 5-chloro-3-fluoro-4-hydroxy-2-methoxybenzaldehyde (3.0mmol) and (S) -4-bromo-2, 3-dihydro-1H-inden-1-ol (4.5mmol) were dissolved in 20mL of anhydrous tetrahydrofuran solution, triphenylphosphine (4.5mmol) was added, and DIAD (4.5mmol) was slowly added dropwise and reacted at room temperature for about 12 hours. The reaction was stopped, concentrated under reduced pressure to remove most of the reaction solvent, and the resulting concentrate was purified by silica gel column chromatography to give compound (R) -4- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-3-fluoro-2-methoxybenzaldehyde (0.72g) in 60% yield.
Then, referring to the reaction scheme and procedure of example 2, the target compound (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 (12mg), LC-MS (ESI-MS):722[ M + H] + 。
Example 69: preparation of (S) -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
Figure GDA0003709489340000791
With reference to the procedure for the synthesis of example 68, by replacing (R) -pyrrolidine-3-carboxylic acid with (S) -pyrrolidine-3-carboxylic acid, the objective compound (S) -1- (5-chloro-4- ((((R) -4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole, 5-c) was produced]Pyridine-2-carboxamido) 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: preparation of methyl 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylate
Figure GDA0003709489340000792
Referring to the synthesis method of example 2, 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as a target compound can be prepared by replacing pyrrolidine-3-carboxylic acid with methyl pyrrolidine-3-carboxylate]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid methyl ester (13mg), LC-MS (ESI-MS):736[ M + H] + 。
Example 71: preparation of methyl 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-carboxylate
Figure GDA0003709489340000793
By substituting pyrrolidine-3-carboxylic acid with pyrrolidine-3-carboxylic acid methyl ester according to the synthesis method of reference example 1, the objective compound 1- (4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetra-methyl) formate was preparedhydro-1H-imidazo [4,5-c ]]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2,3,5, 6-tetrafluorobenzyl) pyrrolidine-3-carboxylic acid methyl ester (15mg), LC-MS (ESI-MS):726[ M + H ] 726 ] + 。
Example 72: preparation of 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-carboxamide
Figure GDA0003709489340000801
With reference to the synthesis method of example 2, the objective compound 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 ] is prepared by replacing pyrrolidine-3-carboxylic acid with dimethylamine hydrochloride]Pyridine-2-carboxamide (13mg), LC-MS (ESI-MS):652[ M + H] + 。
Example 73: preparation of 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-2-carboxylic acid
Figure GDA0003709489340000802
With reference to the synthesis method of example 2, 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as a target compound can be prepared by replacing pyrrolidine-3-carboxylic acid with piperidine-2-carboxylate]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) piperidine-2-carboxylic acid (8mg), LC-MS (ESI-MS):736[ M + H ] + 。
Example 74: preparation of 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
Figure GDA0003709489340000803
Referring to the synthesis method of example 2, 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) ] as the target compound can be prepared by replacing pyrrolidine-3-carboxylic acid with proline]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) proline (7mg), LC-MS (ESI-MS): 722[ M + H] + 。
Example 75: preparation of (2S) -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) -3-hydroxy-2-methylpropionic acid
Figure GDA0003709489340000811
By substituting pyrrolidine-3-carboxylic acid with (S) -2-amino-3-hydroxy-2-methylpropionic acid according to the synthesis method of reference example 2, the objective compound (2S) -2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) can be produced]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) amino) -3-hydroxy-2-methylpropionic acid (6mg), LC-MS (ESI-MS):726[ M + H ] + 。
Example 76: preparation of (2R) -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) -3-hydroxy-2-methylpropionic acid
Figure GDA0003709489340000812
By substituting pyrrolidine-3-carboxylic acid with (R) -2-amino-3-hydroxy-2-methylpropionic acid according to the synthesis method of reference example 2, the objective compound (2R) -2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) can be produced]Pyridine-2-Carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) amino) -3-hydroxy-2-methylpropionic acid (7mg), LC-MS (ESI-MS):726[ M + H] + 。
Example 77: preparation of 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
Figure GDA0003709489340000813
With reference to the synthesis method of example 2, substituting pyrrolidine-3-carboxylic acid with serine gave 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-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) serine (6mg), LC-MS (ESI-MS): 712[ M + H ] + 。
Example 78: preparation of methyl ((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
Figure GDA0003709489340000821
With reference to the synthesis method of example 2, the target compound ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) was prepared by replacing pyrrolidine-3-carboxylic acid with serine methyl ester]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -3-fluoro-2-methoxybenzyl) serine methyl ester (10mg), LC-MS (ESI-MS):726[ M + H: [ ESI-MS ]] + 。
EXAMPLE 79 preparation of 1- (5-chloro-4- ((6- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -7-methyl-2, 3-dihydro-1H-indan-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000822
With reference to the synthesis method of example 2, 1- (5-chloro-4- ((6- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]) as a target compound can be prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 6-bromo-7-methyl-2, 3-dihydro-1H-indan-1-ol]Pyridine-2-carboxamido) phenyl) -7-methyl-2, 3-dihydro-1H-indan-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (7mg), LC-MS (ESI-MS):736[ M + H ] + 。
EXAMPLE 80 preparation of 1- (5-chloro-4- ((7-chloro-6- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000823
With reference to the synthesis procedure of example 2, the title compound, 1- (5-chloro-4- ((7-chloro-6- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c), was prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 6-bromo-7-chloro-2, 3-dihydro-1H-indan-1-ol]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (8mg), LC-MS (ESI-MS):756[ M + H] + 。
Example 81: preparation of 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
Figure GDA0003709489340000831
Referring to the synthesis of example 2, the title 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 (8mg), LC-MS (ESI-MS):747[ M + H ] + 。
Example 82: preparation of 1- (5-chloro-4- ((5- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -4-methyl-2, 3-dihydrobenzofuran-3-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340000832
Referring to the synthesis method of example 2, the target compound 1- (5-chloro-4- ((5- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)) can be prepared by replacing 4-bromo-2, 3-dihydro-1H-inden-1-ol with 5-bromo-4-methyl-2, 3-dihydrobenzofuran-3-ol]Pyridine-2-carboxamido) phenyl) -4-methyl-2, 3-dihydrobenzofuran-3-yl) oxy) -3-fluoro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid (11mg), LC-MS (ESI-MS):738[ M + H] + 。
Example 083: preparation of 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) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340000833
Step 1: reacting 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Pyridine-5 (4H) -carboxylic acid tert-butyl ester (refer to patent WO2018119224A1 and CN110267953 preparation) (4g) is dissolved in 40mL dichloromethane, 4mL trifluoroacetic acid is added, the mixture is heated to 40 ℃ for reaction for 3H, TLC detection reaction is complete, and decompression rotary evaporation is carried out to evaporate the solvent; extracting with dichloromethane and water, separating organic phase, concentrating under reduced pressure, purifying the crude product by silica gel column chromatography to obtain white solid product N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] ]Pyridine compound2-carboxamide (2.8g), yield 89%, 1 H NMR(500MHz,CDCl3)δ9.86(s,1H),8.46(d,J＝ 8.3Hz,1H),7.39(d,J＝8.0Hz,1H),7.18(t,J＝8.2Hz,1H),3.94(s,3H),3.98-3.92(m,2H), 3.20(t,J＝5.5Hz,2H),2.73(t,J＝5.3Hz,2H),2.55(brs,1H)。
and 2, step: mixing N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamide (4g) and ((4- (4,4,5, 5-tetramethyl-1, 3-dioxapentan-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxy) tert-butyldimethylsilane (8.1g) were dissolved in 20ml of 1, 4-epoxyhexacyclic ring, H was added 2 0(10mL)，Na 2 CO 3 (2.3g), Pd(dppf)Cl 2 (787mg), heating to 90 ℃ for overnight reaction, evaporating the solvent under reduced pressure after HPLC detection, extracting with ethyl acetate and water, separating the organic phase, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography to obtain a solid product 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 (3.8g) in 66% yield.
And 3, step 3: 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 of tetrahydrofuran, 28mL of TBAF (1mol/L in THF) was added, and the reaction was heated to 40 ℃ overnight. After TLC detection reaction is completed, the solvent is evaporated to dryness under reduced pressure, then ethyl acetate EA and water are used for extraction, the separated organic phase is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography to obtain a light yellow solid product 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-formamide (1.4g) with the yield of 59%.
And 4, step 4: mixing 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 the mixture was stirred at room temperature for 0.5 hour, followed by addition of sodium borohydride acetate (752mg), and the reaction was allowed to proceed overnight at room temperature. After TLC detection reaction is completed, using dichloromethane and water to make extraction, separating organic phase, concentrating under reduced pressure, making the crude product undergo the process of silica gel column chromatography purification to obtain 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)]Pyridin-5 (4H) -yl) benzoic acid propyl ester (440mg) in 64% yield. 1 H NMR(500MHz,CDCl3)δ9.84(s,1H),8.46(t,J＝7.1Hz,1H),8.04(d,J＝ 7.9Hz,2H),7.56(t,J＝7.2Hz,1H),7.51–7.41(m,3H),7.34(dd,J＝14.3,7.2Hz,2H), 7.18(d,J＝7.4Hz,1H),7.00(s,1H),5.33(d,J＝21.7Hz,1H),4.58–4.53(m,1H),4.36– 4.29(m,1H),3.95(s,3H),3.77(s,2H),3.38–4.53(dt,J＝13.0,6.6Hz,1H),3.04(t,J＝5.5 Hz,2H),2.87–2.74(m,1H),2.75–2.64(m,2H),2.58–2.44(m,2H),1.92(brs,1H),1.27 (d,J＝6.3Hz,3H)。
And 5: 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde (1.02g) and methyl 1-aminocyclobutylbenzoate hydrochloride (1.66g) were dissolved in 20mL of dichloromethane, and triethylamine (1.3mL) and sodium borohydride acetate (2.12g) were added to react at room temperature overnight. After TLC detection reaction is finished, dichloromethane and water are used for extraction, separated organic phase is decompressed and concentrated, a crude product is purified by silica gel column chromatography to obtain a solid product 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester (1.11g), the yield is 70 percent, 1 H NMR(500MHz,CDCl 3 )δ6.27(d,J＝1.4Hz,1H),3.83 (s,3H),3.79(s,3H),3.54(d,J＝1.2Hz,2H),2.55–2.47(m,2H),2.32–2.24(m,2H),2.15 –2.08(m,1H),2.04–1.97(m,1H)。
Step 6: dissolving propyl 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 ] pyridin-5 (4H) -yl) benzoate (70mg) and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate (57mg) in 2mL 2-methyltetrahydrofuran, adding triphenylphosphine (78mg), dropwise adding DIAD (60mg) under nitrogen protection, reacting at room temperature for 30 minutes, after HPLC (high performance liquid chromatography) reaction is finished, adding silica gel, stirring, and purifying to obtain a light yellow solid product, namely 2- (2- ((2-chloro-3) column chromatography Propyl- (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-imidazo [4,5-c ] pyridin-5 (4H) -yl) benzoate (45mg) yield 43%.
And 7: 2- (2- ((2-chloro-3- (1- (2-chloro-3-fluoro-5-methyl)Oxy-4- ((1- (methoxycarbonyl) cyclobutyl) amino) methyl) phenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4,5-c]Pyridine-5 (4H) -propyl benzoate (45mg) is dissolved in 2mL methanol, lithium hydroxide (24mg) is added to react at room temperature overnight, after TLC detection reaction is completed, 1 drop of AcOH is dropwise added into the reaction liquid, then silica gel is added to mix the sample, and column chromatography purification is carried out to obtain a solid product 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) amino) cyclobutanecarboxylic acid (35mg) in 89% yield. 766[ M + H ] LC-MS (ESI-MS)] + 。
Example 084: preparation of 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-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340000851
Step 1, 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)]Dissolving pyridine-2-formamide (405mg) and 2-bromoethyl benzoate (286mg) in 10mL DMF, adding DIPEA (269mg), heating to 60 deg.C for overnight reaction, detecting by TLC after reaction is complete, adding ethyl acetate and water for extraction, separating organic phase, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography to obtain 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 ] as product]Pyridin-5 (4H) -yl) benzoic acid ethyl ester (300mg), yield 55%. 1 H NMR(500MHz,CDCl 3 )δ9.85 (s,1H),8.46(t,J＝6.6Hz,1H),8.05(d,J＝7.7Hz,2H),7.56(t,J＝7.5Hz,1H),7.46(dt,J＝ 15.3,7.6Hz,3H),7.34(dd,J＝14.0,7.1Hz,2H),7.19(d,J＝7.4Hz,1H),7.01(brs,1H), 5.33(d,J＝23.1Hz,1H),4.55(dd,J＝10.2,4.4Hz,2H),3.95(s,3H),3.73(s,2H),3.09– 3.05(m,2H),3.04–2.98(m,2H),2.92–2.83(m,1H),2.79–2.74(m,1H),2.73–2.68(m, 2H),2.52–2.43(m,1H),1.96–1.87(m,1H)。
Step 2, dissolving ethyl 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 ] pyridin-5 (4H) -yl) benzoate (75mg) and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate (60mg) in 2mL 2-methyltetrahydrofuran, adding triphenylphosphine (80mg), dropwise adding DIAD (65mg) under the protection of nitrogen, reacting for 30 minutes at room temperature, after the HPLC detection reaction is finished, adding silica gel, stirring the sample, and purifying by column chromatography to obtain a solid product, namely 2- (2- ((2-chloro-3-yl) 2 Ethyl- (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-imidazo [4,5-c ] pyridin-5 (4H) -yl) benzoate (50mg) yield 44%.
Step 3, 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-imidazo [4, 5-c)]Dissolving pyridine-5 (4H) -ethyl benzoate (40mg) in 2mL methanol, adding lithium hydroxide (22mg), reacting at room temperature overnight, detecting by TLC after the reaction is complete, dropwise adding AcOH into the reaction solution, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product 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) amino) cyclobutanecarboxylic acid (30mg) in 86% yield. LC-MS (ESI-MS):752[ M + H] + 。
Example 085: preparation of 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (2-hydroxypropyl) -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
Figure GDA0003709489340000852
Step 1, dissolving 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) in 5mL of ethanol, adding 2-methylepoxypropane (82mg) and DIPEA (183mg), and heating to 80 ℃ for overnight reaction; after TLC detection reaction is completed, the solvent is evaporated to dryness under reduced pressure, then the mixture is extracted by ethyl acetate and water, the separated organic phase is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography to obtain a white solid product, namely 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-imidazo [4,5-c ] pyridine-2-formamide (170mg), with the yield of 75%.
Step 2, dissolving 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-imidazo [4,5-c ] pyridine-2-carboxamide (63mg) and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate (60mg) in 2mL 2-methyltetrahydrofuran, adding triphenylphosphine (80mg), dropwise adding DIAD (65mg) under nitrogen protection, reacting for 30 minutes at room temperature, after HPLC detection reaction is finished, adding silica gel to mix samples, and purifying to obtain a solid product 2- (2- ((2-chloro-3 column chromatography) column chromatography Ethyl- (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-imidazo [4,5-c ] pyridin-5 (4H) -yl) benzoate (41mg) yield 40%.
Step 3, 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-imidazo [4, 5-c)]Dissolving pyridine-5 (4H) -ethyl) benzoate (41mg) in 2mL methanol, adding lithium hydroxide (22mg), reacting at room temperature overnight, detecting by TLC after the reaction is complete, dropwise adding 1 drop of AcOH into the reaction solution, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (2-hydroxypropyl) -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 (23mg) in 58% yield. 766[ M + H ] LC-MS (ESI-MS)] + 。
Example 086: preparation of 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) cyclopropanecarboxylic acid
Figure GDA0003709489340000861
Referring to the synthesis method of example 083, propyl 2-carbobenzoate was replaced with paraformaldehyde, and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((6-chloro-4-hydroxy-2-methoxy-3-methylbenzyl) amino) cyclopropanecarboxylate (synthesized from 2-chloro-4-hydroxy-5-methyl-6-methoxybenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride), to synthesize the objective compound 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) cyclopropanecarboxylic acid (31mg), LC-MS (ESI-MS):704[ M + H] + 。
Example 087: preparation of 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) -2, 6-difluorobenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000862
Referring to the synthesis of example 083, propyl 2-carbobenzoate was replaced with paraformaldehyde, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((3-chloro-2, 6-difluoro-4-hydroxybenzyl) amino) cyclopropanecarboxylate (synthesized from 2-fluoro-4-hydroxy-5-chloro-6-fluorobenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride), and the synthesis yielded 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, 6-difluorobenzyl) amino) cyclopropanecarboxylic acid (45mg), LC-MS (ESI-MS):696[ M + H] + 。
Example 088: preparation of 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, 6-difluorobenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000871
Referring to the synthesis method of example 083, propyl 2-carbonylbenzoate was replaced with paraformaldehyde, and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((3, 5-dichloro-2, 6-difluoro-4-hydroxybenzyl) amino) cyclopropanecarboxylate (synthesized from 2-fluoro-3-chloro-4-hydroxy-5-chloro-6-fluorobenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride), to synthesize the objective 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, 6-difluorobenzyl) amino) cyclopropanecarboxylic acid (18mg), LC-MS (ESI-MS):730[ M + H] + 。
Example 089: preparation of 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) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340000872
Referring to the synthesis method of example 083, propyl 2-carbobenzoate was replaced with paraformaldehyde, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((3, 5-difluoro-4-hydroxy-2-methoxybenzyl) amino) cyclobutanecarboxylate (synthesized from 2-methoxy-3-fluoro-4-hydroxy-5-fluorobenzaldehyde and methyl 1-aminocyclobutanecarboxylate hydrochloride), 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-inden-1-yl) oxy) -3, 5-difluoro-2-methoxybenzyl) amino) cyclobutanecarboxylic acid (26mg), LC-MS (ESI-MS):706[ M + H] + 。
Example 090: preparation of 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) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340000873
Referring to the synthesis method of example 083, propyl 2-carbonyl benzoate was replaced with paraformaldehyde and reacted with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate to synthesize the objective 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) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid (31mg), LC-MS (ESI-MS): 722[ M + H] + 。
Example 091: preparation of 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) -2, 6-dimethoxybenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340000881
Reference example 083 Synthesis procedure replacement of propyl 2-Carbonylbenzoate with Paraformaldehyde and 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde with 2-methoxy-3-chloro-4-hydroxy-6-methoxybenzaldehyde to afford 1- ((3-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c) as the target Compound]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2, 6-dimethoxybenzyl) amino) cyclobutanecarboxylic acid (29mg), LC-MS (ESI-MS):734[ M + H ] + 。
Example 092: preparation of 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
Figure GDA0003709489340000882
Referring to the synthesis method of example 085, 2-methylpropylene oxide was replaced with 2, 2-dimethylethylene oxide, and 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) as a target compound was synthesized]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: preparation of 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
Figure GDA0003709489340000883
Referring to the synthesis method of example 084, 2-bromoethyl benzoate was replaced with 1-bromo-2-methoxyethane, and synthesis was carried out to give 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: preparation of 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) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000891
Referring to the synthesis of example 083, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylateReplacement with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride according to example 083 step 5) gave the title 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) -3]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid (33mg), LC-MS (ESI-MS):752[ M + H] + 。
Example 095: preparation of 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
Figure GDA0003709489340000892
Reference example 083 Synthesis procedure substituting methyl 1-Aminocyclobutanecarboxylate hydrochloride 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: preparation of 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-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000893
Reference example 084 Synthesis procedure for substituting methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehydePrepared by reacting with 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride according to example 083 step 5), to synthesize 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (2-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) as a target compound]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid (33mg), LC-MS (ESI-MS):738[ M + H ] + 。
Example 097: preparation of 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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000901
Reference example 083 Synthesis procedure substituting propyl 2-Carbophenylbenzoate with paraformaldehyde and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate to afford 1- ((3-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] imidazole, a target Compound]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: preparation of 1- ((3-chloro-4- ((4- (2-chloro-3- (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
Figure GDA0003709489340000902
Step 1, dissolving 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) in 3mL 2-methyltetrahydrofuran, adding methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate (86mg) and triphenylphosphine (124mg), dropwise adding DIAD (96mg) under the protection of nitrogen, reacting for 1 hour at room temperature, after the HPLC detection reaction is finished, adding silica gel, stirring, and purifying to obtain a solid product 1- ((3-chloro-4- ((4- (2-chloro-3- Methyl (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) cyclopropanecarboxylate (67mg), yield 40%.
And 2, step: mixing 1- ((3-chloro-4- ((4- (2-chloro-3- (1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ]]Dissolving pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropane carboxylic acid methyl ester (50mg) in 2mL methanol, adding lithium hydroxide (20mg), reacting overnight at room temperature, after TLC detection reaction is completed, dropwise adding 1 drop of AcOH into reaction liquid, then adding silica gel, stirring, and performing column chromatography purification to obtain a solid product 1- ((3-chloro-4- ((4- (2-chloro-3- (1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] to obtain a solid product]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid (33mg) in 68% yield. LC-MS (ESI-MS):694[ M + H ]] + 。
Example 099 preparation of 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-fluoro-2-methoxybenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340000903
Referring to the synthesis procedure of example 083, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((3-chloro-6-fluoro-4-hydroxy-2-methoxybenzyl) amino) cyclobutanecarboxylate (prepared from 2-methoxy-3-chloro-4-hydroxy-6-fluorobenzaldehyde and methyl 1-aminocyclobutanecarboxylate hydrochloride according to step 5 of example 83) to synthesize the title 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) -6-fluoro-2-methoxybenzyl) amino) cyclobutanecarboxylic acidAcid (31mg), LC-MS (ESI-MS):766[ M + H] + 。
Example 100: preparation of 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-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000911
Referring to the synthesis procedure of example 084, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with 1- (3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) azetidin-3-ol (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and 3-hydroxyazetidine hydrochloride according to example 083, step 5) to synthesize 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-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamide (20mg), LC-MS (ESI-MS) 710[ M + H] + 。
Example 101: preparation of 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-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000912
Referring to the synthesis method of example 084, 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 (prepared from 2-fluoro-3-chloro-4-hydroxy-6-methoxyformaldehyde and 4-amino-3-isoxazolidone according to step 5 of example 83), and N- (2-chloro-3- (1- (2-chloro-3-fluoro-5-methoxy-4- ((3-oxazolidin-4-yl) amino) methyl) phenoxy) -2, the objective compound, was synthesized, 3-dihydro-1H-inden-4-yl) phenyl) -5- (2-hydroxyethyl) -1-methyl-4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamide (26mg), LC-MS (ESI-MS):739[ M + H] + 。
Example 102: preparation of 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 [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000913
Referring to the synthesis method of example 084, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl (1- (3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) pyrrolidin-2-yl) acetate (3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and methyl pyrrolidin-2-yl acetate prepared according to step 5 in example 83), and N- (2-chloro-3- (1- (2-chloro-3-fluoro-4- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) -5-methoxyphenoxy) -2) which is a target compound was synthesized, 3-dihydro-1H-inden-4-yl) phenyl) -5- (2-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]Pyridine-2-carboxamide (16mg), LC-MS (ESI-MS):738[ M + H] + 。
Example 103: preparation of 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-fluoro-2-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000921
Referring to the synthesis procedure of example 083, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((3-chloro-6-fluoro-4-hydroxy-2-methoxybenzyl) amino) cyclopropanecarboxylate (prepared from 3-chloro-6-fluoro-4-hydroxy-2-methoxybenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride according to example 083, step 5) to synthesize 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) -6-fluoro-2-methoxybenzyl) amino) cyclopropanecarboxylic acid (23mg), LC-MS (ESI-MS):752[ M + H] + 。
Example 104: preparation of 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (3-hydroxypropyl) -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
Figure GDA0003709489340000922
Referring to the synthesis method of example 084, 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (3-hydroxypropyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) was synthesized by replacing 2-bromoethylbenzoate with 3-bromopropylbenzoate and replacing methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid (26mg), LC-MS (ESI-MS):752[ M + H] + 。
Example 105: preparation of 1- ((3-chloro-4- ((4- (2-chloro-3- (5- ((3- (hydroxymethyl) oxatan-3-yl) methyl) -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
Figure GDA0003709489340000923
Referring to the synthesis method of example 084, 1- ((3-chloro-4- ((4- (2-chloro-3- (5- ((3- (hydroxymethyl) oxatan-3-yl) methyl) cyclopropanecarboxylate, which is a target compound, was synthesized by replacing 2-bromoethylbenzoate with methyl (3- (bromomethyl) oxatan-3-yl) benzoate and 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate 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 (12mg), LC-MS (ESI-MS):794[ M + H] + 。
Example 106: preparation of 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
Figure GDA0003709489340000931
Referring to the synthesis method of example 083, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 4- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) butanoate to synthesize the objective 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) imidazo]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: preparation of 1- ((3-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000932
Referring to the synthesis of example 083, 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Replacement of pyridine-5 (4H) -carboxylic acid tert-butyl ester with 2- ((3-bromo-2-methylphenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Pyridine-5 (4H) -carboxylic acid tert-butyl ester, propyl 2-carbobenzoate by paraformaldehyde, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate by 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cycloMethyl propane carboxylate to obtain the target compound 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) cyclopropanecarboxylic acid (18mg), 1 H NMR(500MHz,DMSO)δ9.75(s,1H),7.66(d,J＝8.0Hz,1H),7.47–7.32(m,2H), 7.27(t,J＝7.6Hz,1H),7.17(d,J＝6.9Hz,1H),7.03(dd,J＝27.7,7.3Hz,1H),6.87(brs, 1H),6.11(d,J＝21.0Hz,1H),3.88(s,3H),3.85(s,3H),3.82(brs,2H),3.36(s,3H),2.72– 2.65(m,4H),2.39(s,3H),2.06–1.97(m,4H),1.23(brs,2H),1.11–1.06(m,2H),0.83– 0.79(m,2H).LC-MS(ESI-MS):688[M+H] + 。
example 108: preparation of 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) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000933
Referring to the synthesis of example 083, 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c) ]Replacement of pyridine-5 (4H) -carboxylic acid tert-butyl ester with 2- ((3-bromo-2-methylphenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Pyridine-5 (4H) -carboxylic acid tert-butyl ester, wherein 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester is replaced by 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylic acid methyl ester, and the target compound 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropyl-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid (25mg), LC-MS (ESI-MS):732[ M + H] + 。
Example 109: preparation of 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) cyclopropanecarboxylic acid
Figure GDA0003709489340000941
Referring to the synthesis of example 083, 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Replacement of pyridine-5 (4H) -carboxylic acid tert-butyl ester with 2- ((3-bromo-2-cyanophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Pyridine-5 (4H) -carboxylic acid tert-butyl ester, replacing 2-carbonyl propyl benzoate with paraformaldehyde, replacing 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester with 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylic acid methyl ester, and synthesizing the target compound 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) cyclopropanecarboxylic acid (21mg), LC-MS (ESI-MS):699[ M + H] + 。
Example 110: preparation of 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) cyclopropanecarboxylic acid
Figure GDA0003709489340000942
Referring to the synthesis of example 083, 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Replacement of pyridine-5 (4H) -carboxylic acid tert-butyl ester with 2- ((3-bromo-2-cyanophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Pyridine-5 (4H) -carboxylic acid tert-butyl ester, wherein 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester is replaced by 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylic acid methyl ester, and the target compound 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) is synthesized]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-Methoxybenzyl) amino) cyclopropanecarboxylic acid (13mg), LC-MS (ESI-MS): 743[ M + H ] + 。
Example 111: preparation of 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-fluoro-2-methoxybenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340000951
With reference to the synthesis method of example 083, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((3-chloro-6-fluoro-4-hydroxy-2-methoxybenzyl) amino) cyclobutanecarboxylate to synthesize the objective 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) -6-fluoro-2-methoxybenzyl) amino) cyclobutanecarboxylic acid (18mg), LC-MS (ESI-MS):766[ M + H] + 。
Example 112: preparation of 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) -6-fluoro-2-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340000952
Reference example 083 Synthesis procedure substituting propyl 2-Carbophenylbenzoate with paraformaldehyde and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with methyl 1- ((3-chloro-6-fluoro-4-hydroxy-2-methoxybenzyl) amino) cyclopropanecarboxylate to afford 1- ((3-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] imidazole, a target Compound ]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-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
Figure GDA0003709489340000953
Referring to the synthesis procedure of example 083, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl (1- (3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) piperidin-3-yl) acetate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and methyl piperidin-3-ylacetate according to example 083, step 5) to synthesize the objective 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-1H-imidazo [4,5-c]Pyridine-2-carboxamide (35mg), LC-MS (ESI-MS):766[ M + H] + 。
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
Figure GDA0003709489340000961
Reference example 083 Synthesis procedure for substituting methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with 5- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) methylaminomethyl) pyrrolidin-2-one (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and 3-aminomethylpyrrolidin-2-one according to example 083, step 5) to synthesize 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-tetrahydro-1H-imidazo [4,5-c]Pyridine-2Formamide (19mg), LC-MS (ESI-MS):765[ M + H] + 。
Example 115: n- (2-chloro-3- (1- (2-chloro-3-fluoro-4- ((3-hydroxypyrrolidin-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-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000962
Referring to the synthesis procedure of example 083, the title compound N- (2-chloro-3- (1- (2-chloro-3-fluoro-4- ((3-hydroxypyrrolidin-1-yl) methyl) -5-methoxyphenoxy) -2 was synthesized by substituting 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester with 1- (3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) pyrrolidine-3-acetate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and pyrrolidine-3-acetate according to example 083, step 5), 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 (26mg), LC-MS (ESI-MS):738[ M + H] + 。
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-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000963
Reference example 083 Synthesis procedure for substituting methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with 2-chloro-4- ((cyclobutaneamino) methyl) -3-fluoro-5-methoxyphenol (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and cyclobutylamine according to example 083, step 5) to afford N- (2-chloro-3- (1- (2-chloro-4- ((cyclobutaneamino) methyl) -3-fluoro-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -5- (1-hydroxypropane-5- (1-carboxylic acid methyl ester as the target Compound -2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamides (11mg)， LC-MS(ESI-MS):722[M+H] + 。
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-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000971
Reference example 083 Synthesis procedure for substituting methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with 2- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) -2-methylpropyl acetate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and 2-amino-2-methylpropyl acetate according to example 083, step 5) to synthesize the title 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-1H-imidazo [4,5-c ]Pyridine-2-carboxamide (19mg), LC-MS (ESI-MS):740[ M + H] + 。
Example 118: 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, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340000972
Reference example 083 Synthesis procedure for substituting methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with methyl (1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropyl) acetate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde and methyl (1-aminocyclopropyl-1-) acetate according to example 083 step 5), synthesizing to obtain the target compound N- (2-chloro-3- (1- (2-chloro-3-fluoro-4- (((1- (hydroxymethyl) cyclopropyl) amino) 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-imidazo [4,5-c]Pyridine-2-carboxamide (22mg), LC-MS (ESI-MS):738[ M + H] + 。
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) cyclopropanecarboxylic acid
Figure GDA0003709489340000973
Referring to the synthesis of example 083, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((3-chloro-6-ethoxy-2-fluoro-4-hydroxybenzyl) amino) cyclopropanecarboxylate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-ethoxybenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride according to example 083, step 5) to synthesize 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) -6-ethoxy-2-fluorobenzyl) amino) cyclopropanecarboxylic acid (30mg), LC-MS (ESI-MS):766[ M + H] + 。
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) cyclopropanecarboxylic acid
Figure GDA0003709489340000981
Referring to the synthesis of example 083, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with methyl 1- ((3-chloro-6- (cyclopropylmethoxy) -2-fluoro-4-hydroxybenzyl) amino) cyclopropanecarboxylate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-cyclopropylmethoxybenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride according to example 083 step 5), Synthesizing to obtain 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) -6- (cyclopropylmethoxy) -2-fluorobenzyl) amino) cyclopropanecarboxylic acid (28mg), LC-MS (ESI-MS): 792[ M + H] + 。
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) cyclopropanecarboxylic acid
Figure GDA0003709489340000982
Referring to the synthesis method of example 083, 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (1-hydroxypropyl-2-yl) -1-methyl-4) is synthesized by substituting methyl 1- ((3-chloro-6- (difluoromethoxy) -2-fluoro-4-hydroxybenzyl) amino) cyclopropanecarboxylate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-difluoroethoxybenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride according to example 083 step 5) to give 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) cyclopropanecarboxylic acid (15mg), LC-MS (ESI-MS): 788[ M + H ] + 。
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) cyclobutanecarboxylic acid
Figure GDA0003709489340000983
Reference example 083 Synthesis procedure for substitution of methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate with 1- ((3-chloro-6- (cyclobutylmethoxy) -2-fluoro-4-hydroxybenzyl) amino) Methyl cyclobutanecarboxylate (prepared from 3-chloro-2-fluoro-4-hydroxy-6-cyclobutylmethoxybenzaldehyde and methyl 1-aminocyclobutanecarboxylate hydrochloride according to example 083, step 5) was synthesized to give the title 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) -6- (cyclobutylmethoxy) -2-fluorobenzyl) amino) cyclobutanecarboxylic acid (26mg), LC-MS (ESI-MS): 820[ M + H] + 。
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) cyclobutanecarboxylic acid
Figure GDA0003709489340000991
Referring to the synthesis procedure of example 083, 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (1-hydroxypropyl-2-yl) -1-methyl-4) is synthesized by substituting 1- ((3-chloro-6- (isopropoxy) -2-fluoro-4-hydroxybenzyl) amino) cyclobutanecarboxylic acid methyl ester (prepared from 3-chloro-2-fluoro-4-hydroxy-6-isopropyloxybenzaldehyde and 1-aminocyclobutanecarboxylic acid methyl ester hydrochloride according to example 083 step 5) to give the objective 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) -2-fluoro-6-isopropoxybenzyl) amino) cyclobutanecarboxylic acid (36mg), LC-MS (ESI-MS):794[ M + H] + 。
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) cyclobutanecarboxylic acid
Figure GDA0003709489340000992
Synthesis of reference example 083Substituting 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester with 1- ((3-chloro-2-fluoro-4-hydroxy-6- (2,2, 2-trifluoroethoxy) benzyl) amino) cyclobutanecarboxylic acid methyl ester (prepared from 3-chloro-2-fluoro-4-hydroxy-6- (2,2, 2-trifluoroethoxy) benzaldehyde and 1-aminocyclobutanecarboxylic acid methyl ester hydrochloride according to example 083, step 5) to synthesize the target compound 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) cyclobutanecarboxylic acid (22mg), LC-MS (ESI-MS):834[ M + H] + 。
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) cyclobutanecarboxylic acid
Figure GDA0003709489340001001
With reference to the synthesis method of 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 (prepared from 3-chloro-2-fluoro-4-hydroxy-6- (pyridin-3-ylmethoxy) benzaldehyde and 1-aminocyclobutanecarboxylic acid methyl ester hydrochloride according to example 083 step 5) to synthesize the objective 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) -2-fluoro-6- (pyridin-3-ylmethoxy) benzyl) amino) cyclobutanecarboxylic acid (19mg), LC-MS (ESI-MS):843[ M + H] + 。
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-inden-1-yl) oxy) -2-fluorobenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340001002
Referring to the synthesis procedure of example 083, 1- ((6- (benzyloxy) -3-chloro-4-hydroxy-3- (5- (1-hydroxypropyl-2-yl) -1-methyl-4) is synthesized by substituting 1- ((3-chloro-2-fluoro-4-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester with 1- ((6- (benzyloxy) -3-chloro-2-fluoro-4-hydroxy-6-benzyloxybenzaldehyde and 1-aminocyclobutanecarboxylic acid methyl ester hydrochloride prepared according to example 083 step 5) to give the objective 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-dihydro-1H-inden-1-yl) oxy) -2-fluorobenzyl) amino) cyclobutanecarboxylic acid (15mg), LC-MS (ESI-MS):842[ M + H] + 。
Example 127: 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-indenyl-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001003
Step 1: dissolving 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) in 10mL of 2-methyltetrahydrofuran, adding triphenylphosphine (0.79g), dropwise adding DIAD (0.59mL) under the protection of nitrogen, reacting at room temperature for 1 hour, after the reaction of HPLC detection, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product N- (2-chloro-3- (1- (2-chloro-3-fluoro-4-formyl-5- Methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (0.73g) in 60% yield.
Step 2: dissolving N- (2-chloro-3- (1- (2-chloro-3-fluoro-4-formyl-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (0.61g) in 5mL of dichloromethane, adding methanesulfonic acid chloride (171mg) and triethylamine (202mg), stirring at room temperature for 2 hours, detecting by TLC, adding water and dichloromethane for extraction, separating organic phase, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography to obtain a solid product N- (2-chloro-3- (1- (2-chloro-3-fluoro-4-formyl) N- (2-chloro-3-methyl-4-methyl-3-methyl-1H-imidazo [4,5, 6, 7-tetrahydro-1H-imidazole [4,5-c ] pyridine-2-carboxamide -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-5- (methylsulfonyl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (0.58g) in 85% yield.
And step 3: n- (2-chloro-3- (1- (2-chloro-3-fluoro-4-formyl-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-5- (methylsulfonyl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (500mg) and methyl 1-aminocyclopropanecarboxylate hydrochloride (220mg) were dissolved in 4mL1, 2-dichloroethane, stirred at room temperature for 30 minutes, then added sodium borohydride (464mg) acetate and reacted at room temperature overnight. After TLC detection reaction is completed, dichloromethane and water are used for extraction, separated organic phase is subjected to pressure concentration, and a crude product is subjected to silica gel column chromatography purification to obtain a white solid product 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-formamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropane carboxylic ester (189mg), wherein the yield is 33%.
And 4, step 4: 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-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropane carboxylate (79mg) is dissolved in 3mL methanol, lithium hydroxide (25mg) is added to react at room temperature overnight, after TLC detection reaction is completed, silica gel is added to mix samples, and column chromatography purification is carried out to obtain a solid product 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-methoxybenzyl) amino) cyclopropanecarboxylic acid (33mg) in 43% yield. LC-MS (ESI-MS):772[ M + H] + 。
Example 128: 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (cyclopropylsulfonyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-indenyl-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001011
With reference to the procedure for the synthesis of example 127, methanesulfonic acid chloride was replaced with cyclopropanesulfonic acid chloride, and 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (cyclopropylsulfonyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) which is a target compound was synthesized ]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
Figure GDA0003709489340001021
Step 1: 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) and propyl 2-carbonylbenzoate (0.55g) were dissolved in 10mL of dichloromethane, DIPEA (0.5mL) was added, stirred at room temperature for 0.5 hour, then added with sodium borohydride acetate (0.85mg), and reacted at room temperature overnight. After the TLC detection reaction was completed, the mixture was extracted with dichloromethane and water, the separated organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give propyl 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 ] pyridin-5 (4H) -yl) benzoate (0.96g) as a white solid in 82% yield.
And 2, step: dissolving 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 ] pyridin-5 (4H) -yl) propyl benzoate (0.88g) and 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde (0.41g) in 10mL of 2-methyltetrahydrofuran, adding triphenylphosphine (0.52g), dropwise adding DIAD (0.4mL) under the protection of nitrogen, reacting for 2 hours at room temperature, after the HPLC detection reaction is finished, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product 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 ] pyridin-5 (4H) -yl) benzoic acid propyl ester (0.78g) in 67% yield.
And step 3: dissolving propyl 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 ] pyridin-5 (4H) -yl) benzoate (0.6g) in 6mL of methanol, adding lithium hydroxide (120mg), reacting at room temperature overnight, detecting by TLC, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product 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 (312mg), yield 60%.
And 4, step 4: 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 4mL1, 2-dichloroethane, stirred at room temperature for 30 minutes, and then added with sodium borohydride acetate (71mg) and reacted at room temperature overnight. After TLC detection reaction is completed, dichloromethane and water are used for extraction, separated organic phase is subjected to pressure concentration, and a crude product is subjected to silica gel column chromatography purification to obtain a white solid product (2R) -methyl 2- ((3-chloro-4- ((4- (2-chloro-3- (5- (1-hydroxypropane-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 (51mg) in 55% yield (LC-MS (ESI-MS):770[ M + H] + 。
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
Figure GDA0003709489340001022
Mixing (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)]Dissolving pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) -3-hydroxypropionate (30mg) in 2mL of methanol, adding lithium hydroxide (10mg), reacting at room temperature overnight, detecting by TLC (thin layer chromatography), adding silica gel, stirring, and purifying by column chromatography to obtain a solid product (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) after TLC (thin layer chromatography) is completed]Pyridin-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) -3-hydroxypropionic acid (15mg) in 51% yield, LC-MS (ESI-MS):756[ M + H] + 。
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) cyclopropanecarboxylic acid
Figure GDA0003709489340001031
Referring to the synthesis procedures of reference example 129 and example 130, propyl 2-carbonylbenzoate was replaced with diester 2-oxopropane-1, 3-dibenzoate and methyl D-serine hydrochloride was replaced with methyl 1-aminocyclopropane carboxylate hydrochloride to synthesize the objective 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 + H] + 。
Example 132: n- (2-chloro-3- (1- (2-chloro-3-fluoro-4- ((((1-hydroxycyclopropanyl) methyl) 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-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001032
With reference to the synthesis procedure of example 129, D-serine methyl ester hydrochloride was replaced with 1- (aminomethyl) cyclopropanol to synthesize the title compound N- (2-chloro-3- (1- (2-chloro-3-fluoro-4- (((((1-hydroxycyclopropanyl) methyl) 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-imidazo [4,5-c ] o ]Pyridine-2-carboxamide (13mg), 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
Figure GDA0003709489340001033
With reference to the procedure for the synthesis of example 129, replacement of D-serine methyl ester hydrochloride with (S) -piperidine-2-carboxylic acid methyl ester gave the title compound (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-carboxylic acid ester (33mg), LC-MS (ESI-MS):794[ M + H] + 。
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
Figure GDA0003709489340001041
Reacting (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)]Dissolving pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) piperidine-2-carboxylic acid ester (18mg) in 1mL methanol, adding lithium hydroxide (8mg), reacting at room temperature overnight, detecting by TLC (thin layer chromatography) after the reaction is completed, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product (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 (11mg) in 61% yield (LC-MS (ESI-MS):780[ M + H: -M)] + 。
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) -2-fluoro-6-methoxybenzyl) pyrrolidine-2-carboxylate
Figure GDA0003709489340001042
With reference to the procedure for the synthesis of example 129, methyl D-serine hydrochloride was replaced with methyl (S) -pyrrolidine-2-carboxylate to synthesize the desired compound (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) -2-fluoro-6-methoxybenzyl) pyrrolidine-2-carboxylic acid ester (42mg), LC-MS (ESI-MS):780[ M + H] + 。
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
Figure GDA0003709489340001043
Mixing (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-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) pyrrolidine-2-carboxylate (22mg) is dissolved in 1mL of methanol, lithium hydroxide (10mg) is added, the reaction is carried out overnight at room temperature, after the TLC detection reaction is completed, silica gel is added, a sample is stirred, and then column chromatography purification is carried out to obtain a solid product (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 (13mg) in 60% yield LC-MS (ESI-MS):766[ M + H] + 。
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) -6-cyclopropyl-2-fluorobenzyl) amino) -3-hydroxypropanoate
Figure GDA0003709489340001051
With reference to the procedure for the synthesis of reference example 129, 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde was replaced with 3-chloro-6-cyclopropyl-2-fluoro-4-hydroxybenzaldehyde to synthesize the target compound (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) -6-cyclopropyl-2-fluorobenzyl) amino) -3-hydroxypropionate (48mg), LC-MS (ESI-MS):780[ M + H] + 。
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
Figure GDA0003709489340001052
Mixing (2R) -methyl 2- ((3-chloro-4- ((4- (2-chloro-3- (5- (1-hydroxypropan-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1)H-imidazo [4,5-c]Dissolving pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -6-cyclopropyl-2-fluorobenzyl) amino) -3-hydroxypropionate (25mg) in 1mL of methanol, adding lithium hydroxide (10mg), reacting at room temperature overnight, detecting by TLC (thin layer chromatography), adding silica gel, stirring, and purifying by column chromatography to obtain a solid product (2R) -2- ((3-chloro-4- ((4- (2-chloro-3- (5- (1-hydroxypropane-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) after TLC (thin layer chromatography) detection is completed]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-cyclopropyl-2-fluorobenzyl) amino) -3-hydroxypropionic acid (16mg) in 65% yield, LC-MS (ESI-MS):766[ M + H] + 。
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) cyclopropanecarboxylate
Figure GDA0003709489340001053
With reference to the synthesis procedure of example 129, 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) as a target compound was synthesized by substituting 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde with 3-chloro-6-cyclopropyl-2-fluoro-4-hydroxybenzaldehyde and D-serine methyl ester hydrochloride with 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-cyclopropyl-2-fluorobenzyl) amino) cyclopropanecarboxylate (38mg), LC-MS (ESI-MS):776[ M + H ] M] + 。
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) cyclopropanecarboxylic acid
Figure GDA0003709489340001061
Reacting 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-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -6-cyclopropyl-2-fluorobenzyl) amino) cyclopropane carboxylic ester (20mg) is dissolved in 1mL of methanol, lithium hydroxide (8mg) is added to react at room temperature overnight, after TLC detection reaction is completed, silica gel is added to mix samples, and column chromatography purification is carried out to obtain a solid product 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) cyclopropanecarboxylic acid (13mg) in 66% yield (LC-MS (ESI-MS):762[ M + H ] M] + 。
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-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001062
With reference to the procedure for the synthesis of example 129, D-serine methyl ester hydrochloride was replaced with trans-4 aminocyclohexanol and the title compound N- (2-chloro-3- (1- (2-chloro-3-fluoro-4- (((((1 r, 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-imidazo [4,5-c ] e]Pyridine-2-carboxamide (21mg), 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
Figure GDA0003709489340001063
Referring to the synthesis methods of example 129 and example 130, D-serine methyl ester Replacing the ester hydrochloride with (R) -2-amino-4-hydroxybutyric acid methyl ester hydrochloride, and synthesizing to obtain the target compound (2R) -2- ((3-chloro-4- ((4- (2-chloro-3- (5- (1-hydroxypropane-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 (13mg), 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-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001071
With reference to the procedure of example 129, D-serine methyl ester hydrochloride was replaced with (1S, 2S) -2-aminocyclopentanol hydrochloride to synthesize the objective 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-imidazo [4,5-c ] ol]Pyridine-2-carboxamide (11mg), LC-MS (ESI-MS):752 [ M + H] + 。
Example 144: (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-methoxypropionic acid
Figure GDA0003709489340001072
With reference to the synthesis procedures of examples 129 and 130, 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) was synthesized by replacing D-serine methyl ester hydrochloride with (R) -2-amino-3-methoxypropionic acid methyl ester hydrochloride]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-indene-1-Yl) oxy) -2-fluoro-6-methoxybenzyl) amino) -3-methoxypropionic acid (13mg), LC-MS (ESI-MS) 770[ M + H] + 。
Example 145: 3- ((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) benzoic acid
Figure GDA0003709489340001073
With reference to the syntheses in examples 129 and 130, D-serine methyl ester hydrochloride was replaced with methyl 3-aminobenzoate to synthesize the title compound 3- ((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) benzoic acid (15mg), LC-MS (ESI-MS):788[ M + H] + 。
Example 146: 4- ((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) benzoic acid
Figure GDA0003709489340001081
With reference to the synthesis methods of example 129 and example 130, methyl D-serine hydrochloride was replaced with methyl 4-aminobenzoate to synthesize the objective compound 4- ((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) benzoic acid (12mg), LC-MS (ESI-MS):788[ M + H] + 。
Example 147: 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) benzoic acid
Figure GDA0003709489340001082
With reference to the synthesis methods of example 129 and example 130, methyl D-serine hydrochloride was replaced with methyl 2-aminobenzoate to synthesize the objective 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) -l]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) benzoic acid (11mg), LC-MS (ESI-MS):788[ M + H] + 。
Example 148: 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) -3-fluorobenzoic acid
Figure GDA0003709489340001083
With reference to the synthesis methods of example 129 and example 130, D-serine methyl ester hydrochloride was replaced with methyl 3-fluoro-4-aminobenzoate to synthesize the objective 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) -3-fluorobenzoic acid (16mg), LC-MS (ESI-MS):806[ M + H] + 。
Example 149: 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) -3-methoxybenzoic acid
Figure GDA0003709489340001091
Referring to the synthesis of example 129 and example 130, D-serineThe acid methyl ester hydrochloride is replaced by 3-methoxy-4-methyl aminobenzoate, and 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) is synthesized]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) -3-methoxybenzoic acid (13mg), LC-MS (ESI-MS): 818[ M + H] + 。
Example 150: 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) amino) cyclobutanecarboxylate
Figure GDA0003709489340001092
With reference to the procedure for the synthesis of example 129, methyl D-serine hydrochloride was replaced with methyl 1-aminocyclobutanecarboxylate hydrochloride to synthesize the title compound 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) amino) cyclobutanecarboxylic acid methyl ester (20mg), LC-MS (ESI-MS):780[ M + H] + 。
Example 151: 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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylate
Figure GDA0003709489340001093
With reference to the procedure for the synthesis of example 129, methyl D-serine hydrochloride was replaced with methyl 1-aminocyclopropanecarboxylate hydrochloride to synthesize the title compound 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) amino) ringMethyl propane carboxylate (15mg), LC-MS (ESI-MS):766[ M + H] + 。
Example 152: methyl 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) cyclobutanecarboxylate
Figure GDA0003709489340001101
Referring to the synthesis of example 129, 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)]Replacement of pyridine-2-carboxamide with N- (3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine-2-formamide, wherein D-serine methyl ester hydrochloride is replaced by 1-aminocyclobutanecarboxylic acid methyl ester hydrochloride to synthesize a target compound 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropane-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester (17mg), LC-MS (ESI-MS):760[ M + H + ESI-MS] + 。
Example 153: methyl 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) cyclopropanecarboxylate
Figure GDA0003709489340001102
Referring to the synthesis of example 129, 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)]Replacement of pyridine-2-carboxamide with N- (3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] ]Pyridine-2-formamide, replacing D-serine methyl ester hydrochloride with 1-aminocyclopropane methyl formate hydrochloride to synthesize the targetThe compound 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid methyl ester (21mg), LC-MS (ESI-MS):746[ M + H] + 。
Example 154: (2R) -methyl 2- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) -3-hydroxypropionate
Figure GDA0003709489340001103
Referring to the synthesis of example 129, 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)]Replacement of pyridine-2-carboxamide with N- (3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine-2-formamide, and synthesizing to obtain a target compound (2R) -2- ((3-chlorine-2-fluorine-4- ((4- (3- (5- (1-hydroxy propane-2-group) -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) -6-methoxybenzyl) amino) -3-hydroxypropionic acid methyl ester (27mg), LC-MS (ESI-MS):750[ M + H ] + 。
Example 155: (2R) -2- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) -3-hydroxypropionic acid
Figure GDA0003709489340001111
Mixing (2R) -2- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropan-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) -6-methoxybenzyl) amino) -3-hydroxypropionic acid methyl ester (15mg) dissolvedAdding lithium hydroxide (6mg) into 1mL of methanol, reacting at room temperature overnight, detecting by TLC (thin layer chromatography), adding silica gel, mixing, and purifying by column chromatography to obtain solid product (2R) -2- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropane-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) ((2-chloro-2-fluoro-4))]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-methoxybenzyl) amino) -3-hydroxypropionic acid (11mg) in 74% yield and LC-MS (ESI-MS):736[ M + H] + 。
Example 156: 1- ((3-chloro-4- ((4- (3- (5- (2, 2-difluoroethyl) -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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001112
Step 1, dissolving methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate (0.45g) and N- (3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamide (0.41g) in 8mL 2-methyltetrahydrofuran, adding triphenylphosphine (0.52g), dropwise adding DIAD (0.4mL) under the protection of nitrogen, reacting for 2 hours at room temperature, adding silica gel after the HPLC detection reaction is finished, stirring the sample, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-2-fluoro-6-methoxy-4) Methyl (- ((4- (2-methyl-3- (1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) benzyl) amino) cyclopropanecarboxylate (0.43g) yield 63%.
Step 2: mixing 1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-3- (1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c))]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) benzyl) amino) cyclopropanecarboxylic acid methyl ester (0.34g), 2-difluoroethanol (0.3mL) and DIPEA (0.45mL) were dissolved in 2mL DMF and SO prepared now was passed through 2 F 2 (about 2mmol, prepared by mixing 1, 1' -sulfonyldiimidazole, anhydrous potassium fluoride and trifluoroacetic acid), heating to 40 deg.C for about 2 hours, detecting by TLC, adding 2N hydrochloric acid and dichloromethane, and separating Separating the organic phase, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography to obtain a solid product 1- ((3-chloro-4- ((4- (3- (5- (2, 2-difluoroethyl) -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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid methyl ester (192mg) in 51% yield.
And step 3: mixing 1- ((3-chloro-4- ((4- (3- (5- (2, 2-difluoroethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c))]Dissolving pyridine-2-formamido) -2-methylphenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropane carboxylic acid methyl ester (75mg) in 3mL methanol, adding lithium hydroxide (30mg), reacting at room temperature overnight, after TLC detection reaction is completed, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-4- ((4- (3- (5- (2, 2-difluoroethyl) -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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid (52mg) in 69% yield (LC-MS (ESI-MS):738[ M + H + ESI-MS)] + 。
Example 157: 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (2, 2-difluoroethyl) -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
Figure GDA0003709489340001121
Referring to the synthesis of example 156, N- (3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Replacement of pyridine-2-carboxamide by 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-formamide, and synthesizing to obtain a target compound 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (2, 2-difluoroethyl) -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 (35mg), LC-MS (ESI-MS):758[ M + H] + 。
Example 158: 1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-3- (1-methyl-5- (2,2, 2-trifluoroethyl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001122
With reference to the synthesis procedure in example 156, 2, 2-difluoroethanol was replaced with trifluoroethanol, and synthesis was performed to obtain the target compound 1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-3- (1-methyl-5- (2,2, 2-trifluoroethyl) -4,5,6, 7-tetrahydro-1H-imidazo [4, 5-c) -e]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid (29mg), LC-MS (ESI-MS):756[ M + H ] + 。
Example 159: 1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-3- (1-methyl-5- (1,1, 1-trifluoropropan-2-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001123
With reference to the procedure for the synthesis of example 156, 2-difluoroethanol was replaced with 1,1, 1-trifluoroisopropanol, and 1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-3- (1-methyl-5- (1,1, 1-trifluoropropan-2-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4, 5-c) a target compound was synthesized]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid (33mg), LC-MS (ESI-MS):770[ M + H] + 。
Example 160: 1- ((3-chloro-4- ((4- (3- (5- (difluoromethyl) -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) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001131
Step 1: dissolving methyl 1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-3- (1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) benzyl) amino) cyclopropanecarboxylate (0.15g) in 3mL of DMF, adding difluoroiodomethane (0.12g) and DIPEA (0.5mL), heating to 60 ℃ for reacting for about 12 hours, adding water and ethyl acetate for extraction, separating organic phase, carrying out vacuum concentration, and carrying out silica gel column chromatography purification on the crude product to obtain a solid product 1- ((3-chloro-4- ((4- (3- (5- (difluoromethyl) -1-methyl- Methyl 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylate (56mg), yield 35%.
Step 2: mixing 1- ((3-chloro-4- ((4- (3- (5- (difluoromethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Dissolving pyridine-2-formamido) -2-methylphenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropane carboxylic acid methyl ester (35mg) in 2mL methanol, adding lithium hydroxide (15mg), reacting at room temperature overnight, after TLC detection reaction is completed, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-4- ((4- (3- (5- (difluoromethyl) -1-methyl-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) cyclopropanecarboxylic acid (17mg) in 49% yield using LC-MS (ESI-MS) 724[ M + H] + 。
Example 161: 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (isopropyloxycarbonyl) -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
Figure GDA0003709489340001132
Step 1: dissolving methyl 1- ((3-chloro-4- ((4- (2-chloro-3- (1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylate (0.14g) in 2mL of DMF, adding isopropyl chloride (73g) and DIPEA (0.3mL), reacting at room temperature for about 12 hours, adding water and ethyl acetate for extraction, separating organic phase, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography to obtain a solid product isopropyl 2- ((2-chloro-3- (1- (2-chloro-3-fluoro-5-methoxy- 4- ((1- (methoxycarbonyl) cyclopropyl) amino) methyl) phenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4,5-c ] pyridine-5 (4H) -carboxylate (83mg), yield 52%.
Step 2: isopropyl 2- ((2-chloro-3- (1- (2-chloro-3-fluoro-5-methoxy-4- ((1- (methoxycarbonyl) cyclopropyl) amino) methyl) phenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Dissolving pyridine-5 (4H) -carboxylate (48mg) in 2mL methanol, adding lithium hydroxide (15mg), reacting at room temperature overnight, detecting by TLC, adding silica gel, mixing, and purifying by column chromatography to obtain solid product 1- ((3-chloro-4- ((4- (2-chloro-3- (5- (isopropoxycarbonyl) -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 (13mg) in 28% yield (LC-MS (ESI-MS):780[ M + H: -M)] + 。
Example 162: 1- ((3-chloro-6-ethoxy-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) benzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001141
Referring to the synthesis of example 119, 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Replacement of pyridine-5 (4H) -carboxylic acid tert-butyl ester with 2- ((3-bromo-2-methylphenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c) ]Pyridine-5 (4H) -carboxylic acid tert-butyl ester, and synthesizing to obtain the target compound 1- ((3-chlorine-6-ethoxy-2-fluorine-4- ((4- (3- (5- (1-hydroxypropyl-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid (20mg), LC-MS (ESI-MS):746[ M + H] + 。
Example 163: 1- ((3-chloro-6- (difluoromethoxy) -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) benzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001142
With reference to the synthesis procedure of example 121, 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Replacement of pyridine-5 (4H) -carboxylic acid tert-butyl ester with 2- ((3-bromo-2-methylphenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Pyridine-5 (4H) -carboxylic acid tert-butyl ester, and synthesizing to obtain the target compound 1- ((3-chloro-6- (difluoromethoxy) -2-fluoro-4- ((4- (3- (5- (1-hydroxypropyl-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid (16mg), LC-MS (ESI-MS):768[ M + H ] + 。
Example 164: n- (3- (1- (2-chloro-3-fluoro-4- (((1- (hydroxymethyl) cyclopropyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- (1-hydroxypropan-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001143
With reference to the synthesis of example 118, 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Replacement of pyridine-5 (4H) -carboxylic acid tert-butyl ester with 2- ((3-bromo-2-methylphenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Pyridine-5 (4H) -carboxylic acid tert-butyl ester, and synthesizing to obtain a target compound N- (3- (1- (2-chloro-3-fluoro-4- (((1- (hydroxymethyl) cyclopropyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-indene-4-yl) -2-methylphenyl) -5- (1-hydroxypropane-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamide (19mg), LC-MS (ESI-MS):718[ M + H] + 。
Example 165: n- (3- (1- (2-chloro-3-fluoro-4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- (1-hydroxypropan-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001151
Referring to the procedure for the synthesis of example 132, 2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c) ]Replacement of pyridine-5 (4H) -carboxylic acid tert-butyl ester with 2- ((3-bromo-2-methylphenyl) carbamoyl) -1-methyl-6, 7-dihydro-1H-imidazo [4, 5-c)]Pyridine-5 (4H) -carboxylic acid tert-butyl ester, and synthesizing to obtain a target compound N- (3- (1- (2-chloro-3-fluoro-4- ((((1-hydroxycyclopropyl) methyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-indene-4-yl) -2-methylphenyl) -5- (1-hydroxypropane-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ]]Pyridine-2-carboxamide (11mg), LC-MS (ESI-MS):718[ M + H] + 。
Example 166: 1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-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) benzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001152
Referring to the synthesis of example 127, 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 ]]Replacement of pyridine-2-carboxamide by N- (2-methyl-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-formamide, synthesizing to obtain a target compound 1- ((3-chloro-2-fluoro-6-methoxy-4- ((4- (2-methyl-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) benzyl) amino) cyclopropanecarboxylic acid (15mg), LC-MS (ESI-MS):752[ M + H] + 。
Example 167: 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (isopropyloxycarbonyl) -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) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001153
Referring to the synthesis of example 161, 1- ((3-chloro-4- ((4- (2-chloro-3- (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 methyl ester was replaced with 1- ((3-chloro-4- ((4- (2-methyl-3- (1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropane carboxylic acid methyl ester, and a target compound 1- ((3-chloro-2-fluoro-4- ((4- (3- (5- (isopropyloxycarbonyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c) is synthesized]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid (13mg), LC-MS (ESI-MS):760[ M + H] + 。
Example 168: 3- ((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) -6-methoxybenzyl) amino) benzoic acid
Figure GDA0003709489340001161
Referring to the synthesis method of example 145, 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 ]]Replacement of pyridine-2-carboxamide by N- (2-methyl-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-carboxylic acid amidesAmine is synthesized to obtain a target compound 3- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropyl-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-methoxybenzyl) amino) benzoic acid (15mg), LC-MS (ESI-MS):768[ M + H] + 。
Example 169: 4- ((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) -6-methoxybenzyl) amino) -3-methoxybenzoic acid
Figure GDA0003709489340001162
Referring to the synthesis of example 149, 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 ]]Replacement of pyridine-2-carboxamide with N- (2-methyl-3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] e]Pyridine-2-formamide, and synthesizing to obtain a target compound 4- ((3-chloro-2-fluoro-4- ((4- (3- (5- (1-hydroxypropyl-2-yl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c) ]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-methoxybenzyl) amino) -3-methoxybenzoic acid (12mg), LC-MS (ESI-MS):798[ M + H] + 。
Example 170 1- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxyphenyl) amine) cyclopropyl-1-carboxylic acid
Figure GDA0003709489340001163
Step 1 Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxylic acid (3mmol) and 2-chloro-3-bromoaniline (3mmol) were dissolved in 20 mL DMF and HATU (3.3mmol) and DIPEA (4.5mmol) were added and reacted at room temperature for 12H. The reaction was quenched with water, extracted with ethyl acetate, the organic phase separated and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate, and purifying by silica gel column chromatography to obtain Boc protected N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide with yield of 78%.
And 2, dissolving Boc protected N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamide (2mmol) in 10 ml of dichloromethane, cooling in an ice bath, dropwise adding 5 ml of trifluoroacetic acid, stirring for 30 minutes in the ice bath, removing the ice bath, and continuing the reaction for 2 hours at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure and basified by addition of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate, and directly carrying out methylation reaction without purification. The deprotected crude product and paraformaldehyde (3mmol) were dissolved in methanol and 1% acetic acid was added. After stirring for 10 min, sodium cyanoborohydride (4mmol) was added, the reaction was carried out overnight at room temperature, and the solvent was removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate, and the organic phase was washed once with sodium hydrogencarbonate, water and brine, respectively, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate, and purifying by silica gel column chromatography to obtain the N- (3-bromo-2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamide, wherein the total yield of the 2 steps is 66%.
Step 3, adding N- (3-bromo-2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ]]Pyridine-2-carboxamide (1mmol) and TBDMS-protected pinacol-4-borate-1-indanol (1mmol) are dissolved in a mixed solvent of 10 ml of 1, 4-dioxane and 3 ml of pure water, and Pd (PPh) is added 3 ) 4 (0.1mmol) and sodium carbonate (2.0mmol), the reaction mixture was heated to reflux for about 24 hours. Then, the temperature was reduced to room temperature, water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain compound N- (3- (1- ((tert-butyl-dimethyl silicon) ether) -2, 3-dihydro-1H-4-indenyl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamide. Yield: and 47 percent.
Step 4. N- (3- (1- ((tert-butyl-dimethyl-silicon) ether) -2, 3-dihydro-1H-4-indenyl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (1mmol) is dissolved in THF, tetrabutylammonium fluoride (2mmol) is added in an ice bath, the temperature is slowly raised to room temperature, after a reaction time of 2 hours, the solvent is removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate, and the organic phase was washed with pure water and saturated brine for 3 times, respectively, and then collected and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, draining, dissolving the obtained crude product, 2-methoxy-4-hydroxy-5-chlorobenzaldehyde (1mmol) and triphenylphosphine (1mmol) in anhydrous THF, cooling to 0 ℃, slowly dropwise adding DIAD under the protection of nitrogen, continuing to react for 30 minutes at 0 ℃ after dropwise adding, then heating to room temperature, and reacting for 16 hours. The reaction mixture was removed of the solvent under reduced pressure, redissolved in ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography to obtain N- (2-chloro-3- (1- (2-chloro-4-carboxaldehyde-5-methoxyphenyl) -2, 3-dihydro-1H-4-indenyl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] pyridine-2-formamide. Yield: 53 percent.
Step 5, N- (2-chloro-3- (1- (2-chloro-4-carboxaldehyde-5-methoxyphenyl) -2, 3-dihydro-1H-4-indenyl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamide (0.5mmol) and 1-aminocyclopropane-1-carboxylic acid (1.0mmol) were dissolved in a solution of 5mL of methanol and 5mL of dichloromethane, acetic acid (1.2mmol) was added, the reaction mixture was mixed and stirred for about 1 hour, and then sodium borohydride triacetate (2.0mmol) was added. After about 20 hours of reaction at room temperature, the organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase preparative HPLC chromatography to give compound 1- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxybenzyl) amine) cyclopropyl-1-carboxylic acid in 15% yield. LC-MS (ESI-MS):690.2 [ M + H] + 。
Example 171: 1- ((4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) benzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2, 5-dimethylphenyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001181
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 2-methoxy-4-hydroxy-5-chlorobenzaldehyde with 2, 5-dimethyl-4-hydroxy-benzaldehyde in step 4. LC-MS (ESI-MS):654.3[ M + H ] + 。
Example 172.1- ((4- ((4- (3- (5-acetyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) -2-chlorobenzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -5-chloro-2-methoxyphenyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001182
Referring to the synthesis method of example 170, a reductive amination reaction with paraformaldehyde was replaced with a condensation reaction with acetyl chloride in step 2 to synthesize the target compound. LC-MS (ESI-MS):718.2[ M + H] + 。
Example 173.1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) benzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxyphenyl) piperidine-2-carboxylic acid
Figure GDA0003709489340001183
Referring to the synthesis procedure of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with piperidine-2-carboxylic acid in step 5, and the title compound was synthesized. 1 H NMR(500MHz,CDCl 3 )δ9.93–9.84(m,1H),8.49(d,J＝8.2Hz,1H),7.62–7.43(m,2H),7.35(brs,2H),7.24(d,J＝7.3Hz,1H),7.10–6.95(m,1H), 6.73–6.63(m,1H),5.90–5.78(m,1H),4.47–4.26(m,2H),3.98(brs,2H),3.94–3.80(m, 3H),3.57–3.40(m,4H),2.95–2.65(m,7H),2.55(d,J＝10.0Hz,3H),2.33–2.16(m,3H), 2.08–1.90(m,2H),1.83–1.72(m,2H),0.92–0.81(m,2H).LC-MS(ESI-MS): 718.3[M+H] + 。
Example 174.1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) benzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxyphenyl) piperidine-2-carboxylic acid methyl ester
Figure GDA0003709489340001184
Referring to the synthesis procedure of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with piperidine-2-carboxylic acid methyl ester in step 5, and the title compound was synthetically prepared. 1 H NMR(500MHz,CDCl 3 )δ9.98–9.83(m,1H),8.49(d, J＝7.5Hz,1H),7.60–7.43(m,1H),7.41–7.30(m,3H),7.23(d,J＝7.3Hz,1H),7.15– 6.94(m,1H),6.69–6.56(m,1H),5.91–5.75(m,1H),3.97(s,3H),3.90–3.69(m,6H), 3.66–3.60(m,2H),3.53(s,2H),3.18(d,J＝4.1Hz,1H),3.08–2.87(m,2H),2.87–2.62 (m,5H),2.60–2.46(m,4H),2.38–1.98(m,4H),1.95–1.71(m,2H)，1.02–0.85(m,2H). LC-MS(ESI-MS):732.3[M+H] + 。
Example 175.2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) benzyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxyphenyl) amino) -2-methylpropionic acid
Figure GDA0003709489340001191
Referring to the synthesis procedure of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 2-methylalanine in step 5, and the title compound was synthetically prepared. 1 H NMR(500MHz,CDCl 3 )δ9.86(d,J＝11.4Hz,1H),8.46 (d,J＝8.0Hz,1H),7.61(brs,1H),7.41(d,J＝11.4Hz,1H),7.36–7.24(m,2H),7.19(d,J＝ 7.3Hz,1H),7.00(d,J＝6.4Hz,1H),6.64(brs,1H),5.83–5.68(m,1H),4.07–3.92(m,5H), 3.87(brs,3H),3.52(s,2H),3.00–2.60(m,6H),2.58–2.42(m,4H),2.15(brs,1H),1.48(s, 6H).LC-MS(ESI-MS):692.2[M+H] + 。
Example 176N- (2-chloro-3- (1- (2-chloro-4- ((3-hydroxy-1-azetidinyl) methyl) -5-methoxyphenyl) -2, 3-dihydro-1H-4-indenyl) benzyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001192
Referring to the procedure for the synthesis of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 3-hydroxycyclopropylamine in step 5, and the title compound was synthetically prepared. 1 H NMR(500MHz,CDCl 3 )δ9.86(d,J＝12.8Hz,1H),8.48 (d,J＝8.1Hz,1H),7.54–7.42(m,1H),7.39–7.30(m,2H),7.28(s,1H),7.23(d,J＝7.4Hz, 1H),7.11–6.93(m,1H),6.71–6.57(m,1H),5.90–5.77(m,1H),4.57–4.43(m,1H),4.36 –4.03(m,2H),3.96(s,3H),3.88–3.77(m,5H),3.73(s,2H),3.52(s,2H),3.27(brs,2H), 3.06–2.86(m,1H),2.84–2.76(m,2H),2.75–2.70(m,2H),2.58–2.45(m,4H),2.35– 2.18(m,1H).LC-MS(ESI-MS):662.2[M+H] + 。
Example 177.1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-1-indenyl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001193
Referring to the synthesis method of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with pyrrole-3-carboxylic acid in step 5, and the objective compound was synthetically prepared. 1 H NMR(500MHz,DMSO)δ9.94(s,1H),8.34–8.29(m, 1H),8.27(s,1H),7.46(t,J＝7.7Hz,2H),7.38(t,J＝7.2Hz,1H),7.29(s,1H),7.26(d,J＝7.2Hz,1H),7.22–7.07(m,1H),6.99(brs,1H),6.13–5.98(m,1H),3.90(s,3H),3.85(s, 3H),3.57–3.47(m,3H),3.37(s,1H),2.95–2.85(m,2H),2.75(d,J＝7.2Hz,3H),2.69(s, 3H),2.67–2.57(m,3H),2.38(s,2H),2.08–2.01(m,2H),1.94(dd,J＝14.8,7.9Hz,2H). LC-MS(ESI-MS):704.2[M+H] + 。
Example 178N- (2-chloro-3- (1- (2-chloro-4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H- -4-indenyl) benzyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001201
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with R-3-hydroxypyrrole in step 5. 1H NMR (500MHz, CDCl) 3 )δ9.90–9.81(m,1H),8.48(d,J＝ 8.2Hz,1H),7.54–7.45(m,2H),7.40–7.32(m,2H),7.25(d,J＝7.4Hz,1H),7.09–6.97 (m,1H),6.73–6.63(m,1H),5.92–5.83(m,2H),4.54–4.48(m,1H),4.20–4.07(m,2H), 3.98(s,3H),3.92–3.78(m,3H),3.66(s,2H),3.63–3.56(m,2H),3.43–3.35(m,2H),3.08 (dd,J＝11.8,5.3Hz,1H),3.02–2.63(m,4H),2.80(t,J＝5.4Hz,2H),2.35–2.20(m,3H), 2.17–2.08(m,2H).LC-MS(ESI-MS):676.2[M+H] + 。
EXAMPLE 179 (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) serine
Figure GDA0003709489340001202
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with serine in step 5. LC-MS (ESI-MS):694.2[ M + H] + 。
Example 180.1- (4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2, 5-dimethylbenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001203
Referring to the synthesis of example 170, 2-methoxy-4-hydroxy-5-chlorobenzaldehyde was replaced with 2, 5-dimethyl-4-hydroxy-benzaldehyde in step 4 and 1-aminocyclopropane-1-carboxylic acid was replaced with 2, 5-dimethyl-4-hydroxy-benzaldehyde in step 5Is pyrrole-3-formic acid, and is synthesized to obtain the target compound. 1 H NMR(500MHz,CDCl 3 )δ9.94–9.83(m,1H),8.48(d,J＝7.7Hz, 1H),7.48–7.40(m,1H),7.34(t,J＝7.7Hz,2H),7.24–7.13(m,2H),7.11–6.98(m,2H), 6.87(s,1H),5.85–5.70(m,1H),4.17–4.07(m,1H),4.03–3.90(m,4H),3.67(brs,1H), 3.54(s,2H),3.22(brs,1H),3.11–2.92(m,2H),2.89–2.76(m,4H),2.75–2.70(m,2H), 2.68–2.59(m,1H),2.53(s,3H),2.41(s,3H),2.25–2.07(m,5H).LC-MS(ESI-MS):668.3 [M+H] + 。
Example 181.1- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclobutane-1-carboxylic acid
Figure GDA0003709489340001211
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 1-aminocyclobutane-1-carboxylic acid in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.85(d,J＝13.2Hz, 1H),8.46(d,J＝8.2Hz,1H),7.43–7.22(m,4H),7.18(d,J＝7.4Hz,1H),7.04–6.91(m, 1H),6.68–6.57(m,1H),5.75–5.62(m,1H),4.07–3.88(m,6H),3.84(brs,2H),3.50(brs, 2H),2.95–2.60(m,6H),2.58–2.45(m,5H),2.41–2.22(m,3H),2.18–1.91(m,3H). LC-MS(ESI-MS):704.2[M+H] + 。
Example 182.1- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopentane-1-carboxylic acid
Figure GDA0003709489340001212
Referring to the synthesis procedure of example 170, the target compound was synthesized by substituting 1-aminocyclopropane-1-carboxylic acid with 1-aminocyclopentane-1-carboxylic acid in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.86(d,J＝15.6Hz, 1H),8.47(d,J＝8.1Hz,1H),7.51–7.13(m,5H),7.04–6.93(m,1H),6.67–6.58(m,1H), 5.75–5.60(m,1H),4.04–3.85(m,6H),3.52(brs,3H),2.98–2.57(m,7H),2.55–2.41(m, 5H),2.13–1.94(m,4H),1.86–1.73(m,4H).LC-MS(ESI-MS):718.3[M+H] + 。
EXAMPLE 183 (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) leucine
Figure GDA0003709489340001213
Referring to the synthesis method of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with leucine in step 5, and the title compound was synthetically prepared. 1 H NMR(500MHz,CDCl 3 )δ9.86(d,J＝12.2Hz,1H),8.47(d,J＝ 8.2Hz,1H),7.50(brs,1H),7.45–7.29(m,3H),7.21(d,J＝5.8Hz,1H),7.05–6.93(m,1H), 6.69–6.62(m,1H),5.85–5.68(m,1H),4.29–4.04(m,2H),3.97(s,3H),3.92–3.83(m, 3H),3.51(s,2H),3.43(brs,1H),3.01–2.62(m,6H),2.58–2.47(m,4H),2.25–2.12(m, 1H),1.92–1.55(m,3H),0.92(d,6.4Hz,3H),0.84(d,J＝6.3Hz,3H).LC-MS(ESI-MS): 720.3[M+H] + 。
Example 184.2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) -3, 3-dimethylbutyrate methyl ester
Figure GDA0003709489340001221
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 3, 3-dimethyl-2-amino-butyric acid methyl ester in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.95–9.80 (m,1H),8.47(d,J＝7.6Hz,1H),8.25(s,1H),7.49(dd,J＝24.6,7.0Hz,1H),7.39–7.32(m, 1H),7.30(s,1H),7.23(d,J＝7.4Hz,1H),7.17–6.99(m,1H),6.70–6.54(m,1H),5.86– 5.73(m,1H),3.97(d,J＝10.5Hz,3H),3.87–3.74(m,3H),3.65(d,J＝14.5Hz,2H),3.62 (d,J＝4.6Hz,2H),3.06(s,2H),3.00–2.87(m,6H),2.87–2.78(m,3H),2.63(d,J＝21.6 Hz,3H),2.59–2.43(m,1H),2.34–2.19(m,1H),0.96(s,9H).LC-MS(ESI-MS):734.3 [M+H] + 。
Example 185.2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) -3- (4-fluorobenzene) propionic acid
Figure GDA0003709489340001222
Referring to the procedure for synthesis of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 4-fluorophenylmethylalanine in step 5, and the title compound was synthesized. 1 H NMR(500MHz,CDCl 3 )δ9.87(d,J＝13.8Hz,1H), 8.48(d,J＝7.7Hz,1H),7.86–6.71(m,12H),6.60–6.43(m,1H),5.85–5.67(m,1H),4.12 –3.88(m,4H),3.72–3.50(m,4H),3.38(brs,1H),3.31–2.93(m,3H),2.90–2.71(m,4H), 2.58–2.43(m,4H),2.23–2.09(m,1H),1.92–1.80(m,1H).LC-MS(ESI-MS):772.2 [M+H] + 。
Example 186.1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) piperidine-3-carboxylic acid
Figure GDA0003709489340001223
Referring to the synthesis procedure of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with piperidine-3-carboxylic acid in step 5, and the title compound was synthesized. 1 H NMR(500MHz,CDCl 3 )δ9.95–9.83(m,1H),8.49(d,J＝ 8.1Hz,1H),7.57–7.44(m,1H),7.43–7.12(m,4H),7.13–6.94(m,1H),6.77–6.62(m, 1H),5.93–5.76(m,1H),3.97(s,3H),3.92–3.80(m,3H),3.70–3.62(m,1H),3.54(brs, 3H),3.24–2.98(m,2H),2.97–2.65(m,6H),2.63–2.47(m,4H),2.47–1.93(m,4H),1.94 –1.50(m,3H).LC-MS(ESI-MS):718.3[M+H] + 。
Example 187.1 Ethyl- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) (methyl) amino) cyclopropane-1-carboxylate
Figure GDA0003709489340001231
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with ethyl 1-methylaminocyclopropane-1-carboxylate in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.86(d,J＝ 20.3Hz,1H),8.47(d,J＝8.0Hz,1H),7.49(dd,J＝26.6,7.0Hz,1H),7.39–7.31(m,2H), 7.22(d,J＝7.5Hz,1H),7.20(s,1H),7.14–6.97(m,1H),6.67–6.57(m,1H),5.88–5.73 (m,1H),4.18(d,J＝7.1Hz,2H),3.98–3.92(m,3H),3.82–3.76(m,2H),3.67–3.58(m, 2H),2.97–2.95(m,1H),2.82–2.79(m,2H),2.61–2.58(m,3H),2.48(s,3H),2.44–2.37 (m,6H),1.33–1.22(m,6H),1.06(d,J＝3.4Hz,2H).LC-MS(ESI-MS):732.2[M+H] + 。
EXAMPLE 188 (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) arginine
Figure GDA0003709489340001232
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with arginine in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.92–9.82(m,1H),8.47(d,J＝8.2 Hz,1H),7.55(brs,1H),7.47–7.36(m,1H),7.34–7.27(m,2H),7.21(d,J＝7.4Hz,1H), 7.07–6.96(m,1H),6.72–6.58(m,1H),5.88–5.73(m,1H),4.40–4.03(m,2H),3.96(s, 3H),3.95–3.82(m,4H),3.52(brs,2H),3.28(s,1H),3.03–2.65(m,6H),2.58–2.43(m, 3H),2.41–2.11(m,2H),1.04(dd,J＝16.4,6.4Hz,6H).LC-MS(ESI-MS):706.3[M+H] + 。
EXAMPLE 189 (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) glycine
Figure GDA0003709489340001233
Referring to the synthesis procedure of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with glycine in step 5 to synthetically prepare the objective compound. 1 H NMR(500MHz,CDCl 3 )δ9.92–9.82(m,1H),8.47(d,J＝8.1 Hz,1H),7.53(s,1H),7.43(dd,J＝20.1,6.9Hz,1H),7.36–7.28(m,2H),7.20(d,J＝7.4Hz, 1H),7.00(d,J＝7.4Hz,1H),6.68–6.62(m,1H),5.83–5.72(m,1H),4.10(brs,2H),3.96(s, 3H),3.86(s,3H),3.52(s,2H),3.44(brs,2H),2.85–2.69(m,5H),2.56–2.47(m,3H),2.23 –2.11(m,1H),1.32–1.22(m,2H),0.89(t,J＝6.8Hz,1H).LC-MS(ESI-MS):664.2 [M+H] + 。
EXAMPLE 190 (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) proline
Figure GDA0003709489340001241
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with proline in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.93–9.83(m,1H),8.53–8.44(m, 1H),7.53–7.42(m,1H),7.40(d,J＝4.7Hz,1H),7.34(d,J＝7.2Hz,2H),7.24(d,J＝7.4 Hz,1H),7.05–6.98(m,1H),6.77–6.64(m,1H),5.90–5.77(m,1H),4.27(d,J＝10.4Hz, 1H),4.08–4.01(m,1H),3.96(d,J＝8.6Hz,3H),3.94–3.88(m,3H),3.79–3.71(m,1H), 3.52(s,3H),2.86–2.75(m,3H),2.74–2.71(m,2H),2.54(d,J＝14.4Hz,3H),2.36– 2.17(m,2H),2.02–1.90(m,2H),1.27–1.18(m,2H),0.89(t,J＝6.7Hz,1H).LC-MS (ESI-MS):704.2[M+H] + 。
Example 191.1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) -2-methylpyrrolidine-2-carboxylic acid
Figure GDA0003709489340001242
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 1-methylproline in step 5. LC-MS (ESI-MS) 718.3[ M + H] + 。
Example 192N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((((5-pyrrolidin-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
Figure GDA0003709489340001243
Referring to the procedure for the synthesis of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 5-aminomethylpyrrolidin-2-one in step 5 to synthesize the objective compound. 1 H NMR(500MHz,CDCl 3 )δ9.88(d,J＝13.8Hz, 1H),8.49(dd,J＝7.7,3.9Hz,1H),7.54–7.43(m,1H),7.35(d,J＝6.5Hz,2H),7.24(d,J＝ 7.1Hz,2H),7.07–6.98(m,1H),6.70–6.60(m,1H),6.33(brs,1H),5.86–5.77(m,1H), 3.97(d,J＝8.5Hz,3H),3.86–3.82(m,3H),3.80–3.72(m,3H),3.53(brs,2H),2.85–2.70 (m,5H),2.56(s,2H),2.53(brs,3H),2.36(t,J＝8.0Hz,2H),2.27–2.18(m,2H),1.80–1.73(m,1H),0.91–0.81(m,2H).LC-MS(ESI-MS):703.2[M+H] + 。
Example 193N- (2-chloro-3- (1- (2-chloro-4- (((1-cyanocyclopropyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001251
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 1-cyano-1-aminocyclopropane in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.85(d,J＝19.3Hz, 1H),8.47(d,J＝8.2Hz,1H),7.47(dd,J＝29.3,7.2Hz,1H),7.38–7.29(m,2H),7.25–7.21(m,2H),7.08–6.98(m,1H),6.68–6.59(m,1H),5.85–5.74(m,1H),3.98(s,3H), 3.90(s,2H),3.85(d,J＝18.1Hz,3H),3.70(s,2H),3.00(s,2H),2.82(t,J＝5.3Hz,2H), 2.62(s,3H),2.33–2.18(m,2H),1.27–1.22(m,3H),1.12–1.04(m,2H).LC-MS(ESI-MS): 671.2[M+H] + 。
Example 194N- (3- (1- (4- (((1-amino-3-methyl-1-oxobutan-2-yl) amino) methyl) -2-chloro-5-methoxyphenyl) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001252
Referring to the synthesis procedure of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 2-amino-3-methylbutanamide in step 5 to prepare a target compound synthetically. 1 H NMR(500MHz,CDCl 3 )δ9.93–9.83(m,1H), 8.49(d,J＝8.2Hz,1H),7.54–7.42(m,1H),7.41–7.31(m,3H),7.24(d,J＝7.4Hz,1H), 7.21(s,1H),7.07–6.99(m,1H),6.69(brs,0.5H),6.62(d,J＝11.0Hz,0.5H),5.86–5.77(m, 1H),5.73(d,J＝4.3Hz,1H),3.98(s,3H),3.88–3.81(m,3H),3.77(d,J＝13.1Hz,1H), 3.56(brs,3H),2.96(d,J＝4.1Hz,1H),2.83(d,J＝5.5Hz,2H),2.82–2.77(m,1H),2.74(t, J＝5.2Hz,2H),2.57–2.51(m,3H),2.34–2.21(m,1H),2.16–2.07(m,1H),2.08–1.99 (m,1H),1.29–1.23(m,2H),0.96(d,J＝6.9Hz,3H),0.92(d,J＝6.9Hz,3H).LC-MS (ESI-MS):705.3[M+H] + 。
Example 195N- (3- (1- (4- (((1-amino-4-methyl-1-oxopentan-2-yl) amino) methyl) -2-chloro-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001253
Referring to the procedure for the synthesis of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 2-amino-4-methylpentanamide in step 5, and the title compound was synthetically prepared. 1 H NMR(500MHz,CDCl 3 )δ9.93–9.81(m,1H), 8.48(d,J＝7.5Hz,1H),7.53–7.42(m,1H),7.40–7.15(m,4H),7.10–6.91(m,1H),6.72 –6.57(m,1H),5.88–5.75(m,1H),5.57(brs,1H),3.97(brs,2H),3.89–3.73(m,3H),3.65 –3.38(m,3H),3.13(d,J＝7.2Hz,1H),3.08–2.89(m,2H),2.83–2.64(m,4H),2.52(s, 3H),2.26(brs,2H),2.17–1.80(m,2H),1.75–1.40(m,3H),0.97–0.76(m,6H).LC-MS (ESI-MS):719.3[M+H] + 。
Example 196N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- (((2-oxopiperidin-3-yl) 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
Figure GDA0003709489340001261
Referring to the procedure for the synthesis of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 3-aminopiperidin-2-one in step 5 to synthesize the objective compound. 1 H NMR(500MHz,CDCl 3 )δ9.93–9.84(m,1H),8.47 (d,J＝7.8Hz,1H),7.54–7.43(m,1H),7.37–7.30(m,2H),7.29(s,1H),7.23(d,J＝7.3Hz, 1H),7.09–6.98(m,1H),6.68–6.57(m,1H),5.85–5.74(m,2H),3.96(d,J＝8.7Hz,3H), 3.86(brs,2H),3.84(d,J＝10.4Hz,2H),3.70(d,J＝13.6Hz,1H),3.52(brs,2H),3.36– 3.27(m,2H),3.17(dd,J＝10.0,5.9Hz,1H),3.05–2.86(m,1H),2.83–2.75(m,3H),2.73 (d,J＝4.8Hz,1H),2.58–2.50(m,3H),2.30–1.93(m,6H),1.85–1.73(m,1H),0.91–0.83 (m,1H).LC-MS(ESI-MS):703.3[M+H] + 。
Example 197.2- ((5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amine) -2- (2-chlorophenyl) acetic acid
Figure GDA0003709489340001262
Referring to the procedure for synthesizing example 170, the target compound was synthesized by substituting 1-aminocyclopropane-1-carboxylic acid with 2- (2-chlorophenyl) glycine in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.85(s,1H),8.46(d, J＝7.6Hz,1H),7.68(brs,1H),7.45–7.36(m,1H),7.34–7.23(m,3H),7.22–7.10(m,3H), 7.05–6.93(m,1H),6.50–6.35(m,1H),5.78–5.64(m,1H),5.01(brs,1H),3.95(d,J＝8.4 Hz,3H),3.89–3.71(m,2H),3.60(brs,2H),3.52(s,2H),3.00–2.91(m,1H),2.80(d,J＝ 5.3Hz,1H),2.76(d,J＝5.0Hz,2H),2.72(d,J＝5.2Hz,1H),2.66–2.57(m,1H),2.53(d,J ＝12.9Hz,3H),2.48–2.39(m,1H),2.26–2.08(m,1H),1.28–1.18(m,3H),0.88–0.82(m, 1H).LC-MS(ESI-MS):774.2[M+H] + 。
Example 198.1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) -4-fluoropyrrolidine-2-carboxylic acid
Figure GDA0003709489340001271
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 4-fluoropyrrolidine-2-carboxylic acid in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.84(d,J＝8.5Hz,1H), 8.47(d,J＝8.1Hz,1H),7.49–7.41(m,1H),7.38(s,1H),7.36–7.28(m,2H),7.22(d,J＝ 7.5Hz,1H),7.10–6.93(m,1H),6.77–6.59(m,1H),5.90–5.73(m,1H),4.24(d,J＝12.3 Hz,1H),3.96(d,J＝9.5Hz,3H),3.92–3.83(m,4H),3.75–3.56(m,3H),3.18(dd,J＝24.6, 13.0Hz,1H),3.04–2.95(m,1H),2.92–2.84(m,3H),2.83–2.73(m,3H),2.68–2.61(m, 1H),2.57(d,J＝5.7Hz,3H),2.37–2.16(m,2H),1.32–1.17(m,1H),0.88–0.76(m,1H). LC-MS(ESI-MS):722.2[M+H] + 。
Example 199N- (3- (1- (4- (((1-carbamoylcyclopropyl) amino) methyl) -2-chloro-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001272
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 1-aminocyclopropane-1-carboxamide in step 5. LC-MS (ESI-MS):689.2[ M + H] + 。
Example 200N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((((R) -3-oxoisoxazol-4-yl) 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
Figure GDA0003709489340001273
Referring to the procedure for synthesis of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with (R) -4-aminoisoxazolin-3-one in step 5 to synthetically prepare the objective compound. 1 H NMR(500MHz,CDCl 3 )δ9.85(s,1H),8.46(s, 1H),7.53–7.40(m,1H),7.38–7.28(m,2H),7.26–7.21(m,1H),7.10–6.95(m,1H),6.71 –6.52(m,1H),5.87–5.74(m,1H),4.47(brs,1H),4.09(brs,1H),3.96(d,J＝8.1Hz,3H), 3.85(s,1H),3.84–3.73(m,4H),3.57(d,J＝8.4Hz,2H),2.87(brs,1H),2.85–2.72(m,3H), 2.55(d,J＝7.4Hz,3H),2.35–2.18(m,2H),1.32–1.15(m,2H),0.90–0.78(m,1H). LC-MS(ESI-MS):691.2[M+H] + 。
Example 201N- (2-chloro-3- (1- (2-chloro-4- (((1- (hydroxycarbamoyl) cyclopropyl) amino) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001281
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 1-amino-N- (hydroxy) cyclopropane-1-carboxamide in step 5. LC-MS (ESI-MS):705.2[ M + H ] +
Example 202N- (3- (1- (4- (((1- (tert-Butylcarbamoyl) cyclopropyl) amino) methyl) -2-chloro-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001282
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 1-amino-N- (tert-butyl) cyclopropane-1-carboxamide in step 5. 1 H NMR(500MHz,CDCl 3 )δ9.84 (d,J＝12.7Hz,1H),8.47(dd,J＝8.2,2.4Hz,1H),7.59(s,1H),7.48(d,J＝13.7Hz,1H), 7.34(brs,2H),7.23(d,J＝5.1Hz,2H),7.07–6.97(m,1H),6.68–6.57(m,1H),5.84–5.75 (m,1H),3.97(d,J＝14.5Hz,3H),3.86–3.77(m,3H),3.76–3.72(m,1H),3.64(s,2H), 3.59(brs,1H),3.10–2.98(m,2H),2.90–2.76(m,4H),2.73–2.67(m,2H),2.60(s,1H), 2.35–2.20(m,2H),2.04–1.98(m,2H),1.34(s,9H).LC-MS(ESI-MS):745.3[M+H] + 。
Example 203.1- ((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-methoxybenzyl) (methyl) amino) cyclopropyl-1-carboxylic acid
Figure GDA0003709489340001283
Referring to the synthesis of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 1-methylamine in step 5And (3) synthesizing cyclopropane-1-formic acid to obtain the target compound. 1 H NMR(500MHz,CDCl 3 )δ9.87(d,J＝11.3Hz, 1H),8.48(d,J＝7.9Hz,1H),7.55–7.43(m,1H),7.36(brs,2H),7.24(d,J＝7.3Hz,1H), 7.16(brs,1H),7.09–6.98(m,1H),6.73–6.56(m,1H),5.88–5.76(m,2H),3.98(s,3H), 3.93–3.80(m,4H),3.66–3.55(m,3H),2.96–2.86(m,3H),2.83–2.75(m,2H),2.59(s, 3H),2.31–2.18(m,2H),1.42–1.18(m,4H),0.93–0.79(m,2H).LC-MS(ESI-MS):704.2 [M+H] + 。
Example 204.2- ((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) -2-methoxybenzyl) amino) -3-hydroxy-2-methylpropionic acid
Figure GDA0003709489340001291
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing 1-aminocyclopropane-1-carboxylic acid with 2-amino-3-hydroxy-2-methylpropionic acid in step 5. LC-MS (ESI-MS):708.2[ M + H ] + 。
Example 205.1- ((4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2, 6-difluorobenzyl) amino) cyclopropyl-1-carboxylic acid
Figure GDA0003709489340001292
Referring to the synthesis method of example 170, the target compound was synthesized by substituting 2-methoxy-4-hydroxy-5-chlorobenzaldehyde with 4-hydroxy-2, 6-difluoro-benzaldehyde in step 4. LC-MS (ESI-MS):662.2[ M + H] + 。
Example 206: 1- ((5-chloro-4- ((4- (2-chloro-3- (5-cyclopentanyl-1-methyl-4, 5,6,7 tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopentane-1-carboxylic acid
Figure GDA0003709489340001293
Referring to the synthesis method of example 170, paraformaldehyde was replaced with cyclopentanone in step 2, and the title compound was synthesized. LC-MS (ESI-MS):744.3[ M + H] + 。
Example 207: 1- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (tetrahydro-2H-pyran-4-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropyl-1-carboxylic acid
Figure GDA0003709489340001294
Referring to the synthesis method of example 170, paraformaldehyde was replaced with pyran-4-one in step 2, and the objective compound was synthetically prepared. LC-MS (ESI-MS):760.3[ M + H ] + 。
Example 208: 1- ((5-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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001301
Referring to the synthesis method of example 170, paraformaldehyde was replaced with 2-hydroxyacetone in step 2 to synthesize the objective compound. LC-MS (ESI-MS):734.2[ M + H] + 。
Example 209: 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) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001302
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing paraformaldehyde with hydroxyacetaldehyde in step 2. LC-MS. (ESI-MS):720.2[ M + H] + 。
Example 210: 1- ((4- ((4- (3- (5- (carboxymethyl) -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-2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001303
Step 1 Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxylic acid (3mmol) and 2-chloro-3-bromoaniline (3mmol) were dissolved in 20 mL DMF and HATU (3.3mmol) and DIPEA (4.5mmol) were added and reacted at room temperature for 12H. The reaction was quenched with water, extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure, and purification by silica gel column chromatography gave Boc-protected N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide in 78% yield.
And 2, dissolving Boc protected N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamide (2mmol) in 10 ml of dichloromethane, cooling in an ice bath, dropwise adding 5 ml of trifluoroacetic acid, stirring for 30 minutes in the ice bath, removing the ice bath, and continuing the reaction for 2 hours at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure and basified by addition of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and directly carrying out the next reaction without purification. The deprotected crude product and ethyl bromoacetate (2mmol) were dissolved in ACN, TEA (3mmol) was added, and the reaction mixture was reacted at room temperature for 6 hours, and then the solvent was removed under reduced pressure. Purifying by silica gel column chromatography to obtain 2- (2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridin-5-yl) ethyl acetate, with a total yield of 70% in 2 steps
Step 3, 2- (2- ((3-bromo-2-chlorophenyl) formamido) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazole [4, 5-c)]Pyridin-5-yl) Dissolving ethyl acetate (1mmol) and TBDMS-protected pinacol 4-borate-1-indanol (1mmol) in a mixed solvent of 10 ml of 1, 4-dioxane and 3 ml of pure water, and adding Pd (PPh) 3 ) 4 (0.1mmol) and sodium carbonate (2.0mmol), the reaction mixture was heated to reflux for about 24 hours. Then, the temperature was reduced to room temperature, water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain compound 2- (2- ((3- (1- ((tert-butyl dimethyl silicon) oxy) -2, 3-dihydro-1H-indene-4-yl) -2-chlorphenyl) formamido) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazole [4,5-c]Pyridin-5-yl) acetic acid ethyl ester. Yield: and 55 percent.
Step 4. Ethyl 2- (2- ((3- (1- ((tert-butyldimethylsilyl) oxy) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) carboxamido) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridin-5-yl) acetate (1mmol) was dissolved in THF, tetrabutylammonium fluoride (2mmol) was added in an ice bath, the temperature was slowly raised to room temperature, after 2 hours of reaction, the solvent was removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate, and the organic phase was washed with pure water and saturated brine for 3 times, respectively, and then collected and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure, dissolution of the crude product with 2-methoxy-4-hydroxy-5-chlorobenzaldehyde (1mmol) and triphenylphosphine (1mmol) in anhydrous THF, cooling to 0 deg.C, and slow dropwise addition of DIAD under nitrogen. After the addition, the reaction was continued at 0 ℃ for 30 minutes, and then slowly warmed to room temperature and reacted for 16 hours. The reaction mixture was removed of the solvent under reduced pressure, redissolved in ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography to obtain ethyl 2- (2- ((2-chloro-3- (1- (2-chloro-4-formaldehyde-5-methoxyphenoxy) -2, 3-dihydro-1H-indene-4-yl) phenyl) formamido) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazole [4,5-c ] pyridin-5-yl) acetate. Yield: and 43 percent.
Step 5 ethyl 2- (2- ((2-chloro-3- (1- (2-chloro-4-carboxaldehyde-5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) carboxamido) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridin-5-yl) acetate (0.5mmol) and methyl 1-aminocyclopropane-1-carboxylate (1.0mmol) were dissolved in a solution of 5mL of methanol and 5mL of dichloromethane, acetic acid (1.2mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium triacetoxyborohydride (2.0mmol) was added. After about 20 hours of reaction at room temperature, the organic solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography to give the compound methyl 1- ((5-chloro-4- ((4- (2-chloro-3- (5- (2-ethoxy-2-oxoethyl) -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-methoxybenzyl) amino) cyclopropane-1-carboxylate.
Yield: 25 percent of
Step 6, 1- ((5-chloro-4- ((4- (2-chloro-3- (5- (2-ethoxy-2-oxoethyl) -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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid methyl ester (0.5mmol) was dissolved in THF/water (9: 1) adding lithium hydroxide aqueous solution (1.5eq) into the solution in an ice bath, reacting at room temperature for 3 hours after dropwise addition is finished, removing the solvent under reduced pressure to obtain a reaction crude product, and purifying by preparative HPLC to obtain the target compound 1- ((4- ((4- (3- (5- (carboxymethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c) ]Pyridine-2-carboxamido) -2-chlorophenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid. Yield: 10 percent. LC-MS (ESI-MS):734.2[ M + H] + 。
Example 211: 1- ((5-chloro-4- ((4- (2-chloro-3- (5- (2-fluoroethyl) -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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001311
Referring to the synthesis method of example 210, the target compound was synthetically prepared by replacing ethyl bromoacetate with bromofluoroethane in step 2 and replacing 1-aminocyclopropane-1-carboxylic acid methyl ester with 1-aminocyclopropane-1-carboxylic acid in step 5. LC-MS (ESI-MS):722.2[ M + H] + 。
Example 212: 1- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (oxetan-3-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001321
Referring to the synthesis method of example 170, the target compound was synthetically prepared by replacing paraformaldehyde with 3-oxooxetane in step 2. LC-MS (ESI-MS) 732.2[ M + H] + 。
Example 213: n- (2-chloro-3- (1- (2, 5-dichloro-4- (2- (3-hydroxypyrrolidin-1-yl) ethoxy) 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
Figure GDA0003709489340001322
Steps 1-3 the synthesis of example 170 was referenced.
Step 4. dissolve 2, 5-dichlorohydroquinone (1mmol) and triphenylphosphine (1mmol) in anhydrous THF, cool to-10 deg.C, and slowly add DIAD (1.2mmol) dropwise under nitrogen. After the dropwise addition, the reaction was continued at-10 ℃ for 30 minutes, and then 1- (2-hydroxyethyl) pyrrolidin-3-ol (1mmol) was slowly added thereto, and after the dropwise addition, the temperature was raised to room temperature, and the reaction was allowed to proceed overnight. The reaction mixture was removed of the solvent under reduced pressure, redissolved in ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain 1- (2- (2, 5-dichloro-4-hydroxyphenoxy) ethyl) pyrrolidine-3-ol. Yield: 41 percent.
Step 5 1- (2- (2, 5-dichloro-4-hydroxyphenoxy) ethyl) pyrrolidin-3-ol (0.5mmol), triphenylphosphine (1mmol) were dissolved in anhydrous THF, cooled to-10 ℃ and DIAD was slowly added dropwise under nitrogen. After the dropwise addition, the reaction was continued at-10 ℃ for 30 minutes, and then N- (2-chloro-3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] was slowly added]After the pyridine-2-formamide is addedThe temperature was raised to room temperature and the reaction was allowed to proceed overnight. The reaction mixture was removed the solvent under reduced pressure, redissolved in ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain N- (2-chloro-3- (1- (2, 5-dichloro-4- (2- (3-hydroxypyrrolidine-1-yl) ethoxy) phenoxy) -2, 3-dihydro-1H-indene-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c) ]Pyridine-2-carboxamide. Yield: 26 percent. LC-MS (ESI-MS) 710.2[ M + H] + 。
Example 214: 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-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001323
Steps 1-3 the synthesis of example 170 was referenced.
Step 4. pyrrolidine-3-carboxylic acid tert-butyl ester (1mmol) and 2-methoxy-4-hydroxy-5-chlorobenzoic acid (1mmol) were dissolved in 10 ml of DMF, and HATU (1.1mmol) and DIPEA (1.5mmol) were added and reacted at room temperature for 12 hours. The reaction was quenched with water, extracted with ethyl acetate, the organic phase separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography to obtain 1- (5-chloro-4-hydroxy-2-methoxybenzyl) pyrrolidine-3-carboxylic acid tert-butyl ester. Yield: 81 percent.
Step 5. 1- (5-chloro-4-hydroxy-2-methoxybenzyl) pyrrolidine-3-carboxylic acid tert-butyl ester (0.5mmol), triphenylphosphine (1mmol) were dissolved in anhydrous THF, cooled to-10 deg.C, and DIAD was slowly added dropwise under nitrogen. After the dropwise addition, the reaction is continued for 30 minutes at-10 ℃, and then N- (2-chloro-3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] pyridine-2-formamide is slowly added, and after the dropwise addition, the temperature is raised to room temperature, and the reaction is carried out overnight. The reaction mixture was removed the solvent under reduced pressure, redissolved in ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography to obtain the tert-butyl 1- (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylate. Yield: 20 percent.
Step 6 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-methoxybenzyl) pyrrolidine-3-carboxylic acid tert-butyl ester (0.5mmol) was dissolved in 10 ml dichloromethane, 5 ml TFA was added in ice bath, reaction was carried out at room temperature for 40 minutes, the solvent was removed under reduced pressure, and separation by preparative HPLC gave 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) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid. Yield: 19 percent. LC-MS (ESI-MS):718.2[ M + H] + 。
Example 215: (5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxyphenyl) glycine
Figure GDA0003709489340001331
The procedure was followed in accordance with the synthesis of example 214. And 4, performing condensation reaction by using glycine and 2-methoxy-4-hydroxy-5-chloroaniline. The target compound 5-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c) is obtained]Pyridine-2-carboxamide) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxyphenyl) glycine. LC-MS (ESI-MS): 650.2[ M + H] + 。
Example 216: n- (2-chloro-3- (1- (2-chloro-4- ((1- (hydroxymethyl) -3-azabicyclo [3.1.0] hex-3-yl) methyl) -5-methoxyphenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure GDA0003709489340001332
Step referring to the Synthesis of example 170, step 5 1-AmmoniaReplacement of cyclopropane-1-carboxylic acid with (3-azabicyclo [ 3.1.0)]Cyclohexyl-1-yl) methanol to prepare the target compound. LC-MS (ESI-MS):702.3[ M + H] + 。
Example 217: n- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((6-oxo-5-oxa-2, 7-diazaspiro [3.4] oct-2-cyclyl) 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
Figure GDA0003709489340001341
Step referring to the synthetic method of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 5-oxa-2, 7-diazaspiro [3.4] in step 5]Cyclooctyl-6-ketone to obtain the target compound. LC-MS (ESI-MS):717.2[ M + H] + 。
Example 218: n- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((6-oxo-2, 5, 7-triazaspiro [3.4] oct-2-cyclyl) 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
Figure GDA0003709489340001342
Step referring to the Synthesis method of example 170, 1-aminocyclopropane-1-carboxylic acid was replaced with 2,5, 7-triazaspiro [3.4] in step 5]Cyclooctyl-6-ketone to obtain the target compound. LC-MS (ESI-MS) 716.2[ M + H] + 。
Example 219: 1- (5-chloro-4- (4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -1H-indole-1-carbonyl) -2-methoxyphenyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001343
Step with reference to the Synthesis method of example 170, substituting 4-pinacol borate ester-1-indenol in step 3 with 4-pinacol borate esterAnd (7) a step of. Step 4 is changed into condensation reaction (N- (3- (1H-indol-4-yl) -2-chlorphenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamide reacts with 2-chloro-4-formyl-5-methoxybenzoic acid by condensation); in step 5, 1-aminocyclopropane-1-carboxylic acid is replaced with pyrrolidine-3-carboxylic acid. Finally obtaining the target compound. LC-MS (ESI-MS) 715.2[ M + H] + 。
Example 220: 1- (5-chloro-4- (4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) indoline-1-carbonyl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001344
Step referring to the synthesis method of example 170, in step 3, 4-boronic acid pinacol ester-1-indenol was replaced with 4-boronic acid pinacol ester indoline. Step 4, changing into condensation reaction; in step 5, the 1-aminocyclopropane-1-carboxylic acid is replaced with pyrrolidine-3-carboxylic acid. Finally obtaining the target compound. LC-MS (ESI-MS):717.2[ M + H] + 。
Example 221: 1- (5-chloro-4- ((7- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide) phenyl) -2, 3-dihydrobenzofuran-3-yl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001351
Step with reference to the synthesis method of example 170, 4-boronic acid pinacol ester-1-indanol was replaced with 3-hydroxy-7-boronic acid pinacol ester benzofuran in step 3; in step 5, 1-aminocyclopropane-1-carboxylic acid is replaced with pyrrolidine-3-carboxylic acid. Finally obtaining the target compound. LC-MS (ESI-MS):706.2[ M + H] + 。
Example 222: 1- (5-chloro-4- ((1- (2' -chloro-3 ' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) - [1,1' -biphenyl ] -3-yl) -2,2, 2-trifluoroethyl) amino) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001352
Steps 1-3 the synthesis of reference example 170 wherein pinacol 4-borate ester-1-indenol was replaced with pinacol 3-trifluoroacetylphenylborate in step 3 gave N- (2-chloro-3 '- (2,2, 2-trifluoroacetyl) - [1,1' -biphenyl ] -3-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide.
Step 4. pyrrolidine-3-carboxylic acid tert-butyl ester (1mmol) and 2-methoxy-4-amino-5-chlorobenzaldehyde (1mmol) were dissolved in a solution of 5mL methanol and 5mL dichloromethane, acetic acid (1.2mmol) was added, the reaction was mixed and stirred for about 1 hour, and then sodium borohydride triacetate (2.0mmol) was added. After the reaction at room temperature for about 10 hours, the organic solvent was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1- (4-amino-5-chloro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid tert-butyl ester. Yield: 51 percent.
Step 5. dissolve 1- (4-amino-5-chloro-2-methoxybenzyl) pyrrolidine-3-carboxylic acid tert-butyl ester (0.5mmol) and N- (2-chloro-3 '- (2,2, 2-trifluoroacetyl) - [1,1' -biphenyl ] -3-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (0.5mmol) in a solution of 5mL of methanol and 5mL of dichloromethane, add acetic acid (1.2mmol), mix the reaction for about 1 hour, then add sodium triacetoxyborohydride (1.0 mmol). After about 10 hours of reaction at room temperature, the organic solvent was concentrated under reduced pressure and purified by silica gel column chromatography to give tert-butyl 1- (5-chloro-4- ((1- (2' -chloro-3 ' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) - [1,1' -biphenyl ] -3-yl) -2,2, 2-trifluoroethyl) amino) -2-methoxybenzyl) pyrrolidine-3-carboxylate. Yield: 27 percent.
Step 6, 1- (5-chloro-4- ((1- (2 '-chloro-3' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c))]Pyridine-2-carboxamido) - [1,1' -biphenyl]-3-yl) -2,2, 2-trifluoroethyl) amino) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid tert-butyl ester (0.1mmol) was dissolved in 10 ml dichloromethane, 5ml TFA was added in ice bath, reaction was carried out at room temperature for 40 minutes, the solvent was removed under reduced pressure, and separation by preparative HPLC gave 1- (5-chloro-4- ((1- (2 '-chloro-3' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamido) - [1,1' -biphenyl]-3-yl) -2,2, 2-trifluoroethyl) amino) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid. Yield: 19 percent. LC-MS (ESI-MS) 745.2[ M + H] + 。
Example 223: 1- (5-chloro-4- (1- (2' -chloro-3 ' - (1, 5-dimethyl-4, 5,6, 7-tet-rahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) - [1,1' -biphenyl ] -3-yl) cyclopropyl) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001361
Step referring to the synthesis method of example 170, the target compound was prepared by replacing 4-boronic acid pinacol ester-1-indanol with 1- (3- (4,4,5, 5-tetramethyl-1, 3-dioxaborolan-2-yl) phenyl) cyclopropane-1-ol in step 3 and replacing 1-aminocyclopropane-1-carboxylic acid with pyrrolidine-3-carboxylic acid in step 5. LC-MS (ESI-MS) 704.2[ M + H] + 。
Example 224: 1- (5-chloro-4- ((3- (2' -chloro-3 ' - (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) - [1,1' -biphenyl ] -3-yl) oxetan-3-yl) oxy) -2-methoxybenzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001362
Step referring to the synthesis of example 170, the title compound was prepared by substituting 4-boronic acid pinacol ester-1-indanol with 1- (3- (4,4,5, 5-tetramethyl-1, 3-dioxaborolan-2-yl) phenyl) oxetan-3-ol in step 3 and 1-aminopropane-1-carboxylic acid with pyrrolidine-3-carboxylic acid in step 5. LC-MS (ESI-MS) 720.2 [ M + H ] + 。
Example 225: (R) -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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001363
Referring to the synthesis method in example 170, the target compound was prepared by replacing pinacol 4-borate-1-indanol with (R) pinacol 4-borate-1-indanol in step 3. LC-MS (ESI-MS):690.2[ M + H] + 。
Example 226: (S) -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-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001364
Referring to the synthesis method in example 170, the target compound was prepared by replacing pinacol 4-borate-1-indanol with (S) pinacol 4-borate-1-indanol in step 3. LC-MS (ESI-MS):690.2[ M + H] + 。
Example 227: 1- ((5-chloro-4- ((4- (2-chloro-3- (5-methyl-4, 5,6, 7-tetrahydrooxazolo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001371
Step with reference to the synthesis of example 170, Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] in step 1 ]Replacement of pyridine-2-carboxylic acid with Boc-protected 4,5,6, 7-tetrahydro-1H-oxazolo [4,5-c ]]And preparing the target compound from the pyridine-2-formic acid. LC-MS (ESI-MS):677.2[ M + H] + 。
Example 228: 1- ((5-chloro-4- ((4- (2-chloro-3- (5-methyl-4, 5,6, 7-tetrahydrothiazole [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001372
Step with reference to the synthesis of example 170, Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] in step 1]Replacement of pyridine-2-carboxylic acid with Boc-protected 4,5,6, 7-tetrahydro-1H-thiazolo [4,5-c ]]And preparing the target compound from the pyridine-2-formic acid. LC-MS (ESI-MS):693.2[ M + H] +
Example 229: 1- ((5-chloro-4- ((4- (2-chloro-3- (6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [1,5-c ] pyrimidine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001373
Step with reference to the synthesis of example 170, Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] in step 1]Replacement of pyridine-2-carboxylic acid with Boc-protected 4,5,6, 7-tetrahydro- [1,2,4] -carboxylic acid]Triazolo [1,5-c ]]Preparing the target compound from the pyrimidine-2-formic acid. LC-MS (ESI-MS) 677.2[ M + H ] + 。
Example 230: 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) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001374
Step with reference to the synthesis of example 170, Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] in step 1]Replacement of pyridine-2-carboxylic acid with Boc-protected 3, methyl-4, 5,6, 7-tetrahydroimidazo [1,2-a ]]And preparing the target compound from the pyrazine-2-formic acid. LC-MS (ESI-MS):690.2[ M + H] + 。
Example 231: 1- ((5-chloro-4- ((4- (2-chloro-3- (7-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyrazine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001381
Step with reference to the synthesis of example 170, Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] in step 1]Replacement of pyridine-2-carboxylic acid with Boc-protected 5,6,7, 8-tetrahydro- [1,2,4]]Triazolyl [1,5-a ]]And preparing the target compound from the pyrazine-2-formic acid. LC-MS (ESI-MS):677.2[ M + H] + 。
Example 232: 1- ((5-chloro-4- ((4- (2-chloro-3- (3, 6-dimethyl-4, 5,6, 7-tetrahydropyrazolo [1,5-c ] pyrimidine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001382
Step with reference to the synthesis of example 170, Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] in step 1]Replacement of pyridine-2-carboxylic acid with Boc-protected 3-methyl-4, 5,6, 7-tetrahydropyrazolyl [1,5-c]Preparing the target compound from the pyrimidine-2-formic acid. LC-MS (ESI-MS):690.2[ M + H] + 。
Example 233: 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) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001383
Referring to the synthesis method in example 170, the target compound was prepared by replacing pinacol 4-borate-1-indanol with pinacol 6-borate-1-indanol in step 3. LC-MS (ESI-MS):690.2[ M + H ] +.
Example 234: 1- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d 3) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001384
With reference to the synthesis method of example 170, step 2 was adjusted as follows to prepare the objective compound. LC-MS (ESI-MS):693.2[ M + H] + 。
Step 2, Boc protected N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) ]Pyridine-2-carboxamide (2mmol) was dissolved in 10 ml dichloromethane, cooled in an ice bath, 5 ml trifluoroacetic acid was added dropwise and stirred under ice bath conditions for 30 minutes, after which the ice bath was removed and the reaction was continued for 2 hours at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure and basified by addition of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate, and directly carrying out methylation reaction without purification. Removing the protective crude product and CD 3 I (2mmol) was dissolved in DCM and DIPEA (2mmol) was added. After 3 hours at room temperature, the solvent was removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate, and the organic phase was washed once with sodium hydrogencarbonate, water and brine, respectively, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and purifying with silica gel column chromatography to obtain N- (3-bromo-2-chlorophenyl) -1-methyl-5- (methyl-d) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-formamide with a total yield of 36% in 2 steps
EXAMPLE 235N- (3- (1- (4- (((1-carboxamidocyclopropyl) amino) methyl) -2-chloro-5-methoxyphenyl) -2, 3-dihydro-1H-inden-4-yl) -2-chlorophenyl) -1-methyl-5- (methyl-d) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamides
Figure GDA0003709489340001391
Step with reference to the synthesis of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with 1-aminocyclopropane-1-carboxamide in step 5. LC-MS (ESI-MS):692.2[ M + H] + 。
Example 236 (5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) glycine
Figure GDA0003709489340001392
Step with reference to the synthesis of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with glycine in step 5. LC-MS (ESI-MS):667.2[ M + H] + 。
Example 237- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclobutane-1-carboxylic acid
Figure GDA0003709489340001393
Step with reference to the synthesis of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with 1-aminocyclobutane-1-carboxylic acid in step 5. LC-MS (ESI-MS):707.3[ M + H] + 。
Example 238- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) -2-methylpropionic acid
Figure GDA0003709489340001394
Step referring to the synthesis of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with 2-amino-2-methylpropionic acid in step 5. LC-MS (ESI-MS) 695.2[ M + H ] + 。
Example 239:1- (5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d) 3 ) -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 methyl esterAcid(s)
Figure GDA0003709489340001401
Step with reference to the synthesis of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with pyrrolidine-3-carboxylic acid in step 5. LC-MS (ESI-MS):707.2[ M + H] + 。
Example 240 (5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) arginine
Figure GDA0003709489340001402
Step with reference to the synthesis method of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with valine in step 5. LC-MS (ESI-MS):709.3[ M + H] + 。
Example 241- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) -3-hydroxy-2-methylpropionic acid
Figure GDA0003709489340001403
Step referring to the synthesis of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with 2-methylserine in step 5. LC-MS (ESI-MS) 711.2[ M + H] + 。
Example 242 (5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) serine
Figure GDA0003709489340001404
Step with reference to the synthesis of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with serine in step 5. LC-MS (ESI-MS):697.2[ M + H] + 。
Example 243N- (2-chloro-3- (1- (2-chloro-4- ((3-hydroxyazetidin-1-yl) methyl) -5-methoxyphenyl) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-5- (methyl-d 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamides
Figure GDA0003709489340001411
Step with reference to the synthetic procedure of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with 3-hydroxyazetidine in step 5. LC-MS (ESI-MS):665.2[ M + H] + 。
Example 244N- (2-chloro-3- (1- (2-chloro-5-methoxy-4- ((6-oxo-2, 5, 7-triazaspiro [3.4 ]]Cycloneoalkan-2-yl) methyl) phenoxy) -2, 3-dihydro-1H-inden-4-yl) phenyl) -1-methyl-5- (methyl-d 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamides
Figure GDA0003709489340001412
Step with reference to the synthetic method of example 234, 1-aminocyclopropane-1-carboxylic acid was replaced with 2,5, 7-triazaspiro [3.4 ] in step 5]Cyclooctyl-6-one. LC-MS (ESI-MS):719.2[ M + H] + 。
Example 245- ((5-chloro-4- ((4- (2-chloro-3- (5-methyl-1- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001413
Step reference example 170 Synthesis method of Boc protected 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] in step 1]Pyridine-2-carboxylic acid substitutionIs Boc protected 1-deuterated methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxylic acid to obtain the target compound. LC-MS (ESI-MS):693.2[ M + H] + 。
Example 246- ((5-chloro-4- ((4- (2-chloro-3- (5-methyl-1- (methyl-d)) 3 ) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-methoxybenzyl) amino) cyclobutane-1-carboxylic acid
Figure GDA0003709489340001414
Step with reference to the synthesis of example 245, 1-aminocyclopropane-1-carboxylic acid was replaced with 1-aminocyclobutane-1-carboxylic acid in step 5. LC-MS (ESI-MS):707.2[ M + H] + 。
Example 247 1- (5-chloro-4- ((4- (2-chloro-3- (5-methyl-1- (methyl-d) 3 ) -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
Figure GDA0003709489340001421
Step referring to the synthesis of example 245, 1-aminocyclopropane-1-carboxylic acid was replaced with pyrrolidine-3-carboxylic acid in step 5. LC-MS (ESI-MS) 707.3[ M + H ] + 。
Example 248- ((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- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001422
Step referring to the Synthesis method of example 170, 2-methoxy-4-hydroxy-5-chlorobenzaldehyde in step 4 was replaced with 2- (methoxy-d) 3 ) 4-hydroxy-5-chlorobenzaldehyde to prepare the target compound. L isC-MS(ESI-MS):693.2 [M+H] + 。
Example 249 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- (methoxy-d 3 ) Benzyl) pyrrolidine-3-carboxylic acid
Figure GDA0003709489340001423
Step with reference to the synthesis of example 248, 1-aminocyclopropane-1-carboxylic acid was replaced with pyrrolidine-3-carboxylic acid in step 5. LC-MS (ESI-MS):707.3[ M + H] + 。
Example 250- ((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- (methoxy-d 3 ) Benzyl) amino) -2-methylpropanoic acid
Figure GDA0003709489340001424
Step referring to the synthesis of example 248, 1-aminocyclopropane-1-carboxylic acid was replaced with 2-amino 2-methylpropionic acid in step 5. LC-MS (ESI-MS) 695.3[ M + H ] + 。
Example 251- ((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- (methoxy-d 3 ) Benzyl) amino) cyclobutane-1-carboxylic acid
Figure GDA0003709489340001431
Step with reference to the synthesis of example 248, 1-aminocyclopropane-1-carboxylic acid was replaced with 1-aminocyclobutane-1-carboxylic acid in step 5. LC-MS (ESI-MS):707.2[ M + H] + 。
Example 252 (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- (methoxy-d 3 ) Benzyl) glycine
Figure GDA0003709489340001432
Procedure the synthesis of example 248 was followed by replacing 1-aminocyclopropane-1-carboxylic acid with glycine in step 5. LC-MS (ESI-MS) 667.2[ M + H] + 。
Example 253 (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- (methoxy-d 3 ) Benzyl) serine
Figure GDA0003709489340001433
Step referring to the synthesis of example 248, 1-aminocyclopropane-1-carboxylic acid was replaced with serine in step 5. LC-MS (ESI-MS) 697.2[ M + H] + 。
Example 254 (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- (methoxy-d 3 ) Benzyl) leucine
Figure GDA0003709489340001434
Step with reference to the synthesis of example 248, 1-aminocyclopropane-1-carboxylic acid was replaced with leucine in step 5. LC-MS (ESI-MS):723.2[ M + H] + 。
Example 255- ((4- ((4- (3- (5-acetyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c))]Pyridine-2-carboxamido) -2-chlorobenzene) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001441
The procedure was as in example 248, with minor modifications to step 2. LC-MS (ESI-MS):721.2[ M + H] + 。
And 2, dissolving Boc protected N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamide (2mmol) in 10 ml of dichloromethane, cooling in an ice bath, dropwise adding 5 ml of trifluoroacetic acid, stirring for 30 minutes in the ice bath, removing the ice bath, and continuing the reaction for 2 hours at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure and basified by addition of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and directly performing acetylation reaction without purification. The deprotected crude product and acetic anhydride (2.2mmol) were dissolved in DCM and pyridine (0.5mmol) and triethylamine (3mmol) were added. After 1 hour of ice-bath reaction, the solvent was removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate, and the organic phase was washed once with sodium hydrogencarbonate, water and brine, respectively, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate, and purifying by silica gel column chromatography to obtain the N- (3-bromo-2-chlorophenyl) -5-acetyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] pyridine-2-formamide with the total yield of 80 percent in 2 steps.
Example 256- ((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) -2- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001442
The procedure was followed by the synthetic procedure of example 248, with slight modification of step 2, to afford the title compound. LC-MS (ESI-MS):723.3[ M + H] + 。
And 2, dissolving Boc protected N- (3-bromo-2-chlorophenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-formamide (2mmol) in 10 ml of dichloromethane, cooling in an ice bath, dropwise adding 5 ml of trifluoroacetic acid, stirring for 30 minutes in the ice bath, removing the ice bath, and continuing the reaction for 2 hours at room temperature. The solvent and trifluoroacetic acid were removed under reduced pressure and basified by addition of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and directly performing acetylation reaction without purification. The deprotected crude product and bromoethanol (2mmol) were dissolved in ACN, triethylamine (3 mmol). After 2 hours at room temperature, the solvent was removed under reduced pressure. The reaction mixture was dissolved in ethyl acetate, and the organic phase was washed once with sodium hydrogencarbonate, water and brine, respectively, and the organic phase was separated and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate, and purifying by silica gel column chromatography to obtain the N- (3-bromo-2-chlorphenyl) -5- (2-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] pyridine-2-formamide, wherein the total yield of 2 steps is 80%.
Example 257- ((5-chloro-4- ((4- (2-chloro-3- (5- (2-fluoroethyl) -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- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001451
With reference to the synthesis method of example 256, the target compound was prepared by substituting bromoethanol with 1-iodo-2-fluoroethane in step 2. LC-MS (ESI-MS):725.2[ M + H] + 。
Example 258 1- ((4- ((4- (3- (5- (carboxymethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamido) -2-chlorobenzene) -2, 3-dihydro-1H-inden-1-yl) oxy) -5-chloro-2- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001452
Step with reference to the Synthesis of example 210, 5-chloro-2-methoxy-4-hydroxybenzaldehyde was replaced with 5-chloro-2- (methoxy-d) in step 4 3 ) Preparing the target compound from the 4-hydroxybenzaldehyde. LC-MS (ESI-MS):737.2 [ M + H] + 。
Example 259- ((5-chloro-4- ((4- (2-chloro)-3- (5-cyclopentyl-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- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001453
Step referring to the Synthesis of example 206, 5-chloro-2-methoxy-4-hydroxybenzaldehyde was replaced with 5-chloro-2- (methoxy-d) in step 4 3 ) Preparing the target compound from the 4-hydroxybenzaldehyde. LC-MS (ESI-MS):747.2 [ M + H] + 。
Example 260- ((5-chloro-4- ((4- (2-chloro-3- (1-methyl-5- (oxocyclobutane-3-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2- (methoxy-d 3 ) Benzyl) amino) cyclopropane-1-carboxylic acid
Figure GDA0003709489340001454
Step referring to the synthesis of example 212, 5-chloro-2-methoxy-4-hydroxybenzaldehyde was replaced with 5-chloro-2- (methoxy-d) in step 4 3 ) Preparing the target compound from the 4-hydroxybenzaldehyde. LC-MS (ESI-MS):735.3 [ M + H] + 。
Example 261: 1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-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
Figure GDA0003709489340001461
Step 1, 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 (422mg) and acetone (180mg) were dissolved in 8mL of dichloromethane, and DIPEA (390mg) and sodium borohydride acetate (636mg) were added to react at room temperature overnight.After TLC detection reaction is completed, dichloromethane and water are used for extraction, the separated organic phase is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography to obtain a solid product N- (2-chloro-3- (1-hydroxy-2, 3-dihydro-1H-indene-4-yl) phenyl) -5-isopropyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] as a [4,5-c ] imidazole ]Pyridine-2-carboxamide (260mg), yield 56%, 1 H NMR(500MHz,CDCl 3 )δ9.86(s,1H),8.48 (d,J＝8.3Hz,1H),7.48(d,J＝7.4Hz,1H),7.39–7.31(m,2H),7.19(d,J＝7.4Hz,1H), 7.01(brs,1H),5.35(brs,1H),3.97(d,J＝6.9Hz,3H),3.66(s,1H),3.55(s,1H),3.10–3.01 (m,1H),2.91(d,J＝5.6Hz,1H),2.85(t,J＝5.9Hz,1H),2.78–2.67(m,3H),2.53(s,1H), 2.52–2.45(m,1H),1.95–1.87(m,1H),1.18(d,J＝6.5Hz,6H)。
step 2, 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde (0.5g) and methyl 1-aminocyclopropanecarboxylate hydrochloride (0.8g) were dissolved in 10mL of dichloromethane, and triethylamine (0.6mL) and sodium borohydride acetate (1.1g) were added to react at room temperature overnight. After TLC detection reaction is finished, dichloromethane and water are used for extraction, separated organic phase is decompressed and concentrated, a crude product is purified by silica gel column chromatography to obtain a solid product of 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropane carboxylic acid methyl ester (0.49g), the yield is 66 percent, 1 H NMR(500MHz,CDCl 3 )δ6.27(s,1H),3.87(d,J＝1.7Hz, 2H),3.83(s,3H),3.71(s,3H),1.34(dd,J＝7.3,4.2Hz,2H),1.17(dd,J＝7.3,4.2Hz,2H)。
step 3, dissolving N- (2-chloro-3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) phenyl) -5-isopropyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (94mg) and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate (121mg) in 2-methyltetrahydrofuran (4mL), adding triphenylphosphine (105mg), dropwise adding DIAD (90mg) under the protection of nitrogen, reacting at room temperature for about 1 hour, after the HPLC detection reaction is finished, adding silica gel, stirring the sample, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-4- ((4-4) Methyl- (2-chloro-3- (5-isopropyl-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) cyclopropanecarboxylate (63mg) yield 42%.
And 4, step 4: 1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-1-)Methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Dissolving pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropane carboxylic acid methyl ester (45mg) in 2mL methanol, adding lithium hydroxide (24mg), reacting at room temperature overnight, after TLC detection reaction is completed, dropwise adding 1 drop of AcOH into the reaction liquid, then adding silica gel, stirring the sample, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] which is a solid product]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclopropanecarboxylic acid (31mg) in 72% yield. 1 H NMR(500MHz,CDCl 3 )δ8.36(d,J＝7.8Hz,1H),7.42 –7.33(m,2H),7.31–7.24(m,1H),7.19–7.14(m,1H),7.09–6.99(m,1H),6.77(brs,1H), 6.05–5.94(m,1H),4.31(brs,2H),3.93(s,3H),3.83–3.75(m,2H),3.29(brs,1H),3.25(s, 3H),3.17–3.08(m,2H),2.98–2.89(m,1H),2.82(brs,2H),2.75–2.68(m,1H),1.89(brs, 2H),1.31(brs,2H),1.28–1.15(m,6H),1.09(brs,2H).LC-MS(ESI-MS):736[M+H]+。
Example 262: 1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-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
Figure GDA0003709489340001471
Referring to the procedure for synthesis of example 261, methyl 1-aminocyclopropanecarboxylate hydrochloride was replaced with methyl 1-aminocyclobutanecarboxylate hydrochloride to synthesize the target compound 1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-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 (22mg), LC-MS (ESI-MS):750[ M + H + ESI-MS] + 。
Example 263 1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-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) cyclopropanecarboxylic acid
Figure GDA0003709489340001472
Referring to the synthesis procedure of example 261, 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde was replaced with 3-chloro-2-fluoro-4-hydroxy-6-ethoxybenzaldehyde, and 1- ((3-chloro-4- ((4- (2-chloro-3- (5-isopropyl-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) cyclopropanecarboxylic acid (26mg) was synthesized as a target compound, LC-MS (ESI-MS) 750[ M + H ] +.
Example 264- ((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) -6-ethoxy-2-fluorobenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001473
Referring to the synthesis procedure of example 261, acetone was replaced with paraformaldehyde and 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde was replaced with 3-chloro-2-fluoro-4-hydroxy-6-ethoxybenzaldehyde, and 1- ((3-chloro-4- ((4- (2-chloro-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c), a target compound, was synthesized ]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-ethoxy-2-fluorobenzyl) amino) cyclopropanecarboxylic acid (30mg), LC-MS (ESI-MS): 722[ M + H] + 。
Example 265- ((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) -6-ethoxy-2-fluorobenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340001481
Referring to the synthesis of example 261, acetone was replaced with paraformaldehyde and 3-chloro-2-fluoro-4-hydroxy-6-methoxybenzaldehyde was replaced withReplacing 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride with 1-aminocyclobutanecarboxylic acid methyl ester hydrochloride for 3-chloro-2-fluoro-4-hydroxy-6-ethoxybenzaldehyde, and synthesizing to obtain 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-ethoxy-2-fluorobenzyl) amino) cyclobutanecarboxylic acid (17mg), LC-MS (ESI-MS):736[ M + H] + 。
Example 266: 1- ((3-chloro-2-fluoro-4- ((4- (3- (5-isopropyl-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) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001482
Step 1, N- (3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c)]Pyridine-2-carboxamide (402mg) and acetone (180mg) were dissolved in 8mL of dichloromethane, and DIPEA (390mg) and sodium borohydride acetate (636mg) were added to react at room temperature overnight. After TLC detection reaction is completed, dichloromethane and water are used for extraction, organic phase separation and pressure concentration are carried out, and the crude product is purified by silica gel column chromatography to obtain a solid product N- (2-chloro-3- (1-hydroxy-2, 3-dihydro-1H-indene-4-yl) phenyl) -5-isopropyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] as a [4 ] intermediate product]Pyridine-2-carboxamide (204mg), yield 46%, 1 H NMR(500MHz,CDCl 3 )δ9.18(d,J＝6.7 Hz,1H),8.01(dd,J＝12.4,8.0Hz,1H),7.44(d,J＝7.6Hz,1H),7.33(t,J＝7.5Hz,1H), 7.30–7.25(m,1H),7.14(d,J＝7.2Hz,1H),6.99(dd,J＝14.0,7.6Hz,1H),5.36–5.32(m, 1H),3.97(s,3H),3.64(brs,2H),3.10–3.00(m,1H),2.94–2.85(m,2H),2.76–2.70(m, 2H),2.65–2.56(m,1H),2.53–2.44(m,2H),2.12(d,J＝19.9Hz,3H),1.95–1.86(m,1H), 1.18(d,J＝6.5Hz,6H).
step 2, dissolving N- (2-chloro-3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) phenyl) -5-isopropyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (89mg) and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate (121mg) in 2-methyltetrahydrofuran (4mL), adding triphenylphosphine (105mg), dropwise adding DIAD (90mg) under the protection of nitrogen, reacting for about 1 hour at room temperature, after the HPLC detection reaction is finished, adding silica gel, stirring the sample, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-2-fluoro- Methyl 4- ((4- (3- (5-isopropyl-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) -6-methoxybenzyl) amino) cyclopropanecarboxylate (73mg) yield 50%.
And step 3: mixing 1- ((3-chloro-2-fluoro-4- ((4- (3- (5-isopropyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c))]Dissolving pyridine-2-formamido) -2-methylphenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -6-methoxybenzyl) amino) cyclopropane carboxylic acid methyl ester (50mg) in 2mL methanol, adding lithium hydroxide (24mg), reacting at room temperature overnight, after TLC detection reaction is completed, dropwise adding 1 drop of AcOH into the reaction liquid, then adding silica gel, stirring, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-2-fluoro-4- ((4- (3- (5-isopropyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] to obtain a solid product]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-methoxybenzyl) amino) cyclopropanecarboxylic acid (26mg) in 53% yield. LC-MS (ESI-MS):716[ M + H] + 。
Example 267: 1- ((3-chloro-2-fluoro-4- ((4- (3- (5-isopropyl-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) -6-methoxybenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340001491
Referring to the synthesis procedure of example 266, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate was replaced with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate to synthesize the objective compound 1- ((3-chloro-2-fluoro-4- ((4- (3- (5-isopropyl-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) -6-methoxybenzyl) amino) cyclobutanecarboxylic acid (20mg), LC-MS (ESI-MS):730[ M + H] + 。
Example 268: 1- ((3-chloro-6-ethoxy-2-fluoro-4- ((4- (3- (5-isopropyl-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) benzyl) amino) cyclopropanecarboxylic acid
Figure GDA0003709489340001492
With reference to the synthesis procedure of example 267, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate was replaced with methyl 1- ((3-chloro-6-ethoxy-2-fluoro-4-hydroxybenzyl) amino) cyclopropanecarboxylate, and 1- ((3-chloro-6-ethoxy-2-fluoro-4- ((4- (3- (5-isopropyl-1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] -c) that is an objective compound was synthesized]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) benzyl) amino) cyclopropanecarboxylic acid (23mg), LC-MS (ESI-MS) 730[ M + H] + 。
Example 269: 1- ((3-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-ethoxy-2-fluorobenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340001493
With reference to the synthesis procedure of example 267, acetone was replaced with paraformaldehyde, methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate was replaced with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-ethoxybenzyl) amino) cyclobutanecarboxylate, and 1- ((3-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c) carboxylic acid, an objective compound, was synthesized ]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -6-ethoxy-2-fluorobenzyl) amino) cyclobutanecarboxylic acid (20mg), LC-MS (ESI-MS):716[ M + H] + 。
Example 270: 1- ((3-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid
Figure GDA0003709489340001501
Referring to the synthesis procedure of example 267, methyl 1- ((3-chloro-4- ((4- (3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)) was synthesized by replacing acetone with paraformaldehyde and replacing methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclopropanecarboxylate with methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate]Pyridine-2-carboxamido) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid (16mg), LC-MS (ESI-MS):702[ M + H] + 。
Example 271: 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) cyclobutanecarboxylic acid
Figure GDA0003709489340001502
Step 1, N- (2-cyano-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 (205mg) and paraformaldehyde (60mg) were dissolved in 4mL of dichloromethane, and DIPEA (185mg) and sodium borohydride acetate (310mg) were added to react at room temperature overnight. After TLC detection reaction is completed, dichloromethane and water are used for extraction, organic phase separation and pressure concentration are carried out, and the crude product is purified by silica gel column chromatography to obtain a solid product N- (2-cyano-3- (1-hydroxy-2, 3-dihydro-1H-indene-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] as a [4 ] intermediate product]Pyridine-2-carboxamide (88mg) in 41% yield, 1H NMR (500MHz, CDCl) 3 )δ9.90(s,1H),8.47 (d,J＝8.3Hz,1H),7.63(t,J＝8.1Hz,1H),7.53(d,J＝7.4Hz,1H),7.38(t,J＝7.5Hz,1H), 7.29(s,1H),7.13(d,J＝7.7Hz,1H),5.36–5.32(m,1H),3.97(s,3H),3.60(s,2H),3.41– 3.36(m,3H),2.90(t,J＝9.5Hz,2H),2.79(d,J＝6.6Hz，2H),2.57(s,3H),2.00–1.90(m, 2H).
Step 2, dissolving N- (2-cyano-3- (1-hydroxy-2, 3-dihydro-1H-inden-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (60mg) and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate (98mg) in 2-methyltetrahydrofuran (3mL), adding triphenylphosphine (85mg), dropwise adding DIAD (80mg) under nitrogen protection, reacting at room temperature for about 1 hour, after the HPLC detection reaction is finished, adding silica gel, stirring, and purifying to obtain a solid product, namely 1- ((3-chloro-4- ((4- (2-chloro-4- (2 column chromatography) Methyl (39mg) 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) cyclobutanecarboxylate, yield 38%.
And step 3: mixing 1- ((3-chloro-4- ((4- (2-cyano-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4, 5-c))]Dissolving pyridine-2-formamido) phenyl) -2, 3-dihydro-1H-indene-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid methyl ester (30mg) in 2mL methanol, adding lithium hydroxide (20mg), reacting overnight at room temperature, after TLC (thin layer chromatography) detection reaction is completed, dropwise adding 1 drop of AcOH into a reaction solution, adding silica gel, stirring, and purifying by column chromatography to obtain a solid product 1- ((3-chloro-4- ((4- (2-cyano-3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole [4,5-c ] after a sample is stirred and subjected to column chromatography]Pyridine-2-carboxamido) phenyl) -2, 3-dihydro-1H-inden-1-yl) oxy) -2-fluoro-6-methoxybenzyl) amino) cyclobutanecarboxylic acid (18mg) in 61% yield. LC-MS (ESI-MS):713[ M + H] + 。
Example 272: 1- ((3-chloro-4- ((4- (2-cyano-3- (5-isopropyl-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
Figure GDA0003709489340001511
With reference to the synthesis procedure of example 271, paraformaldehyde was replaced with acetone, and methyl 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) amino) cyclobutanecarboxylate was replaced with 1- ((3-chloro-2-fluoro-4-hydroxy-6-methoxybenzyl) carboxylic acid Methyl ester of amino) cyclopropane carboxylic acid, and synthesizing the target compound 1- ((3-chloro-4- ((4- (2-cyano-3- (5-isopropyl-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) cyclopropanecarboxylic acid (23mg), LC-MS (ESI-MS):727[ M + H] + 。
Example 273: in vitro PD-1/PD-L1 protein interaction blocking experiment
The experiment was carried out in a white-bottomed 96-well plate using the cisbio PD-1/PD-L1 HTRF kit (cisbio:64ICP01PEG), with a final volume of 20. mu.l per well. The compound was diluted with DMSO at 5-fold concentration gradient to prepare stock solutions of different concentrations, with final DMSO concentration of 1%. mu.L of Tag 1-PD-L1 protein (final concentration 5nM), 2. mu.L of compound (shown in Table 1), 4. mu.L of Tag 2-PD1 protein (final concentration 50nM) were added to each well and incubated at room temperature for 15 min. Adding 10 mu L (1:1) of mixed anti-Tag1-Eu 3+ (final concentration 5nM) and anti-Tag2-XL665 (final concentration 50nM), capped, incubated at room temperature for 2 h; the cover was removed and the OD values at 665nM and 620nM were measured by a microplate reader (SynergyNEO2) and the ratio of the OD values at 665nM and 620nM for different compound concentrations was calculated. Fitting of IC by PrismGraphad7.0 50 。
TABLE 1 in vitro PD-1/PD-L1 protein interaction Block experiment Activity test results
Figure GDA0003709489340001512
Figure GDA0003709489340001521
Figure GDA0003709489340001531
Figure GDA0003709489340001541
Note: +. IC 50 <10nM；++:10nM<IC 50 <100nM；+++:100nM<IC 50 <1000nM；++++:1000nM<IC 50
Compound a is example 21 of patent WO2018119224 a1, with the structure:
Figure GDA0003709489340001551
the results in Table 1 show that most of the compounds of the present invention exhibited strong PD-1/PD-L1 blocking activity, IC 50 Less than 10 nM.
Example 274: in vitro Co-incubation experiments
Solutions of the compounds were prepared at different concentrations, with a final DMSO concentration of 0.1%. 293T-OS8-PDL1 (purchased from Beijing Congyuan Bo Chuang) cells were trypsinized, added with 10. mu.g/ml mitomycin C (Aibisin: abs817873), incubated for 1.5 hours, washed 3 times with PBS and counted, resuspended in RPMI 1640 medium and added to a round bottom 96-well cell culture plate at 5 ten thousand per well. The cells were preincubated overnight in 293T-OS8-PDL1 plated in 96-well plates with varying concentrations of compound. Adding 15 million pass CD per hole 3+ The resulting human primary T cells were screened with magnetic beads (BD Pharmingen:552593), incubated for 48 hours, and the supernatant was passed through an ELISA kit (R)&DY285B-05) to determine the interleukin-2 level of each group. And the fold increase was calculated in comparison to the DMSO blank. The results are shown in FIG. 1.
Compound a is example 21 of patent WO2018119224 a1, having the following structure:
Figure GDA0003709489340001552
in vitro co-incubation experiments show that the compound can reverse the function of T cells inhibited by PD-L1; examples 261, 107 were more active than control compound a.
Example 275: NFAT reporter gene assay
The experimental procedure was as follows:
1. reviving Hep3B-OS8-hPDL1 cells;
2. regulating cell densityDegree to 1.25 x 10 5 /ml；
3. Cell plate, 100 uL/well;
4. adding different compounds to each well;
5. the compound was incubated with Hep3B-OS8-hPDL1 cells for 5 hours;
6. 1.25 x 10 additions per well 4 Jurkat-NFAT-PD1 cells;
7. after 6 hours incubation, 100. mu.l of ONE-Glo was added per well TM Luciferase Assay System；
8. Absorbance was read by incubating for 3 minutes, and the administration group and DMSO control group were compared to calculate the fold increase in fluorescence, which is shown in fig. 2.
Compound a is example 21 of patent WO2018119224 a1, with the structure:
Figure GDA0003709489340001553
the NFAT reporter gene result shows that the compound can activate the NFAT signal channel inhibition caused by PD-1/PD-L1 combination, and the activity is better than that of the control compound A.
Example 276: pharmacokinetic experiment of rat
SD female rats were 3 animals kept for at least 3 days before the test to acclimatize. Animals were fasted overnight and had free access to water prior to dosing.
The experimental steps are as follows:
1. the compound was prepared into 1mg/ml solution with 5% DMSO, 10% Solutol and 85% physiological saline, respectively.
2. The prepared solution was administered to 3 rats by oral gavage (10 mg/kg).
3. 100 microliters of rat tail vein blood was taken at 5, 15, 30 minutes, 1, 2, 4, 8, 24 hours, placed in EDTA anticoagulation tubes, and placed on ice.
4. Plasma was extracted by centrifugation at 8000rpm at 4 degrees for 5 minutes within 30 minutes after blood sample acquisition.
5. Rat plasma of 20 microliters was taken, 60 microliters of ACN solution (containing 50ng/ml isopropyl alcohol, 200ng/ml tolbutamide and 500ng/ml Die) was added, vortex mixing was performed, low-temperature centrifugation (4 ℃) was performed for 10 minutes (13000rpm) after vortex mixing, 50 microliters of supernatant and 150 microliters of deionized water were added to a 96-well plate, and 2 microliters was taken for LC-MS/MS analysis after shaking mixing for 10 minutes.
The experimental results are as follows:
TABLE 2 results of the plasma concentration test for oral administration (10mg/kg) in rats
Numbering C max Number of C max
052 ++ 200 142ng/ml
083 ++ 236 ++
094 251ng/ml 251 ++
107 430ng/ml 255 ++
108 ++ 261 344ng/ml
119 1105ng/ml 265 290ng/ml
158 1900ng/ml Compound A 22ng/ml
168 1108ng/ml
Note: b is C max ≤100ng/ml；++:100ng/ml<C max <300ng/ml；+++:300ng/ml≤C max ；
Compound a is example 21 of patent WO2018119224 a1, having the following structure:
Figure GDA0003709489340001561
the results show that the compounds of the invention are orally absorbed and superior to the control compound a.

Claims (14)

1. A compound having the structure of formulae III-A-III-G or III-A 'to III-G':
Figure FDA0003709489330000011
Figure FDA0003709489330000021
or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof;
wherein:
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 、R 3 Each independently selected from H, F, C 1 ～C 3 Alkyl radical, C 1 ～C 3 An alkoxy group;
when G is 1 Is NR 6 When, G 2 Is CR 7 R 7 ，CR 7 R 7 Two of R 7 May be different;
when G is 1 Is CR 6 R 6 When, G 2 Is NR 7 ，CR 6 R 6 Two of R 6 May be different;
R 4 selecting H, F, methyl, deuterated methyl, ethyl, cyano and hydroxyethyl;
R 5 ，R 6 ，R 7 Are respectively and independently selected from H, halogen and C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Hydroxyalkyl radical, C 3 -C 10 Cycloalkyl group, 3-to 10-membered heterocyclic group, C (O) R b 、-(C 1 -C 6 Alkyl) OR b 、-(C 1 -C 6 Alkyl) -C (O) R b 、-SO 2 R b (ii) a Wherein R is b Independently selected from H, OH, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Hydroxyalkyl, C 3 -C 10 Cycloalkyl and 3-to 10-membered heterocyclic group;
or, two adjacent R 5 Form a ring with an adjacent atom, the ring being C 3 -C 10 Cycloalkyl and 3-to 10-membered heterocyclic group;
R 8 h, methyl, ethyl, cyano, F, hydroxyethyl; or two R 8 When substituted on two adjacent carbon atoms, form a cyclopropyl group; or two R 5 When substituted on one carbon atom, form a cyclopropyl group;
m is independently selected from an integer of 0-4;
R 9 selected from H, Cl, methyl, ethyl, F, cyano;
L 1 selected from O, NH, CH 2 、S、SO 2 、CO、-NHCH(CF 3 )-、-CH(CF 3 )NH-、
Figure FDA0003709489330000022
Figure FDA0003709489330000023
-NHCF 2 -、
Figure FDA0003709489330000024
-OCH(CF 3 )-；
Said R is 10 、R 11 、R 13 、R 14 Each independently selected from H, F, Cl, cyano, C 1 ～C 3 Alkyl radical, C 1 ～C 3 Alkoxy and 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-to 5-membered cycloalkyl substituted C 1 ～C 3 Alkoxy, C containing one or more deuterium atoms 1 ～C 3 Alkoxy, one or more fluorine substituted C 1 ～C 3 Alkoxy, phenyl, C 3 ～C 6 A cycloalkyl group; the substituted phenyl is cyano-substituted phenyl Methyl-substituted phenyl or hydroxy-substituted phenyl; the substituted pyridine is cyano-substituted pyridine, methyl-substituted pyridine or hydroxyl-substituted pyridine;
R 12 is selected from
Figure FDA0003709489330000031
Figure FDA0003709489330000032
Figure FDA0003709489330000041
J 1 N, CR';
J 2 is CR ', CR' R ', N, NR', O, S, C (O), S (O) 2 ；
J 3 Is CR ' R ', NR ', O, S, C (O), S (O) 2 ；
J 2 、J 3 Not NR', O, S, C (O), S (O) 2 (ii) a Wherein J 2 、J 3 Can be a double bond or a single bond;
when J 1 When is N, J 2 、J 3 Not NR', O, S, C (O), S (O) 2 ；
R' is independently selected from H, halogen and C 1 -C 6 Alkyl radical, C 1 -C 6 A haloalkyl group;
r' is independently selected from H, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 3 -C 6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl ring, OR '", NR'" R '", wherein in R'", both R '"may be different, each R'" being independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 A haloalkyl group;
one H or two H of R ', R' may be replaced by said R 8 Substituted, with two or more R's on the A ring 8 When a substituent is present, each R 8 May be different;
r is an integer of 0 to 4;
s is an integer of 0 to 3.
2. The compound of claim 1, wherein:
X 1 is CR 1 ，X 2 Is CR 2 ，X 3 Is CR 3 。
3. The compound of claim 1, wherein:
G 1 Is NR 6 ，G 2 Is CR 7 R 7 ；
m is 0, 1 or 2.
4. The compound of claim 1, wherein:
Figure FDA0003709489330000051
part is selected from
Figure FDA0003709489330000052
Figure FDA0003709489330000053
5. The compound of claim 1, wherein:
a is selected from
Figure FDA0003709489330000061
Figure FDA0003709489330000062
R 5 、R 6 、R 7 Each independently selected from H, F, methyl, deuterated methyl, ethyl, cyano, hydroxyethyl, acetyl, hydroxyisopropyl, hydroxyisobutylmethoxyethyl, oxetanyl, hydroxypropylMethylsulfonyl, cyclobutyl sulfonyl, dihydroxyisopropyl, fluoroethyl, fluoroisopropyl, isopropyl, fluoromethyl, oxacyclohexyl, cyclopentyl, carboxyethyl, oxacyclobutyl, methoxyethyl, isopropyl ester group; or, two adjacent R 5 And the adjacent atoms form a ring, and the ring is cyclopropyl or oxetanyl.
6. Compound according to claim 1, characterized in that it is one or more of the following compounds:
Figure FDA0003709489330000063
Figure FDA0003709489330000071
Figure FDA0003709489330000081
Figure FDA0003709489330000091
Figure FDA0003709489330000101
Figure FDA0003709489330000111
Figure FDA0003709489330000121
Figure FDA0003709489330000131
Figure FDA0003709489330000141
Figure FDA0003709489330000151
Figure FDA0003709489330000161
Figure FDA0003709489330000171
Figure FDA0003709489330000181
Figure FDA0003709489330000191
Figure FDA0003709489330000201
Figure FDA0003709489330000211
Figure FDA0003709489330000221
Figure FDA0003709489330000231
or a stereoisomer of the above compound or a mixture of stereoisomers of the above compound or a pharmaceutically acceptable salt of the above compound.
7. Compound according to claim 1, characterized in that said salt is citrate, fumarate, oxalate, acetate, tartrate, maleate, malate, lactate, succinate, camphorsulfonate, citrate, benzenesulfonate, glutamate, aspartate, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, hydrohalite, nitrate, carbonate, sulfate, phosphate.
8. A pharmaceutical composition comprising one or more of the compounds of any one of claims 1 to 7.
9. A pharmaceutical formulation comprising one or more of the compounds of any one of claims 1 to 6.
10. The pharmaceutical formulation of claim 9, comprising a tablet, powder, capsule, injectable formulation, granular formulation, spray.
11. Use of a compound as claimed in any one of claims 1 to 6 for the manufacture of a medicament for the treatment of a disease, disorder or condition that benefits from the inhibition of PD1 or PD-L1 activity, alone or in combination with other medicaments.
12. The use of claim 11, wherein the other drug is selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulator, a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent, an anti-fibrotic agent, radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and an antiproliferative agent.
13. The use of claim 11, wherein the disease, disorder or condition is selected from the group consisting of infectious diseases, immune diseases, inflammatory diseases and cancer.
14. The use of claim 13, wherein the disease, disorder or condition is selected from the group consisting of: melanoma, esophageal tumor, lymphoma, prostate carcinoma, synovioma, meningioma, sarcoma, sepsis, biliary tract tumor, thymus tumor, adrenal cancer, merkel cell carcinoma, neural tumor, leukemia, multiple myeloma, myelodysplastic syndrome, lung cancer, mesothelioma, breast cancer, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, ductal adenocarcinoma of the pancreas, head and neck cancer, hepatitis a, hepatitis b, hepatitis c, hepatitis d, bone cancer, skin cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, small intestine cancer, cancer of the endocrine system, urinary tract cancer, penile cancer, bladder cancer, kidney cancer, ureter cancer, spinal cord axis tumor, pituitary adenoma, epidermoid carcinoma, asbestos stasis, papillary carcinoma, cystadenocarcinoma, transitional cell carcinoma, choriocarcinoma, embryonal carcinoma, adenoma pleomorphis, renal tubular adenoma, leiomyoma, rhabdomyoma, hemangioma, lipoma and fibroma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory enteritis, autoimmune hemolytic anemia, ankylosing spondylitis, pemphigus, urticaria, asthma, psoriasis, chronic obstructive airway disease, dermatitis, alopecia.
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