Compounds targeting p53 mutations

Abstract

The present disclosure provides a class of compounds useful for restoring the wild-type function of the mutant p53, pharmaceutical compositions containing the compounds, and methods of treating cell proliferative diseases, such as cancer, using the compounds of the disclosure. The compound has a structure as shown in a formula (I-C). # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicinal chemistry, and particularly relates to compounds for restoring the wild-type function of mutant p53, pharmaceutical compositions containing the compounds, and methods for treating cell proliferative diseases such as cancer using the compounds of the present disclosure. Background Art

[0002] The tumor suppressor gene protein p53 is a transcription factor composed of 393 amino acids and exists in the form of a tetramer in vivo. It can respond to cellular stresses such as UV radiation, hypoxia, oncogene activation, and DNA damage, and inhibit tumorigenesis and development through multiple mechanisms such as the initiation of apoptosis, maintenance of genomic stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis. In normal cells, p53 is maintained at a low level by a series of regulatory factors. For example, MDM2 is a key negative regulator of p53 and can mediate the degradation of p53. Under various cellular stress conditions such as DNA damage, oncogene activation, telomere erosion, and ribonucleotide depletion, the N-terminal domain of p53 is phosphorylated by protein kinases, resulting in the activation of p53, which can then transduce upstream stress signals. The activation of p53 can induce the endogenous apoptosis pathway, the exogenous apoptosis pathway, cell cycle arrest, senescence, and DNA repair. Studies have found that the p53 tumor suppressor gene plays a crucial role in the occurrence and development of cancer. The p53 protein is encoded by the TP53 gene, and the mutation rate of this gene in cancer patients is as high as 50%. Its mutation is an important driving force for the occurrence, development, treatment resistance, and poor prognosis of cancer.

[0003] The high-frequency TP53 mutations found in tumor cells may be caused by selective pressure that contributes to the survival of mutant cells that evade tumor suppression. Most TP53 cancer mutations occur in the DNA-binding core domain of the protein, which consists of a central β-sandwich structure formed by two antiparallel β-sheets and serves as the basic scaffold for the DNA-binding surface. The DNA-binding surface is composed of two β-turn loops (L2 and L3) stabilized by zinc ions and a loop-fold-helix motif. These structural elements together form an extended DNA-binding surface rich in positively charged amino acids and form specific contacts with various p53 response elements. p53 Y220C is one of the most common p53 mutation types, in which tyrosine (Tyr) at position 220 is changed to cysteine (Cys), resulting in an overall conformational change, reduced protein thermal stability, and loss of its DNA-binding ability, thereby causing p53 to lose its normal transcriptional regulatory function. At the same time, the Y220C mutation results in a unique surface crack region locally. Compounds that bind to and occupy this region can stabilize the p53 structure and restore the wild-type conformation of p53, which provides the possibility for targeted drug development.

[0004] Although a large number of prior arts currently disclose compounds that can restore the wild-type p53 DNA-binding activity, there are few molecules in the clinical stage, and all are in the early clinical stage. Therefore, developing a new class of compounds for restoring the wild-type function of mutant p53 has great research significance. Summary of the Invention

[0005] The purpose of the present disclosure is to provide a class of compounds for restoring the wild-type function of mutant p53, pharmaceutical compositions containing the compounds, and the application of the compounds in the treatment of cancer.

[0006] The present disclosure provides a compound represented by formula (I-C), a pharmaceutically acceptable salt thereof, and its stereoisomers.

[0007]

[0008] Wherein,

[0009] Z is selected from N or CR 4 ;

[0010] Structural unit Selected from Where R 9 Is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, R 10 Is selected from hydrogen, halogen, C 1-4An alkyl group, p is selected from 0, 1, 2, 3;

[0011] R 1 is selected from C 1-4 haloalkyl;

[0012] M is selected from O, S(O)2 or NR 2 ;

[0013] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or wherein the C 1-4 alkyl may further optionally be substituted by 1-3 groups selected from the following: hydroxyl, halogen, C 1-4 alkoxy, deuterium atom;

[0014] R 3 is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3, where ring B is cyclobutane, R Ba is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, r is selected from 1, 2, 3; ring C is C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, R Ca is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, q is selected from 1, 2, 3;

[0015] R 4 , R 5 , R 6 , R 7 are each independently selected from H, C 1-4 alkoxy;

[0016] and / or R 6 , R 7 and the atoms connected thereto cyclize into a 5-6 membered heterocyclic group, 5-6 membered heteroaryl, wherein the 5-6 membered heterocyclic group, 5-6 membered heteroaryl may optionally be substituted by s R 6a ; R 6a is selected from hydrogen, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, deuterium, -C 1-4 alkylene-C 1-4 alkoxy, -C 1-4Alkylene-OH; or two adjacent Rs 6a Or two Rs attached to the same carbon 6a Together with the atoms to which it is attached form a C 3-6 Cycloalkyl, wherein said C 3-6 The cycloalkyl may optionally be substituted with t Rs 6b : R 6b Selected from hydrogen, hydroxy, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl; s is selected from 0, 1, 2 or 3; t is selected from 0, 1, 2 or 3;

[0017] And / or R 3 、R 4 And together with the atoms to which it is attached cyclize to form a substituted or unsubstituted 5- to 6-membered heterocyclic group;

[0018] And / or R 4 、R 5 And together with the atoms to which it is attached cyclize to form a substituted or unsubstituted 5- to 6-membered heterocyclic group, a substituted or unsubstituted 5- to 6-membered cycloalkyl group;

[0019] R 8 Each independently selected from C 1-4 Alkyl, halogen or C 1-4 Alkoxy, n is selected from 0, 1, 2, 3 or 4;

[0020] R 11 Selected from hydrogen, deuterium, C 1-4 Alkyl;

[0021] R 12 Selected from hydrogen, deuterium, C 1-4 Alkyl;

[0022] And, when R 3 、R 4 And together with the atoms to which it is attached cyclize to form a 5- to 6-membered heterocyclic group, R 7 Is not hydrogen or R 6 Is not methoxy;

[0023] When R 3 Is -S(O)2CH3, -S(O)2CF3, When, R 7 Is not hydrogen or R 6 Is not methoxy.

[0024] The present disclosure provides a compound represented by formula (I-B), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof,

[0025]

[0026] Among them,

[0027] structural unit is selected from wherein R 9 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, R 10 is selected from hydrogen, halogen, C 1-4 alkyl, and p is selected from 0, 1, 2, 3;

[0028] R 1 is selected from C 1-4 haloalkyl;

[0029] M is selected from O, S(O)2 or NR 2 ;

[0030] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or wherein the C 1-4 alkyl may further optionally be substituted by 1-3 groups selected from the following: hydroxyl, halogen, C 1-4 alkoxy, deuterium atom;

[0031] R 3 is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3, where ring B is cyclobutane, R Ba is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, r is selected from 1, 2, 3; ring C is C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, R Ca is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, q is selected from 1, 2, 3;

[0032] R 4 、R 5 、R 6 、R 7 are each independently selected from H, C 1-4 alkoxy;

[0033] and / or R 6 、R 7Cyclize with the atoms connected thereto to form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group and the 5-6 membered heteroaryl group may be optionally substituted by 1, 2 or 3 R 6a ; R 6a is selected from hydrogen, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl; or two adjacent R 6a and the atoms connected thereto together form a C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl may be optionally substituted by 1, 2 or 3 of the following groups: hydrogen, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl;

[0034] and / or R 3 , R 4 and the atoms connected thereto together cyclize to form a substituted or unsubstituted 5-6 membered heterocyclic group;

[0035] and / or R 4 , R 5 and the atoms connected thereto together cyclize to form a substituted or unsubstituted 5-6 membered heterocyclic group, a substituted or unsubstituted 5-6 membered cycloalkyl group;

[0036] R 8 are each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, and n is selected from 0, 1, 2, 3 or 4;

[0037] R 11 is selected from hydrogen, deuterium, C 1-4 alkyl;

[0038] R 12 is selected from hydrogen, deuterium, C 1-4 alkyl;

[0039] And, when R 3 , R 4 and the atoms connected thereto together cyclize to form a 5-6 membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy;

[0040] When R 3 is -S(O)2CH3, -S(O)2CF3, , R 7 is not hydrogen or R 6 is not methoxy.

[0041] The present disclosure provides a compound represented by formula (I-A), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof.

[0042]

[0043] Wherein,

[0044] The structural unit is selected from wherein R 9 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, R 10 is selected from hydrogen, halogen, C 1-4 alkyl, and p is selected from 0, 1, 2, 3;

[0045] R 1 is selected from C 1-4 haloalkyl;

[0046] M is selected from O, S(O)2 or NR 2 ;

[0047] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or wherein the C 1-4 alkyl may further optionally be substituted by 1 - 3 groups selected from the following: hydroxyl, halogen, C 1-4 alkoxy, deuterium atom;

[0048] R 3 is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3, where ring B is cyclobutane, R Ba is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, r is selected from 1, 2, 3; ring C is C 3-6 cycloalkyl, 5 - 6 membered heteroaryl, 4 - 6 membered heterocycloalkyl, R Ca is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, q is selected from 1, 2, 3;

[0049] R 4 , R 5 , R 6 , R 7 are each independently selected from H, C 1-4 alkoxy;

[0050] and / or R 6 、R 7 and the atoms connected thereto cyclize into a substituted or unsubstituted 5- or 6-membered heterocyclic group, a substituted or unsubstituted 5- or 6-membered heteroaryl group;

[0051] and / or R 3 、R 4 and the atoms connected thereto cyclize into a substituted or unsubstituted 5- or 6-membered heterocyclic group;

[0052] and / or R 4 、R 5 and the atoms connected thereto cyclize into a substituted or unsubstituted 5- or 6-membered heterocyclic group, a substituted or unsubstituted 5- or 6-membered cycloalkyl group;

[0053] R 8 are each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, and n is selected from 0, 1, 2, 3 or 4;

[0054] And when R 3 、R 4 and the atoms connected thereto cyclize into a 5- or 6-membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy;

[0055] When R 3 is -S(O)2CH3, -S(O)2CF3, then R 7 is not hydrogen or R 6 is not methoxy.

[0056] The present disclosure provides a compound represented by formula (I-A), a pharmaceutically acceptable salt thereof and a stereoisomer thereof,

[0057]

[0058] wherein,

[0059] The structural unit is selected from wherein R 9 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, R 10 is selected from hydrogen, halogen, C 1-4 alkyl, and p is selected from 0, 1, 2, 3;

[0060] R 1 is selected from C 1-4 haloalkyl;

[0061] M is selected from O, S(O)2 or NR 2 ;

[0062] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or wherein the C 1-4 alkyl may further optionally be substituted by 1 - 3 groups selected from the following: hydroxyl, halogen, C 1-4 alkoxy, deuterium atom;

[0063] R 3 is selected from where ring B is cyclobutane, R Ba is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, r is selected from 1, 2, 3; ring C is C 3-6 cycloalkyl, 5 - 6 - membered heteroaryl, 4 - 6 - membered heterocycloalkyl, R Ca is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, q is selected from 1, 2, 3;

[0064] R 4 、R 5 、R 6 、R 7 are each independently selected from H, C 1-4 alkoxy;

[0065] and / or R 6 、R 7 and the atoms connected thereto cyclize to form a substituted or unsubstituted 5 - 6 - membered heterocyclic group, a substituted or unsubstituted 5 - 6 - membered heteroaryl;

[0066] and / or R 3 、R 4 and the atoms connected thereto cyclize to form a substituted or unsubstituted 5 - 6 - membered heterocyclic group;

[0067] and / or R 4 、R 5 and the atoms connected thereto cyclize to form a substituted or unsubstituted 5 - 6 - membered heterocyclic group, a substituted or unsubstituted 5 - 6 - membered cycloalkyl;

[0068] R 8 are each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, n is selected from 0, 1, 2, 3 or 4;

[0069] And when R 3 , R 4 and the atom connected thereto cyclize into a 5- to 6-membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy;

[0070] When R 3 is , R 7 is not hydrogen or R 6 is not methoxy.

[0071] The present disclosure provides a compound represented by formula (I-A), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof,

[0072]

[0073] wherein,

[0074] The structural unit is selected from wherein R 9 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, R 10 is selected from hydrogen, halogen, C 1-4 alkyl, and p is selected from 0, 1, 2, 3;

[0075] R 1 is selected from C 1-4 haloalkyl;

[0076] M is selected from O, S(O)2 or NR 2 ;

[0077] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or wherein the C 1-4 alkyl may be further optionally substituted with 1 to 3 groups selected from the following: hydroxyl, halogen, C 1-4 alkoxy,, deuterium atom;

[0078] R 3 is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0079] R 4 , R 5 , R 6 , R 7 are each independently selected from H, C 1-4 alkoxy;

[0080] and / or R 6 、R 7 and the atoms connected thereto are cyclized into a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group;

[0081] and / or R 3 、R 4 and the atoms connected thereto are cyclized into a 5- to 6-membered heterocyclic group;

[0082] and / or R 4 、R 5 and the atoms connected thereto are cyclized into a 5- to 6-membered heterocyclic group or a 5- to 6-membered cycloalkyl group;

[0083] R 8 are each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, and n is selected from 0, 1, 2, 3 or 4;

[0084] And when R 3 、R 4 and the atoms connected thereto are cyclized into a 5- to 6-membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy;

[0085] When R 3 is -S(O)2CH3, -S(O)2CF3, then R 7 is not hydrogen or R 6 is not methoxy.

[0086] The present disclosure provides a compound represented by formula ((I), a pharmaceutically acceptable salt thereof and its stereoisomers:

[0087]

[0088] Wherein,

[0089] The structural unit is selected from

[0090] R 1 is selected from C 1-4 haloalkyl;

[0091] M is selected from O, S(O)2 or NR 2 ;

[0092] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or Wherein the C 1-4 alkyl may further optionally be substituted by 1 to 3 groups selected from the following: hydroxyl, halogen, C 1-4Alkoxy, deuterium atom;

[0093] R 3 Selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3, where ring B is cyclobutane, R Ba is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, r is selected from 1, 2, 3; ring C is C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, R Ca is halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, q is selected from 1, 2, 3;

[0094] R 4 、R 5 、R 6 、R 7 are each independently selected from H, C 1-4 alkoxy;

[0095] and / or R 6 、R 7 and the atoms connected thereto cyclize into a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, where the 5-6 membered heterocyclic group and the 5-6 membered heteroaryl group may be optionally substituted by 1, 2 or 3 R 6a ; R 6a is selected from hydrogen, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl; or two adjacent R 6a and the atoms connected thereto together form a C 3-6 cycloalkyl, where the C 3-6 cycloalkyl may be optionally substituted by 1, 2 or 3 of the following groups: hydrogen, hydroxyl, amino, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl;

[0096] and / or R 3 、R 4 and the atoms connected thereto cyclize into a substituted or unsubstituted 5-6 membered heterocyclic group;

[0097] and / or R 4 、R 5Cyclize with the atoms connected thereto to form a substituted or unsubstituted 5- to 6-membered heterocyclic group or a substituted or unsubstituted 5- to 6-membered cycloalkyl group;

[0098] R 8 Each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, and n is selected from 0, 1, 2, 3 or 4;

[0099] And when R 3 、R 4 and the atoms connected thereto cyclize to form a substituted or unsubstituted 5- to 6-membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy;

[0100] When R 3 is -S(O)2CH3, -S(O)2CF3, then R 7 is not hydrogen or R 6 is not methoxy.

[0101] The present disclosure provides a compound of formula ((I), a pharmaceutically acceptable salt thereof and a stereoisomer thereof:

[0102]

[0103] Wherein,

[0104] The structural unit is selected from

[0105] R 1 is selected from C 1-4 haloalkyl;

[0106] M is selected from O, S(O)2 or NR 2 ;

[0107] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or wherein the C 1-4 alkyl may further optionally be substituted by 1 to 3 groups selected from the following: hydroxyl, halogen, C 1-4 alkoxy, deuterium atom;

[0108] R 3 is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3, where ring B is cyclobutane, R Bais halogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, r is selected from 1, 2, 3; ring C is C 3-6 cycloalkyl, 5- or 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, R Ca is halogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, q is selected from 1, 2, 3;

[0109] R 4 、R 5 、R 6 、R 7 are each independently selected from H, C 1-4 alkoxy;

[0110] and / or R 6 、R 7 and the atoms connected thereto together cyclize to form a substituted or unsubstituted 5- or 6-membered heterocyclic group, a substituted or unsubstituted 5- or 6-membered heteroaryl;

[0111] and / or R 3 、R 4 and the atoms connected thereto together cyclize to form a substituted or unsubstituted 5- or 6-membered heterocyclic group;

[0112] and / or R 4 、R 5 and the atoms connected thereto together cyclize to form a substituted or unsubstituted 5- or 6-membered heterocyclic group, a substituted or unsubstituted 5- or 6-membered cycloalkyl;

[0113] R 8 are each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, n is selected from 0, 1, 2, 3 or 4;

[0114] And, when R 3 、R 4 and the atoms connected thereto together cyclize to form a 5- or 6-membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy;

[0115] When R 3 is -S(O)2CH3, -S(O)2CF3, then R 7 is not hydrogen or R 6 is not methoxy.

[0116] The present disclosure provides a compound represented by formula ((I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof:

[0117]

[0118] wherein,

[0119] the structural unit is selected from

[0120] R 1 is selected from C 1-4 haloalkyl;

[0121] M is selected from O, S(O)2 or NR 2 ;

[0122] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or wherein said C 1-4 alkyl may further optionally be substituted by 1 - 3 groups selected from the following: hydroxyl, halogen, C 1-4 alkoxy, deuterium atom;

[0123] R 3 is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0124] R 4 、R 5 、R 6 、R 7 are each independently selected from H, C 1-4 alkoxy;

[0125] and / or R 6 、R 7 and the atoms connected thereto cyclize to form a 5 - 6 membered heterocyclic group, 5 - 6 membered heteroaryl;

[0126] and / or R 3 、R 4 and the atoms connected thereto cyclize to form a 5 - 6 membered heterocyclic group;

[0127] and / or R 4 、R 5 and the atoms connected thereto cyclize to form a 5 - 6 membered heterocyclic group, 5 - 6 membered cycloalkyl;

[0128] R 8 are each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, and n is selected from 0, 1, 2, 3 or 4;

[0129] And when R3 , R 4 When R and the atoms connected thereto cyclize into a 5- or 6-membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy;

[0130] When R 3 is -S(O)2CH3, -S(O)2CF3, then R 7 is not hydrogen or R 6 is not methoxy.

[0131] The present disclosure provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof,

[0132]

[0133] wherein,

[0134] The structural unit is selected from

[0135] R 1 is selected from C 1-4 haloalkyl;

[0136] M is selected from O, S(O)2, or NR 2 ;

[0137] R 2 is selected from C 1-4 alkyl, -C(O)CH3, or wherein the C 1-4 alkyl may be further optionally substituted with 1-3 substituents selected from hydroxy, halogen, C 1-4 alkoxy;

[0138] R 3 is selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3,

[0139] R 4 , R 5 , R 6 , R 7 are each independently selected from H, C 1-4 alkoxy;

[0140] and / or R 6 , R 7 and the atoms connected thereto cyclize into a 5- or 6-membered heterocyclic group, a 5- or 6-membered heteroaryl;

[0141] and / or R 3 , R4 Cyclize with the atom connected thereto to form a 5- or 6-membered heterocyclic group;

[0142] and / or R 4 、R 5 Cyclize with the atom connected thereto to form a 5- or 6-membered heterocyclic group, a 5- or 6-membered cycloalkyl group;

[0143] R 8 Each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, and n is selected from 0, 1, 2, 3 or 4;

[0144] And, when R 3 、R 4 Cyclize with the atom connected thereto to form a 5- or 6-membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy;

[0145] When R 3 is -S(O)2CH3, -S(O)2CF3, then R 7 is not hydrogen or R 6 is not methoxy.

[0146] The present disclosure provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof and its stereoisomers,

[0147]

[0148] wherein,

[0149] The structural unit is selected from

[0150] R 1 is selected from C 1-4 haloalkyl;

[0151] M is selected from O, S(O)2 or NR 2 ;

[0152] R 2 is selected from C 1-4 alkyl, -C(O)CH3 or wherein the C 1-4 alkyl may further optionally be substituted by 1-3 substituents selected from hydroxy, halogen, C 1-4 alkoxy;

[0153] R 3 is selected from -S(O)2CH3,

[0154] R 4, R 5 , R 6 , R 7 are each independently selected from H, C 1-4 alkoxy;

[0155] and / or R 6 , R 7 and the atoms connected thereto cyclize to form a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group;

[0156] and / or R 3 , R 4 and the atoms connected thereto cyclize to form a 5- to 6-membered heterocyclic group;

[0157] and / or R 4 , R 5 and the atoms connected thereto cyclize to form a 5- to 6-membered heterocyclic group or a 5- to 6-membered cycloalkyl group;

[0158] R 8 are each independently selected from C 1-4 alkyl, halogen or C 1-4 alkoxy, and n is selected from 0, 1, 2, 3 or 4;

[0159] And when R 3 , R 4 and the atoms connected thereto cyclize to form a 5- to 6-membered heterocyclic group, R 7 is not hydrogen or R 6 is not methoxy.

[0160] In some embodiments of the present disclosure, Z is selected from CR 4 , R 4 as defined above.

[0161] In some embodiments of the present disclosure, ring C is selected from

[0162] In some embodiments of the present disclosure, R Ba is selected from fluorine, hydroxyl, methyl.

[0163] In some embodiments of the present disclosure, R Ca is selected from fluorine, hydroxyl, methyl.

[0164] The structural unit is selected from

[0165] The structural unit is selected from

[0166] In some embodiments of the present disclosure, R 6 and R 7or R 3 and R 4 or R 4 and R 5 The 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, 5-6 membered cycloalkyl group formed by cyclization together with the atom(s) connected thereto may optionally be substituted by 1, 2, or 3 of the following groups: C 1-6 alkyl, hydroxy, amino, methylamino, methoxy.

[0167] In some embodiments of the present disclosure, R 3 is selected from -S(O)2CH3,

[0168] In some embodiments of the present disclosure, R 3 is selected from -S(O)2CH3,

[0169] In some embodiments of the present disclosure, R 3 is selected from

[0170] In some embodiments of the present disclosure, R 3 is selected from

[0171] In some embodiments of the present disclosure, R 3 is selected from

[0172] In some embodiments of the present disclosure, R 1 is selected from CF3CH2-.

[0173] In some embodiments of the present disclosure, R 9 is selected from hydrogen, halogen.

[0174] In some embodiments of the present disclosure, R 9 is selected from hydrogen, fluorine.

[0175] In some embodiments of the present disclosure, R 10 is selected from hydrogen, halogen.

[0176] In some embodiments of the present disclosure, R 10 is selected from hydrogen, fluorine.

[0177] In some embodiments of the present disclosure, the structural unit is selected from

[0178] In some embodiments of the present disclosure, the structural unit is selected from

[0179] In some embodiments of the present disclosure, R 2 is selected from methyl, ethyl, isopropyl, tert-butyl, -CD3,

[0180] In some embodiments of the present disclosure, R 2 is selected from methyl, ethyl, isopropyl, tert-butyl,

[0181] In some embodiments of the present disclosure, R 2 is selected from

[0182] In some embodiments of the present disclosure, R 2 is selected from -CD3.

[0183] In some embodiments of the present disclosure, R 2 is selected from

[0184] In some embodiments of the present disclosure, R 8 is selected from F.

[0185] In some embodiments of the present disclosure, R 6 is selected from methoxy.

[0186] In some embodiments of the present disclosure, R 6a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, -CH2OCH3, -CH2OH.

[0187] In some embodiments of the present disclosure, R 7a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, -CH2OCH3, -CH2OH.

[0188] In some embodiments of the present disclosure, R 6 , R 7 and the atoms connected thereto cyclize to form wherein R 6a , s are as defined above.

[0189] In some embodiments of the present disclosure, R 6 , R 7 and the atoms connected thereto cyclize to form

[0190] In some embodiments of the present disclosure, R 6 , R 7Cyclize with the atoms connected thereto into

[0191] In some embodiments of the present disclosure, R 6 、R 7 Cyclize with the atoms connected thereto into

[0192] In some embodiments of the present disclosure, R 6 、R 7 Cyclize with the atoms connected thereto into

[0193]

[0194] In some embodiments of the present disclosure, R 6 、R 7 Cyclize with the atoms connected thereto into Wherein R 6a 、R 6b 、s、t are defined as above.

[0195] In some embodiments of the present disclosure, R 6 、R 7 Cyclize with the atoms connected thereto into

[0196] In some embodiments of the present disclosure, R 6 、R 7 Cyclize with the atoms connected thereto into

[0197] In some embodiments of the present disclosure, R 3 、R 4 Cyclize with the atoms connected thereto into

[0198] In some embodiments of the present disclosure, R 3 、R 4 Cyclize with the atoms connected thereto into

[0199] In some embodiments of the present disclosure, R 3 、R 4 Cyclize with the atoms connected thereto into

[0200] In some embodiments of the present disclosure, R 3 、R 4Cyclize together with the atoms connected thereto to form

[0201] In some embodiments of the present disclosure, R 4 、R 5 Cyclize together with the atoms connected thereto to form

[0202] In some embodiments of the present disclosure, the structural unit is selected from wherein, R 3 、R 4 、R 5 、R 6 、R 6a 、s are as defined above.

[0203] In some embodiments of the present disclosure, the structural unit is selected from

[0204]

[0205] In some embodiments of the present disclosure, the structural unit is selected from

[0206] In some embodiments of the present disclosure, the structural unit is selected from

[0207] In some embodiments of the present disclosure, the structural unit is selected from

[0208] In some embodiments of the present disclosure, the structural unit is selected from

[0209]

[0210] In some embodiments of the present disclosure, the structural unit is selected from

[0211] In some embodiments of the present disclosure, the structural unit is selected from

[0212] In some embodiments of the present disclosure, the structural unit is selected from wherein R 3 , R 4 , R 5 , R 6a , s, R 6b , t are defined as above.

[0213] In some embodiments of the present disclosure, the structural unit is selected from

[0214] In some embodiments of the present disclosure, the structural unit is selected from

[0215] In some embodiments of the present disclosure, the structural unit is selected from

[0216] In some embodiments of the present disclosure, the structural unit is selected from

[0217] In some embodiments of the present disclosure, the structural unit is selected from wherein R 2 , R 8 , n are defined as above.

[0218] In some embodiments of the present disclosure, the structural unit is selected from

[0219] In some embodiments of the present disclosure, the structural unit is selected from

[0220] In some embodiments of the present disclosure, the structural unit is selected from In some embodiments of the present disclosure, the structural unit is selected from

[0221] In some embodiments of the present disclosure, the structural unit is selected from

[0222] In some embodiments of the present disclosure, the structural unit selected from

[0223] In some embodiments of the present disclosure, the structural unit selected from

[0224] In some embodiments of the present disclosure, the structural unit selected from

[0225] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof and stereoisomers thereof are selected from the compounds, pharmaceutically acceptable salts thereof and stereoisomers thereof shown below,

[0226]

[0227] wherein, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n, R 6a , R 6b , s, t are as defined above.

[0228] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof and stereoisomers thereof are selected from the compounds, pharmaceutically acceptable salts thereof and stereoisomers thereof shown in formula (II),

[0229]

[0230] wherein, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n are as defined above.

[0231] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof and stereoisomers thereof are selected from the compounds, pharmaceutically acceptable salts thereof and stereoisomers thereof shown in formula (III),

[0232]

[0233] wherein, R 2 , R 3 , R 8 , n are as defined above.

[0234] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (IV), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0235]

[0236] wherein R 2 、R 3 、R 8 、n are as defined above.

[0237] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (V), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0238]

[0239] wherein R 2 、R 3 are as defined above.

[0240] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (VI), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0241]

[0242] wherein R 2 、R 3 are as defined above.

[0243] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (VII), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0244]

[0245] wherein R 2 、R 3 are as defined above.

[0246] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (VIII), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0247]

[0248] wherein R 2 、R 3 、R8 , n is defined as above.

[0249] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (IX), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0250]

[0251] wherein, R 2 , R 3 is defined as above.

[0252] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (A-IV), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0253]

[0254] wherein, wherein, R 2 , R 3 , R 8 , n, R 6a , s is defined as above.

[0255] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (A-VI), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0256]

[0257] wherein, wherein, R 2 , R 3 , R 6a , s is defined as above.

[0258] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (A-VIII), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0259]

[0260] wherein, wherein, R 2 , R 3 , R 6b , R 8 , n, t is defined as above.

[0261] In some embodiments of the present disclosure, the compound of formula (I), pharmaceutically acceptable salt thereof, and stereoisomers thereof are selected from the compounds of formula (A-IX), pharmaceutically acceptable salts thereof, and stereoisomers thereof,

[0262]

[0263] wherein, R 2 , R 3 , R 6b , t are as defined above.

[0264] In some embodiments of the present disclosure, the structural unit is selected from wherein, R 3 , R 4 , R 5 , R 6a , s are as defined above.

[0265] In some embodiments of the present disclosure, the structural unit is selected from wherein, R 3 , R 4 , R 5 , R 6b , t are as defined above.

[0266] In some embodiments of the present disclosure, the structural unit is selected from

[0267] In some embodiments of the present disclosure, the structural unit is selected from

[0268] In some embodiments of the present disclosure, the structural unit is selected from

[0269] In some embodiments of the present disclosure, the structural unit is selected from

[0270] The present disclosure also provides the following compounds, pharmaceutically acceptable salts thereof, and stereoisomers thereof, wherein the compound is selected from any of the following structures,

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] The present disclosure also provides the following compounds, pharmaceutically acceptable salts thereof, and stereoisomers thereof, wherein the compounds are selected from any of the following structures:

[0278]

[0279]

[0280]

[0281] The present disclosure also provides the following compounds, pharmaceutically acceptable salts thereof, and stereoisomers thereof, wherein the compounds are selected from any of the following structures:

[0282]

[0283]

[0284]

[0285] The present disclosure also provides the following compounds, pharmaceutically acceptable salts thereof, and stereoisomers thereof, wherein the compounds are selected from any of the following structures:

[0286]

[0287]

[0288]

[0289] The present disclosure also provides a pharmaceutical composition comprising (preferably in a therapeutically effective amount) the above-mentioned compounds, pharmaceutically acceptable salts or stereoisomers thereof, and a pharmaceutically acceptable carrier.

[0290] The present disclosure also provides the use of the above-mentioned compounds, pharmaceutically acceptable salts or stereoisomers thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating p53 mutation-mediated cancers.

[0291] The present disclosure also provides the above-mentioned compounds, pharmaceutically acceptable salts or stereoisomers thereof, or the above-mentioned pharmaceutical composition for treating p53 mutation-mediated cancers.

[0292] The present disclosure also provides a method for treating p53 mutation-mediated cancers, which comprises administering to a patient a therapeutically effective amount of the above-mentioned compounds, pharmaceutically acceptable salts or stereoisomers thereof, or the above-mentioned pharmaceutical composition.

[0293] In certain embodiments of the present invention, in the pharmaceutical composition, the content of the compound, stereoisomer or its pharmaceutically acceptable salt is selected from 0.1 mg to 1000 mg.

[0294] In certain embodiments of the present invention, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0295] In some embodiments of the present disclosure, in the above uses and methods, the p53 mutation is the p53 Y220C mutation.

[0296] In some embodiments of the present disclosure, in the above uses and methods, the cancer is selected from solid tumors. Preferably, the solid tumors are selected from gastric cancer, liver cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, endometrial cancer, colorectal cancer, pancreatic cancer, ovarian cancer, etc. carrying the p53 Y220C mutation.

[0297] Technical effects

[0298] The compounds of the present disclosure have good DNA binding activity and good selectivity for cells with the Y220C mutation.

[0299] Description and definitions

[0300] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood according to its ordinary meaning.

[0301] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0302] The term "pharmaceutically acceptable salt" refers to a derivative prepared from the compounds of the present disclosure and a relatively non-toxic acid or base. These salts can be prepared during the synthesis, separation, and purification of the compound, or the free form of the purified compound alone can be reacted with a suitable acid or base. When the compound contains a relatively acidic functional group, it reacts with an alkali metal, alkaline earth metal hydroxide, or organic amine to obtain a base addition salt, including cations based on alkali metals and alkaline earth metals, as well as non-toxic ammonium, quaternary ammonium, and amine cations, and also includes salts of amino acids, etc. When the compound contains a relatively basic functional group, it reacts with an organic acid or inorganic acid to obtain an acid addition salt.

[0303] The term "pharmaceutically acceptable carrier" refers to a medium that is generally acceptable in the art for delivering a bioactive agent to an animal, particularly a mammal, and includes, depending on the mode of administration and the nature of the dosage form, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants. Pharmaceutically acceptable carriers are formulated within the purview of one of ordinary skill in the art based on a number of factors. These include, but are not limited to: the type and nature of the active agent being formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media as well as a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers include many different components and additives, and such additional components included in a formulation for a variety of reasons (such as stabilizing the active agent, binders, etc.) are well known to one of ordinary skill in the art.

[0304] The term "effective prophylactic or therapeutic amount" means an amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof that is sufficient to treat a disorder with a reasonable benefit / risk ratio applicable to any medical treatment and / or prophylaxis. It should be recognized, however, that the total daily dosage of the compounds or pharmaceutically acceptable salts and compositions of formula I of the present disclosure must be decided by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed; and like factors well known in the medical arts.

[0305] The compounds of the present disclosure exist as geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereoisomers, racemic mixtures and other mixtures, and all such mixtures are within the scope of the present disclosure.

[0306] The compounds of the present disclosure exist as "tautomers", and the term "tautomer" refers to a type of functional group isomer that has different points of attachment through the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers.

[0307] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0308] The term "diastereomer" refers to stereoisomers in which a molecule has two or more chiral centers and the relationship between the molecules is non-mirror image.

[0309] The term "cis-trans isomer" refers to the configuration that exists when the double bond or the single bond of the ring carbon atom in a molecule cannot rotate freely.

[0310] Unless otherwise specified, the wedge solid line bond and the wedge dashed line bond are used to represent the absolute configuration of a stereocenter, and the straight solid line bond and the straight dashed line bond are used to represent the relative configuration of the stereocenter.

[0311] The compounds of the present invention and their salts may also exist in the form of solvates, such as hydrates, and the present invention includes various solvates and mixtures thereof.

[0312] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has the advantages of reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All isotope composition transformations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0313] The stereoisomers of the compounds disclosed in the present invention can be prepared by chiral synthesis, chiral reagents or other conventional techniques. For example, one enantiomer of a certain compound disclosed in the present invention can be prepared by asymmetric catalysis technology or chiral auxiliary derivative technology. Or by chiral resolution technology, a compound with a single stereoconfiguration can be obtained from the mixture. Or directly prepared using a chiral starting material. The separation of optically pure compounds in the present disclosure is usually accomplished using preparative chromatography, with a chiral chromatographic column, to achieve the purpose of separating chiral compounds.

[0314] The absolute stereoconfiguration of a compound can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method, and the absolute configuration of the compound can also be confirmed by the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Or after resolution, the stereoconfiguration is determined by comparison with a product with a determined absolute configuration. Compounds labeled as "unknown absolute configuration" in this article are usually obtained by chiral preparative SFC to resolve a racemic compound into a single isomer, and then characterized and tested.

[0315] The term "optionally" means that it can be substituted or not, unless otherwise specified. The type and number of substituents can be arbitrary on the basis of being chemically achievable. For example, the term "optionally substituted by one or more R d " means that it can be substituted by one or more R d or not substituted by R d .

[0316] When any variable (such as R d ) appears more than once in the composition or structure of a compound, its definition in each case is independent. For example, means that the cyclopentyl group is substituted by 3 R d , and each R d has independent options.

[0317] When the bond of a substituent can cross - link to two atoms on a ring, this substituent can be bonded to any atom on this ring. For example, the structural unit means that the substituent R1 can be substituted at any position on the benzene ring.

[0318] When it is not specified which atom of the listed substituents is connected to the compound included but not specifically mentioned in the chemical structure formula, this substituent can be bonded through any of its atoms. For example, pyrazole as a substituent means that any carbon atom or nitrogen atom on the pyrazole ring is connected to the group to be substituted; when appears in the structure, it means that this atom is the bonding atom. For example means that the N atom on the morpholine ring is the bonding atom.

[0319] Unless otherwise specified, "ring" means saturated, partially saturated or unsaturated monocyclic and polycyclic rings. "Polycyclic" includes spiro rings, fused rings or bridged rings. Representative "rings" include substituted or unsubstituted heterocyclic groups, cycloalkyl groups, heterocycloalkyl groups, cycloalkenyl groups, heterocycloalkenyl groups, cycloalkynyl groups, heterocycloalkynyl groups, aryl groups or heteroaryl groups. The term "hetero" represents substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, also called heteroatomic groups. The heteroatoms are generally selected from N, O, S, P. The oxidized forms generally include NO, P(O), SO, S(O)2. The nitrogen atom can be substituted, i.e., NR (R is H or other substituents defined in the text); the number of atoms on the ring is usually defined as the ring member number. For example, "3 - 6 - membered heterocycloalkyl" means a ring formed by 3 - 6 atoms arranged in a ring, and each ring optionally contains 1 - 3 heteroatoms and / or heteroatomic groups, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR, and each ring is optionally substituted by the R group, where R is the group defined in the text.

[0320] Unless otherwise specified, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group. Cycloalkyl is preferably a C 3-8 monocyclic alkyl group, more preferably a C 3-6 monocyclic alkyl group. Examples of these monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0321] Unless otherwise specified, "heterocyclic group" refers to a non-aromatic monocyclic or polycyclic ring containing a certain number of heteroatoms and / or heteroatomic groups. The ring can be saturated or partially saturated. The heteroatoms and / or heteroatomic groups are generally selected from N, O, S, NO, SO, S(O)2, P(O), and NR, where the carbon atoms in the heterocycle are optionally oxo-substituted, i.e., form -C(O)-. "Heterocyclic group" is preferably a 3- to 8-membered monocyclic heterocyclic group, more preferably a 5- to 6-membered monocyclic heterocyclic group. Examples of these monocyclic heterocyclic groups include, but are not limited to, oxiranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc. The "heterocyclic group" described herein can be optionally fused to a benzene ring, for example fused to a benzene ring to form the structure.

[0322] Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom or heteroatomic group (N, O, S, NO, SO, S(O)2 or NR). Preferred are 5- or 6-membered monocyclic heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl.

[0323] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched-chain saturated hydrocarbon group. Preferably a C 1-6 alkyl group, more preferably a C 1-4 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, n-hexyl, etc.

[0324] Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected by an oxygen bridge, i.e., a group obtained by replacing the hydrogen atom in a hydroxyl group with an alkyl group. Preferably a C 1-6 alkoxy group, more preferably a C 1-4 alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy.

[0325] Unless otherwise specified, the term "halogen" denotes a fluorine, chlorine, bromine, or iodine atom.

[0326] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. Preferably C 1-6 haloalkyl, more preferably C 1-4 haloalkyl. Examples of haloalkyl include but are not limited to fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc.

[0327] Specifically noted, combinations of all substituents and / or their variants herein are permitted only if such combinations result in stable compounds.

[0328] In the embodiments of the present disclosure, the naming of the title compound is converted from the compound structure by means of Chemdraw. If there is an inconsistency between the compound name and the compound structure, it can be determined by comprehensively considering relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structural formula shall prevail.

[0329] The preparation methods of some compounds in the present disclosure refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the cited preparation methods, the feed ratios of reactants, reaction solvents, reaction temperatures, etc. can be appropriately adjusted according to the differences in reactants.

[0330] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure.

[0331] The abbreviations used in the embodiments of the present disclosure and their corresponding chemical names are as follows:

[0332] Specific Embodiments

[0333] The compound structures of the present disclosure are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography - mass spectrometry (LC - MS), or ultra - performance liquid chromatography - mass spectrometry (UPLC - MS). NMR chemical shifts (δ) are given in parts per million (ppm). The NMR measurements are performed using a Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic instrument. The solvents for measurement are deuterated dimethyl sulfoxide (DMSO - d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and heavy water (D2O), and the internal standard is tetramethylsilane (TMS).

[0334] The determination of liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260-6125B single quadrupole mass spectrometer (the ion source was electrospray ionization).

[0335] The determination of ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (the ion source was electrospray ionization).

[0336] The determination of HPLC was performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0337] The preparative HPLC was performed using Waters 2555-2489 (10 μm, ODS 250 cm × 5 cm).

[0338] The starting materials in the embodiments of the present disclosure are known and commercially available, or can be synthesized by methods known in the art or according to such methods.

[0339] Unless otherwise specified, all reactions in the present disclosure were carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent was a dry solvent, and the reaction temperature unit was degrees Celsius.

[0340] I. Preparation Examples

[0341] Intermediate INT-1: 2-Iodo-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine

[0342]

[0343] Operating procedure:

[0344] Step A: Dissolve 4-nitro-1H-indole (10 g, 51.02 mmol) in N,N-dimethylformamide (100 mL), add sodium hydride (60%) (3.06 g, 76.53 mmol) at 0 °C and react for 30 minutes, then add benzenesulfonyl chloride (11.71 g, 66.33 mmol) and heat to room temperature and react for 16 hours. TLC monitoring showed that the raw materials disappeared. Quench the reaction solution by adding it to ice water, then extract twice with ethyl acetate. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain 15 g of 4-nitro-1-(phenylsulfonyl)-1H-indole by silica gel column chromatography.

[0345] MS(ESI) M / Z: 303.0 [M+H] + .

[0346] 1 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.3 Hz, 1H), 8.24 (dd, J = 8.5, 5.9 Hz, 2H), 8.15–8.06 (m, 2H), 7.76 (t, J = 7.5 Hz, 1H), 7.65–7.61 (m, 3H), 7.38 (dd, J = 3.7, 0.4 Hz, 1H).

[0347] Step B: Dissolve 2,4-dinitro-1-(phenylsulfonyl)-1H-indole (15 g, 49.67 mmol) in tetrahydrofuran (300 ml), cool to -78 °C and add lithium diisopropylamide (45 ml, 90 mmol, 1 M in THF) dropwise. Stir the reaction mixture at -78 °C for 1 hour and 20 minutes. Dissolve iodine (30 g, 118.20 mmol) in tetrahydrofuran and slowly add it to the reaction mixture. Continue the reaction at -78 °C for 40 minutes. LCMS monitoring shows that the product content is 67%. Quench the reaction mixture with saturated aqueous ammonium chloride solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 17.8 g of 2-iodo-4-nitro-1-(phenylsulfonyl)-1H-indole.

[0348] MS (ESI) M / Z: 427.9 [M-H] + 。

[0349] Step C: Dissolve 2-iodo-4-nitro-1-(phenylsulfonyl)-1H-indole (17.8 g, 41.59 mmol) in methanol (640 mL) and tetrahydrofuran (320 mL), add 3 mol / L sodium hydroxide solution (637 mL, 1913.14 mmol), and react at 80 °C for 1 hour. TLC and LCMS monitoring show that the starting materials have disappeared. Concentrate the reaction mixture under reduced pressure, adjust the pH to <7 with dilute hydrochloric acid, add water to the reaction mixture, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 10.68 g of 2-iodo-4-nitro-1H-indole.

[0350] MS (ESI) M / Z: 287.9 [M-H] + 。

[0351] Step D: Dissolve 2-iodo-4-nitro-1H-indole (10.68 g, 37.08 mmol) in tetrahydrofuran (20 mL). Add sodium hydride (60%) (7.42 g, 185.40 mmol) at 0 °C. Stir the reaction mixture at 0 °C for 30 minutes, then add 2,2,2-trifluoroethyl trifluoromethanesulfonate (43.01 g, 185.40 mmol). After the addition, warm the reaction mixture to room temperature and react for 2 hours. Monitor the disappearance of the starting material by LCMS. Quench the reaction mixture with saturated ammonium chloride, extract twice with ethyl acetate, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 9.6 g of 2-iodo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-indole.

[0352] MS(ESI) M / Z: 371.0 [M+H] + 。

[0353] Step E: Dissolve the compound 2-iodo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-indole (9.6 g, 25.95 mmol) in glacial acetic acid (100 mL), then add reduced iron powder (8.70 g, 155.70 mmol). React at 50 °C for 2 hours. Monitor the disappearance of the starting material by LCMS. Filter the reaction mixture, concentrate the filtrate under reduced pressure, adjust the pH of the solution with saturated aqueous sodium bicarbonate, extract twice with ethyl acetate, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain 7.3 g of 2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine.

[0354] MS(ESI) M / Z: 341.0 [M+H]+.

[0355] Step F: Dissolve 2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (7.3 g, 19.73 mmol) in glacial acetic acid (70 mL) and 1,2-dichloroethane (25 mL), then add 1-methylpiperidin-4-one (19.66 g, 98.65 mmol) and sodium cyanoborohydride (6.20 g, 98.65 mmol). Replace the air with nitrogen three times and react at 50 °C for 6 hours. Monitor the disappearance of the starting material by LCMS. Add water to the reaction mixture, extract twice with ethyl acetate, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 6.72 g of 2-iodo-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine.

[0356] MS(ESI) M / Z: 438.0 [M+H] + 。

[0357] Intermediate INT-3-A (N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine) and Intermediate INT-3-B (N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine)

[0358]

[0359]

[0360] Step A: Dissolve 2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (12 g, 35.3 mmol) and tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (38 g, 176.4 mmol) in glacial acetic acid (360 mL) and 1,2-dichloroethane (120 mL). Add sodium cyanoborohydride (11 g, 176.4 mmol) under an ice-water bath. Replace the gas with nitrogen three times and then heat the mixture to 50 °C and react for 16 hours. Conduct the reaction in parallel twice.

[0361] LCMS monitoring showed that the raw materials disappeared. Concentrate the reaction solution, add water, adjust the pH to 10 with sodium hydroxide solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 6.4 g of tert-butyl Z-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-yl)amino)piperidine-1-carboxylate.

[0362] Step B: Separate tert-butyl Z-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-yl)amino)piperidine-1-carboxylate (1 g) by chiral HPLC. Separation conditions: Chiral column AD 250*25 mm 10 μm; Mobile phase: MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), Flow rate: 70 mL / min, Gradient: 30%, Detection wavelength: 214 nm, to obtain 500 mg of tert-butyl (3S,4R)-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-yl)amino)piperidine-1-carboxylate (peak elution time 1.002 min) and 470 mg of tert-butyl (3R,4S)-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-yl)amino)piperidine-1-carboxylate (peak elution time 1.649 min).

[0363] (3S,4R)-tert-Butyl 3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate:

[0364] MS(ESI) M / Z: 542.10 [M+H] + 。

[0365] 1 H NMR(400 MHz, DMSO-d6) δ 7.25 (s, 1H), 6.93 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.51 (d, J = 8.9 Hz, 1H), 5.01 (q, J = 8.9 Hz, 2H), 4.84 (d, J = 49.0 Hz, 1H), 4.14 (d, J = 78.3 Hz, 2H), 3.80 (d, J = 29.5 Hz, 1H), 3.27–2.78 (m, 2H), 1.86–1.65 (m, 2H), 1.41 (s, 9H).

[0366] (3R,4S)-tert-Butyl 3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate:

[0367] MS(ESI) M / Z: 542.10 [M+H + 。

[0368] 1 H NMR(400 MHz, DMSO-d6) δ 7.25 (s, 1H), 6.93 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.51 (d, J = 8.8 Hz, 1H), 5.01 (q, J = 8.9 Hz, 2H), 4.84 (d, J = 49.9 Hz, 1H), 4.14 (d, J = 78.7 Hz, 2H), 3.80 (d, J = 29.8 Hz, 1H), 3.21–2.80 (m, 2H), 1.90–1.65 (m, 2H), 1.40 (d, J = 5.5 Hz, 9H).

[0369] The absolute configurations of the above two compounds were determined by comparison with compounds of known absolute configuration purchased.

[0370] Step C: Dissolve tert-butyl (3S,4R)-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate (400 mg, 0.74 mmol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL), and react at 25 °C for 1 hour.

[0371] LCMS monitoring showed the disappearance of the starting material. The reaction solution was concentrated to obtain 325 mg of crude product N-((3S,4R)-3-fluoropiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (INT-2-A), which was used directly in the next step without purification.

[0372] MS(ESI) M / Z: 442.0 [M+H] + 。

[0373] Dissolve tert-butyl (3R,4S)-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate (400 mg, 0.74 mmol) in dichloromethane (4 mL), then add trifluoroacetic acid (2 mL), and react at 25 °C for 1 hour.

[0374] LCMS monitoring showed the disappearance of the starting material. The reaction solution was concentrated to obtain 320 mg of crude product N-((3R,4S)-3-fluoropiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (INT-2-B), which was used directly in the next step without purification.

[0375] MS(ESI) M / Z: 442.0 [M+H + 。

[0376] Step D: Dissolve N-((3S,4R)-3-fluoropiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (1.2 g, 2.72 mmol) in methanol (15 mL), then successively add paraformaldehyde (408 mg, 13.61 mmol), sodium cyanoborohydride (857 mg, 13.61 mmol) and acetic acid (2.5 mL). Replace the gas with nitrogen three times and react at 50 °C for 3 hours.

[0377] LCMS monitoring showed the disappearance of the starting material. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 1.02 g of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (INT-3-A).

[0378] MS(ESI) m / z: 456.3 [M+H] + 。

[0379] 1 1H NMR (400 MHz, DMSO-d6) δ 7.26 (s, 1H), 6.97–6.88 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.24 (d, J = 7.7 Hz, 1H), 5.41 (d, J = 8.7 Hz, 1H), 5.06–4.92 (m, 2H), 3.65–3.48 (m, 0H), 3.10–2.98 (m, 1H), 2.90–2.75 (m, 2H), 2.19 (s, 3H), 2.15–2.04 (m, 1H), 2.01–1.86 (m, 1H), 1.75–1.65 (m, 1H).

[0380] In the same manner, 910 mg of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (INT-3-B) was synthesized from N-((3R,4S)-3-fluoropiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (1.29 g, 2.5 mmol).

[0381] MS(ESI) m / z: 456.2 [M+H]+.

[0382] 1H NMR (400 MHz, DMSO-d6) δ 7.26 (s, 1H), 6.97–6.88 (m, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.24 (d, J = 7.7 Hz, 1H), 5.44 (d, J = 8.7 Hz, 1H), 5.08–4.94 (m, 2H), 3.73–3.50 (m, 1H), 3.19–3.04 (m, 1H), 2.95–2.80 (m, 1H), 2.26 (s, 3H), 2.25–2.14 (m, 1H), 2.06–1.87 (m, 1H), 1.77–1.67 (m, 1H).

[0383] Example 1:

[0384] N-(1-Methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl)-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine

[0385] Reaction route:

[0386]

[0387] Step A: Dissolve 2,3-dihydrobenzofuran-7-amine (500 mg, 3.69 mmol) in N,N-dimethylformamide (10 mL), then add N-bromosuccinimide (725 mg, 4.06 mmol) portionwise at 0 °C. After the addition is complete, raise the reaction mixture to room temperature and react for 3 hours. TLC monitoring shows the disappearance of the starting material. Add water to the reaction mixture and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 500 mg of 4-bromo-2,3-dihydrobenzofuran-7-amine.

[0388] MS(ESI) M / Z: 214.0 [M+H] + .

[0389] Step B: Dissolve 4-bromo-2,3-dihydrobenzofuran-7-amine (300 mg, 1.41 mmol) in dimethyl sulfoxide (5 mL), add sodium methylsulfinate (288 mg, 2.81 mmol) and copper(I) iodide (134 mg, 0.71 mmol). After purging with nitrogen three times, react the reaction mixture at 120 °C for 16 hours. TLC monitoring shows the disappearance of the starting material. Add water to the reaction mixture and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 55 mg of 4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amine.

[0390] MS(ESI) M / Z: 214.1 [M+H] + 。

[0391] Step C: Dissolve 4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amine (50 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL), and successively add propargyl bromide (42 mg, 0.35 mmol) and potassium carbonate (17 mg, 0.12 mmol). After purging with nitrogen three times, react the reaction mixture at 50 °C for 16 hours. After LCMS monitoring shows the completion of the reaction, add water to the reaction mixture and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 40 mg of 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine.

[0392] MS(ESI) M / Z: 252.0 [M+H] + 。

[0393] Step D: Dissolve 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine (40 mg, 0.16 mmol) in dimethyl sulfoxide (2 mL), add INT-1 (58 mg, 0.13 mmol), then successively add copper(I) iodide (5.06 mg, 0.03 mmol), N,N-diisopropylethylamine (52 mg, 0.39 mmol), bis(triphenylphosphine)palladium(II) dichloride (19 mg, 0.03 mmol), displace with nitrogen three times, and react the reaction solution at 50 °C for 16 hours. LCMS monitoring shows the disappearance of the starting material. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by HPLC to obtain 22 mg of N-(1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine.

[0394] MS(ESI) M / Z: 561.5 [M+H]+.

[0395] 1H NMR (400 MHz, Methanol-d4) δ 7.34 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.92 (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.32 (d, J = 7.7 Hz, 1H), 4.76 (q, J = 8.8 Hz, 2H), 4.68 (t, J = 8.9 Hz, 2H), 4.37 (s, 2H), 3.77–3.59 (m, 1H), 3.52 (t, J = 8.9 Hz, 2H), 3.04 (s, 3H), 2.96–2.82 (m, 2H), 2.71 (s, 3H), 2.28–2.13 (m, 2H), 1.82–1.70 (m, 2H).

[0396] Example 2:

[0397] 1-(3-methoxy-4-(3-(1-methylpiperidin-4-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenyl)-4,5-dihydro-3H-isothiazol-1-oxide

[0398] Reaction route:

[0399]

[0400] Step A: Dissolve 4-fluoro-2-methoxy-1-nitrobenzene (15 g, 87.65 mmol) in N,N-dimethylformamide (150 mL), then successively add potassium carbonate (15.143 g, 109.56 mmol) and 3-mercaptopropan-1-ol (8.077 g, 87.65 mmol). The reaction mixture is reacted at 100 °C for 16 hours. TLC monitoring shows the disappearance of the starting material. The reaction mixture is cooled to room temperature, and LCMS monitoring shows the disappearance of the starting material. Water is added to the reaction mixture, and it is extracted twice with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain 23 g of 3-((3-methoxy-4-nitrophenyl)thio)propan-1-ol.

[0401] MS(ESI) M / Z: 244.0 [M+H] + 。

[0402] Step B: Dissolve 3-((3-methoxy-4-nitrophenyl)thio)propan-1-ol (1.628 g, 6.69 mmol) in dichloromethane (20 mL), add thionyl chloride (1.991 g, 16.73 mmol), and the reaction mixture is reacted at 40 °C for 3 hours. The reaction mixture is directly concentrated under vacuum to obtain 2.19 g of crude (3-chloropropyl) 3-methoxy-4-nitrophenyl sulfone, which is used directly in the next step without purification.

[0403] MS(ESI) M / Z: 261.02 [M+H] + 。

[0404] Step C: Dissolve (3-chloropropyl) 3-methoxy-4-nitrophenyl sulfone (2.190 g, 6.69 mmol) in anhydrous methanol (20 mL), and successively add iodobenzene diacetate (5.389 g, 16.73 mmol) and ammonium carbamate (980 mg, 12.55 mmol). The reaction mixture is reacted at room temperature for 2 hours. LCMS monitoring shows that about 32% is converted. Water is added to the reaction mixture, and it is extracted twice with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain 934 mg of 3-chloropropyl)(imino)(3-methoxy-4-nitrophenyl)-λ 6 sulfamide ketone.

[0405] MS(ESI) M / Z: 293.0 [M+H] + 。

[0406] Step D: For the compound 3-chloropropyl)(imino)(3-methoxy-4-nitrophenyl)-λ 6Sulfanone (934 mg, 3.19 mmol) was dissolved in ammonia water (20 mL), and the reaction solution was reacted at 80 °C for 2 hours. LCMS monitoring showed that the raw materials disappeared. The reaction solution was cooled to room temperature, water was added to the reaction solution, and it was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 642 mg of 1-(3-methoxy-4-nitrophenyl)-4,5-dihydro-3H-isothiazole 1-oxide.

[0407] MS(ESI) M / Z: 257.0 [M+H] + 。

[0408] Step E: 1-(3-Methoxy-4-nitrophenyl)-4,5-dihydro-3H-isothiazole-1-oxide (492 mg, 1.92 mmol) was dissolved in acetic acid (10 mL), and then iron powder (1.608 g, 28.79 mmol) was added. The reaction solution was reacted at 50 °C for 2 hours. LCMS monitoring detected the product signal. The reaction solution was filtered, concentrated under reduced pressure to remove acetic acid, adjusted to pH = 10 with aqueous sodium hydroxide solution, extracted twice with dichloromethane solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 324 mg of 1-(4-amino-3-methoxyphenyl)-4,5-dihydro-3H-isothiazole-1-oxide.

[0409] MS(ESI) M / Z: 227.0 [M+H] + 。

[0410] Step F: 1-(4-Amino-3-methoxyphenyl)-4,5-dihydro-3H-isothiazole-1-oxide (600 mg, 2.65 mmol) was dissolved in dichloromethane (15 mL), two drops of acetic acid were added dropwise, and then 3-(trimethylsilyl)propanal (335 mg, 2.65 mmol) was added. The reaction solution was reacted at 40 °C for 1 hour, and then sodium triacetoxyborohydride (2.248 g, 10.61 mmol) was added. The reaction solution was reacted at 35 °C for 16 hours. LCMS monitoring showed about 26% conversion. The reaction solution was cooled to room temperature, adjusted to pH = 10 with aqueous sodium hydroxide solution, extracted twice with dichloromethane solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 365 mg of 1-(3-methoxy-4-(3-(trimethylsilyl)propyl-2-yn-1-ylamino)phenyl)-4,5-dihydro-3H-isothiazole-1-oxide.

[0411] MS(ESI) M / Z: 337.1 [M+H] + 。

[0412] Step G: Dissolve 1-(3-methoxy-4-(3-(trimethylsilyl)prop-2-yn-1-ylamino)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide (365 mg, 1.08 mmol) in tetrabutylammonium fluoride (5 mL), and react the reaction solution at room temperature for 1 hour. LCMS monitoring shows the disappearance of the raw material. Concentrate the reaction solution, and purify the residue by HPLC to obtain 214 mg of 1-(3-methoxy-4-prop-2-ynylamino)phenyl)-4,5-dihydro-3H-isothiazole-1-oxide.

[0413] MS(ESI) M / Z: 265.0 [M+H + .

[0414] Step H: Dissolve 1-(3-methoxy-4-prop-2-ynylamino)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide (214 mg, 0.81 mmol) in dimethyl sulfoxide (3 mL). Sequentially add 2-iodo-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (295 mg, 0.67 mmol), copper(I) iodide (38 mg, 0.20 mmol), N,N-diisopropylethylamine (262 mg, 2.02 mmol) and bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.13 mmol). After purging with nitrogen three times, react the reaction solution at 50 °C for 16 hours. LCMS monitoring shows the disappearance of the raw material. Add water to the reaction solution, extract with dichloromethane twice, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by HPLC to obtain 24.4 mg of 1-(3-methoxy-4-(3-(1-methylpiperidin-4-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenyl)-4,5-dihydro-3H-isothiazole-1-oxide.

[0415] MS(ESI) M / Z: 574.3 [M+H] + .

[0416] 11H NMR (400 MHz, CD3OD) δ 7.69–7.54 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.99–6.89 (m, 2H), 6.67 (d, J = 8.2 Hz, 1H), 6.29 (d, J = 7.7 Hz, 1H), 4.81–4.70 (m, 2H), 4.39 (s, 2H), 3.94 (s, 3H), 3.91–3.72 (m, 3H), 3.55–3.34 (m, 4H), 2.97–2.90 (m, 2H), 2.57–2.36 (m, 1H), 2.34 (s, 3H), 2.31–2.20 (m, 3H), 2.14–2.04 (m, 2H), 1.69–1.51 (m, 2H).

[0417] Example 3:

[0418] 1-(7-(3-(4-(1-Methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)propyl-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl) phosphoran-1-oxide

[0419] Reaction route:

[0420]

[0421] Step A: Dissolve diethyl phosphite (1 g, 7.24 mmol) in ultradry THF (6 mL), slowly add allylmagnesium bromide (1 M in Et2O, 23.89 mL, 23.89 mmol) dropwise at 0 °C, and then stir at room temperature for 16 h. Monitor the disappearance of the starting materials by TLC. Pour the reaction mixture into a cold potassium carbonate solution, filter, wash the filter cake with ethanol, evaporate the filtrate to dryness, dissolve it in dichloromethane, filter again, and concentrate the filtrate under reduced pressure to obtain 848 mg of crude diallylphosphine oxide, which is used directly in the next step without purification.

[0422] 1 1H NMR (400 MHz, CD3OD) δ 5.95–5.76 (m, 1H), 5.38–5.25 (m, 2H), 2.80 (dd, J = 15.8, 7.4 Hz, 2H).

[0423] Step B: Dissolve the compound 7-amino-2,3-dihydrobenzofuran (1 g, 7.39 mmol) in DMF (5 mL), dissolve N-bromosuccinimide (1.38 g, 7.76 mmol) in DMF (3 mL) and slowly dropwise add it to the reaction solution at 0°C, and then react the reaction solution at 0°C for 3 hours. LCMS shows that the raw material disappears, and the reaction solution is poured into water, extracted twice with ethyl acetate, and the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is chromatographed on a silica gel column to obtain 1.4 g of 4-bromo-2,3-dihydrobenzofuran-7-amine.

[0424] MS (ESI) M / Z: 213.9 [M+H] + .

[0425] Step C: 4-bromo-2,3-dihydrobenzofuran-7-amine (2g, 9.3mmol) was dissolved in DMF (1mL), and diallylphosphine oxide (815mg, 14.0mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (646mg, 1.1mmol), potassium phosphate (2.96g, 14.0mmol), palladium acetate (209mg, 0.93mmol) were added in sequence, nitrogen was replaced three times, and microwave was reacted at 150°C for 30 minutes. Water was added to the reaction solution, and ethyl acetate was extracted twice, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was extracted with EA / NH4Cl, spin-dried, and scraped to obtain 500mg diallyl(7-amino-2,3-dihydrobenzofuran-4-yl)phosphine oxide.

[0426] MS (ESI) M / Z: 264.1 [M+H] + .

[0427] Step D: Diallyl (7-amino-2,3-dihydrobenzofuran-4-yl) phosphine oxide (268 mg, 1.02 mmol) was dissolved in dichloromethane (40 mL), Grubbs second generation catalyst (87 mg, 0.1 mmol) was added, nitrogen was replaced three times, and the reaction solution was reacted at 25° C. for 16 hours. LCMS monitored the disappearance of the raw material, the reaction solution was added with water, extracted twice with ethyl acetate, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by reverse phase (FA) to obtain 148.8 mg of 1-(7-amino-2,3-dihydrobenzofuran-4-yl)-2,5-dihydrophosphine-1-oxide.

[0428] MS (ESI) M / Z: 236.1 [M+H] + .

[0429] Step E: Dissolve 1-(7-amino-2,3-dihydrobenzofuran-4-yl)-2,5-dihydrophosphole-1-oxide (173 mg, 0.74 mmol) in a mixed solution of THF (5 mL) and methanol (5 mL). Add 10% palladium on carbon (86.63 mg, 0.081 mmol). Replace the air with nitrogen three times, and then replace it with hydrogen three times. Stir at room temperature for 2 hours under a hydrogen atmosphere. Monitor by LCMS until the raw material disappears. Filter the reaction solution to remove palladium on carbon, and concentrate the filtrate under reduced pressure to obtain 159 mg of 1-(7-amino-2,3-dihydrobenzofuran-4-yl)phosphole-1-oxide.

[0430] MS(ESI) M / Z: 238.1 [M+H] + 。

[0431] Step F: Dissolve 1-(7-amino-2,3-dihydrobenzofuran-4-yl)phosphole-1-oxide (41 mg, 0.17 mmol) in DMF (2 mL). Add potassium carbonate (11.75 mg, 0.085 mmol) and 3-bromopropyne (40.45 mg, 0.34 mmol) successively. After the addition, react the reaction solution at 50 °C for 16 h. Monitor by TLC for the formation of new spots. LCMS shows the presence of raw material and product. Add water to the reaction solution and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by reverse phase (FA) to obtain 23 mg of 1-(7-amino-2,3-dihydrobenzofuran-4-yl)phosphole-1-oxide.

[0432] MS(ESI) M / Z: 276.1 [M+H] + 。

[0433] Step G: Dissolve 1-(7-amino-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide (66 mg, 0.24 mmol) in DMSO (8 mL). Sequentially add 2-iodo-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (104.94 mg, 0.24 mmol), N,N-diisopropylethylamine (0.12 mL, 0.72 mmol), copper(I) iodide (22.85 mg, 0.12 mmol), and bis(triphenylphosphine)palladium(II) dichloride (25.27 mg, 0.036 mmol). After displacing the air with nitrogen three times, react the reaction mixture at 50 °C for 16 h. Monitor the disappearance of the starting materials by LCMS. Add water to the reaction mixture, extract twice with dichloromethane, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the residue by HPLC to obtain 22.73 mg of 1-(7-(3-(4-(1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl) phospholane-1-oxide.

[0434] MS(ESI) M / Z: 585.7 [M+H] + 。

[0435] 1 H NMR (400 MHz, CD3OD) δ 7.15–7.04 (m, 2H), 6.92 (s, 1H), 6.81 (dd, J = 8.2, 2.6 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 7.8 Hz, 1H), 4.75 (q, J = 8.8 Hz, 2H), 4.65 (t, J = 8.8 Hz, 2H), 4.35 (s, 2H), 3.82–3.67 (m, 1H), 3.56–3.45 (m, 2H), 3.42 (t, J = 8.7 Hz, 2H), 3.22–3.02 (m, 2H), 2.85 (s, 3H), 2.43–2.24 (m, 2H), 2.23–2.04 (m, 4H), 2.02–1.87 (m, 4H).

[0436] Example 4:

[0437] N-(1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine

[0438] Reaction route:

[0439]

[0440] Step A: Dissolve triethyl phosphonoacetate (30.3 g, 135.2 mmol) in ultradry tetrahydrofuran (150 mL). Add sodium hydride (2.4 g, 101.4 mmol) portionwise to the mixture at 0 °C. After reacting for 30 minutes, add 1-benzofuran-5-carbaldehyde (10 g, 67.6 mmol) to the mixture. Then continue stirring at room temperature for 2 hours. LCMS monitoring shows the disappearance of the starting materials. Quench the reaction mixture by adding saturated ammonium chloride, extract twice with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain 14.5 g of ethyl (Z)-3-(benzofuran-5-yl)acrylate.

[0441] MS(ESI) M / Z: 217.1 [M+H] + 。

[0442] Step B: Dissolve ethyl (Z)-3-(benzofuran-5-yl)acrylate (14.5 g, 67.1 mmol) in a mixed solution of tetrahydrofuran (50 mL), methanol (50 mL), and water (50 mL). Add sodium hydroxide (13.4 g, 335.64 mmol) and heat the mixture to 40 °C for 16 hours. LCMS monitoring shows the disappearance of the starting materials. Concentrate the reaction mixture, wash the residue with 2 M hydrochloric acid, precipitate a solid, and filter to obtain 12 g of (Z)-3-(benzofuran-5-yl)acrylic acid.

[0443] MS(ESI) M / Z: 189.1 [M+H] + 。

[0444] Step C: Dissolve (Z)-3-(benzofuran-5-yl)acrylic acid (12 g, 63.8 mmol) in acetic acid (100 mL). Add palladium on carbon (2 g, 1.9 mmol, 10%) and displace the air with hydrogen three times. React at room temperature for 16 hours. LCMS monitoring shows the disappearance of the starting materials. Filter the reaction mixture to remove palladium on carbon, and concentrate the filtrate to obtain 12 g of 3-(2,3-dihydrobenzofuran-5-yl)propanoic acid.

[0445] MS(ESI) M / Z: 192.21 [M-H] + 。

[0446] Step D: Dissolve 3-(2,3-dihydrobenzofuran-5-yl)propanoic acid (12 g, 62.5 mmol) in thionyl chloride (100 mL), and heat the mixture to 80 °C for reaction for 2 hours. After monitoring by TLC shows that the raw materials disappear, concentrate to remove thionyl chloride. Dissolve the residue in ultradry 1,2-dichloroethane (120 mL), and add aluminum trichloride (9.9 g, 75.0 mmol) portionwise at 0 °C. React at room temperature for 16 hours. LCMS monitoring shows that the raw materials disappear. Add water to the reaction solution, and extract with ethyl acetate. The combined organic phases are washed successively with 1 M hydrochloric acid, 1 N sodium hydroxide, water, and saturated brine. Dry and concentrate the organic phase, and obtain 2.6 g of 2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one by column chromatography.

[0447] MS(ESI) M / Z: 175.1 [M+H] + 。

[0448] Step E: Dissolve 2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (2.6 g, 14.9 mmol) in concentrated sulfuric acid (15 mL), and add concentrated nitric acid (1.38 g, 14.9 mmol, 68%) dropwise with stirring at 0 °C. React the obtained solution at 0 °C for 1 hour. LCMS monitoring shows that the raw materials disappear. Extract twice with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain 1.6 g of 8-nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one by silica gel column chromatography of the residue.

[0449] MS(ESI) M / Z: 220.1 [M+H] + 。

[0450] Step F: Dissolve 8-nitro-2,3,5,6-tetrahydro-7H-indeno[5,6-b]furan-7-one (1.6 g, 7.3 mmol) in methanol (20 mL), add methanesulfonic acid (1.4 g, 14.6 mmol) and palladium hydroxide / carbon (0.8 g, 1.2 mmol, 20%). Replace with hydrogen three times, and heat to 50 °C for reaction for 16 hours. LCMS shows that the reaction is complete. Filter the reaction solution to remove palladium carbon, concentrate the filtrate, dissolve the obtained residue in ethyl acetate, and wash successively with saturated sodium bicarbonate, brine, and water to obtain 960 mg of 3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine.

[0451] MS(ESI) M / Z: 176.1 [M+H] + 。

[0452] 11H NMR (400 MHz, DMSO-d6) δ 6.35 (s, 1H), 4.45 (t, J = 8.6 Hz, 2H), 4.33 (s, 2H), 3.05 (t, J = 8.5 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.02–1.90 (m, 2H).

[0453] Step G:

[0454] Dissolve 3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine (1.14 g, 6.51 mmol) in acetonitrile (30 mL), add N-bromosuccinimide (1.39 g, 7.81 mmol) under an ice-water bath, and react at 25 °C for 1.5 h. LCMS shows that the reaction is complete. Quench the reaction mixture with water, extract twice with ethyl acetate, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by HPLC (FA) reverse phase to obtain 700 mg of 4-bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine.

[0455] MS (ESI) M / Z: 254.0 [M+H] + .

[0456] Step H: Dissolve 4-bromo-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine (700 mg, 2.77 mmol) in methyl sulfoxide (10 mL), and successively add sodium methylsulfinate (565 mg, 5.54 mmol) and copper(I) iodide (264 mg, 1.39 mmol). React at 120 °C for 16 h under N2 protection. LCMS shows that the conversion of the starting material is about 65%. Dilute the reaction mixture with water, extract three times with ethyl acetate, wash the organic phase with water twice, dry, concentrate, and purify the residue by silica gel column chromatography to obtain 350 mg of 4-(methylsulfonyl)-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine.

[0457] MS (ESI) M / Z: 254.1 [M+H + .

[0458] Step J: Dissolve compound 4-(methylsulfonyl)-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine (300 mg, 1.19 mmol) in N,N-dimethylformamide (5 mL). Add sodium hydride (71 mg, 1.78 mmol) under an ice-water bath. After reacting at 0 °C for 30 minutes, add propargyl bromide (251 mg, 2.13 mmol). React at room temperature for 2 hours. LCMS shows that the conversion rate of the raw material is about 30%. Pour the reaction solution into water for quenching, extract it three times with ethyl acetate, dry the organic phase, concentrate it, and purify it by column chromatography to obtain 60 mg of 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine.

[0459] MS(ESI) M / Z: 292.1 [M+H + .

[0460] Step K: Dissolve compound 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-amine (60 mg, 0.21 mmol) in dimethyl sulfoxide (2 mL). Sequentially add 2-iodo-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (90 mg, 0.21 mmol), copper(I) iodide (29 mg, 0.15 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and bis(triphenylphosphine)palladium(II) dichloride (29 mg, 0.04 mmol). After displacing with nitrogen three times, react at 50 °C for 16 hours. LCMS monitoring shows that the raw material has disappeared. Add water to the reaction solution, extract it with ethyl acetate, dry the organic phase, concentrate it, and purify the residue by HPLC (FA) to obtain 45.60 mg of N-(1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-3,5,6,7-tetrahydro-2H-indeno[5,6-b]furan-8-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine.

[0461] MS(ESI) M / Z: 601.40 [M+H] + 。

[0462] 11H NMR (400 MHz, CD3OD) δ 7.06 (t, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.31 (d, J = 7.7 Hz, 1H), 4.72–4.55 (m, 4H), 4.49 (s, 2H), 3.67–3.53 (m, 1H), 3.48 (t, J = 8.8 Hz, 2H), 3.24–3.10 (m, 4H), 3.02 (s, 3H), 2.84 (t, J = 7.5 Hz, 2H), 2.77–2.65 (m, 2H), 2.60 (s, 3H), 2.22–2.05 (m, 4H), 1.79–1.63 (m, 2H).

[0463] Example 5:

[0464] (R)-N-(3,3-Difluoro-1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl)-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine

[0465] and

[0466] (S)-N-(3,3-Difluoro-1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl)-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine

[0467] Reaction route:

[0468]

[0469]

[0470] Step A: Dissolve compound 2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (1.19 g, 3.5 mmol) in glacial acetic acid (15 mL) and 1,2-dichloroethane (10 mL), then add tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (4.11 g, 17.5 mmol) and sodium cyanoborohydride (1.099 g, 17.5 mmol). Replace the air with nitrogen three times and react at 50 °C for 16 hours. LCMS monitoring shows that the raw materials disappear. Add water to the reaction solution and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain 1 g of tert-butyl 3,3-difluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate. The obtained product is separated by chiral HPLC. Separation conditions: chiral column OJ 250*25 mm 10 μm; mobile phase: MeOH / DEA, flow rate: 1.5 mL / min, gradient: 5% - 40%, detection wavelength: 214 nm, to obtain two intermediate compounds with a peak time of 2.501 min (500 mg) and a peak time of 2.789 min (300 mg), namely (R)-tert-butyl 3,3-difluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate and (S)-tert-butyl 3,3-difluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate.

[0471] MS(ESI)M / Z:560.10[M+H] + 。

[0472] Step B: Dissolve the compound with a peak time of 2.501 min obtained in Step A (500 mg, 0.89 mmol) in dichloromethane (5 mL), then add trifluoroacetic acid (2.5 mL). Replace the air with nitrogen three times and react at 25 °C for 1 hour. LCMS monitoring shows that the raw materials disappear. Concentrate the reaction solution to obtain 400 mg of N-(3,3-difluoropiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine of the corresponding stereoconfiguration, which is directly used in the next step without purification.

[0473] MS(ESI)M / Z:460.0[M+H] + 。

[0474] Step C: Dissolve N-(3,3-difluoropiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (400 mg, 0.87 mmol) with the corresponding stereoconfiguration obtained in Step B in methanol (10 mL), then successively add paraformaldehyde (130.5 mg, 4.35 mmol), sodium cyanoborohydride (273 mg, 4.35 mmol) and acetic acid (20 mg), displace with nitrogen three times, and react at 50 °C for 6 hours.

[0475] LCMS monitoring showed that the raw materials disappeared. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 168 mg of N-(3,3-difluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine with the corresponding configuration.

[0476] MS(ESI) M / Z: 473.9 [M+H] + 。

[0477] Step D: Dissolve N-(3,3-difluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (168 mg, 0.36 mmol) with the corresponding stereoconfiguration obtained in Step C in dimethyl sulfoxide (3 mL), successively add 4-(methylsulfonyl)-N-prop-2-yn-1-yl-2,3-dihydrobenzofuran-7-amine (90 mg, 0.36 mmol), copper iodide (34 mg, 0.18 mmol), N,N-diisopropylethylamine (139 mg, 1.08 mmol) and bis(triphenylphosphine)palladium dichloride (38 mg, 0.05 mmol), displace with nitrogen three times, and react at 50 °C for 16 hours.

[0478] LCMS monitoring showed that the raw materials disappeared. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the residue by HPLC preparative separation. Separation conditions: preparative column: Waters SUNFIRE C18 10um OBD 19*250mm, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 25%-40%, detection wavelength: 214 nm / 254 nm, to obtain 56.35 mg of (R)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (retention time: 10.49 min), and this compound is denoted as 5A:

[0479] MS(ESI) M / Z: 597.40 [M+H] + 。

[0480] 1 H NMR (400 MHz, CD3OD) δ 7.34 (d, J = 8.5 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 0.8 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 7.7 Hz, 1H), 4.80–4.72 (m, 2H), 4.68 (t, J = 8.8 Hz, 2H), 4.37 (s, 2H), 3.98–3.79 (m, 1H), 3.63–3.43 (m, 2H), 3.24–3.11 (m, 0H), 3.04 (s, 3H), 2.98–2.89 (m, 1H), 2.63–2.50 (m, 1H), 2.41 (s, 3H), 2.39–2.30 (m, 1H), 2.12–2.00 (m, 1H), 1.95–1.82 (m, 1H).

[0481] 300 mg of the compound with an elution time of 2.789 min obtained in step A was prepared successively by the same method as above to obtain 62.07 mg of N-(3,3-difluoro-1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl)-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine of the corresponding stereoconfiguration. Preparation column: Waters SUNFIRE C18 10um OBD 19*250 mm, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 25% - 40%, detection wavelength: 214 nm / 254 nm, retention time: 10.69 min. This compound is denoted as 5B:

[0482] MS(ESI) M / Z: 597.40 [M+H] + 。

[0483] 11H NMR (400 MHz, CD3OD) δ 7.34 (d, J = 8.5 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 0.8 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 4.75 (q, J = 8.8 Hz, 2H), 4.68 (t, J = 8.9 Hz, 2H), 4.37 (s, 2H), 3.98–3.82 (m, 1H), 3.52 (t, J = 8.9 Hz, 2H), 3.24–3.11 (m, 0H), 3.04 (s, 3H), 2.97–2.88 (m, 1H), 2.63–2.47 (m, 1H), 2.41 (s, 3H), 2.39–2.31 (m, 1H), 2.12–2.00 (m, 1H), 1.96–1.83 (m, 1H).

[0484] Example 6:

[0485] (S)-1-(3-Methoxy-4-((3-(4-((1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenyl)-4,5-dihydro-3H-isothiazol-1-oxide

[0486] and

[0487] (R)-1-(3-Methoxy-4-((3-(4-((1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenyl)-4,5-dihydro-3H-isothiazol-1-oxide

[0488] Reaction route:

[0489]

[0490] Step A: Dissolve 4-fluoro-2-methoxy-1-nitrobenzene (15 g, 87.65 mmol) in N,N-dimethylformamide (150 mL), then successively add potassium carbonate (15.143 g, 109.56 mmol) and 3-mercaptopropan-1-ol (8.077 g, 87.65 mmol), and react the reaction solution at 100 °C for 16 hours.

[0491] TLC monitoring showed the disappearance of the starting material. The reaction solution was cooled to room temperature. LCMS monitoring showed the disappearance of the starting material. Water was added to the reaction solution, and it was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 23 g of 3-((3-methoxy-4-nitrophenyl)thio)propan-1-ol.

[0492] MS(ESI) M / Z: 244.0 [M+H] + 。

[0493] Step B: Dissolve 3-((3-methoxy-4-nitrophenyl)thio)propanol (1.628 g, 6.69 mmol) in dichloromethane (20 mL), add thionyl chloride (1.991 g, 16.73 mmol), and react the reaction solution at 40 °C for 3 hours.

[0494] The reaction solution was directly concentrated under vacuum to obtain 2.19 g of crude (3-chloropropyl) 3-methoxy-4-nitrophenyl sulfone, which was used directly in the next step without purification.

[0495] MS(ESI) M / Z: 261.02 [M+H] + 。

[0496] Step C: Dissolve (3-chloropropyl) 3-methoxy-4-nitrophenyl sulfone (2.190 g, 6.69 mmol) in anhydrous methanol (20 mL), and successively add iodobenzene diacetate (5.389 g, 16.73 mmol) and ammonium carbamate (980 mg, 12.55 mmol). React the reaction solution at room temperature for 2 hours.

[0497] LCMS monitoring showed that approximately 32% was converted. Water was added to the reaction solution, and it was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 934 mg of (3-chloropropyl)(imino)(3-methoxy-4-nitrophenyl)-λ 6 aminosulfoxonium.

[0498] MS(ESI) M / Z: 293.0 [M+H] + 。

[0499] Step D: Dissolve (3-chloropropyl)(imino)(3-methoxy-4-nitrophenyl)-λ 6 aminosulfoxonium (934 mg, 3.19 mmol) in ammonia water (20 mL), and react the reaction solution at 80 °C for 2 hours.

[0500] LCMS monitoring showed the disappearance of the starting material. The reaction solution was cooled to room temperature, water was added to the reaction solution, and it was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 642 mg of 1-(3-methoxy-4-nitrophenyl)-4,5-dihydro-3H-isothiazole 1-oxide.

[0501] MS(ESI) M / Z: 257.0 [M+H] + 。

[0502] Step E: Dissolve 1-(3-methoxy-4-nitrophenyl)-4,5-dihydro-3H-isothiazole 1-oxide (492 mg, 1.92 mmol) in acetic acid (10 mL), and then add iron powder (1.608 g, 28.79 mmol). The reaction solution was reacted at 50 °C for 2 hours.

[0503] LCMS monitored the product signal. The reaction solution was filtered, concentrated under reduced pressure to remove acetic acid, the pH was adjusted with aqueous sodium hydroxide solution, and it was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 324 mg of 1-(4-amino-3-methoxyphenyl)-4,5-dihydro-3H-isothiazole 1-oxide.

[0504] MS(ESI) M / Z: 227.0 [M+H] + 。

[0505] Step F: Dissolve 1-(4-amino-3-methoxyphenyl)-4,5-dihydro-3H-isothiazole 1-oxide (600 mg, 2.65 mmol) in dichloromethane (15 mL), add two drops of acetic acid, and then add 3-(trimethylsilyl)propanal (335 mg, 2.65 mmol). The reaction solution was reacted at 40 °C for 1 hour, and then sodium triacetoxyborohydride (2.248 g, 10.61 mmol) was added. The reaction solution was reacted at 35 °C for 16 hours.

[0506] LCMS monitoring showed approximately 26% conversion. The reaction solution was cooled to room temperature, the pH was adjusted with aqueous sodium hydroxide solution, and it was extracted twice with dichloromethane solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 365 mg of 1-(3-methoxy-4-((3-(trimethylsilyl)prop-2-yn-1-yl)amino)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide.

[0507] MS(ESI) M / Z: 337.1 [M+H] + 。

[0508] Step G: Dissolve 1-(3-methoxy-4-((3-(trimethylsilyl)prop-2-yn-1-yl)amino)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide (365 mg, 1.08 mmol) in tetrabutylammonium fluoride (5 mL), and react the reaction solution at room temperature for 1 hour.

[0509] LCMS monitoring showed the disappearance of the starting material. The reaction solution was concentrated, and the residue was purified by HPLC reverse phase to obtain 214 mg of 1-(3-methoxy-4-prop-2-ynylamino)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide.

[0510] MS(ESI) M / Z: 265.0 [M+H] + 。

[0511] Step H: Dissolve 1-(3-methoxy-4-prop-2-ynylamino)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide (214 mg, 0.81 mmol) in dimethyl sulfoxide (3 mL). Then, successively add 2-iodo-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (295 mg, 0.67 mmol), copper(I) iodide (38 mg, 0.20 mmol), N,N-diisopropylethylamine (262 mg, 2.02 mmol) and bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.13 mmol). After purging with nitrogen three times, react the reaction solution at 50 °C for 16 hours. LCMS monitoring showed the disappearance of the starting material. Add water to the reaction solution, extract it twice with dichloromethane solution. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by prep-HPLC to obtain 27 mg of 1-(3-methoxy-4-((3-(4-((1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide. The obtained product was separated by chiral HPLC. Separation conditions: chiral column Whelk_o1(s.s) 4.6 * 150 mm 5 um; Mobile phase: n - Hexane:EtOH(0.2%DEA) = 50:50, Flow rate: 1.0 mL / min, Gradient: 5% - 40%, Detection wavelength: 254 nm, Obtained 2.59 mg with retention time of 24.433 min (denoted as 6A) and 5.09 mg with retention time of 16.330 min (denoted as 6B). The compound has no corresponding relationship with the compounds (S)-1-(3 - methoxy - 4 - ((3-(4 - ((1 - methylpiperidin - 4 - yl)amino)-1-(2,2,2 - trifluoroethyl)-1H - indol - 2 - yl)prop - 2 - yn - 1 - yl)aminoamino)phenyl)-4,5 - dihydro - 3H - isothiazole - 1 - oxide and (R)-1-(3 - methoxy - 4 - ((3-(4 - ((1 - methylpiperidin - 4 - yl)amino)-1-(2,2,2 - trifluoroethyl)-1H - indol - 2 - yl)prop - 2 - yn - 1 - yl)aminoamino)phenyl)-4,5 - dihydro - 3H - isothiazole - 1 - oxide.

[0512] Compound 6A:

[0513] MS(ESI) M / Z: 574.3 [M + H] +

[0514] 1 H NMR(400 MHz, CD3OD) δ 7.49(dd, J = 8.5, 2.1 Hz, 1H), 7.26(d, J = 2.1 Hz, 1H), 7.08(t, J = 8.0 Hz, 1H), 6.95(d, J = 8.5 Hz, 1H), 6.93(s, 1H), 6.71(d, J = 8.3 Hz, 1H), 6.32(d, J = 7.8 Hz, 1H), 4.83–4.69(m, 2H), 4.40(s, 2H), 3.92–3.83(m, 1H), 3.85–3.72(m, 1H), 3.54–3.35(m, 2H), 3.29–3.20(m, 2H), 2.92–2.72(m, 2H), 2.64(s, 3H), 2.54–2.38(m, 1H), 2.37–2.28(m, 1H), 2.27–2.14(m, 2H), 1.89–1.62(m, 2H).

[0515] Compound 6B:

[0516] MS(ESI) M / Z: 574.3 [M + H] +

[0517] 11H NMR (400 MHz, CD3OD) δ 7.49 (dd, J = 8.5, 2.1 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.93 (s, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.32 (d, J = 7.7 Hz, 1H), 4.78 (q, J = 8.9 Hz, 2H), 4.61 (s, 1H), 4.40 (s, 2H), 3.94 (s, 3H), 3.92–3.85 (m, 1H), 3.83–3.73 (m, 1H), 3.45–3.35 (m, 1H), 2.68 (s, 3H), 2.53–2.38 (m, 1H), 2.36–2.27 (m, 1H), 2.26–2.12 (m, 2H), 1.84–1.68 (m, 2H).

[0518] Example 7:

[0519] 5-(3-(4-(1-Methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)propyl-2-ynyl-1-amino)-2,3,7,8-tetrahydrobenzofuro[5,4-d]isothiazole 1,1-dioxide

[0520] Reaction route:

[0521]

[0522] Step A: Dissolve methyl 4-fluoro-7-nitro-2,3-dihydrobenzofuran-5-carboxylate (2 g, 8.30 mmol) in DMF (30 mL), then successively add potassium carbonate (3.4 g, 24.9 mmol) and benzyl mercaptan (1.5 g, 12.5 mmol). Replace the gas with nitrogen three times and react at 25 °C for 16 hours.

[0523] TLC plate detection showed that the raw materials disappeared. Add the reaction solution to ice water and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 1.5 g of methyl 4-(benzylthio)-7-nitro-2,3-dihydrobenzofuran-5-carboxylate.

[0524] MS (ESI) M / Z: 346.0 [M+H] + .

[0525] Step B: Dissolve NCS (4.7 g, 35.5 mmol) in acetonitrile (300 mL), add concentrated hydrochloric acid (7.5 mL, 90.3 mmol) at -10 °C, react the reaction solution at -10 °C for 30 minutes, then dissolve methyl 4-(benzylthio)-7-nitro-2,3-dihydrobenzofuran-5-carboxylate (1.5 g, 4.3 mmol) in acetonitrile (15 mL) and slowly add it dropwise to the reaction solution. Raise the reaction solution to room temperature and continue stirring for 1 hour.

[0526] LCMS showed that the raw materials disappeared. Concentrate the reaction solution, then add ammonia water (30 mL) and continue to react at 25 °C for 16 hours. After LCMS showed that most of the raw materials had reacted, filter the reaction solution, concentrate the filtrate, add ethanol (30 mL) to the residue, stir for 30 minutes and then filter. Collect the filter cake to obtain 2.02 g of crude product 5-nitro-7,8-dihydrobenzofuro[5,4-d]isothiazol-3(H)-one 1,1-dioxide, which is directly used for the next step without further purification.

[0527] MS(ESI) M / Z: 269.0 [M-H] - 。

[0528] 1 H NMR(400 MHz, DMSO-d6) δ 7.94 (s, 1H), 4.98 (t, J = 8.8 Hz, 2H), 3.42 (d, J = 4.4 Hz, 2H).

[0529] Step C: Dissolve the crude compound 5-nitro-7,8-dihydrobenzofuro[5,4-d]isothiazol-3(2H)-one 1,1-dioxide (2.02 g, 4.3 mmol) in methanol (15 mL) and tetrahydrofuran (15 mL), then add palladium on carbon (1.38 g, 13.0 mmol). After purging with nitrogen three times, pass hydrogen gas into the reaction solution and react at 25 °C for 2 hours.

[0530] LCMS monitoring showed that the raw materials disappeared. Filter the reaction solution to remove palladium on carbon, and concentrate the filtrate under reduced pressure to obtain 2.4 g of crude product 5-amino-7,8-dihydrobenzofuro[5,4-d]isothiazol-3(2H)-one 1,1-dioxide, which is directly used for the next step without further purification.

[0531] MS(ESI) M / Z: 241.0 [M+H] + 。

[0532] Step D: Dissolve 5-amino-7,8-dihydrobenzofuran[5,4-d]isothiazole-3(2H)-one 1,1-dioxide (2.4 g, 4.3 mmol) in THF (43 mL), then add borane tetrahydrofuran complex (1 M, 3 mL, 4.3 mmol), displace with nitrogen three times, and react at 70 °C for 16 hours.

[0533] LCMS monitoring showed the disappearance of the starting material. The reaction solution was quenched with methanol and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 250 mg of 5-amino-2,3,7,8-tetrahydrobenzofuran[5,4-d]isothiazole 1,1-dioxide.

[0534] MS(ESI) M / Z: 227.0 [M+H + .

[0535] Step E: Dissolve compound 5-amino-2,3,7,8-tetrahydrobenzofuran[5,4-d]isothiazole-1,1-dioxide (20 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL), add potassium carbonate (12 mg, 0.09 mmol) and 3-bromopropyne (21 mg, 0.18 mmol). React at 50 °C for 16 hours.

[0536] LCMS showed that the conversion rate of the starting material was about 20%. The reaction solution was poured into water for quenching, extracted with ethyl acetate three times, the organic phase was dried, concentrated, and purified by preparative plate to obtain 5 mg of 5-(prop-2-yn-1-ylamino)-2,3,7,8-tetrahydrobenzofuran[5,4-d]isothiazole 1,1-dioxide.

[0537] MS(ESI) M / Z: 265.1 [M+H] + .

[0538] Step F: Dissolve compound 5-(prop-2-yn-1-ylamino)-2,3,7,8-tetrahydrobenzofuran[5,4-d]isothiazole-1,1-dioxide (5 mg, 0.019 mmol) in dimethyl sulfoxide (2 mL), and successively add 2-iodo-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (8 mg, 0.019 mmol), copper(I) iodide (3 mg, 0.016 mmol), N,N-diisopropylethylamine (7 mg, 0.057 mmol) and bis(triphenylphosphine)palladium(II) dichloride (3 mg, 0.004 mmol). After displacing with nitrogen three times, react at 50 °C for 16 hours.

[0539] LCMS monitoring showed the disappearance of the starting material. The reaction solution was added with water, extracted with ethyl acetate, the organic phase was dried, concentrated, and the residue was purified by prep-HPLC to obtain 3.01 mg of 5-(3-(4-(1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)propyl-2-ynyl-1-amino)-2,3,7,8-tetrahydrobenzofuro[5,4-d]isothiazole 1,1-dioxide.

[0540] MS(ESI) M / Z: 574.4 [M+H] + 。

[0541] 1 H NMR(400 MHz, CD3OD) δ 7.09 (t, J = 8.0 Hz, 1H), 6.92 (s, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.65 (s, 1H), 6.33 (d, J = 7.8 Hz, 1H), 4.82–4.67 (m, 4H), 4.35 (s, 4H), 3.84–3.64 (m, 1H), 3.53–3.34 (m, 4H), 3.15–2.95 (m, 2H), 2.80 (s, 3H), 2.29–2.25 (m, 2H), 1.88–1.72 (m, 2H).

[0542] Example 8:

[0543] 5-(3-(4-(1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)propyl-2-ynyl-1-amino)-2,3,7,8-tetrahydrothieno[2,3-e]benzofuran-1,1-dioxide

[0544]

[0545] Step A: 2-Bromo-3-fluorophenol (105 g, 0.55 mol) was dissolved in acetonitrile (2.1 L), then potassium carbonate (229 g, 1.66 mol) and 1,2-dibromoethane (209 g, 1.11 mol) were added successively. After three replacements with nitrogen, the reaction was carried out at 85 °C for 16 hours.

[0546] TLC plate detection showed the disappearance of the starting material. The reaction solution was added to ice water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 123.2 g of 2-bromo-1-(2-bromoethoxy)-3-fluorobenzene.

[0547] 11H NMR (400 MHz, CDCl3) δ 7.29–7.15 (m, 1H), 6.80 (td, J = 8.3, 1.1 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.35 (t, J = 6.4 Hz, 2H), 3.69 (t, J = 6.4 Hz, 2H).

[0548] Step B: Dissolve 2-bromo-1-(2-bromoethoxy)-3-fluorobenzene (123.2 g, 0.42 mol) in THF (2.5 L), then slowly add n-butyllithium (1.6 M, 288 mL, 0.46 mol) dropwise at -78 °C, and then react the reaction mixture at -78 °C for 2 hours.

[0549] TLC plate detection showed that the raw materials disappeared. Add the reaction mixture to ice-cold saturated ammonium chloride solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 29.5 g of 4-fluoro-2,3-dihydrobenzofuran.

[0550] 1 1H NMR (400 MHz, DMSO-d6) δ 7.13 (dd, J = 14.3, 8.0 Hz, 1H), 6.69–6.57 (m, 2H), 4.60 (t, J = 8.7 Hz, 2H), 3.22 (t, J = 8.7 Hz, 2H).

[0551] Step C: Dissolve 4-fluoro-2,3-dihydrobenzofuran (29.5 g, 0.21 mol) in acetonitrile (300 mL), then add NBS (29.5 g, 0.24 mol), displace with nitrogen three times, and react at 25 °C for 1 hour.

[0552] TLC plate detection showed that the raw materials disappeared. Add the reaction mixture to ice water, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 40.5 g of 5-bromo-4-fluoro-2,3-dihydrobenzofuran.

[0553] 1 1H NMR (400 MHz, DMSO-d6) δ 7.38 (dd, J = 8.2, 7.7 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 4.64 (t, J = 8.8 Hz, 2H), 3.28 (t, J = 8.7 Hz, 2H).

[0554] Step D: Place compound 5-bromo-4-fluoro-2,3-dihydrobenzofuran (11 g, 50.9 mmol) in an autoclave, dissolve it in methanol (165 mL), then successively add triethylamine (25 g, 254.6 mol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (6.2 g, 7.6 mmol), displace with nitrogen three times, then introduce CO, and react at 140 °C for 16 hours.

[0555] TLC plate detection showed that the raw materials disappeared. Filter the reaction solution, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 7 g of methyl 4-fluoro-2,3-dihydrobenzofuran-5-carboxylate.

[0556] 1 1H NMR (400 MHz, DMSO-d6) δ 7.73 (t, J = 8.1 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 4.72 (t, J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.26 (t, J = 8.8 Hz, 2H).

[0557] Step E: Dissolve methyl 4-fluoro-2,3-dihydrobenzofuran-5-carboxylate (4.5 g, 18.7 mmol) in TFA (67.5 mL), then add sodium nitrite (2.58 g, 37.3 mmol) portionwise at 0 °C, displace with nitrogen three times, and react at 30 °C for 16 hours.

[0558] LCMS monitoring showed that the raw materials disappeared. Dilute the reaction solution with ethyl acetate, then adjust the pH with aqueous sodium hydroxide solution (1 M), extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 3.2 g of methyl 4-fluoro-7-nitro-2,3-dihydrobenzofuran-5-carboxylate.

[0559] 1 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 6.4 Hz, 1H), 5.00 (t, J = 8.7 Hz, 2H), 3.98–3.81 (m, 3H), 3.39 (t, J = 8.7 Hz, 2H).

[0560] Step F: Dissolve methyl 4-fluoro-7-nitro-2,3-dihydrobenzofuran-5-carboxylate (3.2 g, 13.3 mmol) in DMF (3 mL), then add sodium methanesulfinate (4.2 g, 39.9 mmol), displace with nitrogen three times, and react at 25 °C for 16 hours.

[0561] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.0 g of methyl 4-(methylsulfonyl)-7-nitro-2,3-dihydrobenzofuran-5-carboxylate.

[0562] MS(ESI) M / Z: 323.9 [M+Na] + 。

[0563] 1 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 4.97 (t, J = 8.8 Hz, 2H), 3.97 (s, 3H), 3.77 (t, J = 8.8 Hz, 2H), 3.38 (s, 3H).

[0564] Step G: Methyl 4-(methylsulfonyl)-7-nitro-2,3-dihydrobenzofuran-5-carboxylate (3.0 g, 10.0 mmol) was dissolved in THF (60 mL), and then sodium hydride (60%, 997 mg, 24.9 mmol) was added. After purging with nitrogen three times, the reaction was carried out at 25 °C for 16 h.

[0565] TLC plate detection showed the disappearance of the starting material. The reaction solution was diluted with ethyl acetate, the residue was filtered, the filter cake was rinsed with ethyl acetate, the filter cake was collected, then 50 mL of ethanol was added, stirred for 20 minutes and then filtered, the filter cake was rinsed with ethanol, and the filter cake was collected to obtain 1.77 g of 5-nitro-7,8-dihydrothieno[2,3-e]benzofuran-3(2H)-one-1,1-dioxide.

[0566] MS(ESI) M / Z: 268.0 [M-H] - 。

[0567] 1 1H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 5.14 (dd, J = 8.6, 6.8 Hz, 2H), 4.71 (d, J = 2.2 Hz, 2H), 3.58 (d, J = 7.2 Hz, 2H).

[0568] Step H: 5-Nitro-7,8-dihydrothieno[2,3-e]benzofuran-3(2H)-one-1,1-dioxide (1.77 g, 6.6 mmol) was dissolved in methanol (60 mL), and then sodium borohydride (1.0 g, 26.3 mmol) was added. After purging with nitrogen three times, the reaction was carried out at 25 °C for 2 h.

[0569] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 827 mg of 3-hydroxy-5-nitro-2,3,7,8-tetrahydrothieno[3,2-e]thiophene-1,1-dioxide.

[0570] MS(ESI) M / Z: 270.0 [M-H] - 。

[0571] 1 H NMR(400 MHz, CD3OD) δ 8.14 (s, 1H), 5.54–5.36 (m, 1H), 4.98 (t, J = 8.9 Hz, 2H), 3.96 (dd, J = 13.6, 6.8 Hz, 1H), 3.53 (td, J = 8.5, 2.8 Hz, 2H), 3.43 (dd, J = 13.7, 4.9 Hz, 1H).

[0572] Step I: 3-Hydroxy-5-nitro-2,3,7,8-tetrahydrothieno[3,2-e]thiophene-1,1-dioxide (827 mg, 3.1 mmol) was dissolved in dichloromethane (60 mL), then triethylamine (1.0 g, 9.15 mmol) and methanesulfonyl chloride (524 mg, 4.6 mmol) were added at 0 °C. After purging with nitrogen three times, the reaction was carried out at 25 °C for 2 h.

[0573] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 710 mg of 5-nitro-7,8-dihydrothieno[2,3-e]benzofuran-1,1-dioxide.

[0574] 1 H NMR(400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.68 (d, J = 6.9 Hz, 1H), 7.39 (d, J = 6.9 Hz, 1H), 5.02 (t, J = 8.6 Hz, 2H), 3.53 (t, J = 8.6 Hz, 2H).

[0575] Step J: 5-Nitro-7,8-dihydrothieno[2,3-e]benzofuran-1,1-dioxide (100 mg, 0.40 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), then palladium on carbon (84 mg, 0.79 mmol) was added. After purging with nitrogen three times, the reaction solution was purged with hydrogen and the reaction was carried out at 25 °C for 16 h.

[0576] The LCMS monitoring showed the disappearance of the raw material. The reaction solution was filtered to remove palladium carbon, and the filtrate was concentrated under reduced pressure to obtain 74 mg of 5-amino-2,3,7,8-tetrahydrothieno[2,3-e]benzofuran-1,1-dioxide.

[0577] MS(ESI) M / Z: 226.0 [M+H] + 。

[0578] 1 H NMR(400 MHz, DMSO-d6) δ 6.39 (s, 1H), 5.58 (s, 2H), 4.63 (t, J = 8.9 Hz, 2H), 3.47–3.42 (m, 2H), 3.25 (t, J = 8.9 Hz, 2H), 3.12 (t, J = 6.8 Hz, 2H).

[0579] Step K: Dissolve the compound 5-amino-2,3,7,8-tetrahydrothieno[2,3-e]benzofuran-1,1-dioxide (74 mg, 0.32 mmol) in DMF (2 mL), and successively add potassium carbonate (45 mg, 0.32 mmol) and 3-bromopropyne (57 mg, 0.48 mmol). After the addition is complete, react the reaction solution at 50 °C for 16 h.

[0580] TLC monitoring showed the formation of a new spot. LCMS showed that there was approximately 40% of the product. The reaction solution was added with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse phase to obtain 26 mg of 5-(prop-2-yn-1-ylamino)-2,3,7,8-tetrahydrothieno[2,3-e]benzofuran-1,1-dioxide.

[0581] MS(ESI) M / Z: 264.0 [M+H] + 。

[0582] Step L: Dissolve the compound 5-(prop-2-yn-1-ylamino)-2,3,7,8-tetrahydrothieno[2,3-e]benzofuran-1,1-dioxide (26 mg, 0.099 mmol) in DMSO (1 mL), and successively add 2-iodo-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (43 mg, 0.099 mmol), N,N-diisopropylethylamine (38 mg, 0.297 mmol), copper(I) iodide (9.4 mg, 0.050 mmol), and bis(triphenylphosphine)palladium(II) dichloride (10.5 mg, 0.015 mmol). After purging with nitrogen three times, react the reaction solution at 50 °C for 16 hours.

[0583] The raw materials were monitored by LCMS. The reaction solution was added with water and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by HPLC to obtain 8.1 mg of 5-(3-(4-(1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)propyl-2-ynyl-1-amino)-2,3,7,8-tetrahydrothieno[2,3-e]benzofuran-1,1-dioxide.

[0584] MS(ESI) M / Z: 573.7 [M+H] + 。

[0585] 1 H NMR(400 MHz, CD3OD) δ 7.08 (t, J = 8.0, 2.1 Hz, 1H), 6.92 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 6.32 (d, J = 7.7, 2.0 Hz, 1H), 4.81–4.65 (m, 3H), 4.35 (s, 2H), 3.72–3.60 (m, 1H), 3.57–3.43 (m, 2H), 3.42–3.34 (m, 3H), 2.99–2.85 (m, 2H), 2.72 (s, 3H), 2.39–2.16 (m, 2H), 1.88–1.67 (m, 2H).

[0586] Example 9:

[0587] 1-(7-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)aminoamino)-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide

[0588] and

[0589] 1-(7-((3-(4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)aminoamino)-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide

[0590] Reaction route:

[0591]

[0592] Step A: Dissolve 2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (1.5 g, 4.4 mmol) in acetic acid (45 mL) and 1,2-dichloroethane (15 mL). Then, successively add tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (4.8 g, 22.1 mol) and sodium cyanoborohydride (1.4 g, 22.1 mmol) at 0 °C. Replace the gas with nitrogen three times and react at 50 °C for 16 hours.

[0593] LCMS detection showed that the raw materials disappeared. Concentrate the reaction solution to remove acetic acid. Then, add the residue to an aqueous sodium bicarbonate solution to adjust the pH, extract twice with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 750 mg of tert-butyl 3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate.

[0594] MS(ESI) M / Z: 542.0 [M+H] + 。

[0595] Step B: Dissolve tert-butyl 3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate (502 mg, 0.93 mmol) in dichloromethane (5 mL). Then, add trifluoroacetic acid (2.5 mL). Replace the gas with nitrogen three times and react at 25 °C for 1 hour.

[0596] LCMS monitoring showed that the raw materials disappeared. Concentrate the reaction solution to obtain 408 mg of the crude product N-(3-fluoropiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine, which is directly used in the next step without purification.

[0597] MS(ESI) M / Z: 441.9 [M+H] + 。

[0598] Step C: Dissolve N-(3-fluoropiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (408 mg, 0.93 mmol) in methanol (10 mL). Then, successively add paraformaldehyde (139.3 mg, 4.65 mmol), sodium cyanoborohydride (291.4 mg, 4.65 mmol), and acetic acid (0.41 mL). Replace the gas with nitrogen three times and react at 50 °C for 7.5 hours.

[0599] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 289 mg of N-(3-fluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine.

[0600] MS(ESI) M / Z: 455.9 [M+H] + 。

[0601] Step D: N-(3-Fluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (246 mg, 0.54 mmol) was dissolved in dimethyl sulfoxide (10 mL). 1-(7-(Prop-2-yn-1-ylamino)-2,3-dihydrobenzofuran-4-yl)phosphane 1-oxide (150 mg, 0.54 mmol), copper(I) iodide (51.4 mg, 0.27 mmol), N,N-diisopropylethylamine (209 mg, 1.62 mmol) and bis(triphenylphosphine)palladium(II) dichloride (56.9 mg, 0.081 mmol) were added successively. After purging with nitrogen three times, the reaction was carried out at 50 °C for 16 h.

[0602] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain 120 mg of Z-1-(7-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)phospholane 1-oxide.

[0603] Step E: The obtained product was separated by chiral HPLC. Separation conditions: chiral column OJ 200 * 25 mm 10 μm; Mobile phase: MeOH / DEA, Flow rate: 2.0 mL / min, Gradient: 15% isocratic, Detection wavelength: 214 nm, Obtained 39.94 mg of a compound with a retention time of 3.193 min (denoted as 9A) and 19.30 mg of a compound with a retention time of 4.250 min (denoted as 9B). The two compounds that have no corresponding relationship are 1-(7-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)aminoamino)-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide and 1-(7-((3-(4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)aminoamino)-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide.

[0604] Compound 9A:

[0605] MS(ESI) M / Z: 603.7 [M+H] + 。

[0606] 1 H NMR(400 MHz, CD3OD) δ 7.13 (d, J = 8.2 Hz, 1H), 7.11–7.03 (m, 2H), 6.91 (s, 1H), 6.82 (dd, J = 8.2, 2.7 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 4.78–4.70 (m, 2H), 4.65 (t, J = 8.8 Hz, 2H), 4.62 (s, 1H), 4.35 (s, 2H), 3.74–3.56 (m, 2H), 3.45–3.37 (m, 2H), 3.28–3.19 (m, 2H), 3.03–2.93 (m, 1H), 2.35 (s, 3H), 2.23–2.06 (m, 4H), 2.04–1.87 (m, 6H).

[0607] Compound 9B:

[0608] MS(ESI) M / Z: 603.7 [M+H] + 。

[0609] 11H NMR (400 MHz, CD3OD) δ 7.19–7.03 (m, 2H), 6.91 (d, J = 0.8 Hz, 1H), 6.82 (dd, J = 8.2, 2.7 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 7.8 Hz, 1H), 4.78–4.70 (m, 2H), 4.65 (t, J = 8.8 Hz, 2H), 4.62 (s, 1H), 4.35 (s, 2H), 3.72–3.56 (m, 2H), 3.46–3.38 (m, 2H), 3.26–3.16 (m, 1H), 3.00–2.87 (m, 1H), 2.31 (s, 3H), 2.29–2.21 (m, 2H), 2.20–2.06 (m, 4H), 2.00–1.89 (m, 6H).

[0610] Example 10:

[0611] (R)-1-((3S,4R)-3-Fluoro-4-((2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl)-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol

[0612] and

[0613] (R)-1-((3R,4S)-3-Fluoro-4-((2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl)-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol

[0614] Reaction route:

[0615]

[0616] Step A: Dissolve 2,3-dihydrobenzofuran-7-amine (5 g, 36.99 mmol) in N,N-dimethylformamide (50 mL), then dissolve N-bromosuccinimide (6.9 g, 38.84 mmol) in N,N-dimethylformamide (20 mL) and add it portionwise at 0 °C. After the addition is complete, react the reaction mixture at 0 °C for 3 hours.

[0617] TLC monitoring showed that the raw materials disappeared. Add water to the reaction mixture and extract it twice with ethyl acetate. Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain 7 g of 4-bromo-2,3-dihydrobenzofuran-7-amine by silica gel column chromatography.

[0618] MS(ESI)M / Z: 214.0 / 216.0 [M+H] + 。

[0619] Step B: Dissolve 4-bromo-2,3-dihydrobenzofuran-7-amine (3 g, 14.02 mmol) in dimethyl sulfoxide (30 mL), add sodium methylsulfinate (2.86 g, 42.06 mmol) and copper(I) iodide (1.3 g, 7.01 mmol). After displacing nitrogen three times, the reaction mixture is reacted at 120 °C for 16 hours.

[0620] TLC monitoring shows the disappearance of the starting material. Add water to the reaction mixture, extract twice with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 1.9 g of 4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amine.

[0621] MS(ESI)M / Z: 214.1 [M+H] + 。

[0622] Step C: Dissolve 4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amine (1.9 g, 8.92 mmol) in N,N-dimethylformamide (20 mL), and successively add 3-bromopropyne (2.1 g, 17.84 mmol) and potassium carbonate (615.48 mg, 4.46 mmol). After displacing nitrogen three times, the reaction mixture is reacted at 50 °C for 16 hours.

[0623] LCMS monitoring shows 57% of the product. Add water to the reaction mixture, extract twice with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 1.3 g of 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine.

[0624] MS(ESI)M / Z: 252.0 [M+H] + 。

[0625] Step D: Dissolve 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine (1.1 g, 4.21 mmol) in dimethyl sulfoxide (25 mL), then add 4-bromo-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole (1.7 g, 4.21 mmol), copper(I) iodide (160 mg, 0.84 mmol), N,N-diisopropylethylamine (1.6 g, 12.63 mmol) and bis(triphenylphosphine)palladium(II) dichloride (590 mg, 0.84 mmol). After displacing nitrogen three times, stir at 50 °C for 16 h.

[0626] LCMS monitoring showed the disappearance of the starting material. The reaction solution was added to water, and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.2 g of N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amine.

[0627] MS(ESI) M / Z: 528.9 [M+H] + 。

[0628] Step E: Dissolve N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amine (1.2 g, 2.28 mmol) in 1,4-dioxane (10 mL). Sequentially add tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (745 mg, 3.42 mmol), cesium carbonate (2.2 g, 6.84 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (213 mg, 0.46 mmol), (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (206 mg, 0.23 mmol). The reaction is carried out in a sealed tube. After the addition is completed, the sealed tube is purged with nitrogen three times. The reaction solution is reacted at 90 °C for 16 h.

[0629] LCMS monitoring showed the disappearance of the starting material. The reaction solution was added with water and extracted with dichloromethane twice. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 630 mg of tert-butyl 3-fluoro-4-((2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-2-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate.

[0630] MS(ESI) M / Z: 665.0 [M+H] + 。

[0631] Step F: Add tert-butyl 3-fluoro-4-((2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-2-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate (630 mg, 0.95 mmol) to hydrochloric acid-ethyl acetate solution (3 M, 5 ml). The reaction solution is reacted at room temperature for 2 hours.

[0632] The raw material disappearance was monitored by LCMS. Saturated sodium bicarbonate solution (10 ml) was added to the reaction solution under an ice bath to adjust the pH. Then, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 510 mg of N-(3-fluoropiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine).

[0633] MS(ESI) M / Z: 565.1 [M+H] + 。

[0634] Step G: tert-Butyl 3-fluoro-4-((2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate (255 mg, 0.45 mmol) was dissolved in acetonitrile (5 ml). Potassium carbonate (312 mg, 2.26 mmol) and (R)-2-(methoxymethyl)oxirane (199 mg, 2.26 mmol) were added successively. The reaction solution was placed in a sealed tube and reacted at 80 °C for 48 hours.

[0635] The raw material disappearance was monitored by LCMS. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase prep-HPLC to obtain 110 mg of the compound (Z)-(R)-1-(-3-fluoro-4-((2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol..

[0636] MS(ESI) M / Z: 653.7 [M+H] + 。

[0637] Step H: The obtained product was further separated by chiral HPLC. Separation conditions: Preparation column: OJ25 * 250 mm, mobile phase: MEOH (+0.1% 7.0 mol / l Ammonia in MEOH), flow rate: 120 mL / min, gradient: 40%, detection wavelength: 214 nm / 254 nm, obtained 19.57 mg of a compound with an elution time of 2.805 min (denoted as compound 10A) and 9.11 mg of a compound with an elution time of 4.610 min (denoted as 10B). The two compounds that have no corresponding relationship are (R)-1-((3S,4R)-3-fluoro-4-((2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl)-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol and (R)-1-((3R,4S)-3-fluoro-4-((2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)propyl)-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol.

[0638] Compound 10A:

[0639] MS(ESI) M / Z: 653.7 [M+H] + 。

[0640] 1 H NMR(400 MHz, DMSO-d6) δ 7.22 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 7.08–6.94 (m, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.40 (t, J = 6.3 Hz, 1H), 6.23 (d, J = 7.9 Hz, 1H), 5.49 (d, J = 8.7 Hz, 1H), 5.13–4.88 (m, 2H), 4.63 (t, J = 8.8 Hz, 2H), 4.32 (d, J = 6.2 Hz, 2H), 3.80–3.67 (m, 1H), 3.51–3.41 (m, 2H), 3.25 (s, 3H), 3.18–3.07 (m, 1H), 3.05 (s, 3H), 2.97–2.86 (m, 1H), 2.46–2.15 (m, 5H), 1.99–1.82 (m, 1H), 1.74–1.61 (m, 1H).

[0641] Compound 10B:

[0642] MS(ESI) M / Z: 653.7 [M+H] + 。

[0643] 1 1H NMR (400 MHz, DMSO-d6) δ 7.22 (d, J = 8.5 Hz, 1H), 7.17 (s, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.40 (t, J = 6.3 Hz, 1H), 6.23 (d, J = 7.8 Hz, 1H), 5.48 (d, J = 8.6 Hz, 1H), 4.98–4.88 (m, 2H), 4.63 (t, J = 8.8 Hz, 2H), 4.32 (d, J = 6.2 Hz, 2H), 3.79–3.67 (m, 1H), 3.45 (t, J = 8.9 Hz, 2H), 3.24 (s, 3H), 3.23–3.12 (m, 1H), 3.05 (s, 3H), 2.95–2.81 (m, 1H), 2.45–2.08 (m, 5H), 2.03–1.79 (m, 1H), 1.74–1.58 (m, 1H).

[0644] Example 11:

[0645] 1-(7-((3-(4-(((3S,4R)-3-Fluoro-1-((R)-2-hydroxy-3-methoxypropyl)piperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)aminoamino)-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide

[0646] and

[0647] 1-(7-((3-(4-(((3R,4S)-3-Fluoro-1-((R)-2-hydroxy-3-methoxypropyl)piperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)aminoamino)-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide

[0648] Reaction route:

[0649]

[0650]

[0651] Step A: Dissolve compound INT-2-A (325 mg, 0.74 mmol) in acetonitrile (6 mL), then successively add (R)-2-methoxymethyloxirane (325 mg, 3.7 mmol) and potassium carbonate (306 mg, 2.22 mmol), and react at 80 °C for 16 hours.

[0652] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 330 mg of (R)-1-((3S,4R)-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol.

[0653] MS(ESI) 529.9 [M+H] + 。

[0654] Step B: (R)-1-((3S,4R)-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidin-1-yl)-3-methoxypropan-2-ol (144 mg, 0.27 mmol) was dissolved in dimethyl sulfoxide (2 mL). 1-(7-(Prop-2-yn-1-ylamino)-2,3-dihydrobenzofuran-4-yl)phosphine 1-oxide (75 mg, 0.27 mmol), copper(I) iodide (38 mg, 0.20 mmol), N,N-diisopropylethylamine (104 mg, 0.81 mmol) and bis(triphenylphosphine)palladium(II) dichloride (38 mg, 0.054 mmol) were added successively. After purging with nitrogen three times, the reaction was carried out at 50 °C for 16 h.

[0655] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution and once with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain 42.35 mg of 1-(7-((3-(4-(((3S,4R)-3-fluoro-1-((R)-2-hydroxy-3-methoxypropyl)piperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)amino)-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide (Compound 11A).

[0656] MS(ESI) M / Z: 677.5 [M+H] + 。

[0657] 11H NMR (400 MHz, CD3OD) δ 7.20–7.00 (m, 2H), 6.90 (s, 1H), 6.81 (dd, J = 8.2, 2.7 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 7.7 Hz, 1H), 4.79–4.70 (m, 2H), 4.65 (t, J = 8.8 Hz, 2H), 4.34 (s, 2H), 4.01–3.89 (m, 1H), 3.82–3.61 (m, 1H), 3.53–3.38 (m, 4H), 3.37 (s, 3H), 3.19–3.07 (m, 1H), 2.79–2.45 (m, 4H), 2.34–2.00 (m, 6H), 2.05–1.85 (m, 5H).

[0658] By the same method, 32.45 mg of 1-(7-((3-(4-(((3R,4S)-3-fluoro-1-((R)-2-hydroxy-3-methoxypropyl)piperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)aminoamino)-2,3-dihydrobenzofuran-4-yl)phospholane-1-oxide (Compound 11B) was synthesized from 325 mg of INT-2-B.

[0659] MS (ESI) M / Z: 677.50 [M+H] + 。

[0660] 1 1H NMR (400 MHz, CD3OD) δ 7.19–7.03 (m, 2H), 6.90 (s, 1H), 6.82 (dd, J = 8.2, 2.7 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 4.79–4.70 (m, 2H), 4.65 (t, J = 8.8 Hz, 2H), 4.35 (s, 2H), 4.00–3.89 (m, 1H), 3.81–3.59 (m, 2H), 3.51–3.38 (m, 5H), 3.37 (s, 3H), 3.18–3.03 (m, 1H), 2.80–2.61 (m, 2H), 2.60–2.41 (m, 4H), 2.32–2.05 (m, 4H), 2.05–1.81 (m, 7H).

[0661] Example 12:

[0662] 5-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino

[0663] and

[0664] 5 - ((3 - (4 - (((3R,4S)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-1-(2,2,2 - trifluoroethyl)-1H - indol - 2 - yl)prop - 2 - yn - 1 - yl)amino

[0665] Reaction route:

[0666]

[0667] Step A: Dissolve 5 - nitro - 7,8 - dihydrobenzofuro[5,4 - d]isothiazol - 3(2H)-one 1,1 - dioxide (1 g, 3.7 mmol) in THF (40 mL), then successively add sodium borohydride (2.1 g, 55.6 mmol) and iron(III) chloride (4.8 g, 29.6 mmol) at 0 °C. Replace the atmosphere with nitrogen three times and react at 70 °C for 3 hours.

[0668] LCMS detection showed the disappearance of the starting material. The reaction mixture was quenched by adding it to ice - water, then the residue was filtered. The filtrate was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 267 mg of 5 - amino - 2,3,7,8 - tetrahydrobenzofuro[5,4 - d]isothiazole 1,1 - dioxide.

[0669] MS(ESI) M / Z: 227.0 [M + H] + 。

[0670] Step B: Dissolve 5 - amino - 2,3,7,8 - tetrahydrobenzofuro[5,4 - d]isothiazole 1,1 - dioxide (267 mg, 1.18 mmol) in THF (5 mL), then successively add 3 - (trimethylsilyl)propanal (446 mg, 3.54 mmol), p - toluenesulfonic acid (102 mg, 0.59 mmol) and 3A molecular sieve (534 mg). Replace the atmosphere with nitrogen three times and react at 25 °C for 3 hours.

[0671] TLC plate detection showed the disappearance of the starting material. Sodium cyanoborohydride (222 mg, 3.54 mmol) was added to the reaction mixture, and the reaction was continued at 25 °C for 1 hour.

[0672] LCMS monitoring showed the disappearance of the starting material. The reaction mixture was filtered to remove the molecular sieve, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain 250 mg of 5 - ((3 - (trimethylsilyl)prop - 2 - yn - 1 - yl)amino)-2,3,7,8 - tetrahydrobenzofuro[5,4 - d]isothiazole 1,1 - dioxide.

[0673] MS(ESI) M / Z: 337.0 [M+H] + 。

[0674] Step C: Dissolve 5-((3-(trimethylsilyl)propyl-2-yn-1-yl)amino)-2,3,7,8-tetrahydrobenzofuro[5,4-d]isothiazole 1,1-dioxide (89 mg, 0.26 mmol) in dimethyl sulfoxide (2 mL). Sequentially add INT-3-A (100 mg, 0.22 mmol), copper(I) iodide (31 mg, 0.16 mmol), N,N-diisopropylethylamine (85 mg, 0.66 mmol) and bis(triphenylphosphine)palladium(II) dichloride (31 mg, 0.04 mmol). After purging with nitrogen three times, react at 50 °C for 16 hours.

[0675] LCMS monitoring showed the disappearance of the starting material. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by prep-HPLC to obtain 29.38 mg of 5-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino (Compound 12A).

[0676] MS(ESI) M / Z: 592.4 [M+H] + 。

[0677] 1 H NMR (400 MHz, CD3OD) δ 7.10 (t, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.65 (s, 1H), 5.10–4.92 (m, 2H), 4.84–4.68 (m, 3H), 4.35 (s, 3H), 3.99–3.72 (m, 1H), 3.62–3.51 (m, 1H), 3.39 (t, J = 8.9 Hz, 2H), 3.08–2.89 (m, 1H), 2.88–2.74 (m, 1H), 2.66 (s, 3H), 2.25–1.99 (m, 2H).

[0678] Via the same route, 38.6 mg of 5-((3-(4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino (Compound 12B) was synthesized from 108 mg of N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine. Separation conditions: Preparation column: Sunfire Prep C18 OBD 19*250 mm 10um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 24%-29%, detection wavelength: 214 nm / 254 nm, retention time: 9.07 min.

[0679] MS(ESI) M / Z: 592.4 [M+H]+.

[0680] 1 H NMR(400 MHz, CD3OD) δ 7.10 (t, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.64 (s, 1H), 6.37 (d, J = 7.7 Hz, 1H), 5.10–4.94 (m, 1H), 4.83–4.67 (m, 4H), 4.35 (s, 3H), 3.94–3.71 (m, 1H), 3.64–3.52 (m, 1H), 3.39 (t, J = 8.9 Hz, 2H), 3.35–3.32 (m, 1H), 3.13–2.92 (m, 1H), 2.90–2.78 (m, 1H), 2.68 (s, 3H), 2.27–1.99 (m, 2H).

[0681] Prepare the following target compounds with reference to the synthesis method of the above examples:

[0682]

[0683]

[0684]

[0685]

[0686]

[0687] Example 23: N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

[0688] Reaction route:

[0689]

[0690] Step A: Dissolve 4-bromo-7-azaindole (1 g, 5.08 mmol) in dichloromethane (25 mL), then successively add benzenesulfonyl chloride (1.3 g, 7.61 mmol), 4-dimethylaminopyridine (62 mg, 0.51 mmol), and triethylamine (1.5 g, 15.23 mmol), and react at room temperature for 2 hours.

[0691] LCMS detection showed that the raw materials disappeared. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.7 g of 4-bromo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine.

[0692] MS(ESI) M / Z: 336.8 [M+H] + 。

[0693] Step B: Dissolve 4-bromo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.48 mmol) in anhydrous tetrahydrofuran (10 mL). After purging with nitrogen three times, cool to -78 °C, then dropwise add lithium diisopropylamide (2 M in THF, 0.8 mL, 1.63 mmol), and then stir at -78 °C for 1.5 hours. Dissolve elemental iodine (565 mg, 2.23 mmol) in tetrahydrofuran (1 mL) and slowly drop it into the reaction solution. After addition, continue to react at -78 °C for 1 hour.

[0694] LCMS detection showed that the raw materials disappeared. The reaction solution was quenched with saturated ammonium chloride aqueous solution. The residue was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 480 mg of 4-bromo-2-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine.

[0695] MS(ESI) M / Z: 462.8 [M+H] + 。

[0696] Step C: Dissolve 4-bromo-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (650 mg, 1.40 mmol) in tetrahydrofuran (10 mL) and methanol (21 mL), then add aqueous sodium hydroxide solution (3 M, 21 mL, 63 mmol), and heat the reaction mixture to 80 °C for 2 hours.

[0697] Monitor the disappearance of the starting material by LCMS, concentrate the reaction mixture, add water to the residue, and extract three times with ethyl acetate. Combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 408 mg of 4-bromo-2-iodo-1H-pyrrolo[2,3-b]pyridine.

[0698] MS(ESI) M / Z: 322.8 [M+H] + 。

[0699] Step D: Dissolve 4-bromo-2-iodo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.31 mmol) in anhydrous tetrahydrofuran (5 mL), add sodium hydride (19 mg, 0.46 mmol) at 0 °C and react for half an hour at 0 °C, then add 2,2,2-trifluoroethyl trifluoromethanesulfonate (144 mg, 0.62 mmol), and react at room temperature for 1.5 hours.

[0700] LCMS detection shows the disappearance of the starting material. Quench the reaction mixture with saturated ammonium chloride aqueous solution, extract the residue three times with ethyl acetate, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 100 mg of 4-bromo-2-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine.

[0701] 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 5.14 (q, J = 8.9 Hz, 2H).

[0702] Step E: Dissolve 4-bromo-2-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.25 mmol) in anhydrous dimethyl sulfoxide (3 mL), and successively add 2-methoxy-4-(methylsulfonyl)-N-(prop-2-yn-1-yl)aniline (59 mg, 0.25 mmol), copper(I) iodide (35 mg, 0.18 mmol), N,N-diisopropylethylamine (96 mg, 0.74 mmol) and bis(triphenylphosphine)palladium(II) dichloride (35 mg, 0.05 mmol). After purging with nitrogen three times, react at room temperature for 16 hours.

[0703] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water, extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 97 mg of N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline.

[0704] MS(ESI) M / Z: 515.9 [M+H] + 。

[0705] Step F: Dissolve N-(3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)prop-2-yn-1-yl)-2-methoxy-4-(methylsulfonyl)aniline (100 mg, 0.25 mmol) in anhydrous 1,4-dioxane (5 mL), and successively add (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (60 mg, 0.29 mmol), cesium carbonate (190 mg, 0.58 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (18 mg, 0.04 mmol), Brettphos Pd G3 (18 mg, 0.02 mmol). The reaction was carried out in a sealed tube. After the addition was completed, the sealed tube was purged with nitrogen three times, and the reaction solution was reacted at 90 °C for 16 h.

[0706] LCMS monitoring showed the disappearance of the starting material. Water was added to the reaction solution, and it was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified using a TLC preparative plate to obtain 18 mg of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-4-amine.

[0707] MS(ESI) M / Z: 568.4 [M+H] + 。

[0708] 11H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 5.8 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.99 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 5.8 Hz, 1H), 4.84–4.75 (m, 2H), 4.39 (s, 2H), 3.95 (s, 3H), 3.87–3.69 (m, 1H), 3.28–3.17 (m, 1H), 3.06 (s, 3H), 3.03–2.93 (m, 1H), 2.61–2.38 (m, 1H), 2.36 (s, 3H), 2.24–2.01 (m, 2H), 1.94–1.83 (m, 1H).

[0709] Example 24: 3-Fluoro-N-(1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine

[0710] Reaction route:

[0711]

[0712] Step A: Dissolve 4-bromo-1H-indole-2,3-dione (200 mg, 0.88 mmol) in anhydrous dichloromethane (5 mL), and dropwise add diethylaminosulfur trifluoride (355 mg, 2.2 mmol) under ice bath, then stir at room temperature for 48 hours.

[0713] LCMS detection showed that the raw material disappeared. Quench the reaction solution with saturated aqueous sodium bicarbonate, extract the residue with ethyl acetate three times, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 177 mg of 4-bromo-3,3-difluoroindol-2-one.

[0714] MS (ESI) M / Z: 245.9 / 247.9 [M-H] - 。

[0715] Step B: Dissolve sodium borohydride (229 mg, 6 mmol) in anhydrous tetrahydrofuran (5 mL), dropwise add boron trifluoride diethyl etherate (858 mg, 6 mmol) under ice bath, stir for 1 hour, and then drop the obtained mixed solution into a solution of 4-bromo-3,3-difluoroindol-2-one (500 mg, 2 mmol) in anhydrous tetrahydrofuran (5 mL) under ice bath, and stir at room temperature for 16 hours.

[0716] LCMS analysis showed the disappearance of the starting material. The reaction mixture was quenched with 0.1 M aqueous hydrochloric acid, then adjusted to alkaline with saturated sodium hydroxide solution. The residue was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 360 mg of 4-bromo-3-fluoro-1H-indole.

[0717] MS(ESI) M / Z: 212.0 / 214.0 [M-H] - 。

[0718] Step C: 4-Bromo-3-fluoro-1H-indole (360 mg, 1.69 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL). Sodium hydride (101 mg, 2.53 mmol) was added under ice bath. After stirring for half an hour, benzenesulfonyl chloride (358 mg, 2.03 mmol) was added, and the reaction was carried out at room temperature for 16 hours.

[0719] LCMS analysis showed the disappearance of the starting material. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. The residue was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 400 mg of 4-bromo-3-fluoro-1-phenylsulfonyl-1H-indole.

[0720] 1 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.3 Hz, 1H), 8.04 (dd, J = 8.6, 1.9 Hz, 1H), 8.01 (d, J = 7.4 Hz, 2H), 7.74 (t, J = 7.5 Hz, 1H), 7.63 (t, J = 7.8 Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H).

[0721] Step D: 4-Bromo-3-fluoro-1-phenylsulfonyl-1H-indole (200 mg, 0.57 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL). After purging with nitrogen three times, the temperature was lowered to -78 °C, and then lithium diisopropylamide (2 M in THF, 0.45 mL, 0.9 mmol) was added dropwise. Then, the mixture was stirred at -78 °C for one and a half hours. Iodine (288 mg, 1.13 mmol) was dissolved in tetrahydrofuran (2 mL) and slowly added dropwise to the reaction mixture. After the addition was complete, the reaction was continued at -78 °C for 1 hour.

[0722] LCMS analysis showed the disappearance of the starting material. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the residue was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 190 mg of 4-bromo-3-fluoro-2-iodo-1-(phenylsulfonyl)-1H-indole.

[0723] 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (dd, J = 8.6, 1.6 Hz, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.63 (t, J = 7.8 Hz, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 8.2 Hz, 1H).

[0724] Step E: 4-Bromo-3-fluoro-2-iodo-1-(phenylsulfonyl)-1H-indole (731 mg, 1.53 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (10 mL), and then aqueous sodium hydroxide solution (3 M, 10 mL, 30 mmol) was added. The reaction mixture was heated to 80 °C and reacted for 2 hours.

[0725] LCMS monitoring showed the disappearance of the starting material. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 340 mg of 4-bromo-3-fluoro-2-iodo-1H-indole.

[0726] MS (ESI) M / Z: 337.8 / 339.8 [M-H] - 。

[0727] Step F: 4-Bromo-3-fluoro-2-iodo-1H-indole (300 mg, 0.88 mmol) was dissolved in anhydrous DMF (5 mL). Sodium hydride (19 mg, 0.46 mmol) was added at 0 °C and reacted for half an hour at 0 °C, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (413 mg, 1.77 mmol) was added, and the reaction was carried out at room temperature for 1.5 hours.

[0728] LCMS analysis showed the disappearance of the starting material. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the residue was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 310 mg of 4-bromo-3-fluoro-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole.

[0729] 11H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.20–7.10 (m, 1H), 5.19 (q, J = 9.1 Hz, 2H).

[0730] Step G: Dissolve 4-bromo-3-fluoro-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole (120 mg, 0.48 mmol) in anhydrous dimethyl sulfoxide (5 mL). Sequentially add 4-(methylsulfonyl)-N-(prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine (200 mg, 0.48 mmol), copper(I) iodide (45 mg, 0.24 mmol), N,N-diisopropylethylamine (184 mg, 1.42 mmol), and bis(triphenylphosphine)palladium(II) dichloride (50 mg, 0.07 mmol). After purging with nitrogen three times, react at room temperature for 16 hours.

[0731] LCMS monitoring showed the disappearance of the starting material. Dilute the reaction solution with water and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography to obtain 144 mg of N-(3-(4-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amine.

[0732] MS (ESI) M / Z: 566.9 / 568.9 [M+Na] + 。

[0733] Step H: Dissolve N-(3-(4-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-amine (50 mg, 0.09 mmol) in anhydrous 1,4-dioxane (5 mL). Sequentially add 4-amino-1-methylpiperidine (16 mg, 0.14 mmol), cesium carbonate (90 mg, 0.28 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (7.5 mg, 0.02 mmol), and Brettphos Pd G3 (8.3 mg, 0.01 mmol). Purge with nitrogen three times and react the reaction solution at 95 °C for 16 h.

[0734] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by HPLC to give 6.09 mg of 3-fluoro-N-(1-methylpiperidin-4-yl)-2-(3-((4-(methylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine.

[0735] MS(ESI) M / Z: 579.4 [M+H] + 。

[0736] 1 H NMR (400 MHz, CD3OD) δ 7.34 (d, J = 8.5 Hz, 1H), 7.10 (t, J = 8.1 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 7.9 Hz, 1H), 4.79–4.60 (m, 4H), 4.40 (s, 2H), 3.57–3.45 (m, 3H), 3.11–3.05 (m, 2H), 3.04 (s, 3H), 2.64–2.48 (m, 2H), 2.48 (s, 3H), 2.25–2.07 (m, 2H), 1.76–1.53 (m, 2H).

[0737] Example 25:

[0738] ((7-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)imine)dimethyl-λ6-thione (25A)

[0739] and

[0740] ((7-((3-(4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)imine)dimethyl-λ6-thione (25B)

[0741] Reaction route:

[0742]

[0743] Step A: Dissolve 4-bromo-2,3-dihydrobenzofuran-7-amine (2 g, 9.39 mmol) in dichloromethane (20 mL), and successively add di-tert-butyl dicarbonate (2.87 g, 13.15 mmol) and 4-dimethylaminopyridine (1.15 g, 9.39 mmol).

[0744] React at 25 °C for 16 hours.

[0745] LCMS monitoring shows the disappearance of the raw materials. Add water to the reaction solution, extract twice with dichloromethane, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 1.1 g of tert-butyl (4-bromo-2,3-dihydrobenzofuran-7-yl) carbamate.

[0746] Step B: Dissolve tert-butyl (4-bromo-2,3-dihydrobenzofuran-7-yl) carbamate (500 mg, 1.60 mmol) in 1,4-dioxane (5 mL), and successively add dimethylsulfoximine (298 mg, 3.20 mmol), x-phos (76 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium(0) (147 mg, 0.16 mmol) and cesium carbonate (1.04 g, 3.20 mmol). After purging with nitrogen three times,

[0747] React at 100 °C for 16 hours.

[0748] LCMS monitoring shows the disappearance of the raw materials. Add water to the reaction solution, extract twice with dichloromethane, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 450 mg of tert-butyl (4-((dimethyl(oxo)-λ6-sulfoximine)amino)-2,3-dihydrobenzofuran-7-yl)carbamate.

[0749] MS(ESI) M / Z: 652.9 [2M + H] + 。

[0750] Step C: Dissolve tert-butyl (4-((dimethyl(oxo)-λ6-sulfoximine)amino)-2,3-dihydrobenzofuran-7-yl)carbamate (500 mg, 1.50 mmol) in N,N-dimethylformamide (5 mL), add sodium hydride (72 mg, 1.80 mmol) under an ice-water bath, stir at 0 °C for 30 minutes, then add 3-bromo-1-propyne (271 mg, 2.25 mmol), and react at 25 °C for 2 hours.

[0751] LCMS monitoring showed the disappearance of the starting material. The reaction solution was poured into saturated ammonium chloride aqueous solution for quenching, and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 550 mg of tert-butyl (4-((dimethyl(oxo)-λ6-sulfoximidoyl)amino)-2,3-dihydrobenzofuran-7-yl)(prop-2-yn-1-yl)carbamate.

[0752] MS(ESI) M / Z: 728.9 [2M+H] + 。

[0753] Step D: Dissolve tert-butyl (4-((dimethyl(oxo)-λ6-sulfoximidoyl)amino)-2,3-dihydrobenzofuran-7-yl)(prop-2-yn-1-yl)carbamate (80 mg, 0.22 mmol) in dimethyl sulfoxide (2 mL), and successively add INT-3-A (100 mg, 0.22 mmol), copper(I) iodide (31 mg, 0.16 mmol), N,N-diisopropylethylamine (85 mg, 0.66 mmol) and bis(triphenylphosphine)palladium(II) dichloride (31 mg, 0.04 mmol). After purging with nitrogen three times, react at 50 °C for 16 hours.

[0754] LCMS monitoring showed the disappearance of the starting material. The reaction solution was added with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 100 mg of tert-butyl (4-((dimethyl(oxo)-λ6-sulfenimidoyl)amino)-2,3-dihydrobenzofuran-7-yl)(3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate.

[0755] MS(ESI) M / Z: 691.9 [M+H] + 。

[0756] Step E: Dissolve tert-butyl (4-((dimethyl(oxo)-λ6-sulfenimidoyl)amino)-2,3-dihydrobenzofuran-7-yl)(3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)carbamate (100 mg, 0.14 mmol) in hydrochloric acid / ethyl acetate (2 mol / L, 5 mL, 10 mmol), and react at 25 °C for 1 hour.

[0757] LCMS monitoring showed the disappearance of the starting material. The reaction solution was adjusted to pH with sodium hydroxide solution, extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by HPLC to obtain 19.94 mg of ((7-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)imine)dimethyl-λ6-thione (25A).

[0758] Separation conditions: Preparation column: Sunfire Prep C18 OBD 19*250 mm 10 um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 22% - 25%, detection wavelength: 214 nm / 254 nm, retention time: 8.7 min.

[0759] MS(ESI) M / Z: 592.4 [M+H + .

[0760] 1 H NMR(400 MHz, CD3OD) δ 7.07 (t, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 7.8 Hz, 1H), 4.75–4.63 (m, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.23 (s, 2H), 3.73–3.57 (m, 1H), 3.27–3.16 (m, 2H), 3.15 (s, 7H), 3.02–2.90 2.96 (m, 1H), 2.37–

[0761] 2.22 (m, 4H), 2.07–1.87 (m, 2H).

[0762] Following the same method, 90 mg of ((7-((3-(4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)imine)dimethyl-λ6-thione (25B) was synthesized from INT-3-B (125 mg, 0.275 mmol). Separation conditions: Preparation column: SunfireC8 OBD 19*250 mm 10um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 10%-40%, detection wavelength: 214 nm / 254 nm, retention time: 12.36 min.

[0763] MS(ESI) M / Z: 592.4 [M+H] + 。

[0764] 1 H NMR(400 MHz, CD3OD) δ 7.08 (t, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 4.76–4.65 (m, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.23 (s, 2H), 3.80–3.62 (m, 1H), 3.22–3.17 (m, 2H), 3.15 (s, 6H), 2.59–2.47 (m, 1H), 2.44 (s, 3H), 2.09–1.90 (m, 2H).

[0765]

[0766]

[0767]

[0768] Example 31: 2-(3-((4-((difluoromethylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine

[0769] Reaction route:

[0770]

[0771] Step A: Dissolve 2,3-dihydrobenzofuran-7-amine (5 g, 36.9 mmol) in N,N-dimethylformamide (50 mL), and then dissolve N-bromosuccinimide (7.25 g, 40.6 mmol) in N,N-dimethylformamide (50 mL) and add it portionwise at 0 °C. After the addition is complete, react the reaction solution at 0 °C for 3 hours. TLC monitoring shows that the raw material has disappeared. Add water to the reaction solution, extract it twice with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 5 g of 4-bromo-2,3-dihydrobenzofuran-7-amine.

[0772] MS(ESI) M / Z: 214.0 [M+H] + 。

[0773] Step B: Dissolve 4-bromo-2,3-dihydrobenzofuran-7-amine (2.9 g, 13.55 mmol) in 1,2-dichloroethane (30 mL), add m-chloroperoxybenzoic acid (9.35 g, 54.19 mmol), and stir at 60 °C for 3 hours. LCMS detection shows that the raw material has disappeared. Cool the mixture to room temperature, filter, wash the filter cake with a small amount of dichloromethane, add water to the filtrate, extract it three times with dichloromethane, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 1.6 g of 4-bromo-7-nitro-2,3-dihydrobenzofuran.

[0774] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 4.92 (t, J = 8.8 Hz, 2H), 3.35 (t, J = 8.8 Hz, 2H).

[0775] Step C: Dissolve 4-bromo-7-nitro-2,3-dihydrobenzofuran (800 mg, 3.28 mmol) in dimethyl sulfoxide (8 mL) and water (0.8 ml), add potassium hydroxide (920 mg, 16.39 mmol), copper sulfate pentahydrate (39 mg, 0.16 mmol), 1,2-ethanedithiol (618 mg, 6.56 mmol), displace with nitrogen three times, and then react at 60 °C for 16 hours.

[0776] LCMS detection shows that the raw material has disappeared. Adjust the pH of the reaction solution with 5% hydrochloric acid solution, extract the residue three times with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 394 mg of 7-nitro-2,3-dihydrobenzofuran-4-thiol.

[0777] MS(ESI) M / Z: 196.1 [M-H] - 。

[0778] Step D: Dissolve 7-nitro-2,3-dihydrobenzofuran-4-thiol (200 mg, 1.01 mmol) in dichloromethane (2 mL), add aqueous potassium hydroxide solution (20% wt, 341 mg, 6.08 mmol), after cooling to 0 °C, dissolve difluorobromomethyltrimethylsilane (412 mg, 2.03 mmol) in dichloromethane (2 mL) and slowly add it dropwise to the reaction solution. After the addition is complete, continue the reaction at 0 °C for 20 minutes.

[0779] LCMS detection showed the disappearance of the starting material. Add water to the reaction solution, extract the residue with dichloromethane three times, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 120 mg of 4-(difluoromethylthio)-7-nitro-2,3-dihydrobenzofuran.

[0780] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 4.86 (t, J = 8.8 Hz, 2H), 3.36 (s, 2H).

[0781] Step E: Dissolve 4-(difluoromethylthio)-7-nitro-2,3-dihydrobenzofuran (120 mg, 0.49 mmol) in carbon tetrachloride (1 mL), acetonitrile (1 mL) and water (1.5 mL), then add ruthenium(III) chloride hydrate (1.3 mg, 0.048 mmol) and sodium periodate (260 mg, 1.21 mmol), and react the reaction solution at room temperature for 1 hour.

[0782] LCMS monitoring showed the disappearance of the starting material. Concentrate the reaction solution, add water to the residue, extract it with ethyl acetate three times, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 100 mg of 4-((difluoromethyl)sulfonyl)-7-nitro-2,3-dihydrobenzofuran.

[0783] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.53 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 4.93 (t, J = 8.8 Hz, 2H), 3.65 (t, J = 8.7 Hz, 2H).

[0784] Step F: Dissolve 4-((difluoromethyl)sulfonyl)-7-nitro-2,3-dihydrobenzofuran (100 mg, 0.36 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL), then after purging with nitrogen three times, add palladium on carbon (75 mg, 0.72 mmol). After purging with nitrogen three times again, purge the reaction solution with hydrogen three times, and react at 25 °C for 1 hour.

[0785] LCMS detection showed that the raw material disappeared. Filter the reaction solution to remove palladium on carbon, and concentrate the filtrate under reduced pressure to obtain 80 mg of 4-((difluoromethyl)sulfonyl)-2,3-dihydrobenzofuran-7-amine. It was directly used for the next step without purification.

[0786] MS(ESI) M / Z: 250.1 [M+H] + 。

[0787] Step G: Dissolve 4-((difluoromethyl)sulfonyl)-2,3-dihydrobenzofuran-7-amine (40 mg, 0.16 mmol) in anhydrous dichloromethane (2 mL), and successively add 3-trimethylsilylpropiolaldehyde (41 mg, 0.32 mmol), p-toluenesulfonamide (14 mg, 0.08 mmol), 3A molecular sieve (80 mg). After purging with nitrogen three times, react at room temperature for 2 hours. TLC monitoring showed that the raw material disappeared. Add sodium cyanoborohydride (20 mg, 0.32 mmol) and react at room temperature for 0.5 hour. Monitor by LCMS, dilute the reaction solution with water, extract twice with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 30 mg of 4-((difluoromethyl)sulfonyl)-N-(3-(trimethylsilyl)prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine.

[0788] MS(ESI) M / Z: 360.1 [M+H] + 。

[0789] Step H: Dissolve 4-((difluoromethyl)sulfonyl)-N-(3-(trimethylsilyl)prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine (25 mg, 069 mmol) in anhydrous dimethyl sulfoxide (1 mL), and successively add compound INT-3-A (32 mg, 0.069 mmol), copper(I) iodide (10 mg, 0.055 mmol), bis(triphenylphosphine)palladium(II) dichloride (15 mg, 0.02 mmol), N,N-diisopropylethylamine (27 mg, 0.208 mmol), purge with nitrogen three times, and react at 65 °C by microwave for 1.5 hours

[0790] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by HPLC to give 6.44 mg of 2-(3-((4-((difluoromethylsulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine.

[0791] Separation conditions: Preparation column: Waters sunfire C18 OBD 19*250 mm 10 μm, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 31% - 39%, detection wavelength: 214 nm / 254 nm, retention time: 11.0 min.

[0792] MS(ESI) M / Z: 615.5 [M+H] + 。

[0793] 1 1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 8.6 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.57 (t, J = 53.4 Hz, 1H), 6.38 (d, J = 7.7 Hz, 1H), 4.84–4.73 (m, 2H), 4.67 (t, J = 8.9 Hz, 2H), 4.40 (s, 2H), 3.99–3.80 (m, 1H), 3.77–3.63 (m, 1H), 3.52 (t, J = 8.9 Hz, 2H), 3.47–3.38 (m, 1H), 3.16–2.98 (m, 2H), 2.79 (s, 3H), 2.21–2.08 (m, 3H).

[0794] Example 32: N-(3-Fluoro-1-methylpiperidin-4-yl)-2-(3-((4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine

[0795] Reaction route:

[0796]

[0797] Step A: Sodium sulfite (698 mg, 5.54 mmol) and sodium bicarbonate (465 mg, 5.54 mmol) were dissolved in water (3 mL) and heated to 80 °C. Then 1-methyl-1H-pyrazole-4-sulfonyl chloride (500 mg, 2.77 mmol) was dissolved in 1,4-dioxane (3 mL), slowly added to the reaction solution, and stirred at the maintained temperature for 1 hour. Then the reaction solution was concentrated under reduced pressure, ethanol was added to the residue, and the temperature was raised to 80 °C and the reaction continued for 1 hour. The supernatant was separated, ethanol was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, the filtrate was combined with the previously separated supernatant, and ethanol was evaporated under reduced pressure to obtain 450 mg of crude sodium 1-methyl-1H-pyrazole-4-carboxylate.

[0798] 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.49 (s, 1H), 7.34 (d, J = 0.4 Hz, 1H), 7.27 (s, 1H), 3.78 (d, J = 1.4 Hz, 6H).

[0799] Step B: Sodium 1-methyl-1H-pyrazole-4-carboxylate (413 mg, 2.46 mmol) was dissolved in N,N-dimethylformamide (10 mL), then 4-bromo-7-nitro-2,3-dihydrobenzofuran (300 mg, 1.23 mmol) and pyridine (117 mg, 1.47 mmol) were added, the temperature was raised to 70 °C, and the reaction was carried out for 16 hours.

[0800] LCMS detection showed that the raw materials disappeared. The reaction solution was washed with saturated copper sulfate solution, extracted three times with ethyl acetate, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 215 mg of 1-methyl-4-((7-nitro-2,3-dihydrobenzofuran-4-yl)sulfonyl)-1H-pyrazole.

[0801] MS (ESI) M / Z: 310.0 [M + H] + 。

[0802] Step C: 1-methyl-4-((7-nitro-2,3-dihydrobenzofuran-4-yl)sulfonyl)-1H-pyrazole (200 mg, 0.65 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), then palladium on carbon (22 mg) was added. After purging with nitrogen three times, hydrogen was introduced, and the reaction solution was reacted at room temperature for 16 hours. LCMS monitored the disappearance of the raw materials. The reaction solution was filtered to remove palladium on carbon, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 175 mg of 4-((1-methyl-1H-pyrazole-4-yl)sulfonyl)-2,3-dihydrobenzofuran-7-amine.

[0803] MS(ESI) M / Z: 280.0 [M+H] + 。

[0804] Step D: Dissolve 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-2,3-dihydrobenzofuran-7-amine (150 mg, 0.54 mmol) in tetrahydrofuran (5 mL), then successively add 3-(trimethylsilyl)propanal (135 mg, 1.08 mmol), p-toluenesulfonic acid (46 mg, 0.27 mmol) and 3A molecular sieve (534 mg), displace with nitrogen three times, and react at room temperature for 3 hours.

[0805] TLC plate detection showed that the raw materials disappeared. Add sodium cyanoborohydride (34 mg, 1.08 mmol) to the reaction solution and continue to react at room temperature for 1 hour. LCMS monitoring showed that the raw materials disappeared. Filter the reaction solution to remove the molecular sieve, concentrate the filtrate, and purify the residue by silica gel column chromatography to obtain 200 mg of 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-N-(3-(trimethylsilyl)prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine.

[0806] MS(ESI) M / Z: 390.1 [M+H] + 。

[0807] Step E: Dissolve 4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-N-(3-(trimethylsilyl)prop-2-yn-1-yl)-2,3-dihydrobenzofuran-7-amine (85 mg, 0.22 mmol) in anhydrous dimethyl sulfoxide (5 mL), successively add compound INT-3-A (100 mg, 0.22 mmol), copper(I) iodide (31 mg, 0.16 mmol), N,N-diisopropylethylamine (85 mg, 0.66 mmol) and bis(triphenylphosphine)palladium(II) dichloride (31 mg, 0.04 mmol), displace with nitrogen three times, and react at 50 °C for 16 hours.

[0808] LCMS monitoring showed that the raw materials disappeared. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by prep-HPLC to obtain 27.51 mg of compound N-(3-fluoro-1-methylpiperidin-4-yl)-2-(3-((4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine.

[0809] Separation conditions: Preparation column: Sunfire Prep C18 OBD 19*250mm 10um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 25%-35%, detection wavelength: 214nm / 254nm, retention time: 9.87 min.

[0810] MS(ESI) M / Z: 645.5 [M+H] + 。

[0811] 1 H NMR(400 MHz, CD3OD) δ 8.12(s, 1H), 7.75(d, J = 0.8 Hz, 1H), 7.42(d, J = 8.5 Hz, 1H), 7.09(t, J = 8.0 Hz, 1H), 6.92(s, 1H), 6.80(d, J = 8.5 Hz, 1H), 6.75(d, J = 8.3 Hz, 1H), 6.36(d, J = 7.7 Hz, 1H), 4.77–4.66(m, 2H), 4.63(t, J = 8.9 Hz, 2H), 4.35(s, 2H), 3.88(s, 3H), 3.85–3.68(m, 2H), 3.58–3.37(m, 4H), 3.25–3.17(m, 1H), 2.97–2.75(m, 2H), 2.74–2.64(m, 1H), 2.58(s, 3H).

[0812] Example 33: N-(3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-5-methoxy-1H-indazol-6-amine

[0813] Reaction route:

[0814]

[0815] Step A: Dissolve 5-methoxy-6-nitroindazole (200 mg, 1.03 mmol) in THF (4 mL) and methanol (4 mL), then after purging with nitrogen three times, add palladium on carbon (221 mg, 2.07 mmol). After purging with nitrogen three times again, purge the reaction solution with hydrogen three times and react at 25 °C for 3 hours.

[0816] LCMS detection showed that the raw material disappeared. Filter the reaction solution to remove palladium on carbon, and concentrate the filtrate under reduced pressure to obtain 170 mg of 5-methoxy-1H-indazol-6-amine. It is used directly in the next step without purification.

[0817] MS(ESI) M / Z: 164.1 [M+H]+ .

[0818] Step B: Dissolve 5-methoxy-1H-indazole-6-amine (170 mg, 1.03 mmol) in THF (5 mL), then successively add 3-(trimethylsilyl)propanal (261 mg, 2.07 mmol), p-toluenesulfonic acid (71 mg, 0.41 mmol) and 3A molecular sieve (340 mg). Replace the gas with nitrogen three times and react at 25 °C for 3 hours.

[0819] TLC plate detection shows that the raw materials disappear. Add sodium cyanoborohydride (222 mg, 3.54 mmol) to the reaction solution and continue to react at 25 °C for 1 hour. LCMS monitoring shows that the raw materials disappear. Filter the reaction solution to remove the molecular sieve, concentrate the filtrate, and purify the residue by silica gel column chromatography to obtain 69 mg of 5-methoxy-N-(3-(trimethylsilyl)propyl-2-yn-1-yl)-1H-indazole-6-amine.

[0820] MS(ESI) M / Z: 274.1 [M+H] + .

[0821] Step C: Dissolve the compound 5-methoxy-N-(3-(trimethylsilyl)propyl-2-yn-1-yl)-1H-indazole-6-amine (46 mg, 0.17 mmol) in dimethyl sulfoxide (2 mL), and successively add INT-3-A (77 mg, 0.17 mmol), copper iodide (16 mg, 0.08 mmol), N,N-diisopropylethylamine (66 mg, 0.51 mmol) and bis(triphenylphosphine)palladium dichloride (18 mg, 0.03 mmol). After replacing the gas with nitrogen three times, react at 50 °C for 16 hours.

[0822] LCMS monitoring shows that the raw materials disappear. Add water to the reaction solution and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by prep-HPLC to obtain 6.64 mg of N-(3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)-5-methoxy-1H-indazole-6-amine.

[0823] Separation conditions: Preparation column: Sunfire Prep C18 OBD 19*250 mm 10um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 25%-32%, detection wavelength: 214 nm / 254 nm, retention time: 8.73 min.

[0824] MS(ESI) M / Z: 529.4 [M+H] + 。

[0825] 1 H NMR (400 MHz, CD3OD) δ 7.78 (s, 1H), 7.21–6.97 (m, 5H), 6.90 (s, 1H), 6.78 (s, 2H), 6.71 (d, J = 8.3 Hz, 2H), 6.33 (d, J = 7.7 Hz, 3H), 4.77–4.63 (m, 2H), 4.36 (s, 2H), 3.92 (s, 3H), 3.72–3.54 (m, 1H), 3.26–3.15 (m, 1H), 3.03–2.88 (m, 1H), 2.46–2.37 (m, 1H), 2.32 (s, 3H), 2.31–2.21 (m, 2H), 2.10–1.87 (m, 3H).

[0826] Example 34: N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)-2-(3-((4-(5-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine

[0827] Reaction route:

[0828]

[0829] Step A: tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-7-yl)carbamate (0.29 g, 0.80 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (0.064 g, 1.6 mmol) and 3-bromopropyne (0.14 g, 1.20 mmol) were added under ice-water bath and stirring. The reaction was stirred for 0.5 h.

[0830] LC-MS showed the reaction was completed. After adding water (50 mL) to the reaction solution, it was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the obtained crude residue was separated by silica gel column chromatography to give 303 mg of tert-butyl prop-2-yn-1-yl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-7-yl)carbamate.

[0831] MS(ESI) M / Z: 344.2 [M-71+H] + 。

[0832] Step B: At room temperature, dissolve tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-7-yl)(prop-2-yn-1-yl)carbamate (150 mg, 0.37 mmol) in dimethyl sulfoxide (5 mL), add tert-butyl (3S,4R)-3-fluoro-4-((2-iodo-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate (0.200 g, 0.37 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.029 g, 0.037 mmol), N,N-diisopropylethylamine (0.14 g, 1.11 mmol), and copper(I) iodide (0.014 g, 0.074 mmol). Under nitrogen protection, stir the reaction at 50 °C for 16 h. LC-MS shows that the reaction is complete.

[0833] Add water (50 mL) to the reaction solution and extract with ethyl acetate (3 × 100 mL). Wash the combined organic phases with saturated brine (50 mL), dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate, and separate the resulting crude residue by silica gel column chromatography to obtain 150 mg of tert-butyl (3S,4R)-4-((2-(3-((tert-butoxycarbonyl))(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino.

[0834] Step C: tert-Butyl (3S,4R)-4-((2-(3-((tert-butoxycarbonyl))(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino (150 mg, 0.18 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). Under stirring, 3-bromo-5-methyl-1H-pyrazole (59 mg, 0.37 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.013 g, 0.018 mmol), and potassium carbonate (0.074 g, 0.54 mmol) were added. The reaction mixture was then heated to 110 °C and stirred for 16 h. After LC-MS showed the reaction was completed, water (50 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude residue was separated by silica gel column chromatography to obtain 65 mg of tert-Butyl (3S,4R)-4-((2-(3-(tert-butoxycarbonyl)(4-(5-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino.

[0835] Step D: At room temperature, tert-Butyl (3S,4R)-4-((2-(3-(tert-butoxycarbonyl)(4-(5-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino (65 mg, 0.084 mmol) was added to HCl / EA (5 mL), and the reaction mixture was stirred for 1 h.

[0836] LC-MS showed that the starting material disappeared and the product was formed. The reaction mixture was concentrated to obtain 51 mg of N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((4-(5-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine, which was used directly in the next step without purification.

[0837] MS(ESI) M / Z: 284.3 [M / 2 + H] + 。

[0838] Step E: Under an ice-water bath, N-((3S,4R)-3-fluoropiperidin-4-yl)-2-(3-((4-(5-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (51 mg, crude product) was added to a methanol (10 mL) solution, followed by the addition of formaldehyde (0.5 mL) and acetic acid (0.5 mL). The reaction was carried out at 0 °C for ten minutes, and then sodium cyanoborohydride (76 mg, 0.36 mmol) was added.

[0839] The reaction was carried out at 0 °C for 1 hour.

[0840] LC-MS showed that the reaction was completed. The reaction mixture was made alkaline with an aqueous NaHCO3 solution and then extracted with ethyl acetate (2 × 50 mL). The extract was concentrated and filtered. 12.19 mg of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((4-(5-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine was prepared.

[0841] MS (ESI) m / z: 581.6 [M+H] + .

[0842] 1 1H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 7.8 Hz, 1H), 6.19 (s, 1H), 5.74–5.41 (m, 2H), 5.13–4.83 (m, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.26 (d, J = 6.5 Hz, 2H), 3.08–2.95 (m, 1H), 2.88–2.75 (m, 1H), 2.30–2.24 (m, 1H), 2.22 (s, 3H), 2.18 (s, 3H), 2.16–2.03 (m, 1H), 2.01–1.86 (m, 1H), 1.69 (d, J = 12.9 Hz, 1H).

[0843] Example 35: 7-(3-(3-Fluoro-1-methylpiperidin-4-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)propyl-2-yn-1-yl)amino)-N-methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide

[0844] Reaction route:

[0845]

[0846] Step A: Dissolve 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid (500 mg, 2.79 mmol) in N,N-dimethylformamide (5 mL). Sequentially add N,N-diisopropylethylamine (1.14 g, 11.16 mmol), HATU (1.27 g, 3.35 mmol) and deuterated methylamine hydrochloride (1.97 g, 27.93 mmol), and react at 115 °C for 16 hours. LCMS monitoring shows that the raw material disappears. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 300 mg of 7-amino-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide.

[0847] MS(ESI) M / Z: 196.1 [M+H] + 。

[0848] Step B: Dissolve 7-amino-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide (250 mg, 1.28 mmol) in N,N-dimethylformamide (3 mL). Sequentially add 3-bromo-1-propyne (304 mg, 2.56 mmol) and potassium carbonate (88 mg, 0.64 mmol), and react at 50 °C for 4 hours.

[0849] LCMS monitoring shows that the raw material disappears. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by prep-HPLC to obtain 100 mg of N-(methyl-d3)-7-(prop-2-yn-1-ylamino)-2,3-dihydrobenzofuran-4-carboxamide.

[0850] MS(ESI) M / Z: 234.2 [M+H] + 。

[0851] Step C: Dissolve N-(methyl-d3)-7-(prop-2-yn-1-ylamino)-2,3-dihydrobenzofuran-4-carboxamide (55 mg, 0.24 mmol) in dimethyl sulfoxide (2 mL). Sequentially add INT-3-A (107 mg, 0.24 mmol), copper(I) iodide (23 mg, 0.12 mmol), N,N-diisopropylethylamine (93 mg, 0.72 mmol) and bis(triphenylphosphine)palladium(II) dichloride (25 mg, 0.04 mmol). After displacing with nitrogen three times, react at 50 °C for 16 hours.

[0852] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain 14.37 mg of 7-(3-(3-fluoro-1-methylpiperidin-4-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)propyl)-2-yn-1-yl)amino)-N-methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide.

[0853] Separation conditions: Preparation column: Sunfire Prep C18 OBD 19*250 mm 10 μm, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 22% - 32%, detection wavelength: 214 nm / 254 nm, retention time: 9.82 min.

[0854] MS(ESI) M / Z: 561.5 [M+H] + 。

[0855] 1 H NMR(400 MHz, CD3OD) δ 7.16 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 7.7 Hz, 1H), 4.80–4.68 (m, 2H), 4.60 (t, J = 8.8 Hz, 2H), 4.33 (s, 2H), 3.97–3.79 (m, 2H), 3.74–3.60 (m, 2H), 3.47 (t, J = 8.8 Hz, 2H), 3.44–3.36 (m, 1H), 3.26–2.93 (m, 3H), 2.76 (s, 3H), 2.27–2.04 (m, 2H).

[0856] Example 36: 1-(7-((3-(4-(((3S,4R)-3-fluoro-1-(methyl-D3)piperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)phosphine 1-oxide

[0857] Reaction route:

[0858]

[0859] Step A: Dissolve tert-butyl (4-bromo-2,3-dihydrobenzofuran-7-yl)carbamate (3 g, 9.6 mmol) in DMA (100 mL). Sequentially add diallylphosphine oxide (1.87 g, 14.4 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (833 mg, 1.44 mmol), potassium phosphate (3.05 g, 14.4 mmol), and palladium(II) acetate (216 mg, 0.96 mmol). Replace the atmosphere with nitrogen three times and react at 150 °C under microwave irradiation for 30 minutes. Add water to the reaction mixture and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by reverse phase (FA) to obtain 1.5 g of tert-butyl (4-(diallylphosphoryl)-2,3-dihydrobenzofuran-7-yl)carbamate.

[0860] MS(ESI) M / Z: 364.2 [M+H] + 。

[0861] Step B: Dissolve tert-butyl (4-(diallylphosphoryl)-2,3-dihydrobenzofuran-7-yl)carbamate (980 mg, 2.7 mmol) in dichloromethane (400 mL). Add Grubbs second generation catalyst (460 mg, 0.54 mmol). Replace the atmosphere with nitrogen three times and react the reaction mixture at 25 °C for 16 hours.

[0862] Monitor the disappearance of the starting material by LCMS. Add water to the reaction mixture and extract twice with ethyl acetate. Combine the organic phases, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by reverse phase (FA) to obtain 680 mg of tert-butyl (4-(1-oxido-2,5-dihydropyrazin-1-yl)-2,3-dihydrobenzofuran-7-yl)carbamate.

[0863] MS(ESI) M / Z: 336.1 [M+H] + 。

[0864] Step C: Dissolve tert-butyl (4-(1-oxido-2,5-dihydropyrazin-1-yl)-2,3-dihydrobenzofuran-7-yl)carbamate (680 mg, 2.0 mmol) in a mixed solution of THF (5 mL) and methanol (5 mL). Add 10% palladium on carbon (340 mg, 0.32 mmol). Replace the atmosphere with nitrogen three times and then replace it with hydrogen three times. Stir at room temperature for 2 hours under a hydrogen atmosphere.

[0865] Monitor the disappearance of the starting material by LCMS. Filter the reaction mixture to remove the palladium on carbon. Concentrate the filtrate under reduced pressure to obtain 500 mg of tert-butyl (4-(1-oxidophospholanyloxy)-2,3-dihydrobenzofuran-7-yl)carbamate, which is used directly in the next step without purification.

[0866] MS (ESI) M / Z: 338.2 [M+H] + .

[0867] Step D: Dissolve tert-butyl (4-(1-phosphine oxide heterocyclopentyloxy)-2,3-dihydrobenzofuran-7-yl)(prop-2-yn-1-yl)carbamate (500 mg, 1.5 mmol) in DMF (8 mL), add sodium hydride (60%, 90 mg, 2.2 mmol) under ice-water bath, stir for half an hour, then add 3-bromopropyne (210 mg, 1.8 mmol) dropwise therein, and stir at room temperature for 2 hours after the addition is complete.

[0868] The disappearance of the starting material was monitored by LCMS, and the reaction solution was quenched by adding saturated ammonium chloride, and then extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to give 500 mg of 1-(7-((3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)phosphoramide oxide.

[0869] MS (ESI) M / Z: 376.2 [M+H] + .

[0870] Step E: 1-(7-((3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)phosphoramide oxide (490 mg, 1.31 mmol) was dissolved in DMSO (8 mL), and 4-bromo-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole (527 mg, 1.31 mmol), N,N-diisopropylethylamine (507 mg, 1.60 mmol), cuprous iodide (124 mg, 0.65 mmol), and bistriphenylphosphine palladium dichloride (138 mg, 0.20 mmol) were added in sequence. After nitrogen substitution three times, the reaction solution was reacted at 50°C for 16 hours.

[0871] The disappearance of the starting material was monitored by LCMS, and water was added to the reaction solution. The product was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column to give 662 mg of 1-(7-((3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)phosphinamide 1-oxide.

[0872] MS (ESI) M / Z: 651.1 [M+H] + .

[0873] Step F: Dissolve 1-(7-((3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)phosphonamide 1-oxide (669 mg, 1.03 mmol) in anhydrous 1,4-dioxane (15 mL). Sequentially add tert-butyl (3S,4R)-4-((tert-butoxycarbonyl)amino)-3-fluoropiperidine-1-carboxylate (335 mg, 1.53 mmol), cesium carbonate (1030 mg, 3.16 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (94 mg, 0.20 mmol), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (94 mg, 0.1 mmol). The reaction is carried out in a sealed tube. After the addition, replace the gas in the sealed tube with nitrogen three times. React the reaction solution at 90 °C for 16 h.

[0874] Monitor the disappearance of the starting material by LCMS. Add water to the reaction solution and extract twice with dichloromethane. Combine the organic phases. Dry the organic phases over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to obtain 630 mg of tert-butyl (3S,4R)-3-fluoro-4-((2-(3-((4-(phosphono-1-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate.

[0875] MS(ESI) M / Z: 789.3 [M+H] + 。

[0876] Step G: Dissolve tert-butyl (3S,4R)-3-fluoro-4-((2-(3-((4-(phosphono-1-yl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino)piperidine-1-carboxylate (649 mg, 0.82 mmol) in hydrochloric acid / ethyl acetate (15 mL, 2 mol / L, 30 mmol) and react at 25 °C for 1 h.

[0877] LCMS monitoring showed the disappearance of the starting material. The reaction solution was adjusted to pH with sodium bicarbonate solution, extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 488 mg of 1-(7-((3-(4-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)phosphoryl propane 1-oxide. It was used directly in the next step without purification.

[0878] MS(ESI) M / Z: 589.3 [M+H] + 。

[0879] Step H: Dissolve 1-(7-((3-(4-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)phosphoryl propane 1-oxide (50 mg, 0.085 mmol) in methanol (2 mL), and successively add paraformaldehyde-d2 (13 mg, 0.43 mmol) and sodium cyanoborodeuteride-d3 (27 mg, 0.43 mmol), and react at 50 °C for 20 minutes.

[0880] LCMS monitoring showed the disappearance of the starting material. The reaction solution was quenched with ammonia water and 20.67 mg of 1-(7-((3-(4-(((3S,4R)-3-fluoro-1-(methyl-D3)piperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-2,3-dihydrobenzofuran-4-yl)phosphate 1-oxide was obtained by prep-HPLC (NH3H2O).

[0881] MS(ESI) M / Z: 606.5 [M+H] + 。

[0882] 1 H NMR (400 MHz, CD3OD) δ 7.16–7.04 (m, 2H), 6.90 (s, 1H), 6.81 (dd, J = 8.2, 2.7 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 7.7 Hz, 1H), 4.78–4.68 (m, 2H), 4.65 (t, J = 8.8 Hz, 2H), 4.34 (s, 2H), 3.73–3.55 (m, 1H), 3.47–3.36 (m, 2H), 3.25–3.15 (m, 1H), 2.99–2.88 (m, 1H), 2.44–2.07 (m, 6H), 2.02–1.85 (m, 6H).

[0883] Referring to the above embodiments, the following compound was synthesized:

[0884]

[0885]

[0886]

[0887] Example 45: 7-((3-(4-((3S,4R)-3-Fluoro-1-(methyl-d3)piperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide

[0888] Reaction route:

[0889]

[0890] Step A: Dissolve 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid (500 mg, 2.79 mmol) in N,N-dimethylformamide (5 mL), and successively add N,N-diisopropylethylamine (1.14 g, 11.16 mmol), HATU (1.27 g, 3.35 mmol) and deuterated methylamine hydrochloride (1.97 g, 27.93 mmol), and react at 115 °C for 16 hours.

[0891] LCMS monitoring showed that the raw materials disappeared. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 300 mg of 7-amino-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide.

[0892] MS(ESI) M / Z: 196.1 [M+H] + .

[0893] Step B: Dissolve 7-amino-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide (250 mg, 1.28 mmol) in N,N-dimethylformamide (3 mL), and successively add 3-bromo-1-propyne (304 mg, 2.56 mmol) and potassium carbonate (88 mg, 0.64 mmol), and react at 50 °C for 4 hours.

[0894] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC in the reverse phase to obtain 100 mg of N-(methyl-d3)-7-(prop-2-yn-1-ylamino)-2,3-dihydrobenzofuran-4-carboxamide.

[0895] MS(ESI) M / Z: 234.2 [M+H] + 。

[0896] Step C: N-(methyl-d3)-7-(prop-2-yn-1-ylamino)-2,3-dihydrobenzofuran-4-carboxamide (150 mg, 0.64 mmol) was dissolved in dimethyl sulfoxide (3 mL). 4-Bromo-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole (312 mg, 0.77 mmol), copper(I) iodide (51 mg, 0.52 mmol), and N,N-diisopropylethylamine (250 mg, 1.93 mmol) were added successively. The mixture was degassed with nitrogen three times and reacted at 50 °C for 16 h.

[0897] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 90 mg of 7-((3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide.

[0898] MS(ESI) M / Z: 509.4 / 511.4 [M+H] + 。

[0899] Step D: 7-((3-(4-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide (90 mg, 0.18 mmol) was dissolved in 1,4-dioxane (3 mL). (3S,4R)-tert-Butyl 4-amino-3-fluoropiperidine-1-carboxylate (46 mg, 0.21 mmol), cesium carbonate (173 mg, 0.53 mmol), RuPhos (16 mg, 0.035 mmol), and Brettphos Pd G3 (16 mg, 0.017 mmol) were added successively. The mixture was degassed with nitrogen three times and reacted at 75 °C for 16 h.

[0900] LCMS monitoring showed the disappearance of the starting material. The reaction solution was added with water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 60 mg of (3S,4R)-3-fluoro-4-((2-(3-((4-((methyl-d3)carbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino).

[0901] MS(ESI) M / Z: 647.4 [M+H] + 。

[0902] Step E: (3S,4R)-3-fluoro-4-((2-(3-((4-((methyl-d3)carbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)prop-1-yn-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)amino) (60 mg, 0.093 mmol) was dissolved in hydrochloric acid / ethyl acetate (2 moL / L, 1 mL, 2 mmol), and reacted at 25 °C for 1 hour.

[0903] LCMS monitoring showed the disappearance of the starting material. The reaction solution was added with water, adjusted to pH with sodium hydroxide solution, extracted with ethyl acetate, the organic phase was dried and concentrated to obtain 50 mg of 7-((3-(4-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amine)-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide.

[0904] MS(ESI) M / Z: 547.3 [M+H] + 。

[0905] Step F: 7-((3-(4-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amine)-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide (50 mg, 0.092 mmol) was dissolved in methanol (1 mL), and paraformaldehyde-d2 (15 mg, 0.46 mmol) and sodium cyanoborodeuteride-d3 (30 mg, 0.46 mmol) were added successively, and reacted at 50 °C for 1 hour.

[0906] LCMS monitoring showed the disappearance of the raw material. The reaction solution was quenched with ammonia water, and 2.60 mg of 7-((3-(4-((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-N-(methyl-d3)-2,3-dihydrobenzofuran-4-carboxamide was obtained by prep-HPLC (NH3H2O).

[0907] The obtained product was separated by HPLC. Separation conditions: Preparation column: Sunfire Prep C18 OBD 19*250mm 10um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 24%-29%, detection wavelength: 214 nm / 254 nm, retention time: 10.29 min.

[0908] MS(ESI) M / Z: 564.5 [M+H] + 。

[0909] 1 H NMR(400 MHz, CD3OD) δ 7.16 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.73 (t, J = 7.4 Hz, 2H), 6.35 (d, J = 7.7 Hz, 1H), 4.80–4.67 (m, 2H), 4.60 (t, J = 8.8 Hz, 2H), 4.33 (s, 2H), 3.87–

[0910] 3.59 (m, 2H), 3.47 (t, J = 8.8 Hz, 2H), 3.14–3.02 (m, 1H), 2.77–2.34 (m, 3H), 2.15–1.92 (m, 2H).

[0911]

[0912]

[0913]

[0914]

[0915]

[0916] Example 63:

[0917] 3-(3-(3S,4R)-3-Fluoro-1-methylpiperidin-4-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-ynyl)amino)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide

[0918] Reaction route:

[0919]

[0920] Step A: Dissolve 3-bromo-2-hydroxybenzaldehyde (35 g, 175 mmol) in N,N-dimethylformamide (500 mL), then add 1,2-dibromoethane (165.5 g, 875 mmol) and potassium carbonate (150 g, 1.09 mol), and react at 60 °C for 16 hours. TLC plate detection shows that the raw materials disappear. Filter the potassium carbonate from the reaction solution, dilute with water, extract three times with ethyl acetate, wash the organic phase twice with saturated ammonium chloride solution, dry, concentrate, and obtain 42 g of 3-bromo-2-(2-bromoethoxy)benzaldehyde by silica gel column chromatography.

[0921] MS(ESI) M / Z: 308.9 [M+H] + .

[0922] Step B: Dissolve 3-bromo-2-(2-bromoethoxy)benzaldehyde (10 g, 32.47 mmol) in ultradry tetrahydrofuran (100 mL), then add potassium tert-butoxide solution (1 mol / L, 65 mL, 65 mmol) at -30 °C and react at -30 °C for 5 hours. TLC plate detection shows that the raw materials disappear. Pour the reaction solution into saturated ammonium chloride solution to quench, extract three times with ethyl acetate, dry the organic phase, concentrate, and obtain 7 g of 3-bromo-2-(vinyloxy)benzaldehyde by silica gel column chromatography.

[0923] 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.07 (dd, J = 7.9, 1.5 Hz, 1H), 7.84 (dd, J = 7.7, 1.4 Hz, 1H), 7.53 (dd, J = 7.9, 1.4 Hz, 1H), 6.96 (dd, J = 14.3, 5.9 Hz, 1H), 4.42 (dd, J = 6.3, 2.8 Hz, 1H), 4.14 (d, J = 2.8 Hz, 1H).

[0924] Step C: Dissolve 3-bromo-2-(vinyloxy)benzaldehyde (7 g, 30.97 mmol) in methanol (70 mL), then add 4-methylbenzenesulfonylhydrazide (6.3 g, 34.07 mmol) and react at 25 °C for 18 hours.

[0925] LCMS analysis showed that the reaction was completed. The reaction mixture was concentrated, and silica gel column chromatography was performed to obtain 4.7 g of 3-bromo-2-vinyloxybenzylidene-4-methylbenzenesulfonylhydrazide.

[0926] MS(ESI) M / Z: 395.0 / 397.0 [M+H] + 。

[0927] Step D: 3-Bromo-2-vinyloxybenzylidene-4-methylbenzenesulfonylhydrazide (3.2 g, 8.12 mmol) was dissolved in dry toluene (35 mL), then lithium tert-butoxide (4.06 mL, 2.2 mol / L, 8.93 mmol) and rhodium octanoate (632 mg, 0.81 mmol) were added. The reaction system was purged with nitrogen three times and then reacted at 100 °C for 3 hours.

[0928] LCMS analysis showed that the starting material had disappeared. The reaction mixture was filtered, and silica gel column chromatography was performed on the filtrate to obtain 1.37 g of 3-bromo-1a,6b-dihydro-1H-cyclopropa[b]benzofuran.

[0929] 1 1H NMR (400 MHz, CDCl3) δ 7.32–7.17 (m, 2H), 6.74 (t, J = 7.7 Hz, 1H), 4.92–4.89 (m, 1H), 2.71–2.67 (m, 1H), 1.06–1.03 (m, 1H), 0.46–0.32 (m, 1H).

[0930] Step E: 3-Bromo-1a,6b-dihydro-1H-cyclopropa[b]benzofuran (1.7 g, 8.1 mmol) and tert-butyl carbamate (1.89 g, 16.2 mmol) were dissolved in dry 1,4-dioxane (35 mL), then cesium carbonate (7.9 g, 24.3 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (936 mg, 1.62 mmol) and tris(dibenzylideneacetone)dipalladium (1.48 g, 1.62 mmol) were added. The reaction was carried out at 90 °C for 4 hours.

[0931] LCMS analysis showed that the starting material had disappeared. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 1.6 g of tert-butyl (1a,6b-dihydro-1H-cyclopropa-3-yl)carbamate.

[0932] MS(ESI) M / Z: 192.0 [M+H-56] + 。

[0933] Step F: Dissolve tert-butyl (1a,6b-dihydro-1H-cyclopropa[e]benzofuran-3-yl)carbamate (1.0 g, 4.05 mmol) in dichloromethane (10 mL), then add trifluoroacetic acid (3 mL), and react at 25 °C for 2 hours.

[0934] LCMS detection showed that the raw material disappeared. Dilute the reaction solution with water, adjust the pH to 10 with sodium hydroxide, extract with dichloromethane, dry the organic phase, concentrate, and purify by silica gel column chromatography to obtain 560 mg of compound 1a,6b-dihydro-1H-cyclopropa[e]benzofuran-3-amine.

[0935] MS(ESI) M / Z: 148.1[M+H] + 。

[0936] Step G: Dissolve compound 1a,6b-dihydro-1H-cyclopropa[e]benzofuran-3-amine (557 mg, 3.78 mmol) in N,N-dimethylformamide (5 mL), then add N-bromosuccinimide (610 mg, 3.40 mmol), and react at 0 °C for 6 minutes.

[0937] LCMS detection showed that the reaction was completed. Dilute the reaction solution with water, extract with ethyl acetate, dry the organic phase, concentrate, and purify by silica gel column chromatography to obtain 630 mg of compound 6-bromo-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-3-amine.

[0938] MS(ESI) M / Z: 226.0 / 228.0[M+H] + 。

[0939] Step H: Dissolve compound 6-bromo-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-3-amine (510 mg, 2.27 mmol) in toluene / ethanol (10 mL / 2 mL), then successively add 4-dimethylaminopyridine (1.17 g, 9.6 mmol), palladium acetate (25 mg, 0.11 mmol), dicobalt octacarbonyl (660 mg, 1.93 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (131 mg, 0.227 mmol), displace with nitrogen three times, and react at 105 °C for 16 hours.

[0940] LCMS detection showed that the raw material disappeared. Filter the reaction solution through diatomaceous earth, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 180 mg of compound ethyl 3-amino-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxylate.

[0941] MS(ESI) M / Z: 220.1[M+H] + 。

[0942] Step I: Dissolve ethyl 3-amino-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxylate (200 mg, 0.91 mmol) in ethanol (9 mL), then add sodium hydroxide solution (5 mol / L, 3.6 mL, 18 mmol), and react at 60 °C for 2 hours.

[0943] TLC plate detection showed that the raw materials disappeared. The reaction solution was concentrated, diluted with water, adjusted to pH = 3 with 1 M dilute hydrochloric acid, extracted three times with ethyl acetate, the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate to obtain 170 mg of 3-amino-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxylic acid.

[0944] MS(ESI) M / Z: 192.1 [M+H] + 。

[0945] Step J: Dissolve 3-amino-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxylic acid (170 mg, 0.89 mmol) and methylamine hydrochloride (601 mg, 8.9 mmol) in N,N-dimethylformamide (3 mL), successively add N,N-diisopropylethylamine (459 mg, 3.56 mmol), HATU (406 mg, 1.07 mmol), and react at 25 °C for 16 hours.

[0946] LCMS monitoring showed that the raw materials disappeared. The reaction solution was added with water, extracted twice with ethyl acetate, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 170 mg of 3-amino-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide.

[0947] MS(ESI) M / Z: 205.1 [M+H] + 。

[0948] Step K: Dissolve 3-amino-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide (170 mg, 0.83 mmol) in N,N-dimethylformamide (2 mL), successively add 3-bromo-1-propyne (196 mg, 1.66 mmol) and potassium carbonate (57 mg, 0.42 mmol), and react at 50 °C for 3 hours.

[0949] LCMS monitoring showed that the raw materials disappeared. The reaction solution was added with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC (FA) to obtain 80 mg of compound N-methyl-3-propyl-2-propynylamino-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide.

[0950] MS(ESI) M / Z: 243.1 [M+H] + 。

[0951] Step L: Dissolve compound N-methyl-3-propyl-2-propynylamino-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide (20 mg, 0.08 mmol) in dimethyl sulfoxide (1.5 mL). Then add compound INT-3-A (38 mg, 0.08 mmol), copper(I) iodide (11 mg, 0.06 mmol), N,N-diisopropylethylamine (31 mg, 0.24 mmol) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.016 mmol) in sequence. After purging with nitrogen three times, react at 50 °C for 16 hours.

[0952] LCMS monitoring showed that the raw materials disappeared. The reaction solution was added with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by HPLC (FA) to obtain 18.34 mg of compound 3-(3-(3S,4R)-3-fluoro-1-methylpiperidin-4-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-ynyl)amino)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide.

[0953] Separation conditions: Preparation column: Sunfire Prep C18 OBD 19*250 mm 10 um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 25%-29%, detection wavelength: 214 nm / 254 nm, retention time: 9.16 min.

[0954] MS(ESI) M / Z: 570.4 [M+H] + 。

[0955] 11H NMR (400 MHz, CD3OD) δ 7.17 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 0.9 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 4.76–4.67 (m, 2H), 4.31 (s, 2H), 3.85–3.60 (m, 1H), 3.43–3.32 (m, 2H), 3.19–3.01 (m, 2H), 2.91 (s, 3H), 2.77–2.50 (m, 2H), 2.48 (s, 3H), 2.15–1.92 (m, 2H), 1.18–1.00 (m, 1H), 0.37–0.17 (m, 1H).

[0956] Example 64

[0957] (1aS,6bS)-3-((3-(4-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide

[0958] and

[0959] (1aR,6bR)-3-((3-(4-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide

[0960]

[0961] The compound prepared in Example 63 was separated by chiral HPLC. Separation conditions: chiral column AD 250 * 30 mm, 10 μm; Mobile phase: MEOH(+0.1% 7.0 mol / l Ammonia in MEOH), Flow rate: 100 mL / min, Gradient: 40%, Detection wavelength: 214 nm, Obtained 18.27 mg of compound 64A with elution time of 2.710 min and 17.06 mg of compound 64B with elution time of 3.701 min. The two compounds that have no corresponding relationship are (1aS,6bS)-3-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-ynyl)amino)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide and (1aR,6bR)-3-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide.

[0962] 64A:

[0963] MS(ESI) M / Z: 285.7 [M / 2 + H] + 。

[0964] 1 H NMR(400 MHz, CD3OD) δ 7.17(d, J = 8.3 Hz, 1H), 7.08(t, J = 8.0 Hz, 1H), 6.89(s, 1H), 6.72(d, J = 8.2 Hz, 1H), 6.70(d, J = 8.4 Hz, 1H), 6.34(d, J = 7.7 Hz, 1H), 4.94–4.88(m, 2H), 4.78–4.66(m, 2H), 4.31(s, 2H), 3.82–3.54(m, 1H), 3.26–3.16(m, 1H), 3.19–3.01(m, 1H), 3.00–2.90(m, 1H), 2.91(s, 3H), 2.32(s, 3H), 2.32–2.15(m, 2H), 2.04–1.82(m, 2H), 1.17–0.99(m, 1H), 0.44–0.14(m, 1H).

[0965] 64B:

[0966] MS(ESI) M / Z: 285.7 [M / 2 + H] +

[0967] 11H NMR (400 MHz, CD3OD) δ 7.17 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.88 (s, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 7.7 Hz, 1H), 4.93–4.88 (m, 2H), 4.78–4.65 (m, 2H), 4.31 (s, 2H), 3.79–3.54 (m, 1H), 3.25–3.14 (m, 1H), 3.13–3.01 (m, 1H), 3.01–2.92 (m, 1H), 2.91 (s, 3H), 2.31 (s, 3H), 2.30–2.16 (m, 2H), 2.03–1.84 (m, 2H), 1.14–1.00 (m, 1H), 0.27–0.20 (m, 1H).

[0968] The target compound was prepared according to the synthesis method of the reference example as follows:

[0969]

[0970]

[0971]

[0972]

[0973]

[0974] Example 75:

[0975] 3-((3-(4-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-1-(methoxymethyl)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide

[0976] Reaction route:

[0977]

[0978]

[0979] Reaction route:

[0980] Step A: Dissolve 7-bromobenzofuran (7 g, 35.53 mmol) and rhodium acetate (1.57 g, 3.53 mmol) in dichloromethane (70 mL). Replace the gas with nitrogen three times. Dissolve ethyl diazoacetate (12.15 g, 106.58 mmol) in dichloromethane (30 mL) under an ice bath and slowly add it dropwise to the reaction solution. After the addition, stir at room temperature overnight.

[0981] TLC detection shows that the raw materials have basically disappeared. Pour the reaction solution into water and extract with ethyl acetate. Dry the organic phase, concentrate it, and purify it by Flash (FA) reverse phase to obtain 4 g of ethyl 3-bromo-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate.

[0982] 1 1H NMR (400 MHz, CDCl3) δ 7.34–7.29 (m, 2H), 6.85–6.79 (m, 1H), 5.15 (dd, J = 5.4, 1.1 Hz, 1H), 4.18 (qd, J = 7.1, 2.3 Hz, 2H), 3.33 (dd, J = 5.4, 3.2 Hz, 1H), 1.35 (dd, J = 3.2, 1.1 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H)

[0983] Step B: Dissolve ethyl 3-bromo-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylate (4 g, 14.13 mmol) in dichloromethane (40 mL). Replace the gas with nitrogen three times. Add diisobutylaluminum hydride (1.5 M, 60 mL, 84.78 mmol) dropwise at -78 °C. After the addition, stir at -78 °C for 2 hours.

[0984] TLC detection shows that the raw materials have disappeared. Pour the reaction solution into a solution of potassium sodium tartrate and stir for 2 hours. Let it stand for layering. After separating the organic phase, extract the aqueous phase with dichloromethane twice. Combine the organic phases, dry them, concentrate them, and purify them by silica gel column chromatography to obtain 3.3 g of (3-bromo-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)methanol.

[0985] 1 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 2H), 6.76 (t, J = 7.7 Hz, 1H), 4.79 (dd, J = 5.6, 1.2 Hz, 1H), 3.73–3.60 (m, 2H), 2.74 (dd, J = 5.6, 3.4 Hz, 1H), 0.98 (td, J = 6.9, 3.4 Hz, 1H).

[0986] Step C: Dissolve (3-bromo-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)methanol (3.3 g, 13.69 mmol) in tetrahydrofuran (30 mL). Add sodium hydride (1.1 g, 27.38 mmol) under an ice bath. After the addition is complete, stir for half an hour, then add iodomethane (5.8 g, 41.07 mmol) dropwise, and stir at 25 °C for 2 hours.

[0987] TLC detection shows that the raw materials disappear. Pour the reaction solution into saturated ammonium chloride solution, then extract with ethyl acetate. Dry the organic phase, concentrate it, and purify it by silica gel column chromatography to obtain 3.2 g of 3-bromo-1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran.

[0988] 1 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 10.6, 3.6 Hz, 2H), 6.77–6.72 (m, 1H), 4.76 (dd, J = 5.5, 1.3 Hz, 1H), 3.50 (dd, J = 10.6, 6.2 Hz, 1H), 3.36 (s, 3H), 3.31 (dd, J = 10.6, 7.2 Hz, 1H), 2.73 (dd, J = 5.5, 3.4 Hz, 1H), 0.96 (m, 1H).

[0989] Step D: Dissolve 3-bromo-1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran (3.1 g, 12.11 mmol) and tert-butyl carbamate (2.84 g, 24.22 mmol) in ultradry 1,4-dioxane (35 mL), then add cesium carbonate (11.84 g, 36.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.4 g, 2.42 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.4 g, 2.42 mmol), and react at 120 °C for 16 hours.

[0990] LCMS detection shows that the raw materials disappear. Pour the reaction solution into water, extract with ethyl acetate. Dry the organic phase, concentrate it, and purify it by silica gel column chromatography to obtain 2.7 g of tert-butyl (1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-3-yl)carbamate.

[0991] MS (ESI) M / Z: 236.1 [M+H-56] + 。

[0992] Step E: Dissolve tert-butyl (1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-3-yl)carbamate (2.7 g, 9.27 mmol) in dichloromethane (20 mL), then add trifluoroacetic acid (10 mL), and react at 25 °C for 2 hours.

[0993] LCMS detection showed that the raw material disappeared. The reaction solution was diluted with water, the pH was adjusted to 10 with sodium hydroxide, and extracted with dichloromethane. The organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 1.6 g of 1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-3-amine.

[0994] MS(ESI) M / Z: 192.1[M+H] + 。

[0995] Step F: Dissolve 1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-3-amine (1.6 g, 8.47 mmol) in N,N-dimethylformamide (16 mL), then add N-bromosuccinimide (1.58 g, 8.89 mmol) under ice bath, and react at room temperature for 2 hours.

[0996] LCMS detection showed that the reaction was completed. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, the organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 1.8 g of 6-bromo-1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-3-amine.

[0997] MS(ESI) M / Z: 269.9 / 271.9[M+H] + 。

[0998] Step G: Dissolve 6-bromo-1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-3-amine (1 g, 3.7 mmol) in toluene / ethanol (15 mL / 3 mL), then successively add 4-dimethylaminopyridine (1.91 g, 15.65 mmol), palladium acetate (42 mg, 0.19 mmol), dicobalt octacarbonyl (1.27 g, 3.7 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (210 mg, 0.37 mmol). Replace with nitrogen three times and react at 105 °C for 16 hours.

[0999] LCMS detection showed that the raw material disappeared. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 470 mg of ethyl 3-amino-1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxylate.

[1000] MS(ESI) M / Z: 527.1 [2M + H] + 。

[1001] Step H: Dissolve ethyl 3-amino-1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxylate (470 mg, 1.79 mmol) in ethanol (5 mL), then add sodium hydroxide solution (5 mol / L, 5 mL, 25 mmol), and react at 60 °C for 2 hours.

[1002] TLC plate detection showed that the raw materials disappeared. The reaction solution was concentrated, diluted with water, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid. It was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 444 mg of 3-amino-1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxylic acid.

[1003] MS(ESI) M / Z: 234.2 [M - H] - 。

[1004] Step I: Dissolve 3-amino-1-(methoxymethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxylic acid (444 mg, 1.89 mmol) and methylammonium hydrochloride (1.28 g, 18.9 mmol) in N,N-dimethylformamide (10 mL). Sequentially add N,N-diisopropylethylamine (977 mg, 7.56 mmol) and HATU (1.08 g, 2.83 mmol), and react at 25 °C for 16 hours.

[1005] LCMS monitoring showed that the raw materials disappeared. The reaction solution was added with water, extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 360 mg of 3-amino-1-(methoxymethyl)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide.

[1006] MS(ESI) M / Z: 271.1 [M + Na] + 。

[1007] Step J: Dissolve 3-amino-1-(methoxymethyl)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide (360 mg, 1.45 mmol) in N,N-dimethylformamide (5 mL). Sequentially add 3-bromo-1-propyne (345 mg, 2.9 mmol) and potassium carbonate (200 mg, 1.45 mmol), and react at 50 °C for 16 hours.

[1008] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC (FA) to obtain 180 mg of 1-(methoxymethyl)-N-methyl-3-(prop-2-yn-1-ylamino)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide.

[1009] MS(ESI) M / Z: 309.1 [M+Na] + 。

[1010] Step K: 1-(Methoxymethyl)-N-methyl-3-(prop-2-yn-1-ylamino)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide (151 mg, 0.53 mmol) was dissolved in dimethyl sulfoxide (5 mL). INT-3-A (217 mg, 0.48 mmol), copper(I) iodide (50 mg, 0.27 mmol), N,N-diisopropylethylamine (206 mg, 1.59 mmol) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.08 mmol) were added successively. After three nitrogen purges, the reaction was carried out at 50 °C for 16 h.

[1011] LCMS monitoring showed the disappearance of the starting material. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC (FA) to obtain 154 mg of 3-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amino)-1-(methoxymethyl)-N-methyl-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carboxamide (Compound 75). Separation conditions: Preparation column: Sunfire Prep C18 OBD 19*250 mm 10 um, mobile phase: 0.1% FA in water / CH3CN, flow rate: 20 mL / min, gradient: 45%-52%, detection wavelength: 214 nm / 254 nm, retention time: 9.50 min.

[1012] MS(ESI) M / Z: 614.7 [M+H] + 。

[1013] 11H NMR (400 MHz, CD3OD) δ 7.18 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.88 (s, 1H), 6.71 (t, J = 7.7 Hz, 2H), 6.33 (d, J = 7.7 Hz, 1H), 4.90–4.82 (m, 1H), 4.79–4.77 (m, 1H), 4.72 (q, J = 8.8 Hz, 2H), 4.31 (s, 2H), 3.63 (ddd, J = 17.0, 12.2, 4.4 Hz, 1H), 3.50 (dd, J = 10.7, 6.7 Hz, 1H), 3.38–3.33 (m, 4H), 3.24–3.14 (m, 1H), 3.10 (dd, J = 5.4, 3.3 Hz, 1H), 2.96–2.85 (m, 4H), 2.41–2.21 (m, 5H), 2.02–1.88 (m, 2H), 0.85–0.78 (m, 1H).

[1014] After separation by chiral HPLC, the separation conditions were as follows: chiral column REGIS (S,S) WHELK-O1 250 * 25 mm 10 μm; mobile phase: EtOH (+0.2% 7.0 mol / l Ammonia in MEOH), flow rate: 35 mL / min, gradient: 40%, detection wavelength: 214 nm. 75-P1 (19.35 mg, retention time 6.059 min) and 75-P2 (29.84 mg, retention time 5.01 min) were obtained.

[1015]

[1016] 75-P1:

[1017] MS (ESI) m / z: 614.4 [M + H] + 。

[1018] 11H NMR (400 MHz, CD3OD) δ 7.19 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.79–6.61 (m, 2H), 6.34 (d, J = 7.7 Hz, 1H), 4.83–4.77 (m, 2H), 4.77–4.67 (m, 2H), 4.32 (s, 2H), 3.81–3.56 (m, 2H), 3.58–3.45 (m, 1H), 3.38 (s, 3H), 3.25–3.04 (m, 3H), 3.02–2.92 (m, 1H), 2.90 (s, 3H), 2.32 (s, 3H), 2.31–2.19 (m, 2H), 2.04–1.81 (m, 2H), 1.10–0.72 (m, 1H).

[1019] 75-P2:

[1020] MS (ESI) M / Z: 614.7 [M+H] + 。

[1021] 1 1H NMR (400 MHz, CD3OD) δ 7.22–7.16 (m, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.72 (t, J = 7.9 Hz, 2H), 6.34 (d, J = 7.7 Hz, 1H), 4.79 (d, J = 5.3 Hz, 1H), 4.76–4.67 (m, 2H), 4.32 (s, 2H), 3.76–3.57 (m, 1H), 3.57–3.43 (m, 1H), 3.38 (s, 3H), 3.37–3.32 (m, 1H), 3.26–3.04 (m, 2H), 2.90 (s, 3H), 2.32 (s, 3H), 2.30–2.19 (m, 1H), 2.13–1.85 (m, 2H), 1.02–0.70 (m, 1H).

[1022] Example 76:

[1023] 7 - ((3 - (4 - ((((3S,4R)-3 - fluoro - 1 - methylpiperidin - 4 - yl)amino)-1-(2,2,2 - trifluoroethyl)-1H - indol - 2 - yl)prop - 2 - yn - 1 - yl)amine)-2-(methoxymethyl)-N - methyl - 2,3 - dihydrobenzofuran - 4 - carboxamide

[1024] Reaction route:

[1025]

[1026] Step A: Dissolve 2-hydroxy-3-nitrobenzaldehyde (12.4 g, 74 mmol) in DMF (62 mL), then successively add potassium carbonate (30.8 g, 223 mmol) and diethyl bromomalonate (26.6 g, 111 mmol), and then cool the temperature to 90 °C and react for 16 hours. TLC color development monitoring shows that the raw materials disappear. Add saturated ammonium chloride aqueous solution to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 17.25 g of ethyl 7-nitrobenzofuran-2-carboxylate.

[1027] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (dd, J = 8.1, 1.1 Hz, 1H), 8.28 (dd, J = 7.8, 1.1 Hz, 1H), 7.99 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).

[1028] Step B: Dissolve ethyl 7-nitrobenzofuran-2-carboxylate (14.5 g, 62 mmol) in dichloromethane (145 mL), add 1.5 M diisobutylaluminum hydride (1 M in toluene, 185 mL, 185 mmol), after displacing with nitrogen three times, react the reaction solution at -78 °C for 2 hours.

[1029] TLC color development monitoring shows that the raw materials disappear. Add 10% aqueous solution of potassium sodium tartrate to the reaction solution, stir vigorously for 4 hours, then let it stand for liquid separation, separate the organic phase, extract the aqueous phase twice with dichloromethane, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 7 g of (7-nitrobenzofuran-2-yl)methanol.

[1030] 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J = 18.0, 7.9 Hz, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.03 (s, 1H), 5.68 (t, J = 5.9 Hz, 1H), 4.67 (d, J = 5.9 Hz, 2H).

[1031] Step C: Dissolve (7-nitrobenzofuran-2-yl)methanol (4 g, 21 mmol) in tetrahydrofuran (40 mL), add sodium hydride (60%, 1.7 g, 41 mmol) at 0 °C and react for 0.5 hour, then add iodomethane (8.9 g, 63 mmol) and raise the temperature to room temperature and react for 2 hours.

[1032] After monitoring the reaction by TLC until completion, the reaction mixture was quenched with saturated aqueous ammonium chloride, extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3.42 g of 2-(methoxymethyl)-7-nitrobenzofuran.

[1033] 1 1H NMR (400 MHz, DMSO-d6) δ 8.14 (ddd, J = 19.2, 7.9, 1.1 Hz, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.18 (s, 1H), 4.64 (s, 2H), 3.36 (s, 3H).

[1034] Step D: 2-(Methoxymethyl)-7-nitrobenzofuran (1.2 g, 5.8 mmol) was dissolved in methanol (24 mL), and then the reaction mixture was purged with nitrogen three times and palladium on carbon (614 mg, 5.8 mmol) was added. After purging with nitrogen three times again, the reaction mixture was purged with hydrogen three times and reacted at 25 °C for 3 h.

[1035] LCMS analysis showed the disappearance of the starting material. The reaction mixture was filtered to remove palladium on carbon, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 734 mg of 2-(methoxymethyl)-2,3-dihydrobenzofuran-7-amine. It was used directly in the next step without further purification.

[1036] MS (ESI) m / z: 180.1 [M+H] + 。

[1037] Step E: 2-(Methoxymethyl)-2,3-dihydrobenzofuran-7-amine (734 mg, 4.1 mmol) was dissolved in N,N-dimethylformamide (8 mL), and then N-bromosuccinimide (766 mg, 4.3 mmol) was added. The reaction was carried out at 0 °C for 6 min.

[1038] LCMS analysis showed the completion of the reaction. The reaction mixture was diluted with saturated aqueous ammonium chloride, extracted with ethyl acetate, the organic phase was dried, concentrated, and purified by silica gel column chromatography to give 830 mg of 4-bromo-2-(methoxymethyl)-2,3-dihydrobenzofuran-7-amine.

[1039] MS (ESI) m / z: 258.0 / 259.0 [M+H] + 。

[1040] Step F: Dissolve 4-bromo-2-(methoxymethyl)-2,3-dihydrobenzofuran-7-amine (830 mg, 3.2 mmol) in toluene / ethanol (10 mL / 2 mL), then successively add 4-dimethylaminopyridine (1.7 g, 13.8 mmol), palladium acetate (36 mg, 0.16 mmol), dicobalt octacarbonyl (930 mg, 2.72 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (185 mg, 0.32 mmol). Replace the air with nitrogen three times and react at 105 °C for 16 hours.

[1041] LCMS detection shows that the raw materials disappear. Filter the reaction solution through diatomaceous earth, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 330 mg of ethyl 7-amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylate.

[1042] MS(ESI) M / Z: 252.1 [M+H] + 。

[1043] Step G: Dissolve ethyl 7-amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylate (330 mg, 1.3 mmol) in ethanol (5 mL), then add sodium hydroxide solution (5 mol / L, 5.2 mL, 26 mmol) and react at 60 °C for 2 hours.

[1044] TLC plate detection shows that the raw materials disappear. Concentrate the reaction solution, dilute it with water, adjust the pH to 3 with 1 M dilute hydrochloric acid, extract with ethyl acetate three times, combine the organic phases, and dry the organic phases with anhydrous sodium sulfate to obtain 280 mg of 7-amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid.

[1045] MS(ESI) M / Z: 224.0 [M+H] + 。

[1046] Step H: Dissolve 7-amino-2-(methoxymethyl)-2,3-dihydrobenzofuran-4-carboxylic acid (280 mg, 1.3 mmol) and methylamine hydrochloride (850 mg, 12.6 mmol) in N,N-dimethylformamide (3 mL), successively add N,N-diisopropylethylamine (1.6 g, 12.6 mmol), HATU (599 mg, 1.6 mmol), and react at 25 °C for 16 hours.

[1047] LCMS monitoring shows that the raw materials disappear. Add water to the reaction solution, extract with ethyl acetate twice, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain 261 mg of 7-amino-2-(methoxymethyl)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide.

[1048] MS(ESI) M / Z: 273.1 [M+H] + 。

[1049] Step I: Dissolve 7-amino-2-(methoxymethyl)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (261 mg, 1.1 mmol) in N,N-dimethylformamide (3 mL), sequentially add 3-bromo-1-propyne (262 mg, 2.2 mmol) and potassium carbonate (76 mg, 0.55 mmol), and react at 50 °C for 3 hours.

[1050] LCMS monitoring showed the disappearance of the starting material. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by prep-HPLC (FA) to obtain 129 mg of 2-(methoxymethyl)-N-methyl-7-(prop-2-yn-1-ylamino)-2,3-dihydrobenzofuran-4-carboxamide.

[1051] MS(ESI) M / Z: 275.1 [M+H] + 。

[1052] Step J: Dissolve 2-(methoxymethyl)-N-methyl-7-(prop-2-yn-1-ylamino)-2,3-dihydrobenzofuran-4-carboxamide (129 mg, 0.47 mmol) in dimethyl sulfoxide (5 mL), sequentially add compound N-(3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-1-(2,2,2-trifluoroethyl)-1H-indole-4-amine (214 mg, 0.47 mmol), copper(I) iodide (45 mg, 0.24 mmol), N,N-diisopropylethylamine (182 mg, 1.41 mmol) and bis(triphenylphosphine)palladium(II) dichloride (49 mg, 0.07 mmol). After purging with nitrogen three times, react at 50 °C for 16 hours.

[1053] LCMS monitoring showed the disappearance of the starting material. Add water to the reaction solution, extract twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the residue by HPLC (FA) to obtain 45 mg of 7-((3-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)prop-2-yn-1-yl)amine)-2-(methoxymethyl)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (Compound 76).

[1054] Separation conditions: Preparation column: Waters Xbridge C18 19*250mm 10um, mobile phase: 0.1% NH3H2O in water / CH3CN, flow rate: 20 mL / min, gradient: 45%-50%, detection wavelength: 214nm / 254nm, retention time: 9.43 min.

[1055] MS(ESI) M / Z: 602.3 [M+H] + 。

[1056] 1 H NMR(400 MHz, CD3OD) δ 7.17 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.73 (s, 1H), 6.71 (s, 1H), 6.34 (d, J = 7.7 Hz, 1H), 5.06–4.94 (m, 1H), 4.76–4.61 (m, 2H), 4.32 (s, 2H), 3.76–3.47 (m, 4H), 3.41 (s, 3H), 3.28–3.14 (m, 2H), 3.01–2.89 (m, 1H), 2.86 (s, 3H), 2.42–2.35 (m, 1H), 2.30 (s, 3H), 2.28–2.18 (m, 2H), 2.09–1.85 (m, 3H).

[1057] The obtained product was separated by chiral HPLC. Separation conditions: Preparation column: AD 250*25mm 10μm, mobile phase: MEOH(+0.1% 7.0mol / l Ammonia in MEOH), flow rate: 120 mL / min, gradient: 40%, detection wavelength: 214nm, to obtain 76-P1 (15.05 mg, elution time: 1.834 min), 76-P2 (15.15 mg, elution time: 2.861 min).

[1058]

[1059] 76-P1

[1060] MS(ESI) M / Z: 602.3 [M+H] + 。

[1061] 11H NMR (400 MHz, CD3OD) δ 7.16 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.72 (d, J = 8.4 Hz, 2H), 6.33 (d, J = 7.7 Hz, 1H), 4.98 (t, J = 6.6 Hz, 1H), 4.90 (s, 1H), 4.78 (s, 1H), 4.72 (q, J = 8.8 Hz, 2H), 4.32 (s, 2H), 3.70–3.49 (m, 5H), 3.41 (s, 3H), 3.27–3.16 (m, 2H), 2.93 (d, J = 12.7 Hz, 1H), 2.86 (s, 3H), 2.41–2.20 (m, 5H), 2.02–1.89 (m, 2H).

[1062] 76-P2

[1063] MS (ESI) M / Z: 602.3 [M+H] + 。

[1064] 1 1H NMR (400 MHz, CD3OD) δ 7.17 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.71 (s, 1H), 6.34 (d, J = 7.7 Hz, 1H), 5.05–4.93 (m, 1H), 4.77–4.64 (m, 2H), 4.32 (s, 2H), 3.86–3.47 (m, 4H), 3.41 (s, 3H), 3.28–3.09 (m, 3H), 3.00–2.90 (m, 1H), 2.86 (s, 3H), 2.50–2.35 (m, 1H), 2.31 (s, 3H), 2.29–2.14 (m, 2H), 2.08–1.85 (m, 3H).

[1065] The target compounds were prepared as follows according to the synthesis method of the reference example:

[1066]

[1067]

[1068]

[1069] II. Biological activity experiments

[1070] (I) In vitro DNA binding experiment

[1071] The binding ability of p53 protein to DNA was tested in vitro by homogeneous time-resolved fluorescence (HTRF) method, and the half-maximal effective concentration (EC) of the compound to restore the binding ability of p53 Y220C protein to DNA was obtained. 50 .

[1072] 1. Experimental materials

[1073]

[1074]

[1075] 2. Experimental methods

[1076] The compounds were serially diluted with DMSO in a 384PP Plate compound dilution plate, and 0.1 μL of the compound was transferred to a 384-well reaction microplate (Greiner 784075) using an Echo to ensure that the final DMSO content was 1% (in duplicate). 2.5 μL of P53-Y220C enzyme solution was added to each well of the 384-well reaction microplate and incubated at 25 °C for 10 minutes. 2.5 μL of MAb-Anti-His-Tb solution was added to each well and incubated at 30 °C for 60 minutes. 5 μL of Streptavidin-d2 and dsDNA mixed solution was added to each well and incubated for another 60 minutes (final concentration: 20 mM Hepes (pH 7.5), 75 mM KCl, 1 mM MgCl2, 0.1% BSA, 1 mM DTT, 50 nM P53-Y220C, 10 nM dsDNA, 1×MAb-Anti-His-Tb, 1×Streptavidin-d2). The wells containing 10 μM positive drug and enzyme were used as high control, and the wells containing the same amount of DMSO and enzyme were used as low control. The HTRF signal was read on a BMG (PHERAstar FSX) microplate reader, and the HTRF ratio of each well was calculated using the following formula: HTRF ratio = (signal F665 / signal F620) * 10000. The activation percentage of the compound-treated wells was normalized between the high control and low control (% activation = (HTRF ratio low control - HTRF ratio 化合物处理 ) / (HTRF ratio low control - HTRF ratio high control ) * 100). Then, a four-parameter EC 50 curve was fitted and analyzed by XLfit 5.5.0, and the EC50 It is the compound concentration corresponding to 50% activation degree on the curve.

[1077] 3. Experimental results

[1078] The DNA binding data of the compounds in the embodiments of the present disclosure in vitro are shown in Table 1. It can be seen that the compounds in the embodiments of the present disclosure have good DNA binding activity. The EC 50 of the compounds is generally less than 1000 nM. Preferably, the EC 50 of some compounds is less than 500 nM. More preferably, the EC 50 of some compounds is less than 300 nM. Further preferably, the EC 50 of some compounds is less than 100 nM.

[1079] Table 1

[1080]

[1081]

[1082]

[1083] (2) Cell proliferation inhibition experiment

[1084] The inhibitory proliferation effect of the compounds on NUGC-3, HuH-7, BxPC-3, AGS, BT-549 and NCI-H1299 cell lines was detected by the method of measuring the intracellular ATP content (CellTiter-Glo) by fluorescence method, and the half inhibitory concentration IC of the compounds on the above cell lines was obtained 50 .

[1085] 1. Experimental materials

[1086] RPMI-1640 medium, DMEM medium, fetal bovine serum (FBS), 100X Pen / Strep, and GlutaMAX-I Supplement were purchased from GIBCO; NUGC-3, AGS and BT-549 cell lines were purchased from Nanjing Kebai Biotechnology Co., Ltd., NCI-H1299 and BxPC-3 cell lines were purchased from the American Type Culture Collection (ATCC), and HuH-7 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences; Cell Titer-Glo luminescence cell viability detection reagent was purchased from Promega.

[1087] 2. Experimental method

[1088] 1) Cells were seeded in 384-well culture plates at a density of 200 NUGC-3 cells per well, 200 HuH-7 cells per well, 300 BxPC-3 cells per well, 300 BT-549 cells per well, 200 NCI-H1299 cells per well, or 100 AGS cells per well, with 50 μL per well. Cells were seeded in 96-well culture plates at a density of 500 NUGC-3 cells per well, 800 HuH-7 cells per well, 1000 BxPC-3 cells per well, or 200 AGS cells per well, with 100 μL per well. The plates were incubated overnight in an incubator (37 °C, 5% CO2).

[1089] 2) Day 0: 200 nL (for 384-well plates) or 400 nL (for 96-well plates) of serially diluted test compounds (starting concentration 10 μM, 9 concentrations, diluted at a 1:3 ratio) were added to the cells in the culture plates using a D300e (TECAN). The final concentration of DMSO was 0.4%. The plates were incubated in a cell culture incubator for 168 hours (37 °C, 5% CO2). For the blank control, 200 nL (for 384-well plates) or 400 nL (for 96-well plates) of DMSO were added to each well.

[1090] 3) Day 7: 20 μL (for 384-well plates) or 50 μL (for 96-well plates) of Cell Titer-Glo reagent were added to each well, and the plates were shaken at 500 rpm for 10 minutes and then incubated in the dark at room temperature for 10 minutes to stabilize the luminescence signal.

[1091] 4) The luminescence signal was detected using an Envision microplate reader (PerkinElmer).

[1092] 5) Data analysis was performed using GraphPad Prism software to calculate the IC 50 .

[1093] Table 2

[1094]

[1095]

[1096] The data in Table 2 show that the compounds of the embodiments of the present disclosure have good selectivity for cells with the Y220C mutation.

[1097] (III) In vivo pharmacokinetic determination in mice

[1098] Using mice as the test animals, after intravenous bolus injection and oral injection of the compounds of the present disclosure, plasma samples were collected at specific time points, and the compound concentrations in the plasma were detected by LC-MS / MS to calculate the PK parameters, reflecting the in vivo plasma pharmacokinetic behavior of the compounds of the present disclosure.

[1099] 1. Test protocol

[1100] 1.1 Test drugs:

[1101] Compound 26A, 64A, 64B of the embodiments of the present disclosure and control compound PC14586.

[1102] Structure of the control compound:

[1103] 1.2 Test animals

[1104] Mice, balb / c nude, female, supplied by Shanghai Jihui Laboratory Animal Breeding Co., Ltd.

[1105] Compound 26A, 64A, 64B and control compound PC14586 were all prepared by ourselves.

[1106] 1.3 Drug administration

[1107] Mouse drug administration information for Example 26A, 64A, 64B and the control compound: In both the IV (intravenous bolus) and PO (oral) experimental groups, there were 3 mice. The IV administration dose of Compound 26A, 64A, 64B and the control compound for mice was 2 mg / kg, the administration volume was 5 mL / kg, and the solvent was 5% DMSO + 10% Solutol + 85% Saline; the PO administration dose of mice was 100 mg / kg, the administration volume was 10 mL / kg, and the solvent was 10% DMSO + 20% Solutol + 70% water.

[1108] 1.4 Experimental equipment

[1109] The centrifuge was purchased from Eppendorf, and the pipette was purchased from Eppendorf.

[1110] 1.5 Sample collection

[1111] After drug administration to mice, at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8, and 24 hours, 0.025 mL and 0.2 mL of venous blood were collected respectively, placed in an EDTA-K2 test tube, centrifuged at 4°C and 2000 g for 10 min to separate the plasma, and stored at -80°C.

[1112] 1.6 Sample treatment

[1113] Mouse plasma sample treatment:

[1114] 1) Add 5 μL of plasma sample to 10 μL of blank plasma matrix, then add 200 μL of acetonitrile for precipitation, vortex mix and then centrifuge for 15 minutes.

[1115] 2) Take 90 μL of the supernatant and analyze the concentration of the compound to be tested by LC / MS / MS.

[1116] 2. Experimental results

[1117] The pharmacokinetic parameters were calculated using WinNonlin. The pharmacokinetic parameters of intravenous injection and oral administration in mice are shown in Table 3. Among them, C max represents the maximum plasma concentration, CL represents the clearance rate, Vss represents the steady-state volume of distribution, T 1 / 2 represents the terminal elimination half-life, and AUC represents the area under the plasma concentration-time curve.

[1118] Table 3

[1119]

[1120] Note: " / " indicates not measured

[1121] Result: As can be seen from Table 6, the compounds of the embodiments of the present disclosure have good exposure and excellent pharmacokinetic properties.

[1122] (IV) In vivo pharmacodynamic study experiment

[1123] 1. Experimental purpose

[1124] Evaluate the anti-tumor activity and toxic side effects of compound 26A after continuous oral administration for 19 days on the NUGC-3 gastric cancer model.

[1125] 2. Experimental materials

[1126] BALB / c-nu mice, female, SPF grade, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[1127] NUGC-3 cells, purchased from JCRB of Japan (product number: CBP60492).

[1128] 3. Experimental procedures

[1129] 3.1 Cell culture

[1130] NUGC-3 was cultured in RPMI 1640 medium containing 10% FBS in a 37 °C, 5% carbon dioxide incubator; cells in the exponential growth phase were collected for inoculation.

[1131] 3.2 Cell inoculation

[1132] Under sterile conditions, take the in vitro cultured NUGC-3 cell suspension, centrifuge and adjust the cell concentration to 5×10 8 cells / mL (containing 50% Matrigel), and inoculate subcutaneously into the right axilla of the mice (0.1 mL / mouse).

[1133] 3.3 Tumor grouping, drug administration and measurement

[1134] a. When the average tumor volume is about 150 mm 3 , 18 mice with moderately sized tumors were selected for the study. They were randomly divided into 3 groups according to tumor volume: G1: vehicle control group, G2: compound 26A (50 mg / kg), and G3: compound 26A (100 mg / kg), with 6 mice in each group.

[1135] b. After animal grouping, drug administration began. The day of starting drug administration was designated as D0. The administration volume was 10 mL / kg for oral administration (po); the animals were weighed and administered drugs once a day for 19 consecutive days; the tumor diameter was measured 2 times a week.

[1136] c. Tumor volume (TV): The tumor volume was measured 2 times a week to observe the change in tumor mass volume and growth rate. Tumor volume V = 1 / 2 × a × b 2 , where a and b represent the long diameter and short diameter of the tumor, respectively. The growth inhibitory effect of the compound on tumor tissue was evaluated using the tumor growth inhibition rate TGI (%). TGI (%) = [1 - (average tumor volume of a certain drug administration group - average tumor volume on the day of grouping of this drug administration group) / (average tumor volume of the negative control group - average tumor volume on the day of grouping of the negative control group)] × 100%. The data of the drug administration group and the negative control group were taken on the same day.

[1137] d. During the experiment, the living conditions of the mice were closely observed, including appearance signs, general behavioral activities, mental state, food intake, respiratory state, feces and urine characteristics, injection site, and other toxic manifestations.

[1138] e. After the experiment reached the end point, the mice were euthanized, and the animal corpses were frozen in a freezer and transferred to a qualified medical waste disposal unit for disposal.

[1139] 4 Experimental results

[1140] The experimental results are shown in Table 4.

[1141]

[1142] a, mean ± standard error;

[1143] b, P values were analyzed statistically for tumor volume. Compared with group G1, *P < 0.05; **P < 0.01; ***P < 0.01.

[1144] 5 Experimental conclusions

[1145] As can be seen from the above results, compound 26A can significantly inhibit tumor growth, showing an obvious dose-effect relationship, and the mice have good tolerance. During the treatment period, the general behavior of the mice was normal, and no obvious clinical symptoms were observed.

[1146] (V) Solubility Test

[1147] 1. Experimental Purpose

[1148] Test the solubility of compound 26A, compound example 64B, and compound (PC14586).

[1149] 2. Experimental Materials

[1150] Compound 26A, compound example 64B, and compound (PC14586) were all prepared by ourselves.

[1151] The control compound was purchased from Sigma. PBS pH 7.4 was prepared by our laboratory.

[1152] Add 1.42 g of Na2HPO4 to 100 mL of deionized water to prepare a 100 mM Na2HPO4 solution.

[1153] Add 1.20 g of NaH2PO4 to 100 mL of deionized water to prepare a 100 mM NaH2PO4 solution.

[1154] Mix 100 mM Na2HPO4 and 100 mM NaH2PO4 to pH 7.4.

[1155] 3. Solubility Determination Method

[1156] First, add 50 μL of the stock solution (10 mM) of each sample to the vials of an uncovered solubility sample plate. The determination is repeated. Then evaporate DMSO using a centrifugal vacuum evaporator. Add 500 μL of buffer to dissolve the samples respectively. Place a stir bar in each vial and seal it with a molded PTFE / silicone stopper. Then transfer the solubility sample plate to an Eppendorf Thermomixer Comfort plate shaker and shake at 1100 RPM at 25 °C for 24 hours. After 24 hours, remove the stir bar with a large magnet and transfer the samples from the solubility sample plate to a filter plate. Centrifuge the supernatant at 4,000 rpm and 25 °C for 30 minutes. Transfer 350 μL aliquots from the supernatant. Dip the pipette tip into acetonitrile for 5 seconds and then into water for 5 seconds. Then discard the first 25 μL into the waste liquid. Then aliquot 300 μL into another 96-well glass insert plate and centrifuge again (4,000 rpm, 25 °C, 30 minutes). Take 5 μL aliquots of the supernatant and 5 μL of DMSO, and then add 490 μL of a mixture of H2O and acetonitrile containing an internal standard (1:1). Dilute the diluent with a certain proportion of ultrapure water according to the peak shape. The dilution factor varies according to the solubility value and LC-MS signal response.

[1157] 4. Preparation of Standards (STD)

[1158] Add 50 μL of the stock solution (10 mM) of each sample to the vials of an uncovered solubility sample plate. The determination is repeated. Then evaporate DMSO using a centrifugal vacuum evaporator. Add 500 μL of DMSO to dissolve the samples. Place a stir bar in each vial and seal it with a molded PTFE / silicone stopper. Then transfer the solubility sample plate to an Eppendorf Thermomixer Comfort plate shaker and shake at 1100 RPM at 25 °C for 2 hours. After 2 hours, each compound should be completely dissolved. Take 10 μL aliquots and then add 990 μL of a mixture of H2O and acetonitrile containing an internal standard (1:1) to 10 μM. The concentration of the standard sample may vary according to the LC / MS signal response.

[1159] 5. Data Analysis

[1160] All calculations are performed using Microsoft Excel. Analyze the samples using LC / MS / MS and perform quantitative analysis according to the standards of known concentration. Calculate the solubility of the test compound as follows:

[1161]

[1162] DF represents the dilution factor.

[1163] 6. Experimental Results

[1164] From the experimental results in Table 5, it can be concluded that the compounds of the embodiments of the present invention have better solubility properties than the PC14586 molecule.

[1165] Table 5. Solubility data of the test compounds in PBS pH 7.4

[1166] Compound Solubility(μM) Solubility (μg / ml) PC14586 9.14 4.99 26A 24.81 14.13 64B 27.37 15.26

[1167] (VI) Tissue distribution of the compounds of the present invention

[1168] NUGC-3 tumor cells (JCRB, catalog number CBP60492) were cultured in RPMI 1640 medium containing inactivated 10% fetal bovine serum, supplemented with 1% penicillin-streptomycin double antibody. They were cultured in an incubator at 37 °C and 5% CO2. Subculture was performed every 3 to 4 days when the cells were confluent. Under sterile conditions, the in vitro cultured NUGC-3 cell suspension was taken, centrifuged, and then added with, adjusted to a cell concentration of 1×10 8 cells / mL, added with an equal volume of Matrigel, and inoculated subcutaneously into the back of the right forelimb of mice (BALB / c nude mice, female, Beijing Vital River Laboratory Animal Technology Co., Ltd.) (0.1 mL / mouse). 10 days after inoculation, the average tumor volume was in the range of 120-170 mm 3 range. Random grouping was performed according to tumor size and mouse body weight, and the administration of the compounds was started for testing.

[1169] The experiment was divided into a solvent control group, a positive control group, and a test group, with 6 mice in each group. The specific experimental protocol and the administration doses and frequencies of each group are shown in the following table. For the test compound administration group, a test compound administration preparation was configured with 10% DMSO + 20% Solutol + 70% Water as the solvent and administered by gavage, once or twice a day. The experiment ended after 21 days of administration. PK plasma (EDTA-K2 anticoagulated) samples were collected, and the mice were euthanized 4 h and 24 h after the last administration to collect tumor samples.

[1170] Tumor concentration test method:

[1171] All tumor samples were added with PBS at a ratio of 1:9 (9 mL of solvent was added per g of tumor), and ground using a cryogenic homogenizer to obtain tumor sample solutions.

[1172] Preparation method of standard curve and diluted quality control samples:

[1173] Standard curve: Gradient dilute the DMSO stock solution of the compound to be tested with an aqueous solution of acetonitrile:DMSO (v:v = 80:20) to obtain a series of working solutions with different concentrations. Take 5 μL of the working solution and add it to 95 μL of the blank Balb / c nude mouse tumor sample solution to obtain standard curve solutions with concentrations ranging from 0.5 to 1000 ng, with concentrations of 0.5, 1, 2, 10, 30, 100, 300, 1000, 2700, and 3000 ng / mL respectively, and the total volume is 100 μL.

[1174] Dilute the quality control sample: Take 5 μL of the working solution and add it to 95 μL of the blank Balb / c nude mouse tumor sample solution, with a concentration of 10000 ng / mL and a total volume of 100 μL. Then take 3 μL of the diluted quality control sample and add it to 27 μL of the blank Balb / c nude mouse tumor sample solution, with a concentration of 1000 ng / mL and a total volume of 30 μL.

[1175] Take 30 μL of the sample (including the standard curve, diluted quality control sample, and sample to be tested), add 300 μL of a protein precipitant containing acetonitrile to precipitate proteins, vortex for 5 mins, then centrifuge at 4°C and 1400 rpm for 15 min, and aspirate 0.5 μL of the supernatant for LC-MS / MS quantitative analysis.

[1176] Table 6. Dosage and frequency of administration for each group

[1177]

[1178] The experimental results are shown in Table 7:

[1179] Table 7. Test results of the tumor tissue concentration of the compounds of the present disclosure

[1180]

[1181] The above experimental results show that the tumor tissue concentration of the compounds in the embodiments of the present invention after 24 hours of drug administration is significantly better than that of PC14586, indicating that the compounds in the embodiments of the present invention have better potential anti-tumor activity.

Claims

1. A compound represented by formula (IC), a pharmaceutically acceptable salt and a stereoisomer thereof, in, Z is selected from N or CR 4 ; Structural unit Selected from Where R 9 Selected from hydrogen, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, R 10 Selected from hydrogen, halogen, C 1-4 Alkyl, p is selected from 0, 1, 2, 3; R 1 Selected from C 1-4 Haloalkyl; M is selected from O, S(O)2 or NR 2 ; R 2 Selected from C 1-4 Alkyl, -C(O)CH3 or The C 1-4 The alkyl group may be further optionally substituted by 1-3 groups selected from the following groups: hydroxyl, halogen, C 1-4 an alkoxy group or a deuterium atom; R 3 Selected from -S(O)2CH3, -S(O)2CHF2, -S(O)2CF3, Wherein ring B is cyclobutane, R Ba Halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 haloalkyl, r is selected from 1, 2 or 3; ring C is C 3-6 Cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocycloalkyl, R Ca Halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Haloalkyl, q is selected from 1, 2 or 3; R 4 , R 5 , R 6 , R 7 Each independently selected from H or C 1-4 Alkoxy; and / or R 6 , R 7 and the atoms to which it is attached are cyclized to form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group may be optionally replaced by s R 6a Replaced by; R 6a Selected from hydrogen, hydroxy, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, deuterium, -C 1-4 Alkylene-C 1-4 Alkoxy, -C 1-4 Alkylene -OH; or two adjacent R 6a Or two R attached to the same carbon 6a The atoms connected to it have the same shape as C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group may be optionally substituted with t R 6b Replaced by: R 6b Selected from hydrogen, hydroxy, amino, halogen, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 haloalkyl; s is selected from 0, 1, 2 or 3; t is selected from 0, 1, 2 or 3; and / or R 3 , R 4 Cyclize together with the atoms to which it is attached to form a substituted or unsubstituted 5-6 membered heterocyclic group; and / or R 4 , R 5 Cyclizes together with the atoms to which it is attached to form a substituted or unsubstituted 5-6 membered heterocyclyl, or a substituted or unsubstituted 5-6 membered cycloalkyl; R 8 Each independently selected from C 1-4 Alkyl, halogen or C 1-4 Alkoxy, n is selected from 0, 1, 2, 3 or 4; R 11 Selected from hydrogen, deuterium or C 1-4 alkyl; R 12 Selected from hydrogen, deuterium or C 1-4 alkyl; And, when R 3 , R 4 When R is cyclized together with the atoms to which it is attached to form a 5-6 membered heterocyclic group, 7 Not hydrogen or R 6 Not methoxy; When R 3 -S(O)2CH3, -S(O)2CF3, When R 7 Not hydrogen or R 6 Not methoxy.

2. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to claim 1, characterized in that: R Ba With R Ca Each is independently selected from fluoro, hydroxy or methyl.

3. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 2, characterized in that: Ring C is selected from 4. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 3, characterized in that: R 3 Selected from -S(O)2CH3, 5. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 4, characterized in that: Structural unit Selected from 6. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 5, characterized in that: R 2 is selected from methyl, ethyl, isopropyl, tert-butyl, -CD3, 7. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 6, characterized in that: R 8 Selected from F.

8. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 7, characterized in that: R 6 , R 7 Cyclize with the atoms to which it is attached Where R 6a , R 6b , s, t as defined in any one of claims 1-7; preferably, R 6 , R 7 Cyclize with the atoms to which it is attached 9. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 8, characterized in that: Structural unit Selected from 10. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 8, characterized in that: Structural unit Selected from Among them, R 3 , R 4 , R 5 , R 6a ,s,R 6b , t as defined in any one of claims 1-8.

11. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 10, characterized in that: Structural unit Selected from Where R 2 , R 8 , n as defined in any one of claims 1-10.

12. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to claim 11, characterized in that: Structural unit Selected from 13. The compound, pharmaceutically acceptable salt and stereoisomer thereof according to any one of claims 1 to 12, characterized in that: It is selected from the following compounds, pharmaceutically acceptable salts and stereoisomers thereof, Among them, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 ,n,R 6a , R 6b , s, t as defined in any one of claims 1-12.

14. A compound, a pharmaceutically acceptable salt and a stereoisomer thereof, characterized in that: It is selected from, 15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

16. Use of the compound, pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating cancer mediated by p53 mutation, wherein the p53 mutation is p53 Y220C mutation.

17. The use according to claim 16, wherein the cancer is selected from solid tumors; preferably, the solid tumor is selected from gastric cancer, liver cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, endometrial cancer, colorectal cancer, pancreatic cancer and ovarian cancer carrying p53Y220C mutation.

Images