AROMATIC HETEROCYCLIC COMPOUND, ITS PHARMACEUTICAL COMPOSITION AND APPLICATION

Abstract

An aromatic heterocyclic compound, and a pharmaceutical composition and an application thereof. Specifically disclosed are a compound as represented by formula I-A, a stereoisomer thereof, a diastereoisomer thereof, or a pharmaceutically acceptable salt of any one of the described substances, or a crystalline form or a solvate of any one of the described substances. The aromatic heterocyclic compound is novel in structure, and has good CDK7 inhibitory activity and good selectivity.

Description

Aromatic heterocyclic compounds, pharmaceutical compositions and applications thereof

[0001] This application claims priority to Chinese patent application No. 2020115524787, filed on December 24, 2020. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to aromatic heterocyclic compounds, pharmaceutical compositions and applications thereof. Background Art

[0003] Members of the cyclin-dependent kinase (CDK) family play a key regulatory role in proliferation. CDK7 is unique among mammalian CDKs, with integrated kinase activity, regulating the cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is thought to act as a CDK1 / 2 activating kinase (CAK), whereby phosphorylation of conserved residues in CDK1 / 2 by CDK7 is required for full catalytic CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase (RNAP) II general transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNAP II, an essential step for the initiation of gene transcription. The two functions of CDK7 (i.e., CAK and CTD phosphorylation) together support key aspects of cell proliferation, cell cycle, and transcription.

[0004] Disruption of RNAP IICTD phosphorylation has been shown to preferentially affect proteins with short half-lives, including the anti-apoptotic BCL-2 family. Cancer cells have demonstrated the ability to circumvent pro-cell death signaling by upregulating BCL-2 family members. Therefore, inhibition of human CDK7 kinase activity may result in anti-proliferative activity.

[0005] The high sequence and structural similarity of the kinase domains of CDK family members has hindered the discovery of selective inhibitors of CDK7. Therefore, there is a need to discover and develop selective CDK7 inhibitors. Such CDK7 inhibitors hold promise as therapeutic agents for the treatment of CLL and other cancers.

[0006] For oral medications to exert their pharmacological effects in vivo, they must undergo absorption and distribution to reach the appropriate site of action. A drug's membrane permeability reflects its absorption and transport capacity within the body. Passive diffusion of a drug is positively correlated with its biomembrane permeability, and drugs with good biomembrane permeability are more easily absorbed by the gastrointestinal tract. The excretion rate of an oral drug is a key parameter characterizing its absorption; a lower excretion rate indicates better absorption within the gastrointestinal tract.

[0007] Patent WO2018013867A1 discloses a CDK7 inhibitor. Based on this, the researchers of the present invention found that the compound disclosed in the patent document has poor membrane permeability and high efflux rate in the Caco-2 monolayer permeation test model, which will affect the absorption of the drug in the gastrointestinal tract. However, the researchers of the present invention were surprised to find that after creative structural modification of the compound disclosed in the patent document, the obtained compound of the present invention can maintain high biological activity while also having higher membrane permeability and lower efflux rate in the Caco-2 monolayer permeation test model, which will be more conducive to oral absorption.

[0008] Summary of the Invention

[0009] The technical problem to be solved by the present invention is to address the defects of existing CDK7 inhibitors such as low membrane permeability and high efflux rate, and to provide a CDK7 inhibitor with a novel structure, high CDK7 inhibitory activity, better membrane permeability and low efflux rate. The compound of the present invention can solve the problems of low oral availability and low gastrointestinal absorption rate of existing CDK7 inhibitors.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The present invention provides a compound represented by Formula IA, its stereoisomers, its diastereomers, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound represented by Formula IA, its stereoisomers, or its diastereomers), or a crystalline form or solvate of any of the foregoing (referring to the aforementioned compound represented by Formula IA, its stereoisomers, its diastereomers, or pharmaceutically acceptable salts):

[0012]

[0013] R 1 is CF3, CHF2, F, Cl, Br, C1-C6 alkyl, -C(=O)NH2 or CN;

[0014] R 5 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0015] X is N or C(R 4 ), R 4 is -P(=O)Me2;

[0016] Z is N or CH;

[0017] R 2 H, halogen, "a 5-10 membered heteroaryl group having 1 to 4 heteroatoms and selected from one or more of N, O and S", one or more Ra-1 Substituted "5-10 membered heteroaryl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", "4-12 membered heterocycloalkyl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", a-2 Substituted "4-12 membered heterocycloalkyl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", "4-12 membered heterocycloalkenyl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", a-3 Substituted "4-12 membered heterocycloalkenyl group having 1 to 4 heteroatoms selected from one or more of N, O and S", C2-C6 alkynyl, C1-C6 alkyl, C1-C6 alkoxy or CN;

[0018] R a-1 、R a-2 and R a-3 are independently CN, oxo, or one or more R a-1-1 Substituted C1-C6 alkyl, NH2, OH or C1-C6 alkyl; R a-1-1 are independently CN, OH or halogen;

[0019] R 3 For one or more R b-1 Substituted C3-C8 cycloalkyl, one or more R b-2 Substituted C1-C6 alkyl, By one or more R b-3 Substituted "4-12 membered heterocycloalkyl group wherein the heteroatom is O and the number of heteroatoms is 1-4", or “a 5-10 membered heteroaryl group having 1 to 4 heteroatoms selected from one or more of N, O and S”;

[0020] R b-1 are independently halogen, OH, -NR b-1-1 R b-1-2 , C1-C6 alkyl or "surrounded by one or more R b-1-3 "substituted C1-C6 alkyl";

[0021] R b-1-1 and R b-1-2 are independently H or C1-C6 alkyl;

[0022] R b-1-3 are independently OH or NR b-1-4 R b-1-5 ; R b-1-4 and R b-1-5 are independently H or C1-C6 alkyl;

[0023] Rb-2 are independently OH, halogen, C3-C8 cycloalkyl, b-2-1 Substituted C3-C8 cycloalkyl, heteroatom is O, 4-12 membered heterocycloalkyl with 1-4 heteroatoms or "substituted by one or more R b-2-2 The substituted heteroatom is O, and the number of heteroatoms is 1 to 4 4-12 membered heterocycloalkyl";

[0024] R b-2-1 and R b-2-2 independently OH, C1-C6 alkyl, or "C1-C6 alkyl substituted by one or more OH";

[0025] p1 is 0, 1, 2, or 3;

[0026] p2 is 2 or 3, R 3-1 is H or C1-C6 alkyl;

[0027] R 3-2 and R 3-3 are independently H, C1-C6 alkyl, or "C1-C6 alkyl substituted by one or more halogens";

[0028] Y is O or CH2, n1 is 1 or 2, n2, n3 and n4 are independently 0, 1, 2 or 3, and n2 and n4 are not 0 at the same time;

[0029] R b-3 are independently halogen, OH, C1-C6 alkyl, or "C1-C6 alkyl substituted by one or more OH groups".

[0030] In certain preferred embodiments of the present invention, certain groups in the compound of Formula IA, its stereoisomers, its diastereomers, or pharmaceutically acceptable salts of any of the foregoing, or crystalline forms or solvates of any of the foregoing are defined as follows. Unmentioned groups are the same as those described in any embodiment of the present application (referred to as "in a certain embodiment of the present invention").

[0031] When R 1 When it is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, such as methyl.

[0032] In one embodiment of the present invention, when R 5 When it is a halogen, the halogen is F, Cl, Br or I, for example, F.

[0033] In one embodiment of the present invention, when R 5 When it is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0034] In one embodiment of the present invention, when R5 When it is a C1-C6 alkoxy group, the C1-C6 alkoxy group is a C1-C3 alkoxy group, preferably a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group, such as a methoxy group.

[0035] In one embodiment of the present invention, when R 2 When it is a halogen, the halogen is F, Cl, Br or I, for example, F.

[0036] In one embodiment of the present invention, when R 2 When it is a “5-10 membered heteroaryl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms are 1-4”, the “5-10 membered heteroaryl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms are 1-4” means a “5-6 membered heteroaryl group whose heteroatoms are selected from one or more of N and O, and whose heteroatoms are 1-4”, for example

[0037] In one embodiment of the present invention, when R 2 For one or more R a-1 When the substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4, the substituted one or more R a-1 The substituted "5-10 membered heteroaryl group having 1 to 4 heteroatoms selected from one or more of N, O and S" is a substituted a-1 The substituted "heteroatom is selected from one or more of N and O, and the number of heteroatoms is 1-4 5-6 membered heteroaryl", for example

[0038] In one embodiment of the present invention, when R 2 "a 4-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and 1 to 4 heteroatoms" or "a 4-12 membered heterocycloalkyl group with one or more heteroatoms selected from N, O and S, and 1 to 4 heteroatoms" a-2 When the substituted “heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4, the 4-12-membered heterocycloalkyl group” is a monocyclic, bicyclic or bridged ring, and the bicyclic ring includes a spiro ring or a condensed ring.

[0039] In one embodiment of the present invention, when R 2 When it is “a 4-12-membered heterocycloalkyl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms are 1-4”, the “a 4-12-membered heterocycloalkyl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms are 1-4” means “a 4-12-membered heterocycloalkyl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms are 1-2”, for example Azetidinyl, oxazepanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl or morpholinyl, for example For example Preferably, it is a "4-12 membered heterocycloalkyl group having two heteroatoms selected from one or more of N, O and S".

[0040] In one embodiment of the present invention, when R 2 For one or more R a-2 When the substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4, the substituted one or more R a-2 The substituted "4-12 membered heterocycloalkyl group having 1 to 4 heteroatoms selected from one or more of N, O and S" is a substituted alkyl group having 1 to 4 heteroatoms. a-2 Substituted "4-12 membered heterocycloalkyl group having 1-2 heteroatoms selected from one or more of N, O and S", for example, substituted by 1 or 2 R a-2 Substituted morpholinyl, 1 or 2 R a-2 Substituted azetidinyl, substituted by 1 or 2 R a-2 Substituted tetrahydrofuranyl, substituted by 1 or 2 R a-2 Substituted tetrahydropyranyl, substituted by 1 or 2 R a-2 Substituted piperidinyl, substituted by 1 or 2 R a-2 Substituted pyrrolidinyl, substituted by 1 or 2 R a-2 substituted piperazinyl or "substituted by 1 or 2 R a-2 Substituted thiomorpholinyl", for example For example Preferably, one or two R a-2 The substituted "4- to 12-membered heterocycloalkyl group having 2 heteroatoms selected from one or more of N, O and S".

[0041] In one embodiment of the present invention, when R 2 When it is a "4-12 membered heterocycloalkenyl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms are 1-4", the "4-12 membered heterocycloalkenyl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms are 1-4" is a "4-12 membered heterocycloalkenyl group whose heteroatoms are selected from one or more of N, O and S, and whose heteroatoms are 1-2", for example, dihydrofuranyl, and for example

[0042] In one embodiment of the present invention, when R a-1 、Ra-2 and R a-3 Independently by one or more R a-1-1 In the case of a substituted C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0043] In one embodiment of the present invention, when R a-1 、R a-2 and R a-3 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0044] In one embodiment of the present invention, when R a-1-1 When it is a halogen, the halogen is F, Cl, Br or I, for example, F.

[0045] In one embodiment of the present invention, when R 2 When it is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0046] In one embodiment of the present invention, when R 2 When it is a C1-C6 alkoxy group, the C1-C6 alkoxy group is a C1-C3 alkoxy group, preferably a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group, such as a methoxy group.

[0047] In one embodiment of the present invention, when R 3 For one or more R b-1 When the C3-C8 cycloalkyl group is substituted, the cycloalkyl group is replaced by one or more R b-1 The substituted C3-C8 cycloalkyl group is substituted by 1, 2 or 3 R b-1 Substituted C3-C6 cycloalkyl, for example, substituted by 1, 2 or 3 R b-1 Substituted cyclopropyl, 1, 2 or 3 R b-1 Substituted cyclobutyl or "substituted by 1, 2 or 3 R b-1 Substituted cyclopentyl", for example Preferably, the one or more R b-1 The substituted C3-C8 cycloalkyl group is substituted by 1, 2 or 3 R b-1 Substituted C3-C5 cycloalkyl.

[0048] In one embodiment of the present invention, when R b-1 When independently halogen, the halogen is F, Cl, Br or I, for example F.

[0049] In one embodiment of the present invention, when R b-1 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0050] In one embodiment of the present invention, when R b-1 Independently "by one or more R b-1-3 When the term "substituted C1-C6 alkyl" is used, the C1-C6 alkyl is a C1-C3 alkyl, preferably a methyl, ethyl, n-propyl or isopropyl, such as a methyl group.

[0051] In one embodiment of the present invention, when R b-1-1 and R b-1-2 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0052] In one embodiment of the present invention, when R b-1-4 and R b-1-5 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0053] In one embodiment of the present invention, when R 3 For one or more R b-2 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl; preferably, the alkyl group substituted by one or more R b-2 The substituted C1-C6 alkyl group is

[0054] In one embodiment of the present invention, when R b-2 When independently halogen, the halogen is F, Cl, Br or I, for example F.

[0055] In one embodiment of the present invention, when R b-2 When independently a C3-C8 cycloalkyl group, the C3-C8 cycloalkyl group is a C3-C7 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0056] In one embodiment of the present invention, when R b-2 Independently by one or more R b-2-1 When the C3-C8 cycloalkyl group is substituted, the cycloalkyl group is replaced by one or more R b-2-1 The substituted C3-C8 cycloalkyl group is substituted by one or two R b-2-1 Substituted C3-C7 cycloalkyl, for example, substituted by 1 or 2 R b-2-1Substituted cyclopropyl, 1 or 2 R b-2-1 Substituted cyclobutyl, 1 or 2 R b-2-1 Substituted cyclopentyl, 1 or 2 R b-2-1 Substituted cyclohexyl or 1 or 2 R b-2-1 Substituted cycloheptyl, for example

[0057] In one embodiment of the present invention, when R b-2 Each of the above groups is independently a “C3-C8 cycloalkyl group substituted by one or more OH groups”, wherein the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group, for example, a cyclobutyl group.

[0058] In one embodiment of the present invention, when R b-2 When the heteroatom is O and the number of heteroatoms is 1-4, the "4-12-membered heterocycloalkyl group having a heteroatom of O and a heteroatom number of 1-4" is "a 4-6-membered heterocycloalkyl group having a heteroatom of O and a heteroatom number of 1"; for example, tetrahydrofuranyl or tetrahydropyranyl, and for example

[0059] In one embodiment of the present invention, when R b-2 Independently "by one or more R b-2-2 When the heteroatom substituted is O, and the number of heteroatoms is 1 to 4, the "substituted by one or more R b-2-2 The substituted heteroatom is O, and the number of heteroatoms is 1-4 4-12 membered heterocycloalkyl group is "substituted by 1 or 2 R b-2-2 The substituted heteroatom is O, and the number of heteroatoms is 1 4-6 membered heterocycloalkyl"; for example, "substituted by 1 or 2 R b-2-2 Substituted tetrahydrofuranyl" or "substituted by 1 or 2 R b-2-2 Substituted tetrahydropyranyl", for example

[0060] In one embodiment of the present invention, when R b-2-1 and R b-2-2 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0061] In one embodiment of the present invention, when R b-2-1 and R b-2-2 When independently a "C1-C6 alkyl group substituted by one or more OH groups", the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0062] In one embodiment of the present invention, when R 3-1 When it is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0063] In one embodiment of the present invention, when R 3-2 and R 3-3 When independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0064] In one embodiment of the present invention, when R 3 for hour, for

[0065] In one embodiment of the present invention, when R 3 For one or more R b-3 When the substituted "heteroatom is O, and the number of heteroatoms is 1-4 4-12 membered heterocycloalkyl", the one or more R b-3 The substituted "4-12 membered heterocycloalkyl group having 1 to 4 heteroatoms and 0 as the heteroatom" is a substituted alkyl group having 1 to 2 R b-3 The substituted "4-6 membered heterocycloalkyl group having 1-2 heteroatoms and 1-2 heteroatoms" is, for example, substituted by 1 or 2 R b-3 Substituted oxetane, 1 or 2 R b-3 Substituted tetrahydrofuranyl or "substituted by 1 or 2 R b-3 Substituted tetrahydropyranyl", for example

[0066] In one embodiment of the present invention, when R b-3 When independently a "C1-C6 alkyl group substituted by one or more OH groups", the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group, such as a methyl group.

[0067] In one embodiment of the present invention, when R 3 When it is a "4-12-membered heterocycloalkyl group whose heteroatom is O and whose heteroatoms are 1-4" substituted by one or more OH groups, the "4-12-membered heterocycloalkyl group whose heteroatom is O and whose heteroatoms are 1-4" substituted by one or more OH groups is a "4-6-membered heterocycloalkyl group whose heteroatom is O and whose heteroatoms are 1-2" substituted by one OH group, for example, tetrahydrofuranyl group substituted by one OH group or "tetrahydropyranyl group substituted by one OH group", for example

[0068] In one embodiment of the present invention, when R3 When it is a "5-10 membered heteroaryl group having 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", the "5-10 membered heteroaryl group having 1-4 heteroatoms and one or more heteroatoms selected from N, O and S" is a "5-6 membered heteroaryl group having 1-4 heteroatoms and one or more heteroatoms selected from N", for example, pyrazolyl, and another example

[0069] In a certain embodiment of the present invention, wherein R 3 Indicates -(CR M1 R M2 ) m -(L) s -(CR N1 R N2 ) t -M;

[0070] Among them, R M1 、R M2 、R N1 、R N2 Each independently represents hydrogen, C1-C6 alkyl substituted by 0, 1, or 2 hydroxyl groups, C1-C6 alkyl groups, or halogen groups, or C3-C6 cycloalkyl groups; or R M1 、R M2 , R N1 、R N2 Each independently forms a 3-6 membered ring together with the carbon atoms to which it is commonly attached, wherein the ring optionally contains 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, or 2 substituents selected from halogen, C1-C6 alkyl, and hydroxyl;

[0071] Among them, L represents -CR Q1 R Q2 -or -C3-C6 cycloalkyl-; wherein R Q1 、R Q2 Each independently represents hydrogen, C1-C6 alkyl substituted by 0, 1, or 2 hydroxyl groups, C1-C6 alkyl groups, or halogen groups, or C3-C6 cycloalkyl groups; or R Q1 、R Q2 Each independently forms a 3-6 membered ring together with the carbon atoms to which it is commonly attached, wherein the ring optionally contains 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, or 2 substituents selected from halogen, C1-C6 alkyl, and hydroxyl;

[0072] Wherein, M represents hydrogen, hydroxyl, or C1-C6 alkyl or C3-C6 cycloalkyl substituted by 0, 1, or 2 groups selected from hydroxyl, C1-C6 alkyl, or halogen;

[0073] Wherein, m, s, and t each independently represent 0, 1, 2, and 3;

[0074] Among them, -(CR M1 R M2 ) m -(L) s -(CR N1 R N2 ) t At least one group in -M is substituted by a hydroxyl group.

[0075] In one embodiment of the present invention, R 1 is CF3, Cl, Br or CN.

[0076] In one embodiment of the present invention, R 1 It is CF3.

[0077] In one embodiment of the present invention, R 5 is H, halogen (F) or C1-C6 alkoxy (OCH3).

[0078] In one embodiment of the present invention, R 5 For H.

[0079] In one embodiment of the present invention, X is C(R 4 ).

[0080] In one embodiment of the present invention, Z is CH.

[0081] In one embodiment of the present invention, R 2 H, halogen, one or more R a-1 Substituted "5-10 membered heteroaryl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", "4-12 membered heterocycloalkyl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", a-2 Substituted "4-12 membered heterocycloalkyl group having 1 to 4 heteroatoms and one or more heteroatoms selected from N, O and S", "4-12 membered heterocycloalkenyl group having 1 to 4 heteroatoms and one or more heteroatoms selected from N, O and S", C1-C6 alkoxy group or CN.

[0082] In one embodiment of the present invention, R 2 H, one or more R a-1 Substituted "5-10 membered heteroaryl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", "4-12 membered heterocycloalkyl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", a-2The substituted "4- to 12-membered heterocycloalkyl group having 1 to 4 heteroatoms selected from one or more of N, O and S" or CN.

[0083] In one embodiment of the present invention, R a-1 and R a-2 are independently C1-C6 alkyl.

[0084] In one embodiment of the present invention, R 2 For H, F, CN, -OCH3,

[0085] In one embodiment of the present invention, R 2 For H, CN,

[0086] In one embodiment of the present invention, p1 is 0 or 3, for example, 3.

[0087] In one embodiment of the present invention, when Y is O, n1 is 1, and n3 is 0 or 1; preferably, when Y is O, n1 is 1, and n3 is 0.

[0088] In one embodiment of the present invention, when R b-1 When the number of is one, R b-1 OH, -NR b-1-1 R b-1-2 or "by one or more R b-1-3 Substituted C1-C6 alkyl"; when R b-1 When there are multiple R b-1 It is OH or "C1-C6 alkyl group substituted by one or more OH groups".

[0089] In one embodiment of the present invention, when R b-2 When the number of is one, R b-2 OH, one or more R b-2-1 Substituted C3-C8 cycloalkyl, or "substituted by one or more R b-2-2 The substituted heteroatom is O, and the number of heteroatoms is 1-4 4-12 membered heterocycloalkyl"; when R b-2 When there are multiple R b-2 OH, one or more R b-2-1 Substituted C3-C8 cycloalkyl, or "substituted by one or more R b-2-2 The substituted heteroatom is O, and the number of heteroatoms is 1-4 4-12 membered heterocycloalkyl"; wherein, when R b-2-1 When the number of is one, R b-2-1 is OH or "C1-C6 alkyl substituted by one or more OH", when R b-2-1 When there are multiple Rb-2-1 is OH or "C1-C6 alkyl substituted by one or more OH", when R b-2-2 When the number of is one, R b-2-2 is OH or "C1-C6 alkyl substituted by one or more OH", when R b-2-2 When there are multiple R b-2-2 It is OH or "C1-C6 alkyl group substituted by one or more OH groups".

[0090] In one embodiment of the present invention, when R b-3 When the number of is one, R b-3 is OH or “C1-C6 alkyl substituted by one or more OH groups”; when R b-3 When there are multiple R b-3 It is OH or "C1-C6 alkyl group substituted by one or more OH groups".

[0091] In one embodiment of the present invention, R 3 For one or more R b-2 Substituted C1-C6 alkyl, or by one or more R b-3 The substituted "4- to 12-membered heterocycloalkyl group wherein the heteroatom is O and the number of heteroatoms is 1 to 4".

[0092] In one embodiment of the present invention, R 3 for

[0093] In one embodiment of the present invention, R 3 for

[0094] In one embodiment of the present invention, the compound shown in formula IA is

[0095]

[0096] in,

[0097] R 1 is CF3, F, Cl, Br or CN;

[0098] R 5 is H or halogen;

[0099] X is N or C(R 4 ), R 4 is -P(=O)Me2;

[0100] R 2H, halogen, "a 5-10 membered heteroaryl group having 1 to 4 heteroatoms and selected from one or more of N, O and S", one or more R a-1 Substituted "5-10 membered heteroaryl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", "4-12 membered heterocycloalkyl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", a-2 Substituted "4-12 membered heterocycloalkyl group having 1 to 4 heteroatoms selected from one or more of N, O and S", C2-C6 alkynyl or CN;

[0101] R a-1 and R a-2 are independently CN, oxo, or one or more R a-1-1 Substituted C1-C6 alkyl, NH2, OH or C1-C6 alkyl; R a-1-1 are independently CN, OH or halogen;

[0102] R 3 For one or more R b-1 Substituted C3-C8 cycloalkyl, one or more R b-2 Substituted C1-C6 alkyl, "4-12 membered heterocycloalkyl group with 1 to 4 heteroatoms and a heteroatom of O" substituted by one or more OH groups, or “a 5-10 membered heteroaryl group having 1 to 4 heteroatoms selected from one or more of N, O and S”;

[0103] R b-1 are independently halogen, OH, -NR b-1-1 R b-1-2 or "by one or more R b-1-3 "substituted C1-C6 alkyl";

[0104] R b-1-1 and R b-1-2 are independently H or C1-C6 alkyl;

[0105] R b-1-3 are independently OH or NR b-1-4 R b-1-5 ; R b-1-4 and R b-1-5 are independently H or C1-C6 alkyl;

[0106] R b-2 are independently OH, halogen or "C3-C8 cycloalkyl substituted by one or more OH";

[0107] p1 is 0, 1, 2, or 3;

[0108] p2 is 2 or 3, R 3-1 is H or C1-C6 alkyl;

[0109] R 3-2 and R 3-3 are independently H, C1-C6 alkyl, or "C1-C6 alkyl substituted by one or more halogens";

[0110] Y is O or CH2, n1 is 1 or 2, n2, n3 and n4 are independently 0, 1, 2 or 3, and n2 and n4 are not 0 at the same time.

[0111] In one embodiment of the present invention, when X is C(R 4 ), R 4 When it is -P(=O)Me2, R 2 is H, halogen, C1-C6 alkoxy or CN; when X is N, R 2 For one or more R a-1 Substituted "5-10 membered heteroaryl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", "4-12 membered heterocycloalkyl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", a-2 Substituted "4- to 12-membered heterocycloalkyl group having 1 to 4 heteroatoms and one or more heteroatoms selected from N, O and S", "4- to 12-membered heterocycloalkenyl group having 1 to 4 heteroatoms and one or more heteroatoms selected from N, O and S" or CN.

[0112] In one embodiment of the present invention, when X is C(R 4 ), R 4 When it is -P(=O)Me2, R 2 is H or CN; when X is N, R 2 For one or more R a-1 Substituted "5-10 membered heteroaryl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", "4-12 membered heterocycloalkyl group with 1-4 heteroatoms and one or more heteroatoms selected from N, O and S", a-2 The substituted "4- to 12-membered heterocycloalkyl group having 1 to 4 heteroatoms selected from one or more of N, O and S" or CN.

[0113] In one embodiment of the present invention, when X is C(R 4 );R 4 When it is -P(=O)Me2, R 3 For one or more R b-1 Substituted C3-C8 cycloalkyl, When X is N, R 3 For one or more R b-1 Substituted C3-C8 cycloalkyl, one or more R b-2 Substituted C1-C6 alkyl,

[0114] In one embodiment of the present invention, R 3 For one or more R b-1 Substituted C3-C8 cycloalkyl, one or more R b-2 Substituted C1-C6 alkyl, When Y is 0, n1 is 1 and n3 is 0.

[0115] In one embodiment of the present invention, the compound represented by Formula IA is not the following compound:

[0116] or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug of any one of the above.

[0117] In one embodiment of the present invention, the compound represented by Formula IA is any one of the following compounds:

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] Preferably, the compound represented by formula IA is any one of the following compounds:

[0127] The compound with a retention time of 2.187 min under the following conditions is The chromatographic column was Chiralpak AD-3, 250 mm x 30 mm, 10 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / isopropanol in phase B, with a gradient of 5% to 40% phase B over 2 minutes, followed by a 40% phase B hold for 1.2 minutes and then a 5% phase B hold for 0.8 minutes; the flow rate was 2.5 mL / min.

[0128] The compound with a retention time of 2.877 min under the following conditions is The chromatographic column was Chiralpak AD-3, 250 mm x 30 mm, 10 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / isopropanol in phase B, with a gradient of 5% to 40% phase B over 2 minutes, followed by a 40% phase B hold for 1.2 minutes and then a 5% phase B hold for 0.8 minutes; the flow rate was 2.5 mL / min.

[0129] The compound with a retention time of 2.343 min under the following conditions is The chromatographic column was Chiralpak IG-3, 250 mm x 30 mm, 10 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 2 minutes, then 40% phase B for 1.2 minutes, and then 5% phase B for 0.8 minutes; the flow rate was 4 mL / min.

[0130] The compound with a retention time of 2.847 min under the following conditions is The chromatographic column was Chiralpak IG-3, 250 mm x 30 mm, 10 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 2 minutes, then 40% phase B for 1.2 minutes, and then 5% phase B for 0.8 minutes; the flow rate was 4 mL / min.

[0131] The compound with a retention time of 3.934 min under the following conditions is A stereoisomer in the chromatographic column: Chiralpak AD-3, 250 mm x 30 mm, 10 μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4.5 minutes, maintaining 5% phase B for 1.5 minutes, flow rate: 2.5 mL / min;

[0132] The compound with a retention time of 4.355 min under the following conditions is A stereoisomer in the chromatographic column: Chiralpak AD-3, 250 mm x 30 mm, 10 μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4.5 minutes, maintaining 5% phase B for 1.5 minutes, flow rate: 2.5 mL / min;

[0133] The compound with a retention time of 3.788 min under the following conditions is A stereoisomer in the chromatographic column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4 minutes, maintain 40% phase B for 2.5 minutes, then maintain 5% phase B for 1.5 minutes, flow rate: 2.8 mL / min;

[0134] The compound with a retention time of 4.110 min under the following conditions is A stereoisomer in the chromatographic column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4 minutes, maintain 40% phase B for 2.5 minutes, then maintain 5% phase B for 1.5 minutes, flow rate: 2.8 mL / min;

[0135] The compound with a retention time of 0.887 min under the following conditions is The chromatographic column was DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm. The mobile phases were carbon dioxide in phase A and 0.05% diethylamine / isopropanol in phase B. The gradient was 5% to 40% phase B in 2 minutes, followed by a 1.2-minute hold at 40% phase B and a 0.8-minute hold at 5% phase B. The flow rate was 4 mL / min.

[0136] The compound with a retention time of 1.00 min under the following conditions is The chromatographic column was DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm. The mobile phases were carbon dioxide in phase A and 0.05% diethylamine / isopropanol in phase B. The gradient was 5% to 40% phase B in 2 minutes, followed by a 1.2-minute hold at 40% phase B and a 0.8-minute hold at 5% phase B. The flow rate was 4 mL / min.

[0137] The compound with a retention time of 1.979 min under the following conditions is The chromatographic column was DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm. The mobile phases were carbon dioxide in phase A and 0.05% diethylamine / isopropanol in phase B. The gradient was 5% to 40% phase B in 2 minutes, followed by a 1.2-minute hold at 40% phase B and a 0.8-minute hold at 5% phase B. The flow rate was 4 mL / min.

[0138] The compound with a retention time of 2.643 min under the following conditions is The chromatographic column was DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm. The mobile phases were carbon dioxide in phase A and 0.05% diethylamine / isopropanol in phase B. The gradient was 5% to 40% phase B in 2 minutes, followed by a 1.2-minute hold at 40% phase B and a 0.8-minute hold at 5% phase B. The flow rate was 4 mL / min.

[0139] The compound with a retention time of 5.650 min under the following conditions is The chromatographic column was ChiralPak IG-3, 100 × 4.6 mm, 3 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 5.5 minutes, then 40% phase B for 3 minutes, and then 5% phase B for 1.5 minutes; the flow rate was 2.5 mL / min.

[0140] The compound with a retention time of 5.985 min under the following conditions is The chromatographic column was ChiralPak IG-3, 100 × 4.6 mm, 3 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 5.5 minutes, then 40% phase B for 3 minutes, and then 5% phase B for 1.5 minutes; the flow rate was 2.5 mL / min.

[0141] The compound with a retention time of 6.338 min under the following conditions is The chromatographic column was Chiralpak AD-3, 150 mm x 4.6 mm, 3 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 5 minutes, then 40% phase B for 2.5 minutes, and then 5% phase B for 2.5 minutes; the flow rate was 2.5 mL / min.

[0142] The compound with a retention time of 7.132 min under the following conditions is The chromatographic column was Chiralpak AD-3, 150 mm x 4.6 mm, 3 μm; phase A was carbon dioxide, phase B was 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5 minutes, maintained at 40% phase B for 2.5 minutes, and then maintained at 5% phase B for 2.5 minutes; flow rate: 2.5 mL / min;

[0143] The compound with a retention time of 1.798 min under the following conditions is The chromatographic column was Chiralpak AD-3; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / isopropanol in phase B; the gradient was 5% to 40% phase B in 2 minutes, the 40% phase B was maintained for 1.2 minutes, and then the 5% phase B was maintained for 0.8 minutes; the flow rate was 4 mL / min.

[0144] The compound with a retention time of 2.023 min under the following conditions is The chromatographic column was Chiralpak AD-3; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / isopropanol in phase B; the gradient was 5% to 40% phase B in 2 minutes, the 40% phase B was maintained for 1.2 minutes, and then the 5% phase B was maintained for 0.8 minutes; the flow rate was 4 mL / min.

[0145] The compound with a retention time of 5.096 min under the following conditions is The chromatographic column was Chiralpak AD-3; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 5 minutes, then 40% to 5% phase B in 0.5 minutes, and then maintained at 5% phase B for 1.5 minutes; the flow rate was 2.5 mL / min.

[0146] The compound with a retention time of 5.388 min under the following conditions is The chromatographic column was Chiralpak AD-3; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 5 minutes, then 40% to 5% phase B in 0.5 minutes, and then maintained at 5% phase B for 1.5 minutes; the flow rate was 2.5 mL / min.

[0147] The compound with a retention time of 2.177 min under the following conditions is The chromatographic column was Chiralpak AS-3, 100 mm x 4.6 mm, 3 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 4 minutes, then 40% phase B for 2.5 minutes, and then 5% phase B for 1.5 minutes. The flow rate was 2.8 mL / min.

[0148] The compound with a retention time of 2.318 min under the following conditions is The chromatographic column was Chiralpak AS-3, 100 mm x 4.6 mm, 3 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 4 minutes, then 40% phase B for 2.5 minutes, and then 5% phase B for 1.5 minutes. The flow rate was 2.8 mL / min.

[0149] The compound with a retention time of 4.512 min under the following conditions is A stereoisomer in: chromatographic column: Chiralpak AD-3, 150mm*4.6mm, 3μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5 minutes, maintain 40% phase B for 2.5 minutes, then maintain 5% phase B for 2.5 minutes; flow rate: 2.5 ml / min; under the following conditions, the compound with a retention time of 6.985 min is A stereoisomer in: chromatographic column: Chiralpak AD-3, 150mm*4.6mm, 3μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5 minutes, maintain 40% phase B for 2.5 minutes, then maintain 5% phase B for 2.5 minutes; flow rate: 2.5 ml / min. Under the following conditions, the compound with a retention time of 6.809 min is The chromatographic column was Chiralpak AD-3, 150 x 4.6 mm, 3 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 5.5 minutes, then 40% phase B for 3 minutes, and then 5% phase B for 1.5 minutes; the flow rate was 2.5 mL / min.

[0150] The compound with a retention time of 7.460 min under the following conditions is The chromatographic column was Chiralpak AD-3, 150 x 4.6 mm, 3 μm; the mobile phase was carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B; the gradient was 5% to 40% phase B in 5.5 minutes, then 40% phase B for 3 minutes, and then 5% phase B for 1.5 minutes; the flow rate was 2.5 mL / min.

[0151] The compound with a retention time of 6.744 min under the following conditions is The chromatographic column was Chiralpak AD-3, 150 × 4.6 mm, 3 μm. The mobile phases were carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B. The gradient was 5% to 40% phase B in 5.5 minutes, followed by 40% phase B for 3 minutes and then 5% phase B for 1.5 minutes. The flow rate was 2.5 mL / min.

[0152] The compound with a retention time of 7.642 min under the following conditions is The chromatographic column was Chiralpak AD-3, 150 × 4.6 mm, 3 μm. The mobile phases were carbon dioxide in phase A and 0.05% diethylamine / ethanol in phase B. The gradient was 5% to 40% phase B in 5.5 minutes, followed by 40% phase B for 3 minutes and then 5% phase B for 1.5 minutes. The flow rate was 2.5 mL / min.

[0153] The compound with a retention time of 4.114 min under the following conditions is A stereoisomer in the chromatographic column: DAICEL CHIRALPAK AD, 250 mm*30 mm, 10 μm, mobile phase: phase A is carbon dioxide; phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4.5 minutes, then maintain 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min;

[0154] The compound with a retention time of 4.316 min under the following conditions is A stereoisomer in the chromatographic column: DAICEL CHIRALPAK AD, 250 mm*30 mm, 10 μm, mobile phase: phase A is carbon dioxide; phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4.5 minutes, then maintain 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min;

[0155] The compound with a retention time of 4.156 min under the following conditions is The chromatographic column was Chiralpak IG-3, 100 mm x 4.6 mm x 3 μm. The mobile phases were carbon dioxide in phase A and 0.05% diethylamine / methanol in phase B. The gradient was from 5% to 40% phase B in 4 minutes, followed by 2.5 minutes of 40% phase B and then 2.5 minutes of 5% phase B. The flow rate was 2.8 mL / min.

[0156] The compound with a retention time of 4.543 min under the following conditions is The chromatographic column was Chiralpak IG-3, 100 mm x 4.6 mm x 3 μm. The mobile phases were carbon dioxide in phase A and 0.05% diethylamine / methanol in phase B. The gradient was from 5% to 40% phase B in 4 minutes, followed by 2.5 minutes of 40% phase B and then 2.5 minutes of 5% phase B. The flow rate was 2.8 mL / min.

[0157] The compound with a retention time of 1.017 min under the following conditions is A stereoisomer in the chromatographic column: DAICEL CHIRALCEL OJ, 250 mm*30 mm, 10 μm, mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B is maintained at 40%; flow rate: 2.8 ml / min;

[0158] The compound with a retention time of 2.833 min under the following conditions is A stereoisomer in the chromatographic column: DAICEL CHIRALCEL OJ, 250 mm*30 mm, 10 μm, mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B is maintained at 40%; flow rate: 2.8 ml / min;

[0159] The compound with a retention time of 1.615 min under the following conditions is Chiralpak AD-3 50mm*4.6mm, 3um, mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 2 minutes, hold 40% phase B for 1.2 minutes, then hold 5% phase B for 0.8 minutes, flow rate: 4mL / min;

[0160] The compound with a retention time of 1.917 min under the following conditions is Chiralpak AD-3 50mm*4.6mm, 3um, mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 2 minutes, hold 40% phase B for 1.2 minutes, then hold 5% phase B for 0.8 minutes, flow rate: 4mL / min;

[0161] The compound with a retention time of 5.293 min under the following conditions is Chiralpak AD-3 150mm*4.6mm, 3um, mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5.5 minutes, maintain 40% phase B for 3 minutes, then maintain 5% phase B for 1.5 minutes, flow rate: 2.5 ml / min;

[0162] The compound with a retention time of 5.960 min under the following conditions is A stereoisomer in the 5′-[4-(2-amino-3-oxo-1-oxo-4-nitropropene]-1-yl]-4-nitropropene]-1-oxo-2 ...

[0163] The above retention time test conditions do not limit the compounds. As long as the retention time obtained by measurement using the above test conditions is the same as or within the error range of the above record, and the compound is a stereoisomer of the compound defined by the retention time, it falls within the scope of protection of the present invention.

[0164] The compounds of the present invention can be prepared by applying synthetic methods known in the art and those outlined in the schemes set forth below.

[0165] General synthetic method 1:

[0166]

[0167] As shown in general synthetic method 1, the compound represented by formula (I-1) reacts with a suitable halogenating agent (such as but not limited to elemental iodine) to obtain a halogenated product I-2. The NH functional group in the structure of the product I-2 is protected by a suitable protecting group (such as but not limited to phenylsulfonyl). The compound having the chemical formula (I-2) can be protected with a phenylsulfonyl group at low temperature (e.g., 0°C) to obtain compound I-3. Subsequently, under a suitable catalyst, the compound I-5 is generated by reacting with compound I-8 through a one-pot stile coupling, or the halogenated compound I-3 is first converted into the corresponding borate (or boronic acid) compound I-4 under suitable reaction conditions, and compound I-4 is reacted with compound I-8 through Suzuki coupling under a suitable catalyst to obtain compound I-5; compound I-5 is heated under a suitable chlorination agent (such as but not limited to SO2Cl2) to obtain chloro intermediate I-6, or thiomethyl ether is oxidized to sulfone I-10 (sulfoxide I-9 or "a mixture of sulfone I-10 and sulfoxide I-9") by a suitable oxidant (such as but not limited to m-CPBA). Chloro intermediate I-6 (I-10, or a mixture of I-9 / I-10) is heated under suitable alkaline conditions (such as but not limited to DIEA) and reacted with a compound of formula R 3 NH2 reaction to obtain a compound of formula (I-7), which is heated under suitable alkaline conditions (such as but not limited to NaOH) and deprotected to obtain the final product of formula (I). 3 If the group contains other protecting groups (such as but not limited to Boc protecting group), compound I is reacted under appropriate acidic conditions (such as but not limited to TFA / DCM) to obtain the final compound.

[0168] General Synthesis Method 2: In the compound shown in Formula I, when X is N, we creatively synthesized a new key intermediate compound II-6, through which the final compound II of the present invention (corresponding to compound I where X is N) can be conveniently synthesized.

[0169]

[0170] As shown in general synthetic method 2, the compound represented by formula (II-1) reacts with a suitable halogenating agent (such as but not limited to elemental iodine) to obtain a halogenated product II-2. The NH functional group in the structure of the product II-2 is protected by a suitable protecting group (such as but not limited to phenylsulfonyl). For example, the compound II-3 can be obtained by reacting with phenylsulfonyl chloride at a low temperature (e.g., 0°C) and protecting with phenylsulfonyl. Subsequently, under a suitable catalyst, the compound II-5 is generated by a one-pot stile coupling reaction with compound II-6, or compound II-3 is first halogenated and converted into the corresponding borate (or boronic acid) compound II-4 under suitable reaction conditions, and compound II-4 is reacted with compound II-6 by Suzuki coupling under a suitable catalyst to obtain compound II-5; compound II-5 is oxidized under suitable conditions (such as but not limited to m-CPBA) to obtain nitrogen oxide compound II-6, and nitrogen oxide compound II-6 is reacted with a suitable activating reagent (such as but not limited to dimethyl sulfate) under heating conditions to generate active pyridine nitrogen oxide methyl ether, and the active intermediate is reacted with an amino compound R in the presence of a suitable base (such as but not limited to DIEA) 2 H reaction to obtain a compound as shown in formula (II), if R 3 If the group contains other protecting groups (such as but not limited to Boc protecting group), compound II is reacted under appropriate acidic conditions (such as but not limited to TFA / DCM) to obtain the final compound.

[0171] Compound II-5 is heated under suitable halogenation conditions in the presence of a suitable chlorinating agent or brominating agent (such as but not limited to methyl chloroformate) to obtain a chloro intermediate II-7 or a corresponding bromo intermediate. The chloro intermediate II-7 is reacted with a corresponding boron ester / boronic acid or amino compound R under suitable catalytic conditions through suitable coupling conditions (such as but not limited to Suzuki coupling or Buchwald coupling). 2 H reaction to obtain a compound of formula (II), if R 3 If the group contains other protecting groups (such as but not limited to Boc protecting group), compound II is reacted under appropriate acidic conditions (such as but not limited to TFA / DCM) to obtain the final compound.

[0172] General Synthesis Method 3: In the compound shown in Formula I, when X is C(R 4 );R 4 When X is -P(=O)Me2, we creatively synthesized a novel key intermediate compound III-4. Through this intermediate III-4, a simple substitution reaction can be performed to conveniently synthesize the final compound III ((corresponding to X being C(R 4 );R 4 Compound I) is -P(=O)Me2).

[0173]

[0174] As shown in general synthetic method 3, the compound represented by formula (III-1) (such as but not limited to the bromo compound) is subjected to a coupling reaction with a suitable reagent (such as but not limited to dimethylphosphine oxide) in the presence of a suitable catalyst to obtain product III-2. The product III-2 is reacted with compound (III-3) in the presence of a suitable acidic reagent (such as but not limited to trifluoromethanesulfonic acid or aluminum chloride) and a suitable solvent (such as but not limited to 1,1,1,3,3,3-hexafluoropropane-2-ol or dichloromethane) at a suitable temperature (such as but not limited to 60°C or 0°C) to obtain compound III-4. The chlorinated intermediate III-4 is heated under suitable alkaline conditions (such as but not limited to DIEA) and reacted with a compound of formula R 3 NH2 reaction to obtain a compound of formula (III). 3 If the group contains other protecting groups (such as but not limited to Boc protecting groups), compound I is reacted under suitable acidic conditions (such as but not limited to TFA / DCM) to obtain the final compound

[0175] The present invention also provides a pharmaceutical composition comprising the aforementioned compound as shown in Formula IA, its stereoisomers, its diastereomers, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound as shown in Formula IA, its stereoisomers or its diastereomers), or a crystalline form or solvate of any of the foregoing (referring to the aforementioned compound as shown in Formula IA, its stereoisomers, its diastereomers or pharmaceutically acceptable salts), and pharmaceutical excipients.

[0176] The present invention also provides the use of the compound of Formula IA, its stereoisomers, its diastereomers, or any of the foregoing (referring to the compound of Formula IA, its stereoisomers, or its diastereomers), or any of the foregoing (referring to the compound of Formula IA, its stereoisomers, or its diastereomers), or any of the foregoing (referring to the compound of Formula IA, its stereoisomers, its diastereomers, or pharmaceutically acceptable salts), or any of the foregoing (referring to the compound of Formula IA, its stereoisomers, its diastereomers, or pharmaceutically acceptable salts), or the pharmaceutical composition thereof in the preparation of a medicament. Preferably, the medicament is used to prevent and / or treat a proliferative disease.

[0177] The present invention also provides a method for preventing and / or treating a proliferative disease, comprising administering to a patient a therapeutically effective amount of the above-mentioned compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof (referring to the aforementioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof), or the above-mentioned pharmaceutical composition.

[0178] Preferably, the proliferative disease is cancer (e.g., leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, breast cancer, ovarian cancer, brain cancer, lung cancer, liver cancer, small cell lung cancer, melanoma, bladder cancer, colon cancer, esophageal cancer, bone cancer, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer epithelial sarcoma, soft tissue sarcoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory disease, autoinflammatory disease or autoimmune disease.

[0179] The compounds of the present invention, their stereoisomers, their diastereomers, or pharmaceutically acceptable salts of any of the foregoing, or crystal forms or solvates, pharmaceutical compositions of any of the foregoing can be administered topically or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans). Exemplary combinations for rectal administration include suppositories, which can include, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at room temperature but melt and / or dissolve in the rectal cavity to release the drug. The compounds of the present invention can also be administered parenterally, for example, by inhalation, injection, or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or input.

[0180] The therapeutically effective amount of the active ingredient is as defined above and below and depends on the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated and the mode of administration. For enteral administration, such as oral administration, the compounds of the present invention can be formulated into a wide variety of dosage forms.

[0181] The effective amount of the compound, its pharmaceutically acceptable salt, solvate or pharmaceutical composition of the present invention can be easily determined by routine experiments, and the most effective and convenient administration route and the most appropriate formulation can also be determined by routine experiments.

[0182] Unless otherwise specified, the terms used in this invention have the following meanings:

[0183] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0184] The carbon atom marked with “*” indicates a chiral carbon atom, which is either S or R configuration.

[0185] The term "pharmaceutically acceptable salt" refers to salts prepared from compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, and diethanolamine salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a neat solution or a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids, inorganic acids, or organic acids. When compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0186] The term "solvate" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof combined with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or non-ordered arrangement. Such solvents include, but are not limited to, water, methanol, and ethanol.

[0187] The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may exist as a single stereoisomer or a mixture thereof (e.g., a racemate) if stereoisomers exist. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution by bonding with other chiral compounds (chemical bonding, etc.) or salt formation (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.

[0188] The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may exist as a single tautomer or a mixture thereof, if tautomers exist, preferably in a form in which the more stable tautomer predominates.

[0189] The atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "pharmaceutically acceptable salt solvate" may exist in their natural abundance or in a non-natural abundance form. For example, hydrogen atoms in their natural abundance form are approximately 99.985% protium and approximately 0.015% deuterium; and in their non-natural abundance form are approximately 95% deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "pharmaceutically acceptable salt solvate" may exist in a non-natural abundance form.

[0190] When any variable (such as R a-1 ) appears multiple times in the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R a-1 group substituted, that is, the group may be replaced by up to 3 R a-1 Replace, the position R a-1 Definition and other positions R a-1 In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0191] The term "plurality" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0192] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0193] The term "cycloalkyl" refers to a saturated monocyclic, polycyclic, or bridged carbocyclic substituent consisting of carbon atoms and hydrogen atoms, and which can be connected to the rest of the molecule by a single bond via any suitable carbon atom; when polycyclic, it can be a fused ring system or a spiro ring system that is connected in a paracyclic manner or a spiro ring (i.e., two geminal hydrogen atoms on a carbon atom are replaced by alkylene groups). The cycloalkyl substituent can be connected to the central molecule via any suitable carbon atom. In some embodiments, a ring having 3-8 carbon atoms can be represented as a C3-C8 cycloalkyl. In some embodiments, C3-C6 cycloalkyl includes cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), bicyclo[1.1.1]pentane, and cyclohexyl (C6).

[0194] The term "heterocycloalkyl" refers to a saturated cyclic group having a heteroatom, including monocyclic, polycyclic or bridged rings. When it is polycyclic, it can be a fused ring system or a spirocyclic system connected in parallel or spirocyclic rings. Preferably, it is a 4-12-membered saturated cyclic group containing 1-4 ring heteroatoms independently selected from N, O and S. Exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, glycidyl, thietanyl, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolane, oxathiofuranyl, dithiofuranyl, or isomers and stereoisomers thereof. Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thiocyclopentanyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, oxazepanyl, and diazepanyl, or isomers and stereoisomers thereof.

[0195] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably an aromatic 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring containing 1-4 groups independently selected from nitrogen, oxygen and sulfur. When it is a bicyclic ring, at least one ring is aromatic, for example, furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl, etc.

[0196] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and in the preparation of prescriptions. These are all substances contained in pharmaceutical preparations, in addition to the active ingredient. For a complete list, see Part IV of the Pharmacopoeia of the People's Republic of China (2015 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

[0197] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0198] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0199] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0200] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0201] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0202] The reagents and raw materials used in the present invention are commercially available.

[0203] The positive progress of the present invention is that the present invention provides an aromatic heterocyclic compound, which has a novel structure, good CDK7 inhibitory activity, good selectivity (relative to CDK2, CDK9 and CDK12), and has a very good inhibitory effect on human breast cancer cells HCC70 and ovarian cancer A2780, while having better membrane permeability and lower efflux rate. DETAILED DESCRIPTION

[0204] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0205] Preparation of Intermediate C: (S)-3-methyl-4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0206]

[0207] Step 1: 1H-pyrrolo[2,3-b]pyridine-7-oxide

[0208]

[0209] The compound 1H-pyrrolo[2,3-b]pyridine (130.00 g, 1.10 mol) was dissolved in tetrahydrofuran (1.20 L), and m-chloroperbenzoic acid (80% purity, 356.05 g, 1.65 mol) was added, and then stirred at 20 ° C for 16 hours. The system was a yellow suspension. The reaction solution was concentrated and half of the solvent was removed by rotation. The solid was filtered out and washed with tetrahydrofuran (50 mL). The solid was dried under vacuum to obtain a crude product 1H-pyrrolo[2,3-b]pyridine-7-oxide (50% purity, 275.00 g) as a white solid. The crude product was used directly in the next step without purification. LCMS (ESI): [M+H] + =135.1.

[0210] Step 2: (S)-3-Methyl-4-(1H-pyrrolo[2,3-b]pyridin-6-yl)-morpholine

[0211]

[0212] 1H-Pyrrolo[2,3-b]pyridine-7-oxide (50% purity, 55.00 g, 205.07 mmol) was dissolved in acetonitrile (535 mL), and dimethyl sulfate (21 mL, 225.51 mmol) was added. The mixture was heated to 60°C and stirred for 16 hours. After cooling to 0°C, (3S)-3-methylmorpholine (103.68 g, 1.03 mol) was added. The mixture was heated to 60°C and stirred for 20 hours. After cooling and concentration, the residue was extracted with dichloromethane (200 mL) and a 10% aqueous sodium carbonate solution (200 mL). The aqueous phase was extracted with dichloromethane (200 mL x 2). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to give (S)-3-methyl-4-(1H-pyrrolo[2,3-b]pyridin-6-yl)-morpholine (8.64 g, 39.76 mmol, 19% yield) as a yellow solid. LCMS (ESI): [M+H] + =218.1.

[0213] 1H NMR(400MHz,CD3OD)δppm 7.75(d,J=8.5Hz,1H),7.03(d,J=3.3Hz,1H),6.58(d,J=8.5Hz,1H),6.29(d,J=3.5Hz,1H),4.31(q,J=6.5Hz,1H),4.00(dd ,J=3.1,11.2Hz,1H),3.84-3.71(m,3H),3.65(dt,J=3.0,11.4Hz,1H),3.22(dt,J=3.8,12.3Hz,1H),1.18(d,J=6.8Hz,3H)

[0214] Step 3: (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine

[0215]

[0216] Compound (S)-3-methyl-4-(1H-pyrrolo[2,3-b]pyridin-6-yl)-morpholine (8.34 g, 38.39 mmol) was dissolved in dimethylformamide (40 mL), and potassium hydroxide (5.37 g, 95.96 mmol) was added. A solution of iodine (9.75 g, 38.39 mmol) in dimethylformamide (40 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour. After concentration, the residue was added with water (100 mL) and extracted with dichloromethane (100 mL*3). The organic phases were combined and dried over magnesium sulfate. Filtered and concentrated to give the crude product, compound (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (14.70 g). LCMS (ESI): [M+H] + =344.0.

[0217] Step 4: (S)-4-(3-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine

[0218]

[0219] Compound (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (14.70 g, 34.27 mmol) was dissolved in tetrahydrofuran (150 mL). Sodium tert-butoxide (4.94 g, 51.40 mmol) was added at 0°C and stirred at 0°C for 30 minutes. Benzenesulfonyl chloride (6.6 mL, 51.40 mmol) was added, and the reaction mixture was stirred at 20°C for 2 hours. After concentration, the residue was purified by flash column chromatography (silica gel, 0-40% gradient of tetrahydrofuran / petroleum ether) to obtain compound (S)-4-(3-iodo-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (4.60 g, 9.52 mmol, 28% yield) as a yellow solid. LCMS (ESI): [M+H] + =484.0.

[0220] Step 5: (S)-3-Methyl-4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0221]

[0222] Compound (S)-4-(3-iodo-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (500 mg, 1.03 mmol) and 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (512 mg, 1.35 mmol) were dissolved in xylene (10 mL) under nitrogen. Tetrakis(triphenylphosphine)palladium (120 mg, 0.10 mmol) and hexamethyltin (407 mg, 1.24 mmol) were added at room temperature. The reaction mixture was stirred at 100°C for 2 hours and then heated to 140°C for an additional 12 hours. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain (S)-3-methyl-4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (220 mg) as a yellow solid. LCMS (ESI): [M+H] + =550.3

[0223] Step 6: (S)-3-Methyl-4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0224]

[0225] To a suspension of compound (S)-3-methyl-4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (800 mg, 1.46 mmol) and sodium sulfate (202 mg, 1.60 mmol) in dichloromethane (59 mL) was added m-chloroperbenzoic acid (85% purity, 650 mg, 3.20 mmol) in portions at 0°C. The resulting reaction system was stirred at 25°C for 40 minutes. The mixture was filtered and the filtrate was used directly in the next reaction. LCMS (ESI): [M+H] + =582.1.

[0226] Preparation of Intermediate D: 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0227]

[0228] Step 1: 4-(1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0229]

[0230] The compound 1H-pyrrolo[2,3-b]pyridine-7-oxide (50% purity, 35.00 g, 0.13 mol) was dissolved in acetonitrile (250 mL), and dimethyl sulfate (14 mL, 0.14 mol) was added, followed by stirring at 60°C for 16 hours. The reaction system was cooled to 0°C, and morpholine (230 mL, 2.61 mol) was added, followed by stirring at 60°C for 20 hours, resulting in a yellow solution. The reaction system was cooled and concentrated, and dichloromethane (300 mL) and a 10% aqueous sodium carbonate solution (200 mL) were added to the residue. After separating the organic phase, the aqueous phase was extracted with dichloromethane (200 mL x 2). The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was dried to give 80 g of a residue. The residue was purified by flash column chromatography (C18, 0-100% gradient of acetonitrile / water) to give 4-(1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine as a yellow solid (13.50 g, 66.44 mmol, 51% yield). LCMS (ESI): [M+H] + =204.2.

[0231] Step 2: 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0232]

[0233] Compound 4-(1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (9.70 g, 47.74 mmol) was dissolved in dimethylformamide (50 mL), potassium hydroxide (6.66 g, 118.72 mmol) was added, and the reaction was stirred for 30 minutes. At 0 ° C, a solution of iodine element (12.10 g, 47.68 mmol) in dimethylformamide (50 mL) was added dropwise to the reaction solution and reacted at 20 ° C for 1 hour. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL * 3). The organic phases were combined, dried over magnesium sulfate, filtered, and the filtrate was dried to obtain crude 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (11.80 g), which was a brown oil. The crude product was directly used for the next reaction without purification. LCMS (ESI): [M+H] + =330.0.

[0234] Step 3: 4-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0235]

[0236] Compound 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (14.50 g, 44.06 mmol) was dissolved in tetrahydrofuran (145 mL), and sodium tert-butoxide (6.35 g, 66.08 mmol) was added at 0°C and stirred for 30 minutes. Benzenesulfonyl chloride (15.50 g, 87.76 mmol) was then added at 0°C, and the reaction mixture was reacted at 20°C for 2 hours. The solvent was then removed by vortexing and the residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to obtain compound 4-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (12.70 g, 27.06 mmol, yield 61%). LCMS (ESI): [M+H] + =470.0.

[0237] Step 4: 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0238]

[0239] 4-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (5.50 g, 11.72 mmol) and 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (3.48 g, 15.24 mmol) were dissolved in xylene (100 mL). Tetrakis(triphenylphosphine)palladium (1.35 g, 1.17 mmol) and hexamethyltin (3 mL, 15.24 mmol) were added under a nitrogen atmosphere. The mixture was reacted at 100°C for 2 hours and then at 140°C for 14 hours under nitrogen protection. The resulting solution was a black suspension. The system was concentrated under reduced pressure to give a brown solid, which was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give compound 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (4.10 g, 6.12 mmol, 52% yield). LCMS (ESI): [M+H] + =536.1.

[0240] Step 5: 4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-ol hydrochloride

[0241]

[0242] Compound 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (8.00 g, 14.94 mmol) was dissolved in a mixture of glacial acetic acid (100 mL) and water (50 mL), and concentrated hydrochloric acid (50 mL) was added at room temperature. The resulting reaction solution was stirred at 100°C for 16 hours. The reaction solution was concentrated, and ethyl acetate (40 mL) was added to the resulting residue and stirred at room temperature for one hour. The solid was filtered and dried in vacuo to obtain the crude compound 4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-ol hydrochloride (6.80 g). This compound was used directly in the next reaction. LCMS (ESI): [M+H] + =366.1.

[0243] Step 6: 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0244]

[0245] Compound 4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-ol hydrochloride (2.20 g, 6.02 mmol) was dissolved in phosphorus oxychloride (40 mL) and stirred at 80°C for 16 hours. The reaction solution was concentrated, and the resulting residue was purified by flash column chromatography (silica gel, 0-90% gradient of ethyl acetate / petroleum ether) to obtain compound 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (1.40 g, 2.92 mmol, two-step yield 48%) as a yellow solid. LCMS (ESI): [M+H] + =384.1.

[0246] 1 H NMR (400MHz, DMSO-d6) δppm 9.00 (s, 1H), 8.58-8.42 (m, 1H), 7.84 (d, J = 1.8Hz, 1H), 6.99-6.81 (m, 1H), 3.79-3.66 (m, 4H), 3.57-3.40 (m, 4H).

[0247] Preparation of Intermediate E: (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0248]

[0249] Step 1: (1H-indol-7-yl)dimethylphosphine oxide

[0250]

[0251] Compound 7-bromo-1H-indole (2.00 g, 10.20 mmol) and dimethylphosphine oxide (2.39 g, 30.60 mmol) were dissolved in 1,4-dioxane (50 mL) under nitrogen protection. Triethylamine (7 mL, 51.00 mmol) and [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-diphenyl]palladium(II) methanesulfonate dichloromethyl adduct (20 mg, 0.02 mmol) were added at 25°C. The reaction system was heated to 100°C for 16 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (silica gel, 0-100% gradient of tetrahydrofuran / petroleum ether) to obtain compound (1H-indol-7-yl)dimethylphosphine oxide (220 mg, 1.08 mmol, 11% yield) as a yellow solid. LCMS(ESI):[M+H] + =194.1.

[0252] Step 2: (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0253]

[0254] (1H-indol-7-yl)dimethylphosphine oxide (220 mg, 1.08 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (220 μL, 1.63 mmol) were dissolved in hexafluoroisopropanol (10 mL). Trifluoromethanesulfonic acid (106 μL, 1.20 mmol) was added dropwise at 0°C. The reaction system was stirred at 60°C for 16 hours. The mixture was cooled to room temperature, poured into saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (15 mL x 2). The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified on preparative silica gel (petroleum ether / tetrahydrofuran, 1:2 volume ratio) to afford (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (200 mg, 0.38 mmol, 34% yield) as a yellow oil. LCMS(ESI):[M+H] + =374.0.

[0255] Preparation of intermediate F: The following intermediate F (7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile) was prepared using the same method as Example 4 of patent WO2020093011A1

[0256]

[0257] Compound intermediate F, light yellow solid. LCMS (ESI): [M+H] + =401.2;

[0258] 1 H NMR (400MHz, DMSO-d6) δppm 13.00 (br s, 1H), 9.16 (s, 1H), 8.36 (d, J = 8.4Hz, 1H), 8.16 (d, J = 2.4Hz, 1H), 7.71 (d, J = 8.4Hz, 1H)

[0259] Preparation example of intermediate G: 3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

[0260]

[0261] Step 1: 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

[0262]

[0263] A mixture of 6-bromo-1H-pyrrolo[2,3-b]pyridine (4.00 g, 20.30 mmol), zinc powder (133 mg, 2.03 mmol), zinc cyanide (1.67 g, 14.21 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride in dichloromethane (829 mg, 1.02 mmol) in dimethylformamide (10 mL) was degassed and purged with nitrogen three times, and then stirred at 140° C. under nitrogen for 5 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (100 mL) and saturated brine (100 mL*2), dried over sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, 10-33% gradient of ethyl acetate / petroleum ether) to give 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (85% purity, 1.50 g, 8.91 mmol, 44% yield) as a white solid. LCMS (ESI): [M+H] + =144.2.

[0264] Step 2: 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

[0265]

[0266] A solution of 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (85% purity, 26.00 g, 154.44 mmol) and potassium hydroxide (22.93 g, 408.66 mmol) in dimethylformamide (150 mL) was cooled to 0°C, and then a solution of elemental iodine (41.49 g, 163.46 mmol) in dimethylformamide (150 mL) was added dropwise. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and the filtrate was dried. The crude product was washed three times with water (100 mL*3) and dried under vacuum to give the crude compound 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (53.00 g). LCMS (ESI): [M+H] + =270.0.

[0267] Step 3: 3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

[0268]

[0269] A solution of 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (50.00 g, 148.68 mmol) in tetrahydrofuran (2.50 L) was cooled to 0°C and sodium hydroxide (60% purity, 10.71 g, 267.63 mmol) was added under nitrogen. Benzenesulfonyl chloride (28 mL, 223.01 mmol) was then added. The mixture was stirred at 25°C for 3 hours and then quenched by the addition of acetic acid (20 mL) and water (200 mL) at 0°C. The tetrahydrofuran in the solution was removed by rotary evaporation, and the precipitated solid was filtered and dried under vacuum to obtain a crude product. The crude product was slurried with methyl tert-butyl ether (100 mL) and filtered to obtain a white solid compound, 3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (45.00 g, 110.04 mmol, 63% yield). LCMS(ESI):[M+H] + =410.0.

[0270] Step 4: 3-(2-methylthio-5-trifluoromethylpyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

[0271]

[0272] Under nitrogen protection, tetrakis(triphenylphosphine)palladium (1.27 g, 1.10 mmol) was added to a solution of 3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (5.00 g, 11.00 mmol), 4-chloro-2-methylthio-5-trifluoromethylpyrimidine (3.27 g, 14.30 mmol), and hexamethylditin (4.72 g, 14.30 mmol) in xylene (100 mL). The reaction mixture was stirred at 100°C for 2 hours under nitrogen protection, and then heated to 140°C for 16 hours. The reaction mixture was dried in spun-column form, and the residue was purified by flash column chromatography (silica gel, 5-10% gradient of tetrahydrofuran / petroleum ether) to give 3-(2-methylthio-5-trifluoromethylpyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (3.10 g, 6.52 mmol, 59% yield) as a yellow solid. LCMS (ESI): [M+H] + =476.2.

[0273] Step 5: 3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

[0274]

[0275] The compound 3-(2-methylthio-5-trifluoromethylpyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (200 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), and m-chloroperbenzoic acid (80% purity, 181 mg, 0.84 mmol) and sodium sulfate (50 mg, 0.35 mmol) were added. The resulting reaction system was stirred at 20°C for 2 hours. Saturated sodium sulfite solution (1 mL) and saturated sodium bicarbonate solution (5 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined and concentrated to give the crude compound 3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (230 mg) as a yellow oil. The crude product was used directly in the next reaction. LCMS (ESI): [M+H] + =508.0.

[0276] Preparation of Intermediate H: 3,5-dimethyl-4-(3-(2-methylsulfonyl-5-trifluoromethylpyrimidin-4-yl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)isoxazole

[0277]

[0278] Referring to patent WO2019143719, Example 11, intermediate H was prepared using the same synthesis method.

[0279] Example 35. N-(4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[4.4]nonan-7-amine (Compound 35)

[0280]

[0281] Step 1: tert-Butyl 7-((4-(6-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate

[0282]

[0283] Tert-butyl 7-amino-2-azaspiro[4.4]nonane-2-carboxylate (30 mg, 0.125 mmol) and diisopropylethylamine (103 μL, 0.62 mmol) were dissolved in tetrahydrofuran (100 μL). 3,5-dimethyl-4-(3-(2-methylsulfonyl-5-trifluoromethylpyrimidin-4-yl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)isoxazole (87 mg, 0.15 mmol) was added. The reaction was stirred at 25°C for 12 hours. Water (2 mL) was added, and the mixture was extracted with ethyl acetate (2 mL x 3). The organic phases were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the crude compound tert-butyl 7-((4-(6-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (100 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + =738.3.

[0284] Step 2: 7-((4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate

[0285]

[0286] The compound tert-butyl 7-((4-(6-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (90% purity, 100 mg, 0.12 mmol) was dissolved in methanol (1 mL). Aqueous sodium hydroxide solution (4 M, 153 uL, 0.61 mmol) was added and the reaction was stirred at 25°C for 1 hour. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL*3). The organic phases were combined and dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the crude compound 7-((4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (100 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + =612.3.

[0287] Step 3: N-(4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[4.4]nonan-7-amine

[0288]

[0289] Compound 7-((4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (100 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and hydrogen chloride / dioxane solution (4 M, 1 mL, 4.00 mmol) was added at 0°C, and the reaction was stirred at 25°C for 1 hour. The residue was concentrated and purified by preparative HPLC to give N-(4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[4.4]nonan-7-amine (formate salt, 12.11 mg, 21 umol, 12% yield) as a white solid. LCMS (ESI): [M+H] + =498.3,

[0290] 1 H NMR(400MHz,CD3OD)δppm 8.85(m,1H),8.56(m,2H),8.03(s,1H),7.36(m,1H),4.61(m,1H),3.36(m,2H),3.28-3. 15(m,2H),2.63(s,3H),2.47(s,3H),2.31(m,2H),2.13-1.92(m,3H),1.90-1.71(m,3H).

[0291] We used the same method to synthesize compound 35, using 3,5-dimethyl-4-(3-(2-methylsulfonyl-5-trifluoromethylpyrimidin-4-yl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)isoxazole to react with the corresponding amine to synthesize the following compounds:

[0292] Example 36. (R)-N-(4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[3.3]heptan-5-amine (Compound 36)

[0293]

[0294] Compound 36 (2.02 mg, yellow solid). LC-MS (ESI): [M+H] + =470.2;

[0295] 1 H NMR(400MHz,CD3OD)δppm 9.20-8.50(m,2H),8.09(m,1H),7.57-7.28(m,1H),4.64(m,2H),4.28(m,1H),4.12- 3.66(m,2H),2.70(s,3H),2.50(s,3H),2.35(m,1H),2.21(m,2H),2.12-1.98(m,1H).

[0296] Example 37. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-6-azaspiro[3.4]octan-1-amine (Compound 37)

[0297]

[0298] Step 1: Benzyl 1-((tert-Butyloxycarbonyl)amino)-6-azaspiro[3.4]octane-6-carboxylate

[0299]

[0300] The compound tert-butyl (6-azaspiro [3.4] octan-1-yl) carbamate hydrochloride (100 mg, 0.44 mmol) was dissolved in tetrahydrofuran (500 μL). Sodium bicarbonate (111 mg, 1.32 mmol), benzyl chloroformate (500 μL), and triethylamine (92 μL, 0.66 mmol) were added at 25°C. The mixture was reacted at 25°C for 4 hours, resulting in a yellow suspension. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 4). The organic phases were combined, dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain crude benzyl 1-((tert-butoxycarbonyl)amino)-6-azaspiro [3.4] octane-6-carboxylate (134 mg). The crude product was carried on to the next step without purification. LCMS (ESI): [M-56+H]. + =305.1.

[0301] Step 2: Benzyl-1-amino-6-azaspiro[3.4]octane-6-carboxylate

[0302]

[0303] Benzyl 1-((tert-butyloxycarbonyl)amino)-6-azaspiro[3.4]octane-6-carboxylate (134 mg, 0.37 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (276 μL, 3.72 mmol) was added at 0°C. The reaction was stirred at 25°C for 2 hours, resulting in a yellow suspension. The reaction mixture was concentrated to give crude benzyl 1-amino-6-azaspiro[3.4]octane-6-carboxylate (185 mg). The crude product was carried on to the next step without purification. LCMS (ESI): [M+H] + =261.1.

[0304] Step 3: 4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0305]

[0306] A suspension of the compound 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (80% purity, 3.50 g, 5.23 mmol) and sodium sulfate (725 mg, 5.75 mmol) in dichloromethane (59 mL) was cooled to 0°C, and m-chloroperbenzoic acid (85% purity, 2.34 g, 11.50 mmol) was added in portions. After the addition was complete, the mixture was reacted at 25°C for 40 minutes. The system became a yellow suspension, and the mixture was filtered, and the filtrate was used directly in the next reaction. LCMS (ESI): [M+H] + =568.1.

[0307] Step 4: Benzyl 1-((4-(6-morpholinyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-azaspiro[3.4]octane-6-carboxylate

[0308]

[0309] A solution of compound 4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (180 mg, 0.32 mmol) in dichloromethane (2 mL) was cooled to 0°C and diisopropylethylamine (1048 uL, 6.34 mmol) was added. Then, a solution of compound 1-amino-6-azaspiro[3.4]octane-6-carboxylic acid benzyl ester (50% purity, 185 mg, 0.35 mmol) in dichloromethane (700 μL) was added dropwise. After completion of the addition, the mixture was reacted at 25°C for 18 hours. The system formed a yellow suspension. The mixture was concentrated to dryness and purified by flash column chromatography (silica gel, 0-26% gradient of ethyl acetate / petroleum ether) to give benzyl 1-((4-(6-morpholinyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-azaspiro[3.4]octane-6-carboxylate (132 mg, 0.18 mmol, 56% yield) as a white solid. LCMS (ESI): [M+H] + =748.3.

[0310] Step 5: Benzyl 1-((4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-azaspiro[3.4]octane-6-carboxylate

[0311]

[0312] To a solution of benzyl 1-((4-(6-morpholinyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-azaspiro[3.4]octane-6-carboxylate (132 mg, 0.18 mmol) in n-butanol (1200 μL) was added aqueous sodium hydroxide (4 M, 221 μL, 0.88 mmol). The reaction mixture was allowed to react at 25°C for 18 hours. A yellow suspension formed. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The organic phases were combined and dried over magnesium sulfate, filtered, and the filtrate was dried to give a crude compound, benzyl 1-((4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-azaspiro[3.4]octane-6-carboxylate (85 mg). LCMS (ESI): [M+H] + =608.3.

[0313] Step 6: N-(4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-6-azaspiro[3.4]octan-1-amine

[0314]

[0315] Under nitrogen protection, benzyl 1-((4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-azaspiro[3.4]octane-6-carboxylate (98 mg, 0.16 mmol) was dissolved in ethyl acetate (2 mL). Dry Pd / C (10%, 50 mg) was added, the atmosphere was replaced with a hydrogen balloon, and the mixture was stirred at 24°C for 18 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC to give N-(4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-6-azaspiro[3.4]octan-1-amine (0.89 mg, 2.00 umol, 1.17% yield over two steps) as a white solid. LCMS (ESI): [M+H] + =474.2;

[0316] 1 H NMR(400MHz,CD3OD)δppm 8.69-8.43(m,2H),7.72(m,1H),6.95-6.69(m,1H),4.20-4.10(m,1H),3.90- 3.76(m,4H),3.62-3.48(m,4H),2.33-2.15(m,3H),2.04(m,5H),1.62(m,2H).

[0317] We used the same method to synthesize compound 37, reacting 4-(3-(2-methylsulfonyl-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine with a commercially available or simply synthesized amino compound, and then deprotecting (benzyl chloroformate or tert-butyloxycarbonyl) to obtain the following compound:

[0318] Example 38. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1-azaspiro[4.5]dec-7-amine (Compound 38)

[0319]

[0320] Compound 38 (4.16 mg, yellow solid). LCMS (ESI): [M+H] + =502.2;

[0321] 1H NMR (400MHz, CD3OD): δppm 8.62-8.47(m,2H),7.75(br s,1H),6.80(d,J=8.8Hz,1H),3.89-3.85(m,5H),3.55(br d,J=4.0Hz,4H),3.21(br t,J=6.8Hz,2H),2.03-1.92(m,4H),1.86(br t,J=7.2Hz,2H),1.80-1.74(m,2H),1.70(br d,J=15.2Hz,4H).

[0322] Example 39. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[3.3]heptan-5-amine (Compound 39)

[0323]

[0324] Compound 39 (10.74 mg, yellow solid). LCMS (ESI): [M+H] + =460.2;

[0325] 1 H NMR(400MHz,CD3OD)δppm 8.80-8.37(m,2H),7.75(m,1H),6.81(m,1H),4.24(m,1H),3.95(m,2H),3. 88-3.80(m,6H),3.61-3.50(m,4H),2.24-2.10(m,2H),2.10-1.93(m,2H).

[0326] Example 40. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[4.4]nonan-7-amine (Compound 40)

[0327]

[0328] Compound 40 (5.05 mg, white solid). LCMS (ESI): [M+H] + =488.3;

[0329] 1H NMR (400MHz, CD3OD): δppm 8.62-8.42(m,2H),7.74(m,1H),6.79(m,1H),3.93-3.82(m,5H),3.55(m,4 H),3.16(m,2H),3.02(s,2H),2.25(m,2H),1.90(m,3H),1.80-1.69(m,3H)

[0330] Example 41. N-(4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-3-azaspiro[5.5]undecan-8-amine, formate salt (Compound 41)

[0331]

[0332] Compound 41 (2.22 mg, white solid). LCMS (ESI): [M+H] + =460.2;

[0333] 1 H NMR(400MHz,CD3OD)δppm 8.61-8.44(m,3H),7.72(m,1H),6.78(m,1H),4.32-4.03(m,1H),3.91-3.81(m,4H), 3.55(m,4H),3.26-2.77(m,4H),2.17(m,2H),1.85-1.52(m,6H),1.45-1.10(m,4H).

[0334] Example 42. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-8-azaspiro[4.5]dec-2-amine (Compound 42)

[0335]

[0336] Compound 42 (6.76 mg, white solid). LCMS (ESI): [M+H] + =502.3;

[0337] 1H NMR(400MHz,CD3OD)δppm 9.03-8.74(m,1H),8.56(s,1H),8.02(m,1H),7.05(m,1H),4.76-4.38(m,1H),3.96-3. 83(m,4H),3.78-3.63(m,4H),3.29-3.12(m,4H),2.38-2.19(m,2H),1.96-1.62(m,8H).

[0338] Example 45. (3aR,4R,7aS)-N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)octahydro-1H-isoindol-4-amine (Compound 45)

[0339]

[0340] Compound 45 (5.20 mg, white solid). LCMS (ESI): [M+H] + =488.2;

[0341] 1 H NMR (400MHz, CD3OD) δppm 8.51(m,2H),7.74(s,1H),6.80(m,1H),3.85(m,4H),3.54(br s,4H),3.47-3.36(m,1H),3.19(m,2H),2.45(br s,1H),1.99-1.82(m,5H),1.80-1.78(m,1H),1.78-1.41(m,2H),1.35-1.17(m,1H).

[0342] Example 46. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]n-hexane-6-amine (Compound 46)

[0343]

[0344] Compound 46 (20.45 mg, yellow solid). LCMS (ESI): [M+H] + =446.2;

[0345] 1H NMR (400MHz, CD3OD) δppm 8.71-8.45(m,2H),7.74(s,1H),6.80(m,1H),4.62(m,1H),3.90-3.78(m,4H),3.61-3.41(m,6H),2.02(br s,2H),1.94(s,2H).

[0346] Example 47. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)azepan-4-amine, formate salt (Compound 47)

[0347]

[0348] Compound 47 (51 mg, white solid). LCMS (ESI): [M+H] + =462.2;

[0349] 1 H NMR(400MHz,CD3OD)δppm 8.73-8.35(m,3H)7.75(s,1H)6.79(m,1H)4.29(br s,1H)3.93-3.80(m,4H)3.61-3.50(m,4H)3.46-3.34(m,2H)3.29-3.19(m,2H)2.33(br s,2H)2.16-1.76(m,4H).

[0350] Compound 47 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: phase A is carbon dioxide; phase B is 0.1% ammonia water / isopropanol; phase B is maintained at 65%; flow rate: 60 ml / min) to obtain optically pure target compounds 48 and 49.

[0351] Example 48. After SFC separation of compound 47, a chiral monomer compound (compound 48) with a shorter elution time

[0352]

[0353] (Carbon atoms marked with "*" are chiral carbon atoms, either S or R configuration)

[0354] Compound 48 (9.70 mg, white solid). LCMS (ESI): [M+H] +=462.2; SFC analysis (column: Chiralpak AD-3 (250 mm*30 mm, 10 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / isopropanol, gradient: phase B from 5% to 40% over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 2.5 ml / min): RT = 2.187 min; ee = 98.98%.

[0355] 1 H NMR(400MHz,CD3OD)δppm 8.45-8.35(m,2H),7.60(s,1H),6.65(br d,J=8.40Hz,1H),4.15(m,1H),3.74-3.71(m,4H),3.44-3.41(m,4H),2.90-2.83(m,4H),2.20-2.00(m,2H),1.76-1.66(m,4H).

[0356] Example 49. After SFC separation of compound 47, a chiral monomer compound (compound 49) with a longer elution time

[0357]

[0358] Compound 49 (11.70 mg, white solid). LCMS (ESI): [M+H] + =462.2; SFC analysis (column: Chiralpak AD-3 (250 mm*30 mm, 10 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / isopropanol, gradient: phase B from 5% to 40% over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 2.5 ml / min): RT = 2.877 min, ee = 98.06%.

[0359] 1 H NMR(400MHz,CD3OD)δppm 8.45-8.35(m,2H),7.60(s,1H),6.65(br d,J=8.4Hz,1H),4.15(m,1H),3.74-3.71(m,4H),3.44-3.41(m,4H),2.90-2.83(m,4H),2.20-2.00(m,2H),1.76-1.66(m,4H).

[0360] Example 50. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1-oxo-7-azaspiro[4.5]dec-3-amine (Compound 50)

[0361]

[0362] Compound 50 (36.73 mg, yellow solid). LCMS (ESI): [M+H] + =504.2;

[0363] 1 H NMR(400MHz,DMSO-d6)δppm 11.88(br s,1H),8.74-8.35(m,2H),8.09(br d,J=6.7Hz,1H),7.71-7.47(m,1H),6.93-6.64(m,1H),4.75-4.41(m,1H),3.98-4.11(m,1H),3. 82-3.65(m,4H),3.48(m,2H),2.81-2.54(m,4H),2.39-2.27(m,1H),1.89(s,4H),1.79-1.51(m, 4H),1.38(br s,1H).

[0364] Example 51. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1-oxo-8-azaspiro[4.5]dec-3-amine (Compound 51)

[0365]

[0366] Compound 51 (60.55 mg, yellow solid). LCMS (ESI): [M+H] + =504.2;

[0367] 1 H NMR(400MHz,DMSO-d6)δppm 11.88(br s,1H),8.68-8.45(m,2H),8.41(m,1H),7.61(m,1H),6.78(m,1H),4.75-4.41(m,1H),4.11-3.98(m,1 H),3.75(m,5H),3.48(m,4H),2.81-2.45(m,4H),2.27-2.39(m,1H),1.89(m,1H),1.66-1.55(m,4H).

[0368] Example 52. 4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(pyrrolidin-3-ylmethyl)-5-(trifluoromethyl)pyrimidin-2-amine, formate salt (Compound 52)

[0369]

[0370] Compound 52 (2.77 mg, white solid). LCMS (ESI): [M+H] + =448.2;

[0371] 1 H NMR(400MHz,CD3OD)δppm 8.85-8.24(m,3H),7.73(s,1H),6.80(m,1H),3.96-3.82(m,3H),3.98-3.76(m,1H),3.72-3.49(m,6H),3.42(m,2H),3.29(br s,1H),3.08(br s,1H),2.81(br s,1H),2.22(m,1H),1.86(m,1H).

[0372] Example 53. N-((2S,4R)-2-methylpiperidin-4-yl)-4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine, formate salt (Compound 53)

[0373]

[0374] Compound 53 (110.74 mg, yellow solid). LCMS (ESI): [M+H] + =462.2;

[0375] 1 H NMR(400MHz,CD3OD)δppm 8.55(m,3H),7.73(br s,1H),6.78(d,J=8.8Hz,1H),4.44(m,1H),3.85(m,4H),3.62(m,1H),3.54 (m,4H),3.34(m,2H),2.24(m,2H),2.07(m,1H),1.90(m,1H),1.37(m,3H).

[0376] Example 54. N-((2R,4R)-2-methylpiperidin-4-yl)-4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 54)

[0377]

[0378] Compound 54 (29.62 mg, yellow solid). LCMS (ESI): [M+H] + =462.2

[0379] 1 H NMR(400MHz,DMSO-d6)δppm 11.87(m,1H),8.71-8.40(m,2H),7.87(m,1H),7.62(m,1H),6.78(m,1H)3.94(m,1H),3.75(br s,4H),3.47(br s,4H),3.03(m,1H),2.76-2.54(m,3H),1.88(m,2H),1.48-1.29(m,1H),1.21-0.97(m,4H).

[0380] Example 55. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine, formate salt (Compound 55)

[0381]

[0382] Compound 55 (16 mg, yellow solid). LCMS (ESI): [M+H] + =474.2

[0383] 1 H NMR(400MHz,CD3OD)δppm 8.60-8.54(m,3H),7.73(s,1H),6.79(s,1H),4.48(s,1H),3.86(m,4H), 3.55(m,6H),3.13-2.83(m,4H),2.11(m,1H),1.91(m,2H),1.68(m,1H).

[0384] Compound 55 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water / ethyl acetate; phase B is maintained at 50%, flow rate: 60 ml / min), and the two components were further purified by preparative HPLC to obtain target compounds 56 and 57, respectively.

[0385] Example 56. After chiral resolution of compound 55, the chiral monomer (compound 56) with a shorter elution time

[0386]

[0387] Compound 56 (1.91 mg, yellow solid, formate salt). LCMS (ESI): [M+H] + =474.2; SFC analysis (column: Chiralpak IG-3 (50 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 4 ml / min): RT = 2.343 min, ee = 100%.

[0388] 1 H NMR(400MHz,CD3OD)δppm 8.70-8.50(m,3H),7.72(m,1H),6.79(m,1H),4.46(m,1H),3.86(m,4H), 3.55(m,6H),3.10-2.80(m,4H),2.10(m,1H),1.91(m,2H),1.68(m,1H).

[0389] Example 57. After chiral resolution of compound 55, the chiral monomer (compound 57) with a longer elution time

[0390]

[0391] Compound 57 (1.01 mg, yellow solid, formate salt). LCMS (ESI): [M+H] + = 474.2; SFC analysis (column: Chiralpak IG-3 (50 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 4 ml / min): RT = 2.847 min, ee = 96.88%.

[0392] 1 H NMR(400MHz,CD3OD)δppm 8.70-8.50(m,3H),7.72(s,1H),6.79(m,1H),4.46(m,1H),3.86(m,4H), 3.55(m,6H),3.10-2.80(m,4H),2.10(m,1H),1.91(m,2H),1.68(m,1H).

[0393] Example 58. N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1-oxa-6-azaspiro[3.3]heptan-3-amine (Compound 58)

[0394]

[0395] Compound 58 (25.64 mg, yellow solid). LCMS (ESI): [M+H] + =462.2;

[0396] 1 H NMR(400MHz,CD3OD)δppm 8.87-8.38(m,2H),7.73(s,1H),6.80(s,1H),5.36-5.11(m,1H),4.78(s,1H),4.55( s,1H),4.17(s,1H),4.01(m,1H),3.90-3.79(m,5H),3.75(s,1H),3.61-3.50(m,4H).

[0397] Example 59. (R)-N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[3.3]heptan-5-amine (Compound 59)

[0398]

[0399] Compound 59 (10.74 mg, yellow solid). LCMS (ESI): [M+H] + =460.2;

[0400] 1 H NMR(400MHz,CD3OD)δppm 8.71-8.67(m,2H),7.75(m,1H),6.80(br s,1H),4.24(m,1H),4.10-3.78(m,8H),3.61-3.50(m,4H),2.30(m,1H),2.24-2.10(m,2H),2.10-1.93(m,1H).

[0401] Example 61. (R)-3-(2-((2-Azaspiro[3.3]heptane-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (Compound 61)

[0402]

[0403] Step 1: Tert-butyl (R)-5-((4-(6-cyano-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0404]

[0405] Compound 3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine- 6-Formonitrile (230 mg, 0.32 mmol) and tert-butyl (R)-5-amino-2-azaspiro[3.3]heptane-2-carboxylate hydrochloride (79 mg, 0.32 mmol) were dissolved in tetrahydrofuran (3 mL). Diisopropylethylamine (524 μL, 3.17 mmol) was added at 20°C. The resulting reaction system was stirred at 20°C for 1 hour and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give tert-butyl (R)-5-((4-(6-cyano-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (140 mg, 0.22 mmol, yield 69%) as a yellow solid. LCMS (ESI): [M-56+H] + =584.1;

[0406] Step 2: Tert-butyl (R)-5-((4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0407]

[0408] The compound tert-butyl (R)-5-((4-(6-cyano-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (120 mg, 0.19 mmol) was dissolved in 1,4-dioxane (2 mL), and aqueous sodium hydroxide solution (4 M, 375 μL, 1.50 mmol) was added, and the resulting reaction system was reacted at 20°C for 2 hours. Water (2 mL) was added, and the mixture was extracted with ethyl acetate (3 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give crude tert-butyl (R)-5-((4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (122 mg). LCMS (ESI): [M-100+H] + =400.1.

[0409] Step 3: (R)-3-(2-((2-azaspiro[3.3]heptane-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

[0410]

[0411] Tert-butyl (R)-5-((4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (122 mg, 0.17 mmol) was dissolved in trifluoroethanol (2 mL). Tetrafluoroboric acid-ether adduct (50% content, 111 mg, 0.34 mmol) was added at 0°C. The resulting reaction system was stirred at 20°C for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC to obtain (R)-3-(2-((2-azaspiro[3.3]heptane-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (20.64 mg, 47 μmol, 27% yield) as a white solid. LCMS(ESI):[M+H] + =399.9;

[0412] 1H NMR (400MHz, CD3OD) δppm 9.07(m,1H),8.73(m,1H)8.27(m,1H),7.68(br d,J=8.28Hz,1H),4.64-4.48(m,2H),4.24(m,1H),4.00(br s,2H),2.31(m,1H),2.23-2.14(m,2H),2.06-1.98(m,1H).

[0413] We used the same method to synthesize compound 61, using intermediate 7 (3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile) to react with the corresponding amine to synthesize the following compounds:

[0414] Example 62. 3-(2-((3,3-Dimethyl-1,4-oxazepan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (Compound 62)

[0415]

[0416] Compound 62 (6.64 mg, yellow solid). LCMS (ESI): [M+H] + =432.1;

[0417] 1 H NMR(400MHz,CD3OD)δppm 8.73(m,1H),8.60(br s,1H),8.21(br s,1H),7.68(br s,1H),4.44(m,1H),4.06(m,1H),3.76(m,1H),3.56(m,2H),3.07(m,2H),1.14(m,6H)

[0418] Compound 62 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: phase A is carbon dioxide; phase B is 0.1% ammonia water / ethanol; phase B is maintained at 70%, flow rate: 70 ml / min) to give compounds 63 and 64.

[0419] Example 63. After SFC separation of compound 62, the chiral monomer (compound 63) with a shorter elution time

[0420]

[0421] Compound 63 (7.24 mg, yellow solid). LCMS (ESI): [M+H]+ =432.1; SFC analysis (column: ChiralPak AD-3 (150 mm*4.6 mm), 3 μm; mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4.5 minutes, maintaining 5% phase B for 1.5 minutes, flow rate: 2.5 ml / min): RT = 3.934 min, ee = 100%

[0422] 1 H NMR(400MHz,CD3OD)δppm 8.73(m,1H),8.60(br s,1H),8.21(br s,1H),7.68(br s,1H),4.44(m,1H),4.06(m,1H),3.76(m,1H),3.56(m,2H),3.07(m,2H),1.14(m,6H)

[0423] Example 64. After SFC separation of compound 62, the chiral monomer (compound 64) with a longer elution time

[0424]

[0425] Compound 64 (7.10 mg, yellow solid). LCMS (ESI): [M+H] + =432.2; SFC analysis (column: ChiralPak AD-3 (150 mm*4.6 mm), 3 um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4.5 minutes, maintain 5% phase B for 1.5 minutes, flow rate: 2.5 ml / min): RT=4.355 min, ee=99.33%.

[0426] 1 H NMR(400MHz,CD3OD)δppm 8.78(m,1H),8.59(br s,1H),8.21(br s,1H),7.67(br s,1H),4.39(m,1H),4.06(m,1H),3.75(m,1H),3.55(m,2H),3.07(m,2H),1.14(m,6H).

[0427] Example 65. 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (Compound 65)

[0428]

[0429] Compound 65 (12.10 mg, white solid). LCMS (ESI): [M+H] + =388.1;

[0430] 1 H NMR(400MHz,CD3OD)δppm 8.78(m,1H),8.59(br s,1H),8.20(br s,1H),7.67(br s,1H),4.58(m,1H),3.58(m,1H),2.31(m,2H),2.01(m,2H),1.95(m,1H),1.72(m,1H).

[0431] Example 66. 3-(2-((1S,3S)-3-(dimethylamino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile (Compound 66)

[0432]

[0433] Compound 66 (8.64 mg, white solid). LCMS (ESI): [M+H] + =416.1;

[0434] 1 H NMR(400MHz,CD3OD)δppm 8.98-8.97(m,1H),8.56(br s,1H),8.20(br s,1H),7.67(br s,1H),4.54(m,1H),3.32(m,1H),2.61-2.56(m,6H),2.31-2.29(m,2H),2.01(m,2H)1.77-1.74(m,2H).

[0435] Example 67. (R)-N-(4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[3.3]heptan-5-amine (Compound 67)

[0436]

[0437] Step 1: Tert-butyl (R)-5-((4-(6-((S)-3-methylmorpholinyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0438]

[0439] (S)-3-Methyl-4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (2.3 g, 1.58 mmol) and diisopropylethylamine (5 mL, 31.64 mmol) were dissolved in tetrahydrofuran (20 mL). Tert-butyl (R)-5-amino-2-azaspiro[3.3]heptane-2-carboxylate (390 mg, 1.58 mmol) was added, and the resulting reaction system was stirred at 25°C for 12 hours. The tetrahydrofuran was removed by vortexing the reaction system, and water (20 mL) was added and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give tert-butyl (R)-5-((4-(6-((S)-3-methylmorpholinyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (340 mg, 0.48 mmol, 30% yield) as a brown solid. LCMS (ESI): [M+H] + =714.2.

[0440] Step 2: Tert-butyl (R)-5-((4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0441]

[0442] To a solution of tert-butyl (R)-5-((4-(6-((S)-3-methylmorpholinyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (340 mg, 0.48 mmol) in 1,4-dioxane (14 mL) was added aqueous sodium hydroxide (4 M, 953 μL, 3.81 mmol). The resulting reaction was stirred at 100°C for 0.5 hours. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude compound tert-butyl (R)-5-((4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (310 mg). LCMS (ESI): [M+H] +=574.3.

[0443] Step 3: (R)-N-(4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[3.3]heptan-5-amine

[0444]

[0445] The compound tert-butyl (R)-5-((4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (310 mg, 0.54 mmol) was dissolved in trifluoroethanol (6 mL) and tetrafluoroboric acid-diethyl ether adduct (50% content, 2.63 g, 0.81 mmol) was added at 0°C, and the reaction system was stirred at 25°C for 1 hour. Water (10 mL) was added to dilute the mixture and lyophilized. The residue was purified by preparative HPLC to give (R)-N-(4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azaspiro[3.3]heptane-5-amine (34 mg, 0.072 mmol, 13% yield) as a yellow solid. LCMS (ESI): [M+H] + =474.2;

[0446] 1 H NMR(400MHz,CD3OD)δppm 8.77-8.36(m,2H),7.70(s,1H),6.74(d,J=8.8Hz,1H),4.52(s,1H),4.42(s,1H),4.21-3.85(m,4H),3.82(d,J=1.8Hz,2H),3.72-3.36(m,3H), 3.26(dt,J=3.6,12.6Hz,1H),2.27(s,1H),2.18-2.09(m,1H),2.08-1.88(m,2H),1.24(d,J=6.8Hz,3H).

[0447] We used the same method to synthesize compound 67, using (S)-3-methyl-4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine as the starting material and reacting it with the corresponding amine to synthesize the following compounds:

[0448] Example 68. (1S,3R)-N1-(4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)cyclopentane-1,3-diamine, formate salt (Compound 68)

[0449]

[0450] Compound 68 (15.10 mg, white solid). LCMS (ESI): [M+H] + =462.2;

[0451] 1 H NMR(400MHz,CD3OD)δppm 8.54(m,3H),7.71(s,1H),6.74(m,1H),4.44(m,2H),4.02(m,1H),3.83(m,3H),3.66( m,2H),3.25(m,1H),2.65(m,1H),2.18(m,2H),1.86(m,2H),1.65(m,1H),1.23(m,3H).

[0452] Example 76. 3-(2-((3,3-Dimethyl-1,4-oxazepan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 76)

[0453]

[0454] Step 1: tert-Butyl 6-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,3-dimethyl-1,4-oxazepane-4-carboxylate

[0455]

[0456] 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (160 mg, 0.40 mmol) and tert-butyl 6-amino-3,3-dimethyl-1,4-oxazepane-4-carboxylate (107 mg, 0.44 mmol) were dissolved in 1-methyl-2-pyrrolidone (4 mL), and diisopropylethylamine (493 μL, 2.99 mmol) was added at 25° C. The temperature was raised to 130° C. and the reaction was allowed to proceed at this temperature for 3 hours. The reaction system was cooled to room temperature, and the residue was purified by flash column chromatography (C18, 0-40% gradient of acetonitrile / water) to obtain tert-butyl 6-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,3-dimethyl-1,4-oxazepane-4-carboxylate (120 mg, 0.20 mmol, 50% yield) as a white solid. LCMS (ESI): [M+H] + =609.2.

[0457] Step 2: tert-Butyl 6-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,3-dimethyl-1,4-oxazepane-4-carboxylate

[0458]

[0459] Tert-butyl 6-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,3-dimethyl-1,4-oxazepane-4-carboxylate (100 mg, 0.21 mmol) and dimethylphosphine oxide (15 mg, 0.20 mmol) were dissolved in 1,4-dioxane (2 mL). Under nitrogen, triethylamine (68 μL, 0.49 mmol) and methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl]palladium(II) dichloromethane adduct (16 mg, 16.00 umol) were added at 25°C. The reaction system was stirred at 100°C for 2 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography (C18, 0-95% gradient of acetonitrile / water) to give tert-butyl 6-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,3-dimethyl-1,4-oxazepane-4-carboxylate (58 mg, 86 umol, 41% yield) as a yellow solid. LCMS (ESI): [M+H] + =607.3;

[0460] Step 3: 3-(2-((3,3-dimethyl-1,4-oxazepan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile

[0461]

[0462] The compound tert-butyl 6-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,3-dimethyl-1,4-oxazepane-4-carboxylate (110 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (135 μL, 1.81 mmol) was added dropwise at 0°C. The reaction system was stirred at 0°C for 1 hour. The residue was purified by preparative HPLC to obtain 3-(2-((3,3-dimethyl-1,4-oxazepane-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (2.16 mg, 4 μmol, 2.2% yield) as a white solid. LCMS (ESI): [M+H] + =507.1.

[0463] 1 H NMR (400MHz, CD3OD) δppm 8.46-8.81(m,2H),8.19(br s,1H),7.68(br s,1H),4.48(br s,1H),4.09(br s,1H),3.76(br s,1H),3.61(br s,2H),3.08-3.29(m,2H),2.16(s,3H),2.13(s,3H),1.21(br s,6H).

[0464] Example 77. (R)-3-(2-((2-Azaspiro[3.3]heptane-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile (Compound 77)

[0465]

[0466] Step 1: tert-Butyl (R)-5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0467]

[0468] 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (200 mg, 0.50 mmol) and tert-butyl (R)-5-amino-2-azaspiro[3.3]heptane-2-carboxylate (136 mg, 0.55 mmol) were dissolved in 1-methyl-2-pyrrolidone (8 mL), and diisopropylethylamine (610 μL, 3.74 mmol) was added at 25°C. The reaction system was reacted at 130°C for 3 hours. The mixture was cooled to room temperature and filtered, and the residue was purified by flash column chromatography (C18, 0-40% gradient of acetonitrile / water) to give tert-butyl (R)-5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (270 mg, 0.47 mmol, 93% yield) as a white solid. LCMS (ESI): [M-56+H] + =520.0.

[0469] Step 2: Tert-butyl (R)-5-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0470]

[0471] Tert-butyl (R)-5-((4-(7-bromo-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (270 mg, 0.47 mmol) and dimethylphosphine oxide (44 mg, 0.56 mmol) were dissolved in 1,4-dioxane (2.5 mL). Under nitrogen, triethylamine (195 μL, 1.40 mmol) and methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl]palladium(II) dichloromethane adduct (44 mg, 47 μmol) were added at 25°C. The resulting reaction system was reacted at 100°C for 4 hours. After cooling to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give tert-butyl (R)-5-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (50 mg, 87 umol, 18% yield) as a yellow solid. LCMS (ESI): [M+H] + =575.3.

[0472] Step 3: (R)-3-(2-((2-azaspiro[3.3]heptan-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile

[0473]

[0474] The compound tert-butyl (R)-5-((4-(6-cyano-7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (50 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (129 μL, 1.74 mmol) was added at 20°C. The resulting reaction system was reacted at 20°C for 16 hours. The reaction solution was concentrated, and the resulting residue was purified by preparative HPLC to give the title compound (R)-3-(2-((2-azaspiro[3.3]heptane-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile as a yellow solid (2.58 mg, 3 μmol, 3.4% yield). LCMS(ESI):[M+H] + =475.2.

[0475] 1 H NMR (400MHz, CD3OD) δppm 8.52-8.91 (m, 2H) 8.08-8.33 (m, 1H) 7.69 (br s, 1H) 4.62 (br s, 4H) 4.25 (br d, J=10.8Hz, 1H) 3.65-4.08 (m, 2H) 2.30 (br s,1H)2.15(d,J=13.8Hz,6H)1.97-2.08(m,2H)1.62(br s,1H).

[0476] The following compounds were synthesized using the same method as compound 77:

[0477] Example 78. 3-(2-(((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile, formate (Compound 78)

[0478]

[0479] Compound 78 (18.30 mg, white solid). LCMS (ESI): [M+H] + =463.2.

[0480] 1H NMR(400MHz,CD3OD)δppm 8.74-8.55(m,3H),8.20(br s,1H),7.66(m,1H),4.63(m,1H),3.80(m,1H),2.36(m,2H),2.23-2.13(m,8H),1.83–1.70(m,2H).

[0481] Example 79. (S)-7-(Dimethylphosphoryl)-3-(2-((1-hydroxy-propan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile (Compound 79)

[0482]

[0483] Compound 79 (41.44 mg, white solid). LCMS (ESI): [M+H] + =438.1.

[0484] 1 H NMR(400MHz,CD3OD)δppm 8.74-8.50(m,2H),8.17(br s,1H),7.64(br s,1H),4.28(br s,1H),3.63(m,2H),2.14(s,3H),2.11(s,3H),1.28(d,J=6.8Hz,3H).

[0485] Example 80. (R)-(3-(2-(2-Azaspiro[3.3]heptane-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 80)

[0486]

[0487] Step 1: tert-Butyl (R)-5-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

[0488]

[0489] (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (168 mg, 0.45 mmol) and tert-butyl (R)-5-amino-2-azaspiro[3.3]heptane-2-carboxylate (123 mg, 0.49 mmol) were dissolved in 1,4-dioxane (100 μL), and diisopropylethylenediamine (446 μL, 2.70 mmol) was added at 25°C. The reaction system was heated to 100°C and stirred for 3 hours. The reaction was complete after LCMS analysis, and the mixture was cooled to room temperature and concentrated to give the crude compound tert-butyl (R)-5-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (150 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + =450.0.

[0490] Step 2: (R)-(3-(2-((2-azaspiro[3.3]heptan-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0491]

[0492] The compound tert-butyl (R)-5-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.36 mmol) was dissolved in trifluoroethanol (2 mL). Tetrafluoroboric acid-diethyl ether adduct (50% content, 236 mg, 0.73 mmol) was added at 0°C. The ice-salt bath was removed, and the reaction solution was stirred at 20°C for 1 hour. The reaction solution was lyophilized to obtain a crude product, which was purified by preparative HPLC to afford the title compound (R)-(3-(2-((2-azaspiro[3.3]heptan-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide as a yellow solid (67.85 mg, 0.15 mmol, 39% yield). LCMS(ESI):[M+H] + =450.1.

[0493] 1H NMR (400MHz, CD3OD) δppm 8.48-8.75 (m, 2H), 7.98 (br s, 1H), 7.52 (m, 1H), 7.35 (br t, J=6.3Hz, 1H), 4.54 (br s,1H),3.90-4.35(m,2H),3.39-3.80(m,2H),2.00-2.34(m,3H),1.93(m,7H).

[0494] Using the same method for synthesizing compound 80, 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide was reacted with the corresponding amino compound to synthesize the following compound:

[0495] Example 81. (3-(2-((1S,3S)-3-aminocyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 81)

[0496]

[0497] Compound 81 (4.52 mg, yellow solid). LCMS (ESI): [M+H] + =438.2.

[0498] 1 H NMR(400MHz,CD3OD)δppm 8.57(m,2H),8.06(br s,1H),7.53(m,1H),7.34(m,1H),4.64(m,1H),3.81(m,1H),2.36(m,2H),2.33-2.19(m,2H),1.95(s,3H),1.92(s,3H),1.83-1.71(m,2H).

[0499] Example 82. (S)-(3-(2-((1-hydroxypropyl-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 82)

[0500]

[0501] Compound 82 (11.12 mg, white solid). LCMS (ESI): [M+H] + =413.1.

[0502] 1H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.67-8.55(m,2H),7.91(m,1H),7.68(m,1H),7.49(m,1H),7.25(m,1H ),4.78(m,1H),4.15(m,1H),3.51(m,2H),1.80(s,6H),1.18(d,J=6.8Hz,3H)

[0503] Example 83. 3-(2-(((1S,3S)-3-hydroxycyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 83)

[0504]

[0505] Compound 83 (13.02 mg, white solid). LCMS (ESI): [M+H] + =439.1.

[0506] 1 H NMR(400MHz,CD3OD)δppm 8.67-8.51(m,2H),7.97(m,1H),7.51(m,1H),7.35(m,1H),4.71(m,1H),4.41(m,1 H),2.32(m,1H),2.13(m,2H),1.95(s,3H),1.91(s,3H),1.87(m,1H),1.65(m,2H).

[0507] Example 84. (3-(2-((1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 84)

[0508]

[0509] Compound 84 (23.12 mg, white solid). LCMS (ESI): [M+H] + =421.1.

[0510] 1 H NMR(400MHz,DMSO-d6)δppm 12.64(br s,1H),11.64(br s,1H),10.12(br s,1H),8.80-8.00(m,2H),7.97-7.60(m,3H),7.57(m,1H),7.37-7.27(m,1H),1.91(s,3H),1.87(s,3H).

[0511] Example 85. (3-(2-((1-Hydroxy-2-methylpropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 85)

[0512]

[0513] Compound 85 (25.21 mg, white solid). LCMS (ESI): [M+H] + =427.1.

[0514] 1 H NMR (400MHz, DMSO-d6) δppm 11.51(br s,1H),8.59-7.70(m,3H),7.49(m,1H),7.26(m,1H),7.18(br s,1H),4.93(br s,1H),3.56(br s,2H),1.83(s,3H),1.80(s,3H),1.37(br s,6H).

[0515] Example 86. (S)-(3-(2-((2-Fluoro-3-hydroxypropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 86)

[0516]

[0517] Compound 86 (25.21 mg, white solid). LCMS (ESI): [M+H] + =431.1.

[0518] 1 H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.65-8.58(m,2H),8.14-8.05(m,1H),7.94(m,1H),7.50(m,1H),7.27(br s,1H),5.04(br s,1H),4.77(m,1H),3.80-3.40(m,4H),1.83(s,3H),1.80(s,3H)

[0519] Example 87. (3-(2-((3S,4R)-4-Hydroxytetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 87)

[0520]

[0521] Compound 87 (23.90 mg, white solid). LCMS (ESI): [M+H] + =441.1.

[0522] 1 H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.70-8.38(m,2H),8.13(m,1H),7.94(m,1H),7.51(m,1H),7.29(m,1H),5.29(m,1H),4. 35-4.25(m,2H),4.06(m,1H),4.04(m,1H),3.71(m,1H),3.58(m,1H),1.83(s,3H),1.80(s,3H).

[0523] Example 88. (S)-(3-(2-((1-hydroxybutan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 88)

[0524]

[0525] Compound 88 (27.13 mg, white solid). LCMS (ESI): [M+H] + =427.1.

[0526] 1 H NMR(400MHz,DMSO-d6)δppm 11.53(br s,1H),8.65-8.40(m,2H),7.94-7.89(m,1H),7.59-7.46(m,2H),7.27(m,1H),4.72(t,J=5.6Hz,1H) ,4.02(m,1H),3.50-3.30(m,2H),1.82(s,3H),1.79(s,3H),1.68(m,1H),1.50(m,1H),0.91(m,3H).

[0527] Example 89. (3-(2-((3-Hydroxypropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 89)

[0528]

[0529] Compound 89 (21.97 mg, white solid). LCMS (ESI): [M+H] + =413.0.

[0530] 1H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.61-8.48(m,2H),7.93-7.85(m,2H),7.50(m,1H),7.27(m,1H),4.5 0(t,J=5.2Hz,1H),3.53-3.30(m,4H),1.83(s,3H),1.80(s,3H),1.75(m,2H)

[0531] Example 90. (3-(2-((1-Hydroxycyclobutyl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 90)

[0532]

[0533] Compound 90 (26.17 mg, white solid). LCMS (ESI): [M+H] + =439.1.

[0534] 1 H NMR(400MHz,DMSO-d6)δppm 11.54(br s,1H),8.68-8.45(m,2H),7.95-7.89(m,1H),7.55-7.46(m,2H),7.26(m,1H),5.24(m,1H),3.6 3-3.57(m,2H),2.06(m,2H),1.96(m,2H),1.83(s,3H),1.80(s,3H),1.65(m,1H),1.48(m,1H).

[0535] Using the same method for synthesizing compound 80, 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide was reacted with 3,3-dimethyl-1,4-oxazin-6-amine to synthesize the racemic compound (3-(2-((3,3-dimethyl-1,4-oxacyclo-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide. The compound was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia water / methanol; phase B is maintained at 65%; flow rate: 70 ml / min) to obtain compounds 91 and 92.

[0536] Example 91. (3-(2-((3,3-Dimethyl-1,4-oxazepan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide: A short-lived chiral monomer (Compound 91) after SFC resolution.

[0537]

[0538] Compound 91 (19.72 mg, yellow solid). LCMS (ESI): [M+H] + =482.2; SFC analysis (column: Cellulose-2 (100 mm*4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 4 minutes, hold at 40% phase B for 2.5 minutes, then hold at 5% phase B for 1.5 minutes; flow rate: 2.8 ml / min): RT = 3.788 min, ee = 93.88%.

[0539] 1 H NMR(400MHz,CD3OD)δppm 8.62-8.40(m,2H),7.97(br s,1H),7.52(m,1H),7.36(m,1H),4.63(m,1H),4.17(m,1H),3.83-3.57(m,3H),3.40(m,2H),1.98(s,3H),1.95(s,3H),1.36(m,6H).

[0540] Example 92. Chiral Monomer (Compound 92) with Longer Emission Time After SFC Separation of (3-(2-((3,3-Dimethyl-1,4-oxazepan-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0541]

[0542] Compound 92 (22.30 mg, yellow solid). LCMS (ESI): [M+H] + = 482.2; SFC analysis (column: Cellulose-2 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 2 minutes, hold at 40% phase B for 2.5 minutes, then hold at 5% phase B for 1.5 minutes; flow rate: 2.8 ml / min): RT = 4.110 min, ee = 99.32%.

[0543] 1H NMR(400MHz,CD3OD)δppm 8.62-8.40(m,2H),7.97(br s,1H),7.52(m,1H),7.36(m,1H),4.63(m,1H),4.17(m,1H),3.83-3.57(m,3H),3.40(m,2H),1.98(s,3H),1.95(s,3H),1.36(m,6H).

[0544] Example 93. (R)-(3-(2-((1-hydroxypropyl-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 93)

[0545]

[0546] Compound 93 (21.22 mg, white solid). LCMS (ESI): [M+H] + =413.1.

[0547] 1 H NMR(400MHz,DMSO-d6)δppm 11.52(br s,1H),8.67-8.55(m,2H),7.92(m,1H),7.69(m,1H),7.50(m,1H),7.28(m,1H),4.7 9(m,1H),4.15(m,1H),3.52(m,2H),1.83(s,3H),1.80(s,3H),1.18(d,J=6.4Hz,3H)

[0548] Example 94. (3-(2-((1-(Hydroxymethyl)cyclopropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 94)

[0549]

[0550] Compound 94 (27.21 mg, white solid). LCMS (ESI): [M+H] + =425.1.

[0551] 1H NMR(400MHz,DMSO-d6)δppm 11.58(br s,1H),8.70-8.50(m,2H),8.26-8.13(m,1H),7.95(s,1H),7.49(m,1H),7.28( m,1H),4.79-4.69(m,1H),3.59(m,2H),1.83(s,3H),1.80(s,3H),0.81(m,4H).

[0552] Example 95. (3-(2-((2-Hydroxy-2-methylpropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 95)

[0553]

[0554] Compound 95 (21.40 mg, white solid). LCMS (ESI): [M+H] + =427.2.

[0555] 1 H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.67-8.47(m,2H),7.95-7.89(m,1H),7.68-7.61(m,1H),7.49(m,1H),7.2 7(m,1H),4.62-4.57(m,1H),3.44(m,2H),1.83(s,3H),1.80(s,3H),1.15(s,6H).

[0556] Example 96. (3-(2-((3,3-Difluoro-1-(hydroxymethyl)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 96)

[0557]

[0558] Compound 96 (26.10 mg, white solid). LCMS (ESI): [M+H] + =475.1.

[0559] 1 H NMR(400MHz,DMSO-d6)δppm 11.56(m,1H),8.71-7.83(m,4H),7.50(m,1H),7.28(m,1H),5.19(m,1H),3.70(br s,2H),2.89(m,4H),1.83(s,3H),1.80(s,3H).

[0560] Example 97. (3-(2-((2-Hydroxyethyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 97)

[0561]

[0562] Compound 97 (31.10 mg, white solid). LCMS (ESI): [M+H] + =399.0.

[0563] 1 H NMR(400MHz,DMSO-d6)δppm 11.54(br s,1H),8.65-8.40(m,2H),7.95-7.75(m,2H),7.49(m,1H),7.27(m,1H), 4.79(m,1H),3.58(m,2H),3.51-3.30(m,2H),1.83(s,3H),1.80(s,3H).

[0564] Using the same method for synthesizing compound 80, 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide was reacted with tert-butyl 7-amino-2-azaspiro[4.4]nonane-2-carboxylate, and after deprotection, the racemic compound (3-(2-((2-azaspiro[4.4]non-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide was obtained. The compound was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A: carbon dioxide, phase B: 0.1% ammonia / ethanol; phase B was maintained at 45%; flow rate: 80 ml / min) to give the target compounds 98, 99, and 100.

[0565] Example 98. A mixture (1:1) of a (3-(2-(((5R,7S)-2-azaspiro[4.4]non-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide compound and a (3-(2-(((5S,7R)-2-azaspiro[4.4]non-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide compound with the first and second elution times after SFC resolution (Mixed Compound 98)

[0566]

[0567] Mixed compound 98 (3.10 mg, yellow solid). LCMS (ESI): [M+H]+ =478.2; Column: DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm; Mobile phase: Phase A: carbon dioxide, Phase B: 0.05% diethylamine / isopropanol; Gradient: 5% to 40% Phase B over 2 minutes, hold at 40% Phase B for 1.2 minutes, then hold at 5% Phase B for 0.8 minutes; Flow rate: 4 mL / min; RT = 0.887 min, 1.00 min; Total ee: 90%.

[0568] 1 H NMR(400MHz,CD3OD)δppm 8.58-8.52(m,2H),7.95(br s,1H),7.51(m,1H),7.33(m,1H),4.54(m,1H),3.24(m,2H),2.92(m,2H),2.22(m,2H),1.93-1.70(m,12H).

[0569] Example 99. (3-(2-(((5R,7R)-2-Azaspiro[4.4]non-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 99)

[0570]

[0571] Compound 99 (10.10 mg, yellow solid). LCMS (ESI): [M+H] + =478.2;

[0572] SFC analysis (column: Chiralpak IG-3 (250 mm x 30 mm, 10 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / isopropanol; gradient: 5% to 40% phase B over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 4 ml / min): RT = 1.979 min, ee = 100%.

[0573] 1 H NMR(400MHz,CD3OD)δppm 8.61-8.56(m,2H),7.97(br s,1H),7.53(m,1H),7.35(m,1H),4.58(m,1H),3.15(m,2H),3.02(m,2H),2.28(m,2H),1.96-1.70(m,12H).

[0574] Example 100. (3-(2-(((5S,7S)-2-Azaspiro[4.4]non-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide compound (Compound 100)

[0575]

[0576] Compound 100 (11.05 mg, yellow solid). LCMS (ESI): [M+H] + =478.2;

[0577] SFC analysis (column: Chiralpak IG-3 (250 mm x 30 mm, 10 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / isopropanol; gradient: 5% to 40% phase B over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 4 ml / min): RT = 2.643 min, ee = 100%.

[0578] 1 H NMR(400MHz,CD3OD)δppm 8.61-8.56(m,2H),7.98(br s,1H),7.54(m,1H),7.35(m,1H),4.58(m,1H),3.11(m,2H),2.98(m,2H),2.28(m,2H),1.96-1.70(m,12H).

[0579] Example 101. (S)-N-(Piperidin-3-yl)-4-(6-(pyrrolidin-1-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 101, Compound 213 of Patent CN201780057760.8)

[0580]

[0581] We synthesized compound 213 (116.75 mg, light yellow solid) of patent CN201780057760.8 using the same synthesis method as Example 49 of patent CN201780057760.8. LC-MS: [M+H] + =431.2.

[0582] 1H NMR (400MHz, CD3OD): δppm 8.35(br s,1H),8.29(s,1H),7.65(br s,1H),6.72(br s,1H),6.63(d,J=8.4Hz,1H),4.22(m,1H),3.37-3.30(m,5H),3.10(m,1H),2.80(m,2H),2.21-1.86(m,6H),1.73-1.52(m,2H)

[0583] Using the same method for synthesizing compound 80, 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide was reacted with the corresponding amino compound to synthesize the following compound:

[0584] Example 102. (3-(2-((2,2-difluoro-3-hydroxypropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 102)

[0585]

[0586] Compound 102 (15.21 mg, white solid). LCMS (ESI): [M+H] + =449.0.

[0587] 1 H NMR (400MHz, DMSO-d6) δppm 8.70-8.45(m,2H),8.23-8.16(m,1H),7.99-7.92(m,1H),7.50(m,1H),7.27(br s,1H),5.57(br s,1H),4.00(m,2H),3.69(t,J=13.6Hz,2H),1.83(s,3H),1.80(s,3H)

[0588] Example 103. (S)-(3-(5-Chloro-2-((1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 103)

[0589]

[0590] Compound 103 (4.52 mg, yellow solid). LCMS (ESI): [M+H] + =438.2.

[0591] 1H NMR (400MHz, CD3OD) δppm 8.88(m,1H),8.57(s,1H),8.24(s,1H),7.54-7.36(m,2H),4.25(m,1H),3.68(m,2H),1.93(br d,J=13.5Hz,6H),1.32(br d,J=7.20Hz,3H).

[0592] Example 104. (S)-(3-(2-(((1-hydroxypropyl-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-5-methoxy-1H-indol-7-yl)dimethylphosphine oxide (Compound 104)

[0593]

[0594] Step 1: 1-(2-amino-3-bromo-5-methoxyphenyl)-2-chloroethanone

[0595]

[0596] 2-Bromo-4-methoxyaniline (3.30 g, 16.33 mmol) was dissolved in dichloromethane (120 mL). 2-Chloroacetonitrile (2 mL, 31.03 mmol) and a dichloromethane solution of boron tribromide (1 M, 25 mL, 25.00 mmol) were added dropwise at 0°C. Titanium tetrachloride (3 mL, 24.50 mmol) was then added dropwise at 0°C. The mixture was heated to 40°C and allowed to react for 72 hours. The reaction solution was slowly added to a mixture of hydrochloric acid (2 M, 40 mL) and ice. The pH was adjusted to 5 with sodium hydroxide. The mixture was extracted three times with ethyl acetate (150 mL*3). The organic phase was concentrated to obtain a crude product, which was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to obtain 1-(2-amino-3-bromo-5-methoxyphenyl)-2-chloroethanone (1.20 g, 4.24 mmol, 26% yield) as a yellow solid. LCMS(ESI):[M+H] + =277.0.

[0597] Step 2: 7-Bromo-5-methoxy-1H-indole

[0598]

[0599] 1-(2-Amino-3-bromo-5-methoxyphenyl)-2-chloroethanone (1.20 g, 4.31 mmol) was dissolved in dioxane (54 mL) and water (9 mL), and sodium borohydride (0.23 g, 6.03 mmol) was added. The temperature was raised to 100°C and the reaction mixture was reacted for 16 hours. After cooling, hydrochloric acid (0.1 M, 10 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (20 mL*3). The organic phase was concentrated to obtain a crude product, which was purified by flash column chromatography (silica gel, 0-40% gradient of ethyl acetate / petroleum ether) to obtain the compound 7-bromo-5-methoxy-1H-indole (0.39 g, 1.72 mmol, 40% yield) as a yellow oil. LCMS (ESI): [M+H] + =226.0;

[0600] Step 3: 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-methoxy-1H-indole

[0601]

[0602] 7-Bromo-5-methoxy-1H-indole (320 mg, 1.42 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (460 mg, 2.12 mmol) were dissolved in hexafluoroisopropanol (3 mL). Trifluoromethanesulfonic acid (138 μL, 1.56 mmol) was added dropwise at 0°C. The reaction mixture was reacted at 60°C for 16 hours. 3 mL of ethyl acetate was added to the slurry. The filtered solid was vacuum dried to obtain the crude compound 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-methoxy-1H-indole (270 mg) as a yellow solid. LCMS (ESI): [M+H] + =406.0.

[0603] Step 4: 7-Bromo-5-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole

[0604]

[0605] 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-methoxy-1H-indole (260 mg, 0.64 mmol) and potassium tert-butoxide (358 mg, 3.20 mmol) were added to trifluoroethanol (3 mL), and the temperature was raised to 60°C for 16 hours. The reaction solution was concentrated, and the residue was washed with water and dried in vacuo to give the crude compound 7-bromo-5-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (120 mg) as a white solid. LCMS (ESI): [M+H] +=470.0;

[0606] Step 5: (5-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0607]

[0608] 7-Bromo-5-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (100 mg, 0.21 mmol), dimethylphosphine oxide (0.03 g, 0.43 mmol) and triethylamine (90 uL, 0.64 mmol) were dissolved in xylene (1 mL). In a glove box, methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl]palladium (II) dichloromethane adduct (20 mg, 0.02 mmol) was added to the reaction solution, and the temperature was raised to 140 ° C for 16 hours. The reaction solution was concentrated to obtain a crude compound (5-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (150 mg). LCMS (ESI): [M+H] + =468.1;

[0609] Step 6: (S)-(3-(2-(((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-5-methoxy-1H-indol-7-yl)dimethylphosphine oxide

[0610]

[0611] (5-Methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (30% purity, 100 mg, 64 umol) and (S)-2-(methylamino)propan-1-ol (1 mL) were added to a reaction flask and the temperature was raised to 100°C for 4 hours. The residue was purified by preparative HPLC to give the title compound (S)-(3-(2-(((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-5-methoxy-1H-indol-7-yl)dimethylphosphine oxide (7 mg, 16 umol, 25% yield) as a white solid. LCMS (ESI): [M+H] + =443.1.

[0612] 1H NMR(400MHz,CD3OD)δppm 8.53(br s,1H),8.10(br s,1H),7.93(br s,1H),7.15(dd,J=2.4,14.4Hz,1H),4.53-4.19(m,1H),3.92(s,3H),3.71-3.61(m,2H),1.96-1.89(m,6H),1.31(d,J=6.8Hz,3H).

[0613] Using the same method for synthesizing compound 80, 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide was reacted with the corresponding amino compound to synthesize the following compound:

[0614] Example 105. (3-(2-((3-Fluoro-1-(hydroxymethyl)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 105)

[0615]

[0616] Compound 105 (6.45 mg, brown solid). LCMS (ESI): [M+H] + =457.1.

[0617] 1H NMR (400MHz, CD3OD) δppm 8.57 (d, J = 3.9Hz, 2H), 7.92 (br s,1H),7.50(dd,J=13.6,7.2Hz,1H),7.34(td,J=7.7,2.4Hz,1H),5.39-4.93(m,1H),3 .90(s,1H),3.76(s,1H),2.95-2.74(m,2H),2.60-2.40(m,2H),1.93(d,J=13.3Hz,6H).

[0618] Example 106. (S)-(3-(2-((1-Hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indol-7-yl)dimethylphosphine oxide (Compound 106)

[0619]

[0620] Step 1: 1-(2-amino-3-bromo-4-methoxyphenyl)-2-chloroethane-1-one

[0621]

[0622] A solution of boron trichloride in dichloromethane (1M, 109mL, 108.88mmol) was added dropwise to a solution of 2-bromo-3-methoxyaniline (20.00g, 98.99mmol) in dichloromethane (60mL) at 0°C. Chloroacetonitrile (8mL, 118.78mmol) was then added dropwise at 0°C, and aluminum trichloride (14.52g, 108.89mmol) was added in three portions. The reaction mixture was stirred at 50°C for 12 hours. The reaction mixture was then cooled to 0°C, and hydrochloric acid (1M, 300mL) was slowly added, resulting in the formation of a white precipitate. The mixture was then stirred at 50°C for 1 hour. The mixture was filtered, and the mother liquor was extracted with dichloromethane (200mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. 1-(2-amino-3-bromo-4-methoxyphenyl)-2-chloroethane-1-one (18.00 g, 64.63 mmol, 65% yield) was obtained as a gray solid. LCMS (ESI): [M+H] + =277.9.

[0623] Step 2: 7-Bromo-6-methoxy-1H-indole

[0624]

[0625] To a solution of 1-(2-amino-3-bromo-4-methoxyphenyl)-2-chloroethane-1-one (18.00 g, 64.63 mmol) in 1,4-dioxane (270 mL) and water (27 mL) was added sodium borohydride (2.44 g, 64.62 mmol) in three portions at 0°C. The reaction mixture was stirred at 100°C for 12 hours. Water (100 mL) was added, extracted with ethyl acetate (100 mL*3), dried over anhydrous sodium sulfate, filtered and dried. The crude product was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give 7-bromo-6-methoxy-1H-indole (8.50 g, 37.59 mmol, 58% yield) as a white solid. LCMS (ESI): [M+H] + =227.9.

[0626] Step 3: 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indole

[0627]

[0628] To a solution of 7-bromo-6-methoxy-1H-indole (8.50 g, 37.59 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (12.24 g, 56.40 mmol) in dichloroethane (85 mL) was added aluminum chloride (7.52 g, 56.40 mmol) in three portions at 0°C. The reaction mixture was stirred at 60°C for 45 minutes. 50 mL of water was added at 0°C, and the mixture was extracted with dichloromethane (50 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indole (5.20 g, 12.79 mmol, 34% yield) as a white solid. LCMS (ESI): [M+H] + =405.9.

[0629] Step 4: 7-Bromo-6-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole

[0630]

[0631] To a solution of 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indole (1.00 g, 2.46 mmol) in trifluoroethanol (8 mL, 49.19 mmol) and tetrahydrofuran (8 mL) was added potassium tert-butoxide (0.82 g, 7.38 mmol) at 0 ° C. The reaction mixture was stirred at 60 ° C for 16 hours. The crude product was spin-dried, water (2 mL) was added to the slurry and filtered, and the solid was dried to give 7-bromo-6-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (1.00 g, 2.13 mmol, 86% yield) as a white solid. LCMS (ESI): [M+H] + =470.0.

[0632] Step 5: (6-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0633]

[0634] Under nitrogen protection in a glove box, to a xylene (10 mL) solution of 7-bromo-6-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (500 mg, 1.06 mmol), diisopropylethylenediamine (526 uL, 3.19 mmol) and dimethylphosphine (163 mg, 2.13 mmol) was added methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl]palladium (II) dichloromethane adduct (110 mg, 0.11 mmol), and the reaction mixture was stirred at 140 ° C. under nitrogen for 12 hours. The crude product was spin-dried, and ethyl acetate (2 mL) and methyl tert-butyl ether (2 mL) were added, slurried, filtered, and dried to give the crude compound (6-methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (540 mg) as a yellow solid. LCMS (ESI): [M+H] + =468.2;

[0635] Step 6: (S)-(3-(2-(((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indol-7-yl)dimethylphosphine oxide

[0636]

[0637] (6-Methoxy-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (100 mg, 0.21 mmol) and (S)-2-aminopropan-1-ol (321 mg, 4.28 mmol) were mixed, and the mixture was stirred at 100° C. for 1 hour under nitrogen. Purification by preparative HPLC gave the title compound (S)-(3-(2-(((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indol-7-yl)dimethylphosphine oxide (47 mg, 0.11 mmol, 50% yield). LCMS (ESI): [M+H] + =443.1.

[0638] 1 H NMR(400MHz,CD3OD)δppm 8.73-8.34(m,2H),7.87(s,1H),7.08(s,1H),4.50-4.16(m,1H),4.00(s,3H),3.74-3.58(m,2H),1.91(d,J=14.1Hz,6H),1.31(d,J=6.7Hz,3H)

[0639] Using the same method for synthesizing compound 80, 3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide was reacted with the corresponding amino compound to synthesize the following compound:

[0640] Example 107. (3-(2-((5-Azaspiro[2.4]heptan-1-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 107)

[0641]

[0642] Compound 107 (150 mg, white solid). LCMS (ESI): [M+H] + =450.0.

[0643] Compound 107 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A: carbon dioxide, phase B: 0.1% ammonia / ethanol; phase B maintained at 35%; flow rate: 70 ml / min) to obtain the optically pure target compounds: the chiral monomer with the shortest elution time (compound 108); the chiral monomer with the second shortest elution time (compound 109); the chiral monomer with the third shortest elution time (compound 110); and the chiral monomer with the longest elution time (compound 111).

[0644] Example 108. After SFC resolution of compound 107, the chiral monomer (compound 108) with the shortest elution time

[0645]

[0646] Compound 108 (14.17 mg, white solid). LCMS (ESI): [M+H] + =450.0;

[0647] SFC analysis (column: ChiralPak IG-3 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: 5% to 40% phase B over 5.5 minutes, hold at 40% phase B for 3 minutes, then hold at 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 5.650 min, chiral purity: 100%.

[0648] 1H NMR (400MHz, CD3OD) δppm 8.72-8.51(m,2H),8.00(s,1H),7.51(br d,J=13.3Hz,1H),7.36(br s,1H),3.26-2.56(m,5H),1.93(br d,J=13.6Hz,6H),1.84-1.53(m,2H),1.34-1.18(m,1H),0.97(br s,1H).

[0649] Example 109. The chiral monomer (Compound 109) with the second shortest elution time after SFC resolution of Compound 107

[0650]

[0651] Compound 109 (24.22 mg, yellow solid). LCMS (ESI): [M+H] + =450.0;

[0652] SFC analysis (column: ChiralPak IG-3 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: 5% to 40% phase B over 5.5 minutes, hold at 40% phase B for 3 minutes, then hold at 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 5.985 min, chiral purity 98.94%.

[0653] 1 H NMR (400MHz, CD3OD) δppm 8.75-8.54(m,2H),8.05-7.95(m,1H),7.60-7.46(m,1H),7.35(br s,1H),3.21-2.25(m,5H),1.97-1.90(m,6H),1.84(m,2H),1.24(m,1H),0.96-0.85(m,1H).

[0654] Example 110. The chiral monomer (Compound 110) with the third shortest elution time after SFC resolution of Compound 107

[0655]

[0656] Compound 110 (38.84 mg, white solid). LCMS (ESI): [M+H] + =450.0;

[0657] SFC analysis (column: ChiralPak IG-3 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: 5% to 40% phase B over 5.5 minutes, hold at 40% phase B for 3 minutes, then hold at 5% phase B for 1.5 minutes; flow rate: 2.5 mL / min): RT = 6.307 min, chiral purity 98.53%.

[0658] 1 H NMR (400MHz, CD3OD) δppm 8.75-8.54(m,2H),8.05-7.95(m,1H),7.60-7.46(m,1H),7.35(br s,1H),3.21-2.25(m,5H),1.97-1.75(m,7H),1.31-1.24(m,2H),0.91(br d,J=7.0Hz,1H).

[0659] Example 111. After SFC resolution of compound 107, the chiral monomer (compound 111) with a longer elution time

[0660]

[0661] Compound 111 (16.52 mg, white solid); LCMS (ESI): [M+H] + =499.9;

[0662] SFC analysis (column: ChiralPak IG-3 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: 5% to 40% phase B over 5.5 minutes, hold at 40% phase B for 3 minutes, then hold at 5% phase B for 1.5 minutes; flow rate: 2.5 mL / min): RT = 6.843 min, chiral purity 98.85%.

[0663] 1 H NMR (400MHz, CD3OD) δppm 8.72-8.51 (m, 2H), 8.00 (s, 1H), 7.51 (br d, J = 13.3Hz, 1H), 7.36 (br s,1H),3.26-2.56(m,5H),1.93-1.75(m,7H),1.34-1.18(m,2H),0.97(br s,1H)

[0664] Example 112. (S)-(3-(2-((2-hydroxy-1-(1-methylcyclopropyl)ethyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 112)

[0665]

[0666] Compound 112 (11.57 mg, white solid). LCMS (ESI): [M+H] + =452.9.

[0667] 1 H NMR (400MHz, CD3OD) δppm 8.65-8.46(m,2H),7.95(s,1H),7.50(dd,J=13.5,7.2Hz,1H),7.41-7.27(m,1H),4.03(br s,1H),3.87(br dd,J=11.3,4.0Hz,1H),3.82-3.70(m,1H),1.93(d,J=13.3Hz,6H),1.16(s,3H),0.70(br s,1H),0.53(br s,1H),0.41-0.16(m,2H).

[0668] Example 113. (R)-(3-(2-((1-cyclobutyl-2-hydroxyethyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 113)

[0669]

[0670] Compound 113 (63.08 mg, white solid). LCMS (ESI): [M+H] + =452.9.

[0671] 1 H NMR (400MHz, DMSO-d6) δppm 11.55 (br s, 1H), 8.73-8.40 (m, 2H), 7.98-7.85 (m, 1H), 7.68-7.44 (m, 2H), 7.27 (br t, J=7.4Hz, 1H), 4.62 (br s,1H),4.33-4.10(m,1H),3.55-3.38(m,2H),2.57(br d,J=5.8Hz,1H),2.03-1.66(m,12H).

[0672] Example 114. (3-(2-((3-(Hydroxymethyl)oxetan-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 114)

[0673]

[0674] Compound 114 (8.57 mg, white solid). LCMS (ESI): [M+H] + =441.1.

[0675] 1 H NMR(400MHz,DMSO-d6)δppm 11.65-11.47(m,1H),8.78-8.36(m,3H),8.13-7.76(m,1H),7.50(dd,J=7.2,12.9Hz,1H),7.28(dt,J=2.1,7.6Hz,1H),5.17(br s,1H),4.66(br d,J=6.0Hz,2H),4.62-4.50(m,2H),3.83(br s,2H),1.82(d,J=13.6Hz,6H).

[0676] Example 115 (S)-(3-(2-((1-hydroxy-3-methylbutan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 115)

[0677]

[0678] Compound 115 (20.45 mg, white solid). LCMS (ESI): [M+H] + =441.1.

[0679] 1 H NMR (400MHz, DMSO-d6) δppm 11.55 (br s, 1H), 8.71-8.38 (m, 2H), 7.92 (br d, J=18.8Hz, 1H), 7.61 (br dd,J=4.5,9.0Hz,1H),7.50(dd,J=7.0,12.8Hz,1H),7.30-7.24(m,1H),4.62(t,J=5.4Hz,1H),4.01(br dd,J=7.5,13.8Hz,1H),3.62-3.49(m,2H),2.03-1.93(m,1H),1.82(d,J=13.6Hz,6H),0.98-0.90(m,6H).

[0680] Example 116. (3-(2-((1-(Hydroxymethyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 116)

[0681]

[0682] Compound 116 (32.93 mg, white solid). LCMS (ESI): [M+H] + =452.9.

[0683] 1 H NMR(400MHz,DMSO-d6)δppm 11.60-11.46(m,1H),8.72-8.15(m,2H),7.98-7.74(m,1H),7.53-7.42(m,2H),7.26(t,J=6.7Hz ,1H),4.94-4.74(m,1H),3.74-3.60(m,2H),2.14-2.00(m,2H),1.82(d,J=13.3Hz,10H),1.56(br s,2H).

[0684] Example 117. (3-(2-((3-(Hydroxymethyl)tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 117)

[0685]

[0686] Compound 117 (2.46 mg, white solid). LCMS (ESI): [M+H] + =454.9.

[0687] 1 H NMR(400MHz,DMSO-d6)δppm 11.57(br s,1H),8.78-8.54(m,2H),8.21-7.76(m,2H),7.50(dd,J=6.8,13.1Hz,1H),7.27(dt,J=2.3,7.7Hz,1H),5.04-4.94(m,1H),3.98(br d,J=8.0Hz,1H),3.88-3.67(m,5H),2.31(br d,J=16.3Hz,1H),2.16-2.04(m,1H),1.82(d,J=13.6Hz,6H).

[0688] Compound 117 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: phase A: carbon dioxide, phase B: 0.1% ammonia / ethanol; phase B maintained at 45%; flow rate: 80 ml / min) to obtain optically pure target compounds: a chiral monomer with a shorter elution time (compound 118) and a chiral monomer with a longer elution time (compound 119).

[0689] Example 118. After SFC separation of compound 117, the chiral monomer (compound 118) with a shorter elution time

[0690]

[0691] Compound 118 (10.80 mg, white solid). LCMS (ESI): [M+H] + =455.0.

[0692] SFC analysis (column: Chiralpak AD-3 (150 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: 5% to 40% phase B over 5 minutes, hold at 40% phase B for 2.5 minutes, then hold at 5% phase B for 2.5 minutes; flow rate: 2.5 ml / min): RT = 6.338 min, ee = 99.96%.

[0693] 1 H NMR (400MHz, DMSO-d6) δppm 11.30 (br s, 1H), 8.94-8.48 (m, 2H), 8.08-7.79 (m, 2H), 7.55 (dd, J = 7.1, 12.9Hz, 1H), 7.41-7.21 (m, 1H), 5.06 (br s,1H),4.02(br s,1H),3.93-3.70(m,5H),2.36(br d,J=13.6Hz,1H),2.24-2.08(m,1H),1.87(d,J=13.4Hz,6H).

[0694] Example 119. After SFC resolution of compound 117, the chiral monomer (compound 119) with a longer elution time

[0695]

[0696] Compound 119 (9.84 mg, white solid). LCMS (ESI): [M+H] + =455.1.

[0697] SFC analysis (column: Chiralpak AD-3 (150 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 5 minutes, maintained at 40% phase B for 2.5 minutes, then maintained at 5% phase B for 2.5 minutes; flow rate: 2.5 ml / min): RT = 7.132 min, ee = 99.50%.

[0698] 1 H NMR(400MHz,DMSO-d6)δppm 11.60-11.35(m,1H),8.72-8.47(m,2H),7.94-7.68(m,2H),7.43(dd,J=7.1,12.8Hz,1H),7.20(dt,J=2.2,7.7Hz,1H),4.95(br s,1H),3.96-3.85(m,1H),3.70(br d,J=17.9Hz,5H),2.22(br s,1H),2.10-1.96(m,1H),1.75(d,J=13.5Hz,6H).

[0699] Example 120. (3-(2-((3-Hydroxytetrahydrofuran-3-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 120)

[0700]

[0701] Compound 120 (37 mg, white solid). LCMS (ESI): [M+H] + =455.2.

[0702] 1 H NMR (400MHz, DMSO-d6) δppm 11.40 (br s, 1H), 8.72-8.40 (m, 2H), 8.05-7.74 (m, 2H), 7.50 (dd, J=6.8, 13.1Hz, 1H), 7.27 (br t,J=7.5Hz,1H),5.10(s,1H),3.87-3.72(m,2H),3.71-3.61(m,3H),3.51(br dd,J=4.5,8.8Hz,1H),2.04-1.91(m,1H),1.82(d,J=13.6Hz,7H).

[0703] Compound 120 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: phase A: carbon dioxide, phase B: 0.1% ammonia / ethanol; phase B maintained at 40%, flow rate: 80 ml / min) to obtain optically pure target compounds: a chiral monomer with a shorter elution time (compound 121) and a chiral monomer with a longer elution time (compound 122).

[0704] Example 121. After SFC separation of compound 120, the chiral monomer (compound 121) with a shorter elution time

[0705]

[0706] Compound 121 (9.69 mg, white solid). LCMS (ESI): [M+H] + =455.1.

[0707] SFC analysis (column: Chiralpak AD-3 (50 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / isopropanol; gradient: 5% to 40% phase B over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 4 ml / min): RT = 1.798 min, ee = 99.16%.

[0708] 1 H NMR(400MHz,DMSO-d6)δppm 11.57(br s,1H),8.68-8.41(m,2H),7.96(br s,1H), 7.99-7.78(m,1H),7.50(dd,J=6.7,12.9Hz,1H),7.31-7.24(m,1H),5.10(s,1H),3.86-3.74(m,2H),3.72-3.61(m,3H),3.51(br dd,J=4.8,9.0Hz,1H),1.97(br d,J=7.5Hz,1H),1.82(d,J=13.3Hz,7H).

[0709] Example 122. After SFC separation of compound 120, the chiral monomer (compound 122) with a longer elution time

[0710]

[0711] Compound 122 (11.69 mg, white solid). LCMS (ESI): [M+H] + =455.2.

[0712] SFC analysis (column: Chiralpak AD-3 (50 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / isopropanol; gradient: 5% to 40% phase B over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 4 ml / min): RT = 2.023 min, ee = 98.70%.

[0713] 1 H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.68-8.41(m,2H),7.99-7.75(m,2H),7.50(dd,J=6.8,13.1Hz,1H),7 .31-7.24(m,1H),5.10(s,1H),3.86-3.74(m,2H),3.71-3.62(m,3H),3.51(br dd,J=4.8,8.3Hz,1H),2.02-1.91(m,1H),1.82(d,J=13.3Hz,7H).

[0714] Example 123. (3-(2-((3,3-Difluoro-2-hydroxypropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 123)

[0715]

[0716] Compound 123 (51 mg, white solid). LCMS (ESI): [M+H] + =449.1.

[0717] 1 H NMR(400MHz,DMSO-d6)δppm 11.58(br s,1H),8.72-8.42(m,2H),8.03-7.88(m, 2H),7.50(dd,J=7.2,12.9Hz,1H),7.33-7.21(m,1H),6.16-5.77(m,2H),4.0 5-3.92(m,1H),3.73-3.58(m,1H),3.54-3.40(m,1H),1.82(d,J=13.6Hz,6H).

[0718] Compound 123 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: phase A: carbon dioxide, phase B: 0.1% ammonia / ethanol; phase B maintained at 35%; flow rate: 70 ml / min) to obtain optically pure target compounds: a chiral monomer with a shorter elution time (compound 124) and a chiral monomer with a longer elution time (compound 125).

[0719] Example 124. After SFC separation of compound 123, the chiral monomer (compound 124) with a shorter elution time

[0720]

[0721] Compound 124 (2.34 mg, white solid). LCMS (ESI): [M+H] + =449.1.

[0722] SFC analysis (column: Chiralpak AD-3 (150 mm*4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5 minutes, then from 40% to 5% in 0.5 minutes, and then maintained at 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 5.096 min, ee = 100%

[0723] 1 H NMR(400MHz,DMSO-d6)δppm 11.58(br s,1H),8.72-8.42(m,2H),8.03-7.88(m,2H),7.50(dd,J=7.2,12.9Hz,1H),7.33-7.21(m,1H),6. 16-5.77(m,2H),4.05-3.92(m,1H),3.73-3.58(m,1H),3.54-3.40(m,1H),1.82(d,J=13.6Hz,6H).

[0724] Example 125. After SFC resolution of compound 123, the chiral monomer (compound 125) with a longer elution time

[0725]

[0726] Compound 125 (12.28 mg, white solid). LCMS (ESI): [M+H] + =449.0.

[0727] SFC analysis (column: Chiralpak AD-3 (150 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B: 5% to 40% over 5 minutes, then from 40% to 5% over 0.5 minutes, then maintained at 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 5.388 min, ee = 98.64%.

[0728] 1 H NMR(400MHz,DMSO-d6)δppm 11.58(br s,1H),8.73-8.38(m,2H),8.04-7.85(m,2H),7.50(dd,J=7.1,12.9Hz,1H),7.36-7.14(m,1H),6.17-5.74(m,2H),3.98(br s,1H),3.73-3.56(m,1H),3.54-3.39(m,1H),1.82(d,J=13.5Hz,6H).

[0729] Example 126. (3-(2-(((3-Hydroxycyclobutyl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 126)

[0730]

[0731] Compound 126 (40.84 mg, white solid). LCMS (ESI): [M+H] + =439.2.

[0732] 1 H NMR (400MHz, DMSO-d6) δppm 11.57 (br s, 1H), 8.66-8.40 (m, 2H), 8.19-7.89 (m, 2H), 7.50 (br dd, J=7.3, 12.8Hz, 1H), 7.31-7.21 (m, 1H), 4.97 (br s,1H),3.91(quin,J=7.5Hz,1H),3.49-3.42(m,2H),2.36-2.23(m,2H),2.04(td,J=7.6,14.6Hz,1H),1.82(d,J=13.6Hz,6H),1.56(br d,J=8.0Hz,2H).

[0733] Example 127. (3-(2-(((trans-3-hydroxy-3-methylcyclobutyl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 127)

[0734]

[0735] Compound 127 (22.99 mg, white solid). LCMS (ESI): [M+H] + =453.2.

[0736] 1 H NMR(400MHz,DMSO-d6)δppm 11.57(br s,1H),8.65-8.41(m,2H),8.04-7.89(m,2H),7.50(br dd,J=7.4,12.7Hz,1H),7.31-7.18(m,1H),4.80(s,1H),3.52-3.40(m,2H),2.68-2.53( m,1H),2.16-2.00(m,2H),1.82(d,J=13.6Hz,6H),1.79-1.73(m,2H),1.29-1.16(m,3H).

[0737] Example 128. (3-(2-(((2S)-3-Hydroxybutan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 128)

[0738]

[0739] Compound 128 (103 mg, white solid). LCMS (ESI): [M+H] + =427.2.

[0740] 1 H NMR (400MHz, CD3OD) δppm 8.54 (br s, 2H), 7.97 (s, 1H), 7.51 (dd, J = 7.3, 13.6Hz, 1H), 7.34 (dt, J = 2.4, 7.7Hz, 1H), 4.25 (br s,1H),3.98-3.87(m,1H),1.95(s,3H),1.92(s,3H),1.32-1.27(m,3H),1.24(dd,J=3.6,6.4Hz,3H).

[0741] Compound 128 was separated by SFC (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / ethanol; phase B is maintained at 15%; flow rate: 60 ml / min) to obtain: a chiral monomer with a shorter elution time (compound 129) and a chiral monomer with a longer elution time (compound 130).

[0742] Example 129. After SFC separation of compound 128, the chiral monomer (compound 129) with a shorter elution time

[0743]

[0744] Compound 129 (36.61 mg, white solid). LCMS (ESI): [M+H] + =427.2.

[0745] SFC analysis (column: Chiralpak AS-3 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 4 minutes, maintained at 40% phase B for 2.5 minutes, then maintained at 5% phase B for 1.5 minutes; flow rate: 2.8 ml / min): RT = 2.177 min, de = 100%.

[0746] 1 H NMR (400MHz, CD3OD) δppm 8.53 (br s, 2H), 7.97 (s, 1H), 7.51 (dd, J=13.6, 7.3Hz, 1H), 7.34 (td, J=7.7, 2.5Hz, 1H), 4.30-4.09 (m, 1H), 3.94 (br s,1H),1.93(d,J=13.6Hz,6H),1.26(dd,J=15.7,6.7Hz,6H).

[0747] Example 130. After SFC resolution of compound 128, the chiral monomer (compound 130) with a longer elution time

[0748]

[0749] Compound 130 (17.37 mg, white solid). LCMS (ESI): [M+H] + =427.1.

[0750] SFC analysis (column: Chiralpak AS-3 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 4 minutes, hold at 40% phase B for 2.5 minutes, then hold at 5% phase B for 1.5 minutes; flow rate: 2.8 ml / min): RT = 2.318 min, decimal point = 87.76%.

[0751] 1H NMR(400MHz,CD3OD)δppm 8.55(br s,2H),7.96(s,1H),7.51(dd,J=13.6,6.8Hz,1H),7.34(td,J=7.7,2.5Hz,1H),4 .34-4.12(m,1H),3.93-3.84(m,1H),1.93(d,J=13.3Hz,6H),1.33-1.20(m,6H).

[0752] Example 131. (3-(2-((cis-2-(aminomethyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 131)

[0753]

[0754] Step 1: 2-Aminocyclopentane-1-carbonitrile

[0755]

[0756] To a solution of 2-aminocyclopent-1-ene-1-carbonitrile (8.60 g, 79.53 mmol) in methanol (50 mL) was added a 4 M solution of hydrochloric acid in methanol (10 mL). Then, sodium cyanoborohydride (10.46 g, 166.45 mmol) was slowly added in four portions. During this process, 4 M hydrochloric acid in methanol was added several times to maintain the reaction pH below 7. The reaction mixture was stirred at 25°C for 1 hour. The reaction solution was then dried under reduced pressure, and an aqueous sodium hydroxide solution (1M, 200 mL) was added, followed by sodium chloride (20.00 g). The reaction mixture was extracted with dichloromethane (100 mL*3), and the organic phases were combined and extracted with hydrochloric acid (2M, 50 mL*3). The hydrochloric acid and aqueous phases were combined and adjusted to alkalinity with an aqueous sodium hydroxide solution (4 M) under ice cooling, and then extracted with dichloromethane (100 mL*4). The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and dried to give a colorless liquid compound 2-aminocyclopentane-1-carbonitrile (7.90 g, 71.82 mmol, yield 90%).

[0757] 1 H NMR (400MHz, CDCl3) δppm 3.59-3.46(m,1H),2.88-2.34(m,1H),2.24-2.00(m,2H),1.99-1.48(m,4H),1.47-1.40(m,2H).

[0758] Step 2: Benzyl (2-cyanocyclopentyl)carbamate

[0759]

[0760] To a mixed solution of 2-aminocyclopentane-1-carbonitrile (2.00 g, 18.16 mmol) and sodium carbonate (3.76 g, 27.23 mmol) in tetrahydrofuran (40 mL) and water (40 mL) was added benzyl chloroformate (3.41 g, 19.97 mmol) dropwise under ice-cooling. The mixture was stirred at 25°C for 12 hours, then the reaction mixture was extracted with ethyl acetate (40 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by flash column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to obtain benzyl (2-cyanocyclopentyl)carbamate (3.60 g, 14.75 mmol, yield 81%) as a colorless liquid. LCMS (ESI): [M+H] + =245.1.

[0761] Step 3: Benzyl (2-(aminomethyl)cyclopentyl)carbamate

[0762]

[0763] A solution of benzyl (2-cyanocyclopentyl)carbamate (3.60 g, 14.75 mmol) in tetrahydrofuran (50 mL) was added dropwise to a borane / tetrahydrofuran solution (1 M, 29.47 mL, 29.47 mmol) at 0°C in an ice bath. The mixture was stirred at 25°C for 12 hours. The reaction mixture was then spin-dried to give the crude compound (benzyl (2-(aminomethyl)cyclopentyl)carbamate (3.90 g) as a colorless liquid. LCMS (ESI): [M+H] + =249.1.

[0764] Step 4: cis-benzyl 2-((((tert-Butoxycarbonyl)amino)methyl)cyclopentyl)carbamate and trans-benzyl 2-((((tert-Butoxycarbonyl)amino)methyl)cyclopentyl)carbamate

[0765]

[0766] To a solution of benzyl (2-(aminomethyl)cyclopentyl)carbamate (3.90 g, 15.71 mmol) and triethylamine (5 mL, 39.26 mmol) in tetrahydrofuran (40 mL) was added dropwise under an ice bath to di-tert-butyl dicarbonate (4.11 g, 18.85 mmol). The mixture was stirred at 25°C for 12 hours, then water (40 mL) was added to the reaction mixture and extracted with ethyl acetate (40 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to yield two epimers. 2D NMR identification indicated that the more polar compound was the trans isomer.

[0767] The least polar compound was obtained first: cis-benzyl 2-((((tert-butyloxycarbonyl)amino)methyl)cyclopentyl)carbamate (1.00 g, 2.87 mmol, 18% yield), as a white solid. LCMS (ESI): [M-100+H] + =249.1.

[0768] 1 H NMR (400MHz, CDCl3) δppm 7.41-7.30(m,5H),5.46(s,1H),5.21-5.01(m,2H),4.74(m,1H),4.20-4.04(m,1 H),3.43(m,1H),2.73(m,1H),2.11-1.50(m,6H),1.45(s,9H),1.27-1.11(m,1H).

[0769] The compound with the highest polarity was trans-benzyl 2-((((tert-butyloxycarbonyl)amino)methyl)cyclopentyl)carbamate (1.20 g, 3.44 mmol, 22% yield) as a white solid. LCMS (ESI): [M-100+H] + =249.1.

[0770] 1 H NMR (400MHz, CDCl3) δppm 7.47-7.29(m,5H),5.37(s,1H),5.22-4.98(m,2H),4.76(m,1H),3.80-3.57(m,1H),3.29-2.96(m,2 H),2.11-1.98(m,1H),1.91-1.77(m,2H),1.69-1.58(m,2H),1.52-1.38(m,10H),1.37-1.26(m,1H).

[0771] Step 5: tert-Butyl cis-((2-aminocyclopentyl)methyl)carbamate

[0772]

[0773] A solution of compound cis-2-(((tert-butyloxycarbonyl)amino)methyl)cyclopentyl)benzyl carbamate (0.25 g, 0.72 mmol) in ethyl acetate (25 mL) was added to wet palladium on carbon (10% content, 0.10 g). The mixture was stirred at 25 ° C. under a 15 psi hydrogen balloon for 12 hours. The reaction mixture was then filtered and dried to obtain compound cis-tert-butyl ((2-aminocyclopentyl)methyl)carbamate (0.13 g, 0.61 mmol, 85% yield) as a colorless liquid. LCMS (ESI): [M+H] + =215.1.

[0774] Step 6: tert-Butyl ((cis-2-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)methyl)carbamate

[0775]

[0776] To a solution of the compound (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (0.21 g, 0.55 mmol) and diisopropylethylamine (0.91 mL, 5.51 mmol) in 1,4-dioxane (3 mL) was added the compound cis-tert-butyl((2-aminocyclopentyl)methyl)carbamate (0.13 g, 0.61 mmol). The mixture was stirred at 100° C. for 4 hours, then the reaction mixture was spin-dried and the residue was purified by flash column chromatography (C18, 0-60% gradient of acetonitrile / water) to give tert-butyl ((cis-2-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)methyl)carbamate (0.23 g, 0.42 mmol, 76% yield) as a white solid. LCMS (ESI): [M+H] + =552.2.

[0777] Step 7: (3-(2-((cis-2-(aminomethyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide, formate

[0778]

[0779] A solution of the compound tert-butyl ((cis-2-((4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)methyl)carbamate (35 mg, 0.06 mmol) in dichloromethane (1 mL) was added to a hydrogen chloride / dioxane solution (4 M, 320 uL, 1.28 mmol) at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was spin-dried and the residue was purified by preparative HPLC to give a white solid compound (3-(2-((cis-2-(aminomethyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (formate, 14 mg, 31 umol, 49% yield) as a white solid. LCMS (ESI): [M+H] + =452.2.

[0780] 1 H NMR(400MHz,CD3OD)δppm 8.84-8.36(m,3H),8.01(s,1H),7.53(s,1H),7.37(s,1H),4.65-4.39(m,1H),3.12-2.71(m,2H) ,2.39-2.13(m,2H),2.03(s,1H),1.93(d,J=13.3Hz,8H),1.85-1.72(m,1H),1.61-1.44(m,1H).

[0781] Example 132. (3-(2-((trans-2-(aminomethyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 132)

[0782] Using the intermediate benzyl trans-2-((((tert-butyloxycarbonyl)amino)methyl)cyclopentyl)carbamate as the starting material, compound 132 was obtained by the same method as in steps 5, 6, and 7 above.

[0783]

[0784] Compound 132 (formate salt, 20 mg, white solid). LCMS (ESI): [M+H] + =452.2.

[0785] 1H NMR(400MHz,CD3OD)δppm 8.82-8.25(m,3H),8.07-7.87(m,1H),7.53(s,1H), 7.35(s,1H),4.15(s,1H),3.17-2.68(m,2H),2.36-2.00(m,3H),1.93(m,9H),1.47(s,1H).

[0786] Example 133. (3-(2-((cis-2-((dimethylamino)methyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 133)

[0787]

[0788] Step 1: (3-(2-((cis-2-((dimethylamino)methyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide, formate

[0789]

[0790] Compound (3-(2-((cis-2-(aminomethyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (130 mg, 0.29 mmol) and formaldehyde solution (37% content, 234 mg, 2.88 mmol) in methanol (5 mL) were added sodium cyanoborohydride (36 mg, 0.58 mmol). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was spin-dried. The residue was purified by preparative HPLC to give compound (3-(2-((cis-2-((dimethylamino)methyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (formate, 20 mg, 0.04 mmol, yield 14%) as a yellow solid. LCMS (ESI): [M+H] + =480.3.

[0791] 1 H NMR(400MHz,CD3OD)δppm 8.72(s,1H),8.56(s,1H),8.37(s,1H),7.98(s,1H),7.66-7.31(m,2H),4.47-4.34(m,1 H),2.90(s,4H),2.59-2.16(m,2H),2.08-1.91(m,12H),1.88-1.76(m,2H),1.50(s,1H).

[0792] Example 134. (3-(2-((trans-2-((dimethylamino)methyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide, formate (Compound 134)

[0793]

[0794] Step 1:

[0795]

[0796] To a solution of compound (3-(2-((trans-2-(aminomethyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (130 mg, 0.29 mmol) and formaldehyde solution (37% content, 234 mg, 2.88 mmol) in methanol (5 mL) was added sodium cyanoborohydride (36 mg, 0.58 mmol). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was spin-dried. The residue was purified by preparative HPLC to give compound (3-(2-((trans-2-((dimethylamino)methyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (formate, 24 mg, 0.05 mmol, yield 17%) as a yellow solid. LCMS (ESI): [M+H] + =480.4.

[0797] 1 H NMR(400MHz,CD3OD)δppm 8.75-8.24(m,3H),8.14-7.83(m,1H),7.53(s,1H),7.37(s,1H),4.12(d,J=5.8Hz,1H ),3.20-2.95(m,1H),2.84(s,3H),2.49-2.03(m,6H),2.01-1.77(m,10H),1.42(m,1H)

[0798] (3-(2-((trans-2-((dimethylamino)methyl)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 134) was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / ethanol; phase B is maintained at 40%; flow rate: 80 ml / min) to obtain chiral monomer compound 135 with a shorter elution time and chiral monomer compound 136 with a longer elution time.

[0799] Example 135. After SFC resolution of compound 134, the chiral monomer (compound 135) with a shorter elution time

[0800]

[0801] Compound 135 (41.50 mg, white solid). LCMS (ESI): [M+H] + =480.2.

[0802] SFC analysis (column: Chiralpak AD-3 (150 mm*4.6 mm, 3 μm); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5 minutes, maintaining 40% phase B for 2.5 minutes, and then maintaining 5% phase B for 2.5 minutes; flow rate: 2.5 ml / min): RT = 4.512 min, ee = 100%

[0803] 1 H NMR(400MHz,CD3OD)δppm 8.53(s,2H),7.96(s,1H),7.51(dd,J=7.3,13.6Hz,1H),7.34(dt,J=2.5,7.7Hz,1H),4.26-3.99(m,1H), 2.53(dd,J=4.1,12.2Hz,1H),2.46-2.02(m,10H),1.93(d,J=13.3Hz,6H),1.84-1.51(m,3H),1.42(s,1H)

[0804] Example 136. Chiral monomer (Compound 136) with a longer elution time after chiral resolution of Compound 134

[0805]

[0806] Compound 136 (36.26 mg, white solid). LCMS (ESI): [M+H] + =480.3.

[0807] SFC analysis (column: Chiralpak AD-3 (150 mm*4.6 mm, 3 μm); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5 minutes, maintaining 40% phase B for 2.5 minutes, and then maintaining 5% phase B for 2.5 minutes; flow rate: 2.5 ml / min): RT = 6.895 min, ee = 100%

[0808] 1H NMR (400MHz, CD3OD) δppm 8.74-8.31(m,2H),7.96(s,1H),7.51(dd,J=7.3,13.6Hz,1H),7.34(dt,J=2.5,7.8Hz,1H),4.13(br d,J=14.8Hz,1H),2.56(s,1H),2.49-2.01(m,10H),1.93(d,J=13.3Hz,6H),1.86-1.55(m,3H),1.45-1.36(m,1H)

[0809] Referring to the synthetic method of compound 133, the following compounds were prepared:

[0810] Example 137. (3-(2-(((1S,3S)-3-(Dimethylamino)cyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide, formate (Compound 137)

[0811]

[0812] Compound 137 (52.92 mg, gray solid). LCMS (ESI): [M+H] + =466.0;

[0813] 1 H NMR (400MHz, CD3OD) δppm 8.56 (br d, J=11.86Hz, 3H), 7.96 (s, 1H), 7.51 (dd, J=13.45, 7.21Hz, 1H), 7.34 (td, J=7.67, 2.38Hz, 1H), 4.60 (br s,1H),3.62(br s,1H),2.77(br s,5H),2.42-2.26(m,2H),2.25-2.11(m,2H),1.93(d,J=13.45Hz,7H),1.88-1.69(m,2H).

[0814] The following compounds were prepared by referring to the synthesis method of compound 80:

[0815] Example 138. (3-(2-((2-cyclobutyl-2-hydroxyethyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 138)

[0816]

[0817] Compound 138 (50.31 mg, gray solid). LCMS (ESI): [M+H] +=453.1;

[0818] 1 H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.68-8.41(m,2H),7.92(br d,J=14.6Hz,1H),7.83-7.64(m,1H),7.50(dd,J=7.2,12.8Hz,1H),7.26(q,J=7.1Hz,1H),4.77(br d,J=4.9Hz,1H),3.63(br d,J=5.1Hz,1H),3.50-3.39(m,1H),3.20(td,J=6.5,12.9Hz,1H),2.42-2.27(m,1H),2.00-1.60(m,12H).

[0819] Compound 138 was separated by SFC (column: DAICEL ChiralPak AD (250*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / ethanol; phase B is maintained at 45%, flow rate: 60 ml / min) to obtain the target compounds: a chiral monomer with a shorter elution time (compound 139) and a chiral monomer with a longer elution time (compound 140).

[0820] Example 139. Chiral monomer (Compound 139) with shorter elution time after chiral resolution of Compound 138

[0821]

[0822] Compound 139 (25.31 mg, white solid), LCMS (ESI): [M+H] + =453.1;

[0823] SFC analysis (column: Chiralpak AD-3 (150*4.6 mm, 3 um); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5.5 minutes, maintaining 40% phase B for 3 minutes, and then maintaining 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 6.809 min, ee = 100%.

[0824] 1H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.68-8.41(m,2H),7.92(br d,J=14.6Hz,1H),7.83-7.64(m,1H),7.50(dd,J=7.2,12.8Hz,1H),7.26(q,J=7.1Hz,1H),4.77(br d,J=4.9Hz,1H),3.63(br d,J=5.1Hz,1H),3.50-3.39(m,1H),3.20(td,J=6.5,12.9Hz,1H),2.42-2.27(m,1H),2.00-1.60(m,12H).

[0825] Example 140. After chiral resolution of compound 138, the chiral monomer (compound 140) with a longer elution time

[0826]

[0827] Compound 140 (25.49 mg, white solid). LCMS (ESI): [M+H] + =453.1;

[0828] SFC analysis (column: Chiralpak AD-3 (150*4.6 mm, 3 um); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5.5 minutes, maintaining 40% phase B for 3 minutes, and then maintaining 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 7.460 min, ee = 100%.

[0829] 1 H NMR(400MHz,DMSO-d6)δppm 11.56(br s,1H),8.74-8.38(m,2H),7.93(br d,J=14.6Hz,1H),7.83-7.62(m,1H),7.50(dd,J=7.2,12.8Hz,1H),7.26(q,J=7.1Hz,1H),4.77(br d,J=4.9Hz,1H),3.63(br d,J=4.5Hz,1H),3.51-3.40(m,1H),3.27-3.13(m,1H),2.44-2.28(m,1H),1.99-1.63(m,12H).

[0830] The following compounds were prepared by referring to the synthesis method of compound 80:

[0831] Example 141. (3-(2-((((1S,2R)-2-(Hydroxymethyl)cyclopropyl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 141)

[0832]

[0833] Compound 141 (3.12 mg, white solid). LCMS (ESI): [M+H] + =439.2;

[0834] 1 H NMR (400MHz, DMSO-d6) δppm 11.54 (br s, 1H), 8.70-8.34 (m, 2H), 8.02-7.72 (m, 2H), 7.49 (dd, J = 7.0, 13.3Hz, 1H), 7.27 (br s, 1H), 4.69 (br s,1H),3.84-3.58(m,4H),1.81(d,J=13.6Hz,6H),1.30-1.00(m,2H),0.67(br s,1H),0.19(br s,1H).

[0835] The following compounds were prepared by referring to the synthesis method of compound 80:

[0836] Example 142. (3-(2-(((trans-2-(hydroxymethyl)cyclopropyl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 142)

[0837]

[0838] Compound 142 (39.14 mg, white solid). LCMS (ESI): [M+H] + =439.1.

[0839] 1 H NMR(400MHz,DMSO-d6)δppm 11.54(br s,1H),8.66-8.40(m,2H),8.07-7.86(m,1H),8.07-7.86(m,1H),7.50(dd,J=7.1,12.9Hz,1H),7.32-7.18( m,1H),4.52-4.40(m,1H),3.30-3.19(m,4H),1.82(d,J=13.5Hz,6H),1.01-0.76(m,2H),0.50-0.30(m,2H).

[0840] Compound 142 was separated by SFC (column: DAICEL ChiralPak AD (250*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / ethanol; phase B is maintained at 40%, flow rate: 80 ml / min) to obtain the target compounds: a chiral monomer with a shorter elution time (compound 143) and a chiral monomer with a longer elution time (compound 144).

[0841] Example 143. After chiral resolution of compound 142, the chiral monomer (compound 143) with a shorter elution time

[0842]

[0843] Compound 143 (13.14 mg, white solid). LCMS (ESI): [M+H] + =439.1;

[0844] SFC analysis (column: ChiralPak AD-3 (150×4.6 mm, 3 um); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5.5 minutes, maintaining 40% phase B for 3 minutes, and then maintaining 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 6.744 min, ee = 100%.

[0845] 1 H NMR(400MHz,DMSO-d6)δppm 11.54(br s,1H),8.66-8.40(m,2H),8.07-7.86(m, 1H),7.50(dd,J=7.1,12.9Hz,1H),7.32-7.18(m,1H),4.52-4.40(m,1H),3.3 0-3.19(m,4H),1.82(d,J=13.5Hz,6H),1.01-0.76(m,2H),0.50-0.30(m,2H).

[0846] Example 144. After chiral resolution of compound 142, the chiral monomer (compound 144) with a longer elution time

[0847]

[0848] Compound 144 (9.13 mg, white solid). LCMS (ESI): [M+H] + =439.1;

[0849] SFC analysis (column: ChiralPak AD-3 (150×4.6 mm ID, 3 um); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5.5 minutes, maintaining 40% phase B for 3 minutes, and then maintaining 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT=7.642 min, ee=100%.

[0850] 1 H NMR (400MHz, DMSO-d6) δppm 11.56 (br s, 1H), 8.68-8.39 (m, 2H), 8.10-7.84 (m, 2H), 7.50 (dd, J=7.2, 12.9Hz, 1H), 7.28 (br t, J=7.4Hz, 1H), 4.47 (br d,J=5.9Hz,1H),3.27(br d,J=5.3Hz,4H),1.82(d,J=13.4Hz,6H),1.07-0.81(m,2H),0.49-0.29(m,2H).

[0851] Referring to the synthetic method of compound 80, the following compounds were prepared:

[0852] Example 145. Dimethyl(3-(2-((3,3,3-trifluoro-2-hydroxypropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)phosphine oxide (Compound 145)

[0853]

[0854] Compound 145 (82.39 mg, white solid). LCMS (ESI): [M+H] + =467.3;

[0855] 1 H NMR (400MHz, DMSO-d6) δppm 11.57(br s,1H),8.69-8.36(m,2H),8.17-7.89(m,2H),7.50(dd,J=13.0,7.0Hz,1H),7.33-7.13(m,1H),6.53(br s,1H),4.28(br s,1H),3.87– 3.49(m,2H),1.82(d,J=13.4Hz,6H).

[0856] Compound 145 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / ethanol; phase B is maintained at 25%; flow rate: 60 ml / min) to obtain the target compounds: a chiral monomer with a shorter elution time (compound 146) and a chiral monomer with a longer elution time (compound 147).

[0857] Example 146. After chiral resolution of compound 145, the chiral monomer (compound 146) with a shorter elution time

[0858]

[0859] Compound 146 (18.28 mg, white solid). LCMS (ESI): [M+H] + =467.1;

[0860] SFC analysis (column: ChiralPak AD-3 (150*4.6mm, 3um); mobile phase: phase A is carbon dioxide; phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4.5 minutes, and then maintain 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 4.114 min; ee = 100%.

[0861] 1 H NMR(400MHz,DMSO-d6)δppm 11.58(br s,1H),8.71-8.40(m,2H),8.19–7.88(m,2H),7.50(dd,J=12.8,7.0Hz,1H),7.36-7.14(m,1H),6.52(br t,J=5.3Hz,1H),4.40-4.16(m,1H),3.82-3.67(m,1H),3.58-3.47(m,1H),1.82(d,J=13.5Hz,6H).

[0862] Example 147. After chiral resolution of compound 145, the chiral monomer (compound 147) with a longer elution time

[0863]

[0864] Compound 147 (21.21 mg, white solid). LCMS (ESI): [M+H] + =467.1;

[0865] SFC analysis (column: ChiralPak AD-3 (150*4.6mm, 3um); mobile phase: phase A is carbon dioxide; phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4.5 minutes, and then maintain 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 4.316 min; ee = 99.20%.

[0866] 1 H NMR(400MHz,DMSO-d6)δppm 11.58(br s,1H),8.69-8.37(m,2H),8.18-7.87(m,2H),7.50(dd,J=13.0,7.0Hz,1H),7.31-7.15(m,1H),6.52 (t,J=5.3Hz,1H),4.41-4.19(m,1H),3.84-3.67(m,1H),3.58-3.49(m,1H),1.82(d,J=13.5Hz,6H).

[0867] Referring to the synthetic method of compound 80, the following compounds were prepared:

[0868] Example 148. (3-(2-((3-Hydroxy-2-methylpropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 148)

[0869]

[0870] Compound 148 (68 mg, white solid). LCMS (ESI): [M+H] + =427.1;

[0871] 1 H NMR(400MHz,DMSO-d6)δppm 11.55(br s,1H),8.63-8.46(m,2H),7.92(br s,2H),7.49(dd,J=12.9,7.2Hz,1H),7.26(td,J=7.7,2.3Hz,1H),4.72-4.35(m,1H),3.47-3.3 5(m,2H),3.32-3.18(m,2H),2.01-1.86(m,1H),1.81(d,J=13.6Hz,6H),0.90(d,J=6.5Hz,3H).

[0872] Compound 148 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide; phase B is 0.1% ammonia / methanol; phase B is maintained at 40%; flow rate: 80 ml / min) to obtain chiral monomer compounds: a chiral monomer with a shorter elution time (compound 149) and a chiral monomer with a longer elution time (compound 150).

[0873] Example 149. After chiral resolution of compound 148, the chiral monomer (compound 149) with a shorter elution time

[0874]

[0875] Compound 149 (27.33 mg, white solid). LCMS (ESI): [M+H] + =427.1;

[0876] SFC analysis (column: Chiralpak IG-3 (100 mm*4.6 mm*3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / methanol; gradient: phase B from 5% to 40% in 4 minutes, maintained at 40% phase B for 2.5 minutes, then maintained at 5% phase B for 2.5 minutes, flow rate: 2.8 ml / min): RT = 4.156 min, ee = 100%

[0877] 1 H NMR(400MHz,DMSO-d6)δppm 11.55(br s,1H),8.63-8.46(m,2H),7.92(br s,2H),7.49(dd,J=12.9,7.2Hz,1H),7.26(td,J=7.7,2.3Hz,1H),4.72-4.35(m,1H),3.47-3.3 5(m,2H),3.32-3.18(m,2H),2.01-1.86(m,1H),1.81(d,J=13.6Hz,6H),0.90(d,J=6.5Hz,3H).

[0878] Example 150. After chiral resolution of compound 148, the chiral monomer (compound 150) with a longer elution time

[0879]

[0880] Compound 150 (25.86 mg, white solid). LCMS (ESI): [M+H] + =427.1.

[0881] SFC analysis (column: Chiralpak IG-3 (100 mm*4.6 mm*3 um); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / methanol; gradient: phase B from 5% to 40% in 4 minutes, maintaining 40% phase B for 2.5 minutes, and then maintaining 5% phase B for 2.5 minutes, flow rate: 2.8 ml / min): RT = 4.543 min, ee = 99.7%.

[0882] 1 H NMR(400MHz,DMSO-d6)δppm 11.29-11.87(m,1H),8.64-8.46(m,2H),7.91(br s,2H),7.49(dd,J=12.9,7.4Hz,1H),7.26(td,J=7.5,2.3Hz,1H),4.50(dt,J=13.9,5.2Hz,1H),3.4 5-3.35(m,2H),3.32-3.19(m,2H),1.96-1.86(m,1H),1.81(d,J=13.6Hz,6H),0.90(d,J=6.8Hz,3H).

[0883] Example 151. (3-(2-((1-Hydroxycyclopentyl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1-hydrogen-indol-7-yl)dimethylphosphine oxide (Compound 151)

[0884]

[0885] Compound 151 (32.12 mg, white solid). LCMS (ESI): [M+H] + =453.2;

[0886] 1 H NMR(400MHz, DMSO-d6)δppm 11.55(br s,1H),8.73-8.39(m,2H),7.91(br d,J=16.1Hz,1H),7.71-7.56(m,1H),7.49(dd,J=12.8,6.8Hz,1H),7.26(br d,J=7.0Hz,1H),4.54(d,J=8.5Hz,1H),3.55(br dd,J=15.9,5.9Hz,2H),1.80(d,J=13.3Hz,6H),1.73-1.46(m,8H).

[0887] Example 152. (3-(6-((1-Hydroxycycloheptyl)methyl)amino)-3-(trifluoromethyl)pyrimidin-2-yl)-1-hydrogen-indol-7-yl)dimethylphosphine oxide (Compound 152)

[0888]

[0889] Compound 152 (74.47 mg, white solid). LCMS (ESI): [M+H] + =481.2;

[0890] 1 H NMR(400MHz,DMSO-d6)δppm 11.19(br s,1H),8.67-8.39(m,2H),7.89(br d,J=18.8Hz,1H),7.63-7.38(m,2H),7.31-7.09(m,1H),4.40(d,J=18.1 Hz,1H),3.49-3.36(m,2H),1.78(d,J=13.55Hz,6H),1.63-1.24(m,12H).

[0891] Example 153. (3-(2-(((1R,2R)-2-Hydroxycyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 153)

[0892]

[0893] Compound 153 (52.51 mg, white solid). LCMS (ESI): [M+H] + =425.2;

[0894] 1 H NMR (400MHz, DMSO-d6) δppm 11.54(br s,1H),8.70-8.43(m,2H),8.21(br t,J=8.2Hz,1H),7.91(br d,J=18.8Hz,1H),7.50(br dd,J=12.6,7.28Hz,1H),7.37-7.21(m,1H),5.32(dd,J=11.3,7.0Hz,1H),4.43-4.22(m,1H) ,4.04(quin,J=7.5Hz,1H),1.97(q,J=8.0Hz,2H),1.81(d,J=13.6Hz,6H),1.50-1.28(m,2H).

[0895] Example 154. (3-(2-(((1S,2S)-2-Hydroxycyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 154)

[0896]

[0897] Compound 154 (57.90 mg, white solid). LCMS (ESI): [M+H] + =425.1;

[0898] 1 H NMR (400MHz, DMSO-d6) δppm 11.55(br s,1H),8.75-8.43(m,2H),8.21(br t,J=8.2Hz,1H),7.92(br d,J=18.8Hz,1H),7.49(br dd,J=12.7,7.2Hz,1H),7.39-7.18(m,1H),5.32(dd,J=11.3,7.0Hz,1H),4.42-4.21(m,1H ),4.04(quin,J=7.5Hz,1H),1.91-2.05(m,2H),1.81(d,J=13.6Hz,6H),1.50-1.27(m,2H).

[0899] Example 155. (3-(2-(((1S,2S)-2-Hydroxycyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 155)

[0900]

[0901] Compound 155 (16.38 mg, white solid). LCMS (ESI): [M+H] + =439.2;

[0902] 1 H NMR (400MHz, DMSO-d6) δppm 11.52(br s,1H),8.67-8.48(m,2H),7.98-7.80(m,2H),7.49(dd,J=12.9,6.9Hz,1H),7.26(td,J=7.6,2.3Hz,1H),4.79(br d,J=10.3Hz,1H),4.25-3.93(m,2H),2.12-1.85(m,2H),1.81(d,J=13.5Hz,6H),1.66(br s,2H),1.57-1.43(m,2H).

[0903] Example 156. (3-(2-((1R,2R)-2-Hydroxycyclopentyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 156)

[0904]

[0905] Compound 156 (19.17 mg, white solid). LCMS (ESI): [M+H] + =439.1;

[0906] 1 H NMR (400MHz, DMSO-d6) δppm 11.54(br s,1H),8.77-8.45(m,2H),8.05-7.82(m,2H),7.58-7.11(m,2H),4.79(br d,J=10.5Hz,1H),4.29-3.92(m,2H),2.13-1.86(m,2H),1.81(d,J=13.6Hz,6H),1.67(br s,2H),1.58-1.44(m,2H).

[0907] Example 157. (S)-(3-(5-Fluoro-2-((1-hydroxypropyl-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 157)

[0908]

[0909] Step 1: 7-Bromo-3-(2-chloro-5-fluoropyrimidin-4-yl)-1H-indole

[0910]

[0911] To a solution of 7-bromo-1H-indole (1.00 g, 5.10 mmol) in hexafluoroisopropanol (10 mL) was added 2,4-dichloro-5-fluoropyrimidine (0.85 g, 5.10 mmol), followed by the addition of trifluoromethanesulfonic acid (540 uL, 5.91 mmol) dropwise at 0 ° C. The reaction was stirred at 60 ° C for 16 hours. The mixture was concentrated and slurried with water to give 7-bromo-3-(2-chloro-5-fluoropyrimidin-4-yl)-1 hydrogen-indole (2.10 g, 4.85 mmol, 95% yield) as a yellow solid. LCMS (ESI): [M+H] + =326.0.

[0912] Step 2: 7-Bromo-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole

[0913]

[0914] To a solution of 7-bromo-3-(2-chloro-5-fluoropyrimidin-4-yl)-1H-indole (1.00 g, 2.45 mmol) in trifluoroethanol (20 mL) was added tetrahydrofuran (20 mL) and potassium tert-butoxide (0.82 g, 7.35 mmol), and the solution was stirred at 60 ° C for 16 hours. The reaction was diluted with water and concentrated under reduced pressure to remove trifluoroethanol and tetrahydrofuran. The mixture was filtered and the solid was dried under vacuum to obtain 7-bromo-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole (0.86 g, 2.16 mmol, 88% yield). LCMS (ESI): [M+H] + =392.0.

[0915] Step 3: (3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0916]

[0917] To a xylene (5 mL) solution of 7-bromo-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole (0.50 g, 1.22 mmol) was added triethylamine (0.37 g, 3.65 mmol) and dimethylphosphine oxide (0.19 g, 2.44 mmol). Methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene)(2-amino-1,1-biphenyl)palladium(II) dichloromethane adduct (60 mg, 0.06 mmol) was then added under nitrogen. The mixture was stirred at 140° C. for 16 hours. The mixture was purified by flash column chromatography (silica gel, 0-18% gradient of methanol / dichloromethane) to give (3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (0.43 g, 0.94 mmol, 77% yield) as a yellow solid. LCMS (ESI): [M+H] + =388.0.

[0918] Step 4: (S)-(3-(5-Fluoro-2-((1-hydroxypropyl-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0919]

[0920] A mixture of (3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (100 mg, 0.26 mmol) and (S)-2-aminopropan-1-ol (500 uL) was stirred at 145° C. for 16 hours. The mixture was purified by preparative HPLC to give a white solid compound (16.40 mg, 47 umol, 18% yield). LCMS (ESI): [M+H] + =363.1;

[0921] 1 H NMR(400MHz,CD3OD)δppm 9.02(d,J=8.3Hz,1H),8.23(d,J=3.0Hz,1H),8.14(d,J=4.3Hz,1H),7.52(dd,J=6.5,13.6Hz,1H),7.38(dt,J=2.6,7.7 Hz,1H),4.29-4.14(m,1H),3.72(d,J=5.5Hz,1H),3.66(d,J=5.5Hz,1H),1.93(d,J=13.6Hz,6H),1.33(d,J=6.5Hz,3H).

[0922] Example 158. (S)-(5-Fluoro-3-(2-(((1-hydroxypropyl-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 158)

[0923]

[0924] Step 1: 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-fluoro-1H-indole

[0925]

[0926] Compound 7-bromo-5-fluoro-1H-indole (250 mg, 1.17 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (304 mg, 1.40 mmol) were dissolved in hexafluoroisopropanol (6 mL), and trifluoromethanesulfonic acid (110 uL, 1.28 mmol) was slowly added dropwise at 0°C. The reaction system was heated to 60°C and the reaction was continued for 16 hours. After cooling to room temperature, ethyl acetate (2 mL) was added to the reaction solution, and a solid precipitated from the solution. The solid was collected by filtration and dried to obtain the crude compound 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-fluoro-1H-indole (380 mg) as a yellow solid. LCMS (ESI): [M+H] + =394.0.

[0927] Step 2: 7-Bromo-5-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole

[0928]

[0929] The compound 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-fluoro-1H-indole (350 mg, 0.89 mmol) was dissolved in trifluoroethanol (8 mL), potassium tert-butoxide (299 mg, 2.66 mmol) was added at 20°C, and the mixture was stirred at 60°C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, water (4 mL) was added, and the mixture was stirred for 1 hour. A solid precipitated from the solution, which was collected by filtration and dried in vacuo to obtain the crude compound 7-bromo-5-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (300 mg) as a white solid. LCMS (ESI): [M+H] + =458.0.

[0930] Step 3: (5-Fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0931]

[0932] The compound 7-bromo-5-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (270 mg, 0.59 mmol) and dimethylphosphine oxide (68 mg, 0.88 mmol) were dissolved in xylene (5 mL) under nitrogen. Triethylamine (410 μL, 2.95 mmol) and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene)(2-amino-1,1-biphenyl)palladium(II) dichloromethane adduct (31 mg, 30 μmol) were added at 20°C. The reaction system was heated to 140°C and the reaction continued for 16 hours. The mixture was cooled to room temperature and concentrated. The resulting residue was added to water (3 mL) and extracted with ethyl acetate (4 mL x 2). The organic phases were combined, dried over magnesium sulfate, and concentrated to give the crude compound (5-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (290 mg) as a yellow solid. LCMS (ESI): [M+H] + =456.1.

[0933] Step 4: (S)-(5-Fluoro-3-(2-(((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0934]

[0935] The compound (5-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (290 mg, 0.64 mmol) was dissolved in L-aminopropanol (2 mL, 25.48 mmol). The reaction system was heated to 100°C and reacted for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give (S)-(5-fluoro-3-(2-(((1-hydroxypropyl-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (97.14 mg, 0.23 mmol, 35%) as a white solid. LCMS (ESI): [M+H] + =431.1.

[0936] 1 H NMR(400MHz,DMSO-d6)δppm 11.63(br s,1H),8.56(br d,J=10.6Hz,1H),8.52-8.14(m,1H),8.07-7.95(m,1H),7.88-7.61(m,1H),7.54-7.38(m,1H),4.77(t,J=5.5Hz,1H), 4.14(dt,J=13.1,6.5Hz,1H),3.58-3.37(m,2H),1.84(d,J=13.6Hz,6H),1.19(d,J=6.6Hz,3H).

[0937] Referring to the synthetic method of compound 80, the following compounds were prepared:

[0938] Example 159. (R)-(3-(2-((1-cyclopropyl-2-hydroxyethyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 159)

[0939]

[0940] Compound 159 (35.44 mg, white solid). LCMS (ESI): [M+H] + =439.1;

[0941] 1H NMR(400MHz,DMSO-d6)δppm 11.53(br s,1H),8.74-8.31(m,2H),8.00-7.86(m,1H),7.79-7.59(m,1H),7.49(dd,J=13.0,7.3Hz,1H),7.27(br d,J=6.2Hz,1H),4.7(br s,1H),3.78(br s,1H),3.66-3.55(m,2H),1.82(d,J=13.5Hz,6H),1.04(br s,1H),0.52-0.11(m,4H).

[0942] Example 160. (3-(2-((1-(Hydroxymethyl)cyclopropyl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 160)

[0943]

[0944] Compound 160 (42.70 mg, white solid. LCMS (ESI): [M+H] + =439.1;

[0945] 1 H NMR (400MHz, DMSO-d6) δppm 11.55(br s,1H),8.67-8.40(m,2H),8.01-7.73(m,2H),7.50(dd,J=13.0,6.5Hz,1H),7.28(td,J=7.7,2.4Hz,1H),4.59(br d,J=5.5Hz,1H),3.61-3.43(m,4H),1.82(d,J=13.5Hz,6H),0.59-0.25(m,4H).

[0946] Example 161. (R)-(3-(2-((1-hydroxy-2-methylbutan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 161)

[0947]

[0948] Compound 161 (4.26 mg, white solid). LCMS (ESI): [M+H] + =441.3;

[0949] 1H NMR(400MHz,DMSO-d6)δppm 11.53(br s,1H),8.58(s,1H),8.71-7.72(m,2H),7.50(br dd,J=12.8,7.3Hz,1H),7.32-7.21(m,1H),7.07(s,1H),4.87(br s,1H),3.67(br s,1H),3.48(br s,1H),1.82(br d,J=13.3Hz,8H),1.30(br s,3H),0.82(br t,J=7.3Hz,3H).

[0950] Example 162. (3-(2-((2-Hydroxy-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 162)

[0951]

[0952] Compound 162 (3.30 mg, white solid). LCMS (ESI): [M+H] + =441.1;

[0953] 1 H NMR(400MHz,DMSO-d6)δppm 11.55(br s,1H),8.71-8.43(m,2H),7.93(br d,J=13.1Hz,1H),7.82-7.64(m,1H),7.50(dd,J=13.0,6.5Hz,1H),7.25(dt,J=14.8,7.3Hz,1H),3.58-3.46(m,2H),4.72(br s,1H),3.30(br d,J=5.6Hz,1H),1.82(d,J=13.5Hz,6H),1.69(br d,J=6.8Hz,1H),0.96-0.84(m,6H).

[0954] Example 163. (S)-(3-(2-((3-Hydroxy-3-methylbutan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 163)

[0955]

[0956] Compound 163 (64.21 mg, white solid). LCMS (ESI): [M+H] + =441.2.

[0957] 1H NMR (400MHz, DMSO-d6) δppm 11.54 (br s, 1H), 8.67-8.38 (m, 2H), 7.91 (br d, J=17.9Hz, 1H), 7.50 (dd, J=7.1, 12.9Hz, 1H), 7.39-7.22 (m, 2H), 4.49 (br d,J=7.2Hz,1H),4.24-4.08(m,1H),1.82(d,J=13.5Hz,6H),1.25-1.10(m,9H).

[0958] Example 164. (3-(2-((1-Hydroxycyclopropyl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 164)

[0959]

[0960] Compound 164 (32.77 mg, white solid). LCMS (ESI): [M+H] + =425.1;

[0961] 1 H NMR (400MHz, DMSO-d6) δppm 11.54(br s,1H),8.74-8.40(m,2H),8.00-7.70(m,2H),7.50(dd,J=7.1,12.9Hz,1H),7.28(dt,J=1.9,7.7Hz,1H),5.47(br d,J=14.3Hz,1H),3.69-3.53(m,2H),1.82(d,J=13.5Hz,6H),0.58(br d,J=11.4Hz,4H).

[0962] Example 165. (3-(2-(((1S,2S)-2-Hydroxycyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yldimethylphosphine oxide (Compound 165)

[0963]

[0964] Compound 165 (35.29 mg, white solid). LCMS (ESI): [M+H] + =453.1;

[0965] 1H NMR (400MHz, DMSO-d6) δppm 11.54(br s,1H),8.74-8.45(m,2H),7.93(br s,1H),7.67(br d,J=7.9Hz,1H),7.50(br dd,J=7.1,12.6Hz,1H),7.26(br s,1H),4.74(br s,1H),3.93-3.54(m,2H),1.96(br s,2H),1.82(br d,J=13.4Hz,6H),1.67(br s,2H),1.25(br s,4H).

[0966] Example 166. (3-(2-((4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 166)

[0967]

[0968] Compound 166 (19.03 mg, white solid). LCMS (ESI): [M+H] + =469.2;

[0969] 1 H NMR(400MHz,DMSO-d6)δppm 11.51(br s,1H),8.80-7.67(m,3H),7.58-7.16(m,3H),4.83(br s,1H),3.79-3.56(m,6H),2.28(br s,2H),1.82(d,J=13.4Hz,6H),1.64(br s,2H).

[0970] Example 167. (3-(2-((3R,4R)-4-Hydroxytetrahydro-2H-pyran-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 167)

[0971]

[0972] Compound 167 (52.41 mg, white solid). LCMS (ESI): [M+H] + =455.2;

[0973] 1H NMR(400MHz,DMSO-d6)δppm 11.55(br s,1H),8.74-8.40(m,2H),8.01-7.87(m,1H),7.74(br dd,J=7.9,18.4Hz,1H),7.50(dd,J=7.2,13.0Hz,1H),7.33-7.21(m,1H),5.02(br s,1H),4.02-3.79(m,3H),3.68(br d,J=8.3Hz,1H),3.36-3.28(m,1H),3.10(br t,J=10.3Hz,1H),2.00-1.90(m,1H),1.82(d,J=13.4Hz,6H),1.59-1.42(m,1H).

[0974] Example 168. (3-(2-((1-(Hydroxymethyl)cyclobutyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 168)

[0975]

[0976] Compound 168 (57.14 mg, white solid). LCMS (ESI): [M+H] + =439.2;

[0977] 1 H NMR (400MHz, DMSO-d6) δppm 11.52 (br d, J=16.3Hz, 1H), 8.81-8.13 (m, 2H), 7.99-7.74 (m, 2H), 7.49 (dd, J=7.2, 12.9Hz, 1H), 7.26 (br t,J=6.9Hz,1H),4.87(br s,1H),3.72(br d,J=11.1Hz,2H),2.40-2.06(m,4H),1.82(d,J=13.4Hz,8H).

[0978] Example 169. (S)-(3-(2-((1-cyclohexyl-2-hydroxyethyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 169)

[0979]

[0980] Compound 169 (71.56 mg, white solid). LCMS (ESI): [M+H] + =481.2;

[0981] 1 H NMR (400MHz, DMSO-d6) δppm 11.54(br s,1H),8.75-8.36(m,2H),8.00-7.83(m,1H),7.65-7.43(m,2H),7.34-7.17(m,1H),4.63(br s,1H),4.09-3.94(m,1H),3.64-3.51(m,1H),3.51-3.48(m,1H),1.88-1.54(m,12H),1.27-0.96(m,5H).

[0982] Example 170. (R)-(3-(2-((1-hydroxyhexan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 170)

[0983]

[0984] Compound 170 (70.30 mg, white solid). LCMS (ESI): [M+H] + =455.2;

[0985] 1 H NMR (400MHz, DMSO-d6) δppm 11.54 (br s, 1H), 8.70-8.37 (m, 2H), 8.00-7.83 (m, 1H), 7.67-7.43 (m, 2H), 7.26 (q, J=8.0Hz, 1H), 4.74 (br s,1H),4.09(br dd,J=6.1,14.4Hz,1H),3.47(br dd,J=5.1,10.4Hz,2H),1.82(d,J=13.5Hz,6H),1.66(br d,J=5.0Hz,1H),1.56-1.44(m,1H),1.42-1.20(m,4H),0.86(br d,J=6.8Hz,3H).

[0986] Example 171. (S)-Dimethyl(3-(2-((1,1,1-trifluoro-3-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)phosphine oxide (Compound 171)

[0987]

[0988] Compound 171 (18.89 mg, white solid). LCMS (ESI): [M+H] + =467.1;

[0989] 1 H NMR (400MHz, DMSO-d6) δppm 11.70 (br s, 1H), 8.90-8.33 (m, 3H), 8.17-7.96 (m, 1H), 7.61 (dd, J=7.1, 12.9Hz, 1H), 7.37 (br d, J=6.0Hz, 1H), 5.34 (br s,1H),5.17-5.01(m,1H),3.99-3.73(m,2H),1.91(d,J=13.4Hz,6H).

[0990] Example 172. (R)-(3-(2-((2-Hydroxypropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 172)

[0991]

[0992] Compound 172 (57.27 mg, white solid). LCMS (ESI): [M+H] + =413.1;

[0993] 1 H NMR(400MHz,DMSO-d6)δppm 11.53(br s,1H),8.67-8.42(m,2H),8.01-7.73(m,2H),7.50(dd,J=7.2,12.9Hz,1H),7.27(dt,J=2.3,7.6Hz,1H),4.84-4.70(m,1H),3.88(br d,J=5.5Hz,1H),3.34(br d,J=2.0Hz,2H),1.82(d,J=13.4Hz,6H),1.11(d,J=6.2Hz,3H).

[0994] Example 173. (S)-(3-(2-((2-Hydroxypropyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 173)

[0995]

[0996] Compound 173 (48.95 mg, white solid). LCMS (ESI): [M+H] + =413.1;

[0997] 1H NMR(400MHz,DMSO-d6)δppm 11.53(br s,1H),8.67-8.39(m,2H),7.98-7.73(m,2H),7.50(dd,J=7.3,12.9Hz,1H),7.27(dt,J=2.1,7.7Hz,1H),4.85-4.76(m,1H),3.88(br d,J=5.8Hz,1H),3.34(br d,J=6.4Hz,2H),1.82(d,J=13.5Hz,6H),1.11(d,J=6.1Hz,3H)

[0998] Example 174. (3-(2-((3-Hydroxybicyclo[1.1.1]pentan-1-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 174)

[0999]

[1000] Compound 174 (9.33 mg, white solid). LCMS (ESI): [M+H] + =437.1;

[1001] 1 H NMR (400MHz, DMSO-d6) δppm 11.51(br s,1H),8.71-8.47(m,2H),8.39-8.05(m,1H),7.99-7.71(m,1H),7.50(br dd,J=7.1,12.6Hz,1H),7.38-7.17(m,1H),6.20(br s,1H),2.13(br d,J=19.3Hz,6H),1.82(br d,J=13.4Hz,6H)

[1002] Example 175. (3-(2-((4-Hydroxytetrahydro-2H-pyran-4-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 175)

[1003]

[1004] Compound 175 (48.79 mg, white solid). LCMS (ESI): [M+H] + =469.1;

[1005] 1H NMR(400MHz,DMSO-d6)δppm 11.54(br s,1H),8.70-8.41(m,2H),7.93(br d,J=18.1Hz,1H),7.77-7.60(m,1H),7.50(dd,J=7.1,12.9Hz,1H),7.28(dt,J=2.1,7.6Hz,1H),4.70(br d,J=13.0Hz,1H),3.65-3.46(m,6H),1.82(d,J=13.4Hz,6H),1.67-1.38(m,4H)

[1006] Example 176. (R)-(3-(2-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine (Compound 176)

[1007]

[1008] Compound 176 (47.40 mg, white solid). LCMS (ESI): [M+H] + =455.1;

[1009] 1 H NMR(400MHz,CD3OD)δppm 8.48-8.63(m,2H),7.93(br s,1H),7.49(dd,J=13.55,7.03Hz,1H),7.32(td,J=7.65,2.51Hz,1H),4.39-4.19(m,1H), 3.91(dd,J=11.42,3.39Hz,1H),3.75-3.56(m,1H),1.91(d,J=13.55Hz,6H),1.02(s,9H).

[1010] Example 177. (S)-(3-(5-Bromo-2-((1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 177)

[1011]

[1012] Step 1: (1H-indol-7-yl)dimethylphosphine oxide

[1013]

[1014] 7-Bromo-1H-indole (5.00 g, 25.50 mmol), [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-diphenyl]palladium(II) methanesulfonate dichloromethyl adduct (2.60 g, 2.50 mmol), diisopropylethylamine (16.48 g, 127.52 mmol) and dimethylphosphine oxide (3.98 g, 51.01 mmol) were added to anisole (50 mL) under nitrogen protection, and the mixture was stirred at 145 ° C for 16 hours. The reaction mixture was dried and the residue was purified by flash column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to give a white solid compound (1H-indol-7-yl) dimethylphosphine oxide (80% purity, 4.50 g, 23.30 mmol, yield 73%). LCMS (ESI): [M+H] + =194.1.

[1015] Step 2: (3-(5-bromo-2-chloropyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[1016]

[1017] At 15 ° C, to (1H-indol-7-yl) dimethylphosphine oxide (300 mg, 1.55 mmol) and 2,4-dichloro-5-bromopyrimidine (530 mg, 2.33 mmol) in hexafluoroisopropanol (3 mL) was added trifluoromethanesulfonic acid (260 mg, 1.71 mmol). The solution was stirred at 60 ° C for 16 hours. The solution was slurried with ethyl acetate to give a yellow solid (3- (5-bromo-2-chloropyrimidin-4-yl) -1H-indol-7-yl) dimethylphosphine oxide (500 mg, 1.30 mmol, yield 84%). LCMS (ESI): [M+H] + =386.0.

[1018] Step 3: (S)-(3-(5-Bromo-2-((1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[1019]

[1020] To a solution of (3-(5-bromo-2-chloropyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (0.10 g, 0.26 mmol) in dimethyl sulfoxide (1 mL) was added (S)-2-amino-1-propanol (0.03 g, 0.39 mmol) and diisopropylethylamine (230 uL, 1.30 mmol) at room temperature. The mixture was stirred at 100° C. for 2 hours. The residue was purified by preparative HPLC to give (S)-(3-(5-bromo-2-((1-hydroxypropane-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (25.49 mg, 59 umol, 23% yield) as a white solid. LCMS (ESI): [M+H] + =425.1;

[1021] 1 H NMR (400MHz, DMSO-d6) δppm 11.55(br s,1H),8.92-8.30(m,3H),7.49(dd,J=6.6,12.9Hz,1H),7.27(dt,J=2.3,7.7Hz,1H),7.17-6.88(m,1H),4.76(br s,1H),4.03(br s,1H),3.59-3.47(m,2H),1.81(d,J=13.5Hz,6H),1.18(d,J=6.6Hz,3H).

[1022] Example 178. (S)-(3-(2-(((1-Hydroxypropyl-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 178)

[1023]

[1024] Step 1: 7-Bromo-3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole

[1025]

[1026] To a solution of 7-bromoindole (1.00 g, 5.10 mmol) and 2,4-dichloro-5-methylpyrimidine (1.00 g, 6.12 mmol) in hexafluoroisopropanol (10 mL) was added trifluoromethanesulfonic acid (0.84 g, 5.61 mmol) at 25 ° C. The solution was stirred at 60 ° C for 16 hours. The reaction solution was slurried with ethyl acetate (20 mL) and filtered to give compound 7-bromo-3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (1.80 g, 5.10 mmol, 98% yield) as a yellow solid. LCMS (ESI): [M+H] +=322.0.

[1027] Step 2: 7-Bromo-3-(5-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole

[1028]

[1029] To a solution of 7-bromo-3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (1.00 g, 3.10 mmol) in trifluoroethanol (10 mL) was added potassium tert-butoxide (1.04 g, 9.30 mmol) at 0°C. The solution was stirred at 60°C for 16 hours. The solution was slurried and filtered with ethyl acetate (20 mL) to give a crude compound 7-bromo-3-(5-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole (1.60 g) as a yellow solid. LCMS (ESI): [M+H] + =386.0.

[1030] Step 3: Dimethyl(3-(5-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indol-7-yl)phosphine oxide

[1031]

[1032] Under a nitrogen atmosphere, [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-diphenyl]palladium(II) methanesulfonate dichloromethyl adduct (80 mg, 0.08 mmol) was added to a solution of 7-bromo-3-(5-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole (297 mg, 0.77 mmol), dimethylphosphine oxide (119 mg, 1.54 mmol), and triethylamine (536 uL, 3.85 mmol) in xylene (3 mL). The reaction mixture was stirred at 140°C for 16 hours. The mixture was concentrated to obtain the crude product. The residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / petroleum ether) to give dimethyl(3-(5-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indol-7-yl)phosphine oxide as a white solid (80% purity, 300 mg, 0.63 mmol, 81% yield). LCMS (ESI): [M+H] + =384.1.

[1033] Step 4: (S)-(3-(2-(((1-hydroxypropan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[1034]

[1035] A mixture of dimethyl (3-(5-methyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indol-7-yl)phosphine oxide (80% purity, 300 mg, 0.63 mmol) and compound (S)-2-aminopropan-1-ol (0.65 g, 8.61 mmol) was stirred at 100°C for 3 hours. The solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL*3). The organic phase was dried to dryness to obtain a residue. The residue was purified by preparative HPLC to obtain the white solid compound (S)-(3-(2-(((1-hydroxypropan-2-yl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (17.18 mg, 47 umol, 8% yield). LCMS (ESI): [M+H] + =359.2;

[1036] 1 H NMR (400MHz, DMSO-d6) δppm 11.42 (br s, 1H), 8.78 (br d, J = 7.6Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.55-7.18 (m, 2H), 6.44 (br d,J=7.9Hz,1H),4.13-3.98(m,1H),3.55-3.51(m,2H),2.28(s,3H),1.81(d,J=13.4Hz,6H),1.18(d,J=6.6Hz,3H).

[1037] Example 179. (S)-4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-2-((1-hydroxypropan-2-yl)amino)pyrimidine-5-carbonitrile (Compound 179)

[1038]

[1039] Step 1: Preparation of 4-(7-bromo-1H-indol-3-yl)-2-chloropyrimidine-5-carbonitrile

[1040]

[1041] The compound 7-bromo-1H-indole (700 mg, 3.57 mmol) was dissolved in hexafluoroisopropanol (14 mL), followed by the addition of 2,4-dichloropyrimidine-5-carbonitrile (932 mg, 5.36 mmol). Trifluoromethanesulfonic acid (589 mg, 3.93 mmol) was added at 0°C, and the reaction was stirred at 60°C for 16 hours. After completion of the reaction, the reaction solution was spin-dried and slurried with ethyl acetate (5 mL) to obtain 4-(7-bromo-1H-indol-3-yl)-2-chloropyrimidine-5-carbonitrile (950 mg, 2.75 mmol, 77% yield) as an orange solid. LCMS (ESI): [M+H] + =333.0.

[1042] Step 2: Preparation of 4-(7-bromo-1H-indol-3-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile

[1043]

[1044] 4-(7-Bromo-1H-indol-3-yl)-2-chloropyrimidine-5-carbonitrile (500 mg, 1.44 mmol) was dissolved in trifluoroethanol (5 mL) and tetrahydrofuran (1 mL), and potassium tert-butoxide (484 mg, 4.32 mmol) was added. The reaction was stirred at 60 ° C for 16 hours. After the reaction was completed, the reaction solution was dried, and the crude product was slurried with water (5 mL) to obtain 4-(7-Bromo-1H-indol-3-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile (400 mg, 0.98 mmol, yield 68%) as a yellow solid. LCMS (ESI): [M+H] + =398.8.

[1045] Step 3: Preparation of 4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile

[1046]

[1047] In a glove box, 4-(7-bromo-1H-indol-3-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile (350 mg, 0.87 mmol) was dissolved in xylene (3.5 mL), followed by the addition of dimethylphosphine oxide (136 mg, 1.75 mmol), triethylamine (267 mg, 2.64 mmol) and [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-diphenyl]palladium(II) methanesulfonate dichloromethyl adduct (84 mg, 0.09 mmol), and the reaction was stirred at 145 ° C for 16 hours. After the reaction, the reaction solution was evaporated to dryness, and the residue was purified by flash column chromatography (silica gel, 0-5% gradient of methanol / dichloromethane) to obtain 4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile (70% purity, 300 mg, 0.52 mmol, 60% yield) as a brown solid. LCMS (ESI): [M+H] + =395.1.

[1048] Step 4: Preparation of (S)-4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-2-((1-hydroxypropan-2-yl)amino)pyrimidine-5-carbonitrile

[1049]

[1050] 4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile (70% purity, 100 mg, 0.18 mmol) was dissolved in dioxane (1 mL), followed by the addition of (S)-2-aminopropan-1-ol (133 mg, 1.77 mmol). The reaction was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was spin-dried and the residue was purified by preparative HPLC to afford (S)-4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-2-((1-hydroxypropan-2-yl)amino)pyrimidine-5-carbonitrile (33 mg, 0.09 mmol, 50% yield) as a white solid. LCMS (ESI): [M+H] + =370.1.

[1051] 1H NMR(400MHz,DMSO-d6)δppm 11.73(br s,1H),8.95-8.54(m,3H),8.06-7.83(m,1H),7.53(dd,J=12.80,7.28Hz,1H),7.37-7.25(m,1H),4.82(dt,J=10. 73,5.55Hz,1H),4.32-4.03(m,1H),3.63-3.39(m,2H),1.81(d,J=13.30Hz,6H),1.21(dd,J=16.06,6.78Hz,3H).

[1052] Example 180. (S)-4-(7-(Dimethylphosphoryl)-1H-indol-3-yl)-2-((1-hydroxypropan-2-yl)amino)pyrimidine-5-carboxamide (Compound 180)

[1053]

[1054] Step 1: Preparation of 2-chloro-4-(7-(dimethylphosphoryl)-1H-indol-3-yl)pyrimidine-5-carboxamide

[1055]

[1056] The compound (1H-indol-7-yl) dimethylphosphine oxide (200 mg, 0.83 mmol) was dissolved in hexafluoroisopropanol (2 mL), and then 2,4-dichloropyrimidine-5-carboxamide (170 mg, 0.91 mmol) was added. Trifluoromethanesulfonic acid (140 mg, 0.91 mmol) was added at 0 ° C. The reaction was stirred at 60 ° C for 16 hours. After the reaction was completed, the reaction solution was spin-dried and slurried with ethyl acetate (5 mL) to obtain the crude compound 2-chloro-4-(7-(dimethylphosphoryl)-1H-indol-3-yl)pyrimidine-5-carboxamide (600 mg) as an orange solid. LCMS (ESI): [M+H] + =349.1.

[1057] Step 2: Preparation of ((S)-4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-2-((1-hydroxypropan-2-yl)amino)pyrimidine-5-carboxamide

[1058]

[1059] 2-Chloro-4-(7-(dimethylphosphoryl)-1H-indol-3-yl)pyrimidine-5-carboxamide (35% purity, 600 mg, 0.60 mmol) was dissolved in anisole (2 mL), and then (S)-2-aminopropan-1-ol (452 ​​mg, 6.02 mmol) was added. The reaction was stirred at 145° C. for 16 hours. After completion of the reaction, the reaction solution was spin-dried and the residue was purified by preparative HPLC to give ((S)-4-(7-(dimethylphosphoryl)-1H-indol-3-yl)-2-((1-hydroxypropan-2-yl)amino)pyrimidine-5-carboxamide (33.77 mg, 87 μmol, 14% yield) as a white solid. LCMS (ESI): [M+H] + =388.1.

[1060] 1 H NMR(400MHz,DMSO-d6)δppm 11.76-11.02(m,1H),8.67(br s,1H),8.20(s,1H),8.01(s,1H),7.79(br s,1H),7.53-7.36(m,2H),7.24(td,J=7.65,2.3Hz,1H),7.02(br s,1H),4.74(t,J=5.5Hz,1H),4.10(br s,1H),3.54(dt,J=10.5,5.4Hz,1H),3.39(br d,J=4.8Hz,1H),1.80(d,J=13.3Hz,6H),1.19(d,J=6.5Hz,3H).

[1061] Example 181. (S)-2-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol (Compound 181)

[1062]

[1063] Step 1: 6-Chloro-1-(phenylsulfonyl)-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine

[1064]

[1065] 6-Chloro-3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.00 g, 11.94 mmol) was added to xylene (50 mL), followed by 4-chloro-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (3.35 g, 11.94 mmol) and hexamethyldistanane (5.09 g, 15.53 mmol). Tetrakis(triphenylphosphine)palladium (1.38 g, 1.19 mmol) was then added under a nitrogen atmosphere. The reaction was stirred at 100°C for 2 hours, then transferred to 140°C for 16 hours. After completion of the reaction, potassium fluoride (5 g) was added to the organic phase, stirred at 25°C for 1 hour, and concentrated to mix. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of ethyl acetate / petroleum ether) to afford 6-chloro-1-(phenylsulfonyl)-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (3.74 g, 6.92 mmol, 58% yield) as a yellow solid. LCMS (ESI): [M+H] + =537.0.

[1066] Step 2: (S)-2-((4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol

[1067]

[1068] 6-Chloro-1-(phenylsulfonyl)-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (2.00 g, 3.35 mmol) was added to (S)-2-aminopropane-1-ol (10 mL). The mixture was then stirred at 145 ° C for 16 hours. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of methanol / dichloromethane) to give (S)-2-((4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol (1.02 g, 2.31 mmol, 69% yield). LCMS (ESI): [M+H] + =372.1.

[1069] Step 3: (S)-2-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol

[1070]

[1071] (S)-2-((4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol (200 mg, 0.48 mmol) was added to 1,4-dioxane (2 mL), and H2O (40 ul), sodium carbonate (154 mg, 1.45 mmol), and 3,6-dihydro-2H-pyran-4-boronic acid naphthalene ester (153 mg, 0.73 mmol) were added, and then 1,1-bis(diphenylmethane) was added under nitrogen. A mixture of 2-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol (54.86 mg, 0.13 mmol, 27% yield)) was added to a mixture of 2-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol (54.86 mg, 0.13 mmol, 27% yield). LCMS (ESI): [M+H] + =420.2.

[1072] 1H NMR (400MHz, CD3OD) δppm 8.82-8.46 (m, 2H), 7.97 (s, 1H), 7.47 (br d, J = 8.5Hz, 1H), 6.70 (br s,1H),4.39(q,J=2.6Hz,2H),4.34-4.19(m,1H),3.98(t,J=5.5Hz,2H),3.74-3.61(m,2H),2.75(br d,J=2.0Hz,2H),2.68(s,3H),1.32(d,J=6.5Hz,3H).

[1073] The following compounds were prepared by referring to the synthesis method of compound 181:

[1074] Example 182. (2S)-2-((4-(6-(tetrahydro-2H-pyran-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propanol (Compound 182)

[1075]

[1076] Compound 182 (90 mg, white solid). LCMS (ESI): [M+H] + =422.2.

[1077] 1H NMR(400MHz,CD3OD)δppm 8.88-8.66(m,1H),8.53(br s,1H),7.97(s,1H),7.37(d,J=8.5Hz,1H),4.59-4.51(m,1H),4.45-4.22(m,1H),4.21-4. 12(m,1H),3.77-3.60(m,3H),2.06-1.96(m,2H),1.83-1.61(m,4H),1.31(d,J=6.5Hz,3H).

[1078] Compound 182 was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; phase B is maintained at 50%; flow rate: 80 mL / min) to obtain the following compounds: a chiral monomer compound with a shorter elution time (compound 183) and a chiral monomer compound with a longer elution time (compound 184).

[1079] Example 183. After SFC separation of compound 182, a chiral monomer compound (compound 183) with a short elution time

[1080]

[1081] Compound 183 (26.62 mg, white solid). LCMS (ESI): [M+H] + =422.2;

[1082] SFC analysis (column: Chiralcel OJ-3 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B maintained at 40%; flow rate: 2.8 ml / min): RT = 1.017 min, de = 100%.

[1083] 1H NMR(400MHz,CD3OD)δppm 8.88-8.66(m,1H),8.53(br s,1H),7.97(s,1H),7.37(d,J=8.5Hz,1H),4.59-4.51(m,1H),4.45-4.22(m,1H),4.21-4. 12(m,1H),3.77-3.60(m,3H),2.06-1.96(m,2H),1.83-1.61(m,4H),1.31(d,J=6.5Hz,3H)

[1084] Example 184. After SFC separation of compound 182, a chiral monomer compound (compound 184) with a long elution time

[1085]

[1086] Compound 184 (23.32 mg, white solid). LCMS (ESI): [M+H] + =422.2;

[1087] SFC analysis (column: Chiralcel OJ-3 (100 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B maintained at 40%; flow rate: 2.8 ml / min): RT = 2.833 min, decimal point = 98.30%.

[1088] 1H NMR(400MHz,CD3OD)δppm 8.88-8.66(m,1H),8.53(br s,1H),7.97(s,1H),7.37(d,J=8.5Hz,1H),4.59-4.51(m,1H),4.45-4.22(m,1H),4.21-4. 12(m,1H),3.77-3.60(m,3H),2.06-1.96(m,2H),1.83-1.61(m,4H),1.31(d,J=6.5Hz,3H)

[1089] Example 185. (S)-2-((4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol (Compound 185)

[1090]

[1091] Compound 185 (23.84 mg, white solid). LCMS (ESI): [M+H] + =422.2.

[1092] 1 H NMR (400MHz, CD3OD) δppm 8.70 (br s, 1H), 8.52 (br s, 1H), 7.94 (s, 1H), 7.20 (br d, J=8.0Hz, 1H), 4.37 (br s,1H),4.10(dd,J=3.3,11.3Hz,2H),3.71-3.60(m,4H),3.08(tt,J=3.7, 11.7Hz,1H),2.07-1.95(m,2H),1.94-1.87(m,2H),1.32(d,J=6.8Hz,3H)

[1093] Example 186. (S)-(3-(2-(((1-Hydroxypropan-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 186)

[1094]

[1095] Step 1: 7-Bromo-3-(2-chloropyrimidin-4-yl)-1H-indole

[1096]

[1097] 7-Bromo-1H-indole (0.90 g, 4.59 mmol) and 2,4-dichloropyrimidine (1.03 g, 6.89 mmol) were dissolved in hexafluoroisopropanol (7 mL), and trifluoromethanesulfonic acid (450 μL, 5.05 mmol) was added dropwise at 0°C. The reaction mixture was reacted at 60°C for 16 hours, cooled to room temperature, and slurried with ethyl acetate (7 mL). The mixture was filtered and the solid was dried under vacuum to obtain 7-bromo-3-(2-chloropyrimidin-4-yl)-1H-indole (1.73 g, 3.90 mmol, 85% yield) as a yellow solid. LCMS (ESI): [M+H] + =308.0.

[1098] Step 2: 7-Bromo-3-(2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole

[1099]

[1100] 7-Bromo-3-(2-chloropyrimidin-4-yl)-1H-indole (1.20 g, 2.33 mmol) and potassium tert-butoxide (2.18 g, 11.67 mmol) were added to a mixed solution of trifluoroethanol (8 mL) and tetrahydrofuran (8 mL). The temperature was raised to 60°C and the reaction mixture was allowed to react for 16 hours. The reaction solution was concentrated, the residue was washed with water and filtered, and the solid was dried under vacuum to obtain the compound 7-bromo-3-(2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole (0.67 g, 1.79 mmol, 77% yield) as a gray solid. LCMS (ESI): [M+H] + =372.0.

[1101] Step 3: Dimethyl(3-(2-(2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indol-7-yl)phosphine oxide

[1102]

[1103] In a glove box, 7-bromo-3-(2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indole (0.30 g, 0.81 mmol), dimethylphosphine oxide (0.19 g, 2.42 mmol), and triethylamine (340 uL, 2.42 mmol) were dissolved in xylene (2 mL). Methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl]palladium(II) dichloromethane adduct (0.08 g, 0.08 mmol) was added to the reaction solution. The temperature was raised to 140°C and the reaction was allowed to proceed for 16 hours. The reaction solution was concentrated to obtain the crude compound dimethyl(3-(2-(2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1H-indol-7-yl)phosphine oxide (0.27 g). LCMS (ESI): [M+H] + =370.1.

[1104] Step 4: (S)-(3-(2-(((1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[1105] e

[1106] Dimethyl (3-(2-(2-(2,2,2-trifluoroethoxy) pyrimidin-4-yl)-1H-indol-7-yl) phosphine oxide (140 mg, 0.04 mmol) and (S)-2-amino-1-propanol (1 mL) were added to a reaction flask, and the temperature was raised to 100° C. for 2 hours. The residue was purified by preparative HPLC to give (S)-(3-(2-(((1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (5.03 mg, 15 μmol, yield 38%) as a brown solid. LCMS (ESI): [M+H] + =345.0.

[1107] 1 H NMR (400MHz, CD3OD) δppm 8.82(d,J=8.1Hz,1H),8.24(s,1H),8.13(br s,1H),7.61-7.44(m,1H),7.38(t,J=7.3Hz,1H),7.11(d,J=5.6Hz,1H),4.29(br s,1H),3.71(t,J=6.0Hz,2H),1.93(d,J=13.4Hz,6H),1.35(d,J=6.6Hz,3H).

[1108] Examples 187 and 188. (3-(2-(cis-4,4-difluoro-2-hydroxycyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 187) and (3-(2-(trans-4,4-difluoro-2-hydroxycyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 188)

[1109]

[1110] Step 1: tert-Butyl-(cyclopent-3-en-1-yloxy)-diphenylsilane

[1111]

[1112] To a solution of 3-cyclopenten-1-ol (5.00 g, 59.44 mmol) in dichloromethane (300 mL) at 0°C were added tert-butyldiphenylsilyl chloride (20.08 g, 73.05 mmol) and imidazole (11.13 g, 163.45 mmol). After the addition was complete, the mixture was stirred at 20°C for 16 hours. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (600 mL x 3). The organic layer was dried over sodium sulfate, filtered, and then concentrated to yield tert-butyl-(cyclopent-3-en-1-yloxy)-diphenylsilane (20.00 g, 55.80 mmol, 94% yield) as a yellow oil.

[1113] 1 H NMR(400MHz,DMSO-d6)δppm 7.71-7.57(m,4H),7.49-7.35(m,6H),5.66-5.59(s,2H),4.52(tt,J=3.5,6. 8Hz, 1H), 2.41 (dd, J = 6.7, 15.4Hz, 2H), 2.37-2.21 (m, 2H), 1.02-0.95 (s, 9H).

[1114] Step 2: (6-Oxabicyclo[3.1.0]hexan-3-yloxy)-tert-butyl-diphenylsilane

[1115]

[1116] At 0 ° C, m-chloroperbenzoic acid (85% purity, 15.64 g, 77.02 mmol) was slowly added to a solution of tert-butyl-(cyclopent-3-ene-1-yloxy)-diphenylsilane (20.00 g, 55.80 mmol) in dichloromethane (300 mL). The mixture was stirred at 20 ° C for 16 hours. The mixture was diluted with saturated sodium bicarbonate (400 mL) and extracted with dichloromethane (400 mL * 3). The organic layer was dried over anhydrous sodium sulfate and filtered, then concentrated. The residue was purified by flash column chromatography (silica gel, 0-5% gradient of tetrahydrofuran / dichloromethane) to give a yellow oily compound (6-oxabicyclo [3.1.0] hex-3-yloxy) -tert-butyl-diphenylsilane (20.00 g, 54.50 mmol, yield 94%). LCMS (ESI): [M+H] + =338.3.

[1117] Step 3: 2-(Benzylamino)-4-((tert-butyldiphenylsilyl)oxy)cyclopentanol

[1118]

[1119] To a solution of (6-oxabicyclo[3.1.0]hexan-3-yloxy)-tert-butyl-diphenylsilane (20.00 g, 54.50 mmol) in benzylamine (200 mL) was added tetraisopropyl titanate (1.86 g, 6.54 mmol). The mixture was stirred at 130 ° C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 0-20% gradient of tetrahydrofuran / dichloromethane) to give a yellow oily compound 2-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)cyclopentanol (27.00 g, 48.50 mmol, yield 89%). LCMS (ESI): [M+H] + =446.3.

[1120] Step 4: Cyclopentyl 2-(N-benzylacetamido)-4-((tert-butyldiphenylsilyl)oxy)acetate

[1121]

[1122] To a solution of 2-(benzylamino)-4-((tert-butyldiphenylsilyl)oxy)cyclopentanol (26.00 g, 43.75 mmol) in pyridine (200 mL) was added acetic anhydride (34.45 g, 291.69 mmol). The mixture was stirred at 75 ° C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / dichloromethane) to give a yellow oily compound 2-(N-benzylacetamido)-4-((tert-butyldiphenylsilyl)oxy)acetic acid cyclopentyl ester (11.00 g, 15.75 mmol, 36% yield). LCMS (ESI): [M+H] + =530.3.

[1123] Step 5: N-Benzyl-N-(4-((tert-butyldiphenylsilyl)oxy)-2-hydroxycyclopentyl)acetamide

[1124]

[1125] To a solution of 2-(N-benzylacetamido)-4-((tert-butyldiphenylsilyl)oxy)cyclopentyl acetate (2.00 g, 3.78 mmol) in methanol (16 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.24 g, 5.66 mmol). The mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated in vacuo to obtain a residue. The residue was diluted with water (5 mL) and extracted with dichloromethane (5 mL * 3). The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a yellow oily compound N-benzyl-N-(4-((tert-butyldiphenylsilyl)oxy)-2-hydroxycyclopentyl)acetamide crude product (1.70 g, 3.14 mmol, yield 83%). LCMS (ESI): [M+H] + =488.3.

[1126] Step 6: N-Benzyl-N-(2-(benzyloxy)-4-((tert-butyldiphenylsilyl)oxy)cyclopentyl)acetamide

[1127]

[1128] To a solution of N-benzyl-N-(4-((tert-butyldiphenylsilyl)oxy)-2-hydroxycyclopentyl)acetamide (1.70 g, 3.14 mmol) in tetrahydrofuran (40 mL) was added sodium hydride (60% purity; 0.17 g, 4.25 mmol) at 0°C and stirred for 15 minutes. Benzyl bromide (1.34 g, 7.84 mmol) was then added. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with aqueous ammonium chloride (10 mL) and extracted with tetrahydrofuran (20 mL * 3). The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the crude compound N-benzyl-N-(2-(benzyloxy)-4-((tert-butyldiphenylsilyl)oxy)cyclopentyl)acetamide (2.50 g) as a yellow oily liquid. LCMS (ESI): [M+H] + =578.4.

[1129] Step 7: N-Benzyl-N-(2-(benzyloxy)-4-hydroxycyclopentyl)acetamide

[1130]

[1131] To a solution of N-benzyl-N-(2-(benzyloxy)-4-((tert-butyldiphenylsilyl)oxy)cyclopentyl)acetamide (2.50 g, 4.33 mmol) in tetrahydrofuran (50 mL) was added tetrabutylammonium fluoride (5.94 g, 22.71 mmol). The mixture was stirred at 25 ° C for 16 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL * 3). The organic layer was concentrated to give a residue. The residue was purified by flash column chromatography (silica gel, 0-18% gradient of tetrahydrofuran / dichloromethane) to give N-benzyl-N-(2-(benzyloxy)-4-hydroxycyclopentyl)acetamide (0.78 g, 2.30 mmol, yield 53%) as a colorless oil. LCMS (ESI): [M+H] + =340.2.

[1132] Step 8: N-Benzyl-N-(2-(benzyloxy)-4-oxocyclopentyl)acetamide

[1133]

[1134] To a solution of N-benzyl-N-(2-(benzyloxy)-4-hydroxycyclopentyl)acetamide (783 mg, 2.30 mmol) in dichloromethane (10 mL) was added Dess-Martin reagent (1.40 g, 3.23 mmol) at 0°C. The mixture was stirred at 25°C for 16 hours. The residue was purified by flash column chromatography (silica gel, 0-8% gradient of tetrahydrofuran / dichloromethane) to give N-benzyl-N-(2-(benzyloxy)-4-oxocyclopentyl)acetamide (521 mg, 1.54 mmol, 67% yield) as a yellow oil. LCMS (ESI): [M+H] + =338.2.

[1135] Step 9: N-Benzyl-N-(2-(benzyloxy)-4,4-difluorocyclopentyl)acetamide

[1136]

[1137] At 0 ° C, N-benzyl-N-(2-(benzyloxy)-4-oxocyclopentyl)acetamide (400 mg, 1.19 mmol) was added to bis(2-methoxyethyl)aminosulfur trifluoride (4 mL). The mixture was stirred at 25 ° C for 16 hours. The residue was purified by flash column chromatography (silica gel, 0-10% gradient of tetrahydrofuran / dichloromethane) to give a brown oily compound N-benzyl-N-(2-(benzyloxy)-4,4-difluorocyclopentyl)acetamide (220 mg, 0.61 mmol, yield 51%). LCMS (ESI): [M+H] + =360.2.

[1138] Step 10: 2-(Benzylamino)-4,4-difluorocyclopentanol

[1139]

[1140] A solution of N-benzyl-N-(2-(benzyloxy)-4,4-difluorocyclopentyl)acetamide (220 mg, 0.61 mmol) in hydrochloric acid (6 M, 6 mL) was stirred at 100 ° C for 16 hours. The mixture was washed with ethyl acetate (1 mL), and the organic phase was extracted with water (1 mL * 2). The combined aqueous phases were concentrated in vacuo to give the crude compound 2-(benzylamino)-4,4-difluorocyclopentanol (200 mg) as a white solid. LCMS (ESI): [M+H] + =228.1.

[1141] Step 11: 2-Amino-4,4-difluorocyclopentanol

[1142]

[1143] To a solution of 2-(benzylamino)-4,4-difluorocyclopentanol (50% purity, 200 mg, 0.44 mmol) in isopropanol (10 mL) was added dry palladium carbon (10% content, 47 mg) and hydrochloric acid (6 M, 73 uL, 0.44 mmol). The reaction was stirred at 50 ° C for 16 hours in a hydrogen atmosphere of 50 psi. After the reaction was completed, the dry palladium carbon was filtered and recovered. The filtrate was concentrated in vacuo to give a crude compound 2-amino-4,4-difluorocyclopentanol (50 mg) as a white solid. LCMS (ESI): [M+H] + =138.1.

[1144] Step 12: (3-(2-(trans-4,4-difluoro-2-hydroxycyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide and (3-(2-(cis-4,4-difluoro-2-hydroxycyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[1145]

[1146] To a solution of (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (2.50 g, 6.69 mmol) and 2-amino-4,4-difluorocyclopentanol (50% purity, 1.80 g, 6.56 mmol) in dioxane (20 mL) was added diisopropylethylamine (8.00 g, 61.92 mmol). The reaction was stirred at 100° C. for 12 hours. The mixture was concentrated in vacuo to a residue. The residue was purified by flash column chromatography (C18, 0-33% gradient of acetonitrile / water) to afford Peak 1: (3-(2-(trans-4,4-difluoro-2-hydroxycyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (710 mg, 1.50 mmol, 23% yield) and Peak 2: (3-(2-(cis-4,4-difluoro-2-hydroxycyclopentylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (400 mg, 0.84 mmol, 13% yield), both as white solid compounds. 2D-NMR analysis showed that Peak 1 was the trans isomer and Peak 2 was the cis isomer. 2D-NMR analysis showed that Peak 1 was the trans isomer 188 and Peak 2 was the cis isomer 187.

[1147] Peak 2: cis compound 187: LCMS (ESI): [M+H] + =475.1.

[1148] 1H NMR (400MHz, CD3OD) δppm 8.58(m,2H),7.99(br s,1H),7.51(dd,J=6.9,13.7Hz,1H),7.34(dt,J=2.5,7.7Hz,1H),4.62(m,1H),4.46(br s,1H),2.65-2.23(m,4H),1.93(d,J=13.3Hz,6H)

[1149] Peak 1: trans compound 188: LCMS (ESI): [M+H] + =475.1.

[1150] H NMR(400MHz,CD3OD)δppm 8.61(br s,2H),7.98(s,1H),7.51(dd,J=7.3,13.6Hz,1H),7.34(dt,J=2.5,7.7Hz,1H),4.67-4.41( m,1H),4.32(q,J=7.4Hz,1H),2.83-2.55(m,2H),2.24-2.06(m,2H),1.93(d,J=13.3Hz,6H)

[1151] The cis-form compound 187 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / ethanol; phase B is maintained at 40%; flow rate: 80 ml / min) to obtain chiral monomer compound 189 with a shorter elution time and chiral monomer compound 190 with a longer elution time.

[1152] Example 189. After SFC separation of compound 187, a chiral monomer compound (compound 189) with a short elution time

[1153]

[1154] Compound 189 (16.60 mg, white solid). LCMS (ESI): [M+H] + =475.2;

[1155] SFC analysis (column: Chiralpak AD-3 (50 mm*4.6 mm, 3 um); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 2 minutes, maintaining 40% phase B for 1.2 minutes, and then maintaining 5% phase B for 0.8 minutes; flow rate: 4 ml / min): RT = 1.615 min, ee = 99.78%.

[1156] 1 H NMR (400MHz, CD3OD) δppm 8.59 (br s, 2H), 7.98 (br s, 1H), 7.51 (dd, J=7.3, 13.6Hz, 1H), 7.34 (m, 1H), 4.62 (s, 1H), 4.46 (br s,1H),2.67-2.24(m,4H),1.93(d,J=13.6Hz,6H).

[1157] Example 190, Compound 187 was separated by SFC, and the chiral monomer compound (Compound 190) with a short elution time was obtained.

[1158]

[1159] Compound 190 (18.09 mg, white solid). LCMS (ESI): [M+H] + =475.2;

[1160] SFC analysis (column: Chiralpak AD-3 (50 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 2 minutes, hold at 40% phase B for 1.2 minutes, then hold at 5% phase B for 0.8 minutes; flow rate: 4 ml / min): RT = 1.917 min, ee = 99.74%.

[1161] 1 H NMR (400MHz, CD3OD) δppm 8.59 (br s, 2H), 7.98 (br s, 1H), 7.51 (dd, J=7.3, 13.6Hz, 1H), 7.34 (m, 1H), 4.62 (s, 1H), 4.46 (br s,1H),2.67-2.24(m,4H),1.93(d,J=13.6Hz,6H).

[1162] The trans compound 188 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonia / ethanol; phase B is maintained at 35%; flow rate: 60 ml / min) to obtain chiral monomer compound 191 with a shorter elution time and chiral monomer compound 192 with a longer elution time.

[1163] Example 191, after SFC separation of compound 188, a chiral monomer compound (compound 191) with a short elution time

[1164]

[1165] Compound 191 (138.93 mg, white solid). LCMS (ESI): [M+H] + =475.1;

[1166] SFC analysis (column: Chiralpak AD-3 (150 mm*4.6 mm, 3 um); mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 5.5 minutes, maintaining 40% phase B for 3 minutes, and then maintaining 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 5.293 min, ee = 100%.

[1167] 1 H NMR (400MHz, DMSO-d6) δppm 11.58(br s,1H),8.72-8.45(m,2H),8.16-8.07(m,1H),7.95(br d,J=17.8Hz,1H),7.51(dd,J=7.2,12.9Hz,1H),7.27(br d,J=7.3Hz,1H),5.45(br s,1H),4.47-4.30(m,1H),4.30-4.21(m,1H),2.71-2.54(m,2H),2.23-1.96(m,2H),1.82(d,J=13.3Hz,6H).

[1168] Example 192, Compound 188 was separated by SFC, and the chiral monomer compound (Compound 192) with a short elution time was obtained.

[1169]

[1170] Compound 192 (138.55 mg, white solid). LCMS (ESI): [M+H] + =475.1;

[1171] SFC analysis (column: Chiralpak AD-3 (150 mm x 4.6 mm, 3 μm); mobile phase: phase A: carbon dioxide, phase B: 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% over 5.5 minutes, hold at 40% phase B for 3 minutes, then hold at 5% phase B for 1.5 minutes; flow rate: 2.5 ml / min): RT = 5.960 min, ee = 100%.

[1172] 1H NMR (400MHz, DMSO-d6) δppm 11.54(br s,1H),8.70-8.47(m,2H),8.12(br s,1H),7.94(br d,J=17.3Hz,1H),7.51(dd,J=7.2,12.7Hz,1H),7.27(br d,J=7.5Hz,1H),5.45(br s,1H),4.49-4.19(m,2H),2.70-2.55(m,2H),2.10(m,2H),1.82(d,J=13.3Hz,6H).

[1173] Example 193 Synthesis of (S)-(3-(2-((1-hydroxypropyl-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indazol-7-yl)dimethylphosphine oxide (Compound 193)

[1174]

[1175] Step 1: 7-Bromo-3-iodo-1H-indazole

[1176]

[1177] At 0 ° C, potassium hydroxide (3.56 g, 63.44 mmol) was added to a solution of 7-bromo-1H-indazole (5.00 g, 25.38 mmol) in dimethylformamide (25 mL), and then a solution of iodine (7.73 g, 30.45 mmol) in dimethylformamide (25 mL) was added dropwise. The reaction was stirred at 25 ° C for 16 hours. The mixture was diluted with water (80 mL) and extracted with dichloromethane (80 mL * 4). The organic phase was concentrated in vacuo to obtain a residue, which was slurried with water (20 mL) and filtered. The solid was dried in vacuo to give a yellow solid 7-bromo-3-iodo-1H-indazole (7.95 g, 23.35 mmol, 92% yield). LCMS (ESI): [M+H] + =324.8;

[1178] Step 2: 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indazole

[1179]

[1180] Under nitrogen, tetrakis(triphenylphosphine)palladium (1.36 g, 1.18 mmol) was added to a solution of 7-bromo-3-iodo-1H-indazole (4.00 g, 11.77 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.32 g, 15.30 mmol), and hexamethyldistanane (5.01 g, 15.30 mmol) in xylene (40 mL). The reaction was stirred at 100°C for 16 hours. The mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL x 3). The organic phase was concentrated in vacuo to a residue. The residue was purified by flash column chromatography (silica gel, 0-15% gradient of ethyl acetate / petroleum ether) to afford 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indazole (0.30 g, 0.82 mmol, 7% yield) as a yellow solid. LCMS(ESI):[M+H] + =378.9;

[1181] Step 3: (S)-2-((4-(7-bromo-1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol

[1182]

[1183] To a solution of 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indazole (280 mg, 0.74 mmol) and (S)-2-amino-propan-1-ol (836 mg, 11.12 mmol) in 1,4-dioxane (3 mL) was added diisopropylethylamine (575 mg, 4.45 mmol). The reaction was stirred at 100°C for 16 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give the crude compound (S)-2-((4-(7-bromo-1H-indazole-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol (464 mg) as a yellow oily liquid. LCMS (ESI): [M+H] + =416.0;

[1184] Step 4: (S)-(3-(2-((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indazol-7-yl)dimethylphosphine oxide

[1185]

[1186] To a solution of (S)-2-((4-(7-bromo-1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)propan-1-ol (200 mg, 0.48 mmol) in anisole (3 mL) were added diisopropylethylamine (311 mg, 2.40 mmol) and dimethylphosphine oxide (74 mg, 0.96 mmol). Methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl]palladium(II) dichloromethane adduct (46 mg, 0.05 mmol) was then added under nitrogen. The mixture was stirred at 140°C for 6 hours. The mixture became a brown suspension. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The organic phase was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give (S)-(3-(2-((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indazol-7-yl)dimethylphosphine oxide (46.05 mg, 0.11 mmol, 23% yield) as a white solid compound.

[1187] LCMS(ESI):[M+H] + =414.1.

[1188] 1 H NMR (400MHz, DMSO-d6) δppm 13.71(br s,1H),8.72-8.45(m,2H),8.02-7.75(m,2H),7.42(br t,J=7.4Hz,1H),4.80(t,J=5.5Hz,1H),4.22-4.08(m,1H),3.54(td,J=5.4,10.6Hz,1H),3.43(br d, J=5.3Hz, 1H), 1.86 (d, J=13.3Hz, 6H), 1.21 (d, J=6.5Hz, 3H).

[1189] Example 194 Synthesis of (3-(2-((1,3-dihydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 194)

[1190]

[1191] To a solution of (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (100 mg, 0.27 mmol) in dioxane (1 mL) were added 2-aminopropane-1,3-diol (37 mg, 0.40 mmol) and N,N-diisopropylethylamine (208 mg, 1.61 mmol). The mixture was stirred at 100°C for 2 hours. Aqueous solution (2 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3*2 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give (3-(2-((1,3-dihydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (59.87 mg, 0.14 mmol, 52% yield) as a white solid compound. LCMS (ESI): [M+H] + =429.1.

[1192] 1 H NMR (400MHz, DMSO-d6) δppm 11.55(br s,1H),8.73-8.40(m,2H),8.01-7.85(m,1H),7.56-7.39(m,2H),7.27(br t,J=6.8Hz,1H),4.72(br s,2H),4.21-4.01(m,1H),3.58(br s,4H),1.82(d,J=13.6Hz,6H)

[1193] Example 195. (S)-(6-Fluoro-3-(2-(((1-hydroxypropyl-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (Compound 195)

[1194]

[1195] Step 1: 7-Bromo-6-fluoro-1H-indole

[1196]

[1197] To a solution of 2-bromo-1-fluoro-3-nitrobenzene (6.00 g, 27.27 mmol) in tetrahydrofuran (36 mL) was added vinylmagnesium bromide (1 M in tetrahydrofuran, 82 mL, 82 mmol) at -78°C. The reaction was stirred at 25°C for 12 hours. The reaction solution was poured into saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to afford 7-bromo-6-fluoro-1H-indole (0.82 g, 3.83 mmol, 14% yield) as a brown oil.

[1198] 1 H NMR (400MHz, CDCl3) δppm 8.34 (br s, 1H), 7.56-7.48 (m, 1H), 7.27-7.25 (m, 1H), 6.97 (dd, J = 8.7, 9.3Hz, 1H), 6.62 (dd, J = 2.2, 3.2Hz, 1H)

[1199] Step 2: 7-Bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole

[1200]

[1201] A solution of compound 7-bromo-6-fluoro-1H-indole (810 mg, 3.78 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (985 mg, 4.54 mmol) in hexafluoroisopropanol (8.1 mL) was cooled to 0°C, trifluoromethanesulfonic acid (370 uL, 4.16 mmol) was added, and then stirred at 60°C under nitrogen for 12 hours. The reaction solution was slurried with ethyl acetate (8 mL), filtered, and the solid was vacuum dried to obtain a white solid compound 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole (1270 mg, 3.22 mmol, yield 85%). LCMS (ESI): [M+H] + =395.9.

[1202] Step 3: 7-Bromo-6-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole

[1203]

[1204] A solution of compound 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole (1250 mg, 3.17 mmol) and trifluoroethanol (12.5 mL) in tetrahydrofuran (25 mL) was cooled to 0 ° C, potassium tert-butoxide (1067 mg, 9.50 mmol) was added, and then stirred at 60 ° C under nitrogen protection for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was slurried with water (2 mL), filtered, and the solid was vacuum dried to give a white solid compound 7-bromo-6-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (1080 mg, 2.36 mmol, yield 74%). LCMS (ESI): [M+H] + =459.9.

[1205] Step 4: (6-Fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[1206]

[1207] In a glove box, to a solution of 7-bromo-6-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (700 mg, 1.53 mmol), triethylamine (760 μL, 4.58 mmol), and dimethylphosphine oxide (235 mg, 3.06 mmol) in xylene (14 mL) was added methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2-amino-1,1-biphenyl]palladium(II) dichloromethane adduct (158 mg, 0.15 mmol). The reaction was stirred under nitrogen at 140°C for 12 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was slurried with water (2 mL) and methyl tert-butyl ether (2 mL), filtered, and the solid was dried in vacuo to give a yellow solid compound (6-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (88% purity, 710 mg, 1.37 mmol, yield 89%). LCMS (ESI): [M+H] + =456.1.

[1208] Step 5: (S)-(6-Fluoro-3-(2-((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[1209]

[1210] The compound (6-fluoro-3-(2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (88% purity, 710 mg, 1.37 mmol) was dissolved in (S)-2-aminopropan-1-ol (1.2 g, 15.6 mmol). The reaction was stirred at 100° C. for 2 hours under nitrogen protection. The mixture was purified by flash column chromatography (C18, 0-50% gradient of acetonitrile / water) to obtain a white solid compound (S)-(6-fluoro-3-(2-((1-hydroxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (360 mg, 0.84 mmol, yield 61%). LCMS (ESI): [M+H] + =431.1

[1211] 1 H NMR(400MHz,CD3OD)δppm 8.54(br s,2H),7.96(s,1H),7.21-6.95(m,1H),4.30(br s,1H),3.75-3.56(m,2H),1.97(dd,J=1.0,13.9Hz,6H),1.30(d,J=6.7Hz,3H).

[1212] Control compound:

[1213]

[1214] (Compound 353 from WO2018013867)

[1215] Effect Example 1: In vitro enzymatic inhibition activity test of compounds CDK7, CDK2, CDK9 and CDK12

[1216] The assay was performed in a U-bottom 384-well plate (Corning, #4512) at 27°C. CDK7 / CyclinH was diluted in assay buffer (20 mM MES pH 6.75, 0.01% Tween 20, 50 μg / mL BSA, 6 mM MgCl2) to obtain an enzyme solution with a concentration of 2.4×. CDK2 / CyclinE1 was diluted in assay buffer (20 mM MES pH 6.75, 0.01% Tween 20, 50 μg / mL BSA, 6 mM MgCl2) to obtain an enzyme solution with a concentration of 2.4×. CDK9 / CyclinT1 was diluted in assay buffer (20 mM MES pH 6.75, 0.01% Tween 20, 50 μg / mL BSA, 10 mM MgCl2) to obtain an enzyme solution with a concentration of 2.4×. CDK12 / CyclinK was diluted in assay buffer (80 mM MES pH 6.5, 0.01% Tween 20, 50 μg / mL BSA, 10 mM MgCl2) to obtain a 2.4× enzyme solution. Compounds were dissolved in dimethyl sulfoxide (DMSO) at a 10 mM concentration. Upon use, the compounds were diluted with DMSO to a 10-fold concentration gradient from 25 nM to 500 μM, each diluted 8.3-fold in assay buffer to obtain a 6× compound solution. Peptide substrate and ATP were diluted in assay buffer to obtain a 2.4× peptide substrate and ATP mixed solution. 2 μl of test compound solution was mixed with 5 μl of enzyme solution and incubated for 10 minutes. Then, 5 μl of the peptide substrate and ATP mixed solution was added and incubated at 27°C for 180 minutes. The reaction was terminated by adding 4 μL of 120 mM EDTA to each sample. Assay buffer containing 20 uM staurosporine was used instead of the compound solution as a 100% inhibition control, and DMSO was used instead of the compound solution as a 0% inhibition control, with at least two parallel controls per experiment. Specifically, the CDK7 inhibition assay used the CDK7 / cyclin H / MAT1 complex (6 nM) and the "5-FAMCD K 7 tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK, where "5-FAM" refers to 5-carboxyfluorescein).The CDK9 inhibition assay used the CDK9 / cyclin T1 complex (8 nM) and the "5-FAM-CDK9tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-GSRTPMY-NH2, 5-FAM is as defined above and NH2 represents the C-terminal amide), the CDK12 inhibition assay used the CDK12 (aa686-1082) / cyclin K complex (50 nM) and the "5-FAM-CDK9tide" (2 μM) as defined above, and the CDK2 inhibition assay used the CDK2 / cyclin E1 complex (0.5 nM) and the "5-FAM-CDK7tide" (2 μM) as defined above.

[1217] The reaction mixtures were analyzed by electrophoretic separation of the fluorescent substrate and phosphorylated product on a Caliper EZ Reader II. Data were calculated using GraphPad Prism version 6.0, and IC50 values ​​were calculated using a nonlinear regression model of the dose-response curves.

[1218] The IC50 results of these assays are shown in Table 1 below, where "A" indicates a calculated IC50 of less than 20 nM; "B" indicates a calculated IC50 of 20 nM to less than 200 nM; "C" indicates a calculated IC50 of 200 nM to less than 5 μM; "D" indicates a calculated IC50 of 5 μM to less than 50 μM; and "E" indicates a calculated IC50 greater than or equal to 50 μM.

[1219] Table 1

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226]

[1227] Note: --- indicates that the test was not conducted

[1228] As shown in the table above, the compounds synthesized in this application have demonstrated excellent inhibitory activity against CDK7 kinases with good selectivity, as determined by in vitro bioactivity screening using staurosporine as a control. These compounds are expected to be developed into drugs for modulating CDK7 kinase activity or treating CDK7-related diseases.

[1229] Effect Example 2: Cell Biological Activity Detection

[1230] A2780 and HCC70 cells were trypsinized, and the cell suspensions were transferred to 15 mL centrifuge tubes and centrifuged at 800 rpm for 5 min. The supernatant was discarded and the cells were resuspended in fresh culture medium (RPMI 1640 + 10% FBS). After counting, the cells were seeded at 2000 / well in a 384-well plate (50 μL 1640 + 10% FBS culture medium was added to columns 2 and 23 of the 384-well plate, and 50 μL DPBS was added to the surrounding wells). The plates were placed in an incubator (37°C, 5% CO2) and incubated overnight.

[1231] On the second day, the compounds were added to the well plates. The highest concentration of the compound was 10 μM, diluted 1:4, for a total of 9 concentrations. The highest concentration of the positive compound, Paclitaxel, was 1 μM, diluted 1:3, for a total of 9 concentrations. The DMSO content in each well was standardized to 0.2%. The cell plate was centrifuged at 800 rpm for 30 seconds and placed in an incubator (37°C, 5% CO2) for 72 hours. On the fourth day, Cyquant reagent (3X) was prepared according to the kit instructions. Each 384-well plate was prepared according to the following ratio: 11.568 mL of DPBS, Direct nucleic acid stain 72μL, Direct background suppressor (360 μL), mix thoroughly, and set aside at room temperature. Remove the cell plate and allow it to equilibrate at room temperature for 30 minutes. Dispense 25 μL of Cyquant reagent (3X) per well of the 384-well plate using a Multi-Drop flow cytometer. Incubate at 37°C for at least 60 minutes. Read the plate using an Acumen reader (Acumen settings: 488 nm excitation wavelength). IC50 results were analyzed using XLFIT5 from IDBS.

[1232] The results of these assays are shown in Table 2 below, where "A" indicates a calculated IC50 of less than 20 nM; "B" indicates a calculated IC50 of 20 nM to less than 200 nM; "C" indicates a calculated IC50 of 200 nM to less than 5 μM; "D" indicates a calculated IC50 of 5 μM to less than 50 μM; and "E" indicates a calculated IC50 greater than or equal to 50 μM.

[1233] Table 2

[1234]

[1235]

[1236]

[1237]

[1238]

[1239] Note: --- indicates that the test was not conducted.

[1240] As can be seen from Table 2, the compounds of the present invention have very good inhibitory effects on human breast cancer cells HCC70 and ovarian cancer A2780.

[1241] Effect Example 3: Caco-2 permeability and efflux rate

[1242] Resuscitated Caco-2 cell suspensions were seeded into TRANSWELL plates and cultured for 14-18 days. After 14 days of culture, cells were confluent and differentiated, ready for transport experiments. Remove the Caco-2 cell plates from the incubator. Prepare stock solutions of test and control compounds in DMSO and dilute them in HBSS (10 mM HEPES, pH 7.4) to a final concentration of 5 μM. Add test compound and control solutions to each well (apical side) of the insert, and add HBSS (10 mM HEPES, pH 7.4) to each well (basolateral side) of the test compound receiver plate. To measure the rate of compound transport from the basolateral to the apical side, add test compound and control solutions to each well (basolateral side) of the receiver plate, and add HBSS (10 mM HEPES, pH 7.4) to each well (apical side) of the test compound solution insert. Incubate at 37°C in a CO2 incubator for 2 hours. After the transport experiment, vortex at 1000 rpm for 10 minutes. After quenching the samples at each time point, LC / MS / MS analysis was performed. Fluorescence values ​​were measured after the two-hour transport experiment. Lucifer yellow solution was added to the Transwell chamber (top) and transport buffer was added to the basolateral end. The cells were incubated at 37°C in a CO2 incubator for 30 minutes. The solution was directly removed from the top and basolateral ends (using the basolateral wells) and transferred to a new 96-well plate. Cell fluorescence values ​​(to detect membrane integrity) were measured using a microplate reader with an excitation wavelength of 485 nM and an emission wavelength of 530 nM. All data were calculated using Microsoft Excel, and peak areas were calculated based on the chromatograms. The apparent permeability coefficient (Papp, unit: 10-6, cm / s) and efflux rate (ER) of the compound in Caco-2 cells were calculated based on the specific concentrations at the receiving and administration ends.

[1243] The measurement results are shown in Table 3 below.

[1244] Table 3

[1245]

[1246]

[1247]

[1248] As can be seen from Table 3, the compounds of the present invention have better Caco-2 membrane permeability and lower efflux rate.

[1249] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by formula IA, its stereoisomer, or a pharmaceutically acceptable salt of any of the described substances: R1 is CF3; R5 represents H; X represents N; Z represents CH; R2 is "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from one or more of N, O and S", "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from one or more of N, O and S", and substituted with one or more Ra-2, "4-12 membered heterocycloalkenyl containing 1-4 heteroatoms selected from one or more of N, O and S", "4-12 membered heterocycloalkenyl containing 1-4 heteroatoms selected from one or more of N, O and S", and substituted with one or more Ra-3, or CN; each Ra-2 independently represents CN, oxo, C1-C6 alkyl substituted with one or more Ra-1-1, NH2, OH or C1-C6 alkyl; Ra-1-1 independently represents CN, OH or halogen; R3 is C3-C8 cycloalkyl substituted with one or more Rb-1, C1-C6 alkyl substituted with one or more Rb-2, "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from O" and substituted with one or more Rb-3, or "5-10 membered heteroaryl containing 1-4 heteroatoms selected from one or more of N, O, and S"; Rb-1 is independently halogen, OH, -NRb-1-1Rb-1-2, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more Rb-1-3"; Rb-1-1 and Rb-1-2 independently represent H or C1-C6 alkyl; Rb-1-3 is independently OH or NRb-1-4Rb-1-5; Rb-1-4 and Rb-1-5 independently represent H or C1-C6 alkyl; Rb-2 is independently OH, halogen, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more Rb-2-1, 4-12 membered heterocycloalkyl containing 1-4 heteroatoms that are O, or "4-12 membered heterocycloalkyl containing 1-4 heteroatoms that are O and substituted with one or more Rb-2-2"; Rb-2-1 and Rb-2-2 independently represent OH, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more OH"; p1 is 0, 1, 2 or 3; p2 is 2 or 3, R3-1 is H or C1-C6 alkyl; R3-2 and R3-3 independently represent H, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more halogens"; Y is O or CH2, n1 is 1 or 2, n2, n3, and n4 are independently 0, 1, 2, or 3, and n2 and n4 are not both 0; Rb-3 is independently halogen, OH, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more OH"; or R3 is -(CRM1RM2)m-(L)s-(CRN1RN2)tM; wherein RM1, RM2, RN1 and RN2 each independently represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl substituted with 0, 1 or 2 substituents selected from hydroxyl, C1-C6 alkyl and halogen; or RM1, RM2, RN1 and RN2 each independently, together with the carbon atoms to which they are attached, form a 3-6-membered ring, and said ring contains 0, 1, 2 heteroatoms selected from O, N and S; furthermore, said ring is substituted with 0, 1 or 2 substituents selected from halogen, C1-C6 alkyl and hydroxyl; wherein L is -CRQ1RQ2- or -C3-C6 cycloalkyl-; wherein RQ1 and RQ2 each independently represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl substituted with 0, 1, or 2 substituents selected from hydroxyl, C1-C6 alkyl, and halogen; or RQ1 and RQ2 each independently, together with the carbon atom to which they are attached, form a 3-6-membered ring, and said ring contains 0, 1, or 2 heteroatoms selected from O, N, and S; furthermore, said ring is substituted with 0, 1, or 2 substituents selected from halogen, C1-C6 alkyl, and hydroxyl; wherein M is hydrogen, hydroxyl, C1-C6 alkyl or C3-C6 cycloalkyl substituted with 0, 1 or 2 substituents selected from hydroxyl, C1-C6 alkyl and halogen; where m, s and t, each independently, are equal to 0, 1, 2 or 3; wherein at least one group in -(CRM1RM2)m-(L)s-(CRN1RN2)tM is substituted by hydroxyl.

2. A compound represented by formula IA, its stereoisomer, or a pharmaceutically acceptable salt of any of the substances described: R1 is CF3; R5 represents H; X is C(R4), and R4 is -P(=O)Me2; Z represents CH; R2 is H or halogen; R3 is C3-C8 cycloalkyl substituted with one or more Rb-1, C1-C6 alkyl substituted with one or more Rb-2, "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from O" and substituted with one or more Rb-3, or "5-10 membered heteroaryl containing 1-4 heteroatoms selected from one or more of N, O, and S"; Rb-1 is independently halogen, OH, -NRb-1-1Rb-1-2, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more Rb-1-3"; Rb-1-1 and Rb-1-2 independently represent H or C1-C6 alkyl; Rb-1-3 is independently OH or NRb-1-4Rb-1-5; Rb-1-4 and Rb-1-5 independently represent H or C1-C6 alkyl; Rb-2 is independently OH, halogen, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more Rb-2-1, 4-12 membered heterocycloalkyl containing 1-4 heteroatoms that are O, or "4-12 membered heterocycloalkyl containing 1-4 heteroatoms that are O and substituted with one or more Rb-2-2"; Rb-2-1 and Rb-2-2 independently represent OH, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more OH"; p1 is 0, 1, 2, or 3; p2 represents 2 or 3, R3-1 is H or C1-C6 alkyl; R3-2 and R3-3 independently represent H, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more halogens"; Y is O or CH2, n1 is 1 or 2, n2, n3, and n4 independently represent 0, 1, 2, or 3, and n2 and n4 do not simultaneously represent 0; Rb-3 is independently halogen, OH, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more OH"; or R3 is -(CRM1RM2)m-(L)s-(CRN1RN2)tM; where RM1, RM2, RN1 and RN2 each independently represent hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl substituted with 0, 1 or 2 substituents selected from hydroxyl, C1-C6 alkyl and halogen; or RM1, RM2, RN1 and RN2 together with the carbon atoms to which they are attached form a 3-6 membered ring, and said ring contains 0, 1 or 2 heteroatoms selected from O, N and S; furthermore, said ring is substituted with 0, 1 or 2 substituents selected from halogen, C1-C6 alkyl and hydroxyl; where L is -CRQ1RQ2- or -C3-C6 cycloalkyl-; RQ1 and RQ2 each independently represent hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl substituted with 0, 1 or 2 substituents selected from hydroxyl, C1-C6 alkyl and halogen; or RQ1 and RQ2 together with the carbon atoms to which they are attached form a 3-6 membered ring, and said ring contains 0, 1 or 2 heteroatoms selected from O, N and S; and said ring is substituted with 0, 1 or 2 substituents selected from halogen, C1-C6 alkyl and hydroxyl; where M is hydrogen, hydroxyl, C1-C6 alkyl or C3-C6 cycloalkyl substituted with 0, 1 or 2 substituents selected from hydroxyl, C1-C6 alkyl and halogen; where m, s, and t each independently represent 0, 1, 2, or 3; where at least one group in -(CRM1RM2)m-(L)s-(CRN1RN2)tM is substituted by hydroxy.

3. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the substances described according to claim 1, wherein R2 is "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from one or more of N, O and S" or "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from one or more of N, O and S" and substituted with one or more Ra-2.

4. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 3, characterized in that R3 is -(CRM1RM2)m-(L)s-(CRN1RN2)tM; wherein RM1, RM2, RN1 and RN2 each independently represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl substituted with 0, 1 or 2 substituents selected from hydroxyl, C1-C6 alkyl and halogen; or RM1, RM2, RN1 and RN2 each independently, together with the carbon atoms to which they are attached, form a 3-6-membered ring, and said ring contains 0, 1, 2 heteroatoms selected from O, N and S; furthermore, said ring is substituted with 0, 1 or 2 substituents selected from halogen, C1-C6 alkyl and hydroxyl; wherein L is -CRQ1RQ2- or -C3-C6 cycloalkyl-; wherein RQ1 and RQ2 each independently represent hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl substituted with 0, 1 or 2 substituents selected from hydroxyl, C1-C6 alkyl and halogen; or RQ1 and RQ2 together with the carbon atom to which they are attached form a 3-6-membered ring, and said ring contains 0, 1, 2 heteroatoms selected from O, N and S; furthermore, said ring is substituted with 0, 1 or 2 substituents selected from halogen, C1-C6 alkyl and hydroxyl; where M is hydrogen, hydroxyl, C1-C6 alkyl or C3-C6 cycloalkyl substituted with 0, 1 or 2 substituents selected from hydroxyl, C1-C6 alkyl and halogen; where m, s, and t each independently represent 0, 1, 2, or 3; where at least one group in -(CRM1RM2)m-(L)s-(CRN1RN2)tM is substituted with hydroxyl.

5. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of paragraphs 1 and 3, characterized in that R3 is C3-C6 cycloalkyl substituted with 1, 2, or 3 Rb-1, methyl substituted with one or more Rb-2, ethyl substituted with one or more Rb-2, n-propyl substituted with one or more Rb-2, isopropyl substituted with one or more Rb-2, n-butyl substituted with one or more Rb-2, isobutyl substituted with one or more Rb-2, sec-butyl substituted with one or more Rb-2, "4- to 6-membered heterocycloalkyl containing 1-2 heteroatoms that are O" and substituted with 1 or 2 Rb-3, or "5- to 6-membered heteroaryl containing 1-4 heteroatoms selected from one or more N." 6. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of paragraphs 1-3 and 5, characterized in that Rb-1 is independently F, Cl, Br, I, OH, -NRb-1-1Rb-1-2, C1-C3 alkyl, or "C1-C3 alkyl substituted with one or more Rb-1-3"; and / or Rb-2 is independently OH, F, Cl, Br, I, C3-C7 cycloalkyl or C3-C7 cycloalkyl substituted with 1 or 2 Rb-2-1, a 4- to 6-membered heterocycloalkyl containing 1 heteroatom that is O, or a 4- to 6-membered heterocycloalkyl containing 1 heteroatom that is O and substituted with 1 or 2 Rb-2-2; wherein Rb-2-1 and Rb-2-2 are independently OH, C1-C3 alkyl or C1-C3 alkyl substituted with one or more OH; and / or Rb-3 is independently F, Cl, Br, I, OH, C1-C3 alkyl, or C1-C3 alkyl substituted with one or more OH.

7. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 6, characterized in that Rb-1-1 and Rb-1-2 independently represent H or C1-C3 alkyl; and Rb-1-4 and Rb-1-5 independently represent H or C1-C3 alkyl.

8. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 7, characterized in that R3-1 is H or C1-C3 alkyl; and / or R3-2 and R3-3 independently represent H, C1-C3 alkyl, or "C1-C3 alkyl substituted with one or more halogens." 9. A compound represented by formula IA, its stereoisomer or a pharmaceutically acceptable salt of any of the described substances in accordance with at least one of paragraphs 1-8, characterized in that in R3: the fragment is C3-C8 cycloalkyl substituted with one or more Rb-1 is cyclopropyl substituted with 1, 2, or 3 Rb-1, cyclobutyl substituted with 1, 2, or 3 Rb-1, cyclopentyl substituted with 1, 2, or 3 Rb-1; and in Rb-1, halogen is F, C1-C6 alkyl is methyl, ethyl, n-propyl, or isopropyl, and "C1-C6 alkyl substituted with one or more Rb-1-3" is ethyl, n-propyl, or isopropyl substituted with one or more Rb-1-3; and / or C1-C6 alkyl substituted with one or more Rb-2 is and / or "4-12 membered heterocycloalkyl containing 1-4 heteroatoms that are O" and substituted with one or more Rb-3 is oxetanyl substituted with 1 or 2 Rb-3, tetrahydrofuranyl substituted with 1 or 2 Rb-3, or "tetrahydropyranyl substituted with 1 or 2 Rb-3"; and wherein in Rb-3 the C1-C6 alkyl substituted with one or more OH is methyl, ethyl, n-propyl, or isopropyl substituted with one or more OH; and / or "5-10 membered heteroaryl containing 1-4 heteroatoms selected from one or more of N, O and S" is pyrazolyl.

10. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 and 3 to 9, characterized in that in R2, "4-12-membered heterocycloalkyl containing 1-4 heteroatoms selected from one or more of N, O, and S" is azetidinyl, oxazepanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, or morpholinyl; "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from one or more of N, O and S" and substituted with one or more Ra-2 is morpholinyl substituted with 1 or 2 Ra-2, azetidinyl substituted with 1 or 2 Ra-2, tetrahydrofuranyl substituted with 1 or 2 Ra-2, tetrahydropyranyl substituted with 1 or 2 Ra-2, piperidyl substituted with 1 or 2 Ra-2, pyrrolidinyl substituted with 1 or 2 Ra-2, piperazinyl substituted with 1 or 2 Ra-2, thiomorpholinyl substituted with 1 or 2 Ra-2; "4-12 membered heterocycloalkenyl containing 1-4 heteroatoms selected from one or more of N, O and S" is dihydrofuranyl; or "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from one or more of N, O and S" is "4-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from one or more of N, O and S" and substituted with one or more Ra-2 is "4-12 membered heterocycloalkenyl containing 1-4 heteroatoms selected from one or more of N, O and S" is 11. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 10, characterized in that in Rb-1-1 and Rb-1-2, C1-C6 alkyl independently represents methyl, ethyl, n-propyl, or isopropyl; and / or in Rb-1-4 and Rb-1-5 C1-C6 alkyl is independently methyl, ethyl, n-propyl or isopropyl.

12. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of paragraphs 1 to 11, characterized in that in Rb-2, the halogen is F; C3-C8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; C3-C8 cycloalkyl substituted with one or more Rb-2-1 is cyclopropyl substituted with 1 or 2 Rb-2-1, cyclobutyl substituted with 1 or 2 Rb-2-1, cyclopentyl substituted with 1 or 2 Rb-2-1, cyclohexyl substituted with 1 or 2 Rb-2-1, or cycloheptyl substituted with 1 or 2 Rb-2-1; "4- to 12-membered heterocycloalkyl containing 1 to 4 heteroatoms that are O" is tetrahydrofuranyl or tetrahydropyranyl; "4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms that are O and substituted with one or more Rb-2-2" is "tetrahydrofuranyl substituted with 1 or 2 Rb-2-2" or "tetrahydropyranyl substituted with 1 or 2 Rb-2-2"; and in Rb-2-1 and Rb-2-2, and C1-C6 alkyl independently represents methyl, ethyl, n-propyl, or isopropyl; "C1-C6 alkyl substituted with one or more OH" independently represents "methyl, ethyl, n-propyl, or isopropyl substituted with one or more OH"; or wherein in Rb-2 C3-C8 cycloalkyl substituted by one or more Rb-2-1 is "4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms that are O" is "4-12 membered heterocycloalkyl containing 1-4 heteroatoms that are O and substituted with one or more Rb-2-2" is or 13. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 12, characterized in that in R3-1, R3-2, and R3-3, C1-C6 alkyl independently represents methyl, ethyl, n-propyl, or isopropyl.

14. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 13, characterized in that in R3, C3-C8 cycloalkyl substituted by one or more Rb-1 is "4-12 membered heterocycloalkyl containing 1-4 heteroatoms that are O" and substituted with one or more Rb-3 is "5-10 membered heteroaryl containing 1-4 heteroatoms selected from one or more of N, O and S" is 15. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 14, characterized in that Y is O, n1 is 1, and n3 is 0 or 1.

16. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of paragraphs 1 to 15, characterized in that if the number of Rb-1 is one, then Rb-1 is OH, -NRb-1-1Rb-1-2, or "C1-C6 alkyl substituted with one or more Rb-1-3"; if the number of Rb-1 is several, then at least one Rb-1 is OH or "C1-C6 alkyl substituted with one or more OH"; and / or if the number of Rb-2 is one, then Rb-2 is OH, C3-C8 cycloalkyl substituted with one or more Rb-2-1, or "4-12-membered heterocycloalkyl containing 1-4 heteroatoms that are O and substituted with one or more Rb-2-2"; if the number of Rb-2 is several, then at least one Rb-2 is OH, C3-C8 cycloalkyl substituted with one or more Rb-2-1, or "4-12-membered heterocycloalkyl containing 1-4 heteroatoms that are O and substituted with one or more Rb-2-2"; wherein if the number of Rb-2-1 is one, then Rb-2-1 is OH or "C1-C6 alkyl substituted with one or more OH"; if the number of Rb-2-1 is several, then at least one Rb-2-1 is OH or "C1-C6 alkyl substituted with one or more OH"; if the number of Rb-2-2 is one, then Rb-2-2 is OH or "C1-C6 alkyl substituted with one or more OH";if the number of Rb-2-2 is several, then at least one Rb-2-2 is OH or "C1-C6 alkyl substituted with one or more OH"; and / or if the number of Rb-3 is one, then Rb-3 is OH or "C1-C6 alkyl substituted with one or more OH; if the number of Rb-3 is several, then at least one Rb-3 is OH or "C1-C6 alkyl substituted with one or more OH". ; 17. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of paragraphs 1 and 3-16, characterized in that R2 is 18. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of paragraphs 1 to 17, characterized in that R3 is 19. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of paragraphs 2-18, characterized in that X is C(R4), and R4 is -P(=O)Me2, R2 is H or halogen; and R3 is C3-C8 cycloalkyl substituted with one or more Rb-1, 20. A compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 19, characterized in that the compound represented by formula IA is any of the following compounds:

21. A pharmaceutical composition comprising a compound represented by formula IA, its stereoisomer or a pharmaceutically acceptable salt of any of the described substances in accordance with at least one of claims 1 to 20 and a pharmaceutical excipient.

22. The use of a compound represented by formula IA, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the described substances according to at least one of claims 1 to 20, or a pharmaceutical composition according to claim 21 for the treatment of a disease associated with CDK7 activity, wherein said disease is a cancer disease, a benign neoplasm, angiogenesis, an inflammatory disease, an autoinflammatory disease, or an autoimmune disease.

23. The use according to claim 22, wherein the cancer disease is leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, breast cancer, ovarian cancer, brain cancer, lung cancer, liver cancer, small cell lung cancer, melanoma, bladder cancer, colon cancer, esophageal cancer, bone cancer, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, epithelial sarcoma, soft tissue sarcoma, multiple myeloma.

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