Aromatic heterocyclic compounds, pharmaceutical compositions, and their use

Abstract

Aromatic heterocyclic compounds, pharmaceutical compositions and their uses.Specifically, the compound shown in formula I, its stereoisomers, its diastereomers, or any one of the above pharma-ceutically acceptable salts, or any one of the above crystalline forms or solvates are disclosed.The aromatic heterocyclic compounds have novel structures, good CDK7 inhibitory activity, and good selectivity. [Formula 1] TIFF2024502301000180.tif51170

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 2020115524787, filed on 24 December 2020. This application incorporates the full text of the aforementioned Chinese Patent Application.

[0002] This invention relates to aromatic heterocyclic compounds, methods for preparing the same, pharmaceutical compositions thereof, and uses thereof. [Background technology]

[0003] Members of the cyclin-dependent kinase (CDK) family play a crucial role in cell proliferation. CDK7 is unique to mammalian CDKs and integrates kinase activity, regulating the cell cycle and transcription. In the cytoplasm, CDK7 exists as a heterotrimeric complex and is thought to act as CDK1 / 2-activated kinase (CAK). Therefore, CDK7 phosphorylation of conserved residues of CDK1 / 2 is required for full catalytic CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the general transcription factor complex of RNA polymerase (RNAP) II and is involved in the phosphorylation of the C-terminal domain (CTD) of RNAP II, a step necessary for gene transcription initiation. CDK7 has two functions (i.e., phosphorylation of CAK and CTD) that together support important aspects of cell proliferation, the cell cycle, and transcription.

[0004] Disruption of RNAP II CTD phosphorylation has been shown to preferentially affect short-half-life proteins (including proteins of the anti-apoptotic BCL-2 family). Cancer cells have demonstrated the ability to evade the promotion of cell death signaling by upregulating members of the BCL-2 family. Therefore, inhibition of human CDK7 kinase activity may result in antiproliferative activity.

[0005] The high sequence and structural similarity of the kinase domains of members of the CDK family hinders the discovery of selective CDK7 inhibitors. Therefore, there is a need to discover and develop selective CDK7 inhibitors. Such CKD7 inhibitors are expected to be therapeutic agents for treating CLL and other cancers. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The present invention aims to provide aromatic heterocyclic compounds, methods for preparing them, pharmaceutical compositions, and uses thereof in order to overcome the shortcomings of existing single-structure CDK7 inhibitors in this technical problem. The compounds of the present invention have novel structures, as well as good activity and selectivity. [Means for solving the problem]

[0007] The present invention solves the above technical problems by using the following technical solutions.

[0008] The present invention provides a compound represented by formula I, its stereoisomer, its diastereomer, or any one of the aforementioned pharmaceutically acceptable salts (referring to the compound represented by formula I, its stereoisomer, or diastereomer), or any one of the aforementioned crystalline form or solvate (referring to the compound represented by formula I, its stereoisomer, its diastereomer, or pharmaceutically acceptable salt), [ka] R 1 However, it is CF3, F, Cl, Br, or CN, R 5 However, it is H or halogen, X is N, R 2 but, [ka] "4- to 12-member heterocyclic alkyl containing 1 to 4 heteroatoms O", one or more Rs 2-8 "4- to 12-member heterocyclic alkyl containing 1 to 4 heteroatoms O" substituted with one or more Rs 2-9 "4- to 12-member heterocyclic alkyl containing 1 to 4 heteroatoms N" substituted with

Chemical formula

[0009] In certain preferred embodiments of the present invention, certain groups in the compound represented by Formula I, its stereoisomers, its diastereomers, or any of the pharmaceutically acceptable salts described herein, or any of the crystalline forms or solvates described herein, are defined as follows, and any groups not mentioned herein are the same as those described in any of the solutions of this application (referred to as "Specific Solutions of the Invention").

[0010] R 2-1 , R 2-2 , R 2-3 , and R 2-4 However, if independently, it is a C1-C6 alkyl or a "C1-C6 alkyl substituted with one or more halogens", then the C1-C6 alkyl is a C1-C3 alkyl, preferably methyl, ethyl, n-propyl, or isopropyl, for example, methyl or ethyl, and in another example, methyl.

[0011] In a particular solution of the present invention, R 2 but, [ka] If that is the case, [ka] teeth, [ka] That is the case.

[0012] In a particular solution of the present invention, each R 2-5 However, if it is independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

[0013] In a particular solution of the present invention, R 2-6 and R 2-7 However, if it is independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

[0014] In a particular solution of the present invention, R 2 but, [ka] If that is the case, [ka] teeth, [ka] for example, [ka] That is the case.

[0015] In a particular solution of the present invention, R 2 However, it is a "4-12 member heterocyclic alkyl group containing 1-4 heteroatoms O" or one or more R 2-8 If the substituted "4-12 member heterocyclic alkyl group containing 1-4 heteroatoms O", then the "4-12 member heterocyclic alkyl group containing 1-4 heteroatoms O" is a "4-6 member heterocyclic alkyl group containing 1 heteroatom O", for example, tetrahydrofuranyl or tetrahydropyranyl, in another example, [ka] That is the case.

[0016] In a particular solution of the present invention, each R 2-8 However, if it is independently a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

[0017] In a particular solution of the present invention, R 2 However, one or more R 2-9 If it is a "4-12 member heterocyclic alkyl containing 1-4 heteroatoms N" substituted with one or more R 2-9 A "4-12 member heterocyclic alkyl group containing 1-4 heteroatoms N" substituted with one or two R 2-9 A "4-6 member heterocyclic alkyl group containing 1-2 heteroatoms N" substituted with, for example, 1 or 2 R 2-9 Azetidinyl substituted with, 1 or 2 R 2-9 Pyrrolidinyl substituted with, 1 or 2 R 2-9 Piperidyl substituted with, or "1 or 2 R 2-9 In another example, "piperazinyl substituted with," [ka] That is the case.

[0018] In a particular solution of the present invention, each R 2-9 However, if independently, it is a C1-C6 alkyl or a "C1-C6 alkyl substituted with one or more OH groups", then the C1-C6 alkyl is a C1-C3 alkyl, preferably methyl, ethyl, n-propyl, or isopropyl, for example, methyl.

[0019] In a particular solution of the present invention, each R 2-9 However, if independently, "a 4-12 member heterocyclic alkyl group containing 1-4 heteroatoms selected from one or more of O, S, and N," then "a 4-12 member heterocyclic alkyl group containing 1-4 heteroatoms selected from one or more of O, S, and N" is "a 4-6 member heterocyclic alkyl group containing 1 or 2 heteroatoms O," for example, oxetanyl, in another example, [ka] That is the case.

[0020] In a particular solution of the present invention, R 1 However, it is CF3, F, Cl, Br, or CN, R 5 However, it is H or halogen, X is N, R 2 but, [ka] "A 4-12 member heterocyclic alkyl group containing 1-4 heteroatoms O", one or more R 2-8 A "4-12 member heterocyclic alkyl group containing 1-4 heteroatoms O" substituted with one or more R 2-9 A "4-12 member heterocyclic alkyl group containing 1-4 heteroatoms N" substituted with, [ka] And, Z 1 However, it is N or CH, and Z 2 However, it is O or S (=O)², and R 2-1 , R 2-2 , R 2-3 , and R 2-4 However, independently, these are H, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more halogens," or R 2-1 However, R 2-2 It combines with -(CH2) m - Forms a structure, or R 2-1 However, R 2-3 It combines with -(CH2) m - Forms a structure, or R 2-1 However, R 2-4 It combines with -(CH2) m - Forms a structure, or R 2-2 However, R 2-3 It combines with -(CH2) m -Forms a structure where m is 1, 2, or 3, and n 11 However, it is either 1 or 2, Each R 2-5 However, independently, they are H or C1-C6 alkyl, n5, n6, n7, and n8 are independently 0, 1, 2, or 3, and n5 and n7 are not simultaneously 0, and n6 and n8 are not simultaneously 0, R 2-6 and R 2-7 However, independently, they are NH2 or C1-C6 alkyl, and n9 and n 10 However, independently, they are 0, 1, or 2. Each R 2-8 However, independently, it is a C1-C6 alkyl group. Each R 2-9 However, independently, these are OH, CN, C1-C6 alkyl, C1-C6 alkyl substituted with one or more OH groups, or "a 4-12 member heterocyclic alkyl group containing one to four heteroatoms selected from one or more of O, S, and N". R 3 but, [ka] is as follows.

[0021] In a specific solution of the present invention, R 1 is CF3.

[0022] In a specific solution of the present invention, R 2-1 , R 2-2 , R 2-3 , and R 2-4 are independently H or C1-C6 alkyl, or R 2-1 is bonded to R 2-3 to form a -(CH2) m - structure, or R 2-1 is bonded to R 2-4 to form a -(CH2) m - structure, or R 2-2 is bonded to R 2-3 to form a -(CH2) m - structure.

[0023] In a specific solution of the present invention,

Chemical formula

[0024] In a particular solution of the present invention, [ka] In Z 1 However, N is Z 2 However, S(=O)2 and R 2-1 , R 2-2 , R 2-3 , and R 2-4 However, H is independent of n 11 is either 0 or Z 1 However, N is Z 2 However, O and R 2-1 , R 2-2 , R 2-3 , and R 2-4 However, it is either H or C1-C6 alkyl, or R 2-1 However, R 2-3 It binds to form a -CH2- or -(CH2)2- structure, or R 2-1 However, R 2-4 It binds to form a -CH2- structure, n 11 However, it is either 0 or 1, or Z 1 However, it is CH, and Z 2 However, O and R 2-1 , R 2-2 , R 2-3 , and R 2-4 However, all are H, and n 11 However, it is 0.

[0025] In a particular solution of the present invention, n5 is 1 or 2, n7 is 1, 2, or 3, n6 is 0, 1, or 2, and n8 is 0, 1, 2, or 3.

[0026] In a particular solution of the present invention, n9 is 0, and n 10 However, it is 0, 1, or 2.

[0027] In a particular solution of the present invention, R2 However, -P(=O)Me2, [ka] And preferably, R 2 However, -P(=O)Me2, [ka] That is the case.

[0028] In a particular solution of the present invention, R 3 but, [ka] That is the case.

[0029] In a particular solution of the present invention, the compound represented by formula I is one of the following compounds: [ka] TIFF0007840334000024.tif226170TIFF0007840334000025.tif226170TIFF0007840334000026.tif226170

[0030] In a particular solution of the present invention, the compound represented by formula I is one of the following compounds: [ka] A compound exhibiting stereoisomerism with a retention time of 6.763 minutes under the following conditions: Chromatography column: Cellulose 2 (150 mm × 4.6 mm), 5 μm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / methanol; Gradient: Phase B increases from 5% to 40% within 5 minutes, 40% Phase B is held for 2.5 minutes, 5% Phase B is held for 2.5 minutes, Flow rate: 2.5 ml / min; [ka] A compound exhibiting stereoisomerism with a retention time of 7.118 minutes under the following conditions: Chromatography column: Cellulose 2 (150 mm × 4.6 mm), 5 μm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / methanol; Gradient: Phase B increases from 5% to 40% within 5 minutes, 40% Phase B is held for 2.5 minutes, 5% Phase B is held for 2.5 minutes, Flow rate: 2.5 ml / min; [ka] A compound exhibiting stereoisomerism under the following conditions has a retention time of 3.598 minutes: Chromatography column: Chiralcel OJ-3 (100 mm × 4.6 mm), 3 μm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / ethanol; Gradient: Phase B increases from 5% to 40% within 4 minutes, holding the 40% Phase B for 0.5 minutes, holding the 5% Phase B for 1.5 minutes, flow rate: 2.8 ml / min; [ka] A compound exhibiting stereoisomerism with a retention time of 4.426 minutes under the following conditions: Chromatography column: Chiralcel OJ-3 (100 mm × 4.6 mm), 3 μm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / ethanol; Gradient: Phase B increases from 5% to 40% within 4 minutes, holding the 40% Phase B for 0.5 minutes, holding the 5% Phase B for 1.5 minutes, Flow rate: 2.8 ml / min.

[0031] The above test conditions for retention time are not used to limit the compounds. A compound must be within the scope of protection of the present invention as long as its retention time, obtained under the above test conditions, is the same as that recorded above or within the margin of error, and the compound is a stereoisomer of the above-mentioned compound as defined by its retention time.

[0032] The compounds of the present invention can be prepared by using synthetic methods known in the art and synthetic methods summarized in the solutions described below.

[0033] Common synthesis method 1: [ka] As shown in General Synthesis Method 1, the compound represented by formula (I-1) reacts with a suitable halogenating agent (e.g., element iodine) to obtain halogenated product I-2, the NH functional group in its structure is protected by selecting a suitable protecting group (e.g., but not limited to benzenesulfonyl) in product I-2, and the compound represented by chemical formula (I-2) is protected using benzenesulfonyl at a low temperature (e.g., 0°C) to obtain compound I-3. Next, the compound reacts with compound I-8 under a suitable catalyst to produce compound I-5 by a one-pot reaction via Still coupling, or compound I-3 is first converted to the corresponding borate (or boric acid) compound I-4 by halogenation under suitable reaction conditions, compound I-4 reacts with compound I-8 under a suitable catalyst to obtain compound I-5 by Suzuki coupling, and compound I-5 is heated under conditions of a suitable chlorinating reagent (e.g., SOCl2, but not limited) to obtain chlorination intermediate I-6, or thiomethyl ether is oxidized to sulfone I-10 (sulfoxide I-9 or "a mixture of sulfone I-10 and sulfone I-9") using a suitable oxidizing agent (e.g., m-CPBA, but not limited). Chlorination intermediate I-6 (I-10 or a mixture of I-9 / I-10) is heated under suitable alkaline conditions (e.g., DIEA, but not limited) to R 3 The compound shown in formula (I-7) is reacted with NH2 to obtain the compound shown in formula (I-7), and the compound shown in formula (I-7) is heated under suitable alkaline conditions (e.g., NaOH, but not limited to) for deprotection to obtain the final product shown in formula (I). 3 If the group contains other protecting groups (e.g., Boc protecting groups, but not limited to them), the final compound of compound I can be obtained under suitable acidic conditions (e.g., TFA / DCM, but not limited to them).

[0034] General synthesis method 2: In the compound shown in formula I, if X is N, a novel important intermediate compound II-6 can be creatively synthesized, and the final compound II of the present invention (corresponding to compound I where X is N) can be conveniently synthesized using intermediate II-6. [ka]

[0035] As shown in General Synthesis Method 2, the compound represented by formula (II-1) reacts with a suitable halogenating agent (e.g., element iodine, but not limited) to obtain halogenated product II-2, and the NH functional group in the structure is protected by selecting a suitable protecting group (e.g., benzenesulfonyl, but not limited) in product II-2, for example, the reaction with benzenesulfonyl chloride at low temperatures (e.g., 0°C) can be protected by using benzenesulfonyl to obtain compound II-3. Next, the compound reacts with compound II-6 under a suitable catalyst to produce compound II-5 by Still coupling in a one-pot reaction, or compound II-3 is first converted to the corresponding borate (or boric acid) compound II-4 by halogenation under suitable reaction conditions, compound II-4 reacts with compound II-6 under a suitable catalyst to obtain compound II-5 by Suzuki coupling, and azoxy compound II-6 is obtained from compound II-5 under suitable oxidation conditions (e.g., m-CPBA, but not limited), and azoxy compound II-6 reacts with a suitable activating reagent (e.g., dimethyl sulfate, but not limited) to produce active pyridineazoxymethyl ether under heating conditions. The active intermediate is then converted to amino compound R in the presence of a suitable alkali (e.g., DIEA, but not limited). 2 It reacts with H to obtain the compound shown in formula (II). 3 If the group contains other protecting groups (e.g., but not limited to Boc protecting groups), the final compound of compound II is obtained under suitable acidic conditions (e.g., but not limited to TFA / DCM).

[0036] Compound II-5 is heated under suitable halogenation conditions with a suitable chlorinating or brominating reagent (e.g., methyl chloroformate, but not limited) to obtain chlorination intermediate II-7 or the corresponding brominating intermediate. Chlorination intermediate II-7 is converted under suitable catalytic conditions (e.g., Suzuki coupling or Buchwald coupling, but not limited) to the corresponding borate / boric acid or amino compound R 2 It reacts with H to obtain the compound shown in formula (II). 3 If the group contains other protecting groups (e.g., but not limited to Boc protecting groups), the final compound of compound II is obtained under suitable acidic conditions (e.g., but not limited to TFA / DCM).

[0037] General synthesis method 3: In the compound shown in formula I, X is C(R 4 ) and R 4 However, if -P(=O)Me2, a novel and important intermediate compound III-4 is creatively synthesized, and the final compound III(X) of the present invention is C(R 4 ) and R 4 However, compound I, which is -P(=O)Me2, can be conveniently synthesized using intermediates III-4 via a simple substitution reaction. [ka]

[0038] As shown in General Synthesis Method 3, the compound represented by formula (III-1) (e.g., a brominated compound, but not limited to it) is reacted with a suitable reagent (e.g., dimethylphosphine oxide, but not limited to it) under a suitable catalyst in the presence of a suitable acidic reagent (e.g., trifluoroacetic acid or aluminum trichloride) to obtain product III-2 by coupling reaction. Product III-2 is reacted with compound (III-3) at a suitable temperature (e.g., 60°C or 0°C) under a suitable solvent (e.g., 1,1,1,3,3,3-hexafluoropropan-2-ol or dichloromethane, but not limited to it) in the presence of a suitable acidic reagent (e.g., trifluoroacetic acid or aluminum trichloride, but not limited to it) to obtain compound III-4. The chlorinated intermediate III-4 is heated under suitable alkaline conditions (e.g., DIEA, but not limited to it) to obtain R 3 It is reacted with NH2 to obtain the compound shown in formula (III). 3 If the group contains other protecting groups (e.g., Boc protecting groups, but not limited to them), the final compound of compound I can be obtained under suitable acidic conditions (e.g., TFA / DCM, but not limited to them).

[0039] The present invention further provides a pharmaceutical composition comprising a compound represented by formula I, its stereoisomer, its diastereomer, or any one of the aforementioned pharmaceutically acceptable salts (referring to the compound represented by formula I, its stereoisomer, or its diastereomer), or any one of the aforementioned crystalline form or solvate, and a pharmaceutical adjuvant.

[0040] The present invention further provides the use of a compound represented by formula I, its stereoisomer, its diastereomer, or any one of the aforementioned pharmaceutically acceptable salts (referring to the compound represented by formula I, its stereoisomer, or its diastereomer), or any one of the aforementioned crystalline forms or solvates, or the above-mentioned pharmaceutical compositions, in the preparation of a drug. Preferably, the drug is used to prevent and / or treat proliferative disorders.

[0041] The present invention further provides a method for preventing and / or treating proliferative disorders. The method comprises administering to a patient a therapeutically effective amount of the compound represented by Formula I, its stereoisomer, its diastereomer, or any one of the aforementioned pharmaceutically acceptable salts (referring to the compound represented by Formula I, its stereoisomer, or its diastereomer), or any one of the aforementioned crystalline form or solvate, or the above-mentioned pharmaceutical composition.

[0042] Preferably, proliferative disorders include cancer (e.g., leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, breast cancer, ovarian carcinoma, brain cancer, lung cancer, liver cancer, small cell lung cancer, melanoma, bladder cancer, colon cancer, esophageal cancer, bone cancer, neuroblastoma, ovarian carcinoma cancer, pancreatic cancer, prostate cancer, epithelial sarcoma, soft tissue sarcoma, and multiple myeloma), benign warts, angiogenesis, inflammatory diseases, autoinflammatory diseases, or autoimmune diseases.

[0043] The compounds of the present invention, their stereoisomers, their diastereomers, or any one of the pharmaceutically acceptable salts described herein, or any one of the crystalline forms or solvates described herein, and pharmaceutical compositions may be administered topically or systemically, for example, by enteral administration, e.g., rectally or orally, or parenterally to mammals (referring particularly to humans). Exemplary combinations for rectal administration include suppositories, which may contain, for example, a suitable non-irritating excipient (e.g., cocoa butter, synthetic glycerides, or polyethylene glycol) that is solid at room temperature but melts and / or dissolves in the rectal cavity to release the drug. The compounds of the present invention may also be administered parenterally, for example, by inhalation, injection, or infusion (e.g., intravenous, intra-arterial, intraosseous, intramuscular, intracerebral, extraventricular, intrabursal, intrasternal, intrathecal, intrafocal, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion).

[0044] The therapeutically effective dose of the active ingredient is defined herein and depends on the mammalian species, body weight, age, individual condition, individual pharmacokinetic parameters, the disease being treated, and the mode of administration. For enteral administration, such as oral administration, the compounds of the present invention can be prepared in a wide range of dosage forms.

[0045] The effective amounts of the compounds described in the present invention, their pharmaceutically acceptable salts, and their solvates or pharmaceutical compositions can be easily determined using conventional experiments, and the most effective and convenient route of administration and the most appropriate preparation can also be determined using conventional experiments.

[0046] Unless otherwise specified, the terms used in this invention have the following meanings. In accordance with the conventions and practices used in the art, the structural formula of the base described in the present invention is used [ka] Those skilled in the art should understand that this refers to the fact that the corresponding group is bonded to other fragments and groups of the compound by its site.

[0047] A carbon atom with an asterisk represents a chiral carbon atom in either an S configuration or an R configuration.

[0048] The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention, as well as relatively non-toxic and pharmaceutically acceptable acids or alkalis. If the compounds of the present invention contain relatively acidic functional groups, alkali addition salts can be obtained by allowing a sufficient amount of pharmaceutically acceptable alkali to come into contact with the neutral form of the compound in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable alkali addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. If the compounds of the present invention contain relatively alkaline functional groups, acid addition salts can be obtained by allowing a sufficient amount of pharmaceutically acceptable acid to come into contact with the neutral form of the compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids, inorganic acids, or organic acids. If the compounds of the present invention contain relatively acidic and relatively alkaline functional groups, the compounds can be converted into alkali addition salts or acid additions. For specifics, please refer to 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).

[0049] The term "solvate" refers to a substance formed by combining the compound of the present invention or a pharmaceutically acceptable salt thereof with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may exist in ordered or unordered configurations. Solvents include, but are not limited to, water, methanol, and ethanol.

[0050] If stereoisomers exist, 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). The term “stereoisomer” refers to a cis-trans isomer or optical isomer. These stereoisomers can be separated, purified, and concentrated using asymmetric synthesis or chiral separation methods (including, but not limited to, thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, and high-pressure liquid chromatography), and can be obtained by chiral resolution through bonding to other chiral compounds (including chemical bonding) or chlorination (including physical bonding). The term “single stereoisomer” means that the mass content of one stereoisomer of the compound of the present invention is 95% or more of all stereoisomers of the compound.

[0051] If tautomers exist, the terms “compound,” “pharmaceutically acceptable salt,” “solvate,” and “solvate of a pharmaceutically acceptable salt” may exist as a single tautomer or a mixture thereof, preferably as a relatively stable tautomer.

[0052] In the terms “compound,” “pharmaceutically acceptable salt,” “solvate,” and “solvate of a pharmaceutically acceptable salt,” atoms may exist in either naturally occurring or unnaturally occurring abundances. For example, with respect to hydrogen, the naturally occurring abundance would be approximately 99.985% protium and approximately 0.015% deuterium, while the unnatural abundance would be approximately 95% deuterium. In other words, one or more atoms in the terms “compound,” “pharmaceutically acceptable salt,” “solvate,” and “solvate of a pharmaceutically acceptable salt” may exist in unnaturally occurring abundances.

[0053] Any variable (for example, R a-1When a group appears several times in the definition of a compound, the definition of each position of the variable is independent of the definitions of other positions, and their meanings are independent of each other and do not influence one another. Therefore, if a group has one, two, or three R groups a-1 If substituted with a group, that is, the group has up to three R a-1 It may be replaced by R at this position a-1 The definition of is R at other locations a-1 This definition is independent of the definition of [the compound]. In addition, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0054] The term "more" refers to 2, 3, 4, or 5, preferably 2 or 3.

[0055] The term "alkyl" refers to a linear or branched alkyl group containing a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-amyl, n-hexyl, n-heptyl, n-octyl, and similar alkyl groups.

[0056] The term "cycloalkyl" refers to a saturated monocyclic, polycyclic, or bridging carbocyclic substituent consisting of carbon and hydrogen atoms, which may be bonded to the remainder of the molecule by single bonds via any preferred carbon atom, and if polycyclic, may be a fused or helical ring system (parallel or helical bond) (i.e., two geminal hydrogens on the carbon atom are substituted with alkylene). The cycloalkyl substituent may be bonded to the central molecule via any preferred carbon atom. In some examples, a ring containing 3 to 8 carbon atoms can represent a C3-C8 cycloalkyl. In some examples, C3-C6 cycloalkyls include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), dicyclo[1.1.1]pentane, and cyclohexyl (C6).

[0057] The term "heterocyclic alkyl" refers to a saturated cyclic group containing heteroatoms, including monocyclic, polycyclic, or intracyclic conditions, which, if polycyclic, may be a fused or helical system (parallel or helical linkage). Preferably, it is a 4-12 member saturated cyclic group containing 1-4 cyclic heteroatoms independently selected from N, O, and S. Exemplary 4-membered heterocyclic groups include, but are not limited to, azetidinyl, epoxypropyl, thiacyclobutanil, or their isomers and stereoisomers. Exemplary 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanil, oxythiofuranil, dithiofuranil, dithiofuranil, or their isomers and stereoisomers. Examples of six-membered heterocyclic groups include, but are not limited to, piperidyl, tetrahydropyranyl, thiocyclopentyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or their isomers and stereoisomers. Examples of seven-membered heterocyclic groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, oxazepanyl, diazepanyl, or their isomers and stereoisomers.

[0058] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably an aromatic 5-6 member monocycle or 9-10 member bicycle containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where, if bicyclic, at least one ring is aromatic, and includes, for example, furyl, pyridyl, pyridyl, pyridadinyl, pyrimidyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoazolyl, quinolyl, and isoquinolyl.

[0059] The term "pharmaceutical adjuvant" refers to excipients and additives used in the manufacture and dispensing of drugs, and includes all substances contained in pharmaceutical preparations excluding the active ingredient. See Pharmacopoeia of the People's Republic of China (Edition 2015), Volume IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0060] The term “to treat” refers to therapeutic treatment. With respect to a particular condition, treating means (1) alleviating one or more biological symptoms of a disease or condition; (2) (a) interfering with one or more points in the biological cascade that causes or leads to the condition or (b) interfering with one or more biological symptoms of the condition; (3) improving 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 treatment; or (4) delaying the progression of the condition or one or more biological symptoms of the condition.

[0061] The term "prevention" refers to reducing the risk of contracting or developing a disease or disability.

[0062] The term "therapeutic dose" refers to the amount of a compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic dose" will vary depending on the compound, its condition and severity, and the age of the patient being treated, but may be adjusted as needed by those skilled in the art.

[0063] The term “patient” refers to any animal, preferably a mammal, most preferably a human, that would or has received an administration of the compound or composition according to the 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 (most preferably humans).

[0064] Exemplary embodiments of the present invention can be obtained by freely combining the above preferred conditions, provided that they do not violate the ordinary general knowledge of the art.

[0065] All reagents and raw materials used in this invention are commercially available.

[0066] The present invention provides an aromatic heterocyclic compound that exhibits a novel structure, good CDK7 inhibitory activity, and good selectivity, thus demonstrating a positive progressive effect. [Modes for carrying out the invention]

[0067] The present invention is further illustrated by the following examples, but is not limited to the scope of these examples. Experimental methods without specific conditions in the following examples shall be selected according to conventional methods and conditions or according to commercial specifications. [Examples]

[0068] Preparation of intermediate A: (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide [ka] Step 1: (3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-tert-butylformate [ka] Compound 2,4-dichloro-5-trifluoromethylpyrimidine (2.00 g, 9.22 mmol) was dissolved in tetrahydrofuran (2 mL). Triethylamine (1400 uL, 10.07 mmol) was added. Under nitrogen protection, a solution of zinc chloride in tetrahydrofuran (2 M, 10 mL, 20.00 mmol) was added dropwise at 0°C. After addition, the mixture was reacted at 25°C for 1 hour. A solution of compound 3-aminopiperidine-1-tert-butylformate (2 mL, 10.49 mmol) in tetrahydrofuran (2 mL) was added to the above reaction system. After addition, the mixture was continued to react at 25°C for 16 hours. The formation of a principal point (Rf = 0.38, target compound) was monitored on a thin-layer chromatography plate (silica gel, ethyl acetate / petroleum ether volume ratio 1 / 3). Meanwhile, small new spots (Rf=0.44, isomer) were formed, leaving some of the starting material, 2,4-dichloro-5-trifluoromethylpyrimidine (Rf=0.66). The reaction mixture was concentrated. The resulting residue was purified by flash column chromatography (silica gel, ethyl acetate / petroleum ether gradient 0-11.5%) to obtain the white solid compound (3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-tert-butylformate (purity: 85%, 900 mg, 2.36 mmol, yield: 26%). LCMS(ESI):[M-56+H] + =325.2; 1 H NMR(400MHz,CDCl3):δ ppm 8.52-8.25(m,1H),5.58(br s,1H),3.96(m,1H),3.58(m,1H),3.31(m,3H),1.83(m,1H),1.61(m,3H),1.35(br d,J=12.3Hz,9H).

[0069] Step 2: 1-(benzenesulfonyl)-3-bromo-1H-pyrrolo[2,3-b]pyridine [ka] 3-Bromo-1H-pyrrolo[2,3-b]pyridine (100.00 g, 507.54 mmol) was dissolved in tetrahydrofuran (40 mL). Sodium tert-butoxide (58.50 g, 609.04 mmol) was added at 0°C. Then, benzenesulfonyl chloride (78 mL, 609.04 mmol) was added. The reaction mixture was stirred at 30°C for 1 hour. The reaction mixture was poured into ice water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phases were combined and dried over sodium sulfate. After filtration, the filtrate was concentrated to obtain the crude product 1-(benzenesulfonyl)-3-bromo-1H-pyrrolo[2,3-b]pyridine (170.00 g) as a yellow solid. LCMS(ESI):[M+H] + = 337.2.

[0070] Step 3: 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine [ka] Compound 1-(benzenesulfonyl)-3-bromo-1H-pyrrolo[2,3-b]pyridine (170.00 g, 504.15 mmol), bispinacol boronate (192.00 g, 756.23 mmol), and potassium acetate (98.95 g, 1.01 mol) were dispersed in 1,4-dioxane (1700 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (39.23 g, 50.42 mmol) was added at room temperature. The reaction mixture was heated to 100 °C and stirred for 16 hours. Concentration was performed. The residue was purified by flash column chromatography (silica gel, ethyl acetate / petroleum ether gradient 0-10%) to obtain the white solid compound 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (100.00 g, 260.23 mmol, yield: 52%). LCMS(ESI):[M+H] + = 385.2.

[0071] Step 4: (S)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-tert-butylcarboxylate [ka] Under nitrogen protection, tetra(triphenylphosphine)palladium (12.69 g, 10.98 mmol) was added to a solution of 1,4-dioxane (1400 mL), compound 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (46.00 g, 120.80 mmol), (3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-tert-butylformate (42.20 g, 109.82 mmol), and cesium carbonate (71.56 g, 219.63 mmol). The reaction system was heated to 100°C and reacted for 16 hours. The reaction mixture was cooled to room temperature. A sodium hydroxide aqueous solution (5M, 66 mL, 330.00 mmol) was added. The reaction mixture was heated to 70°C and stirred for 4 hours. After the reaction mixture cooled to room temperature, the pH was adjusted to 3 with dilute HCl (1M). Extraction was carried out with ethyl acetate (200 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain a yellow oily liquid (S)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-tert-butylcarboxylate (16.00 g, 34.60 mmol, yield: 32%). LCMS(ESI):[M+H] + = 463.3.

[0072] Step 5: (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (intermediate A) [ka] Compound (S)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-tert-butylcarboxylate (12.00 g, 25.95 mmol) was dissolved in dichloromethane (150 mL). m-chloroperoxybenzoic acid (purity: 85%, 6.32 g, 31.14 mmol) was added at 0°C. The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated. The residue was purified by flash column chromatography (silica gel, tetrahydrofuran / petroleum ether gradient 0-50%) to obtain the crude product. The crude product was purified again by flash column chromatography (C18, acetonitrile / water gradient 0-37%) to obtain the pure white solid product (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (purity: 90%, 5.00 g, 9.41 mmol, yield: 36%). LCMS(ESI):[M+H] + = 479.3.

[0073] Preparation of intermediate B: Methyl(3S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-chloro-1-carboxylate [ka] Step 1: Methyl(3S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-chloro-1-carboxylate (intermediate B) [ka] Compound (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (1.00 g, 1.88 mmol) was dissolved in tetrahydrofuran (12 mL). Under nitrogen protection, hexamethyldisilazane (439 μL, 2.07 mmol) and methyl chloroformate (948 μL, 12.28 mmol) were added at 0°C. The reaction mixture was stirred at 30°C for 16 hours. Saturated sodium bicarbonate solution (10 mL) was added. Extraction was performed with ethyl acetate (15 mL x 3). The organic phase was washed with a saturated salt solution (20 mL). Drying was performed over anhydrous sodium sulfate. Filtration and concentration were carried out. The residue was purified by flash column chromatography (silica gel, tetrahydrofuran / petroleum ether gradient 0-50%) to obtain the white solid compound methyl(3S)-3-(2-(1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-chloro-1-carboxylate (600 mg, 0.92 mmol, yield: 48%). LCMS(ESI):[M+H] + =555.2; 1 H NMR(400MHz,CDCl3) δ ppm 8.71-8.56(m,1H),8.51-8.32(m,1H),8.25(br s,1H),7.45-7.30(m,1H),5.70-5.53(m,1H),4.17(s,4H),3.84-3.70(m,1H),3.45(br s,3H),2.00(br s,1H),1.78(br s,1H),1.55-1.32(m,11H).

[0074] Preparation of intermediate C: (S)-3-methyl-4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-6-yl)morpholine [ka] Step 1: 1H-pyrrolo[2,3-b]pyridine-7-oxide [ka] Compound 1H-pyrrole[2,3-b]pyridine (35.00 g, 296.61 mmol) was dissolved in THF (1.20 L). m-chloroperoxybenzoic acid (purity: 85%, 90.00 g, 443.31 mmol) was added. The mixture was then stirred at 20°C for 16 hours. The system was a yellow suspension. The reaction substrate was concentrated, and half of the solvent was removed by spinning. The solid was filtered and washed with tetrahydrofuran (50 mL). The solid was dried under vacuum to obtain a white solid crude product (purity: 50%, 35.00 g). The crude product was used directly in the next step without purification. LCMS(ESI):[M+H] + = 135.1.

[0075] Step 2: (S)-3-methyl-4-(1H-pyrrolo[2,3-b]pyridine-6-yl)morpholine [ka] 1H-pyrrolo[2,3-b]pyridine-7-oxide (purity: 50%, 55.00 g, 205.07 mmol) was dissolved in acetonitrile (535 mL). Dimethyl sulfate (21 mL, 225.51 mmol) was added. The mixture was heated to 60°C and stirred for 16 hours. When the mixture cooled 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. Cooling and concentration were performed. The residue was separated and extracted with dichloromethane (200 mL) and 10% sodium carbonate aqueous solution (200 mL). The aqueous phase was extracted with dichloromethane (200 mL x 2). The organic phases were combined and dried over anhydrous magnesium sulfate. Concentration was performed. The residue was purified by flash column chromatography (silica gel, tetrahydrofuran / petroleum ether gradient 0-25%) to obtain a yellow solid (S)-3-methyl-4-(1H-pyrrolo[2,3-b]pyridine-6-yl)morpholine (8.64 g, 39.76 mmol, yield: 19%). LCMS(ESI):[M+H] + = 218.1.

[0076] 1 H NMR(400MHz,CD3OD) δ ppm 7.75(d,J=8.5 Hz,1H),7.03(d,J=3.3 Hz,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,1 H),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)

[0077] Step 3: (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridine-6-yl)-3-methylmorpholine [ka] Compound (S)-3-methyl-4-(1H-pyrrolo[2,3-b]pyridine-6-yl)morpholine (8.34 g, 38.39 mmol) was dissolved in dimethylformamide (40 mL). 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. Concentration was performed. Water (100 mL) was added to the residue. Extraction was carried out with dichloromethane (100 mL x 3). The organic phases were combined and then dried over magnesium sulfate. Filtration and concentration were performed to obtain the crude compound (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridine-6-yl)-3-methylmorpholine (14.70 g). LCMS(ESI):[M+H] + =344.0.

[0078] Step 4: (S)-4-(3-iodo-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-6-yl)-3-methylmorpholine [ka] Compound (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridine-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. The mixture was stirred at 0°C for 30 minutes. Benzenesulfonyl chloride (6.6 mL, 51.40 mmol) was added. The reaction mixture was stirred at 20°C for 2 hours. The mixture was then concentrated. The residue was purified by flash column chromatography (silica gel, tetrahydrofuran / petroleum ether gradient 0-40%) to obtain the yellow solid compound (S)-4-(3-iodo-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-6-yl)-3-methylmorpholine (4.60 g, 9.52 mmol, yield: 28%). LCMS(ESI):[M+H] + = 484.0.

[0079] Step 5: (S)-3-Methyl-4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

Chemical formula

[0080] Step 6: (S)-3-Methyl-4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

Chemical formula

[0081] Preparation of intermediate D: 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrole[2,3-b]pyridine-6-yl)morpholine [ka] Step 1: 4-(1H-pyrrole[2,3-b]pyridin-6-yl)morpholine [ka] Compound 1H-pyrrolo[2,3-b]pyridine-7-oxide (purity: 50%, 35.00 g, 0.13 mol) was dissolved in acetonitrile (250 mL). Dimethyl sulfate (14 mL, 0.14 mol) was added. The mixture was then stirred at 60°C for 16 hours. The reaction system was cooled to 0°C. Morpholine (230 mL, 2.61 mol) was then added. The mixture was then stirred at 60°C for 20 hours. The system was a yellow solution. The reaction system was cooled and concentrated. Dichloromethane (300 mL) and 10% sodium carbonate aqueous 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 phase was dried over magnesium sulfate and filtered. The filtrate was spin-dried to obtain 80 g of residue. The residue was purified by flash column chromatography (C18, acetonitrile / water gradient 0-100%) to obtain a yellow solid 4-(1H-pyrrole[2,3-b]pyridin-6-yl)morpholine (13.50 g, 66.44 mmol, yield: 51%). LCMS(ESI):[M+H] + = 204.2.

[0082] Step 2: 4-(3-iodo-1H-pyrrolo[2,3-b]pyridine-6-yl)morpholine [ka] Compound 4-(1H-pyrrole[2,3-b]pyridine-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. The resulting reaction mixture was stirred for 30 minutes. At 0°C, a solution of elemental iodine (12.10 g, 47.68 mmol) in dimethylformamide (50 mL) was added dropwise to the reaction mixture. The mixture was reacted at 20°C for 1 hour. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined and dried over magnesium sulfate. The mixture was filtered. The filtrate was spin-dried to obtain the brown, oily crude product 4-(3-iodo-1H-pyrrole[2,3-b]pyridine-6-yl)morpholine (11.80 g). The crude product was used directly in the next step of the reaction without purification. LC-MS(ESI):[M+H] + =330.0.

[0083] Step 3: 4-(3-iodo-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-6-yl)morpholine [ka] Compound 4-(3-iodo-1H-pyrrolo[2,3-b]pyridine-6-yl)morpholine (14.50 g, 44.06 mmol) was dissolved in tetrahydrofuran (145 mL). Sodium tert-butoxide (6.35 g, 66.08 mmol) was added at 0°C. The mixture was stirred for 30 minutes. Then, benzenesulfonyl chloride (15.50 g, 87.76 mmol) was added at 0°C. The reaction mixture was allowed to react at 20°C for 2 hours. The mixture was then concentrated under reduced pressure, and the solvent was removed by spinning. The residue was purified by flash column chromatography (silica gel, tetrahydrofuran / petroleum ether gradient 0-25%) to obtain compound 4-(3-iodo-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-6-yl-)morpholine (12.70 g, 27.06 mmol, yield: 61%). LCMS(ESI):[M+H] + = 470.0.

[0084] Step 4: 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-6-yl)morpholine [ka] Compound 4-(3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (5.50 g, 11.72 mmol) and compound 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (3.48 g, 15.24 mmol) were dissolved in xylene (100 mL). Under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (1.35 g, 1.17 mmol) and hexamethylditin (3 mL, 15.24 mmol) were added. Under nitrogen protection, the mixture was reacted at 100 °C for 2 hours and then at 140 °C for 14 hours. The system was a black suspension. The system was concentrated under reduced pressure to obtain a brown solid. The brown solid was purified by flash column chromatography (silica gel, the gradient of ethyl acetate / petroleum ether was 0 - 30%) to obtain compound 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (4.10 g, 6.12 mmol, yield: 52%). LCMS(ESI): [M+H] + =536.1。

[0085] Step 5: 4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-ol hydrochloride

Chemical formula

[0086] Step 6: 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrole[2,3-b]pyridine-6-yl)morpholine [ka] Compound 4-(6-morpholinyl-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-ol hydrochloride (2.20 g, 6.02 mmol) was dissolved in phosphorus oxychloride (40 mL). The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated. The resulting residue was purified by flash column chromatography (silica gel, ethyl acetate / petroleum ether gradient 0-90%) to obtain the yellow solid compound 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrole[2,3-b]pyridin-6-yl)morpholine (1.40 g, 2.92 mmol, yield of step 2: 48%). LCMS(ESI):[M+H] + =384.1.

[0087] 1H NMR (400MHz, DMSO-d6) δ ppm 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).

[0088] Preparation of intermediate E: (3-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-indole-7-yl)dimethylphosphine oxide [ka] Step 1: (1H-indole-7-yl)dimethylphosphine oxide [ka] Compounds 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(diphenylphosphinoxanthene)][2-amino-1,1-diphenyl]palladium(II) methanesulfonic acid dichloromethane adduct (20 mg, 0.02 mmol) were added at 25°C. The reaction system was heated to 100°C and reacted for 16 hours. The reaction system was cooled to room temperature and filtered. The filtrate was concentrated. The resulting residue was purified by flash column chromatography (silica gel, tetrahydrofuran / petroleum ether gradient 0-100%) to obtain the yellow solid compound (1H-indole-7-yl)dimethylphosphine oxide (220 mg, 1.08 mmol, yield: 11%). LCMS(ESI):[M+H] + =194.1.

[0089] Step 2: (3-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-indole-7-yl)dimethylphosphine oxide [ka] Compound (1H-indole-7-yl)dimethylphosphine oxide (220 mg, 1.08 mmol) and compound 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 reaction system was cooled to room temperature, poured into saturated sodium bicarbonate aqueous solution (20 mL), and extracted with ethyl acetate (15 mL x 2). The organic phases were combined and dried over magnesium sulfate. Filtration and concentration of the filtrate were performed. The residue was purified by preparative silica gel plate (with a volume ratio of petroleum ether / tetrahydrofuran of 1:2) to obtain a yellow oily compound (3-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-indole-7-yl)dimethylphosphine oxide (200 mg, 0.38 mmol, yield: 34%). LCMS(ESI):[M+H] + =374.0.

[0090] Preparation of intermediate F: The following intermediate F (7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-indole-6-nitrile) was prepared using the same method as in Example 4 of Patent WO2020 / 093011A1. [ka] Compound Intermediate F (9.21 g, pale yellow solid). LCMS(ESI):[M+H] + =401.2; 1H NMR (400MHz, DMSO-d6) δ ppm 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).

[0091] Preparation of intermediate G: 3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-6-formonitrile [ka] Step 1: 1H-pyrrolo[2,3-b]pyridine-6-formonitrile [ka] 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 a mixture of 1,1-bis(diphenylphosphino)ferrocenedichloropalladium and dichloromethane (829 mg, 1.02 mmol) were degassed in dimethylformamide (10 mL) and purged three times with nitrogen. The mixture was then stirred at 140 °C for 5 hours under nitrogen protection. The reaction mixture was diluted with ethyl acetate (50 mL) and washed sequentially with saturated sodium bicarbonate aqueous solution (100 mL) and saturated salt solution (100 mL x 2). The reaction mixture was dried over sodium sulfate and filtered. The filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, ethyl acetate / petroleum ether gradient of 10% to 33%) to obtain the white solid compound 1H-pyrrolo[2,3-b]pyridine-6-formonitrile (purity: 85%, 1.50 g, 8.91 mmol, yield: 44%). LCMS(ESI):[M+H] + = 144.2.

[0092] Step 2: 3-iodine-1H-pyrrolo[2,3-b]pyridine-6-formonitrile [ka] A solution of 1H-pyrrolo[2,3-b]pyridine-6-formonitrile (purity: 85%, 26.00 g, 154.44 mmol) and potassium hydroxide (22.93 g, 408.66 mmol) in dimethylformamide (150 mL) was cooled to 0°C. 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 subjected to suction filtration. The filtrate was spin-dried. The resulting crude product was washed three times with water (100 mL x 3) and dried under vacuum to obtain the crude compound 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-formonitrile (53.00 g). LCMS(ESI):[M+H] + =270.0.

[0093] Step 3: 3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-formonitrile [ka] A solution of 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-formonitrile (50.00 g, 148.68 mmol) in tetrahydrofuran (2.50 L) was cooled to 0°C, and sodium hydride (purity: 60%, 10.71 g, 267.63 mmol) was added under nitrogen protection. Then, benzenesulfonyl chloride (28 mL, 223.01 mmol) was added. The mixture was stirred at 25°C for 3 hours. Then, acetic acid (20 mL) and water (200 mL) were added at 0°C to quench the mixture. Tetrahydrofuran was removed from the solution by rotary evaporation. The precipitated solid was filtered and dried under vacuum to obtain the crude product. The crude product was pulped with methyl tert-butyl ether (100 mL) and filtered to obtain the white solid compound 3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-formonitrile (45.00 g, 110.04 mmol, yield: 63%). LCMS(ESI):[M+H] + = 410.0.

[0094] Step 4: 3-(2-methylthio-5-trifluoromethylpyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-formonitrile [ka] Under nitrogen protection, tetra(triphenylphosphine)palladium (1.27 g, 1.10 mmol) was added to a solution of 3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-formonitrile (5.00 g, 11.00 mmol), 4-chloro-2-methylthio-5-trifluoromethylpyrimidine (3.27 g, 14.30 mmol), and hexamethyltin (4.72 g, 14.30 mmol) in xylene (100 mL). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours, then heated to 140 °C and reacted for 16 hours. The reaction mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, tetrahydrofuran / petroleum ether gradient of 5%-10%) to obtain the yellow solid compound 3-(2-methylthio-5-trifluoromethylpyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-formonitrile (3.10 g, 6.52 mmol, yield: 59%). LCMS(ESI):[M+H] + = 476.2.

[0095] Step 5: 3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-6-formonitrile [ka] Compound 3-(2-methylthio-5-trifluoromethylpyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-formonitrile (200 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL). m-chloroperoxybenzoic acid (purity: 80%, 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 mixture. Extraction was performed with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated to obtain the yellow, oily crude compound 3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-6-formonitrile (230 mg). The crude product was used directly in the reaction in the next step. LCMS(ESI):[M+H] + = 508.0.

[0096] Preparation of intermediate H: 3,5-dimethyl-4-(3-(2-methylsulfonyl-5-trifluoromethylpyrimidine-4-yl)-1-benzenesulfonyl-1H-pyrrole[2,3-b]pyridine-6-yl) isoxazole [ka] Intermediate H was prepared using the same synthesis method as in Example 11 of Patent WO2019 / 143719.

[0097] Preparation of intermediate J: tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] Step 1: 6-chloro-3-iodo-1H-pyrrole[2,3-b]pyridine [ka] A solution of compound 6-chloro-1H-pyrrole[2,3-b]pyridine (5.00 g, 32.77 mmol) and potassium hydroxide (5.52 g, 98.31 mmol) in dimethylformamide (50 mL) was cooled to 0°C. Then, a solution of elemental iodine (8.32 g, 32.77 mmol) in dimethylformamide (50 mL) was added dropwise. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with 10% aqueous sodium sulfite solution (100 mL). The mixture was extracted with dichloromethane (100 mL x 3) and spin-dried. The crude product was washed with water (20 mL x 3) and filtered. The resulting solid was dried under vacuum to obtain the yellow solid compound 6-chloro-3-iodo-1H-pyrrole[2,3-b]pyridine (7.30 g, 23.60 mmol, yield: 72%). LCMS(ESI):[M+H] + =278.9;

[0098] Step 2: 6-Chloro-3-iodo-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine [ka] Sodium tert-butoxide (0.98 g, 10.23 mmol) was added to a solution of compound 6-chloro-3-iodo-1H-pyrrole[2,3-b]pyridine (2.00 g, 6.82 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 25°C for 30 minutes. The reaction mixture was then cooled to 0°C. Benzenesulfonyl chloride (1.81 g, 10.23 mmol) was added. The mixture was stirred at 25°C for 4 hours. Tetrahydrofuran was removed from the solution by rotary evaporation. Water (20 mL) was added to the residue. The solid was filtered to obtain the crude product. The crude product was pulped with methyl tert-butyl ether (10 mL) and filtered to obtain the white solid compound 6-chloro-3-iodo-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (2.55 g, 5.71 mmol, yield: 85%). LCMS(ESI):[M+H] + =418.9;

[0099] Step 3: tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] Under nitrogen protection, tetra(triphenylphosphine)palladium (0.28 g, 0.24 mmol) was added to a solution of the compounds 6-chloro-3-iodo-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (1.00 g, 2.39 mmol), tert-butyl(S)-3-((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (1.18 g, 3.11 mmol), and hexamethyltin (1.02 g, 3.11 mmol) in xylene (10 mL). Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 2 hours. Then, the reaction mixture was heated to 140 °C and reacted for 16 hours. The reaction mixture was spin-dried. The residue was purified by flash column chromatography (silica gel, ethyl acetate / petroleum ether gradient of 0-25%) to obtain the yellow solid compound tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (0.53 g, 0.74 mmol, yield: 31%). LCMS(ESI):[M+H] + = 637.3.

[0100] Example 1. (S)-4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 1) [ka] Step 1: tert-butyl(S)-3-((4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (150 mg, 0.31 mmol) was dissolved in acetonitrile (400 μL). Dimethyl sulfate (33 μL, 0.34 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. Then the reaction mixture was cooled to 0°C. After that, morphol (441 uL, 5.02 mmol) was added. The reaction mixture was then reacted at 80°C for 16 hours. Two batches of the same reaction mixture were cooled to room temperature and concentrated to obtain a brown, oily crude product, tert-butyl(S)-3-((4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (300 mg). LCMS(ESI):[M+H] + = 548.3

[0101] Step 2: (S)-4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine [ka] The compound tert-butyl(S)-3-((4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (purity: 55%, 300 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (895 μl, 12.05 mmol) was added. The mixture was then stirred at 20 °C for 16 hours. The reaction mixture was concentrated. The residue was purified by preparative HPLC to obtain the red solid (S)-4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (53.11 mg, 0.12 mmol, yield: 40%). LCMS(ESI):[M+H]+ =448.3; 1 H NMR(400MHz,CD3OD) δ ppm 8.60-8.47(m,2H),7.72(s,1H),6.79(br d,J=8.8Hz,1H),4.35(m,1H),3.91-3.76(m,5H),3.62-3.49(m,5H),3.12-2.91(m,2H),2.27-2.02(m,2H),1.95-1.69(m,2H).

[0102] The following compounds were prepared by reacting (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (intermediate A) with a suitable amine compound, using the same synthetic method as for synthesizing compound 1.

[0103] Example 2.4-(6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 2) [ka] Compound 2 (53.11 mg, red solid). LCMS(ESI):[M+H] + = 460.2.

[0104] 1H NMR (400MHz, CD3OD) δ ppm 8.66-8.41(m,2H) 7.66(s,1H) 6.53(br s,1H) 4.73(s,1H) 4.10(br s,1H) 3.83-3.95(m,2H) 3.55-3.69(m,1H) 3.55-3.69(m,1H) 3.42(br d,J=9.78Hz,1H) 3.25(br d,J=11.98Hz,1H) 2.92-3.04(m,1H) 2.55-2.71(m,2H) 1.95-2.23(m,3H) 1.75-1.88(m,1H) 1.51-1.72 (m, 2H)

[0105] Example 3. (S)-1-(3-(2-(ピペリジン-3-イルアミノ))-5-(トリフルオロメチル)ピリミジン-4-イル)-1H-ピロロ[2,3-b]ピリジン-6-イル)ピペリジン-4-オール (Compound 3)

change

[0106] 1 H NMR (400MHz, CD3OD), δ ppm 8.54-8.30(m,2H),7.60(s,1H),6.74(br s,1H),4.12-4.01(m,1H),4.07(m,2H),3.80-3.71(m,1H),3.16(br d,J=11.4Hz,1H),3.06(br t,J=10.9Hz,2H),2.87(br d,J=12.6Hz,1H),2.61-2.45(m,2H),2.12-1.95(m,1H),1.88(br dd,J=12.5,3.1Hz,2H),1.77-1.64(m,1H),1.62-1.40(m,4H)

[0107] Example 4. (S)-1-(3-(2-(piperidine-3-ylamino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)piperidine-4-yl)methanol (Compound 4) [ka] Compound 4 (55.55 mg, yellow solid). LCMS(ESI):[M+H] + = 476.3.

[0108] 1 H NMR(400MHz,CD3OD),δ ppm 8.68-8.37(m,2H),7.69(s,1H),6.82(br s,1H),4.39(br d,J=12.6Hz,2H),4.24-3.94(m,1H),3.46(d,J=6.4Hz,2H),3.25(br d,J=11.8Hz,1H),3.01-2.81(m,3H),2.68-2.51(m,2H),2.24-2.00(m,1H),1.88-1.50(m,6H),1.32(qd,J=12.3,3.9Hz,2H)

[0109] Example 5. N-((S)-piperidine-3-yl)-4-(6-(tetrahydro-1H-furan[3,4-c]pyrrole-5(3H)-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 5) [ka] Compound 5 (19.05 mg, yellow solid). LCMS(ESI):[M+H] + = 474.2.

[0110] 1H NMR(400MHz,CD3OD),δ ppm 8.51-8.29(m,2H),7.56(s,1H),6.45(br s,1H),3.90(m,3H),3.63-3.52(m,4H),3.40(m,2H),3.15(m,1H),3.02(m,2H),2.86(br d,J=12.9Hz,1H),2.60-2.42(m,2H),2.16-1.95(m,1H),1.78-1.68(m,1H),1.62-1.40(m,2H).

[0111] Example 6. 3-Methyl-1-(3-(2-(((S)-piperidine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)pyrrolidine-3-ol (Compound 6) [ka] Compound 6 (56.83 mg, yellow solid). LCMS(ESI):[M+H] + = 462.2.

[0112] 1 H NMR(400MHz,CD3OD),δ ppm 8.63-8.32(m,2H),7.63(s,1H),6.46(br s,1H),4.11(br s,1H),3.74-3.63(m,2H),3.60-3.54(m,1H),3.46(m,1H),3.26(m,1H),2.98(br s, 1H), 2.70-2.54 (m, 2H), 2.20-2.00 (m, 3H), 1.87-1.77 (m, 1H), 1.70-1.54 (m, 2H), 1.49 (s, 3H).

[0113] Example 7.4-(6-(2-oxa-7-azaspiro[4.5]decane-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (compound 7) [ka] Compound 7 (16.15 mg, yellow solid). LCMS(ESI):[M+H] + = 502.2.

[0114] 1 H NMR(400MHz,CD3OD):δ ppm 8.64-8.43(m,2H),7.69(s,1H),6.90-6.74(m,1H),4.12(br s,1H),3.99(q,J=7.6Hz,1H),3.88(m,1H),3.78(m,1H),3.65(br s,1H),3.60-3.54(m,1H),3.53-3.42(m,3H),3.30-3.22(m,1H),2.98(m,1H),2.64(m,2H),2. 20-2.06(m,1H),1.94(m,1H),1.88-1.80(m,1H),1.76(s,1H),1.75-1.66(m,5H),1.62(m,1H).

[0115] Example 8. (S)-4-(6-(2-oxa-6-azaspiro[3,4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 8) [ka] Compound 8 (9.35 mg, yellow solid). LCMS(ESI):[M+H] + = 474.2.

[0116] 1H NMR(400MHz,CD3OD):δ ppm 8.54(s,2H),7.65(s,1H),6.47(br d,J=8.3Hz,1H),4.76-4.73(m,2H),4.72-4.68(m,2H),4.32(br s,1H),3.79(s,2H),3.58-3.47(m,3H),3.27(br d,J=12.0Hz,1H),3.04-2.91(m,2H),2.36(t,J=6.9Hz,2H),2.26-2.14(m,1H),2.11-2.01(m,1H),1.91-1.81(m,1H),1.75(br d,J=10.5Hz,1H).

[0117] Example 9. (S)-4-(6-(2-oxa-8-azaspiro[4.5]decane-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 9) [ka] Compound 9 (23.92 mg, white solid). LCMS(ESI):[M+H] + = 502.3.

[0118] 1 H NMR(400MHz,CD3OD):δ ppm 8.65-8.43(m,2H),7.70(s,1H),6.89-6.76(m,1H),4.18-4.00(m,1H),3.92(t,J=7.2H z,2H),3.72-3.64(m,2H),3.63(s,2H),3.61-3.54(m,2H),3.30-3.21(m,1H),2.97(br d,J=12.8Hz,1H),2.68-2.55(m,2H),2.23-2.05(m,1H),1.91-1.79(m,3H),1.72(br t,J=5.4Hz,4H),1.67-1.57(m,2H).

[0119] Example 10. (S)-4-(6-(9-oxa-2-azaspiro[5.5]undecane-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 10) [ka] Compound 10 (10.64 mg, yellow solid). LCMS(ESI):[M+H] + = 516.3.

[0120] 1 H NMR(400MHz,CD3OD):δ ppm 8.49(br s,2H),7.66(s,1H),6.84-6.73(m,1H),4.20-4.10(m,1H),3.83-3.56(m,9H),3.05(br d,J=12.8Hz,1H),2.77-2.66(m,2H),2.20-2.09(m,1H),1.93-1.85(m,1H),1.77-1.69(m,3H),1.65-1.55(m,5H),1.51(m,2H).

[0121] Example 11. (S)-4-(6-(6-oxa-2-azaspiro[3,4]octan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 11) [ka] Compound 11 (19.51 mg, white solid). LCMS(ESI):[M+H] + = 474.3.

[0122] 1H NMR(400MHz,CD3OD):δ ppm 8.55(s,2H),7.68(s,1H),6.37(br d,J=8.0Hz,1H),4.34(br s,1H),4.03(s,4H),3.93(s,2H),3.89(t,J=7.0Hz,2H),3.61-3.36(m,1 H),3.31-3.23(m,1H),3.09-2.92(m,2H),2.24(t,J=6.9Hz,2H),2.18(br d,J=6.8Hz,1H),2.11-2.03(m,1H),1.92-1.83(m,1H),1.82-1.69(m,1H).

[0123] Example 12. (3S,4S)-3-methyl-8-(3-(2-(((S)-piperidine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrole[2,3-b]pyridine-6-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine (Compound 12) [ka] Compound 12 (14.98 mg, brown solid). LCMS(ESI):[M+H] + = 531.3.

[0124] 1 H NMR(400MHz,CD3OD):δ ppm 8.54(s,2H),7.71(s,1H),6.82(br d,J=8.8Hz,1H),4.41-4.25(m,2H),4.23-4.06(m,2H),3.96(d,J=9.0Hz,1H),3.84(d,J=9.0Hz,1H),3.49-3.63(m,1H) ,3.26-3.32(m,2H),2.95-3.23(m,4H),2.15-2.26(m,1H),2.03-2.13(m,1H),1.68-1.92(m,6H),1.31(d,J=6.5Hz,3H).

[0125] Example 13.4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1H-pyrrolo[13,3-b]pyridine-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (compound 13) [ka] Compound 13 (17.77 mg, black solid). LCMS(ESI):[M+H] + = 460.2.

[0126] 1 H NMR(400MHz,CD3OD):δ ppm 8.54(s,2H),7.66(s,1H),6.50(br d,J=8.5Hz,1H),4.72(s,1H),4.35(br s,1H),3.94-3.87(m,2H),3.62(d,J=9.8Hz,1H),3.54(br d,J=10.8Hz,1H),3.46-3.35(m,1H),3.33-3.25(m,2H),3.10-2.93(m,2H),2.27-2.1 4(m,1H),2.11-2.02(m,2H),2.02-1.96(m,1H),1.91-1.83(m,1H),1.82-1.70(m,1H).

[0127] Example 14. (S)-4-(6-(2-oxa-6-azaspiro[3,3]heptan-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 14) [ka] Compound 14 (27.03 mg, white solid). LCMS(ESI):[M+H] + = 460.2.

[0128] 1H NMR(400MHz,CD3OD),δ ppm 8.64-8.39(m,2H),7.67(s,1H),6.39(br s,1H),4.88-4.84(m,4H),4.22(s,4H),4.06(m,1H),3.27-3.23(m,1H),2.96(m,1H),2.69-2.55(m,2H),2.13(br s, 1H), 1.87-1.78 (m, 1H), 1.71-1.52 (m, 2H).

[0129] Example 15. (S)-4-(6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 15) [ka] Compound 15 (43.52 mg, yellow solid). LCMS(ESI):[M+H] + = 488.3.

[0130] 1H NMR(400MHz,CD3OD),δ ppm 8.51(m,2H),7.69(br s,1H),6.80(br s,1H),4.51(br s,4H),4.22(br s,1H),3.54(br s,4H),3.40(br s,1H),3.14(br s,1H), 2.83(br s,2H), 2.16(br s, 2H), 1.96(br s, 4H),1.76(br s,2H).

[0131] Example 16. (S)-4-(6-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 16) [ka] Compound 16 (3.52 mg, yellow solid). LCMS(ESI):[M+H] + = 488.2.

[0132] 1H NMR(400MHz,CD3OD),δ ppm 8.57(m,2H),7.71(br s,1H),6.77(br s,1H),4.20(br s,1H),4.00(m,2H),3.80(m,2H),3.70(m,2H),3.40(m,1H),3.10(m,1H) ,2.79(m,2H),2.28(m,4H),2.19(m,1H),1.92(m,2H),1.84-1.56(m,3H).

[0133] Example 17. (S)-4-(6-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 17) [ka] Compound 17 (27.05 mg, yellow solid). LCMS(ESI):[M+H] + = 488.2.

[0134] 1 H NMR(400MHz,CD3OD),δ ppm 8.68-8.38(m,2H),7.66(s,1H),6.38(m,1H),4.08(m,1H),3.84(m,2H),3.80-3 .72(m,4H),3.70-3.64(m,2H),3.26(m,1H),2.97(m,1H),2.62(m,2H),2.15(br s, 1H), 1.88-1.99 (m, 2H), 1.81 (m, 1H), 1.67 (m, 4H).

[0135] Example 18. 4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 18)

change

[0136] 1 H NMR (400MHz, CD3OD), δ ppm 8.55 (m, 2H), 7.70 (m, 1H), 6.74 (br s,1H),4.47-4.23(m,2H),4.03(m,1H),3.92-3.76(m,3H),3.66(m,1H),3.52(m,1H),3.27(m,2H),2.98(br s,2H),2.30-2.00(m,2H),1.92-1.68(m,2H),1.24(m,3H)

[0137] Example 19.4-(6-((R)-3-メチルモルホリニル)-1H-ピロロ[2,3-b]ピリジン-3-イル)-N-((S)-ピペリジン-3-イル)-5-(トリフルオロメチル)ピリミジン-2-アミン(Compound 19)

change

[0138] 1 H NMR (400MHz, CD3OD): δ ppm 8.55(m,2H),7.70(m,1H),6.74(br s,1H),4.47-4.23(m,2H),4.03(m,1H),3.92-3.76(m,3H),3.66(m,1H),3.52(m, 1H),3.27(m,2H),2.98(m,2H),2.30-2.00(m,2H),1.92-1.68(m,2H),1.25(m,3H)

[0139] Example 20. (S)-1-(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)piperidine-4-nitrile (Compound 20) [ka] Compound 20 (22.21 mg, yellow solid). LCMS(ESI):[M+H] + = 471.2.

[0140] 1 H NMR(400MHz,CD3OD):δ ppm 8.57(m,2H),7.71(m,1H),6.84(m,1H),4.11(m,1H),3.93(m,2H),3.49(m,2H) ,3.29(m,1H),3.05(m,2H),2.65(m,2H),2.09(m,3H),1.95(m,3H),1.64(m,2H)

[0141] Example 21. (S)-3-methyl-1-(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)azetidine-3-formonitrile (Compound 21) [ka] Compound 21 (24.60 mg, yellow solid). LCMS(ESI):[M+H] + = 457.2.

[0142] 1 H NMR(400MHz,CD3OD):δ ppm 8.57(m,2H),7.70(m,1H),6.43(m,1H),4.36(m,2H),4.01(m,3H),3.26(m,1H) ,2.97(m,1H),2.63(m,2H),2.22(m,1H),1.81(m,1H),1.76(s,3H),1.64(m,2H)

[0143] Example 22. (S)-4-(6-(1,4-oxazepan-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 22) [ka] Compound 22 (24.19 mg, yellow solid). LCMS(ESI):[M+H] + = 462.2.

[0144] 1 H NMR(400MHz,CD3OD):δ ppm 8.57(m,2H),7.65(m,1H),6.68(m,1H),4.10(m,1H),3.88(m,6H),3.72(m,2H) ,3.27(m,1H),2.96(m,1H),2.63(m,2H),2.04(m,3H),1.81(m,1H),1.64(m,2H)

[0145] Example 23. (S)-4-methyl-1-(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)piperidine-4-ol (Compound 23) [ka] Compound 23 (39.78 mg, yellow solid). LCMS(ESI):[M+H] + = 476.3.

[0146] 1 H NMR(400MHz,CD3OD):δ ppm 8.55(m,2H),7.69(m,1H),6.80(m,1H),4.36(m,1H),3.88(m,2H),3.52(m, 3H),3.31(m,1H),3.03(m,2H),2.09(m,2H),1.68-1.87(m,6H),1.28(s,3H)

[0147] Example 24. (S)-4-(6-(4-(oxetan-3-yl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 24) [ka] Compound 24 (8.06 mg, yellow solid). LCMS(ESI):[M+H] + = 503.2.

[0148] 1 H NMR(400MHz,CD3OD):δ ppm 8.55(m,2H),7.72(m,1H),6.79(m,1H),4.77-4.67(m,4H),4.36(m,1H),3. 66-3.56(m,7H),3.04(m,2H),2.53(m,4H),2.09(m,2H),1.88-1.77(m,2H)

[0149] Example 25. (S)-4-(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)thiomorpholine-1,1-dioxide (compound 25) [ka] Step 1: tert-butyl(S)-3-((4-(6-thiomorpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] (S)-3-(2-((1-(tert-butoxycarbonyl)piperidine-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrole[2,3-b]pyridine-7-oxide (300 mg, 0.627 mmol) was dissolved in acetonitrile (5 mL). Dimethyl sulfate (65 μL, 0.69 mmol) was added. The reaction mixture was heated to 70°C and stirred for 16 hours. The reaction mixture was cooled to 0°C. Thiomorpholine (951 μL, 10.03 mmol) was added. The reaction mixture was heated to 70°C and stirred for 20 hours. Concentration was performed. The residue was purified by flash column chromatography (silica gel, ethyl acetate / petroleum ether gradient 0-85%) to obtain a yellow solid tert-butyl(S)-3-((4-(6-thiomorpholinyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (170 mg, 0.30 mmol, yield: 48%). LCMS(ESI):[M+H] + = 564.3.

[0150] Step 2: tert-butyl(S)-3-((4-(6-(1,1-dioxothiomorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] The compound tert-butyl(S)-3-((4-(6-thiomorpholinyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (160 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL). Osmart potassium dihydrate (5 mg, 14 mL) and N-methylmorpholine oxide (133 mg, 1.14 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added. Extraction was performed with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated to obtain the crude product tert-butyl(S)-3-((4-(6-(1,1-dioxothiomorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (100 mg). LCMS(ESI):[M+H] + = 596.2.

[0151] Step 3: (S)-4-(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)thiomorpholine-1,1-dioxide [ka] The compound tert-butyl(S)-3-((4-(6-(1,1-dioxothiomorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (100 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 mL, 13.46 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated. Ammonium hydroxide (1 mL) was added. The mixture was concentrated again. The residue was purified by preparative HPLC to obtain a gray solid (S)-4-(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)thiomorpholine-1,1-dioxide (41.54 mg, 84 umol, yield: 50%). LCMS(ESI):[M+H] + =496.2; 1 H NMR(400MHz,CD3OD):δ ppm 8.56(m,2H),7.75(s,1H),6.93(br d,J=8.5Hz,1H),4.33(br s,1H),4.23(br s,4H),3.53(br d,J=12.3Hz,1H),3.31-3.22(m,1H),3.19-3.13(m,4H),3.04-2.92(m,2H), 2.24-2.16(m,1H),2.11-2.03(m,1H),1.89-1.83(m,1H),1.79-1.71(m,1H).

[0152] Example 26. N-((S)-6,6-dimethylpiperidine-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 26) [ka] Step 1: N-((S)-6,6-dimethylpiperidine-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine [ka] Compound (S)-6,6-dimethylpiperidine-3-amine (purity: 55%, 1.56 g, 6.69 mmol) and diisopropylethylamine (2 mL, 12.90 mmol) were added to a solution of compound (S)-3-methyl-4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-6-yl)morpholine (750 mg, 1.29 mmol) in dichloromethane (13 mL). The reaction system was stirred at 25°C for 2 hours. Concentration was performed. The residue was purified by preparative HPLC to obtain a yellow, oily N-((S)-6,6-dimethylpiperidine-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (400 mg, 0.64 mmol, yield: 49%). LCMS(ESI):[M+H] + = 630.3.

[0153] Step 2: N-((S)-6,6-dimethylpiperidine-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine [ka] The compound N-((S)-6,6-dimethylpiperidine-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (750 mg, 0.89 mmol) was dissolved in 1,4-dioxane (5 mL). A sodium hydroxide aqueous solution (4 M, 1787 uL, 7.15 mmol) was added. After the addition, the mixture was reacted at 100°C for 1 hour. After cooling, the pH was adjusted to 7 with hydrochloric acid. The mixture was concentrated. The residue was purified by preparative HPLC to obtain the white solid compound N-((S)-6,6-dimethylpiperidine-3-yl)-4-(6-(S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (35.91 mg, 73 umol, yield: 8%). LCMS(ESI):[M+H] + =490.3; 1 H NMR(400MHz,CD3OD):δ ppm 8.67-8.52(m,1H),8.48(br s,1H),7.70(s,1H),6.80-6.70(m,1H),4.41(br d,J=6.2Hz,1H),4.13-3.92(m,2H),3.91-3.80(m,3H),3.66(m,1H),3.31-3.22(m,1H),3.16-3.07(m,1H),2.89-2.7 5(m,1H),2.11-1.93(m,1H),1.84-1.64(m,2H),1.60-1.49(m,1H),1.24(d,J=6.4Hz,3H),1.22(s,3H),1.19(s,3H).

[0154] Example 27. (S)-4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 27) [ka] Step 1: tert-butyl(S)-3-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] The intermediate tert-butyl(S)-3-((4-(6-chloro-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (0.30 g, 0.60 mmol), compound 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (0.19 g, 0.91 mmol), and aqueous sodium carbonate solution (1 M, 1810 uL, 1.81 mmol) were dissolved in 1,4-dioxane (10.00 mL). Under nitrogen protection, 1,1-bis(diphenylphosphin)ferrocenedichloropalladium (0.04 g, 0.06 mmol) was added. The reaction system was heated to 100 °C and reacted for 12 hours. The reaction system was cooled to room temperature and concentrated. The resulting residue was purified by flash column chromatography (silica gel, ethyl acetate / petroleum ether gradient 0-70%) to obtain the white solid compound tert-butyl(S)-3-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (0.22 g, 0.40 mmol, yield: 67%). LCMS(ESI):[M+H] + = 545.2.

[0155] Step 2: (S)-4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine [ka] The compound tert-butyl(S)-3-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (75 mg, 0.14 mmol) was dissolved in dichloromethane (300 uL). Trifluoroacetic acid (0.09 mL, 1.38 mmol) was added at room temperature. The reaction mixture was stirred at 25°C for 12 hours. Concentration was performed. The resulting residue was purified by preparative HPLC to obtain the white solid compound (S)-4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (28.86 mg, 63 umol, yield: 45%). LCMS(ESI):[M+H] + = 445.2.

[0156] 1 H NMR(400MHz,CD3OD) δ ppm 8.58(m,2H),7.97(s,1H),7.48(d,J=7.6Hz,1H),6.70(s,1H),4.39(m,2H),4.29(s,1H),3.98(t,J=5.6Hz,2H),3.49(d, J=8.4Hz,1H),3.22(s,1H),2.92(t,J=10.8Hz,2H),2.75(d,J=1.8Hz,2H),2.19(s,1H),2.01(s,1H),1.93-1.64(m,2H).

[0157] Example 28. (S)-N-(piperidine-3-yl)-4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amineformate (Compound 28) [ka] Step 1: tert-butyl(S)-3-((4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] tert-butyl(S)-3-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (70 mg, 0.13 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (10 mL). Wet palladium carbon (content: 10%, 0.1 g) was added. The reaction mixture was stirred and the reaction was carried out at 25°C for 12 hours in hydrogen at 15 psi. The reaction mixture was filtered and concentrated to obtain the brown, oily product tert-butyl(S)-3-((4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (60 mg, 0.11 mmol, yield: 77%). LCMS(ESI):[M+H] + = 547.3.

[0158] Step 2: (S)-N-(piperidine-3-yl)-4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine [ka] The compound tert-butyl(S)-3-((4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL). 1,4-dioxane solution (4 M, 200 uL, 0.80 mmol) was added dropwise at 25°C. After the addition, the reaction mixture was stirred at 25°C for 1 hour and then concentrated. The resulting residue was purified by preparative HPLC to obtain the yellow solid compound (S)-N-(piperidine-3-yl)-4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (formate, 24.98 mg, 51 umol, yield: 46%). LCMS(ESI):[M+H] + = 447.3.

[0159] 1 H NMR(400MHz,CD3OD):δ ppm 8.79-8.59(m,3H),7.95(m,1H),7.20(m,1H),4.35(m,1H),4.12-4.09(m,2H),3. 66-3.60(m,3H),3.33(m,1H),3.10-2.96(m,3H),2.23(m,1H),2.10-1.78(m,7H).

[0160] The same chloro intermediate, tert-butyl(S)-3-((4-(6-chloro-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate, was coupled with other substrates (and further reduced as necessary) to prepare the following compounds using the same method as for synthesizing compound 28.

[0161] Example 29. N-((S)-piperidine-3-yl)-4-(6-(tetrahydrofuran-3-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amineformate (Compound 29) [ka] Compound 29 (12.13 mg, yellow solid). LCMS(ESI):[M+H] + =433.1; 1 H NMR(400MHz,CD3OD):δ ppm 8.76-8.49(m,2H),8.35(br s,1H),7.91(m,1H),7.18(m,1H),4.14-3.64(m,6H),3.36(m,1H),2.96( m,1H),2.63(m,2H),2.34-2.21(m,2H),1.77-1.57(m,2H),1.56(m,2H).

[0162] Compound 29 was separated by SFC (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm), mobile phase: Phase A is carbon dioxide, Phase B is 0.1% ammonium hydroxide / methanol, with Phase B maintained at 30%, flow rate: 60 ml / min). The two components were then purified by preparative HPLC to obtain target compound 107 and compound 108 (both formates).

[0163] Example 107. Chiral monomer (compound 107) having a short appearance time after chiral resolution of compound 29. [ka] Compound 107 (7.11 mg, yellow solid). LCMS(ESI):[M+H] + =432.9; SFC analysis (column: cellulose 2 (150 mm × 4.6 mm), 5 μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / methanol; gradient: phase B is 5% to 40% within 5 minutes, 40% phase B is maintained for 2.5 minutes, 5% phase B is maintained for 2.5 minutes, flow rate: 2.5 ml / min): RT = 6.763 min, de = 100%; 1H NMR(400MHz,CD3OD) δ ppm 8.77-8.35(m,2H),7.83(s,1H),7.41-7.20(m,1H),7.11(br s,1H),4.09(br t,J=8.0Hz,2H),4.01(td,J=8.1,5.0Hz,1H),3.92-3.79(m,2H),3.69-3.52(m,1H),3.37-3.27(m,1H),3.03(br s,1H),2.80-2.63(m,2H),2.39-2.26(m,1H),2.25-2.14(m,1H),2.12-1.99(m,1H),1.95-1.77(m,1H),1.73-1.46(m,2H).

[0164] Example 108. Chiral monomer (compound 108) with a long appearance time after chiral resolution of compound 29. [ka] Compound 108 (7.43 mg, white solid). LCMS(ESI):[M+H] + =432.9; SFC analysis (column: cellulose 2 (150 mm × 4.6 mm), 5 μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / methanol; gradient: phase B is 5% to 40% within 5 minutes, 40% phase B is maintained for 2.5 minutes, 5% phase B is maintained for 2.5 minutes, flow rate: 2.5 ml / min): RT = 7.118 min, de = 93.17%; 1H NMR(400MHz,CD3OD) δ ppm 8.75-8.33(m,2H),7.83(s,1H),7.39-7.18(m,1H),7.10(br s,1H),4.15-3.95(m,3H),3.92-3.80(m,2H),3.68-3.53(m,1H),3.30(m,1H),2.91(br d,J=12.5Hz,1H),2.64-2.50(m,2H),2.39-2.26(m,1H),2.20(dq,J=12.3,7.8Hz,1H),2.07(dt,J=15.1,7.5Hz,1H),1.75(br d,J=12.1Hz,1H),1.64-1.42(m,2H).

[0165] Example 30. N-((S)-piperidine-3-yl)-4-(6-(tetrahydropyran-2-yl)-1H-pyrrolo-[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-amineformate [ka] Compound 30 (12.19 mg, white solid). LCMS(ESI):[M+H] + = 447.2.

[0166] 1 H NMR(400MHz,DMSO-d6):δ ppm 12.32(br s,1H),8.78-8.56(m,2H),8.34(br s,1H),7.91(m,2H),7.35-7.27(m,1H),4.46(m,1H),4.06(m,3H),3.20(m,1H),2.94(m,1H),2.60(m,2H),1.91(m,3H),1.61-1.54(m,7H)

[0167] Example 31.4-(6-(3-oxabicyclo[4.1.0]heptan-6-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amineformate (Compound 31) [ka] Compound 31 (2.14 mg, yellow solid). LCMS(ESI):[M+H] + = 459.2.

[0168] 1H NMR(400MHz,CD3OD):δ ppm 8.77-8.56(m,3H),7.93(m,1H),7.25(m,1H),4.63(m,1H),4.25(m,1H),4.00(m,1H),3.67(m,1H),3.52-3.33(m,2 H),3.27(m,1H),2.86(m,2H),2.58(m,1H),2.19(m,2H),2.00(m,1H),1.77-1.72(m,3H),1.35(m,1H),1.05(m,1H).

[0169] Example 32.4-(6-(2-oxo-5-azabicyclo[2.2.2]octan-5-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (compound 32) [ka] Step 1: tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]octan-5-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] In a nitrogen cabinet, bis(tri-tert-butylphosphine)palladium (8 mg, 0.02 mmol) was added to a suspension of the compounds tert-butyl(3S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (100 mg, 0.16 mmol), 2-oxa-5-azabicyclo[2.2.2]octane(oxalate, 99 mg, 0.31 mmol), and sodium bicarbonate (132 mg, 1.57 mmol) in 1,4-dioxane (1500 uL). The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was filtered. The resulting mother solution was concentrated to 1 mL. The solution was used directly in the reaction in the next step. LCMS(ESI):[M+H] + = 714.3.

[0170] Step 2: tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]octan-5-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] An aqueous solution of sodium hydroxide (2M, 420uL, 0.84 mmol) was added to a solution of the above compound tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]octan-5-yl)-1-(benzenesulfonyl)-1H-pyrrole[2.3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate in 1 mL of 1,4-dioxane. The reaction mixture was then heated to 100°C and stirred for 1 hour. Water (10 mL) was added to the mixture. Extraction was then carried out with ethyl acetate (10 mL x 2). The organic phase was dried over sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude compound was separated by preparative silica gel plate (volume ratio of silica gel, petroleum ether / tetrahydrofuran was 1:1) to obtain the yellow oily compound tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]octan-5-yl)-1H-pyrrole[2.3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (28 mg, 0.05 mmol, two-step yield: 31%). LCMS(ESI):[M+H] + = 574.3.

[0171] Step 3: 4-(6-(2-oxo-5-azabicyclo[2.2.2]octan-5-yl)-1H-pyrrole[2.3-b]pyridine-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine [ka] The compound tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]octan-5-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (28 mg, 0.05 mmol) was dissolved in dichloromethane (100 μL). Trifluoroacetic acid (36 μL, 0.49 mmol) was added. The reaction mixture was stirred at 20°C for 2 hours. After the reaction, the reaction mixture was directly concentrated and dried to obtain the crude product. The crude product was purified by preparative HPLC to obtain the yellow solid compound 4-(6-(2-oxo-5-azabicyclo[2.2.2]octan-5-yl)-1H-pyrrole[2.3-b]pyridine-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (4.52 mg, 9.6 umol, yield: 16%). LCMS(ESI):[M+H] + = 474.2.

[0172] 1 H NMR(400MHz,CD3OD):δ ppm 8.75-8.50(m,2H),7.66(m,1H),6.54(m,1H),4.67(m,1H),4.30(m,1H),4.18-4.13(m,3H),3.90(m,1) H),3.64(m,1H),3.52-3.48(m,1H),3.22(m,1H),2.93(m,2H),2.21-2.02(m,5H),1.84-1.75(m,3H).

[0173] The same chloro intermediate, tert-butyl(3S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate, was coupled with other substrates and, after deprotection, the following compounds were prepared using the same method as for synthesizing compound 32.

[0174] Example 33. N-((S)-piperidine-3-yl)-5-(trifluoromethyl)-4-(6-((R)-3-(trifluoromethyl)morpholinyl)-1H-pyrrole[2,3-b]pyridine-3-yl)pyrimidine-2-amine (Compound 33) [ka] Compound 33 (3.92 mg, yellow solid). LCMS(ESI):[M+H] + = 516.3.

[0175] 1 H NMR(400MHz,CD3OD):δ ppm 8.77-8.54(m,2H),7.73(m,1H),6.79(m,1H),5.30(m,1H),4.66(m,1H),4.30(m,2H),4.06-3.83(m,2H) ,3.66(m,1H),3.52-3.43(m,2H),3.27(m,1H),2.94(m,2H),2.19(m,1H),2.04(m,1H),1.82-1.76(m,2H)

[0176] Example 34.4-(6-(6-oxo-3-azabicyclo[3.1.1]heptan-3-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (compound 34) [ka] Compound 34 (2.05 mg, yellow solid). LCMS(ESI):[M+H] + = 460.2.

[0177] 1H NMR(400MHz,CD3OD):δ ppm 8.75-8.50(m,2H),7.69(m,1H),6.66(m,1H),4.83(m,2H),4.33(m,1H),3.90-3.72( m,4H),3.55(m,1H),3.27(m,1H),2.99(m,2H),2.21-2.04(m,3H),1.89-1.75(m,3H).

[0178] Example 43. (1R,4R,7R)-N-(4-(6-morpholinyl-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)-2-azabicyclo[2.2.1]heptan-7-amineformate (Compound 43) [ka] Compound 43 (2.01 mg, white solid). LCMS(ESI):[M+H] + = 460.2.

[0179] 1 H NMR(400MHz,CD3OD) δ ppm 8.56(m,3H),7.74(s,1H),6.83(m,1H),4.25-4.06(m,1H),3.86(m,4H),3.63-3.4 9(m,5H),3.07(m,1H),2.80(m,1H),2.13(m,2H),1.95-1.79(m,1H),1.67(m,1H). 1.28(m,1H),

[0180] Example 44. (S)-N-(4-(6-morpholinyl-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)quinin-3-amineformate (Compound 44) [ka] Compound 44 (22.76 mg, gray solid). LCMS(ESI):[M+H] + = 474.1.

[0181] 1 H NMR(400MHz,CD3OD) δ ppm 8.78-8.32(m,3H),7.71(m,1H),6.77(m,1H),4.51(s,1H),3.90-3.71(m,5H),3.59-3.49(m ,4H),3.31(s,4H),3.21(m,1H),2.42(s,1H),2.27(s,1H),2.14-2.00(m,2H),1.89(s,1H).

[0182] Example 60. (S)-N-(6,6-dimethylpiperidine-3-yl)-4-(6-morpholinyl-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 60) [ka] Compound 60 (28.88 mg, gray solid). LCMS(ESI):[M+H] + =476.3;

[0183] 1 H NMR(400MHz,CD3OD) δ ppm 8.78-8.35(m,2H),7.71(s,1H),6.80(s,1H),4.03(s,1H),3.92-3.79(m,4H),3.63-3.48(m,4H),3.17- 3.06(m,1H),2.87(m,1H),2.03(s,1H),1.86-1.64(m,2H),1.62-1.49(m,1H),1.23(s,3H),1.20(s,3H).

[0184] (S)-3-methyl-4-(3-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-6-yl)morpholine was used as a starting material and reacted with the corresponding amine to synthesize the following compounds.

[0185] Example 69.4-(6-((S)-3-methylmorpholine)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-((3S,6S)-6-methylpiperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 69) [ka] Compound 69 (51.77 mg, yellow solid). LCMS(ESI):[M+H] + = 476.2.

[0186] 1 H NMR(400MHz,CD3OD) δ ppm 8.61-8.30(m,2H),7.70(br s,1H),6.73(m,1H),4.42-4.25(m,2H),4.03(m,1H),3.89-3.82(m,3H),3.67-3.64(m,2H),3.30-3.25(m,2 H),2.78(m,1H),2.32(m,1H),2.10(m,1H),1.69-1.66(m,2H),1.36(d,J=6.8Hz,3H),1.24(d,J=6.8Hz,3H)

[0187] Example 70. (S)-N-(4-(6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)-4-azaspiro[2.5]octane-6-amineformate (Compound 70) [ka] Compound 70 (32.21 mg, white solid). LCMS(ESI):[M+H] + = 488.2.

[0188] 1H NMR(400MHz,CD3OD) δ ppm 8.61-8.53(m,3H),7.70(br s,1H),6.74(m,1H),4.44(m,1H),4.35(m,1H),4.03(m,1 H),3.89-3.82(m,3H),3.67-3.66(m,1H),3.40-3.25(m,2H),3.01(m,1H),2.20(m,1 H),1.90(m,1H),1.88(m,1H),1.62(m,1H),1.24(d,J=6.4Hz,3H),0.88-0.72(m,4H)

[0189] Example 71. N-((S)-5,5-difluoropiperidine-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 71) [ka] Compound 71 (3.87 mg, white solid). LCMS(ESI):[M+H] + = 498.2.

[0190] 1 H NMR(400MHz,CD3OD) δ ppm 8.61-8.54(m,2H),7.72(br s,1H),6.73(m,1H),4.41(m,2H),4.02(m,1H),3.89-3.82(m,3H),3.67-3.66(m,1H),3 .25(m,2H),3.21(m,1H),2.88(m,1H),2.61(m,2H),2.07(m,1H),1.24(d,J=6.4Hz,3H).

[0191] Example 72. 4-(6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-((3S,5R)-5-methylpiperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 72) [ka] Compound 72 (7.67 mg, white solid). LCMS(ESI):[M+H] + = 476.2.

[0192] 1 H NMR(400MHz,CD3OD) δ ppm 8.61-8.50(m,2H),7.70(br s,1H),6.75(m,1H),4.42(m,1H),4.29(m,1H),4.02(m,1H),3.89-3.82(m,3H) 3.67-3.66(m,1H) 3.46-3.21(m,3H),3.11(m,1H),2.55(m,1H),2.28-2.23(m,2H),1.86(m,1H),1.24(m,3H),1.00(d,J=6.0Hz,3H)

[0193] Example 73. N-((3S,5S)-5-fluoropyridine-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 73) [ka] Compound 73 (21.65 mg, white solid). LCMS(ESI):[M+H] + =480.2;

[0194] 1 H NMR(400MHz,CD3OD) δ ppm 8.61-8.50(m,2H),7.72(br s,1H),6.73(m,1H),4.64(m,1H),4.41(m,1H),4.02(m,2H),3.89-3.82(m,3H),3.67-3.66(m,1H),3.26-3 .21(m,2H),2.97-2.88(m,2H),2.68(m,1H),2.55-2.45(m,1H),1.96-1.72(m,1H),1.24(d,J=6.8Hz,3H).

[0195] Example 74. N-((3S,5R)-5-fluoropyridine-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 74) [ka] Compound 74 (4.56 mg, white solid). LCMS(ESI):[M+H] + =480.2;

[0196] 1 H NMR(400MHz,CD3OD) δ ppm 8.61-8.50(m,2H),7.71(br s,1H),6.75(m,1H),4.64(m,1H),4.40(m,1H),4.02(m,1H),3.89-3.82(m,3H),3.67-3.66(m,1H ),3.26(m,3H),3.17(m,1H),2.78-2.68(m,2H),2.43(m,1H),1.92(m,1H),1.24(d,J=6.8Hz,3H).

[0197] Example 75. 4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amineformate (Compound 75) [ka] Step 1: tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] A solution of the compound tert-butyl(S)-3-((4-(6-((S)-3-methylmorpholinyl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (0.50 g, 0.71 mmol) in acetonitrile (20 mL) was cooled to -20°C. Then, a solution of 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanbis(tetrafluoroborate) (0.76 g, 2.14 mmol) in acetonitrile (5 mL) was slowly added dropwise. The temperature was controlled to below -20°C. The reaction mixture was stirred at -20°C for 1 hour. Then, saturated sodium sulfite aqueous solution (30 mL) was added at -20°C for quenching. The reaction mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated salt solution (30 mL) and dried over anhydrous sodium sulfate. Suction filtration and spin drying were performed. The crude product was purified by flash column chromatography (silica gel, ethyl acetate / petroleum ether gradient 0-50%) to obtain the oily brown compound tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (60 mg, 0.08 mmol, yield: 12%). LCMS(ESI):[M+H] + = 720.3.

[0198] Step 2: tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate [ka] A sodium hydroxide aqueous solution (4M, 0.21 mL, 0.83 mmol) was added to a solution of the compound tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (75 mg, 0.10 mmol) in 1,4-dioxane (3 mL). The mixture was stirred at 100°C for 30 minutes. Then, water (3 mL) was added. The reaction mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate. Vacuum filtration and spin drying were performed to obtain the oily brown crude compound tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (60 mg). LCMS(ESI):[M+H] + = 580.3.

[0199] Step 3: 4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine [ka] A solution of the compound tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate (60 mg, 0.10 mmol) in dichloromethane (2 mL) was cooled to 0°C. A solution of hydrogen chloride in dioxane (4 M, 0.52 mL, 2.08 mmol) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was spin-dried and purified by preparative HPLC to obtain the white solid compound 4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (formate, 11.68 mg, 22 umol, yield: 22%). LCMS(ESI):[M+H] + =480.2; 1 H NMR(400MHz,CD3OD) δ ppm 8.76-8.32(m,3H),7.85(s,1H),4.29(s,1H),4.09(td,J=3.2,6.4Hz,1H),4.01-3.87(m,2H),3.85-3.74(m,1H),3.67(dd,J=3.3,11.2Hz,1H) ,3.56-3.40(m,3H),3.25(d,J=12.3Hz,1H),3.04-2.86(m,2H),2.20(s,1H),2.05(d,J=14.3Hz,1H),1.94-1.65(m,2H),1.21(d,J=6.6Hz,3H)

[0200] Example 101. (S)-N-(piperidine-3-yl)-4-(6-(pyrrolidine-1-yl)-1H-indole-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 101, Compound 213 in Patent CN2017 / 80057760.8) [ka] Compound 213 (116.75 mg) of the yellow solid compound of patent CN2017 / 80057760.8 was synthesized using the same method as in Example 49 of patent CN2017 / 80057760.8; LC-MS:[M+H] + =431.2; 1 H NMR:(400MHz,CD3OD):δ ppm 8.47(s,1H),8.16(br s,1H),7.65(bs,1H),6.67(m,1H),6.59(m,1H),4.23(br s,1H),3.40(m,1H),3.30-3.11(m,5H),2.91-2.78(m,2H),2.25-1.86(m,6H),1.78-1.60(m,2H).

[0201] The same chloro intermediate, tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate, was coupled with other substrates and, using the same method as for synthesizing compound 32, the following compounds were prepared after deprotection.

[0202] Example 103. 4-(6-(3-oxo-6-azabicyclo[3.1.1]heptan-6-yl)-1H-pyrrole[2.3-b]pyridine-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amineformate (Compound 103) [ka] Compound 103 (33.22 mg, yellow solid). LCMS(ESI):[M+H] + =460.2;

[0203] 1H NMR(400MHz,CD3OD) δ ppm 8.56(s,3H),7.70(br s,1H),6.50(br d,J=8.5Hz,1H),4.51-4.28(m,5H),3.79(d,J=10.3Hz,2H),3.55(br d,J=10.1Hz,1H),3.29(br s,1H),3.10-2.95(m,2H),2.82(q,J=6.6Hz,1H),2.26-2.03(m,2H),1.97(d,J=8.1Hz,1H),1.92-1.69(m,2H).

[0204] Example 104.4-(6-((S)-3-エチルモルホリニル)-1H-ピロール[2,3-b]ピリジン-3-イル)- N-((S)-ピペリジン-3-イル)-5-(トリフルオロメチル)ピリミジン-2-アミンホルマート (Compound 104)

change

[0205] 1 H NMR (400 MHz, CD3OD) δ ppm 8.65-8.37(m,3H),7.69(s,1H),6.71(br d,J=8.6Hz,1H),4.29(br s,1H),4.15(br s,1H),4.03-3.92(m,3H),3.75-3.60(m,2H),3.49(br d,J=11.1Hz,1H),3.26(dt,J=3.8,12.7Hz,2H),2.93(br t,J=9.8Hz,2H),2.19(br s,1H),2.03(br d,J=14.5Hz,1H),1.95-1.80(m,2H),1.76-1.62(m,2H),0.96(t,J=7.4Hz,3H)

[0206] The same chloro intermediate, tert-butyl(S)-3-((4-(6-chloro-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-carboxylate, was coupled with other substrates (and further reduced as necessary) to prepare the following compounds using the same method as for synthesizing compound 27.

[0207] Example 105. (S)-4-(6-(2,5-dihydropyran-3-yl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (compound 105) and a mixture of (S)-4-(6-(4,5-dihydropyran-3-yl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (compound 106) [ka] A mixture of compound 105 and compound 106 (2.29 mg, white solid). LCMS (ESI): [M+H] + =476.2;

[0208] Compound 105 accounted for 60.7% in HPLC. Compound 106 accounted for 38.2% in HPLC.

[0209] 1 H NMR(400MHz,DMSO-d6) δ ppm 8.79-8.40(m,2H),7.94-7.86(m,2H),7.76-6.79(m,2H),5.04(br s,1H),4.81(br s,1H),4.50(t,J=9.5Hz,1H),4.21-3.82(m,2H),3.24(br s,1H),3.12-2.99(m,2H),2.83(br d,J=11.5Hz,1H),2.46-2.41(m,1H),2.02-1.89(m,1H),1.67(br d,J=4.2Hz,1H),1.47(br d,J=8.5Hz,2H).

[0210] Example 109. (S)-4-(6-(3,4-dihydropyran-6-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 109) [ka] Compound 109 (5.20 mg, white solid). LCMS(ESI):[M+H] + =445.2; 1 H NMR(400MHz,DMSO-d6) δ ppm 12.78-11.84(m,1H),8.64-8.51(m,1H),8.78(d,J=8.2Hz,1H),7.91(br d,J=4.5Hz,1H),7.80(br t,J=7.2Hz,1H),7.44(dd,J=17.7,8.4Hz,1H),6.00(br s,1H),4.24-4.11(m,2H),3.89(br s,1H),3.07(br t,J=10.9Hz,1H),2.81(br s,1H),2.47-2.39(m,2H),2.29-2.18(m,2H),2.03-1.77(m,3H),1.71-1.59(m,1H),1.45(br s,2H).

[0211] Example 110. 4-(6-(3-methyltetrahydropyran-4-yl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amineformate (Compound 110) [ka] Compound 110 (6.08 mg, white solid). LCMS(ESI):[M+H] + =461.2; 11H NMR (400MHz, CD3OD) δ ppm 8.90-8.40(m,3H),7.95(s,1H),7.18(d,J=8.0Hz,1H),4.31(s,1H),4.08(d d,J=4.1,11.4Hz,1H),4.00(dd,J=4.4,11.4Hz,1H),3.65-3.43(m,2H),3.29 -3.16(m,2H),2.95(t,J=10.5Hz,2H),2.66(dt,J=3.5,11.4Hz,1H),2.29-2 .13(m,2H),2.04(dd,J=4.4,12.7Hz,2H),1.78(m,3H),0.67(d,J=6.8Hz,3H)

[0212] Example 111. N-((S)-piperidine-3-yl)-4-(6-(tetrahydropyran-2-yl)-1H-pyrrole[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 111) [ka] Compound 111 (21.20 mg, white solid). LCMS(ESI):[M+H] + =447.2; 1 H NMR(400MHz,CD3OD) δ ppm 8.96-8.62(m,1H),8.53(s,1H),7.97(s,1H),7.40(s,1H),4.64-4.46(m,1H),4.29-3.98(m,2H),3.72(dt,J=2.6,11.5 Hz,1H),3.26(dd,J=3.4,12.0Hz,1H),2.97(d,J=12.8Hz,1H),2.71-2.54(m,2H),2.26-1.93(m,3H),1.88-1.59(m,7H).

[0213] Compound 111 was separated by SFC (column: DAIEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: phase A is carbon dioxide, phase B is 0.1% ammonium hydroxide / ethanol, with phase B retained at 40%, flow rate: 80 ml / min) to obtain target compound 112 and compound 113.

[0214] Example 112. Chiral monomer (compound 112) having a short appearance time after chiral resolution of compound 111. [ka] Compound 112 (1.15 mg, white solid). LCMS(ESI):[M+H] + =447.3; SFC analysis (column: Chiralcel OJ-3 (100mm x 4.6mm), 3um; mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / ethanol; gradient: Phase B is 5% to 40% within 4 minutes, 40% Phase B is maintained for 0.5 minutes, 5% Phase B is maintained for 1.5 minutes, flow rate: 2.8 ml / min): RT=3.598 min, ee=100%; 1 H NMR(400MHz,CD3OD) δ ppm 8.96-8.62(m,1H),8.53(s,1H),7.97(s,1H),7.40(s,1H),4.64-4.46(m,1H),4.29-3.98(m,2H),3.72(dt,J=2.6,11.5 Hz,1H),3.26(dd,J=3.4,12.0Hz,1H),2.97(d,J=12.8Hz,1H),2.71-2.54(m,2H),2.26-1.93(m,3H),1.88-1.59(m,7H).

[0215] Example 113. Chiral monomer (compound 113) having a long appearance time after chiral resolution of compound 111. [ka] Compound 113 (1.25 mg, white solid). LCMS(ESI):[M+H] + =447.3; SFC analysis (column: Chiralcel OJ-3 (100mm x 4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B is 5% to 40% within 4 minutes, 40% phase B is maintained for 0.5 minutes, 5% phase B is maintained for 1.5 minutes, flow rate: 2.8 ml / min): RT=4.426 min, ee=98.80%; 1H NMR(400MHz,CD3OD) δ ppm 8.96-8.62(m,1H),8.53(s,1H),7.97(s,1H),7.40(s,1H),4.64-4.46(m,1H),4.29-3.98(m,2H),3.72(dt,J=2.6,11.5 Hz,1H),3.26(dd,J=3.4,12.0Hz,1H),2.97(d,J=12.8Hz,1H),2.71-2.54(m,2H),2.26-1.93(m,3H),1.88-1.59(m,7H)

[0216] Example 114. (S)-Dimethyl(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)phosphine oxide formate (Compound 114) [ka] Step 1: tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-formate [ka] In a glove box, tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-formate (150 mg, 0.24 mmol), methanesulfonate[9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene][2-amino-1,1-biphenyl]palladium(II) dichloromethane adduct (24 mg, 24 mmol), triethylamine (119 mg, 1.18 mmol), and dimethylphosphine oxide (36 mg, 0.47 mmol) were added to xylene (1500 μL). The mixture was then stirred at 145°C for 16 hours. The reaction mixture was filtered. The filtrate was spin-dried. The residue was purified by flash column chromatography (silica gel, tetrahydrofuran / petroleum ether gradient of 1% to 20%) to obtain the crude compound tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-formate (165 mg) as a white solid. LCMS(ESI):[M-100+H] + = 579.2.

[0217] Step 2: tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-formate [ka] A sodium hydroxide aqueous solution (4M, 304 uL, 1.22 mmol) was added to a solution of tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-formate (165 mg, 0.24 mmol) in 1,4-dioxane (1650 uL). The mixture was then stirred at 50°C for 16 hours. 1,4-dioxane was spin-dried. Extraction was performed with ethyl acetate (2 mL x 2). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was spin-dried to obtain the crude compound tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-formate (130 mg) as a white solid. LCMS(ESI):[M+H] + = 539.2. Step 3: (S)-Dimethyl(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)phosphine oxide formate [ka]

[0218] A hydrogen chloride / dioxane solution (4M, 200uL, 0.80 mmol) was added to a solution of tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)piperidine-1-formate (130 mg, 0.19 mmol) in dichloromethane (1500uL). The reaction mixture was then stirred at 50°C for 16 hours. The reaction mixture was spin-dried and purified by preparative HPLC to obtain a white solid (S)-dimethyl(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-yl)phosphine oxide (formate, 21.69 mg, 49uol, yield: 26%). LCMS(ESI):[M+H] + =438.9; 1 H NMR(400MHz,CD3OD) δ ppm 9.16-8.89(m,1H),8.64(s,1H),8.55(s,1H),8.15(br s,1H),7.87(dd,J=5.5,7.8Hz,1H),4.33(br s,1H),3.65-3.44(m,1H),3.30(m,1H),3.00(br t,J=10.3Hz,2H),2.19(br s,1H),2.09(br d,J=14.1Hz,1H),1.86(d,J=13.6Hz,8H).

[0219] (S)-3-methyl-4-(3(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine-6-yl)morpholine was used as a starting material and reacted with the corresponding amine to synthesize the corresponding compound:

[0220] Example 115. 4-(6-((S)-3-methylmorpholinyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-N-((3S,5S)-5-methylpiperidine-3-yl)-5-(trifluoromethyl)pyrimidine-2-amine (Compound 115) [ka] Compound 115 (19.05 mg, white solid). LCMS (ESI): [M+H] + =476.2; 1 H NMR (400MHz, CD3OD) δ ppm 8.58(s,2H),7.72(s,1H),6.73(d,J=9.0Hz,1H),4.48-4.35(m,2H),4.03(dd,J=3.0,11.3Hz,1H),3.91-3.78 (m,3H),3.73-3.61(m,2H),3.30-3.20(m,2H),3.16(dd,J=2.8,13.1Hz,1H),2.69(t,J=11.7Hz,1H),2.29(br s,1H),2.13(br d,J=14.6Hz,1H),1.74-1.65(m,1H),1.24(d,J=6.5Hz,3H),1.08(d,J=6.5Hz,3H)

[0221] Effect Example 1: Test of enzyme-inhibiting activity of compounds CDK7, CDK2, CDK9, and CDK12 The tests were performed in a U-shaped bottom 384-well plate (Corning, 4512#) at a reaction temperature of 27°C. CDK7 / CyclinH was diluted in test buffer (20 mM MES pH 6.75, 0.01% Tween20, 50 ug / mL BSA, 6 mM MgCl2) to obtain the corresponding enzyme solution at a 2.4× concentration. CDK2 / CyclinE1 was diluted in test buffer (20 mM MES pH 6.75, 0.01% Tween20, 50 ug / mL BSA, 6 mM MgCl2) to obtain the corresponding enzyme solution at a 2.4× concentration. CDK9 / CyclinT1 was diluted in test buffer (20 mM MES pH 6.75, 0.01% Tween20, 50 ug / mL BSA, 10 mM MgCl2) to obtain the corresponding enzyme solution at a 2.4× concentration. CDK12 / CyclinK was diluted in test buffer (80 mM MES pH 6.5, 0.01% Tween20, 50 ug / mL BSA, 10 mM MgCl2) to obtain the corresponding enzyme solution at a 2.4× concentration. The compounds were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mM. During use, the compounds were diluted with DMSO to 10 different concentration gradients ranging from 25 nM to 500 uM, and these were each diluted 8.3 times in the test buffer to obtain 6× concentration compound solutions. The polypeptide substrate and ATP were diluted in the test buffer to obtain a 2.4× concentration mixed solution of polypeptide substrate and ATP. 2 µl of the test compound solution was mixed with 5 µl of the enzyme solution. After incubation for 10 minutes, 5 µl of the polypeptide substrate and ATP mixed solution was added. After incubation at 27°C for 180 minutes, 4 µl of 120 mM EDTA was added to each sample to stop the reaction. Test buffer containing 20 µM staurosporine replaced the compound solution as a 100% inhibitory control, and DMSO replaced the compound solution as a 0% inhibitory control. Each test included at least two parallel controls.Specifically, to test CDK7 inhibition, the CDK7 / Cyclin H / MAT1 complex (6 nM) and the "5-FAMCDK7tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide having the following sequence: 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK (where "5-FAM" refers to 5-carboxyfluorescein)) were used. To test CDK9 inhibition, the CDK9 / Cyclin T1 complex (8 nM) and the "5-FAM-CDK9tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide having the following sequence: 5-FAM-GSRTPMY-NH2 (where 5-FAM is as defined above, and NH2 represents the C-terminal amide)) were used. CDK12 inhibition was tested using the K complex (50 nM) and the "5-FAM-CDK9tide" defined above (2 μM). CDK2 inhibition was tested using the CDK2 / Cyclin E1 complex (0.5 nM) and the "5-FAM-CDK7tide" defined above (2 μM).

[0222] The reaction mixture was analyzed by electrophoretic separation using a Caliper EZ Reader II with a fluorescent substrate and phosphorylation product. Data were calculated using GraphPad Prism version 6.0. IC50 values ​​were adjusted using a nonlinear regression model with dose-response curves.

[0223] The test results for these IC50s are shown in Table 1 below. [Table 1] TIFF0007840334000150.tif97170

[0224] The table above shows that, using staurosporine as a reference substance, in vitro biological activity screening revealed that the compounds of the present invention possess good inhibitory activity and selectivity against CDK7 kinase. Several compounds are far superior to compound 213 (Example 101), which is structurally closest to compound 213 in patent CN2017 / 80057760.8, and are expected to be developed as drugs for regulating CDK7 kinase activity or for treating CDK7-related diseases.

[0225] Example of effect 2: Detection of the biological activity of cells Trypsin treatment was performed on A2780 cells and HCC70 cells. The cell suspensions were transferred to 15 mL centrifuge tubes and centrifuged at 800 rpm for 5 minutes. The supernatant was discarded. The cells were resuspended in fresh medium (RPMI1640 + 10% FBS). After counting, the cells were seeded at a rate of 2000 cells / well in a 384-well plate (50 μL of 1640 + 10% FBS culture medium was added to the second and 23rd lines of the 384-well plate, and 50 μL of DPBS was added to the surrounding wells). The cells were incubated overnight in an incubator (37°C, 5% CO2).

[0226] The following day, the compounds were added to the well plates. The compounds had a maximum concentration of 10 μM, which was diluted in a 1:4 ratio to form nine different concentrations. The positive compound, paclitaxel, had a maximum concentration of 1 μM, which was diluted in a 1:3 ratio to form nine different concentrations. The DMSO content in each well was standardized to 0.2%. The cell plates were centrifuged at 800 rpm for 30 seconds. Incubation was performed in an incubator (37°C, 5% CO2) for 72 hours. On the fourth day, the CyQuant reagent (3×) was prepared according to the kit instructions. Each 384-well plate was prepared in the following proportions: DPBS: 11.568 mL, CyQuant® direct nucleic acid stain: 72 μL, CyQuant® direct background suppressor: 360 μL. The plates were mixed uniformly and left at room temperature in a ready-to-plate state. The cell plates were removed and balanced at room temperature for 30 minutes. Cells were distributed into each well of a 384-well plate using a 25 μL (3×) Cyquant reagent via a multi-drop dispenser. Incubation was performed at 37°C for at least 60 minutes. The plates were read by Acumen (configured to have an excitation wavelength of 488 nm). IC50 results were analyzed using XLFIT5 from IDBS.

[0227] These test results are shown in Table 2 below. [Table 2] TIFF0007840334000152.tif69170

[0228] Table 2 shows that the compounds of the present invention have excellent inhibitory effects against human breast cancer cells HCC70 and ovarian cancer cells A2780. The activity of some compounds is tens of times better than that of compound 213 (Example 101), which is structurally closest to compound CN2017 / 80057760.8.

[0229] Although specific embodiments of the present invention are described above, those skilled in the art will understand that these examples are merely illustrative, and that various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Accordingly, the scope of protection of the present invention is limited by the appended claims.

Claims

1. The compound shown in Formula I or a pharmaceutically acceptable salt thereof, or any one of the aforementioned crystals or solvates: 【Chemistry 1】 R １ However, CF ３ , F, Cl, Br, or CN, R ５ However, it is H or halogen, X is N, R ２ が、-P(=O)Me 2 、 【Chemistry 23】 And, R ３ but, 【Chemistry 4】 That is the case.

2. R2 is 【Chemistry 24】 The compound represented by formula I or a pharmaceutically acceptable salt thereof, or any one of the aforementioned crystals or solvates, as described in claim 1.

3. R ２ but, 【Chemistry 9】 The compound represented by formula I or a pharmaceutically acceptable salt thereof, or any one of the aforementioned crystals or solvates, as described in claim 1 or 2.

4. R ２ but, 【Chemistry 13】 The compound represented by formula I or a pharmaceutically acceptable salt thereof, or any one of the aforementioned crystals or solvates, as described in claim 1 or 2.

5. R ２ but, 【Chemistry 14】 The compound represented by formula I or a pharmaceutically acceptable salt thereof, or any one of the aforementioned crystals or solvates, as described in claim 1 or 2.

6. R ２ is 【Chemistry 15】 The compound represented by formula I or a pharmaceutically acceptable salt thereof, or any one of the aforementioned crystals or solvates, as described in claim 1 or 2.

7. R １ However, CF ３ A compound represented by formula I or a pharmaceutically acceptable salt thereof, or a crystal or solvate of any one of the above, as described in any one of claims 1 to 6.

8. The aforementioned R ３ but, [Chemistry 18] A compound represented by formula I or a pharmaceutically acceptable salt thereof, or a crystal or solvate of any one of the above, as described in any one of claims 1 to 7.

9. The compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a crystal or solvate of any one of the aforementioned compounds, according to any one of claims 1, 7, and 8, wherein the compound represented by formula I is one of the following compounds. 【Chemistry 22】 【change】 【change】 【change】

10. A pharmaceutical composition comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof, or any one of the aforementioned crystals or solvate, and a pharmaceutical adjuvant, as described in any one of claims 1 to 9.

11. A compound represented by formula I or a pharmaceutically acceptable salt thereof, or any one of the aforementioned crystals or solvates, or a pharmaceutical composition according to claim 10, for use in the prevention and / or treatment of proliferative disorders.

12. The compound or pharmaceutical composition according to claim 11, wherein the proliferative disorder is selected from the group consisting of cancer, benign warts, angiogenesis, inflammatory diseases, and autoimmune diseases.

13. The compound or composition according to claim 12, wherein the cancer is selected from the group consisting of 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, pancreatic cancer, prostate cancer, testicular cancer, epithelial sarcoma, soft tissue sarcoma, and multiple myeloma.

14. The compound or composition according to claim 13, wherein the leukemia is selected from the group consisting of acute myeloid leukemia and acute lymphoblastic leukemia.

15. The compound or composition according to claim 12, wherein the inflammatory disease is an autoinflammatory disease.

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