Aromatic heterocyclic compounds, pharmaceutical compositions and their applications

Abstract

An aromatic heterocyclic compound, a pharmaceutical composition, and their applications are disclosed. Specifically, a compound of Formula I, its stereoisomer, its diastereomer, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or solvate of any of the foregoing, is disclosed. This aromatic heterocyclic compound has a novel structure, good CDK7 inhibitory activity, and good selectivity.

Description

[0001] This application claims priority to Chinese patent application 2020115524787, filed on December 24, 2020. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to aromatic heterocyclic compounds, their preparation methods, pharmaceutical compositions, and their applications. Background Technology

[0003] Members of the cyclin-dependent kinase (CDK) family play crucial regulatory roles in proliferation. CDK7, unique among mammalian CDKs, possesses integrated kinase activity, regulating cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is believed to act as CDK1 / 2 activated kinase (CAK), whereby phosphorylation of conserved residues in CDK1 / 2 is essential for fully catalytic CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase (RNAP)II general transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNAPII, a necessary step in gene transcription initiation. These two functions of CDK7—CAK and CTD phosphorylation—together support key aspects of cell proliferation, cell cycle, and transcription.

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

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

[0006] The technical problem to be solved by the present invention is to address the deficiency of the relatively simple structure of existing CDK7 inhibitors. The present invention provides an aromatic heterocyclic compound, its preparation method, pharmaceutical composition and its application. The compound of the present invention has a novel structure and good activity and selectivity.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides a compound of Formula I, its stereoisomers, its diastereomers, or a pharmaceutically acceptable salt thereof (referring to the compound of Formula I, its stereoisomers, or its diastereomers), or a crystal form or solvate thereof (referring to the compound of Formula I, its stereoisomers, its diastereomers, or a pharmaceutically acceptable salt thereof):

[0009]

[0010] R 1 It can be CF3, F, Cl, Br or CN;

[0011] R 5 It is H or halogen;

[0012] X is N;

[0013] R 2 for "4-12 membered heterocyclic alkyl groups with O as the heteroatom and 1-4 heteroatoms", and consisting of one or more R... 2-8 The substituted "4-12 membered heterocyclic alkyl group with O as the heteroatom and 1-4 heteroatoms", and the one or more R 2 -9 Substituted "4-12 membered heterocyclic alkyl groups with N heteroatoms and 1-4 heteroatoms", or -P(=O)R 2-10 R 2-11 ;

[0014] Z 1 For N or CH; Z 2 For O or S(=O)2, R 2-1 R 2-2 R 2-3 and R 2-4 Independently H, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more halogens", or R 2-1 and R 2-2 Linkage forms -(CH2) m - Structure, or R 2-1 and R 2-3 Linkage forms -(CH2) m - Structure, or R 2-1 and R 2-4 Linkage forms -(CH2) m - Structure, or R 2-2 and R 2-3 Linkage forms -(CH2) m - Structure, m is 1, 2 or 3; n 11 It can be 1 or 2;

[0015] Each R 2-5 Independently H or C1-C6 alkyl;

[0016] n5, n6, n7, and n8 are independently 0, 1, 2, or 3, and n5 and n7 are not both 0, and n6 and n8 are not both 0. R 2-6 and R 2-7 Independently NH2 or C1-C6 alkyl; n9 and n 10 Independently 0, 1, or 2;

[0017] Each R 2-8 Independently, it is a C1-C6 alkyl group;

[0018] Each R 2-9 Independently OH, CN, C1-C6 alkyl, C1-C6 alkyl substituted with one or more OH, or "4-12 membered heterocyclic alkyl with one or more heteroatoms selected from O, S and N";

[0019] R 2-10 and R 2-11 Independently, it is a C1-C6 alkyl group;

[0020]

[0021] In certain preferred embodiments of the present invention, certain groups in the compound represented by Formula I, its stereoisomers, its diastereomers, or pharmaceutically acceptable salts of any of the foregoing, or in the crystal forms or solvates of any of the foregoing, are defined as follows, and groups not mentioned are as described in any embodiment of this application (hereinafter referred to as "in one embodiment of the present invention").

[0022] When R 2-1 R 2-2 R 2-3 and R 2-4 When independently a C1-C6 alkyl or "a C1-C6 alkyl substituted with one or more halogens", the C1-C6 alkyl is a C1-C3 alkyl, preferably methyl, ethyl, n-propyl or isopropyl, for example methyl or ethyl, and again for example methyl.

[0023] In one aspect of the present invention, when R 2 for hour, for

[0024] In one aspect of the present invention, when each R 2-5When 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.

[0025] In one aspect of the present invention, when R 2-6 and R 2-7 When 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.

[0026] In one aspect of the present invention, when R 2 for hour, for For example

[0027] In one aspect of the present invention, when R 2 "A 4-12 membered heterocyclic alkyl group with O as the heteroatom and 1-4 heteroatoms" or "a group consisting of one or more R atoms" 2-8 When replacing "4-12 membered heterocyclic alkyl groups with O as the heteroatom and 1-4 heteroatoms", the "4-12 membered heterocyclic alkyl groups with O as the heteroatom and 1-4 heteroatoms" is "4-6 membered heterocyclic alkyl groups with O as the heteroatom and 1 heteroatom," such as tetrahydrofuranyl or tetrahydropyranyl, and for example...

[0028] In one aspect of the present invention, when each R 2-8 When 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.

[0029] In one aspect of the present invention, when R 2 For one or more R 2-9 When the "4-12 membered heterocyclic alkyl group with N heteroatoms and 1-4 heteroatoms is substituted", the substance is replaced by one or more R 2-9 The substituted "4-12 membered heterocyclic alkyl group with N heteroatoms and 1-4 heteroatoms" is replaced by one or two R atoms. 2-9 The substituted "4-6 membered heterocyclic alkyl group with N as the heteroatom and 1-2 heteroatoms", for example, by 1 or 2 R 2-9 Substituted nitrogen-containing heterocyclic butyl groups, with one or two R atoms 2-9 Substituted pyrroleyl groups, with one or two R... 2-9 Substituted piperidinyl or "with one or two R" 2-9 "Substituted piperazine group", for example

[0030] In one aspect of the present invention, when each R 2-9 When independently a C1-C6 alkyl or "a C1-C6 alkyl substituted with one or more OH groups", the C1-C6 alkyl is a C1-C3 alkyl, preferably methyl, ethyl, n-propyl or isopropyl, for example methyl.

[0031] In one aspect of the present invention, when each R 2-9 When independently defined as "a 4-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of O, S, and N, and whose heteroatoms number 1-4", the phrase "a 4-12 membered heterocyclic alkyl group whose heteroatoms are selected from one or more of O, S, and N, and whose heteroatoms number 1-4" is defined as "a 4-6 membered heterocyclic alkyl group whose heteroatoms are selected from O, and whose heteroatoms number 1-2", for example, oxobutyric acid, and another example...

[0032] In one aspect of the present invention, R 1 It can be CF3, F, Cl, Br or CN;

[0033] R 5 It is H or halogen;

[0034] X is N;

[0035] R 2 for "4-12 membered heterocyclic alkyl groups with O as the heteroatom and 1-4 heteroatoms", and consisting of one or more R... 2-8 The substituted "4-12 membered heterocyclic alkyl group with O as the heteroatom and 1-4 heteroatoms", and the one or more R 2 -9 Substituted "4-12 membered heterocyclic alkyl groups with N heteroatoms and 1-4 heteroatoms",

[0036] Z 1 For N or CH; Z 2 For O or S(=O)2, R 2-1 R 2-2 R 2-3 and R 2-4 Independently H, C1-C6 alkyl, or "C1-C6 alkyl substituted with one or more halogens", or R 2-1 and R 2-2 Linkage forms -(CH2) m - Structure, or R 2-1 and R 2-3 Linkage forms -(CH2) m - Structure, or R 2-1 and R 2-4Linkage forms -(CH2) m - Structure, or R 2-2 and R 2-3 Linkage forms -(CH2) m - Structure, m is 1, 2 or 3; n 11 It can be 1 or 2;

[0037] Each R 2-5 Independently H or C1-C6 alkyl;

[0038] n5, n6, n7, and n8 are independently 0, 1, 2, or 3, and n5 and n7 are not both 0, and n6 and n8 are not both 0. R 2-6 and R 2-7 Independently NH2 or C1-C6 alkyl; n9 and n 10 Independently 0, 1, or 2;

[0039] Each R 2-8 Independently, it is a C1-C6 alkyl group;

[0040] Each R 2-9 Independently OH, CN, C1-C6 alkyl, C1-C6 alkyl substituted with one or more OH, or "4-12 membered heterocyclic alkyl with one or more heteroatoms selected from O, S and N";

[0041] R 3 for

[0042] In one aspect of the present invention, R 1 It is CF3.

[0043] In one aspect of the present invention, R 2-1 R 2-2 R 2-3 and R 2-4 Independently H or C1-C6 alkyl, or R 2-1 and R 2-3 Linkage forms -(CH2) m - Structure, or R 2-1 and R 2-4 Linkage forms -(CH2) m - Structure, or R 2-2 and R 2-3 Linkage forms -(CH2) m -structure.

[0044] In one aspect of the present invention, In the middle, Z 1 For N, Z 2 For S(=O)2, R 2-1 R 2-2R 2-3 and R 2-4 Independently H or C1-C6 alkyl; or, Z 1 For N, Z 2 For O, R 2-1 R 2-2 R 2-3 and R 2-4 It is H or C1-C6 alkyl, or R 2-1 and R 2-3 The connection forms a -CH2- or -(CH2)2- structure, or R 2-2 and R 2-3 The connection forms a -CH2- structure; or, Z 1 For CH, Z 2 For O, R 2 -1 R 2-2 R 2-3 and R 2-4 All are H.

[0045] In one aspect of the present invention, In the middle, Z 1 For N, Z 2 For S(=O)2, R 2-1 R 2-2 R 2-3 and R 2-4 H, n independently 11 =0; or, Z 1 For N, Z 2 For O, R 2-1 R 2-2 R 2-3 and R 2-4 It is H or C1-C6 alkyl, or R 2-1 and R 2-3 The connection forms a -CH2- or -(CH2)2- structure, or R 2-1 and R 2-4 The connection forms a -CH2- structure, n 11 It can be 0 or 1; or, Z 1 For CH, Z 2 For O, R 2-1 R 2-2 R 2-3 and R 2-4 Both are H, n 11 It is 0.

[0046] In one embodiment 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.

[0047] In one embodiment of the present invention, n9 is 0; n 10 It can be 0, 1, or 2.

[0048] In one aspect of the present invention, R 2 For -P(=O)Me2, Ideally, R 2 For -P(=O)Me2,

[0049] In one aspect of the present invention, R 3 for,

[0050] In one aspect of the present invention, the compound represented by Formula I is any of the following compounds:

[0051]

[0052]

[0053]

[0054]

[0055] In one aspect of the present invention, the compound represented by Formula I is any of the following compounds:

[0056] The compound with a retention time of 6.763 min under the following conditions is... One of the stereoisomers: Column: Cellulose 2 (150mm*4.6mm), 5um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / methanol; Gradient: Phase B from 5% to 40% in 5 minutes, hold at 40% for 2.5 minutes, hold at 5% for 2.5 minutes, flow rate: 2.5 mL / min;

[0057] The compound with a retention time of 7.118 min under the following conditions is... One of the stereoisomers: Column: Cellulose 2 (150mm*4.6mm), 5µm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / methanol; Gradient: Phase B from 5% to 40% over 5 minutes, hold at 40% for 2.5 minutes, hold at 5% for 2.5 minutes; Flow rate: 2.5 mL / min

[0058] The compound with a retention time of 3.598 min under the following conditions is... One of the stereoisomers: Column: Chiralcel OJ-3 (100mm*4.6mm), 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / ethanol; Gradient: Phase B from 5% to 40% in 4 minutes, hold 40% Phase B for 0.5 minutes, hold 5% Phase B for 1.5 minutes, flow rate: 2.8 mL / min;

[0059] The compound with a retention time of 4.426 min under the following conditions is... One of the stereoisomers: Column: Chiralcel OJ-3 (100mm*4.6mm), 3um; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine / ethanol; Gradient: Phase B from 5% to 40% in 4 minutes, hold 40% Phase B for 0.5 minutes, hold 5% Phase B for 1.5 minutes, flow rate: 2.8 mL / min.

[0060] The above retention time test conditions are not a limitation on the compound. As long as the above test conditions are used to determine the retention time, and the obtained retention time is the same as or within the error range described above, and the compound is a stereoisomer of the compound limited by the retention time described above, then it falls within the protection scope of this invention.

[0061] The compounds of the present invention can be prepared by applying synthetic methods known in the art and the synthetic methods outlined in the schemes described below.

[0062] General Synthesis Method 1:

[0063]

[0064] As shown in General Synthesis Method 1, the compound represented by formula (I-1) is reacted with a suitable halogenating agent (such as, but not limited to, elemental iodine) to give a halogenated product I-2. The NH functional group in the structure of product I-2 is protected by a suitable protecting group (such as, but not limited to, benzoyl group). The compound having the chemical formula (I-2) can be protected with benzoyl group at low temperature (e.g., 0°C) to give compound I-3. Subsequently, under a suitable catalyst, compound I-8 is reacted with compound I-8 via a one-pot Stile coupling to generate compound I-5, or compound I-3 is first halogenated to the corresponding borate ester (or boric acid) compound I-4 under suitable reaction conditions. Compound I-4 is then reacted with compound I-8 via Suzuki coupling under a suitable catalyst to obtain compound I-5. Compound I-5 is heated under suitable chlorination conditions (such as, but not limited to, SOCl2) to give chlorinated intermediate I-6, or methyl thioether is oxidized to sulfone I-10 (sulfone I-9 or "a mixture of sulfone I-10 and sulfone I-9") by a suitable oxidizing agent (such as, but not limited to, m-CPBA). Chlorinated intermediate I-6 (I-10, or a mixture of I-9 / I-10) is heated under suitable alkaline conditions (such as, but not limited to, DIEA) with formula R 3 The reaction with NH2 yields a compound of formula (I-7), which, upon heating under suitable alkaline conditions (such as, but not limited to, NaOH), undergoes deprotection to give the final product of formula (I). If R 3 If the group contains other protecting groups (such as, but not limited to, Boc protecting groups), then compound I yields the final compound under suitable acidic conditions (such as, but not limited to, TFA / DCM).

[0065] General Synthesis Method 2: In the compound shown in Formula I, when X is N, we creatively synthesized a novel key intermediate compound II-6, through which the final compound II of this invention (corresponding to compound I when X is N) can be conveniently synthesized.

[0066]

[0067] As shown in General Synthesis Method 2, the compound represented by formula (II-1) is reacted with a suitable halogenating agent (such as, but not limited to, elemental iodine) to give a halogenated product II-2, which is protected by a suitable protecting group (such as, but not limited to, benzoyl group) to protect the NH functional group in the structure. For example, it can be protected with benzoyl chloride at low temperature (e.g., 0°C) to give compound II-3. Subsequently, under a suitable catalyst, compound II-6 is reacted with compound II-6 via a one-pot Stille coupling to generate compound II-5, or compound II-3 is first halogenated to the corresponding borate ester (or boric acid) compound II-4 under suitable reaction conditions. Compound II-4 is then reacted with compound II-6 via Suzuki coupling under a suitable catalyst to obtain compound II-5. Compound II-5 is then reacted with nitroxide compound II-6 under suitable oxidation conditions (such as, but not limited to, m-CPBA). Nitrogen oxide compound II-6 reacts with a suitable activating agent (such as, but not limited to, dimethyl sulfate) under heating conditions to generate an active pyridine oxymethyl ether. This active intermediate reacts with an amino compound R in the presence of a suitable base (such as, but not limited to, DIEA). 2 The H reaction yields a compound as shown in formula (II), if R 3 If the group contains other protecting groups (such as, but not limited to, Boc protecting groups), then compound II yields the final compound under suitable acidic conditions (such as, but not limited to, TFA / DCM).

[0068] Compound II-5, under suitable halogenation conditions and heating with a suitable chlorinating or brominating agent (such as, but not limited to, methyl chloroformate), yields chlorinated intermediate II-7 or the corresponding brominated intermediate. Chlorinated intermediate II-7, under suitable catalytic conditions, is coupled with the corresponding boronic ester / boronic acid or amino compound R via suitable coupling conditions (such as, but not limited to, Suzuki coupling or Buchwald coupling). 2 The H reaction yields the compound of formula (II), if R 3 If the group contains other protecting groups (such as, but not limited to, Boc protecting groups), then compound II yields the final compound under suitable acidic conditions (such as, but not limited to, TFA / DCM).

[0069] General Synthetic Method 3: In the compound shown in Formula I, when X is C(R) 4 ); R 4 When the value is -P(=O)Me2, we creatively synthesized a novel key intermediate compound III-4. Through this intermediate III-4, the final compound III((corresponding to X being C(R)) of this invention can be conveniently synthesized via a simple substitution reaction. 4 ); R 4 Compound I is a -P(=O)Me2 compound.

[0070]

[0071] As shown in General Synthesis Method 3, the compound represented by formula (III-1) (such as, but not limited to, a brominated compound) undergoes a coupling reaction with a suitable reagent (such as, but not limited to, dimethylphosphine oxide) in the presence of a suitable catalyst to give product III-2. Product III-2 then reacts with compound (III-3) in the presence of a suitable acidic reagent (such as, but not limited to, trifluoroacetic acid or aluminum trichloride) in a suitable solvent (such as, but not limited to, 1,1,1,3,3,3-hexafluoropropane-2-ol or dichloromethane) at a suitable temperature (such as, but not limited to, 60°C or 0°C) to give compound III-4. The chlorinated intermediate III-4 is then heated under suitable alkaline conditions (such as, but not limited to, DIEA) with formula R... 3 The reaction with NH2 yields the compound of formula (III). If R 3 If compound I contains other protecting groups (such as, but not limited to, Boc protecting groups), then under suitable acidic conditions (such as, but not limited to, TFA / DCM), the final compound is obtained.

[0072] The present invention also provides a pharmaceutical composition comprising the compound of Formula I, its stereoisomer, its diastereomer, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound of Formula I, its stereoisomer, or its diastereomer), or a crystal form or solvate of any of the foregoing, and pharmaceutical excipients.

[0073] The present invention also provides the use of the compounds represented by Formula I, their stereoisomers, their diastereomers, or pharmaceutically acceptable salts of any of the foregoing (referring to the compounds represented by Formula I, their stereoisomers, or their diastereomers), or crystal forms or solvates of any of the foregoing, or the use of the above pharmaceutical compositions in the preparation of a medicament. Preferably, the medicament is used for the prevention and / or treatment of proliferative diseases.

[0074] The present invention also provides a method for preventing and / or treating proliferative diseases, comprising administering to a patient a therapeutically effective amount of the above-described compound as shown in Formula I, its stereoisomer, its diastereomer, or a pharmaceutically acceptable salt of any of the foregoing (referring to the above-described compound as shown in Formula I, its stereoisomer or its diastereomer), or a crystal form or solvate of any of the foregoing, or the above-described pharmaceutical composition.

[0075] Preferably, the proliferative disease is cancer (e.g., leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, breast cancer, ovarian cancer, brain cancer, lung cancer, liver cancer, small cell lung cancer, melanoma, bladder cancer, colon cancer, esophageal cancer, bone cancer, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, testicular epithelial sarcoma, soft tissue sarcoma, multiple myeloma), benign growths, angiogenesis, inflammatory diseases, autoinflammatory diseases, or autoimmune diseases.

[0076] The compounds of the present invention, their stereoisomers, their diastereomers, or pharmaceutically acceptable salts of any of the foregoing, or crystalline forms or solvates of any of the foregoing, and pharmaceutical compositions thereof, may be administered topically or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans). Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glycerides, or polyethylene glycol, which are solid at room temperature but melt and / or dissolve in the rectal lumen to release the drug. The compounds of the present invention may also be administered parenterally, for example, by inhalation, injection, or infusion, such as via intravenous, intra-arterial, intra-bone, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal, intralesional, intralesional, intracranial, intratumoral, intradermal, and subcutaneous injection or infusion.

[0077] The therapeutically effective amount of the active ingredient is as defined in the context and depends on the mammal species, weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated, and the route of administration. For enteral administration, such as oral administration, the compounds of the present invention can be formulated into a wide variety of dosage forms.

[0078] The effective amounts of the compounds described in this invention, their pharmaceutically acceptable salts, their solvates, or pharmaceutical compositions can be readily determined by routine experiments. The most effective and convenient route of administration and the most appropriate formulation can also be determined by routine experiments.

[0079] Unless otherwise specified, the terms used in this invention have the following meanings:

[0080] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0081] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, and have either an S or R configuration.

[0082] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base 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. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, which can be either inorganic or organic acids. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0083] The term "solvate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate may exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0084] The terms "compound," "pharmaceutically acceptable salt," "solvent," and "solvent of a pharmaceutically acceptable salt," if stereoisomers exist, can exist as a single stereoisomer or a mixture thereof (e.g., a racemic mixture). The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthetic methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.), and can also be obtained by chiral resolution through bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention is not less than 95% relative to all stereoisomers of the compound.

[0085] The terms “compound,” “pharmaceutical acceptable salt,” “solvent,” and “solvent of pharmaceutically acceptable salt” may exist as a single tautomer or a mixture thereof, preferably as the more stable tautomer.

[0086] The atoms in the terms "compound," "pharmaceutically acceptable salt," "solvent," and "solvent of a pharmaceutically acceptable salt" can exist in either their natural or non-natural abundance forms. For example, the natural abundance form of a hydrogen atom refers to approximately 99.985% protium and approximately 0.015% deuterium; its non-natural abundance form refers to approximately 95% deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvent," and "solvent of a pharmaceutically acceptable salt" can be atoms existing in a non-natural abundance form.

[0087] When any variable (e.g., R) a-1 When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... a-1 Group substitution, meaning that the group can be replaced by up to 3 R groups. a-1 Replace, the position R a-1 Definition and other positions R a-1 The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0088] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0089] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyl groups.

[0090] The term "cycloalkyl" refers to a saturated monocyclic, polycyclic, or bridging carbocyclic substituent composed of carbon and hydrogen atoms, which may be connected to the rest of the molecule via a single bond through any suitable carbon atom; when polycyclic, it may be a fused-ring or spirocyclic system with fused ring linkage or spirocyclic linkage (i.e., the two geminal hydrogens on the carbon atom are replaced by alkylene rings). The cycloalkyl substituent may be connected to the central molecule via any suitable carbon atom. In some embodiments, a ring having 3-8 carbon atoms may be represented as a C3-C8 cycloalkyl. In some embodiments, C3-C6 cycloalkyl includes cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), bicyclo[1.1.1]pentane, and cyclohexyl (C6).

[0091] The term "heterocyclic alkyl" refers to a saturated cyclic group having heteroatoms, including monocyclic, polycyclic, or bridged rings. When polycyclic, it can be a fused or spirocyclic system with fused or spirocyclic linkages. Preferably, it is a 4- to 12-membered saturated cyclic group containing 1-4 independently selected cyclic heteroatoms chosen from N, O, and S. Exemplary 4-membered heterocyclic groups include, but are not limited to, azirrobutyl, propylene oxide, thioheterobutyl, or their isomers and stereoisomers; exemplary 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, dioxopentyl, oxathiofuranyl, dithiofuranyl, or their isomers and stereoisomers. Exemplary 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, sulfide cyclopentyl, morpholinyl, thiomorpholinyl, dithiaalkyl, dioxyl, piperazine, triazinealkyl, or their isomers and stereoisomers; Exemplary 7-membered heterocyclic groups include, but are not limited to, azirheptanyl, oxacycloheptanyl, thioheptanyl, oxazacycloheptanyl, and diazacycloheptanyl, or their isomers and stereoisomers.

[0092] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably containing 1-4 independent 5-6 membered monocyclic or 9-10 membered bicyclic aromatic rings selected from nitrogen, oxygen, and sulfur. When it is a bicyclic ring, at least one ring is aromatic, such as furanyl, pyridinyl, pyridinyl, pyrazinyl, thiophene, isozolyl, oxazolyl, diazolyl, imidazole, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazole, indolyl, inzolyl, benzothiazolyl, benziisothiazolyl, benzozolyl, quinolinyl, isoquinolinyl, etc.

[0093] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0094] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations 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 its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0095] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0096] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0097] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention, with humans being the most preferred. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0098] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0099] The reagents and raw materials used in this invention are all commercially available.

[0100] The positive and progressive effects of this invention are as follows: This invention provides an aromatic heterocyclic compound with a novel structure, good CDK7 inhibitory activity, and good selectivity. Detailed Implementation

[0101] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0102] Preparation of intermediate A: (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0103]

[0104] Step 1: (3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0105]

[0106] Compound 2,4-dichloro-5-trifluoromethylpyrimidine (2.00 g, 9.22 mmol) was dissolved in tetrahydrofuran (2 mL), and triethylamine (1400 μL, 10.07 mmol) was added. Under nitrogen protection, a tetrahydrofuran solution of zinc chloride (2 M, 10 mL, 20.00 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. A tetrahydrofuran solution of compound 3-aminopiperidine-1-carboxylic acid tert-butyl ester (2 mL, 10.49 mmol) was added to the above reaction system, and the reaction was continued at 25 °C for 16 hours after the addition was complete. Thin-layer chromatography (TLC) monitoring (silica gel, 1 / 3 volume ratio ethyl acetate / petroleum ether) showed the formation of the main spot (Rf = 0.38, target compound), along with a smaller new spot (Rf = 0.44, isomer) and some of the starting material 2,4-dichloro-5-trifluoromethylpyrimidine (Rf = 0.66) remaining. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (silica gel, 0-11.5% gradient ethyl acetate / petroleum ether) to give a white solid compound (3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (85% purity, 900 mg, 2.36 mmol, yield 26%). LCMS (ESI): [M-56+H] + =325.2;

[0107] 1 H NMR (400MHz, CDCl3): δppm 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).

[0108] Step 2: 1-(benzenesulfonyl)-3-bromo-1H-pyrrolo[2,3-b]pyridine

[0109]

[0110] 3-Bromo-1H-pyrrolo[2,3-b]pyridine (100.00 g, 507.54 mmol) was dissolved in tetrahydrofuran (40 mL), and sodium tert-butoxide (58.50 g, 609.04 mmol) was added at 0 °C, followed by benzenesulfonyl chloride (78 mL, 609.04 mmol). The reaction mixture was stirred at 30 °C for 1 hour. The mixture was poured into ice water (200 mL) and extracted with ethyl acetate (200 mL * 2). The organic phases were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated to give crude 1-(benzenesulfonyl)-3-bromo-1H-pyrrolo[2,3-b]pyridine (170.00 g), a yellow solid. LCMS (ESI): [M + H] + =337.2;

[0111] Step 3: 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[2,3-b]pyridine

[0112]

[0113] Compound 1-(benzenesulfonyl)-3-bromo-1H-pyrrolo[2,3-b]pyridine (170.00 g, 504.15 mmol), bis(phenylpyridine)boronic acid ester (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(diphenylphosphine)ferrocene palladium chloride (39.23 g, 50.42 mmol) was added at room temperature. The reaction was heated to 100 °C and stirred for 16 hours. The residue was concentrated and purified by rapid column chromatography (silica gel, 0–10% gradient of ethyl acetate / petroleum ether) to give a white solid 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[2,3-b]pyridine (100.00 g, 260.23 mmol, yield 52%). LCMS (ESI): [M+H] + =385.2.

[0114] Step 4: (S)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester

[0115]

[0116] To a solution of compound 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrrolo[2,3-b]pyridine (46.00 g, 120.80 mmol), (3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (42.20 g, 109.82 mmol) and cesium carbonate (71.56 g, 219.63 mmol) in 1,4-dioxane (1400 mL) and water (280 mL), under nitrogen protection, tetra(triphenylphosphine)palladium (12.69 g, 10.98 mmol) was added, and the reaction system was heated to 100 °C and reacted for 16 hours. The reaction mixture was cooled to room temperature, and an aqueous sodium hydroxide solution (5M, 66 mL, 330.00 mmol) was added. The reaction mixture was then heated to 70°C and stirred for 4 hours. After cooling to room temperature, the pH was adjusted to 3 with dilute HCl (1M), and the mixture was extracted with ethyl acetate (200 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (S)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (16.00 g, 34.60 mmol, yield 32%), a yellow oily liquid. LCMS (ESI): [M + H) + =463.3.

[0117] Step 5: (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (intermediate A)

[0118]

[0119] Compound (S)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (12.00 g, 25.95 mmol) was dissolved in dichloromethane (150 mL), and m-chloroperoxybenzoic acid (85% purity, 6.32 g, 31.14 mmol) was added at 0 °C. The reaction mixture was stirred at 30 °C for 16 hours. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (silica gel, 0-50% gradient of tetrahydrofuran / petroleum ether) to obtain a crude product. This crude product was then purified again by rapid column chromatography (C18, 0-37% gradient of acetonitrile / water) to give a white solid (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (90% purity, 5.00 g, 9.41 mmol, yield 36%). LCMS (ESI): [M+H]+ =479.3.

[0120] Preparation of intermediate B: (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-chloro-1-carboxylic acid methyl ester

[0121]

[0122] Step 1: (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-chloro-1-carboxylic acid methyl ester (intermediate B)

[0123]

[0124] Compound (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)-amino-5-(trifluoromethyl)pyrimidin-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, and 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. A saturated sodium bicarbonate solution (10 mL) was added, and ethyl acetate was used for extraction. Take (15 mL * 3). Wash the combined organic phases with saturated brine (20 mL), dry to anhydrous sodium sulfate, filter, concentrate, and purify the residue by rapid column chromatography (silica gel, 0-50% gradient of tetrahydrofuran / petroleum ether) to give a white solid compound (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-6-chloro-1-carboxylic acid methyl ester (600 mg, 0.92 mmol, yield 48%). LCMS (ESI): [M+H] + =555.2;

[0125] 1 H NMR (400MHz, CDCl3) δppm 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).

[0126] Preparation of intermediate C: (S)-3-methyl-4-(3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0127]

[0128] Step 1: 1H-pyrrolo[2,3-b]pyridine-7-oxide

[0129]

[0130] Compound 1H-pyrrolo[2,3-b]pyridine (35.00 g, 296.61 mmol) was dissolved in THF (1.20 L), and m-chloroperoxybenzoic acid (85% purity, 90.00 g, 443.31 mmol) was added. The mixture was then stirred at 20 °C for 16 hours, resulting in a yellow suspension. The reaction substrate was concentrated, and half of the solvent was removed by rotary evaporation. The solid was filtered off, washed with tetrahydrofuran (50 mL), and dried under vacuum to give a crude product (50% purity, 35.00 g), a white solid. The crude product was used directly in the next step without further purification. LCMS (ESI): [M+H] + =135.1.

[0131] Step 2: (S)-3-methyl-4-(1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0132]

[0133] 1H-pyrrolo[2,3-b]pyridine-7-oxide (50% purity, 55.00 g, 205.07 mmol) was dissolved in acetonitrile (535 mL), and dimethyl sulfate (21 mL, 225.51 mmol) was added. The mixture was heated to 60 °C and stirred for 16 hours. After cooling to 0 °C, (3S)-3-methylmorpholine (103.68 g, 1.03 mol) was added. The mixture was heated to 60 °C and stirred for 20 hours. After cooling, the mixture was concentrated, and the residue was extracted separately with dichloromethane (200 mL) and 10% sodium carbonate aqueous solution (200 mL). The aqueous phase was extracted with dichloromethane (200 mL * 2). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by rapid column chromatography (silica gel, 0-25% gradient of tetrahydrofuran / petroleum ether) to a yellow solid (S)-3-methyl-4-(1H-pyrrolo[2,3-b]pyridin-6-yl)-morphorline (8.64 g, 39.76 mmol, yield 19%). LCMS (ESI): [M+H] + =218.1.

[0134] 1H NMR(400MHz,CD3OD)δppm 7.75(d,J=8.5Hz,1H),7.03(d,J=3.3Hz,1H),6.58(d,J=8.5Hz,1H),6.29(d,J=3.5Hz,1H),4.31(q,J=6.5Hz,1H),4.00(dd ,J=3.1,11.2Hz,1H),3.84-3.71(m,3H),3.65(dt,J=3.0,11.4Hz,1H),3.22(dt,J=3.8,12.3Hz,1H),1.18(d,J=6.8Hz,3H)

[0135] Step 3: (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine

[0136]

[0137] Compound (S)-3-methyl-4-(1H-pyrrolo[2,3-b]pyridin-6-yl)-morphorline (8.34 g, 38.39 mmol) was dissolved in dimethylformamide (40 mL), potassium hydroxide (5.37 g, 95.96 mmol) was added, and 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. The mixture was concentrated, and the residue was extracted with water (100 mL) and dichloromethane (100 mL x 3). The combined organic phases were dried over magnesium sulfate. The mixture was filtered and concentrated to give crude compound (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorphorline (14.70 g). LCMS (ESI): [M+H] + =344.0.

[0138] Step 4: (S)-4-(3-iodo-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine

[0139]

[0140] Compound (S)-4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (14.70 g, 34.27 mmol) was dissolved in tetrahydrofuran (150 mL), and sodium tert-butoxide (4.94 g, 51.40 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 30 min. Benzenesulfonyl chloride (6.6 mL, 51.40 mmol) was added, and the reaction mixture was stirred at 20 °C for 2 h. The mixture was concentrated, and the residue was purified by rapid column chromatography (silica gel, 0-40% gradient tetrahydrofuran / petroleum ether) to give a yellow solid compound (S)-4-(3-iodo-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (4.60 g, 9.52 mmol, yield 28%). LCMS (ESI): [M+H] + =484.0.

[0141] 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

[0142]

[0143] Compound (S)-4-(3-iodo-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (500 mg, 1.03 mmol) and 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (512 mg, 1.35 mmol) were dissolved in xylene (10 mL). Under nitrogen protection, tetra(triphenylphosphine)palladium (120 mg, 0.10 mmol) and hexamethyldistin (407 mg, 1.24 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C for 2 hours, and then heated to 140 °C for 12 hours. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (silica gel, 0–50% gradient of ethyl acetate / petroleum ether) to give a yellow solid compound (S)-3-methyl-4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (220 mg). LCMS (ESI): [M+H] + =550.3

[0144] Step 6: (S)-3-methyl-4-(3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0145]

[0146] To a suspension of compound (S)-3-methyl-4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (800 mg, 1.46 mmol) and sodium sulfate (202 mg, 1.60 mmol) in dichloromethane (59 mL), m-chloroperoxybenzoic acid (85% purity, 650 mg, 3.20 mmol) was added in portions at 0 °C. The resulting reaction mixture was stirred at 25 °C for 40 minutes. The mixture was filtered, and the filtrate was used directly for the next reaction. LCMS (ESI): [M+H] + =582.1.

[0147] Preparation of intermediate D: 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0148]

[0149] Step 1: 4-(1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0150]

[0151] Compound 1H-pyrrolo[2,3-b]pyridine-7-oxide (50% purity, 35.00 g, 0.13 mol) was dissolved in acetonitrile (250 mL), and dimethyl sulfate (14 mL, 0.14 mol) was added. The mixture was then stirred at 60 °C for 16 hours. The reaction mixture was cooled to 0 °C, and morpholine (230 mL, 2.61 mol) was added. The mixture was then stirred at 60 °C for 20 hours, resulting in a yellow solution. The reaction mixture was cooled and concentrated, and dichloromethane (300 mL) and a 10% aqueous sodium carbonate solution (200 mL) were added to the residue. After separating the organic phase, the aqueous phase was extracted with dichloromethane (200 mL * 2). The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 80 g of residue. The residue was purified by rapid column chromatography (C18, 0–100% gradient of acetonitrile / water) to give 4-(1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine as a yellow solid (13.50 g, 66.44 mmol, yield 51%). LCMS (ESI): [M + H) + =204.2.

[0152] Step 2: 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0153]

[0154] Compound 4-(1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (9.70 g, 47.74 mmol) was dissolved in dimethylformamide (50 mL), and potassium hydroxide (6.66 g, 118.72 mmol) was added. The 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, and the reaction was carried out at 20 °C for 1 hour. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL * 3). The organic phases were combined, dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain crude 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (11.80 g), which was a brown oil. This crude product was used directly for the next reaction without purification. LCMS (ESI): [M + H] + =330.0.

[0155] Step 3: 4-(3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0156]

[0157] Compound 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (14.50 g, 44.06 mmol) was dissolved in tetrahydrofuran (145 mL), and sodium tert-butoxide (6.35 g, 66.08 mmol) was added at 0 °C, followed by stirring for 30 minutes. Then, benzenesulfonyl chloride (15.50 g, 87.76 mmol) was added at 0 °C, and the reaction mixture was reacted at 20 °C for 2 hours. The solvent was then removed by vacuum concentration, and the residue was purified by rapid column chromatography (silica gel, 0-25% gradient tetrahydrofuran / petroleum ether) to give compound 4-(3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (12.70 g, 27.06 mmol, yield 61%). LCMS (ESI): [M+H] + =470.0.

[0158] Step 4: 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0159]

[0160] 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). Tetra(triphenylphosphine)palladium (1.35 g, 1.17 mmol) and hexamethyldistin (3 mL, 15.24 mmol) were added under a nitrogen atmosphere. The reaction was carried out at 100 °C for 2 h under nitrogen protection, followed by a reaction at 140 °C for 14 h. The system was a black suspension. The system was concentrated under reduced pressure to give a brown solid, which was purified by rapid column chromatography (silica gel, 0-30% gradient of ethyl acetate / petroleum ether) to give compound 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (4.10 g, 6.12 mmol, yield 52%). LCMS (ESI): [M+H + =536.1.

[0161] Step 5: 4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-ol hydrochloride

[0162]

[0163] Compound 4-(3-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (8.00 g, 14.94 mmol) was dissolved in a mixture of glacial acetic acid (100 mL) and water (50 mL), and concentrated hydrochloric acid (50 mL) was added at room temperature. The resulting reaction solution was stirred at 100 °C for 16 hours. The reaction solution was concentrated, and the residue was added to ethyl acetate (40 mL) and stirred at room temperature for one hour. The solid was filtered off and dried under vacuum to give crude compound 4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-ol hydrochloride (6.80 g). This compound was used directly in the next reaction. LCMS (ESI): [M+H] + =366.1.

[0164] Step 6: 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine

[0165]

[0166] Compound 4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-ol hydrochloride (2.20 g, 6.02 mmol) was dissolved in phosphorus oxychloride (40 mL) and stirred at 80 °C for 16 hours. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (silica gel, 0-90% gradient of ethyl acetate / petroleum ether) to give compound 4-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (1.40 g, 2.92 mmol, two-step yield 48%), as a yellow solid. LCMS (ESI): [M+H] + =384.1.

[0167] 1 H NMR (400MHz, DMSO-d6) δppm 9.00 (s, 1H), 8.58-8.42 (m, 1H), 7.84 (d, J = 1.8Hz, 1H), 6.99-6.81 (m, 1H), 3.79-3.66 (m, 4H), 3.57-3.40 (m, 4H).

[0168] Preparation of intermediate E: (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0169]

[0170] Step 1: (1H-indol-7-yl)dimethylphosphine oxide

[0171]

[0172] Compound 7-bromo-1H-indole (2.00 g, 10.20 mmol) and dimethylphosphine oxide (2.39 g, 30.60 mmol) were dissolved in 1,4-dioxane (50 mL) under nitrogen protection. Triethylamine (7 mL, 51.00 mmol) and the dichloromethane adduct of [9,9-dimethyl-4,5-bis(diphenylphospho)oxanthracene][2-amino-1,1-diphenyl]palladium(II)methanesulfonate (20 mg, 0.02 mmol) were added at 25 °C. The reaction mixture was heated to 100 °C and reacted for 16 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by rapid column chromatography (silica gel, 0-100% gradient of tetrahydrofuran / petroleum ether) to give compound (1H-indole-7-yl)dimethylphosphine oxide (220 mg, 1.08 mmol, yield 11%) as a yellow solid. LCMS(ESI):[M+H] + =194.1.

[0173] Step 2: (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide

[0174]

[0175] Compound (1H-indol-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, and the reaction mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the mixture was poured into a saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (15 mL * 2). The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative silica gel plate treatment (1:2 v / v petroleum ether / tetrahydrofuran) to give a yellow oily compound (3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-7-yl)dimethylphosphine oxide (200 mg, 0.38 mmol, yield 34%). LCMS(ESI):[M+H] + =374.0.

[0176] Preparation of intermediate F: The following intermediate F (7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-6-nitrile) was prepared using the same method as in Example 4 of patent WO2020093011A1.

[0177]

[0178] Intermediate F (9.21 g, pale yellow solid). LCMS (ESI): [M+H] + =401.2;

[0179] 1 H NMR (400MHz, DMSO-d6) δppm 13.00 (br s, 1H), 9.16 (s, 1H), 8.36 (d, J = 8.4Hz, 1H), 8.16 (d, J = 2.4Hz, 1H), 7.71 (d, J = 8.4Hz, 1H)

[0180] Example of intermediate G preparation: 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile

[0181]

[0182] Step 1: 1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile

[0183]

[0184] A mixture of 6-bromo-1H-pyrrolo[2,3-b]pyridine (4.00 g, 20.30 mmol), zinc powder (133 mg, 2.03 mmol), zinc cyanide (1.67 g, 14.21 mmol), and a mixture of 1,1-bis(diphenylphosphine)ferrocene palladium chloride dichloromethane (829 mg, 1.02 mmol) in dimethylformamide (10 mL) was degassed 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), washed successively with saturated aqueous sodium bicarbonate solution (100 mL) and saturated brine (100 mL x 2), dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silica gel, 10-33% gradient of ethyl acetate / petroleum ether) to give compound 1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile (85% purity, 1.50 g, 8.91 mmol, yield 44%), as a white solid. LCMS (ESI): [M+H] + =144.2.

[0185] Step 2: 3-Iodo-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile

[0186]

[0187] A solution of 1H-pyrrolo[2,3-b]pyridine-6-carboxylonitrile (85% purity, 26.00 g, 154.44 mmol) and potassium hydroxide (22.93 g, 408.66 mmol) in dimethylformamide (150 mL) was cooled to 0 °C, and then a solution of elemental iodine (41.49 g, 163.46 mmol) in dimethylformamide (150 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, the filtrate was evaporated to dryness, and the crude product was washed three times with water (100 mL * 3) and dried under vacuum to give the crude compound 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-carboxylonitrile (53.00 g). LCMS (ESI): [M + H] + =270.0.

[0188] Step 3: 3-Iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile

[0189]

[0190] A solution of 50.00 g (148.68 mmol) of 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile in tetrahydrofuran (2.50 L) was cooled to 0 °C and sodium hydrogen (60% purity, 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, and then quenched at 0 °C with acetic acid (20 mL) and water (200 mL). The tetrahydrofuran in the solution was removed by rotary evaporation, and the precipitated solid was filtered and dried under vacuum to obtain a crude product. The crude product was slurried with methyl tert-butyl ether (100 mL) and filtered to obtain a white solid compound, 3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile (45.00 g, 110.04 mmol, yield 63%). LCMS(ESI):[M+H] + =410.0.

[0191] Step 4: 3-(2-methylthio-5-trifluoromethylpyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile

[0192]

[0193] Tetra(triphenylphosphine)palladium (1.27 g, 1.10 mmol) was added to a xylene (100 mL) solution of 3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylonitrile (5.00 g, 11.00 mmol), 4-chloro-2-methylthio-5-trifluoromethylpyrimidine (3.27 g, 14.30 mmol), and hexamethyldistin (4.72 g, 14.30 mmol). The reaction mixture was stirred at 100 °C for 2 h under nitrogen protection, and then the temperature was increased to 140 °C for 16 h. The reaction mixture was evaporated to dryness, and the residue was purified by rapid column chromatography (silica gel, 5-10% gradient of tetrahydrofuran / petroleum ether) to give a yellow solid 3-(2-methylthio-5-trifluoromethylpyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile (3.10 g, 6.52 mmol, yield 59%). LCMS (ESI): [M+H] + =476.2.

[0194] Step 5: 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile

[0195]

[0196] Compound 3-(2-methylthio-5-trifluoromethylpyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile (200 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), and m-chloroperoxybenzoic acid (80% purity, 181 mg, 0.84 mmol) and sodium sulfate (50 mg, 0.35 mmol) were added. The resulting reaction mixture 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, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined and concentrated to give crude compound 3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile (230 mg), which is a yellow oil. This crude product was used directly in the next reaction. LCMS (ESI): [M+H] + =508.0.

[0197] Preparation of intermediate H: 3,5-dimethyl-4-(3-(2-methanesulfonyl-5-trifluoromethylpyrimidin-4-yl)-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-6-yl)isoxazole

[0198]

[0199] Referring to patent WO2019143719, Example 11, intermediate H was prepared using the same synthesis method.

[0200] Preparation of intermediate J: tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0201]

[0202] Step 1: 6-Chloro-3-iodo-1H-pyrrole[2,3-b]pyridine

[0203]

[0204] A solution of 6-chloro-1H-pyrrolo[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, and 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 a 10% aqueous solution of sodium sulfite (100 mL), and the mixture was extracted with dichloromethane (100 mL x 3) and evaporated to dryness. The crude product was washed with water (20 mL x 3), filtered, and the resulting solid was dried under vacuum to give a yellow solid of 6-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (7.30 g, 23.60 mmol, yield 72%). LCMS (ESI): [M+H] + =278.9;

[0205] Step 2: 6-Chloro-3-iodo-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine

[0206]

[0207] Sodium tert-butoxide (0.98 g, 10.23 mmol) was added to a tetrahydrofuran (20 mL) solution of 6-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.82 mmol). The reaction mixture was stirred at 25 °C for 30 min. Then, the temperature was lowered to 0 °C, and benzenesulfonyl chloride (1.81 g, 10.23 mmol) was added. The mixture was stirred at 25 °C for 4 h, and the tetrahydrofuran in the solution was removed by rotary evaporation. The residue was diluted with water (20 mL), and the solid was filtered to obtain the crude product. The crude product was slurried with methyl tert-butyl ether (10 mL) and filtered to obtain a white solid compound 6-chloro-3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.55 g, 5.71 mmol, yield 85%). LCMS (ESI): [M+H] + =418.9;

[0208] Step 3: tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0209]

[0210] Under nitrogen protection, tetra(triphenylphosphine)palladium (0.28 g, 0.24 mmol) was added to a xylene (10 mL) solution of 6-chloro-3-iodo-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.39 mmol), tert-butyl(S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (1.18 g, 3.11 mmol), and hexamethyldistin (1.02 g, 3.11 mmol). The reaction mixture was heated to 100 °C and stirred for 2 h under nitrogen protection, and then the temperature was increased to 140 °C and the reaction was carried out for 16 h. The reaction mixture was evaporated to dryness, and the residue was purified by rapid column chromatography (silica gel, 0-25% gradient of ethyl acetate / petroleum ether) to give a yellow solid, tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (0.53 g, 0.74 mmol, yield 31%). LCMS (ESI): [M+H + =637.3.

[0211] Example 1. (S)-4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 1)

[0212]

[0213] Step 1: tert-butyl(S)-3-((4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0214]

[0215] (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (150 mg, 0.31 mmol) was dissolved in acetonitrile (400 μL), and dimethyl sulfate (33 μL, 0.34 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours. Afterward, it was cooled to 0 °C, and then... Caffeine (441 μL, 5.02 mmol) was reacted at 80 °C for 16 h. Two identical batches of the reaction were cooled to room temperature and concentrated to give a brown, oily crude product, tert-butyl(S)-3-((4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (300 mg). LCMS (ESI): [M+H]+ =548.3

[0216] Step 2: (S)-4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0217]

[0218] The compound tert-butyl(S)-3-((4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (55% purity, 300 mg, 0.30 mmol) was dissolved in dichloromethane (5 mL), and 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, and the residue was purified by preparative HPLC to give a red solid (S)-4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (53.11 mg, 0.12 mmol, yield 40%). LCMS (ESI): [M+H] + =448.3;

[0219] 1 H NMR(400MHz,CD3OD)δppm 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).

[0220] We synthesized the following compounds using the same method as for compound 1, by reacting (3S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (intermediate A) with a suitable amine:

[0221] Example 2. 4-(6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 2)

[0222]

[0223] Compound 2 (53.11 mg, red solid). LCMS (ESI): [M+H] + =460.2.

[0224] 1 H NMR(400MHz,CD3OD)δppm 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)

[0225] Example 3. (S)-1-(3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-4-ol (Compound 3)

[0226]

[0227] Compound 3 (56.76 mg, yellow solid). LCMS (ESI): [M+H] + =462.2.

[0228] 1 H NMR (400MHz, CD3OD), δppm 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(brdd,J=12.5,3.1Hz,2H),1.77-1.64(m,1H),1.62-1.40(m,4H)

[0229] Example 4. (S)-(1-(3-(2-(piperidin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-4-yl)methanol (compound 4)

[0230]

[0231] Compound 4 (55.55 mg, yellow solid). LCMS (ESI): [M+H] + =476.3.

[0232] 1 H NMR (400MHz, CD3OD), δppm 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)

[0233] Example 5. N-((S)-piperidin-3-yl)-4-(6-(tetrahydro-1H-furan[3,4-c]pyrrolo-5(3H)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 5)

[0234]

[0235] Compound 5 (19.05 mg, yellow solid). LCMS (ESI): [M+H] + =474.2.

[0236] 1 H NMR (400MHz, CD3OD), δppm 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).

[0237] Example 6. 3-Methyl-1-(3-(2-(((S)-piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)pyrrolidine-3-ol (Compound 6)

[0238]

[0239] Compound 6 (56.83 mg, yellow solid). LCMS (ESI): [M+H] + =462.2.

[0240] 1 H NMR (400MHz, CD3OD), δppm 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(brs,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).

[0241] Example 7. 4-(6-(2-oxa-7-azaspiro[4.5]decane-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 7)

[0242]

[0243] Compound 7 (16.15 mg, yellow solid). LCMS (ESI): [M+H] + =502.2.

[0244] 1 H NMR (400MHz, CD3OD): δppm 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).

[0245] Example 8. (S)-4-(6-(2-oxa-6-azaspiro[3.4]octane-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 8)

[0246]

[0247] Compound 8 (9.35 mg, yellow solid). LCMS (ESI): [M+H] + =474.2.

[0248] 1 H NMR (400MHz, CD3OD): δppm 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).

[0249] Example 9. (S)-4-(6-(2-oxa-8-azaspiro[4.5]decane-8-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 9)

[0250]

[0251] Compound 9 (23.92 mg, white solid). LCMS (ESI): [M+H] + =502.3.

[0252] 1H NMR (400MHz, CD3OD): δppm 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).

[0253] Example 10. (S)-4-(6-(9-oxa-2-azaspiro[5.5]undecane-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 10)

[0254]

[0255] Compound 10 (10.64 mg, yellow solid). LCMS (ESI): [M+H] + =516.3.

[0256] 1 H NMR (400MHz, CD3OD): δppm 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).

[0257] Example 11. (S)-4-(6-(6-oxa-2-azaspiro[3.4]octane-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 11)

[0258]

[0259] Compound 11 (19.51 mg, white solid). LCMS (ESI): [M+H] + =474.3.

[0260] 1 H NMR (400MHz, CD3OD): δppm 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).

[0261] Example 12. (3S,4S)-3-methyl-8-(3-(2-(((S)-piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-oxa-8-azaspiro[4.5]dec-4-amine (Compound 12)

[0262]

[0263] Compound 12 (14.98 mg, brown solid). LCMS (ESI): [M+H] + =531.3.

[0264] 1 H NMR (400MHz, CD3OD): δppm 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).

[0265] Example 13. 4-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 13)

[0266]

[0267] Compound 13 (17.77 mg, black solid). LCMS (ESI): [M+H] + =460.2.

[0268] 1 H NMR (400MHz, CD3OD): δppm 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).

[0269] Example 14. (S)-4-(6-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 14)

[0270]

[0271] Compound 14 (27.03 mg, white solid). LCMS (ESI): [M+H] + =460.2.

[0272] 1 H NMR (400MHz, CD3OD), δppm 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).

[0273] Example 15. (S)-4-(6-(2-oxa-7-azaspiro[3.5]non-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 15)

[0274]

[0275] Compound 15 (43.52 mg, yellow solid). LCMS (ESI): [M+H] + =488.3.

[0276] 1H NMR (400MHz, CD3OD), δppm 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).

[0277] Example 16. (S)-4-(6-(1-oxa-7-azaspiro[3.5]non-7-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 16)

[0278]

[0279] Compound 16 (3.52 mg, yellow solid). LCMS (ESI): [M+H] + =488.2.

[0280] 1H NMR (400MHz, CD3OD), δppm 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).

[0281] Example 17. (S)-4-(6-(6-oxa-2-azaspiro[3.5]non-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 17)

[0282]

[0283] Compound 17 (27.05 mg, yellow solid). LCMS (ESI): [M+H] + =488.2.

[0284] 1 H NMR (400MHz, CD3OD), δppm 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).

[0285] Example 18. 4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 18)

[0286]

[0287] Compound 18 (12.05 mg, yellow solid). LCMS (ESI): [M+H] + =462.3.

[0288] 1 H NMR (400MHz, CD3OD), δppm 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)

[0289] Example 19. 4-(6-((R)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 19)

[0290]

[0291] Compound 19 (3.69 mg, white solid). LCMS (ESI): [M+H] + =462.2.

[0292] 1 H NMR (400MHz, CD3OD): δppm 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)

[0293] Example 20. (S)-1-(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-4-onitrile (Compound 20)

[0294]

[0295] Compound 20 (22.21 mg, yellow solid). LCMS (ESI): [M+H] + =471.2.

[0296] 1 H NMR (400MHz, CD3OD): δppm 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)

[0297] Example 21. (S)-3-methyl-1-(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)azacyclobutane-3-carboxylonitrile (Compound 21)

[0298]

[0299] Compound 21 (24.60 mg, yellow solid). LCMS (ESI): [M+H] + =457.2.

[0300] 1H NMR (400MHz, CD3OD): δppm 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)

[0301] Example 22. (S)-4-(6-(1,4-oxazacyclohept-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 22)

[0302]

[0303] Compound 22 (24.19 mg, yellow solid). LCMS (ESI): [M+H] + =462.2.

[0304] 1 H NMR (400MHz, CD3OD): δppm 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)

[0305] Example 23. (S)-4-methyl-1-(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)piperidin-4-ol (Compound 23)

[0306]

[0307] Compound 23 (39.78 mg, yellow solid). LCMS (ESI): [M+H] + =476.3.

[0308] 1 H NMR (400MHz, CD3OD): δppm 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)

[0309] Example 24. (S)-4-(6-(4-(oxacyclobut-3-yl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 24)

[0310]

[0311] Compound 24 (8.06 mg, yellow solid). LCMS (ESI): [M+H] + =503.2.

[0312] 1 H NMR (400MHz, CD3OD): δppm 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)

[0313] Example 25. (S)-4-(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)thiomorpholine-1,1-dioxide (Compound 25)

[0314]

[0315] Step 1: tert-butyl(S)-3-((4-(6-thiomorpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0316]

[0317] (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (300 mg, 0.627 mmol) was dissolved in acetonitrile (5 mL), and dimethyl sulfate (65 μL, 0.69 mmol) was added. The reaction mixture was heated to 70 °C and stirred for 16 hours. After cooling to 0 °C, thiomorpholine (951 μL, 10.03 mmol) was added. The mixture was then heated to 70 °C and stirred for 20 hours. The residue was concentrated and purified by rapid column chromatography (silica gel, ethyl acetate / petroleum ether gradient 0-85%) to give a yellow solid tert-butyl(S)-3-((4-(6-thiomorpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (170 mg, 0.30 mmol, yield 48%). LCMS (ESI): [M+H] + =564.3.

[0318] Step 2: tert-butyl(S)-3-((4-(6-(1,1-thiomorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0319]

[0320] The compound tert-butyl(S)-3-((4-(6-thiomorpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (160 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and potassium osmium tetroxide dihydrate (5 mg, 14 μmol) 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, and the mixture was extracted with ethyl acetate (5 mL * 3). The combined organic phases were concentrated to yield crude tert-butyl(S)-3-((4-(6-(1,1-thiomorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (100 mg). LCMS (ESI): [M+H] + =596.2.

[0321] Step 3: (S)-4-(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)thiomorpholine-1,1-dioxide

[0322]

[0323] The compound tert-butyl(S)-3-((4-(6-(1,1-thiomorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (100 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL, 13.46 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The solution was concentrated, ammonia water (1 mL) was added, and the solution was concentrated again. The residue was purified by preparative HPLC to obtain a gray solid (S)-4-(3-(2-(piperidine-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)thiomorpholine-1,1-dioxide (41.54 mg, 84 μmol, yield 50%). LCMS(ESI):[M+H] + =496.2;

[0324] 1 H NMR (400MHz, CD3OD): δppm 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).

[0325] Example 26. N-((S)-6,6-dimethylpiperidin-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 26)

[0326]

[0327] Step 1: N-((S)-6,6-dimethylpiperidin-3-yl)-4-(6-((S)-3-methylmorpholino)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0328]

[0329] To a solution of compound (S)-3-methyl-4-(3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (750 mg, 1.29 mmol) in dichloromethane (13 mL), compound (S)-6,6-dimethylpiperidin-3-amine (55% purity, 1.56 g, 6.69 mmol) and diisopropylethylamine (2 mL, 12.90 mmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. The residue was concentrated and purified by preparative HPLC to obtain a yellow oily substance, N-((S)-6,6-dimethylpiperidin-3-yl)-4-(6-((S)-3-methylmorpholino)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (400 mg, 0.64 mmol, yield 49%). LCMS (ESI): [M+H + =630.3.

[0330] Step 2: N-((S)-6,6-dimethylpiperidin-3-yl)-4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0331]

[0332] The compound N-((S)-6,6-dimethylpiperidin-3-yl)-4-(6-((S)-3-methylmorpholino)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (750 mg, 0.89 mmol) was dissolved in 1,4-dioxane (5 mL), and an aqueous solution of sodium hydroxide (4 M, 1787 μL, 7.15 mmol) was added. After the addition was complete, the reaction was carried out at 100 °C for 1 hour. The mixture was cooled, the pH adjusted to 7 with hydrochloric acid, concentrated, and the residue purified by preparative HPLC to give a white solid compound N-((S)-6,6-dimethylpiperidin-3-yl)-4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (35.91 mg, 73 μmol, yield 8%). LCMS (ESI): [M+H + =490.3;

[0333] 1H NMR (400MHz, CD3OD): δppm 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).

[0334] Example 27. (S)-4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 27)

[0335]

[0336] Step 1: tert-butyl(S)-3-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0337]

[0338] The intermediate tert-butyl(S)-3-((4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (0.30 g, 0.60 mmol), compound 3,6-dihydro-2H-pyran-4-boronic acid pyrrolyl ester (0.19 g, 0.91 mmol), and sodium carbonate aqueous solution (1 M, 1810 μL, 1.81 mmol) were dissolved in 1,4-dioxane (10.00 mL) under nitrogen protection, and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.04 g, 0.06 mmol) was added. The reaction system was heated to 100 °C and reacted for 12 hours. Cool to room temperature, concentrate, and purify the residue by rapid column chromatography (silica gel, 0–70% gradient of ethyl acetate / petroleum ether) to give a white solid compound tert-butyl(S)-3-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (0.22 g, 0.40 mmol, yield 67%). LCMS (ESI): [M+H] + =545.2.

[0339] Step 2: (S)-4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0340]

[0341] The compound tert-butyl(S)-3-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (75 mg, 0.14 mmol) was dissolved in dichloromethane (300 μL), and trifluoroacetic acid (0.09 mL, 1.38 mmol) was added at room temperature. The reaction mixture was stirred at 25 °C for 12 hours. After concentration, the residue was purified by preparative HPLC to give a white solid compound (S)-4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidine-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (28.86 mg, 63 μmol, yield 45%). LCMS(ESI):[M+H] + =445.2.

[0342] 1H NMR(400MHz,CD3OD)δppm 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).

[0343] Example 28. (S)-N-(piperidin-3-yl)-4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-aminocarbamate (Compound 28)

[0344]

[0345] Step 1: tert-butyl(S)-3-((4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0346]

[0347] 70 mg (0.13 mmol) of tert-butyl(S)-3-((4-(6-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester was dissolved in methanol (5 mL) and tetrahydrofuran (10 mL), and wet palladium on carbon (10% content, 0.1 g) was added. The reaction mixture was stirred at 25 °C under 15 psi hydrogen atmosphere for 12 hours. The reaction solution was filtered and concentrated to give tert-butyl(S)-3-((4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (60 mg, 0.11 mmol, yield 77%), which is a brown oil. LCMS (ESI): [M+H] + =547.3.

[0348] Step 2: (S)-N-(piperidin-3-yl)-4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0349]

[0350] The compound tert-butyl(S)-3-((4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid ester (60 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), and a solution of 1,4-dioxane (4 M, 200 μL, 0.80 mmol) of hydrogen chloride was added dropwise at 25 °C. After the addition was complete, the reaction was stirred at 25°C for 1 hour, concentrated, and the residue was purified by preparative HPLC to obtain a yellow solid compound (S)-N-(piperidin-3-yl)-4-(6-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (formate, 24.98 mg, 51 μmol, yield 46%), which was a yellow solid. LCMS (ESI): [M+H] + =447.3.

[0351] 1 H NMR (400MHz, CD3OD): δppm 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).

[0352] Using the same method as that used to synthesize compound 28, and employing the same chlorine intermediate tert-butyl(S)-3-((4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid ester, coupled with other substrates (and further reduced if necessary), we obtained the following compounds:

[0353] Example 29. N-((S)-piperidin-3-yl)-4-(6-(tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-aminocarbamate (Compound 29)

[0354]

[0355] Compound 29 (12.13 mg, yellow solid). LCMS (ESI): [M+H] + =433.1;

[0356] 1H NMR (400MHz, CD3OD): δppm 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).

[0357] Compound 29 was separated by SFC (column: Phenomenex-Cellulose-2 (250 mm * 30 mm, 10 μm); mobile phase: phase A was carbon dioxide; phase B was 0.1% ammonia / methanol; phase B was maintained at 30%, flow rate: 60 mL / min). The two components were then purified by preparative HPLC to obtain target compounds 107 and 108, both of which are formate salts.

[0358] Example 107. Chiral monomer with shorter elution time after chiral resolution of compound 29 (compound 107).

[0359]

[0360] Compound 107 (7.11 mg, yellow solid. LCMS (ESI): [M+H)) + =432.9; SFC analysis (column: Cellulose2 (150mm*4.6mm), 5um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / methanol; gradient: phase B from 5% to 40% in 5 minutes, hold phase B at 40% for 2.5 minutes, hold phase B at 5% for 2.5 minutes, flow rate: 2.5 mL / min): RT = 6.763 min, de = 100%;

[0361] 1H NMR (400MHz, CD3OD) δppm 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).

[0362] Example 108. Chiral monomer with a longer elution time after chiral resolution of compound 29 (compound 108).

[0363]

[0364] Compound 108 (7.43 mg, white solid). LCMS (ESI): [M+H] + =432.9; SFC analysis (column: Cellulose 2 (150mm*4.6mm), 5um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / methanol; gradient: phase B from 5% to 40% in 5 minutes, hold phase B at 40% for 2.5 minutes, hold phase B at 5% for 2.5 minutes, flow rate: 2.5 mL / min): RT = 7.118 min, de = 93.17%;

[0365] 1H NMR (400MHz, CD3OD) δppm 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).

[0366] Example 30. N-((S)-piperidin-3-yl)-4-(6-(tetrahydropyran-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-aminocarbamate

[0367]

[0368] Compound 30 (12.19 mg, white solid). LCMS (ESI): [M+H] + =447.2.

[0369] 1H NMR (400MHz, DMSO-d6): δppm 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)

[0370] Example 31. 4-(6-(3-oxabicyclo[4.1.0]hept-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2-aminocarbamate (Compound 31)

[0371]

[0372] Compound 31 (2.14 mg, yellow solid). LCMS (ESI): [M+H] + =459.2.

[0373] 1 H NMR (400MHz, CD3OD): δppm 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).

[0374] Example 32. 4-(6-(2-oxo-5-azabicyclo[2.2.2]oct-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 32)

[0375]

[0376] Step 1: tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]octane-5-yl)-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0377]

[0378] In a nitrogen-filled chamber, di(tert-butylphosphine)palladium (8 mg, 0.02 mmol) was added to a turbid solution of tert-butyl(3S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (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 μL). The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was filtered, and the resulting mother liquor was concentrated to 1 mL. This solution was used directly in the next reaction step. LCMS (ESI): [M+H] + =714.3.

[0379] Step 2: tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]oct-5-yl)-1H-pyrrole[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0380]

[0381] A 1 mL solution of tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]octane-5-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester was added to a solution 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 reaction mixture, followed by extraction with ethyl acetate (10 mL x 2). The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude compound was separated by preparative silica gel plate chromatography (silica gel, petroleum ether / tetrahydrofuran, 1:1 v / v) to give a yellow oily compound tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]oct-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (28 mg, 0.05 mmol, two-step yield 31%). LCMS (ESI): [M+H + =574.3.

[0382] Step 3: 4-(6-(2-oxo-5-azabicyclo[2.2.2]oct-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0383]

[0384] The compound tert-butyl(3S)-3-((4-(6-(2-oxo-5-azabicyclo[2.2.2]oct-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (28 mg, 0.05 mmol) was dissolved in dichloromethane (100 μL), and trifluoroacetic acid (36 μL, 0.49 mmol) was added. The reaction solution was stirred at 20 °C for 2 hours. After the reaction was complete, the reaction solution was directly concentrated to dryness to obtain the crude product. The crude product was purified by preparative HPLC to give a yellow solid compound 4-(6-(2-oxo-5-azabicyclo[2.2.2]oct-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (4.52 mg, 9.6 μmol, yield 16%). LCMS (ESI): [M+H] + =474.2.

[0385] 1 H NMR (400MHz, CD3OD): δppm 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).

[0386] Using the same method as in the synthesis of compound 32, and employing the same chlorine intermediate tert-butyl(3S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid ester, coupled with other substrates, we obtained the following compounds after deprotection:

[0387] Example 33. N-((S)-piperidin-3-yl)-5-(trifluoromethyl)-4-(6-((R)-3-(trifluoromethyl)morpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (Compound 33)

[0388]

[0389] Compound 33 (3.92 mg, yellow solid). LCMS (ESI): [M+H] + =516.3.

[0390] 1 H NMR (400MHz, CD3OD): δppm 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)

[0391] Example 34. 4-(6-(6-oxo-3-azabicyclo[3.1.1]hept-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 34)

[0392]

[0393] Compound 34 (2.05 mg, yellow solid). LCMS (ESI): [M+H] + =460.2.

[0394] 1 H NMR (400MHz, CD3OD): δppm 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).

[0395] Example 43. (1R,4R,7R)-N-(4-(6-morpholinyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-2-azabicyclo[2.2.1]hept-7-aminocarbamate (Compound 43)

[0396]

[0397] Compound 43 (2.01 mg, white solid). LCMS (ESI): [M+H] + =460.2.

[0398] 1 H NMR(400MHz,CD3OD)δppm 8.56(m,3H),7.74(s,1H),6.83(m,1H),4.25-4.06(m,1H),3.86(m,4H),3.63-3.49(m,5 H),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),

[0399] Example 44. (S)-N-(4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)quinine-3-aminocarbamate (Compound 44)

[0400]

[0401] Compound 44 (22.76 mg, gray solid). LCMS (ESI): [M+H] + =474.1.

[0402] 1 H NMR(400MHz,CD3OD)δppm 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).

[0403] Example 60. (S)-N-(6,6-dimethylpiperidin-3-yl)-4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 60)

[0404]

[0405] Compound 60 (28.88 mg, gray solid). LCMS (ESI): [M+H] + =476.3;

[0406] 1H NMR(400MHz,CD3OD)δppm 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).

[0407] The following compounds were synthesized by reacting (S)-3-methyl-4-(3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine with the corresponding amine:

[0408] Example 69. 4-(6-((S)-3-methylmorpholine)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((3S,6S)-6-methylpiperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 69)

[0409]

[0410] Compound 69 (51.77 mg, yellow solid). LCMS (ESI): [M+H] + =476.2.

[0411] 1 H NMR(400MHz,CD3OD)δppm 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)

[0412] Example 70. (S)-N-(4-(6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4-azaspiro[2.5]octyl-6-aminocarbamate (Compound 70)

[0413]

[0414] Compound 70 (32.21 mg, white solid). LCMS (ESI): [M+H] + =488.2.

[0415] 1 H NMR(400MHz,CD3OD)δppm 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,1H),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,1H),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)

[0416] Example 71. N-((S)-5,5-difluoropiperidin-3-yl)-4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 71)

[0417]

[0418] Compound 71 (3.87 mg, white solid). LCMS (ESI): [M+H] + =498.2.

[0419] 1 H NMR(400MHz,CD3OD)δppm 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).

[0420] Example 72. 4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((3S,5R)-5-methylpiperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 72)

[0421]

[0422] Compound 72 (7.67 mg, white solid). LCMS (ESI): [M+H] + =476.2.

[0423] 1 H NMR(400MHz,CD3OD)δppm 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)

[0424] Example 73. N-((3S,5S)-5-fluoropyridin-3-yl)-4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 73)

[0425]

[0426] Compound 73 (21.65 mg, white solid). LCMS (ESI): [M+H] + =480.2;

[0427] 1 H NMR(400MHz,CD3OD)δppm 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).

[0428] Example 74. N-((3S,5R)-5-fluoropyridin-3-yl)-4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 74)

[0429]

[0430] Compound 74 (4.56 mg, white solid). LCMS (ESI): [M+H] + =480.2;

[0431] 1 H NMR(400MHz,CD3OD)δppm 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).

[0432] Example 75. 4-(5-fluoro-6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2-aminocarbamate (Compound 75)

[0433]

[0434] Step 1: tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholino)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0435]

[0436] A solution of tert-butyl(S)-3-((4-(6-((S)-3-methylmorpholino)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (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]octanedi(tetrafluoroborate) salt (0.76 g, 2.14 mmol) in acetonitrile (5 mL) was slowly added dropwise, maintaining the temperature below -20 °C. The reaction mixture was stirred at -20 °C for 1 hour. The reaction mixture was then quenched by adding a saturated aqueous sodium sulfite solution (30 mL) at -20 °C. The reaction mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by rapid column chromatography (silica gel, 0-50% gradient of ethyl acetate / petroleum ether) to give an oily brown compound, tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholino)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (60 mg, 0.08 mmol, yield 12%). LCMS (ESI): [M+H + =720.3.

[0437] Step 2: tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0438]

[0439] Add an aqueous solution of sodium hydroxide (4M, 0.21mL, 0.83mmol) to a 1,4-dioxane (3mL) solution of tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholino)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (75mg, 0.10mmol). 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 * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude, oily brown compound, tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (60 mg). LCMS (ESI): [M+H] + =580.3.

[0440] Step 3: 4-(5-fluoro-6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

[0441]

[0442] A solution of tert-butyl(S)-3-((4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester (60 mg, 0.10 mmol) in dichloromethane (2 mL) was cooled to 0 °C, and a solution of dioxane (4 M, 0.52 mL, 2.08 mmol) containing hydrogen chloride was added. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was evaporated to dryness and purified by preparative HPLC to give a white solid compound 4-(5-fluoro-6-((S)-3-methylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidine-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (formate, 11.68 mg, 22 μmol, yield 22%). LCMS(ESI):[M+H] + =480.2;

[0443] 1H NMR(400MHz,CD3OD)δppm 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)

[0444] Example 101. (S)-N-(piperidin-3-yl)-4-(6-(pyrrolidin-1-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 101, Compound 213 of Patent CN201780057760.8)

[0445]

[0446] Following the same synthetic method as Example 49 of patent CN201780057760.8, we synthesized compound 213 (116.75 mg), a yellow solid; LC-MS: [M+H] + =431.2;

[0447] 1 H NMR: (400MHz, CD3OD): δppm 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).

[0448] We synthesized compound 32 using the same method as for other substrates, employing the same chlorine intermediate tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester, and after deprotection, we obtained the following compounds:

[0449] Example 103. 4-(6-(3-oxo-6-azabicyclo[3.1.1]hept-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2-aminocarbamate (Compound 103)

[0450]

[0451] Compound 103 (33.22 mg, yellow solid). LCMS (ESI): [M+H] + =460.2;

[0452] 1 H NMR (400MHz, CD3OD) δppm 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).

[0453] Example 104. 4-(6-((S)-3-ethylmorpholinyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2-aminocarbamate (Compound 104)

[0454]

[0455] Compound 104 (11.72 mg, yellow solid). LCMS (ESI): [M+H] + =476.2;

[0456] 1H NMR (400MHz, CD3OD) δppm 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(brd,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)

[0457] Using the same method as that used to synthesize compound 27, and employing the same chlorine intermediate tert-butyl(S)-3-((4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid ester, coupled with other substrates (and further reduced if necessary), we obtained the following compounds:

[0458] Example 105: A mixture of (S)-4-(6-(2,5-dihydropyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (compound 105) and (S)-4-(6-(4,5-dihydropyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (compound 106).

[0459]

[0460] A mixture of compounds 105 and 106 (2.29 mg, white solid). LCMS (ESI): [M+H] + =476.2;

[0461] Compound 105 accounted for 60.7% of the total HPLC concentration. Compound 106 accounted for 38.2% of the total HPLC concentration.

[0462] 1H NMR (400MHz, DMSO-d6) δppm 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).

[0463] Example 109. (S)-4-(6-(3,4-dihydropyran-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 109)

[0464]

[0465] Compound 109 (5.20 mg, white solid). LCMS (ESI): [M+H] + =445.2;

[0466] 1 H NMR (400MHz, DMSO-d6) δppm 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).

[0467] Example 110. 4-(6-(3-methyltetrahydropyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine-2-aminocarbamate (Compound 110)

[0468]

[0469] Compound 110 (6.08 mg, white solid). LCMS (ESI): [M+H] + =461.2;

[0470] 1 H NMR (400MHz, CD3OD) δppm 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)

[0471] Example 111. N-((S)-piperidin-3-yl)-4-(6-(tetrahydropyran-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 111)

[0472]

[0473] Compound 111 (21.20 mg, white solid). LCMS (ESI): [M+H] + =447.2;

[0474] 1 H NMR(400MHz,CD3OD)δppm 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).

[0475] Compound 111 was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm); mobile phase: phase A was carbon dioxide, phase B was 0.1% ammonia / ethanol; phase B was maintained at 40%; flow rate: 80 mL / min) to obtain target compounds 112 and 113.

[0476] Example 112. Chiral monomer with shorter elution time after chiral resolution of compound 111 (compound 112).

[0477]

[0478] Compound 112 (1.15 mg, white solid). LCMS (ESI): [M+H] + =447.3; SFC analysis (column: Chiralcel OJ-3 (100mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4 minutes, hold phase B at 40% for 0.5 minutes, hold phase B at 5% for 1.5 minutes, flow rate: 2.8 mL / min): RT = 3.598 min, ee = 100%;

[0479] 1 H NMR(400MHz,CD3OD)δppm 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).

[0480] Example 113. Chiral monomer (compound 113) with a longer elution time after chiral resolution of compound 111.

[0481]

[0482] Compound 113 (1.25 mg, white solid). LCMS (ESI): [M+H] +=447.3; SFC analysis (column: Chiralcel OJ-3 (100mm*4.6mm), 3um; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine / ethanol; gradient: phase B from 5% to 40% in 4 minutes, hold phase B at 40% for 0.5 minutes, hold phase B at 5% for 1.5 minutes, flow rate: 2.8 mL / min): RT = 4.426 min, ee = 98.80%;

[0483] 1H NMR(400MHz,CD3OD)δppm 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)

[0484] Example 114. (S)-Dimethyl(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phosphonocarbamate (Compound 114)

[0485]

[0486] Step 1: tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

[0487]

[0488] 150 mg (0.24 mmol) of tert-butyl(S)-3-((4-(6-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate, 24 mg (24 μmol) of methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphine)xanthan][2-amino-1,1-biphenyl]palladium(II)dichloromethane adduct, 119 mg (1.18 mmol) of triethylamine, and 36 mg (0.47 mmol) of dimethylphosphine oxide were added to xylene (1500 μL) in a glove box, and the mixture was stirred at 145 °C for 16 hours. The reaction mixture was filtered, the filtrate was evaporated to dryness, and the residue was purified by rapid column chromatography (silica gel, 1-20% gradient of tetrahydrofuran / petroleum ether) to give the crude compound tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (165 mg), a white solid. LCMS (ESI): [M-100+H] + =579.2.

[0489] Step 2: tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

[0490]

[0491] An aqueous solution of sodium hydroxide (4M, 304 μL, 1.22 mmol) was added to 1,4-dioxane (1650 μL) of tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (165 mg, 0.24 mmol), and the mixture was then stirred at 50 °C for 16 hours. The 1,4-dioxane was evaporated to dryness, extracted with ethyl acetate (2 mL * 2), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness to give crude tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (130 mg). LCMS (ESI): [M + H + =539.2.

[0492] Step 3: (S)-Dimethyl(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phosphonocarbamate

[0493]

[0494] A solution of tert-butyl(S)-3-((4-(6-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylate (130 mg, 0.19 mmol) in dichloromethane (1500 μL) was added to a solution of hydrogen chloride / dioxane (4 M, 200 μL, 0.80 mmol), and the mixture was stirred at 50 °C for 16 hours. The reaction solution was evaporated to dryness and purified by preparative HPLC to obtain a white solid (S)-dimethyl(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)phosphine oxide (formate, 21.69 mg, 49 μmol, yield 26%). LCMS (ESI): [M+H] + =438.9;

[0495] 1 H NMR (400MHz, CD3OD) δppm 9.16-8.89(m,1H),8.64(s,1H),8.55(s,1H),8.15(brs,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).

[0496] The corresponding compounds were synthesized by reacting (S)-3-methyl-4-(3-(2-(methanesulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine with the corresponding amines:

[0497] Example 115. 4-(6-((S)-3-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((3S,5S)-5-methylpiperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Compound 115)

[0498]

[0499] Compound 115 (19.05 mg, white solid). LCMS (ESI): [M+H] + =476.2;

[0500] 1 H NMR(400MHz,CD3OD)δppm 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)

[0501] Example 1: In vitro enzymatic inhibitory activity test of compounds CDK7, CDK2, CDK9 and CDK12

[0502] The assay was performed in a U-bottom 384-well plate (corning, 4512#) at a reaction temperature of 27°C. CDK7 / Cyclin H was diluted in assay buffer (20 mM MES, pH 6.75, 0.01% Tween 20, 50 μg / mL BSA, 6 mM MgCl2) to obtain the corresponding 2.4× enzyme solution. CDK2 / Cyclin E1 was diluted in assay buffer (20 mM MES, pH 6.75, 0.01% Tween 20, 50 μg / mL BSA, 6 mM MgCl2) to obtain the corresponding 2.4× enzyme solution. CDK9 / Cyclin T1 was diluted in assay buffer (20 mM MES, pH 6.75, 0.01% Tween 20, 50 μg / mL BSA, 10 mM MgCl2) to obtain the corresponding 2.4× enzyme solution. CDK12 / CyclinK was diluted in assay buffer (80 mM MES, pH 6.5, 0.01% Tween 20, 50 μg / mL BSA, 10 mM MgCl2) to obtain enzyme solutions of the corresponding 2.4× concentration. The compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mM. Before use, the compound was diluted with DMSO to 10 concentration gradients from 25 nM to 500 μM, and each gradient was 8.3-fold diluted in assay buffer to obtain 6× concentration compound solutions. The peptide substrate and ATP were diluted in assay buffer to obtain 2.4× concentration peptide substrate and ATP mixed solutions. 2 μL of the test compound solution was mixed with 5 μL of the enzyme solution and incubated for 10 min. Then, 5 μL of the peptide substrate and ATP mixed solution was added, and the mixture was incubated at 27°C for 180 min. The reaction was then terminated by adding 4 μL of 120 mM EDTA to each sample. A 100% inhibition control was achieved by replacing the compound solution with an assay buffer containing 20 μM astrocytoxin, and a 0% inhibition control was achieved by replacing the compound solution with DMSO. At least two parallel controls were performed for each assay. Specifically, the CDK7 inhibition assay used the CDK7 / cyclin H / MAT1 complex (6 nM) and the "5-FAMCDK7tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK, where "5-FAM" refers to 5-carboxyfluorescein).The CDK9 inhibition assay used a CDK9 / cyclin T1 complex (8 nM) and a “5-FAM-CDK9tide” peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-GSRTPMY-NH2, where 5-FAM is as defined above and NH2 represents the C-terminal amide). The CDK12 inhibition assay used a CDK12 (aa686-1082) / cyclin K complex (50 nM) and a “5-FAM-CDK9tide” (2 μM) as defined above. The CDK2 inhibition assay used a CDK2 / cyclin E1 complex (0.5 nM) and a “5-FAM-CDK7tide” (2 μM) as defined above.

[0503] The reaction mixture was analyzed by electrophoretic separation of the fluorescent substrate and phosphorylation product on a Caliper EZ Reader II. Data were calculated using GraphPad Prism version 6.0, and IC50 values ​​were adjusted using a nonlinear regression model of the dose-response curve.

[0504] The IC50 results of these measurements are shown in Table 1 below:

[0505] Table 1

[0506]

[0507]

[0508]

[0509] Note: --- indicates that this test was not performed.

[0510] As shown in the table above, through in vitro bioactivity screening using staurosporine as a control, the compounds of this invention all exhibit excellent inhibitory activity against CDK7 kinase with good selectivity. Furthermore, some compounds are significantly better than compound 213 (Example 101), the closest in structure to compound 213 in patent CN201780057760.8, and hold promise for development into drugs for regulating CDK7 kinase activity or treating CDK7-related diseases.

[0511] Example 2: Cell bioactivity detection

[0512] A2780 and HCC70 cells were trypsinized, and the cell suspension was transferred to 15 mL centrifuge tubes. The cells were centrifuged at 800 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in fresh medium (RPMI 1640 + 10% FBS). After counting, the cells were seeded at 2000 cells / well in 384-well plates (50 μL of RPMI 1640 + 10% FBS was added to columns 2 and 23, and 50 μL of DPBS was added to the surrounding wells). The plates were incubated overnight at 37°C, 5% CO2.

[0513] On the second day, the compounds were added to the well plates. The highest concentration of the compounds was 10 μM, diluted 1:4, for a total of 9 concentrations. The highest concentration of the positive compound, Paclitaxel, was 1 μM, diluted 1:3, for a total of 9 concentrations. The DMSO content in each well was uniformly 0.2%. The cell plates were centrifuged at 800 rpm for 30 seconds and incubated in an incubator (37°C, 5% CO2) for 72 hours. On the fourth day, Cyquant reagent (3X) was prepared according to the kit instructions. For each 384-well plate, the following proportions were used: 11.568 mL of DPBS. Directnucleic acid stain 72μL, 360 μL of direct background suppressor was mixed and allowed to stand at room temperature. The cell culture plate was removed and allowed to equilibrate at room temperature for 30 min. 25 μL of Cyquant reagent (3X) was added to each well of a 384-well plate using a multi-drop assay. The cells were incubated at 37°C for at least 60 min. The plate was read using Acumen (Acumen settings: 488 nm excitation wavelength). IC50 results were analyzed using an IDBS XLFIT5 analyzer.

[0514] The results of these measurements are shown in Table 2 below.

[0515] Table 2

[0516]

[0517]

[0518]

[0519] Note: --- indicates that this test was not performed.

[0520] As shown in Table 2, the compounds of this invention have very good inhibitory effects on human breast cancer cells HCC70 and ovarian cancer A2780. Furthermore, some compounds are tens of times more active than compound 213 (Example 101), which is structurally closest to compound 213 in patent CN201780057760.8.

[0521] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: R 1 It can be CF3, F, Cl, Br or CN; R 5 It is H or halogen; X is N; R 2 For P(=O)Me2, R 3 for 2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 for 3. The compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 for 4. The compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 for 5. The compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 for 6. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 for 7. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 It is CF3.

8. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The R mentioned 3 for 9. A compound as shown in Formula I or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any of the following compounds:

10. A pharmaceutical composition comprising a compound of Formula I as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

11. Use of the compound of Formula I as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in claim 10, for the preparation of a medicament for the prevention and / or treatment of proliferative diseases.

12. The use as described in claim 11, characterized in that, The proliferative diseases mentioned are cancer, benign growths, angiogenesis, inflammatory diseases, or autoimmune diseases.

13. The use as described in claim 12, characterized in that, The cancers mentioned are leukemia, breast cancer, ovarian cancer, brain cancer, lung cancer, liver cancer, melanoma, bladder cancer, colon cancer, esophageal cancer, bone cancer, neuroblastoma, pancreatic cancer, prostate cancer, testicular cancer, epithelial sarcoma, soft tissue sarcoma, or multiple myeloma.

14. The use as described in claim 12, characterized in that, The cancers mentioned are small cell lung cancer, acute myeloid leukemia, or acute lymphoblastic leukemia.

15. The use as described in claim 12, characterized in that, The proliferative disease mentioned is an autoinflammatory disease.

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