TWI912370B - Aromatic heterocyclic compounds, pharmaceutical compositions and their applications - Google Patents

Abstract

This invention discloses an aromatic heterocyclic compound, a pharmaceutical composition, and its applications. Specifically, it discloses a compound as shown in Formula I, its stereoisomer, its diastereomer, or a pharmaceutically acceptable salt of any of the foregoing, or a crystalline form or solvent compound of any of the foregoing. The aromatic heterocyclic compound of this invention has a novel structure, good CDK7 inhibitory activity, and good selectivity.

Description

Aromatic heterocyclic compounds, pharmaceutical compositions and their applications

This application claims priority to Chinese Patent Application 2020115524787, filed on December 24, 2020, and Chinese Patent Application 2021109928237, filed on August 27, 2021. The full text of the aforementioned Chinese patent applications is incorporated herein by reference.

This invention relates to aromatic heterocyclic compounds, their preparation methods, pharmaceutical compositions, and their applications.

Members of the cell cycle protein-dependent kinase (CDK) family play crucial regulatory roles in proliferation. CDK7 is unique among mammalian CDKs, possessing integrated kinase activity and regulating the cell cycle and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is considered to act as the CDK1/2 initiation kinase (CAK), thus phosphorylation of conserved residues in CDK1/2 by CDK7 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. CDK7’s two functions (CAK and CTD phosphorylation) together support key aspects of cell proliferation, cell cycle and transcription.

Disruption of RNAP IICTD phosphorylation has been shown to preferentially affect proteins with short half-lives, including anti-apoptotic BCL-2 family proteins. 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.

The high sequence and structural similarity of the 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 CKD7 inhibitors hold promise as treatments for CLL and other cancers.

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

The present invention solves the above-mentioned technical problems through the following technical solution.

This invention provides a pharmaceutically acceptable salt of a compound of Formula I, its stereoisomer, its diastereomer, or any of the foregoing (referring to the compound of Formula I, its stereoisomer, or its diastereomer), or a crystal form or solvent of any of the foregoing (referring to the compound of Formula I, its stereoisomer, its diastereomer, or a pharmaceutically acceptable salt): ^R1 is _CF3 , F, Cl, Br, or CN; ^R5 is H or a halogen; X is N; ^R2 is... , , , "4-12 membered heterocycloalkyl groups with O as the heteroatom and 1-4 heteroatoms", "4-12 membered heterocycloalkyl groups with O as the heteroatom and 1-4 heteroatoms" substituted with one or more R ^2-8 atoms, and "4-12 membered heterocycloalkyl groups with N as the heteroatom and 1-4 heteroatoms" substituted with one or more R ^2-9 atoms. , , , Or -P(=O) R ^2-10 R ^2-11 ; Z ¹ is N or CH; Z ² is O or S(=O) ₂ , R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are independently H, C ₁ -C ₆ alkyl or "C ₁ -C ₆ alkyl substituted with one or more halogens", or R ^2-1 and R ^2-2 are linked to form a -(CH ₂ ) _m- structure, or R ^2-1 and R ^2-3 are linked to form a -(CH ₂ ) _m- structure, or R ^2-1 and R ^2-4 are linked to form a -(CH ₂ ) _m- structure, or R ^2-2 and R ^2-3 are linked to form a -(CH ₂ ) _m- structure, m is 1, 2 or 3; n ₁₁ is 1 or 2; each R ^2-5 is independently H or C ₁ - _C6 alkyl; _n5 , _n6 , _n7 and _n8 are independently 0, 1, 2 or 3, and _n5 and _n7 are not simultaneously 0, _n6 and _n8 are not simultaneously 0; ^R2-6 and ^R2-7 are independently _NH2 or _C1 - _C6 alkyl; _n9 and _n10 are independently 0, 1 or 2; each ^R2-8 is independently _C1 - _C6 alkyl; each ^R2-9 is independently OH, CN, _C1 - _C6 alkyl, _C1 - _C6 alkyl substituted with one or more OH atoms, or "a 4-12 membered heterocycloalkyl with one to four heteroatoms selected from one or more of O, S and N"; ^R2-10 and ^R2-11 are independently _C1 - _C6 alkyl; ^R3 is , , , , , , , , , , , or .

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 form or solvent of any of the foregoing, are defined as follows, and unmentioned groups are as described in any embodiment of the present application (hereinafter referred to as "in a certain embodiment of the present invention"). When ^R2-1 , ^R2-2 , ^R2-3 , and ^R2-4 are independently _C1 - _C6 alkyl or " _C1 - _C6 alkyl substituted with one or more halogens", the _C1 - _C6 alkyl is _C1 - _C3 alkyl, preferably methyl, ethyl, n-propyl, or isopropyl, for example methyl or ethyl, and again for example methyl.

In one embodiment of this invention, when ^R² is Hour, for , , , , , , , , , , , or .

In one aspect of the invention, when each ^R2-5 is independently a _C1 - _C6 alkyl group, the _C1 - _C6 alkyl group is a _C1 - _C3 alkyl group, preferably methyl, ethyl, n-propyl or isopropyl, for example methyl.

In one aspect of the invention, when ^R2-6 and ^R2-7 are independently _C1 - _C6 alkyl, the _C1 - _C6 alkyl is _C1 - _C3 alkyl, preferably methyl, ethyl, n-propyl or isopropyl, for example methyl.

In one embodiment of this invention, when ^R² is Hour, for , , , , , , , , or ,For example , , or .

In one aspect of this invention, when ^R2 is a "4-12 membered heterocycloalkyl group with O as the heteroatom and 1-4 heteroatoms" or a "4-12 membered heterocycloalkyl group with O as the heteroatom and 1-4 heteroatoms replaced by one or more ^R2-8 ", the "4-12 membered heterocycloalkyl group with O as the heteroatom and 1-4 heteroatoms" is a "4-6 membered heterocycloalkyl group with O as the heteroatom and 1 heteroatom," such as tetrahydrofuranyl or tetrahydropyranyl, and for example... , or .

In one aspect of the invention, when each of ^R2-8 is independently a _C1 - _C6 alkyl group, the _C1 - _C6 alkyl group is a _C1 - _C3 alkyl group, preferably methyl, ethyl, n-propyl or isopropyl, for example methyl.

In one embodiment of the present invention, when ^R2 is a " ^4-12- membered heterocycloalkyl group with N as the heteroatom and 1-4 heteroatoms substituted by one or more ^R2-9 groups," the "4-12-membered heterocycloalkyl group with N as the heteroatom and 1-4 heteroatoms substituted by one or more ^R2-9 groups" is a "4-6-membered heterocycloalkyl group with N as the heteroatom and 1-2 heteroatoms substituted by one or two R2-9 groups, such as an aziridine substituted by one or two ^R2-9 groups, a pyrrolidinyl substituted by one or two ^R2-9 groups, a piperidinyl substituted by one or two ^R2-9 groups, or a "piperazinyl substituted by one or two ^R2-9 groups," and for example... , , , , , or .

In one aspect of the invention, when each ^R2-9 is 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.

In one embodiment of this invention, when each R ^2-9 is independently "a 4-12 membered heterocycloalkyl group with one or more heteroatoms selected from O, S, and N, and having 1-4 heteroatoms", the "4-12 membered heterocycloalkyl group with one or more heteroatoms selected from O, S, and N, and having 1-4 heteroatoms" is "a 4-6 membered heterocycloalkyl group with one or more heteroatoms selected from O, and having 1-2 heteroatoms", for example, oxocyclobutane, and for another example... .

In one embodiment of this invention, ^R1 is _CF3 , F, Cl, Br, or CN; ^R5 is H or a halogen; X is N; ^R2 is... , , , "4-12 membered heterocycloalkyl groups with O as the heteroatom and 1-4 heteroatoms", "4-12 membered heterocycloalkyl groups with O as the heteroatom and 1-4 heteroatoms" substituted with one or more R ^2-8 atoms, and "4-12 membered heterocycloalkyl groups with N as the heteroatom and 1-4 heteroatoms" substituted with one or more R ^2-9 atoms. , , or ^Z1 is N or CH; ^Z2 is O or S(=O) ₂ ; ^R2-1 , ^R2-2 , ^R2-3 and ^R2-4 are independently H, _C1 - _C6 alkyl or " _C1 - _C6 alkyl substituted with one or more halogens", or ^R2-1 and ^R2-2 are linked to form a -( _CH2 ) _m- structure, or ^R2-1 and ^R2-3 are linked to form a -( _CH2 ) _m- structure, or ^R2-1 and ^R2-4 are linked to form a -( _CH2 ) _m- structure, or ^R2-2 and ^R2-3 are linked to form a -( _CH2 ) _m- structure, where m is 1, 2 or 3; _n11 is 1 or 2; each ^R2-5 is independently H or _C1 - _C6 alkyl; _n5 , _n6 , n _R7 and _n8 are independently 0, 1, 2, or 3, and _n5 and _n7 are not simultaneously 0, _n6 and _n8 are not simultaneously 0; ^R2-6 and ^R2-7 are independently _NH2 or _C1 - _C6 alkyl; _n9 and _n10 are independently 0, 1, or 2; each ^R2-8 is independently _C1 - _C6 alkyl; each ^R2-9 is independently OH, CN, _C1 - _C6 alkyl, _C1 -C6 alkyl substituted with one or more OH atoms, or " _a 4-12 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of O, S, and N"; ^R3 is , , , , , , , , , , , or .

In one embodiment of this invention, ^R1 is _CF3 .

In one embodiment of the present invention, ^R2-1 , ^R2-2 , ^R2-3 and ^R2-4 are independently H or _C1 - _C6 alkyl, or ^R2-1 and ^R2-3 are linked to form a -( _CH2 ) _m- structure, or ^R2-1 and ^R2-4 are linked to form a -( _CH2 ) _m- structure, or ^R2-2 and ^R2-3 are linked to form a -( _CH2 ) _m- structure.

In one aspect of this invention, In this configuration, ^Z1 is N, ^Z2 is S(=O) ₂ , and ^R2-1 , ^R2-2 , ^R2-3 , and ^R2-4 are independently H or _C1 - _C6 alkyl; or ^Z1 is N, ^Z2 is O, and ^R2-1 , ^R2-2 , ^R2-3 , and ^R2-4 are H or _C1 - _C6 alkyl, or ^R2-1 and ^R2-3 are connected to form a _-CH2- or -( _CH2 ) _2- structure, or ^R2-2 and ^R2-3 are connected to form a _-CH2- structure; or ^Z1 is CH, ^Z2 is O, and ^R2-1 , ^R2-2 , ^R2-3 , and ^R2-4 are all H.

In one aspect of this invention, In this configuration, ^Z1 is N, ^Z2 is S(=O) ₂ , ^R2-1 , ^R2-2 , ^R2-3 , and ^R2-4 are independently H, and _n11 is 0; or, ^Z1 is N, ^Z2 is O, ^R2-1 , ^R2-2 , ^R2-3 , and ^R2-4 are H or _C1 - _C6 alkyl, or ^R2-1 and ^R2-3 are linked to form a _-CH2- or -( _CH2 ) _2- structure, or ^R2-1 and ^R2-4 are linked to form a _-CH2- structure, and _n11 is 0 or 1; or, ^Z1 is CH, ^Z2 is O, ^R2-1 , ^R2-2 , ^R2-3 , and ^R2-4 are all H, and _n11 is 0.

In one embodiment of this 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.

In one embodiment of this invention, _n9 is 0; _n10 is 0, 1, or 2.

In one embodiment of this invention, ^R² is -P(=O) _Me² . , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Preferably, ^R² is -P(=O) _Me² . , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In one embodiment of this invention, ^R3 is... , , , , , or .

In one aspect of this invention, the compound represented by Formula I is any of the following compounds: .

In one aspect of this invention, the compound represented by Formula I is any of the following compounds:

The compound with a retention time of 6.763 min under the following conditions is... One stereoisomer: Chromatographic column: Cellulose 2 (150 mm × 4.6 mm), 5 μm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/methanol; Gradient: Phase B from 5% to 40% in 5 minutes, holding at 40% for 2.5 minutes, holding at 5% for 2.5 minutes, Flow rate: 2.5 mL/min;

The compound with a retention time of 7.118 min under the following conditions is... One stereoisomer: Chromatographic column: Cellulose 2 (150 mm × 4.6 mm), 5 μm; Mobile phase: Phase A was carbon dioxide, Phase B was 0.05% diethylamine/methanol; Gradient: Phase B increased from 5% to 40% over 5 minutes, held at 40% for 2.5 minutes, then held at 5% for 2.5 minutes; Flow rate: 2.5 mL/min

The compound with a retention time of 3.598 min under the following conditions is... One stereoisomer: Chromatographic column: Chiralcel OJ-3 (100 mm × 4.6 mm), 3 μm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 4 min, holding 40% Phase B for 0.5 min, holding 5% Phase B for 1.5 min, Flow rate: 2.8 mL/min;

The compound with a retention time of 4.426 min under the following conditions is... One stereoisomer in the study: Chromatographic column: Chiralcel OJ-3 (100 mm × 4.6 mm), 3 μm; Mobile phase: Phase A is carbon dioxide, Phase B is 0.05% diethylamine/ethanol; Gradient: Phase B from 5% to 40% in 4 minutes, holding 40% Phase B for 0.5 minutes, holding 5% Phase B for 1.5 minutes, Flow rate: 2.8 mL/min.

The above-mentioned test conditions for retention time are not a limitation on the compound. As long as the above test conditions are used for measurement, and the obtained retention time is the same as or within the error range of the above-described retention time, and the compound is a stereoisomer of the compounds defined by the retention time, it falls within the protection scope of this invention.

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

General Synthesis Method 1:

As shown in General Synthetic Method 1, the compound represented by formula (I-1) reacts with a suitable halogenating agent (such as, but not limited to, elemental iodine) to give halogenated product I-2, which, by selecting a suitable protecting group (such as, but not limited to, benzoxanthyl), protects the NH functional group in the structure. The compound having formula (I-2) can be protected with benzoxanthyl at low temperature (e.g., 0°C) to give compound I-3. Subsequently, under suitable catalyst, compound I-8 is reacted with compound I-5 via 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, and compound I-4 is reacted with compound I-8 via Suzuki coupling under 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 sulfide I-10 (sulfide I-9 or "a mixture of sulfide I-10 and sulfide I-9") by suitable oxidant (such as, but not limited to, m-CPBA). The chlorinated intermediate I-6 (I-10, or a mixture of I-9/I-10) reacts with R ^-3 NH _-2 under suitable alkaline conditions (such as, but not limited to, DIEA) upon heating to give a compound of formula (I-7). This compound of formula (I-7) is then deprotected under suitable alkaline conditions (such as, but not limited to, NaOH) to give the final product of formula (I). If the R- ³ group contains other protecting groups (such as, but not limited to, Boc protecting groups), compound I is then reacted under suitable acidic conditions (such as, but not limited to, TFA/DCM) to give the final compound.

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.

As shown in General Synthesis Method 2, the compound represented by Formula (II-1) reacts with a suitable halogenating agent (such as, but not limited to, elemental iodine) to give halogenated product II-2, which selects a suitable protecting group (such as, but not limited to, benzoxenyl) to protect the NH functional group in the structure. For example, it can be protected with benzoxenyl chloride at low temperature (e.g., 0°C) to give compound II-3. Subsequently, under suitable catalysts, compound II-6 is reacted with compound II-5 via a one-pot Stille coupling, 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 suitable catalysts to obtain compound II-5. Compound II-5 is then reacted with nitrogen oxide compound II-6 under suitable oxidation conditions (such as, but not limited to, m-CPBA). Nitrogen oxide compound II-6 is then reacted 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 is then reacted with an amino compound ^R2H in the presence of a suitable alkali (such as, but not limited to, DIEA) to obtain the compound shown in formula (II). If the ³ -group contains other protecting groups (such as, but not limited to, Boc protecting groups), then compound II is given as the final compound under suitable acidic conditions (such as, but not limited to, TFA/DCM).

Compound II-5 is heated under suitable halogenation conditions with a suitable chlorination or bromination reagent (such as, but not limited to, methyl chloroformate) to give chlorinated intermediate II-7 or the corresponding brominated intermediate. Chlorinated intermediate II-7 is reacted with the corresponding borate/boronic acid or amino compound ^R2H under suitable catalytic conditions via suitable coupling conditions (such as, but not limited to, Suzuki coupling or Buchwald coupling) to give the compound of formula (II). If the ^R3 group contains other protecting groups (such as, but not limited to, Boc protecting groups), compound II is given the final compound under suitable acidic conditions (such as, but not limited to, TFA/DCM).

General Synthesis Method 3: In the compound shown in Formula I, when X is C( ^R4 ) and ^R4 is -P(=O) _Me2 , we creatively synthesized a novel key intermediate compound III-4. Through this intermediate III-4, the final compound III of this invention can be conveniently synthesized (corresponding to compound I with X being C( ^R4 ) and ^R4 being -P(=O) _Me2 ) via a simple substitution reaction.

As shown in General Synthetic Method 3, the compound represented by formula (III-1) (such as, but not limited to, brominated compounds) is coupled 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 is then reacted with compound (III-3) in the presence of a suitable acidic reagent (such as, but not limited to, trifluoroacetic acid or aluminum trichloride), with 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 with ^R3NH2 under suitable alkaline conditions (such as, but not limited to, DIEA) to give the compound of formula (III). If the ^R3 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).

The present invention also provides a pharmaceutical composition comprising the compound represented by Formula I, its stereoisomer, its diastereoisomer, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound represented by Formula I, its stereoisomer or its diastereoisomer), or a crystal form or solvent compound of any of the foregoing, and a pharmaceutical excipient.

This 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 solvents of any of the foregoing, or the pharmaceutical compositions thereof, in the preparation of pharmaceuticals. Preferably, the pharmaceuticals are used for the prevention and/or treatment of proliferative diseases.

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 compound represented by Formula I, its stereoisomer, its diastereomer, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound represented by Formula I, its stereoisomer or its diastereomer), or a crystal form or solvent of any of the foregoing, or a pharmaceutical composition thereof.

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.

The compounds of the present invention, their stereoisomers, their diastereomers, or pharmaceutically acceptable salts of any of the foregoing, or crystalline or solvent forms of any of the foregoing, pharmaceutical compositions may be administered locally or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans). Exemplary compositions for rectal administration include suppositories that 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 this invention can also be administered parenterally, for example by inhalation, injection or infusion, such as via intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal, intrathecal, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.

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 invention can be formulated into a wide variety of dosage forms.

The effective amounts of the compounds described in this invention, their pharmaceutically acceptable salts, their solvents, or drug combinations can be readily determined by routine experiments. The most effective and convenient route of administration and the most suitable formulation can also be determined by routine experiments.

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

Those skilled in the art will understand that, according to convention used in the art, the use of "..." in the structural formulas describing the radicals of this invention is appropriate. "" means that the corresponding group is connected to other segments and groups in the compound through this site.

Carbon atoms marked with an asterisk (*) are chiral carbon atoms, which are either S or R in configuration.

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, alkali addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable alkali addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, both inorganic and organic. When the compounds of the present invention contain both relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. 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).

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

The terms "compound," "pharmaceutically acceptable salt," "solvent compound," and "solvent compound 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 synthesis or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-pressure liquid chromatography, etc.), and can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the content of one stereoisomer of the compound is not less than 95% relative to all stereoisomers of the compound.

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

The atoms in the terms "compound," "pharmaceutically acceptable salt," "solvent," and "solvent of a pharmaceutically acceptable salt" can exist in either their natural abundance or non-natural abundance. For example, a hydrogen atom in its natural abundance form is approximately 99.985% protium and approximately 0.015% deuterium; in its non-natural abundance form, it is 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.

When any variable (e.g., Ra ^-1 ) appears multiple times in the definition of a compound, the definition of that variable at each position is independent of the definitions at other positions; their meanings are mutually independent and do not affect each other. Therefore, if a group is substituted by one, two, or three Ra ^-1 groups—that is, if the group may be substituted by a maximum of three Ra ^{-1 groups} —the definition of Ra ^-1 at that position is independent of the definitions of ^Ra-1 at other positions. Furthermore, combinations of substituents and/or variables are only permitted if the combination produces a stable compound.

The term "multiple" refers to 2, 3, 4 or 5, with 2 or 3 being preferred.

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, tributyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyl groups.

The term "cycloalkyl" refers to a saturated monocyclic, polycyclic, or bridging carbocyclic substituent composed of carbon and hydrogen atoms, which may be linked to the remainder of the molecule via a single bond through any suitable carbon atom; when polycyclic, it may be a fused or spirocyclic system with fused or spirocyclic linkages (i.e., the two geminal hydrogen atoms on the carbon atom are replaced by an alkyl group). Cycloalkyl substituents may be linked 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 group. In some embodiments, the _C3 to _C6 cycloalkyl groups include cyclopropyl ( _C3 ), cyclobutyl ( _C4 ), cyclopentyl ( _C5 ), bicyclo[1.1.1]pentane, and cyclohexyl ( _C6 ).

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 ring system or a spirocyclic system with fused or spirocyclic linkages. Preferably, it is a 4-12 saturated cyclic group containing 1-4 independent cyclic heteroatoms selected from N, O, and S. Exemplary 4-membered heterocyclic groups include, but are not limited to, aziridine, glyoxypropyl, thiocyclobutane, 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, oxothiofuranyl, 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, piperazinyl, triazinyl, or their isomers and stereoisomers; Exemplary 7-membered heterocyclic groups include, but are not limited to, aziridine, oxo-aziridine, thio-aziridine, oxo-aziridine, diaziridine, or their isomers and stereoisomers.

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 groups selected from nitrogen, oxygen, and sulfur. When it is a bicyclic group, at least one ring is aromatic. Examples include furanyl, pyridinyl, darazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isozolyl, oxazolyl, diazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, inzolyl, benzothiazolyl, benzoisothiazolyl, benzozolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, etc.

The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation 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).

The term “treatment” refers to therapeutic methods. When a specific condition is involved, treatment means: (1) relieving one or more biological manifestations of a disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or induces a condition or (b) one or more biological manifestations of a condition; (3) improving one or more symptoms, effects or side effects associated with a condition, or one or more symptoms, effects or side effects associated with a condition or its treatment; or (4) alleviating the development of a condition or one or more biological manifestations of a condition.

The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disability.

The term "therapeutic effective amount" refers to the amount of a compound that, when administered to a patient, is sufficient to effectively treat the disease or condition described herein. 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.

The term "patient" refers to any animal that has been or will be given the compound or combination of the present invention, according to embodiments of the invention; mammals are preferred, with humans being the most preferred. The term "mammalian" 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.

Without violating common sense in this field, the above-mentioned preferred conditions can be combined in any way to obtain various better examples of this invention.

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

The advantages of this invention are: it provides an aromatic heterocyclic compound with a novel structure, good CDK7 inhibitory activity and good selectivity.

The invention is further illustrated below by way of examples, but this does not limit the invention to the scope of the examples described. Experimental methods in the following examples that do not specify specific conditions are performed according to conventional methods and conditions, or according to the product instructions.

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

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

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 tributyl ester (2 mL, 10.49 mmol) was added to the above reaction system, and the reaction was continued at 25 ^° C for 16 hours. Thin-layer chromatography (TLC) monitoring (silicone, 1/3 volume ratio of 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 (silicone, 0-11.5% gradient of ethyl acetate/petroleum ether) to give a white solid compound (3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tributyl ester (85% purity, 900 mg, 2.36 mmol, yield 26%). LCMS (ESI): [M-56+H] ⁺ = 325.2;

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 8.52-8.25 (m, 1H), 5.58 (br s, 1H), 3.96 (m, 1H), 3.58 (m, 1H), 3.31(m, 3H), 1.83 (m, 1H), 1.61 (m, 3H), 1.35 (br d, J = 12.3 Hz, 9H).

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

3-Bromo-1H-pyrrolo[2,3-b]pyridine (100.00 g, 507.54 mmol) was dissolved in tetrahydrofuran (40 mL). Sodium terbutoxide (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 product 1-(benzenesulfonyl)-3-bromo-1H-pyrrolo[2,3-b]pyridine (170.00 g), a yellow solid. LCMS (ESI): [M+H] ⁺ = 337.2.

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

Compound 1-(benzenesulfonyl)-3-bromo-1H-pyrrolo[2,3-b]pyridine (170.00 g, 504.15 mmol), bis(pinnatrol)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. Concentration and purification of the residue by rapid column chromatography (silicone, ethyl acetate/petroleum ether gradient 0–10%) yielded a white solid compound 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)pyrrolo[2,3-b]pyridine (100.00 g, 260.23 mmol, yield 52%). LCMS (ESI): [M+H] ⁺ = 385.2.

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

To a solution of compound 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)pyrrolo[2,3-b]pyridine (46.00 g, 120.80 mmol), tributyl (3S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylic acid (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), tetra(triphenylphosphine)palladium (12.69 g, 10.98 mmol) was added under nitrogen protection, and the reaction system was heated to 100 ^° C for 16 hours. The reaction was cooled to room temperature, and an aqueous sodium hydroxide solution (5 M, 66 mL, 330.00 mmol) was added. The reaction 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 (1 M), 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 tributyl ester (16.00 g, 34.60 mmol, yield 32%), a yellow oily liquid. LCMS (ESI): [M+H] ⁺ = 463.3.

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)

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 (silicone, 0-50% gradient of tetrahydrofuran/petroleum ether) to obtain the 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 pure product (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.

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

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)

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, 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 the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was rinsed with saturated brine (20 mL). Washed with anhydrous sodium sulfate (mL), dried, filtered, concentrated, and the residue purified by rapid column chromatography (silicone, 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;

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.71-8.56 (m, 1H), 8.51-8.32 (m, 1H), 8.25 (br s, 1H), 7.45-7.30 (m, 1H), 5.70-5.53 (m, 1H), 4.17 (s, 4H), 3.84-3.70 (m, 1H), 3.45 (br s, 3H), 2.00 (br s, 1H), 1.78 (br s, 1H), 1.55-1.32 (m, 11H).

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

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

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, half of the solvent was removed by rotary evaporation, and 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 purification. LCMS (ESI): [M+H] ⁺ = 135.1.

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

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

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

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

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

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

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 terbutoxide (4.94 g, 51.40 mmol) was added at 0 ^° C, and the mixture was stirred at 0 ^° C for 30 minutes. Benzenesulfonyl chloride (6.6 mL, 51.40 mmol) was then added, and the reaction mixture was stirred at 20 °C for 2 hours. Concentration and purification of the residue by rapid column chromatography (silicone, 0-40% gradient of tetrahydrofuran/petroleum ether) yielded 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, 28% yield). LCMS (ESI): [M+H] ⁺ = 484.0.

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

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 (silicone, ethyl acetate/petroleum ether gradient 0–50%) 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.

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

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 system was stirred at 25 ^° C for 40 min. The mixture was filtered, and the filtrate was used directly in the next reaction. LCMS (ESI): [M+H] ⁺ = 582.1.

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

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

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 system 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 system was cooled and concentrated, and dichloromethane (300 mL) and a 10% sodium carbonate aqueous solution (200 mL) were added to the residue. After separating the organic phase, the aqueous phase was extracted with dichloromethane (200 mL × 2). The combined organic phases were dried with magnesium sulfate, filtered, and the filtrate was evaporated 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, a yellow solid (13.50 g, 66.44 mmol, yield 51%). LCMS (ESI): [M+H] ⁺ = 204.2.

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

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 min. 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 obtain crude product 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (11.80 g), which was a brown oil. This crude product was directly used in the next reaction without purification. LCMS (ESI): [M+H] ⁺ = 330.0.

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

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 terbutoxide (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 depressurization and concentration. The residue was purified by rapid column chromatography (silicone, 0-25% gradient of 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.

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

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 nitrogen atmosphere. The reaction was carried out at 100 ^° C for 2 hours under nitrogen protection, followed by a reaction at 140 ^° C for 14 hours. 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 (silicone, ethyl acetate/petroleum ether gradient 0-30%) 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.

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

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 the crude product compound 4-(6-morpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-ol hydrochloride (6.80 g). This compound was used directly in the next reaction. LCMS (ESI): [M+H] ⁺ = 366.1.

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

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 (silicone, ethyl acetate/petroleum ether gradient 0-90%) 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%), which is a yellow solid. LCMS (ESI): [M+H] ⁺ = 384.1;

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.00 (s, 1H), 8.58 - 8.42 (m, 1H), 7.84 (d, J = 1.8 Hz, 1H), 6.99 - 6.81 (m, 1H), 3.79 - 3.66 (m, 4H), 3.57 - 3.40 (m, 4H).

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

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

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 system was heated to 100 ^° C and reacted for 16 hours. The sample was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silicone, 0-100% gradient of tetrahydrofuran/petroleum ether) to give compound (1H-indol-7-yl)dimethylphosphine oxide (220 mg, 1.08 mmol, yield 11%), which was a yellow solid. LCMS (ESI): [M+H] ⁺ = 194.1.

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

The compound (1H-indol-7-yl)dimethylphosphine oxide (220 mg, 1.08 mmol) and the compound 2,4-dichloro-5-(trifluoromethyl)pyrimidine (220 μL, 1.63 mmol) were dissolved in hexafluoroisopropanol (10 mL), and trifluoromethanesulfonic acid (106 μL, 1.20 mmol) was added dropwise at 0 ^° C. The reaction system 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 organic phase was dried with magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparing silicone plates (1:2 volume ratio of 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.

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 Embodiment 4 of Patent WO2020093011A1.

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 13.00 (br s, 1H), 9.16 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H).

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

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

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 dichloromethane chloride (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 sodium bicarbonate aqueous solution (100 mL) and saturated brine (100 mL × 2), dried with sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by rapid column chromatography (silicone, ethyl acetate/petroleum ether gradient of 10-33%) to give compound 1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile (85% purity, 1.50 g, 8.91 mmol, yield 44%), white solid. LCMS (ESI): [M+H] ⁺ = 144.2.

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

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 product compound 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-carboxylonitrile (53.00 g). LCMS (ESI): [M+H] ⁺ = 270.0.

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

A solution of 3-iodo-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile (50.00 g, 148.68 mmol) in tetrahydrofuran (2.50 L) was cooled to 0 ^° C, and sodium hydroxide (60% purity, 10.71 g, 267.63 mmol) was added under nitrogen 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 the crude product. The crude product was slurried with methyl tributyl ether (100 mL) and filtered to give 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.

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

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 hexamethyldisiloxane (4.72 g, 14.30 mmol). The reaction mixture was stirred at 100 ^° C for 2 hours under nitrogen protection, and then the temperature was increased to 140 ^° C for 16 hours. The reaction mixture was evaporated to dryness, and the residue was purified by rapid column chromatography (silicone, 5-10% gradient of tetrahydrofuran/petroleum ether) to give a yellow solid compound 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.

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

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 system was stirred at 20 ^° C for 2 hours. Saturated sodium sulfite solution (1 mL) and saturated sodium bicarbonate solution (5 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). Organic phase concentration yielded the crude product compound 3-(2-(methylsulfonylurea)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonylurea)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile (230 mg), a yellow oil. This crude product was used directly in the next reaction. LCMS (ESI): [M+H] ⁺ = 508.0.

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

Referring to Patent WO2019143719, Embodiment 11 , intermediate H was prepared using the same synthesis method.

Preparation of intermediate J : Tertiary 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

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

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

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

Sodium terbutoxide (0.98 g, 10.23 mmol) was added to a 20 mL solution of 6-chloro-3-iodo-1H-pyrrole[2,3-b]pyridine (2.00 g, 6.82 mmol) in tetrahydrofuran. 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 off to give the crude product. The crude product was slurried with methyl tributyl ether (10 mL) and filtered to give a white solid compound, 6-chloro-3-iodo-1-(benzenesulfonyl)-1H-pyrrole[2,3-b]pyridine (2.55 g, 5.71 mmol, 85% yield). LCMS (ESI): [M+H] ⁺ = 418.9.

Step 3: Tertiary 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

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-pyrrole[2,3-b]pyridine (1.00 g, 2.39 mmol), tert-butyl(S)-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (1.18 g, 3.11 mmol), and hexamethyldisiloxane (1.02 g, 3.11 mmol). The reaction mixture was heated to 100 ^° C and stirred for 2 hours under nitrogen protection, then the temperature was increased to 140 ^° C and the reaction was carried out for 16 hours. The reaction mixture was evaporated to dryness, and the residue was purified by rapid column chromatography (silicone, ethyl acetate/petroleum ether gradient 0-25%) to give a yellow solid compound, tributyl(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.

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

Step 1: Tertiary 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 (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 morpholine (441 μL, 5.02 mmol) was added. The mixture was then stirred at 80 ^°C . The reaction was carried out at C for 16 hours. Two identical batches were cooled to room temperature and concentrated to give a brown, oily crude product: tributyl(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.

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

The compound tributyl(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-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (53.11 mg, 0.12 mmol, yield 40%). LCMS (ESI): [M+H] ⁺ = 448.3;

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.60-8.47 (m, 2H), 7.72 (s, 1H), 6.79 (br d, J = 8.8 Hz, 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).

The following compounds were synthesized using the same method as 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 compound:

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 )

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.66-8.41 (m, 2H) 7.66 (s, 1H) 6.53 (br s, 1H) 4.73 (s, 1H) 4.10 (br s, 1H) 3.83 - 3.95 (m, 2H) 3.55 - 3.69 (m, 1H) 3.55 - 3.69 (m, 1H) 3.42 (br d, J = 9.78 Hz, 1H) 3.25 (br d, J = 11.98 Hz, 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).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD), δ ppm 8.54-8.30 (m, 2H), 7.60 (s, 1H), 6.74 (br s, 1H), 4.12-4.01 (m, 1H), 4.07 (m, 2H), 3.80-3.71 (m, 1H), 3.16 (br d, J = 11.4 Hz, 1H), 3.06 (br t, J = 10.9 Hz, 2H), 2.87 (br d, J = 12.6 Hz, 1H), 2.61-2.45 (m, 2H), 2.12-1.95 (m, 1H), 1.88 (br dd, J = 12.5, 3.1Hz, 2H), 1.77-1.64 (m, 1H), 1.62-1.40 (m, 4H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD), δ ppm 8.68-8.37 (m, 2H), 7.69 (s, 1H), 6.82 (br s, 1H), 4.39 (br d, J = 12.6 Hz, 2H), 4.24-3.94 (m, 1H), 3.46 (d, J = 6.4 Hz, 2H), 3.25 (br d, J = 11.8 Hz, 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, 3.9 Hz, 2H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD), δ ppm 8.51-8.29 (m, 2H), 7.56 (s, 1H), 6.45 (br s, 1H), 3.90 (m, 3H), 3.63-3.52 (m, 4H), 3.40 (m, 2H), 3.15 (m, 1H), 3.02 (m, 2H), 2.86 (br d, J = 12.9 Hz, 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).

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 )

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

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

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.64-8.43 (m, 2H), 7.69 (s, 1H), 6.90-6.74 (m, 1H), 4.12 (br s, 1H), 3.99 (q, J = 7.6 Hz, 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).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.54 (s, 2H), 7.65 (s, 1H), 6.47 (br d, J = 8.3 Hz, 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 = 12.0 Hz, 1H), 3.04-2.91 (m, 2H), 2.36 (t, J = 6.9 Hz, 2H), 2.26-2.14 (m, 1H), 2.11-2.01 (m, 1H), 1.91-1.81 (m, 1H), 1.75 (br d, J = 10.5 Hz, 1H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.65-8.43 (m, 2H), 7.70 (s, 1H), 6.89-6.76 (m, 1H), 4.18-4.00 (m, 1H), 3.92 (t, J = 7.2 Hz, 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 = 12.8 Hz, 1H), 2.68-2.55 (m, 2H), 2.23-2.05 (m, 1H), 1.91-1.79 (m, 3H), 1.72 (br t, J = 5.4 Hz, 4H), 1.67-1.57 (m, 2H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.49 (br s, 2H), 7.66 (s, 1H), 6.84-6.73 (m, 1H), 4.20-4.10 (m, 1H), 3.83-3.56 (m, 9H), 3.05 (br d, J = 12.8 Hz, 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).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.55 (s, 2H), 7.68 (s, 1H), 6.37 (br d, J = 8.0 Hz, 1H), 4.34 (br s, 1H), 4.03 (s, 4H), 3.93 (s, 2H), 3.89 (t, J = 7.0 Hz, 2H), 3.61-3.36 (m, 1H), 3.31-3.23 (m, 1H), 3.09-2.92 (m, 2H), 2.24 (t, J = 6.9 Hz, 2H), 2.18 (br d, J = 6.8 Hz, 1H), 2.11-2.03 (m, 1H), 1.92-1.83 (m, 1H), 1.82-1.69 (m, 1H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.54 (s, 2H), 7.71 (s, 1H), 6.82 (br d, J = 8.8 Hz, 1H), 4.41-4.25 (m, 2H), 4.23-4.06 (m, 2H), 3.96 (d, J = 9.0 Hz, 1H), 3.84 (d, J = 9.0 Hz, 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 = 6.5 Hz, 3H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.54 (s, 2H), 7.66 (s, 1H), 6.50 (br d, J = 8.5 Hz, 1H), 4.72 (s, 1H), 4.35 (br s, 1H), 3.94-3.87 (m, 2H), 3.62 (d, J = 9.8 Hz, 1H), 3.54 (br d, J = 10.8 Hz, 1H), 3.46-3.35 (m, 1H), 3.33-3.25 (m, 2H), 3.10-2.93 (m, 2H), 2.27-2.14 (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).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD), δ ppm 8.64-8.39 (m, 2H), 7.67 (s, 1H), 6.39 (br s, 1H), 4.88-4.84 (m, 4H), 4.22 (s, 4H), 4.06 (m, 1H), 3.27-3.23 (m, 1H), 2.96 (m, 1H), 2.69-2.55 (m, 2H), 2.13 (br s, 1H), 1.87-1.78 (m, 1H), 1.71-1.52 (m, 2H).

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 )

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

1H NMR (400 MHz, CD ₃ OD), δ ppm 8.51 (m, 2H), 7.69 (br s, 1H), 6.80 (br s, 1H), 4.51 (br s, 4H), 4.22 (br s, 1H), 3.54 (br s, 4H), 3.40 (br s, 1H), 3.14 (br s, 1H), 2.83 (br s, 2H), 2.16 (br s, 2H), 1.96 (br s, 4H), 1.76 (br s, 2H).

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 )

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

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

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 )

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

¹ H NMR (400 MHz, CD ₃ OD), δ ppm 8.68-8.38 (m, 2H), 7.66 (s, 1H), 6.38 (m, 1H), 4.08 (m, 1H), 3.84 (m, 2H), 3.80-3.72 (m, 4H), 3.70-3.64 (m, 2H), 3.26 (m, 1H), 2.97 (m, 1H), 2.62 (m, 2H), 2.15 (br s, 1H), 1.88-1.99 (m, 2H), 1.81 (m, 1H), 1.67 (m, 4H).

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 )

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

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

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 )

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

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

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.57 (m, 2H), 7.71 (m, 1H), 6.84 (m, 1H), 4.11 (m, 1H), 3.93 (m, 2H), 3.49 (m, 2H), 3.29 (m, 1H), 3.05 (m, 2H), 2.65 (m, 2H), 2.09 (m, 3H), 1.95 (m, 3H), 1.64 (m, 2H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.57 (m, 2H), 7.70 (m, 1H), 6.43 (m, 1H), 4.36 (m, 2H), 4.01 (m, 3H), 3.26 (m, 1H), 2.97 (m, 1H), 2.63 (m, 2H), 2.22 (m, 1H), 1.81 (m, 1H), 1.76 (s, 3H), 1.64 (m, 2H).

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

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.57 (m, 2H), 7.65 (m, 1H), 6.68 (m, 1H), 4.10 (m, 1H), 3.88 (m, 6H), 3.72 (m, 2H), 3.27 (m, 1H), 2.96 (m, 1H), 2.63 (m, 2H), 2.04 (m, 3H), 1.81 (m, 1H), 1.64 (m, 2H).

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 )

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

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

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.55 (m, 2H), 7.72 (m, 1H), 6.79 (m, 1H), 4.77-4.67 (m, 4H), 4.36 (m, 1H), 3.66-3.56 (m, 7H), 3.04 (m, 2H), 2.53 (m, 4H), 2.09 (m, 2H), 1.88-1.77 (m, 2H).

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

Step 1: Tertiary 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

(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 heated to 70 ^° C and stirred for 20 hours. Concentration and purification of the residue by rapid column chromatography (silicone, ethyl acetate/petroleum ether gradient 0-85%) yielded a yellow solid, tributyl(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.

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

The compound tributyl(S)-3-((4-(6-thiomorpholino-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-carboxylic acid ester (160 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL), and potassium salicylate 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. A saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phase was concentrated to yield the crude product, tributyl(S)-3-((4-(6-(1,1-thiomonolinyl)-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.

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

The compound tributyl(S)-3-((4-(6-(1,1-thiodimethylphosphoninyl)-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 (1 mL) was added, and it was concentrated again. The residue was purified by preparative HPLC to obtain a gray solid (S)-4-(3-(2-(piperidin-3-amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)thiomorpholin-1,1-dioxide (41.54 mg, 84 μmol, yield 50%). LCMS (ESI): [M+H] ⁺ = 496.2;

¹ H NMR (400MHz, CD ₃ OD): δ ppm 8.56 (m, 2H), 7.75 (s, 1H), 6.93 (br d, J = 8.5 Hz, 1H), 4.33 (br s, 1H), 4.23 (br s, 4H), 3.53 (br d, J = 12.3 Hz, 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).

Example 26. 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 (Compound 26 )

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

To a solution of compound (S)-3-methyl-4-(3-(2-(methylsulfonylurea)-5-(trifluoromethyl)pyrimidin-4-yl)-1-(benzenesulfonylurea)-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 system was stirred at 25 ^° C for 2 hours. Concentration and purification of the residue by preparative HPLC yielded a yellow oil, 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.

Step 2: 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

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 sodium hydroxide aqueous solution (4 M, 1787 μL, 7.15 mmol) was added. After addition, the reaction was carried out at 100 ^° C for 1 hour. Cool, adjust pH to 7 with hydrochloric acid, concentrate, and purify the residue 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;

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.67-8.52 (m, 1H), 8.48 (br s, 1H), 7.70 (s, 1H), 6.80-6.70 (m, 1H), 4.41 (br d, J = 6.2 Hz, 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), 2.89-2.75 (m, 1H), 2.11-1.93 (m, 1H), 1.84-1.64 (m, 2H), 1.60-1.49 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H), 1.22 (s, 3H), 1.19 (s, 3H).

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 )

Step 1: Tertiary 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

The 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 (0.30 g, 0.60 mmol), compound 3,6-dihydro-2H-pyran-4-boronate 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. Cooled to room temperature, concentrated, and the resulting residue was purified by rapid column chromatography (silicone, ethyl acetate/petroleum ether gradient 0–70%) to give a white solid compound, tributyl(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.

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

Compound tributyl(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. Concentration was performed, and 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-(piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (28.86 mg, 63 μmol, yield 45%). LCMS (ESI): [M+H] ⁺ = 445.2;

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.58 (m, 2H), 7.97 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 4.39 (m, 2H), 4.29 (s, 1H), 3.98 (t, J = 5.6 Hz, 2H), 3.49 (d, J = 8.4 Hz, 1H), 3.22 (s, 1H), 2.92 (t, J = 10.8 Hz, 2H), 2.75 (d, J = 1.8 Hz, 2H), 2.19 (s, 1H), 2.01 (s, 1H), 1.93-1.64 (m, 2H).

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 )

Step 1: Tertiary 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

Tertiary 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 (70 mg, 0.13 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (10 mL), and wet palladium 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 mixture 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.

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

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). A solution of 1,4-dioxane (4 M, 200 μL, 0.80 mmol) containing hydrogen chloride was added dropwise at 25 °C. After the addition was complete, the reaction proceeded at 25 °C. Stirred at °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 is a yellow solid. LCMS (ESI): [M+H] ⁺ = 447.3;

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.79-8.59 (m, 3H), 7.95 (m, 1H), 7.20 (m, 1H), 4.35 (m, 1H), 4.12-4.09 (m, 2H), 3.66-3.60 (m, 3H), 3.33 (m, 1H), 3.10-2.96 (m, 3H), 2.23 (m, 1H), 2.10-1.78 (m, 7H).

Using the same method as that used to synthesize compound 28 , and employing the same chloro 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:

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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.76-8.49 (m, 2H), 8.35 (br s, 1H), 7.91 (m, 1H), 7.18 (m, 1H), 4.14-3.64 (m, 6H), 3.36 (m, 1H), 2.96 (m, 1H), 2.63 (m, 2H), 2.34-2.21 (m, 2H), 1.77-1.57 (m, 2H), 1.56 (m, 2H).

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), and then the two components were purified by preparative HPLC to obtain target compounds 107 and 108 , both of which are formates.

Example 107. After chiral resolution of compound 29 , the chiral monomer with a shorter elution time (compound 107 )

Compound 107 (7.11 mg, yellow solid. LCMS (ESI): [M+H] ⁺ = 432.9; SFC analysis (column: Cellulose 2 (150 mm × 4.6 mm), 5 μm; mobile phase: phase A is carbon dioxide, phase B is 0.05% diethylamine/methanol; gradient: phase B from 5% to 40% in 5 min, hold phase B at 40% for 2.5 min, hold phase B at 5% for 2.5 min, flow rate: 2.5 mL/min): RT = 6.763 min, de = 100%;

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.77-8.35 (m, 2H), 7.83 (s, 1H), 7.41-7.20 (m, 1H), 7.11 (br s, 1H), 4.09 (br t, J = 8.0 Hz, 2H), 4.01 (td, J = 8.1, 5.0 Hz, 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).

Example 108. After chiral resolution of compound 29 , the chiral monomer with a longer elution time (compound 108 )

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.75-8.33 (m, 2H), 7.83 (s, 1H), 7.39-7.18 (m, 1H), 7.10 (br s, 1H), 4.15-3.95 (m, 3H), 3.92-3.80 (m, 2H), 3.68-3.53 (m, 1H), 3.30 (m, 1H), 2.91 (br d, J = 12.5 Hz, 1H), 2.64-2.50 (m, 2H), 2.39-2.26 (m, 1H), 2.20 (dq, J = 12.3, 7.8 Hz, 1H), 2.07 (dt, J = 15.1, 7.5 Hz, 1H), 1.75 (br d, J = 12.1 Hz, 1H), 1.64-1.42 (m, 2H).

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 12.32 (br s, 1H), 8.78-8.56 (m, 2H), 8.34 (br s, 1H), 7.91 (m, 2H), 7.35-7.27 (m, 1H), 4.46 (m, 1H), 4.06 (m, 3H), 3.20 (m, 1H), 2.94 (m, 1H), 2.60 (m, 2H), 1.91 (m, 3H), 1.61-1.54 (m, 7H).

Example 31. 4-(6-(3-oxadicyclo[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 )

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.77-8.56 (m, 3H), 7.93 (m, 1H), 7.25 (m, 1H), 4.63 (m, 1H), 4.25 (m, 1H), 4.00 (m, 1H), 3.67 (m, 1H), 3.52-3.33 (m, 2H), 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).

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 )

Step 1: Tertiary 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

In a nitrogen cabinet, di(triterenetributylphosphine)palladium (8 mg, 0.02 mmol) was added to a turbid mixture of compound tributyl(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), compound 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 solution was filtered, and the resulting mother liquor was concentrated to 1 mL. This solution was used directly in the next reaction. LCMS (ESI): [M+H] ⁺ = 714.3.

Step 2: Tertiary 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

A sodium hydroxide aqueous solution (2 M, 420 μL, 0.84 mmol) was added to a 1,4-dioxane (1 mL) solution of the above compound, tributyl(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. The reaction solution was then heated to 100 ^° C and stirred for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product compound was separated by preparation of silicone plates (silicone, petroleum ether/tetrahydrofuran in a 1:1 volume ratio) to give a yellow oily compound, tributyl(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.

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

The compound tributyl(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%), which was a yellow solid. LCMS (ESI): [M+H] ⁺ = 474.2;

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.75-8.50 (m, 2H), 7.66 (m, 1H), 6.54 (m, 1H), 4.67 (m, 1H), 4.30 (m, 1H), 4.18-4.13 (m, 3H), 3.90 (m, 1H), 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).

Using the same method as in the synthesis of compound 32 , and employing the same chloro 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:

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

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

¹ H NMR (400 MHz, CD ₃ OD): δ ppm 8.77-8.54 (m, 2H), 7.73 (m, 1H), 6.79 (m, 1H), 5.30 (m, 1H), 4.66 (m, 1H), 4.30 (m, 2H), 4.06-3.83 (m, 2H), 3.66 (m, 1H), 3.52-3.43 (m, 2H), 3.27 (m, 1H), 2.94 (m, 2H), 2.19 (m, 1H), 2.04 (m, 1H), 1.82-1.76 (m, 2H).

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 )

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

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

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

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.56 (m, 3H), 7.74 (s, 1H), 6.83 (m, 1H), 4.25-4.06 (m, 1H), 3.86 (m, 4H), 3.63-3.49 (m, 5H), 3.07 (m, 1H), 2.80 (m, 1H), 2.13 (m, 2H), 1.95-1.79 (m, 1H), 1.67 (m, 1H). 1.28 (m, 1H).

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

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

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

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 )

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

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

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:

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 )

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

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

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

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.61-8.53 (m, 3H), 7.70 (br s, 1H), 6.74 (m, 1H), 4.44 (m, 1H), 4.35 (m, 1H), 4.03 (m, 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 = 6.4 Hz, 3H), 0.88-0.72 (m, 4H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.61-8.54 (m, 2H), 7.72 (br s, 1H), 6.73 (m, 1H), 4.41 (m, 2H), 4.02 (m, 1H), 3.89-3.82 (m, 3H), 3.67-3.66 (m, 1H), 3.25 (m, 2H), 3.21 (m, 1H), 2.88 (m, 1H), 2.61 (m, 2H), 2.07 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H).

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 )

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

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

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 )

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.61-8.50 (m, 2H), 7.72 (br s, 1H), 6.73 (m, 1H), 4.64 (m, 1H), 4.41 (m, 1H), 4.02 (m, 2H), 3.89-3.82 (m, 3H), 3.67-3.66 (m, 1H), 3.26-3.21 (m, 2H), 2.97-2.88 (m, 2H), 2.68 (m, 1H), 2.55-2.45 (m, 1H), 1.96-1.72 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H).

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

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

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

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 )

Step 1: Tertiary 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

A solution of compound tributyl(S)-3-((4-(6-((S)-3-methylmorpholinyl)-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-diazabis[2.2.2]octanedi(tetrafluoroboronic acid) salt (0.76 g, 2.14 mmol) in acetonitrile (5 mL) was slowly added dropwise, keeping the temperature below -20 ^° C. The reaction mixture was stirred at -20 ^° C for 1 hour. The mixture was then quenched at -20 ^° C with 30 mL of saturated sodium sulfite aqueous solution. The reaction mixture was extracted with ethyl acetate (30 mL × 3), the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by rapid column chromatography (silicone, 0-50% gradient of ethyl acetate/petroleum ether) to give an oily brown compound, tributyl(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.

Step 2: Tertiary 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

Add sodium hydroxide aqueous solution (4 M, 0.21 mL, 0.83 mmol) to a 1,4-dioxane (3 mL) 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 (75 mg, 0.10 mmol). 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 give crude product of oily brown compound tributyl(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.

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

A solution of 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, 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) in 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-methylmorpholino)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((S)-piperidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (formate, 11.68 mg, 22 μmol, yield 22%). LCMS (ESI): [M+H] ⁺ = 480.2;

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.76-8.32 (m, 3H), 7.85 (s, 1H), 4.29 (s, 1H), 4.09 (td, J = 3.2, 6.4 Hz, 1H), 4.01-3.87 (m, 2H), 3.85-3.74 (m, 1H), 3.67 (dd, J = 3.3, 11.2 Hz, 1H), 3.56-3.40 (m, 3H), 3.25 (d, J = 12.3 Hz, 1H), 3.04-2.86 (m, 2H), 2.20 (s, 1H), 2.05 (d, J = 14.3 Hz,1H), 1.94-1.65 (m, 2H), 1.21 (d, J = 6.6 Hz, 3H).

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)

According to 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;

¹ H NMR: (400 MHz, CD ₃ OD): δ ppm 8.47 (s, 1H), 8.16 (br s, 1H), 7.65 (bs, 1H), 6.67 (m, 1H), 6.59 (m, 1H), 4.23 (br s, 1H), 3.40 (m, 1H), 3.30–3.11 (m, 5H), 2.91-2.78 (m, 2H), 2.25-1.86 (m, 6H), 1.78-1.60 (m, 2H).

We synthesized compound 32 using the same method, employing the same chlorinated 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, coupled with other substrates. After deprotection, we obtained the following compound:

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

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

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

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

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

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

Using the same method as that used in the synthesis of compound 27 , and employing the same chloro 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:

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 ).

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

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.79-8.40 (m, 2H), 7.94-7.86 (m, 2H), 7.76-6.79 (m, 2H), 5.04 (br s, 1H), 4.81 (br s, 1H), 4.50 (t, J = 9.5 Hz, 1H), 4.21-3.82 (m, 2H), 3.24 (br s, 1H), 3.12-2.99 (m, 2H), 2.83 (br d, J = 11.5 Hz, 1H), 2.46-2.41 (m, 1H), 2.02-1.89 (m, 1H), 1.67 (br d, J = 4.2 Hz, 1H), 1.47 (br d, J = 8.5 Hz, 2H).

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 )

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

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.78-11.84 (m, 1H), 8.64-8.51 (m, 1H), 8.78 (d, J = 8.2 Hz, 1H), 7.91 (br d, J = 4.5 Hz, 1H), 7.80 (br t, J = 7.2 Hz, 1H), 7.44 (dd, J = 17.7, 8.4 Hz, 1H), 6.00 (br s, 1H), 4.24-4.11 (m, 2H), 3.89 (br s, 1H), 3.07 (br t, J = 10.9 Hz, 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).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.90-8.40 (m, 3H), 7.95 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.31 (s, 1H), 4.08 (dd, J = 4.1, 11.4 Hz, 1H), 4.00 (dd, J = 4.4, 11.4 Hz, 1H), 3.65-3.43 (m, 2H), 3.29-3.16 (m, 2H), 2.95 (t, J = 10.5 Hz, 2H), 2.66 (dt, J = 3.5, 11.4 Hz, 1H), 2.29-2.13 (m, 2H), 2.04 (dd, J = 4.4, 12.7 Hz, 2H), 1.78 (m, 3H), 0.67 (d, J = 6.8 Hz, 3H).

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 )

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.96-8.62 (m, 1H), 8.53 (s, 1H), 7.97 (s, 1H), 7.40 (s, 1H), 4.64-4.46 (m, 1H), 4.29-3.98 (m, 2H), 3.72 (dt, J = 2.6, 11.5 Hz, 1H), 3.26 (dd, J = 3.4, 12.0 Hz, 1H), 2.97 (d, J = 12.8 Hz, 1H), 2.71-2.54 (m, 2H), 2.26-1.93 (m, 3H), 1.88-1.59 (m, 7H).

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 .

Example 112. The chiral monomer with a shorter elution time after chiral resolution of compound 111 (compound 112 )

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.96-8.62 (m, 1H), 8.53 (s, 1H), 7.97 (s, 1H), 7.40 (s, 1H), 4.64-4.46 (m, 1H), 4.29-3.98 (m, 2H), 3.72 (dt, J = 2.6, 11.5 Hz, 1H), 3.26 (dd, J = 3.4, 12.0 Hz, 1H), 2.97 (d, J = 12.8 Hz, 1H), 2.71-2.54 (m, 2H), 2.26-1.93 (m, 3H), 1.88-1.59 (m, 7H).

Example 113. After chiral resolution of compound 111 , the chiral monomer with a longer elution time (compound 113 )

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

1H NMR (400 MHz, CD ₃ OD) δ ppm 8.96-8.62 (m, 1H), 8.53 (s, 1H), 7.97 (s, 1H), 7.40 (s, 1H), 4.64-4.46 (m, 1H), 4.29-3.98 (m, 2H), 3.72 (dt, J = 2.6, 11.5 Hz, 1H), 3.26 (dd, J = 3.4, 12.0 Hz, 1H), 2.97 (d, J = 12.8 Hz, 1H), 2.71-2.54 (m, 2H), 2.26-1.93 (m, 3H), 1.88-1.59 (m, 7H).

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

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

The third 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 (150 mg, 0.24 mmol), methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphosphine)xanthate][2-amino-1,1-biphenyl]palladium(II)dichloromethane adduct (24 mg, 24 μmol), triethylamine (119 mg, 1.18 mmol), and dimethylphosphine oxide (36 mg, 0.47 mmol) 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 (silicone, 1-20% gradient of tetrahydrofuran/petroleum ether) to give the crude product compound tributyl(S)-3-((4-(6-(dimethylphosphatidyl)-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.

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

Add sodium hydroxide aqueous solution (4 M, 304 μL, 1.22 mmol) to 1,4-dioxane (1650 μL) of tert-butyl(S)-3-((4-(6-(dimethylphosphonyl)-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 then stir the mixture 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 a white solid crude product, tributyl(S)-3-((4-(6-(dimethylphosphatidyl)-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.

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

A solution of hydrogen chloride/dioxane (4 M, 200 μL, 0.80 mmol) was added to a solution of tert-butyl(S)-3-((4-(6-(dimethylphosphatyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (130 mg, 0.19 mmol) in dichloromethane (1500 μL), and the mixture was then stirred at 50 ^° C for 16 hours. The reaction solution was evaporated to dryness and purified by preparative HPLC to give 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;

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.16-8.89 (m, 1H), 8.64 (s, 1H), 8.55 (s, 1H), 8.15 (br s, 1H), 7.87 (dd, J = 5.5, 7.8 Hz, 1H), 4.33 (br s, 1H), 3.65-3.44 (m, 1H), 3.30 (m, 1H), 3.00 (br t, J = 10.3 Hz, 2H), 2.19 (br s, 1H), 2.09 (br d, J = 14.1 Hz, 1H), 1.86 (d, J = 13.6 Hz, 8H).

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

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 )

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

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.58 (s, 2H), 7.72 (s, 1H), 6.73 (d, J = 9.0 Hz, 1H), 4.48-4.35 (m, 2H), 4.03 (dd, J = 3.0, 11.3 Hz, 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, 13.1 Hz, 1H), 2.69 (t, J = 11.7 Hz, 1H), 2.29 (br s, 1H), 2.13 (br d, J = 14.6 Hz, 1H), 1.74-1.65 (m, 1H), 1.24 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H).

Implementation Examples 1 Compound CDK7, CDK2, CDK9 as well as CDK12 In vitro enzyme inhibitory activity assay

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 an enzyme solution with a concentration of 2.4X. 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 an enzyme solution with a concentration of 2.4X. CDK9/CyclinT1 was diluted in assay buffer (20 mM MES, pH 6.75, 0.01% Tween 20, 50 μg/mL BSA, 10 mM MgCl2 ₎ to obtain an enzyme solution with the corresponding 2.4X concentration. 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 an enzyme solution with the corresponding 2.4X concentration. The compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10 mM. Before use, the compound was diluted with DMSO to create 10 concentration gradients from 25 nM to 500 μM, and each gradient was diluted 8.3-fold in the assay buffer to obtain a 6X concentration compound solution. The peptide substrate and ATP were diluted in the assay buffer to obtain a 2.4X concentration peptide substrate and ATP mixed solution. 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 buffer solution containing 20 μM astrocytoxin was used instead of the compound solution as a 100% inhibition control, and DMSO was used instead of the compound solution as a 0% inhibition control. Each experiment had at least two replicate controls. Specifically, the CDK7 inhibition assay used the CDK7/cell cycle protein H/MAT1 complex (6 nM) and the "5-FAMCDK7 tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK, where "5-FAM" refers to 5-carboxyfluorochrome). The CDK9 inhibition assay used the CDK9/Cycle Protein T1 complex (8 nM) and the "5-FAM-CDK9tide" peptide substrate (2 μM, a synthetic fluorophore-labeled peptide with the following sequence: 5-FAM-GSRTPMY-NH2, where 5-FAM is as defined above and NH2 represents C-terminal acetylamine). The CDK12 inhibition assay used the CDK12 (aa686-1082)/Cycle Protein K complex (50 nM) and the "5-FAM-CDK9tide" as defined above (2 μM). The CDK2 inhibition assay used the CDK2/Cycle Protein E1 complex (0.5 nM) and the "5-FAM-CDK7tide" as defined above (2 μM).

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 obtained by adjusting for nonlinear regression models of dose-response curves.

The IC ₅₀ test results are shown in Table 1 below:

Table 1 Compound number CDK7 IC ₅₀ (nM) CDK2 IC ₅₀ (nM) CDK9 IC ₅₀ (nM) CDK12 IC ₅₀ (nM) 1 13.38 3023 1184 1461 2 10.36 4381 1035 1838 3 17.4 2677 722.3 678.9 4 17.36 1482 681.9 733.2 5 12.11 2253 906.8 1022 6 10.36 4381 1035 1838 7 24.26 4504 3253 2061 8 40.26 17485 15941 9316 9 28.72 7292 4527 1270 10 26.96 2093 4010 822.9 11 27.8 6448 4226 1952 12 17.37 3792 2790 1170 13 7.051 2672 3429 2641 14 7.105 3288 1669 555.4 15 16.49 4149 3320 1116 16 10.84 2881 3582 1226 17 20 5475 4254 1628 18 9.47 6562 2874 2286 19 158.8 >10000 >10000 8718 20 8.425 3275 2974 765.2 twenty one 8.806 4330 2978 818.1 twenty two 7.052 3046 2863 783 twenty three 13.06 4311 2610 782.9 twenty four 17.39 8497 5253 1973 25 6.503 1037 402.3 276.8 26 9.503 >10000 >10000 >10000 27 2.171 1120 1500 417.7 28 6.956 3470 3628 1096 29 7.084 1263 2480 855.2 30 10.52 3262 9531 2151 31 8.128 968 1484 517.2 32 19.94 3627 6515 3432 33 46.78 3232 4425 2007 34 40.25 1270 1663 1092 43 82.85 >10000 >10000 >10000 44 131 >10000 3646 4457 60 8.79 >10000 8072 >10000 69 28.35 47146 >50000 49097 70 41.19 37615 >50000 48963 71 31.67 9302 >50000 6678 72 17.63 3351 1823 2545 73 11.49 4292 3346 3381 74 10.15 27277 >50000 11950 75 8.5 2383 5929 3338 101 28.46 >10000 4615 1600 103 7.258 2826 3683 1389 104 5.854 1552 2751 772.8 A mixture of 105 and 106 2.704 1028 1783 530.5 107 6.399 1509 1444 567.2 108 4.355 946.9 1412 512.2 109 5.621 2150 2872 999.5 110 3.478 2183 4263 1614 112 5.816 --- --- --- 113 4.759 --- --- --- 114 6.729 1723 2468 1210 115 9.523 19524 27675 12873 Staurosporine 796.6 32.5 377.3 3164 Note: --- indicates that the test was not performed.

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

Implementation Example 2 : Cellular Bioactivity Detection

A2780 and HCC70 cells were trypsinized, and the cell suspensions were transferred to 15 mL centrifuge tubes and centrifuged at 800 rpm for 5 min. The supernatant was discarded, and the cells were resuspended in fresh 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 medium was added to columns 2 and 23 of the 384-well plate, and 50 μL of DPBS was added to the surrounding wells). The plates were incubated overnight in an incubator (37ºC, 5% _CO2 ).

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 standardized to 0.2%. The cell plates were centrifuged at 800 rpm for 30 seconds and incubated in an incubator (37ºC, 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 DPBS, 72 μL ^CyQuant® Direct nucleic acid stain, and 360 μL ^CyQuant® Direct background suppressor. The mixture was thoroughly mixed and stored at room temperature for later use. After removing the cell plate and allowing it to equilibrate to room temperature for 30 min, dispense 25 μL of Cyquant reagent (3X) into each well of the 384-well plate using a multi-drop assay. Incubate at 37°C for at least 60 min. Read the plate using an Acumen reader (Acumen setting: 488 nm excitation wavelength). _IC50 results were analyzed using an IDBS XLFIT5 analyzer.

The measurement results are shown in Table 2 below.

Table 2 Compound number HCC70 IC ₅₀ (nM) A2780 IC ₅₀ (nM) 1 14 14 2 15 16 3 7.9 12 4 6.1 8 5 19 17 6 6.7 twenty two 7 28 21.91 8 16 19.13 9 44 36.34 10 102 108.69 11 48 41.17 12 69 90.1 13 29 35.2 14 twenty four 11 15 12 10 16 13 11 17 102 212 18 6.7 7.2 19 220 185 20 13.7 8.3 twenty one 27.8 19 twenty two 10.7 4.7 twenty three 19.9 8.8 twenty four 72 110 25 11 7.9 26 52 30 27 30 5.1 28 7.7 7.8 29 3.1 2.1 30 20 5.6 31 5.8 4.1 32 twenty four 6.3 33 12 2.4 34 15 3.3 43 6068 --- 44 684 253 60 475 36 69 642 --- 70 484 146 71 390 547 72 twenty one 2.8 73 35 6.2 74 199 177 75 9.2 7.4 101 232 157 103 22.3 18.2 104 4.97 5.37 A mixture of 105 and 106 6.30 10.27 107 6.77 6.27 108 3.8 3.9 109 3.98 5.61 110 38.6 38.6 114 18.1 17.6 115 42.0 45.5 Note: --- indicates that the test was not performed.

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. Moreover, some compounds are tens of times more active than compound 213 (Example 101), which has the closest structure in patent CN201780057760.8.

Although the 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 limited by the scope of the appended patent applications.

Claims (5)

A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is: or . A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is: . A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound is: . A pharmaceutical composition comprising a compound as described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient. Use of a compound as described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 4, in the preparation of a medicament for the prevention and/or treatment of proliferative diseases.