Degrader and use thereof

Abstract

The present disclosure relates to a degrader and the use thereof. Specifically, disclosed are a compound as shown in formula (I), a pharmaceutical composition containing same, and the use thereof in the prevention and / or treatment of autoimmune diseases, inflammatory diseases, cancers, and tumors, wherein each group in formula (I) is as defined in the description.

Description

Degradation agent and use thereof

[0001] The present disclosure claims priority to Chinese patent application No. 202411349277.5, filed on September 26, 2024, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure belongs to the field of medicine, and relates to a pyrimidine derivative, a pharmaceutical composition containing the same, and the use thereof for preventing and / or treating autoimmune diseases, inflammatory diseases, cancers, and tumors. BACKGROUND

[0003] Cyclin-dependent kinase 7 (CDK7) is a special member of the CDK family, which has a dual function in cell division regulation and transcription regulation. CDK7 combines with cyclin H and MAT1 to form a trimeric cyclin-activated kinase (CAK), which activates the corresponding CDK kinase activity by phosphorylating the related CDKs (including CDK1, CDK2, CDK4, and CDK6) to complete the regulation of the cell cycle. CDK7 also participates in the auxiliary regulation of transcription as a component of the common transcription factor II H (TFIIH), which is involved in the transcription initiation process through the phosphorylation of the Rbp1 subunit of RNA polymerase II (RNAPII), and then regulates the transcription elongation through the phosphorylation of the CDK9 complex. An important feature of cancer is uncontrolled cell proliferation and transcriptional dysregulation, so CDK7 inhibitors that simultaneously inhibit transcription and cell cycle progression are theoretically feasible targets for treating cancer. Currently, there is no drug on the market that selectively regulates this target.

[0004] Targeted protein degradation is a very promising tool for biological mechanism research and treatment. By directly degrading target proteins, the problem of drug resistance caused by mutations in target proteins can be overcome. PROTAC is a bifunctional compound, one part of which binds to the target protein, and the other part serves as a ligand responsible for recruiting E3 ligase. Therefore, PROTAC brings the target protein very close to the E3 ligase, resulting in ubiquitination on the surface of the target protein, making it a new substrate for proteasome degradation. By selecting a suitable protein targeting moiety, PROTAC has high specificity for the target protein. Therefore, it is necessary to continue to develop new degrading agents for the treatment of related diseases mediated by CDK7 activity.

[0005] Currently, the patents related to CDK7 degrading agents that have been disclosed include WO2021026109A, WO2023239750A, and WO2022093742A. SUMMARY

[0006] This disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. in,

[0007] R 1 Each is independently selected from hydrogen, deuterium, halogens (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, cyano, C 1-6 Alkyl groups (e.g., C1, C2, C3, C4, C5, C6 alkyl groups), C 1-6 Alkoxy groups (e.g., C1, C2, C3, C4, C5, C6 alkoxy groups), 3-6 membered cycloalkyl groups (e.g., 3-, 4-, 5-, 6-membered cycloalkyl groups), 3-12 membered heterocyclic alkyl groups (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heterocyclic alkyl groups, with 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur), C 2-6 Alkenyl groups (e.g., C2, C3, C4, C5, C6 alkenyl groups) and C 2-6 Alkynyl (e.g., C2, C3, C4, C5, C6 alkynyl), wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally surrounded by one or more R groups. A Instead, the R A Selected from hydrogen, deuterium, halogens (e.g., fluorine, chlorine, bromine, iodine), cyano, hydroxyl, alkynyl, C 1-6 Alkoxy groups (e.g., alkoxy groups of C1, C2, C3, C4, C5, and C6), C 1-6 Alkyl groups (e.g., C1, C2, C3, C4, C5, C6 alkyl groups) and 3-6 membered cycloalkyl groups (e.g., 3-, 4-, 5-, 6-membered cycloalkyl groups);

[0008] R 2 and R 3 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl groups (e.g., C1, C2, C3, C4, C5, C6 alkyl groups), cyano groups, C 2-6 Alkenyl groups (e.g., C2, C3, C4, C5, C6 alkenyl groups), C 2-6 Alkynyl groups (e.g., C2, C3, C4, C5, C6 alkynyl groups) and 3-6 membered cycloalkyl groups (e.g., 3-, 4-, 5-, 6-membered cycloalkyl groups), wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group and the 3-6 membered cycloalkyl group are each independently and optionally influenced by one or more R groups. B Instead, the R Bselected from deuterium, halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, cyano, and 3-6 membered cycloalkyl (e.g., 3-, 4-, 5-, 6-membered cycloalkyl);

[0009] R 4 selected from hydrogen, cyano, C 1-6 alkyl (e.g., C1, C2, C3, C4, C5, C6alkyl), 3-6 membered cycloalkyl (e.g., 3-, 4-, 5-, 6-membered cycloalkyl), and 3-12 membered heterocycloalkyl (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heterocycloalkyl, which can be 1-4 in number of heteroatoms selected from nitrogen, oxygen, and sulfur), said C 1-6 alkyl, 3-6 membered cycloalkyl, and 3-12 membered heterocycloalkyl are each independently optionally substituted with one or more R C , said R C selected from hydrogen, deuterium, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, hydroxyl, alkynyl, C 1-6 alkoxy (e.g., C1, C2, C3, C4, C5, C6alkoxy), C 1-6 hydroxyalkyl (e.g., C1, C2, C3, C4, C5, C6hydroxyalkyl), amino, and oxo;

[0010] R 5 each is independently selected from hydrogen, deuterium, cyano, hydroxyl, C 1-6 alkyl (e.g., C1, C2, C3, C4, C5, C6alkyl), halogen (e.g., fluorine, chlorine, bromine, iodine), and C 1-6 alkoxy;

[0011] L1is a bond or C 1-6 alkylene (e.g., C1, C2, C3, C4, C5, C6alkylene), said C 1-6 alkylene is optionally substituted with one or more R D , said R D selected from deuterium, halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, C 1-6 alkoxy (e.g., C1, C2, C3, C4, C5, C6alkoxy), C 1-6 hydroxyalkyl (e.g., C1, C2, C3, C4, C5, C6hydroxyalkyl), amino, and oxo;

[0012] L2 is an alkylene chain or an alkylene chain substituted with an oxo group (=O), wherein either the alkylene chain or the alkylene chain substituted with an oxo group (=O) is optionally interrupted by at least one of the following interrupting groups and / or terminated at any one or both ends by at least one of the following terminating groups: -O-, -S-, -C(O)-, -C≡C-, -S(O)2-, -OS(O)2-, -N(R')C(O)-, -N(R')-, -N(R')S(O-), 3-6-membered cycloalkylene (e.g., 3-, 4-, 5-, 6-membered cycloalkylene), 3-12-membered heteroalkylene (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heteroalkylene, the number of heteroatoms may be 1-4, the heteroatoms being selected from nitrogen, oxygen, and sulfur), or any combination thereof, wherein R' is hydrogen or C 1-6 Alkyl groups (e.g., C1, C2, C3, C4, C5, C6 alkyl groups), wherein the interrupting group and one or two terminal terminating groups may be the same or different;

[0013] Ring A is selected from 3-6-membered cycloalkylene groups (e.g., 3-, 4-, 5-, and 6-membered cycloalkylene groups), 5-12-membered heteroaryl groups (e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered heteroaryl groups, with 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur), 6-12-membered aryl groups (e.g., 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered aryl groups), and 3-12-membered heteroalkylene groups (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered heteroalkylene groups, with 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur). Each of the 3-6-membered cycloalkylene groups, 5-12-membered heteroaryl groups, 6-12-membered aryl groups, and 3-12-membered heteroalkylene groups is independently and optionally selected by one or more R groups. E Instead, the R E Selected from hydroxyl, halogen (e.g., fluorine, chlorine, bromine, iodine), C 1-6 Alkoxy groups (e.g., alkoxy groups of C1, C2, C3, C4, C5, and C6), C 1-6 Alkyl groups (e.g., C1, C2, C3, C4, C5, C6 alkyl groups) and 3-6 membered cycloalkyl groups (e.g., 3-, 4-, 5-, 6-membered cycloalkyl groups);

[0014] n is 0, 1, 2, 3 or 4;

[0015] m can be 0, 1, 2, 3, or 4.

[0016] In some implementation schemes, R 2 It is either hydrogen or deuterium.

[0017] In some specific implementation schemes, R 2 It is hydrogen.

[0018] In some implementation schemes, R 3 C 1-6 alkyl.

[0019] In some specific implementation schemes, R 3 It is a methyl group.

[0020] In some embodiments, the compound represented by formula (I) of this disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is selected from the compounds represented by formulas (Ia-1), (Ia-2), (Ib-1), and (Ib-2):

[0021] Among them, R 1 R 4 R 5 The definitions of L1, L2, ring A, m and n are as described in equation (I).

[0022] In some implementation schemes, R 1 Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl and C 2-6 Alkyne group.

[0023] In some implementation schemes, R 1 It is selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, cyclopropyl, and ethynyl.

[0024] In some implementation schemes, R 4 C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R C Instead, the R C Selected from hydrogen, deuterium, halogens, and C 1-6 Alkoxy and C 1-6 alkyl.

[0025] In some implementation schemes, R 4 C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R C Instead, the R C Selected from hydrogen, deuterium, F, methoxy, and methyl.

[0026] In some specific implementation schemes, R 4 It is a methyl group.

[0027] In some implementation schemes, R 5each independently selected from hydrogen, deuterium, methyl, F, and methoxy.

[0028] In some embodiments, R 5 each independently is hydrogen or deuterium.

[0029] In some embodiments, L1is a bond.

[0030] In some embodiments, L1is C 1-6 alkylene, said C 1-6 alkylene is optionally substituted with one or more R D substituted, said R D is selected from deuterium, hydroxyl, methoxy, hydroxymethyl, and oxo.

[0031] In some embodiments, L1is methylene.

[0032] In some embodiments, L2is an alkylene chain, said alkylene chain is optionally interrupted with at least one interrupting group, and / or terminated at either or both termini with at least one terminating group, selected from -O-, -C(O)-, 3-7 membered heterocycloalkylene, or any combination thereof, wherein the interrupting group and the one or both terminal terminating groups can be the same or different.

[0033] In some embodiments, L2is an alkylene chain, said alkylene chain is optionally interrupted with at least one interrupting group, and / or terminated at either or both termini with at least one terminating group, selected from -O-, or any combination thereof, wherein the interrupting group and the one or both terminal terminating groups can be the same or different.

[0034] In some embodiments, L2is selected from

[0035] In some embodiments, L2is selected from wherein, one end with “*” is connected to ring A.

[0036] In some embodiments, L2is an alkylene chain substituted with oxo (=0), said alkylene chain substituted with oxo (=0) is optionally interrupted with at least one interrupting group, and / or terminated at either or both termini with at least one terminating group, selected from -O-, -C(O)-, 3-7 membered heterocycloalkylene, or any combination thereof, wherein the interrupting group and the one or both terminal terminating groups can be the same or different.

[0037] In some embodiments, L2is an alkylene chain substituted with oxo (=0), the alkylene chain substituted with oxo (=0) is optionally interrupted with at least one of the following interrupting groups and / or terminated at either or both ends with at least one of the following terminating groups: -0-, or any combination thereof, wherein the interrupting group and the one or two end terminating groups can be the same or different.

[0038] In some embodiments, L2is

[0039] In some embodiments, L2is wherein one end with "*" is connected to ring A.

[0040] In some embodiments, ring A is 5-12 membered heteroarylene or 6-12 membered arylene, each independently optionally substituted with one or more R E substituents, the R E substituents are selected from hydroxy, halogen, C 1-6 alkoxy, C 1-6 alkyl and 3-6 membered cycloalkyl.

[0041] In some embodiments, ring A is

[0042] In some embodiments, n is 0 or 1.

[0043] In some embodiments, m is 0 or 1.

[0044] In some embodiments, the compound of formula (I) is selected from: In some embodiments, the compound of formula (I) is selected from:

[0045] In some embodiments, the compound of formula (I) is selected from:

[0046] In some embodiments, the compound of formula (I) is selected from:

[0047] The present disclosure provides an isotopically substituted compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the isotopic substitution is deuterium atom substitution.

[0049] The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (I) or an isotopically-substituted compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0050] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0051] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the compound of Formula (I) or an isotopically-substituted compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the compound of Formula (I) or an isotopically-substituted compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of the compound of Formula (I) or an isotopically-substituted compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 1-99% of the compound of Formula (I) or an isotopically-substituted compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 2-98% of the compound of Formula (I) or an isotopically-substituted compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.

[0052] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 1-99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 2-98% of a pharmaceutically acceptable excipient, based on the total weight of the composition.

[0053] The present disclosure provides a compound of Formula (I) or an isotopically-substituted compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in therapy and / or prophylaxis.

[0054] The present disclosure provides the use of a compound of Formula (I) or an isotopically-substituted compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prophylaxis of a disease or condition associated with CDK7.

[0055] The present disclosure provides use of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or preventing an autoimmune disease, an inflammatory disease, a cancer, or a tumor.

[0056] In some embodiments, the autoimmune disease and the inflammatory disease are selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and vasculitic diseases.

[0057] In some embodiments, the cancer or the tumor is a solid tumor or a hematological cancer.

[0058] In some embodiments, the hematological cancer is selected from leukemia, lymphoma, and multiple myeloma.

[0059] In some embodiments, the solid tumor is selected from breast cancer, brain cancer, pancreatic cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, gastric cancer, lung cancer, colorectal cancer, neuroblastoma, and osteosarcoma.

[0060] The present disclosure provides a method of treating and / or preventing a disease or disorder associated with CDK7, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0061] The present disclosure provides a method of treating and / or preventing an autoimmune disease, an inflammatory disease, a cancer, or a tumor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0062] In some embodiments, the autoimmune disease and the inflammatory disease are selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and vasculitic diseases.

[0063] In some embodiments, the cancer or the tumor is a solid tumor or a hematological cancer.

[0064] In some embodiments, the hematological cancer is selected from leukemia, lymphoma, and multiple myeloma.

[0065] In some embodiments, the solid tumor is selected from breast cancer, brain cancer, pancreatic cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, gastric cancer, lung cancer, colorectal cancer, neuroblastoma, and osteosarcoma.

[0066] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0067] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and / or prevention of a disease or disorder associated with CDK7.

[0068] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and / or prevention of an autoimmune disease, an inflammatory disease, a cancer or a tumor.

[0069] In some embodiments, the autoimmune disease and the inflammatory disease are selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and vasculitic disease.

[0070] In some embodiments, the cancer or the tumor is a solid tumor or a hematological cancer.

[0071] In some embodiments, the hematological cancer is selected from leukemia, lymphoma and multiple myeloma.

[0072] In some embodiments, the solid tumor is selected from breast cancer, brain cancer, pancreatic cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, gastric cancer, lung cancer, colorectal cancer, neuroblastoma and osteosarcoma.

[0073] The present disclosure also provides a preparation method of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: under the action of a base (triethylamine (TEA), N,N-diisopropyl ethylamine (DIPEA)) and a condensing agent (HATU), a compound represented by formula (II) or a pharmaceutically acceptable salt thereof and a compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof undergo condensation reaction in a solvent (dichloromethane (DCM), N,N-dimethylformamide (DMF)) to obtain a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0074] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, L1, L2 and ring A are as described in formula (I) in the present disclosure.

[0075] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof described above can be prepared by subjecting a compound of formula (III) or a pharmaceutically acceptable salt thereof to a deprotection reaction in a solvent (dichloromethane (DCM), 1,4-dioxane) in the presence of an acid (hydrochloric acid (HC1), trifluoroacetic acid (TFA)) to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0076] wherein PG is an amino protecting group (e.g., tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz)), R 2 , R 3 , L1, L2, and ring A are as described in formula (I) of the present disclosure.

[0077] In some embodiments, the PG described above is tert-butoxycarbonyl (BOC).

[0078] The present disclosure also provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: wherein R 2 , R 3 , L1, L2, and ring A are as described in formula (I) of the present disclosure.

[0079] The present disclosure also provides a compound of formula (III) or a pharmaceutically acceptable salt thereof: wherein PG is an amino protecting group (e.g., tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz)), R 2 , R 3 , L1, L2, and ring A are as described in formula (I) of the present disclosure.

[0080] The pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts, and the compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.

[0081] The compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-forms, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, such as those that are enantiomeric or diastereomeric pure, all of which are intended to be within the scope of the present disclosure. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be within the scope of the present disclosure. The compounds of the present disclosure having asymmetric carbon atoms can be isolated in optically active or racemic forms. The optically active forms can be obtained by separation from a mixture of or racemic forms or by synthesis from optically active raw materials.

[0082] Optically active (R)- and (S)-isomers and the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to give the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, diastereomeric salts are formed with an appropriate optically active acid or base, and then separated by conventional means, and the pure enantiomer recovered by chemical cleavage of the auxiliary group. In addition, the separation of the enantiomers and diastereomers is typically accomplished by using chromatography with a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0083] In the chemical structures of the compounds of the disclosure, the bond indicates unspecified configuration, i.e., if chiral isomers are present in the chemical structure, the bond may be or both include two configurations.

[0084] Any isotopically-labeled derivatives of the compounds of the disclosure, or pharmaceutically acceptable salts thereof, or isomers thereof, are also covered by the disclosure. Atoms that can be isotopically-labeled include but are not limited to hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. Isotopically-labeled derivatives of the compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art. 2 H(D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I, etc. are substituted for the commonly occurring atoms.

[0085] Unless otherwise indicated, when a position is designated specifically as deuterium (D), the position is to be understood as having deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). Exemplary compounds having deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium can be at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater. The present disclosure also includes various deuterated forms of the compounds of Formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. One skilled in the art would be able to synthesize deuterated forms of the compounds of Formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds of Formula (I), or they can be synthesized using conventional techniques employing deuterated reagents, including but not limited to deuterated borane, trideuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, among others.

[0086] Terminology

[0087] For the purposes of the present disclosure, certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere in the present disclosure, all other technical and scientific terms used in the present disclosure have the meanings that are commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0088] The prefix "C u-v " indicates that the group that follows has from u to v carbon atoms. For example, "C 1-4 alkyl" indicates that the alkyl group has 1 to 4 carbon atoms, specifically can be an alkyl group having 1, 2, 3, or 4 carbon atoms.

[0089] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups. Alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers thereof, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, preferably one or more groups independently selected from halogen, hydroxyl, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl being optionally substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0090] The term "alkenyl" refers to unsaturated aliphatic straight-chain or branched hydrocarbon groups and contain one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-8 , C 2-7 , C 2-6 , C 2-4 , C 3-12 , and C 3-6 alkenyl. Included, but not limited to, are ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-l-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like. Alkenyl groups used in any context herein are optionally substituted in the same manner as alkyl groups.

[0091] The term "alkynyl" refers to an unsaturated aliphatic straight-chain or branched-chain hydrocarbon group and contains one or more carbon-carbon triple bonds. Exemplary alkynyl groups include C 2-8 , C 2-7 , C 2-6 , C 2-4 , C 3-12 , and C 3-6 alkynyl. Included, but not limited to, are ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and pent-1,4-diynyl. Alkynyl groups used in any context herein are optionally substituted in the same manner as alkyl groups.

[0092] The term "alkylene" denotes the moiety remaining after removal of two hydrogen atoms from an alkane molecule, including straight-chain and branched-chain alkylene groups of 1 to 20 carbon atoms. Alkylene groups containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH2-), ethylene (e.g., -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene groups can be substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point, preferably one or more groups independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0093] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, hydroxyl, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl optionally substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0094] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxyl, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl optionally substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0095] The term "heterocycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (m is an integer from 0 to 2), but excluding ring moieties of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferably, comprising 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably, comprising 5 to 8 ring atoms. Non-limiting examples of "heterocycloalkyl" groups include: and the like.

[0096] The heterocycloalkyl ring can be fused to an aryl or heteroaryl ring, wherein the ring that is attached to the parent structure is a heterocycloalkyl group, non-limiting examples of which include:

[0097] and the like.

[0098] Heterocycloalkyl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxyl, oxo, cyano, amino, C 1-4 alkyl, C 1-4 alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl optionally substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0099] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0100] Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halo, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy.

[0101] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6-12 membered, more preferably 5- or 6-membered. Non-limiting examples include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, and the like.

[0102] The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0103] Heteroaryl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halo, hydroxy, cyano, amino, C 1-6 Alkyl, or C 1-6 Alkoxy.

[0104] The above cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups include residues derived from removal of one hydrogen atom from a parent ring atom, or residues derived from removal of two hydrogen atoms from the same ring atom or two different ring atoms of the parent, i.e. "cycloalkylidene", "heterocycloalkylidene", "arylidene", "heteroarylidene". Non-limiting examples include: and the like. Those skilled in the art will recognize from the context that the number of available valences can be utilized.

[0105] The term "heterocycle" refers to rings composed of atoms other than carbon, including heterocycloalkyl and heteroaryl.

[0106] The term "halo" refers to fluorine, chlorine, bromine or iodine.

[0107] The term "oxo" refers to a =0 substituent.

[0108] The term "hydroxy" refers to an -OH group.

[0109] The term "cyano" refers to -CN.

[0110] The term "amino" refers to -NH2.

[0111] The term "nitro" means -NO2.

[0112] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with the corresponding number of substituents. When the substituent is a ketone or oxo group (i.e., =0), then two (2) hydrogens on the atom are replaced.

[0113] The term "amino protecting group" is a group known in the art that can be used to protect an amino group, see the amino protecting groups in the literature (Protective Groups in Organic Synthesis, 5 Th Ed. T. W. Greene & P. G. M. Wuts). By way of example, but not limited to, carbamate protecting groups such as 2-trimethyl-silyl-ethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenylyl)-ethoxycarbonyl (Bpoc), t-butoxy carbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl and nitrophenylacetyl; sulfonamide-protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimido and dithiasuccinoyl.

[0114] "Pharmaceutical composition" means a mixture that contains one or more active ingredients or physiologically / pharmaceutically acceptable salts or prodrugs thereof, and other chemical components such as carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredients to a subject, and to enhance the effects of the active ingredients on the biological system.

[0115] A "pharmaceutically acceptable carrier, diluent or excipient" includes any material which, when combined with the active ingredient, allows the ingredient to retain its biological activity and which does not have an adverse effect on the intended therapeutic purpose. Examples include, but are not limited to, any standard pharmaceutical carrier, such as a phosphate buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate buffered saline (PBS) or normal (0.9%) saline. Compositions containing such carriers are formulated by well-known conventional methodology (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed., A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and R Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000).

[0116] "Treatment" means the administration of a therapeutic agent to a subject, typically, in an amount effective to alleviate one or more symptoms of a disease to the treated subject or population, by preventing or delaying the onset of symptoms or complications, reducing symptoms or complications, or eliminating the disease, condition, or disorder to any clinically measurable extent. The amount of a therapeutic agent effective to alleviate any particular symptom of a disease (also referred to as the "therapeutically effective amount") can vary according to factors such as the disease state, age, and weight of the subject, and the ability of the drug to elicit a desired effect in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical detection method typically used by a physician or other health care professional to assess the severity or progression of the symptom. While embodiments of the disclosure (e.g., a method of treatment or an article of manufacture) can not be effective in alleviating a target disease symptom in a certain subject, it is determined that the target disease symptom should be alleviated in a statistically significant number of subjects according to any statistical test known in the art, such as the Student t-test, the Chi-square test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), the Jonckheere-Terpstra test, and the Wilcoxon test. The patient to be treated is a mammal, and preferably a human.

[0117] "Prevention" means reducing the risk or incidence of, or eliminating or slowing the progression of, one or more conditions, symptoms, complications, or disorders.

[0118] "Subject," "patient" means a mammal, especially a primate, and especially a human.

[0119] "Optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the phrase "optionally R" means that R can or can not be present such as for example R 1-6 alkylene is optionally substituted by one or more R D "Substituted" means R D may or can not be present, and the description includes instances where R 1-6 alkylene is substituted by one or more R D and instances where R 1-6 alkylene is not substituted by one or more R D .

[0120] Unless the context clearly dictates otherwise, throughout the description and the claims, the words "comprise", "have", "include" and the like are to be construed in the sense of "including but not limited to", rather than in the sense of "consisting of only"; that is, the meaning of "including, but not limited to", is intended. BRIEF DESCRIPTION OF DRAWINGS

[0121] Figure 1. CDK7 degradation experiments of Examples 4 and 5. DETAILED DESCRIPTION

[0122] The present disclosure is further described in the following examples, which do not limit the scope of the disclosure.

[0123] The experimental methods in the examples or test examples of the present disclosure, unless otherwise specified, were generally performed according to conventional methods or according to the manufacturer's instructions of the reagents or commercial suppliers. The reagents, unless otherwise specified, were commercially available and used according to the manufacturer's instructions.

[0124] The structure of the compounds was determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in 10 -6 (ppm). The NMR was measured by a Bruker AVANCE-400 NMR spectrometer with deuterated chloroform (CDC13), deuterated dimethyl sulfoxide (DMSO-d6) as solvent.

[0125] MS determination was performed using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0126] High performance liquid chromatography (HPLC) analysis used Agilent HPLC 1200 DAD, Agilent HPLC 1200 VWD and Waters HPLC e2695-2489 high performance liquid chromatograph.

[0127] Chiral compound preparation and analysis used Waters UPC2 analytical SFC (SFC-H) high performance liquid chromatograph.

[0128] CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0129] Silica gel column chromatography generally used Yantai Yellow Sea silica gel 200-300 mesh silica gel as carrier.

[0130] Known starting materials of the present disclosure can be synthesized or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, J & K, Accela ChemBio Inc, Shanghai Bide Pharmaceutical, Darui Chemicals and the like according to methods known in the art.

[0131] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0132] Argon or nitrogen atmosphere refers to connecting a reaction flask to an argon or nitrogen balloon with a volume of about 1 L.

[0133] Hydrogen atmosphere refers to connecting a reaction flask to a hydrogen balloon with a volume of about 1 L.

[0134] Pressurized hydrogenation reaction used Parr 3916EKX type hydrogenation instrument and Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

[0135] The hydrogenation reaction is usually performed by vacuuming and filling hydrogen repeatedly for 3 times.

[0136] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0137] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20-30°C.

[0138] The reaction progress in the examples is determined by using liquid chromatography-mass spectrometry (HPLC-MS).

[0139] In the present application, the meanings of the abbreviations of the compounds are as follows:

[0140] DCM: dichloromethane;

[0141] m-CPBA: meta-chloroperoxybenzoic acid;

[0142] Boc: tert-butyloxycarbonyl;

[0143] MeOH: methanol;

[0144] HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0145] PdCl2(TPP)2: dichlorobis(triphenylphosphine)palladium;

[0146] Ruphos-Pd-G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate;

[0147] Pd-PEPPSI-IPent: [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride;

[0148] DMF: N,N-dimethylformamide;

[0149] AcOH: acetic acid;

[0150] KHCO3: potassium bicarbonate;

[0151] K2CO3: potassium carbonate;

[0152] CsF: cesium fluoride;

[0153] Cs2CO3: cesium carbonate;

[0154] NaBH(OAc)3: sodium triacetoxyborohydride;

[0155] NMP: N-methylpyrrolidone;

[0156] DIPEA: N,N-Diisopropylethylamine.

[0157] Example 1

[0158] 2-(2,6-dioxopiperidin-3-yl)-5-({5-[4-(4-{[(6R)-6-methyl-7-[(3S,4S)-1-methyl-3-phenylpiperidin-4-carbonyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl]amino}-1H-pyrazol-1-yl)piperidin-1-yl]pentyl}oxy)-2,3-dihydro-1H-isoindole-1,3-dione(1)

[0159] first step

[0160] 4-(4-nitro-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1ec)

[0161] At room temperature, compound 4-nitropyrazole (1eb) (2.0 g, 17.7 mmol) was dissolved in DMF (25 mL), and compound 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (1ea) (7.4 g, 26.5 mmol) and Cs₂CO₃ (17.3 g, 53.0 mmol) were added. The mixture was heated to 90 °C and stirred for 4 h. A suitable amount of water was added to the reaction mixture, and the mixture was stirred for 0.5 h. The mixture was filtered, and the filter cake was washed with 50.0 mL of water. The mixture was dried under vacuum to give compound 1ec (5.0 g, 16.9 mmol).

[0162] MS(ESI): m / z = 259.1 [M+H] + .

[0163] Step 2

[0164] 4-(4-nitro-1H-pyrazole-1-yl)piperidine hydrochloride (1ed)

[0165] At room temperature, compound 1ec (5.2 g, 17.6 mmol) was dissolved in DCM, and HCl (4.0 M 1,4-dioxane solution, 50 mL, 200.0 mmol) was added and stirred for 1 h. The reaction solution was filtered, and the filter cake was washed with 30 mL of DCM. The mixture was dried under vacuum to give compound 1ed (4.0 g, 17.2 mmol).

[0166] MS(ESI): m / z = 197.0 [M+H] + .

[0167] Step 3

[0168] 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylic acid trimethylsilylethyl ester (1ef)

[0169] Compound 1ef (3.5 g, 17.6 mmol) was dissolved in DCM (40 mL) at room temperature, triethylamine (7.4 mL, 52.9 mmol) and compound 2,5-dioxopyrrolidin-1-yl (2- (trimethylsilyl)ethyl) carbonate (1ee) (6.9 g, 26.5 mmol) were added, and stirred for 18 h. 100 mL of water was added to the reaction solution, and extracted with DCM (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product 1ef (6.0 g, 17.6 mmol).

[0170] Fourth step

[0171] 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylic acid trimethylsilylethyl ester (1ef)

[0172] Compound 1ef (1.0 g, 2.9 mmol) was dissolved in ethanol (10 mL) at room temperature, iron powder (0.82 g, 14.7 mmol), water (2.5 mL), and NH4Cl (0.79 g, 14.7 mmol) were added, and stirred at 85°C for 2 h. After filtration, DCM (10 mL x 3) was added for washing. The filtrate was concentrated under reduced pressure in vacuum to obtain compound 1eg (0.91 g).

[0173] MS (ESI): m / z = 311.1 [M+H] + .

[0174] Fifth step

[0175] 4-(4-{[(6R)-7-(tert-butylcarbonyl)-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl]amino}-1H-pyrazol-1-yl)piperidine-1-carboxylic acid trimethylsilylethyl ester (1eh)

[0176] Compound 1eg (398 mg, 1.3 mmol) was dissolved in 1,4-dioxane (4.0 mL) at room temperature, and intermediate Int 1 (280 mg, 0.99 mmol), Cs2CO3 (964 mg, 2.96 mmol) and Pd-PEPPSI-IPent (156 mg, 0.20 mmol) were added. The reaction was stirred at 130 °C for 2 h under N2atmosphere, filtered, washed with DCM (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to give the target product 1eh (6.0 g, 17.6 mmol).

[0177] MS (ESI): m / z = 558.4 [M+H] + .

[0178] Sixth step (6R)-6-methyl-2-{[1-(piperidin-4-yl)-1H-pyrazol-4-yl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (1e)

[0179] Compound 1eh (277 mg, 0.50 mmol) was dissolved in DMF (2.5 mL) at room temperature, and CsF (310.75 mg, 1.99 mmol) was added. The reaction was stirred at 50 °C for 6 h. The reaction was filtered, washed with ethyl acetate (10 mL x 3), and the filter cake was dried and concentrated under vacuum to give compound 1e (179 mg, 0.43 mmol).

[0180] MS (ESI): m / z = 414.2 [M+H] + .

[0181] Seventh step

[0182] 5-[4-(1,3-dioxolan-2-yl)butyloxy]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (1c)

[0183] To a solution of 2-(4-bromo)-1,3-dioxolane (1 b) (841.7 mg, 4.0 mmol) in DMF (5 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (1 a) (920 mg, 3.4 mmol), potassium iodide (556.9 mg, 3.4 mmol) and potassium bicarbonate KHCO3(1007.7 mg, 10.1 mmol) at room temperature. The reaction was heated to 60 °C and stirred for 5 h. The reaction was diluted with 100 mL of water and extracted with ethyl acetate (30 x 3 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative liquid chromatography (C18-SW080 IR, A: 10 mM ammonium bicarbonate in water, B: acetonitrile, gradient: 0 to 100% (v / v), flow rate: 30 mL / min) to give compound 1c (730 mg, 1.8 mmol).

[0184] MS (ESI): m / z = 403.1 [M+H] + .

[0185] Eighth step

[0186] 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxypentanal (1 d)

[0187] To a solution of compound 1c (240 mg, 0.60 mmol) in water was added HC1 (4.0 M in 1,4-dioxane, 3.0 mL) at room temperature. The reaction was stirred for 2 h. The reaction was diluted with water (100 mL) and ethyl acetate (30.0 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give compound 1 d (190 mg, 0.43 mmol).

[0188] MS (ESI): m / z = 359.1 [M+H] + .

[0189] Ninth step

[0190] (6R)-2-((1 -(1 -(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl)-1 H-pyrazol-4-yl)amino)-6-methyl-5,8-dihydropiperido[3,4-d]pyrimidine-7(6H)- carboxylic acid tert-butyl ester (1 f)

[0191] To a solution of compound 1d (166.4 mg, 0.46 mmol) and compound 1e (160 mg, 0.39 mmol) in 1,2-dichloromethane (5.0 mL) was added acetic acid (23.0 mg, 0.39 mmol) at room temperature and stirred for 1 h. To the reaction was added NaBH(OAc)3 (244.8 mg, 1.16 mmol) at 0 oC and stirred for 18 h. The reaction was diluted with water (100.0 mL) and extracted with DCM (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum at reduced pressure. Purification by preparative liquid chromatography (Nouryon-Kromasil-C18-10 pm-25*250 mm, A: 10 mM ammonium bicarbonate in water B: acetonitrile, gradient: 46% to 95% (v / v), flow rate: 30 mL / min) gave compound 1f (170 mg, 0.23 mmol).

[0192] MS (ESI): m / z = 756.3 [M+H] + .

[0193] Tenth step

[0194] 2-(2,6-dioxopiperidin-3-yl)-5-({5-[4-(4-{[(6R)-6-methyl-7-[(3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl]amino}-1H- pyrazol-1-yl)piperidin-1-yl]pentoxy}-2,3-dihydro-1H-indole-1,3-dione (1g)

[0195] To a solution of compound 1f (160 mg, 0.19 mmol) in DCM (2.0 mL) was added HCl (4.0 M in 1,4-dioxane, 2.0 mL) at room temperature and stirred for 1 h. Concentration under pressure gave compound 1g (126.0 mg, 0.192 mmol).

[0196] MS (ESI): m / z = 756.3 [M+H] + .

[0197] Eleventh step

[0198] 2-(2,6-dioxopiperidin-3-yl)-5-({5-[4-(4-{[(6R)-6-methyl-7-[(3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl]amino}-1H- pyrazol-1-yl)piperidin-1-yl]pentoxy}-2,3-dihydro-1H-indole-1,3-dione (1g)

[0199] To a solution of compound 1g (100.0 mg, 0.14 mmol) and compound (3S,4S)-1- methyl-3-phenylpiperidine-4-carboxylic acid (Int 2) (98 mg, 0.21 mmol) (synthesis of Int 2 is referenced in WO 2022064009 Al) in DMF (0.5 mL) was added HATU (80 mg, 0.210 mmol) and DIPEA (91 mg, 0.704 mmol) at room temperature and stirred for 18 h. The reaction mixture was purified by preparative liquid chromatography (Welch-Xtimate-C18-5pm-21.2*150mm, A: 10 mM ammonium bicarbonate in water B: acetonitrile, gradient: 39% to 95% (v / v), flow rate: 20 mL / min) to give compound 1 (27.7 mg, 0.032 mmol).

[0200] MS (ESI): m / z = 858.4 [M+H] + .

[0201] 1 H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 9.25 (s, 1H), 8.14 (d, J = 23.1 Hz, 1H), 7.96 - 7.74 (m, 2H), 7.63 - 7.03 (m, 8H), 5.11 (dd, J = 13.0, 5.4 Hz, 1H), 4.92 - 4.61 (m, 2H), 4.22 - 3.99 (m, 3H), 3.73 (dd, J = 49.2, 18.9 Hz, 1H), 3.20 - 2.58 (m, 9H), 2.46 - 2.25 (m, 3H), 2.20 (s, 3H), 2.14 - 1.62 (m 13H), 1.57 - 1.37 (m, 4H), 1.05 - 0.43 (m, 3H).

[0202] Example 2

[0203] 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(4-(((R)-6-methyl-7-((3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)oxy)isoindoline-1,3-dione

[0204] First step

[0205] tert-Butyl 5-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}pentanoate (2b)

[0206] To a solution of compound 1a (403 mg, 1.47 mmol) in DMF (3.0 mL) was added potassium bicarbonate (441 mg, 4.41 mmol) and potassium iodide (252 mg, 1.52 mmol) at room temperature. Then tert-butyl 5-bromovalerate (2a) (413 mg, 1.74 mmol) was added and the reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give the target product 2b (470 mg, 1.07 mmol).

[0207] Second step

[0208] 5-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]oxy}pentanoic acid (2c)

[0209] Compound 2b (174 mg, 0.404 mmol) was dissolved in formic acid (2.0 mL) at room temperature and stirred at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 2c (151 mg, 0.403 mmol).

[0210] MS (ESI): m / z = 875.1 [M+H] + .

[0211] Third step tert-butyl (6R)-2-((1-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentanoyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (2d)

[0212] To a solution of compound 2c (150 mg, 0.40 mmol) in DMF (0.5 mL) was added compound 1e (150.1 mg, 0.334 mmol), HATU (190.5 mg, 0.50 mmol) and DIPEA (215.8 mg, 1.67 mmol) at room temperature and stirred for 2 h. Water (30 mL) was added to the reaction mixture and stirred for 0.5 h. The mixture was filtered and the filter cake was washed with 5.0 mL of water. The solid was dried to give compound 2d (220 mg, 0.25 mmol).

[0213] MS (ESI): m / z = 770.3 [M+H] + .

[0214] Fourth step

[0215] 2-(2,6-dioxopiperidin-3-yl)-5-({5-[4-(4-{[(6R)-6-methyl-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl]amino}-lH-pyrazol-l-yl)piperidin-l-yl]-5-oxopentyl}oxy)-2,3- dihydro-lH-isoindole-l,3-dione (2e)

[0216] Compound 2e (85 mg, 0.115 mmol) was synthesized following the procedure of Reference Example 1, step 10.

[0217] MS (ESI): m / z = 670.3 [M+H] + .

[0218] Fifth step

[0219] 2-(2,6-dioxopiperidin-3-yl)-5-({5-[4-(4-{[(6R)-6-methyl-7-[(3S,4S)-l-methyl-3- phenylpiperidine-4-carbonyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl]amino}-lH- pyrazol-l-yl)piperidin-l-yl]-5-oxopentyl}oxy)-2,3-dihydro-lH-isoindole-l,3-dione (2)

[0220] Compound 2 (22.8 mg, 0.025 mmol,) was synthesized following the procedure of Reference Example 1, step 10.

[0221] MS (ESI): m / z = 871.4 [M+H] + .

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.28 (s, 1H), 8.14 (d, J = 24 Hz, 1H), 7.89 - 7.81 (m, 3H), 7.63 - 7.06 (m, 8H), 5.11 (dd, J = 12.9, 5.4 Hz, 1H), 4.91 - 4.60 (m, 2H), 4.51 - 4.29 (m, 2H), 4.20 (t, J = 6.4 Hz, 2H), 3.98 (d, J = 12.6 Hz, 1H), 3.73 (dd, J = 45.7, 18.9 Hz, 1H), 3.21 - 3.00 (m, 3H), 2.95 - 2.51 (m, 6H), 2.47 - 2.28 (m, 3H), 2.20 (s, 3H), 2.13 - 1.94 (m, 5H), 1.90 - 1.62 (m, 8H), 1.05 - 0.45 (m, 3H).

[0223] Example 3

[0224] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(((R)-6-methyl-7-((3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)- 1H-pyrazol-1-yl)piperidine-1-carbonyl)piperidin-1-yl)isoindoline-1,3-dione (3)

[0225] First step

[0226] 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidine-4- carboxylic acid tert-butyl ester (3c)

[0227] To a solution of compound 3a (300 mg, 1.09 mmol) in DMSO (2.0 mL) was added tert-butyl piperidine-4-carboxylate (3b) (290 mg, 1.31 mmol), DIPEA (0.9 mL, 5.45 mmol) at room temperature. The reaction was stirred at 80 °C for 18 h. The reaction was treated with water (20.0 mL), stirred for 5 min, filtered, washed with water (5.0 mL x 3), and dried under vacuum to give compound 3c (453 mg, 0.97 mmol).

[0228] MS (ESI): m / z = 442.2 [M+H] + .

[0229] Second step

[0230] 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidine-4- carboxylic acid (3d)

[0231] Compound 3c (220 mg, 0.468 mmol) was dissolved in formic acid (2.5 mL) at room temperature, and the reaction was stirred at 40 °C for 5 h. The reaction was diluted with DCM (20.0 mL) and concentrated under reduced pressure to give compound 3d (180 mg, 0.430 mmol).

[0232] MS (ESI): m / z = 286.1 [M+H] + .

[0233] Step 3 (6R)-2-{[l-(l-{l-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- isoindol-5-yl]piperidine-4-carbonyl}piperidin-4-yl)-lH-pyrazol-4-yl]amino}-6- methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (3e)

[0234] Compound 3d (200 mg, 0.477 mmol) and le (150 mg, 0.334 mmol) were dissolved in DMF (0.5 mL) at room temperature, HATU (190.33 mg, 0.501 mmol) and DIPEA (0.3 mL, 1.815 mmol) were added, and stirred for 18 hours. The reaction solution was added to water (30 mL) and stirred for 0.5 hours. Filtration was performed, the filter cake was washed with water (5.0 mL), and dried under vacuum to obtain compound 3e (170 mg, 0.209 mmol).

[0235] MS (ESI): m / z = 781.4 [M+H] + .

[0236] Fourth Step

[0237] 2-(2,6-Dioxopiperidin-3-yl)-5-{4-[4-(4-{[(6R)-6-methyl-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl]amino}-lH-pyrazol-l-yl)piperidine-l-carbonyl]piperidin-l-yl}-2,3- dihydro-lH-isoindole-l,3-dione (3f)

[0238] Compound 3f (112 mg, 0.138 mmol) was synthesized according to the procedure of Reference Example 1, Step 10.

[0239] MS (ESI): m / z = 681.2 [M+H] + .

[0240] Fifth Step

[0241] 2-(2,6-Dioxopiperidin-3-yl)-5-{4-[4-(4-{[(6R)-6-methyl-7-[(3S,4S)-l-methyl-3- phenylpiperidine-4-carbonyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl]amino}-lH- pyrazol-l-yl)piperidine-l-carbonyl]piperidin-l-yl}-2,3-dihydro-lH-isoindole-l,3-dione (3)

[0242] Compound 3 (47.2 mg, 0.054 mmol) was synthesized according to the procedure of Reference Example 1, Step 11.

[0243] MS (ESI): m / z = 882.4 [M+H] + .

[0244] 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.02 (s, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.72 - 7.46 (m, 2H), 7.31 - 7.12 (m, 7H), 5.03 (dd, J = 12.7, 5.5 Hz, 1H), 4.96 - 4.10 (m, 6H), 4.03 (dt, J = 13.3, 3.9 Hz, 2H), 3.77 (dd, J = 36.8, 24.0 Hz, 2H), 3.08 - 2.99 (m, 6H), 2.92 - 2.76 (m, 3H), 2.65 - 2.54 (m, 3H), 2.38 (d, J = 28.5 Hz, 5H), 2.11 - 2.01 (m, 3H), 1.91 - 1.66 (m, 8H), 1.06 - 0.44 (m, 3H).

[0245] Example 4

[0246] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(4-(4-(((R)-6-methyl-7-((3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (4)

[0247] First step

[0248] Ethyl 4-(((R)-1-phenylethyl)amino)pentanoate (Int 1c)

[0249] Compound (R)-1-phenylethyl-1-amine (Int 1a) 50 g, 412.6 mmol), ethyl 4-oxopentanoate (Int 1b) 65.4 g, 453.9 mmol) were dissolved in dichloromethane (1.0 L), sodium triacetoxyborohydride (131.2 g, 618.9 mmol) was added portionwise, stirred at room temperature overnight. The reaction was poured into saturated sodium bicarbonate solution, separated, the aqueous phase was extracted with dichloromethane (500 mL x 2), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum and reduced pressure to give 100 g of compound Int 1c crude.

[0250] Second step

[0251] 4-((2-ethoxy-2-oxoethyl)((R)-1-phenylethyl)amino)pentanoic acid ethyl ester (Int 1e)

[0252] The crude Int 1c (100 g), 2-oxoacetic acid ethyl ester (Int 1d) 50% toluene solution (158.7 mL, 802.1 mmol) was dissolved in dichloromethane (1.2 L), sodium triacetoxyborohydride (254.9 g, 1203.1 mmol) was added in portions, stirred at room temperature overnight. The reaction was poured into saturated sodium bicarbonate solution, separated, the aqueous phase was extracted with dichloromethane (500 mL x 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 130 g of crude compound Int 1e.

[0253] Third step

[0254] 5-hydroxy-2-methyl-1-((R)-1-phenylethyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester (Int 1f)

[0255] The crude Int 1e (130 g) was dissolved in toluene (1.2 L), potassium tert-butoxide (86.9 g, 775.1 mmol) was added in portions, there was an exothermic phenomenon, and the reaction was carried out at room temperature for 1.5 h. LCMS showed that the starting material was completely converted into the target product. The reaction was poured into saturated ammonium chloride solution, the pH was adjusted to about 8, separated, the aqueous phase was separated, the organic phase was retained, the aqueous phase was extracted with dichloromethane (500 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 110 g of crude Int 1f.

[0256] Fourth step

[0257] (R)-6-methyl-7-((R)-1-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol (Int 1g)

[0258] The compound Int 1f (108.0 g) was dissolved in methanol (1 L), urea (89.7 g, 1492.8 mmol), sodium methoxide methanol solution (30%) (201.6 g, 1119.6 mmol) was added, and the reaction was stirred at 70°C for 18 h. The reaction was concentrated under reduced pressure to dryness, the pH of the reaction was adjusted to about 8 with 3M hydrochloric acid, extracted with dichloromethane (1 L x 3), and the organic phase was filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give the target product. Compound Int 1g 77 g was obtained.

[0259] Fifth step

[0260] (R)-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol (Int 1h)

[0261] Compound Int 1g (60 g, 210.3 mmol) was dissolved in methanol (900 mL), Pd / C (12.0 g) was added and hydrogen was replaced for three times. The reaction was carried out at room temperature overnight. Filtration and concentration under reduced pressure gave compound Int 1h crude 43 g.

[0262] Sixth step

[0263] (R)-2,4-dichloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxylic acid tert-butyl ester (Int 1j)

[0264] Compound Int 1h (43 g) was suspended in phosphorus oxychloride (43 mL) and the temperature was raised to 100 °C and the reaction was carried out overnight. Concentration under reduced pressure gave the crude product which was dissolved in ice water (300 mL) and extracted with dichloromethane (50 mL). The aqueous phase was retained and used directly in the next step without further treatment.

[0265] Seventh step

[0266] (R)-2,4-dichloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)- carboxylic acid tert-butyl ester (Int 1j)

[0267] The aqueous phase of compound Int 1h was adjusted to basic with triethylamine and tert-butyl dicarbonate (77.7 g, 356.0 mmol) was added. The reaction was stirred at room temperature for 2 h. Extraction with dichloromethane (500 mL x 2), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure gave the residue which was purified by column chromatography over neutral alumina (petroleum ether: ethyl acetate = 10: 1) to give Int 1j 38 g.

[0268] Eighth step

[0269] (R)-2-chloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (Int 1)

[0270] Compound Int 1j (10 g, 31.4 mmol) was dissolved in ethanol (100 mL), zinc powder (20.6 g, 314.3 mmol) and glacial acetic acid (18.9 g, 314.3 mmol) were added and the temperature was raised to 80 °C and the reaction was stirred for 1.5 h. Filtration, adjustment of the filtrate to basic with triethylamine and concentration under reduced pressure gave the residue which was dissolved in water (50 mL) and extracted with dichloromethane (100 mL x 3) and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile / water) to give compound Int 1 4.5 g in 50.4% yield.

[0271] MS (ESI): m / z = 284.1 [M+H] + .

[0272] 1 H NMR (400 MHz, CDC13) δ 8.39 (s, 1H), 4.98 (d, J = 20 Hz, 1H), 4.83 (s, 1H), 4.23 (d, J = 20, 1H), 3.08 - 3.02 (m, 1H), 2.59 (d, J = 16 Hz, 1H), 1.48 (s, 9H), 1.09 (d, J = 4 Hz, 3H).

[0273] Ninth step

[0274] Benzyl 4-{[4-(4-nitro-1H-pyrazol-1-yl)piperidin-1-yl]methyl}piperidine-1-carboxylate (4b)

[0275] To a solution of 4-(4-nitro-1H-pyrazol-1-yl)piperidine (1ed) (4.22 g, 21.508 mmol) and benzyl 4-formylpiperidinecarboxylate (4a) (5.85 g, 23.658 mmol) in methanol was added AcOH (0.13 g, 2.15 mmol) and NaBH(OAc)3(9.07 g, 43.015 mmol) at room temperature, stirred at 25 °C, filtered, washed with DCM (20 mL x 3). The filtrate was concentrated under reduced pressure, purified by column chromatography (eluent: DCM containing 0-10% MeOH) to give the target product 4b (7.8 g, 18.2 mmol).

[0276] MS (ESI): m / z = 428.2 [M+H] + .

[0277] Tenth step

[0278] Benzyl 4-{[4-(4-amino-1H-pyrazol-1-yl)piperidin-1-yl]methyl}piperidine-1-carboxylate (4c) Compound 4c (720 mg, 1.81 mmol) was synthesized according to the procedure of Reference Example 1, fourth step.

[0279] MS (ESI): m / z = 681.2 [M+H] + .

[0280] Eleventh step

[0281] (R)-tert-Butyl 2-((1-(1-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (4d)

[0282] Compound 4c (504 mg, 1.27 mmol) was dissolved in toluene (15.0 mL) at room temperature, and intermediate Int 1 (300 mg, 1.06 mmol), sodium tert-butoxide (304 mg, 3.17 mmol) and RuPhos-Pd-G3 (88.0 mg, 0.11 mmol) were added. The reaction was carried out at 130 °C under N2for 1.5 h. The reaction solution was diluted with water (100.0 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (eluent: 0-10% MeOH in DCM) to give the target product 4d (7.8 g, 18.2 mmol).

[0283] MS (ESI): m / z = 645.4 [M+H] + .

[0284] Twelfth step

[0285] (R)-6-methyl-2((1-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)- 5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (4e)

[0286] Compound 4d (180 mg, 0.28 mmol) was added to methanol (15.0 mL) at room temperature, and 10% Pd / C (178 mg, 55 wt% water content) was added. The reaction was carried out under 1 atm of H2for 1 h. The reaction solution was filtered, washed with methanol (5.0 mL x 3), and concentrated under reduced pressure to give compound 4e (140.0 mg, 0.28 mmol).

[0287] MS (ESI): m / z = 511.3 [M+H] + .

[0288] Thirteenth step

[0289] (6R)-2-((1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (4f)

[0290] To a solution of compound 3a (124 mg, 0.45 mmol) in DMSO (3.0 mL) was added compound 4e (154 mg, 0.30 mmol), DIPEA (194 mg, 1.508 mmol) at room temperature. The reaction was heated to 130 °C and stirred for 5 h. The reaction was treated with water (10.0 mL), stirred for 30 min, filtered, washed with water (5.0 mL x 3), and dried under vacuum to give compound 4f (200 mg, 0.26 mmol).

[0291] MS (ESI): m / z = 767.3 [M+H] + .

[0292] Fourteenth step

[0293] 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(4-(((R)-6-methyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline- 1,3-dione (4g)

[0294] Compound 4f (195 mg, 0.25 mmol) was added to DCM (10.0 mL) at room temperature, ZnBr2 (572 mg, 2.54 mmol) was added, stirred for 1 h, concentrated under reduced pressure, and purified by preparative liquid chromatography (Nouryon-Kromasil-C18-10 μm-25*250 mm, A: 10 mM ammonium bicarbonate in water B: acetonitrile, flow rate: 30 mL / min) to give compound 4g (60 mg, 0.09 mmol).

[0295] MS (ESI): m / z = 667.3 [M+H] + .

[0296] Fifteenth step

[0297] 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(4-(((R)-6-methyl-7-((3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (4)

[0298] Compound 4 (35 mg, 0.04 mmol) was synthesized according to the procedure of Reference Example 1, step ten.

[0299] MS (ESI): m / z = 868.4 [M+H] + .

[0300] 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.27 (s, 1H), 8.14 (d, J = 23.1 Hz, 1H), 7.89 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.34 - 7.04 (m, 8H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.93 - 4.60 (m, 2H), 4.05 (d, J = 12.1 Hz, 3H), 3.74 (dd, J = 51.9, 18.9 Hz, 1H), 3.13 - 2.72 (m, 10H), 2.27 - 1.73 (m, 22H), 1.16 (d, J = 11.7 Hz, 2H), 1.05 - 0.47 (m, 3H).

[0301] Example 5

[0302] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(4-(((R)-6-methyl-7-((3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino) phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (5)

[0303] First step

[0304] Benzyl 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}methyl)piperazine-1-carboxylate (5c)

[0305] To a solution of 4-formyl-1-tert-butylcarboxylate (5a) (8.05 g, 37.8 mmol) in dichloromethane (300 mL) was added benzyl piperazine-1-carboxylate (5b) (7.356 mL, 38.1 mmol) and sodium cyanoborohydride (8.36 g, 39.6 mmol) at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (eluent: petroleum ether containing 0-50% ethyl acetate) to give the target product 5c (12 g, 28.7 mmol).

[0306] MS (ESI): m / z = 418.4 [M+H] + .

[0307] Second step

[0308] Benzyl 4-[(piperidin-4-yl)methyl]piperazine-1-carboxylate (5d)

[0309] Compound 5d (11.8 g, 37.2 mmol) was synthesized according to the procedure of Reference Example 1, Step 10.

[0310] MS (ESI): m / z = 318.2 [M+H] + .

[0311] Third Step

[0312] Benzyl 4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate (5f)

[0313] Compound 5d (2.0 g, 6.30 mmol) and 1-fluoro-4-nitrobenzene (5e) (0.557 mL, 5.25 mmol) were dissolved in DMF (20 mL) at room temperature, and K2CO3 (2.18 g, 15.752 mmol) was added. The temperature was raised to 50 °C, and stirred for 1 h. Water was added to the reaction mixture, and stirred for 0.5 h. Filtration and drying under vacuum gave compound 5f (2.3 g, 5.2 mmol).

[0314] MS (ESI): m / z = 439.2 [M+H] + .

[0315] Fourth Step

[0316] Benzyl 4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate (5g)

[0317] Compound 5g (1.11 g, 2.72 mmol) was synthesized according to the procedure of Reference Example 4, Step 10.

[0318] MS (ESI): m / z = 409.4 [M+H] + .

[0319] Fifth Step

[0320] Benzyl 4-{[1-(4-{[(6R)-7-[(tert-butoxy)carbonyl]-6-methyl-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl]amino}phenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate (5h)

[0321] -2-yl]amino}phenyl) piperidin-4-yl]methyl}piperazine-1-carboxylate (5h)

[0322] Compound 5g (500 mg, 1.22 mmol) was dissolved in 1,4-dioxane (6.0 mL) at room temperature, and intermediate Int 1 (315.7 mg, 1.11 mmol), potassium tert-butoxide (374 mg, 3.3 mmol) and RuPhos-Pd-G3 (88.0 mg, 0.11 mmol) were added. The reaction was carried out under N2atmosphere at 130 °C for 1.5 h in microwave. The reaction solution was diluted with water (100.0 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (eluent: DCM containing 0-10% MeOH) to give the target product 5h (7.8 g, 18.2 mmol).

[0323] MS (ESI): m / z = 656.4 [M+H] + .

[0324] Sixth step

[0325] (6R)-6-methyl-2-[(4-{4-[(piperazin-1-yl)methyl]piperidin-1-yl}phenyl)amino]-

[0326] tert-butyl 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (5i)

[0327] Compound 5i (170 mg, 0.326 mmol) was synthesized according to the procedure of Step 12 of Reference Example 4.

[0328] MS (ESI): m / z = 522.5 [M+H] + .

[0329] Seventh step tert-butyl (6R)-2-({4-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3- dihydro-1H-indolin-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}amino)-6-methyl- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (5j)

[0330] Compound 5j (248 mg, 0.319 mmol) was synthesized according to the procedure of Step 13 of Reference Example 4.

[0331] MS (ESI): m / z = 778.4 [M+H] + .

[0332] Eighth step

[0333] 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[(6R)-6-methyl-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl]amino}phenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2,3-dihydro-1H- isoindole-1,3-dione (5k)

[0334] Compound 5k (216 mg, 0.319 mmol) was synthesized following the procedure of Step 10 of Reference Example 1.

[0335] MS (ESI): m / z = 678.3 [M+H] + .

[0336] Ninth Step

[0337] 2-(2,6-dioxopiperidin-3-yl)-5-(4-{[(6R)-6-methyl-7-[(3S,4S)-1-methyl-3- phenylpiperidin-4-yl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino}phenyl)piperidin- 4-yl]methyl}piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione (5)

[0338] Compound 5 (35.4 mg, 0.04 mmol) was synthesized following the procedure of Step 11 of Reference Example 1.

[0339] MS (ESI): m / z = 879.4 [M+H] + .

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.19 (s, 1H), 8.11 (d, J = 23 Hz 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 19.2, 8.8 Hz, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.29 - 7.05 (m, 6H), 6.87 (dd, J = 17.0, 8.9 Hz, 2H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.96 - 4.27 (m, 2H), 3.73 (d, J = 16.4 Hz, 1H), 3.57 (t, J = 13.1 Hz, 2H), 3.44 (s, 4H), 3.24 - 2.73 (m, 6H), 2.69 - 2.51 (m, 7H), 2.37 (d, J = 15.4 Hz, 1H), 2.27 - 1.96 (m, 9H), 1.97 - 1.51 (m, 5H), 1.26 - 1.20 (m, 2H), 1.08 - 0.45 (m, 3H).

[0341] Example 6

[0342] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(4-(((R)-6-methyl-7-((3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino) phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (6)

[0343] First step

[0344] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (6b)

[0345] To a solution of compound 3a (2.7 g, 9.78 mmol) in NMP (35.0 mL) was added piperidin-4-methanol (6a) (1.7 g, 14.76 mmol), DIPEA (6.5 mL, 39.3 mmol) at room temperature. The reaction was heated to 120 °C and stirred for 2 h. The reaction was added to water (200.0 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give the target product 6b (2.5 g, 6.731 mmol).

[0346] MS (ESI): m / z = 372.2 [M+H] + .

[0347] Second step

[0348] 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (6c)

[0349] To a solution of compound 6b (500 mg, 1.35 mmol) in dichloromethane (25.0 mL) was added DMP (1.45 g, 3.42 mmol) at room temperature. The reaction was cooled to 0-5 °C and stirred for 2 h. The reaction was quenched with 10 wt% Na2S2O3 (20.0 mL). The reaction was extracted with dichloromethane (20 mL x 3) and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1) to give the target product 6c (0.34 g, 0.73 mmol).

[0350] MS (ESI): m / z = 370.2 [M+H] + .

[0351] Third step

[0352] 2-(trimethylsilyl)ethyl 4-hydroxypiperidine-1-carboxylate (6f)

[0353] The synthesis of compound 6f (4.7 g, 19.2 mmol) was performed according to the procedure of Reference Example 1, third step.

[0354] MS (ESI): m / z = 268.2 [M+Na] + .

[0355] Fourth step

[0356] 2-(trimethylsilyl)ethyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6g)

[0357] To a solution of compound 6f (2.7 g, 11.0 mmol) in dichloromethane (50.0 mL) was added triethylamine (2.8 mL, 20.1 mmol) and methanesulfonyl chloride (1.0 mL, 12.9 mmol) at 0 °C and stirred for 2 h. The reaction was diluted with water (10.0 mL) and extracted with dichloromethane (20.0 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the target product 6g (3.4 g, 10.5 mmol).

[0358] MS (ESI): m / z = 346.2 [M+Na] + .

[0359] Fifth step

[0360] 2-(trimethylsilyl)ethyl 4-(3-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (6i)

[0361] Compound 6g (3.2 g, 9.40 mmol) was dissolved in acetonitrile (100.0 mL) at room temperature, and 1H-pyrazol-3-yl-methyl-carbamic acid tert-butyl ester (6h) (1.75 g, 8.87 mmol) and Cs2CO3 (9.5 g, 29.2 mmol) were added. The reaction was warmed to 80 °C and stirred for 16 h. The reaction was concentrated under reduced pressure and the crude product was purified by column chromatography (dichloromethane / isopropanol = 10 / 1) to give the target product 6i (630 mg, 1.41 mmol).

[0362] MS (ESI): m / z = 425.2 [M+H] + .

[0363] Sixth step

[0364] (R)-6-methyl-2-(((l-(l-((2-(trimethylsilyl)ethoxy)carbonyl)piperidin-4-yl)-lH- pyrazol-3-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (6j)

[0365] Compound 6i (0.63 g, 1.34 mmol) was dissolved in 1,1,1,3,3,3-hexafluoroisopropanol (6.0 mL) at room temperature, and warmed to 150 °C with stirring for 2 hours. The reaction liquid was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol (0.1% NH3) = 5 / 1) to obtain the target product 6j (330 mg, 0.97 mmol).

[0366] MS (ESI): m / z = 325.2 [M+H] + .

[0367] Seventh Step

[0368] (R)-6-methyl-2-(((l-(l-((2-(trimethylsilyl)ethoxy)carbonyl)piperidin-4-yl)-lH- pyrazol-3-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (6j)

[0369] Compound 6k (300 mg, 0.51 mmol) was synthesized according to the procedure of Reference Example 1, fifth step.

[0370] MS (ESI): m / z = 572.4 [M+H] + .

[0371] Eighth Step

[0372] (R)-6-methyl-2-(((l-(l-((2-(trimethylsilyl)ethoxy)carbonyl)piperidin-4-yl)-lH- pyrazol-3-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (6j)

[0373] Compound 61 (90 mg, 0.18 mmol) was synthesized according to the procedure of Reference Example 1, sixth step.

[0374] MS (ESI): m / z = 428.2 [M+H] + .

[0375] Ninth Step

[0376] (6R)-2-(((1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-3-yl)methyl)amino)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (6m)

[0377] The synthesis of compound 6m (90 mg, 0.11 mmol) followed the procedure of Reference Example 5, step 7.

[0378] MS (ESI): m / z = 782.5 [M+H] + .

[0379] Step 10

[0380] 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(3-(((R)-6-methyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-2-yl)amino)methyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline- 1,3-dione (6n)

[0381] The synthesis of compound 6n (80 mg, 0.12 mmol) followed the procedure of Reference Example 5, step 8.

[0382] MS (ESI): m / z = 681.3 [M+H] + .

[0383] Step 10

[0384] 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(3-(((R)-6-methyl-7-((3S,4S)-1-methyl-3-phenylpiperidin-4- carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)methyl)-1H-pyrazol-1-yl)piperidin-1- yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (6)

[0385] The synthesis of compound 6 (27.03 mg, 0.03 mmol) followed the procedure of Reference Example 1, step 10.

[0386] MS (ESI): m / z = 441.8 [M / 2+H] + .

[0387] 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.03 (d, J = 28.2 Hz, 1H), 7.63 (dd, J = 13.6, 5.3 Hz, 2H), 7.34 - 7.09 (m, 8H), 6.20 - 6.01 (m, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.85 - 4.56 (m, 2H), 4.39 (dd, J = 27.6, 5.9 Hz, 2H), 4.05 (d, J = 10.6 Hz, 3H), 3.69 (d, J = 19.7 Hz, 1H), 3.13 - 2.76 (m, 11H), 2.31 (d, J = 16.3 Hz, 1H), 2.18 - 1.65 (m, 20H), 1.26 - 1.08 (m, 3H), 1.03 - 0.43 (m, 3H).

[0388] Example 7

[0389] 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(4-(((R)-6-methyl-7-((3S,4S)-1-methyl-3- phenylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)- 1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindole-1,3-dione (7)

[0390] First Step

[0391] 2-(2,6-dioxopiperidin-3-yl)-5-[3-(hydroxymethyl)azetidin-1-yl]-2,3-dihydro-1H- isoindole-1,3-dione (7b)

[0392] Compound 7b (621 mg, 1.809 mmol) was synthesized following the procedure of Reference Example 3, first step.

[0393] MS (ESI): m / z = 344.1 [M+H] + .

[0394] Second Step

[0395] 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azetidine-3- carbaldehyde (7c)

[0396] Compound 7c (500 mg, 1.465 mmol) was synthesized following the procedure of Reference Example 6, second step.

[0397] MS (ESI): m / z = 342.0 [M+H] +.

[0398] Third step (6R)-2-({1-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindolin-5-yl]azetidin-3-yl}methyl)piperidin-4-yl]-1H-pyrazol-4-yl}amino-6- methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (7d)

[0399] The synthesis of compound 7d (320 mg, 0.385 mmol) follows the procedure of Reference Example 5, seventh step.

[0400] MS (ESI): m / z = 739.3 [M+H] + .

[0401] Fourth step

[0402] 2-(2,6-dioxopiperidin-3-yl)-5-(3-{[4-(4-{[(6R)-6-methyl-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl]amino}-1H-pyrazol-1-yl)piperidin-1-yl]methyl}azetidin-1-yl)-2,3- dihydro-1H-isoindole-1,3-dione (7e)

[0403] The synthesis of compound 7e (86 mg, 0.12 mmol) follows the procedure of Reference Example 1, tenth step.

[0404] MS (ESI): m / z = 639.3 [M+H] + .

[0405] Fifth step

[0406] 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(4-(((R)-6-methyl-7-((3S,4S)-1-methyl-3- phenylpiperidin-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)- 1H-pyrazol-1-yl)piperidin-1-yl)methyl)azetidin-1-yl)isoindole-1,3-dione (7)

[0407] The synthesis of compound 7 (29.6 mg, 0.035 mmol) follows the procedure of Reference Example 1, eleventh step.

[0408] MS (ESI): m / z = 840.4 [M+H] + .

[0409] 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.27 (d, J = 3.6 Hz, 1H), 8.15 (d, J = 23.5 Hz, 1H), 7.90 (d, J = 3.8 Hz, 1H), 7.63 (dd, J = 8.3, 2.0 Hz, 1H), 7.51 (d, J = 58.3 Hz, 1H), 7.28 - 7.08 (m, 5H), 6.77 (dd, J = 5.1, 2.1 Hz, 1H), 6.57 - 6.52 (m, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.92 - 4.61 (m, 2H), 4.34 - 4.11 (m, 3H), 3.92 - 3.61 (m, 3H), 3.22 - 2.75 (m, 9H), 2.67 - 2.53 (m, 4H), 2.37 (d, J = 15.1 Hz, 1H), 2.20 (s, 3H), 2.16 - 2.06 (m, 4H), 2.00 - 1.82 (m, 5H), 1.76 (s, 2H), 1.07 - 0.47 (m, 3H).

[0410] Biological evaluation

[0411] The present disclosure is further described in connection with the test examples below, but these examples are not meant to limit the scope of the present disclosure.

[0412] Test Example 1

[0413] Test Example 1. Inhibition activity test of the compounds of the present disclosure on ovarian cancer cells (OVCAR3)

[0414] 1.1 Experimental materials and instruments (see Table 1)

[0415] Table 1 Experimental materials and instruments

[0416] 1.2 Experimental steps

[0417] Ovarian cancer cells OVCAR3 (commercially available) were cultured in RPMI 1640 medium with 10% FBS in a cell incubator at 37%, 5% CO2. On the first day, cells were plated in 96-well plates, and the plating cell concentration was 2500 cells / well, and cultured in the incubator overnight. On the second day, compound treatment was performed, and the highest concentration of compound treatment was 10 μM, 3-fold dilution, 9 concentrations, and the final concentration of DMSO was 0.1%. After the cells continued to be cultured in the incubator for 5 days, the cell viability was tested using the Celltiter Glo test kit (Promega), and the test method was consistent with the operation method provided by the kit. The data were processed using GraphPad Prism 8 and the IC 50 .

[0418] Y = Bottom + (Top - Bottom) / (1 + 10^((X - LogIC 50 50))).

[0419] X: Log value of compound concentration; Y: % inhibition; Bottom represents the lowest inhibition rate; Top represents the highest inhibition rate; HillSlope represents the slope of the curve.

[0420] Table 2. IC50 of the compounds of the present disclosure against OVCAR3 50 (nM)

[0421] Test Example 2

[0422] Test Example 2. CDK7 degradation activity test of the compounds of the present disclosure against ovarian cancer cells (OVCAR3)

[0423] 2.1 Experimental materials and instruments (see Table 3)

[0424] Table 3 Experimental materials and instruments

[0425] 2.2 Experimental steps

[0426] OVCAR-3 cells were seeded in 12-well plates at 1.5 x 10 5 cells / well, and the next day, the cells were treated with different concentrations of compounds (500 nM, 100 nM, 10 nM, 1 nM, DMSO). After 24 h of incubation at 37 °C in 5% CO2, the cells were collected, washed with pre-cooled PBS, and the supernatant was discarded. The cells were then placed on ice and treated with RIPA lysis buffer containing protease and phosphatase inhibitors. The cell suspension containing the lysis buffer was frozen at -80 °C for 1 h, thawed, and then lysed on ice for another 30 min. After centrifugation at 12,000 rpm for 20 min at 4 °C, the supernatant was collected. The concentration of all protein samples was determined using a BCA kit. An equal amount of protein was taken and added to the loading buffer, and denatured at 95 °C for 10 min. Then, gel electrophoresis was performed, and the protein loading amount was 15 μg, and the loading volume was 10 μL. After transfer using iblot3, the membrane was blocked with blocking solution for 1 h. The primary antibody was diluted 1:1000 with blocking solution and incubated at 4 °C overnight. The secondary antibody was diluted 1:20,000 with blocking solution and incubated at room temperature for 1 h. After the experiment, the signal was detected using the Odyssey imaging instrument M imaging system.

[0427] The results show that Example 4 and Example 5 can effectively degrade CDK7 protein in the range of drug test concentrations (see Figure 1).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl group, the C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is independently and optionally influenced by one or more R groups. A Instead, the R A Selected from deuterium, halogen, cyano, hydroxyl, alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl and 3-6 membered cycloalkyl; R 2 and R 3 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl and 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group and the 3-6 membered cycloalkyl group are each independently and optionally influenced by one or more R groups. B Instead, the R B Selected from deuterium, halogens, hydroxyl groups, cyano groups, and 3-6 membered cycloalkyl groups; R 4 Selected from hydrogen, cyano, C 1-6 Alkyl, 3-6 membered cycloalkyl and 3-12 membered heterocycloalkyl, wherein C 1-6 Alkyl, 3-6 membered cycloalkyl and 3-12 membered heterocycloalkyl are each independently and optionally influenced by one or more R C Instead, the R C Selected from deuterium, halogen, cyano, hydroxyl, alkynyl, C 1-6 Alkoxy, C 1-6 Alkyl, 3-6 membered cycloalkyl and 3-7 membered heterocycloalkyl; R 5 each independently is selected from the group consisting of hydrogen, deuterium, cyano, hydroxyl, C 1-6 alkyl, halogen and C 1-6 alkoxy; L1 represents a chemical bond or C. 1-6 Alkylene, the C 1-6 Alkylenes are optionally subjected to one or more R D Instead, the R D Selected from deuterium, halogens, hydroxyl groups, and C 1-6 Alkoxy, C 1-6 Hydroxyl, amino, and oxo groups; L2is an alkylene chain or an alkylene chain substituted with oxo (=0), either of which is optionally interrupted with at least one of the following interrupting groups: -0-, -S-, -C(O)-, -CºC-, -S(O)2-, -OS(O)2-, -N(R')C(O)-, -N(R')-, -N(R')S(O)-, 3-6 membered cycloalkylene, 3-12 membered heterocycloalkylene, or any combination thereof, wherein R' is hydrogen or C1-4alkyl, and / or terminated at either or both ends with at least one of the following terminating groups: -O-, -S-, -C(O)-, -CºC-, -S(O)2-, -OS(O)2-, -N(R')C(O)-, -N(R')-, -N(R')S(O)-, 3-6 membered cycloalkyl, 3-12 membered heterocycloalkyl, or any combination thereof, wherein R' is hydrogen or C1-4alkyl; 1-6 alkyl, wherein the interrupting group and the one or two end terminating groups are the same or different; Ring A is selected from 3-6-membered cycloene alkyl, 5-12-membered heteroaryl, 6-12-membered aryl, and 3-12-membered heterocyclic alkyl, wherein each of the 3-6-membered cycloene alkyl, 5-12-membered heteroaryl, 6-12-membered aryl, and 3-12-membered heterocyclic alkyl groups is independently optionally separated by one or more R groups. E Instead, the R E Selected from hydroxyl, halogen, C 1-6 Alkoxy, C 1-6 Alkyl and 3-6 membered cycloalkyl; n is 0, 1, 2, 3, or 4; and m is 0, 1, 2, 3, or 4.

2. The compound of claim 1, represented by formula (I): ###0001### or a pharmaceutically acceptable salt thereof, wherein, R 2 is hydrogen or deuterium.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein, R 3 is C 1-6 alkyl; preferably, R 3 is methyl.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein The compound of formula (I) is selected from the group consisting of a compound of formula (la-1), formula (la-2), formula (lb-1), and formula (lb-2): wherein R 1 , R 4 , R 5 , L1, L2, ring A, m and n are as defined in claim 1.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein L2is an alkylene chain, which is optionally interrupted by at least one interrupting group, and / or terminated at either or both ends by at least one terminating group, selected from the group consisting of -O-, -C(O)-, 3-7 membered heterocycloalkylene, or any combination thereof, wherein the interrupting group and the one or both end terminating groups are the same or different; Preferably, L2is selected from an alkylene chain, which alkylene chain is optionally interrupted by at least one of the following interrupting groups and / or terminated at either or both ends by at least one of the following terminating groups: -O-, or any combination thereof, wherein the interrupting group and the one or both end terminating groups are the same or different; More preferably, L2is selected from 6. The compound of Formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L2is an alkylene chain substituted with an oxo (=0) group, which is optionally interrupted by at least one interrupting group, and / or terminated at either or both ends by at least one terminating group, selected from the group consisting of -O-, -C(O)-, 3-7 membered heterocycloalkylene, or any combination thereof, wherein the interrupting group and the one or both end terminating groups are the same or different; Preferably, L2is an alkylene chain, which is optionally interrupted by at least one of the following interrupting groups and / or terminated at either or both ends by at least one of the following terminating groups: -O-, or any combination thereof, wherein the interrupting group and the one or both end terminating groups are the same or different; More preferably, L2 is 7. The compound of formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-12-membered heteroaryl or a 6-12-membered aryl, wherein the 5-12-membered heteroaryl and the 6-12-membered aryl are each independently and optionally converted by one or more R E Instead, the R E Selected from hydroxyl, halogen, C 1-6 Alkoxy, C 1- 6-alkyl and 3-6-membered cycloalkyl; preferably, ring A is 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 each independently is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; R is preferably selected from hydrogen, chloro, cyano, methyl, methoxy, cyclopropyl and ethynyl. More preferably, R is selected from hydrogen, chloro, cyano and ethynyl. Most preferably, R is selected from hydrogen and chloro. In particular, R is hydrogen. 1 each independently is selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy, cyclopropyl and 9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 4 is C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more R C , said R C is selected from the group consisting of deuterium, halogen, C 1-6 alkoxy and C 1-6 alkyl; Preferred, R 4 C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R C Instead, the R C Selected from hydrogen, deuterium, F, methoxy, and methyl; More preferably, R 4 is methyl.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 5 each independently is selected from the group consisting of hydrogen, deuterium, methyl, F and methoxy; preferably, R 5 each independently is hydrogen or deuterium.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein L1is a chemical bond.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein L1is C 1-6 alkylene, said C 1-6 alkylene is optionally substituted with one or more R D substituted, said R D is selected from deuterium, hydroxyl, methoxy, hydroxymethyl, and oxo. Preferably, L1is a methylene group.

13. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein, n is 0 or 1, and / or, m is 0 or 1.

14. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, wherein, selected from 15. The compound of Formula (I) according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from: Preferably, the compound of formula (I) is selected from:

16. An isotopically-substituted compound of Formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof. Preferably, the isotope is deuterium.

17. A pharmaceutical composition comprising a compound of Formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound according to claim 16, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

18. Use of a compound of Formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound according to claim 16, or a pharmaceutical composition according to claim 17, for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder associated with CDK7.

19. Use of a compound of Formula (I) according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound according to claim 16, or a pharmaceutical composition according to claim 17, for the manufacture of a medicament for the treatment and / or prevention of an autoimmune disease, an inflammatory disease, a cancer, or a tumor; Preferably, the cancer or tumor is a solid tumor or a hematological cancer; More preferably, the hematological cancer is selected from the group consisting of leukemia, lymphoma, and multiple myeloma; the solid tumor is selected from the group consisting of breast cancer, brain cancer, pancreatic cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, gastric cancer, lung cancer, colorectal cancer, neuroblastoma, and osteosarcoma.

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