PKMYT1 inhibitors, methods of manufacture, pharmaceutical compositions and uses thereof

Abstract

The present invention relates to the field of medicine and discloses a PKMYT1 inhibitor, a preparation method, a pharmaceutical composition, and its use. The present invention provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof. The PKMYT1 inhibitor of the present invention can be used to treat tumor diseases associated with CCNE1 amplification or FBXW7 inactivating mutation. [Formula 1] JPEG2025538617000262.jpg50169

Description

Detailed Description of the Invention

[0001] This application claims the priority of Chinese patent application No. 2022114881146, filed on November 25, 2022, the priority of Chinese patent application No. 202310519621X, filed on May 9, 2023, the priority of Chinese patent application No. 2023111342853, filed on September 4, 2023, and the priority of Chinese patent application No. 2023114943221, filed on November 9, 2023. This application cites the above Chinese patent applications in their entirety.

[0002] [Technical field] The present invention relates to the field of medicine, and specifically to PKMYT1 inhibitor compounds, their pharmaceutically acceptable salts, their isomers, their preparation methods, their pharmaceutical compositions, and their pharmaceutical uses.

[0003] [Background technology] Cyclin E (Cyclin E), a member of the cell cycle protein-dependent kinase 2 (CDK2) family, binds to CDK2 in the G1 phase to form an activated CDK2-Cyclin E complex, promoting the transition from G1 to S phase of the cell cycle, where DNA replication begins. The cyclin E1 (CCNE1) gene is the major protein encoded by cyclin E and plays a key role in regulating the transition from G1 to S phase of the cell cycle. Several studies have shown that overexpression of CCNE1 protein increases the expression level of its encoded cyclin E protein, enhancing the activity of the CDK2-Cyclin E complex, potentially inducing premature cell cycle transitions, increasing DNA replication pressure, and potentially resulting in genomic instability. CCNE1 amplification is common in many tumor types, particularly in aggressive gynecological and gastrointestinal cancers, such as ovarian cancer (HGSOC), uterine cancer, and gastroesophageal cancer, and is associated with resistance to cytotoxic and targeted therapies.

[0004] CCNE1 itself is not considered a druggable target, and current research focuses on treating CCNE1-amplified tumors by using multitargeted CDK inhibitors to target its downstream cell cycle protein, CDK2. Therefore, there are currently few treatment options for CCNE1-amplified tumors, making the development of new therapies for this type of tumor a significant unmet need. To investigate therapeutic targets for CCNE1-amplified tumors, researchers from Mount Sinai Hospital in Toronto, Canada, the University of Toronto, and Repare Therapeutics, Inc., USA, collaborated to discover that CCNE1 amplification and PKMYT1 inhibition constitute a synthetic lethal pair. These results were published in the April 20, 2022, issue of Nature. They conducted a genome-wide CRISPR-Cas9-based synthetic lethal screen in a cellular model of CCNE1 amplification. The results showed that PKMYT1 is essential in CCNE1-amplified cells but not in other healthy cells with normal CCNE1 levels. Therefore, PKMYT1 is a synthetic lethal gene for CCNE1, and PKMYT1 inhibitors can be used to treat CCNE1-amplified tumor diseases. Furthermore, the protein encoded by the FBXW7 gene is a target protein recognition component of cullin-RING ubiquitin ligase, and the FBXW7 protein targets and binds to CCNE1 via the ubiquitin-dependent proteolytic pathway. Therefore, FBXW7-inactivating mutations lead to elevated CCNE1 levels, and PKMYT1 inhibitors can also be used to treat tumor diseases associated with FBXW7-inactivating mutations.

[0005] PKMYT1 kinase, also known as MYT1, is a member of the WEE family of kinases. It phosphorylates the threonine 14 site of CDK1 kinase during cell cycle transition, inactivating the CDK1-cyclin B complex and negatively regulating the cell cycle checkpoint from G2 to M, which has an important effect on tumor cell proliferation, migration, and xenograft tumor formation.

[0006] Based on the discovery of the synthetic lethal relationship between CCNE1 and PKMYT1, a research team at Mount Sinai Hospital in Toronto developed the selective PKMYT1 inhibitor RP-6306, which demonstrated single-agent activity and durable tumor regression when combined with gemcitabine in CCNE1-amplified models. RP-6306 treatment triggered selective and unplanned activation of CDK1 in CCNE1-overexpressing cells, promoting premature mitosis in DNA-synthesizing cells. CCNE1 overexpression disrupts CDK1 homeostasis, at least in part through premature activation of the MMB-FOXM1 mitotic transcription program. They concluded that PKMYT1 inhibition is a promising strategy for treating CCNE1-amplified cancers.

[0007] Currently, RP-6306 is still in clinical trials and few therapeutic options are available, making it clinically important to continue developing selective PKMYT1 inhibitors to expand the range and availability of therapeutic options.

[0008] [Summary of the Invention] The problem to be solved by the present disclosure is to provide a PKMYT1 inhibitor with a novel structure that overcomes one or more of the drawbacks of existing PKMYT1 inhibitors, such as limited variety, poor pharmaceutical availability, low PKMYT1 enzyme inhibitory activity, low HCC1569 cell inhibitory activity, short half-life, rapid clearance rate, poor metabolic stability, poor antitumor activity, and poor solubility. The PKMYT1 inhibitor of the present invention has one or more advantages, such as high PKMYT1 enzyme inhibitory activity, high HCC1569 cell inhibitory activity, long half-life, slow clearance, good metabolic stability, good antitumor activity, and good solubility, and can be used for the treatment of tumor diseases associated with CCNE1 amplification or FBXW7 inactivating mutations.

[0009] The present invention mainly solves the above technical problems through the following technical solutions.

[0010] In a first aspect, the present disclosure provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof:

[0011] [ka]

[0012] however, X 1 is N or CR 5 is selected from X 2 is N or CR 6 is selected from X 3 is N or CR 7 is selected from X 4 is N or CR 8 is selected from X 5 is selected from N or C; X 6 is selected from N or C; X 7 is selected from N or C; The condition is X 2 But, CR 6 Selected from and X 5 is selected from C and X 6 is selected from N and X 7 If is selected from C, then X 3 and X 4 At the same time, CH is not R 1 and R 2 are each independently a halogen, C 1-4 Alkyl, C 1-4 Alkoxy, Hydroxy C 1-4 Alkyl or deuterated C 1-4 alkyl, R 3 -H, -CN, -OH, -N(R a )(R b ), halogens, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -LR c , phenyl, C3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, deuterated C 1-4 alkyl, or 5-6 membered heteroaryl, wherein the phenyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, and 5- to 6-membered heteroaryl may optionally be substituted with one or more R 3a wherein R 3a is a halogen, C 1-4 Alkyl or C 1-4 alkoxy; L is C 2-4 Alkynylene, C 1-4 Alkylene, or C 2-4 alkenylene; R c is C 1-4 Alkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, 1-4 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocyclyl may optionally be one or more R ca wherein R ca is selected from halogen or —OH; R a and R b are independently -H, C 1-4 Alkyl, phenyl, p-methoxybenzyl, C 1-4 Alkyl-C(O)-, C 3-6 Cycloalkyl or haloC 1-4 alkyl, or R a , R b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl optionally substituted by halogen; R 4 -H, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy or haloC1-4 alkyl, R 5 , R 7 , and R 8 are each independently -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl, C 1-4 Alkoxy or haloC 1-4 alkyl, R 6 -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl, C 1-4 Alkoxy, -COOH, HaloC 1-4 Alkyl, HaloC 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-S(O)2-, HydroxyC 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 cycloalkyl-O-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or -CD3, wherein said C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, phenyl, and 5- to 6-membered heteroaryl may optionally be substituted with one or more R 6a wherein R 6a is a halogen, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 1-4 alkoxy; R d and R eare independently -H, C 1-4 Alkyl, -S(O)2-N(R f )(R g ), -C(O)-aryl, -C(O)-NR f -aryl, or -(C=S)-NR f -aryl, R f and R g are each independently -H or C 1-4 alkyl, Or, R 2 , R 8 C together with the atoms to which they are connected 5-6 forming a cycloalkenyl, and / or R 3 , R 6 together with the atom to which they are attached, phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 forming a cycloalkenyl or a 5- to 6-membered heteroaryl; and / or R 4 , R 6 together with the atom to which they are attached, phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 forming a cycloalkenyl or a 5- to 6-membered heteroaryl; The phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkenyl, and C 5-6 The cycloalkenyl may optionally be halogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, and C 1-6 It is further substituted by one or more substituents selected from alkyl-C(O)-.

[0013] In another aspect, the present disclosure provides a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or an isomer thereof:

[0014] [ka]

[0015] however, X 1 is N or CR 5 is selected from X 2 is N or CR 6 is selected from X 3 is N or CR 7 is selected from X 4 is N or CR 8 is selected from X 5 is selected from N or C; X 6 is selected from N or C; X 7 is selected from N or C; The condition is X 2 But, CR 6 Selected from and X 5 is selected from C and X 6 is selected from N and X 7 If is selected from C, then X 3 and X 4 At the same time, CH is not R 1 and R 2 are each independently a halogen, C 1-4 Alkyl, C 1-4 Alkoxy, Hydroxy C 1-4 Alkyl or deuterated C 1-4 alkyl, R 3 -H, -CN, -OH, -N(R a )(R b ), halogens, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -LR c , phenyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, deuterated C 1-4alkyl, or 5-6 membered heteroaryl, wherein the phenyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, and 5- to 6-membered heteroaryl may optionally be substituted with one or more R 3a wherein R 3a is a halogen, C 1-4 Alkyl or C 1-4 alkoxy; L is C 2-4 Alkynylene, C 1-4 Alkylene, or C 2-4 alkenylene; R c is C 1-4 Alkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, 1-4 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocyclyl may optionally be one or more R ca wherein R ca is selected from halogen or —OH; R a and R b are independently -H, C 1-4 Alkyl, phenyl, p-methoxybenzyl, C 1-4 Alkyl-C(O)-, C 3-6 Cycloalkyl or haloC 1-4 alkyl, or R a , R b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl optionally substituted by halogen; R 4 -H, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy or haloC 1-4 alkyl, R 5 , R 7 and R 8are each independently -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl, C 1-4 Alkoxy or haloC 1-4 alkyl, R 6 -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl, C 1-4 Alkoxy, -COOH, HaloC 1-4 Alkyl, HaloC 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-S(O)2-, HydroxyC 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 cycloalkyl-O-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or -CD3, wherein said C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, phenyl, and 5- to 6-membered heteroaryl may optionally be substituted with one or more R 6a wherein R 6a is a halogen, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 1-4 alkoxy; R d and R e are independently -H, C 1-4 Alkyl, -S(O)2-N(R f )(R g ), -C(O)-aryl, -C(O)-NRf -aryl, or -(C=S)-NR f -aryl, R f and R g are each independently -H or C 1-4 alkyl, Or, R 2 , R 8 C together with the atoms to which they are connected 5-6 forming a cycloalkenyl, and / or R 3 , R 6 together with the atom to which they are attached, phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 forming a cycloalkenyl or a 5- to 6-membered heteroaryl; and / or R 4 , R 6 together with the atom to which they are attached, phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 forming a cycloalkenyl or a 5- to 6-membered heteroaryl; The phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkenyl, and C 5-6 The cycloalkenyl may optionally be halogen, C 1-4 Alkyl, HaloC 1-4 Alkyl and C 1-4 It is further substituted by one or more substituents selected from alkoxy.

[0016] In some embodiments, X 1 is N or CR 5 is selected from X 2 is N or CR 6 is selected from X 3 is N or CR 7 is selected from X 4 is N or CR 8 is selected from X 5 is selected from N or C; X 6is selected from N or C; X 7 is selected from N or C; The condition is X 2 But, CR 6 Selected from and X 5 is selected from C and X 6 is selected from N and X 7 If is selected from C, then X 3 and X 4 At the same time, CH is not R 1 and R 2 are each independently a halogen, C 1-4 Alkyl, C 1-4 Alkoxy or hydroxy C 1-4 alkyl, R 3 -H, -CN, -OH, -N(R a )(R b ), halogens, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -LR c , phenyl, C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocyclyl, or 3- to 6-membered heterocycloalkenyl, wherein said phenyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3- to 6-membered heterocyclyl, and 3- to 6-membered heterocycloalkenyl optionally have one or more R 3a wherein R 3a is a halogen, C 1-4 Alkyl or C 1-4 alkoxy; L is C 2-4 Alkynylene, C 1-4 Alkylene, or C 2-4 alkenylene; R c is C 1-4 Alkyl, C 3-6cycloalkyl, or 4- to 6-membered heterocyclyl, 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl optionally have one or more R ca wherein R ca is selected from halogen or —OH; R a and R b are independently -H, C 1-4 Alkyl, phenyl, p-methoxybenzyl, C 1-4 Alkyl-C(O)-, C 3-6 Cycloalkyl or haloC 1-4 alkyl, or R a , R b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl optionally substituted by halogen; R 4 -H, halogen, C 1-4 Alkyl or C 3-6 cycloalkyl; R 5 , R 7 and R 8 are each independently -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl, C 1-4 Alkoxy or haloC 1-4 alkyl, R 6 -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl, C 1-4 Alkoxy, -COOH, HaloC 1-4 Alkyl, HaloC 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl-S(O)2-, HydroxyC 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 cycloalkyl-O-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, phenyl, or 5- to 6-membered heteroaryl, wherein said C 1-4 Alkyl, C 3-6 Cycloalkyl, C 5-6 Cycloalkenyl, C 3-6 Cycloalkyl-C 1-4 Alkyl, C 3-6 Cycloalkyl-O-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, phenyl, and 5- to 6-membered heteroaryl may optionally be substituted with one or more R 6a wherein R 6a is a halogen, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 1-4 alkoxy; R d and R e are independently -H, C 1-4 Alkyl, -S(O)2-N(R f )(R g ), -C(O)-aryl, -C(O)-NR f -aryl, or -(C=S)-NR f -aryl, R f and R g are each independently -H or C 1-4 alkyl, Or, R 2 , R 8 C together with the atoms to which they are connected 5-6 forming a cycloalkenyl, and / or R 3 , R 6 together with the atom to which they are attached form phenyl, 5- to 6-membered heterocycloalkenyl, or C 5-6 forming a cycloalkenyl, and / or R 4 , R 6 together with the atom to which they are attached form phenyl, 5- to 6-membered heterocycloalkenyl, or C5-6 Forms a cycloalkenyl.

[0017] In a preferred embodiment of formula (I), the compound, a pharmaceutically acceptable salt thereof or an isomer thereof.

[0018] [ka]

[0019] however, X 1 is N or CR 5 is selected from X 2 is N or CR 6 is selected from X 3 is N or CR 7 is selected from X 4 is N or CR 8 is selected from X 5 is selected from N or C; X 6 is selected from N or C; X 7 is selected from N or C; The condition is X 2 But, CR 6 Selected from and X 5 is selected from C and X 6 is selected from N and X 7 If is selected from C, then X 3 and X 4 At the same time, CH is not R 1 and R 2 are each independently C 1-4 alkyl, R 3 -H, -CN, -N(R a )(R b ), halogens, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C2-4 Alkynyl, -LR c , phenyl, C 3-6 C-membered cycloalkyl 3-6 3- to 6-membered cycloalkenyl, 3- to 6-membered heterocyclyl, or 3- to 6-membered heterocycloalkenyl; L is C 2-4 alkynylene, R c is C 1-4 Alkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, 1-4 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocyclyl may optionally be one or more R ca wherein R ca is selected from halogen or —OH; R a and R b are independently -H, C 1-4 alkyl, phenyl, or p-methoxybenzyl, or R a , R b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl optionally substituted by halogen; R 4 is -H, halogen, or C 1-4 alkyl, R 5 , R 6 , R 7 and R 8 are each independently -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl or C 1-4 alkoxy; R d and R e are each independently -H or C 1-4 alkyl, Or, R 2 , R 8 C together with the atoms to which they are connected 5-6Forms a cycloalkenyl.

[0020] In another aspect, the present invention provides a compound represented by the following general formula (I):

[0021] [ka]

[0022] however, X 1 is N or CR 5 is selected from X 2 is N or CR 6 is selected from X 3 is N or CR 7 is selected from X 4 is N or CR 8 is selected from X 5 is selected from N or C; X 6 is selected from N or C; X 7 is selected from N or C; The condition is X 2 But, CR 6 Selected from and X 5 is selected from C and X 6 is selected from N and X 7 If is selected from C, then X 3 and X 4 At the same time, CH is not R 1 and R 2 are each independently C 1-4 alkyl, R 3 -H, -CN, -N(R a )(R b ), halogens, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkenyl, C 1-4Alkynyl, -LR c , phenyl, C 3-6 C-membered cycloalkyl 3-6 3- to 6-membered cycloalkenyl, 3- to 6-membered heterocyclyl, or 3- to 6-membered heterocycloalkenyl; L is C 1-4 alkynylene, R c is C 1-4 Alkyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocyclyl, 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclyl are optionally substituted with halogen or -OH; R a and R b are independently -H, C 1-4 alkyl, phenyl, or p-methoxybenzyl, or R a , R b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl optionally substituted by halogen; R 4 is -H, halogen, or C 1-4 alkyl, R 5 , R 6 , R 7 and R 8 are each independently -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl or C 1-4 alkoxy; R d and R e are each independently -H or C 1-4 alkyl, Or, R 2 , R 8 together with the atom to which they are attached form a 5- to 6-membered cycloalkenyl.

[0023] In a preferred embodiment of formula (I), X1 is CR 5 Selected from X 2 is selected from N, and X 5 is selected from C, and X 6 is selected from N, and X 7 is selected from C.

[0024] In a preferred embodiment of formula (I), X 1 and X 2 are all selected from N, and X 5 is selected from C, and X 6 is selected from N, and X 7 is selected from C.

[0025] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —Cl, —F, —Br, —OCH 3 , —CH 2 OH, or —CD 3 .

[0026] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

[0027] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —Cl, —F, —Br, —OCH 3 , or —CH 2 OH.

[0028] In a preferred embodiment of formula (I), R 1 and R 2 are each selected from -CH3.

[0029] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from -CD3.

[0030] In a preferred embodiment of formula (I), R1 and R 2 are each selected from -CH3 or -CD3.

[0031] In a preferred embodiment of formula (I), R 3 are -H, -CN, -NH2, -F, -Br, -Cl, -CH3, -CH2CH3, -CH2CH(CH3)2, -CF3, -OCH3, -OCH2CH3, -CH=CH2, -N(CH3)2, -N(CH2CH3)2, -NHPMB, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0032] [ka]

[0033] Ethynyl, -C≡CR c , -OH, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -OCH3, -CH2F, -CHF2, -CH=CH2, -CH=C(CH3)2, -CH=CHCH3, -C(CH3)=CH2, -NHCH3, -NHCH2CH3, -NHC(O)CH3,

[0034] [ka]

[0035] or -CD3, and R c optionally one or more R ca is selected from the following groups: methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, oxetanyl, or azetidinyl, substituted by ca is selected from -F, -Cl, or -OH.

[0036] In a preferred embodiment of formula (I), R 3are -H, -CN, -NH2, -F, -Br, -Cl, -CH3, -CH2CH3, -CH2CH(CH3)2, -CF3, -OCH3, -OCH2CH3, -CH=CH2, -N(CH3)2, -N(CH2CH3)2, -NHPMB, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0037] [ka]

[0038] Ethynyl, or -C≡CR c Selected from R c optionally one or more R ca is selected from the following groups: methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, oxetanyl, or azetidinyl, substituted by ca is selected from -F, -Cl, or -OH.

[0039] In a preferred embodiment of formula (I), R 3 is -OH, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -OCH3, -CH2F, -CHF2, -CH=CH2, -CH=C(CH3)2, -CH=CHCH3, -C(CH3)=CH2, -NHCH3, -NHCH2CH3, -NHC(O)CH3,

[0040] [ka]

[0041] is selected from.

[0042] In a preferred embodiment of formula (I), R 3 teeth,

[0043] [ka]

[0044] or -CD3.

[0045] In a preferred embodiment of formula (I), -C≡CR c is -C≡C-CH3,

[0046] [ka]

[0047] is selected from.

[0048] In a preferred embodiment of formula (I), R 4 is selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, cyclopropyl, methoxy, or -CH2CF3.

[0049] In a preferred embodiment of formula (I), R 4 is selected from -H, -Cl, -F, -Br, -CH3, or -CH2CH3.

[0050] In a preferred embodiment of formula (I), R 4 is selected from cyclopropyl.

[0051] In a preferred embodiment of formula (I), R 4 is selected from -H.

[0052] In a preferred embodiment of formula (I), R 4 is selected from methoxy, or —CH 2 CF 3 .

[0053] In a preferred embodiment of formula (I), R 5 is selected from -H, -Cl, -F, -CH3, -CN, -CF3, or -OCH3.

[0054] In a preferred embodiment of formula (I), R 5 is selected from -H, -Cl, -F, -CH3, or -OCH3.

[0055] In a preferred embodiment of formula (I), R 7 and R 8 are each independently selected from —H, —OH, —CN, —NH 2 , —F, —Br, —Cl, —CH 3 , —CH 2 CH 3 , —OCH 3 , or —OCH 2 CH 3 .

[0056] In a preferred embodiment of formula (I), R 7 and R 8 are both H.

[0057] In a preferred embodiment of formula (I), R 7 and R 8 are both F.

[0058] In a preferred embodiment of formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has the structure shown in any one of the following formulae:

[0059] [ka]

[0060] However, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 is as defined in any of the previous embodiments.

[0061] In another preferred embodiment of formula (I), X 1 is selected from N, and X 2 is CR 6 Selected from X 3 is N or CR 7 Selected from X 5 is selected from C, and X 6 is selected from N, and X 7 is selected from C and X 3 and X 4 is not CH at the same time.

[0062] In another preferred embodiment of formula (I), X 1 is selected from N, and X 2 is CR 6 Selected from X 5 is selected from C, and X 6 is selected from N, and X 7 is selected from C, and X 3 is N or CR 7 Selected from X 4 is N or CR 8 Selected from and X 3 and X 4 is not CH at the same time.

[0063] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —CH, —CHCH, —CH(CH), —Cl, —F, —Br, —OCH, —CHOH, or —CD, preferably R 1 and R 2 are each selected from -CH3 or -CD3; R 3 -CH3, -NH2, -OH, -F, -Cl, -Br, -CH(CH3)2, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -OCH3, -CH2F, -CHF2, -CF3, -CH=CH2, -CH=C(CH3)2, -CH=CHCH3, -C(CH3)=CH2, -NHCH3, -NHCH2CH3, -NHC(O)CH3,

[0064] [ka]

[0065] or -CD3, R 4 is selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, cyclopropyl, or -CH2CF3; R 6-CH3, -H, -OH, -Cl, -F, -Br, -COOH, -CN, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CF3, -CHF2, -CH2F, -CF2C H3, -CF(CH3)2, -OCH3, -OCH(CH3), -OCF3, -OCH2CF3, -N(CH3)2, -CH=CH2, -C(CH3)=CH2, -C≡CH, -S(O)2CH3,

[0066] [ka]

[0067] selected from -CH2CH2CH=CH2, -OCH(CH3)2, -CH2OH, -CH2CF3, or -CD3; X 3 is N or CR 7 Selected from X 4 is N or CR 8 is selected from R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH, -CH, -CHCH, -Cl, -F, -Br, -OCH, or -OCHCH; and R 7 and R 8 is not H at the same time, Or, R 2 , R 8 C together with the atoms to which they are connected 5-6 Forms a cycloalkenyl.

[0068] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —CH, —CHCH, or —CH(CH), preferably R 1 and R 2 are all selected from -CH3, R 3 is selected from -CH3, R 4 is selected from -H, R 6is selected from -CH3, X 3 is N or CR 7 Selected from X 4 is N or CR 8 Selected from and X 3 and X 4 At the same time, CH is not R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH2, -CH3, -CH2CH3, -Cl, -F, -OCH3, or -OCH2CH3; R 7 and R 8 is not H at the same time, Or, R 2 , R 8 C together with the atoms to which they are connected 5-6 Forms a cycloalkenyl.

[0069] In a preferred embodiment of formula (I), X 3 is CR 7 and X 4 is CR 8 and R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH, -CH, -CHCH, -Cl, -F, -OCH, or -OCHCH; R 7 and R 8 is not H at the same time.

[0070] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —Cl, —F, —Br, —OCH 3 , or —CH 2 OH.

[0071] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from -CD3.

[0072] In a preferred embodiment of formula (I), R 3-NH2, -OH, -F, -Cl, -Br, -CH(CH3)2, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -OCH3, -CH2F, -C HF2, -CF3, -CH=CH2, -CH=C(CH3)2, -CH=CHCH3, -C(CH3)=CH2, -NHCH3, -NHCH2CH3, -NHC(O)CH3,

[0073] [ka]

[0074] is selected from.

[0075] In a preferred embodiment of formula (I), R 3 teeth,

[0076] [ka]

[0077] or -CD3.

[0078] In a preferred embodiment of formula (I), R 4 is selected from -Cl, -F, -Br, -CH3, -CH2CH3, or cyclopropyl.

[0079] In a preferred embodiment of formula (I), R 4 is selected from -CH2CF3.

[0080] In a preferred embodiment of formula (I), R 6 -H, -OH, -Cl, -F, -Br, -COOH, -CN, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -OCH3, -OCH(CH3), -OCF3, -OCH2CF3, -N(CH3)2, -CH=CH2, -C(CH3)=CH2, -C≡CH, -S(O)2CH3,

[0081] [ka]

[0082] is selected from.

[0083] In a preferred embodiment of formula (I), R 6 teeth,

[0084] [ka]

[0085] It is selected from -CH2CH2CH=CH2, -OCH(CH3)2, -CH2OH, -CH2CF3, or -CD3.

[0086] In a preferred embodiment of formula (I), R 7 and R 8 are each independently selected from -Br.

[0087] In a preferred embodiment of formula (I), R 7 and R 8 are each independently selected from -H or -F, and R 7 and R 8 At least one of is -F.

[0088] In a preferred embodiment of formula (I), X 3 is CR 7 Selected from X 4 is CR 8 is selected from R 1 and R 2 is C 1-4 Alkyl or deuterated C 1-4 alkyl, preferably R 1 , and R 2 is selected from -CH3 or -CD3; R 3 is C 1-4 alkyl, preferably R 3is selected from -CH3 or -CH2CH3, R 4 is selected from -H, R 6 is a halogen or haloC 1-4 alkyl, preferably R 6 is selected from -Cl, -Br, or -CF3; R 7 and R 8 are each independently selected from —H or halogen, and R 7 and R 8 is not simultaneously hydrogen, preferably R 7 and R 8 are each independently selected from —H or F, and R 7 and R 8 is not hydrogen at the same time.

[0089] In a preferred embodiment of formula (I), X 1 is selected from N, and X 2 is CR 6 Selected from X 3 is CR 7 Selected from X 4 is CR 8 Selected from X 5 is selected from C, and X 6 is selected from N, and X 7 is selected from C, R 1 and R 2 are each independently C 1-4 alkyl, preferably -CH3; R 3 is C 1-4 alkyl, preferably -CH3; R 4 is selected from -H, R 7 is selected from halogen, preferably F, and R 8 is selected from -H, R 6 is a halogen or haloC 1-4It is selected from alkyl, preferably Br or -CF3, more preferably -CF3.

[0090] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —CH, —CHCH, —CH(CH), —Cl, —F, —Br, —OCH, —CHOH, or —CD, preferably R 1 and R 2 are each selected from -CH3 or -CD3; R 3 , R 6 together with the atoms to which they are attached form the following groups:

[0091] [ka]

[0092] Forming R 4 is selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, or cyclopropyl; X 3 is N or CR 7 Selected from X 4 is N or CR 8 is selected from R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH2, -CH3, -CH2CH3, -Cl, -F, -Br, -OCH3, or -OCH2CH3.

[0093] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —CH, —CHCH, —CH(CH), —Cl, —F, —Br, —OCH, or —CHOH, preferably R 1 and R 2 are all selected from -CH3, R 3 , R 6together with the atoms to which they are attached form the following groups:

[0094] [ka]

[0095] Forming R 4 is selected from -H, -Cl, -F, -Br, -CH3, -CH2CH3, or cyclopropyl; X 3 is N or CR 7 Selected from X 4 is N or CR 8 is selected from R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH2, -CH3, -CH2CH3, -Cl, -F, -Br, -OCH3, or -OCH2CH3.

[0096] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —CH, —CHCH, —CH(CH), —Cl, —F, —Br, —OCH, —CHOH, or —CD, preferably R 1 and R 2 are each selected from -CH3 or -CD3; R 3 is selected from -H, -CH3, or -CH2CH3; R 4 , R 6 together with the atoms to which they are attached form the following groups:

[0097] [ka]

[0098] Forming X 3 is N or CR 7 Selected from X 4 is N or CR8 is selected from R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH2, -CH3, -CH2CH3, -Cl, -F, -Br, -OCH3, or -OCH2CH3.

[0099] In a preferred embodiment of formula (I), R 1 and R 2 are each independently selected from —CH, —CHCH, —CH(CH), —Cl, —F, —Br, —OCH, or —CHOH, preferably R 1 and R 2 are all selected from -CH3, R 3 is selected from -H, -CH3, or -CH2CH3; R 4 , R 6 together with the atoms to which they are attached form the following groups:

[0100] [ka]

[0101] Forming X 3 is N or CR 7 Selected from X 4 is N or CR 8 is selected from R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH2, -CH3, -CH2CH3, -Cl, -F, -Br, -OCH3, or -OCH2CH3.

[0102] In some embodiments, R 1 and R 2 are all selected from -CD3.

[0103] In some embodiments, R 3 , R 6together with the atoms to which they are attached form the following groups:

[0104] [ka]

[0105] Form.

[0106] In some embodiments, R 4 , R 6 together with the atoms to which they are connected

[0107] [ka]

[0108] Form.

[0109] In a preferred embodiment of formula (I), X 3 is CR 7 and X 4 is CR 8 and X 6 is N and X 5 and X 7 is C and X 1 is CH and X 2 is CR 6 and R 1 and R 2 are each independently selected from —CH, —CHCH, —CH(CH), —Cl, —F, —Br, —OCH, —CHOH, or —CD, preferably R 1 and R 2 are each selected from -CH3 or -CD3; R 3 is -CH3 or -CH2CH3, R 4 , R 6 together with the atoms to which they are attached form the following groups:

[0110] [ka]

[0111] Forming R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH, -CH, -CHCH, -Cl, -F, -Br, -OCH, or -OCHCH, preferably R 7 and R 8 are each independently selected from -H or -F.

[0112] In a preferred embodiment of formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has the structure shown in any one of the following formulae:

[0113] [ka]

[0114] Ring A and ring B are each independently phenyl, 5- to 6-membered heterocycloalkenyl, or C 5-6 cycloalkenyl; However, R 1 , R 2 , R 3 , R 4 , R 6 , X 3 , X 4 , R 7 and R 8 is as defined in any of the previous embodiments.

[0115] In some embodiments, ring A and ring B are each independently selected from phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 cycloalkenyl, or 5- to 6-membered heteroaryl, and 5-6 Cycloalkenyl and 5-6 membered heteroaryl are optionally substituted with halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, HydroxyC 1-6Alkyl, and C 1-6 It is further substituted by one or more substituents selected from alkoxy.

[0116] In a preferred embodiment of formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has the structure shown in any one of the following formulae:

[0117] [ka]

[0118] Each ring A is independently phenyl, 5- to 6-membered heterocycloalkenyl, or C 5-6 cycloalkenyl; However, R 1 , R 2 , R 3 , R 4 , R 6 , X 3 , X 4 , R 7 , and R 8 is as described in any of the previous embodiments.

[0119] In a preferred embodiment of formula (I), ring A is selected from the group consisting of phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 cycloalkenyl, or 5- to 6-membered heteroaryl, and 5-6 Cycloalkenyl and 5-6 membered heteroaryl are optionally substituted with halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, HydroxyC 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 It is further substituted by one or more substituents selected from alkyl-C(O)-.

[0120] In another aspect, the present disclosure provides a compound represented by the following general formula (II), a pharmaceutically acceptable salt thereof, or an isomer thereof:

[0121] [ka]

[0122] X 1 is N or CR 5 is selected from X 3 is N or CR 7 is selected from X 4 is N or CR 8 is selected from R 1 and R 2 are each independently a halogen, C 1-4 Alkyl, C 1-4 Alkoxy, Hydroxy C 1-4 Alkyl or deuterated C 1-4 alkyl, R 3 -CN, -OH, -N(R a )(R b ), halogens, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -LR c , phenyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, 3-6 membered heterocycloalkenyl, deuterated C 1-4 alkyl, or 5-6 membered heteroaryl, wherein the phenyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, and 5- to 6-membered heteroaryl may optionally be substituted with one or more R 3a wherein R 3a is a halogen, C 1-4 Alkyl or C 1-4 alkoxy; L is C 2-4 Alkynylene, C 1-4 Alkylene, or C 2-4alkenylene; R c is C 1-4 Alkyl, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl, 1-4 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocyclyl may optionally be one or more R ca wherein R ca is selected from halogen or —OH; R a and R b are independently -H, C 1-4 Alkyl, phenyl, p-methoxybenzyl, C 1-4 Alkyl-C(O)-, C 3-6 Cycloalkyl or haloC 1-4 alkyl, or R a , R b together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl optionally substituted by halogen; R 4 , R 6 together with the atom to which they are attached, phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 cycloalkenyl, or 5- to 6-membered heteroaryl, and the phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkenyl, and C 5-6 Cycloalkenyl is optionally substituted with halogen, CN, C 1-6 Alkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 alkyl-C(O)-; R 5 , R 7 and R 8 are each independently -H, -OH, -CN, -N(R d )(R e ), halogens, C 1-4 Alkyl, C 1-4 Alkoxy or haloC1-4 alkyl.

[0123] In a preferred embodiment of formula (II), R 1 , R 2 are each independently selected from —CH, —CHCH, —CH(CH), —Cl, —F, —Br, —OCH, —CHOH, or —CD; R 3 is -CH3 or -CH2CH3, R 4 , R 6 together with the atoms to which they are attached form the following groups:

[0124] [ka]

[0125] Forming R 5 -H, -CN, HaloC 1-3 selected from alkyl or halogen; R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH2, -CH3, -CH2CH3, -Cl, -F, -Br, -OCH3, or -OCH2CH3.

[0126] In a preferred embodiment of formula (II), X 1 is CR 5 is selected from R 1 and R 2 are each selected from -CH3 or -CD3; R 3 is -CH3 or -CH2CH3, R 4 , R 6 together with the atoms to which they are attached form the following groups:

[0127] [ka]

[0128] Forming R 5 is selected from -H or -F; R 7 and R 8 are each independently selected from -H or -F.

[0129] In a preferred embodiment of formula (II), X 1 is CR 5 Selected from X 3 is CR 7 Selected from X 4 is CR 8 is selected from R 1 and R 2 are each independently C 1-4 alkyl, preferably -CH3; R 3 is C 1-4 alkyl, preferably -CH3; R 4 , R 6 together with the atom to which they are attached form a 5-6 membered heteroaryl, preferably pyridyl, more preferably

[0130] [ka]

[0131] and R 5 is selected from —H or halogen, preferably H or F, more preferably H; R 7 , R 8 are each independently selected from —H.

[0132] In a preferred embodiment of formula (II), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has the structure shown in any one of the following formulae:

[0133] [ka]

[0134] Each ring B is independently phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 cycloalkenyl, or 5- to 6-membered heteroaryl, and 5-6 Cycloalkenyl and 5-6 membered heteroaryl are optionally substituted with halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, HydroxyC 1-6 Alkyl, and C 1-6 further substituted by one or more substituents selected from alkoxy; However, R 3 , R 4 , R 5 , R 6 , X 3 , X 4 , R 7 and R 8 is as defined in any of the previous embodiments.

[0135] In another preferred embodiment of formula (I), X 1 is selected from N, and X 5 is selected from N, and X 2 is CR 6 Selected from X 6 is selected from C, and X 7 is selected from C.

[0136] In another preferred embodiment of formula (I), X 1 is selected from N, and X 2 is CR 6 Selected from X 5 is selected from C, and X 6 is selected from C, and X 7 is selected from N.

[0137] In a preferred embodiment of formula (I), R 1 and R 2are each independently selected from —CH, —CHCH, or —CH(CH), preferably R 1 and R 2 are all selected from -CH3, R 3 is selected from -CH3, R 4 is selected from -H, R 6 is selected from -CH3, X 3 is N or CR 7 Selected from X 4 is N or CR 8 is selected from R 7 and R 8 are each independently selected from -H, -OH, -CN, -NH2, -CH3, -CH2CH3, -Cl, -F, -OCH3, or -OCH2CH3; Or, R 2 , R 8 C together with the atoms to which they are connected 5-6 Forms a cycloalkenyl.

[0138] In a preferred embodiment of formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has the structure shown in any one of the following formulae:

[0139] [ka]

[0140] However, R 1 , R 2 , R 3 , R 4 , R 6 , X 3 , and X 4 is as described in formula (I).

[0141] In a preferred embodiment of Formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has a structure represented by Formula (I-E1):

[0142] [ka]

[0143] However, R 3 is H, -CH3 or -CD3, R 6 are -Br, -Cl, -CH3, -CD3-, (CH3)2CH-, (CH3)2CHCH2-, CF3, CF3CH2-, OH(CH3)2C-, CH3-S(O)2-, cyclopropyl,

[0144] [ka]

[0145] and R 4 is H or R 4 , R 6 together with the C atoms connected to them

[0146] [ka]

[0147] Form.

[0148] In a preferred embodiment of formula (I-E1), R 3 is -CH3 or -CD3.

[0149] In a preferred embodiment of formula (I-E1), R 6 is -Br, -Cl, -CD3, -CF3, CF3CH2- or CH3-S(O)2-.

[0150] In a preferred embodiment of formula (I-E1), R 4 is H.

[0151] In a preferred embodiment of Formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has a structure represented by Formula (I-E2):

[0152] [ka]

[0153] However, R 3 is -H, -CH3 or -CD3, R 6 are -Br, -Cl, -CH3, -CD3-, (CH3)2CH-, (CH3)2CHCH2-, CF3, CF3CH2-, OH(CH3)2C-, CH3-S(O)2-, cyclopropyl,

[0154] [ka]

[0155] and R 4 is H or R 4 , R 6 together with the C atoms connected to them

[0156] [ka]

[0157] Form.

[0158] In a preferred embodiment of formula (I-E2), R 3 is H, -CH3 or -CD3.

[0159] In a preferred embodiment of formula (I-E2), R 6 is -Br, -Cl, -CF3 or cyclopropyl.

[0160] In a preferred embodiment of formula (I-E2), R 4 is H.

[0161] In a preferred embodiment of Formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has a structure represented by Formula (I-F1):

[0162] [ka]

[0163] However, R 3 is -H, Cl, -CH3, CH3CH2-, -CD3, -CH=CH2 or

[0164] [ka]

[0165] and R 6 -Cl, -Br, -F, -CH3, CH3CH2-, (CH3)2CH-, -CF3, CH2=C(CH3)-, -CH=CH2, CH3O-,

[0166] [ka]

[0167] or cyclopropyl, R 4 is H, Or, R 4 , R 6 together with the C atoms connected to them

[0168] [ka]

[0169] Forming Or, R 3 , R 6 together with the C atoms connected to them

[0170] [ka]

[0171] Form.

[0172] In a preferred embodiment of formula (I-F1), R 3 is -H, -CH3, CH3CH2- or -CH=CH2.

[0173] In a preferred embodiment of formula (I-F1), R 6 -Cl, -Br, -F, -CH3, CH3CH2-, (CH3)2CH-, -CF3, CH2=C(CH3)-, -CH=CH2, CH3O-,

[0174] [ka]

[0175] or cyclopropyl.

[0176] In a preferred embodiment of formula (I-F1), R 3 , R 6 together with the C atoms connected to them

[0177] [ka]

[0178] Form.

[0179] In a preferred embodiment of formula (I-F1), R 4 , R 6 together with the C atoms connected to them

[0180] [ka]

[0181] Form.

[0182] In a preferred embodiment of Formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has a structure represented by Formula (I-F2):

[0183] [ka]

[0184] However, R 3 is -H, Cl, -CH3, CH3CH2-, -CD3, -CH=CH2 or

[0185] [ka]

[0186] and R 6 -Cl, -Br, -F, -CH3, CH3CH2-, (CH3)2CH-, -CF3, CH2=C(CH3)-, -CH=CH2, CH3O-,

[0187] [ka]

[0188] or cyclopropyl, R 4 is H, Or, R 4 , R 6 together with the C atoms connected to them

[0189] [ka]

[0190] Forming Or, R 3 , R 6 together with the C atoms connected to them

[0191] [ka]

[0192] Form.

[0193] In a preferred embodiment of formula (I-F2), R 3 is -H, -CH3, CH3CH2- or -CH=CH2.

[0194] In a preferred embodiment of formula (I-F2), R 6 -Cl, -Br, -F, -CH3, CH3CH2-, (CH3)2CH-, -CF3, CH2=C(CH3)-, -CH=CH2, CH3O-,

[0195] [ka]

[0196] or cyclopropyl.

[0197] In a preferred embodiment of formula (I-F2), R 3 , R 6 together with the C atoms connected to them

[0198] [ka]

[0199] Form.

[0200] In a preferred embodiment of formula (I-F1), R 4 , R 6 together with the C atoms connected to them

[0201] [ka]

[0202] Form.

[0203] In a preferred embodiment of Formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has a structure represented by Formula (I-G1):

[0204] [ka]

[0205] However, R 3 is CH3-, CH3CH2CH2-, (CH3)2CHCH2-, CH3CH=CH-,

[0206] [ka]

[0207] and R 4 is H, CH3- or cyclopropyl.

[0208] In a preferred embodiment of formula (I-G1), R 3 is CH3CH2CH2-, (CH3)2CHCH2-, CH3CH=CH-,

[0209] [ka]

[0210] is.

[0211] In a preferred embodiment of formula (I-G1), R 4 is H.

[0212] In a preferred embodiment of Formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has a structure represented by Formula (I-G2):

[0213] [ka]

[0214] However, R 3 is CH3-, (CH3)2CHCH2-,

[0215] [ka]

[0216] CH3CH2CH2-,

[0217] [ka]

[0218] CHCH=CH-, or

[0219] [ka]

[0220] and R 4 is H, CH3- or cyclopropyl.

[0221] In a preferred embodiment of formula (I-G2), R 4 is H.

[0222] In a preferred embodiment of Formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has a structure represented by Formula (I-H1):

[0223] [ka]

[0224] R 3 is -CH3, R 7 is H or F, R 8 is H or F, R 4 , R 6 together with the C atoms connected to them

[0225] [ka]

[0226] Forming In a preferred embodiment of formula (I-H1), R 7 is H and R 8 is H.

[0227] In a preferred embodiment of formula (I-H1), R 7 is H and R 8 is F.

[0228] In a preferred embodiment of formula (I-H1), R 7 is F and R 8 is H.

[0229] In a preferred embodiment of Formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof has a structure represented by Formula (I-H2):

[0230] [ka]

[0231] R 3 is -CH3, R 7 is H or F, R 8 is H or F, R 4 , R 6 together with the C atoms connected to them

[0232] [ka]

[0233] Forming In a preferred embodiment of formula (I-H1), R 7is H and R 8 is H.

[0234] In a preferred embodiment of formula (I-H1), R 7 is H and R 8 is F.

[0235] In a preferred embodiment of formula (I-H1), R 7 is F and R 8 is H.

[0236] Any substituents and any groups in the technical solutions described in the present disclosure can be combined with each other to form a new complete technical solution, and the formed new technical solution has the same or similar technical effect as the solution described in the present disclosure, and all are included in the scope of the present disclosure.

[0237] In a preferred embodiment of formula (I), the compound, a pharmaceutically acceptable salt thereof, or an isomer thereof, the compound is selected from any of the following structures:

[0238] [ka] TIFF2025538617000068.tif211169 TIFF2025538617000069.tif232169TIFF2025538617000070.tif224169TIFF2025538617000071.tif232169TIFF2025538617000072.tif213169 TIFF2025538617000073.tif214169TIFF2025538617000074.tif217169TIFF2025538617000075.tif232169TIFF2025538617000076.tif233169

[0239] .

[0240] In a second aspect, the present disclosure also provides a pharmaceutical composition comprising a compound described in any embodiment of the present disclosure, a pharmaceutically acceptable salt or isomer thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition may be in any pharmaceutically acceptable dosage form.

[0241] According to the present disclosure, a pharmaceutically acceptable excipient is a substance that is non-toxic, compatible with the active ingredient, and biologically suitable for use in an organism. The selection of a specific excipient depends on the administration method or the type and condition of the disease intended to be treated in a specific patient. Examples of pharmaceutically acceptable excipients include, but are not limited to, conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonicity agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, hydrating agents, emulsification enhancers, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, antioxidants, etc., used in the pharmaceutical field. Flavoring agents, preservatives, sweeteners, etc. can be added to the pharmaceutical formulation composition as needed.

[0242] In a third aspect, the present disclosure further provides a pharmaceutical comprising a compound described in any embodiment of the present disclosure, a pharmaceutically acceptable salt thereof, or an isomer thereof for preventing and / or treating a tumor disease mediated by PKMYT1.

[0243] In another embodiment, the PKMYT1-mediated neoplastic disease is a neoplastic disease caused by CCNE1 overexpression and / or FBXW7 inactivating mutations.

[0244] In another aspect, the present disclosure further provides a pharmaceutical composition comprising a compound described in any embodiment of the present disclosure, a pharmaceutically acceptable salt thereof, or an isomer thereof, for preventing and / or treating a tumor disease caused by CCNE1 overexpression and / or FBXW7 inactivating mutation.

[0245] In another embodiment, said neoplastic disease is selected from one or more of ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, endometrial cancer, and colorectal cancer.

[0246] In a fourth aspect, the present disclosure further provides a method for treating a neoplastic disease mediated by PKMYT1 by administering to a subject a therapeutically effective amount of a compound described in any embodiment of the present disclosure, a pharmaceutically acceptable salt thereof, or an isomer thereof.

[0247] In another embodiment, the PKMYT1-mediated neoplastic disease is a neoplastic disease caused by CCNE1 overexpression and / or FBXW7 inactivating mutations.

[0248] In another embodiment, said neoplastic disease is selected from one or more of ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, endometrial cancer, and colorectal cancer.

[0249] In another aspect, the present disclosure further provides a method for treating a neoplastic disease caused by CCNE1 overexpression and / or FBXW7 inactivating mutations by administering to a subject a therapeutically effective amount of a compound described in any embodiment of the present disclosure, a pharmaceutically acceptable salt thereof, or an isomer thereof.

[0250] [Technical Effects] The compounds of the present disclosure have good PKMYT1 inhibitory activity, good in vivo and in vitro tumor inhibitory activity, and pharmacokinetic properties. The compounds of the present disclosure also have good physical and chemical properties, such as better solubility, which are useful for drug absorption and formulation development.

[0251] [Explanation and definition] In this disclosure, unless otherwise explained, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. However, in order to better understand this disclosure, definitions of some terms are provided below. If the definitions of terms provided in this disclosure are inconsistent with the meanings that are commonly understood by those skilled in the art, the definitions and interpretations of terms provided in this disclosure shall prevail.

[0252] The term "PKMYT1-mediated disease" referred to in the present disclosure refers to a disease associated with a PKMYT1 target, and may be a disease caused by abnormal expression due to mutation or deletion of PKMYT1 itself, or a disease caused by abnormal expression of PKMYT1 due to abnormalities in other related genes / targets (such as genes / targets in a synthetic lethal relationship with PKMYT1).

[0253] "CCNE1 overexpression," as used herein, means that the expression level of CCNE1 is higher than that of normal cells. Compared to normal cells, cells that overexpress CCNE1 exhibit higher CCNE1 activity. For example, normal diploid cells exhibit a copy number of 2, while CCNE1-overexpressing cells exhibit a copy number of at least 3. CCNE1 overexpression can be measured by determining the expression level of the gene product in the cell (e.g., CCNE1 mRNA transcript number or CCNE1 protein level).

[0254] The "FBXW7 inactivating mutations" referred to in this disclosure include various types of mutations that inactivate FBXW7 gene expression, including, but not limited to, base insertions, deletions, mutations, substitutions, chemical modifications, etc.

[0255] The term "pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment and are suitable for contact with the tissues of human beings and animals without appreciable toxicity, irritation, allergic response or other problem or complication and exhibit a reasonable benefit / risk ratio.

[0256] The term "pharmaceutically acceptable salt" as used herein refers to a salt formed between an acidic functional group (e.g., -COOH, -OH, -SOH, etc.) present in a compound and a suitable inorganic or organic cation (base), including salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases, as well as salts formed between a basic functional group (e.g., -NH, etc.) present in a compound and a suitable inorganic or organic anion (acid), and salts formed with inorganic or organic acids (e.g., carboxylic acids, etc.).

[0257] The terms "therapeutically effective amount" and "effective amount" refer to a range of dosages of a compound of the present disclosure that, when administered to a subject, is sufficient to produce a beneficial or desired effect and can be tolerated by the subject, which effect may be to prevent tumor development, and / or inhibit tumor growth, and / or limit tumor spread, and / or reduce tumor volume, and / or ameliorate clinical symptoms or indicators associated with cancer. It should be recognized, however, that the total daily dose of a compound of Formula I of the present disclosure should be determined by the attending physician within the scope of sound medical judgment.

[0258] The "isomers" referred to in this disclosure exist as geometric and stereoisomers, such as atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemates and other mixtures thereof, and all such mixtures are included within the scope of this disclosure. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "tautomer" refers to a type of functional group isomer that has different hydrogen attachment points due to the displacement of one or more double bonds; for example, a ketone and its enol form are keto-enol tautomers. The term "diastereomer" refers to a stereoisomer in which the molecules have two or more chiral centers and are not mirror images of each other. The term "cis-trans isomer" refers to a different spatial arrangement in a molecule due to the inability to freely rotate double bonds or single bonds of ring carbon atoms. The term "atropisomer" refers to stereoisomers that can be separated due to hindered or very slow rotation of single bonds.

[0259] Stereoisomers of the compounds of the present disclosure can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, enantiomers of specific compounds of the present disclosure can be prepared by asymmetric catalysis or chiral-assisted derivatization techniques. Alternatively, compounds of a single configuration can be obtained from a mixture by chiral resolution techniques. Alternatively, they can be prepared directly from chiral starting materials. Separation of optically pure compounds of the present disclosure is typically achieved by preparative chromatography, using a chiral column to achieve the purpose of separating chiral compounds.

[0260] In the case of atropisomers of the compounds of the present disclosure, such structures can be viewed as extensions of the chiral center. Looking along the C1-C1' axis, the groups on either side of the carbon center C1 closest to the observer are ranked in the first two positions of priority, and the groups on either side of the opposite C1' are ranked in the third and fourth positions, and then rearranged according to group priority, clockwise for the R configuration and counterclockwise for the S configuration. It should be noted that the observations are the same at either end of the C-C' axis. In the present disclosure, compound structures are represented by solid bonds.

[0261] [ka]

[0262] When adopting a symmetrical symmetry, it means that the symmetry lies above the plane in which most atoms in the compound molecule lie, e.g.

[0263] [ka]

[0264] When the double condensation and the ring are considered to be a plane, the structure represented by the solid line bond in the benzene ring structure means that it is located above that plane.

[0265] Those skilled in the art know that a cyclic compound is aromatic if it has a coplanar delocalized system and the number of π electrons is 4n+2, and the aromatic structure in the compound can be represented by dotted lines representing the delocalization of electrons or by alternating single and double bonds. For example, a benzene ring has the structure

[0266] [ka]

[0267] It can be drawn as

[0268] [ka]

[0269] It can also be depicted as

[0270] "Optionally substituted" as used in this disclosure refers to two situations in which one or more hydrogen atoms of a substituent may be "substituted" or "unsubstituted" by one or more substituents.

[0271] "PMB" refers to p-methoxybenzyl.

[0272] In the substituent structure

[0273] [ka]

[0274] When a broken bond appears in the formula, it indicates that the bond is a connecting bond of the substituents, e.g.,

[0275] [ka]

[0276] indicates that the pyrimidine ring is connected to a specific group or a specific structural formula via a C atom.

[0277] [ka]

[0278] The occurrence of " indicates a point of attachment of a substituent, for example, -SCH3 is attached to a particular group or particular structural formula through the sulfur atom.

[0279] If the bond of a substituent can cross-link two atoms on the ring, then the substituent can be attached to any atom on the ring. For example, the structural unit

[0280] [ka]

[0281] means that the substituent R can be substituted at any position on the benzene ring.

[0282] When a given substituent does not indicate through which atom it is linked to a given group or to a given structural formula, the substituent may be linked through any of its available atoms.

[0283] In the present disclosure, the structural unit "

[0284] [ka]

[0285] " and R 3 , R 6 are defined to form the following ring structure with the carbon atom to which they are attached:

[0286] [ka]

[0287] Newly formed ring

[0288] [ka]

[0289] are defined as "heterocycloalkenyl" and "cycloalkenyl", respectively, due to the presence of the covalent double bond. 2 , R 8 C together with the atoms to which they are connected 5-6 "Forming a cycloalkenyl," "R 3 , R 6 together with the atom to which they are attached, phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 "Forming a cycloalkenyl," "R 4 , R 6 together with the atom to which they are attached, phenyl, 5- to 6-membered heterocycloalkenyl, C 5-6 "Forming a cycloalkenyl" is a generalized translation of the term "cycloalkenyl" and applies to this definition.

[0290] As used herein, "alkyl" refers to a group derived by removing one hydrogen atom from a branched or straight-chain saturated aliphatic alkane having the specified number of carbon atoms. For example, "C 1-10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 Contains alkyl, "C 1-6 Alkyl," "C 1-4 Alkyl," "C 1-3 Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, and the like.

[0291] The term "haloalkyl" as used herein refers to a group in which one or more hydrogen atoms of an alkyl group are replaced by halogen atoms. For example, "fluoromethyl" includes monofluoromethyl, difluoromethyl, and trifluoromethyl. Preferably, the term "haloalkyl" as used herein refers to a group in which one or more hydrogen atoms of an alkyl group are replaced by halogen atoms. 1-6 Alkyl, HaloC 1-4 Alkyl is as defined above.

[0292] The term "hydroxyalkyl" as used herein refers to a group in which one or more hydrogen atoms of an alkyl are replaced by hydroxyl; the ... 1-6 Alkyl, Hydroxy C 1-4 Specific examples include -CHOH, -CHCHOH, -CH(OH)CH, -CHCHCHOH,

[0293] [ka]

[0294] Including, but not limited to, the following:

[0295] "Alkoxy," as used herein, refers to an alkyl group, as defined herein, attached to another group through an oxygen atom, i.e., "alkyl-O-." 1-6 Alkoxy" (structure is C 1-6 alkyl-O-), "C 1-4 Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc. Preferably, the "alkoxy" described in the present disclosure is 1-4 Alkoxy, more preferably C 1-3 It is an alkoxy.

[0296] The term "haloalkoxy" as used herein refers to a group in which one or more hydrogen atoms of an alkoxy group are replaced by halogen atoms, and preferably, the term "haloalkoxy" as used herein refers to a group in which one or more hydrogen atoms of an alkoxy group are replaced by halogen atoms. 1-6 Alkoxy, Halo C 1-4 Specific examples of "fluoromethoxy" and the like as used herein include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, and also include, but are not limited to, -OCHCF, -OCHFCH, and the like. Alkoxy is as defined above.

[0297] As used herein, "alkenyl" refers to a group derived from a straight-chain or branched alkene (containing at least one double bond) by removing one hydrogen atom, and includes "C 2-6 alkenyl," "C 2-5 alkenyl," "C 2-4 alkenyl," "C 2-3 alkenyl," specific examples include, but are not limited to, -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, and the like.

[0298] As used herein, "alkynyl" refers to a group derived from a straight-chain or branched alkyne (containing at least one triple bond) by removing one hydrogen atom, and includes "C 2-5 alkynyl", "C 2-4 alkynyl", "C 2-3 alkynyl," specific examples include, but are not limited to, -C≡CH, -C≡CHCH3, CH≡CHCH2-, CH≡CC≡C-, and the like.

[0299] The term "alkylene" as used herein refers to a group derived from a branched or straight-chain saturated aliphatic alkane by removing two hydrogen atoms, and the removed hydrogen atoms may be from the same carbon atom or different carbon atoms. The term "alkylene" as used herein is preferably a "straight-chain alkylene," and the term "alkylene" is also used herein as a "C 1-6 alkylene," "C 1-4 alkylene," "C 1-2 Specific examples include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH2)CH2-, -CH2CH2CH2CH2-, -CH(CH2)CH2CH2-, -CH(CH2)CH2CH2-, -C(CH2)(CH2)CH2-, -CH2CH2CH2CH2CH2-, and the like.

[0300] In the present disclosure, "alkenylene" refers to a group derived from a straight-chain or branched alkene (containing at least one double bond) by removing two hydrogen atoms, and the removed hydrogen atoms may be from the same or different carbon atoms, and the "alkenylene" is also referred to as "C 2-6 alkenylene," "C 2-4 Specific examples include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH2CH=CH-, -CH2CH=CHCH2-, and -CH2CH=CHCH2CH2-.

[0301] The term "alkynylene" as used herein refers to a group derived from a straight-chain or branched alkyne (containing at least one triple bond) by removing two hydrogen atoms, where the removed hydrogen atoms may be from the same or different carbon atoms, and the term "alkynylene" is also used herein to refer ...). 2-6 alkynylene," "C 2-4 alkynylene," and specific examples include, but are not limited to, -C≡C-, -C≡C-CH2-, -C≡C-CH2CH2CH2-, -CH2-C≡C-CH2CH2CH2-, -C≡C-CH2C≡C-, and -C≡C-CH2CH≡CH-.

[0302] In the present disclosure, "cycloalkyl" refers to a saturated cyclic group derived from a monocyclic cycloalkane by removing one hydrogen atom, and in the cycloalkyl, other ring carbon atoms, except for the carbon atom attached to the specified group or the specified structural formula, may be further oxidized, i.e., to form C(O). The cycloalkyl includes "3- to 8-membered cycloalkyl," "3- to 6-membered cycloalkyl," "3- to 5-membered cycloalkyl," and "4- to 6-membered cycloalkyl." Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0303] The "cycloalkenyl" described in the present disclosure means that one or more ring-forming bonds in the "cycloalkyl" are double bonds and do not have aromaticity. In the cycloalkenyl, other ring carbon atoms, except for the carbon atoms bonded to a specific group or a specific structural formula, may be further oxidized, i.e., to form C(O). The cycloalkenyl includes "3- to 8-membered cycloalkenyl", "3- to 6-membered cycloalkenyl", "3- to 5-membered cycloalkenyl", and "5- to 6-membered cycloalkenyl". Specific examples include:

[0304] [ka]

[0305] These include, but are not limited to:

[0306] In the present disclosure, "heterocyclyl" refers to a saturated cyclic group derived from one or more ring carbon atoms in a cycloalkyl that are replaced by a heteroatom. The heteroatom is generally selected from N, O, and S. The carbon atoms or heteroatoms in the heterocyclic group may be further oxidized, i.e., to form C(O), N(O), SO, and SO. Preferably, the heteroatoms are independently selected from 1 to 3 N and / or O. The heterocyclyl includes "3- to 8-membered heterocyclyl," "3- to 6-membered heterocyclyl," "3- to 5-membered heterocyclyl," "4- to 6-membered heterocyclyl," and "5- to 6-membered heterocyclyl." Specific examples include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydropyranyl, and morpholinyl.

[0307] The term "heterocycloalkenyl" as used herein means that one or more ring-forming bonds in the "heterocyclyl" are double bonds and the heterocyclyl does not have aromaticity. Preferably, the heteroatoms are independently selected from 1 to 3 N and / or O. The heterocyclyl includes "3 to 8-membered heterocycloalkenyl", "3 to 6-membered heterocycloalkenyl", "3 to 5-membered heterocycloalkenyl", and "5 to 6-membered heterocycloalkenyl". Specific examples include:

[0308] [ka]

[0309] These include, but are not limited to:

[0310] As used herein, "aryl" refers to a monocyclic or polycyclic group having aromatic character composed of ring carbon atoms, and specific examples include, but are not limited to, phenyl and naphthyl.

[0311] The term "heteroaryl" as used herein refers to a monocyclic group having aromaticity, in which at least one ring atom is a heteroatom, which is generally selected from N, O, and S. Carbon atoms or heteroatoms in the heterocyclic group may be further oxidized, generally according to the rules and conditions for the formation of valence bonds to form C(O), N(O), SO, and SO, and preferably, the heteroatoms are independently selected from 1 to 3 N and / or O. The heteroaryl includes "5- to 6-membered heteroaryl," and specific examples include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, and pyrimidinyl.

[0312] Combinations of substituents and / or variables described in this disclosure should be permissible only if such combinations produce stable compounds or useful synthetic intermediates, and one of ordinary skill in the art can exclude from this disclosure any situations that are clearly beyond the conventional knowledge or are unreasonable in the art. A stable compound or stable structure refers to a compound that is sufficiently stable to withstand chemical reactions, be isolated to a useful degree of purity, and be manufactured into an effective therapeutic agent.

[0313] [Mode for Carrying Out the Invention] In the examples of this disclosure, the names of the title compounds are converted from the compound structures by Chemdraw. Any discrepancies between the compound names and the compound structures are resolved by integrating relevant information and reaction pathways. The structural formula of a given compound shall prevail if not otherwise confirmed.

[0314] The preparation methods of some compounds in the present disclosure refer to the preparation methods of similar compounds described above. Those skilled in the art should understand that when using or referring to the preparation methods cited therein, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to different reactants.

[0315] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitution forms known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0316] 1. Experimental equipment overview: The structures of the compounds of the present disclosure are determined by nuclear magnetic resonance (NMR) and / or liquid crystal mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR measurements were performed using a Varian 400M or Bruker Ascend 400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or heavy water (DO) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0317] The starting materials in the examples of the present disclosure are known and commercially available or can be synthesized using or according to methods known in the art.

[0318] 2. Synthesis Examples Purification methods described in the examples of this disclosure include, but are not limited to, methods known in the art such as silica gel chromatography, preparative HPLC chromatography, and the like.

[0319] The compounds of the present disclosure are primarily synthesized using the following protocol.

[0320] Protocol 1

[0321] [ka]

[0322] The compound of formula A can be prepared from intermediate 1 through the following steps: intermediate 1 is brominated to prepare intermediate 2, which is then hydroxychlorinated to give intermediate 3, which is then subjected to a substitution reaction with 3-methoxy-2,6-dimethylaniline in a base and an organic solvent, or a coupling reaction under the catalysis of palladium / chiral phosphine ligand to prepare intermediate 4. Intermediate 4 is coupled with malonic acid to prepare intermediate 5. Intermediate 5 is prepared by adding an acid in an organic solvent to prepare a compound of formula A, which is then subjected to a chiral synthesis method to obtain two chiral isomers.

[0323] Protocol 2

[0324] [ka]

[0325] As shown in Protocol 2, intermediate 6 can be used as the starting reactant to produce products 7 and 12, which can be subjected to a cyano substitution or bromination reaction to produce products 7 and 8, which can be coupled with an organoboron reagent to produce intermediate 9, which can be reacted with R 3 When is an olefin substituent, intermediate 9 was reduced to produce product 10. Intermediate 6 was coupled with an alkyne reagent to produce product 11, which was then substituted with an amine compound to produce product 12.

[0326] R m , R P , R q are independently H, C 1-4 Alkyl, C 3-6 or R m and R q The group linked to C 3-6 3-membered cycloalkenyl or 3- to 6-membered heterocycloalkenyl.

[0327] Protocol 3

[0328] [ka]

[0329] As shown in Protocol 3, 12-15 can be prepared from intermediate 9, which was then substituted with an amine to produce intermediate 13, which was then subjected to acidolysis as described in Protocol 1 above to produce product 12. Intermediate 9 was then coupled with an organoboron reagent to produce intermediate 14, which was then subjected to acidolysis to produce product 15.

[0330] Protocol 4

[0331] [ka]

[0332] As described in Protocol 4, compounds of general formula A can be prepared from compounds of general formula intermediate 16 by the following steps: intermediate 16 is subjected to bromination to give intermediate 17, intermediate 17 is subjected to Sandermeyer bromination of the amino group to give intermediate 18, and intermediate 18 is subjected to aromatic amination, malonyldicyano coupling cyclization, and acidolysis as described in Protocol 1 above to give compounds of general formula A.

[0333] Protocol 5

[0334] [ka]

[0335] As described in Protocol 5, compounds of general formula A can be prepared from intermediates of general formula 19 by aromatic amination, malonyldicyano coupling cyclization, and acidolysis as described in Protocol 1 above.

[0336] Protocol 6

[0337] [ka]

[0338] As described in Protocol 5, compounds of general formula A can be prepared from intermediates of general formula 22 by aromatic amination, malonyldicyano coupling cyclization, and acidolysis as described in Protocol 1 above.

[0339] The products and racemic intermediate compounds of the above Protocols 2 to 5 can each be used to obtain two chiral isomers through the chiral production method shown in Protocol 1.

[0340] [Synthesis Examples of Specific Compounds] Example 1 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0341] [ka]

[0342] In a single-neck flask, 5-bromo-4-chloro-2-methylpyrimidine (9 g, 43.48 mmol), 3-methoxy-2,6-dimethylaniline (7.88 g, 52.19 mmol), and 2,6-dimethylpyridine (8.61 g, 86.96 mmol) were dissolved in N-methylpyrrolidone (180 mL) and stirred at 130 °C for 40 hours. After completion of the reaction by TLC monitoring, the reaction mixture was extracted with saturated aqueous ammonium chloride (300 mL) and ethyl acetate (200 mL). After phase separation, the ethyl acetate phase was collected, and the aqueous phase was extracted again with ethyl acetate (100 mL). The combined organic phases were extracted and washed sequentially with saturated ammonium chloride (100 mL x 2), water (100 mL), and saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent, yielding the crude reaction product. The resulting crude product was purified to give 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (2.3 g). MS (ESI) M / Z: 323.7 [M+H + ].

[0343] Malononitrile (2.34 g, 35.50 mmol) and sodium tert-butoxide (3.40 g, 35.50 mmol) were dissolved in tetrahydrofuran (44 mL) under nitrogen gas protection and reacted at room temperature for 30 minutes. 5-Bromo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (2.3 g, 7.10 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (520 mg, 0.71 mmol) were added to the solution, and the reaction mixture was further purged with nitrogen gas and reacted at 100 °C for 3 hours. After TLC monitoring confirmed the disappearance of the raw materials, water (60 mL) and ethyl acetate (40 mL) were added and stirred, followed by phase separation. The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (1.2 g). MS (ESI) M / Z: 308.0 [M+H + ].

[0344] 6-Amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (1.2 g, 3.91 mmol) was dissolved in sulfuric acid / water (13 / 1, 6 mL), methylsulfonic acid (14 g, 144.63 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Next, DL-methionine (2.33 g, 15.64 mmol) was added to the reaction mixture, and the mixture was stirred at 40 °C overnight. After TLC monitoring confirmed the disappearance of the starting material, the reaction was stopped. The pH of the reaction mixture was adjusted to approximately 7 by dropwise addition of aqueous sodium hydroxide / dipotassium hydrogen phosphate solution, and the crude product was filtered and purified to give 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (690 mg). MS (ESI) M / Z: 311.8 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.88 (s, 1H), 7.11-7.03 (m, 3H), 6.94 (d, J = 8.3 Hz, 1H), 6.85 (s, 2H), 2.44 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H).C 16 H 17 N5O2.

[0345] Example 2 S-6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0346] [ka]

[0347] 100 mg of the compound of Example 1 was purified by chiral HPLC to obtain 29.9 mg (yield: 30%). [α] 20 D =+55.54°(c=0.088, MeOH), >99%ee.

[0348] The chiral HPLC analysis conditions were: chiral column: Daicel OZ-3 4.6 × 100 mm 3 μm, temperature: 40 °C, mobile phase: CO2 / IPA [1% NH3 (7 M in MeOH)], flow rate: 3.0 mL / min, back pressure: 2000 psi, detection wavelength: 280 nm, cycle time: 3 min, RT = 1.117 min.

[0349] SFC separation conditions were: equipment: SFC-150 mgm (water), chiral column: Daicel OZ (25 × 250 mm, 10 μm), temperature: 30 °C, mobile phase: CO2 / IPA [0.5% NH3 (7 M in MeOH)] = 65 / 35, flow rate: 100 mL / min, back pressure: 100 bar, detection wavelength: 214 nm, cycle time: 5.36 min, sample solution: 100 mg dissolved in 45 mL MeOH, injection volume: 2.1 mL.

[0350] MS (ESI) M / Z: 312.2 [M+H + ]. 1 H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 8.88 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.04 (s, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.83 (s, 2H), 2.44 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H).

[0351] Example 3 R-6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0352] [ka]

[0353] 100 mg of the compound of Example 1 was purified by chiral HPLC to obtain 32.1 mg (yield: 32%). [α] 20 D =-1.99°(c=0.100, MeOH), 98%ee.

[0354] The chiral HPLC analysis conditions were: chiral column: Daicel OZ-3 4.6 × 100 mm 3 μm, temperature: 40 °C, mobile phase: CO2 / IPA [1% NH3 (7 M in MeOH)], flow rate: 3.0 mL / min, back pressure: 2000 psi, detection wavelength: 280 nm, cycle time: 3 min, RT = 1.511 min.

[0355] SFC separation conditions were: equipment: SFC-150 mgm (water), chiral column: Daicel OZ (25 × 250 mm, 10 μm), temperature: 30 °C, mobile phase: CO2 / IPA [0.5% NH3 (7 M in MeOH)] = 65 / 35, flow rate: 100 mL / min, back pressure: 100 bar, detection wavelength: 214 nm, cycle time: 5.36 min, sample solution: 100 mg dissolved in 45 mL MeOH, injection volume: 2.1 mL.

[0356] MS (ESI) M / Z: 312.2 [M+H + ]. 1 H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 8.88 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.04 (s, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.83 (s, 2H), 2.44 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H).

[0357] Example 4 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0358] [ka]

[0359] 2-(Trifluoromethyl)pyrimidin-5-amine (9.5 g, 58.3 mmol) was dissolved in acetonitrile (100 ml), N-bromosuccinimide (12.5 g, 70 mmol) was added, and the mixture was allowed to react at room temperature overnight. After TLC monitoring confirmed the disappearance of the starting material, the reaction was stopped, and water (200 ml) and ethyl acetate (200 ml) were added to extract the reaction system. The organic phase was washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent, yielding a crude product mixture. The resulting crude product was purified to yield 4-bromo-2-(trifluoromethyl)pyrimidin-5-amine (9.2 g). 1 H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 4.56 (br, 2H). C5H3BrF3N3.

[0360] 4-Bromo-2-(trifluoromethyl)pyrimidin-5-amine (4 g, 16.6 mmol) was dissolved in acetonitrile (40 mL), and tert-butyl nitrite (2.56 g, 25 mmol) was added in an ice-water bath. Copper(I) bromide (2.83 g, 19.92 mmol) was then added and the mixture was stirred at 60 °C for 2 hours. After TLC monitoring confirmed the disappearance of the raw materials, water (100 mL) and ethyl acetate (100 mL) were added, the reaction mixture was extracted, and the organic phase was collected. The mixture was then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product mixture, which was then purified to obtain 4,5-dibromo-2-(trifluoromethyl)pyrimidine (700 mg). 1 H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H). C5HBr2F3N3.

[0361] 4,5-Dibromo-2-(trifluoromethyl)pyrimidine (700 mg, 2.31 mmol), 3-methoxy-2,6-dimethylaniline (384 mg, 2.54 mmol), and 2,6-dimethylpyridine (400 mg, 3.74 mmol) were dissolved in N-dimethylpyrrolidone (20 mL), and the mixture was stirred at 95°C overnight. After TLC monitoring confirmed the disappearance of the starting material, water (30 mL) and ethyl acetate (30 mL) were added, stirred, and separated. The separated organic phase was then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product mixture. The resulting crude product was purified to give 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2-(trifluoromethyl)pyrimidin-4-amine (650 mg). MS (ESI) M / Z: 378.2 [M+H + ].

[0362] Malononitrile (585 mg, 8.6 mmol) was dissolved in ethylene glycol dimethyl ether (40 mL). Sodium tert-butoxide (845 mg, 8.6 mmol) was added to the reaction mixture, which was then purged with nitrogen and stirred at room temperature for 30 minutes. After stirring, 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2-(trifluoromethyl)pyrimidin-4-amine (650 mg, 1.72 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (130 mg, 0.16 mmol) were added to the reaction mixture and the mixture was stirred at 120 °C for 4 hours. After TLC monitoring confirmed the disappearance of the starting materials, water (20 mL) and ethyl acetate (40 mL) were added, stirred, and separated. The organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (300 mg). MS (ESI) M / Z: 361.9 [M+H + ].

[0363] 6-Amino-2-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (50 mg, 0.14 mmol) was dissolved in sulfuric acid / water (0.1 mL, sulfuric acid / water = 13 / 1). Methylsulfonic acid (500 mg, 5.14 mmol) was then added to the reaction mixture and stirred at room temperature for 2 hours. DL-methionine (83 mg, 0.55 mmol) was then added to the reaction mixture and stirred at 40 °C overnight. After TLC monitoring confirmed the disappearance of the starting materials, an aqueous solution of sodium hydroxide / dipotassium hydrogen phosphate (20 mL) was added dropwise to the reaction mixture to adjust the pH to approximately 7. Dichloromethane and methanol were added, and the mixture was separated. The organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10.43 mg). MS (ESI) M / Z: 365.5 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.13 (s, 1H), 7.51 (s, 2H), 7.16-7.09 (m, 3H), 6.98 (d, J = 8.3 Hz, 1H), 1.75 (s, 3H), 1.67 (s, 3H).C 16 H 14 F3N5O2.

[0364] Example 5 6-Amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0365] [ka]

[0366] 5-Bromo-2,4-dichloropyrimidine (2 g, 8.78 mmol) was dissolved in NMP (20 ml), and 3-methoxy-2,6-dimethylaniline (1.5 g, 9.65 mmol) and 2,6-dimethylpyridine (1.5 g, 14.22 mmol) were added. The reaction mixture was stirred at 95°C overnight. After TLC monitoring confirmed the disappearance of the starting material, the reaction was stopped. Water (50 ml) and ethyl acetate (100 ml) were then added to the cooled reaction mixture, followed by stirring, extraction, and separation. The organic phase was collected. The organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding a crude product mixture. The resulting mixture was purified to give 5-bromo-2-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyrimidin-4-amine (1.8 g). MS (ESI) M / Z: 342.0 [M+H + ].

[0367] Malononitrile (288.6 mg, 4.37 mmol) was dissolved in ethylene glycol dimethyl ether (7.8 mL). Sodium tert-butoxide (420.3 mg, 4.37 mmol) was added to the reaction mixture. The mixture was purged with nitrogen gas and stirred at room temperature for 30 minutes. Under a nitrogen atmosphere, 5-bromo-2-chloro-N-(3-methoxy-2,6-dimethylphenyl)pyrimidin-4-amine (300 mg, 0.87 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (55 mg, 0.067 mmol) were added to the reaction mixture. The reaction mixture was stirred at 120 °C for 4 hours. After TLC monitoring confirmed the disappearance of the starting materials, water (20 mL) and ethyl acetate (20 mL) were added, stirred, and separated. The organic phase was collected, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product mixture. The crude product was purified to give 6-amino-2-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (120 mg). MS (ESI) M / Z: 328.44 [M+H + ].

[0368] 6-Amino-2-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (120 mg, 0.37 mmol) was dissolved in sulfuric acid / water (13 / 1, 0.3 mL), methylsulfonic acid (1.3 g, 13.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. DL-methionine (219 mg, 1.47 mmol) was then added to the reaction mixture, and the mixture was stirred at 40 °C overnight. After TLC monitoring confirmed the disappearance of the starting material, the pH of the reaction mixture was adjusted to approximately 7 by adding aqueous sodium hydroxide / dipotassium hydrogen phosphate. A solid precipitated and was filtered to obtain the crude product mixture. The resulting crude product was purified to give 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (50 mg). MS (ESI) M / Z: 331.3 [M+H + ]. 1 C 15 H 14 ClN5O2.

[0369] Example 6 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0370] [ka]

[0371] Step A: 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (200 mg, 0.6 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (279.2 mg, 1.8 mmol), potassium carbonate (250.2 mg, 1.8 mmol), and tetrakis(triphenylphosphine)palladium (69.8 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide / water (5 / 1, 7.2 mL) and heated under nitrogen. The reaction was carried out overnight at 100°C under atmospheric pressure. After the disappearance of the raw material was confirmed by LCMS monitoring, the mixture was cooled to room temperature. Water (20 ml) and ethyl acetate (20 ml) were added for extraction and post-treatment. The organic phase was collected, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product mixture. The obtained crude product was purified to obtain 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (83.84 mg). MS (ESI) M / Z: 324.5 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.97 (s, 1H), 7.19 (s, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.98 - 6.90 (m, 3H), 6.63 (dd, J = 17.2, C 17 H 17 N5O2.

[0372] Example 7 6-Amino-2-bromo-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0373] [ka]

[0374] 6-Amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 0.3 mmol) was dissolved in 33% hydrobromic acid / acetic acid solution (1 mL), heated to 80 °C, and reacted overnight. After LCMS monitoring confirmed the disappearance of the starting material, the reaction mixture was cooled to room temperature. Saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL) were added, stirred, and separated. The organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product mixture. The resulting crude product was purified to give 6-amino-2-bromo-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (45.58 mg). MS (ESI) M / Z: 376.0 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) C 15 H 14 BrN5O2.

[0375] Example 8 6-Amino-2-ethyl-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0376] [ka]

[0377] 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-vinyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (80 mg, 0.25 mmol) was dissolved in methanol (10 mL), 10% palladium-carbon (100 mg) was added, and hydrogen gas was introduced at atmospheric pressure for 3 hours. After LCMS monitoring confirmed the disappearance of the starting material, the mixture was filtered and the filtrate was concentrated to obtain a crude product mixture. The resulting crude product was purified to give 6-amino-2-ethyl-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (17.13 mg). MS (ESI) M / Z: 326.4 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.90 (s, 1H), 7.12 - 7.03 (m, 3H), 6.93 (d, J = 8.2 Hz, 1H), 6.86 (s, 2H), 2.69 (q, J = 7.3 Hz, 2H), 1.76 (s, 3H), 1.67 (s, 3H), 1.15 (t, J = 7.6 Hz, 3H).C 17 H 19 N5O2.

[0378] Example 9 6-Amino-2-(cyclohexyl-1-en-1-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0379] [ka]

[0380] As in Example 6, 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 0.30 mmol) and 2-(cyclohexyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (115 mg, 0.91 mmol) were reacted to give 6-amino-2-(cyclohexyl-1-en-1-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (19.8 mg). MS (ESI) M / Z: 377.5 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.92 (s, 1H), 7.16 - 7.05 (m, 3H), 6.93 (m, 1H), 6.87 (m, 2H) 6.82 - 6.75 (m, 1H), 2.39 (m, 2H), 2.18 - 2.05 (m, 2H), 1.77 (s, 3H), 1.69 (s, 3H), 1.66 - 1.51 (m, 4H). 21 H 23 N5O2.

[0381] Example 10 6-Amino-2-cyclohexyl-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0382] [ka]

[0383] 6-Amino-2-(cyclohexyl-1-en-1-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (15 mg, 0.04 mmol) was dissolved in methanol (2 mL), 10% Pd / C (3 mg) was added, hydrogen gas was introduced at atmospheric pressure, and the reaction was carried out at room temperature for 1.5 hours. After LCMS monitoring confirmed the disappearance of the starting material, the mixture was filtered, and the filtrate was collected and concentrated to give 6-amino-2-cyclohexyl-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13.89 mg). MS (ESI) M / Z: 380.3 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.89 (s, 1H), 7.12 - 7.01 (m, 3H), 6.95 (d, J = 8.3 Hz, 1H), 6.84 (s, 2H), 2.59 (tt, J = 11.6, C 21 H 25 N5O2.

[0384] Example 11 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0385] [ka]

[0386] 6-Amino-2-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (50 mg, 0.15 mmol), phenylboronic acid (37.3 mg, 0.31 mmol), potassium carbonate (63.3 mg, 0.46 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.8 mg, 0.012 mmol) were dissolved in dioxane / water (5 / 1, 3 mL) and reacted at 120 °C for 4.5 hours under a nitrogen atmosphere. After complete reaction of the starting materials was confirmed by LCMS monitoring, the reaction mixture was cooled to room temperature. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture, followed by stirring, extraction, and separation. The organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (50 mg). MS (ESI) M / Z: 370.3 [M+H + ].

[0387] 6-Amino-7-(3-methoxy-2,6-dimethylphenyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (50 mg, 0.14 mmol) was dissolved in sulfuric acid / water (13 / 1, 0.5 ml), and then methylsulfonic acid (483.2 mg, 5.03 mmol) was added to the reaction system. The mixture was stirred at room temperature for 2 hours, and then DL-methionine (81.1 mg, 0.54 mmol) was added to the reaction solution, and the reaction solution was stirred at 40°C overnight. After TLC monitoring confirmed that the raw materials had completely reacted, the reaction mixture was adjusted to pH 7 by adding an aqueous solution of sodium hydroxide / dipotassium hydrogen phosphate, and filtered to obtain a crude product mixture. The crude product was purified to obtain 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5.82 mg). MS (ESI) M / Z: 373.3 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.09 (s, 1H), 8.17 - 8.10 (m, 2H), 7.45 - 7.32 (m, 3H), 7.23 (s, 2H), 7.13 (d, J = 8.3 Hz, 1H), 7.01 - 6.93 (m, 3H), 1.82 (s, 3H), 1.73 (s, 3H). C 21 H 19 N5O2.

[0388] Example 12 6-Amino-2-(cyclopropylethynyl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0389] [ka]

[0390] 6-Amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 0.30 mmol), cyclopropylacetylene (100 mg, 1.52 mmol), bis(acetonitrile)dichloropalladium(II) (10 mg, 0.04 mmol), cesium carbonate (165 mg, 0.51 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (28 mg, 0.07 mmol) were dissolved in acetonitrile (4 mL) and stirred overnight at 90 °C under a nitrogen atmosphere. After TLC monitoring confirmed complete reaction of the raw materials, the reaction mixture was cooled to room temperature. Next, water (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture, followed by stirring, extraction, and separation. The organic phase was collected, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product mixture, which was purified to give 6-amino-2-(cyclopropylethynyl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10.4 mg).

[0391] MS (ESI) M / Z: 362.3 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.91 (s, 1H), 7.29 (s, 2H), 7.10 (d, J = 8.3 Hz, 1H), 6.99-6.92 (m, 3H), 1.74 (s, 3H), 1.65 (s, 3H), 1.50 (tt, J = 8.2, 5.0 Hz, 1H), 0.90-0.81 (m, 2H), 0.74 (dt, J = 4.9, 3.1 Hz, 2H).C 20 H 19 N5O2.

[0392] Example 13 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0393] [ka]

[0394] 6-Amino-2-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (100 mg, 0.31 mmol) was dissolved in n-butanol (2 mL), followed by the addition of piperidine (1 mL) and N,N-diisopropylethylamine (118.6 mg, 0.93 mmol). The reaction mixture was stirred at 150°C for 8 hours. After TLC monitoring confirmed that the starting materials had completely reacted, the mixture was cooled to room temperature. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL). After stirring and separation, the organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (90 mg). MS (ESI) M / Z: 377.4 [M+H + ].

[0395] 6-Amino-7-(3-methoxy-2,6-dimethylphenyl)-2-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (70 mg, 0.19 mmol) was dissolved in sulfuric acid / water (13 / 1, 0.6 ml), and methylsulfonic acid (662 mg, 6.9 mmol) was added to the reaction system. The reaction solution was stirred at room temperature for 2 hours, and then DL-methionine (111.1 mg, 0.74 mmol) was added to the reaction solution and stirred overnight at 40 ° C. LCMS monitoring confirmed that the raw materials had completely reacted. The reaction mixture was adjusted to a pH of about 7 by adding an aqueous solution of sodium hydroxide / dipotassium hydrogen phosphate, and the crude product was purified to give 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (18.9 mg). MS (ESI) M / Z: 380.2 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.60 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.73 (s, 2H), 6.66 (s, 2H), 3.49 (t, J = 5.4 Hz, 4H), 1.80 (s, 3H), 1.71 (s, 3H), 1.52 (m, 2H), 1.42 (m, 4H). C 20 H 24 N6O2.

[0396] Example 14 6-Amino-2-cyano-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0397] [ka]

[0398] 6-Amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (90 mg, 0.27 mmol), zinc cyanide (25 mg, 0.21 mmol), 1,1'-bis(diphenylphosphino)ferrocene (12 mg, 0.02 mmol), zinc powder (6 mg, 0.09 mmol), and tris(dibenzylideneacetone)dipalladium (6 mg, 0.006 mmol) were dissolved in dimethylacetamide (3.5 mL) and stirred at 150 °C for 3 hours under a nitrogen atmosphere. After TLC monitoring confirmed complete reaction of the starting materials, the mixture was cooled to room temperature. The reaction mixture was extracted with water (20 mL) and ethyl acetate (20 mL). After stirring and separation, the organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product mixture. The resulting crude product was purified to give 6-amino-2-cyano-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (25.55 mg). MS (ESI) M / Z: 322.4 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.10 (s, 1H), 7.69 (d, J = 6.0 Hz, 2H), 7.17 (s, 2H), 7.12 (d, J = 8 Hz, 1H), 7.03-6.95 (d, J = 8 Hz, 1H), 1.75 (s, 3H), 1.67 (s, 3H).C 16 H 14 N6O2.

[0399] Example 15 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0400] [ka]

[0401] 6-Amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 0.3 mmol) was dissolved in n-butanol (2 mL). 4-Methoxybenzylamine (1 mL) and N,N-diisopropylethylamine (117.1 mg, 0.91 mmol) were then added to the reaction mixture, which was stirred at 150°C for 8 hours. After TLC monitoring confirmed that the starting materials had completely reacted, the mixture was cooled to room temperature. Water (20 mL) and ethyl acetate (20 mL) were added, followed by extraction and separation. The organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (64.44 mg). MS (ESI) M / Z: 432.19 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.51 (s, 1H), 7.21 - 7.02 (m, 4H), 6.96 - 6.83 (m, 1H), 6.80 - 6.70 (m, 2H), 6.69 - 6.58 (m, C 23 H 24 N6O3.

[0402] Example 16 6-Amino-2-(3,6-dihydro-2H-pyran-4-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0403] [ka]

[0404] As in Example 6, 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (120 mg, 0.36 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (240 mg, 1.14 mmol) were reacted to give 6-amino-2-(3,6-dihydro-2H-pyran-4-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (25.21 mg). MS (ESI) M / Z: 379.2 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.96 (s, 1H), 7.16 (d, J = 9.4 Hz, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.97 -6.88 (m, 3H), 6.78 - 6.71 (m, 1H), 4.20 (q, J = 2.8 Hz, 2H), 3.74 (t, J = 5.4 Hz, 2H), 1.78 (s, 3H), 1.69 (s, 3H). 20 H 21 N5O3.

[0405] Example 17 6-Amino-2-(diethylamino)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0406] [ka]

[0407] As in Example 15, 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (100 mg, 0.3 mmol) and diethylamine (1 ml) were reacted to give 6-amino-2-(diethylamino)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9.29 mg). MS (ESI) M / Z: 369.0 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.58 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.68 (s, 2H), 6.62 (s, 2H), 3.45 -3.35 (m, 4H), 1.80 (s, 3H), 1.72 (s, 3H), 0.99 (t, J = 6.9 Hz, 6H). C 19 H 24 N6O2.

[0408] Example 18 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0409] [ka]

[0410] 6-Amino-2-(3,6-dihydro-2H-pyran-4-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (19 mg, 0.05 mmol) was dissolved in methanol (2 mL), 10% Pd / C (10 mg) was added, hydrogen gas was introduced at atmospheric pressure, and the reaction was carried out at room temperature for 1.5 hours. After LCMS monitoring confirmed the disappearance of the starting material, the mixture was filtered, and the filtrate was collected and concentrated to give 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (7.03 mg). MS (ESI) M / Z: 382.3 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.98 (s, 1H), 7.20 - 7.10 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 6.92 (s, 2H), 3.92 (dt, J = 11.1, C 20 H 23 N5O3.

[0411] Example 19 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0412] [ka]

[0413] 2,6-Dimethylpyrimidin-4-ol (2.0 g, 16.11 mmol) was dissolved in chloroform (20 mL), and liquid bromine (3.2 mL, 64.5 mmol) was added dropwise to the reaction mixture in an ice bath. After the addition was complete, the reaction mixture was heated to 80°C and stirred overnight. After TLC monitoring confirmed the disappearance of the starting material, the solvent was removed under reduced pressure, ethyl acetate (50 mL) was added, and the mixture was concentrated under reduced pressure three times. The crude product mixture was adjusted to pH 7-8 with saturated NaHCO3. The mixture was extracted with ethyl acetate (80 mL x 3) and dichloromethane / isopropanol (7 / 3, 50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 5-bromo-2,6-dimethylpyrimidin-4-ol (1.316 g). MS (ESI) M / Z: 205.1 [M+H + ]. 1 H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 2.33 (s, 3H), 2.24 (s, 3H).

[0414] A solution of 5-bromo-2,6-dimethylpyrimidin-4-ol (1.316 g, 6.48 mmol) in phosphorus oxychloride (20 mL) was added to a single-neck flask, and the reaction mixture was stirred at 110 °C overnight. After TLC monitoring confirmed the disappearance of the raw materials, the solvent was removed under reduced pressure. Ethyl acetate (50 mL) was added to dissolve the raw material, and the pH was adjusted to 8-9 with saturated NaHCO3 in an ice bath. Extraction was performed with ethyl acetate (80 mL x 3), and the separated organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then purified to give 5-bromo-4-chloro-2,6-dimethylpyrimidine (1.096 g). MS (ESI) M / Z: 223.0 [M+H + ]. 1 H NMR (400 MHz, DMSO) δ 2.60 (s, 3H), 2.54 (s, 3H).

[0415] A solution of 5-bromo-4-chloro-2,6-dimethylpyrimidine (1.096 g, 4.9 mmol) in N-methylpyrrolidone (7 mL) was added to a 20 mL sealed tube. Under a nitrogen atmosphere, 3-methoxy-2,6-dimethylaniline (0.9 g, 5.9 mmol) and 2,6-dimethylpyridine (1.06 g, 9.9 mmol) were slowly added, and the mixture was microwaved at 130 °C for 54 hours. LCMS confirmed the formation of the product. After extraction with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product mixture. The resulting mixture was purified to give 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2,6-dimethylpyrimidin-4-amine (883 mg). MS (ESI) M / Z: 336.2 [M+H + ].

[0416] Under a nitrogen atmosphere, sodium tert-butoxide (71 mg, 0.744 mmol), ethylene glycol dimethyl ether (1 mL), and malononitrile (49 mg, 0.744 mmol) were added to a 10 mL sealed tube. The reaction mixture was stirred at room temperature in a sealed container for 30 minutes. Next, under a nitrogen atmosphere, 5-bromo-N-(3-methoxy-2,6-dimethylphenyl)-2,6-dimethylpyrimidin-4-amine (50 mg, 0.148 mmol) and PdCl(dppf) were added to the sealed tube. The reaction tube was sealed and heated to 100 °C in an oil bath and stirred overnight. TLC detection confirmed the formation of a new spot, and the reaction mixture was poured into ice water. Extraction with ethyl acetate (10 ml x 3) was performed, and the combined organic phases were then washed with saturated brine (5 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (30 mg). MS (ESI) M / Z: 322.2 [M+H + ].

[0417] 6-Amino-7-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (30 mg, 0.09 mmol) was dissolved in concentrated sulfuric acid (1 mL) at room temperature. The reaction solution was stirred at room temperature for 5 hours. After LCMS monitoring confirmed the disappearance of the starting material, the reaction solution was quenched by adding crushed ice, and the pH of the reaction solution was then adjusted to 9 with concentrated aqueous ammonia. The mixture was extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10 mg). MS (ESI) M / Z: 340.4 [M+H + ].

[0418] A 50 mL three-neck flask was charged with 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10 mg, 0.029 mmol) and anhydrous dichloromethane (0.5 mL). A solution of BBr3 in dichloromethane (1 mL of 1 mol of dichloromethane) was added dropwise to the reaction mixture in an ice bath, and the mixture was stirred at room temperature for 1 hour. After TLC monitoring confirmed the disappearance of the starting material, the reaction mixture was quenched with ice water, the pH was adjusted to 9 with concentrated aqueous ammonia, and then concentrated under reduced pressure to give a crude product mixture. The resulting crude product was purified to give 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4 mg). MS (ESI) M / Z: 326.2 [M+H +]. 1H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.85 (s, 2H), 6.47 (s, 2H), 2.70 (s, 3H), 2.38 (s, 3H), 1.75 (s, 3H), 1.66 (s, 3H).

[0419] Example 20 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0420] [ka]

[0421] 3-Fluoro-5-methoxyaniline (8.0 g, 56.68 mmol) was dissolved in N,N-dimethylformamide (160 mL) and the reaction mixture was stirred at room temperature to give N-chlorosuccinimide (7.57 g, 56.68 mmol). The reaction mixture was stirred overnight at room temperature. After TLC monitoring confirmed the disappearance of the starting materials, the reaction mixture was poured into 600 mL of water. The mixture was extracted with ethyl acetate (300 mL x 3), and the organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 4-chloro-3-fluoro-5-methoxyaniline (6.025 g, yield: 60.74%). 1 H NMR (400 MHz, DMSO) δ 6.19 - 6.13 (m, 1H), 6.09 (dd, J = 11.6, 2.3 Hz, 1H), 5.58 (s, 2H), 3.76 (s, 3H).

[0422] A solution of 4-chloro-3-fluoro-5-methoxyaniline (6.0 g, 34.3 mmol) in acetonitrile (170 mL) was added to a single-neck flask. N-bromosuccinimide (24.4 g, 137.1 mmol) was added to the reaction mixture at room temperature, and the reaction mixture was stirred overnight at room temperature. After TLC monitoring confirmed the disappearance of the raw materials, the solvent was removed under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 2,6-dibromo-4-chloro-3-fluoro-5-methoxyaniline (9.783 g, yield: 85.56%). 1 H NMR (400 MHz, DMSO) δ 5.94 (s, 2H), 3.32 (s, 3H).

[0423] 2,6-Dibromo-4-chloro-3-fluoro-5-methoxyaniline (4.5 g, 13.5 mmol) was dissolved in 1,4-dioxane / water (60 mL / 6 mL). Under a nitrogen atmosphere, potassium carbonate (6.53 g, 47.24 mmol), methyl boronic acid (4.04 g, 67.5 mmol), and PdCl(dppf) (493 mg, 0.67 mmol) were slowly added, and the reaction mixture was stirred at 100 °C overnight. After TLC monitoring confirmed the disappearance of the starting materials, the solvent was removed under reduced pressure, and 50 mL of purified water was added to the reaction mixture. The mixture was extracted with ethyl acetate (150 mL x 3), and the combined organic phase was washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 4-chloro-3-fluoro-5-methoxy-2,6-dimethylaniline (1.919 g, yellow liquid, yield: 69.80%).

[0424] A solution of 4-chloro-3-fluoro-5-methoxy-2,6-dimethylaniline (2.0 g, 9.82 mmol) in methanol (80 mL) was added to a single-neck flask. Under a nitrogen atmosphere, ammonium formate (12.4 g, 196.43 mmol) and Pd / C (2.0 g, 18.8 mmol) were slowly added, and the reaction mixture was stirred overnight at 65 °C. After TLC monitoring confirmed the disappearance of the raw materials, the mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-fluoro-5-methoxy-2,6-dimethylaniline (1.417 g, yield: 85.38%). 1 H NMR (400 MHz, DMSO) δ 6.07 (d, J = 12.1 Hz, 1H), 4.84 (s, 2H), 3.67 (s, 3H), 1.95-1.82 (m, 6H). MS (ESI) M / Z: 170.0 [M+H + ].

[0425] 3-Fluoro-5-methoxy-2,6-dimethylaniline (707 mg, 4.18 mmol) was dissolved in ethylene glycol dimethyl ether (25 mL) at room temperature, and 2,3-dibromo-5,6-dimethylpyridine (1.0 g, 3.8 mmol), cesium carbonate (3.095 g, 9.5 mmol), Pd2dba3 (348 mg, 0.38 mmol), and XantPhos (440 mg, 0.76 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C overnight. After the disappearance of the starting materials was confirmed by LCMS monitoring, the reaction mixture was quenched with purified water. The mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel plate chromatography to give 3-bromo-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (1.166 g, yield: 91.9%). 1H NMR (400 MHz, DMSO) δ 7.60 (s, 1H), 7.41 (s, 1H), 6.77 (d, J = 11.8 Hz, 1H), 3.78 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 1.92 (d, J = 2.0 Hz, 3H), 1.90 (s, 3H). MS (ESI) M / Z: 355.0 [M+H + ].

[0426] Sodium tert-butoxide (1.578 g, 16.42 mmol) was added to a 20 mL sealed tube, and under a nitrogen stream, ethylene glycol dimethyl ether (3 mL) was added, followed by the dropwise addition of malononitrile (1.084 g, 16.42 mmol) at room temperature. After the addition was complete, the vessel was sealed, and the reaction mixture was stirred at room temperature for 30 minutes. Under a nitrogen stream, 3-bromo-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (1.16 g, 3.28 mmol) and PdCl2(dppf) (240 mg) were added to the sealed tube. The reaction tube was sealed, and the oil bath was heated to 100 °C and stirred overnight. TLC detection confirmed the formation of a new spot, and the reaction mixture was poured into pure water. The reaction mixture was extracted with ethyl acetate (150 mL × 3), and the combined organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (950 mg, yield: 85.6%). 1 H NMR (400 MHz, DMSO) δ 7.40 (s, 1H), 7.10 (d, J = 11.7 Hz, 1H), 6.92 (s, 2H), 3.86 (s, 3H), 2.25 (s, 3H), 2.25 (s, 3H), 1.69 (d, J = 1.7 Hz, 3H), 1.64 (s, 3H). MS (ESI) M / Z: 339.1 [M+H + ].

[0427] At 0 °C, 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (950 mg, 2.8 mmol) was dissolved in concentrated sulfuric acid (8 mL). The reaction solution was stirred at room temperature for 3 h. After the disappearance of the starting material was confirmed by LCMS monitoring, the reaction solution was quenched by adding crushed ice and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel plate chromatography to give 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (732 mg, yield: 73.65%). 1 H NMR (400 MHz, DMSO) δ 7.85 (s, 1H), 7.09 (d, J = 11.8 Hz, 1H), 6.87 (s, 2H), 6.67 (s, 2H), 3.86 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.69 (d, J = 1.5 Hz, 3H), 1.65 (s, 3H). MS (ESI) M / Z: 357.2 [M+H] + .

[0428] A 50 mL three-neck flask was charged with 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (732 mg, 2.05 mmol) and anhydrous dichloromethane (20 mL). A 2N dichloromethane solution of BBr3 (10.3 mL, 20.5 mmol) was added dropwise in an ice bath, and the reaction mixture was stirred at room temperature for 2 hours. After TLC monitoring confirmed the disappearance of the starting material, the reaction mixture was quenched with methanol, the pH was adjusted to 8 with concentrated aqueous ammonia, and the mixture was concentrated under reduced pressure to give a crude product. The resulting residue was purified by preparative high performance liquid chromatography to give the final product 2-amino-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (4 mg, yield: 71.3%). 1 H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 7.84 (s, 1H), 6.85 (s, 2H), 6.79 (d, J = 11.1 Hz, 1H), 6.66 (s, 2H), 2.26 (s, 3H), 2.25 (s, 3H), 1.65 (d, J = 1.6 Hz, 3H), 1.62 (s, 3H). MS (ESI) M / Z: 343.3 [M+H] + ..

[0429] Example 21 S-6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0430] [ka]

[0431] 100 mg of the compound of Example 20 was prepared by chiral HPLC. SFC separation method: Equipment: SFC-150 mg (water), Chiral column: Daicel-OZ (25 × 250 mm, 10 μm), Temperature: 30 °C, Mobile phase: CO / IPA [0.5% NH (7N in MeOH)] = 60 / 40, Flow rate: 100 mL / min, Back pressure: 100 bar, Detection wavelength: 214 nm, Cycle time: 8.68 min, RT = 1.643 min. [α] 20 D = +66.47° (c = 0.10065, MeOH), 100% ee. 1 H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 7.84 (s, 1H), 6.84 (s, 2H), 6.79 (d, J = 11.1 Hz, 1H), 6.66 (s, 2H), 2.26 (s, 3H), 2.25 (s, 3H), 1.65 (d, J = 1.6 Hz, 3H), 1.62 (s, 3H). MS (ESI) M / Z: 343.3 [M+H] + ..

[0432] Example 22 R-6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2,4-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0433] [ka]

[0434] 100 mg of the compound of Example 20 was prepared by chiral HPLC. The SFC method was the same as that of Example 21, RT=2.472 min. α] 20 D = -6.42°(c = 0.10275, MeOH), 96% ee. 1H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 7.84 (s, 1H), 6.85 (s, 2H), 6.79 (d, J = 11.1 Hz, 1H), 6.66 (s, 2H), 2.26 (s, 3H), 2.25 (s, 3H), 1.65 (d, J = 1.6 Hz, 3H), 1.62 (s, 3H). MS (ESI) M / Z: 343.3 [M+H] + ..

[0435] Example 23 2-Amino-1-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0436] [ka]

[0437] 4-Fluoro-3-methoxyaniline (1 g, 7.09 mmol) was dissolved in dichloromethane (5 ml) and methanol (5 ml). Liquid bromine (0.96 ml), dichloromethane (5 ml), and methanol (5 ml) were added dropwise to the reaction mixture, which was then stirred at room temperature for 4 hours. After LCMS monitoring confirmed the disappearance of the starting material, aqueous sodium thiosulfate (20 ml) and aqueous sodium carbonate (20 ml) were added, and the mixture was stirred for 10 minutes. The mixture was then extracted twice with ethyl acetate (40 ml). The combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2,6-dibromo-4-fluoro-3-methoxyaniline (1.9 g). 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 10.4 Hz, 1H), 4.31 (br, 2H), 3.94 (d, J = 1.6 Hz, 3H). C7H6Br2FNO. MS (ESI) M / Z: 299.9 [M+H + ].

[0438] 2,6-Dibromo-4-fluoro-3-methoxyaniline (500 mg, 1.67 mmol) was dissolved in dioxane / water (10 / 1, 5.5 mL), methylboronic acid (301 mg, 5.02 mmol), potassium carbonate (692.3 mg, 5.02 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (61.3 mg, 0.08 mmol) were added, and the mixture was purged with nitrogen gas three times. The reaction mixture was stirred overnight at 100 °C. After LCMS monitoring confirmed the disappearance of the starting material, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-fluoro-3-methoxy-2,6-dimethylaniline (600 mg). 1 H NMR (400 MHz, CDCl3) δ 6.70 (d, J = 12 Hz, 1H), 3.83 (s, 3H) , 3.47 (br, 2H), 2.12 (d, J = 4.4 Hz, 6H). C9H 12 FNO. MS (ESI) M / Z: 169.7 [M+H + ].

[0439] Ethylene glycol dimethyl ether (5 ml) was added to 2,3-dibromo-5,6-dimethylpyridine (200 mg, 0.76 mmol), 4-fluoro-3-methoxy-2,6-dimethylaniline (135.5 mg, 0.8 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39.7 mg, 0.069 mmol), cesium carbonate (622.1 mg, 1.91 mmol), and tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol). The mixture was purged with nitrogen gas three times and reacted at 90°C overnight. After confirming the disappearance of the raw material by LCMS monitoring, water (30 ml) was added and extracted twice with ethyl acetate (20 ml). The organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-N-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (165 mg). MS (ESI) M / Z: 353.2 [M+H + ].

[0440] Malononitrile (92.8 mg, 1.41 mmol) was dissolved in dioxane (2 ml), sodium tert-butoxide (225.2 mg, 2.34 mmol) was added, the mixture was purged with nitrogen gas, and the reaction was carried out at room temperature for 30 minutes. 3-Bromo-N-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-5,6-dimethylpyridin-2-amine (165 mg, 0.47 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg, 0.047 mmol) were added, the mixture was purged with nitrogen gas, and the reaction was carried out at 120°C for 2.5 hours. After LCMS monitoring confirmed that the raw material had disappeared, water (10 ml) was added and extracted twice with ethyl acetate (20 ml). The organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-amino-1-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (100 mg). MS (ESI) M / Z: 339.2 [M+H + ].

[0441] 2-Amino-1-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (100 mg, 0.3 mmol) was dissolved in sulfuric acid / water (0.5 ml), methylsulfonic acid (1.05 g, 10.95 mmol) was added, and the mixture was reacted at room temperature for 1.5 hours. Methionine (176.6 mg, 1.18 mmol) was added, and the mixture was reacted at 40°C overnight. After LCMS monitoring confirmed that the raw material had disappeared, the mixture was cooled, and the pH was adjusted to neutral with sodium hydroxide and dipotassium hydrogen phosphate aqueous solution. The mixture was extracted with ethyl acetate (20 ml x 2). The organic phase was dried and concentrated to dryness to obtain the crude product. The crude product was prepared to give 2-amino-1-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (5.02 mg). MS (ESI) M / Z: 343.5 [M+H + ].1 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.83 (s, 1H), 7.10 (d, J = 11.5 Hz, 1H), 6.83 (s, 2H), 6.66 (s, 2H), 2.25 (d, J = 7.7 Hz, 6H), 1.76 (s, 3H), 1.70 (s, 3H). C 18 H 19 FN4O2.

[0442] Example 24

[0443]

Chem.

[0444] The compound of Example 23 was prepared by chiral HPLC. SFC separation method: Instrument: SFC-150mgm (waters), chiral column: YMC Cellulose-SC (20×250mm, 5um), temperature: 30 °C, mobile phase: CO2 / MeOH[0.2%NH3(7M in MeOH)] = 65 / 35, flow rate: 50 ml / min, back pressure: 100 bar, detection wavelength: 214 nm, cycle time: 8.68 min. [α] 20 D = -35.95°(c = 0.10015, MeOH); >99% ee. MS (ESI) M / Z: 343.3 [M+H + . 1 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.82 (s, 1H), 7.09 (d, J = 11.5 Hz, 1H), 6.81 (s, 2H), 6.64 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.75 (s, 3H), 1.70 (s, 3H).

[0445] Example 25

[0446]

Chem.

[0447] The compound of Example 23 was prepared by chiral HPLC. SFC separation method: Instrument: SFC-150 mg / ml (water), Chiral column: YMC Cellulose-SC (20 x 250 mm, 5 μm), Temperature: 30°C, Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 65 / 35, Flow rate: 50 ml / min, Back pressure: 100 bar, Detection wavelength: 214 nm, Cycle time: 8.68 min. [α] 20 D = +46.32°(c = 0.10125, MeOH); >99% ee. MS (ESI) M / Z: 343.3 [M+H + ]. 1 H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 7.82 (s, 1H), 7.09 (d, J = 11.5 Hz, 1H), 6.81 (s, 2H), 6.64 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.75 (s, 3H), 1.70 (s, 3H).

[0448] Example 26 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0449] [ka]

[0450] The synthesis method was the same as in Example 12. 6-amino-2-bromo-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and 2-methylbutyn-3-2-ol were used as starting materials to produce 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(3-hydroxy-3-methylbut-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5.01 mg). MS (ESI) M / Z: 380.1 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.95 (s, 1H), 7.32 (s, 2H), 7.10 (d, J = 8.3 Hz, 1H), 7.01 - 6.92 (m, 3H), 5.54 (s, 1H), 1.74 (s, 3H), 1.66 (s, 3H), 1.42 (s, 6H).C 20 H 21 N5O3.

[0451] Example 27 6-Amino-2-(3-fluoro-3-methylpropyl-1-yn-1-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0452] [ka]

[0453] MS (ESI) M / Z: 382.37 [M+H + ].

[0454] Example 28 6-Amino-4-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0455] [ka]

[0456] The synthetic route described in Protocol 1 was used. A solution of 2-methylpyrimidine-4,6-diol (5 g, 39.65 mmol) in chloroform (50 mL) was added to a single-neck flask. The reaction system was purged with nitrogen and cooled to 0 °C. Bromine (4.1 mL, 79.3 mmol) was slowly added to the reaction system, and the system was stirred at 80 °C overnight. After TLC monitoring confirmed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The reaction solution was washed with ethyl acetate (100 mL x 3) and filtered to obtain a pale yellow solid. The resulting solid was adjusted to pH 7-8 with saturated sodium bicarbonate and spin-dried to obtain the crude product, 5-bromo-2-methylpyrimidine-4,6-diol (11 g). Next, the crude product was added to phosphorus oxychloride (15 mL) and stirred overnight at 110 °C under nitrogen gas protection. After the reaction was completed, the mixture was diluted with ethyl acetate (100 ml) and adjusted to pH 8 with saturated sodium bicarbonate. It was then extracted with ethyl acetate (100 ml x 3), washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 5-bromo-4,6-dichloro-2-methylpyrimidine (1.2 g). Using 5-bromo-4,6-dichloro-2-methylpyrimidine as the starting material, 6-amino-4-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (1.47 mg) was prepared according to the synthesis route in Example 1. MS (ESI) M / Z: 346.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 6.85 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 2.22 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H).

[0457] Example 29 2-Amino-7-fluoro-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[3,2-c]nicotinamide

[0458] [ka]

[0459] Diisopropylamine (319 mg, 3.16 mmol) was dissolved in tetrahydrofuran (10 ml) and cooled to -78°C. 1.8 mol / L n-butyllithium (1.75 ml) was slowly added and the mixture was allowed to react at -78°C for 15 minutes. Next, a solution of 5-bromo-3-fluoro-2-methylpyridine (500 mg, 2.63 mmol) in tetrahydrofuran (20 ml) was added. The mixture was stirred at the same temperature for an additional 30 minutes. Next, a solution of iodine (1 g, 3.95 mmol) in tetrahydrofuran (5 ml) was slowly added and the mixture was stirred at room temperature for 2 hours. After LCMS monitoring confirmed that the raw materials had disappeared, the reaction mixture was added to an aqueous ammonium chloride solution (80 ml), and extracted twice with ethyl acetate (40 ml). The organic phases were combined, washed twice with sodium thiosulfate (50 ml), then washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-bromo-3-fluoro-4-iodo-2-methylpyridine (500 mg).

[0460] 5-Bromo-3-fluoro-4-iodo-2-methylpyridine (470 mg, 1.49 mmol) was dissolved in ethylene glycol dimethyl ether (10 ml), 3-methoxy-2,6-dimethylaniline (247 mg, 1.64 mmol), cesium carbonate (1.21 g, 3.72 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (77 mg, 0.13 mmol), and tris(dibenzylideneacetone)dipalladium (68 mg, 0.07 mmol) were added, the atmosphere was purged with nitrogen gas three times, and the reaction solution was stirred at 90°C overnight. After LCMS monitoring confirmed that the raw materials had disappeared, water (30 ml) was added, and the mixture was extracted with ethyl acetate (20 ml). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give 5-bromo-3-fluoro-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyridin-4-amine (400 mg).

[0461] Using 5-bromo-3-fluoro-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyridin-4-amine as the starting material, 2-amino-7-fluoro-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[3,2-c]nicotinamide (15.18 mg) was prepared according to the protocol of Example 1. MS (ESI) M / Z: 328.5 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.89 (dd, J = 22.5, 6.9 Hz, 5H), 2.33 (d, J = 3.2 Hz, 3H), 1.80 (s, 3H), 1.72 (s, 3H).C 17 H 17 FN4O2.

[0462] Example 30 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide

[0463] [ka]

[0464] Using 3,4-dibromopyridine as a starting material, 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2-c]pyridine-3-carboxamide (5.6 mg) was prepared according to the procedure in Protocol 5. MS (ESI) M / Z: 297.4 [M+H + ]. 1 H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 8.92 (s, 1H), 8.01 (d, J = 5.3 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.90 (s, 2H), 6.80 (s, 2H), 6.47 (d, J = 5.3 Hz, 1H), 1.75 (s, 3H), 1.66 (s, 3H).

[0465] Example 31 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide

[0466] [ka]

[0467] Starting from 5-bromo-4-chloro-2-methylpyridine, 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide (3.22 mg) was prepared according to the procedure in Protocol 5. MS (ESI) M / Z: 311.5 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.77 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.83 (s, 2H), 6.75 (s, 2H), 6.31 (s, 1H), 2.37 (s, 3H), 1.75 (s, 3H), 1.66 (s, 3H).C 17 H 18 N4O2.

[0468] Example 32 6-Amino-7-(2,6-diethyl-3-hydroxyphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0469] [ka]

[0470] 5-Bromo-4-chloro-2-methylpyrimidine (1 g, 4.83 mmol) and 2,6-diethyl-3-methoxyaniline (690 mg, 3.86 mmol) were dissolved in tetrahydrofuran (30 mL). Lithium bis(trimethylsilyl)amide (1 M, 14.5 mL, 14.5 mmol) was added in an ice-water bath and the reaction was allowed to proceed overnight at 50 °C. After TLC monitoring confirmed the disappearance of the starting material, the reaction was quenched with aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (40 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromoamine-(2,6-diethyl-3-methoxyphenyl)-2-methylpyrimidin-4-amine (150 mg). Using the method of Example 1 as a starting material, 5-bromo-4-chloro-2-methylpyrimidine and 2,6-diethyl-3-methoxyaniline were used to prepare 6-amino-7-(2,6-diethyl-3-hydroxyphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (15.87 mg). MS (ESI) M / Z: 339.1 [M+H+ ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.87 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.06 - 6.96 (m, 3H), 6.86 (s, 2H), 2.43 (s, 3H), 2.21 - 1.89 (m, 4H), 0.86 (dt, J = 27.7, 7.5 Hz, 6H).C 18 H 21 N5O2.

[0471] Example 33 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0472] [ka]

[0473] 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.15 (s, 1H), 8.73 (s, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.18 - 7.05 (m, 3H), 6.96 - 6.88 (m, 3H), 6.82 - 6.69 (m, 3H), 1.83 (s, 3H), 1.74 (s, 3H). C 21 H 20 N6O2. MS (ESI) M / Z: 388.3 [M+H + ].

[0474] Example 34 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-morpholine-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0475] [ka]

[0476] The preparation method was the same as in Example 13. 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide was reacted with morpholine to prepare 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-morpholine-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (23.97 mg). MS (ESI) M / Z: 383.1 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.66 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.79 (s, 2H), 6.70 (s, 2H), 3.59 (t, J = 4.8 Hz, 4H), 3.42 (t, J = 4.8 Hz, 4H), 1.79 (s, 3H), 1.70 (s, 3H). C 19 H 22 N6O3.

[0477] Example 35 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0478] [ka]

[0479] The preparation method was the same as in Example 13. 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide was reacted with pyrrolidine to prepare 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6.97 mg). MS (ESI) M / Z: 367.2 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.59 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.71 - 6.61 (m, 4H), 3.34 - 3.23 (m, 4H), 1.91 - 1.75 (m, 7H), 1.72 (s, 3H).C 19 H 22 N6O2.

[0480] Example 36 6-Amino-2-(dimethylamino)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0481] [ka]

[0482] The preparation method was the same as in Example 13. 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide was reacted with dimethylamine hydrochloride to prepare 6-amino-2-(dimethylamino)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10.82 mg). MS (ESI) M / Z: 341.3 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.60 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.71 (s, 2H), 6.65 (s, 2H), 2.93 (s, 6H), 1.80 (s, 3H), 1.71 (s, 3H).C 17 H 20 N6O2.

[0483] Example 37 6-Amino-2-(4,4-difluoropiperidin-1-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0484] [ka]

[0485] The preparation method was the same as in Example 13. 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide was reacted with 4,4-difluoropyridine to prepare 6-amino-2-(4,4-difluoropiperidin-1-yl)-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (21.39 mg). MS (ESI) M / Z: 417.3 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.67 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.81 (s, 2H), 6.71 (s, 2H), 3.66 (t, J = 5.7 Hz, 4H), 1.97 - 1.82 (m, 4H), 1.80 (s, 3H), 1.71 (s, 3H). C 20 H 22 F2N6O2.

[0486] Example 40 2,6-Diamino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0487] [ka]

[0488] 6-Amino-2-chloro-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (150 mg, 0.46 mmol) was dissolved in n-butanol (3 mL), N,N-diisopropylethylamine (177.9 mg, 1.38 mmol) and p-methoxybenzylamine (1.5 mL) were added, and the reaction mixture was stirred at 150° C. for 12 hours. Water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-((4-methoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (168 mg). Next, the product was dissolved in sulfuric acid / water (13 / 1, 1 ml), and methylsulfonic acid (1.4 g, 14.52 mmol) was added. The mixture was allowed to react at room temperature for 1.5 hours. Methionine (234.3 mg, 1.57 mmol) was added, and the mixture was allowed to react overnight at 40 °C. After LCMS monitoring confirmed that the raw material had disappeared, sodium hydroxide and dipotassium hydrogen phosphate aqueous solution were added to adjust the pH to neutral, and the mixture was directly concentrated and dried to obtain the crude product, which was prepared as 2,6-diamino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2.01 mg). MS (ESI) M / Z: 313.3 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.52 (s, 1H), 7.08 - 7.00 (m, 1H), 6.93 - 6.85 (m, 1H), 6.77 - 6.60 (m, 4H), 5.99 (s, 2H), 1.80 (s, 3H), 1.71 (s, 3H).C 15 H 16 N6O2.

[0489] Example 41 6-Amino-2-cyclopropyl-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0490] [ka]

[0491] 5-Bromo-4-chloro-2-(methylthio)pyrimidine (4 g, 16.81 mmol) was dissolved in tetrahydrofuran (30 ml), and potassium hydrogen persulfate complex (15.5 g, 50.42 mmol) was dissolved in water (20 ml). The reaction mixture was added dropwise and stirred at room temperature overnight. After the reaction, ethyl acetate (60 ml) was added and extracted twice. The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to give 5-bromo-4-chloro-2-(methylsulfonyl)pyrimidine (4.1 g).

[0492] 5-Bromo-4-chloro-2-(methylsulfonyl)pyrimidine (2 g, 7.33 mmol) was dissolved in tetrahydrofuran (60 mL), cyclopropylmagnesium bromide (17.6 mL, 8.8 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-bromo-4-chloro-2-cyclopropylpyrimidine (510 mg). Using 5-bromo-4-chloro-2-cyclopropylpyrimidine as the starting material, 6-amino-2-cyclopropyl-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5.34 mg) was prepared according to the method of Example 1. MS (ESI) M / Z: 338.2 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.82 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.02 (s, 2H), 6.94 (d, J = 8.3 Hz, 1H), 6.83 (s, 2H), 1.97 (tt, J=7.8, 5.0 Hz, 1H), 1.76 (s, 3H), 1.68 (s, 3H), 0.84 (tt, J=7.7, 2.8 Hz, 4H). 18 H 19 N5O2.

[0493] Example 42 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylprop-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0494] [ka]

[0495] The preparation method was the same as in Example 6. 6-amino-2-chloro-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide was reacted with 2-methylprop-1-en-1-yl)boronic acid to prepare 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylprop-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg). MS (ESI) M / Z: 352.2 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.95 (s, 1H), 7.15 (s, 2H), 7.08 (d, J = 8.3 Hz, 1H), 6.96 - 6.85 (m, 3H), 6.16 (s, 1H), 2.07 (s, 3H), 1.84 (s, 3H), 1.77 (s, 3H), 1.68 (s, 3H).C 19 H 21 N5O2.

[0496] Example 43 2-Amino-1-(4-chloro-3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0497] [ka]

[0498] 2-Amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (200 mg, 0.62 mmol) was dissolved in trifluoroacetic acid (6 ml), N-chlorosuccinimide (197 mg, 1.47 mmol) was added, and the mixture was stirred at room temperature. After the reaction was completed, sodium bicarbonate (30 ml) and dichloromethane (30 ml) were added, and the mixture was stirred and separated. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The resulting crude product was purified to give 2-amino-1-(4-chloro-3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (2.44 mg). MS (ESI) M / Z: 359.2 [M+H + ]. 1 C 18 H 19 ClN4O2.

[0499] Example 44 2-Amino-1-(4-chloro-3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0500] [ka]

[0501] Using the route of Protocol 5, the preparation method was the same as in Example 20. 2,3-dibromo-5,6-dimethylpyridine and 3-fluoro-4-chloro-5-methoxy-2,6-dimethylaniline were used as raw materials to prepare 2-amino-1-(4-chloro-3-fluoro-5-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (4 mg). MS (ESI) M / Z: 377.1, 379.1 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 7.85 (s, 1H), 6.95 (s, 2H), 6.67 (s, 2H), 2.26 (d, J = 7.0 Hz, 6H), 1.74 - 1.66 (m, 6H).

[0502] Example 45 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0503] [ka]

[0504] The production method was the same as in Example 1, and 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (59.74 mg) was produced using 5-bromo-4-chloropyrimidine as a starting material. MS (ESI) M / Z: 298.0 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 7.21 (s, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.98 - 6.90 (m, 3H), 1.75 (s, 3H), 1.67 (s, 3H).C 15 H 15 N5O2.

[0505] Example 46 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0506] [ka]

[0507] 1-Methoxy-2,4-dimethyl-3-nitrobenzene (3.0 g, 17.95 mmol) was dissolved in dichloromethane (30 ml) and a 1 M solution of boron tribromide in dichloromethane (25 ml) was added dropwise at -40°C. After the addition was complete, the mixture was allowed to warm slowly to room temperature and stirred overnight. After the reaction was complete, water (150 ml) and potassium dihydrogen phosphate (11.2 g) were added to the reaction mixture, which was then extracted with dichloromethane (100 ml). The organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2,4-dimethyl-3-nitrophenol (1.9 g). 2,4-Dimethyl-3-nitrophenol (200.0 mg, 1.3 mmol) and 4-methoxybenzyl alcohol (270.8 mg, 1.9 mmol) were dissolved in tetrahydrofuran, triphenylphosphine (514.1 mg, 1.9 mmol) was added, and diisopropyl azodicarboxylate was added dropwise at 0°C. The mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was extracted with water (20 ml) and ethyl acetate (20 ml). The organic phase was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 1-((4-methoxybenzyl)oxy)-2,4-dimethyl-3-nitrobenzene (110 mg). The reaction was then amplified to produce 1-((4-methoxybenzyl)oxy)-2,4-dimethyl-3-nitrobenzene (1.06 g).

[0508] Reduced iron powder (1.34 g, 24.0 mmol), silicon dioxide (2.7 g, 45.6 mmol), and ammonium chloride (790 mg, 14.7 mmol) were added to ethanol (20 mL) and water (20 mL). The reaction mixture was heated to 60 °C. 1-((4-methoxybenzyl)oxy)-2,4-dimethyl-3-nitrobenzene (1.06 g, 3.7 mmol) was dissolved in tetrahydrofuran (20 mL) and added to the reaction mixture. After stirring at 70 °C for 3 hours, saturated brine (30 mL) and ethyl acetate (50 mL) were added to the reaction mixture. The organic phase was separated, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-((4-methoxybenzyl)oxy)-2,6-dimethylaniline (830 mg). Referring to Example 1, 5-bromo-2,4-dichloropyrimidine (800 mg, 3.5 mmol) was dissolved in N-methylpyrrolidone (10 ml), and 2,6-dimethylpyridine (608.5 mg, 5.7 mmol) and 3-((4-methoxybenzyl)oxy)-2,6-dimethyl-aniline (992.5 mg, 3.9 mmol) were added and reacted to prepare 5-bromo-2-chloro-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)pyrimidin-4-amine (1.0 g).

[0509] 5-Bromo-2-chloro-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)pyrimidin-4-amine (400 mg, 0.9 mmol) was dissolved in methanol (8 ml), sodium methoxide (241.6 mg, 4.5 mmol) was added, and the reaction mixture was heated to 80°C and stirred overnight. After LCMS monitoring confirmed that the starting materials had disappeared, the reaction mixture was extracted with water (30 ml) and ethyl acetate (30 ml). After separation, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-bromo-2-methoxy-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)pyrimidin-4-amine (311.1 mg). MS (ESI) M / Z: 446.2 [M+H + ].

[0510] Referring to Example 1, 5-bromo-2-methoxy-N-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)pyrimidin-4-amine was reacted with malononitrile to prepare 6-amino-2-methoxy-7-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (60 mg).

[0511] 6-Amino-2-methoxy-7-(3-((4-methoxybenzyl)oxy)-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (60 mg, 0.14 mmol) was dissolved in concentrated sulfuric acid (1 ml) and stirred at room temperature for 1 hour. After stirring, the reaction mixture was extracted with saturated aqueous sodium bicarbonate (20 ml) and ethyl acetate (20 ml). The organic phase was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting product was 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4.11 mg). MS (ESI) M / Z: 328.3 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.73 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.96 (dd, J = 26.8, 9.2 Hz, 3H), 6.82 (s, 2H), 3.77 (s, 3H), 1.77 (s, 3H), 1.68 (s, 3H).C 16 H 17 N5O3.

[0512] Example 47 6-Amino-2-ethynyl-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0513] [ka]

[0514] 6-Amino-2-bromo-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (200 mg, 0.535 mmol), (triisopropylsilyl)acetylene (481 mg, 2.67 mmol), tetrakis(triphenylphosphine)palladium (124 mg, 0.11 mmol), copper(I) iodide (6 mg, 0.005 mmol) were dissolved in N,N-dimethylformamide (6 mL) and triethylamine ( The mixture was dissolved in 6 ml of water, purged with nitrogen gas, and reacted at 90°C. After completion of the reaction, the mixture was extracted with water (20 ml) and ethyl acetate (30 ml), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting mixture was subjected to column chromatography to give 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-((triisopropylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg).

[0515] 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-((triisopropylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg, 0.146 mmol) was dissolved in tetrahydrofuran (6 ml), tetrabutylammonium fluoride (230 mg, 0.732 mmol) was added in an ice-water bath, and the mixture was stirred for 40 minutes in an ice-water bath. The mixture was then extracted with water (20 ml) and ethyl acetate (30 ml), washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6-amino-2-ethynyl-7-(3-hydroxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (3.46 mg). MS (ESI) M / Z: 321.2 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.96 (s, 1H), 7.37 (s, 2H), 7.10 (d, J = 8.3 Hz, 1H), 7.04 - 6.93 (m, 3H), 4.03 (s, 1H), 1.75 (s, 3H), 1.66 (s, 3H).C 17 H 15 N5O2.

[0516] Example 48 2-Amino-1-(3-chloro-5-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]nicotinamide

[0517] [ka]

[0518] Using the route of Protocol 5, the preparation method was the same as in Example 20, and 2,3-dibromo-5,6-dimethylpyridine and 3-chloro-5-methoxy-2,6-dimethylaniline were used as starting materials to prepare 2-amino-1-(3-chloro-5-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]nicotinamide (24.61 mg). MS (ESI) M / Z: 359.1 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.86 (s, 1H), 7.21 (s, 1H), 6.88 (s, 2H), 6.70 (s, 2H), 2.25 (d, J = 7.0 Hz, 6H), 1.75 (s, 3H), 1.62 (s, 3H).C 18 H 19 ClN4O2.

[0519] Example 50 2-Amino-1-(2-hydroxy-3,5-dimethylpyridin-4-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0520] [ka]

[0521] Using the route of Protocol 5, the preparation method was the same as in Example 20, and 2,3-dibromo-5,6-dimethylpyridine and 2-methoxy-3,5-dimethylpyridin-4-amine were used as starting materials to prepare 2-amino-1-(2-hydroxy-3,5-dimethylpyridin-4-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (3.17 mg). MS (ESI) M / Z: 326.4 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.27 (s, 1H), 7.06 (s, 2H), 6.69 (s, 2H), 2.27 (d, J = 5.1 Hz, 6H), 1.61 (s, 3H), 1.55 (s, 3H).C 17 H 19 N5O2.

[0522] Example 51 2-Amino-1-(5-hydroxy-2,4-dimethylpyrimidin-3-yl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyrimidine-3-carboxamide

[0523] [ka]

[0524] 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 6.97 (s, 2H), 6.69 (s, 2H), 2.25 (d, J = 8.5 Hz, 6H), 1.94 (s, 3H), 1.72 (s, 3H).C 17 H 19 N5O2. MS (ESI) M / Z: 326.2 [M+H + ].

[0525] Example 53 2-Amino-1-(3-hydroxy-2,5,6-trimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0526] [ka]

[0527] Using the route of Protocol 5, the preparation method was the same as in Example 20. 2-Amino-1-(3-hydroxy-2,5,6-trimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (5.13 mg) was prepared from 2,3-dibromo-5,6-dimethylpyridine and 3-methoxy-2,5,6-trimethylaniline. MS (ESI) M / Z: 339.4 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.83 (d, J = 4.7 Hz, 1H), 6.82 (d, J = 5.5 Hz, 1H), 6.75 - 6.56 (m, 4H), 2.30 - 2.18 (m, 9H), 1.66 - 1.57 (m, 6H).C 19 H 22 N4O2.

[0528] Example 54 2-Amino-1-(3,4-difluoro-5-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyrimidine-3-carboxamide

[0529] [ka]

[0530] 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 7.85 (s, 1H), 6.93 (s, 2H), 6.69 (s, 2H), 2.26 (d, J = 5.7 Hz, 6H), 1.71 (s, 3H), 1.67 (s, 3H).C 18 H 18 F2N4O2. MS (ESI) M / Z: 359.9 [M+H + ].

[0531] Example 57 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0532] [ka]

[0533] 6-Amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylprop-1-en-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (60 mg, 0.17 mmol) was dissolved in methanol, 10% Pd / C (3 mg) was added, hydrogen gas was introduced at atmospheric pressure, and the reaction was carried out at room temperature for 2 hours. After LCMS monitoring confirmed the disappearance of the starting material, the mixture was filtered, and the filtrate was concentrated to give 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-2-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (37.03 mg). MS (ESI) M / Z: 354.0 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.90 (s, 1H), 7.12 - 7.03 (m, 3H), 6.94 (d, J = 8.2 Hz, 1H), 6.85 (s, 2H), 2.55 (d, J = 7.2 Hz, C 19 H 23 N5O2.

[0534] Example 58 2-Amino-5-bromo-1-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0535] [ka]

[0536] 3,5-Dibromo-2-fluoro-6-methylpyridine (1 g, 3.72 mmol) was dissolved in tetrahydrofuran (10 ml), 4-fluoro-3-methoxy-2,6-dimethylaniline (628 mg, 3.72 mmol) was added, and lithium hexamethyldisilazide (7.4 ml, 7.44 mmol) was added dropwise and stirred at room temperature for 0.5 hours. After LCMS monitoring confirmed the disappearance of the raw material, ammonium chloride solution (20 ml) was added and stirred for 10 minutes. Ethyl acetate (40 ml) was added twice, and the organic phases were combined. The organic phase was first washed with saturated brine (50 ml), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3,5-dibromo-N-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methylpyridin-2-amine (1.2 g). MS (ESI) M / Z: 418.6 [M+H + ].

[0537] Malononitrile (189.5 mg, 2.89 mmol) was dissolved in dioxane (10 ml), sodium tert-butoxide (331 mg, 3.44 mmol) was added, the mixture was purged with nitrogen gas, and the reaction was carried out at room temperature for 30 minutes. 3,5-dibromo-N-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methylpyridin-2-amine (1.2 g, 2.87 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (234 mg, 0.29 mmol) were added, the mixture was purged with nitrogen gas, and the reaction was carried out at 120°C for 3 hours. After LCMS monitoring confirmed that the raw materials had disappeared, water (10 ml) was added and extracted twice with ethyl acetate (20 ml). The organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-amino-5-bromo-1-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (499 mg). MS (ESI) M / Z: 402.85 [M+H + ].

[0538] 2-Amino-5-bromo-1-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (400 mg, 1 mmol) was dissolved in sulfuric acid / water (3 ml), methylsulfonic acid (3.5 g, 36.8 mmol) was added, and the mixture was reacted at room temperature for 1.5 hours. Methionine (594 mg, 3.98 mmol) was added, and the mixture was reacted at 40°C overnight. After LCMS monitoring confirmed that the raw material had disappeared, the mixture was cooled, and the pH value was adjusted to neutral with sodium hydroxide and dipotassium hydrogen phosphate aqueous solution. The mixture was extracted with ethyl acetate (20 ml × 2). The organic phase was dried and concentrated to dryness to obtain the crude product. The crude product was prepared as 2-amino-5-bromo-1-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (98.91 mg). 1C 17 H 16 BrFN4O2. MS (ESI) M / Z: 407.9 [M+H + ].

[0539] Examples 58.1 and 58.2

[0540]

change

[0541] SFC method: Machine: SFC-150mgm (waters), Crystal color: Daicel OZ-3 (25×250mm, 10μm), Temperature: 30℃, Mobile phase: CO2 / MeOH [0.2%NH3 (7M MeOH)] = 45 / 55, Flow rate: 100mL / min, Back pressure: 100bar, Emission wavelength: 214nm, Cyclic time: 4.84min.

[0542] Example 58.1:40.4mg. SFC RT=1.448min. [α] D 20 = +35.7 o (c = 0.10135, MeOH). 1 H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 8.25 (s, 1H), 7.11 (d, J = 11.5 Hz, 1H), 7.06 (s, 2H), 6.79 (s, 2H), 2.40 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H). MS (ESI) M / Z: 407.8 [M+H + ].

[0543] Example 58.2: 39.8 mg. SFC Rt = 2.031min. α] D20 = -16.5 o (c = 0.1033 g, MeOH). 1 H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 8.25 (s, 1H), 7.11 (d, J = 11.6 Hz, 1H), 7.06 (s, 2H), 6.79 (s, 2H), 2.39 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H). MS (ESI) M / Z: 407.8 [M+H + ].

[0544] Example 59 2-Amino-1-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide

[0545] [ka]

[0546] In a single-neck flask, 6-chloro-5-(trifluoromethyl)pyridin-2-amine (39 g, 0.19 mol) was dissolved in dioxane / water (10:1). Methylboronic acid (23.4 g, 0.39 mol), potassium carbonate (82 g, 0.59 mol), and PdCl(dppf) (8 g, 0.011 mol) were added. The reaction mixture was quenched with pure water and the product was generated after LCMS monitoring. The resulting mixture was extracted with ethyl acetate (700 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 6-methyl-5-(trifluoromethyl)pyridin-2-amine (24 g).

[0547] In a single-neck flask, 6-methyl-5-(trifluoromethyl)pyridin-2-amine (24 g, 0.14 mol) was dissolved in acetonitrile (300 ml). N-bromosuccinimide (29.13 g, 0.164 mol) was added in batches under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting material and the formation of the product by LCMS monitoring, the reaction mixture was poured into 500 ml of water. Extraction was performed with ethyl acetate (400 ml x 3), and the combined organic phase was washed with saturated brine (100 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-amine (26.3 g). MS (ESI) M / Z: 257.0 [M+H + ]. 1 H NMR (400 MHz, CDCl3)δ 8.04 (s, 1H), 5.30 (s, 1H,-NH2), 2.73 - 2.59 (m, 3H).

[0548] In a three-neck flask, 3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-amine (26.3 g, 0.103 mol) was dissolved in bromoform, and bromine (19.9 g, 0.124 mol) was slowly added dropwise at 0 °C. Next, tert-butyl nitrite (32.61 g, 0.31 mol) was slowly added dropwise to the reaction mixture at 0 °C. The mixture was allowed to react at room temperature for 3 hours. After LCMS monitoring confirmed the disappearance of the raw materials and the formation of the product, the reaction mixture was quenched by adding ice water. The organic phase was washed three times with saturated sodium bicarbonate solution, and the resulting organic phase was concentrated under reduced pressure using an oil pump to remove bromoform. The resulting mixture was purified by silica gel column chromatography to give 2,3-dibromo-6-methyl-5-(trifluoromethyl)pyridine (26.5 g). MS (ESI) M / Z: 320.0 [M+H + ].

[0549] In a one-neck flask, 2,3-dibromo-6-methyl-5-(trifluoromethyl)pyridine (15.1 g, 0.047 mol) was dissolved in ethylene glycol dimethyl ether (150 ml), and 4-fluoro-3-methoxy-2,6-dimethylaniline (8.8 g, 0.053 mol), cesium carbonate (38.75 g, 0.12 mol), Pd2dba3 (4.34 g, 4.74 mmol), and XantPhos (5.48 g, 9.48 mmol) were added at room temperature. The reaction system was replaced with a nitrogen gas reaction system, and the reaction system was reacted at 110 °C for 12 hours. After confirming the disappearance of the raw materials and the formation of the product by LCMS monitoring, the reaction mixture was quenched by adding purified water. The mixture was extracted with ethyl acetate (400 ml x 3). The organic phases were combined, washed with saturated brine (100 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 3-bromo-N-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine (10.5 g). MS (ESI) M / Z: 407.1 [M+H] + ..

[0550] Sodium tert-butoxide (12.42 g, 129.3 mmol) was added to a 250 mL three-neck flask, and ethylene glycol dimethyl ether (30 mL) was added under nitrogen gas protection. Then, a solution of malononitrile (8.53 g, 129.3 mmol) in ethylene glycol dimethyl ether (5 mL) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. Then, under nitrogen gas protection, a solution of 3-bromo-N-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine (10.5 g, 25.86 mmol) in ethylene glycol dimethyl ether (30 mL) and PdCl2(dppf) (1.89 g, 2.586 mmol) were added. The reaction mixture was heated at 110 °C for 16 hours. After the formation of the product was confirmed by LCMS, the reaction mixture was poured into ice water. The reaction mixture was extracted with ethyl acetate (300 ml x 3), and the combined organic phases were washed with saturated brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 2-amino-1-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (5.7 g, yield: 56.3%). MS (ESI) M / Z: 393.2 [M+H] + ..

[0551] 2-Amino-1-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (5.7 g, 14.55 mmol) was dissolved in concentrated sulfuric acid (50 ml) in an ice bath. The reaction solution was stirred at room temperature for 2 hours. After LCMS monitoring confirmed the disappearance of the raw materials, the reaction solution was poured into ice water and then adjusted to pH 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, washed with saturated brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 2-amino-1-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (4.4 g). 1 H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 7.26 (d, J = 12.2 Hz, 1H), 7.19 (s, 2H), 6.94 (s, 2H), 3.87 (d, J = 1.0 Hz, 3H), 2.45 (d, J = 1.6 Hz, 3H), 1.82 (s, 3H), 1.78 (s, 3H). MS (ESI) M / Z:411.3 [M+H] + ..

[0552] A 250 mL three-neck flask was charged with 2-amino-1-(4-fluoro-3-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (4.4 g, 10.7 mmol) and anhydrous dichloromethane (40 mL). A 1N dichloromethane solution of BBr3 (107 mL) was added dropwise in an ice bath, and the reaction mixture was stirred at room temperature for 2 hours. After the disappearance of the starting material was confirmed by LCMS, the reaction mixture was quenched with ice water, the pH was adjusted to 9 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was slurried with acetonitrile and purified to give 2-amino-1-(4-fluoro-3-hydroxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (3.1 g). 1 H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 8.27 (s, 1H), 7.19-7.07 (m, 3H), 6.93 (s, 2H), 2.45 (d, J = 1.5Hz, 3H), 1.77 (s, 3H), 1.72 (s, 3H). MS (ESI) M / Z: 397.1 [M+H + ].

[0553] Examples 59.1 and 59.2

[0554] [ka]

[0555] SFC method: Equipment: SFC-150 mgm (water), Chiral column: Daicel OZ (25 x 250 mm, 10 μm), Temperature: 30°C, Mobile phase: CO2 / MeOH [0.2% NH3 (7 M MeOH)] = 65 / 35, Flow rate: 100 mL / min, Back pressure: 100 bar, Detection wavelength: 214 nm, Cycle time: 10 min.

[0556] Example 59.1:2.13mg. SFC RT=1.770min. [α] D 20 = +42.4° (0.10018, MeOH). 1 H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 8.26 (s, 1H), 7.19 - 7.05 (m, 3H), 6.92 (s, 2H), 2.45 (d, J = 1.6 Hz, 3H), 1.77 (s, 3H), 1.72 (s, 3H). MS (ESI) M / Z: 397.1 [M+H + ].

[0557] Example 59.2: 2.36mg. SFC RT=2.480min. [α] D 20 = -26.0° (0.10100, MeOH). 1 H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 8.26 (s, 1H), 7.13 (t, J = 5.6 Hz, 3H), 6.92 (s, 2H), 2.45 (d, J = 1.6 Hz, 3H), 1.76 (s, 3H), 1.72 (s, 3H). MS (ESI) M / Z: 397.1 [M+H + ].

[0558] Example 120

[0559]

change

[0560] The path of rebellion:

[0561]

change

[0562] 6-Chloro-5-(trifluoromethyl)pyridin-2-amine (1 g, 5.01 mmol) was dissolved in dioxane / water (10 / 1, 11 mL), methylboronic acid (910.6 mg, 15.2 mmol), potassium carbonate (2.1 g, 15.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (206.6 mg, 0.25 mmol) were added, and the mixture was purged with nitrogen gas three times. The reaction mixture was stirred overnight at 100 °C. After LCMS monitoring confirmed the disappearance of the starting material, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 6-methyl-5-(trifluoromethyl)pyridin-2-amine (710 mg). MS (ESI) M / Z: 177.0 [M+H + ].

[0563] 6-Methyl-5-(trifluoromethyl)pyridin-2-amine (710 mg, 4.03 mmol) was dissolved in acetonitrile (8 ml), N-bromosuccinimide (861.7 mg, 4.84 mmol) was added, and the mixture was stirred overnight at room temperature. After LCMS monitoring confirmed the disappearance of the starting material, aqueous sodium thiosulfate (20 ml) was added, followed by extraction twice with ethyl acetate (40 ml). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-amine (880 mg). MS (ESI) M / Z: 254.7 [M+H + ].

[0564] 3-Bromo-6-methyl-5-(trifluoromethyl)pyridin-2-amine (580 mg, 2.28 mmol) was dissolved in bromoform (4 mL), liquid bromine (301 mg, 1.9 mmol) was added, and tert-butyl nitrite (500 mg, 4.74 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. After LCMS monitoring confirmed the disappearance of the starting material, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2,3-dibromo-6-methyl-5-(trifluoromethyl)pyridine (280 mg). 1 H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 2.66 (s, 3H). C7H5BrF3NO.

[0565] 2,3-Dibromo-6-methyl-5-(trifluoromethyl)pyridine (280 mg, 0.92 mmol), 3-fluoro-5-methoxy-2,6-dimethylaniline (155 mg, 0.92 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (48 mg, 0.083 mmol), cesium carbonate (748 mg, 2.3 mmol), and tris(dibenzylideneacetone)dipalladium (42 mg, 0.046 mmol) were added to ethylene glycol dimethyl ether (15 mL), the mixture was purged with nitrogen gas three times, and the mixture was reacted at 90°C overnight. After LCMS monitoring confirmed that the raw materials had disappeared, water (30 ml) was added, and the mixture was extracted twice with ethyl acetate (20 ml). The organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine (40 mg). MS (ESI) M / Z: 407.0 [M+H + ].

[0566] Malononitrile (20 mg, 0.3 mmol) was dissolved in dioxane (5 ml), sodium tert-butoxide (50 mg, 0.5 mmol) was added, the mixture was purged with nitrogen gas, and the reaction was carried out at room temperature for 30 minutes. 3-Bromo-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine (40 mg, 0.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.15 mg, 0.01 mmol) were added, the mixture was purged with nitrogen gas, and the reaction was carried out at 120°C for 3 hours. After LCMS monitoring confirmed that the raw material had disappeared, water (10 ml) was added and extracted twice with ethyl acetate (20 ml). The organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (40 mg). MS (ESI) M / Z: 393.2 [M+H + ].

[0567] 2-Amino-1-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (40 mg, 0.102 mmol) was dissolved in sulfuric acid / water (0.15 ml), methylsulfonic acid (400 mg, 3.78 mmol) was added, and the mixture was reacted at room temperature for 1.5 hours. Methionine (61 mg, 0.41 mmol) was then added, and the mixture was reacted at 40°C overnight. After LCMS monitoring confirmed that the raw materials had disappeared, the mixture was cooled, and the pH was adjusted to neutral with sodium hydroxide and dipotassium hydrogen phosphate aqueous solution. The mixture was extracted with ethyl acetate (20 ml x 2). The organic phase was dried and concentrated to dryness to obtain the crude product. The crude product was prepared as 2-amino-1-(3-fluoro-5-hydroxy-2,6-dimethylphenyl)-6-methyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (2.27 mg). MS (ESI) M / Z: 397.0 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.28 (s, 1H), 7.18 (s, 2H), 6.96 (s, 2H), 6.83 (d, J = 11.1 Hz, 1H), 2.46 (s, 3H), 1.65 (d, J = 16.0 Hz, 6H).

[0568] Example 189

[0569] [ka]

[0570] Reaction Pathway:

[0571] [ka]

[0572] 5-Bromoisoquinolin-8-amine (5.0 g, 22.4 mmol), methylboronic acid (4.0 g, 67.2 mmol), and potassium carbonate (9.27 g, 67.2 mmol) were dissolved in dioxane (100 mL) and water (10 mL). [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (900 mg, 1.1 mmol) was added. The atmosphere was purged with nitrogen gas three times, and the reaction mixture was stirred at 100 °C overnight. After TLC monitoring confirmed the disappearance of the starting material, water (100 mL) was added, followed by extraction with ethyl acetate (100 mL) twice. The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-methylisoquinolin-8-amine (3.5 g). MS (ESI) M / Z: 158.7 [M+H + ].

[0573] 5-Methylisoquinolin-8-amine (3.5 g, 27.2 mmol) was dissolved in acetonitrile (80 ml) and N-bromosuccinimide (4.85 g, 27.2 mmol) was added. The reaction was stirred overnight at room temperature. After TLC monitoring confirmed the disappearance of the raw materials, water (100 ml) was added and the mixture was extracted twice with ethyl acetate (100 ml). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7-bromo-5-methylisoquinolin-8-amine (3.2 g). MS (ESI) M / Z: 237.2 [M+H + ]. 1 C 10 H9BrN2.

[0574] 7-Bromo-5-methylisoquinolin-8-amine (1.5 g, 6.3 mmol) was dissolved in hydrochloric acid (37%, 7 ml) and water (1.8 ml), cooled to -15°C, and an aqueous solution (8.4 ml) of sodium nitrite (480 mg, 6.9 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 30 minutes at 0°C. The above reaction solution was slowly added dropwise to an aqueous solution (84 ml) of potassium iodide (9.4 g, 56.7 mmol). After the addition was complete, the mixture was stirred at room temperature overnight. After TLC monitoring confirmed that the raw materials had disappeared, the mixture was cooled, and saturated sodium sulfite solution (30 ml) and saturated sodium bicarbonate solution (30 ml) were added to quench the reaction. The mixture was extracted with dichloromethane (50 ml × 2). The organic phase was washed with brine, dried over sodium sulfate, and concentrated to dryness to obtain a crude product. Finally, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 7-bromo-8-chloro-5-methylisoquinoline (1.1 g). 1 H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 8.65 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 5.9 Hz, 1H), 7.62 (s, 1H), 2.65 (s, 3H).

[0575] 7-Bromo-8-chloro-5-methylisoquinoline (1.1 g, 4.26 mmol), 3-methoxy-2,6-dimethylaniline (600 mg, 4.26 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (240 mg, 0.43 mmol), and cesium carbonate (3.4 g, 10.6 mmol) were dissolved in toluene (22 mL), and tris(dibenzylideneacetone)dipalladium (180 mg, 0.2 mmol) was added. The reaction mixture was purged with nitrogen gas three times and reacted at 100°C overnight. After TLC monitoring confirmed that the raw materials had disappeared, the mixture was cooled, water (50 ml) was added, and the mixture was extracted with ethyl acetate (20 ml × 2). The organic phase was washed with brine, dried with sodium sulfate, and concentrated to dryness to obtain a crude product. Finally, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 8-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methylisoquinolin-7-amine (1.3 g). MS (ESI) M / Z: 327.39 [M+H + ].

[0576] Malononitrile (728.83 mg, 11.04 mmol) was dissolved in N,N-dimethylformamide (15 ml), sodium tert-butoxide (1.59 g, 16.56 mmol) was added, the mixture was purged with nitrogen gas, and the reaction was carried out at room temperature for 30 minutes. 8-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methylisoquinolin-7-amine (900 mg, 2.76 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (225 mg, 0.28 mmol) were added, the mixture was purged with nitrogen gas, and the reaction was carried out at 130°C for 3 hours. After LCMS monitoring confirmed that the raw materials had disappeared, water (30 ml) was added and extracted twice with ethyl acetate (20 ml). The organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl-7H-pyrrolo[2,3-h]isoquinoline-9-carbonitrile (420 mg). MS (ESI) M / Z: 357.39 [M+H + ].

[0577] 8-Amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl-7H-pyrrolo[2,3-h]isoquinoline-9-carbonitrile (420 mg, 1.18 mmol) was dissolved in sulfuric acid (5 mL) and reacted at room temperature for 1 hour. After TLC monitoring confirmed the disappearance of the raw material, the mixture was cooled, the pH was adjusted to neutral with aqueous sodium hydroxide, and extracted with ethyl acetate (30 mL x 2). The organic phase was dried and concentrated to dryness to obtain the crude product, which was finally concentrated under reduced pressure to obtain 8-amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl-7H-pyrrolo[2,3-h]isoquinoline-9-carboxamide (500 mg).

[0578] 8-Amino-7-(3-methoxy-2,6-dimethylphenyl)-5-methyl-7H-pyrrolo[2,3-h]isoquinoline-9-carboxamide (500 mg, 1.37 mmol) was dissolved in dichloromethane (20 mL) and 2 M boron tribromide in dichloromethane (4 mL, 8.0 mmol) was added. The mixture was stirred overnight at room temperature. After LCMS monitoring confirmed the disappearance of the starting material, aqueous sodium bicarbonate (50 mL) was slowly added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and finally concentrated under reduced pressure to give 8-amino-7-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-7H-pyrrolo[2,3-h]isoquinoline-9-carboxamide (3.36 + 52.84 mg). MS (ESI) M / Z: 361.44 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.26 - 8.16 (m, 2H), 8.15 (s, 1H), 7.76 (d, J = 5.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.93 (s, 2H), 6.53 (s, 2H), 2.67 (s, 3H), 1.77 (s, 3H), 1.68 (s, 3H).

[0579] The preparation of the following compounds is based on the preparation methods of the above examples.

[0580] [Table 1] TIFF2025538617000157.tif237169TIFF2025538617000158.tif211169TIFF2025538617000159.tif237169TIFF2025538617000160.tif216169TIFF2025538617000161.tif224169TIFF2025538617000162.tif218169TIFF2025538617000163.tif237169TIFF2025538617000164.tif234169TIFF2025538617000165.tif231169TIFF2025538617000166.tif211169TIFF2025538617000167.tif237169TIFF2025538617000168.tif237169TIFF2025538617000169.tif236169TIFF2025538617000170.tif237169TIFF2025538617000171.tif231169TIFF2025538617000172.tif230169TIFF2025538617000173.tif237169TIFF2025538617000174.tif230169TIFF2025538617000175.tif224169TIFF2025538617000176.tif237169TIFF2025538617000177.tif227169JPEG2025538617000178.jpg237169JPEG2025538617000179.jpg237169JPEG2025538617000180.jpg211169JPEG2025538617000181.jpg237169JPEG2025538617000182.jpg237169JPEG2025538617000183.jpg237169JPEG2025538617000184.jpg237169JPEG2025538617000185.jpg238169JPEG2025538617000186.jpg218169JPEG2025538617000187.jpg230169JPEG2025538617000188.jpg237169JPEG2025538617000189.jpg237169JPEG2025538617000190.jpg235169JPEG2025538617000191.jpg211169JPEG2025538617000192.jpg237169JPEG2025538617000193.jpg237169JPEG2025538617000194.jpg237169JPEG2025538617000195.jpg237169JPEG2025538617000196.jpg237169JPEG2025538617000197.jpg230169JPEG2025538617000198.jpg224169JPEG2025538617000199.jpg238169JPEG2025538617000200.jpg218169JPEG2025538617000201.jpg205169JPEG2025538617000202.jpg237169JPEG2025538617000203.jpg230169JPEG2025538617000204.jpg224169JPEG2025538617000205.jpg230169JPEG2025538617000206.jpg237169JPEG2025538617000207.jpg237169JPEG2025538617000208.jpg218169JPEG2025538617000209.jpg237169JPEG2025538617000210.jpg238169JPEG2025538617000211.jpg224169JPEG2025538617000212.jpg237169JPEG2025538617000213.jpg211169JPEG2025538617000214.jpg237169JPEG2025538617000215.jpg237169JPEG2025538617000216.jpg237169JPEG2025538617000217.jpg237169JPEG2025538617000218.jpg211169JPEG2025538617000219.jpg219169JPEG2025538617000220.jpg237169JPEG2025538617000221.jpg216169JPEG2025538617000222.jpg237169JPEG2025538617000223.jpg229169JPEG2025538617000224.jpg237169JPEG2025538617000225.jpg230169JPEG2025538617000226.jpg205169.

[0581] Biological activity test method: Biological Test Example 1. Enzyme Inhibitory Activity of Compounds of the Present Disclosure The ADP-GLO method was used to verify the enzymatic activity of some example compounds.

[0582] Test materials: PKMYT1 enzyme protein was purchased from Thermo Scientific (product number: A33387), and ADP-GLO kit was purchased from Promega (product number: V9103).

[0583] PKMYT1 enzyme activity reaction buffer: 70 mM HEPES, 3 mM MgCl2, 3 mM MnCl2, 50 μg mL-1 PEG20000, 3 μM sodium orthovanadate, 1.2 mM DTT.

[0584] Experimental steps: Using an ultramicropipette, test compounds (3.33 mM, dissolved in DMSO) were diluted to a starting concentration of 10 μM and serially diluted in a 1:3 ratio over a 10-point gradient (10,000 nM, 3,333 nM, 1,111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1.5 nM, 0.5 nM) and added to a 384-well reaction plate. Two replicate wells were set up for each concentration, and 16 wells were set up for positive and negative controls. The positive control consisted of a replicate well of 1 μM positive compound, and the negative control consisted of a replicate well of DMSO. The reaction plate containing the compounds was centrifuged at 2500 rpm for 1 minute.

[0585] The prepared enzyme solution was added to each well of the reaction plate at 5 μL, resulting in a final enzyme concentration of 10 nM. The plate was centrifuged at 1,000 rpm for 1 minute, and then incubated in a 37°C incubator for 15 minutes.

[0586] 5 μL of the prepared ATP substrate solution was added to the reaction plate to give a final ATP concentration of 5 μM. The plate was centrifuged at 1000 rpm for 1 minute. The plate was sealed with aluminum foil and incubated in a 37°C incubator for 90 minutes.

[0587] 10uL of ADP-glo (商標) The kinase reaction was stopped by adding a reagent to consume the unused ATP, leaving only ADP and a very low background ATP. The plate was then centrifuged at 1000 rpm for 1 minute. The plate was then sealed with aluminum foil and incubated at room temperature for 60 minutes.

[0588] 20 μL of kinase detection reagent was added to convert ADP to ATP, and luciferase and luciferin were introduced to detect ATP. The plate was centrifuged at 1000 rpm for 1 minute. The plate was sealed with aluminum foil and incubated at room temperature for 60 minutes.

[0589] ADP-GLO luminescence signal values ​​were read using a PHERAstar microplate reader and analyzed. The mean percent inhibition of the positive control replicate wells was set to 100% relative inhibition, and the mean percent inhibition of the negative control replicate wells was set to 0% relative inhibition. ADP-GLO readings were converted to relative inhibition and the IC values ​​of compounds were calculated using a four-parameter model. 50 was fitted.

[0590] Test Results: The compounds were shown to have good enzyme inhibitory activity, and the specific results can be seen in Table 1.

[0591] [Table 2] JPEG2025538617000228.jpg236169JPEG2025538617000229.jpg177169

[0592] " / " indicates not tested or low activity.

[0593] Biological Test Example 2. Cell Inhibitory Activity of Compounds of the Present Disclosure The CTG assay (HCC1569) was used to verify the biological activity of some example compounds of the present disclosure.

[0594] Test materials: HCC1569 cells were purchased from ATCC (product number: CRL-2330) and cultured in a cell incubator at 37°C with 5% CO. HCC1569 complete medium: RPMI-1640 liquid medium (product number: Gibico 11875-093), 20% FBS (product number: Gibico 10099-141), 1% Pen-Strep (product number: Gibico 15070-063).

[0595] Test compound: A compound of the Examples of the present disclosure.

[0596] Experimental steps: 75cm 2 HCC1569 cells in a culture flask were digested with 2 mL of trypsin for 2-3 minutes and then neutralized with 2 mL of 1640 complete medium. The cells were centrifuged at 1200 rpm for 5 minutes. The cells were resuspended in 4 mL of 1640 complete medium. 500 μl of the cell suspension was collected and counted using a Vi-CELL-XR cell counter.

[0597] Using a Multidrop apparatus, 1000 HCC1569 cells (50uL of 1640 Growth Media) were seeded per well of a 384-well plate, and drugs were added 24 hours later.

[0598] Using an ultra-micropipette, test compounds (concentration: 3.33 mM, dissolved in DMSO) were diluted to a maximum starting concentration of 10 μM, and then serially diluted in a 1:3 ratio with a gradient of 10 (10000 nM, 3333 nM, 1111 nM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.6 nM, 1.5 nM, 0.5 nM). Drugs were added, and two replicate wells were set up for each concentration. 14 wells were set up for positive and negative controls, with the positive control being a replicate well of 10 μM positive compound and the negative control being a replicate well of DMSO.

[0599] After adding the drugs, the cells were placed in a 37°C incubator and continued to be cultured for 5 days. After 5 days, 25 μL of CTG buffer was added to each well for CTG assay detection, and the plate was read and analyzed using a microplate reader. The CTG readings were analyzed. The average inhibition rate of the positive control replicate wells was set to 100% relative inhibition rate, and the average inhibition rate of the negative control replicate wells was set to 0% relative inhibition rate. The CTG readings were converted to relative inhibition rates, and the inhibition rates (inhibition%) of various concentrations of the test compounds against the cells were calculated according to the following formula: Inhibition %=(bx) / (ba)*100%; a = CTG value (highest concentration), b = CTG value (blank well), x = CTG value (test well value).

[0600] IC using GraphPad PRISM 8 50 The calculation was carried out.

[0601] (1) The corresponding concentrations and inhibition rates for 10,000 nm, 3,333 nm, 1,111 nm, 370 nm, 123 nm, 41 nm, 13.7 nm, 4.6 nm, 1.5 nm, and 0.5 nM were statistically calculated. Statistical calculations were performed using Log10 (A compound concentration). (2) Data was entered into GraphPad PRISM 8 and Analysis was selected. (3) Nonlinear regression (curve fit) was selected. (4) Log (inhibitor) vs. response - Variable slope was selected. (5) A calculation formula was selected and calculated according to the following formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50-X) * HillSlope)), where X is the logarithm of the dose or concentration, Y is the response value, and Top and Bottom are the peak and bottom values. (6) Data was fitted to obtain the IC 50 (7) The fitting conditions were adjusted according to the specific conditions of the data. Appropriate constraint conditions were adjusted for Bottom, Top, and Hillslope. A curve that best matched the actual situation was obtained.

[0602] The experimental results show that the compounds have good cell inhibitory activity, and the specific results can be seen in Table 2.

[0603] [Table 3]

[0604] IC of compounds of the present disclosure against cells 50 was preferably less than 1 μM, preferably less than 0.5 μM, preferably less than 0.1 μM, preferably less than 0.05 μM, more preferably less than 0.02 μM.

[0605] Biological Test Example 3: Study on metabolic stability of compounds in mouse liver microsomes LC / MS / MS was used to detect the concentration of the parent drug in the incubation system, calculate the intrinsic clearance of the test compound in the microsome system, and evaluate its stability. The test concentration of the test compound and positive control compound was 1 μM.

[0606] 1.25 μl of NADPH (10 mmol) or phosphate-buffered saline (100 mmol, pH 7.4) was transferred to the liver microsome incubation system, and 2 μl of the test substance or verapamil at a concentration of 200 μmol was added. For samples with added NADPH, two parallel preparations were performed, and for NADPH-negative samples, one parallel preparation was performed.

[0607] 2. 30 μl of the suspension was collected at 0.5, 5, 15, 30, and 60 minutes, respectively. The reaction was stopped by adding 180 μl of acetonitrile containing an internal standard, and vortexed for 10 minutes.

[0608] 3. The plate was then centrifuged at 3220 g for 20 minutes to precipitate the proteins. The plate was placed in a refrigerator at 4°C for 30 minutes and centrifuged again at 3220 g for 20 minutes. 100 μl of the supernatant was transferred to a sample plate, and 100 μl of pure water was added and mixed uniformly. The plate was then used for UPLC-MS / MS analysis.

[0609] 4. All data calculations were performed through Microsoft Excel software. Peak areas were detected by extracting ion spectra. The in vitro half-life (t 1 / 2 ) was determined by linearly fitting the natural logarithm of the elimination rate of the parent drug with time.

[0610] In vitro half-life (t 1 / 2 ) was calculated from the slope: in vitro t 1 / 2 =0.693 / k Extracorporeal clearance Cl int (Unit: μl / min / mg) Calculation: in vitro C Lint= kV / N; V = culture volume per well (400 μl); V = culture volume per well (400 μl). The specific results are shown in Table 3.

[0611] Positive control: RP-6306, the structure of which is shown below:

[0612] [ka]

[0613] [Table 4]

[0614] Conclusion: Compared to RP-6306, compounds of the present disclosure have significantly longer half-lives, slower clearance, and better metabolic stability.

[0615] Biological Test Example 4 Tissue Distribution of Compounds of the Present Disclosure OVCAR3 tumor cells (ATCC, product number HTB-161) were cultured in RPMI 1640 medium containing 20% ​​inactivated fetal bovine serum, 0.01 mg / mL insulin, and 1% penicillin and streptomycin double antibody. Cultures were performed in an incubator at 37°C with 5% CO2. The medium was changed every other day, and the cells were subcultured every 3–4 days until complete proliferation. Under sterile conditions, a suspension of ex vivo-cultured OVCAR3 cells was collected, centrifuged, and added to a cell concentration of 1 × 10 8 The tumor volume was adjusted to 100 cells / mL, an equal volume of Matrigel was added, and the mixture was subcutaneously inoculated into the dorsum of the right hind leg of mice (BALB / c nude mice, female, Beijing Vital River Laboratory Animal Technology Co., Ltd.) (0.1 mL / mouse). At 31 days after inoculation, the mean tumor volume was 100–150 mm. 3 The mice were randomly assigned to groups based on tumor size and body weight, and treatment with the test compound was initiated.

[0616] The experiment was divided into a vehicle control group, a positive control group, and a test group, with 5-6 mice in each group. The specific experimental protocol and administration frequency for each group are shown in the table below. In the test compound administration group, the test compound was mixed with 0.5% methylcellulose and administered intragastrically twice daily. The experiment was terminated 28 days after administration, and PK plasma (EDTA-K2 anticoagulant) samples were collected (0.5, 1, 2, and 6 hours after administration). The mice were euthanized 2 and 6 hours after the final administration, and tumor samples were collected.

[0617] Tumor Concentration Test Method: All tumor samples were added to pure water in a ratio of 1:3 (3 mL of solvent was added per 1 g of tumor) and pulverized using a freeze homogenizer to obtain tumor sample solutions.

[0618] How to prepare the standard curve: A series of working solutions of test compound powders were prepared by gradient dilution using 50% acetonitrile in water. 3 μL of each working solution (10, 20, 40, 100, 200, 1000, 2000, 10,000, and 20,000 ng / mL) was added to 57 μL of blank Balb / c nude mouse tumor sample solution to obtain calibration standard solutions ranging from 0.5 to 1,000 ng / mL. The concentrations were 0.5, 1, 2, 5, 10, 50, 100, 500, and 1,000 ng / mL, respectively, in a total volume of 60 μL.

[0619] Quality controls were prepared in the same manner as the calibration standards: 3 μL of working solution (30, 60, 120, 1000, 8000, 16000 ng / mL) was taken and added to 57 μL of blank Balb / c nude mouse tumor sample solution to obtain six quality control samples, with concentrations of 1.5 ng / mL, 3 ng / mL, 6 ng / mL, 50 ng / mL, 400 ng / mL, and 800 ng / mL, respectively, in a total volume of 60 μL.

[0620] 30 μL of each sample (including standard solutions, quality control samples, and test samples) was taken, and 200 μL of acetonitrile-containing protein precipitant was added to precipitate the proteins. After vortexing for 30 seconds, the sample was centrifuged at 3900 rpm at 4°C for 15 minutes. The supernatant was aspirated and diluted 3-fold with water. 5 μL of the diluted supernatant was collected and loaded onto the LC / MS / MS system for quantitative analysis.

[0621] [Table 5]

[0622] The experimental results are shown in Table 4.

[0623] [Table 6]

[0624] The above experimental results showed that the tumor tissue concentrations of the compound of the present disclosure 2 hours and 6 hours after administration were significantly superior to those of the positive drug, indicating that the compound of the present disclosure potentially has superior antitumor activity.

[0625] Biological Test Example 5 Metabolic Stability of Compounds of the Present Disclosure in Human Hepatocytes Several 96-well sample precipitation plates were prepared, labeled T0, T15, T30, T60, T90, T120, T240, T0-MC, T240-MC, and blank matrix. The recovery medium and culture medium were removed and placed in a 37°C water bath for preheating. Frozen hepatocytes were removed from the liquid nitrogen tank and immediately immersed in a 37°C water bath (approximately 90 seconds). After thawing and loosening, the plates were poured into centrifuge tubes containing 40 mL of recovery medium and gently inverted to resuspend the cells in the recovery medium. The plates were centrifuged at 100 × g for 5 minutes at room temperature, the supernatant removed, and the hepatocytes resuspended in an appropriate amount of culture medium. Cell viability was calculated using trypan blue staining. 198 μL of hepatocyte suspension (0.51 × 10 cells / mL) was added to the pre-warmed culture plate, and 198 μL of culture medium without hepatocytes was added to the T0-MC and T120-MC culture plates for the medium control group. All culture plates were pre-incubated in a 37°C incubator for 10 minutes.

[0626] 2 μL of the working solution of the test substance and control compound was added and mixed evenly. The culture plate was placed on the shaker of the incubator and the timer was started to initiate the reaction. Two replicate samples were prepared for each compound at each time point. The incubation conditions were 37°C, saturated humidity, and 5% CO2.

[0627] In the test reaction system, the final concentration of the test substance was 1 μM, the final concentration of the control substance was 3 μM, the final concentration of hepatocytes was 0.5 × 10 cells / mL, the final concentration of total organic solvents was 0.96%, of which the final concentration of DMSO was 0.1%. At the end of the corresponding incubation time, the culture plates were removed, and 25 μL of the mixture of compound and control compound with cells was added to a sample plate containing 125 μL of stop solution (acetonitrile solution containing 200 ng / mL tolbutamide and labetalol). For a blank sample plate, 25 μL of culture medium without hepatocytes was directly added. All sample plates were sealed and shaken on a shaker at 600 rpm for 10 minutes, followed by centrifugation at 3220 × g for 20 minutes. The supernatants of the test substance and control substance were diluted 1:3 with ultrapure water. All samples were mixed homogeneously and analyzed using an LC / MS / MS method.

[0628] The experimental results are shown in Table 5.

[0629] [Table 7]

[0630] The results of this initial experiment showed that there was a significant gender difference in the metabolism of RP-6306 in human hepatocytes in vitro, with the metabolic stability of male hepatocytes being significantly lower than that of female hepatocytes. In contrast, the compounds in this initial study showed no gender difference in the metabolic stability of human hepatocytes in vitro, and all had good stability, reducing the risk that gender-related factors may affect the efficacy and safety of the drug and enabling easier clinical application.

[0631] Experimental Example 1: TS-FeSSIF & TS-FeSSGF solubility test 1. Production of FeSSIF Preparation of buffer solution B: 4.040 g of sodium hydroxide, 8.650 g of glacial acetic acid, and 11.874 g of sodium chloride were dissolved in approximately 900 ml of ultrapure water, and the pH of the solution was adjusted to 5.0 with 1 mol / L sodium hydroxide or 1 mol / L hydrochloric acid. The solution was then diluted to 1000 mol with ultrapure water at room temperature.

[0632] Powder addition: 11. 200 g of FaSSIF, FeSSIF, and FaSSGF powders were added to approximately 500 ml of Buffer B. Stir until the powder was completely dissolved. The solution was then diluted to 1000 ml with Buffer B at room temperature.

[0633] Preparation for use: Use within 48 hours at room temperature, or within 24 hours at 37°C.

[0634] 2. Preparation of FeSSGF Preparation of Buffer D: 1.220 g of sodium acetate, 0.514 g of glacial acetic acid, and 6.926 g of sodium chloride were dissolved in approximately 500 ml of ultrapure water.

[0635] Mixing with milk: Mix with milk in equal parts (1:1), and adjust the pH of the solution to 5.0 with 1 mol / L hydrochloric acid.

[0636] Preparation for use: Use within 48 hours at room temperature, or within 24 hours at 37°C.

[0637] 3. Solubility measurement: Stock solutions of the test compounds and control compounds were prepared in DMSO (Solarbio S&T Co., LTD) at a concentration of 10 mmol / L.

[0638] First, 50 μL of each sample stock solution (10 mmol / L) was added to an uncapped vial in the solubility sample plate. This test was performed in duplicate. Next, the DMSO was evaporated using a centrifugal vacuum evaporator. 500 μL of buffer was added to each sample to dissolve it. A stir bar was placed in each vial and sealed with a PTFE / silicone stopper. The sample plate was then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 1100 rpm at 25°C for 24 hours. After this, the stir bar was removed using a large magnet, and the samples were transferred from the solubility sample plate to a filter plate. The supernatant was centrifuged at 4000 rpm for 30 minutes at 25°C. A 350 μL aliquot was transferred from the supernatant. The tip was placed in acetonitrile for 5 seconds, then in water for 5 seconds. The first 25 μL was discarded, and 300 μL was dispensed into another 96-bottle glass insert plate and centrifuged again (4000 rpm, 25°C, 30 minutes). Aliquots of 5 μl and 5 μl of DMSO were removed from the supernatant and 490 μl of a mixture of water and acetonitrile containing the internal standard (1:1) was added. Depending on the peak shape, the dilution was diluted with a predetermined proportion of ultrapure water. The dilution factor was varied based on the solubility value and LC-MS signal response.

[0639] 50 μL of each sample stock solution (10 mmol / L) was added to an uncapped vial of the solubility sample plate. This test was performed in duplicate. DMSO was then evaporated using a centrifugal vacuum evaporator. 500 μL of DMSO was added to dissolve the samples. Each vial was fitted with a stir bar and sealed with a molded PTFE / silicone plug. The solubility sample plate was then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 25°C and 1100 rpm for 2 hours. After 2 hours, each compound was completely dissolved. A 10 μL aliquot was taken and 10 μL of a mixture of water and acetonitrile containing 990 μL of the internal standard (1:1) was added. The concentration of the standard sample may vary based on the LC / MS signal response.

[0640] All calculations were performed using Microsoft Excel. Samples were analyzed and quantified based on standards of known concentration using LC / MS / MS. The solubility of the test compound was calculated according to the following formula: [Sample] = (Area ratio Sample ×DF Sample ×[STD]) / Area ratio STD , DF represents the dilution factor.

[0641] The experimental results are shown in Table 6.

[0642] [Table 8]

[0643] The compounds of the present disclosure have good solubility, which is beneficial for systemic absorption and subsequent formulation development.

Claims

1. A compound represented by general formula (I), a pharmaceutically acceptable salt thereof or an isomer thereof: 【Chemistry 1】 (however, X １ is N or CR ５ is selected from X ２ is N or CR ６ is selected from X ３ is N or CR ７ is selected from X ４ is N or CR ８ is selected from X ５ is selected from N or C; X ６ is selected from N or C; X ７ is selected from N or C; The condition is X ２ But, CR ６ and X ５ is selected from C, and X ６ is selected from N, and X ７ is selected from C, then X ３ and X ４ At the same time, it is not CH, R １ and R ２ are each independently a halogen, C １－４ Alkyl, C １－４ Alkoxy, hydroxy C １－４ Alkyl or deuterated C １－４ alkyl, R ３ is -H, -CN, -OH, -N(R ａ ) (R ｂ ), halogen, C １－４ Alkyl, haloC １－４ Alkyl, C １－４ Alkoxy, C ２－４ Alkenyl, C ２－４ Alkynyl, -L-R ｃ , phenyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, deuterated C １－４ alkyl, or 5-6 membered heteroaryl, wherein said phenyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, and 5- to 6-membered heteroaryl may optionally be one or more R ３ａ and R ３ａ is a halogen, C １－４ Alkyl, or C １－４ alkoxy; L is C ２－４ Alkynylene, C １－４ Alkylene, or C ２－４ alkenylene; R ｃ is C １－４ Alkyl, C ３－６ cycloalkyl, or 4- to 6-membered heterocyclyl, １－４ Alkyl, C ３－６ Cycloalkyl and 4- to 6-membered heterocyclyl optionally have one or more R ｃａ and R ｃａ is selected from halogen or —OH; R ａ and R ｂ are each independently —H, C １－４ Alkyl, phenyl, p-methoxybenzyl, C １－４ Alkyl-C(O)-, C ３－６ Cycloalkyl or haloC １－４ alkyl, or R ａ , R ｂ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl optionally substituted by halogen; R ４ is -H, halogen, C １－４ Alkyl, C ３－６ Cycloalkyl, C １－４ Alkoxy or haloC １－４ alkyl, R ５ , R ７ and R ８ are each independently —H, —OH, —CN, or —N(R ｄ ) (R ｅ ), halogen, C １－４ Alkyl, C １－４ Alkoxy or haloC １－４ alkyl, R ６ is -H, -OH, -CN, -N(R ｄ ) (R ｅ ), halogen, C １－４ Alkyl, C １－４ Alkoxy, —COOH, HaloC １－４ Alkyl, haloC １－４ Alkoxy, C ２－４ Alkenyl, C ２－４ Alkynyl, C １－４ Alkyl-S(O) ２ -, hydroxy C １－４ Alkyl, C ３－６ Cycloalkyl, C ５－６ Cycloalkenyl, C ３－６ Cycloalkyl-C １－４ Alkyl, C ３－６ cycloalkyl-O-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, phenyl, 5- to 6-membered heteroaryl, or -CD ３ wherein said C １－４ Alkyl, C ３－６ Cycloalkyl, C ５－６ Cycloalkenyl, C ３－６ Cycloalkyl-C １－４ Alkyl, C ３－６ Cycloalkyl-O-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, phenyl, and 5- to 6-membered heteroaryl may optionally be substituted with one or more R ６ａ and R ６ａ is a halogen, C １－４ Alkyl, haloC １－４ Alkyl, or C １－４ alkoxy; R ｄ and R ｅ are each independently —H, C １－４ Alkyl, —S(O) ２ -N(R ｆ ) (R ｇ ), —C(O)-aryl, —C(O)—NR ｆ -aryl, or -(C=S)-NR ｆ -aryl, R ｆ and R ｇ are each independently —H or C １－４ alkyl, Or, R ２ , R ８ are C together with the atoms to which they are connected. ５－６ forming a cycloalkenyl, and / or R ３ , R ６ together with the atom to which they are attached represent phenyl, 5- to 6-membered heterocycloalkenyl, C ５－６ forming a cycloalkenyl or a 5- to 6-membered heteroaryl; and / or R ４ , R ６ together with the atom to which they are attached represent phenyl, 5- to 6-membered heterocycloalkenyl, C ５－６ forming a cycloalkenyl or a 5- to 6-membered heteroaryl; The phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkenyl and C ５－６ Cycloalkenyl is optionally substituted with halogen, CN, C １－６ Alkyl, haloC １－６ Alkyl, hydroxy C １－６ Alkyl, C １－６ Alkoxy, and C １－６ and alkyl-C(O)-.

2. X １ is CR ５ is selected from X ２ is selected from N, and X ５ is selected from C, and X ６ is selected from N, and X ７ is selected from C, its pharmaceutically acceptable salt or its isomer.

3. X １ , X ２ are all selected from N, and X ５ is selected from C, and X ６ is selected from N, and X ７ is selected from C, its pharmaceutically acceptable salt or its isomer.

4. R １ , R ２ are each independently —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -Cl, -F, -Br, -OCH ３ , -CH ２ OH or -CD ３ is selected from Preferably, R １ , R ２ are both -CH ３ or -CD ３ The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or an isomer thereof, selected from:

5. R ３ is -H, -CN, -NH ２ , -F, -Br, -Cl, -CH ３ , -CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -CF ３ , -OCH ３ , -OCH ２ CH ３ , -CH=CH ２ , -N(CH ３ ) ２ , -N(CH ２ CH ３ ) ２ , -NHPMB, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 【Chemistry 2】 エチニル、-C≡C-R ｃ 、-OH、-CH(CH ３ ) ２ 、-CH ２ CH ２ CH ３ 、-CH ２ CH(CH ３ ) ２ 、-OCH ３ 、-CH ２ F、-CHF ２ 、-CH=CH ２ 、-CH=C(CH ３ ) ２ 、-CH=CHCH ３ 、-C(CH ３ )=CH ２ 、-NHCH ３ 、-NHCH ２ CH ３ 、-NHC(O)CH ３ 、 【Transformation 3】 or -CD ３ and R ｃ optionally one or more R ｃａ is selected from the following groups: methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, oxetanyl, or azetidinyl, substituted by R ｃａ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or isomer thereof, wherein is selected from -F, -Cl, or -OH.

6. -C≡C-R ｃ is -C≡C-CH ３ , 【Chemistry 4】 The compound according to claim 5, or a pharmaceutically acceptable salt thereof, or an isomer thereof, selected from:

7. R ４ is -H, -Cl, -F, -Br, -CH ３ , -CH ２ CH ３ , cyclopropyl, methoxy, or —CH ２ CF ３ is selected from Preferably, R ４ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or isomer thereof, wherein

8. R ５ is -H, -Cl, -F, -CH ３ , -CN, -CF ３ , or -OCH ３ The compound according to any one of claims 1 to 2 and 4 to 7, or a pharmaceutically acceptable salt or isomer thereof, selected from:

9. R ７ and R ８ are each independently —H, —OH, —CN, or —NH ２ , -F, -Br, -Cl, -CH ３ , -CH ２ CH ３ , -OCH ３ , or -OCH ２ CH ３ is selected from Preferably, R ７ and R ８ are each independently selected from H or F, or a pharmaceutically acceptable salt or isomer thereof according to any one of claims 1 to 8.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or isomer thereof, selected from structures represented by the following general formula: 【Transformation 5】 (X １ , X ２ , R １ , R ２ , R ３ , R ４ , R ５ , R ７ and R ８ is as defined in any one of claims 1 to 9.

11. X １ is selected from N, and X ２ is CR ６ is selected from X ５ is selected from C, and X ６ is selected from N, and X ７ is selected from C, and X ３ is N or CR ７ is selected from X ４ is N or CR ８ and X ３ , X ４ and are not simultaneously CH, or a pharmaceutically acceptable salt or isomer thereof according to any one of claims 1 and 4 to 9.

12. R １ , R ２ are each independently —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -Cl, -F, -Br, -OCH ３ , -CH ２ OH or -CD ３ Preferably, R １ , R ２ are both -CH ３ or -CD ３ is selected from R ３ は、-CH ３ 、-NH ２ 、-OH、-F、-Cl、-Br、-CH(CH ３ ) ２ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ 、-CH ２ CH(CH ３ ) ２ 、-OCH ３ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH=CH ２ 、-CH=C(CH ３ ) ２ 、-CH=CHCH ３ 、-C(CH ３ )=CH ２ 、-NHCH ３ 、-NHCH ２ CH ３ 、-NHC(O)CH ３ 、 【Transformation 6】 or -CD ３ is selected from R ４ is -H, -Cl, -F, -Br, -CH ３ , -CH ２ CH ３ , cyclopropyl, or —CH ２ CF ３ is selected from R ６ は、-CH ３ 、-H、-OH、-C-、-D、-B2、-COOH、-CN、-CH ２ CH ３ ,-EH(EH ３ ) ２ 、-CH ２ HH(H) ３ ) ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CF ２ CH ３ 、-CF(CH ３ ) ２ ,-OCH ３ ,-OCH(CH ３ ) ２ 、-OCF ３ ,-OCH ２ CF ３ 、-N(CH ３ ) ２ 、-EH=EH ２ 、-C(CH ３ )=CH ２ 、-C≡CH、-S(O) ２ CH ３ 、 【Transformation 7】 -CH ２ CH ２ CH=CH ２ , -CH ２ OH, -CH ２ CF ３ , or -CD ３ is selected from X ３ is N or CR ７ is selected from X ４ is N or CR ８ is selected from R ７ and R ８ are each independently —H, —OH, —CN, or —NH ２ , -CH ３ , -CH ２ CH ３ , -Cl, -F, -Br, -OCH ３ , or -OCH ２ CH ３ and R ７ and R ８ At the same time, it is not H, Or, R ２ , R ８ are C together with the atoms to which they are connected. ５－６ The compound according to claim 11, its pharmaceutically acceptable salt or its isomer, which forms a cycloalkenyl.

13. X ３ is CR ７ is selected from X ４ is CR ８ is selected from R １ and R ２ is C １－４ Alkyl or deuterated C １－４ alkyl, preferably R １ , R ２ is -CH ３ or -CD ３ is selected from R ３ is C １－４ alkyl, preferably R ３ is -CH ３ or -CH ２ CH ３ is selected from R ４ is selected from —H; R ６ is halogen or haloC １－４ alkyl, preferably R ６ is —Cl, —Br, or —CF ３ is selected from R ７ and R ８ are each independently selected from —H or halogen, and R ７ and R ８ is not simultaneously hydrogen, preferably R ７ and R ８ are each independently selected from —H or F, and R ７ and R ８ and is not simultaneously hydrogen, a pharmaceutically acceptable salt thereof, or an isomer thereof, according to claim 11.

14. R １ and R ２ are each independently —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -Cl, -F, -Br, -OCH ３ , -CH ２ OH or -CD ３ Preferably, R １ and R ２ are both -CH ３ , or -CD ３ is selected from R ３ and R ６ together with the atoms to which they are attached form the following groups: 【Transformation 8】 Forming R ４ is -H, -Cl, -F, -Br, -CH ３ , -CH ２ CH ３ or cyclopropyl; X ３ is N or CR ７ is selected from X ４ is N or CR ８ is selected from R ７ and R ８ are each independently —H, —OH, —CN, or —NH ２ , -CH ３ , -CH ２ CH ３ , -Cl, -F, -Br, -OCH ３ , or -OCH ２ CH ３ 12. The compound of claim 11, a pharmaceutically acceptable salt thereof, or an isomer thereof, selected from:

15. R １ and R ２ are each independently —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -Cl, -F, -Br, -OCH ３ , -CH ２ OH or -CD ３ Preferably, R １ and R ２ are both -CH ３ , or -CD ３ is selected from R ３ is -H, -CH ３ , or -CH ２ CH ３ is selected from R ４ , R ６ together with the atoms to which they are attached form the following groups: 【Chemistry 9】 Forming X ３ is N or CR ７ is selected from X ４ is N or CR ８ is selected from R ７ and R ８ are each independently —H, —OH, —CN, or —NH ２ , -CH ３ , -CH ２ CH ３ , -Cl, -F, -Br, -OCH ３ , or -OCH ２ CH ３ 12. The compound of claim 11, a pharmaceutically acceptable salt thereof, or an isomer thereof, selected from:

16. 16. The compound according to any one of claims 1 and 11 to 15, having a structure as shown in any one of the following formulas, a pharmaceutically acceptable salt thereof, or an isomer thereof. 【Chemistry 10】 (Ring A is phenyl, 5- to 6-membered heterocycloalkenyl, C ５－６ cycloalkenyl, or 5- to 6-membered heteroaryl, wherein the phenyl, 5- to 6-membered heterocycloalkenyl, C ５－６ Cycloalkenyl and 5- to 6-membered heteroaryl are substituted with halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, hydroxy C １－６ Alkyl, C １－６ Alkoxy, and C １－６ alkyl-C(O)—; However, X ３ , X ４ , R １ , R ２ , R ３ , R ４ , R ６ , X ３ , X ４ , R ７ and R ８ is as defined in any one of claims 1 and 11 to 15.

17. A compound represented by general formula (II), a pharmaceutically acceptable salt thereof or an isomer thereof: 【Chemistry 11】 (X １ is N or CR ５ is selected from X ３ is N or CR ７ is selected from X ４ is N or CR ８ is selected from R １ and R ２ are each independently a halogen, C １－４ Alkyl, C １－４ Alkoxy, hydroxy C １－４ Alkyl or deuterated C １－４ alkyl, R ３ is -CN, -OH, -N(R ａ ) (R ｂ ), halogen, C １－４ Alkyl, haloC １－４ Alkyl, C １－４ Alkoxy, C ２－４ Alkenyl, C ２－４ Alkynyl, -L-R ｃ , phenyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, deuterated C １－４ alkyl, or 5-6 membered heteroaryl, wherein said phenyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkenyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocycloalkenyl, and 5- to 6-membered heteroaryl may optionally be one or more R ３ａ and R ３ａ is a halogen, C １－４ Alkyl, or C １－４ alkoxy; L is C ２－４ Alkynylene, C １－４ Alkylene, or C ２－４ alkenylene; R ｃ is C １－４ Alkyl, C ３－６ cycloalkyl, or 4- to 6-membered heterocyclyl, １－４ Alkyl, C ３－６ Cycloalkyl and 4- to 6-membered heterocyclyl optionally have one or more R ｃａ and R ｃａ is selected from halogen or —OH; R ａ and R ｂ are each independently —H, C １－４ Alkyl, phenyl, p-methoxybenzyl, C １－４ Alkyl-C(O)-, C ３－６ Cycloalkyl or haloC １－４ alkyl, or R ａ , R ｂ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl optionally substituted by halogen; R ４ , R ６ together with the atom to which they are attached represent phenyl, 5- to 6-membered heterocycloalkenyl, C ５－６ cycloalkenyl, or 5- to 6-membered heteroaryl, and the phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkenyl, and C ５－６ Cycloalkenyl is optionally substituted with halogen, CN, C １－６ Alkyl, haloC １－６ Alkyl, hydroxy C １－６ Alkyl, C １－６ Alkoxy, and C １－６ further substituted by one or more substituents selected from alkyl-C(O)—; R ５ , R ７ and R ８ are each independently —H, —OH, —CN, or —N(R ｄ ) (R ｅ ), halogen, C １－４ Alkyl, C １－４ Alkoxy or haloC １－４ alkyl.)

18. R １ and R ２ are each independently —CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -Cl, -F, -Br, -OCH ３ , -CH ２ OH or -CD ３ is selected from R ３ is -CH ３ , -CH ２ CH ３ and R ４ , R ６ together with the atoms to which they are attached form the following groups: 【Chemistry 12】 Forming R ５ -H, -CN, haloC １－３ selected from alkyl or halogen; R ７ and R ８ are each independently —H, —OH, —CN, or —NH ２ , -CH ３ , -CH ２ CH ３ , -Cl, -F, -Br, -OCH ３ , or -OCH ２ CH ３ 18. The compound of claim 17, a pharmaceutically acceptable salt thereof, or an isomer thereof, selected from:

19. X １ is CR ５ is selected from X ３ is CR ７ is selected from X ４ is CR ８ is selected from R １ and R ２ are each independently C １－４ alkyl, preferably —CH ３ and R ３ is C １－４ alkyl, preferably —CH ３ and R ４ , R ６ together with the atom to which they are attached form a 5-6 membered heteroaryl, preferably pyridyl, more preferably 【Chemistry 13】 and R ５ is selected from —H or halogen, preferably H or F, more preferably H; R ７ and R ８ are each independently selected from —H, or a pharmaceutically acceptable salt or isomer thereof according to claim 17 or 18.

20. The compound according to any one of claims 17 to 19, having a structure represented by any one of the following formulas, its pharmaceutically acceptable salt, or its isomer. 【Chemistry 14】 (each ring B is independently phenyl, 5- to 6-membered heterocycloalkenyl, C ５－６ cycloalkenyl, or 5- to 6-membered heteroaryl, wherein the phenyl, 5- to 6-membered heterocycloalkenyl, C ５－６ Cycloalkenyl and 5- to 6-membered heteroaryl are optionally substituted with halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, hydroxy C １－６ Alkyl, and C １－６ further substituted by one or more substituents selected from alkoxy; However, R ３ , R ４ , R ５ , R ６ , X ３ , X ４ , R ７ and R ８ is as defined in any one of claims 17 to 19.

21. X １ is selected from N, and X ５ is selected from N, and X ２ is CR ６ is selected from X ６ is selected from C, and X ７ The compound according to any one of claims 1 and 4 to 9, or a pharmaceutically acceptable salt or isomer thereof, wherein

22. X １ is selected from N, and X ２ is CR ６ is selected from X ５ is selected from C, and X ６ is selected from C, and X ７ The compound according to any one of claims 1 and 4 to 9, or a pharmaceutically acceptable salt or isomer thereof, wherein:

23. R １ and R ２ are each independently —CH ３ , -CH ２ CH ３ , or -CH(CH ３ ) ２ Preferably, R １ and R ２ are both -CH ３ is selected from R ３ is -CH ３ is selected from R ４ is selected from —H; R ６ is -CH ３ is selected from X ３ is N or CR ７ is selected from X ４ is N or CR ８ is selected from R ７ and R ８ are each independently —H, —OH, —CN, or —NH ２ , -CH ３ , -CH ２ CH ３ , -Cl, -F, -OCH ３ , or -OCH ２ CH ３ is selected from Or, R ２ , R ８ are C together with the atoms to which they are connected. ５－６ 23. The compound according to claim 21 or 22, a pharmaceutically acceptable salt thereof or an isomer thereof, which forms a cycloalkenyl.

24. The compound according to any one of claims 21 to 23, having a structure shown in any one of the following formulas, its pharmaceutically acceptable salt, or its isomer. 【Chemistry 15】 (However, R １ , R ２ , R ３ , R ４ , R ６ , X ３ , X ４ is as defined in any one of claims 21 to 23.

25. The compound, its pharmaceutically acceptable salt or its isomer, selected from any one of the following structures: 【Chemistry 16】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt thereof or an isomer thereof, and one or more pharmaceutically acceptable carriers.

27. Use of a compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt thereof or an isomer thereof in the manufacture of a medicament used for the prevention and / or treatment of a tumor disease mediated by PKMYT1, preferably a tumor disease caused by CCNE1 overexpression and / or FBXW7 inactivating mutations.

28. 1. A method for treating a neoplastic disease mediated by PKMYT1, comprising: A method comprising administering to a subject a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 25, its pharmaceutically acceptable salt or its isomer, wherein the PKMYT1-mediated neoplastic disease is preferably a neoplastic disease caused by CCNE1 overexpression and / or FBXW7-inactivating mutation.

29. 29. The use of claim 27 or the method of claim 28, wherein the neoplastic disease is selected from one or more of ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, endometrial cancer, and colorectal cancer.

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