Indole-containing macrocyclic compounds and their use

Abstract

The present invention provides indole-containing macrocyclic compounds and uses thereof, and in particular relates to a compound represented by formula (II) or a pharma- ceutically acceptable salt thereof. JPEG2025506367000095.jpg8296

Description

[Technical Field]

[0001] This application claims the following priority: CN202210108561.8, the filing date is January 28, 2022. The application number is CN202210476398.0, and the filing date is April 29, 2022. CN202210667398.9, the filing date is June 13, 2022. The application number is CN202210894289.0, and the filing date is July 27, 2022. The present invention discloses indole-containing macrocyclic compounds and their uses, specifically, compounds represented by formula (II) or pharmaceutically acceptable salts thereof. [Background technology]

[0002] The cell cycle generally refers to the continuous dynamic process that a continuously dividing cell undergoes from the end of one mitotic division to the end of the next. The mammalian cell cycle consists of four phases: G1 phase (prophase), S phase (phase of DNA synthesis), G2 phase (phase of DNA synthesis), and M phase (phase of mitosis). After the M phase, cytokinesis occurs, forming two daughter cells. The new cells produced after cell cycle division re-enter the cell cycle, but at a specific point in the late G1 phase (called the limit point or R point), the cell cycle regulatory mechanism determines the cell's final fate: whether to continue participating in the cell cycle cycle or to terminate the active proliferation state and enter the arrest (G0) state. Cell cycle regulation is primarily influenced by a series of serine / threonine kinases, also known as cyclin-dependent kinases (CDKs), which bind to their corresponding regulatory subunits, cyclins, to achieve the purpose of regulating the cell cycle.

[0003] Abnormal proliferation of cancer cells and dysregulation of the normal cell cycle are common features of all types of cancer. For this reason, inhibitors of key cell cycle regulators have emerged as attractive new antitumor targets. CDK7 is an important member of the CDKs family, also known as CDKs activating kinase (CAK). CDK7 regulates the cell cycle primarily in two indirect ways. Firstly, the CDK7-cyclin H binary complex or the CDK7-cyclin H-MAT1 ternary complex is activated by phosphorylation to produce active CAKs, which further phosphorylate threonine residues in the active regions of CDK(1,2,3,4,6) to activate their activity and induce cell cycle initiation, progression, and termination. Secondly, the phosphorylated CDK7-cyclin H-MAT1 complex promotes promoter removal and induces transcription initiation by phosphorylating the carboxyl-terminal domain (CTD) large subunit of RNA polymerase II (RNAP II). Furthermore, the CDK7-cyclin H-MAT1 complex is also a subunit component of transcription factor IIH (TFIIH) and is involved in type II transcription and nucleotide cleavage repair. From this, it can be seen that inhibiting the phosphorylation of the active region of CDK7 can inhibit its role in cell cycle regulation, not only blocking the main roles of CDK(1, 2, 3, 4, 6) in the cell cycle but also affecting the transcription process and achieving the goal of inhibiting tumor cell proliferation. Based on the important regulatory role of CDK7 in the cell cycle and transcription, designing CDK7 inhibitors with novel skeletal structures that target CDK7 has become one of the hot spots in the field of anti-tumor drug research.

[0004] Currently, several CDK7 small molecule inhibitors are entering the clinical research stage for cancer treatment. Examples include Syros Pharmaceuticals' SY-5609 and CT-7001. Such CDK7 inhibitors can not only inhibit the activation of the CDK protein but also inhibit the phosphorylation of the C-terminal domain of RNA polymerase II, thereby affecting transcriptional regulation.

[0005] Although many efforts have been made to develop CDK7 inhibitors for the treatment of cancer and other diseases, drugs targeting this have not been commercially available so far. Among the varieties under development, SY-5609 has very high activity but a low maximum clinical tolerance, while CT-7001 has good in vitro activity but low metabolic stability, limiting further development of the drug. Therefore, the development of new, safer and more effective CDK7 inhibitors that can treat various cancers (including breast cancer) remains an urgent situation.

Summary of the Invention

[0006] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

[0007]

Chemical formula

[0008] <000042​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Selected from alkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 and C 3-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 R groups. R c and R d C 1-3 Alkyl and OC 1-3 Selected from alkyl groups, or R c , R d Together with the P atoms linked to them, they form a 4-6 member heterocycloalkyl group, and the -OC 1-3 Alkyl, C 1-3 Alkyl and 4-6 member heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R groups. X is selected from O and S. L1 is -CH2-, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)- are selected, L2 consists of -CH2-, -O-, and -NR e - Selected from, R e H and C 1-3 Selected from alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 R groups. R2 and R3 are independently H and C 1-3 Alkyl and C 2-4 Selected from alkenyls, or R2, R3 together with the C atom linked to them, C 3-6 Forming a cycloalkyl or 3-6 member heterocycloalkyl, the C 1-3 Alkyl, C 2-4 Alkenil, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R groups. R4 is C 1-3 Selected from haloalkyl, CN, F, Cl, Br, and I, R is independently selected from F, Cl, Br, NH2, and CN. n is selected from 0, 1, 2, 3, 4, and 5. m and q are independently selected from 1 and 2. t is selected from 0, 1, 2, and 3.

[0009] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0010] [ka]

[0011] however, R1 is H, CN, F, Cl, Br, I, C 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, S(O) m R a P(X)R c R d , C(O)R a , S(O) m NR a R b and C(O)NR a R b Selected from, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 R groups. R a C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 and C 3-6 Selected from cycloalkyl, R b H and C 1-3 Selected from alkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 and C 3-6The cycloalkyl is optionally substituted by one, two or three Rs, R c and R d are independently selected from C 1-3 alkyl and OC 1-3 alkyl, or R c , R d together with the P atom to which they are attached form a 4- to 6-membered heterocycloalkyl, wherein the -OC 1-3 alkyl, C 1-3 alkyl and 4- to 6-membered heterocycloalkyl are optionally substituted by one, two or three Rs, X is selected from O and S, L1 is selected from -CH2-, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)-, L2 is selected from -CH2-, -O- and -NR e -, R e is selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one, two or three Rs, R2 and R3 are each independently selected from H, C 1-3 alkyl and C 2-4 alkenyl, or R2, R3 together with the C atom to which they are attached form C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, and the C 1-3 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by one, two or three Rs, R4 is selected from C 1-3 haloalkyl, CN, F, Cl, Br and I, R is independently selected from F, Cl, Br, NH2 and CN, n is selected from 0, 1, 2, 3, 4 and 5, m and q are independently selected from 1 and 2.

[0012] In some technical solutions of the present invention, R1 is selected from H, and the other variables are as defined in the present invention.

[0013] In some technical solutions of the present invention, R1 is selected from CN, and the other variables are as defined in the present invention.

[0014] In some technical solutions of the present invention, R1 is selected from F, and the other variables are as defined in the present invention.

[0015] In some technical solutions of the present invention, R1 is selected from Cl, and the other variables are as defined in the present invention.

[0016] In some technical solutions of the present invention, R1 is selected from Br, and the other variables are as defined in the present invention.

[0017] In some technical solutions of the present invention, R1 is C 1-3 Selected from alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 R groups, and the other variables are as defined in this invention.

[0018] In some technical solutions of the present invention, R1 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2Cl, CHCl2, and CCl3, and the other variables are as defined in the present invention.

[0019] In some technical solutions of the present invention, the above R1 is -OC 1-3 Selected from alkyl, the -OC 1-3 The alkyl group is optionally substituted with 1, 2, or 3 R groups, and the other variables are as defined in this invention.

[0020] In some technical solutions of the present invention, R1 is selected from -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, and -OCCl3, and the other variables are as defined in the present invention.

[0021] In some technical solutions of the present invention, R1 is C 3-6 Selected from cycloalkyl, the C 3-6 Cycloalkyls are

[0022] [ka]

[0023] Selected from the above,

[0024] [ka]

[0025] This can be optionally replaced by one, two, or three Rs.

[0026] In some technical solutions of the present invention, R1 is S(O) m R a Selected from, the S(O) m R a teeth,

[0027] [ka]

[0028] The variables are selected from the above, and the other variables are as defined in this invention.

[0029] In some technical solutions of the present invention, R1 is S(O) m NR a R b Selected from, the S(O) m NR a Rb teeth,

[0030] [ka]

[0031] The variables are selected from the above, and the other variables are as defined in this invention.

[0032] In some technical solutions of the present invention, R1 is P(X)R c R d Selected from, the P(X)R c R d teeth,

[0033] [ka]

[0034] X1 is selected from CH2, O, and NH, p is selected from 0 and 1, r is selected from 0 and 1, and the other variables are as defined in this invention.

[0035] In some technical solutions of the present invention, the above

[0036] [ka]

[0037] teeth,

[0038] [ka]

[0039] The variables are selected from the above, and the other variables are as defined in this invention.

[0040] In some technical solutions of the present invention, the above R1 is

[0041] [ka]

[0042] The variables are selected from the above, and the other variables are as defined in this invention.

[0043] In some technical solutions of the present invention, R1 is C(O)R a Selected from, the C(O)R a teeth,

[0044] [ka]

[0045] The variables are selected from the above, and the other variables are as defined in this invention.

[0046] In some technical solutions of the present invention, R1 is C(O)NR a R b Selected from, the C(O)NR a R b teeth,

[0047] [ka]

[0048] The variables are selected from the above, and the other variables are as defined in this invention.

[0049] In some technical solutions of the present invention, the above R1 is

[0050] [ka]

[0051] The variables are selected from the above, and the other variables are as defined in this invention.

[0052] In some technical solutions of the present invention, R2 and R3 are independently selected from H, methyl, ethyl, n-propyl, and isopropyl, or R2 and R3, together with the C atom linked to them, form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the other variables are as defined in the present invention.

[0053] In some technical solutions of the present invention, R2 and R3 are independently selected from H and methyl, respectively, and the other variables are as defined in the present invention.

[0054] In some technical solutions of the present invention, R2 and R3, together with the C atoms linked to them, form a cyclopropyl group, and the other variables are as defined in the present invention.

[0055] In some technical solutions of the present invention, L1 is -CH2-, -O-, -NR e -, -C(O)-, -S(O)-, -S(O)2-, and -P(O)- are selected, and the other variables are as defined in this invention.

[0056] In some technical solutions of the present invention, the above structural unit

[0057] [ka]

[0058] The variables are selected from the above, and the other variables are as defined in this invention.

[0059] In some technical solutions of the present invention, the above structural unit

[0060] [ka]

[0061] teeth,

[0062] [ka]

[0063] The variables are selected from the above, and the other variables are as defined in this invention.

[0064] In some technical solutions of the present invention, the above structural unit

[0065] [ka]

[0066] teeth,

[0067] [ka]

[0068] The variables are selected from the above, and the other variables are as defined in this invention.

[0069] In some technical solutions of the present invention, the above structural unit

[0070] [ka]

[0071] teeth,

[0072] [ka]

[0073] The variables are selected from the above, and the other variables are as defined in this invention.

[0074] In some technical solutions of the present invention, the compounds are represented by formulas (I-1), (I-2), and (II-1),

[0075] [ka]

[0076] Other variables are as defined in this invention.

[0077] In some technical solutions of the present invention, the compounds are represented by formulas (II-1-1) and (II-1-2),

[0078] [ka]

[0079] Other variables are as defined in this invention.

[0080] In some technical solutions of the present invention, the above R e The element is selected from hydrogen, methyl, ethyl, and propyl, and the other variables are as defined in this invention.

[0081] The present invention provides a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof.

[0082] [ka]

[0083] however,

[0084] [ka]

[0085] It is selected from single bonds and double bonds, R1 is H, CN, F, Cl, Br, I, C 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, S(O) m R a P(X)R c R d , C(O)R a , S(O) m NRa R b and C(O)NR a R b Selected from, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 R groups. R a C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 and C 3-6 Selected from cycloalkyl, R b H and C 1-3 Selected from alkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 and C 3-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 R groups. R c and R d C 1-3 Alkyl and OC 1-3 Selected from alkyl groups, or R c , R d Together with the P atoms linked to them, they form a 4-6 member heterocycloalkyl group, and the -OC 1-3 Alkyl, C 1-3 Alkyl and 4-6 member heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R groups. X is selected from O and S. L1 is -CH2-, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)- are selected, L2 is either absent, or -CH2-, -O-, and -NR e - Selected from, R e H and C 1-3 Selected from alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 R groups. R2 and R3 are independently H and C 1-3 Alkyl and C 2-4 Selected from alkenyls, or R2, R3 together with the C atom linked to them, C 3-6 Forming a cycloalkyl or 3-6 member heterocycloalkyl, the C 1-3 Alkyl, C 2-4 Alkenil, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R groups. R4 is C 1-3 Selected from haloalkyl, CN, F, Cl, Br, and I, R is independently selected from F, Cl, Br, NH2, and CN. n is selected from 1, 2, and 3. t is selected from 0, 1, 2, and 3. m and q are independently selected from 0, 1, and 2.

[0086] The present invention provides a compound represented by formula (IB) or a pharmaceutically acceptable salt thereof.

[0087] [ka]

[0088] however,

[0089] [ka]

[0090] It is selected from single bonds and double bonds, R1 is H, CN, F, Cl, Br, I, C 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, S(O) m R a P(X)R c R d , C(O)R a , S(O)m NR a R b and C(O)NR a R b Selected from, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 R groups. R a C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 and C 3-6 Selected from cycloalkyl, R b H and C 1-3 Selected from alkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2 and C 3-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 R groups. R c and R d C 1-3 Alkyl and OC 1-3 Selected from alkyl groups, or R c , R d Together with the P atoms linked to them, they form a 4-6 member heterocycloalkyl group, and the -OC 1-3 Alkyl, C 1-3 Alkyl and 4-6 member heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R groups. X is selected from O and S. L1 is -CH2-, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)- are selected, L2 is either absent, or -CH2-, -O-, and -NR e - Selected from, R e H and C 1-3 Selected from alkyl, the C 1-3The alkyl group is optionally substituted with 1, 2, or 3 R groups. R2 and R3 are independently H and C 1-3 Alkyl and C 2-4 Selected from alkenyls, or R2 and R3 together with the atoms linked to them form a 3-6 member heterocycloalkyl group, and the C 1-3 Alkyl, C 2-4 Alkenyls and 3-6 membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R groups. R4 is C 1-3 Selected from haloalkyl, CN, F, Cl, Br, and I, R is independently selected from F, Cl, Br, NH2, and CN. n is selected from 1, 2, and 3. t is selected from 0, 1, 2, and 3. m and q are independently selected from 0, 1, and 2.

[0091] In some technical solutions of the present invention, R1 is selected from H, and the other variables are as defined in the present invention.

[0092] In some technical solutions of the present invention, R1 is selected from CN, and the other variables are as defined in the present invention.

[0093] In some technical solutions of the present invention, R1 is selected from F, and the other variables are as defined in the present invention.

[0094] In some technical solutions of the present invention, R1 is selected from Cl, and the other variables are as defined in the present invention.

[0095] In some technical solutions of the present invention, R1 is selected from Br, and the other variables are as defined in the present invention.

[0096] In some technical solutions of the present invention, R1 is C 1-3 Selected from alkyl, the C 1-3The alkyl group is optionally substituted with 1, 2, or 3 R groups, and the other variables are as defined in this invention.

[0097] In some technical solutions of the present invention, R1 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2F, CHF2, CF3, CH2Cl, CHCl2, and CCl3, and the other variables are as defined in the present invention.

[0098] In some technical solutions of the present invention, the above R1 is -OC 1-3 Selected from alkyl, the -OC 1-3 The alkyl group is optionally substituted with 1, 2, or 3 R groups, and the other variables are as defined in this invention.

[0099] In some technical solutions of the present invention, R1 is selected from -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, and -OCCl3, and the other variables are as defined in the present invention.

[0100] In some technical solutions of the present invention, R1 is C 3-6 Selected from cycloalkyl, the C 3-6 Cycloalkyls are

[0101] [ka]

[0102] Selected from the above,

[0103] [ka]

[0104] This can be optionally replaced by one, two, or three Rs.

[0105] In some technical solutions of the present invention, the above R1 is S(O) m R a selected from, and the S(O) m R a is

[0106]

Chemical formula

[0107] selected from, and other variables are as defined in the present invention.

[0108] In some technical solutions of the present invention, the above R1 is S(O) m NR a R b selected from, and the S(O) m NR a R b is

[0109]

Chemical formula

[0110] selected from, and other variables are as defined in the present invention.

[0111] In some technical solutions of the present invention, the above R1 is P(X)R c R d selected from, and the P(X)R c R d is

[0112]

Chemical formula

[0114] In some technical solutions of the present invention, the above

[0115] [ka]

[0116] The variables are selected from the above, and the other variables are as defined in this invention.

[0117] In some technical solutions of the present invention, the above R1 is

[0118] [ka]

[0119] The variables are selected from the above, and the other variables are as defined in this invention.

[0120] In some technical solutions of the present invention, R1 is C(O)R a Selected from, the C(O)R a teeth,

[0121] [ka]

[0122] The variables are selected from the above, and the other variables are as defined in this invention.

[0123] In some technical solutions of the present invention, R1 is C(O)NR a R b Selected from, the C(O)NR a R b teeth,

[0124] [ka]

[0125] The variables are selected from the above, and the other variables are as defined in this invention.

[0126] In some technical solutions of the present invention, the above R1 is

[0127]

Chem.

[0128] selected from, and other variables are as defined in the present invention.

[0129] In some technical solutions of the present invention, R2 and R3 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, or R2 and R3 together with the C atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and other variables are as defined in the present invention.

[0130] In some technical solutions of the present invention, R2 and R3 are each independently selected from H and methyl, and other variables are as defined in the present invention.

[0131] ]>In some technical solutions of the present invention, R2 and R3 together with the C atom to which they are attached form cyclopropyl, and other variables are as defined in the present invention.

[0132] In some technical solutions of the present invention, L1 is selected from -CH2-, -O-, -NR e -, -C(O)-, -S(O)-, -S(O)2- and -P(O)-, and other variables are as defined in the present invention.

[0133] In some technical solutions of the present invention, the above structural unit

[0134]

Chem.

[0135] selected from, and other variables are as defined in the present invention.

[0136] [[ID=A8]] In some technical solutions of the present invention, the above structural unit

[0137] [ka]

[0138] teeth,

[0139] [ka]

[0140] The variables are selected from the above, and the other variables are as defined in this invention.

[0141] In some technical solutions of the present invention, the above structural unit

[0142] [ka]

[0143] teeth,

[0144] [ka]

[0145] The variables are selected from the above, and the other variables are as defined in this invention.

[0146] In some technical solutions of the present invention, the compounds are represented by formulas (IA-1) and (IA-2),

[0147] [ka]

[0148] Other variables are as defined in this invention.

[0149] In some technical solutions of the present invention, the compounds are represented by formulas (IA-3) and (IA-4),

[0150] [ka]

[0151] Other variables are as defined in this invention.

[0152] In some technical solutions of the present invention, n=1 and t=0, and the other variables are as defined in the present invention.

[0153] In some technical solutions of the present invention, n=1 and t=1, and the other variables are as defined in the present invention.

[0154] In some technical solutions of the present invention, n=1 and t=2, and the other variables are as defined in the present invention.

[0155] In some technical solutions of the present invention, n=2 and t=0, and the other variables are as defined in the present invention.

[0156] In some technical solutions of the present invention, n=2, t=1, and other variables are as defined in the present invention.

[0157] In some technical solutions of the present invention, n=2 and t=2, and the other variables are as defined in the present invention.

[0158] Some other technical solutions of the present invention are formed by arbitrarily combining the above variables.

[0159] The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof.

[0160] [ka]

[0161] The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof.

[0162] [ka]

[0163] [ka]

[0164] The present invention further provides the use of compounds limited by any of the above technical solutions or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for treating CDK7-related diseases.

[0165] In some technical solutions of the present invention, the above-mentioned CDK7-related disease refers to breast cancer, and the other variables are as defined in the present invention.

[0166] A second aspect of the present invention further provides a pharmaceutical composition comprising a compound limited by any of the above technical solutions or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0167] The present invention further provides a method for treating a CDK7-related disease in a subject of interest, comprising providing a therapeutically effective amount of a compound limited by any of the above technical solutions, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0168] The present invention further provides the use of the above-mentioned compound, its isomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a pharmacopoeia for the treatment of diseases related to CDK7.

[0169] In some technical solutions of the present invention, the disease associated with CDK7 refers to breast cancer, and the other variables are as defined in the present invention.

[0170] Effects of the invention The compounds of the present invention have potent inhibitory activity against CDK7, excellent kinase selectivity, and exhibit excellent in vivo efficacy in a triple-negative breast HCC70 model with primary resistance to CDK4 / 6 inhibitors. They can be used to treat diseases such as CDK4 / 6 inhibitor-resistant HR+Her2- breast cancer and triple-negative breast cancer.

[0171] [Definitions and explanations] Unless otherwise specified, the following terms and phrases used herein have the following meanings. Unless otherwise specifically defined, any particular term or phrase should be understood as having its ordinary definition, not as uncertain or ambiguous. When a trade name is mentioned herein, it refers to the corresponding product or its active ingredient.

[0172] As used herein, “pharmaceutically acceptable salts” refers to those compounds, materials, compositions and / or dosage forms that are within the bounds of reliable medical judgment, suitable for contact with human and animal tissues, with little toxicity, irritation, allergic reaction or other problems or complications, and that meet a reasonable benefit / risk ratio.

[0173] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared with a relatively non-toxic acid or base of a compound having a specific substituent discovered in the present invention. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting these compounds with a sufficient amount of base in a single solution or a suitable inert solvent. pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting these compounds with a sufficient amount of acid in a single solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (e.g., arginine) and organic acids such as glucuronic acid. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate ions, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate ions, hydroiodic acid, and phosphorous acid. The organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Some specific compounds of the present invention contain basic and acidic functional groups and can therefore be converted into any base addition salt or acid addition salt.

[0174] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional methods from a parent compound containing an acidic or basic group. Typically, such salts are produced by reacting these compounds, in the form of a free acid or base, with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof.

[0175] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention envisions all such compounds and includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures containing a large amount of enantiomers or non-enantiomers, all of which are within the scope of the present invention. Other chiral carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are within the scope of the present invention.

[0176] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0177] Unless otherwise explained, the terms "cis-trans isomer" or "geometric isomer" refer to the inability of the double bond or the single bond of the ring-forming carbon atoms to rotate freely.

[0178] Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules are non-mirror images of each other.

[0179] Unless otherwise specified, "(+)" indicates dextrorotatory properties, "(-)" indicates levorotatory properties, and "(±)" indicates a racemic mixture.

[0180] [ka]

[0181] Unless otherwise specified, the term "tautomer" or "tautomer form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly convert to each other. Tautomers can reach chemical equilibrium if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers pentan-2,4-dione and 4-hydroxypento-3-en-2-one.

[0182] Unless otherwise specified, the terms “rich in one isomer,” “isomer-rich,” “rich in one enantiomer,” or “enantiomer-rich” mean that the content of one isomer or enantiomer is less than 100%, and that the content of this isomer or enantiomer is 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or higher.

[0183] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, the isomer or enantiomer excess (ee value) is 80%.

[0184] Optically active (R)- and (S)- isomers, as well as D and L isomers, can be produced by asymmetric synthesis, chiral reagents, or other conventional techniques. To obtain one enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or by induction with a chiral auxiliary agent, where the resulting diastereomer mixture is separated and the auxiliary groups are decomposed to provide the required isolated enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a salt of the diastereomer is formed with a suitable optically active acid or base, and then the diastereomer is divided by a conventional method known in the art, recovered, and isolated enantiomer is obtained. Furthermore, the separation of enantiomers and diastereomers is usually performed by chromatography, using a chiral stationary phase and in combination with any chemical induction method (e.g., producing a carbamate from an amine).

[0185] The compounds of the present invention may contain one or more unnatural atomic isotopes among the atoms constituting the compound. For example, tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14 Compounds can be labeled with radioactive isotopes such as C). Furthermore, for example, deuterium can be substituted with hydrogen to form deuterated drugs. The bond formed between deuterium and carbon is stronger than the bond formed between ordinary hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, improved therapeutic effects, and extended biological half-life. The conversion of the isotopic composition of the compounds of this invention is included within the scope of this invention, whether radioactive or not.

[0186] "Optional" or "at will" means that it is possible depending on the matters or circumstances described below, but it does not necessarily occur, and the description includes cases where the matters or circumstances described therein do not occur.

[0187] The term "substituted" refers to the substitution of one or more hydrogen atoms in a particular atom with a substituent. The substituent may include deuterium and hydrogen variants, provided that the specific valence state is normal and the substituted compound is stable. If the substituent is a keto group (i.e., =O), it means that two hydrogen atoms have been substituted. Keto group substitution does not occur in aromatic groups.

[0188] The term "optionally substituted" means that substitution may or may not occur, and unless otherwise defined, the type and number of substituents are arbitrary as long as they can be chemically stable.

[0189] If any of the variables (e.g., R) appear once or more in the composition or structure of a compound, their definitions are independent in each case. Therefore, for example, if one group is substituted with 0 to 2 R atoms, that group can be substituted with any number of R atoms (2 or fewer), and in each case, R atoms are independently chosen. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0190] When the number of linking groups is 0, for example, -(CRR)0-, it means that the linking group is a single bond.

[0191] If one of the variables is a single bond, the two groups connected by it are directly linked. For example, if L in ALZ represents a single bond, this structure is actually AZ.

[0192] The absence of a substituent indicates that the substituent does not exist; for example, the absence of X in AX indicates that the structure is actually A. If it is not specified which atom the substituent is substituted through for a given substituent, such substituents can be bonded through any of its atoms; for example, a pyridinyl group as a substituent may be bonded through any carbon atom of the pyridine ring.

[0193] If a listed linking group does not specify other linking directions, the linking direction is arbitrary, for example,

[0194] [ka]

[0195] The linking group L in this case is -MW-, and in this case, -MW- forms rings A and B in the same direction as the reading order from left to right.

[0196] [ka]

[0197] It is possible to construct rings A and B in the reverse order of reading from left to right.

[0198] [ka]

[0199] It is also possible. The above combinations of linking groups, substituents, and / or variants thereof are permitted only if they result in a stable compound.

[0200] Unless otherwise specified, if a group has one or more bondable sites, any one or more sites of that group can be bonded to other groups by chemical bonds. If the bonding mode of the chemical bond is delocalized and hydrogen atoms are present at the bondable sites, when a chemical bond is formed, the number of hydrogen atoms at those sites decreases to a group with a corresponding valency in proportion to the number of chemical bonds formed. The chemical bond formed when such sites bond to other groups is:

[0201] [ka]

[0202] This can be represented as follows. For example, a linear solid bond in -OCH3 means that the group is bonded to another group via the oxygen atom of that group.

[0203] [ka]

[0204] The dashed lines in the diagram indicate that both ends of the nitrogen atom within that group are bonded to other groups.

[0205] [ka]

[0206] The wavy lines inside indicate that the phenyl group is bonded to another group via carbon atoms at sites 1 and 2.

[0207] [ka]

[0208] This means that any bondable site of the piperidinyl group can be bonded to another group by one chemical bond, at least

[0209] [ka]

[0210] It includes these four bonding forms, and even if the H atom is depicted as -N-,

[0211] [ka]

[0212] for

[0213] [ka]

[0214] Although this group contains a bond configuration, when one chemical bond is connected, the number of hydrogen atoms at that site decreases by one, resulting in the corresponding monovalent piperidine group.

[0215] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members. For example, a "5- to 7-membered ring" refers to a "ring" of 5 to 7 atoms arranged around it.

[0216] Unless otherwise defined, the term "C 1-3 "Alkyl" refers to a saturated hydrocarbon group composed of 1 to 3 carbon atoms in a straight or branched chain. 1-3 Alkyl contains C 1-2 and C 2-3 Alkyl compounds may be monovalent (e.g., methyl), divalent (e.g., methylene), and polyvalent (e.g., methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), and propyl (including n-propyl and isopropyl).

[0217] Unless otherwise defined, the term "C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the rest of the molecule via an oxygen atom. 1-3 The alkoxy group is C 1-2 , C 2-3 This includes C3 and C2 alkoxys. 1-3 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, and propoxy (including n-propoxy or isopropoxy).

[0218] Unless otherwise defined, the term "C 1-3 "Haloalkyl" refers to monohaloalkyl and polyhaloalkyl groups containing 1 to 3 carbon atoms. 1-3 Haloalkyl is C 1-2 , C 2-3 This includes C3, C2, and C1 haloalkyls. 1-3Examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, and 3-bromopropyl.

[0219] Unless otherwise defined, "C 2-4 "Alkenyl" represents a hydrocarbon group consisting of 2 to 4 carbon atoms, including at least one carbon-carbon double bond in a straight or branched chain, and the carbon-carbon double bond may be at any position in the group. 2-4 Alkenil is C 2-3 , containing C4, C3 and 2 alkenyls, the C 2-4 The alkenyl may be monovalent, divalent, or polyvalent. 2-4 Examples of cycloalkyls include, but are not limited to, vinyl, propenyl, butenyl, and butadienyl. Unless otherwise defined, "C 2-3 "Alkenyl" represents a hydrocarbon group consisting of 2 to 3 carbon atoms, including at least one carbon-carbon double bond in a straight or branched chain, and the carbon-carbon double bond may be at any position in the group. 2~3 Alkenyls include C3 and C2 alkenyls, and the aforementioned C 2-3 The alkenyl may be monovalent, divalent, or polyvalent. 2-3 Examples of cycloalkyl compounds include, but are not limited to, vinyl and propenyl.

[0220] Unless otherwise defined, the term "halogen" or "halo" means a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent.

[0221] Unless otherwise defined, C n-n+m or C n -C n+m This includes any one specific mode of n ~ n + m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 It includes and also includes any one range of n ~ n + m, for example, C1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 This includes, for example, n-membered to n+m-membered rings, where n- to n+m atoms are present in the ring. For example, a 3- to 12-membered ring includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, as well as any one range of n- to n+m. For example, a 3- to 12-membered ring includes 3- to 6-membered, 3- to 9-membered, 5- to 6-membered, 5- to 7-membered, 6- to 7-membered, 6- to 8-membered, and 6- to 10-membered rings.

[0222] Unless otherwise defined, the term "4-6 member heterocycloalkyl" itself, or in combination with other terms, refers to a saturated cyclic group composed of 4-6 ring atoms, where the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms independently selected from O, S, and N, and the remaining atoms are carbon atoms. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). P(where p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridging rings. Furthermore, with respect to "4-6 membered heterocycloalkyls," heteroatoms can occupy positions where they are linked to other parts of the molecule with the heterocycloalkyl. The 4-6 membered heterocycloalkyls include 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls, etc. Examples of 4- to 6-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, or hexahydropyridazinyl.

[0223] Unless otherwise defined, "C 3-6 "Cycloalkyl" is a saturated hydrocarbon group composed of 3 to 6 carbon atoms, and it represents monocyclic and bicyclic ring systems, as mentioned above. 3-6 Cycloalkyl is C 3-5 , C 4-5 or C 5-6 This includes cycloalkyl groups, etc.; they may be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0224] Unless otherwise defined, the term "3-6 membered heterocycloalkyl" itself, or in combination with other terms, refers to a saturated cyclic group composed of 3 to 6 ring atoms, where the 1st, 2nd, 3rd, and 4th ring atoms are independently selected from O, S, and N heteroatoms, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridging rings. Furthermore, with respect to "3-6 membered heterocycloalkyl," the heteroatoms can occupy linkage positions with the heterocycloalkyl and other parts of the molecule. The aforementioned 3-6 membered heteroaryl groups include 4-6 membered, 5-6 membered, 4-membered, 5-membered, and 6-membered heteroaryl groups, etc. Examples of 3- to 6-membered heteroaryl groups include, but are not limited to, heterobutyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydropyran, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, or hexahydropyridazinyl.

[0225] The term "leaving group" refers to a functional group or atom that may be substituted by another functional group or atom in a substitution reaction (e.g., a nucleophilic substitution reaction). For example, typical leaving groups include trifluoromethanesulfonic acid esters, chlorine, bromine, iodine, sulfonic acid ester groups such as methanesulfonic acid esters, toluenesulfonic acid esters, p-bromobenzenesulfonic acid esters, and p-toluenesulfonic acid esters, and acyloxy groups such as acetyloxy groups and trifluoroacetyloxy groups.

[0226] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "mercapto protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Typical amino acid protecting groups include, but are not limited to, formyl group, acyl groups such as alkanoyl groups (e.g., acetyl group, trichloroacetyl group, or trifluoroacetyl group), alkoxycarbonyl groups such as t-butoxycarbonyl (Boc) group, arylmethoxycarbonyl groups such as bentoxiccarbonyl (Cbz) group and 9-fluorenylmethoxycarbonyl (Fmoc) group, benzyl (Bn) group, trityl (Tr) group, arylmethyl groups such as 1,1-bis(4'-methoxyphenyl)methyl, and silyl groups such as trimethylsilyl (TMS) group and t-butyldimethylsilyl (TBS) group. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl. Typical hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl, and t-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenyltyl (Fm), and diphenylmethyl (DPM); and silyl groups such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS).

[0227] The compounds of the present invention can be produced by various synthesis methods familiar to those skilled in the art, including, but not limited to, the specific embodiments listed below, embodiments combined with other chemical synthesis methods, and equivalent alternative methods familiar to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0228] The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, single-crystal X-ray diffraction (SXRD), cultured single crystals are collected by a Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, and after collecting the relevant data, the absolute configuration can be confirmed by direct methods, such as crystal structure analysis (Shelxs97).

[0229] All solvents used in this invention can be obtained from commercially available products. This invention uses the following abbreviations: NH4HCO3 represents ammonium hydrocarbon, and Xantphos Pd G4 represents methanesulfonate[9,9-dimethyl-4,5-bis(diphenylphosphinoxanthene)](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II).

[0230] Compounds were named using the common names in this field or by the ChemDraw® software, and commercially available compounds were named according to the manufacturer's catalog. [Modes for carrying out the invention]

[0231] The present invention will be described in detail below by examples, but this does not mean any adverse limitations on the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed, and it will be apparent to those skilled in the art that various changes and modifications can be made in specific embodiments of the present invention without departing from the spirit and scope of the invention. [Examples]

[0232] Example 1

[0233] [ka]

[0234] [ka]

[0235] Step 1: At 25°C, trifluoromethanesulfonic acid (3.63g) was added to 60ml of hexafluoroisopropanol solvent containing compound 1-1 (5.8g) and compound 1-2 (5.77g). The mixed solution was heated to 65°C and reacted for 16 hours. 50ml of water was added to the reaction solution, and the mixture was further extracted with ethyl acetate (50ml x 3). The combined organic phase was washed once with saline solution (100ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 100:1~1:1) to obtain compound 1-3. LCMS (ESI) m / z: 420.0, 422.0 (M+1).

[0236] Step 2: At 25°C, 1-methyl-2-pyrrolidone (50 ml) was added to a mixed solution of compounds 1-3 (4.3 g) and 1-4 (3.07 g). Diisopropylethylamine (3.96 g) was then added to the mixed solution, and the mixture was stirred at 65°C for 5 hours. After the reaction was complete, water (50 ml) was added to the reaction solution, and then extracted with ethyl acetate (100 ml x 3). The aqueous phase was adjusted to pH 4 with dilute hydrochloric acid (1 M), and further extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compounds 1-5. LC-MS (ESI) m / z: 584.1, 586.1 (M+1).

[0237] Step 3: At 25°C, triethylamine (519.47 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.30 g) were added to a solution of compound 1-5 (1 g) and compound 1-6 (264.80 mg) in N,N-dimethylformamide (2 ml), and the mixed solution was stirred at 25°C for 4 hours. After the reaction was complete, water (20 ml) was added to the reaction solution, and then extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 100:1~0:1) to obtain compound 1-7. LCMS (ESI) m / z: 669.2, 671.2 (M+1).

[0238] 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.98 - 12.31 (m, 1 H) 8.58 - 8.71 (m, 1 H) 7.91 - 8.01 (m, 1 H) 7.76 - 7.89 (m, 1 H) 6.94 - 7.09 (m, 1 H) 5.68 - 5.83 (m, 1 H) 4.21 - 4.60 (m, 1 H) 3.74 - 3.97 (m, 2 H) 3.43 - 3.53 (m, 2 H) 3.21 - 3.28 (m, 1 H) 3.06 - 3.19 (m, 1 H) 2.96 - 3.05 (m, 2 H) 2.72 - 2.80 (m, 2 H) 2.51 - 2.55 (m, 4 H) 1.93 - 1.99 (m, 1 H) 1.74 - 1.88 (m, 1 H) 1.65 - 1.71 (m, 1 H) 1.47 - 1.58 (m, 3 H) 1.24 (br s, 9 H).

[0239] Step 4: At 25°C, p-toluenesulfonyl chloride (149.11 mg), 4-dimethylaminopyridine (4.78 mg), and triethylamine (158.29 mg) were added to a solution of compound 1-7 (630 mg) in dichloromethane (5 ml). The mixed solution was stirred at 25°C under nitrogen gas protection for 12 hours. After the reaction was complete, water (20 ml) was added to the reaction solution, and then extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 100:1~1:1) to obtain compound 1-8. LCMS (ESI) m / z: 823.2, 825.2 (M+1).

[0240] Step 5: At 25°C, trifluoroacetic acid (2.61 g) was added to a solution of compound 1-8 (300 mg) in dichloromethane (6 ml), and the mixed solution was stirred at 25°C under the protection of nitrogen gas for 6 hours. After the reaction was complete, the mixture was concentrated to obtain the trifluoroacetate salts of compounds 1-9. LC-MS (ESI) m / z: 723.2, 725.2 (M+1).

[0241] Step 6: At 25°C, potassium carbonate (171.90 mg) was added to a solution of trifluoroacetate salts (300 mg) of compounds 1-9 in acetonitrile (20 ml), and the mixed solution was stirred at 80°C under the protection of nitrogen gas for 12 hours. After the reaction was complete, water (20 ml) was added to the reaction solution, and then extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 100:1~0:1) to obtain compounds 1-10. LCMS (ESI) m / z: 551.2, 553.2 (M+1).

[0242] Step 7: At 25°C, dimethylphosphine oxide (9.46 mg), Xantphos Pdg4 (17.50 mg), and potassium phosphate (25.736 mg) were added to a solution of compounds 1-10 (35 mg) in dioxane (2 ml). The mixed solution was stirred at 120°C under nitrogen gas protection for 12 hours. Water (50 ml) was added to the reaction solution, and then extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column model: Phenomenex C18 75 x 30 mm x 3 μm; mobile phase: [water (formic acid)-acetonitrile]:acetonitrile%: 8%~38%, 7 min) to obtain the formate of compound 1. LC-MS (ESI) m / z: 549.2 (M+1); 1 HNMR (400 MHz, DMSO-d6) δ ppm 12.00 (br s, 1 H) 8.76 - 8.95 (m, 1 H) 8.52 - 8.60 (m, 1 H) 8.06 (br s, 1 H) 7.66 - 7.79 (m, 1 H) 7.07 - 7.21 (m, 1 H) 3.72 - 3.96 (m, 1 H) 3.45 - 3.54 (m, 1 H) 2.98 (s, 3 H) 2.67 - 2.81 (m, 2 H) 2.54 - 2.64 (m, 1 H) 1.83 - 2.08 (m, 7 H) 1.59 - 1.77 (m, 8 H) 1.31 - 1.55 (m, 4 H).

[0243] Example 2

[0244] [ka]

[0245] [ka]

[0246] Step 1: At 25°C, a mixed solution of compound 1-3 (2.2g) and compound 2-1 (888.26mg, hydrochloride) in 1-methyl-2-pyrrolidone (25ml) was mixed with diisopropylethylamine (2.90g), and the mixture was stirred at 65°C for 12 hours. After the reaction was complete, water (20ml) was added to the reaction solution, and then extracted with ethyl acetate (30ml x 3). The combined organic phase was washed twice with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-2. LCMS (ESI) m / z: 512.1, 514.1 (M+1).

[0247] Step 2: At 25°C, diisopropylethylamine (782.03 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (920.29 mg) were added to a solution of compound 2-2 (620 mg) and compound 1-6 (187.27 mg) in N,N-dimethylformamide (2 ml), and the mixed solution was stirred at 25°C for 12 hours. After the reaction was complete, water (20 ml) was added to the reaction solution, and then extracted with ethyl acetate (50 ml x 3). The combined organic phase was washed with saturated brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, dichloromethane:methanol = 100:1~10:1) to obtain compound 2-4. LCMS(ESI) m / z:597.2, 599.2(M+1).

[0248] Step 3: At 25°C, thionyl chloride (154.81 mg) and pyridine (102.93 mg) were added to a solution of compound 2-4 (500 mg) in dichloromethane (5 ml). The mixed solution was stirred at 50°C under nitrogen gas protection for 2 hours. After the reaction was complete, water (20 ml) was added to the reaction solution, and then extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column model: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (formic acid) - acetonitrile]: acetonitrile %: 18%~48%, 10 min) to obtain compound 2-5. LC-MS (ESI) m / z: 615.0, 617.0 (M+1).

[0249] Step 4: At 25°C, potassium carbonate (136.06 mg) and sodium iodide (47.74 mg) were added to a solution of compound 2-5 (200 mg) in acetonitrile (10 ml). The mixed solution was stirred at 85°C for 24 hours under the protection of nitrogen gas. After the reaction was complete, water (10 ml) was added to the reaction solution, and then extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, dichloromethane:methanol = 100:1~10:1) to obtain compound 2-6. LCMS (ESI) m / z: 579.1, 581.1 (M+1).

[0250] Step 5: At 25°C, dimethylphosphine oxide (4.91 mg), Xantphos Pdg4 (9.09 mg), and potassium phosphate (13.366 mg) were added to a solution of compound 2-6 (20 mg) in dioxane (1 ml). The mixed solution was stirred at 120°C under nitrogen gas protection for 12 hours. Water (20 ml) was added to the reaction solution, and then extracted with ethyl acetate (30 ml x 3). The combined organic phase was washed twice with saturated brine (30 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column model: Phenomenex C18 75 x 30 mm x 3 μm; mobile phase: [water (formic acid)-acetonitrile]:acetonitrile%: 5%~35%, 7 min) to obtain the formate of compound 2. LC-MS (ESI) m / z: 577.3 (M+1). 1 H NMR (400 MHz, CD3OD) δ ppm 8.93 - 9.17 (m, 1 H) 8.48 - 8.58 (m, 1 H) 8.05 - 8.21 (m, 1 H) 7.72 - 7.97 (m, 1 H) 7.22 - 7.32 (m, 1 H) 4.00 - 4.22 (m, 1 H) 3.11 (s, 4 H) 2.84 - 2.97 (m, 1 H) 2.56 - 2.73 (m, 1 H) 2.36 - 2.55 (m, 1 H) 1.94 - 2.07 (m, 6 H) 1.78 - 1.86 (m, 6 H) 1.58 - 1.72 (m, 3H) 1.17 - 1.33 (m, 7 H).

[0251] Example 3

[0252] [ka]

[0253] [ka]

[0254] Step 1: At room temperature, compound 3-1 (1.53 g) and diisopropylethylamine (1.84 g) were added to a solution of compound 1-3 (2 g) in N-methylpyrrolidone (20 ml), and the mixture was reacted at 45°C for 12 hours. The reaction solution was diluted with water (50 ml), extracted with ethyl acetate (30 ml x 2), washed with saturated brine (60 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product compound 3-2. LC-MS (ESI) m / z: 598.1, 600.1 (M+1).

[0255] Step 2: At room temperature, compound 3-3 (775.77 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (3.81 g) and diisopropylethylamine (3.24 g) were added to a solution of compound 3-2 (3 g) in N,N-dimethylformamide (40 ml), and the mixture was reacted at 25°C for 1 hour. The reaction solution was first diluted with water (100 ml), extracted with ethyl acetate (100 ml), the organic phase was further washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain compound 3-4. LCMS (ESI) m / z: 683.1, 685.1 (M+1).

[0256] Step 3: At room temperature, a solution of compound 3-4 (0.5 g) in tetrahydrofuran (10 ml) was mixed with pyridine (115.72 mg) and thionyl chloride (174.05 mg), and the mixture was reacted at 65°C for 1 hour. The reaction solution was first diluted with saturated sodium bicarbonate (20 ml), extracted with ethyl acetate (20 ml x 2), washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0~1 / 1) to obtain compound 3-5. LCMS (ESI) m / z: 601.2, 603.2 (M-100+1).

[0257] Step 4: At room temperature, a solution of compound 3-5 (233 mg) in ethyl acetate (4 ml) was mixed with hydrochloric acid / ethyl acetate (1.98 ml) and reacted at 25°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of the crude product compound 3-6.

[0258] Step 5: At room temperature, potassium carbonate (267.52 mg) and sodium iodide (58.02 mg) were added to a solution of acetonitrile (10 ml) containing hydrochloride salt of compound 3-6 (233 mg), and the mixture was reacted at 100°C for 40 hours. The reaction solution was filtered, and the crude product obtained by concentrating under reduced pressure was purified by column chromatography (ethyl acetate / methanol = 1 / 0 to 10 / 1) to obtain compound 3-7. LCMS (ESI) m / z: 565.2, 567.2 (M+1).

[0259] Step 6: At room temperature, potassium phosphate (360.40 mg) and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphinoxanthene)](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (272.32 mg) were added to a solution of compound 3-7 (160 mg) and dimethylphosphine oxide (441.72 mg) in 1,4-dioxane (3 ml), and the mixture was purged with nitrogen gas three times and reacted at 120°C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by preparative reverse-phase HPLC (column model: Phenomenex C18 75×30mm×3um; mobile phase: [water (formic acid)-acetonitrile]; B%: 8%~38%, 7 min) and preparative normal-phase HPLC (column model: Welch Ultimate XB-SiOH 250×50×10um; mobile phase: [n-hexane-ethanol]; B%: 1%~40%, 15 min) to obtain compound 3. LCMS (ESI) m / z: 563.3 (M+1). 1H NMR (400 MHz, CDCl3): δ = 11.83 (br s, 1H), 8.87 (br s, 1H), 8.51 (br s, 1H), 7.99 (br s, 1H), 7.25 - 7.08 (m, 1H), 5.23 (br d, J = 8.0 Hz, 1H), 3.48 - 3.37 (m, 1H), 3.08 (s, 3H), 2.90 - 2.81 (m, 1H), 2.78 - 2.65 (m, 1H), 2.49 - 2.18 (m, 4H), 2.16 - 2.01 (m, 4H), 1.88 - 1.61 (m, 14H).

[0260] Example 4

[0261] [ka]

[0262] [ka]

[0263] Step 1: At -40°C, vinyl magnesium bromide (1M, 110.09 ml) was added dropwise to a solution of compound 4-1 (6 g) in tetrahydrofuran (60 ml), and the mixture was stirred at -40°C for 2 hours. The mixture was stirred again at -40°C for 1 hour. After the reaction was complete, saturated ammonium chloride aqueous solution (100 ml) was poured into the reaction solution, and then the mixture was extracted twice with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated brine (50 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 20:1~20:1) to obtain compound 4-2. LCMS (ESI) m / z: 210.0, 212.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (br s, 1 H) 9.60 (s, 1 H) 7.32 (d, J=8.31 ​​Hz, 1 H) 7.15 (t, J=2.69 Hz, 1 H) 6.73 (d, J=8.31 ​​Hz, 1 H) 6.41 (dd, J=2.87, 2.14 Hz, 1H).

[0264] Step 2: At 20°C, trifluoromethanesulfonic acid (1.67 ml) was added to a solution of compound 4-2 (4 g) and compound 1-2 (4.91 g) in hexafluoroisopropanol (40 ml), and the mixed solution was stirred at 65°C for 12 hours. The completion of the reaction was detected by LC-MS. After the reaction was complete, the solution was concentrated to obtain the residue, water (50 ml) was added, and then the solution was extracted twice with ethyl acetate (50 ml x 2). The combined organic phase was washed with saturated brine (50 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 20:1~10:1) to obtain compound 4-3. LC-MS (ESI) m / z: 391.8, 393.8 (M+1).

[0265] Step 3: At 20°C, diisopropylethylamine (2.39g) was added to a solution of compound 4-3 (2.42g) and compound 1-4 (1.85g) in N-methylpyrrolidone (30ml), and the mixed solution was stirred at 50°C for 12 hours. After the reaction was complete, the reaction solution was poured into water (50ml), and then extracted twice with ethyl acetate (50ml x 2). The combined organic phase was washed with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether:ethyl acetate = 5:1~3:1) to obtain compound 4-4. LCMS (ESI) m / z: 556.0, 558.0 (M+1).

[0266] Step 4: At 20°C, potassium carbonate (1.68g) was added to a solution of compound 4-4 (2.25g) and compound 4-5 (732.26mg) in N,N-dimethylformamide (20ml), and the mixed solution was stirred at 60°C for 3 hours. After the reaction was complete, the reaction solution was poured into water (50ml), and then extracted twice with ethyl acetate (50ml x 2). The combined organic phase was washed with water (50ml) and saturated brine (50ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether:ethyl acetate = 5:1~2:1) to obtain compound 4-6. LCMS (ESI) m / z: 656.2, 658.2 (M+1).

[0267] Step 5: At 20°C, pyridine (307.23 mg) and thionyl chloride (462.09 mg) were added to a solution of compound 4-6 (1.7 g) in tetrahydrofuran (20 ml), and the mixed solution was stirred at 65°C for 1 hour. After the reaction was complete, water (30 ml) was added to the reaction solution, and then the mixture was extracted twice with ethyl acetate (30 ml x 2). The combined organic phase was washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether:ethyl acetate = 5:1~5:1) to obtain compound 4-7. LCMS (ESI) m / z: 674.2, 676.2 (M+1).

[0268] Step 6: At 20°C, a 10 ml methanol solution of compound 4-7 (1.2 g) was mixed with hydrochloric acid / methanol (4 M, 10 ml), and the mixture was stirred at 20°C for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain the hydrochloride salt of compound 4-8. LC-MS (ESI) m / z: 574.1, 576.1 (M+1).

[0269] Step 7: At 20°C, potassium carbonate (1.13 g) and potassium iodide (271.54 mg) were added to a solution of acetonitrile (20 ml) containing hydrochloride salt of compound 4-8, and the mixture was stirred at 100°C for 16 hours. The mixture was then stirred at 100°C for 24 hours. After the reaction was complete, the reaction solution was filtered, the cake was washed with ethyl acetate (50 ml), and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column model: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (formic acid)-acetonitrile]: 13%~43%, 10 min) to obtain the formate salt of compound 4-9. LC-MS (ESI) m / z: 538.0 (M+1).

[0270] Step 8: At 20°C, methanesulfonate[9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (214.50 mg) and potassium phosphate (141.93 mg) were added to a solution of formate (120 mg) of compound 4-9 and dimethylphosphine oxide (521.88 mg) in 1,4-dioxane (10 ml) and the mixed solution was stirred at 120°C for 24 hours under the protection of nitrogen gas. After the reaction was complete, the reaction solution was filtered, the cake was washed with ethyl acetate (20 ml), and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column model: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]: 52%~82%, 10 min) to obtain compound 4. LCMS (ESI) m / z: 536.2 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 8.50 (s, 1 H) 8.27 (d, J=8.88 Hz, 1 H) 7.70 (s, 1 H) 7.12 (dd, J=9.07, 4.82 Hz, 1 H) 4.59 (dq, J=8.79, 6.37 Hz, 2 H) 4.30 - 4.42 (m, 1 H) 3.72 - 3.89 (m, 2 H) 2.96 (br d, J=11.26 Hz, 1 H) 2.49 - 2.65 (m, 1 H) 2.18 - 2.32 (m, 1 H) 1.97 - 2.07 (m, 1 H) 1.89 (dd, J=18.14, 14.13 Hz, 7 H) 1.58 - 1.80 (m, 5 H) 1.28 - 1.48 (m, 6 H).

[0271] Example 5

[0272] [ka]

[0273] [ka]

[0274] Step 1: At 20°C, hydrochloric acid / ethyl acetate (4M, 4ml) was added to a solution of compound 1-5 (0.5g) in ethyl acetate (4ml), and the mixed solution was stirred at 20°C for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain the crude hydrochloride product of compound 5-1. LCMS (ESI) m / z: 483.9, 485.9 (M+1).

[0275] Step 2: At 20°C, 0.35g of compound 5-1 was added to hydrochloric acid / methanol (4M, 10ml), and the mixed solution was stirred at 50°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to obtain compound 5-2. LC-MS (ESI) m / z: 497.9, 499.9 ((M+1)).

[0276] Step 3: At 20°C, N,N-diisopropylethylamine (297.27 mg) was added to a solution of compound 5-2 (0.41 g) and compound 5-3 (289.98 mg) in N,N-dimethylformamide (20 ml), and the mixed solution was stirred at 80°C for 12 hours. Compound 5-3 (193.32 mg) and N,N-diisopropylethylamine (297.27 mg) were added to the reaction solution, and the mixed solution was stirred at 100°C for 4 hours. After the reaction was complete, the reaction solution was poured into water (20 ml), then extracted with ethyl acetate (20 ml x 2), washed with water (20 ml) and saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 1:1~0:1) to obtain compound 5-4. LCMS(ESI) m / z:669.0,671.0(M+1).

[0277] Step 4: At 20°C, sodium hydroxide (43.01 mg) was added to a solution of compound 5-4 (0.36 g) in methanol (12 ml) and water (4 ml), and the mixed solution was stirred at 50°C for 12 hours. Sodium hydroxide (21.51 mg) was added to the reaction solution, and the mixed solution was stirred at 50°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to obtain the residue, water (20 ml) was added to the residue, the pH of the aqueous phase was adjusted to 5 with hydrochloric acid (1 mol / L), then extracted with ethyl acetate (50 ml x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 5-5. LCMS (ESI) m / z: 655.2, 657.2 (M+1).

[0278] Step 5: At 20°C, 0.15 g of compound 5-5 was dissolved in 10 ml of ethyl acetate, to which hydrochloric acid / ethyl acetate (4 M, 10 ml) was added. The mixed solution was stirred at 20°C for 0.5 hours. After the reaction was complete, the reaction solution was concentrated to obtain the hydrochloride salt of compound 5-6. LC-MS (ESI) m / z: 554.9, 556.9 (M+1).

[0279] Step 6: At 20°C, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (144.55 mg) and N,N-diisopropylethylamine (163.78 mg) were added to a solution of compound 5-6 (0.15 g) in N,N-dimethylformamide (30 ml) and the mixed solution was stirred at 20°C for 2 hours. After the reaction was complete, the reaction solution was poured into water (50 ml), then extracted with ethyl acetate (30 ml x 2), washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by thin-layer chromatography (silica gel, ethyl acetate:methanol = 1:1) to obtain compound 5-7. LCMS (ESI) m / z: 536.9, 538.9 (M+1).

[0280] Step 7: At 20°C, to a solution of compound 5-7 (25 mg) and dimethylphosphine oxide (108.93 mg) in 1,4-dioxane (3 ml), methanesulfonate [9,9-dimethyl-4,5-bis(diphenylphosphinoxanthene)](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (44.77 mg) and potassium phosphate (29.63 mg) were added, and the mixed solution was stirred at 120°C under the protection of nitrogen gas for 20 hours. After the reaction was complete, the reaction solution was filtered, the cake was washed with ethyl acetate (15 ml), and the filtrate was concentrated to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (column model: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]: 25%~55%, 10 min) to obtain compound 5. LCMS (ESI) m / z: 535.3 (M+1).

[0281] 1H NMR (400 MHz, CD3OD) δ ppm 8.96 (br d, J=7.58 Hz, 1 H) 8.49 (s, 1 H) 8.08 (s, 1 H) 7.38 (dd, J=8.25, 3.48 Hz, 1 H) 3.90 - 4.04 (m, 1 H) 3.60 - 3.70 (m, 1 H) 3.04 (br d, J=10.39 Hz, 1 H) 2.84 (ddd, J=14.18, 9.90, 4.77 Hz, 1 H) 2.63 (ddd, J=14.06, 10.33, 5.81 Hz, 1 H) 2.02 - 2.12 (m, 5 H) 1.89 - 2.00 (m, 5 H) 1.73 - 1.87 (m, 3 H) 1.56 - 1.70 (m, 2 H) 1.39 - 1.54 (m, 2 H) 1.09 - 1.24 (m, 1 H).

[0282] Example 6

[0283] [ka]

[0284] [ka]

[0285] Step 1: At 20°C, compound 3-2 (1.5g) was added to a hydrochloric acid / methanol (4M, 30ml) solution, and the mixed solution was stirred at 50°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to obtain the hydrochloride salt of compound 6-1. LCMS (ESI) m / z: 512.1, 514.1 (M+1).

[0286] Step 2: At 20°C, N,N-diisopropylethylamine (824.28 mg) was added to a solution of compound 6-1 hydrochloride (0.7 g) and compound 5-3 (804.07 mg) in N,N-dimethylformamide (20 ml), and the mixed solution was stirred at 100°C for 12 hours. After the reaction was complete, water (30 ml) was added to the reaction solution, and then the mixture was extracted twice with ethyl acetate (30 ml x 2). The combined organic phase was washed with water (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 2:1 ~ ethyl acetate:methanol = 10:1) to obtain compound 6-2. LCMS (ESI) m / z: 683.1, 685.1 (M+1).

[0287] Step 3: At 20°C, sodium hydroxide (138.09 mg) was added to a solution of compound 6-2 (0.59 g) in methanol (15 ml) and water (5 ml), and the mixed solution was stirred at 60°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to obtain the residue, water (20 ml) was added to the residue, and the pH of the aqueous phase was adjusted to 5 with hydrochloric acid (1 mol / L). Next, the solution was extracted twice with ethyl acetate (20 ml x 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6-3. LCMS (ESI) m / z: 669.0, 671.0 (M+1).

[0288] Step 4: At 20°C, 0.6 g of compound 6-3 was dissolved in 10 ml of ethyl acetate, to which hydrochloric acid / ethyl acetate (4 M, 10 ml) was added. The mixed solution was stirred at 20°C for 0.5 hours. After the reaction was complete, the reaction solution was concentrated to obtain the hydrochloride salt of compound 6-4. LC-MS (ESI) m / z: 569.0, 571.0 (M+1).

[0289] Step 5: At 20°C, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (545.99 mg) and N,N-diisopropylethylamine (618.61 mg) were added to a solution of compound 6-4 hydrochloride (0.58 g) in N,N-dimethylformamide (300 ml) and the mixed solution was stirred at 20°C for 0.5 hours. After the reaction was complete, the reaction solution was poured into water (600 ml), then extracted twice with ethyl acetate (150 ml x 2). The combined organic phase was washed with water (200 ml x 2) and saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, eluate, petroleum ether:ethyl acetate = 1:1 ~ ethyl acetate:methanol = 7:1) to obtain compound 6-5. LCMS(ESI) m / z:551.0,553.0(M+1).

[0290] Step 6: At 20°C, a solution of compound 6-5 (0.21 mg) and dimethylphosphine oxide (891.75 mg) in 1,4-dioxane (6 ml) was mixed with methanesulfonate [9,9-dimethyl-4,5-bis(diphenylphosphinoxanthene)](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (366.52 mg) and potassium phosphate (242.52 mg). The mixed solution was stirred at 120°C for 16 hours under the protection of nitrogen gas. After the reaction was complete, the reaction solution was filtered, the cake was washed with ethyl acetate (20 ml), and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column model: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]: 28%~58%, 10 min) to obtain compound 6. LCMS (ESI) m / z: 549.3 (M+1).

[0291] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.98 (br s, 1 H) 8.47 - 8.72 (m, 2 H) 7.90 - 8.16 (m, 2 H) 7.60 - 7.73 (m, 1 H) 7.13 - 7.23 (m, 1 H) 3.89 - 4.09 (m, 1 H) 3.18 (br dd, J=12.96, 4.03 Hz, 1 H) 2.84 - 2.98 (m, 1 H) 2.62 - 2.69 (m, 1 H) 2.06 - 2.39 (m, 5 H) 1.81 - 1.99 (m, 7 H) 1.69 - 1.80 (m, 2H) 1.42 - 1.66 (m, 4 H) 1.35 (br d, J=1.96 Hz, 2 H) 1.00 - 1.17 (m, 1 H).

[0292] In vitro activity test Experimental Example 1: In vitro CDK7 / CyclinT1 enzyme activity test Experimental materials: CDK7 / CyclinH / MAT1 was purchased from CARNA. Ulight-MBP polypeptide, Eu-MBP antibody, and 1× detection buffer were purchased from PerkinElmer. High-purity ATP was purchased from Promega. EDTA was purchased from Sigma. Nivo multi-label analyzer (PerkinElmer).

[0293] Experimental method: Preparation of kinase buffer: The kinase buffer contained 50 mM HEPES, 1 mM EDTA, 10 mM MgCl2, and 0.01% Brij-35, and the pH was adjusted to 7.4.

[0294] 2.38 g of HEPES, 58 mg of EDTA, 406 mg of MgCl2, and 20 mg of Brij-35 were added to 200 ml of buffer solution, and the pH was adjusted to 7.4.

[0295] Manufacturing of stop solution: A stop solution was prepared by mixing 100 μL of 1M EDTA stock solution and 0.625 μL of 1× detection buffer with 1725 μL of distilled water.

[0296] The enzyme, Ulight-MBP polypeptide, ATP, and inhibitor were diluted using kinase buffer.

[0297] The Eu-MBP antibody was diluted to a concentration of 8 nM / L using detection buffer.

[0298] The test compound was pipetteed to eight different concentrations, diluting it fivefold from 40 μM to 0.512 nM, with a final DMSO concentration of 4%. Two wells were prepared under the same conditions. 2.5 μL of each inhibitor concentration gradient, 5 μL of CDK7 / CyclinH / MAT1 enzyme (5 ng), and 2.5 μL of a substrate and ATP mixture (44 mM ATP, 50 nM Ulight-MBP polypeptide) were added to a microplate, diluting the final concentration gradient of the compound from 10 μM to 0.128 nM. The reaction system was placed at 25°C and allowed to react for 60 minutes. After the reaction was complete, 5 μL of stop solution was added to each well, and the reaction was continued at 25°C for 5 minutes. After the reaction was complete, 5 μL of Eu-MBP antibody diluent was added to each well, and the reaction was continued at 25°C for 60 minutes. Data was then collected using the PerkinElmer Nivo multimode microplate reader in TR-FRET mode (excitation wavelength 320 nM, emission wavelength 665 nM).

[0299] Data analysis: The formula (Sample-Min) / (Max-Min)×100% is used to convert the original data to a suppression rate, and IC 50 The values ​​could be determined by curve fitting using four parameters (calculated in GraphPad Prism's log(inhibitor) vs. response--Variable slope mode). Table 1 shows the enzyme inhibitory activity of the compounds of the present invention against CDK7 / CyclinH / MAT1.

[0300] Experimental conclusion: The compounds of the present invention exhibit good activity against CDK7 kinase.

[0301] Experimental Example 2: In vitro CDK2 / CyclinB1 enzyme activity test Experimental materials: CDK2 / CyclinE 1 was purchased from SignalChem. Ulight-4E-BP1 peptide, Eu-anti-phospho-tyrosine antibody, and 1× detection buffer were purchased from PerkinElmer. High-purity ATP was purchased from Promega. EDTA was purchased from Sigma. Nivo multi-label analyzer (PerkinElmer).

[0302] Experimental method: Preparation of kinase buffer: The kinase buffer contained 50 mM HEPES, 1 mM EDTA, 10 mM MgCl2, and 0.01% Brij-35, and the pH was adjusted to 7.4.

[0303] 2.38 g of HEPES, 58 mg of EDTA, 406 mg of MgCl2, and 20 mg of Brij-35 were added to 200 ml of buffer solution, and the pH was adjusted to 7.4.

[0304] Manufacturing of stop solution: A stop solution was prepared by using 100 μL of 1M EDTA stock solution, adding 0.625 μL of 1× detection buffer, and mixing with 1725 μL of distilled water.

[0305] The enzyme, Ulight-4E-BP1 peptide, ATP, and inhibitor were diluted using kinase buffer.

[0306] The Eu-anti-phospho-tyrosine antibody was diluted to a concentration of 8 nM / L using detection buffer.

[0307] The test compound was pipetteed to eight different concentrations, diluted fivefold, from 40 μM to 0.512 nM, with a final DMSO concentration of 4%. Two wells were prepared under the same conditions. 2.5 μL of each inhibitor concentration gradient, 5 μL of CyclinE 1 enzyme (10 ng), and 2.5 μL of a substrate and ATP mixture (4 mM ATP, 100 nM Ulight-4E-BP1 peptide) were added to a microplate, diluting the final concentration gradient of the compound from 10 μM to 0.128 nM. The reaction system was placed at 25°C and allowed to react for 120 minutes. After the reaction was complete, 5 μL of stop solution was added to each well, and the reaction was continued at 25°C for 5 minutes. After the reaction was complete, 5 μL of diluted Eu-anti-phospho-tyrosine antibody was added to each well, and the reaction was continued at 25°C for 60 minutes. Data was then collected using the PerkinElmer Nivo multimode microplate reader in TR-FRET mode (excitation wavelength 320 nM, emission wavelength 665 nM).

[0308] Data analysis: The formula (Sample-Min) / (Max-Min)×100% is used to convert the original data to a suppression rate, and IC 50 The values ​​could be determined by curve fitting using four parameters (calculated in GraphPad Prism's log(inhibitor)vs.response--Variable slope mode). Table 1 shows the enzyme inhibitory activity of the compounds of the present invention against CDK2 / CyclinE 1.

[0309] Experimental conclusion: The compounds of the present invention do not exhibit strong inhibitory activity against CDK2 kinase.

[0310] Experimental Example 3: In vitro CDK9 / CyclinE1 enzyme activity test Experimental materials: CDK9-CyclinT1 was purchased from CARNA. Ulight-4E-BP1 peptide, Eu-anti-phospho-tyrosine antibody, and 1× detection buffer were purchased from PerkinElmer. High-purity ATP was purchased from Promega. EDTA was purchased from Sigma. Nivo multimode microplate reader (PerkinElmer).

[0311] Experimental method: Preparation of kinase buffer: The kinase buffer contained 50 mM HEPES, 1 mM EDTA, 10 mM MgCl2, and 0.01% Brij-35, and the pH was adjusted to 7.4.

[0312] 2.38 g of HEPES, 58 mg of EDTA, 406 mg of MgCl2, and 20 mg of Brij-35 were added to 200 ml of buffer solution, and the pH was adjusted to 7.4.

[0313] Manufacturing of stop solution: A stop solution was prepared by using 100 μL of 1M EDTA stock solution, adding 0.625 μL of 1× detection buffer, and mixing with 1725 μL of distilled water.

[0314] The enzyme, Ulight-4E-BP1 peptide, ATP, and inhibitor were diluted using kinase buffer.

[0315] The Eu-anti-phospho-tyrosine antibody was diluted to a concentration of 8 nM / L using detection buffer.

[0316] The test compound was pipetteed to eight different concentrations, diluting it fourfold from 400 μM to 24.4 nM, with a final DMSO concentration of 4%. Two wells were prepared under the same conditions. 2.5 μL of each inhibitor concentration gradient, 5 μL of CDK9-CyclinT1 enzyme (2 ng), and 2.5 μL of a substrate and ATP mixture (8 mM ATP, 50 nM Ulight-4E-BP1 peptide) were added to a microplate, diluting the final concentration gradient of the compound from 100 μM to 6.1 nM. The reaction system was placed at 25°C and allowed to react for 120 minutes. After the reaction was complete, 5 μL of stop solution was added to each well, and the reaction was continued at 25°C for 5 minutes. After the reaction was complete, 5 μL of diluted Eu-anti-phospho-tyrosine antibody was added to each well, and the reaction was continued at 25°C for 60 minutes. Data was then collected using the PerkinElmer Nivo multimode microplate reader in TR-FRET mode (excitation wavelength 320 nM, emission wavelength 665 nM).

[0317] Data analysis: The formula (Sample-Min) / (Max-Min)×100% is used to convert the original data to a suppression rate, and IC 50 The values ​​could be determined by curve fitting using four parameters (calculated in GraphPad Prism's log(inhibitor) vs. response--Variable slope mode). Table 1 shows the enzyme inhibitory activity of the compounds of the present invention against CDK9-CyclinT1.

[0318] Experimental conclusion: The compounds of the present invention do not exhibit strong inhibitory activity against CDK9 kinase.

[0319] Experimental Example 4: In vitro HCC70 cell activity test Experimental materials: Medium 1640, fetal bovine serum, and penicillin / streptomycin antibiotics were purchased from Vicente. CellTiter-Glo (cell viability chemiluminescence detection reagent) was purchased from Promega. HCC70 cell line was purchased from Nanjing Cobioer Biosciences Co., Ltd. Nivo multimode microplate reader (PerkinElmer).

[0320] Experimental method: HCC70 cells were seeded into a white 96-well plate, with 80 μL of cell suspension in each well, containing 6000 HCC70 cells. The cell plate was cultured overnight in a carbon dioxide incubator.

[0321] The test compound was pipetteed to eight different concentrations, diluting it threefold from 2 μM to 304 nM, and two wells were prepared under the same conditions. 78 μL of culture medium was added to the middle plate, and then 2 μL / well of the gradient-diluted compound was transferred to the middle plate according to the corresponding positions. After uniform mixing, 20 μL / well was transferred to the cell plate. The compound concentration range in the cell plate was 10 μM to 1.52 nM. The cell plate was placed in a carbon dioxide incubator and cultured for 4 days. Another cell plate was prepared, and the signal value on the day of drug addition was read as the maximum value (Max value in the formula below) and included in the data analysis. 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate, and the cells were cultured at room temperature for 10 minutes to stabilize the luminescence signal. The data was read using a multimode microplate reader.

[0322] 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate, and the cells were incubated at room temperature for 10 minutes to stabilize the luminescence signal. The data was read using a multimode microplate reader.

[0323] Data analysis: The original data is converted to the inhibition rate using the formula (Sample-Min) / (Max-Min)×100%. 50The values ​​could be determined by curve fitting using four parameters (calculated in GraphPad Prism's log(inhibitor)vs.response--Variable slope mode). Table 1 shows the inhibitory activity of the compounds of the present invention against HCC70 cell proliferation.

[0324] Experimental conclusion: The compound of the present invention has potent inhibitory activity against HCC70 cells.

[0325] Experimental Example 5: In vitro OVCAR3 cell activity test Experimental materials: Medium 1640, fetal bovine serum, and penicillin / streptomycin antibiotics were purchased from Vicente. CellTiter-Glo (chemiluminescent cell viability detection reagent) was purchased from Promega. OVCAR3 cell line was purchased from Nanjing Cobioer Biosciences Co., Ltd. Nivo multimode microplate reader (PerkinElmer).

[0326] Experimental method: OVCAR3 cells were seeded into a white 96-well plate, with 80 μL of cell suspension in each well, containing 2000 OVCAR3 cells. The cell plate was cultured overnight in a carbon dioxide incubator.

[0327] The test compound was pipetteed to eight different concentrations, diluted fivefold, from 200 μM to 0.512 nM, and two wells were prepared under the same conditions. 78 μL of culture medium was added to the middle plate, and then 2 μL / well of the gradient-diluted compound was transferred to the middle plate according to the corresponding positions. After uniform mixing, 20 μL / well was transferred to the cell plate. The compound concentration range in the cell plate was 1 μM to 0.0026 nM. The cell plate was placed in a carbon dioxide incubator and cultured for 3 days. Another cell plate was prepared, and the signal value on the day of drug addition was read as the maximum value (Max value in the formula below) and included in the data analysis. 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate, and the cells were cultured at room temperature for 10 minutes to stabilize the luminescence signal. Data was read using a multimode microplate reader.

[0328] 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate, and the cells were incubated at room temperature for 10 minutes to stabilize the luminescence signal. The data was read using a multimode microplate reader.

[0329] Data analysis: The original data is converted to the inhibition rate using the formula (Sample-Min) / (Max-Min)×100%. 50 The values ​​could be determined by curve fitting using four parameters (calculated in GraphPad Prism's log(inhibitor)vs.response--Variable slope mode). Table 1 shows the inhibitory activity of the compounds of the present invention against OVCAR3 cell proliferation.

[0330] Experimental conclusion: The compounds of the present invention have potent inhibitory activity against OVCAR3 cells.

[0331] [Table 1]

[0332] Experimental Example 6: In vivo drug efficacy test In vivo efficacy experiments were conducted in BALB / c nude mice that received subcutaneous transplantation of xenografts (CDX) based on human tumor cell lines derived from HCC70 breast cancer patients.

[0333] Experimental procedure: BALB / c nude mice (female, 6-8 weeks old, weight: approximately 19-23g) were housed in individual ventilated cages (6 mice per cage) in a pathogen-free environment. All cages, pads, and water were disinfected before use. All animals were free-roaming on standard, commercially available laboratory diets. The study used a total of 36 mice purchased from the Laboratory Animal Department of the Shanghai Institute of Planned Parenthood Research (formerly Shanghai Sippe-Bk). A 10x10 denture was placed on the right side of each mouse's neck. 6 HCC70 cells were inoculated in a 0.2 mL inoculation volume, with the cell suspension being PBS and Matrigel (1:1). The average tumor volume was approximately 179 mm². 3 Once the target was reached, patients were randomly divided into groups and drug administration was initiated. The dose was 3 mg / kg. Tumor volume was measured twice a week using a two-dimensional caliper, and the volume was measured in mm². 3 The measurement was taken and calculated using the following formula: V = 0.5a × b 2 Here, a and b are the longest and shortest diameters of the tumor, respectively. The experimental results are shown in Table 2.

[0334] [Table 2]

[0335] Experimental conclusion: In an in vivo drug efficacy model of HCC70 breast cancer CDX, the compound of the present invention showed good efficacy and safety. (Note) The inventions disclosed herein include the following embodiments. <Item 1> A compound represented by formula (II) or a pharmaceutically acceptable salt thereof. [ka] (however, R 1 H, CN, F, Cl, Br, I, C 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, S(O) m R a P(X)R c R d , C(O)R a , S(O) m NR a R b and C(O)NR a R b Selected from, the C 1-3 Alkyl, -OC 1-3 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 R groups. R a C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 Selected from cycloalkyl, R b H and C 1-3 Selected from alkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 The cycloalkyl group is optionally substituted with 1, 2, or 3 R groups. R c and R d C 1-3 Alkyl and OC 1-3 Selected from alkyl groups, or R c 、R d Together with the P atoms linked to them, they form a 4-6 member heterocycloalkyl group, and the -OC 1-3 Alkyl, C 1-3 Alkyl and 4-6 member heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R groups. X is selected from O and S. L 1 is, -CH 2 -, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)- are selected, L 2 is, -CH 2 -, -O-, and -NR e - Selected from, R e H and C 1-3 Selected from alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2, or 3 R groups. R 2 and R 3 These are H and C, respectively, independently. 1-3 Alkyl and C 2-4 Selected from Alkenil, or R 2 、R 3 C is, along with the C atoms linked to them. 3-6 Forming a cycloalkyl or 3-6 member heterocycloalkyl, the C 1-3 Alkyl, C 2-4 Alkenil, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R groups. R 4 C 1-3 Selected from haloalkyl, CN, F, Cl, Br, and I, R is independently F, Cl, Br, and NH. 2 and selected from CN, n is selected from 0, 1, 2, 3, 4, and 5. m and q are independently selected from 1 and 2. t is selected from 0, 1, 2, and 3. <Item 2> R 1 is S(O) m R a Selected from, the S(O)m R a teeth,

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Claims

1. A compound selected from the following formulas or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (however, X is O, Structural unit 【Chemistry 2】 teeth, 【Transformation 3】 And; Re is selected from H and C1-3 alkyl groups; R2 and R3 are independently selected from H and C1-3 alkyl groups; n is 2; t is 2.

2. R ２ and R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each is independently selected from H, methyl, ethyl, n-propyl, and isopropyl.

3. R ２ and R ３ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein each is independently selected from H and methyl.

4. Structural unit 【Chemistry 4】 teeth, 【Transformation 5】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. A compound represented by the following formula or a pharmaceutically acceptable salt thereof. 【Transformation 6】

6. A compound represented by the following formula or a pharmaceutically acceptable salt thereof. 【Transformation 7】 【Transformation 8】

7. A pharmaceutical agent for treating CDK7-related disease, comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical product according to claim 7, wherein the CDK7-related disease is breast cancer.

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