Indole-containing macrocyclic compounds and uses thereof

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 priority to: CN202210108561.8, the filing date is January 28, 2022; CN202210476398.0, the filing date is April 29, 2022; CN202210667398.9, the filing date is June 13, 2022; CN202210894289.0, application date is July 27, 2022. The present invention discloses indole-containing macrocyclic compounds and uses thereof, specifically, a compound represented by formula (II) or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] The cell cycle generally refers to the continuous dynamic process that continuously dividing cells undergo from the end of the previous mitosis to the end of the next mitosis. The mammalian cell cycle consists of four phases: G1 (prophase of DNA synthesis), S (prophase of DNA synthesis), G2 (prophase of DNA synthesis), and M (prophase of mitosis). After the M phase, cytokinesis occurs to form two daughter cells. The new cells generated after cell cycle division re-enter the cell cycle, but at a certain point in the late G1 phase (called the restriction point or R point), the cell cycle regulatory mechanism determines the final fate of the cell: whether to continue participating in the cell cycle cycle or to exit the active proliferation state and enter the arrested (G0) state. The regulation of the cell cycle is mainly influenced by a series of serine / threonine kinases, which are also called cyclin-dependent kinases (CDKs), which bind with their corresponding regulatory subunits, cyclins, to achieve the purpose of regulating the cell cycle.

[0003] Abnormal proliferation of cancer cells and dysregulation of normal cell cycle are common features of all kinds of cancer. Therefore, inhibitors of key cell cycle regulators have emerged as attractive new antitumor targets. CDK7 is an important member of the CDKs family, also called CDKs activating kinase (CAK). CDK7 mainly regulates the cell cycle in two indirect ways. First, the CDK7-cyclin H binary complex or CDK7-cyclin H-MAT1 ternary complex can be activated by phosphorylation to generate active CAK, which can further phosphorylate threonine residues in the active regions of CDKs (1, 2, 3, 4, 6) to activate their activities and induce cell cycle initiation, progression and termination. Secondly, the phosphorylated CDK7-cyclin H-MAT1 complex phosphorylates the large subunit of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAP II) to promote promoter removal and induce transcription initiation; moreover, the CDK7-cyclinH-MAT1 complex is also a subunit component of transcription factor IIH (TFIIH) and is involved in type II transcription and nucleotide excision 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, which not only blocks the main role of CDKs (1, 2, 3, 4, 6) in the cell cycle, but also affects the transcription process to achieve the purpose of inhibiting tumor cell proliferation. Based on the important regulatory role of CDK7 on cell cycle and transcription, designing CDK7 inhibitors with new scaffolding structures targeting CDK7 has become one of the hotspots in the field of antitumor drug research.

[0004] At present, there are several CDK7 small molecule inhibitors that have entered the clinical research stage for cancer treatment, such as SY-5609 and CT-7001 from Syros Pharmaceuticals. Such CDK7 inhibitors can not only inhibit the activation of CDK protein, but also inhibit the phosphorylation of the C-terminal domain of RNA polymerase II, thus affecting transcription regulation.

[0005] There have been many efforts to develop CDK7 inhibitors for the treatment of cancer and other diseases, but no drugs targeting this have been commercially available to date. Among the varieties under development, SY-5609 has very high activity but low maximum clinical tolerance, while CT-7001 has good in vitro activity but low metabolic stability, limiting its further development into a drug. Therefore, there remains an urgent need to develop new, safer and more effective CDK7 inhibitors that can treat various cancers (including breast cancer). Summary of the Invention

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

[0007] [ka]

[0008] however, R 1 are H, CN, F, Cl, Br, I, and 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 C is selected from 1-3 Alkyl, -OC 1-3 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R a is C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 cycloalkyl; R b H and C1-3 alkyl, 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R c and R d is independently C 1-3 Alkyl and OC 1-3 alkyl; or R c , R d form a 4- to 6-membered heterocycloalkyl together with the P atom linked thereto, and said -OC 1-3 Alkyl, C 1-3 Alkyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; X is selected from O and S; L 1 -CH 2 -, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)-, L 2 -CH 2 -, -O- and -NR e - selected from R e H and C 1-3 alkyl, 1-3 The alkyl is optionally substituted by 1, 2 or 3 R; R 2 and R 3 are independently H, C 1-3 Alkyl and C 2-4 alkenyl; or R 2 , R 3 are C together with the C atoms connected to them. 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, 1-3 Alkyl, C 2-4 Alkenyl, C 3-6Cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; R 4 is C 1-3 selected from haloalkyl, CN, F, Cl, Br and I; R is independently F, Cl, Br, NH 2 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 pharma- ceutically acceptable salt thereof.

[0010] [ka]

[0011] however, R 1 are H, CN, F, Cl, Br, I, and 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 C is selected from 1-3 Alkyl, -OC 1-3 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R a is C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6cycloalkyl; R b H and C 1-3 alkyl, 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R c and R d is independently C 1-3 Alkyl and OC 1-3 alkyl; or R c , R d form a 4- to 6-membered heterocycloalkyl together with the P atom linked thereto, and said -OC 1-3 Alkyl, C 1-3 Alkyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; X is selected from O and S; L 1 -CH 2 -, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)-, L 2 -CH 2 -, -O- and -NR e - selected from R e H and C 1-3 alkyl, 1-3 The alkyl is optionally substituted by 1, 2 or 3 R; R 2 and R 3 are independently H, C 1-3 Alkyl and C 2-4 alkenyl; or R 2 , R 3 are C together with the C atoms connected to them. 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, 1-3 Alkyl, C 2-4Alkenyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; R 4 is C 1-3 selected from haloalkyl, CN, F, Cl, Br and I; R is independently F, Cl, Br, NH 2 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, the above R 1 is selected from H, and the other variables are as defined herein.

[0013] In some technical solutions of the present invention, the above R 1 is selected from CN, and the other variables are as defined herein.

[0014] In some technical solutions of the present invention, the above R 1 is selected from F, and the other variables are as defined herein.

[0015] In some technical solutions of the present invention, the above R 1 is selected from Cl, and the other variables are as defined herein.

[0016] In some technical solutions of the present invention, the above R 1 is selected from Br, and the other variables are as defined herein.

[0017] In some technical solutions of the present invention, the above R 1 is C 1-3 alkyl, 1-3 The alkyl is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0018] In some technical solutions of the present invention, the above R 1 is CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , C.H. 2 F, CHF 2 , C.F. 3 , C.H. 2 Cl, CHCl 2 and CCl 3 and the other variables are as defined herein.

[0019] In some technical solutions of the present invention, the above R 1 -OC 1-3 alkyl, wherein -OC 1-3 The alkyl is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0020] In some technical solutions of the present invention, the above R 1 -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 Cl, -OCHCl 2 and -OCCl 3 and the other variables are as defined herein.

[0021] In some technical solutions of the present invention, the above R 1 is C 3-6 cycloalkyl, 3-6 Cycloalkyl is

[0022] [ka]

[0023] and

[0024] [ka]

[0025] is optionally substituted by 1, 2 or 3 R.

[0026] In some technical solutions of the present invention, the above R 1 is S(O) m R a wherein S(O) is selected from m R a teeth,

[0027] [ka]

[0028] and the other variables are as defined herein.

[0029] In some technical solutions of the present invention, the above R 1 is S(O) m NR a R b wherein S(O) is selected from m NR a R b teeth,

[0030] [ka]

[0031] and the other variables are as defined herein.

[0032] In some technical solutions of the present invention, the above R 1 is P(X)R c R dwherein P(X)R c R d teeth,

[0033] [ka]

[0034] Selected from X 1 is CH 2 , O and NH; p is selected from 0 and 1; r is selected from 0 and 1, and the other variables are as defined herein.

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

[0036] [ka]

[0037] teeth,

[0038] [ka]

[0039] and the other variables are as defined herein.

[0040] In some technical solutions of the present invention, the above R 1 teeth,

[0041] [ka]

[0042] and the other variables are as defined herein.

[0043] In some technical solutions of the present invention, the above R 1 is C(O)R a wherein C(O)R a teeth,

[0044] [ka]

[0045] and the other variables are as defined herein.

[0046] In some technical solutions of the present invention, the above R 1 is C(O)NR a R b wherein the C(O)NR a R b teeth,

[0047] [ka]

[0048] and the other variables are as defined herein.

[0049] In some technical solutions of the present invention, the above R 1 teeth,

[0050] [ka]

[0051] and the other variables are as defined herein.

[0052] In some technical solutions of the present invention, the above R 2 and R 3 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, or R 2 , R 3 together with the C atom linked thereto form cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with the other variables being as defined herein.

[0053] In some technical solutions of the present invention, the above R 2and R 3 are each independently selected from H and methyl, and the other variables are as defined herein.

[0054] In some technical solutions of the present invention, the above R 2 , R 3 together with the C atom attached thereto form a cyclopropyl, and the other variables are as defined herein.

[0055] In some technical solutions of the present invention, the above L 1 -CH 2 -, -O-, -NR e -, -C(O)-, -S(O)-, -S(O) 2 - and -P(O)-, the other variables being as defined herein.

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

[0057] [ka]

[0058] and the other variables are as defined herein.

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

[0060] [ka]

[0061] teeth,

[0062] [ka]

[0063] and the other variables are as defined herein.

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

[0065] [ka]

[0066] teeth,

[0067] [ka]

[0068] and the other variables are as defined herein.

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

[0070] [ka]

[0071] teeth,

[0072] [ka]

[0073] and the other variables are as defined herein.

[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] The other variables are as defined in the present invention.

[0077] In some technical solutions of the present invention, the compound is as represented by formula (II-1-1) and (II-1-2):

[0078] [ka]

[0079] The other variables are as defined in the present invention.

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

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

[0082] [ka]

[0083] however,

[0084] [ka]

[0085] is selected from a single bond and a double bond; R 1 are H, CN, F, Cl, Br, I, and 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 C is selected from 1-3 Alkyl, -OC1-3 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R a is C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 cycloalkyl; R b H and C 1-3 alkyl, 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R c and R d is independently C 1-3 Alkyl and OC 1-3 alkyl; or R c , R d form a 4- to 6-membered heterocycloalkyl together with the P atom linked thereto, and said -OC 1-3 Alkyl, C 1-3 Alkyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; X is selected from O and S; L 1 -CH 2 -, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)-, L 2 is not present or -CH 2 -, -O- and -NR e - selected from R e H and C 1-3 alkyl, 1-3 The alkyl is optionally substituted by 1, 2 or 3 R; R2 and R 3 are independently H, C 1-3 Alkyl and C 2-4 alkenyl; or R 2 , R 3 are C together with the C atoms connected to them. 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, 1-3 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; R 4 is C 1-3 selected from haloalkyl, CN, F, Cl, Br and I; R is independently F, Cl, Br, NH 2 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 pharma- ceutically acceptable salt thereof.

[0087] [ka]

[0088] however,

[0089] [ka]

[0090] is selected from a single bond and a double bond; R 1 are H, CN, F, Cl, Br, I, and C. 1-3 Alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, S(O) m Ra , P(X)R c R d , C(O)R a , S(O) m NR a R b and C(O)NR a R b C is selected from 1-3 Alkyl, -OC 1-3 Alkyl and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R a is C 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 cycloalkyl; R b H and C 1-3 alkyl, 1-3 Alkyl, -OC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl) 2 and C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R; R c and R d is independently C 1-3 Alkyl and OC 1-3 alkyl; or R c , R d form a 4- to 6-membered heterocycloalkyl together with the P atom linked thereto, and said -OC 1-3 Alkyl, C 1-3 Alkyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; X is selected from O and S; L 1 -CH 2 -, -O-, -NR e -, -C(O)-, -S(O) q - and -P(O)-, L 2is not present or -CH 2 -, -O- and -NR e - selected from R e H and C 1-3 alkyl, 1-3 The alkyl is optionally substituted by 1, 2 or 3 R; R 2 and R 3 are independently H, C 1-3 Alkyl and C 2-4 alkenyl; or R 2 , R 3 together with the atom(s) connected thereto form a 3- to 6-membered heterocycloalkyl, 1-3 Alkyl, C 2-4 alkenyl and 3- to 6-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; R 4 is C 1-3 selected from haloalkyl, CN, F, Cl, Br and I; R is independently F, Cl, Br, NH 2 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, the above R 1 is selected from H, and the other variables are as defined herein.

[0092] In some technical solutions of the present invention, the above R 1 is selected from CN, and the other variables are as defined herein.

[0093] In some technical solutions of the present invention, the above R 1 is selected from F, and the other variables are as defined herein.

[0094] In some technical solutions of the present invention, the above R 1 is selected from Cl, and the other variables are as defined herein.

[0095] In some technical solutions of the present invention, the above R 1 is selected from Br, and the other variables are as defined herein.

[0096] In some technical solutions of the present invention, the above R 1 is C 1-3 alkyl, 1-3 The alkyl is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0097] In some technical solutions of the present invention, the above R 1 is CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , C.H. 2 F, CHF 2 , C.F. 3 , C.H. 2 Cl, CHCl 2 and CCl 3 and the other variables are as defined herein.

[0098] In some technical solutions of the present invention, the above R 1 -OC 1-3 alkyl, wherein -OC 1-3 The alkyl is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0099] In some technical solutions of the present invention, the above R 1 -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH3 , -OCH(CH 3 ) 2 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 Cl, -OCHCl 2 and -OCCl 3 and the other variables are as defined herein.

[0100] In some technical solutions of the present invention, the above R 1 is C 3-6 cycloalkyl, 3-6 Cycloalkyl is

[0101] [ka]

[0102] and

[0103] [ka]

[0104] is optionally substituted by 1, 2 or 3 R.

[0105] In some technical solutions of the present invention, the above R 1 is S(O) m R a wherein S(O) is selected from m R a teeth,

[0106] [ka]

[0107] and the other variables are as defined herein.

[0108] In some technical solutions of the present invention, the above R 1is S(O) m NR a R b wherein S(O) is selected from m NR a R b teeth,

[0109] [ka]

[0110] and the other variables are as defined herein.

[0111] In some technical solutions of the present invention, the above R 1 is P(X)R c R d wherein P(X)R c R d teeth,

[0112] [ka]

[0113] Selected from X 1 is CH 2 , O and NH; p is selected from 0 and 1; r is selected from 0 and 1, and the other variables are as defined herein.

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

[0115] [ka]

[0116] and the other variables are as defined herein.

[0117] In some technical solutions of the present invention, the above R 1 teeth,

[0118] [ka]

[0119] and the other variables are as defined herein.

[0120] In some technical solutions of the present invention, the above R 1 is C(O)R a wherein C(O)R a teeth,

[0121] [ka]

[0122] and the other variables are as defined herein.

[0123] In some technical solutions of the present invention, the above R 1 is C(O)NR a R b wherein the C(O)NR a R b teeth,

[0124] [ka]

[0125] and the other variables are as defined herein.

[0126] In some technical solutions of the present invention, the above R 1 teeth,

[0127] [ka]

[0128] and the other variables are as defined herein.

[0129] In some technical solutions of the present invention, the above R2 and R 3 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, or R 2 , R 3 together with the C atom linked thereto form cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, with the other variables being as defined herein.

[0130] In some technical solutions of the present invention, the above R 2 and R 3 are each independently selected from H and methyl, and the other variables are as defined herein.

[0131] In some technical solutions of the present invention, the above R 2 , R 3 together with the C atom attached thereto form a cyclopropyl, and the other variables are as defined herein.

[0132] In some technical solutions of the present invention, the above L 1 -CH 2 -, -O-, -NR e -, -C(O)-, -S(O)-, -S(O) 2 - and -P(O)-, the other variables being as defined herein.

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

[0134] [ka]

[0135] and the other variables are as defined herein.

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

[0137] [ka]

[0138] teeth,

[0139] [ka]

[0140] and the other variables are as defined herein.

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

[0142] [ka]

[0143] teeth,

[0144] [ka]

[0145] and the other variables are as defined herein.

[0146] In some technical solutions of the present invention, the compound is represented by formula (IA-1) and (IA-2):

[0147] [ka]

[0148] The other variables are as defined in the present invention.

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

[0150] [ka]

[0151] The other variables are as defined in the present invention.

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

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

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

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

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

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

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

[0159] The present invention provides a compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

[0160] [ka]

[0161] The present invention provides a compound represented by the formula: or a pharma- ceutically acceptable salt thereof.

[0162] [ka]

[0163] [ka]

[0164] The present invention further provides the use of a compound defined by any of the above technical solutions or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a CDK7-related disease.

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

[0166] In a second aspect of the present invention, there is further provided a pharmaceutical composition, comprising a compound defined by any of the above technical solutions or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

[0167] The present invention further provides a method for treating a disease associated with CDK7 in a subject in need thereof, comprising providing to the subject a therapeutically effective amount of a compound defined by any of the above technical solutions or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition.

[0168] The present invention further provides use of the above compound, an isomer thereof or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with CDK7.

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

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

[0171] [Definitions and Explanations] Unless otherwise stated, the following terms and phrases used herein have the following meanings. A particular term or phrase, unless otherwise defined, should be understood as being of ordinary definition, not indefinite or unclear. When a trade name is mentioned in this specification, it refers to the corresponding product or its active ingredient.

[0172] As used herein, "pharmaceutically acceptable salts" refer to those compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit / risk ratio.

[0173] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention, which is prepared with a relatively non-toxic acid or base with a compound having certain substituents discovered in this invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds with a sufficient amount of base in a separate solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting these compounds with a sufficient amount of acid in a separate solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (e.g., arginine, etc.), and organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, 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, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into any suitable base or acid addition salt.

[0174] The pharma- ceutically acceptable salts of the present invention can be synthesized in a conventional manner from the parent compound which contains an acidic or basic group. Typically, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0175] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or non-enantiomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are both within the scope of the present invention.

[0176] Unless otherwise stated, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other.

[0177] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

[0178] Unless otherwise explained, the term "diastereomer" is a stereoisomer in which the molecules have two or more centers of chirality and the molecules are not mirror-images of each other.

[0179] Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0180] [ka]

[0181] Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and can be rapidly interconverted at room temperature. Tautomers can reach chemical equilibrium of tautomers when possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of some bond electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0182] Unless otherwise explained, the terms "enriched in one isomer," "isomer-enriched," "enriched in one enantiomer," or "enantiomer-enriched" mean that the amount of one isomer or enantiomer is less than 100% and that the amount of such isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0183] Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0184] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared using asymmetric synthesis or chiral reagents or other conventional techniques. A single enantiomer of a compound of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is decomposed to provide the desired isolated enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers can be resolved by conventional methods known in the art, followed by recovery to provide the isolated enantiomers. Separation of enantiomers and diastereomers is also typically accomplished by chromatographic techniques using chiral stationary phases and any chemical derivatization techniques (e.g., carbamate formation from amines).

[0185] The compounds of the present invention may contain unnatural atomic isotopes at one or more atoms that constitute the compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with radioisotopes such as radioisotopes C). Also, for example, deuterium can be replaced with hydrogen to form deuterated drugs, where the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, improved therapeutic efficacy, and extended biological half-life of the drug. Conversion of the isotopic composition of the compounds of the invention, whether radioactive or not, is within the scope of the invention.

[0186] "Optional" or "optionally" means that the following event or circumstance may occur, but does not necessarily occur, and that the description includes situations where the described event or circumstance does not occur.

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

[0188] The term "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise defined, the type and number of substituents are optional as long as they are chemically stable and feasible.

[0189] When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition is independent in each occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group is optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

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

[0191] When one of the variables is a single bond, the two groups it links are directly linked; for example, when L in ALZ represents a single bond, the structure is actually AZ.

[0192] The absence of a substituent represents that the substituent is not present, for example, the absence of X in AX represents that the structure is actually A. When no atom through which a substituent is substituted for a given substituent is specified, such a substituent may be bonded through any atom thereof, for example, a pyridinyl group as a substituent may be bonded to the substituent through any carbon atom of the pyridine ring.

[0193] If the listed linking group does not specify another linking direction, then the linking direction is arbitrary, for example:

[0194] [ka]

[0195] In the formula, the linking group L is -MW-, and in this case, -MW- constitutes ring A and ring B in the same direction as the reading order from left to right.

[0196] [ka]

[0197] You can also construct rings A and B in the reverse order of reading from left to right.

[0198] [ka]

[0199] Combinations of the above linking groups, substituents and / or variables are permissible only if such combinations result in stable compounds.

[0200] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, the number of H atoms at the site is reduced to a group with a corresponding valence according to the number of bonded chemical bonds. The chemical bond by which the site is bonded to another group is:

[0201] [ka]

[0202] For example, -OCH 3A straight solid bond means that the group is bonded to another group via an oxygen atom of the group.

[0203] [ka]

[0204] A straight dashed bond within a group means that a nitrogen atom within the group is bonded at both ends to other groups.

[0205] [ka]

[0206] The wavy line in the middle means that the phenyl group is bonded to another group via carbon atoms at positions 1 and 2.

[0207] [ka]

[0208] means that any available site on the piperidinyl group can be bonded to another group by one chemical bond, and at least

[0209] [ka]

[0210] It includes the four bond forms, and even if the H atom is drawn as -N-,

[0211] [ka]

[0212] for

[0213] [ka]

[0214] Groups of this bond type are included, but when one chemical bond is attached, one H is removed at that site to become the corresponding monovalent piperidine group.

[0215] Unless otherwise stated, the number of atoms in a ring is generally defined as the number of ring members, e.g., 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 consisting of 1 to 3 carbon atoms in a straight or branched chain. 1-3 Alkyl has C 1-2 and C. 2-3 Alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), 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 remainder of the molecule through an oxygen atom. 1-3 The alkoxy group is C 1-2 , C 2-3 , C 3 and C 2 Alkoxy and the like are included. C 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), and the like.

[0218] Unless otherwise defined, the term "C 1-3 "Haloalkyl" refers to monohaloalkyl and polyhaloalkyl containing 1 to 3 carbon atoms. 1-3 Haloalkyl is C 1-2 , C 2-3 , C 3 , C 2 and C 1 Haloalkyl and the like are included. C 1-3Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl, and the like.

[0219] Unless otherwise defined, "C 2-4 "Alkenyl" refers to a straight or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position in the group. 2-4 Alkenyl is C 2-3 , C 4 , C 3 and 2 alkenyl, 2-4 Alkenyl may be monovalent, divalent or polyvalent. 2-4 Illustrative examples of cycloalkyl include, but are not limited to, vinyl, propenyl, butenyl, butadienyl, and the like. 2-3 "Alkenyl" refers to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position in the group. 2~3 Alkenyl has C 3 and C. 2 alkenyl, etc. 2-3 Alkenyl may be monovalent, divalent or polyvalent. 2-3 Examples of cycloalkyl include, but are not limited to, vinyl, propenyl, and the like.

[0220] Unless otherwise defined, the terms "halogen" or "halo," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0221] Unless otherwise defined, C n-n+m Or C n -C n+m includes any one specific embodiment of n to n+m carbons, for example, C 1-12 is C 1 , C 2 , C 3 , C4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 Including any one of the ranges n to n+m, for example, C 1-12 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 Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of the ranges of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0222] Unless otherwise defined, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group composed of 4 to 6 ring atoms, of which 1, 2, 3, and 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). P, p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Additionally, for "4-6 membered heterocycloalkyl", a heteroatom can occupy the position of the connection between the heterocycloalkyl and the rest of the molecule. Said 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl, etc. Illustrative examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or hexahydropyridazinyl, and the like.

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

[0224] Unless otherwise defined, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms represents a saturated cyclic group composed of 3-6 ring atoms, of which 1, 2, 3, and 4 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 bridged rings. Furthermore, with respect to "3-6 membered heterocycloalkyl", a heteroatom can occupy the position of attachment of the heterocycloalkyl to the rest of the molecule. The 3-6 membered heteroaryl group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heteroaryl groups, etc. Illustrative examples of 3-6 membered heteroaryl groups include, but are not limited to, heterobutyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydropyran, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or hexahydropyridazinyl.

[0225] The term "leaving group" refers to a functional group or atom that may be replaced by another functional group or atom in a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate, chlorine, bromine, iodine, sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like, and acyloxy groups such as acetyloxy, trifluoroacetyloxy, and the like.

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

[0227] The compounds of the present invention can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments given below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and 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 known to those skilled in the art, and when the present invention relates to the absolute configuration of the 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 crystal is collected by Bruker D8 venture diffractometer, light source is CuKα radiation, scanning method: φ / ω scanning, after collecting relevant data, the absolute configuration can be confirmed by direct method (Shelxs97) crystal structure analysis.

[0229] All solvents used in this invention can be obtained from commercial sources. The present invention uses the following abbreviations: NH 4 HCO 3 stands for hydrocarbyl ammonium, and Xantphos Pd G4 stands for methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II).

[0230] Compounds were named according to art-conventional names or ChemDraw® software; for commercially available compounds, manufacturer's catalog names were used. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0231] The present invention will be specifically described below by way of examples, but is not intended to limit the present invention in any adverse manner. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is obvious to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention. EXAMPLES

[0232] Example 1

[0233] [ka]

[0234] [ka]

[0235] Step 1: At 25°C, trifluoromethanesulfonic acid (3.63g) was added to a hexafluoroisopropanol solvent (60ml) of compound 1-1 (5.8g) and compound 1-2 (5.77g), and the mixture 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 further washed once with brine (100ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether: ethyl acetate = 100: 1 to 1: 1) to obtain compound 1-3. LCMS (ESI) m / z: 420.0, 422.0 (M + 1).

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

[0237] Step 3: At 25°C, triethylamine (519.47mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.30g) were added to a solution of compound 1-5 (1g) and compound 1-6 (264.80mg) in N,N-dimethylformamide (2ml), and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, water (20ml) was added to the reaction solution, which was then extracted with ethyl acetate (20ml x 3), and the combined organic phase was washed with saturated saline (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether: ethyl acetate = 100: 1 to 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 (149.11mg), 4-dimethylaminopyridine (4.78mg) and triethylamine (158.29mg) were added to a solution of compound 1-7 (630mg) in dichloromethane (5ml), and the mixture was stirred at 25°C under the protection of nitrogen gas for 12 hours. After the reaction was completed, water (20ml) was added to the reaction solution, which was then extracted with ethyl acetate (20ml x 3), and the combined organic phase was washed with saturated saline (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether:ethyl acetate = 100:1 to 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 (2.61g) was added to a solution of compound 1-8 (300mg) in dichloromethane (6ml), and the mixture was stirred at 25°C under nitrogen gas protection for 6 hours. After the reaction was completed, the mixture was concentrated to give the trifluoroacetate salt of compound 1-9. LCMS (ESI) m / z: 723.2, 725.2 (M+1).

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

[0242] Step 7: At 25°C, dimethylphosphine oxide (9.46mg), Xantphos Pdg4 (17.50mg) and potassium phosphate (25.736mg) were added to a solution of compound 1-10 (35mg) in dioxane (2ml), and the mixture was stirred at 120°C under the protection of nitrogen gas for 12 hours. Water (50ml) was added to the reaction solution, and then it was extracted with ethyl acetate (50ml x 3), and the combined organic phase was washed with saturated saline (50ml), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by preparative HPLC (column model: Phenomenex C18 75 x 30mm x 3um; mobile phase: [water (formic acid)-acetonitrile]: acetonitrile%: 8% to 38%, 7min) to obtain the formate salt of compound 1. LCMS (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, 4H).

[0243] Example 2

[0244] [ka]

[0245] [ka]

[0246] Step 1: At 25°C, diisopropylethylamine (2.90g) was added to a mixed solution of compound 1-3 (2.2g) and compound 2-1 (888.26mg, hydrochloride salt) in 1-methyl-2-pyrrolidone (25ml), and the mixed solution was stirred at 65°C for 12 hours. After the reaction was completed, water (20ml) was added to the reaction solution, which was then extracted with ethyl acetate (30ml x 3), and the combined organic phase was washed twice with saturated saline (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 (782.03mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (920.29mg) were added to a solution of compound 2-2 (620mg) and compound 1-6 (187.27mg) in N,N-dimethylformamide (2ml), and the mixture was stirred at 25°C for 12 hours. After the reaction was completed, water (20ml) was added to the reaction solution, which was then extracted with ethyl acetate (50ml x 3), and the combined organic phase was washed with saturated saline (50ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, dichloromethane:methanol = 100:1 to 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 (154.81mg) and pyridine (102.93mg) were added to a solution of compound 2-4 (500mg) in dichloromethane (5ml), and the mixture was stirred at 50°C for 2 hours under the protection of nitrogen gas. After the reaction was completed, water (20ml) was added to the reaction solution, and then it was extracted with ethyl acetate (50ml x 2), and the combined organic phase was washed with saturated saline (50ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative HPLC (column model: Phenomenex luna C18 150 x 40mm x 15um; mobile phase: [water (formic acid)-acetonitrile]:acetonitrile%: 18%~48%, 10min) to obtain compound 2-5. LCMS (ESI) m / z: 615.0, 617.0 (M+1).

[0249] Step 4: At 25°C, potassium carbonate (136.06mg) and sodium iodide (47.74mg) were added to a solution of compound 2-5 (200mg) in acetonitrile (10ml), and the mixture was stirred at 85°C for 24 hours under the protection of nitrogen gas. After the reaction was completed, water (10ml) was added to the reaction solution, which was then extracted with ethyl acetate (20ml x 3), and the combined organic phase was washed with saturated saline (20ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, dichloromethane:methanol = 100:1 to 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 (4.91mg), Xantphos Pdg4 (9.09mg) and potassium phosphate (13.366mg) were added to a solution of compound 2-6 (20mg) in dioxane (1ml), and the mixture was stirred at 120°C under the protection of nitrogen gas for 12 hours. Water (20ml) was added to the reaction solution, and then it was extracted with ethyl acetate (30ml x 3), and the combined organic phase was washed twice with saturated saline (30ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by preparative HPLC (column model: Phenomenex C18 75 x 30mm x 3um; mobile phase: [water (formic acid)-acetonitrile]:acetonitrile%: 5% to 35%, 7min) to obtain the formate salt of compound 2. LCMS (ESI) m / z: 577.3 (M+1). 1 H NMR (400 MHz, CD 3 OD) 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, 3 H) 1.17 - 1.33 (m, 7H).

[0251] Example 3

[0252] [ka]

[0253] [ka]

[0254] Step 1: 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) at room temperature, 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×2), and the combined organic phase was washed with saturated saline (60 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product compound 3-2. LCMS (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 reacted at 25 ° C for 1 hour. The reaction solution was first diluted with water (100 ml), extracted with ethyl acetate (100 ml), and the organic phase was further washed with saturated saline (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 3-4. LCMS (ESI) m / z: 683.1, 685.1 (M + 1).

[0256] Step 3: At room temperature, pyridine (115.72 mg) and thionyl chloride (174.05 mg) were added to a solution of compound 3-4 (0.5 g) in tetrahydrofuran (10 ml), 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), and the combined organic phase was washed with saturated saline (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound 3-5. LCMS (ESI) m / z: 601.2, 603.2 (M-100+1).

[0257] Step 4: Hydrochloric acid / ethyl acetate (1.98 ml) was added to a solution of compound 3-5 (233 mg) in ethyl acetate (4 ml) at room temperature, and the mixture was reacted for 0.5 hours at 25° C. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of 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 the hydrochloride salt of compound 3-6 (233 mg) in acetonitrile (10 ml), and the mixture was reacted at 100° C. for 40 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (ethyl acetate / methanol=1 / 0-10 / 1) to obtain compound 3-7. LCMS (ESI) m / z: 565.2, 567.2 (M+1).

[0259] Step 6: To a solution of compound 3-7 (160 mg) and dimethylphosphine oxide (441.72 mg) in 1,4-dioxane (3 ml) at room temperature, potassium phosphate (360.40 mg) and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (272.32 mg) were added, the mixture was purged with nitrogen gas three times, and the mixture was 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%, 7min) and preparative normal phase HPLC (column model: Welch Ultimate XB-SiOH 250×50×10um; mobile phase: [n-hexane-ethanol]; B%: 1%-40%, 15min) to obtain compound 3. LCMS(ESI) m / z: 563.3(M+1). 1 H NMR (400 MHz, CDCl 3): 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, vinylmagnesium bromide (1M, 110.09ml) was added dropwise to a solution of compound 4-1 (6g) in tetrahydrofuran (60ml), and the mixture was stirred at -40°C for 2 hours. The mixture was continued to be stirred at -40°C for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (100ml) was poured into the reaction solution, and then it was extracted twice with ethyl acetate (50ml x 2), and the combined organic phase was washed with saturated saline (50ml), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether: ethyl acetate = 20: 1 to 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 (1.67ml) was added to a solution of compound 4-2 (4g) and compound 1-2 (4.91g) in hexafluoroisopropanol (40ml), and the mixture was stirred at 65°C for 12 hours. The completion of the reaction was detected by LCMS. After the reaction was completed, it was concentrated to obtain a residue, water (50ml) was added, and then extracted twice with ethyl acetate (50ml x 2), the combined organic phase was washed with saturated saline (50ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain compound 4-3. LCMS (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 mixture was stirred at 50°C for 12 hours. After the reaction was completed, the reaction solution was poured into water (50ml), then extracted twice with ethyl acetate (50ml x 2), and the combined organic phase was washed with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether:ethyl acetate = 5:1 to 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 mixture was stirred at 60°C for 3 hours. After the reaction was completed, the reaction solution was poured into water (50ml), then extracted twice with ethyl acetate (50ml x 2), the combined organic phase was washed with water (50ml) and saturated saline (50ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain compound 4-6. LCMS (ESI) m / z: 656.2, 658.2 (M+1).

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

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

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

[0270] Step 8: At 20°C, methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (214.50mg) and potassium phosphate (141.93mg) were added to a solution of compound 4-9 formate (120mg) and dimethylphosphine oxide (521.88mg) in 1,4-dioxane (10ml), and the mixture was stirred at 120°C under nitrogen gas protection for 24 hours. After the reaction was completed, the reaction solution was filtered, the cake was washed with ethyl acetate (20ml), and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column model: Waters Xbridge C18 150×50mm×10um; mobile phase: [water (NH 4 HCO 3 )-acetonitrile]: 52% to 82%, 10 min) to give compound 4. LCMS (ESI) m / z: 536.2 (M+1). 1 H NMR (400 MHz, CD 3OD) 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, 4 ml) was added to a solution of compound 1-5 (0.5 g) in ethyl acetate (4 ml), and the mixture was stirred at 20° C. for 1 hour. After completion of the reaction, 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: Compound 5-1 (0.35 g) was added with hydrochloric acid / methanol (4 M, 10 ml) at 20° C., and the mixture was stirred at 50° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound 5-2. LCMS (ESI) m / z: 497.9, 499.9 ((M+1).

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

[0277] Step 4: 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) at 20° C., and the mixture was stirred at 50° C. for 12 hours. Sodium hydroxide (21.51 mg) was added to the reaction solution, and the mixture was stirred at 50° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a residue, water (20 ml) was added to the residue, and the aqueous phase was adjusted to pH 5 with hydrochloric acid (1 mol / L), and then extracted with ethyl acetate (50 ml×2), and 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., hydrochloric acid / ethyl acetate (4M, 10 ml) was added to a solution of compound 5-5 (0.15 g) in ethyl acetate (10 ml), and the mixture was stirred at 20° C. for 0.5 hours. After completion of the reaction, the reaction solution was concentrated to obtain the hydrochloride salt of compound 5-6. LCMS (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 (144.55mg) and N,N-diisopropylethylamine (163.78mg) were added to a solution of compound 5-6 (0.15g) in N,N-dimethylformamide (30ml), and the mixture was stirred at 20°C for 2 hours. After the reaction was completed, the reaction solution was poured into water (50ml), then extracted with ethyl acetate (30ml x 2), and the combined organic phase was washed with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a 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, methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (44.77mg) and potassium phosphate (29.63mg) were added to a solution of compound 5-7 (25mg) and dimethylphosphine oxide (108.93mg) in 1,4-dioxane (3ml), and the mixture was stirred at 120°C under nitrogen gas protection for 20 hours. After the reaction was completed, the reaction solution was filtered, the cake was washed with ethyl acetate (15ml), and the filtrate was concentrated to obtain the residue. The residue was purified by preparative high performance liquid chromatography (column model: Waters Xbridge C18 150×50mm×10μm; mobile phase: [water (NH 4 HCO 3 )-acetonitrile]: 25% to 55%, 10 min) to give compound 5. LCMS (ESI) m / z: 535.3 (M+1).

[0281] 1 H NMR (400 MHz, CD 3OD) 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 (1.5 g) was added with a solution of hydrochloric acid / methanol (4 M, 30 ml), and the mixture was stirred at 50° C. for 12 hours. After the reaction was completed, 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 (824.28mg) was added to a solution of compound 6-1 hydrochloride (0.7g) and compound 5-3 (804.07mg) in N,N-dimethylformamide (20ml), and the mixture was stirred at 100°C for 12 hours. After the reaction was completed, water (30ml) was poured into the reaction solution, which was then extracted twice with ethyl acetate (30ml x 2), and the combined organic phase was washed with water (30ml) and saturated brine (30ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether:ethyl acetate = 2:1 to ethyl acetate:methanol = 10:1) to obtain compound 6-2. LCMS (ESI) m / z: 683.1, 685.1 (M+1).

[0287] Step 3: 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) at 20° C., and the mixture was stirred at 60° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a residue, water (20 ml) was added to the residue, and the aqueous phase was adjusted to pH 5 with hydrochloric acid (1 mol / L), then extracted twice with ethyl acetate (20 ml×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., hydrochloric acid / ethyl acetate (4M, 10 ml) was added to a solution of compound 6-3 (0.6 g) in ethyl acetate (10 ml), and the mixture was stirred at 20° C. for 0.5 hours. After completion of the reaction, the reaction solution was concentrated to obtain the hydrochloride salt of compound 6-4. LCMS (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 (545.99mg) and N,N-diisopropylethylamine (618.61mg) were added to a solution of the hydrochloride salt of compound 6-4 (0.58g) in N,N-dimethylformamide (300ml), and the mixture was stirred at 20°C for 0.5 hours. After the reaction was completed, the reaction solution was poured into water (600ml), then extracted twice with ethyl acetate (150ml x 2), and the combined organic phase was washed with water (200ml x 2) and saturated brine (200ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (silica gel, eluent, petroleum ether:ethyl acetate = 1:1 to 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, methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2-methylamino-1,1-biphenyl-2-yl)palladium(II) (366.52mg) and potassium phosphate (242.52mg) were added to a solution of compound 6-5 (0.21mg) and dimethylphosphine oxide (891.75mg) in 1,4-dioxane (6ml), and the mixture was stirred at 120°C under nitrogen gas protection for 16 hours. After the reaction was completed, the reaction solution was filtered, the cake was washed with ethyl acetate (20ml), and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column model: Waters Xbridge C18 150×50mm×10um; mobile phase: [water (NH 4 HCO 3 )-acetonitrile]: 28% to 58%, 10 min) to give 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 Test 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 multilabel analyzer (PerkinElmer).

[0293] Testing Method: Preparation of kinase buffer: Kinase buffer is 50 mM HEPES, 1 mM EDTA, 10 mM MgCl 2 , 0.01% Brij-35 and pH adjusted to 7.4.

[0294] 2.38 g HEPES, 58 mg EDTA, 406 mg MgCl in 200 ml buffer 2 20 mg of Brij-35 was added and the pH was adjusted to 7.4.

[0295] Preparation of stop solution: A stop solution was made using 100 μL of 1M EDTA stock solution and 0.625 μL of 1× detection buffer, mixed with 1725 μL of distilled water.

[0296] Kinase buffer was used to dilute the enzyme, Ulight-MBP polypeptide, ATP and inhibitors.

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

[0298] The test compounds were diluted 5-fold with a pipette into 8 concentrations, i.e., 40μM to 0.512nM, and the final concentration of DMSO was 4%, and two wells were set up under the same conditions. 2.5μL of each concentration gradient of inhibitor, 5μL of CDK7 / CyclinH / MAT1 enzyme (5ng), and 2.5μL of a mixture of substrate and ATP (44mM ATP, 50nM Ulight-MBP polypeptide) were added to the microplate, and the final concentration gradient of the compounds was diluted from 10μM to 0.128nM. The reaction system was placed at 25℃ and reacted for 60 minutes. After the reaction was completed, 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 completed, 5 μL of Eu-MBP antibody dilution was added to each well and the reaction was continued at 25°C for 60 minutes. Data were then collected using a PerkinElmer Nivo multimode microplate reader in TR-FRET mode (excitation wavelength was 320 nM, emission wavelength was 665 nM).

[0299] Data Analysis: Convert the original data into percent inhibition using the formula (Sample-Min) / (Max-Min) × 100% and calculate IC 50 The values ​​were determined by curve fitting using four parameters (log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides the enzyme inhibitory activity of the compounds of the present invention against CDK7 / CyclinH / MAT1.

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

[0301] Experimental Example 2: In vitro CDK2 / CyclinB1 enzyme activity test Test 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 multilabel analyzer (PerkinElmer).

[0302] Testing Method: Preparation of kinase buffer: Kinase buffer is 50 mM HEPES, 1 mM EDTA, 10 mM MgCl 2 , 0.01% Brij-35 and pH adjusted to 7.4.

[0303] 2.38 g HEPES, 58 mg EDTA, 406 mg MgCl in 200 ml buffer 2 20 mg of Brij-35 was added and the pH was adjusted to 7.4.

[0304] Preparation of stop solution: A stop solution was made 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] Kinase buffer was used to dilute the enzyme, Ulight-4E-BP1 peptide, ATP and inhibitors.

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

[0307] The test compounds were diluted 5-fold with a pipette into 8 concentrations, i.e., 40μM to 0.512nM, and the final concentration of DMSO was 4%, and two wells were set up under the same conditions. 2.5μL of each concentration gradient of inhibitor, 5μL of CyclinE 1 enzyme (10ng), and 2.5μL of a mixture of substrate and ATP (4mM ATP, 100nM Ulight-4E-BP1 peptide) were added to the microplate, and the final concentration gradient of the compounds was diluted from 10μM to 0.128nM. The reaction system was placed at 25℃ and reacted for 120 minutes. After the reaction was completed, 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 completed, 5 μL of Eu-anti-phospho-tyrosine antibody dilution was added to each well and the reaction was continued at 25°C for 60 minutes. Data were then collected using a PerkinElmer Nivo multimode microplate reader in TR-FRET mode (excitation wavelength 320 nM, emission wavelength 665 nM).

[0308] Data Analysis: Convert the original data into percent inhibition using the formula (Sample-Min) / (Max-Min) × 100% and calculate IC 50 The values ​​were determined by curve fitting using four parameters (log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides the enzyme inhibitory activity of the compounds of the present invention against CDK2 / CyclinE1.

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

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

[0311] Testing Method: Preparation of kinase buffer: Kinase buffer is 50 mM HEPES, 1 mM EDTA, 10 mM MgCl 2 , 0.01% Brij-35 and pH adjusted to 7.4.

[0312] 2.38 g HEPES, 58 mg EDTA, 406 mg MgCl in 200 ml buffer 2 20 mg of Brij-35 was added and the pH was adjusted to 7.4.

[0313] Preparation of stop solution: A stop solution was made 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] Kinase buffer was used to dilute the enzyme, Ulight-4E-BP1 peptide, ATP and inhibitors.

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

[0316] The test compounds were diluted 4-fold with a pipette into 8 concentrations, i.e., from 400μM to 24.4nM, and the final concentration of DMSO was 4%, and two wells were set up under the same conditions. 2.5μL of each concentration gradient of inhibitors, 5μL of CDK9-CyclinT1 enzyme (2ng), and 2.5μL of a mixture of substrate and ATP (8mM ATP, 50nM Ulight-4E-BP1 peptide) were added to the microplate, and the final concentration gradient of the compounds was diluted from 100μM to 6.1nM. The reaction system was placed at 25℃ and reacted for 120 minutes. After the reaction was completed, 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 completed, 5 μL of Eu-anti-phospho-tyrosine antibody dilution was added to each well and the reaction was continued at 25°C for 60 minutes. Data were then collected using a PerkinElmer Nivo multimode microplate reader in TR-FRET mode (excitation wavelength 320 nM, emission wavelength 665 nM).

[0317] Data Analysis: Convert the original data into percent inhibition using the formula (Sample-Min) / (Max-Min) × 100% and calculate IC 50 The values ​​were obtained by curve fitting using four parameters (log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides 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 have strong inhibitory activity against CDK9 kinase.

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

[0320] Testing 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 diluted 3-fold with a pipette into eight concentrations, i.e., from 2 μM to 304 nM, and two wells were set up under the same conditions. 78 μL of medium was added to the middle plate, and 2 μL / well of the gradient diluted compound was transferred to the middle plate according to the corresponding position, and 20 μL / well was transferred to the cell plate after uniform mixing. The range of compound concentrations transferred to 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 was included in the data analysis. 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate, and the plate was cultured at room temperature for 10 minutes to stabilize the luminescence signal. The data was read with a multi-mode microplate reader.

[0322] 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 10 min to stabilize the luminescence signal. Data were read on a multimode microplate reader.

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

[0324] Experimental Conclusion: The compounds of the present invention have potent inhibitory activity against HCC70 cells.

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

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

[0327] The test compound was diluted 5-fold with a pipette into 8 concentrations, i.e., from 200 μM to 0.512 nM, and two wells were set up under the same conditions. 78 μL of medium was added to the middle plate, and 2 μL / well of the gradient diluted compound was transferred to the middle plate according to the corresponding position, and after uniform mixing, 20 μL / well was transferred to the cell plate. The range of compound concentrations transferred to 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 was included in the data analysis. 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate, and the plate was cultured at room temperature for 10 minutes to stabilize the luminescence signal. The data was read with a multi-mode microplate reader.

[0328] 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 10 min to stabilize the luminescence signal. Data were read on a multimode microplate reader.

[0329] Data Analysis: Convert the original data into percentage inhibition using the formula (Sample-Min) / (Max-Min) × 100% to IC 50 The values ​​were determined by curve fitting using four parameters (log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides 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: Intracorporeal drug efficacy test In vivo efficacy experiments were performed in BALB / c nude mice subcutaneously implanted with xenografts (CDX) based on a human tumor cell line derived from a patient with HCC70 breast cancer.

[0333] Experimental Procedure: BALB / c nude mice (female, 6-8 weeks old, body weight: approximately 19-23 g) were housed in individual ventilated cages (6 mice per cage) in a specific pathogen-free environment. All cages, pads and water were disinfected before use. All animals were fed a standard certified commercial laboratory diet ad libitum. A total of 36 mice purchased from the Laboratory Animal Department of the Shanghai Institute of Planned Parenthood Research (formerly Shanghai Sippe-Bk) were used in the study. Each mouse was inoculated with 10 × 10 6 HCC70 cells were inoculated, the inoculation volume was 0.2 mL, and the cell suspension was PBS and Matrigel (1:1). The average tumor volume was approximately 179 mm 3 When the tumor volume reached 100 mg / kg, the subjects were randomly assigned to each group and drug administration was started at a dose of 3 mg / kg. Tumor volumes were measured twice a week using two-dimensional calipers, and the volume was expressed in mm 3 The measured value was calculated using the following formula: V=0.5a×b 2 , where a and b are the long and short diameters of the tumor, respectively. The experimental results are shown in Table 2.

[0334] [Table 2]

[0335] Experimental conclusion: In the HCC70 breast cancer CDX in vivo efficacy model, the compounds of the present invention showed good efficacy and safety.

Claims

1. A compound represented by formula (II) or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (however, R １ are 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 N.R. ａ R ｂ and C(O)NR ａ R ｂ and C is selected from １－３ Alkyl, -OC １－３ Alkyl and C ３－６ Cycloalkyl is optionally substituted by 1, 2 or 3 R; R ａ is C １－３ Alkyl, -OC １－３ Alkyl, -NHC １－３ Alkyl, -N(C １－３ Alkyl) ２ and C ３－６ cycloalkyl; R ｂ is H and C １－３ alkyl, １－３ Alkyl, -OC １－３ Alkyl, -NHC １－３ Alkyl, -N(C １－３ Alkyl) ２ and C ３－６ Cycloalkyl is optionally substituted by 1, 2 or 3 R; R ｃ and R ｄ is independently C １－３ Alkyl and O １－３ alkyl, or R ｃ , R ｄ form a 4- to 6-membered heterocycloalkyl together with the P atom to which they are linked, １－３ Alkyl, C １－３ Alkyl and 4- to 6-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; X is selected from O and S; L １ is -CH ２ -, -O-, -NR ｅ -, -C(O)-, -S(O) ｑ - and -P(O)-, L ２ is -CH ２ -, -O- and -NR ｅ - selected from R ｅ is H and C １－３ alkyl, １－３ The alkyl is optionally substituted by 1, 2 or 3 R; R ２ and R ３ are each independently H, C １－３ Alkyl and C ２－４ alkenyl; or R ２ , R ３ are C together with the C atoms connected to them. ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, １－３ Alkyl, C ２－４ Alkenyl, C ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R; R ４ is C １－３ selected from haloalkyl, CN, F, Cl, Br and I; R is independently F, Cl, Br, NH ２ 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.

2. R １ is S(O) ｍ R ａ and said S(O) ｍ R ａ teeth, 【Chemistry 2】 2. The compound of claim 1, selected from:

3. R １ is P(X)R ｃ R ｄ and said P(X)R ｃ R ｄ teeth, 【Chemistry 3】 is selected from １ is CH ２ 2. The compound of claim 1, wherein R is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 108, 109, 109, 109, 109, 108, 109, 110, 1

4. The above 【Chemistry 4】 teeth, 【Chemistry 5】 4. The compound of claim 3, selected from:

5. R １ teeth, 【Chemistry 6】 2. The compound of claim 1, selected from:

6. R １ is C(O)R ａ and said C(O)R ａ teeth, 【Chemistry 7】 2. The compound of claim 1, selected from:

7. R １ teeth, 【Chemistry 8】 2. The compound of claim 1, selected from:

8. R ２ and R ３ are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, or R ２ , R ３ The compound according to claim 1, wherein together with the C atom linked thereto, form cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or a pharma- ceutically acceptable salt thereof.

9. R ２ and R ３ or a pharma- ceutically acceptable salt thereof.

9. The compound of claim 8, wherein each R is independently selected from H and methyl;

10. R ２ , R ３ The compound according to claim 8, wherein together with the C atom to which they are linked form a cyclopropyl, or a pharma- ceutically acceptable salt thereof.

11. R ４ CF ３ 3. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, selected from:

12. L １ is -CH ２ -, -O-, -NR ｅ -, -C(O)-, -S(O)-, -S(O) ２ 2. The compound of claim 1, wherein the compound is selected from - and -P(O)-, or a pharma- ceutically acceptable salt thereof.

13. Structural Units 【Chemistry 9】 teeth, 【Chemistry 10】 2. The compound of claim 1, selected from:

14. Structural Units 【Chemistry 11】 teeth, 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof.

15. Structural Units 【Chemistry 13】 teeth, 【Chemistry 14】 15. The compound of claim 14, selected from:

16. Structural Units 【Chemistry 15】 teeth, 【Chemistry 16】 or a pharma- ceutically acceptable salt thereof.

17. 2. The compound of claim 1, wherein the compound is selected from the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 17】 (However, R １ , R ２ , R ３ , X, n, t, R ｅ , L １ and L ２ is as defined in any one of claims 1 to 16.

18. 18. The compound of claim 17, wherein the compound is selected from the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 18】 (where X, n, t and R ｅ is as defined in any one of claims 1 to 17.

19. R ｅ The compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein is selected from hydrogen and methyl.

20. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 19】 【Chemistry 20】

21. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 21】 【Chemical 22】

22. 22. Use of a compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a CDK7-related disease.

23. The use according to claim 22, wherein the CDK7-related disease refers to breast cancer.

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