Substituted aryl compounds

Abstract

This application describes substituted aryl compounds as RAD51 inhibitors and their pharmaceutically acceptable salts. The compounds have the structure of formula (I) and have the substituents and structural features described in this application. This application also describes pharmaceutical compositions comprising the compounds of formula (I) or their pharmaceutically acceptable salts, and the use of the compounds of formula (I) or their pharmaceutically acceptable salts, and the pharmaceutical compositions comprising them, in the preparation of drugs for preventing or treating RAD51-mediated diseases.

Description

[0001] This application claims the priority of two prior applications, namely, a patent application titled "Substituted Aryl Compounds" with the patent application number 202010102773.6, filed with the China National Intellectual Property Administration on February 19, 2020, and a patent application titled "Substituted Aryl Compounds" with the patent application number 202010738095.2, filed with the China National Intellectual Property Administration on July 28, 2020. The entire texts of the two applications are incorporated into this application by reference. Technical Field

[0002] The present invention relates to a novel substituted aryl compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and its use as a RAD51 inhibitor. Background Art

[0003] RAD51 is a eukaryotic gene. The protein encoded by this gene is a member of the RAD51 protein family, which can help repair DNA double-strand breaks. RAD51 family members are homologous to bacterial RecA, archaeal RadA, and yeast RAD51. From yeast to humans, this protein is highly conserved in most eukaryotic cells. In humans, RAD51 is a protein composed of 339 amino acids and has DNA-dependent ATP kinase activity. It plays an important role in homologous recombination during the DNA double-strand break (DSB) repair process. RAD51 is involved in the reciprocal transfer between the broken sequence and the undamaged homologous sequence, enabling the damaged region to be resynthesized.

[0004] The DNA damage response plays an important role in maintaining the stability of the cell genome and cell survival. DNA double-strand breaks (DSBs) are the most severe form of DNA damage. Homologous recombination repair is one of the important mechanisms involved in DSB damage repair in vivo, and RAD51 is a key factor involved in homologous recombinant DNA repair in vivo. RAD51 is highly expressed in various human tumor tissues, such as breast cancer, non-small cell lung cancer, prostate cancer, etc., and is associated with tumor metastasis and deterioration (Klein et al., DNA Repair (Amst). 2008 May 3; 7(5):686-693). How to effectively downregulate the level of RAD51 in tumor tissues and reduce the DNA damage repair ability of tumor cells, thereby improving the efficacy of tumor treatment, has potential clinical application value.

[0005] Homologous recombination plays multiple roles in DNA damage repair, including repairing DNA double-strand breaks and restoring damage to DNA replication blocks caused by DNA cross-linking agents. Homologous recombination repairs DNA double-strand breaks by locating homologous fragments of DNA and replicating the missing genetic information from homologous templates. A large number of studies have shown that homologous recombination is crucial for maintaining genomic stability. Research has shown that defects in proteins that promote homologous recombination repair in cells are associated with sensitivity to certain DNA damage therapies. This sensitizing effect is particularly significant for DNA cross-linking chemotherapeutic drugs and ionizing radiation (Takata et al., Mol Cell Biol. 2001 Apr; 21(8):2858-2866; Godthelp et al., Nucleic Acids Res. 2002 May 15; 30(10):2172-2182).

[0006] Recently, a research group demonstrated that the sensitivity of cells to DNA damage therapies can be further enhanced by partial inhibition of homologous recombination. For example, the use of a synthetic peptide corresponding to another paralogous protein can inhibit XRCC3 (a paralogous protein of Rad51). This synthetic peptide made Chinese hamster ovary (CHO) cells more sensitive to cisplatin and inhibited the formation of Rad51 foci caused by DNA damage (Connell et al., Cancer Res. 2004 May 1; 64(9):3002-3005).

[0007] Therefore, in view of the fact that defects in proteins related to DNA homologous recombination repair can enhance the sensitivity of cells to DNA damage therapies, there is a need to develop small molecules that can inhibit RAD51 activity. Currently, Cyteir Therapeutics, Inc. has published two patent applications related to RAD51 inhibitors (WO2019014315A1 and WO2019051465A1), which disclose a series of structurally novel RAD51 inhibitors and their pharmaceutical uses, especially for treating diseases such as cancer, autoimmune diseases, immunodeficiency, or neurodegenerative diseases.

[0008] Although certain progress has been made in the treatment of diseases such as tumors and autoimmune diseases, there are still a large number of patients in need of better and more effective clinical treatment drugs and regimens. In view of the huge unmet clinical needs and the potential application value of RAD51 inhibitors in the field of diseases such as tumors, the present invention has designed a series of compounds on the basis of the prior art to provide RAD51 inhibitors with novel structures, better drug efficacy, high bioavailability, and strong drug-likeness. Summary of the Invention

[0009] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011]

[0012] R 1 selected from

[0013] R 7 selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 7a substituents;

[0014] R 7a selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 7b substituents: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclic group oxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 10 aryloxy or 5-10 membered heteroaryloxy;

[0015] R 7b selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 7c substituents: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclic group oxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 10aryloxy or 5-10-membered heteroaryloxy;

[0016] R 7c selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl;

[0017] R 8 selected from H, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl is optionally substituted by one or more R 8a substituents;

[0018] R 8a selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 8b substituents: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10-membered heterocyclic oxy group, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10-membered heteroaryl, C6-C 10 aryloxy or 5-10-membered heteroaryloxy;

[0019] R 8b selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 8c substituents: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10-membered heterocyclic oxy group, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10-membered heteroaryl, C6-C 10Aryloxy or 5-10-membered heteroaryloxy;

[0020] R 8c Selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl;

[0021] R 9 Selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl is optionally substituted by one or more R 9a substituted;

[0022] R 9a Selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 9b substituted: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10-membered heterocyclic aryloxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10-membered heteroaryl, C6-C 10 aryloxy or 5-10-membered heteroaryloxy;

[0023] R 9b Selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 9c substituted: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10-membered heterocyclic aryloxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10-membered heteroaryl, C6-C 10Aryloxy or 5-10-membered heteroaryloxy;

[0024] R 9c Selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl;

[0025] R 10 Selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C6-C 10 aryl or 5-10-membered heteroaryl is optionally substituted by one or more R 10a substituted;

[0026] R 10a Selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 10b substituted: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10-membered heterocyclic aryloxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10-membered heteroaryl, C6-C 10 aryloxy or 5-10-membered heteroaryloxy;

[0027] R 10b Selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 10c substituted: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10-membered heterocyclic aryloxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10-membered heteroaryl, C6-C 10Aryloxy or 5- to 10-membered heteroaryloxy;

[0028] R 10c Selected from F, Cl, Br, I, OH, CN, ═O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl;

[0029] R 11 、R 12 、R 13 Independently selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R 11a substituted;

[0030] Or R 11 and R 12 together with the atoms to which they are attached form a 3- to 10-membered heterocyclic group, and the 3- to 10-membered heterocyclic group is optionally substituted by one or more R 11a substituted;

[0031] R 11a Selected from F, Cl, Br, I, OH, CN, ═O, NO2 or the following groups optionally substituted by one or more R 11b substituted: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3- to 10-membered heteroaryloxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy;

[0032] R 11b Selected from F, Cl, Br, I, OH, CN, ═O, NO2 or the following groups optionally substituted by one or more R 11c substituted: NH2, SH, C1-C 10 alkyl, C3-C 10Cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3- to 10-membered heterocyclic group oxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, C6-C 10 Aryloxy or 5- to 10-membered heteroaryloxy;

[0033] R 11c Selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 Aryl or 5- to 10-membered heteroaryl;

[0034] R 2 、R 3 、R 4 Independently selected from H, F, Cl, Br, I, OH, CN, NO2 or the following groups optionally substituted by one or more R a Substituted: NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3- to 10-membered heterocyclic group oxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, C6-C 10 Aryloxy or 5- to 10-membered heteroaryloxy;

[0035] R a Selected from F, Cl, Br, I, OH, CN, =O, NO2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3- to 10-membered heterocyclic group oxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, C6-C 10 Aryloxy or 5- to 10-membered heteroaryloxy;

[0036] L is selected from

[0037] X1, X2, X3, Y2, Y3, Z1 are independently selected from CR 15 or N;

[0038] Y1, Z2, Z3 are independently selected from O, NH or S;

[0039] m is selected from 0, 1 or 2;

[0040] R 15 is selected from H, F, Cl, Br, I, OH, CN, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, and the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 15a substituents;

[0041] The R 15a is selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclic oxy group, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 10 aryloxy or 5-10 membered heteroaryloxy;

[0042] L1 is selected from phenyl, C7-C 12 spiro group, C6-C 12 fused ring group, C5-C 12 bridged ring group, 7-12 membered spiroheterocyclic group, 6-12 membered fused heterocyclic group, 3-10 membered monocyclic heterocyclic group or 5-12 membered bridged heterocyclic group, and the 7-12 membered spiroheterocyclic group, 6-12 membered fused heterocyclic group, 3-10 membered monocyclic heterocyclic group or 5-12 membered bridged heterocyclic group contains 1 to 3 heteroatoms, and the heteroatoms are selected from O, N or S; the C7-C 12 spiro group, C6-C 12 fused ring group, C5-C 12 bridged ring group, 7-12 membered spiroheterocyclic group, 6-12 membered fused heterocyclic group, 3-10 membered monocyclic heterocyclic group or 5-12 membered bridged heterocyclic group is optionally substituted by one or more R 28 substituents;

[0043] The R 28 is selected from F, Cl, Br, I, OH, CN, NO2 or the following groups optionally substituted by one or more R 28a groups: NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3- to 10-membered heterocyclic oxy group, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy;

[0044] R 28a is selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl;

[0045] W1 and W4 are independently selected from a chemical bond, NR 16 or O;

[0046] R 16 is selected from H, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl, and the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R 16a groups;

[0047] The R 16a is selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3- to 10-membered heterocyclic oxy group, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy;

[0048] R 5 selected from a 3- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group; the 3- to 10-membered heterocyclic group or 5- to 10-membered heteroaryl group is optionally substituted by one or more R 20a substituents;

[0049] n is selected from 0 or 1;

[0050] X5 is selected from N or CR 21 ;

[0051] Y5 and Y6 are independently selected from a chemical bond, NH or CHR 22 ;

[0052] Z5 and Z6 are independently selected from O or NR 23 ;

[0053] R 17 、R 18 、R 25 、R 26 are independently selected from H, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy, the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy is optionally substituted by one or more R 17a substituents;

[0054] R 17a is selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 17b substituents: NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3- to 10-membered heterocyclic group oxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, C6-C 10 aryloxy or 5- to 10-membered heteroaryloxy;

[0055] R 17bSelected from F, Cl, Br, I, OH, CN or optionally substituted by one or more R 17c the following groups: C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group or C6-C 10 aryl;

[0056] R 17c selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl;

[0057] or R 17 , R 18 and the atom X5 to which they are attached together form a 3-10 membered heterocyclic group or C3-C 10 cycloalkyl, the 3-10 membered heterocyclic group or C3-C 10 cycloalkyl is optionally substituted by one or more R 17a substituted;

[0058] R 20 selected from the following groups optionally substituted by one or more R 20a : 5-10 membered heteroaryl, -C(O)-5-10 membered heteroaryl, 5-10 membered heterocyclic group, C6-C 10 aryl or -C(O)-C6-C 10 aryl;

[0059] R 20a selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C1-C 10 alkoxy, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl; the C1-C 10 alkyl, C1-C 10 alkoxy, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 20b substituted;

[0060] R 20b selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH or C3-C 10 cycloalkyl;

[0061] R21 , R 22 , R 27 is independently selected from H, C1-C 10 alkyl or C6-C 10 aryl, and the C1-C 10 alkyl or C6-C 10 aryl is optionally substituted by one or more R 21a substituents;

[0062] R 21a is selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl;

[0063] R 23 is selected from H, CN, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, and the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl is optionally substituted by one or more R 23a substituents;

[0064] R 23a is selected from F, Cl, Br, I, OH, CN, =O, NO2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclic group oxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 10 aryloxy or 5-10 membered heteroaryloxy;

[0065] Alternatively, R 4 , R 5 and the atoms to which they are attached together form a 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, and the 4-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl is optionally substituted by one or more R 24a substituents;

[0066] R 24aSelected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 24b : NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclic oxy group, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 10 aryloxy or 5-10 membered heteroaryloxy;

[0067] R 24b Selected from F, Cl, Br, I, OH, CN, =O, NO2 or the following groups optionally substituted by one or more R 24c : NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 alkoxy, C3-C 10 cycloalkyloxy, 3-10 membered heterocyclic oxy group, C2-C 10 alkenyl, C2-C 10 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 10 aryloxy or 5-10 membered heteroaryloxy;

[0068] R 24c Selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl;

[0069] R 6 Selected from H or the following groups optionally substituted by one or more R 6a : NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl;

[0070] R 6a Selected from F, Cl, Br, I, OH, CN, =O, NO2, C1-C 10 alkyl, C3-C 10Cycloalkyl, 3- to 10-membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy, 3- to 10-membered heterocyclic group oxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, C6-C 10 Aryloxy or 5- to 10-membered heteroaryloxy;

[0071] Provided that: when L1 is phenyl, or R 5 is a 3- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl, R 7 is not

[0072] In some embodiments, R 11 , R 12 independently is C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 Aryl or 5- to 10-membered heteroaryl, the C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 Aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more R 11a .

[0073] In some embodiments, the R 5 is selected from and the Y5, Y6 are independently selected from NH or CHR 22 .

[0074] In some embodiments, R 20 is selected from 5- to 10-membered heteroaryl or C6-C 10 Aryl, the 5- to 10-membered heteroaryl or C6-C 10 Aryl is optionally substituted by R 20a .

[0075] In some embodiments, the R 20a is selected from F, Cl, Br, I, OH, CN, =O, NO2, NH2, SH, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 Aryl or 5- to 10-membered heteroaryl; the C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 Aryl or 5- to 10-membered heteroaryl is optionally substituted by R20b is substituted, and said R 20b is selected from F, Cl, Br, I, OH, CN, ═O, NO2, NH2 or SH.

[0076] In some embodiments, said R 20a is selected from F, Cl, Br, I, OH, CN, ═O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl.

[0077] In some embodiments, L1 is selected from C7-C 12 spiro group, C6-C 12 fused ring group, C5-C 12 bridged ring group, 7- to 12-membered spiroheterocyclic group, 6- to 12-membered fused heterocyclic group, 3- to 10-membered monocyclic heterocyclic group or 5- to 12-membered bridged heterocyclic group, the 7- to 12-membered spiroheterocyclic group, 6- to 12-membered fused heterocyclic group, 3- to 10-membered monocyclic heterocyclic group or 5- to 12-membered bridged heterocyclic group contains 1 to 3 heteroatoms selected from O, N or S; the C7-C 12 spiro group, C6-C 12 fused ring group, C5-C 12 bridged ring group, 7- to 12-membered spiroheterocyclic group, 6- to 12-membered fused heterocyclic group, 3- to 10-membered monocyclic heterocyclic group or 5- to 12-membered bridged heterocyclic group is optionally substituted by R 28a substituted.

[0078] In some embodiments, L1 is selected from C7-C 12 spiro group, C6-C 12 fused ring group, C5-C 12 bridged ring group, 7- to 12-membered spiroheterocyclic group, 6- to 12-membered fused heterocyclic group, 3- to 10-membered monocyclic heterocyclic group or 5- to 12-membered bridged heterocyclic group, the 7- to 12-membered spiroheterocyclic group, 6- to 12-membered fused heterocyclic group, 3- to 10-membered monocyclic heterocyclic group or 5- to 12-membered bridged heterocyclic group contains 1 to 3 heteroatoms selected from O, N or S.

[0079] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0080]

[0081] wherein R 1 , R 2 , R 3 , R 4 , R 5 is as defined in formula (I), and L is selected from

[0082] X1, X3, Y1, Y3, Z1, Z3, L1, W1, W4, and m are as defined in formula (I);

[0083] Provided that when L1 is an optionally R- 28 substituted 3- to 10-membered monocyclic heteroaryl group, W4 is not a chemical bond, where R 28 is as defined in formula (I).

[0084] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0085]

[0086] where R 1 , R 2 , R 3 , R 4 , R 5 are as defined in formula (I), and L is selected from where X1, Y1, Z1, W1, and m are as defined in formula (I).

[0087] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0088]

[0089] where R 1 , R 2 , R 3 , R 4 , R 5 are as defined in formula (I),

[0090] L is X2, Y2, and Z2 are as defined in formula (I);

[0091] Provided that when R 1 is tert-butylsulfamoyl, R 5 is not where X5, Y5, Y6, Z5, Z6, R 17 , R 18 , R 25 , R 26 , R 27 and n are as defined in formula (I).

[0092] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0093]

[0094] wherein R 1 , R 2 , R 3 , R 4 , R 5 is as defined in formula (I),

[0095] L is X2, Y2 and Z2 are as defined in formula (I);

[0096] provided that when R 1 is tert-butylsulfamoyl, R 5 is selected from R 20 is as defined in formula (I).

[0097] In some embodiments, the compound of formula (Ia) does not comprise

[0098] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0099]

[0100] wherein R 1 , R 2 , R 3 , R 4 is as defined in formula (I),

[0101] L is wherein X2, Y2 and Z2 are as defined in formula (I);

[0102] R 5 is provided that R 1 is not tert-butylsulfamoyl.

[0103] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

[0104]

[0105] wherein R 1 , R 2 , R 3 , R 4 , R 5 is as defined in formula (I), provided that R 1 is not tert-butylsulfamoyl.

[0106] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0107]

[0108] wherein R 1 、R 2 、R 3 、R 4 、L are as defined in formula (I).

[0109] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0110]

[0111] wherein R 1 、R 2 、R 3 、R 4 are as defined in formula (I); L is wherein X2, Y2 and Z2 are as defined in formula (I);

[0112] provided that when R 1 is tert-butylsulfamoyl, X2 is CR 15 and Y2 is N, Z2 is not S.

[0113] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0114]

[0115] wherein R 1 、R 2 、R 3 、R 4 are as defined in formula (I); L is wherein X3, Y3, Z3, L1 and W4 are as defined in formula (I); provided that: when L1 is a 3- to 10-membered monocyclic heteroaryl group optionally substituted by R 28 , W4 is not a chemical bond, wherein R 28 is as defined in formula (I).

[0116] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0117]

[0118] wherein R 1 、R 2, R 3 , R 4 as defined in formula (I); L is X1, Y1, Z1, W1 and m are as defined in formula (I).

[0119] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:

[0120]

[0121] wherein R 1 , R 2 , R 3 , R 4 , R 20 , L are as defined in formula (I); and R 1 is not tert-butylsulfamoyl.

[0122] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IIa) or a pharmaceutically acceptable salt thereof:

[0123]

[0124] wherein R 2 , R 3 , R 4 , R 20 are as defined in formula (I); L is wherein X2, Y2 and Z2 are as defined in formula (I); R 1 is and R 7 is not

[0125] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IIb) or a pharmaceutically acceptable salt thereof:

[0126]

[0127] wherein R 2 , R 3 , R 4 are as defined in formula (I);

[0128] L is X1, Y1, Z1, W1 and m are as defined in formula (I).

[0129] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0130]

[0131] wherein R 1 、R 2 、R 3 、R 4 as defined in formula (I), L is selected from

[0132] X1, X2, Y2, Z1 are independently selected from CR 15 or N;

[0133] Y1, Z2 are independently selected from O, NH or S;

[0134] W1 is selected from a chemical bond or NH;

[0135] R 15 is selected from H, F, Cl, Br, I, OH, CN, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl.

[0136] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0137]

[0138] wherein R 1 、R 2 、R 3 、R 4 as defined in formula (I), L is selected from

[0139] provided that: when R 1 is tert-butylsulfamoyl, X2 is CR 15 and Y2 is N, Z2 is not S, wherein R 15 、X2、Y2、Z2、X3、Y3、Z3、L1 and W4 are as defined in formula (I).

[0140] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

[0141]

[0142] wherein R 1 、R 2 、R 3 、R 4 、L1, W4 are as defined in formula (I).

[0143] In some embodiments, the compound of formula (I), formula (II) or formula (IV) or a pharmaceutically acceptable salt thereof is a compound of formula (V) or a pharmaceutically acceptable salt thereof:

[0144]

[0145] wherein R 2 , R 3 , R 4 , L1, W4 are as defined in formula (I).

[0146] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from compounds of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0147]

[0148] wherein R 1 , R 2 , R 3 , R 4 , R 5 , L are as defined in formula (I), and R 5 is not

[0149] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (VII) or a pharmaceutically acceptable salt thereof:

[0150]

[0151] wherein R 2 , R 3 , R 4 , R 5 are as defined in formula (I), and R 5 is not

[0152] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (VII) or a pharmaceutically acceptable salt thereof:

[0153]

[0154] wherein R 2 , R 3 , R 4 are as defined in formula (I), R 5 is selected from provided that when R 5 is , Z5 is NR 23 or Y5 is CHR 22 .

[0155] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (VIII) or a pharmaceutically acceptable salt thereof:

[0156]

[0157] wherein ring Q is selected from 4- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl, and the 4- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R 24a substituents;

[0158] R 1 、R 2 、R 3 、L、R 24a are as defined in formula (I).

[0159] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IX) or a pharmaceutically acceptable salt thereof:

[0160]

[0161] wherein ring Q is selected from 4- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl, and the 4- to 6-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl is optionally substituted with one or more R 24a substituents;

[0162] R 2 、R 3 、R 24a are as defined in formula (I).

[0163] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from compounds of formula I-1, I-7, formula I-11 or a pharmaceutically acceptable salt thereof:

[0164]

[0165] wherein L, R 2 、R 3 、R 4 、R 5 、R 6 、R 8 、R 9 、R 11 、R 12 and R 13 are as defined in formula (I).

[0166] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from compounds of formula I-13, I-23 or formula I-27 or a pharmaceutically acceptable salt thereof:

[0167]

[0168] Among them, R 2 、R 3 、R 4 、R 5 、R 6 、R 8 、R 9 、R 11 、R 12 、R 13 、X2, Z2 and Y2 are defined as in formula (I).

[0169] In some embodiments, R 1 is selected from

[0170] In some embodiments, R 1 is selected from

[0171] In some embodiments, R 1 is selected from

[0172] In some embodiments, R 1 is selected from

[0173] In some embodiments, R 1 is selected from

[0174] In some embodiments, R 1 is selected from

[0175] In some embodiments, R 7 is selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group or C6-C 10 aryl, and the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3-10 membered heterocyclic group or C6-C 10 aryl is optionally substituted by one or more R 7a In some embodiments, R 7 is selected from C1-C 10 alkyl, C3-C 10 cycloalkyl or C6-C 10 aryl, and the C1-C 10 alkyl, C3-C 10 cycloalkyl or C6-C 10The aryl is optionally substituted by one or more R 7a .

[0176] In some embodiments, R 7 is selected from or C1-C 10 alkyl, and the C1-C 10 alkyl is optionally substituted by one or more R 7a .

[0177] In some embodiments, R 7 is selected from 3- to 10-membered heterocyclic groups, and the 3- to 10-membered heterocyclic groups are optionally substituted by one or more R 7a .

[0178] In some embodiments, R 7 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic groups or C6-C 10 aryl, and the C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocyclic groups or C6-C 10 aryl are optionally substituted by one or more R 7a .

[0179] In some embodiments, R 7 is selected from oxetanyl,[[]] or oxolanyl, and the oxetanyl,[[]] or oxolanyl are optionally substituted by one or more R 7a .

[0180] In some embodiments, R 7 is selected from C3-C 10 cycloalkyl, oxetanyl,[[]] oxolanyl or C6-C 10 aryl, and the C3-C 10 cycloalkyl, oxetanyl,[[]] oxolanyl or C6-C 10 aryl are optionally substituted by one or more R 7a .

[0181] In some embodiments, R 7 is selected from C3-C6 cycloalkyl, oxetanyl,[[]] or oxolanyl, and the C3-C6 cycloalkyl, oxetanyl,[[]] or oxolanyl are optionally substituted by one or more R 7a .

[0182] In some embodiments, R 7 is selected from CF3, CH2F, isopropyl, neopentyl, cyclopropyl, cyclobutyl, tert-butyl, oxetanyl, oxolanyl, azetidinyl or phenyl.

[0183] In some embodiments, R 7 is selected from CF3, CH2F, isopropyl, neopentyl, cyclopropyl, cyclobutyl, tert-butyl, oxetanyl, oxolanyl or phenyl.

[0184] In some embodiments, R 7 is selected from CF3, CH2F, isopropyl, neopentyl, cyclopropyl, cyclobutyl, tert-butyl, oxetanyl, oxolanyl or phenyl.

[0185] In some embodiments, R 7 is selected from CF3, CH2F, isopropyl, neopentyl, cyclopropyl, tert-butyl or phenyl.

[0186] In some embodiments, R 7 is selected from cyclopropyl, cyclobutyl, oxetanyl, or oxolanyl.

[0187] In some embodiments, R 8 is selected from H, C1-C 10 alkyl or C3-C 10 cycloalkyl, wherein the C1-C 10 alkyl or C3-C 10 cycloalkyl is optionally substituted with one or more R 8a substituents.

[0188] In some embodiments, R 8 is selected from H, C1-C 10 alkyl or C3-C 10 cycloalkyl, wherein the C1-C 10 alkyl or C3-C 10 cycloalkyl is optionally substituted with one or more R 8a substituents.

[0189] In some embodiments, R 8 is selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with one or more R 8a substituents.

[0190] In some embodiments, R 8 is selected from H, methyl, cyclopropyl or

[0191] In some embodiments, R 9 is selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, or 3-10 membered heterocyclic group, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl, or 3-10 membered heterocyclic group is optionally substituted with one or more R 9a substituents.

[0192] In some embodiments, R 9 is selected from C1-C 10 alkyl or C3-C 10 cycloalkyl, wherein the C1-C 10 alkyl is optionally substituted with one or more R 9a substituents.

[0193] In some embodiments, R 9 is C1-C 10 alkyl, wherein the C1-C 10 alkyl is optionally substituted with one or more R 9a substituents.

[0194] In some embodiments, R 9 is selected from C3-C 10 cycloalkyl or 3-10 membered heterocyclic group, wherein the C3-C 10 cycloalkyl or 3-10 membered heterocyclic group is optionally substituted with one or more R 9a substituents.

[0195] In some embodiments, R 9 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 3-7 membered heterocyclic group is optionally substituted with one or more R 9a substituents.

[0196] In some embodiments, R 9 is selected from methyl, isopropyl, cyclobutyl, oxetanyl, or cyclopropyl.

[0197] In some embodiments, R 9 is selected from methyl, isopropyl, or cyclopropyl.

[0198] In some embodiments, R 9 is selected from cyclopropyl.

[0199] In some embodiments, R 10 is C1-C 10 alkyl, wherein the C1-C 10 alkyl is optionally substituted with one or more R 10a substituents.

[0200] In some embodiments, R 10 is a C1-C6 alkyl group, and the C1-C6 alkyl group is optionally substituted with one or more R 10a .

[0201] In some embodiments, R 10 is tert-butyl. In some embodiments, R 11 , R 12 are independently a C1-C 10 alkyl group, and the C1-C 10 alkyl group is optionally substituted with one or more R 11a .

[0202] In some embodiments, R 11 , R 12 are independently a C1-C6 alkyl group, and the C1-C6 alkyl group is optionally substituted with one or more R 11a .

[0203] In some embodiments, R 11 , R 12 are independently selected from methyl, ethyl or isopropyl.

[0204] In some embodiments, R 11 and R 12 together with the atoms to which they are attached form a 3- to 10-membered heterocyclic group, and the 3- to 10-membered heterocyclic group is optionally substituted with one or more R 11a .

[0205] In some embodiments, R 11 and R 12 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, and the 3- to 7-membered heterocyclic group is optionally substituted with one or more R 11a .

[0206] In some embodiments, R 11 and R 12 together with the atoms to which they are attached form

[0207] In some embodiments, R 11 and R 12 together with the atoms to which they are attached form

[0208] In some embodiments, R 13 is selected from a C1-C 10 alkyl group or a C3-C 10 cycloalkyl group, and the C1-C 10 alkyl group or the C3-C 10 cycloalkyl group is optionally substituted with one or more R 11a .

[0209] In some embodiments, R 13 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, and the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with one or more R 11a substituents.

[0210] In some embodiments, R 13 is selected from isopropyl or cyclopropyl.

[0211] In some embodiments, R 7a , R 8a , R 9a , R 10a , R 11a are independently selected from F, Cl, Br, I, ═O, C2-C 10 alkenyl, C1-C 10 alkyl or C6-C 10 aryl.

[0212] In some embodiments, R 7a , R 8a , R 9a , R 10a , R 11a are independently selected from C1-C 10 alkyl, C6-C 10 aryl, C2-C 10 alkenyl or ═O.

[0213] In some embodiments, R 7a , R 8a , R 9a , R 10a , R 11a are independently selected from F, Cl, Br, I, ═O, C2-C 10 alkenyl or C6-C 10 aryl.

[0214] In some embodiments, R 7a , R 8a , R 9a , R 10a , R 11a are independently selected from F, Cl, Br, ═O, C2-C4 alkenyl, C1-C6 alkyl or C6-C 10 aryl.

[0215] In some embodiments, R 7a is selected from F or phenyl.

[0216] In some embodiments, R 8a is selected from ═O or vinyl.

[0217] In some embodiments, R 1 is selected from

[0218]

[0219] In some embodiments, R 1 is selected from

[0220] In some embodiments, R 1 is selected from

[0221] In some embodiments, R 2 , R 3 , R 4 are independently selected from H, F, Cl, Br, I, OH, CN, or the following groups optionally substituted with R a : NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl, or 5- to 10-membered heteroaryl.

[0222] In some embodiments, R 2 , R 3 , R 4 are independently selected from H, F, Cl, Br, I, OH, CN, NH2, methyl, ethyl, isopropyl, cyclopropyl, or phenyl.

[0223] In some embodiments, R 2 , R 3 , R 4 are independently H.

[0224] In some embodiments, L is selected from

[0225] In some embodiments, X1, X2, X3, Y2, Y3, Z1 are independently selected from N or CH.

[0226] In some embodiments, Y1, Z2, Z3 are independently S.

[0227] In some embodiments, m is selected from 1 or 2.

[0228] In some embodiments, m is selected from 1.

[0229] In some embodiments, W1, W4 are independently selected from NH or a chemical bond.

[0230] In some embodiments, L is selected from

[0231] In some embodiments, L is selected from

[0232] In some embodiments, L is selected from

[0233] In some embodiments, the is selected from phenyl-NH-, C7-C 12 spirocyclic-NH-, 7- to 12-membered spiroheterocyclic, C6-C 12 fused-ring-NH-, 6- to 12-membered fused heteroaryl-NH-, 3- to 10-membered monocyclic heteroaryl-NH- or C5-C 12 bridged-ring-NH-.

[0234] In some embodiments, the is selected from C7-C 12 spirocyclic-NH-, 7- to 12-membered spiroheterocyclic, 6- to 12-membered fused heteroaryl-NH-, 3- to 10-membered monocyclic heteroaryl-NH- or C5-C 12 bridged-ring-NH-.

[0235] In some embodiments, is selected from 7- to 12-membered spiroheterocyclic, 6- to 12-membered fused heteroaryl-NH-, 3- to 10-membered monocyclic heteroaryl-NH- or C5-C 12 bridged-ring-NH-.

[0236] In some embodiments, the 7- to 12-membered spiroheterocyclic, 6- to 12-membered fused heteroaryl or 3- to 10-membered monocyclic heteroaryl contains 1 to 3 nitrogen atoms.

[0237] In some embodiments, the is selected from

[0238] In some embodiments, the is selected from

[0239] In some embodiments, the is selected from

[0240] In some embodiments, the is selected from

[0241] In some embodiments, R17 , R 18 , R 25 , R 26 are independently selected from H, C1-C 10 alkyl, C3-C 10 cycloalkyl or C6-C 10 aryloxy, and the C1-C 10 alkyl, C3-C 10 cycloalkyl or C6-C 10 aryloxy is optionally substituted with one or more R 17a .

[0242] In some embodiments, R 17 , R 18 , R 25 , R 26 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or C6-C 10 aryloxy, and the C1-C6 alkyl, C3-C6 cycloalkyl or C6-C 10 aryloxy is optionally substituted with one or more R 17a .

[0243] In some embodiments, R 17a is selected from F, Cl, Br, I, OH, CN or the following groups optionally substituted with one or more R 17b : C1-C 10 alkyl, C6-C 10 aryl.

[0244] In some embodiments, R 17a is selected from F or phenyl.

[0245] In some embodiments, R 17a is selected from phenyl.

[0246] In some embodiments, R 17 , R 18 are independently selected from H, ethyl, phenyl, phenoxy, isopropyl, benzyl or

[0247] In some embodiments, R 17 , R 18 are independently selected from H, phenyl, phenoxy, isopropyl or benzyl.

[0248] In some embodiments, R 25 , R 26 are independently selected from H, methyl, cyclopropyl or

[0249] In some embodiments, R 25 , R 26Independently selected from H, methyl or cyclopropyl.

[0250] In some embodiments, R 21 , R 22 , R 27 are selected from H or C1-C 10 alkyl.

[0251] In some embodiments, R 21 , R 22 , R 27 are selected from H or methyl.

[0252] In some embodiments, R 17 , R 18 and the atom X5 to which they are attached together form a 3- to 10-membered heterocyclic group or a C3-C 10 cycloalkyl group, and the 3- to 10-membered heterocyclic group or C3-C 10 cycloalkyl group is optionally substituted with one or more R 17a ;

[0253] In some embodiments, R 17 , R 18 and the atom X5 to which they are attached together form a 10-membered heterocyclic group, a cyclopropyl group or a phenyl-substituted cyclopropyl group, and the 10-membered heterocyclic group is

[0254] In some embodiments, R 17 , R 18 and the atom X5 to which they are attached together form a 10-membered heterocyclic group or a phenyl-substituted cyclopropyl group, and the 10-membered heterocyclic group is In some embodiments, R 20 is selected from a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclic group or -C(O)-C6-C 10 aryl group, and the 5- to 10-membered heteroaryl group, 5- to 10-membered heterocyclic group or -C(O)-C6-C 10 aryl group is optionally substituted with one or more R 20a ;

[0255] In some embodiments, R 20 is selected from a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclic group or -C(O)-C6-C 10 aryl group, and the 5- to 10-membered heteroaryl group and 5- to 10-membered heterocyclic group are optionally substituted with one or more R 20a ;

[0256] In some embodiments, R 20 is selected from a 5- to 10-membered heteroaryl group, and the 5- to 10-membered heteroaryl group is optionally substituted with one or more R 20a ;

[0257] In some embodiments, R 20 is selected from 5- to 6-membered heteroaryl, which 5- to 6-membered heteroaryl is optionally substituted with one or more R 20a .

[0258] In some embodiments, R 20a is selected from F, ═O, OH, C1-C 10 alkyl, C1-C 10 alkoxy, C3-C 10 cycloalkyl, C6-C 10 aryl or 3- to 10-membered heterocyclic group, wherein the C1-C 10 alkyl, C1-C 10 alkoxy, C3-C 10 cycloalkyl, C6-C 10 aryl or 3- to 10-membered heterocyclic group is optionally substituted with one or more R 20b .

[0259] In some embodiments, R 20a is selected from ═O, C1-C 10 alkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, wherein the C1-C 10 alkyl is optionally substituted with one or more R 20b .

[0260] In some embodiments, R 20b is selected from F or OH.

[0261] In some embodiments, R 20b is selected from F.

[0262] In some embodiments, R 20a is selected from F, ═O, OH, CH3, CF3, -CH2OH, -CH2CH2OH, -CH2CH2F, cyclopropyl, methoxy, oxetanyl or phenyl.

[0263] In some embodiments, R 20a is selected from ═O, CH3, CF3, cyclopropyl or phenyl.

[0264] In some embodiments, R 20 is selected from 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclic group or -C(O)-C6-C 10 aryl, the 5- to 10-membered heteroaryl being selected from pyrazolyl, pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, 1,2,3-triazolyl, pyridazinyl, triazinyl, benzopyrazolyl or pyridinopyrazolyl, the 5- to 10-membered heterocyclic group being dihydropyridyl, the C6-C10 The aryl group is a phenyl group.

[0265] In some embodiments, R 20 is selected from a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclic group, or C(O)-C6-C 10 aryl group, the 5- to 10-membered heteroaryl group is selected from pyrazole, isoxazole, 1,2,3-triazole, benzopyrazole, or pyridopyrazole, the 5- to 10-membered heterocyclic group is selected from dihydropyridine, and the C6-C 10 aryl group is selected from phenyl.

[0266] In some embodiments, R 20 is selected from a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclic group, or -C(O)-C6-C 10 aryl group, the 5- to 10-membered heteroaryl group is selected from pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, pyridazinyl, benzopyrazolyl, or pyridopyrazolyl, the 5- to 10-membered heterocyclic group is dihydropyridinyl, and the C6-C 10 aryl group is a phenyl group.

[0267] In some embodiments, R 20 is selected from a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclic group, or -C(O)-C6-C 10 aryl group, the 5- to 10-membered heteroaryl group is selected from pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, benzopyrazolyl, or pyridopyrazolyl, the 5- to 10-membered heterocyclic group is dihydropyridinyl, and the C6-C 10 aryl group is a phenyl group.

[0268] In some embodiments, R 23 is selected from CN or C1-C 10 alkyl group.

[0269] In some embodiments, R 23 is CN.

[0270] In some embodiments, X5 is selected from N or CH.

[0271] In some embodiments, Y5 and Y6 are independently selected from a chemical bond, NH, or CH2.

[0272] In some embodiments, Y5 and Y6 are independently selected from NH or CH2.

[0273] In some embodiments, Y5 is selected from a chemical bond, NH, or CH2.

[0274] In some embodiments, Y5 is selected from NH or CH2.

[0275] In some embodiments, Y6 is NH.

[0276] In some embodiments, Z5 and Z6 are independently selected from O or N-CN.

[0277] In some embodiments, Z5 is selected from O or N-CN.

[0278] In some embodiments, Z6 is O.

[0279] In some embodiments, R 5 is selected from a 3- to 7-membered heterocyclic group or a 5- to 6-membered heteroaryl group; the 3- to 7-membered heterocyclic group or 5- to 6-membered heteroaryl group is optionally substituted with one or more R 20a substituents.

[0280] In some embodiments, R 5 is selected from

[0281] In some embodiments, R 5 is selected from

[0282] In some embodiments, R 5 is selected from a 3- to 7-membered heterocyclic group or a 5- to 6-membered heteroaryl group.

[0283] In some embodiments, R 5 is selected from

[0284]

[0285] In some embodiments, R 5 is selected from

[0286] In some embodiments, R 5 is selected from

[0287] In some embodiments, R 5 is selected from

[0288] In some embodiments, R 4 , R 5 and the atoms to which it is attached together form a 4- to 6-membered heterocyclic group, a phenyl group or a 5- to 6-membered heteroaryl group, the 4- to 6-membered heterocyclic group, phenyl group or 5- to 6-membered heteroaryl group is optionally substituted with one or more R 24a substituents.

[0289] In some embodiments, R 4, R 5 and the atoms to which it is attached together form a 4- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, and the 4- to 6-membered heterocyclic group or 5- to 6-membered heteroaryl group is optionally substituted with one or more R 24a substituents.

[0290] In some embodiments, R 4 , R 5 and the atoms to which it is attached together form a 6-membered heterocyclic group or a 5-membered heteroaryl group, and the 6-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with one or more R 24a substituents.

[0291] In some embodiments, ring Q in is selected from a 6-membered heterocyclic group or a 5-membered heteroaryl group, and the 6-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted with R 24a substituents.

[0292] In some embodiments, is selected from 24a optionally substituted with one or more R or 24a optionally substituted with one or more R

[0293] In some embodiments, is selected from

[0294] In some embodiments, R 24a is selected from F, Cl, Br, I, OH, CN, ═O or the following groups optionally substituted with one or more R 24b substituents: NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl.

[0295] In some embodiments, R 24a is selected from ═O or C1-C 24b alkyl optionally substituted with one or more R 10 substituents.

[0296] In some embodiments, R 24a is selected from ═O or methyl optionally substituted with one or more R 24b substituents.

[0297] In some embodiments, R 24b is selected from F, Cl, Br, I, OH, CN, ═O or the following groups optionally substituted with one or more R 24c substituents: NH2, C1-C 10 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl.

[0298] In some embodiments, R 24b is selected from ═O, NH2 optionally substituted with one or more R 24c or C6-C optionally substituted with one or more R 24c aryl. 10

[0299] In some embodiments, R 24b is selected from ═O, -NHCH2CH3 or phenyl.

[0300] In some embodiments, R 24c is selected from F, Cl, Br, I, OH, CN, ═O, NO2, NH2, SH or C1-C 10 alkyl.

[0301] In some embodiments, R 24c is C1-C 10 alkyl.

[0302] In some embodiments, R 24c is ethyl.

[0303] In some embodiments, R 24a is selected from ═O,

[0304] In some embodiments, R 6 is selected from the following groups optionally substituted with one or more R 6a : NH2, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl.

[0305] In some embodiments, R 6a is selected from F, Cl, Br, I, OH, CN, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl.

[0306] In some embodiments, R 6 is C1-C 10 alkyl.

[0307] In some embodiments, R 6 is isopropyl.

[0308] ​In some embodiments, when R 7 is , R 17 , R 18 and the atom X5 to which they are attached together form a 3- to 10-membered heterocyclic group or a C3-C 10 cycloalkyl group, and the 3- to 10-membered heterocyclic group or C3-C 10 cycloalkyl group is optionally substituted with one or more R 17a .

[0309] In some embodiments, when R 7 is , n is 1.

[0310] In some embodiments, when R 7 is , X5 is CR 21 .

[0311] In some embodiments, when R 7 is , Y5 and Y6 are independently CHR 22 .

[0312] In some embodiments, when R 7 is , Z5 and Z6 are independently NR 23 .

[0313] In some embodiments, when R 7 is and when R 5 is , R 17 , R 18 are independently selected from H, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl, C6-C 10 aryl or C6-C 10 aryloxy, and the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl, C6-C 10 aryl or C6-C 10 aryloxy is optionally substituted with one or more R 17a , or R 17 , R 18 and the N atom to which they are attached together form a 3- to 10-membered heterocyclic group, and the 3- to 10-membered heterocyclic group is optionally substituted with one or more R 17a .

[0314] In some embodiments, when R7 When is, and when R 5 is then R 17 , R 18 are independently selected from H, C3-C 10 cycloalkyl or 3- to 10-membered heterocyclic group, and the C3-C 10 cycloalkyl or 3- to 10-membered heterocyclic group is optionally substituted with one or more R 17a or R 17 , R 18 and the N atom to which they are attached together form a 9- to 10-membered heterocyclic group, and the 9- to 10-membered heterocyclic group is optionally substituted with one or more R 17a .

[0315] In some embodiments, when R 7 is then R 25 , R 26 are independently selected from H, C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl, C6-C 10 aryl or C6-C 10 aryloxy, and the C1-C 10 alkyl, C3-C 10 cycloalkyl, 3- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl, C6-C 10 aryl or C6-C 10 aryloxy is optionally substituted with one or more R 17a .

[0316] In some embodiments, when R 7 is then R 25 , R 26 are independently selected from H or C3-C 10 cycloalkyl, R 27 is H, and the C3-C 10 cycloalkyl is optionally substituted with one or more R 17a .

[0317] In some embodiments, when R 7 is then R 25 is C3-C6 cycloalkyl, R 26 , R 27 are both H, and the C3-C6 cycloalkyl is optionally substituted with one or more F, Cl, Br or I.

[0318] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (IV), formula (V), formula (VII), formula (VIII), formula (IX), formula I-1, formula I-7, formula I-11, formula I-13, formula I-23, formula I-27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0328] Furthermore, the present invention relates to the use of a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (IV), formula (V), formula (VII), formula (VIII), formula (IX), formula I-1, formula I-7, formula I-11, formula I-13, formula I-23, formula I-27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating RAD51-related diseases.

[0329] Furthermore, the present invention relates to the use of a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (IV), formula (V), formula (VII), formula (VIII), formula (IX), formula I-1, formula I-7, formula I-11, formula I-13, formula I-23, formula I-27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating RAD51-related diseases.

[0330] Furthermore, the present invention relates to compounds of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (IV), formula (V), formula (VII), formula (VIII), formula (IX), formula I-1, formula I-7, formula I-11, formula I-13, formula I-23, formula I-27 or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for preventing or treating RAD51-related diseases.

[0331] The present invention also relates to a method for treating RAD51-related diseases, which method comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation comprising a compound of formula (I), formula (Ia), formula (Ib), formula (II), formula (IIa), formula (IIb), formula (IV), formula (V), formula (VII), formula (VIII), formula (IX), formula I-1, formula I-7, formula I-11, formula I-13, formula I-23, formula I-27 or a pharmaceutically acceptable salt thereof.

[0332] A preferred embodiment of the present invention, wherein the RAD51-related diseases include but are not limited to tumors (such as breast cancer, non-small cell lung cancer, prostate cancer, etc.) and autoimmune diseases (such as rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus).

[0333] Term Definitions and Explanations

[0334] Unless otherwise specified, the definitions of groups and terms recited in the specification and claims of the present invention, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, etc., can be combined and combined with each other arbitrarily. The defined groups and compound structures after such combination and combination shall fall within the scope recited in the specification of the present invention.

[0335] In the present invention indicates the connection site.

[0336] The term "pharmaceutically acceptable salt" refers to a non-toxic salt of a pharmaceutically acceptable acid or base, including salts of inorganic acids and bases, organic acids and bases.

[0337] The term "stereoisomer" refers to isomers generated by different arrangements of atoms in space in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.

[0338] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms (optical centers) or asymmetric double bonds. Racemates, enantiomers, diastereoisomers, geometric isomers and individual isomers are all included within the scope of the present invention.

[0339] The graphical representation of racemates or enantiomerically pure compounds in this text is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, wedge and dashed wedge bonds are used to represent the absolute configuration of a stereocenter, and solid and dashed bonds are used to represent the cis-trans configuration of alicyclic compounds. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, they include E, Z geometric isomers. Similarly, all tautomeric forms are included within the scope of the present invention.

[0340] 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, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention. The compounds containing asymmetric atoms in the present application may be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0341] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototrophic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are consistent with those of a mixture of compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0342] The term "pharmaceutical composition" denotes a mixture of one or more of the compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

[0343] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0344] The term "optionally" or "optionally" means that the subsequently described event or situation can occur or not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally" substituted by a halogen for an ethyl group means that the ethyl group can be unsubstituted (-CH2CH3), monosubstituted (such as -CH2CH2F), polysubstituted (such as -CHFCH2F, -CH2CHF2, etc.) or fully substituted (-CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0345] When any variable (such as R 7a ) appears more than once in the composition or structure of a compound, its definition in each case is independent.

[0346] The term "halo" or "halogen" means fluorine, chlorine, bromine and iodine.

[0347] The term "C1-C 10 alkyl" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; "C1-C6 alkyl" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6 carbon atoms. Preferably, "C1-C 10 alkyl" can include "C1-C6 alkyl".

[0348] The term "C2-C 10 alkenyl" should be understood to preferably mean a straight-chain or branched-chain monovalent hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0349] The term "C3-C 12"Cycloalkenyl" should preferably be understood to mean a monocyclic or bicyclic hydrocarbon ring containing one or more double bonds, having 3 to 12 carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, etc.

[0350] The term "C2-C 10 alkynyl" should preferably be understood to mean a straight-chain or branched-chain monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0351] The term "C3-C 10 cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as the decahydronaphthalene ring. The term "C3-C6 cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms. Preferably, "C3-C 10 cycloalkyl" may include "C3-C6 cycloalkyl".

[0352] The term "heterocyclic group" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, for example: fused-ring, bridged-ring or spiro-ring) non-aromatic group, the ring atoms of which are composed of carbon atoms and at least one heteroatom selected from nitrogen, oxygen and sulfur.

[0353] The term "3-10 membered heterocyclic group" means a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3-10 ring atoms, which contains 1-5, preferably 1-3 heteroatoms selected from N, O and S. The term "3-7 membered heterocyclic group" means a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3-7 ring atoms, which contains 1-5, preferably 1-3 heteroatoms selected from N, O and S. In particular, the heterocyclic group may include, for example: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl; or partially saturated 6-membered rings such as tetrahydropyridyl; or 7-membered rings such as azepanyl or diazepanyl. Optionally, the 3-10 membered heterocyclic group may be an 8-10 membered benzo-fused heterocyclic group or an 8-10 membered heteroaryl-fused heterocyclic group, including but not limited to, for example, benzopiperidinyl, pyridino-piperidinyl or pyrimido-piperidinyl, etc.; the 3-10 membered heterocyclic group may also include but not limited to 5,5 bicyclic rings such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or 5,6 bicyclic rings such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring containing a nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or, it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. According to the present invention, the heterocyclic group is non-aromatic. The bicyclic hydrocarbon ring includes a bridged ring, a spiro ring or a fused ring structure. Preferably, the "3-10 membered heterocyclic group" may include the "3-7 membered heterocyclic group".

[0354] "3-10 membered monocyclic heterocyclic group" refers to a saturated or partially saturated monocyclic hydrocarbon ring having 3-10 ring atoms, which contains 1-5, preferably 1-3 heteroatoms selected from N, O and S. Preferably, the "3-10 membered monocyclic heterocyclic group" may include the "3-7 membered monocyclic heterocyclic group".

[0355] The term "C7-C 12 spiro group" refers to a monovalent non-aromatic ring system in which two monocyclic rings share a carbon atom, which is composed only of carbon atoms and hydrogen atoms, may be saturated or partially saturated, and which contains 7, 8, 9, 10, 11 or 12 ring atoms and is connected to the parent nucleus by a single bond. "C7-C 12 spiro group" includes but not limited to spiro[2.4]heptan-1-yl, spiro[3.5]nonan-2-yl, etc.

[0356] The term "7- to 12-membered spiroheterocyclic group" refers to a monovalent non-aromatic ring system in which two monocyclic rings share a carbon atom, which is composed of carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, and may be saturated or partially saturated, and which contains 7, 8, 9, 10, 11, or 12 ring atoms and is connected to the parent nucleus by a single bond. "7- to 12-membered spiroheterocyclic group" includes, but is not limited to, 6-oxaspiro[3.3]heptan-2-yl, 7-azaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, etc.

[0357] The term "C6-C 12 fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of ring atoms with the other rings in the system, where one or more rings may contain zero or more double bonds, which contains 6, 7, 8, 9, 10, 11, or 12 ring atoms and the ring atoms are composed only of carbon atoms, and may be substituted or unsubstituted. "C6-C 12 fused ring group" includes, but is not limited to etc.

[0358] The term "6- to 12-membered fused heterocyclic group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of ring atoms with the other rings in the system, where one or more rings may contain zero or more double bonds, which contains 6, 7, 8, 9, 10, 11, or 12 ring atoms and the ring atoms are composed of carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, and may be substituted or unsubstituted. "6- to 12-membered fused heterocyclic group" includes, but is not limited to etc.

[0359] The term "C5-C 12 bridged ring group" refers to a monovalent non-aromatic ring system in which any two monocyclic rings share two non-adjacent carbon atoms, which is composed only of carbon atoms and hydrogen atoms, and may be saturated or partially saturated, and which contains 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms and is connected to the parent nucleus by a single bond. "C5-C 12 bridged ring group" includes, but is not limited to etc.

[0360] The term "5- to 12-membered bridged heterocyclic group" refers to a monovalent non-aromatic ring system in which any two monocyclic rings share two non-adjacent carbon atoms, which is composed of carbon atoms and 1 to 3 heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, and may be saturated or partially saturated, and which contains 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms and is connected to the parent nucleus by a single bond. "5- to 12-membered bridged heterocyclic group" includes, but is not limited to etc.

[0361] The term "C6-C 10 aryl" should be understood to preferably denote a monocyclic, bicyclic or tricyclic hydrocarbon ring that is monovalent, aromatic or partially aromatic and has 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0362] The term "5-10 membered heteroaryl" should be understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which have 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, and which may be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc. Preferably, "5-10 membered heteroaryl" may include "5-6 membered heteroaryl".

[0363] The term "C1-C 10 alkoxy" means a C1-C 10 alkyl that is connected to the remainder of the molecule through an oxygen atom. C1-C 10 alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc. Preferably, "C1-C 10 alkoxy" may include "C1-C6 alkoxy".

[0364] The term "C3-C 10 cycloalkyloxy" means a C3-C 10 cycloalkyl that is connected to the remainder of the molecule through an oxygen atom. C3-C 10 cycloalkyloxy includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Preferably, "C3-C 10 cycloalkyloxy" may include "C3-C6 cycloalkyloxy".

[0365] The term "3- to 10-membered heterocyclic group oxy" refers to a 3- to 10-membered heterocyclic group linked to the remainder of the molecule through an oxygen atom. 3- to 10-membered heterocyclic group oxy includes, for example, oxetanyloxy, tetrahydrofuryloxy, pyrrolidinyloxy, piperidinyloxy, and the like. Preferably, "3- to 10-membered heterocyclic group oxy" may include "3- to 7-membered heterocyclic group oxy".

[0366] The term "C6-C 10 aryloxy" refers to a C6-C 10 aryl linked to the remainder of the molecule through an oxygen atom. C6-C 10 aryloxy includes, for example, phenyloxy, naphthyloxy.

[0367] The term "5- to 10-membered heteroaryloxy" refers to a 5- to 10-membered heteroaryl linked to the remainder of the molecule through an oxygen atom. 5- to 10-membered heteroaryloxy includes, for example, pyrazolyloxy, oxazolyloxy, pyridyloxy, indazolyl oxy, and the like.

[0368] This application also includes isotopically labeled compounds of this application that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0369] Certain isotopically labeled compounds of this application (e.g., those labeled with 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritium labeling (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by substituting an unlabeled reagent with an isotopically labeled reagent by procedures similar to those in the protocols and / or examples disclosed below.

[0370] In addition, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and may thus be preferred in certain situations, where deuterium substitution can be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.

[0371] All isotopic compositional variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0372] The term "treatment" means administering the compounds or formulations described in the present application to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0373] (i) preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not been diagnosed as having the disease state;

[0374] (ii) inhibiting a disease or disease state, i.e., arresting its development;

[0375] (iii) alleviating a disease or disease state, i.e., causing the disease or disease state to subside.

[0376] The term "therapeutically effective amount" means the amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0377] The term "excipient" refers to a pharmaceutically inert ingredient. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents, etc. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and / or adhesiveness. Examples of typical "pharmaceutically acceptable excipients" applicable to the above formulations are: saccharides, starches, celluloses and their derivatives, etc., which are commonly used excipients in pharmaceutical formulations.

[0378] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0379] The words "comprise", "comprises" or "comprising" and their English variants such as "comprises" or "comprising" should be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0380] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0381] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0382] The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugarcoating pill methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0383] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, suspensions, etc. for oral administration to patients.

[0384] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of the tablet or dragee. Suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0385] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0386] In all administration methods of the compounds of general formula (I) described herein, the daily dosage is 0.01 to 100 mg / kg body weight, preferably 0.05 to 50 mg / kg body weight, more preferably 0.1 to 30 mg / kg body weight, in the form of single or divided doses. The compounds of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0387] The compounds of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0388] The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments. Specific Embodiments

[0389] The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the present invention includes, but is not limited to, this.

[0390] The solvents used in the present invention are commercially available. Commercially available compounds use the supplier catalog names.

[0391] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10-6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC50" refers to the half-maximal inhibitory concentration, which is the concentration when half of the maximum inhibitory effect is achieved. The eluents below can be formed by two or more solvents to form a mixed eluent, and the percentage is the volume ratio of each solvent. For example, "tetrahydrofuran / petroleum ether = 0 - 20%" means that in the gradient elution process, the volume ratio of tetrahydrofuran:petroleum ether in the mixed eluent is 0:100 - 20:100.

[0392] The following abbreviations are used in the present invention:

[0393]

[0394]

[0395] Intermediate 1: Synthesis of 5-Amino-N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

[0396]

[0397] Synthesis method

[0398]

[0399] Step 1: Synthesis of 2-Bromo-5-nitro-benzenesulfonyl chloride

[0400] Dissolve 2-bromobenzenesulfonyl chloride (50.0 g, 195.7 mmol) in sulfuric acid (750 mL), and slowly add it to a sulfuric acid (750 mL) solution of nitric acid (37.0 g, 587.1 mmol, 26.5 mL). The entire dropping process takes 30 minutes, and the temperature of the system is maintained at 0 °C in an ice-salt bath environment. After the dropping is complete, the clear reaction solution is stirred at 10 °C for 2 hours. After detecting the completion of the reaction, the reaction solution is slowly added to ice water (2.5 L) with stirring. A white solid precipitates out with stirring. The white solid is filtered, washed with water 1.5 L (0.5 L * 3), and then dried to obtain 2-bromo-5-nitro-benzenesulfonyl chloride (48.0 g).

[0401] Step 2: Synthesis of 2-Bromo-N-tert-butyl-5-nitrobenzenesulfonamide

[0402] Dissolve tert-butylamine (5.9 g, 79.9 mmol) in dichloromethane (0.2 L), and add 2-bromo-5-nitro-benzenesulfonyl chloride (8.0 g, 26.6 mmol) in portions at 0 °C. Add triethylamine (5.4 g, 53.3 mmol) to the reaction solution. The light yellow reaction solution is stirred at 20 °C for 1 hour. After detecting the completion of the reaction by LCMS, add dilute hydrochloric acid (1 M, 200 mL) to the reaction solution for liquid separation, and then add saturated sodium carbonate solution (200 mL) to the organic phase. The organic phase is dried over anhydrous sodium sulfate, filtered, and then the organic phase is concentrated to dryness under reduced pressure. Add methanol (50 mL), and a white solid precipitates out with stirring. After trituration, 2-bromo-N-tert-butyl-5-nitrobenzenesulfonamide (8.0 g) is obtained.

[0403] 1 HNMR(400MHz,DMSO-d6)δ8.69(d,J=2.75Hz,1H),8.29(dd,J=8.63,2.75Hz,1H),8.18-8.04(m,2H),1.22-1.07(m,9H).

[0404] Step 3: Synthesis of 5-Amino-2-bromo-N-tert-butylbenzenesulfonamide

[0405] Dissolve 2-bromo-N-tert-butyl-5-nitrobenzenesulfonamide (5.0 g, 14.8 mmol) in ethanol (0.2 L), and add zinc powder (4.9 g, 74.1 mmol) and ammonium chloride (4.0 g, 74.1 mmol). The reaction mixture was stirred at 40 °C for 1 hour. The reaction mixture was filtered to remove zinc powder, and the mother liquor was concentrated to dryness under reduced pressure. Water (200 mL) was added, and the mixture was extracted with dichloromethane (600 mL, 300 mL×2). The organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the crude product of 5-amino-2-bromo-N-tert-butylbenzenesulfonamide (4.9 g).

[0406] MS m / z (ESI): 307.1, 309.1 [M+H] + ;

[0407] Step 4: Synthesis of 5-amino-N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

[0408] Dissolve 5-amino-2-bromo-N-tert-butylbenzenesulfonamide (1.0 g, 3.3 mmol) in tetrahydrofuran (100 mL), and add 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.3 g, 13.0 mmol) and potassium acetate (958.4 mg, 9.8 mmol). Under nitrogen protection, a mixture of 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane (132.9 mg, 162.8 μmol) was added to the reaction mixture. The dark red reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica gel, tetrahydrofuran / petroleum ether = 0 - 20%) to obtain 5-amino-N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (0.6 g).

[0409] MS m / z (ESI): 355.2 [M+H] + 。

[0410] Intermediate 2: Synthesis of trans-isopropyl N-[4-[5-[4-amino-2-(tert-butylaminosulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0411]

[0412] Synthesis method

[0413]

[0414] Step 1: Synthesis of tert-butyl trans-N-(4-carbamoylcyclohexyl)carbamate

[0415] Dissolve trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (20.0 g, 82.2 mmol) in N,N-dimethylformamide (1.0 L), and add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (117.2 g, 308.3 mmol), ammonium chloride (66.0 g, 1.2 mol), and N,N-diisopropylethylamine (31.4 mg, 242.6 μmol, 42.3 μL). Stir the reaction mixture at 25 °C for 1 h. Concentrate the reaction mixture under reduced pressure to dryness, add methanol (0.2 L) and water (1.0 L), and a white solid precipitates. Then stir at room temperature for 30 min. Filter and wash with 0.9 L of water (0.3 L * 3) to obtain tert-butyl trans-N-(4-carbamoylcyclohexyl)carbamate (13.0 g).

[0416] MS m / z (ESI): 187.1 [M - 55] + ;

[0417] Step 2: Synthesis of tert-butyl trans-N-(4-carbamothioylcyclohexyl)carbamate

[0418] Dissolve tert-butyl trans-N-(4-carbamoylcyclohexyl)carbamate (12.0 g, 49.5 mmol) in tetrahydrofuran (0.5 L), and add Lawesson's reagent (20.0 g, 49.5 mmol). Stir the reaction mixture at 80 °C for 30 min. Adjust the pH of the reaction mixture to 8 - 9 by adding saturated aqueous sodium carbonate solution (0.8 L), and extract three times with ethyl acetate (1.6 L). Dry the organic layer over anhydrous magnesium sulfate, filter by suction, concentrate the filtrate under reduced pressure to dryness, and purify by column chromatography (silica gel, tetrahydrofuran / petroleum ether = 0 - 50%) to obtain tert-butyl trans-N-(4-carbamothioylcyclohexyl)carbamate (6.0 g).

[0419] MS m / z (ESI): 203.1 [M - 55] + ;

[0420] Step 3: Synthesis of trans-4-thiazol-2-ylcyclohexanamine

[0421] Dissolve tert-butyl trans-N-(4-carbamothioylcyclohexyl)carbamate (2.0 g, 7.7 mmol) and bromoacetaldehyde diethyl acetal (3.1 g, 15.5 mmol, 2.4 mL) in anhydrous ethanol (80 mL), and add p-toluenesulfonic acid (2.7 g, 15.5 mmol). The clear reaction solution is stirred at 80 °C for 1 hour. Add saturated aqueous sodium carbonate solution (100 mL) to adjust the pH to 8 - 9, extract with dichloromethane (300 mL) three times, dry the organic layer with anhydrous magnesium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to dryness to obtain crude trans-4-thiazol-2-ylcyclohexylamine (1.5 g).

[0422] MS m / z(ESI): 183.1[M + H] + ;

[0423] Step 4: Synthesis of trans-isopropyl N-(4-thiazol-2-ylcyclohexyl)carbamate

[0424] Dissolve trans-4-thiazol-2-ylcyclohexylamine (1.4 g, 7.7 mmol) and isopropyl chloroformate (2.9 g, 23.3 mmol, 3.3 mL) in dichloromethane (200 mL), and add N,N-diisopropylethylamine (2.0 g, 15.5 mmol, 2.7 mL) and 4-dimethylaminopyridine (472.8 mg, 3.9 mmol). The reaction solution is stirred at 20 °C for 30 minutes. Concentrate the reaction solution to dryness under reduced pressure, and purify by column chromatography (silica gel, ethyl acetate / petroleum ether = 0 - 15%) to obtain trans-isopropyl N-(4-thiazol-2-ylcyclohexyl)carbamate (0.3 g).

[0425] MS m / z(ESI): 269.1[M + H] + ;

[0426] Step 5: Synthesis of trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate

[0427] Dissolve trans-isopropyl N-(4-thiazol-2-ylcyclohexyl)carbamate (0.3 g, 1.1 mmol) in N,N-dimethylformamide (1.5 mL), add N-bromosuccinimide (0.4 g, 2.3 mmol), and stir the reaction solution at 50 °C for 2 hours. Concentrate the reaction solution to dryness under reduced pressure, and purify by column chromatography (silica gel, tetrahydrofuran / petroleum ether = 0 - 10%) to obtain trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (0.1 g).

[0428] MS m / z(ESI): 347.0, 349.0[M + H] + ;

[0429] Step 6: Synthesis of trans-isopropyl N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate Dissolve 5-amino-N-tert-butyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (61.0 mg, 172.8 μmol) and trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (0.1 g, 288.0 μmol) in ethanol (2.0 mL), toluene (2.0 mL), and water (0.7 mL). Add sodium carbonate (30.5 mg, 288.0 μmol), potassium fluoride (16.7 mg, 288.0 μmol), and tetrakis(triphenylphosphine)palladium (16.6 mg, 14.4 μmol). Under nitrogen protection, stir the reaction mixture at 100 °C for 2 hours. Concentrate the reaction mixture under reduced pressure to dryness. Add water (2 mL) to the reaction mixture, and extract three times with dichloromethane (6 mL). Dry the organic layer with anhydrous magnesium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to dryness to obtain the crude product of trans-isopropyl N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (60.0 mg).

[0430] MS m / z (ESI): 495.3 [M+H] + .

[0431] Intermediate 3: Synthesis of trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(methylsulfinyl)phenyl]carbamate

[0432]

[0433] Synthesis method

[0434]

[0435] Step 1: Synthesis of isopropyl-N-(3-methylthiophenyl)carbamate

[0436] Dissolve the reactant 3-(methylthio)aniline (806 mg, 5.79 mmol) in anhydrous tetrahydrofuran (20 mL). Add N,N-diisopropylethylamine (1.50 g, 11.58 mmol, 2.02 mL) and 4-dimethylaminopyridine (353.65 mg, 2.89 mmol) at 0 °C. Then add isopropyl chloroformate (2.13 g, 17.37 mmol, 2.41 mL) to the reaction system at 0 °C, and stir the reaction mixture at 25 °C for 3 hours. Monitor the completion of the reaction by LCMS. Concentrate the reaction mixture under reduced pressure to remove the solvent tetrahydrofuran. Add 20 mL of dichloromethane and extract with saturated aqueous sodium chloride solution three times (20 mL * 3). Separate the organic layer and dry it over anhydrous sodium sulfate. Concentrate the organic layer to dryness under reduced pressure. Purify by thin-layer chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain isopropyl N-(3-(methylthio)phenyl)carbamate (1.16 g) as a yellow liquid. MS m / z (ESI): 226.1 [M+H] + .

[0437] Step 2: Synthesis of isopropyl N-(4-bromo-3-(methylthio)phenyl)carbamate

[0438] Dissolve the reactant isopropyl N-(3-(methylthio)phenyl)carbamate (50 mg, 221.92 μmol) in dichloromethane (2 mL). Add N-bromosuccinimide (39.50 mg, 221.92 μmol) to the reaction system. Stir the reaction mixture at -70 °C for 3 hours. Monitor the completion of the reaction by LCMS. Concentrate the reaction mixture to dryness under reduced pressure. Purify by thin-layer chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the product isopropyl N-(4-bromo-3-(methylthio)phenyl)carbamate (50 mg) as a white solid.

[0439] MS m / z (ESI): 262.0 [M+H-iPr] + ;

[0440] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H) 7.50 - 7.45 (m, 2H) 7.20 (dd, J = 8.57, 1.94 Hz, 1H) 4.97 - 4.87 (m, 1H) 2.44 (s, 3H) 1.27 (d, J = 6.25 Hz, 6H).

[0441] Step 3: Synthesis of isopropyl N-[3-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0442] The reactants isopropyl - N-(4 - bromo - 3 - methylthio - phenyl)carbamate (153 mg, 0.51 mmol) and bis(pinacolato)diboron (510.88 mg, 2.01 mmol) were dissolved in anhydrous tetrahydrofuran (3 mL). Under nitrogen protection, potassium acetate (148.08 mg, 1.51 mmol) and [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (20.54 mg, 25.15 μmol) were added. The reaction mixture was stirred at 80 °C for 2 hours. LCMS showed that the reaction was complete. After the reaction system was evaporated to dryness, it was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the yellow solid isopropyl N - [3 - methylthio - 4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)phenyl]carbamate (141 mg).

[0443] MS m / z(ESI): 352.2 [M + H] + .

[0444] Step 4: Synthesis of trans - isopropyl - N - [4 - [2 - [4 - (isopropoxycarbonylamino)cyclohexyl]thiazol - 5 - yl]-3 - methylthio - phenyl]carbamate Trans - isopropyl - N - [4 - (5 - bromothiazol - 2 - yl)cyclohexyl]carbamate (100 mg, 287.96 μmol), isopropyl N - [3 - methylthio - 4-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)phenyl]carbamate (121.38 mg, 345.55 μmol) and sodium carbonate (61.04 mg, 575.92 μmol) were dissolved in water (600 μL) and 1,4 - dioxane (6 mL). Under nitrogen protection, [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (23.52 mg, 28.80 μmol) was added. The reaction mixture was stirred at 80 °C for 6 hours. LCMS showed the reaction. The reaction mixture was filtered, and the filtrate was evaporated to dryness to remove 1,4 - dioxane. Water (10 mL) was added, and the mixture was extracted with dichloromethane three times (10 mL * 3). After drying over anhydrous sodium sulfate, it was purified by thin - layer chromatography (silica gel, dichloromethane / methanol = 15:1) to obtain the brown solid trans - isopropyl - N - [4 - [2 - [4 - (isopropoxycarbonylamino)cyclohexyl]thiazol - 5 - yl]-3 - methylthio - phenyl]carbamate (133 mg).

[0445] MS m / z(ESI): 492.3 [M + H] + .

[0446] Step 5: Synthesis of trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(methylsulfinyl)phenyl]carbamate

[0447] trans-Isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-methylthio-phenyl]carbamate (140 mg, 284.75 μmol), ammonium carbamate (444.60 mg, 5.69 mmol) and iodobenzene diacetate (917.17 mg, 2.85 mmol) were added to a 4 mL microwave reaction vial, and anhydrous methanol (1 mL) was added. The microwave reaction was carried out at 100 °C for 3 hours. LCMS showed that the reaction was complete. Methanol was removed by concentration under reduced pressure, water (4 mL) was added, and the mixture was extracted with dichloromethane (4 mL * 3). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification by thin layer chromatography (silica gel, dichloromethane / methanol = 15:1) gave the yellow solid compound trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(methylsulfinyl)phenyl]carbamate (47.4 mg). MS m / z (ESI): 523.2 [M+H] + .

[0448] Example 1: Synthesis of trans-isopropyl N-[3-dimethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0449]

[0450] Synthesis method

[0451]

[0452] Step 1: Synthesis of (2-bromophenyl)dimethylphosphine oxide 1-Bromo-2-iodobenzene (5.0 g, 17.6 mmol), potassium phosphate (5.6 g, 26.5 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (613.6 mg, 1.06 mmol) were dissolved in N,N–dimethylformamide (50 mL), and dimethylphosphine oxide (1.7 g, 21.2 mmol) and palladium acetate (198.4 mg, 0.88 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure and then purified by column chromatography (silica gel, dichloromethane / methanol = 20 / 1) to give the product (2-bromophenyl)dimethylphosphine oxide (2.3 g).

[0453] MS m / z (ESI): 233.0, 235.0 [M+H] +;

[0454] Step 2: Synthesis of (2-bromo-5-nitrophenyl)dimethylphosphine oxide

[0455] Dissolve (2-bromophenyl)dimethylphosphine oxide (1.0 g, 4.3 mmol) in concentrated sulfuric acid (15 mL), add concentrated nitric acid (876.6 mg, 13.2 mmol, 626.1 μL), and stir the reaction mixture at 25 °C for 1 hour. Dissolve the reaction mixture in water (200 mL), extract with ethyl acetate (100 mL) three times, concentrate the organic phase under reduced pressure to dryness, and obtain the product (2-bromo-5-nitrophenyl)dimethylphosphine oxide (1.0 g).

[0456] MS m / z (ESI): 277.9, 279.9 [M+H] + ;

[0457] Step 3: Synthesis of (5-amino-2-bromophenyl)dimethylphosphine oxide

[0458] Dissolve (2-bromo-5-nitrophenyl)dimethylphosphine oxide (0.9 g, crude product) in ethanol (10 mL), add iron powder (903.8 mg, 16.2 mmol) and ammonium chloride (865.7 mg, 16.2 μmol). Stir the reaction mixture at 90 °C for 1 hour. Filter the reaction mixture, concentrate the filtrate under reduced pressure to dryness, and then purify by column chromatography (silica gel, dichloromethane / methanol = 20 / 1) to obtain the product (5-amino-2-bromophenyl)dimethylphosphine oxide (0.15 g). MS m / z (ESI): 248.0, 250.0 [M+H] + ;

[0459] Step 4: Synthesis of isopropyl (4-bromo-3-(dimethylphosphoryl)phenyl)carbamate

[0460] Dissolve (5-amino-2-bromophenyl)dimethylphosphine oxide (130 mg, 524.1 μmol) in dichloromethane (10 mL), add isopropyl chloroformate (192.7 mg, 1.6 mmol, 218.2 μL), and then add 4-dimethylaminopyridine (32.1 mg, 262.1 μmol) and triethylamine (106.1 mg, 1.05 mmol, 145.9 μL) at 0 °C. Stir the reaction mixture at 25 °C for 2 hours. Filter the reaction mixture, concentrate the filtrate under reduced pressure to dryness, and then purify by column chromatography (silica gel, dichloromethane / methanol = 20 / 1) to obtain the product isopropyl (4-bromo-3-(dimethylphosphoryl)phenyl)carbamate (0.12 g).

[0461] MS m / z (ESI): 334.1, 336.1 [M+H] + ;

[0462] Step 5: Synthesis of trans-isopropyl N-[3-dimethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate Dissolve isopropyl (4-bromo-3-(dimethylphosphoryl)phenyl)carbamate (60 mg, 179.56 μmol), trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (62.36 mg, 179.56 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (182.39 mg, 718.25 μmol) in tetrahydrofuran (6 mL). Under nitrogen protection, add 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (4.5 mg, 9.0 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (7.1 mg, 9.0 μmol), tris(dibenzylideneacetone)dipalladium (8.2 mg, 9.0 μmol) and potassium acetate (35.3 mg, 359.1 μmol). Stir the reaction mixture at 80 °C for 16 hours. Filter the reaction mixture, concentrate the filtrate under reduced pressure to dryness, and purify by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity as the eluent) to obtain the compound trans-isopropyl N-[3-dimethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (10.4 mg).

[0463] MS m / z (ESI): 522.3 [M+H] + ;

[0464] 11H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (s, 1H), 8.03 (dd, J = 14.26, 2.13 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J = 8.50 Hz, 1H), 7.44 - 7.30 (m, 1H), 7.00 (d, J = 7.38 Hz, 1H), 4.92 (dt, J = 12.51, 6.25 Hz, 1H), 4.74 (dt, J = 12.41, 6.11 Hz, 1H), 3.40 - 3.25 (m, 1H), 2.99 - 2.85 (m, 1H), 2.12 (d, J = 12.13 Hz, 2H), 1.91 (d, J = 10.26 Hz, 2H), 1.63 - 1.49 (m, 2H), 1.44 (d, J = 13.26 Hz, 6H), 1.40 - 1.29 (m, 2H), 1.27 (d, J = 6.25 Hz, 6H), 1.16 (d, J = 6.25 Hz, 6H).

[0465] Example 2: Synthesis of trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-phenyl]carbamate

[0466]

[0467] Synthesis method

[0468]

[0469] Step 1: Preparation of 3-isopropylthioaniline

[0470] Dissolve the reactant 3-aminobenzenethiol (1 g, 7.99 mmol) in N,N-dimethylformamide (10 mL), add isopropyl bromide (1.18 g, 9.59 mmol) and potassium carbonate (1.66 g, 11.98 mmol). The reaction solution was stirred at 25 °C for 3 hours. After the reaction was completed, the solvent N,N-dimethylformamide was evaporated to dryness using a rotary evaporator. Then, 5 mL of dichloromethane was added to the mixture to dissolve the mixture, 5 mL of water was added, and the mixture was extracted with dichloromethane twice (5 mL * 2). The organic layer was separated, and the organic phase was dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure and purified by column chromatography (silica gel, dichloromethane / methanol = 10:1) to obtain the product 3-isopropylthioaniline (1.4 g).

[0471] MS m / z (ESI): 168.0 [M + H] +

[0472] Step 2: Synthesis of isopropyl N-(3-isopropylthiophenyl)carbamate

[0473] Dissolve the reactant 3-isopropylthioaniline (0.1 g, 597.83 μmol) in anhydrous tetrahydrofuran (1 mL), and add N,N-diisopropylethylamine (154.53 mg, 1.20 mmol) and 4-dimethylaminopyridine (36.52 mg, 298.92 μmol). Then add isopropyl chloroformate (87.92 mg, 717.40 μmol) to the reaction system, and stir the reaction solution at 25 °C for 3 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure to remove the solvent dichloromethane, add 1 mL of water, and extract with dichloromethane 3 times (1 mL * 3). Separate the organic phase, and dry the organic phase with anhydrous sodium sulfate. Concentrate the solution to dryness under reduced pressure. Purify by thin layer chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to obtain isopropyl N-(3-isopropylthiophenyl)carbamate (0.08 g).

[0474] MS m / z (ESI): 254.1 [M+H] +

[0475] Step 3: Synthesis of isopropyl N-(4-bromo-3-isopropylthio-phenyl)carbamate

[0476] Dissolve the reactant isopropyl N-(3-isopropylthiophenyl)carbamate (1.22 g, 4.82 mmol) in dichloromethane (15 mL), and add N-bromosuccinimide (857.03 mg, 4.82 mmol) to the reaction system. Stir the reaction solution at -20 °C for 3 hours. After the reaction is completed, concentrate the reaction solution to dryness under reduced pressure, and purify by column chromatography to obtain the product isopropyl N-(4-bromo-3-isopropylthio-phenyl)carbamate (500 mg).

[0477] MS m / z (ESI): 332.0, 334.0 [M+H] +

[0478] Step 4: Synthesis of isopropyl N-[3-isopropylthio-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0479] The reactants isopropyl N-(4-bromo-3-isopropylsulfanyl-phenyl)carbamate (450 mg, 1.35 mmol) and bis(pinacolato)diboron (1.38 g, 5.42 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under nitrogen protection, potassium acetate (398.77 mg, 4.06 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (55.30 mg, 67.72 μmol) were added. The reaction mixture was stirred at 80 °C for 2 h. After the reaction was complete, the system was evaporated to dryness and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5% - 15%) to obtain isopropyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (350 mg).

[0480] MS m / z (ESI): 380.1 [M+H] +

[0481] Step 5: Synthesis of trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate

[0482] The reactants isopropyl N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (50 mg, 131.81 μmol) and isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (50.35 mg, 145.00 μmol) were dissolved in 1,4-dioxane (1 mL). Under nitrogen protection, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (5.38 mg, 6.59 μmol) and sodium carbonate (2 M, 131.81 μL) were added. The reaction mixture was stirred at 80 °C for 2 h. The reaction system was evaporated to dryness to remove 1,4-dioxane, water (2 mL) was added, and the mixture was extracted with dichloromethane three times (2 mL * 3). After drying over anhydrous sodium sulfate, it was purified by thin-layer chromatography (silica gel, petroleum ether / tetrahydrofuran = 3:1) to obtain trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfanyl-phenyl]carbamate (33 mg).

[0483] MS m / z (ESI): 520.1 [M+H] +

[0484] Step 6: Synthesis of trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-phenyl]carbamate

[0485] Dissolve trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylthio-phenyl]carbamate (0.02 g, 38.48 μmol) in anhydrous dichloromethane (1 mL). At -25 °C, add meta-chloroperoxybenzoic acid (15.63 mg, 76.96 μmol). React the reaction solution at 20 °C for 1 hour. Rotavaporize the reaction solution to remove dioxane, add water (2 mL), extract with dichloromethane three times (2 mL * 3), separate the dichloromethane phase, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure to dryness, dissolve with 0.5 mL of methanol as a solvent and then purify. Purify by preparative high performance liquid chromatography (YMCTriart C18 column, 7 μm silica, 50 mm diameter, 250 mm length); (using a mixture of water (containing 0.05% ammonia water) and acetonitrile with decreasing polarity (38% - 78%) as the eluent) to obtain the compound trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-phenyl]carbamate (5.20 mg).

[0486] MS m / z(ESI): 552.2 [M + H] +

[0487] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 8.32 (d, J = 2.25 Hz, 1H), 7.76 (dd, J = 8.44, 2.19 Hz, 1H), 7.69 (s, 1H), 7.49 (d, J = 8.38 Hz, 1H), 7.00 (br d, J = 7.75 Hz, 1H), 4.93 (quin, J = 6.22 Hz, 1H), 4.74 (dt, J = 12.44, 6.28 Hz, 1H), 3.27 (br d, J = 3.75 Hz, 1H), 3.01 - 2.78 (m, 2H), 2.12 (d, J = 12.01 Hz, 2H), 1.91 (d, J = 10.51 Hz, 2H), 1.64 - 1.46 (m, 2H), 1.41 - 1.30 (m, 2H), 1.27 (d, J = 6.25 Hz, 6H), 1.16 (d, J = 6.25 Hz, 6H), 1.05 (d, J = 6.75 Hz, 6H).

[0488] Example 3: Synthesis of trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropylsulfinyl) phenyl]carbamate

[0489]

[0490] Synthesis Method

[0491]

[0492] Trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylthio-phenyl]carbamate (30 mg, 57.72 μmol), ammonium carbamate (90.13 mg, 1.15 mmol) and iodobenzene diacetate (185.93 mg, 577.24 μmol) were added to a 4 mL microwave reaction flask, and 1 mL of anhydrous methanol was added. The microwave reaction was carried out at 100 °C for 2 hours. Methanol was removed by concentration under reduced pressure, water (2 mL) was added, and the mixture was extracted with dichloromethane (2 mL * 3). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification by preparative high performance liquid chromatography (Phenomenex Gemini-NX C18 column, 3 μm silica, 30 mm diameter, 75 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (30% - 70%) as the eluent) gave trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropylsulfinyl) phenyl]carbamate (6.18 mg). MS m / z (ESI): 551.3 [M+H] +

[0493] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1H), 8.34 (d, J = 2.13 Hz, 1H), 7.75 - 7.65 (m, 2H), 7.39 (d, J = 8.38 Hz, 1H), 7.00 (br d, J = 7.50 Hz, 1H), 4.93 (dt, J = 12.48, 6.33 Hz, 1H), 4.81 - 4.70 (m, 1H), 4.35 (s, 1H), 3.26 (br s, 1H), 2.96 - 2.88 (m, 1H), 2.87 - 2.79 (m, 1H), 2.12 (br d, J = 13.01 Hz, 2H), 1.92 (br d, J = 10.51 Hz, 2H), 1.62 - 1.49 (m, 2H), 1.40 - 1.31 (m, 2H), 1.28 (d, J = 6.25 Hz, 6H), 1.17 (d, J = 6.25 Hz, 6H), 1.08 (d, J = 6.75 Hz, 3H), 0.99 (d, J = 6.75 Hz, 3H).

[0494] Example 4: Synthesis of trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropyl-N-prop-2-enoyl-sulfonimidoyl)phenyl]carbamate

[0495]

[0496] Synthesis method

[0497]

[0498] Dissolve trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropylsulfonimidoyl)phenyl]carbamate (0.01 g, 18.16 μmol) and acrylic acid (1.44 mg, 19.97 μmol, 1.37 μL) in anhydrous dichloromethane (1 mL). Add 4-dimethylaminopyridine (1.11 mg, 9.08 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.18 mg, 21.79 μmol) to the reaction system. Stir the reaction solution at 25 °C for 1 hour. Concentrate the reaction solution to dryness under reduced pressure. Purify by preparative high performance liquid chromatography (Phenomenex Gemini-NX C18 column, 3 μm silica, 30 mm diameter, 75 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (36% - 76%) as the eluent) to obtain trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropyl-N-prop-2-enoyl-sulfonimidoyl)phenyl]carbamate (0.84 mg).

[0499] MS m / z (ESI): 627.2 [M+Na] + ;

[0500] 11H NMR: (400 MHz, DMSO-d6) δ ppm 10.18 (s, 1H), 8.33 (d, J = 2.32 Hz, 1H), 7.75 (dd, J = 8.56, 2.08 Hz, 1H), 7.54 (s, 1H), 7.42 (d, J = 8.31 Hz, 1H), 7.02 (br d, J = 8.31 Hz, 1H), 6.09 - 5.90 (m, 2H), 5.68 (dd, J = 9.41, 2.69 Hz, 1H), 4.93 (quin, J = 6.36 Hz, 1H), 4.83 - 4.67 (m, 1H), 3.27 - 3.23 (m, 1H), 2.99 - 2.79 (m, 1H), 2.09 (br d, J = 9.78 Hz, 2H), 1.90 (br d, J = 9.78 Hz, 2H), 1.59 - 1.45 (m, 2H), 1.35 (d, J = 6.72 Hz, 5H), 1.28 (d, J = 6.24 Hz, 6H), 1.23 (brs, 1H), 1.16 (d, J = 6.24 Hz, 6H), 0.99 (d, J = 6.85 Hz, 3H).

[0501] Example 5: Synthesis of trans-Isopropyl N-[3-(tert-butylsulfamoyl)-4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]phenyl]carbamate

[0502]

[0503] Synthesis method

[0504]

[0505] Step 1: Synthesis of tert-Butyl trans-N-[4-(formamidinoaminocarbonyl)cyclohexyl]carbamate

[0506] Dissolve trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (5 g, 20.55 mmol) and formylhydrazine (1.60 g, 26.72 mmol) in N,N-dimethylformamide (80 mL), and add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (9.38 g, 24.66 mmol) and N,N-diisopropylethylamine (6.91 g, 53.43 mmol, 9.31 mL). Stir the reaction mixture at 25 °C for 0.5 h. After the reaction is completed, rotary evaporate the solvent N,N-dimethylformamide (80 mL) to dryness using a rotary evaporator, then add 400 mL of water and 4 mL of methanol to the mixture, filter to obtain the product tert-butyl trans-N-[4-(formamidocarbamoyl)cyclohexyl]carbamate (3 g, 10.51 mmol). MS m / z (ESI): 230.2 [M-55] + ;

[0507] Step 2: Synthesis of tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate

[0508] Dissolve tert-butyl trans-N-[4-(formamidocarbamoyl)cyclohexyl]carbamate (750 mg, 2.63 mmol) in anhydrous tetrahydrofuran (30 mL). Then add Lawesson's reagent (1.28 g, 3.15 mmol) and Burgess reagent (626.37 mg, 2.63 mmol) to the reaction system, and stir the reaction mixture at 80 °C for 16 h. Rotary evaporate tetrahydrofuran under reduced pressure, add water (30 mL) to the remaining organic phase, extract with ethyl acetate three times (10 mL * 3), separate the organic phase, concentrate the organic phase to dryness under reduced pressure, and purify by column chromatography (silica gel, ethyl acetate: petroleum ether = 2 / 1 - 3 / 1) to obtain the product tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (280 mg).

[0509] MS m / z (ESI): 227.9 [M-55] + ;

[0510] Step 3: Synthesis of tert-butyl N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate

[0511] Dissolve the reactant tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (0.1 g, 352.87 μmol) in N,N-dimethylformamide (3 mL), and add N-bromosuccinimide (188.42 mg, 1.06 mmol) to the reaction system. The reaction solution is stirred at 60 °C for 10 hours. Concentrate under reduced pressure to remove the solvent N,N-dimethylformamide (3 mL), add 3 mL of water to the mixture, extract with dichloromethane (3 mL * 2), separate the organic layer, dry the organic phase with anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to dryness under reduced pressure. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 0 - 20%) to obtain the product tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (0.030 g).

[0512] MS m / z(ESI): 307.8[M - 55] +

[0513] Step 4: Synthesis of tert-butyl trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(tert-butylsulfamoyl)phenyl]carbamate Dissolve the reactants tert-butyl trans-(N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (0.02 g, 55.21 μmol) and isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (24.31 mg, 55.21 μmol) in dioxane (1 mL). Under nitrogen protection, add sodium carbonate (2 M, 82.81 μL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (4.51 mg, 5.52 μmol), and stir the reaction solution at 80 °C for 2 hours. After drying the reaction system by rotary evaporation, purify by thin-layer chromatography (silica gel, petroleum ether:tetrahydrofuran = 3:1) to obtain tert-butyl trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(tert-butylsulfamoyl)phenyl]carbamate (27 mg).

[0514] MS m / z(ESI): 596.3[M + H] +

[0515] Step 5: Synthesis of tert-butyl trans-isopropyl (4-(5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate

[0516] The reactant trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(tert-butylsulfamoyl)phenyl]carbamate (0.027 g, 45.32 μmol) was dissolved in anhydrous methanol (2 mL). Hydrochloric acid methanol solution (4 M, 113.30 μL) was added. The reaction solution was stirred at 15 °C for 1 hour. After the reaction system was evaporated to dryness, trans-isopropyl (4-(5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-3-(N-(tert-butyl)sulfamoyl)phenyl)carbamate (0.02 g) was obtained.

[0517] MS m / z (ESI): 496.2 [M+H] + ;

[0518] Step 6: Synthesis of trans-isopropyl N-[3-(tert-butylsulfamoyl)-4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]phenyl]carbamate

[0519] The reactant trans-isopropyl N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-(tert-butylsulfamoyl)phenyl]carbamate (22 mg, 44.39 μmol) was dissolved in dichloromethane (1 mL), pyridine (35.11 mg, 443.86 μmol) and isopropyl chloroformate (16.32 mg, 133.16 μmol) were added, and the reaction solution was stirred at 20 °C for 3 hours. The reaction system was evaporated to dryness. Purification by preparative high performance liquid chromatography (Phenomenex Gemini-NX C18 column, 3 μm silica, 30 mm diameter, 75 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (36%-76%) as the eluent, trans-isopropyl N-[3-(tert-butylsulfamoyl)-4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]phenyl]carbamate (2.78 mg) was obtained. MS m / z (ESI): 582.3 [M+H] + ;

[0520] 1HNMR (400 MHz, DMSO-d6) δ 10.47 - 9.5 (m, 1H), 8.36 (d, J = 2.25 Hz, 1H), 7.74 (dd, J = 8.50, 2.13 Hz, 1H), 7.64 (d, J = 8.50 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J = 8.50 Hz, 1H), 4.94 (quin, J = 6.28 Hz, 1H), 4.75 (dt, J = 12.32, 6.35 Hz, 1H), 3.25 - 3.03 (m, 2H), 2.16 (d, J = 12.38 Hz, 2H), 1.93 (br d, J = 10.26 Hz, 2H), 1.71 - 1.56 (m, 2H), 1.41 - 1.31 (m, 2H), 1.28 (d, J = 6.25 Hz, 6H), 1.17 (d, J = 6.25 Hz, 6H), 1.14 (s, 9H). Example 6: Synthesis of Isopropyl 2-[2-(2-tert-Butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate

[0521]

[0522] Synthesis method

[0523]

[0524] Step 1: Synthesis of tert-Butyl 2-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate

[0525] Isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (100 mg, 313.27 μmol) and tert-butyl 2-bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate (137.95 mg, 313.27 μmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and sodium carbonate (66.41 mg, 626.53 μmol) and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (25.58 mg, 31.33 μmol) were added. Under nitrogen protection, the reaction mixture was stirred at 80 °C for 1 hour. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 mL) three times. The organic layer was dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to dryness. Purification by thin-layer chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) gave the product tert-butyl 2-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate (120 mg).

[0526] MS m / z (ESI): 553.1 [M+H] + ;

[0527] Step 2: Synthesis of isopropyl N-[3-(tert-butylsulfamoyl)-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)phenyl]carbamate

[0528] tert-Butyl 2-[2-(tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate (60 mg, 108.56 μmol) was dissolved in hydrochloric acid-methanol (5 mL, 4 mol / L), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness. The product isopropyl N-[3-(tert-butylsulfamoyl)-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)phenyl]carbamate (45 mg) was obtained.

[0529] MS m / z (ESI): 453.3 [M+H] +

[0530] Step 3: Synthesis of isopropyl 2-[2-(2-tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate

[0531] Isopropyl N-[3-(tert-butylsulfamoyl)-4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)phenyl]carbamate (60 mg, 132.57 μmol) and isopropyl chloroformate (81.23 mg, 662.85 μmol, 92.00 μL) were dissolved in anhydrous dichloromethane (4 mL), and pyridine (314.59 mg, 3.98 mmol, 321.01 μL) was added under an ice bath. The reaction mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography (column: YMC Triart C18; 5 μm silica, 25 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (65% - 85%) as the eluent) gave isopropyl 2-[2-(2-tert-butylsulfamoyl)-4-(isopropoxycarbonylamino)phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylate (5.26 mg).

[0532] MS m / z (ESI): 539.3 [M+H] +

[0533] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 10.18 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.88 (br s, 1H), 7.76 - 7.71 (m, 1H), 7.70 - 7.65 (m, 1H), 4.94 (quin, J = 6.2 Hz, 1H), 4.84 (td, J = 12.4, 6.2 Hz, 1H), 4.72 (s, 2H), 3.75 (t, J = 5.6 Hz, 2H), 2.84 (br s, 2H), 1.28 (d, J = 6.0 Hz, 6H), 1.23 (d, J = 6.3 Hz, 6H), 1.20 (s, 9H).

[0534] Example 7: Synthesis of isopropyl (3-(5-(4-(isopropoxycarbonyl)amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate

[0535]

[0536] Synthesis method

[0537]

[0538] Step 1: Synthesis of tert-butyl (3-carbamoyl bicyclo[1.1.1]pent-1-yl)carbamate

[0539] Dissolve 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (250 mg, 1.10 mmol) in N,N-dimethylformamide (10 mL), add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (627.42 mg, 1.65 mmol), ammonium chloride (176.53 mg, 3.30 mmol) and triethylamine (333.95 mg, 3.30 mmol, 459.36 μL). The reaction solution is a yellow suspension and stirred at 30 °C for 1 hour. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure, diluted with dichloromethane (50 mL), and the organic layer is washed with water (20 mL), and a solid precipitates. After filtration, tert-butyl (3-carbamoyl-bicyclo[1.1.1]pentan-1-yl)carbamate (210 mg) is obtained.

[0540] MS m / z (ESI): 227.0 [M+H] + ;

[0541] Step 2: Synthesis of tert-butyl (3-(methylthiocarbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0542] Dissolve tert-butyl (3-carbamoyl-bicyclo[1.1.1]pentan-1-yl)carbamate (230 mg, 1.02 mmol) in 2-methyltetrahydrofuran (5.00 mL), and add Lawesson's reagent (411.13 mg, 1.02 mmol). The reaction solution is stirred at 80 °C for 1 hour. Add saturated aqueous sodium carbonate solution (10 mL) to the reaction solution to adjust the pH to 8 - 9, and extract three times with ethyl acetate (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain tert-butyl (3-(methylthiocarbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (170 mg).

[0543] MS m / z (ESI): 186.9 [M - 55] + ;

[0544] Step 3: Synthesis of 3-(thiazol-2-yl)bicyclo[1.1.1]pentan-1-amine

[0545] Dissolve tert-butyl (3-(aminothiocarbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate (170 mg, 701.50 μmol) and bromoacetaldehyde diethyl acetal (276.49 mg, 1.40 mmol, 211.06 μL) in anhydrous ethanol (2 mL), and add p-toluenesulfonic acid monohydrate (266.88 mg, 1.40 mmol). The reaction mixture is stirred at 80 °C for 1 hour. The reaction is monitored by LCMS until completion. Add saturated aqueous sodium carbonate solution (10 mL) to adjust the pH to 8 - 9, and extract six times with ethyl acetate (5 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure to dryness to obtain 3-(thiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (80 mg).

[0546] MS m / z (ESI): 167.0 [M+H] + ;

[0547] Step 4: Synthesis of isopropyl (3-(thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0548] Dissolve 3-(thiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (80 mg, 481.22 μmol) and isopropyl chloroformate (117.95 mg, 962.45 μmol, 133.58 μL) in dichloromethane (3 mL), and add N,N-diisopropylethylamine (124.39 mg, 962.45 μmol, 167.64 μL) and 4-dimethylaminopyridine (29.40 mg, 240.61 μmol). The reaction mixture is stirred at 25 °C for 1 hour. The reaction mixture is concentrated under reduced pressure to dryness and purified by thin-layer chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain isopropyl (3-(thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (31 mg).

[0549] MS m / z (ESI): 253.1 [M+H] + ;

[0550] Step 5: Synthesis of isopropyl (3-(5-bromothiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0551] Isopropyl (3-(thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (31 mg, 122.85 μmol) was dissolved in N,N-dimethylformamide (4 mL), and N-bromosuccinimide (65.60 mg, 368.56 μmol) was added. The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain isopropyl (3-(5-bromothiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (34 mg).

[0552] MS m / z (ESI): 331.1, 333.1 [M+H] + ;

[0553] Step 6: Synthesis of isopropyl (3-(5-(4-(isopropoxycarbonyl)amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0554] Isopropyl (3-(5-bromothiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (50 mg, 150.95 μmol) and isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66.47 mg, 150.95 μmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). Sodium carbonate (32.00 mg, 301.91 μmol) and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (12.33 mg, 15.10 μmol) were added. Under nitrogen protection, the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 mL) three times. The organic layer was dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica gel, 50 mm diameter, 250 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity as the eluent) gave the compound isopropyl (3-(5-(4-(isopropoxycarbonyl)amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (11.3 mg). MS m / z (ESI): 565.1 [M+H] +

[0555] 11H NMR (400 MHz, DMSO-d6) δ ppm 10.10 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.94 (br s, 1H), 7.69 - 7.59 (m, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.17 (s, 1H), 4.93 (m, J = 6.3 Hz, 1H), 4.76 (m, J = 6.1 Hz, 1H), 2.34 - 2.32 (m, 1H), 2.33 (s, 5H), 1.28 (d, J = 6.3 Hz, 6H), 1.18 (br d, J = 5.8 Hz, 6H), 1.10 (s, 9H).

[0556] Example 8: Synthesis of Isopropyl 7-(5-(2-(N-(tert-Butyl)sulfamoyl)-4-((isopropoxycarbonyl)amino)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0557]

[0558] Synthesis Method

[0559]

[0560] Step 1: Synthesis of N-(tert-Butyl)-5-nitro-2-(thiazol-5-yl)benzenesulfonamide

[0561] Dissolve the reactant 2-Bromo-N-(tert-butyl)-5-nitrobenzenesulfonamide (2.0 g, 5.93 mmol) in N,N-dimethylacetamide (20 mL), add thiazole (1.51 g, 17.97 mmol), palladium(II) acetate (133.16 mg, 593.14 μmol) and potassium acetate (1.75 g, 17.79 mmol). The reaction mixture is a yellow suspension, and it is stirred at 140 °C for 16 hours. The reaction mixture is dissolved in water (200 mL), filtered, and the filter cake is collected and concentrated to dryness under reduced pressure. Then it is purified by column chromatography (silica gel, petroleum ether / tetrahydrofuran = 3 / 1) to obtain N-(tert-butyl)-5-nitro-2-(thiazol-5-yl)benzenesulfonamide (0.9 g).

[0562] MS m / z (ESI): 342.1 [M+H] + ;

[0563] Step 2: Synthesis of 2-(2-Bromothiazol-5-yl)-N-(tert-butyl)-5-nitrobenzenesulfonamide

[0564] Dissolve N-(tert-butyl)-5-nitro-2-(thiazol-5-yl)benzenesulfonamide (0.8 g, 2.34 mmol) in acetic acid (10.00 mL), and add potassium acetate (1.15 g, 11.72 mmol) and bromine (1.87 g, 11.72 mmol). The reaction mixture was stirred at 80 °C for 3 hours. Add saturated aqueous sodium carbonate solution (100 mL) to the reaction mixture to adjust the pH to 8 - 9, and extract with ethyl acetate (100 mL) three times. The organic phase was dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to dryness to obtain the crude product. The obtained 2-(2-bromothiazol-5-yl)-N-(tert-butyl)-5-nitrobenzenesulfonamide (1.4 g, crude product) was directly used in the next step of the reaction.

[0565] MS m / z (ESI): 420.0, 422.0 [M+H] + ;

[0566] Step 3: Synthesis of 5-amino-2-(2-bromothiazol-5-yl)-N-(tert-butyl)benzenesulfonamide

[0567] Dissolve 2-(2-bromothiazol-5-yl)-N-(tert-butyl)-5-nitrobenzenesulfonamide (1.4 g, 3.33 mmol) in anhydrous ethanol (15 mL), and add iron powder (1.86 g, 33.31 mmol) and ammonium chloride (1.78 g, 33.31 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness, and then purified by column chromatography (silica gel, dichloromethane / methanol = 20 / 1) to obtain 5-amino-2-(2-bromothiazol-5-yl)-N-(tert-butyl)benzenesulfonamide (0.9 g).

[0568] MS m / z (ESI): 390.0, 392.0 [M+H] + ;

[0569] Step 4: Synthesis of tert-butyl 7-(5-(4-amino-2-(N-(tert-butyl)aminosulfonyl)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0570] 5-Amino-2-(2-bromothiazol-5-yl)-N-(tert-butyl)benzenesulfonamide (20 mg, 51.24 μmol) was dissolved in dimethyl sulfoxide (2 mL), and sodium bicarbonate (12.91 mg, 153.72 μmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (23.19 mg, 102.48 μmol) were added. The reaction mixture was stirred at 120 °C under microwave irradiation for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica gel, dichloromethane / methanol = 20 / 1) to obtain tert-butyl 7-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (18 mg).

[0571] MS m / z (ESI): 536.3 [M+H] + ;

[0572] Step 5: Synthesis of 2-(2-(2,7-diazaspiro[3.5]nonan-7-yl)thiazol-5-yl)-5-amino-N-(tert-butyl)benzenesulfonamide Tert-butyl 7-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (18 mg, 33.60 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (180 mg, 1.58 mmol, 116.88 μL) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain 2-(2-(2,7-diazaspiro[3.5]nonan-7-yl)thiazol-5-yl)-5-amino-N-(tert-butyl)benzenesulfonamide (0.14 g).

[0573] MS m / z (ESI): 436.2 [M+H] + ;

[0574] Step 6: Synthesis of isopropyl 7-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((isopropoxycarbonyl)amino)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0575] 2-(2-(2,7-Diazaspiro[3.5]nonan-7-yl)thiazol-5-yl)-5-amino-N-(tert-butyl)benzenesulfonamide (0.14 g, crude) was dissolved in dichloromethane (10 mL), and pyridine (254.22 mg, 3.21 mmol, 259.41 μL) and isopropyl chloroformate (157.55 mg, 1.29 mmol, 178.42 μL) were added. Under nitrogen protection, the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini NX C18 column, 5 μm silica, 30 mm diameter, 150 mm length); (using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity (45% - 65%) as the eluent) to obtain isopropyl 7-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((isopropoxycarbonyl)amino)phenyl)thiazol-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (3.8 mg).

[0576] MS m / z (ESI): 608.1 [M+H] +

[0577] 1 H NMR (400 MHz, DMSO-d6): δ ppm 10.00 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.3, 2.3 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 6.95 (s, 1H), 4.99 - 4.68 (m, 2H), 3.65 (br s, 4H), 3.39 (br s, 4H), 1.79 (br t, J = 5.6 Hz, 4H), 1.31 - 1.05 (m, 21H).

[0578] Example 9 and Example 10: Synthesis of endo and exo isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[6-(isopropoxycarbonylamino)-3-azabicyclo[3.1.0]hex-3-yl]thiazol-5-yl]phenyl]carbamate

[0579]

[0580] Synthesis method

[0581]

[0582] Step 1: Synthesis of tert-butyl (3-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate

[0583] 5-Amino-2-(2-bromothiazol-5-yl)-N-(tert-butyl)benzenesulfonamide (40 mg, 102.48 μmol) was dissolved in dimethyl sulfoxide (2 mL), and sodium bicarbonate (25.83 mg, 307.44 μmol) and tert-butyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate (60.95 mg, 307.44 μmol) were added. The reaction mixture was stirred at 120 °C under microwave for 2 h. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (silica gel, dichloromethane / methanol = 20 / 1) to give tert-butyl (3-(5-(4-amino-2-(N-(tert-butyl)aminosulfonyl)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (80 mg).

[0584] MS m / z (ESI): 508.3 [M+H] + ;

[0585] Step 2: Synthesis of 5-amino-2-(2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)thiazol-5-yl)-N-(tert-butyl)benzenesulfonamide Tert-butyl (3-(5-(4-amino-2-(N-(tert-butyl)aminosulfonyl)phenyl)thiazol-2-yl)-3-azabicyclo[3.1.0]hex-6-yl)carbamate (120 mg, 236.37 μmol) was dissolved in dichloromethane (12 mL), and trifluoroacetic acid (1.2 g, 10.52 mmol, 779.22 μL) was added. The reaction mixture was stirred at 25 °C for 1 h. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness under reduced pressure to give 5-amino-2-(2-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)thiazol-5-yl)-N-(tert-butyl)benzenesulfonamide (0.1 g, crude product). MS m / z (ESI): 408.1 [M+H] + ;

[0586] Step 3: Synthesis of isopropyl N-[3-(tert-butylaminosulfonyl)-4-[2-[6-(isopropoxycarbonylamino)-3-azabicyclo[3.1.0]hex-3-yl]thiazol-5-yl]phenyl]carbamate

[0587] 5-Amino-2-(2-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)-N-(tert-butyl)benzenesulfonamide (0.1 g, crude) was dissolved in dichloromethane (10 mL), and pyridine (194.09 mg, 2.45 mmol, 198.05 μL) and isopropyl chloroformate (180.42 mg, 1.47 mmol, 204.32 μL) were added. Under nitrogen protection, the reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Phenomenex Gemini NX C18 column, 5 μm silica, 30 mm diameter, 150 mm length); (using a mixture of water (containing 0.05% ammonia and 10 mM ammonium bicarbonate) and acetonitrile with decreasing polarity (50%-70%) as the eluent) to obtain two products, namely endo- and exo-isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[6-(isopropoxycarbonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]thiazol-5-yl]phenyl]carbamate (17.0 mg / 17.0 mg), and the specific configuration is unknown.

[0588] Product 1:

[0589] MS m / z (ESI): 580.3 [M+H] +

[0590] 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 8.27 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 8.4, 2.1 Hz, 1H), 7.38 - 7.08 (m, 3H), 7.00 - 6.82 (m, 1H), 4.99 - 4.67 (m, 2H), 3.67 - 3.55 (m, 2H), 3.46 (br d, J = 10.3 Hz, 2H), 2.69 - 2.59 (m, 1H), 2.06 - 1.92 (m, 2H), 1.29 - 1.05 (m, 21H).

[0591] Product 2:

[0592] MS m / z (ESI): 580.3 [M+H] + ;

[0593] 11H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.43 - 7.29 (m, 2H), 7.19 (s, 1H), 6.96 (s, 1H), 4.96 - 4.68 (m, 2H), 3.60 - 3.47 (m, 4H), 2.30 (br s, 1H), 1.83 (br s, 2H), 1.28 - 1.07 (m, 21H).

[0594] Example 11: Synthesis of Isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)azepan-1-yl]thiazol-5-yl]phenyl]carbamate

[0595]

[0596] Synthesis Method

[0597]

[0598] Step 1: Synthesis of tert-Butyl N-[1-[1-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]azetidin-4-yl]carbamate

[0599] The reactants 5-amino-2-(2-bromothiazol-5-yl)-N-tert-butylbenzenesulfonamide (0.03 g, 76.86 μmol), tert-butyl azetidin-4-ylcarbamate (49.41 mg, 230.58 μmol) and sodium bicarbonate (19.37 mg, 230.58 μmol, 8.97 μL) were added into a 4 mL microwave reaction flask, then dimethyl sulfoxide (1 mL) was added, and the mixture was subjected to microwave reaction at 120 °C for 5 hours. 2 mL of water was added to the reaction system, and the mixture was extracted twice with dichloromethane (2 mL * 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The product tert-Butyl N-[1-[1-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]azetidin-4-yl]carbamate (40 mg) was obtained by purification using thin layer chromatography (silica gel, dichloromethane / methanol = 95:5).

[0600] MS m / z (ESI): 524.3 [M + H] + ;

[0601] Step 2: Synthesis of 5-Amino-2-[2-(4-aminoazetidin-1-yl)thiazol-5-yl]-N-tert-butylbenzenesulfonamide

[0602] Dissolve tert-butyl N-[1-[1-[5-[4-amino-2-(tert-butylsulfamoyl)tert-butyl]phenyl]thiazol-2-yl]azetidin-4-yl]carbamate (0.04 g, 76.38 μmol) in anhydrous dichloromethane (5 mL), and add trifluoroacetic acid (383.19 mg, 3.36 mmol, 248.82 μL). Stir the reaction mixture at 25 °C for 1 hour. Detect the completion of the reaction by LCMS. Concentrate the reaction mixture under reduced pressure to remove dichloromethane, and obtain crude 5-amino-2-[2-(4-aminoazetidin-1-yl)thiazol-5-yl]-N-tert-butylbenzenesulfonamide (80 mg, crude product).

[0603] MS m / z (ESI): 424.1 [M+H] + ;

[0604] Step 3: Synthesis of isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)azepan-1-yl]thiazol-5-yl]phenyl]carbamate Dissolve 5-amino-2-[2-(4-aminoazetidin-1-yl)thiazol-5-yl]-N-tert-butylbenzenesulfonamide (32 mg, 75.54 μmol) in anhydrous dichloromethane (2 mL), and add pyridine (3.92 g, 49.56 mmol, 4 mL) and isopropyl chloroformate (55.55 mg, 453.26 μmol, 62.91 μL) to the reaction system. Stir the reaction mixture at 25 °C for 5 hours. LCMS shows that the reaction is complete. Concentrate the reaction mixture under reduced pressure to remove dichloromethane. Purify by preparative high performance liquid chromatography (YMC Triart C18 column, 7 μm silica, 50 mm diameter, 250 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (35%-75%) as the eluent) to obtain the compound isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)azepan-1-yl]thiazol-5-yl]phenyl]carbamate (6.42 mg).

[0605] MS m / z (ESI): 596.3 [M+H] + ;

[0606] 1H-NMR: (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.27 (d, J = 2.20 Hz, 1H), 7.59 (dd, J = 8.38, 2.26 Hz, 1H), 7.35 (d, J = 8.44 Hz, 1H), 7.18 (s, 1H), 7.09 (br d, J = 7.58 Hz, 1H), 6.84 (s, 1H), 4.92 (spt, J = 6.22 Hz, 1H), 4.80 - 4.64 (m, 1H), 3.79 - 3.65 (m, 1H), 3.61 - 3.47 (m, 2H), 3.46 - 3.36 (m, 2H), 2.01 - 1.85 (m, 2H), 1.84 - 1.70 (m, 2H), 1.69 - 1.59 (m, 1H), 1.51 - 1.35 (m, 1H), 1.27 (d, J = 6.24 Hz, 6H), 1.15 (d, J = 6.24 Hz, 6H), 1.10 (s, 9H).

[0607] Example 12: Synthesis of trans-Isopropyl N-[4-[5-[2-(tert-Butylsulfamoyl)-4-(3,4-Dihydro-1H-isoquinoline-2-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0608]

[0609] Synthesis Method

[0610]

[0611] Step 1: Synthesis of trans-(4-Nitrophenyl) N-[3-(tert-Butylsulfamoyl)-4-[2-[4-(Isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate Dissolve the aforementioned intermediate 2, namely trans-isopropyl N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (100 mg, 202.16 μmol) in dichloromethane (6 mL). Add phenyl 4-nitrocarbamate (65.20 mg, 323.45 μmol) at 0 °C, then add 4-dimethylaminopyridine (12.35 mg, 101.08 μmol) and pyridine (47.97 mg, 606.47 μmol, 48.95 μL). Stir the reaction mixture at 20 °C for 0.5 h. Concentrate the reaction mixture under reduced pressure to dryness and obtain the product trans-(4-nitrophenyl) N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (130 mg) without further purification. MS m / z (ESI): 660.3 [M + H] + ;

[0612] Step 2: Synthesis of trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-(3,4-dihydro-1H-isoquinoline-2-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate Dissolve trans-(4-nitrophenyl) N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (133 mg, 201.58 μmol) and 1,2,3,4-tetrahydroisoquinoline (80.55 mg, 604.75 μmol, 75.99 μL) in acetonitrile (4 mL), and add N,N-diisopropylethylamine (65.13 mg, 503.96 μmol, 87.78 μL). Stir the reaction mixture at 80 °C for 1 hour. Cool the reaction mixture to 20 °C and concentrate it to dryness under reduced pressure. Add sodium carbonate (30 mg) dissolved in water (3 mL) to the residue and stir for three minutes. Dry the extracted organic phase with anhydrous magnesium sulfate, filter, and concentrate to dryness. Purify by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity as the eluent) to obtain the product trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-(3,4-dihydro-1H-isoquinoline-2-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate (36 mg).

[0613] MS m / z (ESI): 654.1 [M+H] + ;

[0614] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (s, 1H), 8.33 (d, J = 2.25 Hz, 1H), 7.78 (dd, J = 8.50, 2.13 Hz, 1H), 7.66 (s, 1H), 7.34 (d, J = 8.50 Hz, 1H), 7.20 (s, 4H), 7.03 (br d, J = 7.50 Hz, 1H), 6.80 (s, 1H), 4.74 (dt, J = 12.44, 6.28 Hz, 1H), 4.67 (s, 2H), 3.73 (t, J = 5.88 Hz, 2H), 3.31 (br s, 1H), 2.95 - 2.84 (m, 3H), 2.13 (br d, J = 11.63 Hz, 2H), 1.91 (br d, J = 10.01 Hz, 2H), 1.66 - 1.49 (m, 2H), 1.42 - 1.28 (m, 2H), 1.16 (d, J = 6.25 Hz, 6H), 1.04 (s, 9H).

[0615] Example 13: Synthesis of trans-Isopropyl N-[4-[5-[2-(tert-Butylsulfamoyl)-4-(1,2,3,4-tetrahydroisoquinoline-3-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0616]

[0617] Synthesis Method

[0618]

[0619] Dissolve trans-isopropyl N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 40.43 μmol) and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (21.49 mg, 121.29 μmol) in acetonitrile (0.5 mL), and add tripropyl phosphoric anhydride (0.5 mL). Under nitrogen protection, stir the reaction solution at 80 °C for 1 hour. Concentrate the reaction solution under reduced pressure to dryness. Purify by preparative liquid chromatography (column: BostonPrime C18; 5 μm silica, 30 mm diameter, 150 mm length; use a mixture of water (containing 0.05% ammonia water) and acetonitrile with decreasing polarity (43%-73%) as the eluent) to obtain the compound trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-(1,2,3,4-tetrahydroisoquinoline-3-carbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate (11.87 mg).

[0620] MS m / z (ESI): 654.2 [M+H] + ;

[0621] 1 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 8.4, 2.4 Hz, 1H), 7.69 (s, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.34 - 7.22 (m, 1H), 7.18 - 6.96 (m, 6H), 4.80 - 4.70 (m, 1H), 4.06 - 3.90 (m, 2H), 3.66 (br s, 1H), 3.41 (br d, J = 4.0 Hz, 1H), 3.05 - 2.81 (m, 3H), 2.14 (br d, J = 10.0 Hz, 2H), 1.92 (br d, J = 10.5 Hz, 2H), 1.65 - 1.50 (m, 2H), 1.41 - 1.27 (m, 2H), 1.17 (d, J = 6.3 Hz, 6H), 1.06 (s, 9H).

[0622] Example 14: Synthesis of trans-isopropyl N-[4-[5-[4-[[(E)-N-benzyl-N'-cyanocarbamimidamido]amino]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0623]

[0624] Synthesis method

[0625]

[0626] Step 1: Synthesis of trans-isopropyl N-[4-[5-[4-(benzylaminomethanethioamido)-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0627] Dissolve trans-isopropyl N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (75.0 mg, 151.6 μmol) in N,N-dimethylformamide (5.0 mL), add benzyl isothiocyanate (33.9 mg, 227.4 μmol, 30.0 μL) and N,N-diisopropylethylamine (39.2 mg, 303.2 μmol, 52.8 μL). Stir the reaction mixture at 20 °C for 0.5 h. Concentrate the reaction mixture directly under reduced pressure to dryness and purify by column chromatography (silica gel, methanol / dichloromethane = 1:10) to obtain trans-isopropyl N-[4-[5-[4-(benzylaminomethanethioamido)-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (18.0 mg).

[0628] MS m / z (ESI): 644.3 [M+H] + ;

[0629] Step 2: Synthesis of trans-isopropyl N-[4-[5-[4-[[N-benzyl-N'-cyanoaminocarbonylamino]amino]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate Dissolve trans-isopropyl N-[4-[5-[4-(benzylaminomethanethioylamino)-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (66.0 mg, 105.1 μmol) and cyanamide (113.6 mg, 2.7 mmol) in N,N-dimethylformamide (2.0 mL), and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt (30.2 mg, 157.7 μmol) and N,N-diisopropylethylamine (27.2 mg, 210.3 μmol, 36.6 μl). Stir the reaction mixture at 40 °C for 16 h. Concentrate the reaction mixture to dryness under reduced pressure and separate by high performance liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length); (using a mixture of water (containing 0.05% ammonia water) and acetonitrile with decreasing polarity (48%-68%) as the eluent) to obtain trans-isopropyl N-[4-[5-[4-[[N-benzyl-N'-cyanoaminocarbonylamino]amino]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (1.58 mg). MS m / z (ESI): 652.2 [M+H] +

[0630] 1 HNMR (400 MHz, DMSO-d6) δ 9.48 (br s, 1H), 8.20 - 8.09 (m, 1H), 8.04 - 7.95 (m, 1H), 7.72 - 7.64 (m, 1H), 7.54 - 7.47 (m, 1H), 7.45 - 7.40 (m, 1H), 7.39 - 7.32 (m, 5H), 7.07 - 6.95 (m, 1H), 7.14 - 6.95 (m, 1H), 4.82 - 4.65 (m, 1H), 4.49 (br s, 2H), 2.91 (tt, J = 11.8, 3.5 Hz, 1H), 2.56 - 2.52 (m, 1H), 2.20 - 2.07 (m, 2H), 1.91 (br d, J = 10.27 Hz, 2H), 1.57 (qd, J = 12.72, 2.81 Hz, 2H), 1.40 - 1.27 (m, 2H), 1.16 (d, J = 6.24 Hz, 6H), 1.05 (s, 9H). Example 15: Synthesis of trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(2-phenoxyacetyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0631]

[0632] Synthesis method

[0633]

[0634] Dissolve trans-isopropyl N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (60.0 mg, 121.3 μmol) in dichloromethane (6.0 mL), and add 2-phenoxyacetyl chloride (20.7 mg, 121.3 μmol, 16.7 μL) and N,N-diisopropylethylamine (31.4 mg, 242.6 μmol, 42.3 μL). The reaction solution was stirred at 20 °C for 1 hour. The reaction was completed as detected by LCMS. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (YMC Triart C18 column, 5 μm silica, 25 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia water) and acetonitrile with decreasing polarity as the eluent) to obtain trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(2-phenoxyacetyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (22.3 mg).

[0635] MS m / z (ESI): 629.1 [M+H] +

[0636] 1 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.48 (d, J = 2.00 Hz, 1H), 7.88 (dd, J = 8.44, 2.06 Hz, 1H), 7.68 (s, 1H), 7.44 (d, J = 8.38 Hz, 1H), 7.32 (t, J = 7.94 Hz, 2H), 7.10 - 6.86 (m, 5H), 4.84 - 4.60 (m, 3H), 3.40 - 3.25 (m, 1H), 2.91 (br t, J = 11.94 Hz, 1H), 2.13 (brd, J = 11.51 Hz, 2H), 1.92 (br d, J = 9.63 Hz, 2H), 1.64 - 1.49 (m, 2H), 1.41 - 1.26 (m, 2H), 1.16 (d, J = 6.25 Hz, 6H), 1.05 (s, 9H).

[0637] Example 16: Synthesis of trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-(cyclopropylmethoxycarbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0638]

[0639] Synthesis method

[0640]

[0641] Dissolve trans-(4-nitrophenyl) N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (50 mg, 75.78 μmol) and cyclopropylmethanol (54.64 mg, 757.84 μmol, 59.92 μL) prepared in Example 12 in acetonitrile (4 mL), and add N,N-diisopropylethylamine (24.49 mg, 189.46 μmol, 33.00 μL). The reaction solution was stirred at 80 °C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure at 20 °C, extracted with aqueous sodium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length); (using a mixture of water (containing 0.05% ammonia water) and acetonitrile with decreasing polarity as the eluent) purification to obtain the product trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-(cyclopropylmethoxycarbonylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate (9.2 mg).

[0642] MS m / z (ESI): 615.1 [M+Na] + ;

[0643] 1 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 10.27 - 10.13 (m, 1H), 8.33 (d, J = 2.01 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.39 (d, J = 8.53 Hz, 1H), 7.62 - 7.09 (m, 2H), 4.80 - 4.62 (m, 1H), 3.96 (d, J = 7.28 Hz, 2H), 3.33 - 3.30 (m, 1H), 2.90 (br t, J = 12.17 Hz, 1H), 2.13 (br d, J = 11.54 Hz, 2H), 1.92 (br d, J = 10.54 Hz, 2H), 1.63 - 1.51 (m, 2H), 1.40 - 1.28 (m, 2H), 1.17 (d, J = 6.02 Hz, 6H), 1.10 - 1.06 (m, 1H), 1.07 (s, 7H), 1.09 - 1.05 (m, 1H), 0.60 - 0.52 (m, 2H), 0.37 - 0.29 (m, 2H).

[0644] Example 17: Synthesis of trans-Isopropyl N-[4-[5-[2-(tert-Butylsulfamoyl)-4-[(1-phenylcyclopropyl)carbamoylamino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0645]

[0646] Synthesis Method

[0647]

[0648] Trans-(4-Nitrophenyl) N-[3-(tert-butylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (50 mg, 75.78 μmol) and 1-phenylcyclopropylamine (20.19 mg, 151.57 μmol, 59.92 μL) were dissolved in acetonitrile (4 mL), and N,N-diisopropylethylamine (24.49 mg, 189.46 μmol, 33.00 μL) was added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure to dryness at 20 °C. The residue was extracted with aqueous sodium carbonate solution / dichloromethane, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated to dryness. The product was purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity as the eluent) to obtain trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(1-phenylcyclopropyl)carbamoylamino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (6.18 mg).

[0649] MS m / z (ESI): 654.3 [M+H] + ;

[0650] 1HNMR (400 MHz, DMSO-d6) δ 8.97 (br s, 1H), 8.21 (d, J = 2.26 Hz, 1H), 7.64 (s, 1H), 7.60 (dd, J = 8.41, 2.13 Hz, 1H), 7.30 (dd, J = 14.56, 7.78 Hz, 3H), 7.25 - 7.20 (m, 2H), 7.19 - 7.10 (m, 2H), 7.03 (br d, J = 7.78 Hz, 1H), 6.86 (s, 1H), 4.81 - 4.65 (m, 1H), 3.49 - 3.39 (m, 1H), 3.32 - 3.29 (m, 2H), 2.97 - 2.81 (m, 1H), 2.13 (br d, J = 12.05 Hz, 2H), 1.92 (br d, J = 10.04 Hz, 2H), 1.65 - 1.48 (m, 2H), 1.23 (br d, J = 6.02 Hz, 4H), 1.17 (d, J = 6.27 Hz, 6H), 1.04 (s, 9H).

[0651] Example 18: Synthesis of trans-Isopropyl N-[4-[5-[2-(tert-Butylsulfamoyl)-4-[(2-phenylcyclopropanecarbonyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0652]

[0653] Synthesis Method

[0654]

[0655] Dissolve trans-isopropyl N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (40 mg, 80.86 μmol) and 2-phenylcyclopropanecarboxylic acid (15.74 mg, 97.03 μmol) in acetonitrile (1 mL), and add tri-n-propylphosphoric anhydride (1.07 g, 3.36 mmol, 1 mL) under nitrogen protection. The reaction solution is a yellow suspension and stirred at 80 °C for 1 hour. After completion of the reaction detected by LCMS, add water (15 mL), and extract twice with dichloromethane (15 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length; using a mixture of water (containing 0.05% ammonia water) and methanol with decreasing polarity as the eluent) to obtain the compound trans-isopropyl N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(2-phenylcyclopropanecarbonyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (18.19 mg).

[0656] MS m / z (ESI): 639.1 [M+H] + ;

[0657] 1 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.42 (d, J = 2.13 Hz, 1H), 7.82 (dd, J = 8.44, 2.06 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J = 8.13 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.24 - 7.19 (m, 3H), 7.02 (s, 1H), 6.93 (s, 1H), 4.82 - 4.71 (m, 1H), 3.29 (s, 2H), 2.91 (s, 1H), 2.17 - 2.07 (m, 3H), 1.93 (br d, J = 12.88 Hz, 2H), 1.63 - 1.51 (m, 3H), 1.45 - 1.31 (m, 3H), 1.17 (d, J = 6.25 Hz, 6H), 1.06 (s, 9H).

[0658] Example 19: Synthesis of trans-Isopropyl N-[3-(tert-butylsulfonylamino)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0659]

[0660] Synthesis Method

[0661]

[0662] Step 1: Synthesis of Isopropyl-N-(4-bromo-3-nitro-phenyl)-N-isopropoxycarbonyl-carbamate

[0663] Dissolve 4-bromo-3-nitroaniline (5 g, 23.04 mmol) and isopropyl chloroformate (5.65 g, 46.08 mmol, 6.40 mL) in anhydrous dichloromethane (100 mL), add N,N-diisopropylethylamine (5.96 g, 46.08 mmol, 8.03 mL) and pyridine (9.11 g, 115.20 mmol, 9.30 mL). The reaction mixture is a dark brown suspension and stirred at 20 °C for 0.5 h. The reaction is monitored by LCMS until completion. The reaction mixture is concentrated to dryness under reduced pressure and purified by column chromatography (silica gel, tetrahydrofuran:petroleum ether = 1:6). Isopropyl-N-(4-bromo-3-nitro-phenyl)-N-isopropoxycarbonyl-carbamate (5.6 g, 14.39 mmol) is obtained after purification.

[0664] MS m / z (ESI): 411 / 413 [M+Na] + ;

[0665] Step 2: Synthesis of isopropyl N-(3-amino-4-bromophenyl)carbamate

[0666] Dissolve isopropyl-N-(4-bromo-3-nitrophenyl)-N-isopropoxycarbonyl-carbamate (1 g, 2.57 mmol) in anhydrous methanol (10 mL), and add ferric chloride hexahydrate (891.75 mg, 3.30 mmol). Stir the reaction mixture at 70 °C for 12 min. Then add hydrazine hydrate (1.98 g, 39.59 mmol), and stir the yellow reaction mixture at 70 °C for 3 h. Monitor the reaction by LCMS until completion. Filter and dry the reaction mixture, add ethyl acetate (30 mL), water (30 mL), and saturated brine (30 mL) for extraction. Dry the organic layer with anhydrous magnesium sulfate, filter by suction, concentrate the filtrate under reduced pressure to dryness, and purify by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:4) to obtain isopropyl N-(3-amino-4-bromophenyl)carbamate (300 mg, 1.10 mmol).

[0667] MS m / z (ESI): 273 / 275 [M+H] + ;

[0668] Step 3: Synthesis of isopropyl N-[4-bromo-3-(tert-butylsulfinylamino)phenyl]carbamate

[0669] Dissolve isopropyl N-(3-amino-4-bromophenyl)carbamate (300 mg, 1.10 mmol) in anhydrous dichloromethane (3 mL), add pyridine (260.65 mg, 3.30 mmol, 265.97 μL), and dropwise add tert-butylsulfinyl chloride (185.36 mg, 1.32 mmol, 162.60 μL) under nitrogen protection. Stir the reaction mixture at 20 °C for 7 h. Monitor the reaction by LCMS until completion. Purify by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:4) to obtain isopropyl N-[4-bromo-3-(tert-butylsulfinylamino)phenyl]carbamate (160 mg, 424.07 μmol).

[0670] MS m / z (ESI): 377 / 379 [M+H] + ;

[0671] Step 4: Synthesis of isopropyl N-[4-bromo-3-(tert-butylsulfonylamino)phenyl]carbamate

[0672] Dissolve isopropyl N-[4-bromo-3-(tert-butylsulfinylamino)phenyl]carbamate (150 mg, 397.57 μmol) in anhydrous dichloromethane (1 mL), and add meta-chloroperoxybenzoic acid (171.52 mg, 993.91 μmol) under nitrogen protection. Stir the reaction mixture at 20 °C for 3 h. Monitor the completion of the reaction by LCMS. Pour the reaction mixture into an ice bath of ammonium chloride, extract with dichloromethane (2×15 mL) and saturated brine (15 mL), dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate. Purify by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:4) to obtain isopropyl N-[4-bromo-3-(tert-butylsulfonylamino)phenyl]carbamate (100 mg, 254.26 μmol).

[0673] MS m / z (ESI): 410 / 412 [M+H2O] + ;

[0674] Step 5: Synthesis of isopropyl N-[3-(tert-butylsulfonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0675] Dissolve isopropyl N-[4-bromo-3-(tert-butylsulfonylamino)phenyl]carbamate (50 mg, 127.13 μmol) and bis(pinacolato)diboron (129.13 mg, 508.52 μmol) in anhydrous tetrahydrofuran (5 mL), add potassium acetate (37.43 mg, 381.39 μmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (10.38 mg, 12.71 μmol) under nitrogen protection. Stir the red reaction mixture at 80 °C for 7 h. Monitor the completion of the reaction by LCMS. Purify by thin layer chromatography (silica gel, petroleum ether / tetrahydrofuran = 3 / 1) to obtain isopropyl N-[3-(tert-butylsulfonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (30 mg, 68.13 μmol). MS m / z (ESI): 458 [M+H2O] + ;

[0676] Step 6: Synthesis of trans-Isopropyl N-[3-(tert-butylsulfonylamino)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate Dissolve isopropyl N-[3-(tert-butylsulfonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (30 mg, 68.13 μmol) and trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (23.66 mg, 68.13 μmol) in 1,4-dioxane (4 mL) and water (0.4 mL). Under nitrogen protection, add sodium carbonate (14.44 mg, 136.25 μmol) and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (5.56 mg, 6.81 μmol). Stir the reaction mixture at 80 °C for 7 h. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture under reduced pressure to dryness. Add water (15 mL) to the residue, extract twice with dichloromethane (15 mL), dry the organic layer over anhydrous magnesium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to dryness. Purify by preparative liquid chromatography (BostonPrime C18 column; 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity as the eluent) to obtain trans-isopropyl N-[3-(tert-butylsulfonylamino)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate.

[0677] MS m / z(ESI): 581.1 [M+H] + ;

[0678] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.81 (br s, 1H) 8.80 - 8.91 (m, 1H) 7.86 (s, 1H) 7.73 (s, 1H) 7.32 - 7.44 (m, 2H) 7.04 (br d, J = 7.53 Hz, 1H) 4.86 - 4.96 (m, 1H) 4.69 - 4.81 (m, 1H) 3.32 - 3.32 (m, 1H) 2.90 (br t, J = 11.80 Hz, 1H) 2.08 (br s, 2H) 1.91 (br d, J = 9.54 Hz, 2H) 1.48 - 1.61 (m, 2H) 1.31 - 1.40 (m, 2H) 1.26 (d, J = 6.27 Hz, 6H) 1.13 - 1.20 (m, 15H).

[0679] Example 20: Synthesis of trans-Isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropyl-N-methyl-sulfinyl)phenyl]carbamate

[0680]

[0681] Synthesis Method

[0682]

[0683] Dissolve the reactant trans-Isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(isopropylsulfinyl)phenyl]carbamate (20 mg, 36.32 μmol) in 1,4-dioxane (2 mL). Add cupric acetate anhydrous (9.89 mg, 54.47 μmol) and pyridine (6.89 mg, 87.16 μmol, 7.03 μL) at 20 °C. Stir the reaction solution at 20 °C for 5 minutes, then add methylboronic acid (4.35 mg, 72.63 μmol). Stir the reaction solution at 100 °C for 12 hours. Detect the completion of the reaction by LC-MS. Filter the reaction solution under reduced pressure, concentrate the filtrate to dryness under reduced pressure, and purify by preparative high performance liquid chromatography (Phenomenex Gemini-NX C18 column, 5 μm silica, 30 mm diameter, 100 mm length); (using a mixture of water (containing 0.05% ammonia water) and acetonitrile with decreasing polarity (50%-70%) as the eluent) to obtain trans-Isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(S-isopropyl-N-methyl-sulfinyl)phenyl]carbamate (1.5 mg).

[0684] MS m / z (ESI): 565.3 [M+H] +

[0685] 11H NMR: (400 MHz, METHANOL-d4) δ ppm 8.23 (d, J = 2.26 Hz, 1H), 7.83 - 7.77 (m, 1H), 7.63 (s, 1H), 7.44 (d, J = 8.53 Hz, 1H), 5.05 - 5.00 (m, 1H), 4.92 - 4.80 (m, 1H), 3.55 - 3.45 (m, 1H), 3.17 - 3.09 (m, 1H), 3.06 - 2.96 (m, 1H), 2.26 - 2.21 (m, 2H), 2.15 - 2.02 (m, 2H), 1.74 - 1.63 (m, 2H), 1.49 - 1.40 (m, 2H), 1.35 - 1.32 (m, 12H), 1.24 (br d, J = 6.27 Hz, 6H), 1.11 (d, J = 6.78 Hz, 3H).

[0686] Example 21: Synthesis of Isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[8-(isopropoxycarbonylamino)-3-bicyclo[3.2.1]octyl]thiazol-5-yl]phenyl]carbamate

[0687]

[0688] Synthesis Method

[0689]

[0690]

[0691] Step 1: Synthesis of Methyl 8-oxabicyclo[3.2.1]octane-3-carboxylate

[0692] Dissolve methyl 2-(bromomethyl)acrylate (19.57 g, 109.31 mmol) in acetonitrile (135 mL). Slowly add 1-pyrrolidino-1-cyclopentene (15 g, 109.31 mmol) dissolved in acetonitrile (135 mL) at room temperature, and then add triethylamine (17.81 g, 175.99 mmol). The reaction is stirred at 90 °C for 5 hours. Then add acetic acid (77.46 g, 64.49 mmol), and the reaction is continued to stir at 90 °C for 1 hour. The reaction is completed as detected by LCMS. Concentrate under reduced pressure to dryness. The crude product is purified by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain methyl 8-oxabicyclo[3.2.1]octane-3-carboxylate (12 g).

[0693] 11H NMR (400 MHz, DMSO-d6): δ ppm 3.70 (s, 3H), 2.76 (t, J = 7.82 Hz, 1H), 2.58 - 2.69 (m, 2H), 2.03 - 2.22 (m, 4H), 1.75 - 1.85 (m, 2H), 1.59 - 1.70 (m, 2H).

[0694] Step 2: Synthesis of Isopropyl 8 - ((tert - butylsulfinyl)imino)bicyclo[3.2.1]octane - 3 - carboxylate

[0695] Dissolve methyl 8 - oxobicyclo[3.2.1]octane - 3 - carboxylate (8 g, 43.90 mmol) and 2 - methyl - 2 - propanesulfinamide (15.96 g, 131.71 mmol) in tetrahydrofuran (160 mL), then add titanium(IV) isopropoxide (37.43 g, 131.71 mmol). The reaction is stirred at 60 °C for 2 hours. The reaction is monitored by LCMS until completion. Transesterification occurred in the reaction product, and the isopropyl ester product was obtained. The reaction solution was used directly for the next step without treatment.

[0696] MS m / z (ESI): 314.3 [M + 28] + ;

[0697] Step 3: Synthesis of Isopropyl 8 - (tert - butylsulfinylamino)bicyclo[3.2.1]octane - 3 - carboxylate

[0698] Slowly add sodium borohydride (4.98 g, 131.71 mmol) to the reaction solution of Step 2, and stir the reaction at 30 °C for 4 hours. The reaction is monitored by LCMS until completion. Saturated sodium carbonate (100 mL) is added to the reaction solution, stirred at room temperature for 30 minutes, then extracted twice with dichloromethane (100 mL). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Purification by column chromatography (silica gel, dichloromethane:methanol = 15:1) gives isopropyl 8 - (tert - butylsulfinylamino)bicyclo[3.2.1]octane - 3 - carboxylate (7.7 g).

[0699] 1 1H NMR (400 MHz, DMSO-d6): δ ppm 4.95 - 4.88 (m, 1H), 3.20 - 3.13 (m, 1H), 2.50 - 2.45 (m, 1H), 2.40 - 1.93 (m, 6H), 1.63 - 1.60 (m, 2H), 1.49 - 1.47 (m, 2H), 1.20 - 1.08 (m, 15H).

[0700] Step 4: Synthesis of Isopropyl 8 - aminobicyclo[3.2.1]octane - 3 - carboxylate

[0701] Dissolve isopropyl 8-(tert-butylsulfinylamino)bicyclo[3.2.1]octane-3-carboxylate (2.31 g, 8.05 mmol) in methanol (18 mL), and add hydrochloric acid / dioxane (22 mL). Stir the reaction at 30 °C for 2 hours. Monitor the reaction completion by LCMS. Concentrate under reduced pressure to dryness. Obtain isopropyl 8-aminobicyclo[3.2.1]octane-3-carboxylate (1.2 g, crude product).

[0702] MS m / z (ESI): 212.2 [M+H] +

[0703] Step 5: Synthesis of isopropyl 8-((isopropoxycarbonyl)amino)bicyclo[3.2.1]octane-3-carboxylate

[0704] Dissolve methyl 8-aminobicyclo[3.2.1]octane-3-carboxylate (547 mg, 2.99 mmol) and isopropyl chloroformate (438.98 mg, 3.58 mmol) in dichloromethane (26 mL), and add N,N-diisopropylethylamine (1.93 g, 14.93 mmol). Stir the reaction mixture at 30 °C for 1 hour. Add the reaction mixture to water (10 mL), then extract twice with ethyl acetate (30 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness. Purify by column chromatography (silica gel, petroleum ether:tetrahydrofuran = 3:1) to obtain isopropyl 8-((isopropoxycarbonyl)amino)bicyclo[3.2.1]octane-3-carboxylate (416 mg, 1.54 mmol).

[0705] MS m / z (ESI): 298.3 [M+H] +

[0706] Step 6: Synthesis of 8-(isopropoxycarbonylamino)bicyclo[3.2.1]octane-3-carboxylic acid

[0707] Dissolve isopropyl 8-((isopropoxycarbonyl)amino)bicyclo[3.2.1]octane-3-carboxylate (416 mg, 1.54 mmol) in methanol (4 mL), and add sodium hydroxide (2 M, 2.32 mL). Stir the reaction mixture at 30 °C for 1 hour. Monitor the reaction completion by LCMS. Concentrate under reduced pressure to dryness. Adjust the pH to 3 by adding hydrochloric acid (2 M, 4 mL). Add 3 mL of dichloromethane (1 mL * 3) to the reaction mixture. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 8-(isopropoxycarbonylamino)bicyclo[3.2.1]octane-3-carboxylic acid (360 mg, crude product).

[0708] MS m / z (ESI): 256.2 [M+H] +

[0709] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (s, 1H) 7.12 (br d, J = 3.51 Hz, 1H) 4.70 - 4.80 (m, 1H) 3.33 - 3.34 (m, 1H) 2.36 - 2.48 (m, 1H) 2.10 - 2.04 (m, 2H) 1.79 (br t, J = 12.80 Hz, 2H) 1.63 - 1.72 (m, 2H) 1.42 - 1.52 (m, 2H) 1.33 - 1.41 (m, 2H) 1.13 - 1.22 (m, 6H).

[0710] Step 7: Synthesis of isopropyl (3-carbamoyl-bicyclo[3.2.1]oct-8-yl)carbamate

[0711] Dissolve 8-(isopropoxycarbonylamino)bicyclo[3.2.1]octane-3-carboxylic acid (1.6 g, 6.27 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (2.62 g, 6.89 mmol) in N,N-dimethylformamide (100 mL), add ammonium chloride (1.68 g, 31.33 mmol) and N,N-diisopropylethylamine (4.05 g, 31.33 mmol). Stir the reaction mixture at 30 °C for 1 hour. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture under reduced pressure to dryness and purify by column chromatography (silica gel, petroleum ether:tetrahydrofuran = 3:1) to obtain isopropyl (3-carbamoyl-bicyclo[3.2.1]oct-8-yl)carbamate (500 mg, crude).

[0712] MS m / z (ESI): 255.2 [M + H] +

[0713] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17 (br s, 1H) 7.02 (br d, J = 5.13 Hz, 1H) 6.65 (br s, 1H) 4.81 - 4.72 (m, 1H) 3.40 - 3.30 (m, 1H) 2.30 - 2.45 (m, 1H) 2.15 - 2.06 (m, 2H) 1.63 - 1.81 (m, 4H) 1.41 - 1.50 (m, 2H) 1.23 - 1.32 (m, 2H) 1.18 (d, J = 6.25 Hz, 6H).

[0714] Step 8: Synthesis of isopropyl (3-(methylthio)carbamoyl-bicyclo[3.2.1]oct-8-yl)carbamate

[0715] Dissolve isopropyl (3-carbamoyl bicyclo[3.2.1]oct-8-yl) carbamate (500 mg, 1.97 mmol) in tetrahydrofuran (25 mL), and add Lawesson's reagent (397.59 mg, 983.00 μmol). Stir the reaction mixture at 80 °C for 0.5 h. Monitor the completion of the reaction by LCMS. Add saturated aqueous sodium carbonate solution (50 mL) to adjust the pH to 8 - 9, and extract with ethyl acetate (50 mL) three times. Dry the organic layer over anhydrous magnesium sulfate, filter by suction, concentrate the filtrate under reduced pressure to dryness, and concentrate the reaction solution under reduced pressure to dryness. Purify by column chromatography (silica gel, petroleum ether:tetrahydrofuran = 3:1) to obtain isopropyl (3-(aminomethylthio) bicyclo[3.2.1]oct-8-yl) carbamate (270 mg, 998.56 μmol).

[0716] MS m / z (ESI): 271.1 [M+H] +

[0717] Step 9: Synthesis of isopropyl (3-(thiazol-2-yl) bicyclo[3.2.1]oct-8-yl) carbamate

[0718] Dissolve isopropyl (3-(aminomethylthio) bicyclo[3.2.1]oct-8-yl) carbamate (278 mg, 1.03 mmol) and bromoacetaldehyde diethyl acetal (607.85 mg, 3.08 mmol) in ethanol (4 mL), and add p-toluenesulfonic acid monohydrate (391.14 mg, 2.06 mmol). Stir the reaction mixture at 80 °C for 16 h. Monitor the completion of the reaction by LCMS. Concentrate the reaction solution under reduced pressure to dryness. Add saturated aqueous sodium carbonate solution (20 mL) to adjust the pH to 8 - 9, and extract with dichloromethane (50 mL) three times. Dry the organic layer over anhydrous magnesium sulfate, filter by suction, and concentrate under reduced pressure to dryness. Purify by thin-layer chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to obtain isopropyl (3-(thiazol-2-yl) bicyclo[3.2.1]oct-8-yl) carbamate (100 mg).

[0719] MS m / z (ESI): 295.2 [M+H] +

[0720] 11H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (d, J = 3.26 Hz, 1H) 7.20 (d, J = 3.51 Hz, 1H) 5.05 (br s, 1H) 4.84 - 4.99 (m, 1H) 3.78 (br s, 1H) 3.30 - 3.46 (m, 1H) 2.30 (br s, 2H) 1.83 - 1.90 (m, 4H) 1.64 - 1.69 (m, 2H) 1.24 (d, J = 6.27 Hz, 6H).

[0721] Step 10: Synthesis of Isopropyl (3-(5-bromothiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate

[0722] Dissolve isopropyl (3-(thiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate (52 mg, 176.62 μmol) in N,N-dimethylformamide (3 mL), and then slowly add dropwise to N-bromosuccinimide (62.87 mg, 353.25 μmol) dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 50 °C for 1 hour. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated under reduced pressure to dryness and purified by column chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to obtain isopropyl (3-(5-bromothiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate (50 mg).

[0723] MS m / z (ESI): 373.1 & 375.1 [M+H] +

[0724] 1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (s, 1H) 4.95 - 4.90 (m, 2H) 3.76 (br s, 1H) 3.23 - 3.37 (m, 1H) 2.30 (br s, 2H) 1.95 - 1.76 (m, 6H) 1.70 - 1.63 (m 2H) 1.24 (d, J = 6.27 Hz, 6H).

[0725] Step 11: Synthesis of Isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[8-(isopropoxycarbonylamino)-3-bicyclo[3.2.1]octyl]thiazol-5-yl]phenyl]carbamate

[0726] Isopropyl (3-(5-bromothiazol-2-yl)bicyclo[3.2.1]oct-8-yl)carbamate (30 mg, 80.36 μmol) and isopropyl (3-(N-(tert-butyl)sulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (42.47 mg, 96.44 μmol) were dissolved in water (240 μl) and dioxane (3 mL), and then [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (6.56 mg, 8.04 μmol) and sodium carbonate (25.55 mg, 241.09 μmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 2 hours. The reaction was monitored by LCMS until completion. Water (2 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (6 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to dryness. Purification by preparative liquid chromatography (YMC Triart C18 column, 7 μm silica, 50 mm diameter, 250 mm length; using a decreasing polarity mixture of water (containing 0.05% ammonia) and acetonitrile as the eluent) gave isopropyl N-[3-(tert-butylsulfamoyl)-4-[2-[8-(isopropoxycarbonylamino)-3-bicyclo[3.2.1]octyl]thiazol-5-yl]phenyl]carbamate (30 mg).

[0727] MS m / z (ESI): 607.4 [M+H] +

[0728] 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (s, 1H) 8.31 (d, J = 2.25 Hz, 1H) 7.55 - 7.72 (m, 2H) 7.37 (d, J = 8.38 Hz, 1H) 7.23 (br s, 1H) 6.98 (s, 1H) 4.96 - 4.89 (m, 1H) 4.80 - 4.75 (m, 1H) 3.40 (br s, 1H) 3.37 - 3.46 (m, 1H) 2.26 (br s, 2H) 1.99 (br t, J = 12.07 Hz, 2H) 1.82 - 1.55 (m, 6H) 1.27 (d, J = 6.25 Hz, 6H) 1.17 (d, J = 6.25 Hz, 6H) 1.09 (s, 9H).

[0729] Example 22: Synthesis of trans-propyl (4-(5-(4-((1H-pyrazol-3-yl)amino)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0730]

[0731] Synthesis method

[0732]

[0733] Step 1: Synthesis of trans-isopropyl (-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate: Dissolve trans-isopropyl (4-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (1.4 g, 2.83 mmol) in acetonitrile (30 mL). Under nitrogen protection, add tert-butyl nitrite (437.77 mg, 4.25 mmol, 504.93 μL). Stir the reaction solution at 0 °C for 1 hour. Copper(I) bromide (487.19 mg, 3.40 mmol) is added to the reaction solution under nitrogen protection, and the reaction solution is stirred at 25 °C for 15 hours. LCMS shows that the reaction is complete. After the reaction system is evaporated to dryness, it is purified by column chromatography (silica gel, tetrahydrofuran / petroleum ether = 0 - 20%) to obtain trans-isopropyl (4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (0.9 g, 1.46 mmol).

[0734] MS m / z (ESI): 558.2, 560.2 [M+H] + ;

[0735] Step 2: Synthesis of trans-tert-butyl 3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate:

[0736] Dissolve trans-isopropyl (4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (250 mg, 447.59 μmol) and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (123.00 mg, 671.38 μmol) in anhydrous tetrahydrofuran (6 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) methanesulfonate (40.57 mg, 44.76 μmol) and potassium acetate (131.78 mg, 1.34 mmol). Stir the reaction mixture at 80 °C for 1 hour. LCMS shows that the reaction is complete. After rotary evaporation of the reaction system, extract with ethyl acetate (40 mL * 3 times) to obtain trans-tert-butyl 3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate (235 mg, crude product).

[0737] MS m / z (ESI): 661.4 [M+H] + ;

[0738] Step 3: Synthesis of trans-isopropyl (4-(5-(4-((1H-pyrazol-3-yl)amino)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[0739] Dissolve trans-tert-butyl 3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-(4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-1H-pyrazole-1-carboxylate (200 mg, 302.64 μmol) in methanol (5 mL), add p-toluenesulfonic acid monohydrate (156.35 mg, 907.93 μmol), and stir the reaction mixture at 30 °C for 2 hours. LCMS shows that the reaction is complete. Rotary evaporate the reaction system. Purify by preparative high performance liquid chromatography (Phenomenex Gemini-NX C18 column, 5 μm silica, 30 mm diameter, 150 mm length) (using a mixture of water (containing 0.05% ammonia water and 10 mmol of ammonium bicarbonate) and acetonitrile with decreasing polarity (45% - 65%) as the eluent), and lyophilize to obtain trans-isopropyl (4-(5-(4-((1H-pyrazol-3-yl)amino)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (36.79 mg).

[0740] MS m / z (ESI): 561.3 [M+H] + ;

[0741] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.17 (s, 1H) 9.02 (s, 1H) 8.16 (d, J = 2.32 Hz, 1H) 7.69 - 7.57 (m, 2H) 7.53 (dd, J = 8.44, 2.32 Hz, 1H) 7.25 (d, J = 8.31 Hz, 1H) 7.01 (br d, J = 7.70 Hz, 1H) 6.71 (s, 1H) 5.86 (t, J = 2.08 Hz, 1H) 4.83 - 4.70 (m, 1H) 3.31 - 3.27 (m, 1H) 2.95 - 2.83 (m, 1H) 2.17 - 2.05 (m, 2H) 1.95 - 1.83 (m, 2H) 1.65 - 1.47 (m, 2H) 1.42 - 1.26 (m, 2H) 1.16 (d, J = 6.24 Hz, 6H) 1.07 (s, 9H).

[0742] Example 23: Synthesis of trans-Isopropyl-N-[3-diethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0743]

[0744] Synthesis method

[0745]

[0746] Step 1: Synthesis of (2-bromophenyl)diethylphosphine oxide Dissolve o-bromoiodobenzene (1 g, 3.53 mmol, 454.55 μL), potassium phosphate (1.50 g, 7.07 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (409.06 mg, 706.95 μmol) in N,N-dimethylformamide (15 mL). Under nitrogen protection, add diethylphosphine oxide (750.10 mg, 7.07 mmol) and palladium acetate (158.72 mg, 706.95 μmol). The reaction solution is a light yellow suspension and stir at 100 °C for 1 h. Monitor the reaction by LCMS until completion. Add water (50 mL) to the reaction solution and extract with dichloromethane (100 mL). Dry the organic layer with anhydrous magnesium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to dryness. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain the compound (2-bromophenyl)diethylphosphine oxide (900 mg).

[0747] 11H NMR (400 MHz, DMSO-d6) δ ppm 8.05 - 7.92 (m, 1H) 7.81 - 7.70 (m, 1H) 7.64 - 7.45 (m, 2H) 2.27 - 2.01 (m, 4H) 1.01 - 0.88 (m, 6H).

[0748] Step 2: Synthesis of (2-Bromo-5-nitrophenyl)diethylphosphine Oxide

[0749] Dissolve (2-Bromophenyl)diethylphosphine Oxide (900 mg, 3.45 mmol) in concentrated sulfuric acid (10 mL), and add fuming nitric acid (651.62 mg, 10.34 mmol, 465.44 μL). The reaction solution is a yellow suspension and stirred at 30 °C for 1 h. The reaction is monitored by LCMS until completion. Add water (20 mL) to the reaction solution, and then extract with ethyl acetate (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure to dryness to obtain the crude product (2-Bromo-5-nitrophenyl)diethylphosphine Oxide (840 mg).

[0750] MS m / z (ESI): 306.0, 308.0 [M+H] + ;

[0751] Step 3: Synthesis of (5-Amino-2-bromophenyl)diethylphosphine Oxide

[0752] Dissolve (2-Bromo-5-nitrophenyl)diethylphosphine Oxide (840 mg, 2.74 mmol) in absolute ethanol (3 mL), and add reduced iron powder (919.52 mg, 16.47 mmol) and ammonium chloride (1.47 g, 27.44 mmol) under nitrogen protection. The reaction solution is a yellow suspension and stirred at 80 °C for 12 h. The reaction is monitored by LCMS until completion. The reaction solution is filtered while hot, and the filtrate is concentrated under reduced pressure to dryness. Purify by column chromatography (methylene chloride:methanol = 20:1) to obtain the compound (5-Amino-2-bromophenyl)diethylphosphine Oxide (360 mg).

[0753] MS m / z (ESI): 276.0, 278.0 [M+H] + ;

[0754] Step 4: Synthesis of Isopropyl (4-Bromo-3-(diethylphosphoryl)phenyl)carbamate

[0755] (5-Amino-2-bromophenyl)diethylphosphine oxide (180 mg, 651.92 μmol) was dissolved in anhydrous dichloromethane (3 mL). Under nitrogen protection, pyridine (309.40 mg, 3.91 mmol, 315.71 μL) and isopropyl chloroformate (239.68 mg, 1.96 mmol, 271.43 μL) were added. The reaction mixture was a yellow suspension and stirred at 25 °C for 1 h. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 1:1) gave isopropyl (4-bromo-3-(diethylphosphoryl)phenyl)carbamate (180 mg, 496.97 μmol).

[0756] MS m / z (ESI): 362.0, 364.0 [M+H] + ;

[0757] Step 5: Synthesis of trans-isopropyl-N-[3-diethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0758] Isopropyl (4-bromo-3-(diethylphosphoryl)phenyl)carbamate (80 mg, 220.87 μmol), trans-isopropyl-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (76.70 mg, 220.87 μmol) and bis(pinacolato)diboron (224.35 mg, 883.49 μmol) were dissolved in anhydrous tetrahydrofuran (6 mL). Under nitrogen protection, tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (10.11 mg, 11.04 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5.26 mg, 11.04 μmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-amino-1,1'-biphenyl)]palladium(II) (8.69 mg, 11.04 μmol) and potassium acetate (43.35 mg, 441.75 μmol) were added. The reaction mixture was a yellow suspension and stirred at 80 °C for 16 h. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness under reduced pressure. Water (5 mL) was added and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity as the eluent) gave trans-isopropyl-N-[3-diethylphosphoryl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (10.35 mg).

[0759] MS m / z (ESI): 550.0 [M+H] + ;

[0760] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.92 (s, 1H) 8.14 - 8.00 (m, 1H) 7.75 - 7.68 (m, 2H) 7.40 - 7.30 (m, 1H) 7.08 - 6.97 (m, 1H) 4.98 - 4.86 (m, 1H) 4.80 - 4.67 (m, 1H) 3.32 - 3.27 (m, 1H) 3.00 - 2.86 (m, 1H) 2.19 - 2.06 (m, 2H) 1.97 - 1.85 (m, 2H) 1.76 - 1.63 (m, 2H) 1.63 - 1.50 (m, 4H) 1.40 - 1.30 (m, 2H) 1.27 (d, J = 6.27 Hz, 6H) 1.17 (d, J = 6.27 Hz, 6H) 0.95 - 0.83 (m, 6H).

[0761] Example 24: Synthesis of trans-Isopropyl N-[3-(2,2-Dimethylpropylsulfonyl)-4-[2-[4-(Isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0762]

[0763] Synthesis Method

[0764]

[0765] Step 1: Synthesis of 3-(Neopentylthio)aniline

[0766] Dissolve 3-aminobenzenethiol (400 mg, 3.20 mmol) in N,N–dimethylformamide (10 mL), add 1-bromo-2,2-dimethylpropane (579.12 mg, 3.83 mmol) and potassium carbonate (662.38 mg, 4.79 mmol). Stir the reaction mixture at 25 °C for 3 hours. Dilute the reaction mixture with water (50 mL), extract 4 times with ethyl acetate (15 mL), dry the organic phase, filter, concentrate to dryness, and then purify by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1) to obtain the product 3-(neopentylthio)aniline (230 mg).

[0767] MS m / z (ESI): 196.2 [M+H] + ;

[0768] 11H NMR (400 MHz, methanol-d4) δ ppm 7.01 (t, J = 8.0 Hz, 1H), 6.75 (s, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 2.88 (s, 2H), 1.03 (s, 9H).

[0769] Step 2: Synthesis of isopropyl (3-(neopentylthio)phenyl)carbamate

[0770] At room temperature, diisopropylethylamine (880.04 mg, 6.81 mmol), 4-dimethylaminopyridine (207.97 mg, 1.70 mmol) and isopropyl chloroformate (677.28 mg, 5.53 mmol) were added to a solution of 3-(neopentylthio)aniline (665 mg, 3.40 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water (20 mL), and extracted with ethyl acetate (20 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and then purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1) to obtain the product isopropyl (3-(neopentylthio)phenyl)carbamate (794 mg).

[0771] MS m / z (ESI): 282.2 [M+H] + ;

[0772] Step 3: Synthesis of isopropyl (4-bromo-3-(neopentylthio)phenyl)carbamate

[0773] At -20 °C, N-bromosuccinimide (126.49 mg, 710.7 μmol) was added to a solution of isopropyl (3-(neopentylthio)phenyl)carbamate (200 mg, 710.7 μmol) in dichloromethane (5 mL). The reaction mixture was stirred at -20 °C for 3 hours. It was diluted with dichloromethane (15 mL), and the organic phase was washed with saturated brine (5 mL), dried, filtered, and concentrated to dryness. Then it was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1) to obtain the product isopropyl (4-bromo-3-(neopentylsulfonyl)phenyl)carbamate (85 mg).

[0774] MS m / z (ESI): 361.1 [M+H] + .

[0775] Step 4: Synthesis of isopropyl (4-bromo-3-(neopentylsulfonyl)phenyl)carbamate

[0776] At 0 °C, m-chloroperbenzoic acid (95.79 mg, 471.82 μmol) was added to a solution of isopropyl (4-bromo-3-(neopentylthio)phenyl)carbamate (85 mg, 235.91 μmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature overnight. It was diluted with dichloromethane (20 mL), then washed with saturated sodium sulfite solution (5 mL), dried, filtered, and concentrated to give the product isopropyl (4-bromo-3-(neopentylsulfonyl)phenyl)carbamate (85 mg).

[0777] MS m / z (ESI): 392.0, 394.0 [M+H] + ;

[0778] Step 5: Synthesis of trans-isopropyl N-[3-(2,2-dimethylpropylsulfonyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0779] Under a nitrogen atmosphere, a solution of isopropyl (4-bromo-3-(neopentylsulfonyl)phenyl)carbamate (40 mg, 101.96 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (38.84 mg, 152.94 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (3.73 mg, 5.10 μmol), and potassium acetate (15.01 mg, 152.94 μmol) in tetrahydrofuran (2 mL) was heated to 80 °C and stirred for 2 hours. Then trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (42.49 mg, 122.35 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (3.73 mg, 5.10 μmol), potassium phosphate (43.29 mg, 203.92 μmol), and water (0.5 mL) were added to the above reaction mixture. The reaction mixture was reacted at 80 °C overnight. The reaction mixture was filtered and concentrated. It was purified by preparative liquid chromatography (Agela DuraShell C18 column: 5 μm silica, 25 mm diameter, 150 mm length; using a decreasing polarity mixture of water (containing 0.04% ammonia, 10 mM NH4CO3) and acetonitrile as the eluent) to give the compound trans-isopropyl N-[3-(2,2-dimethylpropylsulfonyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (3.25 mg). MS m / z (ESI): 580.1 [M+H] + ;

[0780] 11H NMR (400 MHz, methanol-d4) δ ppm 8.34 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.67 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 5.06 - 5.00 (m, 1H), 4.99 - 4.83 (m, 1H), 3.51 - 3.47 (m, 1H), 3.08 - 3.02 (m, 1H), 2.91 (s, 2H), 2.23 (d, J = 12.0 Hz, 2H), 2.08 (d, J = 10.0 Hz, 2H), 1.74 - 1.69 (m, 2H), 1.48 - 1.41 (m, 2H), 1.34 (d, J = 6.0 Hz, 6H), 1.24 (d, J = 6.0 Hz, 6H), 1.02 (s, 9H).

[0781] Example 25: Synthesis of trans-Isopropyl N-[4-[5-[4-(Isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfonyl-phenyl]carbamate

[0782]

[0783] Synthesis Method

[0784]

[0785] Step 1: Synthesis of trans-Isopropyl N-[4-[5-[4-(tert-Butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate

[0786] Add [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (4.51 mg, 5.52 μmol) to a solution of isopropyl N-[3-isopropylthio-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (50.26 mg, 132.49 μmol), trans-tert-butyl N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (40 mg, 110.41 μmol) and potassium phosphate (46.87 mg, 220.82 μmol) in tetrahydrofuran (2 mL) and water (0.5 mL). Stir at 80 °C overnight under nitrogen protection. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture to dryness, and then purify by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain the product trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate (35 mg). MS m / z (ESI): 535.2 [M + H]+ ;

[0787] Step 2: Synthesis of trans-N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl] carbamate

[0788] At room temperature, 4M dioxane hydrochloride (0.35 mL) was added to a solution of trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl] carbamate (35 mg, 65.45 μmol) in dioxane (1 mL). The reaction mixture was stirred at room temperature for 4 hours, and the reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness to obtain the product trans-isopropyl N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl] carbamate (28 mg).

[0789] MS m / z (ESI): 435.1 [M+H] + ;

[0790] Step 3: Synthesis of trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl] carbamate Isopropyl chloroformate (9.47 mg, 77.31 μmol) and diisopropylethylamine (24.98 mg, 193.27 μmol) were added to trans-isopropyl N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl] carbamate (28 mg, 64.42 μmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature overnight, and the reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness and purified by thin layer chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain the product trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl] carbamate (23.5 mg).

[0791] MS m / z (ESI): 521.2 [M+H] + ;

[0792] Step 4: Synthesis of trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfonyl-phenyl]carbamate At 0 °C, m-chloroperbenzoic acid (10.99 mg, 54.16 μmol) was added to trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate (23.5 mg, 45.13 μmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 4 h. After dilution with dichloromethane (20 mL), it was washed with saturated aqueous sodium sulfite solution (5 mL, twice), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Purification by preparative liquid chromatography (Agela DuraShell C18 column: 5 μm silica, 25 mm diameter, 150 mm length; using a mixture of water (containing 0.04% ammonia, 10 mM NH4CO3) and acetonitrile with decreasing polarity as the eluent) gave the compound trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylsulfonyl-phenyl]carbamate (1.52 mg).

[0793] MS m / z (ESI): 553.1 [M+H] + ;

[0794] 1 1H NMR (400 MHz, MeOD) δ ppm 8.31 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 5.06 - 5.01 (m, 2H), 4.06 - 4.02 (m, 1H), 3.50 - 3.49 (m, 1H), 3.25 - 3.22 (m, 1H), 2.36 - 2.25 (m, 2H), 2.20 - 2.07 (m, 2H), 1.79 - 1.72 (m, 2H), 1.48 - 1.44 (m, 2H), 1.35 (d, J = 6.4 Hz, 6H), 1.29 (d, J = 6.4 Hz, 6H), 1.25 (d, J = 6.4 Hz, 6H).

[0795] Example 26: Synthesis of trans-isopropyl-(4-(5-(4-(3-benzylureido)-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0796]

[0797] Synthesis method

[0798]

[0799] Step 1: Synthesis of trans-isopropyl (4-(5-(4-amino-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[0800] Dissolve (5-amino-2-bromophenyl)dimethylphosphine oxide (60 mg, 241.88 μmol), trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (84 mg, 241.88 μmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (245.69 mg, 967.52 μmol) in tetrahydrofuran (6 mL). Under nitrogen protection, add 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (5.97 mg, 12.09 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (9.52 mg, 12.09 μmol), tris(dibenzylideneacetone)dipalladium (11.07 mg, 12.09 μmol), and potassium acetate (47.48 mg, 483.76 μmol). Stir the reaction mixture at 80 °C for 16 hours. Filter the reaction mixture, concentrate the filtrate under reduced pressure to dryness, add water (5 mL), and extract with ethyl acetate (15 mL, 5 mL * 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a black oily compound. Further purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:2) to obtain trans-isopropyl (4-(5-(4-amino-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (23 mg).

[0801] MS m / z (ESI): 436.2 [M+H] + .

[0802] Step 2: Synthesis of trans-isopropyl-(4-(5-(4-(3-benzylureido)-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[0803] Dissolve trans-isopropyl (4-(5-(4-amino-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (20 mg, 45.92 μmol) and benzyl isocyanate (12.23 mg, 91.84 μmol) in dichloromethane (4 mL), add N,N-diisopropylethylamine (11.87 mg, 91.84 μmol, 16.00 μL) and 4-dimethylaminopyridine (2.81 mg, 22.96 μmol), and stir the reaction mixture at 45 °C for 2 hours. LCMS shows that the reaction is complete. After rotary evaporation of the reaction system, it is purified by preparative liquid chromatography (Phenomenex Gemini column: 10 μm silica, 50 mm diameter, 250 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (35%-55%) as the eluent) to obtain the white solid compound trans-isopropyl-(4-(5-(4-(3-benzylureido)-2-(dimethylphosphoryl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (4.75 mg).

[0804] MS m / z(ESI): 569.1[M+H] + ;

[0805] 1 H NMR(400 MHz, DMSO-d6) δ ppm 9.02(s, 1H) 7.91(dd, J = 14.31, 2.32 Hz, 1H) 7.80(s, 1H) 7.71(dd, J = 8.44, 1.47 Hz, 1H) 7.39 - 7.28(m, 5H) 7.27 - 7.22(m, 1H) 7.03(br d, J = 7.70 Hz, 1H) 6.76(t, J = 5.93 Hz, 1H) 4.82 - 4.70(m, 1H) 4.32(d, J = 5.99 Hz, 2H) 3.30 - 3.26(m, 1H) 3.02 - 2.85(m, 1H) 2.12(br d, J = 11.25 Hz, 2H) 1.91(br d, J = 9.66 Hz, 2H) 1.63 - 1.49(m, 2H) 1.43(d, J = 13.20 Hz, 6H) 1.39 - 1.26(m, 2H) 1.16(d, J = 6.24 Hz, 6H).

[0806] Example 27: Synthesis of trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(1-oxophospholane-1-yl)phenyl]carbamate

[0807]

[0808] Synthesis method

[0809]

[0810] Step 1: Synthesis of 1-Phenylphospholane 1-Oxide

[0811] Dissolve phenylphosphonic dichloride (4 g, 20.51 mmol) in diethyl ether (15 mL). Under nitrogen protection, add butylmagnesium dibromide (5.43 g, 20.51 mmol) at -30 °C. The reaction mixture is a gray suspension and stirred at 25 °C for 16 h. Monitor the reaction completion by LCMS. Add saturated ammonium chloride (30 mL) to the reaction mixture and extract with ethyl acetate (60 mL). Dry the organic layer with anhydrous magnesium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to dryness. Purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 1-phenylphospholane 1-oxide (830 mg, 4.61 mmol) as a yellow oil.

[0812] MS m / z (ESI): 181.1 [M+H] +

[0813] Step 2: Synthesis of 1-(3-Nitrophenyl)phospholane 1-Oxide

[0814] Dissolve 1-phenylphospholane 1-oxide (700 mg, 3.88 mmol) in concentrated sulfuric acid (10 mL). Add fuming nitric acid (734.40 mg, 11.65 mmol, 524.57 μL) at 0 °C. The reaction mixture is a yellow suspension and stirred at 25 °C for 2 h. Monitor the reaction completion by LCMS. Add water (30 mL) to the reaction mixture and then extract with ethyl acetate (60 mL). Dry the organic layer with anhydrous magnesium sulfate, filter by suction, and concentrate the filtrate under reduced pressure to dryness to obtain the crude product 1-(3-nitrophenyl)phospholane 1-oxide (800 mg) as a yellow oil. MS m / z (ESI): 226.1 [M+H] +

[0815] Step 3: Synthesis of 1-(3-Aminophenyl)phospholane 1-Oxide

[0816] Dissolve 1-(3-nitrophenyl)phospholane-1-oxide (800 mg, 3.55 mmol) in anhydrous ethanol (3 mL) and water (600 μL). Under nitrogen protection, add reduced iron powder (1.19 g, 21.32 mmol) and ammonium chloride (1.90 g, 35.53 mmol). The reaction solution is a black suspension and stirred at 80 °C for 3 hours. LCMS is used to detect the completion of the reaction. The reaction solution is filtered while hot, and the filtrate is concentrated to dryness under reduced pressure. Purification by column chromatography (dichloromethane:methanol = 10:1) gives compound 1-(3-aminophenyl)phospholane-1-oxide (230 mg, 1.18 mmol) as a yellow oil.

[0817] MS m / z (ESI): 196.1 [M+H] +

[0818] Step 4: Synthesis of isopropyl (3-(1-oxidophospholane-1-yl)phenyl)carbamate

[0819] Dissolve 1-(3-aminophenyl)phospholane-1-oxide (230 mg, 1.18 mmol) in anhydrous dichloromethane (3 mL). Under nitrogen protection, add pyridine (559.22 mg, 7.07 mmol, 570.63 μL) and isopropyl chloroformate (433.20 mg, 3.53 mmol, 490.60 μL). The reaction solution is a yellow suspension and stirred at 25 °C for 1 hour. LCMS is used to detect the completion of the reaction. The reaction solution is concentrated to dryness under reduced pressure. Purification by column chromatography (dichloromethane:methanol = 10:1) gives compound isopropyl (3-(1-oxidophospholane-1-yl)phenyl)carbamate (260 mg, 924.32 μmol) as a yellow solid.

[0820] MS m / z (ESI): 282.2 [M+H] +

[0821] Step 5: Synthesis of isopropyl (4-bromo-3-(1-oxidophospholane-1-yl)phenyl)carbamate

[0822] Dissolve isopropyl (3-(1-oxophospholane-1-yl)phenyl)carbamate (260 mg, 924.32 μmol) in N,N-dimethylformamide (5 mL), and add N-bromosuccinimide (493.54 mg, 2.77 mmol). The reaction solution is a yellow suspension and stirred at 50 °C for 16 hours. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Purification by column chromatography (petroleum ether:tetrahydrofuran = 1:1) gives isopropyl (4-bromo-3-(1-oxophospholane-1-yl)phenyl)carbamate (300 mg, 832.91 μmol) as a white solid.

[0823] MS m / z (ESI): 360.1, 362.0 [M+H] +

[0824] Step 6: Synthesis of trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(1-oxophospholane-1-yl)phenyl]carbamate

[0825] Isopropyl (4-bromo-3-(1-oxophospholane-1-yl)phenyl)carbamate (200 mg, 555.27 μmol), trans-isopropyl-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (192.83 mg, 555.27 μmol) and bis(pinacolato)diboron (564.02 mg, 2.22 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). Under nitrogen protection, tris(dibenzylideneacetone)dipalladium(0) (25.42 mg, 27.76 μmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (13.24 mg, 27.76 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (21.84 mg, 27.76 μmol) and potassium acetate (108.99 mg, 1.11 mmol) were added. The reaction solution was a black suspension and stirred at 80 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to dryness under reduced pressure. Water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity as the eluent) gave the compound trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(1-oxophospholane-1-yl)phenyl]carbamate (65.22 mg) as a white solid.

[0826] MS m / z (ESI): 548.1 [M+H] + ;

[0827] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.92 (s, 1H), 8.09 - 8.02 (m, 1H), 7.94 (s, 1H), 7.76 - 7.70 (m, 1H), 7.49 - 7.44 (m, 1H), 7.08 - 7.01 (m, 1H), 5.00 - 4.89 (m, 1H), 4.83 - 4.70 (m, 1H), 3.36 - 3.33 (m, 1H), 3.02 - 2.89 (m, 1H), 2.19 - 2.09 (m, 2H), 1.98 - 1.78 (m, 6H), 1.69 - 1.50 (m, 6H), 1.43 - 1.32 (m, 2H), 1.29 (d, J = 6.3 Hz, 6H), 1.18 (d, J = 6.3 Hz, 6H).

[0828] Example 28: Synthesis of trans-isopropyl (-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0829]

[0830] Synthesis method

[0831]

[0832] Step 1: Synthesis of trans-tert-butyl 3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate Dissolve the intermediate trans-isopropyl-N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (250 mg, 447.59 μmol) of Example 22 and tert-butyl 3-amino-5-methyl-pyrazole-1-carboxylate (264.84 mg, 1.34 mmol) in anhydrous tetrahydrofuran (5 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) acetate (20.29 mg, 22.38 μmol) and potassium acetate (131.78 mg, 1.34 mmol). The reaction solution was stirred at 80 °C for 16 hours. LCMS showed that the reaction was complete. After the reaction system was evaporated to dryness, trans-tert-butyl 3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate (280 mg, crude product) was obtained by liquid-liquid extraction (extracted 3 times with 120 mL of ethyl acetate).

[0833] MS m / z (ESI): 674.9 [M+H] + ;

[0834] Step 2: Synthesis of trans-isopropyl-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate Dissolve trans-tert-butyl-3-((3-(N-(tert-butyl)sulfamoyl)-4-(2-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate (235 mg, 348.21 μmol) in methanol (5 mL), and add p-toluenesulfonic acid (179.89 mg, 1.04 mmol). Stir the reaction solution at 50 °C for 2 hours. LCMS shows that the reaction is complete. Rotate the reaction system to dryness. Add 2 M sodium hydroxide (10 mL), and then extract three times with dichloromethane (120 mL). Purify by preparative high performance liquid chromatography (Phenomenex Gemini-NX column, 5 μm silica, 30 mm diameter, 150 mm length) (using a mixture of water (containing 0.05% ammonia water and 10 mmol of ammonium bicarbonate) and acetonitrile with decreasing polarity (45%-65%) as the eluent). After lyophilization, trans-isopropyl-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (32.73 mg) is obtained.

[0835] MS m / z (ESI): 575.2 [M+H] + ;

[0836] 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (s, 1H) 8.91 (s, 1H) 8.14 (d, J = 2.32 Hz, 1H) 7.60 (s, 1H) 7.50 (dd, J = 8.44, 2.32 Hz, 1H) 7.23 (d, J = 8.31 Hz, 1H) 7.01 (br d, J = 7.46 Hz, 1H) 6.70 (s, 1H) 5.63 (s, 1H) 4.81 - 4.69 (m, 1H) 3.35 - 3.25 (m, 1H) 2.92 - 2.80 (m, 1H) 2.19 (s, 3H) 2.12 (br d, J = 11.62 Hz, 2H) 1.91 (br d, J = 10.15 Hz, 2H) 1.63 - 1.49 (m, 2H) 1.41 - 1.26 (m, 2H) 1.16 (d, J = 6.24 Hz, 6H) 1.07 (s, 9H).

[0837] Example 29: Synthesis of trans-isopropyl-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isoxazol-5-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[0838]

[0839] Dissolve trans-isopropyl-N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (120 mg, 214.84 μmol) and isoxazol-5-amine (72.25 mg, 859.37 μmol) in tetrahydrofuran (5 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) acetate (9.74 mg, 10.74 μmol) and potassium acetate (63.26 mg, 644.52 μmol). Stir the reaction mixture at 90 °C for 1 hour. TLC (dichloromethane:methanol = 15:1) shows that the reaction is complete. After rotary evaporation of the reaction system, purify it by two thin-layer chromatographies (silica gel, dichloromethane:methanol = 10:1) to obtain trans-isopropyl-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isoxazol-5-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (2.35 mg).

[0840] MS m / z (ESI): 562.1 [M+H] + ;

[0841] 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 10.74 (s, 1H) 8.35 (d, J = 2.25 Hz, 1H) 7.78 (dd, J = 8.44, 2.19 Hz, 1H) 7.68 (s, 1H) 7.46 (d, J = 8.25 Hz, 1H) 7.17 - 6.95 (m, 2H) 4.80 - 4.70 (m, 1H) 3.97 (d, J = 4.13 Hz, 1H) 3.31 - 3.25 (m, 1H) 2.99 - 2.86 (m, 1H) 2.19 - 2.05 (m, 2H) 1.92 - 1.87 (m, 2H) 1.68 - 1.50 (m, 2H) 1.43 - 1.27 (m, 2H) 1.16 (d, J = 6.25 Hz, 6H) 1.05 (s, 9H).

[0842] Example 30: Synthesis of trans-isopropyl-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isoxazol-3-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[0843]

[0844] Dissolve trans-isopropyl-N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (300 mg, 537.10 μmol) and isoxazol-3-amine (135.47 mg, 1.61 mmol) in anhydrous tetrahydrofuran (15 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) acetate (24.34 mg, 26.86 μmol) and potassium acetate (158.14 mg, 1.61 mmol). Stir the reaction mixture at 80 °C for 0.5 h. LCMS shows that the reaction is complete. After rotary evaporation of the reaction system, purify it by preparative high performance liquid chromatography (Phenomenex Gemini-NX column, 5 μm silica, 30 mm diameter, 150 mm length) (using a mixture of water (containing 0.05% ammonia and 10 mmol of ammonium bicarbonate) and acetonitrile with decreasing polarity (45%-65%) as the eluent), and lyophilize to obtain trans-isopropyl-(4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isoxazol-3-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (32.79 mg).

[0845] MS m / z (ESI): 562.2 [M+H] + ;

[0846] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H) 8.67 (d, J = 1.59 Hz, 1H) 8.26 (d, J = 2.45 Hz, 1H) 7.71 - 7.57 (m, 2H) 7.40 (d, J = 8.44 Hz, 1H) 7.08 - 6.98 (m, 1H) 6.92 (br s, 1H) 6.25 (d, J = 1.71 Hz, 1H) 4.80 - 4.70 (m, 1H) 3.31 - 3.24 (m, 1H) 2.97 - 2.82 (m, 1H) 2.13 (br d, J = 11.74 Hz, 2H) 1.92 (br d, J = 10.15 Hz, 2H) 1.66 - 1.49 (m, 2H) 1.43 - 1.26 (m, 2H) 1.16 (d, J = 6.11 Hz, 6H) 1.08 (s, 9H).

[0847] Example 31: Synthesis of trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-[isopropyl(methyl)phosphoryl]phenyl]carbamate

[0848]

[0849] Synthesis method

[0850]

[0851] Step 1: Synthesis of ethyl methyl(phenyl)phosphinate

[0852] Dissolve iodobenzene (800 mg, 3.92 mmol, 437.16 μL), potassium phosphate (1.66 g, 7.84 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (453.80 mg, 784.28 μmol) in N,N-dimethylformamide (2 mL), and add ethyl methylphosphonate (1.07 g, 7.84 mmol) and palladium acetate (176.08 mg, 784.28 μmol) under nitrogen protection. The reaction solution is a light yellow suspension and stirred at 100 °C for 16 hours. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Purify by column chromatography (petroleum ether:tetrahydrofuran = 3:1) to obtain the compound ethyl methyl(phenyl)phosphinate (540 mg, 2.93 mmol).

[0853] MS m / z(ESI): 185.1 [M+H] + ;

[0854] Step 2: Synthesis of isopropyl(methyl)(phenyl)phosphine oxide

[0855] Dissolve ethyl methyl(phenyl)phosphinate (200 mg, 1.09 mmol) in anhydrous tetrahydrofuran (3 mL), and add 2.0 M isopropylmagnesium chloride in tetrahydrofuran solution (2 M, 3.26 mL) at -30 °C under nitrogen protection. The reaction solution is a brown suspension and stirred at 40 °C for 16 h. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure, add saturated ammonium chloride (10 mL), and extract twice with ethyl acetate (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by column chromatography (petroleum ether:tetrahydrofuran = 1:2) to obtain the compound isopropyl(methyl)(phenyl)phosphine oxide (115 mg, 631.18 μmol).

[0856] MS m / z(ESI): 183.2 [M+H] + ;

[0857] Step 3: Synthesis of isopropyl(methyl)(3-nitrophenyl)phosphine oxide

[0858] Dissolve isopropyl(methyl)(phenyl)phosphine oxide (115 mg, 631.18 μmol) in concentrated sulfuric acid (2 mL), and add fuming nitric acid (119.32 mg, 1.89 mmol, 85.23 μL) at 0 °C. The reaction solution is a yellow suspension and stirred at 25 °C for 2 h. After the reaction is completed as detected by LCMS, add water (10 mL) to the reaction solution, and then extract with ethyl acetate (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure to dryness to obtain crude isopropyl(methyl)(3-nitrophenyl)phosphine oxide (70 mg).

[0859] MS m / z (ESI): 228.1 [M+H] + ;

[0860] Step 4: Synthesis of (3-aminophenyl)(isopropyl)(methyl)phosphine oxide

[0861] Dissolve isopropyl(methyl)(3-nitrophenyl)phosphine oxide (70 mg, 308.10 μmol) in anhydrous ethanol (3 mL) and water (600 μL), and add reduced iron powder (103.24 mg, 1.85 mmol) and ammonium chloride (164.80 mg, 3.08 mmol) under nitrogen protection. The reaction solution is a black suspension and stirred at 90 °C for 12 h. After the reaction is completed as detected by LCMS, the reaction solution is filtered while hot, and the filtrate is concentrated under reduced pressure to dryness. Purify by column chromatography (dichloromethane:methanol = 10:1) to obtain the compound (3-aminophenyl)(isopropyl)(methyl)phosphine oxide (45 mg, 228.18 μmol).

[0862] MS m / z (ESI): 198.2 [M+H] + ;

[0863] Step 5: Synthesis of isopropyl(3-(isopropyl(methyl)phosphoryl)phenyl)carbamate

[0864] Dissolve (3-aminophenyl)(isopropyl)(methyl)phosphine oxide in anhydrous dichloromethane (3 mL), and add pyridine (108.29 mg, 1.37 mmol, 110.50 μL) and isopropyl chloroformate (83.89 mg, 684.54 μmol, 95.01 μL) under nitrogen protection. The reaction solution is a yellow suspension and stirred at 30 °C for 1 h. After the reaction is completed as detected by LCMS, the reaction solution is concentrated under reduced pressure to dryness. Purify by thin layer chromatography (dichloromethane:methanol = 10:1) to obtain the compound isopropyl(3-(isopropyl(methyl)phosphoryl)phenyl)carbamate (30 mg, 105.89 μmol). MS m / z (ESI): 284.2 [M+H] + ;

[0865] Step 6: Synthesis of Isopropyl (4-bromo-3-(isopropyl(methyl)phosphoryl)phenyl)carbamate

[0866] Dissolve isopropyl (3-(isopropyl(methyl)phosphoryl)phenyl)carbamate (30 mg, 105.89 μmol) in N,N-dimethylformamide (2 mL), and add N-bromosuccinimide (56.54 mg, 317.68 μmol). The reaction solution is a yellow suspension and stirred at 50 °C for 16 h. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the compound isopropyl (4-bromo-3-(isopropyl(methyl)phosphoryl)phenyl)carbamate (30 mg, 82.83 μmol). MS m / z (ESI): 362.1, 364.1 [M+H] + ;

[0867] Step 7: Synthesis of trans-Isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-[isopropyl(methyl)phosphoryl]phenyl]carbamate Dissolve isopropyl (4-bromo-3-(isopropyl(methyl)phosphoryl)phenyl)carbamate (25 mg, 69.02 μmol), trans-isopropyl-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (23.97 mg, 69.02 μmol) and bis(pinacolato)diboron (70.11 mg, 276.09 μmol) in anhydrous tetrahydrofuran (3 mL). Under nitrogen protection, add tris(dibenzylideneacetone)dipalladium(0) (3.16 mg, 3.45 μmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (1.65 mg, 3.45 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (2.72 mg, 3.45 μmol) and potassium acetate (13.55 mg, 138.05 μmol). The reaction solution is a black suspension and stirred at 80 °C for 16 h. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Add water (10 mL), and extract with ethyl acetate (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity as the eluent) to obtain the compound trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-[isopropyl(methyl)phosphoryl]phenyl]carbamate (5.44 mg, 9.89 μmol).

[0868] MS m / z (ESI): 550.1 [M+H] + ;

[0869] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.93 (s, 1H), 8.14 - 8.03 (m, 1H), 7.75 - 7.68 (s, 2H), 7.41 - 7.33 (m, 1H), 7.09 - 7.01 (m, 1H), 5.00 - 4.88 (m, 1H), 4.81 - 4.71 (m, 1H), 3.35 - 3.34 (m, 1H), 3.02 - 2.89 (m, 1H), 2.19 - 2.08 (m, 2H), 1.98 - 1.88 (m, 2H), 1.75 - 1.64 (m, 1H), 1.61 - 1.54 (m, 2H), 1.35 - 1.45 (m, 3H), 1.38 - 1.32 (m, 2H), 1.29 (d, J = 6.3 Hz, 6H), 1.18 (d, J = 6.3 Hz, 6H), 1.00 - 0.83 (m, 5H).

[0870] Example 32: Synthesis of trans-Isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfinyl-phenyl]carbamate

[0871]

[0872] Synthesis method

[0873]

[0874] Step 1: Synthesis of trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylthio-phenyl]carbamate Dissolve trans-isopropyl-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (100 mg, 287.96 μmol), isopropyl-N-[3-isopropylthio-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (131.08 mg, 345.55 μmol) and sodium carbonate (61.04 mg, 575.92 μmol) in water (600 μL) and 1,4-dioxane (6 mL). Under nitrogen protection, add [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (23.52 mg, 28.80 μmol). Stir the reaction solution at 80 °C for 6 hours. LCMS shows the reaction. Filter the reaction solution, rotary evaporate the filtrate to remove 1,4-dioxane, add water (10 mL), and extract with ethyl acetate 3 times (10 mL * 3). After drying over anhydrous sodium sulfate, purify by thin layer chromatography (silica gel, petroleum ether / ethyl acetate = 2:1) to obtain trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylthio-phenyl]carbamate (84.8 mg). MS m / z (ESI): 520.3 [M+H] +

[0875] Step 2: Synthesis of trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfinyl-phenyl]carbamate

[0876] Dissolve trans-isopropyl N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylthio-phenyl]carbamate (75 mg, 144.31 μmol) in dichloromethane (2 mL). Add m-chloroperbenzoic acid (19.92 mg, 115.45 μmol) at 20 °C, and react the reaction solution at 20 °C for 2 hours. LCMS shows the reaction is complete. Filter the reaction solution, rotary evaporate the filtrate to remove dichloromethane, add water (2 mL), and extract with ethyl acetate 3 times (2 mL * 3). Dry the organic phase over anhydrous sodium sulfate and rotary evaporate under reduced pressure to dryness. Purify by preparative high performance liquid chromatography (Phenomenex Gemini-NX C18 column, 5 μm silica gel, 30 mm diameter, 150 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (0% - 70%) as the eluent) to obtain trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfinyl-phenyl]carbamate (16.14 mg).

[0877] MS m / z (ESI): 536.0 [M+H] +

[0878] 1 1H NMR: (400 MHz, METHANOL-d4) δ ppm 8.02 (d, J = 2.26 Hz, 1H) 7.77 - 7.71 (m, 2H) 7.48 (d, J = 8.53 Hz, 1H) 5.05 - 4.95 (m, 1H) 4.88 - 4.82 (m, 1H) 3.52 - 3.44 (m, 1H) 3.08 - 2.98 (m, 1H) 2.82 - 2.73 (m, 1H) 2.24 (br d, J = 11.80 Hz, 2H) 2.09 (br d, J = 10.04 Hz, 2H) 1.77 - 1.66 (m, 2H) 1.48 - 1.38 (m, 2H) 1.34 (d, J = 6.27 Hz, 6H) 1.26 - 0.98 (m, 12H).

[0879] Example 33: Synthesis of trans-Isopropyl N-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0880]

[0881] Synthesis method

[0882]

[0883] Step 1: Synthesis of 3-cyclopropylthioaniline

[0884] Dissolve 3-aminobenzenethiol (6 g, 47.93 mmol) in N,N–dimethylformamide (60 mL), and add sodium hydride (2.01 g, 50.30 mmol) under nitrogen protection. The reaction solution was stirred at 30 °C for 1 hour. Then cyclopropyl bromide (6.09 g, 50.30 mmol) was added to the reaction solution, and the reaction solution was stirred and refluxed at 100 °C for 5 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to dryness under reduced pressure and then purified by column chromatography (silica gel, dichloromethane / methanol = 20 / 1) to obtain 3-cyclopropylthioaniline (1.35 g).

[0885] MS m / z (ESI): 166.0 [M+H] + ;

[0886] Step 2: Synthesis of isopropyl N-(3-cyclopropylthiophenyl)carbamate

[0887] Dissolve 3-cyclopropylthioaniline (1.28 g, 7.75 mmol) and isopropyl chloroformate (1.42 g, 11.62 mmol) in dichloromethane (400 mL), and add pyridine (3.68 g, 46.47 mmol). Stir the reaction mixture at 30 °C for 1 hour. Monitor the completion of the reaction by LCMS. Concentrate the reaction mixture under reduced pressure to dryness, and then purify it by column chromatography (silica gel, dichloromethane / methanol = 20 / 1) to obtain isopropyl N-(3-cyclopropylthiophenyl)carbamate (1.6 g).

[0888] MS m / z (ESI): 252 [M+H] + ;

[0889] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.59 (s, 1H) 7.56 (s, 1H) 7.31 - 7.14 (m, 2H) 6.95 (dt, J = 7.47, 1.41 Hz, 1H) 4.88 (spt, J = 6.27 Hz, 1H) 2.20 (tt, J = 7.40, 4.27 Hz, 1H) 1.27 - 1.22 (m, 1H) 1.24 (s, 3H) 1.11 - 1.02 (m, 2H) 0.66 - 0.50 (m, 2H).

[0890] Step 3: Synthesis of isopropyl N-(4-bromo-3-cyclopropylthiophenyl)carbamate

[0891] Dissolve isopropyl N-(3-cyclopropylthiophenyl)carbamate (300 mg, 1.19 mmol) in dichloromethane (20 mL), and then slowly add N-bromosuccinimide (212.44 mg, 1.19 mmol) dissolved in dichloromethane (10 mL) dropwise to the reaction mixture. Stir the reaction mixture at -20 °C for 3 hours. Monitor the completion of the reaction by LCMS. Concentrate the reaction mixture under reduced pressure to dryness, and purify it by column chromatography (silica gel, petroleum ether:dichloromethane = 1:2) to obtain isopropyl N-(4-bromo-3-cyclopropylthiophenyl)carbamate (201 mg). MS m / z (ESI): 330.1, 332.1 [M+H] + .

[0892] Step 4: Synthesis of isopropyl N-[3-cyclopropylthio-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0893] Isopropyl N-(4-bromo-3-cyclopropylsulfanyl-phenyl)carbamate (600 mg, 1.82 mmol) and bis(pinacolato)diboron (1.85 g, 7.27 mmol) were dissolved in tetrahydrofuran (6 mL). Under nitrogen protection, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (148.37 mg, 181.69 μmol) and potassium acetate (534.93 mg, 5.45 mmol) were added. The reaction mixture was stirred at 80 °C for 16 h. The reaction was monitored by LCMS until completion. 9 mL of dichloromethane (3 mL * 3) and 4 mL of water were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. Purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) gave isopropyl N-[3-cyclopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (400 mg).

[0894] MS m / z (ESI): 378 [M+H] + ;

[0895] Step 5: Synthesis of trans-isopropyl N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0896] Isopropyl N-[3-cyclopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (400 mg, 1.06 mmol) and trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (306.80 mg, 883.46 μmol) were dissolved in water (2.3 mL) and dioxane (24 mL). Then, under nitrogen flow, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (72.15 mg, 88.35 μmol) and sodium carbonate (280.91 mg, 2.65 mmol) were added. The reaction mixture was stirred at 80 °C for 16 h. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated under reduced pressure to dryness. Purification by column chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) gave trans-isopropyl N-[3-cyclopropylsulfanyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (300 mg).

[0897] MS m / z (ESI): 518.3 [M+H] + ;

[0898] Step 6: Synthesis of trans-Isopropyl N-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0899] Dissolve trans-isopropyl N-[3-cyclopropylthio-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (150 mg, 289.74 μmol) in dichloromethane (2 mL), and then slowly add m-chloroperbenzoic acid (117.65 mg, 579.48 μmol) dissolved in dichloromethane (3 mL) dropwise to the reaction solution. Stir the reaction solution at 30 °C for 16 hours. Monitor the reaction completion by LCMS. Concentrate under reduced pressure to dryness, add saturated sodium carbonate (3 mL) and 9 mL dichloromethane (3 mL * 3) for extraction. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to dryness, and purify by preparative liquid chromatography (Phenomenex gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length; use a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity as the eluent) to obtain the compound trans-isopropyl N-[3-cyclopropylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (33.3 mg).

[0900] MS m / z (ESI): 550 3 [M + H] + ;

[0901] 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.14 (s, 1H) 8.29 (d, J = 2.32 Hz, 1H) 7.84 - 7.66 (m, 2H) 7.48 (d, J = 8.44 Hz, 1H) 7.04 (br d, J = 7.82 Hz, 1H) 4.98 - 4.87 (m, 1H) 4.80 - 4.68 (m, 1H) 3.33 - 3.26 (m, 1H) 3.01 - 2.85 (m, 1H) 2.45 - 2.37 (m, 1H) 2.14 (br d, J = 11.86 Hz, 2H) 1.92 (brd, J = 10.27 Hz, 2H) 1.65 - 1.50 (m, 2H) 1.41 - 1.30 (m, 2H) 1.28 (d, J = 6.24 Hz, 6H) 1.17 (d, J = 6.24 Hz, 6H) 1.01 - 0.94 (m, 2H) 0.91 - 0.85 (m, 2H). Example 34: Synthesis of trans-Isopropyl N-[3-tert-butylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0902]

[0903] Synthesis method

[0904]

[0905] Step 1: Synthesis of 3-(tert-butylthio)aniline

[0906] Dissolve 3-bromoaniline (4 g, 23.25 mmol, 2.53 mL) and a 2 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2 M, 27.90 mL) in 1,2-dimethoxyethane (100 mL). Under nitrogen protection, add palladium acetate (261.02 mg, 1.16 mmol), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-tert-butylphosphonium hydride (644.74 mg, 1.16 mmol), and tert-butyl mercaptan (2.10 g, 23.25 mmol, 2.62 mL). The reaction mixture is a black suspension and stirred at 110 °C for 48 h. After completion of the reaction detected by LCMS, the reaction mixture is concentrated to dryness under reduced pressure. Purified by column chromatography (dichloromethane = 1) to obtain the compound 3-(tert-butylthio)aniline (3.68 g, 20.30 mmol). MS m / z (ESI): 182.1 [M+H] + ;

[0907] Step 2: Synthesis of isopropyl N-(3-(tert-butylthio)phenyl)carbamate

[0908] Dissolve 3-(tert-butylthio)aniline (2 g, 11.03 mmol) in anhydrous dichloromethane (30 mL). Under nitrogen protection, add pyridine (5.24 g, 66.19 mmol, 5.34 mL) and isopropyl chloroformate (4.06 g, 33.09 mmol, 4.59 mL). The reaction mixture is a yellow suspension and stirred at 25 °C for 2 h. After completion of the reaction detected by LCMS, the reaction mixture is concentrated to dryness under reduced pressure. Purified by column chromatography (petroleum ether: dichloromethane = 1:2) to obtain the compound isopropyl N-(3-(tert-butylthio)phenyl)carbamate (2 g, 7.48 mmol).

[0909] MS m / z (ESI): 268.2 [M+H] + ;

[0910] Step 3: Synthesis of isopropyl N-(4-bromo-3-(tert-butylthio)phenyl)carbamate

[0911] Dissolve isopropyl N-(3-tert-butylsulfanyl-phenyl)carbamate (2 g, 7.48 mmol) in anhydrous dichloromethane (30 mL), and add dropwise a solution of N-bromosuccinimide (1.33 g, 7.48 mmol) dissolved in anhydrous dichloromethane (30 mL). The reaction mixture is a yellow suspension and stirred at -30 °C for 2 h. The reaction is monitored by LCMS until completion. The reaction mixture is concentrated under reduced pressure to dryness. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) gives isopropyl N-(4-bromo-3-tert-butylsulfanyl-phenyl)carbamate (360 mg, 1.04 mmol). MS m / z (ESI): 347.0 [M+H] + 。

[0912] Step 4: Synthesis of isopropyl N-(4-bromo-3-tert-butylsulfonyl-phenyl)carbamate

[0913] Dissolve isopropyl N-(4-bromo-3-tert-butylsulfanyl-phenyl)carbamate (200 mg, 577.56 μmol) in anhydrous dichloromethane (3 mL), and add m-chloroperbenzoic acid (299.00 mg, 1.73 mmol). The reaction mixture is a yellow suspension and stirred at 20 °C for 3 h. The reaction is monitored by LCMS until completion. Add saturated sodium carbonate (15 mL) to the reaction mixture, and extract with dichloromethane (30 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure to dryness. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) gives isopropyl N-(4-bromo-3-tert-butylsulfonyl-phenyl)carbamate (130 mg, 343.66 μmol).

[0914] MS m / z (ESI): 400.0, 402.0 [M+Na] + ;

[0915] Step 5: Synthesis of isopropyl N-[3-tert-butylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[0916] Isopropyl N-(4-bromo-3-tert-butylsulfonyl-phenyl)carbamate (130 mg, 343.66 μmol) and bis(pinacolato)diboron (349.07 mg, 1.37 mmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Under nitrogen protection, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (28.06 mg, 34.37 μmol) and potassium acetate (101.18 mg, 1.03 mmol) were added. The reaction solution was a red suspension and stirred at 80 °C for 7 h. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to dryness under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) gave isopropyl N-[3-tert-butylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (100 mg, 235.10 μmol).

[0917] MS m / z (ESI): 426.2 [M+H] + ;

[0918] Step 6: Synthesis of trans-isopropyl-N-[3-tert-butylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[0919] Isopropyl N-[3-tert-butylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (100 mg, 235.10 μmol) and trans-isopropyl-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (81.64 mg, 235.10 μmol) were dissolved in anhydrous dioxane (3 mL). Under nitrogen protection, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (19.20 mg, 23.51 μmol), sodium carbonate (49.84 mg, 470.21 μmol) and water (300 μL) were added. The reaction solution was a black suspension and stirred at 80 °C for 7 h. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to dryness under reduced pressure. Water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length; using a decreasing polarity mixture of water (containing 0.05% ammonia) and acetonitrile as the eluent) gave trans-isopropyl-N-[3-tert-butylsulfonyl-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (32.94 mg, 58.22 μmol).

[0920] MS m / z (ESI): 566.1 [M+H] + ;

[0921] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 8.31 - 8.24 (m, 1H), 7.81 - 7.74 (m, 1H), 7.62 - 7.57 (m, 1H), 7.47 - 7.41 (m, 1H), 7.05 - 6.99 (m, 1H), 4.97 - 4.89 (m, 1H), 4.79 - 4.70 (m, 1H), 3.32 - 3.31 (m, 1H), 2.96 - 2.86 (m, 1H), 2.16 - 2.07 (m, 2H), 1.96 - 1.87 (m, 2H), 1.62 - 1.48 (m, 2H), 1.40 - 1.30 (m, 2H), 1.28 (d, J = 6.3 Hz, 6H), 1.17 (d, J = 6.3 Hz, 6H), 1.11 (s, 9H).

[0922] Example 35: Synthesis of trans-Isopropyl-N-[4-[5-[2-isopropylsulfonyl-4-[(2-oxo-1H-pyridin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0923]

[0924] The intermediate of Example 36, trans-isopropyl-N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (50 mg, 94.43 μmol) was dissolved in tetrahydrofuran (1 mL). 3-Amino-1H-pyridin-2-one (12.48 mg, 113.31 μmol) was added. Under nitrogen protection, (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (4.28 mg, 4.72 μmol) and cesium carbonate (92.30 mg, 283.28 μmol) were added, and the reaction mixture was stirred at 100 °C for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove tetrahydrofuran. Water (15 mL) was added, and the mixture was extracted with ethyl acetate three times (15 mL * 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by preparative high performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (38% - 58%) as the eluent) gave trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfinyl-phenyl]carbamate (1.02 mg).

[0925] MS m / z (ESI): 559.0 [M+H] + ;

[0926] 1 H NMR: (400 MHz, METHANOL-d4) δ ppm 7.91 (d, J = 1.96 Hz, 1H) 7.74 (s, 1H) 7.50 - 7.44 (m, 3H) 7.07 (d, J = 6.60 Hz, 1H) 6.42 (t, J = 6.97 Hz, 1H) 5.42 - 5.35 (m, 1H) 3.49 - 3.40 (m, 1H) 3.12 - 2.90 (m, 2H) 2.28 - 2.23 (m, 2H) 2.15 - 2.05 (m, 2H) 1.78 - 1.68 (m, 2H) 1.50 - 1.42 (m, 2H) 1.35 - 1.20 (m, 6H) 1.19 (d, J = 12.00 Hz, 6H).

[0927] Example 36: trans-Isopropyl (-4-(5-(4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[0928]

[0929] Synthesis method

[0930]

[0931] Step 1: Synthesis of tert-butyl-(3-(isopropylthio)phenyl)carbamate

[0932] Dissolve 3-isopropylthioaniline (15 g, 44.88 mmol) in anhydrous dichloromethane (500 mL), and add di-tert-butyl dicarbonate (30.81 g, 141.18 mmol, 32.43 mL) at 0 °C. Pyridine (18.85 g, 235.31 mmol, 18.48 mL) and 4-dimethylaminopyridine (14.37 g, 117.65 mmol). The reaction solution was stirred at 25 °C for 5 hours. The reaction was completed as detected by LCMS. The solvent dichloromethane was removed by concentration under reduced pressure and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain tert-butyl-(3-(isopropylthio)phenyl)carbamate (15 g).

[0933] MS m / z (ESI): 212.1 [M + H - t-Bu] + ;

[0934] Step 2: Synthesis of tert-butyl-(4-bromo-3-(isopropylthio)phenyl)carbamate

[0935] Dissolve tert-butyl-(3-(isopropylthio)phenyl)carbamate (5.0 g, 18.70 mmol) in dichloromethane (200 mL), and add N-bromosuccinimide (3.33 g, 18.70 mmol) to the reaction system. The reaction solution was stirred at -30 °C for 3 hours. The reaction was completed as detected by LCMS. The fraction was concentrated to dryness under reduced pressure and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 20:1) to obtain tert-butyl-(4-bromo-3-(isopropylthio)phenyl)carbamate (2.3 g).

[0936] MS m / z (ESI): 290.0, 292.0 [M + H - t-Bu] + ;

[0937] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 2.3, 8.5 Hz, 1H), 3.43 (spt, J = 6.5 Hz, 1H), 1.47 (s, 9H), 1.31 (d, J = 6.8 Hz, 6H).

[0938] Step 3: Synthesis of tert-butyl-(4-bromo-3-(isopropylsulfonyl)phenyl)carbamate

[0939] Dissolve tert-butyl-(4-bromo-3-(isopropylthio)phenyl)carbamate (1.0 g, 2.89 mmol) in anhydrous dichloromethane (25 mL). At -30 °C, add m-chloroperbenzoic acid (996.68 mg, 5.78 mmol, 85% purity) dissolved in anhydrous dichloromethane (25 mL). The reaction mixture is reacted at -30 °C for 3 hours. LCMS shows that the reaction is complete. Saturated aqueous sodium carbonate solution (50 mL) is added to the reaction mixture, and then extracted twice with dichloromethane (100 mL). After combining the dichloromethane phases, it is dried over anhydrous sodium sulfate and filtered by suction. Purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 20:1) gives tert-butyl-(4-bromo-3-(isopropylsulfonyl)phenyl)carbamate (0.8 g).

[0940] MS m / z (ESI): 322.0, 324.0 [M+H-t-Bu] + ;

[0941] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 2.6, 8.7 Hz, 1H), 3.82 - 3.75 (m, 1H), 1.48 (s, 9H), 1.18 (d, J = 6.9 Hz, 6H).

[0942] Step 4: Synthesis of tert-butyl-(3-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate Dissolve tert-butyl (4-bromo-3-(isopropylsulfonyl)phenyl)carbamate (800 mg, 2.11 mmol) and bis(pinacolato)diboron (2.69 g, 10.57 mmol) in anhydrous tetrahydrofuran (25 mL). Under nitrogen protection, add potassium acetate (207.55 mg, 2.11 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (863.52 mg, 1.06 mmol). The reaction mixture is stirred at 80 °C for 16 hours. LCMS shows that the reaction is complete. After evaporating the reaction system to dryness, purification by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) gives tert-butyl-(3-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (560 mg).

[0943] MS m / z (ESI): 443.3 [M+H+NH3]+ ;

[0944] Step 5: Synthesis of trans-Isopropyl-N-[4-[2-[4-(tert-Butoxycarbonylamino)-2-isopropylsulfonyl-phenyl]thiazol-5-yl]cyclohexyl]carbamate

[0945] Dissolve trans-Isopropyl-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (961.18 mg, 2.77 mmol) and tert-Butyl-(3-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (1.18 g, 2.77 mmol) in an aqueous sodium carbonate solution (2 M, 4.15 mL, 8.30 mmol) and 1,4-dioxane (30 mL). Under nitrogen protection, add [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (113.01 mg, 138.39 μmol). Stir the reaction mixture at 100 °C for 16 hours. LCMS shows that the reaction is complete. Filter the reaction mixture, rotary evaporate the filtrate to remove 1,4-dioxane, add water (10 mL), and extract with dichloromethane three times (10 mL * 3). After drying over anhydrous sodium sulfate, purify by thin layer chromatography (silica gel, petroleum ether / ethyl acetate = 5:1) to obtain trans-Isopropyl-N-[4-[2-[4-(tert-Butoxycarbonylamino)-2-isopropylsulfonyl-phenyl]thiazol-5-yl]cyclohexyl]carbamate (0.8 g).

[0946] MS m / z (ESI): 566.3 [M+H] + ;

[0947] Step 6: Synthesis of trans-Isopropyl-(4-(5-(4-amino-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0948] Dissolve trans-Isopropyl-N-[4-[2-[4-(tert-Butoxycarbonylamino)-2-isopropylsulfonyl-phenyl]thiazol-5-yl]cyclohexyl]carbamate (0.8 g, 1.41 mmol) in anhydrous methanol (20 mL). Add hydrochloric acid / dioxane (4 M, 3.54 mL, 14.14 mmol). Stir the reaction mixture at 25 °C for 1 hour. LCMS shows that the reaction is complete. After rotary evaporating the reaction system, add 1 M aqueous sodium hydroxide solution (10 mL) and then perform liquid-liquid extraction (extract three times with 120 mL of ethyl acetate) to obtain the compound trans-Isopropyl-(4-(5-(4-amino-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (560 mg)

[0949] MS m / z (ESI): 466.2 [M+H] +;

[0950] Step 7: Synthesis of trans-isopropyl-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0951] Dissolve trans-isopropyl-(4-(5-(4-amino-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (0.5 g, 1.07 mmol) in anhydrous acetonitrile (50 mL). Slowly add tert-butyl nitrite (166.1 mg, 1.61 mmol) at 0 °C under nitrogen protection. Stir the reaction solution at 25 °C for 30 minutes. Add copper(I) bromide (184.85 mg, 1.29 mmol) under nitrogen protection and continue to stir the reaction solution at 25 °C for 16 hours. LCMS shows that the reaction is complete. After drying the reaction system by rotary evaporation, add saturated ammonium chloride solution, and perform liquid-liquid extraction (extract 3 times with 120 mL of dichloromethane). Combine the dichloromethane phases, dry with anhydrous sodium sulfate, and filter by suction. Purify by column chromatography (silica gel, dichloromethane / methanol = 20 / 1) to obtain trans-isopropyl-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (350 mg).

[0952] MS m / z (ESI): 529.2, 531.2 [M+H] + ;

[0953] Step 8: trans-Isopropyl (-4-(5-(4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate Dissolve trans-isopropyl (-4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (50 mg, 94.43 μmol) and 1,5-dimethyl-1H-pyrazol-3-amine (26.24 mg, 236.07 μmol) in anhydrous tetrahydrofuran (4 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) acetate (4.28 mg, 4.72 μmol) and potassium acetate (27.8 mg, 283.28 μmol). Stir the reaction mixture at 85 °C for 16 hours. LCMS shows that the reaction is complete. After rotary evaporation of the reaction system, purify by preparative high performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 50 mm diameter, 250 mm length) (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (50%-70%) as the eluent), and lyophilize to obtain trans-isopropyl (-4-(5-(2-(isopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (4.34 mg).

[0954] MS m / z (ESI): 560.1 [M+H] + ;

[0955] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (s, 1H), 7.95 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 2.4, 8.5 Hz, 1H), 7.64 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.02 (br d, J = 7.9 Hz, 1H), 5.66 (s, 1H), 4.80 - 4.68 (m, 1H), 3.64 (s, 3H), 3.31 - 3.20 (m, 1H), 2.97 - 2.81 (m, 2H), 2.21 (s, 3H), 2.12 (br d, J = 12.7 Hz, 2H), 1.91 (br d, J = 10.5 Hz, 2H), 1.62 - 1.48 (m, 2H), 1.39 - 1.27 (m, 2H), 1.16 (d, J = 6.2 Hz, 6H), 1.05 (d, J = 6.7 Hz, 6H).

[0956] Example 37: Synthesis of trans-isopropyl (-4-(5-(2-(isopropylsulfonyl)-4-((5-methylisoxazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0957]

[0958] Dissolve trans-isopropyl (-4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (50 mg, 94.43 μmol) and 3-amino-5-methylisoxazole (23.16 mg, 236.07 μmol) in anhydrous 1,4-dioxane (4 mL). Under nitrogen protection, add tris(dibenzylideneacetone)dipalladium (4.32 mg, 4.72 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.73 mg, 4.72 μmol) and cesium carbonate (92.3 mg, 283.28 μmol). Stir the reaction mixture at 85 °C for 1 hour. LCMS shows that the reaction is complete. After rotary evaporation of the reaction system, a yellow solid compound is obtained by liquid-liquid extraction (extracted 3 times with 12 mL of ethyl acetate), and purified by preparative high performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 50 mm diameter, 250 mm length) (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (45%-65%) as the eluent), and dried by lyophilization to obtain trans-isopropyl (-4-(5-(2-(isopropylsulfonyl)-4-((5-methylisoxazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (15.85 mg).

[0959] MS m / z (ESI): 547.1 [M+H] + ;

[0960] 11H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 2.5, 8.5 Hz, 1H), 7.72 - 7.65 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.02 (br d, J = 7.7 Hz, 1H), 5.96 (d, J = 0.7 Hz, 1H), 4.80 - 4.70 (m, 1H), 3.32 - 3.25 (m, 1H), 3.01 - 2.81 (m, 2H), 2.37 (s, 3H), 2.13 (br d, J = 11.7 Hz, 2H), 1.91 (br d, J = 10.0 Hz, 2H), 1.65 - 1.50 (m, 2H), 1.41 - 1.26 (m, 2H), 1.16 (d, J = 6.2 Hz, 6H), 1.06 (d, J = 6.7 Hz, 6H).

[0961] Example 38: Synthesis of trans-isopropyl N-[4-[5-[2-isopropylsulfonyl]-4-[(3-methylisothiazol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[0962]

[0963] Dissolve trans-isopropyl-N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (20 mg, 37.77 μmol) and 3-methyl-5-aminoisothiazole (10.78 mg, 94.43 μmol) in anhydrous dioxane (4 mL). Under nitrogen protection, add tris(dibenzylideneacetone)dipalladium (1.73 mg, 1.89 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (1.09 mg, 1.89 μmol) and cesium carbonate (36.92 mg, 113.31 μmol). The reaction solution is a black suspension and stirred at 100 °C for 16 h. After completion of the reaction, it is detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Add water (10 mL) and extract with ethyl acetate (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity as the eluent) to obtain the compound trans-isopropyl N-[4-[5-[2-isopropylsulfonyl]-4-[(3-methylisothiazol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (2.62 mg, 4.66 μmol).

[0964] MS m / z (ESI): 563.1 [M+H] + ;

[0965] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (s, 1H), 7.81 - 7.76 (m, 1H), 7.72 (s, 1H), 7.57 - 7.53 (m, 1H), 7.45 - 7.40 (m, 1H), 7.08 - 7.01 (m, 1H), 6.74 (s, 1H), 4.81 - 4.69 (m, 1H), 3.33 - 3.31 (m, 1H), 3.00 - 2.85 (m, 2H), 2.33 (s, 3H), 2.20 - 2.09 (m, 2H), 1.97 - 1.87 (m, 2H), 1.64 - 1.50 (m, 2H), 1.41 - 1.27 (m, 2H), 1.17 (d, J = 6.2 Hz, 6H), 1.08 (d, J = 6.7 Hz, 6H).

[0966] Example 39: Synthesis of trans-isopropyl-(4-(5-(2-(isopropylsulfonyl)-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0967]

[0968] Dissolve trans-isopropyl-(4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (50 mg, 94.43 μmol) and 1-methyl-1H-1,2,3-triazol-4-amine (236.07 mg, 236.07 μmol) in anhydrous tetrahydrofuran (4 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) acetate (4.28 mg, 4.72 μmol) and potassium acetate (27.8 mg, 283.28 μmol). Stir the reaction mixture at 85 °C for 16 h. LCMS shows that the reaction is complete. After rotary evaporation of the reaction system, add water (3 mL) and perform liquid-liquid extraction (extracted 3 times with 12 mL of ethyl acetate) to obtain a yellow solid compound. Purify it by preparative high performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 30 mm diameter, 100 mm length) (using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity (26% - 66%) as the eluent), and lyophilize to obtain trans-isopropyl-(4-(5-(2-(isopropylsulfonyl)-4-((1-methyl-1H-1,2,3-triazol-4-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (8.4 mg).

[0969] MS m / z (ESI): 547.1 [M+H] + ;

[0970] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (s, 1H), 7.87 - 7.80 (m, 2H), 7.65 (s, 1H), 7.47 (dd, J = 2.5, 8.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.02 (br d, J = 7.7 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.03 (s, 3H), 3.35 - 3.28 (m, 1H), 2.98 - 2.80 (m, 2H), 2.12 (br d, J = 12.0 Hz, 2H), 1.91 (br d, J = 9.9 Hz, 2H), 1.62 - 1.49 (m, 2H), 1.41 - 1.27 (m, 2H), 1.16 (d, J = 6.2 Hz, 6H), 1.05 (d, J = 6.7 Hz, 6H).

[0971] Example 40: Synthesis of trans-isopropyl-(4-(5-(2-(isopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[0972]

[0973] Synthesis method

[0974]

[0975] Step 1: Synthesis of trans-tert-butyl 3-((4-(2-(-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)-3-(isopropylsulfonyl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate

[0976] Dissolve trans-isopropyl (4-(5-(4-bromo-2-(isopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (50 mg, 94.43 μmol) and tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (46.56 mg, 236.07 μmol) in anhydrous tetrahydrofuran (4 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) acetate (4.28 mg, 4.72 μmol) and potassium acetate (27.8 mg, 283.28 μmol). Stir the reaction mixture at 85 °C for 16 hours. LCMS shows that the reaction is complete. After rotary evaporation of the reaction system, perform liquid-liquid extraction (extract 3 times with 12 mL of ethyl acetate) to obtain trans-tert-butyl 3-((4-(2-(-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)-3-(isopropylsulfonyl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate (50 mg, crude product)

[0977] MS m / z (ESI): 646.3 [M+H] + ;

[0978] Step 2: Synthesis of trans-isopropyl (4-(5-(2-(isopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[0979] Dissolve trans-tert-butyl 3-((4-(2-(-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)-3-(isopropylsulfonyl)phenyl)amino)-5-methyl-1H-pyrazole-1-carboxylate (50 mg, 77.42 μmol) in methanol (3 mL), and add p-toluenesulfonic acid (73.63 mg, 387.10 μmol). Stir the reaction solution at 50 °C for 2 hours. LCMS shows that the reaction is complete. Rotate the reaction system to dryness. Add saturated sodium bicarbonate (5 mL), and then extract three times with dichloromethane (15 mL). Combine the dichloromethane phases, dry over anhydrous sodium sulfate, and filter by suction. Purify by preparative high performance liquid chromatography (Phenomenex Gemini-NX column, 5 μm silica, 30 mm diameter, 150 mm length) (using a mixture of water (containing 0.05% ammonia water and 10 mmol of ammonium bicarbonate) and acetonitrile with decreasing polarity (45%-65%) as the eluent), and lyophilize to obtain trans-isopropyl (4-(5-(2-(isopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (5.47 mg).

[0980] MS m / z(ESI): 546.1 [M+H] + ;

[0981] 1 H NMR(400 MHz, DMSO-d6) δ ppm 11.88 (s, 1H), 9.08 (s, 1H), 8.10 (s, 1H), 7.71 - 7.62 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 7.03 (br d, J = 7.5 Hz, 1H), 5.63 (s, 1H), 4.81 - 4.68 (m, 1H), 3.32 - 3.26 (m, 1H), 2.98 - 2.78 (m, 2H), 2.20 (s, 3H), 2.12 (br d, J = 11.8 Hz, 2H), 1.91 (br d, J = 9.8 Hz, 2H), 1.62 - 1.47 (m, 2H), 1.40 - 1.27 (m, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.05 (d, J = 6.8 Hz, 6H).

[0982] Example 41: Synthesis of trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(isopropylsulfinyl)phenyl]carbamate

[0983]

[0984] Synthesis method

[0985]

[0986] Step 1: Synthesis of tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate

[0987] Dissolve tert-butyl trans-N-[4-(formamidino carbamoyl)cyclohexyl]carbamate (10 g, 35.05 mmol) in anhydrous tetrahydrofuran (250 mL), then add Lawesson's reagent (17.01 g, 42.06 mmol) and methyl N-(triethylammonium sulfonyl)carbamate (8.35 g, 35.05 mmol). Stir the reaction mixture at 80 °C for 16 h. After detecting that the raw materials have reacted completely, concentrate the reaction mixture under reduced pressure to dryness, and then purify it by column chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to obtain the product tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (5.5 g).

[0988] MS m / z (ESI): 228.1 [M+H-tBu] + ;

[0989] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 6.83 (br d, J = 7.6 Hz, 1H), 3.29 (brdd, J = 3.7, 8.1 Hz, 1H), 3.11 (tt, J = 3.5, 12.0 Hz, 1H), 2.14 - 2.06 (m, 2H), 1.89 (br d, J = 10.1 Hz, 2H), 1.63 - 1.51 (m, 2H), 1.39 (s, 9H), 1.36 - 1.26 (m, 2H).

[0990] Step 2: Synthesis of tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate

[0991] Dissolve tert-butyl trans-N-[4-(1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (2 g, 7.06 mmol) in anhydrous tetrahydrofuran (200 mL), then add N-bromosuccinimide (3.77 g, 21.17 mmol). Stir the reaction mixture at 60 °C for 16 h. After detecting that the raw materials have reacted completely, concentrate the reaction mixture under reduced pressure to dryness, and then purify it by column chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to obtain the product tert-butyl trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamate (1.5 g).

[0992] MS m / z (ESI): 305.8, 307.8 [M+H-tBu]+ ;

[0993] 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.88 - 6.76 (m, 1H), 3.58 - 3.58 (m, 1H), 3.55 (t, J = 6.8 Hz, 1H), 3.42 (t, J = 6.3 Hz, 1H), 2.08 (br d, J = 12.0 Hz, 2H), 1.92 - 1.85 (m, 2H), 1.62 - 1.53 (m, 2H), 1.39 (s, 9H), 1.42 - 1.21 (m, 2H).

[0994] Step 3: Synthesis of trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate Dissolve trans-N-[4-(5-bromo-1,3,4-thiadiazol-2-yl)cyclohexyl]carbamic acid tert-butyl ester (150 mg, 414.04 μmol) and isopropyl N-[3-isopropylthio-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (188.46 mg, 496.85 μmol) in tetrahydrofuran (7 mL). Under nitrogen protection, add [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (33.81 mg, 41.40 μmol) and an aqueous solution of potassium phosphate (2 M, 621.06 μL). Stir the reaction mixture at 80 °C for 16 hours. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture under reduced pressure to dryness and purify by column chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to obtain trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate (120 mg). MS m / z (ESI): 535 [M+H] + ;

[0995] Step 4: Synthesis of trans-isopropyl N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate

[0996] Dissolve trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate (220 mg, 411.42 μmol) in methanol (2 mL), and add hydrochloric acid / dioxane (1.13 mL). Stir the reaction at 30 °C for 3 hours. Monitor the completion of the reaction by LCMS. Concentrate under reduced pressure to dryness. Obtain trans-isopropyl N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate (178 mg).

[0997] MS m / z (ESI): 435.3 [M+H] + ;

[0998] Step 5: Synthesis of trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate Dissolve trans-isopropyl N-[4-[5-(4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate (178 mg, 409.56 μmol) and isopropyl chloroformate (60.23 mg, 491.47 μmol) in dichloromethane (4 mL), and add N,N-diisopropylethylamine (264.66 mg, 2.05 mmol). Stir the reaction mixture at 30 °C for 2 hours. Concentrate the reaction mixture under reduced pressure to dryness, and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate (120 mg).

[0999] MS m / z (ESI): 521.3 [M+H] + ;

[1000] Step 6: Synthesis of trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(isopropylsulfinyl)phenyl]carbamate Dissolve trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-isopropylthio-phenyl]carbamate (38 mg, 72.98 μmol) in ammonia-methanol solution (2 mL), and add iodobenzene diacetate (352.59 mg, 1.09 mmol). Stir the reaction at 60 °C for 16 hours. Detect the completion of the reaction by LCMS. Concentrate to dryness under reduced pressure. Purify by preparative liquid chromatography (Boston Prime C18 column: 5 μm silica, 25 mm diameter, 150 mm length; use a decreasing polarity mixture of water (containing 0.05% ammonia) and acetonitrile as the eluent) to obtain trans-isopropyl N-[4-[5-[4-(isopropoxycarbonylamino)cyclohexyl]-1,3,4-thiadiazol-2-yl]-3-(isopropylsulfinyl)phenyl]carbamate (20 mg).

[1001] MS m / z(ESI): 552.1 [M+H] + ;

[1002] 1 H NMR(400 MHz, DMSO-d6) δ ppm 10.18 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H), 7.76 (br d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.04 (br d, J = 8.0 Hz, 1H), 4.98 - 4.90 (m, 1H), 4.80 - 4.68 (m, 1H), 4.11 (s, 1H), 3.74 - 3.64 (m, 1H), 3.28 - 3.22 (m, 1H), 3.16 - 3.06 (m, 1H), 2.15 (brd, J = 11.0 Hz, 2H), 1.92 (br d, J = 15.0 Hz, 2H), 1.68 - 1.53 (m, 2H), 1.42 - 1.32 (m, 2H), 1.28 (d, J = 6.3 Hz, 6H), 1.19 - 1.09 (m, 12H).

[1003] Example 42: Synthesis of trans-isopropyl N-[4-[2-[2-(isopropylsulfinyl)-4-][(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate:

[1004]

[1005] Synthesis method

[1006]

[1007] Step 1: Synthesis of tert-Butyl N-(3-Isopropylthiophenyl)Carbamate

[1008] Dissolve the reactant 3-isopropylthioaniline (10 g, 59.78 mmol) in anhydrous methanol (400 mL). Add di-tert-butyl dicarbonate (195.71 g, 896.75 mmol, 206.01 mL) at 25 °C, and stir the reaction mixture at 25 °C for 12 hours. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture under reduced pressure to remove the solvent methanol. Add 400 mL of ammonia water and extract with dichloromethane three times (300 mL * 3). Separate the organic layer and dry it over anhydrous sodium sulfate. Concentrate the organic layer to dryness under reduced pressure. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain white solid tert-butyl N-(3-isopropylthiophenyl)carbamate (13.38 g, 50.04 mmol).

[1009] MS m / z (ESI): 212.1 [M-tBu + H] +

[1010] Step 2: Synthesis of tert-Butyl N-(4-Bromo-3-isopropylthiophenyl)Carbamate

[1011] Dissolve the reactant tert-butyl N-(3-isopropylthiophenyl)carbamate (13.38 g, 50.04 mmol) in dichloromethane (500 mL). Add N-bromosuccinimide (8.91 g, 50.04 mmol) to the reaction system. Stir the reaction mixture at -20 °C for 3 hours. Monitor the reaction by LCMS until completion. Concentrate the reaction mixture to dryness under reduced pressure. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the product tert-butyl N-(4-bromo-3-isopropylthiophenyl)carbamate (5.32 g, 15.36 mmol) as a white solid.

[1012] MS m / z (ESI): 290.0 [M-tBu + H] +

[1013] Step 3: Synthesis of tert-Butyl N-[3-Isopropylthio-4-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-yl)phenyl]Carbamate

[1014] Dissolve the reactant tert-butyl-N-(4-bromo-3-isopropylsulfanyl-phenyl)carbamate (2 g, 5.78 mmol) and bis(pinacolato)diboron (5.87 g, 23.10 mmol) in anhydrous tetrahydrofuran (50 mL). Under nitrogen protection, add potassium acetate (1.70 g, 17.33 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (235.83 mg, 288.78 μmol). Stir the reaction mixture at 80 °C for 2 hours. LCMS shows that the reaction is complete. Concentrate the reaction mixture under reduced pressure to remove the solvent tetrahydrofuran, add 50 mL of dichloromethane, extract with water 3 times (50 mL * 3), separate the organic phase, dry the organic phase with anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. Purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the white solid tert-butyl-N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (2.2 g, 5.59 mmol).

[1015] MS m / z(ESI): 394.3 [M+H] +

[1016] Step 4: Synthesis of trans-isopropyl-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfanyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1017] Dissolve tert-butyl-N-[3-isopropylsulfanyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (2 g, 5.08 mmol), trans-isopropyl-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (1.68 g, 4.84 mmol) and sodium carbonate (1.54 g, 14.53 mmol) in water (600 μL) and 1,4-dioxane (6 mL). Under nitrogen protection, add [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (395.45 mg, 484.24 μmol). Stir the reaction mixture at 100 °C for 16 hours. Filter the reaction mixture, rotary evaporate the filtrate to remove 1,4-dioxane, add water (30 mL), and extract with dichloromethane 3 times (30 mL * 3). After drying with anhydrous sodium sulfate, purify by column chromatography (silica gel, petroleum ether / tetrahydrofuran = 2 / 1) to obtain the yellow solid trans-isopropyl-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfanyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate (1 g, 1.87 mmol).

[1018] MS m / z(ESI): 534.1 [M+H] +

[1019] Step 5: Synthesis of trans-isopropyl-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfinyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1020] Dissolve trans-isopropyl-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylthio-phenyl]thiazol-2-yl]cyclohexyl]carbamate (1.03 g, 1.93 mmol) in dichloromethane (50 mL). Add m-chloroperbenzoic acid (333.01 mg, 1.93 mmol) at 0 °C, and the reaction is carried out at 100 °C for 3 hours. LCMS shows that the reaction is complete. Concentrate to dryness under reduced pressure and purify by column chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to obtain the product trans-isopropyl-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfinyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate (725 mg, 1.32 mmol) as a white solid, with a yield of 68.34%.

[1021] MS m / z (ESI): 550.3 [M+H] +

[1022] Step 6: Synthesis of trans-isopropyl-N-[4-[5-(4-amino-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate Dissolve trans-isopropyl-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-isopropylsulfinyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate (200 mg, 363.81 μmol) in methanol (4 mL). Add hydrochloric acid / 1,4-dioxane (4 M, 909.51 μL) at 25 °C, and the reaction is carried out at 25 °C for 12 hours. LCMS shows that the reaction is complete. Spin-dry the reaction solution to remove methanol, add water (5 mL), and extract with dichloromethane 3 times (5 mL * 3). After drying over anhydrous sodium sulfate, purify by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the product trans-isopropyl-N-[4-[5-(4-amino-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (116 mg, 257.99 μmol) as a white solid.

[1023] MS m / z (ESI): 450.1 [M+H] +

[1024] Step 7: Synthesis of trans-Isopropyl-N-[4-[5-(4-bromo-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate Dissolve trans-Isopropyl-N-[4-[5-(4-amino-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (238 mg, 529.33 μmol) in acetonitrile (6 mL). Add tert-butyl nitrite (163.75 mg, 1.59 mmol, 188.87 μL) at 0 °C and stir for 1 hour. Then add copper(I) bromide (189.83 mg, 1.32 mmol) at 25 °C, and stir the reaction mixture at 25 °C for 15 hours. LCMS shows that the reaction is complete. Rotate the reaction mixture to dryness to remove acetonitrile, add saturated ammonium chloride (20 mL), and extract with dichloromethane three times (20 mL * 3). After drying over anhydrous sodium sulfate, purify by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the product trans-Isopropyl-N-[4-[5-(4-bromo-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (198 mg, 385.58 μmol) as a yellow solid. MS m / z (ESI): 515.1 [M+H] +

[1025] Step 8: Synthesis of trans-Isopropyl-N-[4-[5-[2-isopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1026] Dissolve trans-Isopropyl-N-[4-[5-(4-bromo-2-isopropylsulfinyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (212 mg, 412.84 μmol) in tetrahydrofuran (6 mL). Add 5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (82.30 mg, 454.13 μmol) at 25 °C. Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (37.42 mg, 41.28 μmol) and potassium acetate (40.52 mg, 412.84 μmol), and carry out the reaction at 100 °C for 1 hour. LCMS shows that the reaction is complete. Concentrate the reaction mixture to dryness, and purify by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the product trans-Isopropyl-N-[4-[5-[2-isopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (226 mg, 368.18 μmol) as a yellow solid.

[1027] MS m / z (ESI): 614.4 [M+H] +

[1028] Step 9: Synthesis of trans-isopropyl-N-[4-[2-[2-isopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate

[1029] Dissolve trans-isopropyl-N-[4-[5-[2-isopropylsulfinyl]-4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (90 mg, 146.62 μmol) in methanol (2 mL). Add p-toluenesulfonic acid (126.24 mg, 733.10 μmol) at 25 °C, and the reaction is carried out at 50 °C for 2 hours. LCMS shows that the reaction is complete. Rotate the reaction solution to dryness to remove methanol, add it to saturated sodium bicarbonate (5 mL) and stir for 5 minutes. Extract the aqueous phase with dichloromethane 3 times (5 mL * 3). After drying with anhydrous sodium sulfate, purify by thin layer chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the product trans-isopropyl-N-[4-[2-[2-isopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate (30 mg, 56.63 μmol) as a white solid.

[1030] MS m / z (ESI): 530.3 [M+H] +

[1031] Step 10: Synthesis of trans-isopropyl-N-[4-[2-[2-(isopropylsulfinylimino)-4-][(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate trans-Isopropyl-N-[4-[2-[2-isopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate (30 mg, 56.63 μmol), ammonium carbamate (88.43 mg, 1.13 mmol), and iodobenzene diacetate (182.42 mg, 566.34 μmol) were loaded into a microwave vial containing methanol (0.5 mL). The reaction was carried out at 100 °C in a microwave for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified by thin layer chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the crude product, and the crude product was further purified by preparative liquid chromatography (YMC-Actus Triart C18 column: 5 μm silica gel, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity as the eluent) to obtain the product trans-isopropyl-N-[4-[2-[2-(isopropylsulfinylimino)-4-][(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-5-yl]cyclohexyl]carbamate (1.21 mg) as a white solid.

[1032] MS m / z (ESI): 545.3 [M+H] +

[1033] 1 H NMR: (400 MHz, METHANOL-d4) δ ppm 8.01 (s, 1H) 7.67 (s, 1H) 7.49 (br d, J = 7.28 Hz, 1H) 7.31 (d, J = 8.53 Hz, 1H) 5.82 (s, 1H) 4.82 - 4.70 (m, 1H) 3.55 - 3.42 (m, 1H) 2.98 - 3.13 (m, 2H) 2.30 (s, 3H) 2.25 (br d, J = 9.03 Hz, 2H) 2.09 (br d, J = 10.54 Hz, 2H) 1.78 - 1.65 (m, 2H) 1.38 - 1.54 (m, 2H) 1.32 (d, J = 6.2 Hz, 6H) 1.24 (d, J = 6.2 Hz, 6H).

[1034] Example 43: Synthesis of trans-isopropyl-N-[3-(N-cyclopropyl-S-methyl-sulfinylimino)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate

[1035]

[1036] Dissolve trans-isopropyl-N-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-(methylsulfinyl)phenyl]carbamate (40 mg, 76.53 μmol) in 1,4-dioxane (1 mL), add copper(II) acetate (20.85 mg, 114.79 μmol) and pyridine (14.53 mg, 183.67 μmol, 14.82 μL). Stir the reaction mixture at 20 °C for 5 minutes, add cyclopropylboronic acid (13.15 mg, 153.06 μmol), and stir the reaction solution at 100 °C for 12 hours. LCMS shows the reaction. Filter the reaction solution, rotary evaporate the filtrate to remove 1,4-dioxane, add water (15 mL), and extract with ethyl acetate 3 times (15 mL * 3). Dry the organic phase over anhydrous sodium sulfate and rotary evaporate to dryness under reduced pressure. Purify by preparative high performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length); (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (48% - 68%) as the eluent) to obtain trans-isopropyl-N-[3-(N-cyclopropyl-S-methyl-sulfinyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]carbamate (14.12 mg, 25.09 μmol).

[1037] MS m / z (ESI): 563.3 [M+H] +

[1038] 1 H NMR: (400 MHz, DMSO-d6) δ ppm 10.10 (s, 1H) 8.37 (d, J = 2.32 Hz, 1H) 7.74 - 7.68 (m, 2H) 7.43 (d, J = 8.31 Hz, 1H) 7.03 (br d, J = 7.70 Hz, 1H) 4.97 - 4.88 (m, 1H) 4.80 - 4.71 (m, 1H) 2.97 - 2.89 (m, 1H) 2.87 (s, 3H) 2.55 - 2.51 (m, 1H) 2.32 - 2.26 (m, 1H) 2.12 (br d, J = 12.35 Hz, 2H) 1.91 (br d, J = 10.15 Hz, 2H) 1.62 - 1.51 (m, 2H) 1.39 - 1.31 (m, 2H) 1.28 (d, J = 6.24 Hz, 6H) 1.17 (d, J = 6.24 Hz, 6H) 0.44 - 0.33 (m, 2H) 0.33 - 0.20 (m, 2H).

[1039] Example 44: Synthesis of trans-isopropyl N-[4-[5-[2-isopropylsulfonyl-4-(pyridazin-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1040]

[1041] Dissolve trans-isopropyl N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (20 mg, 37.77 μmol) and 3-aminopyridazine (8.98 mg, 94.43 μmol) in dioxane (2 mL), then add tris(dibenzylideneacetone)dipalladium (1.73 mg, 1.89 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.09 mg, 1.89 μmol) and cesium carbonate (36.92 mg, 113.31 μmol) under a nitrogen atmosphere. Stir the reaction mixture at 100 °C for 16 hours. Monitor the reaction by LCMS until completion. Add 9 mL of ethyl acetate (3 mL * 3) and 4 mL of water to the reaction mixture. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. Purify by preparative liquid chromatography (Phenomenex Gemini C18 column: 10 μm silica, 50 mm diameter, 250 mm length; using a decreasing polarity mixture of water (containing 0.05% ammonia) and acetonitrile as the eluent) to obtain trans-isopropyl N-[4-[5-[2-isopropylsulfonyl-4-(pyridazin-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate (7 mg).

[1042] MS m / z (ESI): 544.1 [M+H] + ;

[1043] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 8.77 (d, J = 4.4 Hz, 1H), 8.45 - 8.26 (m, 2H), 7.72 (s, 1H), 7.61 - 7.46 (m, 2H), 7.19 (d, J = 8.8 Hz, 1H), 7.03 (br d, J = 7.6 Hz, 1H), 4.77 - 4.66 (m, 1H), 3.30 - 3.24 (m, 1H), 3.00 - 2.84 (m, 2H), 2.13 (br d, J = 12.0 Hz, 2H), 1.92 (br d, J = 9.6 Hz, 2H), 1.64 - 1.50 (m, 2H), 1.41 - 1.28 (m, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H).

[1044] Example 45: Synthesis of trans-isopropyl N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-isopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate:

[1045]

[1046] Synthesis method

[1047]

[1048] Step 1: Synthesis of tert-butyl trans-5-cyclopropyl-3-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-anilino]pyrazole-1-carboxylate

[1049] Dissolve trans-isopropyl N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (40 mg, 75.54 μmol) and tert-butyl 3-amino-5-cyclopropyl-pyrazole-1-carboxylate (18.55 mg, 83.10 μmol) in tetrahydrofuran (5 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (6.85 mg, 7.55 μmol) and potassium acetate (7.41 mg, 75.54 μmol). Stir the reaction solution at 100 °C for 16 hours. Detect the completion of the reaction by LCMS. Add 9 mL of ethyl acetate (3 mL * 3) and 4 mL of water to the reaction solution. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. Purify by column chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the yellow substance tert-butyl trans-5-cyclopropyl-3-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-anilino]pyrazole-1-carboxylate (30 mg).

[1050] MS m / z (ESI): 672.3 [M + H] + ;

[1051] Step 2: Synthesis of trans-isopropyl N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-isopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1052] tert-Butyl trans-5-cyclopropyl-3-[4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]-3-isopropylsulfonyl-anilino]pyrazole-1-carboxylate (63 mg, 93.77 μmol) was dissolved in methanol (5 mL), and then p-toluenesulfonic acid monohydrate (80.74 mg, 468.84 μmol) was added to the reaction solution. The reaction solution was stirred at 50 °C for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography (Phenomenex Gemini-NX column: 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity as the eluent) gave the white solid trans-isopropyl N-[4-[5-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-isopropylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate (2.9 mg). MS m / z (ESI): 572.1 [M+H] + ;

[1053] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 9.06 (s, 1H), 8.13 (s, 1H), 7.70 - 7.58 (m, 2H), 7.34 (d, J = 8.4 Hz, 1H), 7.02 (br d, J = 7.8 Hz, 1H), 5.54 (s, 1H), 4.82 - 4.70 (m, 1H), 3.31 - 3.27 (m, 1H), 2.98 - 2.79 (m, 2H), 2.12 (br d, J = 11.5 Hz, 2H), 1.96 - 1.88 (m, 2H), 1.88 - 1.82 (m, 1H), 1.63 - 1.47 (m, 2H), 1.41 - 1.25 (m, 2H), 1.16 (d, J = 6.2 Hz, 6H), 1.05 (d, J = 6.8 Hz, 6H), 0.96 - 0.88 (m, 2H), 0.74 - 0.64 (m, 2H).

[1054] Example 46: Synthesis of trans-isopropyl N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1055]

[1056] Dissolve trans-isopropyl N-[4-[5-(4-bromo-2-isopropylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (50 mg, 94.43 μmol) and tert-butyl 3-amino-5-(trifluoromethyl)-1H-pyrazole-1-carboxylate (28.46 mg, 113.31 μmol) in tetrahydrofuran (5 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) acetate (8.56 mg, 9.44 μmol) and potassium acetate (9.27 mg, 94.43 μmol). Stir the reaction mixture at 100 °C for 16 hours. Monitor the reaction by LCMS until completion. Add 9 mL of ethyl acetate (3 mL * 3) and 5 mL of water to the reaction mixture. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. Purify by thin-layer chromatography (silica gel, dichloromethane:methanol = 10:1) to obtain the white solid trans-isopropyl N-[4-[5-[2-cyclopropylsulfinyl]-4-[(5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (2.3 mg).

[1057] MS m / z (ESI): 600.2 [M+H] + ;

[1058] 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.80 - 13.39 (m, 1H), 9.58 - 9.12 (m, 1H), 8.24 - 8.04 (m, 1H), 7.72 - 7.58 (m, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.21 (br s, 1H), 7.02 (br d, J = 7.5 Hz, 1H), 6.49 (br s, 1H), 4.82 - 4.70 (m, 1H), 3.40 - 3.33 (m, 1H), 3.00 - 2.80 (m, 2H), 2.12 (br d, J = 11.8 Hz, 2H), 1.91 (br d, J = 9.8 Hz, 2H), 1.63 - 1.47 (m, 2H), 1.40 - 1.27 (m, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.05 (d, J = 6.8 Hz, 6H).

[1059] Example 47: Synthesis of trans-isopropyl N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1060]

[1061] Synthesis method

[1062]

[1063] Step 1: Synthesis of tert-butyl (3-(1-oxophospholane-1-yl)phenyl)carbamate

[1064] Dissolve 1-(3-aminophenyl)phospholane-1-oxide (340 mg, 1.74 mmol) in methanol (10 mL), and add di-tert-butyl dicarbonate (3.80 g, 17.42 mmol, 4.00 mL) at 25 °C. The reaction solution is a yellow suspension and stirred at 25 °C for 16 h. After completion of the reaction detected by LCMS, the reaction solution is concentrated to dryness under reduced pressure. Add ammonia water (10 mL) to the reaction solution, stir the reaction solution at 25 °C for 2 h, then extract with dichloromethane (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by column chromatography (dichloromethane:methanol = 10:1) to obtain tert-butyl (3-(1-oxophospholane-1-yl)phenyl)carbamate (400 mg, 1.35 mmol) as a white solid.

[1065] MS m / z (ESI): 296.2 [M+H] + ;

[1066] Step 2: Synthesis of tert-butyl N-[4-bromo-3-(1-oxophospholane-1-yl)phenyl]carbamate

[1067] Dissolve tert-butyl (3-(1-oxophospholane-1-yl)phenyl)carbamate (360 mg, 1.22 mmol) in N,N-dimethylformamide (5 mL), and add N-bromosuccinimide (650.91 mg, 3.66 mmol). The reaction solution is a yellow suspension and stirred at 50 °C for 16 h. After completion of the reaction detected by LCMS, the reaction solution is concentrated to dryness under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain tert-butyl N-[4-bromo-3-(1-oxophospholane-1-yl)phenyl]carbamate (320 mg, 855.14 μmol) as a yellow oil.

[1068] MS m / z (ESI): 374.0, 376.0 [M+H] + ;

[1069] 11H NMR (400 MHz, DMSO-d6) δ ppm 9.68 (s, 1H), 8.13 - 8.05 (m, 1H), 7.65 (d, J = 4.0 Hz, 1H), 7.63 - 7.58 (m, 1H), 2.30 - 2.17 (m, 2H), 2.05 - 1.86 (m, 6H), 1.50 (s, 9H).

[1070] Step 3: Synthesis of trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate Dissolve tert-butyl N-[4-bromo-3-(1-oxophospholane-1-yl)phenyl]carbamate (220 mg, 587.91 μmol), trans-isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (204.16 mg, 587.91 μmol) and bis(pinacolato)diboron (597.17 mg, 2.35 mmol) in anhydrous tetrahydrofuran (4 mL). Under nitrogen protection, add tris(dibenzylideneacetone)dipalladium(0) (26.92 mg, 29.40 μmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14.01 mg, 29.40 μmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1'-biphenyl)[2-(2-amino-1,1'-biphenyl)]palladium(II) (23.13 mg, 29.40 μmol) and potassium acetate (115.40 mg, 1.18 mmol). The reaction solution is a black-yellow suspension and stirred at 80 °C for 16 h. The reaction is monitored by LCMS until completion. The reaction solution is concentrated to dryness under reduced pressure. Add water (10 mL) and extract with ethyl acetate (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by column chromatography (dichloromethane:methanol = 10:1) to obtain the compound trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (160 mg, 284.86 μmol) as a yellow oil.

[1071] MS m / z (ESI): 562.2 [M+H] + ;

[1072] Step 4: Synthesis of trans-isopropyl N-[4-[5-[4-amino-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1073] Dissolve trans-isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (160 mg, 284.86 μmol) in anhydrous methanol (2.5 mL), and add hydrochloric acid / dioxane (4 M, 2.5 mL). The reaction solution is a yellow suspension and stirred at 25 °C for 2 h. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Add saturated sodium carbonate solution (10 mL), and extract twice with dichloromethane (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure to obtain the crude product trans-isopropyl N-[4-[5-[4-amino-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (110 mg) as a white solid.

[1074] MS m / z (ESI): 462.2 [M+H] + ;

[1075] Step 5: Synthesis of trans-isopropyl N-[4-[5-[4-bromo-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1076] Dissolve trans-isopropyl N-[4-[5-[4-amino-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (110 mg, 238.32 μmol) in acetonitrile (3 mL), add tert-butyl nitrite (73.73 mg, 714.97 μmol, 85.04 μL) under nitrogen protection at -30 °C, and stir the reaction solution for 1 h. Add copper(I) bromide (85.47 mg, 595.81 μmol, 18.15 μL) under nitrogen protection at -30 °C. The reaction solution is a yellow suspension and stirred at 25 °C for 16 h. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Add saturated ammonium chloride (10 mL), and extract with dichloromethane (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by column chromatography (dichloromethane:methanol = 10:1) to obtain the compound trans-isopropyl N-[4-[5-[4-bromo-2-(1-oxophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (70 mg, 133.22 μmol) as a white solid.

[1077] MS m / z (ESI): 525.1, 527.1 [M+H] + ;

[1078] Step 6: Synthesis of trans-isopropyl N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(1-phospholanyl) phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1079] Dissolve trans-isopropyl N-[4-[5-[4-bromo-2-(1-phospholanyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (35 mg, 66.61 μmol) and 1-Boc-3-amino-5-methylpyrazole (13.28 mg, 73.27 μmol) in anhydrous tetrahydrofuran (3 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (6.04 mg, 6.66 μmol) and potassium acetate (6.54 mg, 66.61 μmol). The reaction solution is a black suspension and stirred at 100 °C for 1 h. The reaction is monitored by LCMS until completion. The reaction solution is concentrated to dryness under reduced pressure. Purify by thin layer chromatography (dichloromethane:methanol = 10:1) to obtain the compound trans-isopropyl N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(1-phospholanyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 31.96 μmol) as a white solid.

[1080] MS m / z (ESI): 626.3 [M+H] + ;

[1081] Step 7: Synthesis of trans-isopropyl N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(1-phospholanyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1082] Dissolve trans-isopropyl N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl)pyrazol-3-yl]amino]-2-(1-oxidophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 31.96 μmol) in anhydrous methanol (3 mL), and add p-toluenesulfonic acid monohydrate (27.52 mg, 159.81 μmol). The reaction solution is a black suspension and stirred at 50 °C for 1 h. The reaction is monitored by LCMS until completion. The reaction solution is concentrated to dryness under reduced pressure. Add saturated sodium carbonate (5 mL), and extract with dichloromethane (10 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography (Phenomenex Gemini C18 column, 10 μm silica, 50 mm diameter, 250 mm length; using a mixture of water (containing 0.05% ammonia water) and acetonitrile with decreasing polarity as the eluent) gives the compound trans-isopropyl N-[4-[5-[4-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(1-oxidophospholane-1-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (1.12 mg, 2.07 μmol) as a white solid.

[1083] MS m / z (ESI): 542.2 [M+H] + ;

[1084] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (s, 1H), 8.86 - 8.78 (m, 1H), 7.99 - 7.91 (m, 1H), 7.86 (s, 1H), 7.59 - 7.53 (m, 1H), 7.34 - 7.28 (m, 1H), 7.06 - 7.00 (m, 1H), 5.69 (s, 1H), 4.83 - 4.66 (m, 1H), 3.35 - 3.29 (m, 1H), 2.97 - 2.85 (m, 1H), 2.20 (s, 3H), 2.16 - 2.07 (m, 2H), 1.96 - 1.78 (m, 6H), 1.67 - 1.48 (m, 6H), 1.40 - 1.29 (m, 2H), 1.17 (d, J = 6.3 Hz, 6H).

[1085] Example 48: Synthesis of trans-isopropyl (-4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[1086]

[1087] Synthesis method

[1088]

[1089] Step 1: Synthesis of trans-isopropyl (-4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[1090] Dissolve the intermediate trans-isopropyl (-4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (150 mg, 284.36 μmol) of Example 55 and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (56.69 mg, 312.8 μmol) in anhydrous tetrahydrofuran (6 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) acetate (25.78 mg, 428.44 μmol) and potassium acetate (83.72 mg, 853.09 μmol). Stir the reaction solution at 100 °C for 1 hour. LCMS shows that the reaction is complete. After drying the reaction system by rotary evaporation, perform liquid-liquid extraction (extract 3 times with 12 mL of ethyl acetate) to obtain the yellow solid compound trans-isopropyl (-4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (150 mg, crude product).

[1091] MS m / z (ESI): 628.3 [M+H] + ;

[1092] Step 2: trans-isopropyl (-4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate

[1093] Dissolve trans-isopropyl (-4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (150 mg, 238.92 μmol) in methanol (5 mL), and add p-toluenesulfonic acid (205.72 mg, 1.19 mmol). Stir the reaction mixture at 50 °C for 30 minutes. LCMS shows that the reaction is complete. Rotate the reaction system to dryness. Add saturated sodium bicarbonate (20 mL), and then extract three times with dichloromethane (60 mL). Combine the dichloromethane phases, dry over anhydrous sodium sulfate, and filter by suction. Purify by preparative high performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 30 mm diameter, 100 mm length) (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (35%-55%) as the eluent), and lyophilize to obtain the white solid compound trans-isopropyl (-4-(5-(2-(cyclopropylsulfonyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (55.59 mg).

[1094] MS m / z (ESI): 544.2 [M+H] + ;

[1095] 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (s, 1H), 9.04 (s, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.02 (br d, J = 7.6 Hz, 1H), 5.64 (s, 1H), 4.80 - 4.69 (m, 1H), 3.31 - 3.23 (m, 1H), 2.98 - 2.88 (m, 1H), 2.42 - 2.32 (m, 1H), 2.20 (s, 3H), 2.13 (br d, J = 12.3 Hz, 2H), 1.91 (br d, J = 10.1 Hz, 2H), 1.65 - 1.47 (m, 2H), 1.42 - 1.25 (m, 2H), 1.16 (d, J = 6.1 Hz, 6H), 1.00 - 0.90 (m, 2H), 0.90 - 0.83 (m, 2H).

[1096] Example 49: Synthesis of trans-isopropyl (-4-(5-(2-(cyclopropylsulfonyl)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate:

[1097]

[1098] Dissolve trans-isopropyl (-4-(5-(4-bromo-2-(cyclopropylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (40 mg, 75.83 μmol) and 1,5-dimethyl-1H-pyrazol-3-amine (10.11 mg, 91.0 μmol) in anhydrous tetrahydrofuran (5 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) acetate (6.87 mg, 7.58 μmol) and potassium acetate (22.33 mg, 227.49 μmol). Stir the reaction mixture at 100 °C for 1 hour. LCMS shows that the reaction is complete. After rotary evaporation of the reaction system, a yellow solid compound is obtained by liquid-liquid extraction (extracted 3 times with 12 mL of ethyl acetate), and purified by preparative high performance liquid chromatography (Phenomenex Gemini-NX column, 10 μm silica, 30 mm diameter, 100 mm length) (using a mixture of water (containing 0.05% ammonia) and acetonitrile with decreasing polarity (40%-60%) as the eluent), and lyophilized to obtain a white solid compound trans-isopropyl (-4-(5-(2-(cyclopropylsulfonyl)-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl)carbamate (4.55 mg).

[1099] MS m / z (ESI): 558.2 [M+H] + ;

[1100] 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (s, 1H), 7.97 (br s, 1H), 7.75 - 7.58 (m, 2H), 7.33 (br d, J = 8.4 Hz, 1H), 7.02 (br d, J = 6.1 Hz, 1H), 5.66 (s, 1H), 4.85 - 4.64 (m, 1H), 3.63 (s, 3H), 3.28 - 3.22 (m, 1H), 3.00 - 2.84 (m, 1H), 2.46 - 2.35 (m, 1H), 2.21 (s, 3H), 2.13 (br d, J = 11.3 Hz, 2H), 1.91 (br d, J = 10.4 Hz, 2H), 1.66 - 1.47 (m, 2H), 1.42 - 1.26 (m, 2H), 1.16 (br d, J = 6.0 Hz, 6H), 1.02 - 0.76 (m, 4H).

[1101] Example 50: Synthesis of trans-Isopropyl N-[4-[5-[2-(Cyclopropylsulfonylimino)-4-]((5-Methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1102]

[1103] Synthesis Method

[1104]

[1105] Step 1: Synthesis of trans-Isopropyl N-[4-[5-[2-Cyclopropylthio]-4-[(3-Methyl-2-tetrahydropyran-2-yl-2H-pyrrol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate Dissolve trans-Isopropyl N-[4-[5-(4-Bromo-2-cyclopropylthio-phenyl)thiazol-2-yl]cyclohexyl]carbamate (20 mg, 40.36 μmol) and 5-Methyl-1-tetrahydropyran-2-yl-pyrazol-3-amine (8.05 mg, 44.40 μmol) in tetrahydrofuran (4 mL), and add (2-Dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-Amino-1,1-biphenyl-2-yl)palladium(II) (3.66 mg, 4.04 μmol) and potassium acetate (3.96 mg, 40.36 μmol). Stir the reaction solution at 100 °C for 2 hours. Detect the completion of the reaction by LCMS. Add 9 mL of ethyl acetate (3 mL * 3) and 5 mL of water to the reaction solution. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to dryness, and then purify by thin-layer chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the product trans-Isopropyl N-[4-[5-[2-Cyclopropylthio]-4-[(3-Methyl-2-tetrahydropyran-2-yl-2H-pyrrol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg).

[1106] MS m / z(ESI): 596.3 [M+H] + ;

[1107] Step 2: Synthesis of trans-isopropyl N-[4-[5-[2-(cyclopropylsulfinyl)-4-]((5-methyl-1-tetrahydropyran-2-yl)pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate Dissolve trans-isopropyl N-[4-[5-[2-cyclopropylthio]-4-[(3-methyl-2-tetrahydropyran-2-yl-2H-pyrrol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (33 mg, 55.39 μmol) in ammonia methanol solution (3 mL), add diacetoxyiodobenzene (267.59 mg, 830.79 μmol), and stir the reaction solution at 60 °C for 16 hours. LCMS was used to detect the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, and then purified by thin layer chromatography (silica gel, dichloromethane:methanol = 15:1) to obtain the product trans-isopropyl N-[4-[5-[2-(cyclopropylsulfinyl)-4-]((5-methyl-1-tetrahydropyran-2-yl)pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg).

[1108] MS m / z(ESI): 627.3 [M+H] + ;

[1109] Step 3: Synthesis of trans-isopropyl N-[4-[5-[2-(cyclopropylsulfinyl)-4-]((5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate Dissolve trans-isopropyl N-[4-[5-[2-(cyclopropylsulfinyl)-4-]((5-methyl-1-tetrahydropyran-2-yl)pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 31.91 μmol) in methanol (2 mL), and add p-toluenesulfonic acid monohydrate (27.47 mg, 159.53 μmol). Stir the reaction solution at 50 °C for 2 hours. LCMS was used to detect the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure. Add 9 mL of dichloromethane (3 mL * 3) and 5 mL of saturated sodium bicarbonate solution to the reaction solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. It was purified by preparative liquid chromatography (Phenomenex Gemini C18 column: 10 μm silica gel, 50 mm in diameter, 250 mm in length; using a mixture of water (containing 0.225% formic acid) and acetonitrile with decreasing polarity as the eluent) to obtain the compound trans-isopropyl N-[4-[5-[2-(cyclopropylsulfinyl)-4-]((5-methyl-1H-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (2.46 mg).

[1110] MS m / z(ESI): 543.3 [M+H]+ ;

[1111] 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (br s, 1H), 8.93 (s, 1H), 8.03 (s, 1H), 7.70 - 7.55 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 7.01 (br d, J = 7.8 Hz, 1H), 5.63 (s, 1H), 4.80 - 4.69 (m, 1H), 4.20 (s, 1H), 3.32 - 3.31 (m, 1H), 2.95 - 2.83 (m, 1H), 2.31 - 2.23 (m, 1H), 2.19 (s, 3H), 2.17 - 2.06 (m, 2H), 1.95 - 1.83 (m, 2H), 1.63 - 1.47 (m, 2H), 1.41 - 1.25 (m, 2H), 1.16 (d, J = 6.3 Hz, 6H), 0.94 - 0.73 (m, 4H).

[1112] Example 51: Synthesis of trans-Isopropyl-N-[4-[5-[4-[(5-Methyl-1H-pyrazol-3-yl)amino]-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1113]

[1114] Synthesis Method

[1115]

[1116] Step 1: Synthesis of tert-Butyl (3-((Trifluoromethyl)thio)phenyl)carbamate Dissolve 3-(trifluoromethylthio)aniline (1 g, 5.18 mmol) in methanol (20 mL), and add BOC anhydride (16.95 g, 77.64 mmol, 17.84 mL) at 25°C. The reaction solution is a yellow suspension and stirred at 25°C for 16 h. LCMS is used to detect the completion of the reaction. The reaction solution is concentrated to dryness under reduced pressure. Add ammonia water (60 mL) to the reaction solution, stir the reaction solution at 25°C for 2 h, then extract with ethyl acetate (60 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the compound tert-Butyl (3-((trifluoromethyl)thio)phenyl)carbamate (600 mg, 2.05 mmol) as a white solid.

[1117] MS m / z (ESI): 238.0 [M + H - tert-butyl] + ;

[1118] Step 2: Synthesis of tert-Butyl N-[4-bromo-3-(trifluoromethylthio)phenyl]carbamate

[1119] Dissolve tert-butyl (3-((trifluoromethyl)thio)phenyl)carbamate (560 mg, 1.91 mmol) in N,N-dimethylformamide (5 mL), and add N-bromosuccinimide (679.64 mg, 3.82 mmol). The reaction solution is a yellow suspension and stirred at 25 °C for 16 h. The reaction is monitored by LCMS until completion. The reaction solution is concentrated to dryness under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the compound tert-butyl N-[4-bromo-3-(trifluoromethylthio)phenyl]carbamate (470 mg, 1.26 mmol) as a yellow oil.

[1120] MS m / z (ESI): 318.0, 316.0 [M + H - tert-butyl] + ;

[1121] Step 3: Synthesis of tert-Butyl N-[4-bromo-3-(trifluoromethylsulfonyl)phenyl]carbamate

[1122] Dissolve tert-butyl N-[4-bromo-3-(trifluoromethylthio)phenyl]carbamate (450 mg, 1.21 mmol) and anhydrous ruthenium(III) chloride (2.51 mg, 12.09 μmol) in acetonitrile (2 mL), carbon tetrachloride (2 mL) and water (4 mL), and add sodium periodate (775.80 mg, 3.63 mmol, 200.98 μL). The reaction solution is a black suspension and stirred at 25 °C for 16 h. The reaction is monitored by LCMS until completion. The reaction solution is concentrated to dryness under reduced pressure, water (10 mL) is added, and the mixture is extracted with dichloromethane (20 mL). The organic layer is washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) gives the compound tert-butyl N-[4-bromo-3-(trifluoromethylsulfonyl)phenyl]carbamate (360 mg, 890.65 μmol) as a yellow oil.

[1123] MS m / z (ESI): 426.0, 428.0 [M + Na] + ;

[1124] Step 4: Synthesis of tert-Butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethylsulfonyl)phenyl]carbamate

[1125] tert-Butyl N-[4-bromo-3-(trifluoromethylsulfonyl)phenyl]carbamate (360 mg, 890.65 μmol) and bis(pinacolato)diboron (904.68 mg, 3.56 mmol) were dissolved in anhydrous tetrahydrofuran (3 mL). Under nitrogen protection, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (72.73 mg, 89.06 μmol) and potassium acetate (262.23 mg, 2.67 mmol) were added. The reaction mixture was a yellow suspension and stirred at 80 °C for 16 h. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) gave tert-Butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethylsulfonyl)phenyl]carbamate (300 mg, 664.80 μmol) as a white solid.

[1126] MS m / z (ESI): 469.2 [M+H2O] + ;

[1127] Step 5: Synthesis of trans-Isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate tert-Butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethylsulfonyl)phenyl]carbamate (300 mg, 664.80 μmol) and trans-Isopropyl N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (230.86 mg, 664.80 μmol) were dissolved in anhydrous dioxane (3 mL). Under nitrogen protection, [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (54.29 mg, 66.48 μmol), sodium carbonate (140.92 mg, 1.33 mmol) and water (400 μL) were added. The reaction mixture was a yellow suspension and stirred at 80 °C for 16 h. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated to dryness under reduced pressure. Purification by column chromatography (dichloromethane:methanol = 10:1) gave trans-Isopropyl N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (300 mg, 507.05 μmol) as a white solid.

[1128] MS m / z (ESI): 592.3 [M+H] + ;

[1129] Step 6: Synthesis of trans-Isopropyl N-[4-[5-[4-amino-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1130] Dissolve trans-isopropyl-N-[4-[5-[4-(tert-butoxycarbonylamino)-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (300 mg, 507.05 μmol) in anhydrous methanol (3 mL), and add hydrochloric acid / dioxane (4 M, 3 mL). The reaction solution is a yellow suspension and stirred at 25 °C for 2 h. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Add saturated sodium carbonate solution (10 mL), and extract twice with dichloromethane (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure to obtain the crude product trans-isopropyl-N-[4-[5-[4-amino-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (230 mg) as a white solid.

[1131] MS m / z (ESI): 492.2 [M+H] + ;

[1132] Step 7: Synthesis of trans-isopropyl-N-[4-[5-[4-bromo-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate Dissolve trans-isopropyl-N-[4-[5-[4-amino-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (230 mg, 467.91 μmol) in acetonitrile (5 mL), add tert-butyl nitrite (144.75 mg, 1.40 mmol, 166.96 μL) under nitrogen protection at -30 °C, and stir the reaction solution for 1 h. Add copper(I) bromide (167.80 mg, 1.17 mmol, 35.63 μL) under nitrogen protection at -30 °C. The reaction solution is a yellow suspension and stirred at 25 °C for 16 h. The reaction is completed as detected by LCMS. The reaction solution is concentrated to dryness under reduced pressure. Add saturated ammonium chloride (10 mL), and extract with dichloromethane (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated to dryness under reduced pressure. Purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the compound trans-isopropyl-N-[4-[5-[4-bromo-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (20 mg, 36.01 μmol) as a white solid.

[1133] MS m / z (ESI): 555.0, 557.0 [M+H] + ;

[1134] Step 8: Synthesis of trans-isopropyl-N-[4-[5-[4-[(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)amino]-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

[1135] Dissolve trans-isopropyl-N-[4-[5-[4-bromo-2-(trifluoromethylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (10 mg, 18.00 μmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (3.59 mg, 19.80 μmol) in anhydrous tetrahydrofuran (2 mL). Under nitrogen protection, add (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) acetate (1.63 mg, 1.80 μmol) and potassium acetate (1.77 mg, 18.00 μmol). The reaction solution is a black suspension and stirred at 100 °C for 1 h. The reaction is monitored by LCMS until completion. The reaction solution is concentrated to dryness under reduced pressure...

Claims

1. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof: R 1 selected from R 7 Selected from C1-C 10 alkyl, C3-C 10 cycloalkyl, oxetanyl, oxolanyl or said C1-C 10 alkyl, C3-C 10 cycloalkyl, oxetanyl, oxolanyl or optionally substituted by one or more R 7a substituted; R 7a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH, C1-C 10 alkyl or C6-C 10 aryl; R 8 Selected from H, C1-C 10 alkyl or C3-C 10 cycloalkyl, the C1-C 10 alkyl or C3-C 10 cycloalkyl is optionally substituted by one or more R 8a substituted; R 8a selected from F, Cl, Br, I, OH, CN, ═O, NO2, NH2, SH, C1-C 10 alkyl or C2-C 10 alkenyl; R 9 Selected from C1-C 10 alkyl, C3-C 10 cycloalkyl or 3- to 10-membered heterocyclic group, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl or 3- to 10-membered heterocyclic group is optionally substituted by one or more R 9a substituents; R 9a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH or C1-C 10 alkyl; R 10 Selected from C1-C 10 alkyl, wherein the C1-C 10 alkyl is optionally substituted by one or more R 10a substituents; R 10a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH or C1-C 10 alkyl; R 11 、R 12 、R 13 are independently selected from C1-C 10 alkyl or C3-C 10 cycloalkyl, and the C1-C 10 alkyl or C3-C 10 cycloalkyl is optionally substituted with one or more R 11a substituents; or R 11 and R 12 together with the atoms to which they are attached form a 3- to 10-membered heterocyclic group, which 3- to 10-membered heterocyclic group is optionally substituted with one or more R 11a substituents; R 11a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH or C1-C 10 alkyl; R 2 、R 3 、R 4 are independently selected from H, F, Cl, Br, I, OH, CN, NO2, NH2 or C1-C 10 alkyl; L is selected from X2 is CR 15 ; Y2 is N; Z2 is S; R 15 selected from H, F, Cl, Br, I, OH or CN; R 5 Selected from a 3- to 10-membered heterocyclic group or a 5- to 10-membered heteroaryl group; the 3- to 10-membered heterocyclic group or 5- to 10-membered heteroaryl group is optionally substituted with one or more R 20a substituents; n is selected from 0 or 1; X5 is selected from N or CR 21 ; Y5 and Y6 are independently selected from a chemical bond, NH or CHR 22 ; Z5 and Z6 are independently selected from O or NR 23 ; R 17 、R 18 、R 25 、R 26 are independently selected from H, C1-C 10 alkyl, C3-C 10 cycloalkyl or C6-C 10 aryloxy, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl or C6-C 10 aryloxy is optionally substituted with one or more R 17a substituents; Or R 17 、R 18 And the atom X5 to which they are attached together form a 3- to 10-membered heterocyclic group or a C3-C 10 cycloalkyl group, and the 3- to 10-membered heterocyclic group or C3-C 10 cycloalkyl group is optionally substituted by one or more R 17a substituents; R 17a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH or C6-C 10 aryl; R 20 selected from the following groups optionally substituted by one or more R 20a groups: 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclic group; R 20a selected from F, Cl, Br, I, OH, CN, ═O, NO2, NH2, SH, C1-C 10 alkyl, C1-C 10 alkoxy, C3-C 10 cycloalkyl or a 3- to 10-membered heterocyclic group; the C1-C 10 alkyl, C1-C 10 alkoxy, C3-C 10 cycloalkyl or a 3- to 10-membered heterocyclic group is optionally substituted by one or more R 20b substituents; R 20b selected from F, Cl, Br, I, OH, CN, NO2, NH2 or SH; R 21 and R 22 and R 27 are independently selected from H or C1-C 10 alkyl, wherein the C1-C 10 alkyl is optionally substituted by one or more R 21a substituents; R 21a selected from F, Cl, Br, I, OH, CN, NO2, NH2 or SH; R 23 selected from H, CN or C1-C 10 alkyl group.

2. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof: R 1 selected from R 7 Selected from C1-C 10 alkyl, C3-C 10 cycloalkyl or 3- to 10-membered heterocyclic group, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl or 3- to 10-membered heterocyclic group is optionally substituted by one or more R 7a substituents; R 7a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH, C1-C 10 alkyl or C6-C 10 aryl; R 8 Selected from H, C1-C 10 alkyl or C3-C 10 cycloalkyl, wherein the C1-C 10 alkyl or C3-C 10 cycloalkyl is optionally substituted by one or more R 8a substituents; R 8a selected from F, Cl, Br, I, OH, CN, ═O, NO2, NH2, SH, C1-C 10 alkyl or C2-C 10 alkenyl; R 9 selected from C1-C 10 alkyl, C3-C 10 cycloalkyl or 3-10 membered heterocyclic group, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl or 3-10 membered heterocyclic group is optionally substituted by one or more R 9a substituents; R 9a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH or C1-C 10 alkyl; R 10 selected from C1-C 10 alkyl, wherein the C1-C 10 alkyl is optionally substituted by one or more R 10a substituents; R 10a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH or C1-C 10 alkyl; R 11 and R 12 and R 13 are independently selected from C1-C 10 alkyl or C3-C 10 cycloalkyl, and the C1-C 10 alkyl or C3-C 10 cycloalkyl is optionally substituted with one or more R 11a substituents; or R 11 and R 12 together with the atoms to which they are attached form a 3- to 10-membered heterocyclic group, which 3- to 10-membered heterocyclic group is optionally substituted with one or more R 11a substituents; R 11a selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH or C1-C 10 alkyl; R 2 、R 3 、R 4 are independently selected from H, F, Cl, Br, I, OH, CN, NO2, NH2 or C1-C 10 alkyl; L is selected from X2 is CR 15 ; Y2 is N; Z2 is S; R 15 selected from H, F, Cl, Br, I, OH or CN; R 5 selected from n is selected from 0 or 1; X5 is selected from N or CR 21 ; Y5 and Y6 are independently selected from NH or CHR 22 ; Z5 and Z6 are independently selected from O or NR 23 ; R 17 、R 18 、R 25 、R 26 are independently selected from H, C1-C 10 alkyl, C3-C 10 cycloalkyl or C6-C 10 aryloxy, wherein the C1-C 10 alkyl, C3-C 10 cycloalkyl or C6-C 10 aryloxy is optionally substituted with one or more R 17a substituents; Or R 17 , R 18 Together with the atom X5 to which they are attached, form a 3- to 10-membered heterocyclic group or a C3-C 10 cycloalkyl group, and the 3- to 10-membered heterocyclic group or C3-C 10 cycloalkyl group is optionally substituted by one or more R 17a substituents; R 17a Selected from F, Cl, Br, I, OH, CN, NO2, NH2, SH or C6-C 10 aryl; R 20 selected from the following groups optionally substituted by one or more R 20a groups: pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, pyridazinyl, benzopyrazolyl, pyridinopyrazolyl or dihydropyridyl; R 20a selected from F, Cl, Br, I, OH, CN, ═O, NO2, NH2, SH, C1-C 10 alkyl, C3-C 10 cycloalkyl or a 3- to 10-membered heterocyclic group; the C1-C 10 alkyl, C1-C 10 alkoxy, C3-C 10 cycloalkyl or a 3- to 10-membered heterocyclic group is optionally substituted by one or more R 20b substituents; R 20b selected from F, Cl, Br, I, OH, CN, NO2, NH2 or SH; R 21 and R 22 and R 27 are independently selected from H or C1-C 10 alkyl, wherein the C1-C 10 alkyl is optionally substituted by one or more R 21a substituents; R 21a selected from F, Cl, Br, I, OH, CN, NO2, NH2 or SH; R 23 selected from H, CN or C1-C 10 alkyl group.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 7 selected from CF3, CH2F, isopropyl, neopentyl, cyclopropyl, cyclobutyl, tert-butyl, oxetanyl, or oxolanyl; R 8 selected from H, methyl, cyclopropyl or R 9 selected from methyl, isopropyl, cyclobutyl, oxetanyl or cyclopropyl; R 10 is tert-butyl; R 11 and R 12 are independently selected from methyl, ethyl or isopropyl; or R 11 together with R 12 and the atoms to which they are attached form together R 13 Selected from isopropyl or cyclopropyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 selected from 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 selected from 6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 1 Selected from 7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: L is 8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 17 、R 18 are independently selected from H, ethyl, phenoxy, isopropyl, benzyl or or R 17 、R 18 together with the atom X5 to which they are attached form cyclopropyl or phenyl-substituted cyclopropyl; R 25 、R 26 are independently selected from H, methyl, cyclopropyl or R 27 Selected from H or methyl; R 20 selected from pyrazolyl, pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, 1,2,3-triazolyl, pyridazinyl, triazinyl, benzopyrazolyl, pyridino-pyrazolyl or dihydropyridyl; X5 is selected from N or CH; Y5 and Y6 are independently selected from a chemical bond, NH or CH2; Z5 and Z6 are independently selected from O or N-CN.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 5 selected from 10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: R 1 selected from R 7 selected from C1-C6 alkyl, C3-C6 cycloalkyl, oxetanyl, oxolanyl or the C1-C6 alkyl, C3-C6 cycloalkyl, oxetanyl, oxolanyl or optionally substituted by one or more R 7a substituted; wherein R 2 、R 3 、R 4 、R 5 、R 7a 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 as defined in claim 1.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof: where L, R 1 , R 2 , R 3 , R 4 as defined in claim 1.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (IIa) or a pharmaceutically acceptable salt thereof: wherein R 1 , R 2 , R 3 , R 4 , L are as defined in claim 1; R 20 is selected from pyrazole, isoxazole, 1,2,3-triazole, pyridazine, benzopyrazole, pyridopyrazole or dihydropyridine.

13. A compound selected from the following or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, and a pharmaceutically acceptable excipient.

15. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing or treating lymphoma.

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