SHP2 inhibitor compound and application thereof

Abstract

The invention discloses an SHP2 inhibitor compound with a structure as shown in a formula (I) or pharmaceutically acceptable salts thereof, and the compound can be used as an SHP2 inhibitor and has relatively good anti-tumor activity.

Description

SHP2 inhibitor compounds and applications thereof Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a SHP2 inhibitor compound and application thereof. Background Art

[0002] SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPNl1 gene that contributes to a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 participates in signaling through the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositide 3-kinase-AKT pathways.

[0003] In the basal state, SHP2 is normally autoinhibited due to an intramolecular interaction between its N-terminal SH2 (N-SH2) domain and its catalytic (PTP) domain, thereby blocking access to the catalytic site. Activation of proteins that interact with the SH2 domain induces a conformational change that reverses this inhibition and allows substrate access to the catalytic site. Mutations in the PTPN11 gene that affect residues in the N-SH2 or PTP domain involved in the basal inhibition of SHP2 produce more readily activated forms of the SHP2 protein that result in unregulated or increased SHP2 activity. Such activated mutants of SHP2 are associated with developmental disorders such as Noonan syndrome, in which nearly all mutant forms of SHP2 display increased PTP activity. Therefore, there is a need for SHP2 phosphatase inhibitor compounds and methods of using such compounds to treat cancer and other conditions.

[0004] Gain-of-function SHP2 mutations lead to increased phosphatase activity, resulting in Noonan syndrome, as well as various forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) and multiple solid tumors (e.g., lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, and prostate cancer). Therefore, SHP2 is a potential therapeutic target for a variety of cancers, and the development of SHP2 inhibitors is attracting increasing attention. Therefore, the discovery and search for SHP2 inhibitors with good druggability has become a hot target in industry and academia. Currently, no SHP2 inhibitors have been approved for marketing, so there is still a clinical need to explore highly active SHP2 inhibitors.

[0005] Summary of the Invention

[0006] The present invention provides a novel SHP2 inhibitor compound and application thereof. In order to solve the technical problem of the present invention, the present invention provides the following technical solutions.

[0007] Compounds having the structure of formula (I), and pharmaceutically acceptable salts, stereoisomers, isotope isomers, solvates, and hydrates thereof:

[0008] Wherein, X1, X3, X4, and X5 each independently represent CR a , O, S or N;

[0009] Among them, X2 represents CR a R b or NR a ;

[0010] Wherein, Cy1 represents a 4-14 membered saturated or unsaturated carbon ring or a 4-14 membered saturated or unsaturated heterocyclic ring; and the Cy1 can be arbitrarily replaced by 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0011] Wherein, Cy2 represents a 4-14 membered saturated or unsaturated carbon ring or a 4-14 membered saturated or unsaturated heterocyclic ring, and the Cy2 can be arbitrarily replaced by 0-3 members selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0012] Among them, L1 means non-existent or NR a ;

[0013] Among them, L2 means absence, O, S, NR a or CR a R b ;

[0014] Among them, R L 、R L’ Each independently represents hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0015] or R L 、R L’ Together with the nitrogen atom connected thereto, it forms a 3-10 membered saturated or unsaturated ring, and in addition to the nitrogen atom, the ring may optionally contain 0-2 heteroatoms selected from O, N, and S, and further, the ring may also be arbitrarily substituted with 0-3 heteroatoms selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2Ra substituted by a substituent;

[0016] Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, and the alkyl or cycloalkyl can be arbitrarily substituted by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent.

[0017] In the preferred technical solution of the structure of formula (I), wherein X1 represents N or CR a , where R a represents hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl.

[0018] In the preferred technical solution of the structure of formula (I), X2 represents CH2 or NH.

[0019] In the preferred technical solution of the structure of formula (I), X3 represents N or CH.

[0020] In the preferred technical solution of the structure of formula (I), X4 represents N or CH.

[0021] In the preferred technical solution of the structure of formula (I), X5 represents N or CH.

[0022] In the preferred technical solution of the structure of formula (I), wherein Cy1 represents a 6-10 membered aryl or a 5-10 membered heteroaryl, and the Cy1 can be arbitrarily replaced by 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent.

[0023] In the preferred technical solution of the structure of formula (I), wherein Cy1 represents Phenyl, pyridyl, thienyl, pyrrolyl, pyridonyl, pyrazinyl, piperidinyl, pyridazinyl, imidazolyl, thiazolyl, oxazolyl, benzopyridinyl, indolyl, benzopiperidinyl, benzopiperazinyl, benzindolyl, benzothiazolyl, benzopyrrolyl, benzothienyl, benzoxazolyl, benzimidazolyl, pyridopiperidinyl, pyridopiperazinyl, pyridothilyl, pyridothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridoxazolyl, pyridoimidazolyl, and the Cy1 can be arbitrarily replaced by 0-3 selected from the group consisting of: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent.

[0024] In the preferred technical solution of the structure of formula (I), wherein Cy1 represents

[0025] In the preferred technical solution of the structure of formula (I), wherein Cy1 represents phenyl or pyridyl, and the Cy1 can be arbitrarily replaced by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a replaced.

[0026] In the preferred technical solution of the structure of formula (I), Cy2 represents the following group:

[0027] Where A represents (CR a R b ) n ;

[0028] Where Y1 represents N or CR T ;

[0029] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Each independently represents hydrogen, C1-C6 alkyl, halogen, OR a ;

[0030] or R 1 、R 2 Together with the carbon atom to which it is attached, they form a 3-6 membered ring;

[0031] or R 3 、R 4 Together with the carbon atom to which it is attached, they form a 3-6 membered ring;

[0032] or R 5 、R 6 Together with the carbon atom to which it is attached, they form a 3-6 membered ring;

[0033] or R 7 、R 8 Together with the carbon atom to which it is attached, they form a 3-6 membered ring;

[0034] Among them, R T represents hydrogen, hydroxyl, halogen, C1-C6 alkyl or 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a、-S(O)3R a 、-S(O)2R a The substituted 6-10 membered aryl group or 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted 5-10 membered heteroaryl;

[0035] Here, n represents an integer of 0, 1, or 2.

[0036] In a preferred technical solution of the structure of formula (I), L1 represents absence or NH.

[0037] In the preferred technical solution of the structure of formula (I), wherein R L 、R L’ Each independently represents hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl or optionally substituted by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a C3-C substituted by a substituent 10 Cycloalkyl, 6-10 membered aryl.

[0038] In the preferred technical solution of the structure of formula (I), wherein R L Represents hydrogen.

[0039] In the preferred technical solution of the structure of formula (I), wherein R L’ represents hydrogen or optionally substituted by 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a C3-C substituted by a substituent 10 Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.

[0040] In the preferred technical solution of the structure of formula (I), wherein R L’ represents phenyl, pyridyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, piperidinyl, pyridazinyl, and said R L’ Randomly 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a substituted by a substituent.

[0041] In addition, the present invention provides a compound having the structure of formula (II), and its pharmaceutically acceptable salts, stereoisomers, isotope isomers, solvates, and hydrates:

[0042] Wherein, X1, X3, X4, and X5 each independently represent CR a , O, S or N;

[0043] Among them, X2 represents CR a R b or NR a ;

[0044] Wherein, Cy1 represents a 4-14 membered saturated or unsaturated carbon ring or a 4-14 membered saturated or unsaturated heterocyclic ring; and the Cy1 can be arbitrarily replaced by 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NRa R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0045] Among them, L1 means non-existent or NR a ;

[0046] Among them, L2 means absence, O, S, NR a or CR a R b ;

[0047] Among them, R L 、R L’ Each independently represents hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0048] or R L 、R L’ Together with the nitrogen atom connected thereto, it forms a 3-10 membered saturated or unsaturated ring, and in addition to the nitrogen atom, the ring may optionally contain 0-2 heteroatoms selected from O, N, and S, and further, the ring may also be arbitrarily substituted with 0-3 heteroatoms selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)ORa 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0049] Where Y1 represents N or CR T ;

[0050] Among them, R T represents hydrogen, hydroxyl, halogen, C1-C6 alkyl or 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a The substituted 6-10 membered aryl group or 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted 5-10 membered heteroaryl;

[0051] Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, C3-C 10Cycloalkyl, and the alkyl or cycloalkyl can be arbitrarily substituted by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0052] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Each independently represents hydrogen, C1-C6 alkyl, halogen, OR a .

[0053] In the preferred technical solution of the structure of formula (II), wherein X1 represents N or CR a , where R a represents hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl.

[0054] In the preferred technical solution of the structure of formula (II), X2 represents CH2 or NH.

[0055] In the preferred technical solution of the structure of formula (II), X3 represents N or CH.

[0056] In the preferred technical solution of the structure of formula (II), X4 represents N or CH.

[0057] In the preferred technical solution of the structure of formula (II), X5 represents N or CH.

[0058] In the preferred technical solution of the structure of formula (II), wherein Cy1 represents a 6-10 membered aryl group or a 5-10 membered heteroaryl group, and the Cy1 can be arbitrarily replaced by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C 10Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent.

[0059] In the preferred technical solution of the structure of formula (II), wherein Cy1 represents Phenyl, pyridyl, thienyl, pyrrolyl, pyridonyl, pyrazinyl, piperidinyl, pyridazinyl, imidazolyl, thiazolyl, oxazolyl, benzopyridinyl, indolyl, benzopiperidinyl, benzopiperazinyl, benzindolyl, benzothiazolyl, benzopyrrolyl, benzothienyl, benzoxazolyl, benzimidazolyl, pyridopiperidinyl, pyridopiperazinyl, pyridothilyl, pyridothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridoxazolyl, pyridoimidazolyl, and the Cy1 can be arbitrarily replaced by 0-3 selected from the group consisting of: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent.

[0060] In the preferred technical solution of the structure of formula (II), wherein Cy1 represents

[0061] In the preferred technical solution of the structure of formula (II), wherein Cy1 represents phenyl or pyridyl, and the Cy1 can be arbitrarily replaced by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C10 Cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a replaced.

[0062] In addition, the present invention provides a compound having a structure of formula (III), and pharmaceutically acceptable salts, stereoisomers, isotope isomers, solvates, and hydrates thereof:

[0063] Wherein, X1, X3, X4, and X5 each independently represent CR a , O, S or N;

[0064] Among them, X2 represents CR a R b or NR a ;

[0065] Wherein, Cy1 represents a 4-14 membered saturated or unsaturated carbon ring or a 4-14 membered saturated or unsaturated heterocyclic ring; and the Cy1 can be arbitrarily replaced by 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0066] Where A represents (CR a R b ) n ;

[0067] Wherein, n represents an integer of 0, 1, or 2;

[0068] Among them, L1 means non-existent or NR a ;

[0069] Among them, L2 means absence, O, S, NR a or CR a R b ;

[0070] Among them, R L 、R L’ Each independently represents hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0071] or R L 、R L’ Together with the nitrogen atom connected thereto, it forms a 3-10 membered saturated or unsaturated ring, and in addition to the nitrogen atom, the ring may optionally contain 0-2 heteroatoms selected from O, N, and S, and further, the ring may also be arbitrarily substituted with 0-3 heteroatoms selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0072] Where Y1 represents N or CR T ;

[0073] Among them, R Trepresents hydrogen, hydroxyl, halogen, C1-C6 alkyl or 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a The substituted 6-10 membered aryl group or 0-3 selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted 5-10 membered heteroaryl;

[0074] Among them, R a 、R b Each independently represents hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, and the alkyl or cycloalkyl can be arbitrarily substituted by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)Ra 、-S(O)3R a 、-S(O)2R a substituted by a substituent;

[0075] Among them, R 1 、R 2 、R 3 、R 4 Each independently represents hydrogen, C1-C6 alkyl, halogen, OR a .

[0076] In the preferred technical solution of the structure of formula (III), wherein X1 represents N or CR a , where R a represents hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl.

[0077] In the preferred technical solution of the structure of formula (III), X2 represents CH2 or NH.

[0078] In the preferred technical solution of the structure of formula (III), X3 represents N or CH.

[0079] In the preferred technical solution of the structure of formula (III), X4 represents N or CH.

[0080] In the preferred technical solution of the structure of formula (III), X5 represents N or CH.

[0081] In the preferred technical solution of the structure of formula (III), A represents CH2 or CH2CH2.

[0082] In the preferred technical solution of the structure of formula (III), wherein Cy1 represents a 6-10 membered aryl group or a 5-10 membered heteroaryl group, and the Cy1 can be arbitrarily replaced by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent.

[0083] In the preferred technical solution of the structure of formula (III), wherein Cy1 represents Phenyl, pyridyl, thienyl, pyrrolyl, pyridonyl, pyrazinyl, piperidinyl, pyridazinyl, imidazolyl, thiazolyl, oxazolyl, benzopyridinyl, indolyl, benzopiperidinyl, benzopiperazinyl, benzindolyl, benzothiazolyl, benzopyrrolyl, benzothienyl, benzoxazolyl, benzimidazolyl, pyridopiperidinyl, pyridopiperazinyl, pyridothilyl, pyridothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridoxazolyl, pyridoimidazolyl, and the Cy1 can be arbitrarily replaced by 0-3 selected from the group consisting of: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O)3R a 、-S(O)2R a substituted by a substituent.

[0084] In the preferred technical solution of the structure of formula (III), wherein Cy1 represents

[0085] In the preferred technical solution of the structure of formula (III), wherein Cy1 represents phenyl or pyridyl, and the Cy1 can be arbitrarily replaced by 0-3 groups selected from: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, nitro, -OR a NR a R b 、-SR a replaced.

[0086] Preferably, the present invention provides the following compound or a pharmaceutically acceptable salt thereof, having the following structure:

[0087] definition

[0088] Unless otherwise indicated, the compounds of the present invention may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.

[0089] Unless otherwise indicated, the following terms used in this patent specification and claims have the meanings discussed below. Furthermore, many of the groups defined herein may be optionally substituted. The list of typical substituents in this definitions section is provided as an example and is not intended to limit the substituents defined elsewhere in this patent specification and claims.

[0090] The term "alkyl" refers to a saturated aliphatic hydrocarbon group or linker, comprising straight and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. "Lower alkyl" particularly refers to an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups include -(CH2)3-, methyl, trifluoromethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Alkyl groups may be substituted or unsubstituted. Typical substituents include cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, thiol, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, C-carboxyl, O-carboxyl, nitro, silanyl, amino, and -NRxRy, wherein Rx and Ry are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl, and combined 5- or 6-membered heterocyclyl rings.

[0091] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0092] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkynyl" group contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.

[0093] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms attached via a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0094] The term "cycloalkyl" refers to a 3- to 8-membered all-carbon monocyclic or bicyclic ring structure, an all-carbon 5-membered / 6-membered or 6-membered / 6-membered fused bicyclic ring, or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares at least one adjacent carbon atom with another ring in the system), wherein one or more rings may contain one or more double bonds, but none of such rings have a complete conjugated π-electron system, or the bicyclic rings may form a spirocycle by sharing a carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, and cycloheptatriene. Bicyclic cycloalkyl groups include bridged, spiro, or fused cycloalkyl groups. Illustrative examples of cycloalkyl groups are derived from, but are not limited to, the following:

[0095] "Aryl" refers to an all-carbon monocyclic ring or fused-ring polycyclic group of 6 to 12 carbon atoms with a complete conjugated π-electron system. Examples of aryl groups are, but are not limited to, phenyl, naphthyl, and anthracenyl. Aryl groups may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, sulfinyl, sulfonyl, amino, and -NR a R b , where R aWith R b As defined above. Aryl-fused saturated or unsaturated cycloalkyl / saturated or unsaturated heterocycloalkyl can be considered as special substituents of aryl, typical examples of which include but are not limited to:

[0096] "Heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O and S, the remaining ring atoms being C, and furthermore, having a complete conjugated π-electron system.Examples of typical heteroaryl groups are, but are not limited to, acridinyl, azetidinyl, azcinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, dihydroindole , indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolidinyl, oxazolopyridinyl, oxazolidinyl, perylene, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiol, phenoxazinyl , phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-"; the present invention also includes fused ring and spiro compounds containing, for example, the above-mentioned heterocycles. The term "heteroaryl" may also include fused saturated or unsaturated cycloalkyl / saturated or unsaturated heterocycloalkyl groups, which can be regarded as special substituents of heteroaryl. Typical examples include, but are not limited to, pyridine fused with the following groups:

[0097] The pharmaceutically acceptable heteroaryl group is sufficiently stable to be attached to the compound of the present invention, formulated into a pharmaceutical composition, and subsequently administered to a patient in need thereof.

[0098] Unless otherwise defined, the definitions of the substituents of the present invention are independent of each other and not related to each other. For example, for a substituent R a (or R b ), they are independent of each other in the definitions of different substituents. Specifically, for R a (or R b ) When a definition is selected in a substituent, it does not mean that the R a (or R b ) has the same definition in other substituents. More specifically, for example (listing only non-exhaustive) for NR a R b In the case of R a (or R b ) is selected from hydrogen, it does not mean that in -C(O)-NR a R b Middle R a (or R b ) must be hydrogen.

[0099] "Halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl," which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.

[0100] "Haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group as defined above with the specified number of carbon atoms attached via an oxygen bridge. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" refers to a haloalkyl group as defined above with the specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0101] In the present disclosure, when referring to certain substituent groups, the expression Cx1-Cx2 is used, which means that the number of carbon atoms in the substituent group may be x1 to x2. For example, C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-C8 means that the group contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms, C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms, C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms, C2-C6 means that the group contains 2, 3, 4, 5 or 6 carbon atoms, and C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.

[0102] In the present disclosure, when referring to a cyclic group (such as an aryl, heteroaryl, cycloalkyl and heterocycloalkyl), the expression "x1-x2 membered ring" is used, which means that the number of ring atoms of the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; the 3-6 membered ring means that the cyclic group can be a 3-, 4-, 5- or 6-membered ring, and the number of its ring atoms can be 3, 4, 5 or 6; the 3-8 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7- or 8-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7 or 8; the 3-9 membered ring means that the cyclic group can be a 3-, 4, 5, 6, 7, 8 or 9-membered ring, and the number of its ring atoms can be 3, 4, 5, 6, 7, The term "4-7 membered ring" refers to a 4-, 5-, 6-, or 7-membered ring having 4, 5, 6, or 7 ring atoms; a 5-, 8-, or 5-membered ring refers to a 5-, 6-, 7-, or 8-membered ring having 5, 6, 7, or 8 ring atoms; a 5-, 12-, or 5-membered ring refers to a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; and a 6-, 12-, or 6-membered ring refers to a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring having 6, 7, 8, 9, 10, 11, or 12 ring atoms. The ring atoms may be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, such as heteroatoms selected from N, O and S.

[0103] In the context of the present invention, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0104] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0105] Where nitrogen atoms (e.g., amines) are present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the invention. Thus, the shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxide to obtain the derivatives of the invention.

[0106] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R groups, then said group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0107] The term "patient" as used herein refers to an organism to be treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., mice, apes / monkeys, horses, cows, pigs, dogs, cats, etc.) and most preferably refer to humans.

[0108] The term "effective amount" as used herein means the amount of a drug or pharmaceutical agent (i.e., a compound of the present invention) that will cause a biological or medical response of a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received the above amount. An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited by a specific formulation or route of administration. The term also includes within its scope an effective amount that enhances normal physiological function.

[0109] The term "treatment" as used herein includes its broad meaning, covering therapeutic treatment and / or prophylactic treatment of a subject. Specifically, the "treatment" includes any treatment that leads to the alleviation, suppression, elimination and improvement and / or prevention of a condition, disease, disorder, etc., such as alleviating, reducing, regulating, improving, eliminating, preventing, preventing or improving its symptoms. The therapeutic treatment includes alleviating, suppressing or improving the symptoms or conditions of the disease; suppressing the occurrence of complications; improving potential metabolic syndrome; suppressing the occurrence of the disease or symptoms, such as controlling the development of the disease or condition; alleviating the disease or symptoms; reducing the disease or symptoms; alleviating complications caused by the disease or symptoms, or treating signs caused by the disease or symptoms. The prophylactic treatment includes prior treatment to prevent, block or delay, slow down the occurrence or development of the disease or condition or reduce the severity of the disease or condition.

[0110] Likewise, "therapeutic agent" also includes agents or reagents that have therapeutic and / or prophylactic effects on a subject.

[0111] The terms "pharmaceutically acceptable" or "pharmaceutically acceptable" are used herein to refer to those compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response and / or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0112] Specific pharmaceutical and medical terms

[0113] The term "cancer," as used herein, refers to an abnormal, uncontrolled growth of cells that can metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or blood tumors (such as non-leukemic leukemias).

[0114] The term "combination administration" or its like, as used herein, refers to the administration of several selected therapeutic agents to a single patient, using the same or different administration routes at the same or different times.

[0115] The terms "enhance" or "enhancing," as used herein, refer to the ability to increase or prolong the potency or duration of a desired effect. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" refers to the ability of the drug to increase or prolong the potency or duration of the drug in a system. "Potentiation," as used herein, refers to the ability of another therapeutic agent to maximize its potency in an ideal system.

[0116] The term "immune disease" refers to a disease or condition that results from an adverse or deleterious response to an endogenous or exogenous antigen. The result is usually cellular dysfunction, or the resulting damage and malfunction of, or destruction of, organs or tissues that may be responsible for the immune condition.

[0117] The terms "kit" and "product packaging" are synonymous.

[0118] The terms "subject," "subject," or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals such as humans, non-human primates such as gorillas, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and experimental animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred embodiment, the mammal is a human.

[0119] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration, regardless of whether the administration is fixed or temporary, continuous or intermittent, and can be attributed to or related to the administration.

[0120] Route of administration

[0121] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, auricular, nasal, and topical administration. In addition, parenteral administration, by way of example only, includes intramuscular, subcutaneous, intravenous, intramedullary, intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0122] The administration of the compounds of the present invention can be local. In certain embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In another embodiment, the drug is administered via a targeted drug delivery system. For example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are selectively directed to and absorbed by a specific organ.

[0123] Pharmaceutical composition and dosage

[0124] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., a lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate, or stearic acid), or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0125] The term "pharmaceutical composition" means a composition comprising a compound of the present invention and optionally other pharmaceutically acceptable carriers. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form.

[0126] The pharmaceutical compositions of the present invention may comprise a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more optional pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one or more other therapeutic agents. The compounds of the present invention may be administered in any suitable manner for any of the above-mentioned uses, for example, orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membrane, such as by inhalation spray; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories; or by intratumoral injection. They can be administered alone, but are typically administered using a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.

[0127] Pharmaceutically acceptable carriers are formulated based on a variety of factors well within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.

[0128] Such carriers may include a variety of ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binding agents, etc. Descriptions of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Preps.

[0129] Of course, the dosage regimen of the compounds of the present invention will vary depending on known factors, such as the pharmacodynamic properties of the specific agent and its mode and route of administration; the species, age, sex, health condition, medical condition, and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect. As a general guide, when used for the specified effect, the daily oral dose of each active ingredient should be from about 0.001 mg / day to about 10-5000 mg / day, preferably from about 0.01 mg / day to about 1000 mg / day, and most preferably from about 0.1 mg / day to about 250 mg / day. The most preferred intravenous dose during a constant rate infusion should be from about 0.01 mg / kg / minute to about 10 mg / kg / minute. The compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three times, or four times daily.

[0130] The compounds are usually administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected according to the intended administration form (e.g., oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.

[0131] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0132] The present invention includes within its scope pharmaceutical compositions comprising (alone or in combination with a pharmaceutically acceptable carrier) a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0133] Regardless of the route of administration selected, the compound of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical composition of the present invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.

[0134] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0135] The selected dosage level will depend upon a variety of factors, including the activity of the specific compound of the present invention being employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the specific compound being employed; the rate and extent of absorption; the duration of the treatment; other drugs, compounds and / or substances used in combination with the specific compound being employed; and factors well known in the medical arts such as the age, sex, weight, condition, general health and prior medical history of the patient being treated.

[0136] A doctor or veterinarian with ordinary skills in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, in order to achieve the desired therapeutic effect, the physician or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than the desired level, and gradually increase the dosage until the desired effect is achieved. Typically, a suitable daily dose of the compound of the present invention will be the amount of the compound at the lowest dose that effectively produces a therapeutic effect. Such an effective dose generally depends on the above factors. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compound of the present invention for patients range from about 0.01 to about 50 mg / kg body weight / day. If necessary, the active compound of the effective daily dose can be administered separately at appropriate intervals in two, three, four, five, six or more subdoses in the middle of the day, optionally in unit dosage form. In certain aspects of the present invention, medication is administered once a day.

[0137] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0138] Kit / Product Packaging

[0139] Kits / product packaging are also described herein for use in treating the aforementioned indications. These kits can consist of a carrier, a pouch, or a container box, each of which can be divided into compartments to accommodate one or more containers, such as vials, test tubes, and the like, each containing a single component of the method. Suitable containers include bottles, vials, syringes, and test tubes. The containers can be made of acceptable materials such as glass or plastic.

[0140] For example, a container may contain one or more compounds described herein, either as a pharmaceutical composition or in admixture with other ingredients described herein. The container may have a sterile delivery port (e.g., an IV bag or bottle with a stopper pierceable by a hypodermic needle). Such a kit may include a compound and instructions, labeling, or operating instructions for use as described herein.

[0141] A typical kit may include one or more containers, each containing one or more materials (e.g., reagents, concentrated stock solutions, and / or instruments) to suit the commercialization and user needs of the compound. These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, delivery devices, bags, containers, bottles, and / or test tubes, accompanied by a list of contents and / or instructions for use, including instructions for use within the packaging. The complete set of instructions should be included.

[0142] The label may be displayed on or closely associated with the container. Labeling on a container means that the label letters, numbers, or other features are affixed, molded, or engraved onto the container. Labels may also appear inside a container or shipping box containing multiple containers, such as in a product insert. A label may indicate a specific therapeutic use of the contents. A label may also indicate instructions for use of the contents, such as those described in the above methods.

[0143] All features described in this specification (including any claims, abstracts and figures), and / or all steps involved in any method or process, may exist in any combination, unless certain features or steps are mutually exclusive in the same combination.

[0144] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features.

[0145] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0146] The units used in the present invention for weight-volume percentages are well known to those skilled in the art, for example, referring to the weight of solute in 100 ml of solution. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0147] The present invention provides a method for synthesizing the compound.

[0148] The following synthetic intermediates are useful in the practice of the present invention.

[0149] Intermediate 1

[0150] Intermediate 1 was synthesized according to https: / / doi.org / 10.1021 / acs.jmedchem.1c01132.

[0151] Intermediate 2

[0152] Intermediate 2 was synthesized with reference to patent WO 2021 / 033153 A1.

[0153] Step 1

[0154] 6-Chloro-1H-pyrazolo[3,4-b]pyrazine (7.0 g, 45.29 mmol) was dissolved in N,N-dimethylformamide (70 ml) at room temperature. N-iodosuccinimide (20.4 g, 90.58 mmol) was added and the mixture was allowed to react at 80°C overnight. The reaction mixture was cooled to room temperature and poured into 500 ml of ice water. Sodium sulfite (11.41 g, 45.29 mmol) was added and stirred for 0.5 hour. The mixture was filtered and the filter cake was washed with petroleum ether / ethyl acetate (10 / 1) and dried to obtain 11.2 g of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine as a yellow solid in an 88.18% yield. MS m / z: 280.9 [M+H].

[0155] Step 2

[0156] 6-Chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (11.2 g, 39.94 mmol) was dissolved in 60 ml of tetrahydrofuran and 60 ml of N,N-dimethylformamide at room temperature. p-Toluenesulfonic acid (0.69 g, 3.99 mmol) and 3,4-dihydro-2H-pyran (16.77 g, 199.7 mmol) were added. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with 300 ml of water and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to afford 9.9 g of 6-chloro-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine as a white solid in a yield of 62.75%. MS m / z: 365.0 [M+H].

[0157] Step 3

[0158] 6-Chloro-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine (7.7 g, 21.12 mmol) was dissolved in dichloromethane / methanol (50 / 150 ml) at room temperature. Silver nitrate (1.79 g, 12.53 mmol) was added. The mixture was heated to 40°C under argon. Ammonium persulfate solution (13.5 g, 59.14 mmol, dissolved in 50 ml of water) was slowly added dropwise over 0.5 hours. The mixture was maintained at 40°C for 2 hours. The reaction mixture was cooled to room temperature and neutralized to neutrality by adding saturated sodium bicarbonate. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to yield 2.5 g of [6-chloro-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol as a white solid in a 30% yield. MS m / z: 395.0 [M+H].

[0159] Intermediate S

[0160] Step 1

[0161] To a solution of 3-chloro-4-iodopyridin-2-amine (17 g, 66.81 mmol) and methyl 3-mercaptopropionate (8.8 g, 73.49 mmol) in dioxane (250 mL) were added palladium acetate (750 mg, 3.34 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.93 g, 3.34 mmol), and N,N-diisopropylethylamine (17.27 ml, 133.62 mmol). The atmosphere was purged with nitrogen three times, then the temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. The product formation was monitored by TLC, and the reaction solution was concentrated in vacuo. The residue was diluted with water (350 mL), then extracted twice with ethyl acetate (500 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to give 15 g of methyl 3-((2-amino-3-chloropyridin-4-yl)thio)propanoate (135_2) as a light yellow solid in a yield of 91%.

[0162] Step 2

[0163] Under nitrogen at room temperature, sodium ethoxide (7.86 ml, 1 M) was slowly added to a solution of methyl 3-((2-amino-3-chloropyridin-4-yl)thio)propanoate (5 g, 20.27 mmol) in tetrahydrofuran (80 ml). The mixture was allowed to react at room temperature for 30 minutes, until the reaction system became light yellow and transparent. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. 25 mL of dichloromethane was added to the reaction solution, followed by continued stirring for 5 minutes. A white precipitate formed, which was then filtered. The filter cake was collected and dried, and 1.5 mL of water was added. 1 M hydrochloric acid solution was slowly added dropwise until the pH reached 6. Filtering afforded 2.6 g of 2-amino-3-chloropyridine-4-thiol (135_3) as a white solid in a yield of 79.8%. MS m / z = 161.0 [M+H], 1 H NMR (400MHz, DMSO-d6) δ = 11.43 (br s, 1H), 7.08 (d, 1H, J = 6.9Hz), 6.72 (s, 2H), 6.67 (d, 1H, J = 6.9Hz)

[0164] Step 3

[0165] To a solution of 2-amino-3-chloropyridine-4-thiol (500 mg, 3.11 mmol) and 6-chloro-3-iodo-1-tetrahydropyran-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (1.2 g, 3.05 mmol) in dioxane (15 ml) were added 1,10-phenanthroline (560.98 mg, 3.11 mmol), potassium phosphate (1321.57 mg, 6.23 mmol), and cuprous iodide (592.86 mg, 3.11 mmol) at room temperature. The atmosphere was purged with nitrogen three times, and the reaction was then carried out at 80°C for 5 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The residue was diluted with water (150 mL) and then extracted twice with ethyl acetate (120 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to afford 430 mg of 3-(2-amino-3-chloropyridin-4-yl)thio)-6-chloro-1-tetrahydropyran-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (Int S) as a white solid in a 32.4% yield. MS m / z = 427.0 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 7.58 (d, J = 5.4Hz, 1H), 6.45 (s, 2H), 6.05 (dd, J = 9.9, 1.8Hz, 1H), 5.74-5.77 (m, 1H), 5.59 (t, J = 6.0Hz, 1H), 4.7 6(d,J=6.0Hz,2H),3.97(d,J=11.5Hz,1H),3.73-3.82(m,1H),2.39-2.47(m,1H),2.03(d,J=9.8Hz,2H),1.74-1.86(m,1H),1.60(s,2H).

[0166] The following synthetic schemes can be used in the practice of the present invention. Specific implementation method.

[0167] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0168] Example 1

[0169] Step 1

[0170] To a solution of N,N-dimethylformamide (20 ml) at 0°C was added 3,5-dichloro-2-(2,3-dichlorobenzoyl)pyrazine (Int 1) (963 mg, 2.99 mmol), tert-butylpiperazine-1-carboxylate (557 mg, 2.99 mmol), and potassium carbonate (827 mg, 5.98 mmol). Stirring was maintained at 0°C for 2 h under nitrogen. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was diluted twice with water (40 mL) and extracted twice with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 1:99 to 20:80) to afford tert-butyl 4-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]piperazine-1-carboxylate (54_3), 1.1 g, as a yellow solid in a yield of 78.0%. MS m / z: 415.0 [M-55]. 1 H NMR (400MHz, DMSO-d6) δ = 8.29 (s, 1H), 7.73 (dd, 1H, J = 1.8, 7.7Hz), 7.4-7.5 (m, 2H), 3.7-3.8 (m, 4H), 3.4-3.5 (m, 4H), 1.42 (s, 9H).

[0171] Step 2

[0172] To an ethanol solution (50 mL) at room temperature, tert-butyl 4-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]piperazine-1-carboxylate (54_3) (1 g, 2.12 mmol) and hydrazine hydrate (5.31 mL, 105.99 mmol) were added. The reaction was allowed to proceed at 80°C for 2 h under nitrogen. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo, and the residue was slurried with ethyl acetate (20 mL), filtered, and washed with ethyl acetate to afford tert-butyl 4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (Int 2), 900 mg, as a yellow solid in a 94.5% yield. MS m / z: 449.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 8.44 (s, 1H), 7.73 (m, 2H), 7.50 (t, 1H, J = 7.9Hz), 3.6-3.8 (m, 4H), 3.4-3.5 (m, 4H), 1.44 (s, 9H).

[0173] Step 3

[0174] To a dichloromethane (50 mL) solution at room temperature, tert-butyl 4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (Int 2) (900 mg, 2 mmol) and trifluoroacetic acid (9.84 mL, 86.28 mmol) were added. The reaction was stirred at room temperature under nitrogen for 1 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with dichloromethane (5 mL). The pH was adjusted to >7 with aqueous sodium carbonate solution, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phase was concentrated in vacuo to afford 700 mg of crude 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (Int 3) as a yellow solid in a yield of 99.8%. MS m / z: 349.1 [M+H].

[0175] Step 4

[0176] To a solution of (4-fluorophenyl)thiourea (54_1) (1.70 g, 9.99 mmol) and iodomethane (2.13 g, 14.98 mmol) in ethanol (20 ml, 100.0%) at room temperature, the mixture was heated to 90°C and refluxed for 3 h under nitrogen. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo, and the residue was diluted twice with ethyl acetate (10 mL) and then spin-dried to give crude N-(4-fluorophenyl)(methylthio)formimide (hydrogen iodide salt) (54_2), 1.80 g, as a yellow solid in a 97.8% yield, which was used directly in the next step. MS m / z: 185.0 [M+H].

[0177] Step 5

[0178] To a solution of isopropanol (5 ml) at room temperature was added 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (Int 3) (35 mg, 0.1 mmol), N-(4-fluorophenyl)(methylthio)carboximide (54_2) (22 mg, 0.12 mmol), and triethylamine (0.2 ml, 1.98 mmol). The mixture was heated to 90°C and refluxed for 18 h under nitrogen. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC (mobile phase: CH3CN:H2O containing 0.1% TFA = 1:99 to 90:10) and lyophilized to afford 8 mg of 4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (ZS5084-054) as a pale yellow solid in a yield of 16.5% and a purity of 98.86%. MS m / z: 485.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.53 (s, 1H), 9.62 (s, 1H), 8.48 (s, 1H), 7.93 (s, 2H), 7.7-7.8 (m,2H),7.51(t,1H,J=7.9Hz),7.31(d,4H,J=6.8Hz),3.9-4.0(m,4H),3.7-3.8(m,4H).

[0179] Example 2

[0180] Step 1

[0181] Tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate (56_1) (1.0 g, 4.46 mmol) was dissolved in dichloromethane (4 ml) in a reaction flask at room temperature. Trifluoroacetic acid (1 ml) was added dropwise and the mixture was allowed to react at room temperature for 2 h. LCMS analysis indicated the formation of the product, 3,5-dichloro-2-(2,3-dichlorobenzoyl)pyrazine (56_2). The reaction solution was concentrated and used directly in the next step. MS m / z: 125.1 [M+H].

[0182] Step 2

[0183] To a reaction flask at room temperature, 3,5-dichloro-2-(2,3-dichlorobenzoyl)pyrazine (56_2) (129 mg, 0.4 mmol), 4-cyano-4-methylpiperidin-1-trifluoroacetate (95 mg, 0.4 mmol), and dipotassium carbonate (276 mg, 2 mmol) were added. The mixture was dissolved in N,N-dimethylformamide (1 ml) and stirred at room temperature for 2 h. LCMS analysis revealed the formation of the product, 1-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-4-methylpiperidin-4-carbonitrile (56_3). The mixture was extracted with ethyl acetate, washed with water, and the organic phase was concentrated and used directly in the next step. MS m / z: 409.0 [M+H].

[0184] Step 3

[0185] 1-[6-Chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-4-methylpiperidine-4-carbonitrile (56_3) (200 mg, 0.49 mmol) was placed in a reaction flask at room temperature, dissolved in ethanol (1 ml), and hydrazine hydrate (1 ml, 19.98 mmol) was added. The temperature was raised to 60°C and stirred for 2 h. LCMS monitoring indicated the disappearance of the starting material and the product. The product was extracted with ethyl acetate, dried, concentrated, and purified by silica gel column chromatography using a mobile phase of petroleum ether:ethyl acetate (3:1). 190 mg of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carbonitrile (56_4) was obtained as a light yellow solid in a 100% yield. MS m / z: 387.1 [M+H].

[0186] Step 4

[0187] 1-[3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carbonitrile (56_4) (20 mg, 0.05 mmol) was added to a reaction flask and dissolved in methanol (5 ml). Hydrogen chloride gas was then introduced for 3 h at room temperature. LCMS analysis indicated the production of methyl 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidate (56_5). The reaction mixture was concentrated and used directly in the next step. MS m / z: 419.1 [M+H].

[0188] Step 5

[0189] 1-[3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (56_5) (40 mg, 0.1 mmol) was added to a reaction flask at room temperature, and 10 mL of a 7 M ammonia methanol solution was added. The mixture was allowed to react overnight at room temperature. LCMS analysis indicated the presence of product. The reaction solution was concentrated and further purified by preparative purification. 1-[3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (ZS5084-056) was obtained as a yellow solid (26.6 mg, 65.8% yield). MS m / z: 404.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ=13.44(s,1H),8.71(s,2H),8.66(s,2H),8.49(s,1H),7.75(dd,J=1.4,8.1H z,1H),7.50(t,J=7.8Hz,1H),3.81-3.70(m,4H),2.12-2.02(m,2H),1.78-1.69(m,2H),1.36(s,3H).

[0190] 3.7 mg of 1-(3-(2,3-dichlorophenyl)pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidine-4-carboxamide (ZS5084-056-6), yellow solid, yield 9%. MS m / z: 405.1 [M+H]. 1H NMR (400MHz, METHANOL-d4) δ = 8.33 (s, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.58 (d, J = 7.3Hz, 1H) ,7.43(t,J=7.8Hz,1H),4.20-4.12(m,2H),3.51(ddd,J=2.8,10.3,13.5Hz,2H),2.21(br d, J=14.4Hz, 2H), 1.60 (ddd, J=3.8, 10.1, 13.7Hz, 2H), 1.30 (s, 3H).

[0191] Example 3

[0192] Step 1

[0193] To a solution of N,N-dimethylformamide (15 ml) at room temperature, tert-butyl 4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (Int 2) (600 mg, 1.34 mmol) and N-bromosuccinimide (713 mg, 4.01 mmol) were added. The mixture was reacted under nitrogen atmosphere at room temperature for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was diluted twice with water (30 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 1:99 to 30:70). Finally, the residue was concentrated to afford tert-butyl 4-[5-bromo-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (57_1), 500 mg, as a yellow solid in a yield of 70.6%. MS m / z: 527.1 [M+H], 471.0 [M-55].

[0194] Step 2

[0195] To a solution of N,N-dimethylformamide (10 ml) at room temperature was added tert-butyl 4-[5-bromo-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (57_1) (461 mg, 0.87 mmol), (tributylstannyl)methanol (838 mg, 2.61 mmol), and tetrakis(triphenylphosphine)palladium (101 mg, 0.09 mmol). The atmosphere was purged with nitrogen three times, then the temperature was raised to 120°C and the reaction was allowed to proceed for 4 hours. The reaction was monitored by LCMS for completion. The reaction mixture was diluted with water (20 mL) and extracted three times with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 1:99 to 20:80). The crude product was lyophilized by Prep-HPLC to afford tert-butyl 4-[3-(2,3-dichlorophenyl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (57_2) as a yellow solid (100 mg, yield 23.9%). MS m / z: 479.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.85 (s, 1H), 7.83-7.63 (m, 2H), 7.56-7.48 (m, 1H), 5.71(s,1H),4.61(s,2H),3.59-3.50(m,4H),3.42-3.30(m,4H),1.44(s,9H).

[0196] Step 3

[0197] To a dichloromethane (2 ml) solution at room temperature, tert-butyl 4-[3-(2,3-dichlorophenyl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (57_2) (48 mg, 0.1 mmol) and trifluoroacetic acid (0.46 ml, 4.08 mmol) were added. Under nitrogen protection, the reaction was stirred at room temperature for 1 hour. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo, and the residue was concentrated in vacuo to give crude [3-(2,3-dichlorophenyl)-6-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (57_3), 37.9 mg, a yellow oil with a yield of 100%, which was used directly in the next step. MS m / z: 379.1 [M+H].

[0198] Step 4

[0199] To a solution of isopropanol (3 ml, 100.0%) at room temperature were added [3-(2,3-dichlorophenyl)-6-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (57_3) (38 mg, 0.1 mmol), N-(4-fluorophenyl)(methylthio)carboximide (hydrogen iodide salt) (54_2) (74 mg, 0.4 mmol), and triethylamine (1 ml, 9.88 mmol). The mixture was heated to 90°C and refluxed for 2 h under nitrogen atmosphere. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC (mobile phase: CH3CN:H2O containing 0.1% TFA = 1:99 to 90:10) and lyophilized to afford 28 mg of 4-[3-(2,3-dichlorophenyl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (ZS5084-057) as a yellow solid in a yield of 54.33% and a purity of 98.5%. MS m / z: 515.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.89 (s, 1H), 9.7 (s, 1H), 7.9-8.0 (m, 2H), 7.8-7.8 (m, 1H), 7.7-7.8 ( m,1H),7.5-7.6(m,1H),7.3-7.4(m,5H),5.56(s,1H),4.7(s,2H),3.7-3.8(m,4H),3.61(m,4H).

[0200] Example 4

[0201] Step 1

[0202] 1-Benzyl-4-phenylpiperidine-4-carbonitrile (58_1) (1.0 g, 3.62 mmol) and palladium hydroxide (100 mg, 0.72 mmol) were added to a reaction flask at room temperature. Methanol (10 ml) was added and the H₂ atmosphere was exchanged three times. The reaction was allowed to proceed overnight at room temperature. LCMS confirmed the production of the product. The reaction mixture was filtered, the mother liquor was concentrated, and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol = 20:1 to afford 160 mg of 4-phenylpiperidine-4-carbonitrile (58_2) as an oil in a 23.7% yield. MS m / z: 187.1 [M+H].

[0203] Step 2

[0204] To a reaction flask at room temperature were added 3,5-dichloro-2-(2,3-dichlorobenzoyl)pyrazine (100 mg, 0.31 mmol), 4-phenylpiperidine-4-carbonitrile (58_2) (45 mg, 0.24 mmol), and potassium carbonate (85 mg, 0.62 mmol). The mixture was dissolved in N,N-dimethylformamide (0.4 ml) and stirred overnight at room temperature. LCMS monitored the product formation. Extraction with ethyl acetate and washing with water was performed. The organic phase was concentrated and purified by silica gel column chromatography to afford 65 mg of 1-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-4-phenylpiperidine-4-carbonitrile (58_3) as a yellow solid in a yield of 44.4%. MS m / z: 471.1 [M+H].

[0205] Step 3

[0206] 1-[6-Chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-4-phenylpiperidine-4-carbonitrile (58_3) (20 mg, 0.04 mmol) was placed in a reaction flask at room temperature, dissolved in ethanol (0.1 ml), and hydrazine hydrate (0.1 ml, 2 mmol) was added. The mixture was heated to 80°C and stirred for 2 h. LCMS monitoring indicated the disappearance of the starting material and the formation of the product. The reaction solution was extracted with ethyl acetate, dried, and concentrated to afford 5 mg of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-phenylpiperidine-4-carbonitrile (58_4), a pale yellow liquid in a yield of 27.9%. MS m / z: 449.1 [M+H].

[0207] Step 4

[0208] 1-[3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-phenylpiperidine-4-carbonitrile (58_4) (50 mg, 0.11 mmol) was added toluene (0.5 ml) at room temperature. The N2 atmosphere was replaced three times, and chloro(methyl)aluminum amine (0.5 ml, 2 M) was slowly added dropwise. The temperature was raised to 95°C and the reaction was allowed to react overnight. LCMS analysis indicated the formation of product, indicating a small amount of residual starting material. The reaction solution was quenched with ice water, filtered, and the filtrate was concentrated and further purified by reverse phase preparative. After lyophilization, 30 mg of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-phenylpiperidine-4-carboximidamide (ZS5084-058) was obtained as a yellow solid in a 58.4% yield. MS m / z: 466.1 [M+H]. 1H NMR (400MHz, METHANOL-d4) δ = 8.38 (s, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.61-7.55 (m, 3H ),7.52(t,J=7.7Hz,2H),7.46-7.42(m,2H),3.97-3.87(m,4H),2.64-2.53(m,4H).

[0209] Example 5

[0210] Step 1

[0211] Potassium carbonate (224 mg, 1.63 mmol) and (R)-1-N-Boc-2-methylpiperazine (130 mg, 0.65 mmol) were added to a DMF solution (6 ml) of 3,5-dichloro-2-(2,3-dichlorobenzoyl)pyrazine (64_1) (262 mg, 0.81 mmol) at -20°C and the reaction was maintained at this temperature for 1 hour. TLC monitored the complete consumption of the starting material. The mixture was diluted with 20 ml of water and extracted twice with 20 ml of ethyl acetate. The ethyl acetate layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of ethyl acetate:petroleum ether = 1:4 to obtain 250 mg of tert-butyl 4-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-2-methylpiperazine-1-carboxylate (64_2) as a yellow oil in a yield of 63.2%. MS m / z: 429.2, 431.0[M-55]; 1 H NMR (400MHz, DMSO-d6) δ = 8.30 (s, 1H), 7.76-7.70 (m, 1H), 7.48-7.39 (m, 2H), 4.35-4.12 (m, 3H), 3.84-3.77 (m, 1H), 3.43 (br dd,J=3.5,13.3Hz,1H),3.27-3.16(m,2H),1.41(s,9H),1.06(d,J=6.6Hz,3H).

[0212] Step 2

[0213] At room temperature, tert-butyl 4-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-2-methylpiperazine-1-carboxylate (64_2) (250 mg, 0.51 mmol) and hydrazine hydrate (3 ml, 59.94 mmol) were added to ethanol (3 ml) and heated to 80°C for 1 h. LCMS monitored the reaction, confirming completion of the reaction. The reaction solution was concentrated, diluted with 20 ml of water, and extracted twice with 20 ml of ethyl acetate. The combined organic layers were washed with saturated brine and concentrated to afford tert-butyl 4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-methylpiperazine-1-carboxylate (64_3), 170 mg of a crude yellow solid in a 72.2% yield, which was used directly in the next step. MS m / z: 463.2, 465.2 [M+H].

[0214] Step 3

[0215] TFA (1 ml, 8.77 mmol) was added to a solution of tert-butyl 4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-methylpiperazine-1-carboxylate (64_3) (170 mg, 0.37 mmol) in dichloromethane (5 ml) at 0°C and allowed to warm to room temperature for 1 h. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated, diluted with ethyl acetate, and quenched by dropwise addition of saturated aqueous sodium bicarbonate until no bubbles formed and the pH was adjusted to 7-8. The solution was diluted with 5 ml of water and extracted twice with 15 ml of ethyl acetate. The organic layers were combined, washed with saturated brine, and concentrated to dryness to yield 165 mg of crude yellow solid 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methylpiperazine (64_4), which was used directly in the next reaction. MS m / z: 363.1, 365.1[M+H].

[0216] Step 4

[0217] 1-[3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methylpiperazine (64_4) (80 mg, 0.22 mmol), N-(4-fluorophenyl)(methylthio)formimine hydroiodide (96 mg, 0.31 mmol), and triethylamine (0.5 ml, 3.61 mmol) were dissolved in isopropanol (2 ml) at room temperature and heated to 100°C for 48 h. The reaction was monitored by LCMS. The reaction mixture was filtered, diluted with methanol, and purified by preparative HPLC. The resulting product was lyophilized to obtain 16 mg of 4-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(4-fluorophenyl)-2-methylpiperazine-1-carboximide (ZS5084-064) as a yellow solid in a yield of 14.6% and a purity of 99.12%. MS m / z: 499.1, 501.1 [M+H]. 1 H NMR(DMSO-d6,400MHz)δ=13.49(br s,1H),9.55(s,1H),8.4-8.6(s,1H),7.9-8.0(brs,2H),7.7-7.8(m,1H),7.7-7.7(m,1H),7.5-7.5(m ,1H),7.32(d,4H,J=6.8Hz),4.3-4.5(m,3H),3.8-3.9(m,1H),3.5-3.7(m,3H),1.30(d,J=6.4Hz,3H).

[0218] Example 6

[0219] Step 1

[0220] To a small reaction vial at room temperature was added 1-(1H-imidazole-1-carboxamidinoyl)-1H-imidazole (65_1) (21 mg, 0.13 mmol) and sodium bicarbonate (11 mg, 0.13 mmol) dissolved in tetrahydrofuran (1 ml). 4-Fluorocyclohexane-1-amine hydrochloride (20 mg, 0.13 mmol) was added and stirred at room temperature for 12 h. LCMS analysis confirmed the formation of the product, N-(4-fluorocyclohexyl)-1H-imidazole-1-carboximidazole (65_2). The reaction solution was used directly in the next step. MS m / z: 211.1 [M+H].

[0221] Step 2

[0222] 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (17 mg, 0.05 mmol) was added to the reaction mixture of the previous step at room temperature, stirred, and heated to 60 0C, and reacted for 12 h. LCMS monitored product formation. The reaction solution was dried, dissolved in methanol, and purified by Prep-HPLC to yield 3.4 mg of 4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorocyclohexyl)piperazine-1-carboximidamide (ZS5084-065) as a white solid in a 13.9% yield. MS m / z: 491.2 [M+H]. 1 H NMR(400MHz, DMSO-d6)δ=9.89-9.73(m,1H),9.56-9.41(m,1H),8.99-8.88(m,1H),8.72(s,1 H),7.92(d,J=8.0Hz,1H),7.74-7.67(m,1H),7.64-7.57(m,1H),4.93-4.50(m,1H),4.03(br s,4H),3.93-3.81(m,1H),2.16-2.01(m,4H),2.01–1.74(m,4H),1.74-1.51(m,4H).

[0223] Example 7

[0224] Step 1

[0225] Cyclopropylamine (0.24 ml, 3.41 mmol) was added to a solution of di(imidazol-1-yl)formimine (66_1) (500 mg, 3.1 mmol) in tetrahydrofuran (8 ml) at room temperature and stirred for 18 h. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated and used directly in the next step. MS m / z: 151.1 [M+H].

[0226] Step 2

[0227] 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (50 mg, 0.14 mmol) and N-cyclopropyl-1H-imidazole-1-carboximide (66_2) (70 mg, 0.47 mmol) were dissolved in DMF (1 ml) at room temperature and allowed to react overnight at 60°C. The reaction was monitored by LCMS. The reaction solution was diluted with methanol and purified by preparative Prep-HPLC. The resulting product was lyophilized to yield 4.01 mg of N-cyclopropyl-4-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperazine-1-carboximide as a pale yellow solid in a 6.6% yield. MS m / z: 431.1, 433.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 13.49 (br s, 1H), 8.45 (s, 1H), 8.06 (s, 1H), 7.83 (br s,2H),7.76(dd,J=1.5,8.0Hz,1H),7.69(dd,J=1.5,7.8Hz,1H),7.50(t,J=7.9Hz,1H),3 .85-3.80(m,4H),3.61-3.57(m,4H),2.56(m,1H),0.87-0.80(m,2H),0.66-0.60(m,2H).

[0228] Example 8

[0229] Step 1

[0230] To a solution of 4-fluoroaniline (0.3 ml, 2.7 mmol) at room temperature was added 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carbonitrile (56_4) (25 mg, 0.06 mmol) and aluminum trichloride (86 mg, 0.65 mmol). The atmosphere was purged with nitrogen three times, and the temperature was raised to 120°C, where the reaction was stirred for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was quenched by adding water (10 mL x 2) and then extracted twice with ethyl acetate (20 mL). The organic phase was concentrated in vacuo, and the residue was purified by Prep-HPLC. The resulting product was lyophilized to obtain 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (ZS5084-067) as a yellow solid (19 mg, yield 63.5%). MS m / z: 498.2 [M+H]. 1 H NMR(400MHz,DMSO-d6)δ=13.45(br s,1H),10.52(s,1H),9.09(s,1H),8.57(s,1H),8.51(s,1H),7.77-7.68(m,2H),7.52 -7.38(m,5H),3.85-3.83(m,4H),2.26-2.23(m,2H),1.87-1.83(m,2H),1.49(s,3H).

[0231] Example 9

[0232] Step 1

[0233] Xantphos Pd G4 (1621274-19-8) (76 mg, 0.08 mmol) was added to a toluene (10 mL) solution of 6-chloro-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine (68-1) (600 mg, 1.65 mmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (221.4 mg, 1.65 mmol), and potassium carbonate (682 mg, 4.94 mmol). The mixture was stirred at 90° C. under nitrogen for 3 h. LCMS indicated the reaction was complete. The mixture was diluted with 10 mL of water and extracted with ethyl acetate (20 mL x 2). The combined ethyl acetate layers were washed once with saturated brine. The organic phase was concentrated and dried by spin-drying. Purification was performed by silica gel column chromatography using a mobile phase of petroleum ether:ethyl acetate in a ratio of 1:1 to afford 500 mg of 1-[6-chloro-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine (68-2) as a yellow solid in a yield of 81.9%. MS m / z: 371.1 [M+H].

[0234] Step 2

[0235] 1-[6-Chloro-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine (68-2) (250 mg, 0.67 mmol) was added to a solution of 3R-3H-spiro[1-benzofuran-2,4'-piperidin]-3-amine (138 mg, 0.67 mmol) and potassium carbonate (280 mg, 2.02 mmol) in dimethyl sulfoxide (5 mL). The reaction was stirred at 60°C for 3 h. LCMS indicated the reaction was complete. Dilute with 10 mL of water and extract with ethyl acetate (20 mL x 2). Combine the ethyl acetate layers and wash once with saturated brine. The organic phase is concentrated and spin-dried to give 300 mg of 1-piperidin-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4'-piperidin]-3-amine (68-3) as a yellow solid in an 83.2% yield. MS m / z: 539.3 [M+H].

[0236] Step 3

[0237] 1-Piperidine-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4'-piperidine]-3-amine (68-3) (300 mg, 0.56 mmol) was added to a solution of trifluoroacetic acid (2 mL) in dichloromethane (8 mL), and the reaction was stirred at 20° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was dried in an air-spin manner and then purified by Prep-HPLC and lyophilized to afford 187 mg of 3R-1-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[1-benzofuran-2,4'-piperidin]-3-amine (ZS5084-068) as a yellow solid in a yield of 74.1%. MS m / z: 455.3 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.02 (br s, 1H), 8.61-8.52 (m, 2H), 8.48 (s, 1H), 8.17 (d, J = 5.3Hz, 1H), 8.08 (br d,J=8.5Hz,1H),7.61-7.51(m,2H),7.38(t,J=7.8Hz,1H),7.06-6.97(m,2H),4.68(br s,1H),4.64-4.54(m,1H),4.54-4.36(m,1H),4.10-4.00(m,2H),3.48-3.30(m,2H),3.20(br t,J=6.3Hz,2H),2.21-1.99(m,4H),1.91-1.79(m,2H).

[0238] Example 10

[0239] Step 1

[0240] To an anhydrous N,N-dimethylformamide (10 ml) solution at room temperature were added 3,5-dichloro-2-(2,3-dichlorobenzoyl)pyrazine (1 g, 3.11 mmol), tert-butyl N-(4-methylpiperidin-4-yl)carbamate (0.67 g, 3.11 mmol), and potassium carbonate (858 mg, 6.21 mmol). The mixture was stirred at room temperature for 12 h under nitrogen. TLC monitoring indicated the disappearance of the starting material and the formation of a large new spot. The reaction mixture was diluted with water (20 mL x 3) and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 1:99 to 30:70) to provide 1.5 g of tert-butyl N-{1-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (17_4A) as a yellow solid in a yield of 96.5%. MS m / z: 443.0 [M-55].

[0241] Step 2

[0242] To an ethanol solution (100 ml) at room temperature, tert-butyl N-{1-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (1 g, 2 mmol) and hydrazine hydrate (2 ml, 39.96 mmol) were added. The mixture was protected with nitrogen and then heated to 90°C with stirring for 18 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: EA:PE = 1:99 to 30:70) to afford 800 mg of tert-butyl N-{4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1-methylcyclohexyl}carbamate (17-5A) as a yellow solid in an 84% yield. MS m / z: 477.1 [M+H].

[0243] Step 3

[0244] To a solution of dichloromethane (25 ml) at room temperature was added tert-butyl N-{4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-1-methylcyclohexyl}carbamate (17-5A) (800 mg, 1.68 mmol) and trifluoroacetic acid (17 ml, 146.97 mmol). Stirring was carried out at room temperature under nitrogen for 1 hour. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with dichloromethane (5 mL). The pH was adjusted to neutral with aqueous ammonia solution, and the mixture was then concentrated in vacuo. The residue was purified by Prep-HPLC (CH3CN:H2O containing 0.1% aqueous ammonia = 5:95 to 95:5) to afford 560 mg of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine (ZS5084-017-YC) as a white solid in an 88.5% yield. MS m / z: 377.1 [M+H].

[0245] Step 4

[0246] To a solution of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine (ZS5084-17YC) (38 mg, 0.1 mmol), tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (93.11 mg, 0.3 mmol), and ethylbis(propan-2-yl)amine (0.3 ml, 2.32 mmol) were added to an acetonitrile (2 ml, 100.0%) solution at room temperature. Under nitrogen, the mixture was heated to 60°C and stirred for 18 hours. LCMS analysis indicated a slight residual starting material and the desired target molecular weight. The reaction mixture was diluted with water (5 mL x 2) and extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 1:99 to 50:50) to provide 25 mg of tert-butyl N-[(E)-{[(tert-butoxy)carbonyl]imino}({1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-yl}amino)methyl]carbamate (69_1) as a yellow solid in a yield of 40.3%. MS m / z: 619.3 [M+H].

[0247] Step 5

[0248] To a solution of dichloromethane (2 ml) at room temperature was added tert-butyl N-[(E)-{[(tert-butoxy)carbonyl]imino}({1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-yl}amino)methyl]carbamate (69-1) (40 mg, 0.06 mmol) and trifluoroacetic acid (0.31 ml, 2.71 mmol). The reaction was stirred at room temperature under nitrogen for 18 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC (mobile phase: acetonitrile:water containing 0.1% TFA = 5:95 to 95:5). The residue was concentrated and lyophilized to afford 3.17 mg of N-{1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-yl}guanidine (ZS5084-069) as a yellow solid in a 12.6% yield. MS m / z: 419.1 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=13.44(s,1H),8.48(s,1H),7.77-7.68(m,2H),7.52-7.48(m,1H),7.42(s,1H),7.23(s,1H),7.10(s,1H),6.98(br d,J=6.3Hz,4H),4.07-4.03(m,2H),3.47-3.41(m,2H),1.99(br d,J=14.3Hz,2H),1.80-1.73(m,2H),1.40(s,3H).

[0249] Example 11

[0250] Step 1

[0251] Piperidine (100 mg, 1.17 mmol) was added to a solution of carbonyldiimidazole (72-1) (189 mg, 1.17 mmol) in tetrahydrofuran (2 mL). The reaction was stirred at 20°C for 16 h. LCMS indicated the reaction was complete. The mixture was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate. The combined ethyl acetate layers were washed once with saturated brine. The organic phase was concentrated and dried to give 200 mg of 1-(1H-imidazole-1-carboximidoyl)piperidine (72-2) as a white solid in a 95.9% yield. MS m / z: 179.1 [M+H].

[0252] Step 2

[0253] 1-(1H-imidazole-1-carboximidoyl)piperidine (72-2) (25 mg, 0.14 mmol) was added to a solution of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (50 mg, 0.14 mmol) in tetrahydrofuran (1 ml). N,N-dimethylpyridin-4-amine (1.71 mg, 0.01 mmol) was then added and stirred at 50°C for 16 h. The reaction mixture was spin-dried and purified by Prep-HPLC (water / acetonitrile, ammonium bicarbonate) and lyophilized to afford 20 mg of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-(piperidine-1-carboximidoyl)piperazine as a white solid in a 31.3% yield. MS m / z: 459.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ=8.52-8.42(m,1H),7.82-7.70(m,1H),7.73-7.62(m,1H),7.58-7.47(m,1H),3.86(br d,J=4.9Hz,4H),3.52(br s,4H),3.34(br s,3H),3.19-3.07(m,2H),1.71-1.48(m,8H).

[0254] Example 12

[0255] Step 1

[0256] To a solution of N,N-dimethylformamide (3 ml) at room temperature were added tert-butyl 4-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (Int 2) (50 mg, 0.11 mmol) and 1-chloropyrrolidine-2,5-dione (73 mg, 0.55 mmol). The mixture was reacted under nitrogen atmosphere for 2 h at room temperature. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was diluted twice with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 60 mg of crude tert-butyl 4-[5-chloro-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (73_1) as a yellow solid, which was used directly in the next step. MS m / z:483.1[M+H].

[0257] Step 2

[0258] To a dichloromethane (3 ml) solution at room temperature, tert-butyl 4-[5-chloro-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (73_1) (50 mg, 0.1 mmol) and trifluoroacetic acid (0.5 ml, 4.34 mmol) were added. Under nitrogen protection, the reaction was stirred at room temperature for 1 hour. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo to give 38 mg of crude 1-[5-chloro-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (73_2) as a yellow oil, which was used directly in the next reaction. MS m / z: 383.1 [M+H].

[0259] Step 3

[0260] To a solution of isopropanol (3 ml) at room temperature was added 1-[5-chloro-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (73_2) (38 mg, 0.1 mmol), N-(4-fluorophenyl)(methylthio)formimine (54_2) (73 mg, 0.4 mmol), and triethylamine (0.99 ml, 9.79 mmol). The mixture was heated to 90°C and refluxed for 18 h under nitrogen. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC (mobile phase: acetonitrile:water containing 0.1% TFA = 1:99 to 90:10) to afford 9.6 mg of 4-[5-chloro-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (ZS5084-073) as a yellow solid in an 18.5% yield. MS m / z: 519.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 14.15 (s, 1H), 9.66 (s, 1H), 7.97 (br s,2H),7.81(dd,J=1.1,8.1Hz,1H),7.67(dd,J=1.3,7.7Hz,1H),7.56-7.52(m,1H),7.31(d,J=6.8Hz,4H),3.74(br d,J=3.6Hz,4H),3.64(br d,J=3.1Hz,4H).

[0261] Example 13

[0262] Step 1

[0263] Bromomethylboronic acid pinacol ester (Int A) (1.2 g, 5.43 mmol) and sodium methoxide (440 mg, 8.15 mmol) were added to a methanol solution (15 ml) at room temperature. The mixture was stirred at room temperature for 18 h under nitrogen atmosphere. TLC (ethyl acetate:petroleum ether = 1:5) revealed the disappearance of the starting material and the formation of a new major spot. The reaction mixture was concentrated in vacuo to yield 934.52 mg of crude 2-(methoxymethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Int B) as a white solid, which was used directly in the next reaction.

[0264] Step 2

[0265] To a mixed solution of 1,4-dioxane (10 ml) and water (2 ml) at room temperature were added tert-butyl 4-[5-bromo-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (57_1) (301 mg, 0.57 mmol), 2-(methoxymethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Int B) (588 mg, 3.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (125 mg, 0.17 mmol), and potassium phosphate (242 mg, 1.14 mmol). The atmosphere was purged with nitrogen three times, then the temperature was raised to 90°C for 5 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted twice with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 1:99 to 30:70) to provide 15 mg of tert-butyl 4-[3-(2,3-dichlorophenyl)-5-(methoxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (74_1) as a yellow solid in a yield of 5.3%. MS m / z: 493.2 [M+H].

[0266] Step 3

[0267] To a dichloromethane (3 ml) solution at room temperature, tert-butyl 4-[3-(2,3-dichlorophenyl)-5-(methoxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (74_1) (15 mg, 0.03 mmol) and trifluoroacetic acid (0.4 ml, 3.51 mmol) were added. The mixture was protected with nitrogen and stirred at room temperature for 1 h. LCMS monitoring showed the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo to give 12 mg of crude 1-[3-(2,3-dichlorophenyl)-5-(methoxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (74_2) as a yellow oil, which was used directly in the next step. MS m / z: 393.1 [M+H].

[0268] Step 4

[0269] To a solution of isopropanol (2 ml) at room temperature was added 1-[3-(2,3-dichlorophenyl)-5-(methoxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (74_2) (9 mg, 0.02 mmol), N-(4-fluorophenyl)(methylthio)carboximide (54_2) (16 mg, 0.09 mmol), and triethylamine (0.16 ml, 1.61 mmol). The mixture was heated to 90°C and refluxed for 18 h under nitrogen. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC (mobile phase: acetonitrile:water = 1:99 to 90:10, 0.1% TFA), followed by concentration and lyophilization to afford 3.8 mg of 4-[3-(2,3-dichlorophenyl)-5-(methoxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (ZS5084-074) as a yellow solid in a 33.1% yield. MS m / z: 529.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.93 (s, 1H), 9.64 (s, 1H), 7.96 (br s,2H),7.80(dd,J=1.4,8.0Hz,1H),7.70(dd,J=1.4,7.7Hz,1H),7.55-7.52(m,1H),7.31(d,J=6.8Hz,4H),4.58(s,2H),3.76(br s,4H),3.59(br s,4H),3.38(s,3H).

[0270] Example 14

[0271] Step 1

[0272] To a mixed solution of 1,4-dioxane (10 ml) and water (2 ml) at room temperature were added tert-butyl 4-[5-bromo-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (57_1) (301 mg, 0.57 mmol), trimethyl-1,3,5,2,4,6-trioxotriborane (0.72 ml, 5.7 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (125 mg, 0.17 mmol), and potassium carbonate (236 mg, 1.71 mmol). The atmosphere was purged with nitrogen three times, then the temperature was raised to 90°C for 5 h. The reaction was monitored by LCMS for completion. The reaction mixture was diluted twice with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 1:99 to 30:70) to afford tert-butyl 4-[3-(2,3-dichlorophenyl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (75_1) as a yellow solid (50 mg, yield 18.9%). MS m / z: 463.2 [M+H].

[0273] Step 2

[0274] To a dichloromethane (3 ml) solution at room temperature, tert-butyl 4-[3-(2,3-dichlorophenyl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboxylate (75_1) (50 mg, 0.11 mmol) and trifluoroacetic acid (0.52 ml, 4.54 mmol) were added. Under nitrogen protection, the reaction was stirred at room temperature for 1 h. LCMS monitored the completion of the reaction. The reaction solution was concentrated in vacuo, and the residue was concentrated in vacuo to afford 50 mg of crude 1-[3-(2,3-dichlorophenyl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (75_2) as a yellow oil, which was used directly in the next reaction. MS m / z: 363.1 [M+H].

[0275] Step 3

[0276] To a solution of isopropanol (5 ml) at room temperature was added 1-[3-(2,3-dichlorophenyl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine (75_2) (50 mg, 0.14 mmol), N-(4-fluorophenyl)(methylthio)carboximide (54_2) (101 mg, 0.55 mmol), and triethylamine (1 ml, 9.88 mmol). The mixture was heated to 90°C and refluxed for 18 h under nitrogen atmosphere. The reaction was monitored by LCMS for completion. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC (mobile phase: acetonitrile:water = 1:99 to 90:10, 0.1% TFA), followed by concentration and lyophilization to afford 25 mg of 4-[3-(2,3-dichlorophenyl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (ZS5084-075) as a yellow solid in a 36.2% yield. MS m / z: 499.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.83 (br s, 1H), 9.70 (s, 1H), 7.99 (br s,2H),7.78(d,J=8.1Hz,1H),7.70(d,J=6.6Hz,1H),7.54-7.50(m,1H),7.32(d,J=6.8Hz,4H),3.74(br s,4H),3.46(br s,4H),2.61(s,3H).

[0277] Example 15

[0278] Step 1

[0279] Potassium carbonate (293 mg, 2.12 mmol) and tert-butyl N-(3-methylazetidin-3-yl)carbamate (168 mg, 0.90 mmol) were added to a solution of 3,5-dichloro-2-(2,3-dichlorobenzoyl)pyrazine (76_1) (342 mg, 1.06 mmol) in DMF (5 ml) at 0°C. The reaction was maintained at this temperature for 2 h. TLC monitored the complete consumption of the starting material. The mixture was diluted with 20 ml of water and extracted twice with 15 ml of ethyl acetate. The combined organic layers were washed once with saturated brine, concentrated, and purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 1:2) to yield 300 mg of crude tert-butyl N-{1-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-3-methylazetidin-3-yl}carbamate (76_2) as a yellow solid. MS m / z:471.1,473.1[M+H].

[0280] Step 2

[0281] At room temperature, tert-butyl N-{1-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-3-methylazetidin-3-yl}carbamate (76_2) (300 mg, 0.64 mmol) and hydrazine hydrate (2 ml, 40.0 mmol) were dissolved in ethanol (8 ml) and the mixture was heated to 80°C for 1 h. LCMS monitoring confirmed complete consumption of the starting material, and the main peak was the desired product. The reaction solution was concentrated, diluted with 20 ml of water, and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated to obtain 255 mg of crude tert-butyl N-{1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-3-methylazetidin-3-yl}carbamate (76_3) as a yellow solid, which was used directly in the next step. MS m / z: 449.1, 451.1 [M+H].

[0282] Step 3

[0283] Trifluoroacetic acid (1.4 ml, 12.3 mmol) was added to a solution of tert-butyl N-{1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-3-methylazetidin-3-yl}carbamate (76_3) (200 mg, 0.45 mmol) in dichloromethane (5 ml) at 0°C. The mixture was allowed to react naturally at room temperature for 1 hour. LCMS monitored the complete consumption of the starting material, and the main peak was the product. The reaction solution was concentrated, quenched with saturated aqueous sodium bicarbonate, and the pH was adjusted to 7-8. The mixture was diluted with 10 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated to obtain 143 mg of crude 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methylazetidin-3-amine (76_4) as a yellow solid, which was used directly in the next reaction. MS m / z: 349.1, 351.1 [M+H].

[0284] Step 4

[0285] At room temperature, 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methylazetidin-3-amine (76_4) (75 mg, 0.21 mmol), tert-butyl N-[(Z)-{[(tert-butyloxy)carbonyl]imino}(1H-pyrazol-1-yl)methyl]carbamate (130 mg, 0.42 mmol), and N,N-diisopropylethylamine (0.07 ml, 0.42 mmol) were dissolved in DMF (1 ml) and the mixture was heated to 60°C and reacted overnight. LCMS monitoring confirmed complete consumption of the starting material and the formation of product. The reaction mixture was filtered and directly purified by preparative Prep-HPLC. The resulting product was lyophilized to obtain 10.0 mg of tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}({1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-3-methylazetidin-3-yl}amino)methyl]carbamate (76-5) as a yellow solid in an 8.1% yield. MS m / z: 591.2, 593.2 [M+H].

[0286] Step 5

[0287] To a solution of tert-butyl N-[(Z)-{[(tert-butoxy)carbonyl]imino}({1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-3-methylazetidin-3-yl}amino)methyl]carbamate (76-5) (10 mg, 0.02 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.50 ml, 4.38 mmol) at 0°C and the mixture was allowed to return to room temperature and react for 3 h. LCMS monitored the complete consumption of the starting material. The reaction mixture was concentrated, diluted with methanol, and purified by preparative HPLC. The resulting product was lyophilized to obtain 6.5 mg of 1-(1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl)-3-methylazetidin-3-yl)guanidine (ZS5084-076) as a yellow solid in an 83.6% yield. MS m / z: 391.1, 393.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.52 (br s, 1H), 8.41 (s, 1H), 7.96 (s, 1H), 7.75 (d, J = 8.1Hz, 1H), 7.67 (d, J = 6.5Hz, 1H), 7.52-7.47 (m, 1H), 7.16 (br s,4H),4.26-4.15(m,4H),1.63(s,3H).

[0288] Example 16

[0289] Step 1

[0290] At room temperature, tert-butyl N-{1-[6-chloro-5-(2,3-dichlorobenzoyl)pyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (77_1) (1.00 g, 2.00 mmol) and hydrazine hydrate (2.00 ml, 40.0 mmol) were dissolved in ethanol (20 ml) and the reaction mixture was heated to 80°C for 1 h. LCMS monitoring confirmed complete consumption of the starting material, and the main peak was the desired product. The reaction solution was concentrated, diluted with 20 ml of water, and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated to obtain 910 mg of crude tert-butyl N-{1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-4-methylpiperidin-4-yl}carbamate (77_2) as a yellow solid, which was used directly in the next step. MS m / z: 477.2, 479.2 [M+H].

[0291] Step 2

[0292] Trifluoroacetic acid (2.50 ml, 21.9 mmol) was added to a solution of tert-butyl N-{1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-4-methylpiperidin-4-yl}carbamate (77-2) (910 mg, 1.91 mmol) in dichloromethane (10 ml) at 0°C and allowed to react naturally at room temperature for 2 h. LCMS monitored complete consumption of the starting material. The reaction solution was concentrated and quenched by adding saturated aqueous sodium bicarbonate until no bubbles were generated and the pH was adjusted to 7-8. The mixture was diluted with 10 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated to obtain 720 mg of crude 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine (17YC) as a yellow solid, which was used directly in the next reaction. MS m / z: 377.1, 379.1 [M+H].

[0293] Step 3

[0294] Cyanogen bromide (100 mg, 0.94 mmol) was dissolved in dichloromethane (2 ml) and stored at 0°C. A solution of 1H-pyrazole (135 mg, 1.98 mmol) and triethylamine (0.29 ml, 2.83 mmol) in dichloromethane (5 ml) was then added, and the reaction mixture was stirred at room temperature for 12 h. LCMS confirmed complete consumption of the starting material, revealing the desired product as the main peak. The reaction mixture was concentrated, diluted with 5 ml of water, and extracted twice with 5 ml of ethyl acetate. The combined organic layers were washed once with saturated brine, concentrated, and purified by silica gel column chromatography using a mobile phase of ethyl acetate:petroleum ether (1:8) to yield 41.0 mg of 1-(1H-pyrazole-1-formyl)-1H-pyrazole (77_3) as a yellow liquid in a yield of 12.9%. MS m / z: 162.1 [M+H].

[0295] Step 4

[0296] At room temperature, 1-(1H-pyrazole-1-formyl)-1H-pyrazole (77_3) (20.0 mg, 0.12 mmol) and 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine (17YC) (46 mg, 0.12 mmol) were added and dissolved in DMF (1 ml). The temperature was raised to 60 ° C and the reaction was reacted for 18 h. LCMS monitored the remaining starting material and the product was generated. The reaction mixture was filtered and directly purified by preparative HPLC. The resulting product was lyophilized to obtain 2.33 mg of N-(1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl)-4-methylpiperidin-4-yl)-1H-pyrazole-1-carboximide (ZS5084-077) as a yellow solid in a 4.1% yield. MS m / z: 470.2, 472.2 [M+H]. 1 H NMR (400MHz, METHANOL-d4) δ = 8.43 (d, J = 2.9Hz, 1H), 8.37 (s, 1H), 7.98 (d, J = 1.3Hz, 1H), 7.66 (dd, J = 1.4, 8.0Hz, 1H), 7. 57(dd,J=1.3,7.7Hz,1H),7.45-7.39(m,1H),6.74(dd,J=1.6,2.6Hz,1H),4.18-4.11(m,2H),3.75-3.67(m,2H),2.36(br d, J=14.5Hz, 2H), 2.06 (ddd, J=3.6, 9.8, 13.9Hz, 2H), 1.67 (s, 3H).

[0297] Example 17

[0298] Step 1

[0299] 1-[3-(2,3-Dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine (17YC) (100 mg, 0.27 mmol), N-(4-fluorophenyl)(methylthio)carboximide hydroiodide (78_1) (248 mg, 0.80 mmol), and triethylamine (0.37 ml, 2.65 mmol) were added to a DMSO (1 ml) solution at room temperature and heated to 100°C for 48 h. The remaining starting material was monitored by LCMS. The reaction solution was diluted with methanol and purified by preparative HPLC. The resulting product was lyophilized to obtain 5.3 mg of 1-(1-(3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl)-4-methylpiperidin-4-yl)-3-(4-fluorophenyl)guanidine (ZS5084-078) as a white solid in a 3.8% yield. MS m / z: 513.2, 515.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ=13.45(br s,1H),9.59(br s,1H),8.50(s,1H),8.05(br s,1H),7.75(d,J=8.0Hz,1H),7.70(d,J=7.5Hz,1H),7.61(br s,1H),7.52-7.47(m,1H),7.27(d,J=1.3Hz,4H),4.07(d,J=13.8Hz,2H),3.56 (t, J=11.1Hz, 2H), 2.14 (d, J=10.8Hz, 2H), 1.77 (d, J=8.8Hz, 2H), 1.48 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ = -116.0.

[0300] Example 18

[0301] Step 1

[0302] To a 25 ml three-necked flask at room temperature was added 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carbonitrile (79_1) (20 mg, 0.05 mmol), dissolved in methanol (5 ml), and HCl gas was introduced for 3 h. The reaction mixture was then stirred for 12 h. TLC and LCMS monitoring revealed the disappearance of the starting material, revealing the product, methyl 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidate (79_2). The reaction mixture was concentrated and used directly in the next step. MS m / z: 419.1 [M+H].

[0303] Step 2

[0304] The product (79_2) from the previous step was dissolved in acetonitrile (0.5 ml) at room temperature, triethylamine (69.5 μl, 0.5 mmol) and 3-methoxyaniline (50.2 μl, 0.5 mmol) were slowly added dropwise, stirring was started, and the temperature was raised to 80 0 The reaction was continued for 12 h. LCMS analysis indicated that no starting material remained, indicating product formation. The reaction solution was dried, dissolved in dimethyl sulfoxide, and submitted to Prep-HPLC to yield 1.53 mg of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (ZS5084-079) as a brown solid in a 6% yield. MS m / z: 510.2 [M+H]. 1 H NMR(400MHz,DEUTERIUM OXIDE)δ=8.07(s,1H),7.50(d,J=7.4Hz,1H),7.42-7.34(m,2H),7.30-7.24(m,1H),7.02(dd,J=2.4,8.5Hz,1H),6.82(d,J= 7.9Hz,1H),6.78(d,J=2.1Hz,1H),3.79-3.69(m,5H),3.64-3.52(m,2H),2.06-1.95(m,2H),1.87-1.75(m,2H),1.45(s,3H).

[0305] Example 19

[0306] Step 1

[0307] To a small reaction vial at room temperature were added 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carbonitrile (80_1) (10 mg, 0.03 mmol), 4-methoxyaniline (86 mg, 0.7 mmol), and aluminum chloride (34 mg, 0.26 mmol). Stirring was initiated, the temperature was raised to 120°C, and the reaction was allowed to proceed for 12 h. LCMS monitoring of product formation was performed. The reaction mixture was dissolved in methanol, filtered through a membrane filter, and the filtrate was dried and dissolved in dimethyl sulfoxide. Prep-HPLC analysis yielded 3.46 mg of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (ZS5084-080) as a purple solid in a 26.2% yield. MS m / z: 510.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.45 (s, 1H), 10.41 (s, DMSO1H), 9.02 (br s,1H),8.52(s,1H),8.44(d,J=0.9Hz,1H),7.76(d,J=7.7Hz,1H),7.70(d,J=7.2Hz,1H),7.50(t,J=7.9Hz,1H),7.31(d, J=8.8Hz,2H),7.10(d,J=8.9Hz,2H),3.87-3.83(m,3H),3.81(s,3H),2.29-2.21(m,2H),1.91-1.78(m,2H),1.48(s,3H).

[0308] Example 20

[0309] Step 1

[0310] In a 25 ml three-necked flask at room temperature, 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carbonitrile (81_1) (50 mg, 0.12 mmol) was dissolved in methanol (5 ml). Hydrochloric acid gas was introduced for 3 hours, and the reaction solution was stirred for 12 hours. TLC and LCMS monitoring revealed the disappearance of the starting material, while the product, 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidomethyl ester (81_2), was produced. The reaction solution was concentrated and used directly in the next step. MS m / z: 419.1 [M+H].

[0311] Step 2

[0312] The product (81_2) from the previous step was dissolved in acetonitrile (0.5 ml) at room temperature. Triethylamine (166 μl, 1.19 mmol) and 2H-1,3-benzodioxol-5-amine (163 mg, 1.19 mmol) were slowly added dropwise. The mixture was stirred and heated to 80°C for 12 h. LCMS analysis revealed no residual starting material, indicating product formation. The reaction solution was dried, dissolved in methanol, and submitted for Prep-HPLC analysis. This yielded 3.4 mg of N-(2H-1,3-benzodioxol-5-yl)-1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-carboximidamide (ZS5084-081) as a white solid in a 5.36% yield. MS m / z: 524.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ=13.47-13.26(m,1H),8.44(s,1H),7.74(dd,J=1.3,7.9Hz,1 H),7.70(dd,J=1.4,7.8Hz,1H),7.49(t,J=7.8Hz,1H),6.79(d,J=8.1Hz,1H),6.34(br s,1H),6.22-6.11(m,1H),5.93(s,2H),5.73(s,H),4.12-4.02(m,2H),3.5 2(d,J=6.1Hz,1H),2.26(d,J=13.8Hz,2H),1.51-1.45(m,2H),1.23(s,3H).

[0313] Example 21

[0314] Step 1

[0315] At room temperature, (4-fluorophenyl)thiourea (83_1) (1.00 g, 5.88 mmol) and iodomethane (0.44 ml, 7.05 mmol) were dissolved in ethanol (10 ml) and the reaction temperature was raised to 80°C for 3 h. TLC monitored the complete consumption of the starting material. The reaction solution was concentrated to yield 1.80 g of crude N-(4-fluorophenyl)(methylthio)formimide (83_2) as a yellow oil, which was used directly in the next reaction. MS m / z: 185.0 [M+H].

[0316] Step 2

[0317] At room temperature, N-(4-fluorophenyl)(methylthio)formimide (83_2) (1.80 g, 9.77 mmol), tert-butyl piperazine-1-carboxylate (2.18 g, 11.7 mmol), and triethylamine (3.64 ml, 25.9 mmol) were added and dissolved in tert-butyl alcohol (10 ml) and heated to 90°C for 12 h. TLC monitored the complete consumption of the starting materials. Aqueous sodium hypochlorite solution was added to the reaction solution for quenching and stirring for at least half an hour until no odor was emitted. 40 ml of water was added for dilution and the mixture was extracted twice with 40 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol = 10:1 to obtain 1.80 g of crude tert-butyl 4-[N-(4-fluorophenyl)carbamoyl]piperazine-1-carboxylate (83_3) as a yellow solid. MS m / z: 323.2 [M+H].

[0318] Step 3

[0319] Trifluoroacetic acid (4.00 ml, 35.1 mmol) was added to a solution of tert-butyl 4-[N-(4-fluorophenyl)carbamoyl]piperazine-1-carboxylate (83_3) (1.80 g, 5.58 mmol) in dichloromethane (10 ml) at 0°C and allowed to warm to room temperature for 1 hour. LCMS confirmed complete consumption of the starting material, with the product as the main peak. The reaction solution was concentrated to yield 3.40 g of the crude TFA salt of N-(4-fluorophenyl)piperazine-1-carboxamide (83_4) as a yellow oil. MS m / z: 223.1 [M+H].

[0320] Step 4

[0321] [6-Chloro-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (Int A) (550 mg, 1.39 mmol) and N-(4-fluorophenyl)piperazine-1-carboxamide (83_4) (759 mg, 2.37 mmol) were dissolved in DMF (10 ml) at room temperature. Potassium carbonate (771 mg, 5.58 mmol) was then added and the mixture was heated to 60°C for 1 h. TLC confirmed complete consumption of the starting material. The mixture was diluted with 40 ml of water and extracted twice with 40 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol in a ratio of 5:1 to obtain 250 mg of N-(4-fluorophenyl)-4-[5-(hydroxymethyl)-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximide (83_5) as a yellow solid in a yield of 30.9%. MS m / z: 581.2 [M+H].

[0322] Step 5

[0323] At room temperature, N-(4-fluorophenyl)-4-[5-(hydroxymethyl)-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximidazole (83_5) (30 mg, 0.05 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15 mg, 0.06 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (3.8 mg, 0.01 mmol), and sodium carbonate (11 mg, 0.10 mmol) were dissolved in a mixture of 1,4-dioxane (1 ml) and water (0.2 ml). The atmosphere was purged with nitrogen three times, and the mixture was heated to 90°C for 2 h. LCMS monitored the complete consumption of the product. The mixture was filtered, and anhydrous sodium sulfate was added to the filtrate for drying. The mixture was filtered again, concentrated, and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol (10:1) to obtain 20 mg of 4-[3-(3-chloropyridin-4-yl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (83_6) as a yellow solid in a yield of 70.8%. MS m / z: 566.3 [M+H].

[0324] Step 6

[0325] To a solution of 4-[3-(3-chloropyridin-4-yl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (83_6) (20 mg, 0.04 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (0.30 ml, 2.63 mmol) at 0°C. The mixture was allowed to warm to room temperature and react overnight. LCMS monitored the complete consumption of the starting material. The reaction mixture was concentrated, diluted with methanol, and purified by preparative HPLC. The resulting product was lyophilized to obtain 3.52 mg of 4-(3-(3-chloropyridin-4-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl)-N-(4-fluorophenyl)piperazine-1-carboximide (ZS5084-083) as a yellow solid in an 18.3% yield. MS m / z: 482.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 14.10 (s, 1H), 9.62 (s, 1H), 8.81 (s, 1H), 8.68 (d, J = 5.0Hz, 1H), 8.14 (d, J = 4.9Hz, 1H), 7.94 (br s,2H),7.31(d,J=6.8Hz,5H),5.60(br s,1H),4.69(s,2H),3.74(d,J=3.5Hz,4H),3.63(d,J=2.0Hz,4H). 19 F NMR (376MHz, DMSO-d6) δ = -116.3.

[0326] Example 22

[0327] Step 1

[0328] N-(4-Fluorophenyl)-4-[5-(hydroxymethyl)-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximide (83_5) (80 mg, 0.14 mmol) and 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (42 mg, 0.17 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1 ml) and water (0.2 ml) at room temperature. Sodium carbonate (29 mg, 0.28 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (10 mg, 0.01 mmol) were then added. The atmosphere was purged with nitrogen three times, and the temperature was raised to 90°C for 2 h. LCMS monitoring indicated complete consumption of the starting material, with the main peak being the product. The mixture was filtered, and anhydrous sodium sulfate was added to the filtrate for drying. The mixture was filtered, concentrated, and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 5:1) to obtain 66 mg of 4-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (84_1) as a yellow solid in a yield of 80.8%. MS m / z: 584.3 [M+H].

[0329] Step 2

[0330] Trifluoroacetic acid (0.80 ml, 7.02 mmol) was added to a solution of 4-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (84_1) (66 mg, 0.11 mmol) in dichloromethane (2 ml) at 0°C. The mixture was allowed to warm to room temperature and react overnight. LCMS monitored the complete consumption of the starting material. The reaction mixture was concentrated, diluted with methanol, and purified by preparative HPLC. The resulting product was lyophilized to obtain 6.1 mg of 4-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]-N-(4-fluorophenyl)piperazine-1-carboxamide (ZS5084-084) as a pale yellow solid in a yield of 10.8%. MS m / z: 500.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ=14.23(s,1H),9.65(s,1H),8.35(d,J=5.0Hz,1H),8.20(d,J=5.1Hz,1H),7.96(br s,2H),7.31(d,J=6.8Hz,4H),5.58(br s, 1H), 4.70 (br s, 2H), 3.72-3.77 (m, 4H), 3.63 (d, J = 2.9Hz, 4H). 19 F NMR (376MHz, DMSO-d6) δ = -70.4, -116.3.

[0331] Example 23

[0332] Step 1

[0333] N,N-Dimethylpyridin-4-amine (12.0 g, 9.82 mmol) was added to a solution of 3-chloro-4-iodopyridin-2-amine (85_1) (5.00 g), di-tert-butyl dicarbonate (25 mg, 117.9 mmol), and triethylamine (11.9 g (117.9 mmol) in tetrahydrofuran (100 mL). The reaction was stirred at 65°C for 16 h. LCMS indicated the reaction was complete. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (200 mL x 2). The combined ethyl acetate layers were washed once with saturated brine. The organic phase was concentrated and dried by spin drying. Purification was performed by silica gel column chromatography using a mobile phase of petroleum ether:ethyl acetate = 3:1. 8.20 g of tert-butyl N-tert-butoxycarbonyl-N-(3-chloro-4-iodopyridin-2-yl)carbamate (85_2) was obtained as a light yellow solid in a yield of 91.8%. MS m / z: 298.9 [M+H-100-56].

[0334] Step 2

[0335] [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (645 mg, 0.88 mmol) was added to a solution of tert-butyl N-tert-butyloxycarbonyl-N-(3-chloro-4-iodopyridin-2-yl)carbamate (85-2) (4.00 g, 8.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.68 g, 10.56 mmol), and potassium acetate (2.6 g, 26.39 mmol) in dimethyl sulfoxide (20 mL). The reaction was stirred at 90°C for 16 h. LCMS showed the presence of product. The mixture was diluted with 10 mL of water and extracted with ethyl acetate (20 mL x 2). The combined ethyl acetate layers were washed once with saturated brine. The organic phase was concentrated and dried by spin-drying. The mixture was then purified by silica gel column chromatography (mobile phase: DCM:MeOH = 10:1) to obtain 2.40 g of tert-butyl N-[tert-butyloxycarbonyl]-N-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (85_3) as a brown oil in a 59.9% yield. MS m / z: 298.9 [M+H-100-56].

[0336] Step 3

[0337] Dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) (6.1 mg, 0.01 mmol) was added to a solution of N-(4-fluorophenyl)-4-[5-hydroxymethyl-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximidamide (50 mg, 0.09 mmol), tert-butyl N-[tert-butoxycarbonyl]-N-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (85_3) (39 mg, 0.05 mmol) and potassium phosphate (54 mg, 0.26 mmol) in 1,4-dioxane (2 ml, 100.0%) and the mixture was stirred at 90°C for 16 h. LCMS showed completion. The mixture was diluted with 10 mL of water and extracted with ethyl acetate (20 mL x 2). The combined ethyl acetate layers were washed once with saturated brine. The organic phase was concentrated and dried, and then purified by silica gel column chromatography using a mobile phase of petroleum ether:ethyl acetate in a ratio of 1:1. 40 mg of N-tert-butyloxycarbonyl-N-[3-chloro-4-(6-{4-[N-(4-fluorophenyl)ureaamidoyl]piperazin-1-yl}-5-hydroxymethyl-1-oxocyclooxy-2-yl-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (85_4) was obtained as a brown solid in a yield of 56.9%. MS m / z: 781.2 [M+H].

[0338] Step 4

[0339] N-tert-Butyloxycarbonyl-N-[3-chloro-4-(6-{4-[N-(4-fluorophenyl)ureamidyl]piperazin-1-yl}-5-hydroxymethyl-1-oxocyclooxy-2-yl-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (85-4) (50 mg, 0.06 mmol) was added to a solution of trifluoroacetic acid (1 mL) in dichloromethane (2 mL). The reaction was stirred at 20°C for 16 h. The reaction was dried and quenched with saturated aqueous NaOH (1 mL). Dilute with 10 mL of water and extract with ethyl acetate (20 mL x 2). Combine the ethyl acetate layers and wash once with saturated brine. The organic phase is concentrated and spin-dried. Purify by Prep-HPLC to obtain 3 mg of 4-[3-(2-amino-3-chloropyridin-4-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximidamide (ZS5084-085) as a yellow solid in a 9.5% yield. MS m / z: 497.2 [M+H]. 1H NMR(400MHz,DMSO-d6)δ=14.02 -13.82(m,1H), 9.67-9.57(m,1H), 8.13(s,1H), 8.03-8.00(m,1H), 7.98-7.91(m,2H), 7 .31(d,J=6.6Hz,4H), 7.06-7.00(m,1H), 6.52-6.40(m,2H), 5.62-5.48(m,1H), 4.66(br s,2H), 3.76-3.72(m,4H), 3.64-3.58(m,4H).

[0340] Example 24

[0341] Step 1

[0342] To a reaction flask at room temperature, 6-chloro-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (98 mg, 0.25 mmol), tert-butyl N-[tert-butyloxycarbonyl]-N-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (86_1) (113 mg, 0.25 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (18 mg, 0.03 mmol) were dissolved in a mixture of 1,4-dioxane (0.4 ml) and water (0.1 ml). The mixture was deoxygenated by nitrogen purging for 3 minutes, and the mixture was heated to 60°C with stirring for 12 hours. LCMS analysis indicated product formation, with the remaining starting material. The reaction mixture was concentrated and purified by silica gel column chromatography to obtain 30 mg of N-tert-butylcarbonyl-N-{3-chloro-4-[6-chloro-5-hydroxymethyl)-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-3-yl]pyridin-2-yl}carbamate (86-2) as a light yellow liquid in a yield of 19.8%. MS m / z: 495.2 [M+H-100].

[0343] Step 2

[0344] At room temperature, tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate (79_1) (500 mg, 2.23 mmol) was added to a reaction flask, dissolved in 4-fluoroaniline (5 ml, 45.02 mmol), and trichloroalane (2.9 g, 22.3 mmol). The mixture was heated to 120°C and stirred overnight. LCMS indicated product production. The reaction solution was quenched with sodium carbonate, and the organic phase was extracted with ethyl acetate, dried, and spin-dried. Purification was performed by silica gel column chromatography using a mobile phase of dichloromethane:methanol (10% triethylamine) in a ratio of 10:1 to afford 465 mg of N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (86_3) as an oil in an 88.6% yield. MS m / z: 236.1 [M+H].

[0345] Step 3

[0346] To a reaction flask at room temperature, N-tert-butylcarbonyl-N-{3-chloro-4-[6-chloro-5-hydroxymethyl)-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-3-yl]pyridin-2-yl}carbamate (86_2) (30 mg, 0.05 mmol) and N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (86_3) (11.8 mg, 0.05 mmol) were added. The mixture was dissolved in DMF (0.5 ml) and stirred at room temperature for 4 h. Product formation was monitored by LCMS, and the reaction solution was concentrated and carried on to the next step. MS m / z: 794.5 [M+H].

[0347] Step 4

[0348] To a reaction flask at room temperature was added N-tert-butyloxycarbonyl-N-[3-chloro-4-(6-{4-[N-(4-fluorophenyl)carbamoyl]-4-methylpiperidin-1-yl}-5-hydroxymethyl-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (86_4) (40 mg, 0.05 mmol), dissolved in dichloromethane (1.5 ml), and trifluoroacetic acid (0.2 ml) was added dropwise. The mixture was stirred and allowed to react for 12 h. 1 ml of 10% sodium hydroxide solution was added dropwise. Product formation was monitored by LCMS. The reaction solution was spin-dried, transferred to MeOH, and purified by preparative purification. 1-[3-(2-amino-3-chloropyridin-4-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (ZS5084-086) was obtained as a white solid in a 29% yield. MS m / z: 510.2 [M+H]. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.10 (d, J = 5.1Hz, 1H), 7.17 (d, J = 5.9Hz, 1H), 7.04-6.99 (m, 2H), 6.81-6.77 (m, 2H), 5.08 (br s,2H),4.81(d,J=4.3Hz,2H),4.47(br s,2H),4.10(br s,1H),3.55-3.40(m,4H),2.37-2.25(m,2H),1.78(d,J=7.0Hz,2H),1.39(s,3H). 19 F NMR (376MHz, CHLOROFORM-d) δ = -121.6.

[0349] Example 25

[0350] Step 1

[0351] At room temperature, N-(4-fluorophenyl)-4-[5-(hydroxymethyl)-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximide (83_5) (130 mg, 0.22 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (50 mg, 0.25 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (16 mg, 0.02 mmol), and sodium carbonate (47 mg, 0.45 mmol) were dissolved in a mixture of 1,4-dioxane (2 ml) and water (0.4 ml). The mixture was purged with nitrogen three times and then heated to 90°C for 2 h. LCMS monitored the substantial consumption of the starting material. The reaction mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using a mobile phase of DCM:MeOH = 5:1 to afford 105 mg of N-(4-fluorophenyl)-4-[5-(hydroxymethyl)-1-(oxal-2-yl)-3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]piperazine-1-carboxamide (92_1) as a yellow solid in a yield of 89.8%. MS m / z: 532.3 [M+H].

[0352] Step 2

[0353] N-(4-Fluorophenyl)-4-[5-(hydroxymethyl)-1-(oxazolidin-2-yl)-3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazol-6-yl]piperazine-1-carboxamide (92_1) (105 mg, 0.20 mmol) was dissolved in methanol (5 ml) at room temperature. A solution of hydrochloric acid in 1,4-dioxane (6.00 ml, 12.0 mmol) was added and the mixture was allowed to react at room temperature for 1 h. LCMS monitored the complete consumption of the starting material. The reaction mixture was concentrated, diluted with methanol, and purified by preparative HPLC. The resulting product was lyophilized to obtain 62 mg of N-(4-fluorophenyl)-4-[5-(hydroxymethyl)-3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximide (ZS5084-092) as a yellow solid in a yield of 70.0%. MS m / z: 448.2 [M+H]. 1 H NMR(DMSO-d6)δ=14.28(br s,1H),9.69(s,1H),8.86(br d,J=4.8Hz,2H),8.63(br d,J=5.0Hz,2H),7.98(br s, 2H), 7.31 (d, J = 6.8Hz, 4H), 4.77 (s, 2H), 3.75 (br d, J = 3.3Hz, 4H), 3.62 (br d, J = 2.6Hz, 4H). 19 F NMR (376MHz, DMSO-d6) δ = -116.3.

[0354] Example 26

[0355] Step 1

[0356] N-Phenylurea aminothioic acid (93_1) (2 g, 13.14 mmol) was added to a reaction flask at room temperature and dissolved in ethanol (160 ml). Methyl iodide (2.8 g, 19.71 mmol) was added dropwise. The temperature was raised to 85°C with stirring and the reaction was refluxed for 3 h. LCMS monitoring indicated product formation, indicating complete reaction of the starting materials. The reaction solution was spin-dried, washed with ethyl acetate, and concentrated to yield 3.5 g of crude N-phenyl(methylthio)formamidine (93_2). MS m / z: 167.2 [M+H].

[0357] Step 2

[0358] N-Phenyl(methylthio)formamidine (93_2) (2.18 g, 13.11 mmol) was added to a reaction flask at room temperature and dissolved in tert-butanol (25 ml). Tert-butyl piperazine-1-carboxylate (2.93 g, 15.73 mmol) and triethylamine (3.98 g, 39.33 mmol) were then added. The temperature was raised to 85°C with stirring and the reaction was continued for 12 hours. The product was monitored by LCMS. The reaction solution was dried and purified by silica gel column chromatography to afford tert-butyl 4-(N-phenylcarbamoyl)piperazine-1-carboxylate (93_3) as a white solid (1.1 g) and 1.9 g of the crude product. MS m / z: 305.2 [M+H].

[0359] Step 3

[0360] tert-Butyl 4-(N-phenylcarbamoyl)piperazine-1-carboxylate (93_3) (1.1 g, 3.61 mmol) was added to a room temperature reaction flask and dissolved in dichloromethane (10 ml). Trifluoroacetic acid (1.3 g, 11.4 mmol) was added dropwise and stirred for 0.5 h. LCMS was used to monitor product formation. The reaction solution was then dried and used in the next step. MS m / z: 205.1 [M+H].

[0361] Step 4

[0362] To a reaction flask at room temperature, 6-chloro-3-(2,3-dichlorophenyl)-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (93_4) (62 mg, 0.15 mmol), N-phenylpiperazine-1-carboximidamide (61 mg, 0.3 mmol), and potassium carbonate (82 mg, 0.6 mmol) were dissolved in N,N-dimethylformamide (1 ml). Stirring was initiated and the temperature was raised to 60°C for 6 h. LCMS analysis indicated product formation, with a small amount of starting material remaining. The reaction solution was extracted with ethyl acetate, washed with brine, and the organic phase was dried to afford crude 4-[3-(2,3-dichlorophenyl)-5-hydroxymethyl-1-oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-phenylpiperazine-1-carboximidamide (93_5), which was used directly in the next reaction. MS m / z: 581.2 [M+H].

[0363] Step 5

[0364] 4-[3-(2,3-Dichlorophenyl)-5-hydroxymethyl-1-oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-phenylpiperazine-1-carboximidamide (93_5) (87 mg, 0.15 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.3 ml) was added dropwise. The mixture was stirred and allowed to react for 12 h. The product formation was monitored by LCMS. The reaction solution was dried and dissolved in 0.5 ml of dimethyl sulfoxide solution. 0.1 ml of 10% aqueous sodium hydroxide solution was added dropwise. Stirring was continued for 0.5 h. Preparative purification was performed to obtain 7.5 mg of 4-[3-(2,3-dichlorophenyl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-phenylpiperazine-1-carboximidamide (ZS5084-094) as a white solid. MS m / z: 497.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ=13.95-13.78(m,1H),9.65(s,1H),8.08-8.00(m,2H),7.78(dd,J=1.5,8.0Hz,1H),7.73(dd,J=1.5, 7.8Hz,1H),7.56-7.50(m,1H),7.46(d,J=7.4Hz,2H),7.28-7.25(m,3H),4.65(s,2H),3.76-3.72(m,4H),3.65-3.55(m,4H).

[0365] Example 27

[0366] Step 1

[0367] At room temperature, (4-fluorophenyl)thiourea (96_1) (2.20 g, 12.9 mmol) and iodomethane (0.97 ml, 15.5 mmol) were dissolved in ethanol (20 ml) and heated to 80°C for 3 h. TLC monitored the complete consumption of the starting material. The reaction solution was concentrated to yield a crude yellow oil, which was used directly in the next reaction. MS m / z: 185.0 [M+H].

[0368] Step 2

[0369] N-(4-Fluorophenyl)(methylsulfanyl)carboximide (96_2) (2.38 g, 12.9 mmol), tert-butyl piperazine-1-carboxylate (2.89 g, 15.5 mmol), and triethylamine (7.26 ml, 51.7 mmol) were added to a solution of tert-butyl alcohol (20 ml) at room temperature and heated to 90°C for overnight reaction. TLC monitored the complete consumption of the starting materials. Aqueous sodium hypochlorite solution was added to the reaction solution for quenching and stirring until no odor was emitted. The solution was diluted with 40 ml of water and extracted twice with 50 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phases were concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol = 10:1 to obtain 4.19 g of tert-butyl 4-[N-(4-fluorophenyl)carbamoyl]piperazine-1-carboxylate (96_3) as a crude yellow oil. MS m / z: 323.1 [M+H].

[0370] Step 3

[0371] Trifluoroacetic acid (9.31 ml, 81.6 mmol) was added to a solution of tert-butyl 4-[N-(4-fluorophenyl)carbamoyl]piperazine-1-carboxylate (96_3) (4.19 g, 13.0 mmol) in dichloromethane (10 ml) at 0°C and allowed to react overnight at room temperature. LCMS monitoring indicated complete consumption of the starting material, with the product as the main peak. The reaction solution was concentrated, diluted with methanol, and purified by preparative Prep-HPLC. The resulting product was lyophilized to yield 1.69 g of N-(4-fluorophenyl)piperazine-1-carboxamide (96_4) as a yellow solid (trifluoroacetate salt). The yield was 58.5%. MS m / z: 223.1 [M+H].

[0372] Step 4

[0373] At room temperature, [6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (Int) (1.10 g, 2.79 mmol) and N-(4-fluorophenyl)piperazine-1-carboxamide (96_4) (trifluoroacetate, 1.58 g, 4.93 mmol) were dissolved in N,N-dimethylformamide (20 ml). Potassium carbonate (1.54 g, 11.2 mmol) was added, and the mixture was heated to 60°C for 1 h. LCMS monitored the complete consumption of the starting material. The mixture was diluted with 60 ml of water and extracted twice with 50 ml of ethyl acetate. The organic layers were combined and concentrated to obtain 627 mg of N-(4-fluorophenyl)-4-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximide (96_5) as a yellow solid in a 38.7% yield. MS m / z: 581.1 [M+H].

[0374] Step 5

[0375] At room temperature, N-(4-fluorophenyl)-4-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximide (96_5) (100 mg, 0.17 mmol), 2-(2,3-difluorophenyl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane (45 mg, 0.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (12 mg, 0.02 mmol), and sodium carbonate (36 mg, 0.34 mmol) were dissolved in a mixture of 1,4-dioxane (1 ml) and water (0.2 ml). The mixture was purged with nitrogen three times and then heated to 90°C for 2 h. LCMS monitored the substantial consumption of the starting material. The reaction mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol (10:1) to afford 76 mg of 4-[3-(2,3-difluorophenyl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (96_6) as a yellow solid in a yield of 78.9%. MS m / z: 567.2 [M+H].

[0376] Step 6

[0377] Trifluoroacetic acid (0.4 ml, 6.84 mmol) was added to a solution of 4-[3-(2,3-difluorophenyl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (96_6) (76 mg, 0.14 mmol) in dichloromethane (2 ml) at room temperature. The mixture was allowed to react overnight at room temperature. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and a small amount of water was added. Solid sodium bicarbonate was then added, and the pH of the reaction solution was adjusted to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 23 mg of 4-[3-(2,3-difluorophenyl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboxamide (ZS5084-096) as a yellow solid in a 35.8% yield. MS m / z: 483.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 13.93 (br s, 1H), 9.66 (s, 1H), 8.07-8.15 (m, 1H), 7.96 (br s,2H),7.47-7.58(m,1H),7.35-7.43(m,1H),7.31(d,J=6.8Hz,4H),5.53(br s,1H),4.70(s,2H),3.69-3.90(m,8H). 19 F NMR (376MHz, DMSO-d6) δ = -116.3, -138.4, -139.3.

[0378] Example 28

[0379] Step 1

[0380] N-(4-Fluorophenyl)-4-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperazine-1-carboximide (98_1) (100 mg, 0.17 mmol) and 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (53 mg, 0.21 mmol) were dissolved in a mixture of 1,4-dioxane (1 ml) and water (0.2 ml) at room temperature. Sodium carbonate (36 mg, 0.34 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (12 mg, 0.02 mmol) were then added. The atmosphere was purged with nitrogen three times, and the reaction temperature was raised to 90°C for 12 h. LCMS monitored the complete consumption of the starting material. The mixture was filtered, and anhydrous sodium sulfate was added to the filtrate for drying. The mixture was filtered, concentrated, and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol = 5:1 to obtain 55 mg of 4-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (98_2) as a yellow solid. MS m / z: 584.2 [M+H].

[0381] Step 2

[0382] At room temperature, 4-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)piperazine-1-carboximide (98_2) (55 mg, 0.09 mmol) and methylamine hydrochloride (7.6 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1 ml). Potassium carbonate (32 mg, 0.24 mmol) was added, and the mixture was heated to 100°C and reacted overnight. LCMS monitored the complete consumption of the starting material. The mixture was diluted with 5 ml of water and extracted twice with 5 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated, diluted with methanol, and purified by Prep-HPLC. After lyophilization, 20 mg of 4-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)piperazine-1-carboxamide (98_3) was obtained as a white solid in a 37.4% yield. MS m / z: 595.2 [M+H].

[0383] Step 3

[0384] Trifluoroacetic acid (0.4 ml, 3.51 mmol) was added to a solution of 4-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)piperazine-1-carboxamide (98_3) (20 mg, 0.03 mmol) in dichloromethane (1 ml) at room temperature and allowed to react for 3 h. LCMS analysis indicated that the starting material was essentially consumed. The reaction solution was concentrated, diluted with methanol, and then sodium hydroxide solution was added to adjust the pH to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to afford 5.1 mg of 4-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)piperazine-1-carboximide (ZS5084-098) as a yellow solid in a 33.1% yield. MS m / z: 511.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ=13.92(br s,1H),9.64(s,1H),8.11(d,J=5.1Hz,1H),7.95(br s,2H),7.31(d,J=6.8Hz,4H),7.03(d,J=5.1Hz,1H),6.79(br s, 1H), 4.66 (s, 2H), 3.74 (d, J = 3.1Hz, 4H), 3.61 (d, J = 2.5Hz, 4H), 2.93 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ = -116.3.

[0385] Example 29

[0386] Step 1

[0387] 1-[3-(2,3-dichlorophenyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-carboximidamide (100_1) (200 mg, 0.41 mmol), cesium carbonate (98 mg, 0.3 mmol) and 5-bromo-2H-1,3-benzodioxole (412 mg, 2.05 mmol) were dissolved in tert-butanol (2 ml) in a reaction flask at room temperature. After stirring for 10 minutes, the mixture was added to the flask. To the reaction flask were added (1E, 4E)-1,5-diphenylpentaene-1,4-dien-3-one bis((1Z, 4E)-1,5-diphenylpenta-1,4-dien-3-one) bispalladium (18 mg, 0.0205 mmol), di-tert-butyl[3,6-dimethoxy-2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (1.9 mg, 0.004 mmol), nitrogen was replaced three times, and the temperature was raised to 85°C for 2 h. Product formation was monitored by LCMS, and the reaction solution was dried to give the crude product of 1-[3-(2,3-dichlorophenyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-hexahydro-2H-1,3-benzodioxol-5-yl)-4-methylpiperidine-4-carboximidamide (100_2), which was used directly in the next reaction. MS m / z: 608.2 [M+H].

[0388] Step 2

[0389] N-(2H-1,3-Benzodioxin-4-yl)-1-[3-(2,3-dichlorophenyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (100_2) (250 mg, 0.41 mmol) was dissolved in 12.7 mL of 4M HCl in methanol at room temperature and stirred at 40°C for 12 h. Product formation was monitored by LCMS. The reaction solution was spin-dried and purified by preparative purification to obtain 71.5 mg of N-(2H-1,3-Benzodioxin-4-yl)-1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (ZS5084-100) as a yellow solid, with a two-step yield of 33.3%. MS m / z: 524.1 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=13.47(br s,1H),10.59(s,1H),9.32(br s,1H),8.80(br s,1H),8.52(s,1H),7.76(dd,J=8.0,1.5Hz,1H),7.70(dd,J=7.7,1.3Hz,1H),7.50(t,J=7.8Hz,1H),7.04(d,J=7.5Hz,1H),6.98(t,J=7 .8Hz,1H),6.84(d,J=8.0Hz,1H),6.13(s,2H),3.85-3.93(m,2H),3.74-3.79(m,2H),2.22-2.29(m,2H),1.81-1.91(m,2H),1.48(s,3H).

[0390] Example 30

[0391] Step 1

[0392] To a solution of N,N-dimethylformamide (20 ml) at room temperature were added 1-[(tert-butyl)carbonyl]-4-methylpiperidine-4-carboxylic acid (2 g, 8.22 mmol), 2-hydro-1,3-phenylenedioxy-5-amine (1.69 g, 12.33 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (4.69 g, 12.33 mmol), and ethylbis(propan-2-yl)amine (2.12 ml, 16.44 mmol). The mixture was allowed to react at room temperature for 18 hours. LCMS indicated the disappearance of the starting material and the desired target molecular weight. TLC (ethyl acetate:petroleum ether = 1:3) indicated the disappearance of the starting material and the formation of a large new spot. The reaction mixture was diluted three times with water (50 mL) and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated aqueous citric acid (20 mL) and saturated aqueous sodium bicarbonate (20 mL), respectively, and finally dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-30%) and concentrated in vacuo to afford 2.9 g of tert-butyl 4-[(2-hydro-1,3-benzodioxy-5-yl)carbamoyl]-4-methylpiperidine-1-carboxylate (2B) as a brown oil in a 97.4% yield. MS m / z: 307.1 [M-55].

[0393] Step 2

[0394] To an ethyl acetate solution (50 mL) at room temperature, tert-butyl 4-[(2-hydrogen-1,3-benzodioxy-5-yl)carbamoyl]-4-methylpiperidine-1-carboxylate (2.9 g, 8.0 mmol) and phosphorus pentasulfide (0.9 g, 4.0 mmol) were added. The mixture was then heated to 90°C and refluxed for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was diluted twice with water (50 mL) and extracted twice with ethyl acetate (100 mL). The organic phase was neutralized with aqueous sodium hydroxide (20 mL), washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The product was concentrated in vacuo to afford 2.7 g of crude tert-butyl 4-[(2-hydrogen-1,3-benzodioxy-5-yl)carbamoyl]-4-methylpiperidine-1-carboxylate (3B) as a yellow solid, which was used directly in the next step. MS m / z: 323.0 [M-55].

[0395] Step 3

[0396] To a tetrahydrofuran (20 ml) solution at room temperature, tert-butyl 4-[(2-hydro-1,3-benzodinitro-5-yl)aminosulfonyl]-4-methylpiperidine-1-carboxylate (1.5 g, 3.96 mmol) and iodomethane (5.63 ml, 39.63 mmol) were added. The mixture was then heated to 30°C and allowed to react for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) to afford 500 mg of tert-butyl 4-[(Z)-[(2-hydro-1,3-benzodinitro-5-yl)imino](methylsulfonyl)methyl]-4-methylpiperidine-1-carboxylate (4B) as a yellow oil in a 32.1% yield. MS m / z: 393.1 [M+H].

[0397] Step 4

[0398] To a high-temperature, high-pressure reactor at room temperature, tert-butyl 4-[(Z)-[(2-hydro-1,3-benzodinitro-5-yl)imino](methylsulfonyl)methyl]-4-methylpiperidine-1-carboxylate (900 mg, 2.29 mmol) was added to an aqueous ammonia solution (15 mL) and N-methylpyrrolidone (3 mL). The reaction was then heated to 120°C and allowed to react for 48 h. LCMS analysis revealed a large amount of residual starting material and a small amount of the desired target molecular weight. The reaction solution was extracted three times with ethyl acetate (20 mL). The organic phase was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-10%). Concentration in vacuo afforded 350 mg of crude tert-butyl 4-[N-(2-hydro-1,3-benzodinitro-5-yl)aminoimidazolyl]-4-methylpiperidine-1-carboxylate (5B) as a yellow oil (containing a large amount of NMP). MS m / z: 362.1 [M+H].

[0399] Step 5

[0400] To a solution of dioxane hydrochloride (5 mL) was added tert-butyl 4-[N-(2-hydrogen-1,3-benzodioxy-5-yl)aminoimidazolyl]-4-methylpiperidine-1-carboxylate (300 mg, 0.84 mmol) at room temperature. The mixture was reacted under nitrogen for 3 h. TLC analysis indicated the disappearance of the starting material and the formation of a highly polar spot. The reaction solution was concentrated in vacuo to afford 200 mg of crude N-(benzo[d][1,3]dioxy-5-yl)-4-methylpiperidine-4-carboximidamide (Int) as a yellow oil, which was used directly in the next reaction. MS m / z: 262.1 [M+H].

[0401] Step 6

[0402] To a solution of N-methylpyrrolidone (2 ml) at room temperature was added N-(benzo[d][1,3]dioxy-5-yl)-4-methylpiperidine-4-carboximidamide (200 mg, 0.77 mmol), [6-chloro-3-(2,3-dichlorophenyl)-1-(oxo-2-yl)-1-hydro-pyrazolin[3,4-b]pyrazin-5-yl]methanol (50 mg, 0.12 mmol), and potassium carbonate (317 mg, 2.3 mmol). Under nitrogen, the mixture was heated to 60°C and stirred for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was diluted with water (5 mL x 2) and extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0:100 to 10:90) to afford 25 mg of 2-(2-H-benzodiphenoxy-5-yl)-1-[3-(2,3-dichlorophenyl)-5-(hydroxymethyl)-1-(oxo-2-yl)-1-hydro-pyrazolin-3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxylic acid amide (101_1) as a yellow solid in a yield of 5.1%. MS m / z: 638.2 [M+H].

[0403] Step 7

[0404] To a solution of dichloromethane (1 ml) at room temperature was added 2-(2-H-)-1,3-benzodiphenoxy-5-yl)-1-[3-(2,3-dichlorophenyl)-5-(hydroxymethyl)-1-(oxo-2-yl)-1-hydro-pyrazolino[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxylic acid oxime (25 mg, 0.04 mmol) and trifluoroacetic acid (0.79 ml, 6.89 mmol). The reaction was stirred at room temperature under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC (mobile phase: CH3CN:H2O containing 0.1% TFA = 5:95 to 95:5) to afford 1.55 mg of N-(2-hydro-1,3-benzodiphenoxy-5-yl)-1-[3-(2,3-dichlorophenyl)-5-(hydroxymethyl)-1-hydro-pyrazolino[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxylic acid amide (ZS5084-101), in a 7.0% yield. MS m / z: 554.1 [M+H]. 1H NMR (400MHz, METHANOL-d4) δ = 7.68-7.63 (m, 2H), 7.45-7.41 (m, 1H), 6.96 (d, J = 8.1Hz, 1H), 6.81-6.75 ( m,2H),6.06(s,2H),4.78(s,2H),3.63-3.54(m,4H),2.40-2.33(m,2H),2.02-1.98(m,2H),1.56(s,3H).

[0405] Example 31

[0406] Step 1

[0407] 1-[3-(2,3-dichlorophenyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (103_1) (200 mg, 0.41 mmol), 5-bromo-2,3-dihydro-1-benzofuran (258 μl, 2.05 mmol), and cesium carbonate (401 mg, 1.23 mmol) were added to a reaction flask at room temperature and dissolved in tert-butanol (2 ml). Stirring was started for 10 min. Minutes later, (1E,4E)-1,5-diphenylpentaene-1,4-diene-3-one bis((1Z,4E)-1,5-diphenylpenta-1,4-diene-3-one) bispalladium (18.8 mg, 0.02 mmol) and di-tert-butyl[3,6-dimethoxy-2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (19.9 mg, 0.04 mmol) were added, N2 was replaced three times, and the temperature was raised to 85°C for 12 h. LCMS monitoring revealed a small amount of remaining starting material, revealing the product, 1-[3-(2,3-dichlorophenyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(2,3-dihydro-1-benzofuran-5-yl)-4-methylpiperidine-4-carboximidamide (103_2). The reaction mixture was diluted with methanol, filtered, and the filtrate concentrated and used directly in the next step. MS m / z: 606.2 [M+H].

[0408] Step 2

[0409] The crude product from the previous step, 1-[3-(2,3-dichlorophenyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(2,3-dihydro-1-benzofuran-5-yl)-4-methylpiperidine-4-carboximidamide (103_2), was dissolved in methanol (2 ml) at room temperature. 4 M methanolic hydrochloric acid (13 ml, 52.0 mmol) was slowly added dropwise. The mixture was stirred, heated to 40°C, and reacted for 12 hours. LCMS monitoring indicated the product was formed, indicating the absence of residual starting material. The reaction solution was spin-dried, dissolved in dimethyl sulfoxide, and sent for Prep-HPLC preparation. 53.83 mg of 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(2,3-dihydro-1-benzofuran-5-yl)-4-methylpiperidine-4-carboximidamide (ZS5084-103) was obtained as a white solid in a yield of 31.2%. MS m / z: 522.1 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=13.46(br s,1H),10.40(br s,1H),9.02(br s,1H),8.43-8.52(m,2H),7.67-7.79(m,2H),7.46-7.56(m,1H),7.25(br s,1H),7.01-7.14(m,1H),6.84-6.98(m,1H),4.61(br s,2H),3.77-3.90(m,4H),3.23(br s,2H),2.23-2.29(m,2H),1.79-1.89(m,2H),1.47(br s,3H).

[0410] Example 32

[0411] Step 1

[0412] 6-Chloro-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (501 mg, 1.27 mmol), 2,3-dichlorophenylboronic acid (106-1) (266 mg, 1.4 mmol), and sodium carbonate (403 mg, 3.81 mmol) were added to a solution of palladium(2+)bis[2-(di-tert-butylphosphino)cyclopenta-2,4-dien-1-yl]ferric chloride (887919-35-9) (82 mg, 0.13 mmol) in water (1 mL) and 1,4-dioxane (5 mL). The reaction mixture was stirred at 90°C under nitrogen for 2 h. LCMS showed the reaction was complete. The mixture was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate. The combined ethyl acetate layers were washed once with saturated brine. The organic phase was concentrated and dried by spin-drying. Purification was performed by silica gel column chromatography using a mobile phase of petroleum ether:ethyl acetate in a ratio of 1:4 to afford 330 mg (0.8 mmol) of 6-chloro-3-(2,3-dichlorophenyl)-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (106-2), in a yield of 62.81%. MS m / z: 413.1 [M+H].

[0413] Step 2

[0414] 6-Chloro-3-(2,3-dichlorophenyl)-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (106-2) (100 mg, 0.24 mmol) and N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (85 mg, 0.36 mmol) were added to a solution of potassium carbonate (33 mg, 0.24 mmol) in dimethylformamide (3 mL), and the mixture was stirred at 60° C. for 5 h. LCMS showed the reaction was complete. The mixture was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate. The combined ethyl acetate layers were washed once with saturated brine. The organic phase was concentrated and spin-dried to dryness to obtain 122 mg of 1-[3-(2,3-dichlorophenyl)-5-hydroxymethyl-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidin-4-carboximidamide (106-3) as a yellow oil in an 82.4% yield. MS m / z: 612.2 [M+H].

[0415] Step 3

[0416] 1-[3-(2,3-dichlorophenyl)-5-hydroxymethyl-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (106-3) (122 mg, 0.2 mmol) was added to a solution of trifluoroacetic acid (1 ml, 8.77 mmol, 43.8 g) in dichloromethane (2 mL) and stirred at 20°C for 16 h. The reaction mixture was spin-dried and purified by Prep-HPLC (H2O / ACN, NH4HCO3) to afford 4.65 mg of 1-[3-(2,3-dichlorophenyl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (ZS5084-106) as a white solid in a 4.4% yield. MS m / z: 528.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.71 (br s, 1H), 7.78-7.72 (m, 2H), 7.51 (t, J = 7.9Hz, 1H), 7.07 (t, J = 8.2Hz, 2H), 6.75-6.67 (m, 2H), 5.75 (br dd,J=2.2,4.2Hz,1H),5.34(t,J=5.7Hz,1H),4.59(d,J=5.8Hz,2H),3.65-3.56(m ,2H),3.31-3.42(m,2H),2.35-2.26(m,2H),1.67-1.56(m,2H),1.31-1.21(s,3H).

[0417] Example 33

[0418] Step 1

[0419] At room temperature, [6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (107_1) (564 mg, 1.43 mmol) and tert-butyl N-[(tert-butoxy)carbonyl]-N-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (650 mg, 1.43 mmol) were dissolved in a mixture of 1,4-dioxane (8 ml) and water (2 ml). Potassium phosphate (607 mg, 2.86 mmol) and bis(4-dimethylaminophenyldi-tert-butylphosphine)palladium dichloride (101 mg, 0.14 mmol) were then added. The atmosphere was purged with nitrogen three times, and the temperature was raised to 55°C for 3 h. LCMS monitoring indicated incomplete consumption of the starting material. The mixture was diluted with 25 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using ethyl acetate:petroleum ether in a mobile phase ratio of 1:2 to obtain 140 mg of tert-butyl N-[(tert-butoxy)carbonyl]-N-{3-chloro-4-[6-chloro-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]pyridin-2-yl}carbamate (107_2) as a yellow solid in a yield of 16.5%. MS m / z: 439.0, 441.0 [M-155].

[0420] Step 2

[0421] At room temperature, tert-butyl N-[(tert-butoxy)carbonyl]-N-{3-chloro-4-[6-chloro-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]pyridin-2-yl}carbamate (107_2) (60 mg, 0.10 mmol), N-(3-fluorophenyl)-4-methylpiperidine-4-carboximide (87_2) (28 mg, 0.12 mmol), and potassium carbonate (27 mg, 0.20 mmol) were added and dissolved in dimethyl sulfoxide (1.5 ml). The mixture was heated to 60°C and reacted for 2 h. LCMS monitored the complete consumption of the starting material. The reaction mixture was diluted with 5 ml of water and extracted twice with 5 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using ethyl acetate:petroleum ether in a mobile phase ratio of 2:1 to obtain 30 mg of tert-butyl N-[(tert-butoxy)carbonyl]-N-[3-chloro-4-(6-{4-[N-(3-fluorophenyl)carbamoylamino]-4-methylpiperidin-1-yl}-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (107_3) as a yellow solid in a yield of 37.5%. MS m / z: 794.3 [M+H].

[0422] Step 3

[0423] Trifluoroacetic acid (0.6 ml, 5.26 mmol) was added to a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-[3-chloro-4-(6-{4-[N-(3-fluorophenyl)carbamoylamino]-4-methylpiperidin-1-yl}-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (107-3) (30 mg, 0.04 mmol) in dichloromethane (1 ml) at room temperature and allowed to react overnight at room temperature. LCMS monitored the complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and then a small amount of water was added, followed by solid sodium bicarbonate, and the pH of the reaction solution was adjusted to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 5.1 mg of 1-[3-(2-amino-3-chloropyridin-4-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(3-fluorophenyl)-4-methylpiperidine-4-carboximide (ZS5084-107) as a pale yellow solid in a 26.3% yield. MS m / z: 510.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.67 (br s,1H),7.98(d,J=5.0Hz,1H),7.27(q,J=7.8Hz,1H),7.06(d,J=4.9Hz,1H),6.71(t d,J=8.5,2.1Hz,1H),6.54(d,J=7.9Hz,1H),6.49(dt,J=10.9,2.0Hz,1H),6.34(br s,2H),5.85(br s,2H),5.29(br s,1H),4.60(s,2H),3.43-3.65(m,4H),2.30(m,2H),1.62(t,J=10.1Hz,2H),1.27(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -113.2.

[0424] Example 34

[0425] Step 1

[0426] To a reaction flask at room temperature, tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate (108_1) (500 mg, 2.23 mmol) was added and dissolved in 2-fluoroaniline (5 ml). Aluminum trichloride (600 mg, 4.5 mmol) was quickly added, and the mixture was heated to 120°C with stirring and allowed to react for 12 hours. LCMS monitored the product formation. 100 ml of ethyl acetate and 100 ml of water were added to the reaction solution, and the aqueous phase was extracted and dried. The solution was dissolved in methanol, filtered, and dried to yield 900 mg of crude purple oily N-(2-fluorophenyl)-4-methylpiperidine-4-carboximidamide (108_2). This crude product was used directly in the next reaction. MS m / z: 236.2 [M+H].

[0427] Step 2

[0428] To a reaction flask, add N-tert-butylcarbonyl-N-{3-chloro-4-[6-chloro-5-hydroxymethyl)-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-3-yl]pyridin-2-yl}carbamate (47 mg, 0.08 mmol), N-(2-fluorophenyl)-4-methylpiperidine-4-carboximidamide (94 mg, 0.4 mmol) (108 mmol), and potassium carbonate (44 mg, 0.32 mmol). Stir and react for 0.5 h. LCMS analysis indicated a small amount of residual starting material and the product was formed. The reaction mixture was dried in vortexes to afford N-tert-butyloxycarbonyl-N-[3-chloro-4-(6-{4-[N-(2-fluorophenyl)ureayl]-4-methylpiperidin-1-yl}-5-hydroxymethyl-1-oxocyclooxy-2-yl-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (108_3) as a purple crude oil, which was directly used in the next reaction. MS m / z: 794.1 [M+H].

[0429] Step 3

[0430] N-tert-Butyloxycarbonyl-N-[3-chloro-4-(6-{4-[N-(2-fluorophenyl)urea]-4-methylpiperidin-1-yl}-5-hydroxymethyl-1-oxocyclooxy-2-yl-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (80 mg, 0.1 mmol) was added to the reaction flask at room temperature and dissolved in DCM (1 ml). 0.4 ml of trifluoroacetic acid was added dropwise, and stirring was started. The reaction was allowed to react for 12 h. The product was monitored by LCMS, purified by preparative method, and lyophilized to give 6.1 mg of 1-[3-(2-amino-3-chloropyridin-4-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(2-fluorophenyl)-4-methylpiperidine-4-carboximidamide) (ZS5084-108) as a yellow solid with a purity of 97.01%. MS m / z: 510.3 [M+H], 1H NMR (400MHz, DMSO-d6)δ=13.91(br s,1H),10.58(br s,1H),9.30(br s,1H),8.93(br s,1H),8.03(d,J=5.3Hz,1H),7.47-7.63(m,3H),7.38-7.44(m,1H),7.13(d,J=5.3Hz,1H),6.59- 6.79(m,1H),4.64(s,2H),3.57-3.61(m,2H),2.34-2.40(m,2H),1.93-2.00(m,2H),1.51(s,3H).

[0431] Example 35

[0432] Step 1

[0433] Potassium carbonate (34 mg, 0.25 mmol) was added to a 1 mL solution of [N-tert-butyloxycarbonyl]-N-{3-chloro-4-[6-chloro-5-hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]pyridin-2-yl}carbamate (109-1) (50 mg, 0.08 mmol) and N-(3,4-difluorophenyl)-4-methylpiperidine-4-carboximidamide (42 mg, 0.17 mmol). The reaction was stirred at 60°C for 2 h. LCMS indicated successful reaction. The mixture was diluted with 10 mL of water and extracted twice with 20 mL of ethyl acetate. The ethyl acetate layers were combined and washed once with saturated brine. The organic phase was concentrated and dried by spin drying. Purification by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) afforded 20 mg of N-[tert-butoxy)carbonyl]-N-[3-chloro-4-(6-{4-[N-(3,4-difluorophenyl)urea]-4-methylpiperidin-1-yl}-5-hydroxymethyl-1-(oxocyclooxy)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (109-2) as a yellow oil in a 30.8% yield. MS m / z: 328.6 [(M+2-100-56) / 2].

[0434] Step 2

[0435] N-[tert-Butoxy)carbonyl]-N-[3-chloro-4-(6-{4-[N-(3,4-difluorophenyl)ureayl]-4-methylpiperidin-1-yl}-5-hydroxymethyl-1-(oxocyclooxy)-1H-pyrazolo[3,4-b]pyrazin-3-yl)pyridin-2-yl]carbamate (20 mg, 0.02 mmol) was added to a solution of 1 mL of trifluoroacetic acid in 2 mL of dichloromethane. The reaction was stirred at 20°C for 16 h. LCMS showed the reaction was successful. The product was dried and purified by Prep-HPLC to yield 9.3 mg of 1-[3-(2-amino-3-chloropyridin-4-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(3,4-difluorophenyl)-4-methylpiperidine-4-carboximidamide (ZSNB1100-109) as a pale yellow solid in an 88.4% yield. MS m / z: 528.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.76 (br s, 1H), 8.32 (br s, 1H), 8.00 (d, J = 5.0Hz, 1H), 7.36-7.16 (m, 1H), 7.03 (d, J = 5.0Hz, 1H), 6.69 (br dd,J=7.4,12.3Hz,1H),6.70(dd,J=7.6,12.0Hz,1H),6.50(d,J=8.4Hz,1H),6.40(s,2H),5.95(br s,1H),5.34(br s,1H),4.60(s,2H),3.40-3.31(m,2H),3.48-3.23(m,2H),2.37-2.25(m,2H),1.61(br t,J=9.9Hz,2H),1.26(s,3H).

[0436] Example 36

[0437] Step 1

[0438] At room temperature, [6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (415 mg, 1.05 mmol) and N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (110_1) (260 mg, 1.1 mmol) were dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (145 mg, 1.05 mmol) was added, and the mixture was heated to 60°C for 2 h. LCMS monitored the complete consumption of the starting material. The mixture was diluted with 20 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and concentrated to obtain 522 mg of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxamide (110_2) as a yellow solid in a yield of 83.8%. MS m / z: 594.1 [M+H].

[0439] Step 2

[0440] N-(4-Fluorophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxamide (110_2) (95 mg, 0.16 mmol) and 1,2,3,4-tetrahydro-1,5-naphthyridine (23 mg, 0.18 mmol) were dissolved in toluene (1.5 ml) at room temperature. Potassium carbonate (66 mg, 0.48 mmol) and Xantphos-Pd-G4 (9 mg, 0.08 mmol) were then added. The atmosphere was purged with nitrogen three times and the mixture was heated to 90°C for overnight reaction. LCMS monitoring indicated incomplete reaction of the starting material. The mixture was diluted with 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 55 mg of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (110_3) as a brown oil in a yield of 57.3%. MS m / z: 600.3 [M+H].

[0441] Step 3

[0442] Trifluoroacetic acid (0.5 ml, 4.38 mmol) was added to a solution of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (110_3) (55 mg, 0.09 mmol) in dichloromethane (1 ml) at room temperature and allowed to react overnight. LCMS monitored the complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and then sodium hydroxide solution was added dropwise to adjust the pH of the reaction solution to alkaline. After filtration, the product was purified by preparative HPLC and lyophilized to afford 6.1 mg of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxamide (ZS5084-110) as a yellow solid in a 13.3% yield. MS m / z: 516.3 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 12.81 (br s,1H),7.91(d,J=3.9Hz,1H),7.45(d,J=8.0Hz,1H),7.06(t,J=8.9Hz,2H),6.96 (dd,J=8.4,4.5Hz,1H),6.70(dd,J=8.6,5.1Hz,2H),5.56-5.89(m,2H),5.26(br s,1H),4.55(s,2H),3.95-4.02(m,2H),3.58(d,J=13.5Hz,2H),2.95(t,J=6.4Hz ,2H),2.26-2.33(m,2H),2.05-2.12(m,2H),1.60(t,J=10.2Hz,2H),1.26(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -123.5.

[0443] Example 37

[0444] Step 1

[0445] N-(4-Fluorophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxamide (111_1) (150 mg, 0.25 mmol) and 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (78 mg, 0.30 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2 ml) and water (0.4 ml) at room temperature. Sodium carbonate (53 mg, 0.51 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (18 mg, 0.03 mmol) were then added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 90°C for 2 h. LCMS monitored the complete consumption of the starting material. The mixture was filtered, and anhydrous sodium sulfate was added to the filtrate for drying. The mixture was filtered, concentrated, and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 98 mg of 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (111_2) as a yellow solid in a yield of 65.7%. MS m / z: 597.2 [M+H].

[0446] Step 2

[0447] At room temperature, 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (111_2) (65 mg, 0.11 mmol), cyclopropaneamine (37.9 μl, 0.54 mmol), and N,N-diisopropylethylamine (21.7 μl, 0.17 mmol) were dissolved in dimethyl sulfoxide (1 ml). The mixture was heated to 100°C and reacted overnight. LCMS monitoring indicated that the starting material was essentially consumed. The mixture was diluted with 5 ml of water and extracted twice with 5 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol = 10:1 to obtain 40 mg of 1-{3-[3-chloro-2-(cyclopropylamino)pyridin-4-yl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)-4-methylpiperidine-4-carboxamide (111_3) as a yellow oil in a yield of 57.9%. MS m / z: 634.2, 635.2 [M+H].

[0448] Step 3

[0449] Trifluoroacetic acid (1 ml, 8.77 mmol) was added to a solution of 1-{3-[3-chloro-2-(cyclopropylamino)pyridin-4-yl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)-4-methylpiperidine-4-carboxamide (111_3) (54 mg, 0.09 mmol) in dichloromethane (1.5 ml) at room temperature and allowed to react overnight. LCMS monitored the substantial consumption of the starting material. The reaction solution was concentrated, diluted with acetonitrile, and a small amount of water was added followed by solid sodium bicarbonate. The pH of the reaction solution was adjusted to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to afford 7.2 mg of 1-{3-[3-chloro-2-(cyclopropylamino)pyridin-4-yl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (ZS5084-111) as a yellow solid in a 15.4% yield. MS m / z: 550.3 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=13.88(br s,1H),10.54(s,1H),9.11(br s,1H),8.61(br s,1H),8.15(d,J=5.3Hz,1H),7.39-7.50(m,4H),7.15(d,J=5.0Hz,1H),6.99(br s,1H),4.62(s,2H),3.52-3.57(m,4H),2.77-2.83(m,1H),2.31-2.37(m,2 H),1.90-1.98(m,2H),1.49(s,3H),0.73-0.80(m,2H),0.59-0.65(m,2H). 19 F NMR (376MHz, DMSO-d6) δ = -112.7.

[0450] Example 38

[0451] Step 1

[0452] 1-Bromo-2-chloro-3-fluorobenzene (3 g, 14.32 mmol) was added to tetrahydrofuran (30 mL) at room temperature. The mixture was then cooled to -78°C and slowly added with lithium diisopropylamide (3.07 mL, 28.64 mmol). The reaction was maintained at this temperature for 30 minutes. N,N-dimethylformamide (2.5 mL) was then added and the reaction was continued at this temperature for 1.5 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was quenched with saturated aqueous ammonium chloride (50 mL) and extracted twice with ethyl acetate (100 mL). The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) and concentrated in vacuo to afford 500 mg of 4-bromo-3-chloro-2-fluorobenzaldehyde (112_2) as a pale yellow solid in a 14.7% yield.

[0453] Step 2

[0454] To ethanol (10 mL) at room temperature, add 4-bromo-3-chloro-2-fluorobenzaldehyde (500 mg, 2.10 mmol) and hydrazine hydrate (0.51 ml, 10.12 mmol). The mixture was heated to 60°C and stirred for 18 h under nitrogen. LCMS monitoring indicated the disappearance of the starting material and the desired molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-30%). The residue was concentrated in vacuo to afford 500 mg of 6-bromo-7-chloro-1-hydrogen-indoleazole (112_3) as a yellow solid in an 85.4% yield. MS m / z: 230.8 [M+H].

[0455] Step 3

[0456] To a tetrahydrofuran (10 ml) solution at room temperature were added 6-bromo-7-chloro-1-(tetrahydro-2H-pyran)-1H-indazole (330 mg, 1.43 mmol), 3,4-dihydro-2H-pyran (359 mg, 4.28 mmol), and p-toluenesulfonic acid monohydrate (49 mg, 0.29 mmol). Under nitrogen, the reaction mixture was heated to 70°C and stirred for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was diluted with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: EA:PE = 0-10%) to afford 400 mg of 6-bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (112_4) as a white solid in an 88.9% yield. MS m / z: 230.9 [M-83].

[0457] Step 4

[0458] To a solution of 1,4-dioxane (10 ml) at room temperature were added 6-bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (400 mg, 1.27 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolan (386 mg, 1.52 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (93 mg, 0.13 mmol), and potassium acetate (373 mg, 3.8 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 110°C for 16 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) and concentrated in vacuo to afford 350 mg of 7-chloro-1-(oxo-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolaN-2-yl)-1H-indazole (112_5) as a white solid in a yield of 75.9%. MS m / z: 279.0 [M-83].

[0459] Step 5

[0460] To a mixed solution of 1,4-dioxane (5 ml) and water (0.5 ml) at room temperature were added 7-chloro-1-(oxo-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolaN-2-yl)-1H-indazole (148 mg, 0.41 mmol), N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxo-2-yl)-1H-pyrazolin[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxylic acid amide (70 mg, 0.12 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (60 mg, 0.08 mmol), and sodium carbonate (86 mg, 0.82 mmol). The atmosphere was purged with nitrogen three times and then heated to 110°C for 5 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to afford 70 mg of 1-{3-[7-chloro-1-(oxo-2-yl)-1H-indazol-6-yl]-5-(hydroxymethyl)-1-(oxo-2-yl)-1H-pyrazolino[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)-4-methylpiperidin-4-carboximidamide (112_6) as a black solid in a yield of 24.3%. MS m / z: 702.3 [M+H].

[0461] Step 6

[0462] At room temperature, 1-{3-[7-chloro-1-(oxo-2-yl)-1H-indazol-6-yl]-5-(hydroxymethyl)-1-(oxo-2-yl)-1H-pyrazolin-6-yl}-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (70 mg, 0.1 mmol) and trifluoroacetic acid (2 ml, 17.54 mmol) were added to a dichloromethane (2 ml) solution. The mixture was stirred at room temperature for 18 h under nitrogen protection. LCMS showed that the starting material disappeared. The reaction mixture was concentrated in vacuo, and the residue was purified by Prep-HPLC (mobile phase: CH3CN:H2O = 5-95%, 0.01% TFA) to yield 3.89 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1H-pyrazolino[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboxylic acid amide (ZS5084-112) as a white solid in a 7.3% yield. MS m / z: 534.2 [M+H]. 1H NMR (400MHz, MeOD-d4) δ = 8.20 (s, 1H), 7.84 (d, J = 8.3Hz, 1H), 7.57 (d, J = 8.3Hz, 1H), 7.36-7.33 (m, 2H), 7.31-7.27 (m, 2H), 4.80 (s, 2H), 3.60 (br s,4H),2.42-2.36(m,2H),2.05-2.01(m,2H),1.58(s,3H).

[0463] Example 39

[0464] Step 1

[0465] At room temperature, 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (114_1) (60 mg, 0.1 mmol), methylamine hydrochloride (13.6 mg, 0.2 mmol), and N,N-diisopropylethylamine (64.9 μl, 0.5 mmol) were dissolved in dimethyl sulfoxide (1 ml) and the mixture was heated to 100°C and reacted overnight. LCMS monitored the complete consumption of the starting material. The mixture was diluted with 5 ml of water and extracted twice with 5 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol = 10:1 to obtain 46 mg of 1-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)-4-methylpiperidine-4-carboxamide (114_2) as a yellow oil in a yield of 72.2%. MS m / z: 608.3 [M+H].

[0466] Step 2

[0467] Trifluoroacetic acid (0.5 ml, 4.38 mmol) was added to a solution of 1-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)-4-methylpiperidine-4-carboxamide (114-2) (46 mg, 0.08 mmol) in dichloromethane (1 ml) at room temperature and allowed to react overnight. LCMS monitored the complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and a small amount of water was added, followed by solid sodium bicarbonate, and the pH of the reaction solution was adjusted to alkaline. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 10 mg of 1-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (ZS5084-114) as a yellow solid in a 25.6% yield. MS m / z: 524.3 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.65 (br s, 1H), 8.09 (d, J = 5.0Hz, 1H), 7.06 (t, J = 8.8Hz, 2H), 7.00 (d, J = 5.0Hz, 1H), 6.66-6.73 (m, 3H), 5.73 (br s,2H),5.34(t,J=5.5Hz,1H),4.60(d,J=5.3Hz,2H),3.57-3.64(m,2H),3.38(s,2H) ,2.92(d,J=4.5Hz,3H),2.31(d,J=14.3Hz,2H),1.61(t,J=10.4Hz,2H),1.27(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -123.4.

[0468] Example 40

[0469] Step 1

[0470] To a reaction flask at room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (116_1) (300 mg, 1.24 mmol), 3-bromopyridine (393 μl, 2.49 mmol) and cesium carbonate (122 mg, 3.73 mmol) were added and dissolved in tert-butanol (6 ml). After stirring for 10 minutes, (1E,4E)-1,5-diphenylpentaene-1,4-dien-3-one bis((1Z,4E)-1,5-diphenylpenta-1,4-dien-3-one) bispalladium (56 mg, 0.06 mmol) and di-tert-butyl [3,6-dimethoxy-2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl] phosphine (60 mg, 0.12 mmol) were added. N2 was replaced three times and the temperature was raised to 85°C for 12 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography using a mobile phase of PE:EA = 1:1 to obtain 460 mg of tert-butyl 4-methyl-4-[N-(pyridin-3-yl)carbamoyl]piperidine-1-carboxylate (116_2) as a brown oil in an 87.4% yield. MS m / z: 319.1 [M+H].

[0471] Step 2

[0472] At room temperature, tert-butyl 4-methyl-4-[N-(pyridin-3-yl)carbamoyl]piperidine-1-carboxylate (116_2) (200 mg, 0.63 mmol) was added to a reaction flask and dissolved in dichloromethane (3.2 ml). Trifluoroacetic acid (0.8 ml, 7.02 mmol) was added dropwise and stirred at room temperature for 1 h. LCMS analysis confirmed complete consumption of the starting material, yielding the product, 4-methyl-N-(pyridin-3-yl)piperidine-4-carboximidamide (116_3). The reaction solution was concentrated in vacuo, and the residue was used directly in the next reaction. MS m / z: 219.1 [M+H].

[0473] Step 3

[0474] To a reaction flask at room temperature, the product from the previous step, 4-methyl-N-(pyridin-3-yl)piperidine-4-carboximidamide (116_3) (156 mg, 0.72 mmol), and 6-chloro-3-(7-chloro-1H-indazol-6-yl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (150 mg, 0.36 mmol), were added. The mixture was dissolved in acetonitrile (1.5 ml) and N,N-diisopropylethylamine (291 μl, 1.67 mmol) was added dropwise. The reaction mixture was heated to 85°C and reacted for 12 h. Product formation was monitored by LCMS. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 20:1) to afford 200 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(pyridin-3-yl)piperidine-4-carboximidamide (116_4) as a brown oil in a 64.7% yield. MS m / z: 601.2 [M+H].

[0475] Step 4

[0476] The product from the previous step, 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(pyridin-3-yl)piperidine-4-carboximidamide (116_4) (200 mg, 0.33 mmol), was placed in a reaction flask at room temperature and dissolved in dichloromethane (1.35 ml). Trifluoroacetic acid (0.65 ml, 5.7 mmol) was added dropwise and stirred at room temperature for 12 hours. The reaction product formation was monitored by LCMS. The reaction solution was spin-dried to dryness, and the residue was dissolved in methanol and neutralized with aqueous sodium carbonate solution. The solution was filtered, and the filtrate was used for Prep-HPLC preparation. 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(pyridin-3-yl)piperidine-4-carboximidamide (ZS5084-116) was obtained as a white solid (10.6% yield). MS m / z: 517.2 [M+H]. 1 H NMR (400MHz, METHANOL-d4) δ = 8.17-8.27 (m, 2H), 8.12 (s, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.58 (d, J = 8.3Hz, 1H),7.34-7.47(m,2H),4.80(s,2H),3.61-3.68(m,2H),3.46-3.54(m,2H),2.35-2.46(m,2H),1.84(br t,J=10.0Hz,2H),1.44(s,3H).

[0477] Example 41

[0478] Step 1

[0479] To a solution of N,N-dimethylformamide (30 mL) at room temperature were added 5-bromo-3-fluorobenzene-1,2-diol (2 g, 9.66 mmol), bromochloromethane (1.88 g, 14.49 mmol), and cesium carbonate (6.3 g, 19.32 mmol). The atmosphere was purged with nitrogen three times, and the temperature was then raised to 60°C for 18 h. TLC monitoring revealed the disappearance of the starting material and the formation of a large new spot. The reaction solution was diluted twice with 30 mL of water and extracted twice with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether = 100%) to afford 650 mg of 6-bromo-4-fluoro-2H-1,3-benzobisoxazole (117_2) as a white oil in a 30.7% yield. The compound was identified as the title compound by NMR. 1 H NMR (400MHz, DMSO-d6) δ = 7.15 (dd, J = 1.7, 9.7Hz, 1H), 7.10 (s, 1H), 6.16 (s, 2H).

[0480] Step 2

[0481] To a 50 ml solution of tert-butanol at room temperature were added 6-bromo-4-fluoro-2H-1,3-benzobisoxazole (450 mg, 2.05 mmol), tert-butyl 4-carbamoimido-4-methylpiperidine-1-carboxylate (495 mg, 2.05 mmol), tris(dibenzylideneacetone)dipalladium (188 mg, 0.21 mmol), di-tert-butyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (99 mg, 0.21 mmol), and cesium carbonate (3347 mg, 10.27 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 85°C for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo, the residue was diluted with 30 mL of water, extracted twice with 50 mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-50%) to give 450 mg of tert-butyl 4-[N-(7-fluoro-2h-1,3-benzenediol-5-yl)aminoimidazole]-4-methylpiperidine-1-carboxylate (117_3) as a brown solid in a yield of 57.7%. MS m / z: 380.1 [M+H].

[0482] Step 3

[0483] To a dichloromethane (8 mL) solution at room temperature, tert-butyl 4-[N-(7-fluoro-2H-1,3-benzodioxol-5-yl)aminoimidazole]-4-methylpiperidine-1-carboxylate (640 mg, 1.69 mmol) and trifluoroacetic acid (1.92 mL, 16.87 mmol) were added. The reaction was stirred at room temperature under nitrogen for 1 h. LCMS confirmed the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo, then diluted with 5 mL of dichloroethane and concentrated in vacuo to afford crude N-(7-fluoro-2H-1,3-benzodioxol-5-yl)-4-methylpiperidine-4-carboximide (117_4) as a brown oil, which was used directly in the next reaction without purification. MS m / z: = 280.1 [M+H].

[0484] Step 4

[0485] To a solution of acetonitrile (10 ml) at room temperature were added N-(7-fluoro-2H-1,3-benzodioxol-5-yl)-4-methylpiperidine-4-carboximide (250 mg, 0.9 mmol), [6-chloro-3-iodo-1-(oxaN-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (176 mg, 0.45 mmol), and ethylbis(propan-2-yl)amine (2.36 ml, 18.23 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 80°C for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with 20 mL of water and extracted twice with 50 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-50%) to provide 300 mg of N-(7-fluorobenzo[d][1,3]dioxan-5-yl)-1-(5-(hydroxymethyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidine-4-carboximide (117_3) as a yellow solid in a yield of 52.5%. MS m / z: 638.1 [M+H].

[0486] Step 5

[0487] To a mixed solution of 1,4-dioxane (10 ml) and H2O (1 ml) was added N-(7-fluorobenzo[d][1,3]dioxan-5-yl)-1-(5-(hydroxymethyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidine-4-carboximide (300 mg, 0. The mixture was stirred for 1 h at 40°C for 2 h. The reaction mixture was stirred for 1 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The ...3 h. The mixture was stirred for 1 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 1 h. The mixture was stirred for 3 h. The mixture was stirred for 1 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with 10 mL of water and extracted twice with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to provide 240 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1-(oxy-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(7-fluoro-2h-1,3-benzodioxy-5-yl)-4-methylpiperidine-4-carboximide (117_5) as a brown solid in a yield of 77.1%. MS m / z: 662.2 [M+H].

[0488] Step 6

[0489] To a solution of dichloromethane (5 ml) at room temperature was added 1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1-(oxy-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(7-fluoro-2H-1,3-benzodioxy-5-yl)-4-methylpiperidine-4-carboximide (240 mg, 0.36 mmol) and trifluoroacetic acid (3.02 ml, 26.47 mmol). The reaction was stirred at room temperature under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, then diluted with 5 mL of dichloroethane and concentrated in vacuo. The residue was diluted with 5 mL of methanol and neutralized with 100 mg of anhydrous sodium carbonate. The mixture was filtered and the filtrate collected. The filtrate was then purified by Prep-HPLC (mobile phase: acetonitrile:water containing 0.1% TFA = 5-95%) to yield 71 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1H-pyrazolino[3,4-b]pyrazin-6-yl]-N-(7-fluoro-2h-1,3-benzenediol-5-yl)-4-methylpiperidine-4-carboximide (ZS5084-117) as a yellow solid in a yield of 34.1%. MS m / z: 578.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.77-13.69 (m, 2H), 10.55 (s, 1H), 9.13 (br s, 1H), 8.66 (br s,1H),8.29(s,1H),7.87(d,J=8.3Hz,1H),7.59(d,J=8.1Hz,1H),7.09(dd,J= 1.6Hz,10.6Hz,1H),7.02(d,J=1.4Hz,1H),6.25(s,2H),4.63(s,2H),3.55(br s,4H),2.35-2.32(m,2H),1.94-1.90(m,2H),1.48(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -137.4.

[0490] Example 42

[0491] Step 1

[0492] At room temperature, [6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (415 mg, 1.05 mmol) and N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (110_1) (260 mg, 1.1 mmol) were dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (145 mg, 1.05 mmol) was added, and the mixture was heated to 60°C for 2 h. LCMS monitored the complete consumption of the starting material. The mixture was diluted with 20 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and concentrated to obtain 522 mg of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxamide (110_2) as a yellow solid in a yield of 83.8%. MS m / z: 594.1 [M+H].

[0493] Step 2

[0494] N-(4-Fluorophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxamide (110_2) (95 mg, 0.16 mmol) and 1,2,3,4-tetrahydro-1,5-naphthyridine (23.6 mg, 0.18 mmol) were dissolved in toluene (1.5 ml) at room temperature. Potassium carbonate (66.4 mg, 0.48 mmol) and Xantphos-Pd-G4 (9.12 mg, 0.08 mmol) were then added. The atmosphere was purged with nitrogen three times and the mixture was heated to 90°C for overnight reaction. LCMS monitoring indicated incomplete reaction of the starting material. The mixture was diluted with 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol = 10:1 to obtain 55 mg of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (110_3) as a brown oil in a yield of 57.3%. MS m / z: 600.3 [M+H].

[0495] Step 3

[0496] Trifluoroacetic acid (0.5 ml, 4.38 mmol) was added to a solution of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-1-(oxan-2-yl)-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (110_3) (55 mg, 0.09 mmol) in dichloromethane (1 ml) at room temperature and allowed to react overnight. LCMS monitored the complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and then sodium hydroxide solution was added dropwise to adjust the pH of the reaction solution to alkaline. After filtration, the product was purified by preparative HPLC and lyophilized to afford 2.1 mg of N-(4-fluorophenyl)-4-methyl-1-[5-methyl-3-(1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]piperidine-4-carboximide (ZS5084-119) as a yellow solid in a 4.7% yield. MS m / z: 500.3 [M+H]. 1 H NMR (400MHz, METHANOL-d4) δ = 7.85 (d, J = 3.5Hz, 1H), 7.23 (dd, J = 8.3, 1.1Hz, 1H), 7 .08(t,J=8.7Hz,2H),6.98(dd,J=8.4,4.8Hz,1H),6.84-6.90(m,2H),3.89-3.98(m, 2H),3.47-3.53(m,2H),3.35-3.40(m,2H),3.05(t,J=6.5Hz,2H),2.59(s,3H),2.3 5(dd,J=12.4,2.9Hz,2H),2.18-2.26(m,2H),1.75-1.84(m,2H),1.38-1.42(m,3H). 19 F NMR (376MHz, DMSO-d6) δ = -123.4.

[0497] Example 43

[0498] Step 1

[0499] To an acetonitrile (4 ml) solution at room temperature were added N-(3-cyanophenyl)-4-methylpiperidine-4-carboximide (508.9 mg, 2.1 mmol), [6-chloro-3-iodo-1-(oxaN-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (248.6 mg, 0.6 mmol), and ethylbis(propan-2-yl)amine (5.5 ml, 42.8 mmol). The mixture was protected by nitrogen and then heated to 80°C for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (100 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-50%) to provide 200 mg of N-(3-cyanophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (135_5) as a yellow solid in a yield of 55.5%. MS m / z: 601.1 [M+H].

[0500] Step 2

[0501] To a 1,4-dioxane (100 ml) solution at room temperature were added 3-chloro-4-iodopyridin-2-amine (3.5 g, 13.75 mmol), methyl 3-mercaptopropionate (1.82 ml, 15.13 mmol), palladium acetate (154 mg, 0.69 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (397 mg, 0.69 mmol), and ethylbis(propan-2-yl)amine (3.56 ml, 27.51 mmol). The atmosphere was purged with nitrogen three times and then heated to 100°C for 18 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (100 mL) and extracted twice with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-50%) to provide 3.1 g of methyl 3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]propanoate (135_2) as a yellow solid in a yield of 91.4%. MS m / z: 246.9 [M+H].

[0502] Step 3

[0503] To a tetrahydrofuran (4 ml) solution at room temperature was added methyl 3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]propanoate (135_2) (240 mg, 0.97 mmol) and sodium ethoxide (0.38 ml, 5.54 mmol). The atmosphere was purged with nitrogen three times, and the mixture was allowed to react at room temperature for 30 minutes. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo to yield 177 mg of crude 3-chloro-4-(disulfanyl)pyridin-2-amine (135_3) as a brown solid, which was used directly in the next step without purification. MS m / z: 160.9 [M+H].

[0504] Step 4

[0505] To a 1,4-dioxane (2 ml) solution at room temperature were added 3-chloro-4-(disulfanyl)pyridin-2-amine (135_3) (100 mg, 0.55 mmol), N-(3-cyanophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (100 mg, 0.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol), tris(dibenzylideneindeneacetone)dipalladium (62 mg, 0.05 mmol), and cesium carbonate (535 mg, 1.64 mmol). The atmosphere was purged with nitrogen three times, and the temperature was then raised to 100°C for 5 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-20%) to afford 40 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfonylamino]-5-(hydroxymethyl)-1-(oxyl-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(3-cyanophenyl)-4-methylpiperidine-4-carboximide (135_4A) as a yellow solid. MS m / z: 633.2 [M+H].

[0506] Step 5

[0507] To a solution of dichloromethane (5 ml) at room temperature was added 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfonyl]-5-(hydroxymethyl)-1-(oxy-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(3-cyanophenyl)-4-methylpiperidine-4-carboximide (135_4A) (40 mg, 0.06 mmol) and trifluoroacetic acid (0.53 ml, 4.61 mmol). The reaction was stirred at room temperature under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, then diluted with dichloroethane (5 mL) and concentrated again in vacuo. The residue was diluted with methanol (5 mL) and neutralized with anhydrous sodium carbonate (100 mg). The mixture was filtered and the filtrate was collected. The filtrate was concentrated by Prep-HPLC (mobile phase: CH3CN:H2O = 5-95%, 0.01% TFA) to afford 7.9 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(3-cyanophenyl)-4-methylpiperidine-4-carboximide (ZS5084-135) as a white solid in a 23.9% yield. MS m / z: 549.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.77-13.69 (m, 2H), 10.55 (s, 1H), 9.13 (br s, 1H), 8.66 (br s,1H),8.29(s,1H),7.87(d,J=8.3Hz,1H),7.59(d,J=8.1Hz,1H),7.09(dd,J= 1.6Hz,10.6Hz,1H),7.02(d,J=1.4Hz,1H),6.25(s,2H),4.63(s,2H),3.55(br s,4H),2.35-2.32(m,2H),1.94-1.90(m,2H),1.48(s,3H).

[0508] Example 44

[0509] Step 1

[0510] To a 1,4-dioxane (10 ml) solution at room temperature were added 3-chloro-4-(disulfanyl)pyridin-2-amine (182 mg, 1 mmol), N-(4-fluoro-3-methoxyphenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxy-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (186 mg, 0.3 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115 mg, 0.2 mmol), tris(dibenzylideneindeneacetone)dipalladium (91 mg, 0.1 mmol), and cesium carbonate (649 mg, 1.99 mmol). The atmosphere was purged with nitrogen three times, and the temperature was then raised to 100°C for 5 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-20%) to afford 70 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfonylamino]-5-(hydroxymethyl)-1-(oxyl-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (135_4) as a brown solid in a 35.6% yield. MS m / z: 656.2 [M+H].

[0511] Step 2

[0512] To a solution of dichloromethane (3 ml) at room temperature was added 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfonylamino]-5-(hydroxymethyl)-1-(oxy-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (70 mg, 0.11 mmol) and trifluoroacetic acid (1.5 ml, 13.15 mmol). The reaction was stirred at room temperature under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, then diluted with dichloroethane (5 mL) and concentrated again in vacuo. The residue was diluted with methanol (5 mL) and neutralized with anhydrous sodium carbonate (100 mg). The mixture was filtered and the filtrate collected. The filtrate was concentrated by Prep-HPLC (mobile phase: acetonitrile:water containing 0.1% TFA = 5-95%) to afford 24 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfonylamino]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (ZS5084-135-1) as a light yellow solid in a yield of 39.6%. MS m / z: 572.1 [M+H].1 H NMR (400MHz, DMSO-d6)δ=14.29(br s,1H),10.58(s,1H),9.09(br s,1H),8.59(br s,1H),7.60(d,J=5.9Hz,1H),7.41(dd,J=8.5,11.3Hz,1H),7.27(dd,J=2.3,7.8Hz,1H),6.99-6.91(m,3H),5.79( d,J=5.8Hz,1H),4.60(s,2H),3.89(s,3H),3.62-3.54(m,4H),2.36-2.32(m,2H),1.95-1.91(m,2H),1.50(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -134.6.

[0513] Example 45

[0514] Step 1

[0515] 4-Bromo-3-chloro-2-fluoropyridine (136_1) (500 mg, 2.38 mmol), methylamine hydrochloride (176 mg, 2.61 mmol), and potassium carbonate (657 mg, 4.75 mmol) were dissolved in dimethyl sulfoxide (8 ml) at room temperature and heated to 120°C for 1 h. LCMS monitored the complete consumption of the starting material. The mixture was diluted with 40 ml of water and extracted twice with 40 ml of ethyl acetate. The combined organic layers were washed once with saturated brine, concentrated, and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 10:1) to afford 4-bromo-3-chloro-N-methylpyridin-2-amine (136_2) (430 mg, 1.94 mmol) as a yellow solid in an 81.7% yield. MS m / z: 222.9 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ = 7.84 (d, J = 5.3 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 6.83 (d, J = 4.1 Hz, 1H), 2.84 (d, J = 4.6 Hz, 3H).

[0516] Step 2

[0517] At room temperature, 4-bromo-3-chloro-N-methylpyridin-2-amine (136_2) (330 mg, 1.49 mmol), methyl 3-mercaptopropionate (197 μl, 1.64 mmol), tris(dibenzylideneacetone)dipalladium (27.3 mg, 0.03 mmol), [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthin-4-yl]diphenylphosphine (43.1 mg, 0.07 mmol), and N,N-diisopropylethylamine (385 μl, 2.98 mmol) were dissolved in 1,4-dioxane (4 ml). After nitrogen substitution three times, the mixture was heated to 85°C and reacted overnight. TLC monitored the complete consumption of the starting material. The mixture was filtered, diluted with 15 ml of water, and extracted twice with 10 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of petroleum ether:ethyl acetate in a ratio of 10:1 to afford 320 mg of methyl 3-{[3-chloro-2-(methylamino)pyridin-4-yl]sulfanyl}propanoate (136_3) as a white solid in an 82.4% yield. MS m / z: 261.0 [M+H].

[0518] Step 3

[0519] At room temperature, a solution of sodium ethoxide (0.12 ml, 1.78 mmol) in ethanol was added to a solution of methyl 3-{[3-chloro-2-(methylamino)pyridin-4-yl]sulfanyl}propanoate (136_3) (155 mg, 0.59 mmol) in tetrahydrofuran (2 ml). The mixture was stirred for 0.5 hour. LCMS confirmed complete consumption of the starting material, with the main peak being the desired product. The reaction solution was concentrated and used directly in the next step. MS m / z: 174.9 [M+H].

[0520] Step 4

[0521] At room temperature, N-(4-fluoro-3-methoxyphenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (135_5) (170 mg, 0.27 mmol), 3-chloro-N-methyl-4-(sodium sulfonyl)pyridin-2-amine (136_4) (107 mg, 0. 55mmol), tris(dibenzylideneacetone)dipalladium (25.0mg, 0.03mmol), [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthine-4-yl]diphenylphosphine (31.6mg, 0.05mmol) and cesium carbonate (178mg, 0.55mmol) were dissolved in 1,4-dioxane (4ml), replaced with nitrogen three times, and then heated to 100℃ for reaction for 5h. The mixture was filtered, and the filtrate was diluted with 20 ml of water. The mixture was extracted twice with 15 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 110 mg of 1-(3-{[3-chloro-2-(methylamino)pyridin-4-yl]sulfanyl}-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (136_5) as a yellow solid in a yield of 60.8%. MS m / z: 670.2 [M+H].

[0522] Step 5

[0523] Trifluoroacetic acid (1.5 ml, 13.2 mmol) was added to a solution of 1-(3-{[3-chloro-2-(methylamino)pyridin-4-yl]sulfanyl}-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (136-5) (95 mg, 0.14 mmol) in dichloromethane (3 ml) at room temperature. The mixture was allowed to react overnight at room temperature. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and solid sodium carbonate was added to adjust the pH of the reaction solution to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 11.12 mg of 1-(3-{[3-chloro-2-(methylamino)pyridin-4-yl]sulfanyl}-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (ZS5084-136) as a white solid in a yield of 13.6%. MS m / z: 586.2 [M+H]. 1H NMR (400MHz, DMSO-d6)δ=14.24(br s,1H),10.57(br s,1H),9.09(br s,1H),8.59(br s,1H),7.67(d,J=5.6Hz,1H),7.41(dd,J=11.1,8.7Hz,1H),7.25-7.29(m,1H),6.94-6.99(m,1H),6.77(br s,1H),5.71(br d,J=5.5Hz,1H),4.59(s,2H),3.88(s,3H),3.56-3.57(m,4H),2.85(s,3H),2.30-2.37(m,2H),1.89-1.96(m,2H),1.49(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -134.6.

[0524] Example 46

[0525] Step 1

[0526] To a tetrahydrofuran (50 mL) solution at room temperature, 1-bromo-2-chloro-3-nitrobenzene (2 g, 8.46 mmol) was added. The atmosphere was purged with nitrogen three times, then the temperature was lowered to -78°C. Vinylmagnesium bromide (33.83 mL, 33.83 mmol) was slowly added dropwise over approximately 20-30 minutes. The reaction was maintained at this temperature and continued for 2.5 hours. TLC (ethyl acetate:petroleum ether = 1:5) was used to monitor the disappearance of the starting material. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (150 mL). The organic phase was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) to afford 800 mg of 6-bromo-7-chloro-1H-indole (137_1B) as a yellow solid in a 41.0% yield. MS m / z: 229.8 [M+H].

[0527] Step 2

[0528] To a mixed solution of tert-butyl alcohol (24 ml), ethanol (18 ml), and acetic acid (24 ml) at room temperature were added 6-bromo-7-chloro-1H-indole (800 mg, 3.47 mmol) and pyridinium tribromide (humidium salt) (3.33 g, 10.41 mmol). The mixture was stirred at room temperature for 2 h under nitrogen. Acetic acid (24 ml) was then added and stirred for an additional hour. Water (H2O) (2 ml) and zinc powder (2.27 g, 34.71 mmol) were added and stirring continued for another hour. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The residual zinc powder was filtered and washed with methanol. The filtrate was concentrated and the slurry residue was stirred in water (100 mL) overnight. The filter cake was collected by filtration and washed with water to remove zinc and pyridinium salts. The mixture was then quenched with saturated aqueous sodium sulfite (20 mL). The resulting filter cake was then extracted with ethyl acetate. The organic phase was collected and concentrated, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-30%) to provide 300 mg of 6-bromo-7-chloro-2,3-dihydro-1H-indol-2-one (137_2) as a yellow solid in a yield of 35.07%. MS m / z: 245.8 [M+H].

[0529] Step 3

[0530] To a 1,4-dioxane (20 ml) solution at room temperature were added 6-bromo-7-chloro-2,3-dihydro-1H-indol-2-one (350 mg, 1.42 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (432 mg, 1.7 mmol), 1,1-bis(diphenylphosphino)diboronium palladium dichloride (208 mg, 0.28 mmol), and potassium acetate (418 mg, 4.26 mmol). The atmosphere was purged with nitrogen three times, then heated to 100°C and reacted for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-30%) to provide 200 mg of 7-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (137_3) as a yellow solid in a yield of 47.98%. MS m / z: 294.5 [M+H].

[0531] Step 4

[0532] To a mixed solution of 1,4-dioxane (10 ml) and water (1 ml) were added N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (120 mg, 0.2 mmol), 7-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (140 mg, 0.48 mmol), 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (29 mg, 0.04 mmol) and sodium carbonate (64 mg, 0.61 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, and then the temperature was raised to 100°C for 5 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (20 mL) and extracted twice with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to afford 130 mg of 1-[3-(7-chloro-2-oxy-2,3-dihydro-1H-indol-6-yl)-5-(hydroxymethyl)-1-(oxy-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (137_6) as a brown solid in a 93.7% yield. MS m / z: 633.2 [M+H].

[0533] Step 5

[0534] To a solution of dichloromethane (4 ml) at room temperature was added 1-[3-(7-chloro-2-oxyl-2,3-dihydro-1H-indol-6-yl)-5-(hydroxymethyl)-1-(oxyl-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (130 mg, 0.21 mmol) and trifluoroacetic acid (3 ml, 26.31 mmol). The reaction was stirred at room temperature under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, then diluted with dichloroethane (5 mL) and concentrated again in vacuo. The residue was diluted with methanol (5 mL) and neutralized with anhydrous sodium carbonate (100 mg). The mixture was filtered and the filtrate collected. The filtrate was concentrated by Prep-HPLC (mobile phase: acetonitrile:water = 5-95%, 0.01% TFA) to afford 38 mg of 1-[3-(7-chloro-2-oxo-2,3-dihydro-1H-indol-6-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximide (ZS5084-137) as a white solid in a 32.9% yield. MS m / z: 549.1 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=13.68(br s,1H),10.84(s,1H),10.56(s,1H),9.12(br s,1H),8.62(br s,1H),7.48-7.31(m,6H),5.48(br s,1H),4.62(s,2H),3.71(s,2H),3.58-3.50(m,4H),2.37-2.30(m,2H),1.96-1.92(m,2H),1.50(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -112.8.

[0535] Example 47

[0536] Step 1

[0537] 6-Hydroxypyridine-2-boronic acid pinacol ester (138_1) (63 mg, 0.29 mmol), N-(4-fluorophenyl)-1-[5-hydroxymethyl-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (85 mg, 0.14 mmol), potassium carbonate (59 mg, 0.43 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (7.36 mg, 0.01 mmol) were added to a reaction flask at room temperature, dissolved in water (0.2 ml) and tetrahydrofuran (0.8 ml), heated to 50°C, stirred, and reacted for 12 h. TLC and LCMS analysis indicated product formation, with some starting material remaining. The reaction mixture was then purified by spin-drying and silica gel column chromatography to afford 50 mg of N-(4-fluorophenyl)-1-[5-hydroxymethyl-1-(oxa-2-yl)-3-(6-oxo-1,6-dihydropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (138_2) as a yellow solid in a yield of 63.7%. MS m / z: 561.2 [M+H].

[0538] Step 2

[0539] N-(4-Fluorophenyl)-1-[5-hydroxymethyl-1-(oxa-2-yl)-3-(6-oxo-1,6-dihydropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (138_2) (50 mg, 0.09 mmol) was added to a reaction flask at room temperature and dissolved in 0.5 ml of dichloromethane. 0.3 ml of trifluoroacetic acid was added dropwise and stirred at room temperature for 12 h. Product formation was monitored by LCMS. The reaction solution was spin-dried, dissolved in methanol, and 200 mg of solid sodium carbonate was added. The mixture was filtered and purified by preparative purification to afford 23 mg of N-(4-fluorophenyl)-1-[5-hydroxymethyl)-3-(6-oxo-1,6-dihydropyridin-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (ZS5084-138) as a yellow solid in a yield of 53.2%. MS m / z: 477.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 13.99 (s, 1H), 11.12 (d, J = 1.3Hz, 1H), 10.54 (s, 1H),9.10(s,1H),8.61(s,1H),7.67-7.57(m,1H),7.50-7.43(m,3H),7.42 (s,1H),7.39-7.24(m,1H),6.42(d,J=9.3Hz,1H),5.68-5.47(m,1H),4.6 9(s,2H),3.59-3.48(m,4H),2.38-2.32(m,2H),1.94(s,2H),1.49(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -112.7.

[0540] Example 48

[0541] Step 1

[0542] 3-Chloro-2-fluoro-4-iodopyridine (139_1) (500 mg, 1.94 mmol) was added to a three-necked flask at room temperature and dissolved in tetrahydrofuran (5 ml). The nitrogen atmosphere was replaced and the flask was placed in a dry ice-ethanol solution with stirring. After the reaction temperature dropped to -78°C, n-butyllithium solution (1.17 ml, 2.91 mmol) was slowly added dropwise. After 10 minutes of reaction, tri(propyl-2-yl) borate (438 μl, 2.33 mmol) was added dropwise. The temperature was raised to room temperature and the reaction was allowed to proceed for 2 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was quenched with saturated sodium carbonate solution and extracted with ethyl acetate. The aqueous phase was neutralized with 2M hydrochloric acid and extracted again with ethyl acetate. The organic phase was dried and concentrated to obtain 176 mg of 3-chloro-2-fluoropyridine-4-boronic acid (139_2) as a yellow solid in a 51.7% yield. MS m / z: 175.9 [M+H].

[0543] Step 2

[0544] To a solution of 1,4-dioxane (3.2 ml) and water (0.8 ml) at room temperature were added N-(4-fluorophenyl)-1-[5-hydroxymethyl-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximidamide (308 mg, 0.52 mmol), 3-chloro-2-fluoropyridine-4-boronic acid (139_2) (140 mg, 0.8 mmol), cyclopenta-1,3-dien-1-yl(diphenyl)phosphine palladium(2+) iron dichloride (39.1 mg, 0.05 mmol), and sodium carbonate (169 mg, 1.6 mmol). The atmosphere was replaced with nitrogen and the reaction temperature was raised to 110°C for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified by silica gel column chromatography using a mobile phase of PE:EA = 1:1 to afford 100 mg of a pale yellow product, 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidin-4-carboximidamide (139_3), in a yield of 30.6%. MS m / z: 597.2 [M+H].

[0545] Step 3

[0546] The product from the previous step, 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (139_3) (50 mg, 0.08 mmol), was placed in a reaction flask at room temperature and dissolved in water (0.3 ml). Acetic acid (0.7 ml, 11.6 mmol) was added dropwise. The atmosphere was purged with nitrogen and the temperature was raised to 100°C for 12 hours. The reaction product formation was monitored by LCMS. The reaction solution was concentrated in vacuo, and the residue was dissolved in methanol and purified by Prep-HPLC. 21.2 mg of 1-[3-(3-chloro-2-hydroxypyridin-4-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluorophenyl)-4-methylpiperidine-4-carboximidamide (ZS5084-139) was obtained as a yellow solid in a 50% yield. MS m / z: 511.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 13.91 (br s, 1H), 12.19-12.28 (m, 1H), 8.13 (s, 1H), 7.51 (br d,J=6.4Hz,1H),7.13-7.30(m,4H),6.76(d,J=6.6Hz,1H),5.42(br t,J=4.9Hz,1H),4.63(d,J=5.6Hz,2H),3.55-3.61(m,2H),3.41-3.49(m,2H),2.30-2.35(m,2H),1.75-1.85(m,2H),1.40(br s,3H); 19 F NMR (376MHz, DMSO-d6) δ = -118.9.

[0547] Example 49

[0548] Step 1

[0549] At room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (118_2) (300 mg, 1.24 mmol), 3-bromopyridine (140_1) (0.59 ml, 3.73 mmol), tris(dibenzylideneacetone)dipalladium (56.9 mg, 0.06 mmol), di-tert-butyl[3,6-dimethoxy-2',4',6'-tri(prop-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (60.3 mg, 0.12 mmol) and cesium carbonate (1.22 g, 3.73 mmol) were added and dissolved in a solution of di-tert-butyl[3,6-dimethoxy-2',4',6'-tri(prop-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (6 ml). After nitrogen substitution three times, the temperature was raised to 85°C and the reaction was carried out overnight. LCMS monitoring indicated product formation. The mixture was diluted with 20 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol (20:1) to obtain 308 mg of tert-butyl 4-methyl-4-[N-(pyridin-3-yl)carbamoyl]piperidine-1-carboxylate (140_2) as a yellow oil in a 78.0% yield. MS m / z: 319.1 [M+H].

[0550] Step 2

[0551] Trifluoroacetic acid (1.5 ml, 13.2 mmol) was added to a solution of tert-butyl 4-methyl-4-[N-(pyridin-3-yl)carbamoyl]piperidine-1-carboxylate (140_2) (308 mg, 0.97 mmol) in dichloromethane (3 ml) at 0°C. The mixture was allowed to warm to room temperature and reacted for 1 hour. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated and used directly in the next reaction. MS m / z: 219.1 [M+H].

[0552] Step 3

[0553] [6-Chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (Int) (330 mg, 0.84 mmol), 4-methyl-N-(pyridin-3-yl)piperidine-4-carboximide (140_3) (202 mg, 0.92 mmol), and N,N-diisopropylethylamine (0.54 ml, 4.2 mmol) were dissolved in acetonitrile (5 ml) at room temperature and heated to 80°C for 2 h. TLC monitored the complete consumption of the starting material. The mixture was diluted with 20 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 420 mg of 1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(pyridin-3-yl)piperidine-4-carboximide (140_4) as a yellow solid in an 86.7% yield. MS m / z: 577.1 [M+H].

[0554] Step 4

[0555] At room temperature, 1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(pyridin-3-yl)piperidine-4-carboximide (140_4) (260 mg, 0.45 mmol) and 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (139 mg, 0.54 mmol) were added and dissolved in a mixed solvent of 1,4-dioxane (1 ml) and water (0.2 ml). Sodium carbonate (95.6 mg, 0.9 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (34.4 mg, 0.05 mmol) were then added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 90°C for 12 h. LCMS monitored complete consumption of the starting material. The filtrate was collected by filtration, dried over anhydrous sodium sulfate, and concentrated. The filtrate was purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 115 mg of 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(pyridin-3-yl)piperidine-4-carboxamide (140_5) as a yellow solid in a yield of 44.1%. MS m / z: 580.2 [M+H].

[0556] Step 5

[0557] 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(pyridin-3-yl)piperidine-4-carboxamide (140_5) (166 mg, 0.29 mmol) was dissolved in a mixture of acetic acid (0.7 ml) and water (0.3 ml) at room temperature. The atmosphere was purged with nitrogen three times and the temperature was raised to 100°C for 4 h. LCMS monitored the reaction for completeness. The reaction solution was diluted with methanol, filtered, and purified by Prep-HPLC. The resulting product was lyophilized to obtain 11.3 mg of 1-[3-(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(pyridin-3-yl)piperidine-4-carboximide (ZS5084-140) as a yellow solid in a yield of 7.8%. MS m / z: 494.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ=13.87(br s,1H),12.22(br s,1H),8.15(d,J=1.9Hz,1H),8.01(br s,1H),7.50(d,J=6.8Hz,1H),7.27(dd,J=7.6,4.7Hz,1H),7.14(br s,1H),6.77(d,J=6.8Hz,1H),5.73-6.33(m,2H),5.34(t,J=5.1Hz,1H),4.61(d,J=4. 6Hz, 2H), 3.56-3.72 (m, 4H), 2.26-2.37 (m, 2H), 1.64 (t, J = 10.0Hz, 2H), 1.29 (s, 3H).

[0558] Example 50

[0559] Step 1

[0560] At room temperature, N-(4-fluoro-3-methoxyphenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (135_5) (150 mg, 0.24 mmol) and 3-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (74.3 mg, 0.29 mmol) were added and dissolved in a mixed solvent of 1,4-dioxane (2 ml) and water (0.4 ml). Sodium carbonate (51 mg, 0.48 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (18.35 mg, 0.02 mmol) were then added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for 12 h. LCMS monitored complete consumption of the starting material. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to afford 60 mg of 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (142-1_1) as a yellow oil in a 39.9% yield. MS m / z: 627.2 [M+H].

[0561] Step 2

[0562] At room temperature, 1-[3-(3-chloro-2-fluoropyridin-4-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (142_1_1) (60 mg, 0.1 mmol), methylamine hydrochloride (12.9 mg, 0.19 mmol), and N,N-diisopropylethylamine (61.8 μl, 0.48 mmol) were dissolved in dimethyl sulfoxide (1 ml). The mixture was heated to 100°C and reacted overnight. LCMS monitored the complete consumption of the starting material. The mixture was diluted with 5 ml of water and extracted twice with 5 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography using a mobile phase of dichloromethane:methanol (10:1) to obtain 60 mg of 1-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (142-1_2) as a yellow oil in a yield of 98.3%. MS m / z: 638.2 [M+H].

[0563] Step 3

[0564] Trifluoroacetic acid (1 ml, 8.77 mmol) was added to a solution of 1-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (142-1_2) (60 mg, 0.09 mmol) in dichloromethane (2 ml) at room temperature. The mixture was allowed to react overnight at room temperature. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and solid sodium carbonate was added to adjust the pH of the reaction solution to 7-8. The filtrate was collected by filtration and purified by preparative HPLC. The resulting product was lyophilized to obtain 10 mg of 1-{3-[3-chloro-2-(methylamino)pyridin-4-yl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (ZS5084-142-1) as a yellow solid in a yield of 19.3%. MS m / z: 554.3 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 13.74 (br s, 1H), 8.09 (d, J = 5.1Hz, 1H), 7.06 (dd,J=11.6,8.5Hz,1H),7.00(d,J=5.0Hz,1H),6.68(q,J=4.5Hz,1H),6.47(d,J=5.6Hz,1H),6.22-6.29(m,1H),5.86(br s,1H),5.75(s,1H),5.35(t,J=5.7Hz,1H),4.60(d,J=5.6Hz,2H),3.79(s,3H),3.56-3.64(m,2H),3.41(br s, 2H), 2.92 (d, J = 4.6Hz, 3H), 2.28 (d, J = 3.4Hz, 2H), 1.63 (t, J = 10.0Hz, 2H), 1.28 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ = -145.2.

[0565] Example 51

[0566] Step 1

[0567] To a 50 ml solution of tert-butanol at room temperature were added 4-bromo-1-fluoro-2-methoxybenzene (1 g, 4.88 mmol), tert-butyl 4-carbamoimido-4-methylpiperidine-1-carboxylate (1.18 g, 4.88 mmol), tris(dibenzylideneacetone)dipalladium (446 mg, 0.49 mmol), di-tert-butyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (236 mg, 0.49 mmol), and cesium carbonate (7950 mg, 24.4 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 90°C for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (30 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-50%) to provide 1.1 g of tert-butyl 4-[N-(4-fluoro-3-methoxyphenyl)carbamoylamino]-4-methylpiperidine-1-carboxylate (120_2) as a brown solid in a yield of 61.6%. MS m / z: 366.2 [M+H].

[0568] Step 2

[0569] To a dichloromethane (10 ml) solution at room temperature, tert-butyl 4-[N-(4-fluoro-3-methoxyphenyl)carbamoylamino]-4-methylpiperidine-1-carboxylate (1.1 g, 3.01 mmol) and trifluoroacetic acid (3.43 ml, 30.1 mmol) were added. Under nitrogen protection, the reaction was stirred at room temperature for 1 hour. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo, then diluted with dichloroethane (10 mL), and concentrated in vacuo again to give crude N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (120_3) as a brown oil, which was used directly in the next step without purification. MS m / z: 266.1 [M+H].

[0570] Step 3

[0571] To an acetonitrile (10 ml) solution at room temperature were added N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (200 mg, 0.75 mmol), 3-iodo-1-(oxaN-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (297 mg, 0.75 mmol), and ethylbis(propyl-2-yl)amine (1.98 ml, 15.35 mmol). The mixture was protected by nitrogen and then heated to 80°C for 2 h. LCMS monitoring indicated a small amount of residual starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (20 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-50%) to provide 100 mg of N-(4-fluoro-3-methoxyphenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxamin-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (120_4) as a yellow solid in a yield of 21.2%. MS m / z: 624.1 [M+H].

[0572] Step 4

[0573] To a mixed solution of 1,4-dioxane (5 ml) and water (0.5 ml) at room temperature were added N-(4-fluoro-3-methoxyphenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxamin-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (100 mg, 0.16 mmol), 7-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (44 mg, 0.16 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (23 mg, 0.03 mmol), and cesium carbonate (51 mg, 0.48 mmol). The atmosphere was purged with nitrogen three times and then heated to 100°C for 5 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to afford 100 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (120_4) as a brown solid in a yield of 96.6%. MS m / z: 648.2 [M+H].

[0574] Step 5

[0575] To dichloromethane (3 ml) at room temperature was added 1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (100 mg, 0.15 mmol) and trifluoroacetic acid (2 ml, 17.54 mmol). The reaction was stirred at room temperature under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, then diluted with dichloroethane (5 mL) and concentrated again in vacuo. The residue was diluted with methanol (5 mL) and neutralized with anhydrous sodium carbonate (100 mg). The mixture was filtered and the filtrate was collected. The filtrate was purified by Prep-HPLC (mobile phase: acetonitrile:water = 5-95%, 0.01% TFA) and concentrated to afford 31 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (ZS5084-120) as a light yellow solid in a yield of 35.6%. MS m / z: 564.1 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 13.79-13.57 (m, 2H), 10.57 (s, 1H), 9.09 (br s, 1H), 8.59 (br s,1H),8.28(s,1H),7.87(d,J=8.3Hz,1H),7.59(d,J=8.3Hz,1H),7.41(dd,J=8.6Hz,11.3H z,1H),7.27(dd,J=2.3Hz,7.8Hz,1H),6.99-6.95(m,1H),4.63(s,2H),3.89(s,3H),3.56(br s,4H),2.37-2.33(m,2H),1.97-1.93(m,2H),1.51(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -134.6.

[0576] Example 52

[0577] Step 1

[0578] To an acetonitrile (20 mL) solution at room temperature, 6-bromo-7-chloro-1H-indazole (1 g, 4.32 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diolium bis(tetrafluoroborate) (1.84 g, 5.18 mmol) were added. The atmosphere was purged with nitrogen three times, and then microwaved to 100°C for 2 h. LCMS analysis revealed a small amount of residual starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (20 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) to afford 340 mg of 6-bromo-7-chloro-3-fluoro-1H-indazole (121_2) as a yellow solid in a 31.5% yield. MS m / z: 248.8 [M+H].

[0579] Step 2

[0580] To a solution of 1,4-dioxane (20 ml) at room temperature were added 6-bromo-7-chloro-3-fluoro-1H-indazole (400 mg, 1.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (610 mg, 2.41 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (117 mg, 0.16 mmol), and potassium acetate (472 mg, 4.81 mmol). The atmosphere was purged with nitrogen three times and then heated to 110°C for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (30 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-20%) to provide 400 mg of 7-chloro-3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (121_2) as a yellow solid in an 84.3% yield. MS m / z: 297.0 [M+H].

[0581] Step 3

[0582] To a mixed solution of 1,4-dioxane (5 ml) and water (0.5 ml) at room temperature were added N-(4-fluoro-3-methoxyphenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxamin-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (100 mg, 0.16 mmol), 7-chloro-3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (47 mg, 0.16 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (23 mg, 0.03 mmol), and sodium carbonate (51 mg, 0.48 mmol). The atmosphere was purged with nitrogen three times and then heated to 110°C for 18 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (10 mL) and extracted twice with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-10%) to afford 80 mg of 1-[3-(7-chloro-3-fluoro-1H-indazol-6-yl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (121_3) as a brown solid in a 75.0% yield. MS m / z: 666.2 [M+H].

[0583] Step 4

[0584] To a solution of dichloromethane (3 ml, 100.0%) at room temperature was added 1-[3-(7-chloro-3-fluoro-1H-indazol-6-yl)-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (80 mg, 0.12 mmol) and trifluoroacetic acid (1 ml, 8.77 mmol). The reaction was stirred at room temperature under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, then diluted with dichloroethane (5 mL) and concentrated again in vacuo. The residue was diluted with methanol (5 mL) and neutralized with anhydrous sodium carbonate. The mixture was filtered and the filtrate was collected. The filtrate was purified by Prep-HPLC (mobile phase: acetonitrile:water containing 0.1% TFA = 5-95%). The filtrate was concentrated to yield 7.9 mg of 1-[3-(7-chloro-3-fluoro-1H-indazol-6-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (ZS5084-121) as a light yellow solid in an 11.3% yield. MS m / z: 582.2 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=13.82(br s,1H),13.25(s,1H),10.57(s,1H),9.09(br s,1H),8.59(br s,1H),7.83(d,J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),7.41(dd,J=8.5,11.3Hz,1H), 7.27(dd,J=2.3,7.8Hz,1H),6.99-6.95(m,1H),4.64(s,2H),3.89(s,3H),3.56(br s,4H),2.37-2.32(m,2H),1.98-1.93(m,2H),1.51(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -133.6, -134.6.

[0585] Example 53

[0586] Step 1

[0587] To a solution of 6-chloro-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (122_1) (1.5 g, 4.11 mmol) and ammonium persulfate (5.63 g, 24.7 mmol) in acetonitrile and water was slowly added portionwise a solution of acetic acid (1.24 ml, 20.6 mmol) and silver nitrate (6.99 g, 41.1 mmol) in acetonitrile and water at 70°C. The mixture was then heated to 85°C and reacted for 4 h. LCMS monitored the complete consumption of the starting material. The mixture was filtered, and the filtrate was diluted with 150 ml of water, extracted twice with 150 ml of ethyl acetate, and the organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography. The mobile phase was petroleum ether:ethyl acetate = 5:1 to obtain 250 mg of 6-chloro-3-iodo-5-methyl-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine (122_3) as a yellow solid crude product. MS m / z: 378.9 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ = 14.39-14.65 (m, 1H), 2.70 (s, 3H); and 6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine (122_2) as a crude yellow solid, MS m / z: 294.9 [M+H].

[0588] Step 2

[0589] 6-Chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine (122_2) (86 mg, 0.29 mmol), 3,4-dihydro-2H-pyran (36.9 μl, 0.44 mmol), and 4-methylbenzene-1-sulfonic acid hydrate (11.1 mg, 0.06 mmol) were added to tetrahydrofuran (2 ml) at room temperature and heated to 60°C for 2 h. Complete consumption of the starting material was monitored by TLC. The mixture was diluted with 10 ml of water and extracted twice with 10 ml of ethyl acetate. The combined organic phases were washed once with saturated brine, concentrated, and purified by silica gel column chromatography using a mobile phase of petroleum ether:ethyl acetate (5:1) to afford crude 6-chloro-3-iodo-5-methyl-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine (122_3) as a pale yellow solid. MS m / z: 378.9 [M+H].

[0590] Step 3

[0591] 6-Chloro-3-iodo-5-methyl-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine (122_3) (120 mg, 0.32 mmol) and 7-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (106 mg, 0.38 mmol) were dissolved in a mixture of 1,4-dioxane (2 ml) and water (0.4 ml) at room temperature. Sodium carbonate (67 mg, 0.63 mmol) and 1,1-bis(diphenylphosphino)diborane iron palladium dichloride (23 mg, 0.03 mmol) were then added. The atmosphere was purged with nitrogen three times, and the mixture was heated to 90°C for 2 h. LCMS monitored the complete consumption of the starting material. The mixture was filtered, and anhydrous sodium sulfate was added to the filtrate for drying. The mixture was filtered, concentrated, and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 3:1) to obtain 7-chloro-6-[6-chloro-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1H-indazole (122_4) as a crude yellow solid. MS m / z: 403.0, 405.0 [M+H].

[0592] Step 4

[0593] 7-Chloro-6-[6-chloro-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-1H-indazole (122_4) (70 mg, 0.17 mmol), N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (55 mg, 0.21 mmol), and N,N-diisopropylethylamine (112 μl, 0.87 mmol) were added to dimethyl sulfoxide (1.5 ml) at room temperature and the mixture was heated to 80°C and reacted overnight. LCMS monitoring indicated that the starting material was essentially consumed. The mixture was diluted with 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 48 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (122_5) as a yellow oil in a yield of 43.8%. MS m / z: 632.2 [M+H].

[0594] Step 5

[0595] Trifluoroacetic acid (1 ml) was added to a solution of 1-[3-(7-chloro-1H-indazol-6-yl)-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (122_5) (48 mg, 0.08 mmol) in dichloromethane (2 ml) at room temperature. The mixture was allowed to react overnight at room temperature. LCMS monitored the complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and solid sodium carbonate was added to adjust the pH of the reaction solution to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 10.3 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximide (ZS5084-122) as a yellow solid in a yield of 24.8%. MS m / z: 548.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 13.56-13.85 (m, 2H), 10.59 (br s, 1H), 9.11 (br s, 1H), 8.59 (br s,1H),8.28(s,1H),7.86(d,J=8.3Hz,1H),7.55(d,J=8.3Hz,1H),7.42(dd,J=10.9,8.7Hz,1H),7.25-7.30(m,1H ),6.94-6.99(m,1H),3.89(s,3H),3.40(s,4H),2.60(s,3H),2.31-2.38(m,2H),1.93-2.00(m,2H),1.51(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -134.6.

[0596] Example 54

[0597] Step 1

[0598] To an ethanol solution (5 ml) at room temperature, 4-bromo-2,3-difluorobenzaldehyde (124_1) (1000 mg, 4.52 mmol) and hydrazine hydrate (5 ml, 99.9 mmol) were added. The mixture was heated to 60°C and stirred for 48 h under nitrogen. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase = ethyl acetate:petroleum ether = 1:100 to 30:70) to afford 6-bromo-7-fluoroindazole (124_2) (705 mg, 3.28 mmol) as a pale yellow solid in a 72.5% yield. MS m / z: 214.9 [M+H].

[0599] Step 2

[0600] To a solution of 1,4-dioxane (22 ml) at room temperature were added 6-bromo-7-fluoroindazole (124_2) (790 mg, 3.67 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.21 g, 4.78 mmol), 1,1-bis(diphenylphosphino)diboronium palladium chloride (270 mg, 0.37 mmol), and potassium acetate (1.08 g, 11.0 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 110°C for 16 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (50 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase = ethyl acetate:petroleum ether = 1:99 to 20:80) to provide 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboronan-2-yl)-1H-indazole (124_3) (680 mg, 2.59 mmol) as a light yellow solid in a yield of 70.6%. MS m / z: 263.0 [M+H].

[0601] Step 3

[0602] To a solution of 1,4-dioxane (1.6 ml) and water (0.4 ml) at room temperature were added 6-chloro-3-iodo-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (150 mg, 0.38 mmol), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (124_3) (130 mg, 0.49 mmol), 1,1-bis(diphenylphosphino)diboraneferronichloridopalladium (27 mg, 0.04 mmol), and sodium carbonate (121 mg, 1.14 mmol). The atmosphere was purged with nitrogen three times, and the mixture was heated to 110°C for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (25 mL) and extracted twice with ethyl acetate (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase = ethyl acetate:petroleum ether = 25:75 to 50:50) to provide 80 mg of 6-chloro-3-(7-fluoro-1H-indazol-6-yl)-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (124_4) as a yellow solid in a yield of 52.2%. MS m / z: 403.0 [M+H].

[0603] Step 4

[0604] 6-Chloro-3-(7-fluoro-1H-indazol-6-yl)-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (124_4) (160 mg, 0.4 mmol) and N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (159 mg, 0.6 mmol) were added to the reaction flask at room temperature and dissolved in acetonitrile (2 ml). N,N-diisopropylethylamine (1026 ul, 7.98 mmol) was added dropwise and the reaction solution was heated to 85 °C for 12 h. Product formation was monitored by LCMS. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: dichloroethane:methanol = 96:4 to 91:9) to afford 1-[3-(7-fluoro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (124-5) (225 mg, 0.18 mmol) as a brown oil in a yield of 89.0%. MS m / z: 632.3 [M+H].

[0605] Step 5

[0606] The product from the previous step, 1-[3-(7-fluoro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (124_5) (225 mg, 0.36 mmol), was placed in a reaction flask at room temperature and dissolved in dichloromethane (1.4 ml). Trifluoroacetic acid (0.65 ml, 5.7 mmol) was added dropwise and stirred at room temperature for 12 hours. The reaction product was monitored by LCMS. The reaction solution was dried, and the residue was dissolved in methanol and neutralized with aqueous sodium carbonate solution. The solution was filtered, and the filtrate was purified by Prep-HPLC. 25.3 mg of 1-[3-(7-fluoro-1H-indazol-6-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-fluoro-3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (ZS5084-124) was obtained as a yellow solid in a yield of 13.8%. MS m / z: 548.3 [M+H]. 1 H NMR (400MHz, METHANOL-d4) δ = 8.08 (d, J = 3.4Hz, 1H), 7.85 (dd, J = 5.8, 8.3Hz, 1H), 7.61 (d, J = 8. 4Hz,1H),7.20(dd,J=8.6,11.0Hz,1H),7.07(dd,J=2.3,7.4Hz,1H),6.88-6.83(m,1H),4.74(br s,2H),3.83(s,3H),3.58-3.48(m,4H),2.34-2.26(m,2H),2.02-1.93(m,2H),1.52(s,3H), 19 F NMR (376MHz, METHANOL-d4) δ = -133.6, -134.9.

[0607] Example 55

[0608] Step 1

[0609] At room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (125_1) (350 mg, 1.45 mmol), 3-bromo-N-methylbenzamide (838 mg, 3.92 mmol), tris(dibenzylideneacetone)dipalladium (66 mg, 0.07 mmol), cesium carbonate (1.41 g, 4.35 mmol), and di-tert-butyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (70 mg, 0.15 mmol) were added and dissolved in tert-butanol (8 ml). After nitrogen substitution three times, the temperature was raised to 85°C and the reaction was allowed to proceed overnight. TLC monitoring indicated the formation of a new main spot. The mixture was diluted with 30 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 360 mg of tert-butyl 4-methyl-4-{N-[3-(methylcarbamoyl)phenyl]carbamoimido}piperidine-1-carboxylate (125_2) as a yellow solid in a yield of 66.3%. MS m / z: 375.2 [M+H].

[0610] Step 2

[0611] Trifluoroacetic acid (2 ml, 17.5 mmol) was added to a solution of tert-butyl 4-methyl-4-{N-[3-(methylcarbamoyl)phenyl]carbamoimido}piperidine-1-carboxylate (125_2) (360 mg, 0.96 mmol) in dichloromethane (4 ml) at 0°C. The mixture was allowed to warm to room temperature and allowed to react for 1 hour. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated and used directly in the next reaction. MS m / z: 275.2 [M+H].

[0612] Step 3

[0613] At room temperature, [6-chloro-3-(7-chloro-1H-indazol-6-yl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl]methanol (Int) (70 mg, 0.17 mmol), N-methyl-3-(4-methylpiperidin-4-imino)benzamide (125_3) (91 mg, 0.33 mmol), and N,N-diisopropylethylamine (108 μl, 0.83 mmol) were dissolved in acetonitrile (2 ml) and the mixture was heated to 85°C and reacted overnight. LCMS monitored the complete consumption of the starting material. The mixture was diluted with 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 100 mg of 3-{1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-imino}-N-methylbenzamide (125_4) as a yellow oil in a yield of 91.1%. MS m / z: 657.2 [M+H].

[0614] Step 4

[0615] Trifluoroacetic acid (1 ml, 8.77 mmol) was added to a solution of 3-{1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-imino}-N-methylbenzamide (125_4) (100 mg, 0.15 mmol) in dichloromethane (2 ml) at room temperature and allowed to react overnight. LCMS monitored the complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and solid sodium carbonate was added to adjust the pH of the reaction solution to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 27.4 mg of 3-{1-[3-(7-chloro-1H-indazol-6-yl)-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-imino}-N-methylbenzamide (ZS5084-125) as a yellow solid in a 31.9% yield. MS m / z: 573.3 [M+H]. 1H NMR (400MHz, DMSO-d6) δ=13.73-13.86(m,1H),13.69(br s,1H),10.66(br s,1H),9.15(br s,1H),8.74(br s,1H),8.56-8.62(m,1H),8.28(s,1H),7.97(d,J=7.9Hz,1H),7.84-7.89(m,2H),7.64-7.70(m,1H),7.57(dd,J=13.6,8.3Hz,2H),5.46(br s,1H),4.63(s,2H),3.55-3.67(m,4H),2.82(d,J=4.4Hz,3H),2.35-2.42(m,2H),1.93-2.01(m,2H),1.52(s,3H).

[0616] Example 56

[0617] Step 1

[0618] To the reaction flask at room temperature were added tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (126_1) (200 mg, 0.75 mmol), 1-bromo-3-methoxybenzene (279 ul, 1.49 mmol), and cesium carbonate (729 mg, 2.24 mmol). The mixture was stirred for 0.5 h. Di-tert-butyl [3,6-dimethoxy-2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl] phosphine (36 mg, 0.07 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one bis((1Z,4E)-1,5-diphenylpenta-1,4-dien-3-one) bispalladium (34 mg, 0.04 mmol) were added. The atmosphere was replaced with nitrogen, the temperature was raised to 85 ° C, and the reaction was continued for 12 h. The product was monitored by LCMS, and the reaction solution was purified by spin drying and silica gel column chromatography to obtain 140 mg of tert-butyl 4-[N-(3-methoxyphenyl)urea]-4-methylpiperidine-1-carboxylate (126_2) as a yellow oily liquid. MS m / z: 348.2 [M+H].

[0619] Step 2

[0620] To a reaction flask at room temperature, tert-butyl 4-[N-(3-methoxyphenyl)urea]-4-methylpiperidine-1-carboxylate (126_2) (180 mg, 0.52 mmol) was dissolved in dichloromethane (2 ml). Trifluoroacetic acid (0.5 ml) was added dropwise and stirred at room temperature for 1 hour. LCMS was used to monitor product formation. The reaction solution was dried to give N-(3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (126_3) as an oily crude product, which was used directly in the next reaction. MS m / z: 248.1 [M+H].

[0621] Step 3

[0622] 6-Chloro-3-(7-chloro-1H-indazol-6-yl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (70 mg, 0.17 mmol) and N-(3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (84 mg, 0.34 mmol) (126_3) were added to a reaction flask at room temperature and dissolved in acetonitrile (1 ml). N,N-diisopropylethylamine (296.9 ul, 1.7 mmol) was added dropwise. Stirring was started, the temperature was raised to 80°C, and the reaction was carried out for 12 h. Product formation was monitored by LCMS, and the reaction solution was purified by spin-drying and silica gel column chromatography to afford 100 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (126_4) as a brown oil. MS m / z: 631.2 [M+H].

[0623] Step 4

[0624] 1-[3-(7-Chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (126_4) (100 mg, 0.16 mmol) was added to a reaction flask at room temperature and dissolved in dichloromethane (1 ml). 1 ml of trifluoroacetic acid was added dropwise, and stirring was started. The reaction was allowed to react for 12 h. LCMS monitoring indicated the formation of the product. The reaction mixture was spin-dried, dissolved in methanol, and added with saturated aqueous sodium bicarbonate. The mixture was purified by preparative purification and lyophilized to afford 19.83 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(3-methoxyphenyl)-4-methylpiperidine-4-carboximidamide (ZS5084-126) as a white solid with a purity of 95.1%. MS m / z: 546.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 13.76 (s, 1H), 13.69 (s, 1H), 10.57 (s, 1H), 9.04-9.16 (m, 1H), 8.57-8.70 (m, 1H), 8.24-8.32 (m, 1 H),7.87(d,J=8.4Hz,1H),7.55-7.63(m,1H),7.49(t,J=8.1Hz,1H),7.07-7.11(m,1H),7.02(s,1H),6.97(s,1H),5.46(br s,1H),4.52-4.71(m,2H),3.81-3.83(m,3H),3.54(d,J=10.0Hz,4H),2.33-2.39(m,2H),1.92-2.00(m,2H),1.48-1.54(m,3H).

[0625] Example 57

[0626] Step 1

[0627] At room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (127_1) (300 mg, 1.24 mmol), cesium carbonate (122 mg, 3.73 mmol) and 5-bromo-1,3-thiazole (408 mg, 2.49 mmol) were added to the reaction flask and dissolved in tert-butanol (6 ml). After stirring for 10 minutes, (1E, 4E)-1,5-diphenylamine was added to the reaction flask. The mixture was treated with 1,4-dien-3-one bis((1Z,4E)-1,5-diphenylpenta-1,4-dien-3-one) bispalladium (56.9 mg, 0.06 mmol) and di-tert-butyl[3,6-dimethoxy-2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (60.3 mg, 0.12 mmol) to displace nitrogen three times. The reaction mixture was then heated to 85°C and allowed to react for 12 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (mobile phase PE:EA = 1:1) to obtain 45 mg of tert-butyl 4-methyl-4-[N-(1,3-thiazol-5-yl)uronyl]piperidine-1-carboxylate (127_2) as a brown oil in an 11.1% yield. MS m / z: 325.1 [M+H].

[0628] Step 2

[0629] At room temperature, tert-butyl 4-methyl-4-[N-(1,3-thiazol-5-yl)uronyl]piperidine-1-carboxylate (127_2) (45 mg, 0.14 mmol) was added to a reaction flask and dissolved in dichloromethane (0.8 ml). Trifluoroacetic acid (0.2 ml, 1.75 mmol) was added dropwise and stirred at room temperature for 1 h. LCMS confirmed complete consumption of the starting material, yielding the product, 4-methyl-N-(1,3-thiazol-5-yl)piperidine-4-carboximidamide (127_3). The reaction mixture was concentrated in vacuo, and the residue was used directly in the next reaction. MS m / z: 225.0 [M+H].

[0630] Step 3

[0631] To a reaction flask at room temperature, the product from the previous step, 4-methyl-N-(1,3-thiazol-5-yl)piperidine-4-carboximidamide (127_3) (31 mg, 0.14 mmol), and 6-chloro-3-(7-chloro-1H-indazol-6-yl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (57.9 mg, 0.14 mmol), were added. The mixture was dissolved in acetonitrile (0.5 ml) and N,N-diisopropylethylamine (482 μl, 2.76 mmol) was added dropwise. The reaction mixture was heated to 80°C and reacted for 4 h. Product formation was monitored by LCMS. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 20:1) to afford 80 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(1,3-thiazol-5-yl)piperidine-4-carboximidamide (127_4) as a brown oil in a yield of 94.1%. MS m / z: 607.2 [M+H].

[0632] Step 4

[0633] The product from the previous step, 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(1,3-thiazol-5-yl)piperidine-4-carboximidamide (127_4) (80 mg, 0.13 mmol), was placed in a reaction flask at room temperature and dissolved in dichloromethane (1 ml). Trifluoroacetic acid (0.5 ml, 4.38 mmol) was added dropwise and stirred at room temperature for 12 hours. The reaction product formation was monitored by LCMS. The reaction solution was spin-dried, and the residue was dissolved in methanol and neutralized with aqueous sodium carbonate solution. The solution was filtered, and the filtrate was used for Prep-HPLC preparation. 5.98 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-N-(1,3-thiazol-5-yl)piperidine-4-carboximidamide (ZS5084-127) was obtained as a yellow solid in an 8.1% yield. MS m / z: 523.1 [M+H]. 1 H NMR(METHANOL-d4)δ=9.05(s,1H),8.10(s,1H),7.90(s,1H),7.74(d,J=8.3Hz,1H),7.46(d,J=8.3Hz,1H),4.70(s,2H),3.43-3.56(m,4H),2.29(br t,J=9.3Hz,2H),1.93-1.99(m,2H),1.52(s,3H).

[0634] Example 58

[0635] Step 1

[0636] tert-Butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (129_1) (200 mg, 0.75 mmol), 4-bromopyridin-2-ol (260 mg, 1.49 mmol), and cesium carbonate (1215 mg, 3.73 mmol) were added to a reaction flask at room temperature and dissolved in 2 ml of tert-butanol. The mixture was stirred for 0.5 h, and di-tert-butyl [3,6-dimethoxy-2,4,6-tri(propyl-2-yl)-[1, The mixture was treated with (1'-biphenyl-2-yl)phosphine (36.15 mg, 0.07 mmol) and (1E,4E)-1,5-diphenylpentaene-1,4-dien-3-one bis((1Z,4E)-1,5-diphenylpenta-1,4-dien-3-one) bispalladium (34 mg, 0.04 mmol). The atmosphere was replaced with nitrogen, the temperature was raised to 85°C, and the reaction was allowed to proceed for 12 hours. The product was monitored by LCMS, and the reaction solution was purified by spin-drying silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to afford 175 mg of tert-butyl 4-[N-(2-hydroxypyridin-4-yl)uronyl]-4-methylpiperidine-1-carboxylate (129_2) as a yellow oil in a yield of 69.7%. MS m / z: 335.1 [M+H].

[0637] Step 2

[0638] To a reaction flask at room temperature, tert-butyl 4-[N-(2-hydroxypyridin-4-yl)uronyl]-4-methylpiperidine-1-carboxylate (129_2) (200 mg, 0.6 mmol) was dissolved in dichloromethane (2 ml). Trifluoroacetic acid (1 ml, 10.2 mmol) was added dropwise and stirred at room temperature for 0.5 h. LCMS analysis indicated product formation, and the reaction solution was dried and used directly in the next reaction. MS m / z: 235.1 [M+H].

[0639] Step 3

[0640] 6-Chloro-3-(7-chloro-1H-indazol-6-yl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (70 mg, 0.17 mmol) and N-(2-hydroxypyridin-4-yl)-4-methylpiperidine-4-carboximidamide (129_3) (79 mg, 0.34 mmol) were added to a reaction flask at room temperature and dissolved in acetonitrile (1 ml). N,N-diisopropylethylamine (297 ul, 1.7 mmol) was added dropwise. Stirring was started, the temperature was raised to 80°C, and the reaction was carried out for 12 h. LCMS monitoring indicated product formation. The reaction mixture was purified by spin-drying silica gel column chromatography (mobile phase: dichloromethane:methanol = 20:1) to afford 90 mg of a brown oily product, 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxacyclo[2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(2-hydroxypyridin-4-yl)-4-methylpiperidine-4-carboximidamide (129_4). The yield was 85.7%. MS m / z: 617.2 [M+H].

[0641] Step 4

[0642] 1-[3-(7-Chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxacyclo[2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(2-hydroxypyridin-4-yl)-4-methylpiperidine-4-carboximidamide (129_4) (90 mg, 0.15 mmol) was added to a reaction flask at room temperature and dissolved in 1 ml of dichloromethane. 1 ml of trifluoroacetic acid was added dropwise, and the mixture was stirred and reacted at room temperature for 12 h. LCMS monitoring indicated product formation. The reaction solution was dried, dissolved in methanol, and added with saturated aqueous sodium carbonate. Preparative purification yielded 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(2-hydroxypyridin-4-yl)-4-methylpiperidine-4-carboximidamide (ZS5084-129) as a yellow solid (18.2 mg, yield 23.3%). MS m / z: 533.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 13.62 (s, 2H), 11.00-10.69 (m, 1H), 8.20 (s, 1H), 7.79 (d, J = 8. 3Hz,1H),7.52(d,J=8.3Hz,1H),7.13(d,J=7.0Hz,1H),5.99(s,2H),5.58(dd,J=1.9,6.9 Hz,1H),5.41(d,J=1.8Hz,1H),5.25(t,J=5.7Hz,1H),4.53(d,J=5.6Hz,2H),3.57-3.46 (m,2H),3.24-3.19(m,2H),2.20(d,J=13.9Hz,2H),1.54(t,J=10.1Hz,2H),1.18(s,3H).

[0643] Example 59

[0644] Step 1

[0645] N-(4-Fluorophenyl)-1-[5-(hydroxymethyl)-3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboxamide (131_1) (100 mg, 0.17 mmol) and 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (25 mg, 0.19 mmol) were dissolved in toluene (1 ml) at room temperature. Potassium carbonate (46 mg, 0.34 mmol) and XantPhos-Pd-G4 (15.9 mg, 0.02 mmol) were then added. The atmosphere was purged with nitrogen three times and the mixture was heated to 100°C for overnight reaction. LCMS monitored the reaction for completeness. The mixture was diluted with 15 ml of water and extracted twice with 10 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 20:1) to obtain 82 mg of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-1-(oxan-2-yl)-3-{1H,2H,3Hpyrido[2,3-b][1,4]oxazin-1-yl}-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (131_2) as a yellow solid in a yield of 80.9%. MS m / z: 602.2 [M+H].

[0646] Step 2

[0647] Trifluoroacetic acid (1 ml, 8.77 mmol) was added to a solution of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-1-(oxan-2-yl)-3-{1H,2H,3H-pyrido[2,3-b][1,4]oxazin-1-yl}-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (131_2) (82 mg, 0.14 mmol) in dichloromethane (2 ml) at room temperature and allowed to react overnight. LCMS monitored the complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and solid sodium carbonate was added to adjust the pH of the reaction solution to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 20 mg of N-(4-fluorophenyl)-1-[5-(hydroxymethyl)-3-{1H,2H,3H-pyrido[2,3-b][1,4]oxazin-1-yl}-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidine-4-carboximide (ZS5084-131) as a yellow solid in a yield of 29.3%. MS m / z: 518.2 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=12.97(br s,1H),10.55(br s,1H),9.11(br s,1H),8.61(br s,1H),8.00(dd,J=1.5,8.0Hz,1H),7.68(dd,J=1.6,4.7Hz,1H),7.49-7.39(m,4H),6.90(dd,J=4.8,8.0Hz,1H),4.60 (s,2H),4.50-4.48(m,2H),4.27-4.25(m,2H),3.57-3.46(m,4H),2.36-2.32(m,2H),1.95-1.91(m,2H),1.49(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -112.8.

[0648] Example 60

[0649] Step 1

[0650] To a reaction flask at room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (134_1) (200 mg, 0.75 mmol), 4-bromobenzonitrile (273 mg, 1.5 mmol), and cesium carbonate (1221 mg, 3.75 mmol) were added and dissolved in 2 ml of tert-butanol. The mixture was stirred for 0.5 h, and di-tert-butyl [3,6-dimethoxy-2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl] phosphine (36 mg, 0.075 mmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one bis((1Z,4E)-1,5-diphenylpenta-1,4-dien-3-one) bispalladium (34.34 mg, 0.0375 mmol) were added. The atmosphere was replaced with nitrogen, the temperature was raised to 85 ° C, and the reaction was continued for 12 h. The product was monitored by LCMS, and the reaction solution was purified by spin-drying silica gel column chromatography to give 167 mg of tert-butyl 4-[N-(4-cyanophenyl)urea]-4-methylpiperidine-1-carboxylate (134_2) as a yellow oily liquid in a yield of 65.0%. MS m / z: 343.1 [M+H].

[0651] Step 2

[0652] To a reaction flask at room temperature, tert-butyl 4-[N-(4-cyanophenyl)uronyl]-4-methylpiperidine-1-carboxylate (134_2) (120 mg, 0.35 mmol) was dissolved in 1 ml of dichloromethane. 0.3 ml of trifluoroacetic acid was added dropwise and stirred at room temperature for 0.5 h. LCMS monitored the formation of the product, and the reaction solution was dried and used directly in the next reaction. MS m / z: 243.2 [M+H].

[0653] Step 3

[0654] 6-Chloro-3-(7-chloro-1H-indazol-6-yl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (134_3) (70 mg, 0.17 mmol) and N-(4-cyanophenyl)-4-methylpiperidine-4-carboximidamide (82 mg, 0.34 mmol) were added to a reaction flask at room temperature and dissolved in acetonitrile (1 ml). Stirring was started and N,N-diisopropylethylamine (0.3 ml, 2.32 mmol) was added continuously. The temperature was raised to 80°C and the reaction was allowed to react for 5 h. LCMS monitoring indicated product formation. The reaction mixture was dried and purified by silica gel column chromatography to afford 100 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-cyanophenyl)-4-methylpiperidine-4-carboximidamide (134_4) as an oily product in a yield of 94.1%. MS m / z: 625.2 [M+H].

[0655] Step 4

[0656] 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-cyanophenyl)-4-methylpiperidine-4-carboximidamide (134-4) (100 mg, 0.16 mmol) was added to a reaction flask at room temperature and dissolved in 1.2 ml of dichloromethane. 1 ml of trifluoroacetic acid was added dropwise and the reaction was allowed to proceed for 12 hours. LCMS analysis indicated product formation, and the reaction solution was dried and purified to yield 4.7 mg of 1-[3-(7-chloro-1H-indazol-6-yl)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-N-(4-cyanophenyl)-4-methylpiperidine-4-carboximidamide (ZS5084-134) as a white solid in a 5.4% yield. MS m / z: 541.1 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=13.81-13.62(m,2H),10.77(s,1H),9.27(s,1H),9.11-8.78(m,1H),8.28(s,1H),8.06(s,2H),7.87(d, J=8.3Hz,1H),7.66(s,2H),7.59(d,J=8.3Hz,1H),5.46(s,1H),4.62(s,2H),3.55(s,4H),2.33(s,2H),1.95(s,2H),1.50(s,3H).

[0657] Example 61

[0658] Step 1

[0659] 5-Bromopyridine-3-carboxaldehyde (147_1) (1 g, 5.38 mmol) was dissolved in dichloromethane (10 ml) at room temperature. After nitrogen purge three times, the temperature was lowered to 0°C, diethylaminosulfur trifluoride (DAST) (0.85 ml, 6.46 mmol) was added, and the mixture was allowed to return to room temperature for 4 hours. LCMS indicated that the starting material was essentially consumed. The pH was adjusted to a weakly alkaline state by adding saturated aqueous sodium carbonate solution. The mixture was extracted twice with 50 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phases were concentrated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 10:1) to afford 548 mg of 3-bromo-5-(difluoromethyl)pyridine (147_2) as a white solid in a 49.0% yield. MS m / z: 207.9, 209.9 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 8.91 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 7.14 (t, J = 55.0Hz, 1H).

[0660] Step 2

[0661] At room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (150 mg, 0.62 mmol), 3-bromo-5-(difluoromethyl)pyridine (147_2) (259 mg, 1.24 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.03 mmol), di-tert-butyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (30.1 mg, 0.06 mmol), and cesium carbonate (608 mg, 1.86 mmol) were added and dissolved in tert-butanol (6 ml). After nitrogen substitution three times, the mixture was heated to 85°C and reacted overnight. LCMS monitoring indicated the formation of the product. The filtrate was filtered, diluted with 25 ml of water, and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:2) to obtain 138 mg of tert-butyl 4-{N-[5-(difluoromethyl)pyridin-3-yl]carbamoyl}-4-methylpiperidine-1-carboxylate (147_3) as a yellow solid in a yield of 60.4%. MS m / z: 369.1 [M+H].

[0662] Step 3

[0663] Trifluoroacetic acid (1.52 ml, 13.3 mmol) was added to a solution of tert-butyl 4-{N-[5-(difluoromethyl)pyridin-3-yl]carbamoyl}-4-methylpiperidine-1-carboxylate (147_3) (138 mg, 0.37 mmol) in dichloromethane (4 ml) at room temperature. The reaction was allowed to proceed for 1 h. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated and used directly in the next step. MS m / z: 269.1 [M+H].

[0664] Step 4

[0665] {3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol (Int S) (100 mg, 0.23 mmol), N-[5-(difluoromethyl)pyridin-3-yl]-4-methylpiperidine-4-carboximide (147_4) (87 mg, 0.33 mmol), and N,N-diisopropylethylamine (0.3 ml, 2.34 mmol) were dissolved in acetonitrile (2 ml) at room temperature and heated to 80°C for 3 h. TLC monitored the complete consumption of the starting material. The mixture was diluted with 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 145 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-[5-(difluoromethyl)pyridin-3-yl]-4-methylpiperidine-4-carboximide (147_5) as a yellow solid in a yield of 95.6%. MS m / z: 659.2 [M+H].

[0666] Step 5

[0667] Trifluoroacetic acid (1.5 ml, 13.2 mmol) was added to a solution of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-[5-(difluoromethyl)pyridin-3-yl]-4-methylpiperidine-4-carboximide (147-5) (145 mg, 0.22 mmol) in dichloromethane (3 ml) at room temperature. The atmosphere was purged with nitrogen three times and the mixture was allowed to react overnight at room temperature. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and solid sodium carbonate was added to adjust the pH to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 56 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-[5-(difluoromethyl)pyridin-3-yl]-4-methylpiperidine-4-carboximide (ZS5084-147) as a yellow solid in a 44.5% yield. MS m / z: 575.2 [M+H]. 1H NMR (400MHz, DMSO-d6)δ=14.31(br s,1H),10.73(br s,1H),9.28(br s,1H),9.03(br s,1H),8.90(s,1H),8.83(s,1H),8.20(s,1H),7.60(dd,J=5.9,1.5Hz,1H),7.25(t,J=52.0Hz,1H),6.97(br s,2H),5.80(br t,J=5.3Hz,1H),4.60(s,2H),3.60(br s,4H),2.31-2.40(m,2H),1.90-2.01(m,2H),1.53(s,3H). 19 F NMR (376MHz, DMSO-d6) δ = -111.6.

[0668] Example 62

[0669] Step 1

[0670] At room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (200 mg, 0.83 mmol), 5-bromo-1-methyl-1,2-dihydropyridin-2-one (149_1) (312 mg, 1.66 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 0.042 mmol), di-tert-butyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (40 mg, 0.083 mmol), and cesium carbonate (810 mg, 2.49 mmol) were dissolved in tert-butanol (6 ml). After nitrogen substitution three times, the mixture was heated to 85°C and reacted overnight. LCMS monitoring indicated product formation. The filtrate was filtered, diluted with 25 ml of water, and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 67 mg of tert-butyl 4-methyl-4-[N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)carbamoyl]piperidine-1-carboxylate (149_2) as a yellow oil, with a yield of 23.2%. MS m / z: 349.3 [M+H].

[0671] Step 2

[0672] Trifluoroacetic acid (0.5 ml, 4.38 mmol) was added to a solution of tert-butyl 4-methyl-4-[N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)carbamoyl]piperidine-1-carboxylate (149_2) (67 mg, 0.19 mmol) in dichloromethane (1.5 ml) at room temperature. The reaction was allowed to proceed for 1 h. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated and used directly in the next reaction. MS m / z: 249.2 [M+H].

[0673] Step 3

[0674] {3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol (Int S) (70 mg, 0.16 mmol), 4-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidine-4-carboxamide (149_3) (48 mg, 0.2 mmol), and N,N-diisopropylethylamine (0.11 ml, 0.82 mmol) were dissolved in acetonitrile (1.5 ml) at room temperature and heated to 80°C for overnight reaction. LCMS monitoring indicated incomplete consumption of the starting material. The mixture was diluted with 15 ml of water and extracted twice with 15 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 60 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-4-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidine-4-carboxamide (149_4) as a yellow oil in a yield of 58.7%. MS m / z: 639.2 [M+H].

[0675] Step 4

[0676] Trifluoroacetic acid (0.64 ml, 5.61 mmol) was added to a solution of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-4-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidine-4-carboxamide (149-4) (60 mg, 0.09 mmol) in dichloromethane (3 ml) at room temperature and allowed to react overnight. LCMS monitored the complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and solid sodium carbonate was added to adjust the pH to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 18.4 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-4-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)piperidine-4-carboximide (ZS5084-149) as a yellow solid, with a yield of 35.3% and a purity of 98.3%. MS m / z: 555.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ = 14.10 (br s, 1H), 7.56 (d, J = 5.4Hz, 1H), 7.05 (br s,1H),6.98(dd,J=9.4,2.6Hz,1H),6.37(s,2H),6.34(d,J=9.4Hz,1H),6.04(br s,2H),5.70(d,J=5.4Hz,1H),5.49(t,J=5.8Hz,1H),4.55(d,J=5.8Hz,2H),3.59-3. 67(m,2H),3.37(s,5H),2.28(d,J=14.1Hz,2H),1.58(t,J=10.1Hz,2H),1.23(s,3H).

[0677] Example 63

[0678] Step 1

[0679] To a tert-butanol (5 ml) solution at room temperature were added 4-bromo-1-methyl-1,2-dihydropyridin-2-one (188 mg, 1 mmol), tert-butyl 4-carbamoimido-4-methylpiperidine-1-carboxylate (482 mg, 2 mmol), tris(dibenzylideneacetone)dipalladium (91 mg, 0.1 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-biphenyl (48.47 mg, 0.1 mmol), and cesium carbonate (1.63 g, 5 mmol). The atmosphere was purged with nitrogen three times, and the reaction temperature was raised to 90°C for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (30 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: methanol:dichloromethane = 0-5%) to provide 250 mg of tert-butyl 4-methyl-4-[N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)carbamoylamino]piperidine-1-carboxylate (150_2) as a brown solid in a yield of 71.75%. MS m / z: 349.2 [M+H].

[0680] Step 2

[0681] To a dichloromethane (4 ml) solution at room temperature were added tert-butyl 4-methyl-4-[N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)carbamoylamino]piperidine-1-carboxylate (250 mg, 0.72 mmol) and trifluoroacetic acid (1 ml, 8.77 mmol). The reaction was stirred at room temperature under nitrogen for 1 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo, then diluted with dichloroethane (10 mL) and concentrated again in vacuo to afford crude 4-methyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-4-carboximide (150_3) as a brown oil, which was used directly in the next step without purification. MS m / z: 249.1 [M+H].

[0682] Step 3

[0683] To an acetonitrile (10 ml) solution at room temperature were added 4-methyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-4-carboximide (130 mg, 0.52 mmol), {3-[(2-amino-3-chloropyridin-4-yl)thio]-6-chloro-1-(oxaN-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol (89 mg, 0.21 mmol), and ethylbis(propyl-2-yl)amine (2 ml, 15.48 mmol). The mixture was protected with nitrogen and then heated to 80°C for 2 h. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was diluted twice with water (20 mL) and extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 0-50%) to afford 110 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfonyl]-5-(hydroxymethyl)-1-(oxo-2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazolin[3,4-b]pyrazin-6-yl}-4-methyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-4-carboximide (150_4) as a yellow solid in a yield of 82.1%. MS m / z: 639.2 [M+H].

[0684] Step 4

[0685] To a solution of dichloromethane (4 ml) at room temperature was added 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfonyl]-5-(hydroxymethyl)-1-(oxo-2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazolino[3,4-b]pyrazin-6-yl}-4-methyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-4-carboximide (130 mg, 0.2 mmol) and trifluoroacetic acid (2.97 ml, 26.06 mmol). The reaction was stirred at room temperature under nitrogen for 18 hours. LCMS monitoring indicated the disappearance of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, then diluted with dichloroethane (5 mL) and concentrated again in vacuo. The residue was diluted with methanol (5 mL) and neutralized with anhydrous sodium carbonate (100 mg). The mixture was filtered and the filtrate collected. The filtrate was concentrated by Prep-HPLC (mobile phase: acetonitrile:water containing 0.1% TFA = 5-95%) to yield 38 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)thio]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-4-methyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-4-carboximide (ZS5084-150) as a white solid in a 34.3% yield. MS m / z: 555.2 [M+H].1 H NMR (400MHz, DMSO-d6) δ=14.29(br s,1H),10.67(s,1H),9.33(br s,1H),9.09(br s,1H),7.91(d,J=7.3Hz,1H),7.59(d,J=5.8Hz,1H),6.89(br s,2H),6.50(br s,1H),6.27(dd,J=2.0Hz,7.1Hz,1H),5.78(d,J=5.8Hz,1H),4.58(s,2H),3.60 -3.50(m,4H),3.46(s,3H),2.33-2.29(m,2H),1.92-1.89(m,2H),1.46(s,3H).

[0686] Example 64

[0687] Step 1

[0688] At room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (200 mg, 0.83 mmol), 5-bromo-1,3-dimethylpyridin-2-one (151_1) (335 mg, 1.66 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol), di-tert-butyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphine (40 mg, 0.08 mmol), and cesium carbonate (810 mg, 2.49 mmol) were dissolved in tert-butanol (4 ml). After nitrogen substitution three times, the mixture was heated to 85°C and reacted overnight. LCMS monitoring indicated product formation. The mixture was diluted with 25 ml of water and extracted twice with 20 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 90 mg of tert-butyl 4-[N-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)carbamoyl]-4-methylpiperidine-1-carboxylate (151_2) as a yellow solid in a yield of 29.9%. MS m / z: 363.2 [M+H].

[0689] Step 2

[0690] Trifluoroacetic acid (1.2 ml, 10.5 mmol) was added to a solution of tert-butyl 4-[N-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)carbamoyl]-4-methylpiperidine-1-carboxylate (151_2) (90 mg, 0.25 mmol) in dichloromethane (3 ml) at room temperature. The reaction was allowed to proceed for 1 h. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated and used directly in the next reaction. MS m / z: 263.2 [M+H].

[0691] Step 3

[0692] {3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol (Int S) (80 mg, 0.19 mmol), N-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methylpiperidine-4-carboximide (151_3) (63 mg, 0.24 mmol), and N,N-diisopropylethylamine (0.12 ml, 0.94 mmol) were added to acetonitrile (2 ml) at room temperature and heated to 80°C for 5 h. LCMS monitoring indicated incomplete consumption of the starting material. The mixture was diluted with 15 ml of water and extracted twice with 15 ml of ethyl acetate. The organic layers were combined and washed once with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to obtain 62 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methylpiperidine-4-carboximide (151_4) as a yellow oil in a 50.0% yield. MS m / z: 653.2 [M+H].

[0693] Step 4

[0694] Trifluoroacetic acid (1 ml, 8.77 mmol) was added to a solution of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methylpiperidine-4-carboximide (151_4) (62 mg, 0.09 mmol) in dichloromethane (2 ml) at room temperature. The atmosphere was purged with nitrogen three times and the mixture was allowed to react overnight at room temperature. LCMS confirmed complete consumption of the starting material. The reaction solution was concentrated, diluted with methanol, and solid sodium carbonate was added to adjust the pH of the reaction solution to 7-8. After filtration, the product was purified by preparative HPLC and lyophilized to obtain 20.9 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methylpiperidine-4-carboximide (ZS5084-151) as a yellow solid in a 38.7% yield. MS m / z: 569.2 [M+H]. 1 H NMR (400MHz, DMSO-d6)δ=14.27(br s,1H),10.25(br s,1H),9.13(br s,1H),8.84(br s,1H),7.89(d,J=2.3Hz,1H),7.59(d,J=5.6Hz,1H),7.32(d,J=1.4Hz,1H),6.74(br s,2H),5.75(d,J=5.6Hz,1H),4.58(s,2H),3.61(d,J=6.9Hz,2H),3.48(br s,2H),3.45(s,3H),2.27-2.34(m,2H),2.05(s,3H),1.86-1.94(m,2H),1.45(s,3H).

[0695] Example 65

[0696] Step 1

[0697] To the reaction flask at room temperature, tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (152_1) (200 mg, 0.83 mmol), 3-bromo-5-fluoropyridine (171.85 ul, 1.66 mmol), and cesium carbonate (1352 mg, 4.15 mmol) were added and dissolved in tert-butanol (2 ml). The mixture was stirred for 0.5 h, and 1,5-diphenylpenta-1,4-dien-3-one palladium (38 mg, 0.04 mmol) and di-tert-butyl [3,6-dimethoxy-2,4,6-tri(propyl-2-yl)-[1,1'-biphenyl]-2-yl] phosphine (40 mg, 0.08 mmol) were added. The mixture was purged with nitrogen for three minutes, and the temperature was raised to 85°C and the reaction was continued for 12 h. The product was generated by LCMS monitoring. The reaction solution was dried and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:1) to obtain 150 mg of tert-butyl 4-[N-(5-fluoropyridin-3-yl)ureamido]-4-methylpiperidine-1-carboxylate (152_2) as a light yellow oil in a yield of 53.7%. MS m / z: 337.1 [M+H].

[0698] Step 2

[0699] To a reaction flask at room temperature, tert-butyl 4-[N-(5-fluoropyridin-3-yl)ureamido]-4-methylpiperidine-1-carboxylate (152_2) (150 mg, 0.45 mmol) was added and dissolved in 2 ml of dichloromethane. 0.5 ml of trifluoroacetic acid was added and stirred at room temperature for 0.5 h. LCMS monitored the product formation, and the reaction mixture was dried and used directly in the next reaction. MS m / z: 237.1 [M+H].

[0700] Step 3

[0701] To a reaction flask at room temperature were added {3-[(2-amino-3-chloropyridin-4-yl)thio]-6-chloro-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-methanol (130 mg, 0.3 mmol) and N-(5-fluoropyridin-3-yl)-4-methylpiperidine-4-carboximidamide (152_3) (107 mg, 0.46 mmol), which were dissolved in 2 ml of acetonitrile. N,N-diisopropylethylamine (393 mg, 3.04 mmol) was then added. The mixture was stirred and heated to 80°C for 12 h. Product formation was monitored by LCMS, and the reaction solution was purified by spin-drying silica gel column chromatography (mobile phase: dichloromethane:methanol = 20:1) to afford 170 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)thio]-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(5-fluoropyridin-3-yl)-4-methylpiperidin-4-carboximidamide (152_4) as a white solid in a yield of 90.3%. MS m / z: 627.2 [M+H].

[0702] Step 4

[0703] 1-{3-[(2-amino-3-chloropyridin-4-yl)thio]-5-hydroxymethyl-1-oxa-2-yl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(5-fluoropyridin-3-yl)-4-methylpiperidine-4-carboximidamide (152_4) (150 mg, 0.24 mmol) was added to a reaction flask at room temperature and dissolved in 2 ml of dichloromethane. 1.5 ml of trifluoroacetic acid was added dropwise, and stirring was started. The reaction was allowed to react at room temperature for 12 h. LCMS monitoring indicated product formation. Solid sodium carbonate was added to the reaction solution, and the filtrate was filtered and dried. The solution was dissolved in methanol and purified by preparative purification to yield 60 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)thio]-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-N-(5-fluoropyridin-3-yl)-4-methylpiperidin-4-carboximidamide (ZS5084-152) as a gray solid in a yield of 46.7%. MS m / z: 543.1 [M+H]. 1H NMR (400MHz, DMSO-d6)δ=14.32(br s,1H),10.80(br s,1H),9.31(br s,1H),9.03(br s,1H),8.74(d,J=2.5Hz,1H),8.55(s,1H),8.07(dt,J=9.5,2.1Hz,1H),7.61(d,J=5.9Hz,1H), 6.93-7.15(m,1H),5.81(d,J=5.8Hz,1H),4.60(s,2H),3.59(br s,4H),2.29-2.41(m,2H),1.88-2.01(m,2H),1.52(s,3H), 19 F NMR (376MHz, DMSO-d6) δ = -125.2.

[0704] Example 66

[0705] Step 1

[0706] To a solution of tert-butyl 4-(N-(5-fluoro-6-methylpyridin-3-yl)urea)-4-methylpiperidine-1-carboxylate (71.43 mg, 0.29 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL, 8.77 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The disappearance of the starting material was monitored by TLC. The mixture was concentrated in vacuo to afford N-(5-fluoro-6-methylpyridin-3-yl)-4-methylpiperidine-4-carboxamidine (153_3) as a light yellow oil, which was used directly in the next step.

[0707] Step 2

[0708] To a solution of N-(5-fluoro-6-methylpyridin-3-yl)-4-methylpiperidine-4-carboximidamide (72 mg, 0.29 mmol) and 3-(2-amino-3-chloropyridin-4-yl)thio)-6-chloro-1-tetrahydropyran-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (98 mg, 0.23 mmol) in acetonitrile (3 mL) was added N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) at room temperature. The reaction was then heated to 80°C and allowed to react for 2 hours. LCMS confirmed complete reaction of the starting material and the desired molecular weight. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol = 10:1) to afford 140 mg of 1-(3-(2-amino-3-chloropyridin-4-yl)thio)-5-hydroxymethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(5-fluoro-6-methylpyridin-3-yl)-4-methylpiperidine-4-carboximidamide (153_4) as a yellow solid in a 94.9% yield. MS m / z: 641.2 [M+H]

[0709] Step 3

[0710] To a solution of 11-(3-(2-amino-3-chloropyridin-4-yl)thio)-5-hydroxymethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(5-fluoro-6-methylpyridin-3-yl)-4-methylpiperidine-4-carboximidamide (140 mg, 0.22 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred at room temperature for 12 hours. LCMS monitored the complete reaction of the starting materials and the desired target molecular weight. The reaction solution was concentrated in vacuo, and the residue was dissolved in methanol. Solid sodium carbonate was added to adjust the pH to a weak base. The product was then purified by Prep-HPLC to yield 37.88 mg of 1-(3-(2-amino-3-chloropyridin-4-yl)thio)-5-hydroxymethyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(5-fluoro-6-methylpyridin-3-yl)-4-methylpiperidine-4-carboximidamide as a white solid in a 31% yield. MS m / z: 557.2 [M+H]. 1H NMR (400MHz, DMSO-d6)δ=14.27(br s,1H),10.6-10.8(m,1H),9.26(br s,1H),8.91(br s,1H),8.40(s,1H),7.96(d,1H,J=10.4Hz),7.6-7.6(m,1H),6.70(br s,2H),5.7-5.8(m,1H),4.59(s,2H),3.58(br s,4H),2.52(d,3H,J=2.6Hz),2.3-2.4(m,2H),1.9-2.0(m,2H),1.50(s,3H) 19 F NMR (376MHz, DMSO-d6) δ = -122.2.

[0711] Example 67

[0712] Step 1

[0713] To a solution of 4-iodo-1-methylpyrazole (200 mg, 0.96 mmol) and tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (208 mg, 0.87 mmol) in acetonitrile (5 mL) at room temperature were added cesium carbonate (939 mg, 2.88 mmol) and cuprous iodide (18 mg, 0.1 mmol). The atmosphere was purged with nitrogen three times, then the temperature was raised to 85°C and the reaction was allowed to proceed for 12 h. LCMS confirmed complete reaction of the starting materials and the desired molecular weight. The reaction mixture was filtered, and the residue was rinsed twice with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford 170 mg of tert-butyl 4-(N-(1-methyl-1H-pyrazol-4-yl)imidazolyl)piperidine-1-carboxylate (154_2) as a yellow solid in a 60.8% yield. MS m / z: 322.2 [M+H].

[0714] Step 2

[0715] To a solution of tert-butyl 4-methyl-4-(N-(1-methyl-1H-pyrazol-4-yl)imidazolinyl)piperidine-1-carboxylate (170 mg, 0.53 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was allowed to proceed for 2 hours. LCMS monitored the complete reaction of the starting material and the desired target molecular weight. The reaction solution was concentrated in vacuo to afford 117 mg of 4-methyl-N-(1-methylpyrazol-4-yl)piperidine-4-carboximidamide (154_3) as a yellow oil, which was used directly in the next step. MS m / z: 222.1 [M+H].

[0716] Step 3

[0717] To a solution of 4-methyl-N-(1-methylpyrazol-4-yl)piperidine-4-carboximidamide (117 mg, 0.53 mmol) and 3-(2-amino-3-chloropyridin-4-yl)thio)-6-chloro-1-tetrahydropyran-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-methanol (226 mg, 0.53 mmol) in acetonitrile (5 mL) was added N,N-diisopropylethylamine (0.46 ml, 2.65 mmol) at room temperature. The reaction was then heated to 80°C for 12 hours. LCMS confirmed complete reaction of the starting material and the desired target molecular weight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to afford 130 mg of 1-(3-(2-amino-3-chloropyridin-4-yl)thio)-5-hydroxymethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)piperidine-4-carboximidamide (154_4) as a yellow solid in a 40.0% yield. MS m / z: 612.2 [M+H].

[0718] Step 4

[0719] To a solution of 1-{3-[(2-amino-3-chloropyridin-4-yl)sulfonyl]-5-hydroxymethyl-1-(oxa-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)piperidine-4-carboximidamide (130 mg, 0.21 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL, 8.77 mmol) at room temperature. The reaction was allowed to proceed at room temperature for 12 hours. LCMS confirmed the complete reaction of the starting material and the desired target molecular weight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in methanol. Solid sodium carbonate was added to adjust the pH to approximately 9, and the product was submitted for Prep-HPLC analysis to yield 20.01 mg of 1-{3-[(2-amino-3-chloropyridin-4-yl)thio]-5-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl}-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)piperidine-4-carboximidamide (ZS5084-154) as a light yellow solid in a 17.7% yield. MS m / z: 528.2 [M+H]. 1H NMR (400MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.58 (s, 1H), 7.56 (d, 1H, J = 5.4Hz), 7.27 (s, 1H), 6.38 (s, 2H), 5.70 (d, 1H, J=5.4Hz),4.56(s,2H),3.79(s,3H),3.5-3.6(m,2H),3.3-3.4(m,2H),2.3-2.3(m,2H),1.69(m,2H),1.30(s,3H).

[0720] Example 68

[0721] Step 1

[0722] To a solution of 4-bromo-2,6-difluoropyridine (300 mg, 1.55 mmol) in dimethyl sulfoxide (3 mL) was added 5 M potassium hydroxide solution (0.17 mL, 3.1 mmol) at room temperature. The reaction was then heated to 100°C for 1 hour. LCMS confirmed complete reaction and the desired molecular weight. The pH of the reaction was adjusted to approximately 5 with hydrochloric acid. The product was extracted with ethyl acetate and washed once with saturated brine. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford 270 mg of 4-bromo-6-fluoro-1,2-di...

Claims

1. A compound having the structure of formula (I), and its pharmaceutically acceptable salts, stereoisomers, isotope isomers, solvates, and hydrates: in, X 1 , X 3 , X 4 , X 5 Each independently represents CR a , O, S or N; Among them, X 2 Represents CR a R b or NR a ; Among them, Cy 1 represents a 4-14 membered saturated or unsaturated carbocyclic ring or a 4-14 membered saturated or unsaturated heterocyclic ring; and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Among them, Cy 2 represents a 4-14 membered saturated or unsaturated carbocyclic ring or a 4-14 membered saturated or unsaturated heterocyclic ring, and the Cy 2 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Among them, L 1 Indicates non-existent or NR a ; Among them, L 2 Indicates absence, O, S, NR a or CR a R b ; Among them, R L , R L’ Each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; or R L , R L’ Together with the N atom connected thereto, it forms a 3-10 membered saturated or unsaturated ring, and in addition to the N atom, the ring may also contain 0-2 heteroatoms selected from O, N, and S, and further, the ring may also be arbitrarily substituted by 0-3 heteroatoms selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Among them, R a , R b Each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, and the alkyl or cycloalkyl can be arbitrarily substituted by 0-3 groups selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent.

2. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 1 Indicates N or CR a , where R a Represents hydrogen, C 1 -C 6 Alkyl or C 3 -C 10 Cycloalkyl.

3. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 2 Indicates CH 2 Or NH.

4. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 3 It represents N or CH.

5. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 4 It represents N or CH.

6. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 5 It represents N or CH.

7. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 1 represents a 6-10 membered aryl or a 5-10 membered heteroaryl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent.

8. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 1 express phenyl, pyridyl, thienyl, pyrrolyl, pyridonyl, pyrazinyl, piperidinyl, pyridazinyl, imidazolyl, thiazolyl, oxazolyl, benzopyridinyl, indolyl, benzopiperidinyl, benzopiperazinyl, benzoindolyl, benzothiazolyl, benzopyrrolyl, benzothienyl, benzoxazolyl, benzimidazolyl, pyridopiperidinyl, pyridopiperazinyl, pyridoindolyl, pyridothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridooxazolyl, pyridoimidazolyl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent.

9. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 1 express 10. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, Cy 1 represents phenyl, pyridyl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a replaced.

11. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 2 Represents the following groups: Where A represents (CR a R b ) n ; Among them, Y 1 Indicates N or CR T ; Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each independently represents hydrogen, C 1 -C 6 Alkyl, halogen, OR a ; or R 1 , R 2 Together with the carbon atom to which it is attached, they form a 3-6 membered ring; or R 3 , R 4 Together with the carbon atom to which it is attached, they form a 3-6 membered ring; or R 5 , R 6 Together with the carbon atom to which it is attached, they form a 3-6 membered ring; or R 7 , R 8 Together with the carbon atom to which it is attached, they form a 3-6 membered ring; Among them, R T Represents hydrogen, hydroxyl, halogen, C 1 -C 6 Alkyl or 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted 6-10 membered aryl or substituted by 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted 5-10 membered heteroaryl; Here, n represents an integer of 0, 1, or 2.

12. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, L 1 Indicates absence or NH.

13. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, R L , R L’ Each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl or optionally substituted by 0-3 groups selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a The C substituted by the substituent 3 -C 10 Cycloalkyl, 6-10 membered aryl.

14. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, R L Represents hydrogen.

15. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, R L’ represents hydrogen or is optionally replaced by 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a The C substituted by the substituent 3 -C 10 Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl.

16. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, R L’ represents phenyl, pyridyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, piperidinyl, pyridazinyl, and said R L’ Randomly 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a substituted by a substituent.

17. A compound having the structure of formula (II), and its pharmaceutically acceptable salts, stereoisomers, isotope isomers, solvates, and hydrates: in, X 1 , X 3 , X 4 , X 5 Each independently represents CR a , O, S or N; Among them, X 2 Represents CR a R b or NR a ; Among them, Cy 1 represents a 4-14 membered saturated or unsaturated carbocyclic ring or a 4-14 membered saturated or unsaturated heterocyclic ring; and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Among them, L 1 Indicates non-existent or NR a ; Among them, L 2 Indicates absence, O, S, NR a or CR a R b ; Among them, R L , R L’ Each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; or R L , R L’ Together with the N atom connected thereto, it forms a 3-10 membered saturated or unsaturated ring, and in addition to the N atom, the ring may also contain 0-2 heteroatoms selected from O, N, and S, and further, the ring may also be arbitrarily substituted by 0-3 heteroatoms selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Among them, Y 1 Indicates N or CR T ; Among them, R T Represents hydrogen, hydroxyl, halogen, C 1 -C 6 Alkyl or 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted 6-10 membered aryl or substituted by 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted 5-10 membered heteroaryl; Among them, R a , R b Each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, and the alkyl or cycloalkyl can be arbitrarily substituted by 0-3 groups selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 Each independently represents hydrogen, C 1 -C 6 Alkyl, halogen, OR a .

18. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, X 1 Indicates N or CR a , where R a Represents hydrogen, C 1 -C 6 Alkyl or C 3 -C 10 Cycloalkyl.

19. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, X 2 Indicates CH 2 Or NH.

20. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, X 3 It represents N or CH.

21. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, X 4 It represents N or CH.

22. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, X 5 It represents N or CH.

23. The compound according to claim 17, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 1 represents a 6-10 membered aryl or a 5-10 membered heteroaryl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent.

24. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, Cy 1 express phenyl, pyridyl, thienyl, pyrrolyl, pyridonyl, pyrazinyl, piperidinyl, pyridazinyl, imidazolyl, thiazolyl, oxazolyl, benzopyridinyl, indolyl, benzopiperidinyl, benzopiperazinyl, benzoindolyl, benzothiazolyl, benzopyrrolyl, benzothienyl, benzoxazolyl, benzimidazolyl, pyridopiperidinyl, pyridopiperazinyl, pyridoindolyl, pyridothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridooxazolyl, pyridoimidazolyl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent.

25. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, Cy 1 express 26. The compound according to claim 17, or a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, or hydrate thereof. in, Cy 1 represents phenyl, pyridyl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a replaced.

27. A compound having the structure of formula (III), and its pharmaceutically acceptable salts, stereoisomers, isotope isomers, solvates, hydrates: in, X 1 , X 3 , X 4 , X 5 Each independently represents CR a , O, S or N; Among them, X 2 Represents CR a R b or NR a ; Among them, Cy 1 represents a 4-14 membered saturated or unsaturated carbocyclic ring or a 4-14 membered saturated or unsaturated heterocyclic ring; and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Where A represents (CR a R b ) n ; Wherein, n represents an integer of 0, 1, or 2; Among them, L 1 Indicates non-existent or NR a ; Among them, L 2 Indicates absence, O, S, NR a or CR a R b ; Among them, R L , R L’ Each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be arbitrarily substituted by 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; or R L , R L’ Together with the N atom connected thereto, it forms a 3-10 membered saturated or unsaturated ring, and in addition to the N atom, the ring may also contain 0-2 heteroatoms selected from O, N, and S, and further, the ring may also be arbitrarily substituted by 0-3 heteroatoms selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Among them, Y 1 Indicates N or CR T ; Among them, R T Represents hydrogen, hydroxyl, halogen, C 1 -C 6 Alkyl or 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted 6-10 membered aryl or substituted by 0-3 selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted 5-10 membered heteroaryl; Among them, R a , R b Each independently represents hydrogen, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, and the alkyl or cycloalkyl can be arbitrarily substituted by 0-3 groups selected from: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent; Among them, R 1 , R 2 , R 3 , R 4 Each independently represents hydrogen, C 1 -C 6 Alkyl, halogen, OR a .

28. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 1 Indicates N or CR a , where R a Represents hydrogen, C 1 -C 6 Alkyl or C 3 -C 10 Cycloalkyl.

29. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 2 Indicates CH 2 Or NH.

30. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 3 It represents N or CH.

31. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 4 It represents N or CH.

32. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, X 5 It represents N or CH.

33. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, A stands for CH 2 or CH 2 CH 2 .

34. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 1 represents a 6-10 membered aryl or a 5-10 membered heteroaryl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent.

35. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 1 express phenyl, pyridyl, thienyl, pyrrolyl, pyridonyl, pyrazinyl, piperidinyl, pyridazinyl, imidazolyl, thiazolyl, oxazolyl, benzopyridinyl, indolyl, benzopiperidinyl, benzopiperazinyl, benzoindolyl, benzothiazolyl, benzopyrrolyl, benzothienyl, benzoxazolyl, benzimidazolyl, pyridopiperidinyl, pyridopiperazinyl, pyridoindolyl, pyridothiazolyl, pyridopyrrolyl, pyridothiphenyl, pyridooxazolyl, pyridoimidazolyl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a 、-C(O)OR a 、-OC(O)R a 、-C(O)NR a R b 、-NR a C(O)R a 、-S(O) 3 R a 、-S(O) 2 R a substituted by a substituent.

36. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 1 express 37. The compound according to claim 27, its pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate, in, Cy 1 represents phenyl, pyridyl, and the Cy 1 Can be arbitrarily selected from 0-3: halogen, cyano, C 1 -C 6 Alkyl, C 3 -C 10 Cycloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, -OR a NR a R b 、-SR a replaced.

38. A compound or a pharmaceutically acceptable salt thereof having any of the following structures:

39. Use of a compound according to claim 1, 17 or 27, a pharmaceutically acceptable salt, stereoisomer, isotope isomer, solvate, hydrate thereof, or a compound according to claim 38 or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment and / or prognosis of a disease; the disease is allosterically related to SHP2.

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