NITROGEN-CONTAINING COMPOUND, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF

Abstract

A compound represented by formula (I), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of the pharmaceutically acceptable salt thereof, a preparation method therefor and an application thereof. The nitrogen-containing compound has good inhibitory activity against NLRP3.

##STR00001##

Claims

1. A compound represented by formula I, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of the pharmaceutically acceptable salt thereof, ##STR00315## among them, Z.sup.1, Z.sup.2 and Z.sup.3 are independently N or CR.sup.Z; each R.sup.Z is independently H, halogen, or C.sub.1C.sub.6 alkyl; or, Z.sup.1 and Z.sup.2 are CR.sup.Z, and the R.sup.Z on Z.sup.1 and Z.sup.2 together form a ring Y with the carbon connected to it; the ring Y is a C.sub.5C.sub.6 cycloalkenyl, a 5-6-membered heteroalkyneyl, a benzene, a 5-6-membered heteroaromatic ring, a C.sub.5-C.sub.6 cycloalkenyl substituted by one or more R.sup.Z-1, a 5- to 6-membered heterocycloalkenyl substituted by one or more R.sup.Z-2, a one or more R.sup.Z-3-substituted benzene ring, or a one or more R.sup.Z-4 substituted 5- to 6-membered heteroaromatic ring; R.sup.Z-1, R.sup.Z-2, R.sup.Z-3 and R.sup.Z-4 are independent C.sub.1C.sub.6 alkyls, C.sub.1C.sub.6 alkoxy or halogens; R is H; R1 is C.sub.1C.sub.6 alkyl, C.sub.3C.sub.6 cycloalkyl, 310-membered heterocycloalkyl, C.sub.1C.sub.6 alkyl group substituted by one or more R.sup.1-1, C.sub.3C.sub.6 cycloalkyl group substituted by one or more R.sup.1-2 or 310-membered heterocycloalkyl group substituted by one or more R.sup.1-3; R.sup.Z-1, R.sup.Z-2 and R.sup.Z-3 are independently NH.sub.2, OH, C.sub.1C.sub.6 alkyl, C.sub.3C.sub.6 cycloalkyl, 36-membered heterocycloalkyl, (SO).sub.2C.sub.1C.sub.6 alkyl, C.sub.1C.sub.6 alkyl group substituted by one or more R.sup.a, C.sub.3C.sub.6 cycloaklyl group substituted by one or more R.sup.b, or 36-membered membered heterocycloalkyl group substituted by one or more R.sup.8; R.sup.a, R.sup.b, and R.sup.g are independently OH, COOH, (CO)NH.sub.2, (CO)NHR, C.sub.3C.sub.6 cycloalkyl, or C.sub.3C.sub.6 cycloalkyl group substituted by one or more R.sup.ds; R.sup.c and R.sup.d are independently OH, C.sub.1C.sub.6 alkyl, C.sub.1C.sub.6 alkyl group substituted by one or more R.sup.c, C.sub.3C.sub.6 cycloalkyl group, or C.sub.3C.sub.6 cycloalkyl group substituted by one or more R.sup.fs; R.sup.e and R.sup.f are independently OH or C.sub.1C.sub.6 alkyls; R.sup.2 is a halogen, C.sub.1C.sub.6 alkyl group or C.sub.1C.sub.6 alkyl group substituted by one or more halogens; as described in the above, the 56-membered heterocycloalkenyl group, 56-membered heteroaromatic ring, and 310-membered heterocycloalkyl group and 36-membered heterocycloalkyl group, the heteroatom is independently one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 independently; the compound shown in general formula i satisfies at least one of the following conditions: (1) at least one of Z.sup.1, Z.sup.2 and Z.sup.3 is N; (2) Z.sup.1 and Z.sup.2 are CR.sup.Zs, and the R.sup.Zs on Z.sup.1 and Z.sup.2 form a ring Y together with the carbon connected to them.

2. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1, characterized in that each satisfies one or more of the following conditions: (1) in R.sup.Z, the C.sub.1C.sub.6 alkyl group is a C.sub.1C.sub.3 alkyl group; (2) in R.sup.Z, the halogen is F, Cl, Br or I; (3) in ring Y, the C.sub.5C.sub.6 alkenyl ring is independently cyclopentenyl; (4) in ring Y, the 5- to 6-membered heterocycloalkenyl ring is independently a dihydrofuran ring; (5) in ring Y, the 5- to 6-membered heteroaromatic ring is independently a furan ring, a pyridine ring or a pyrrole ring; (6) in R.sup.Z-1, R.sup.Z-2, R.sup.Z-3 and R.sup.Z-4, the C.sub.1C.sub.6 alkyl groups are independently C.sub.1C.sub.3 alkyl groups; (7) in R.sup.Z-1, R.sup.Z-2, R.sup.Z-3 and R.sup.Z-4, the C.sub.1C.sub.6 alkoxy groups are independently C.sub.1C.sub.3 alkoxy groups; (8) in R.sup.Z-1, R.sup.Z-2, R.sup.Z-3 and R.sup.Z-4, the halogen is independently F, Cl, Br or I; (9) the carbon atom in R.sup.1 connected to N in the general formula I has chirality; (10) in R.sup.1, the C.sub.1C.sub.6 alkyl groups are independently C.sub.1C.sub.3 alkyl groups; (11) in R.sup.1, the C.sub.3C.sub.6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (12) in R.sup.1, the 3 to 10-membered heterocycloalkyl group is independently a 3 to 10-membered monocyclic or bicyclic heterocycloalkyl group; (13z) in R.sup.1-1, R.sup.1-2 and R.sup.1-3, the C.sub.1C.sub.6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl or isobutyl; (14) among R.sup.1-1, R.sup.1-2 and R.sup.1-3, the C.sub.3C.sub.6 cycloalkyl group is independently cyclopropyl or cyclobutyl; (15) among R.sup.1-1, R.sup.1-2 and R.sup.1-3, the 3 to 6-membered heterocycloalkyl group is independently a 5 to 6-membered heterocycloalkyl group; (16) in R.sup.a and R.sup.b, the C.sub.3C.sub.6 cycloalkyl group is independently a cyclopropyl group; (17) in R.sup.c and R.sup.d, the C.sub.1C.sub.6 alkyl groups are independently C.sub.1C.sub.3 alkyl groups; (18) in R.sup.c and R.sup.d, the C.sub.3C.sub.6 cycloalkyl group is independently a cyclobutyl group; (19) in R.sup.e and R.sup.f, the C.sub.1C.sub.6 alkyl groups are independently C.sub.1C.sub.3 alkyl groups; (20) in R.sup.2, the halogen is independently F, Cl, Br or I; (21) in R.sup.2, the C.sub.1C.sub.6 alkyl group is independently a C.sub.1C.sub.3 alkyl group; (22) the numbers of R.sup.Z-1, R.sup.Z-2, R.sup.Z-3 and R.sup.Z-4 are denoted as a, b, c and d respectively, where a, b, c and d are independently 1, 2 or 3.

3. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 2, characterized in that each satisfies one or more of the following conditions: (1) in R.sup.Z, the C.sub.1C.sub.6 alkyl group is a methyl group; (2) in R.sup.Z, the halogen is F or Cl; (3) in the ring Y, the C.sub.5C.sub.6 alkenyl ring is independently cyclopentene, and in this case, the structure in formula I ##STR00316## (4) in the ring Y, the 56-membered heterocycloalkenyl ring is a dihydrofuran ring independently, and in this case, the structure in formula I ##STR00317## or in General formula I, the ##STR00318## structure is ##STR00319## (5) in ring Y, the 5-6-membered heteroaromatic ring is independently furan ring, pyridine ring or pyrrole ring, and in these cases, the structure in formula I ##STR00320## is ##STR00321## (6) in R.sup.Z-1, R.sup.Z-2, R.sup.Z-3 and R.sup.Z-4, the C.sub.1C.sub.6 alkyl group is a methyl group; (7) in R.sup.Z-1, R.sup.Z-2, R.sup.Z-3 and R.sup.Z-4, the alkoxy group of described C.sub.1C.sub.6 is a methoxy group; (8) in R.sup.Z-1, R.sup.Z-2, R.sup.Z-3 and R.sup.Z-4, the halogen is F; (9) the carbon atom in R.sup.1 connected to N in General formula I is chiral, and the configuration of the carbon atom is R configuration; (10) in R.sup.1, the C.sub.1C.sub.6 alkyl group is a methyl group; (11) in R.sup.1, the C.sub.3C.sub.6 cycloalkyl group is cyclobutyl or cyclohexyl; (12) in R.sup.1, when the 310-membered heterocycloalkyl group is a bicyclic heterocycloalkyl group, it is a 6-membered heterocyclic-ring fusing a 5-membered heterocycloalkyl group; (13) in R.sup.1, when the 310-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group, it is a 36-member heterocycloalkyl group; (14) in R.sup.1-1, R.sup.1-2 and R.sup.1-3, the 36-membered heterocycloalkyl group is a tetrahydropyrrole group; (15) in R.sup.c and R.sup.d, the C.sub.1C.sub.6 alkyl group is isopropyl; (16) in R.sup.e and R.sup.f, the C.sub.1C.sub.6 alkyl group is a methyl group; (17) R.sup.2, the halogen is F or Cl; (18) R.sup.2, the C.sub.1C.sub.6 alkyl group is a methyl group.

4. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 3, characterized in that each satisfies one or more of the following conditions: (1) R.sup.Z is independently H, F, Cl or CH.sub.3; ##STR00322## is ##STR00323## (3) R.sup.Z-1 is F; (4) R.sup.Z-3 is methoxy or F; (5) R.sup.Z-4 is methyl; (6) in R.sup.1, when the 310-membered heterocycloalkyl group is a bicyclic heterocycloalkyl group, it is a piperidine ring and tetrahydropyrrole ring; (7) in R.sup.1, when the 310-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group, it is a piperidine group; (8) R.sup.1-1, R.sup.1-2 and R.sup.1-3, the 36-membered heterocycloalkyl group is ##STR00324## (9) R.sup.1 is any one of the following structures: ##STR00325## ##STR00326## (10) R.sup.2 is CH.sub.3, Cl or CF.sub.3.

5. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1, characterized in that when R.sup.1 is a one or more R.sup.1-1s substituted C.sub.1C.sub.6 alkyl group, a one or more R.sup.1-2s substituted C.sub.3C.sub.6 cycloalkyl group or a one or more R.sup.1-3s substituted 310-membered heterocycloalkyl group, the compound shown in formula I is: ##STR00327##

6. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1, characterized in that each satisfies one or more of the following conditions: (1) Z.sup.1 is N; (2) Z.sup.2 and Z.sup.3 are independent CR.sup.Z; (3) each R.sup.Z is independently H or C.sub.1C.sub.6 alkyl group; (4) when Z.sup.1 and Z.sup.2 are CR.sup.Z, and the R.sup.Z on Z.sup.1 and Z.sup.2 forms a ring Y together with the carbon connected to it, the ring Y is a benzene ring, a 56-membered heteroaromatic ring, a benzene ring substituted by one or more R.sup.Z-3 or a 5-6-membered heteroaromatic ring substituted by one or more R.sup.Z-4s; (5) when Z.sup.1 and Z.sup.2 are CR.sup.Z, and the R.sup.Z on Z.sup.1 and Z.sup.2 together form a ring Y with the carbon connected thereto, the ring Y is a benzene ring, a 56-member heteroaromatic ring, a benzene ring substituted by one or more R.sup.Z-3 or a 5-6-member heteroaromatic ring substituted by one or more R.sup.Z-4, and the R.sup.Z-3 and R.sup.Z-4 are halogens independently; (6) R.sup.1 is C.sub.3C.sub.6 cycloalkyl, 310-membered heterocycloalkyl, C.sub.3C.sub.6 cycloalkyl group substituted by one or more R.sup.1-2 or 310-membered heterocycloalkyl group substituted by one or more R.sup.1-3; (7) R.sup.1-2 and R.sup.1-3 are independently OH, C.sup.1C.sup.6 alkyl, C.sup.3C.sup.6 cycloalkyl or C.sup.1C.sup.6 alkyl group substituted by one or more R.sup.a; (8) R.sup.a is OH independently.

7. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is defined as described in any one of the following scenarios: scenario 1: Z.sup.1 is N; Z.sup.2 and Z.sup.3 are independently for CR.sup.Z; each R.sup.Z is independently of H or C.sub.1C.sub.6 alkyl group; alternatively, Z.sup.1 and Z.sup.2 are CR.sup.Z, and the R.sup.Z on Z.sup.1 and Z.sup.2 forms a ring Y together with the carbon connected to it, and the ring Y is a benzene ring, a 5-6-membered heteroaromatic ring, a benzene ring substituted by one or more R.sub.Z-3 or a 5-6-membered heteroaromatic ring substituted by one or more R.sup.Z-4s; R.sup.Z-3 and R.sup.Z-4 are halogens independently; R is H; R.sup.1 is C.sub.3C.sub.6 cycloalkyl, 310-memberedmembered heterocycloalkyl, C.sub.3C.sub.6 cycloalkyl group substituted by one or more R.sup.1-2 or 310-memberedmembered heterocycloalkyl group substituted by one or more R1-3; R.sup.1-2 and R.sup.1-3 are independently OH, C.sub.1C.sub.6 alkyl, C.sub.3C.sub.6 cycloalkyl or C.sub.1C.sub.6 alkyl group substituted by one or more R.sup.a; R.sup.a is OH independently; scenario 2: the compound shown in general formula I is a compound as shown in general formula I-1 ##STR00328## wherein, R.sup.1 is a C.sub.3C.sub.6 cycloalkyl group substituted by one or more R.sup.1-2s, R.sup.1-2 is NH.sub.2 or OH independently; R is H, each R.sup.Z is independently of H or C.sub.1C.sub.6 alkyl group; R.sup.2 is a C.sub.1C.sub.6 alkyl group substituted by one or more halogens scenario 3: the compound shown in general formula I is a compound as shown in general formula I-1 ##STR00329## wherein R.sup.1 is a cyclohexyl group substituted by one or more R.sup.1-2s, R.sup.1-2 is NH.sub.2 or OH independently; R is H; each R.sup.Z is independently of H or C.sub.1-C.sub.6 alkyl group; R.sup.2 is a C.sub.1C.sub.6 alkyl group substituted by one or more halogens; scenario 4; each satisfies one or more of the following conditions: (1) Z.sup.1 is N; (2) Z.sup.2 is N; (3) Z is N.

8. (canceled)

9. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1, characterized in that compounds shown in formula I is any one of the following structures: ##STR00330## ##STR00331##

10. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound shown in formula I is any one of the following structures: ##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408##

11. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound shown in formula I is any one of the following structures: ##STR00409## ##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429## ##STR00430## ##STR00431## ##STR00432## ##STR00433## ##STR00434##

12. A preparation method for a compound as shown in formula I as claim 1, wherein it is any one of the following methods: method 1: it consists of the following steps: in a solvent, under the action of an acid, compound 1 undergoes a reaction as shown below; ##STR00435## method 2: it consists of the following step: in a solvent, under the action of a base, compound 9 reacts with compound 3 to yield the compound las shown below; ##STR00436## wherein, method 3: it consists of the following step: in a solvent, under the action of a palladium catalyst and a base, compound 4 and compound 5 undergo the reaction as shown below; ##STR00437##

13. A pharmaceutical composition, wherein it comprises the compound represented by Formula 1, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable excipient.

14. A method for prevent or treating a disease related to NLRP3 in a subject in need thereof, comprising administering an effective amount of the compound represented by Formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1 to the subject; the disease related to NLRP3 refers to a disease that responds to NLRP3 inhibition, and the disease is selected from the group consisting of cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystemic inflammatory diseases (NOMID), multiple sclerosis (MS), amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, Alzheimer's disease, Parkinson's disease, Non-alcoholic fatty liver disease, atherosclerosis, asthma, COPD, pulmonary idiopathic fibrosis, chronic kidney disease, inflammatory bowel diseases, tumors, type 1 diabetes, type 2 diabetes, and gout.

15. (canceled)

16. A compound as shown in formula 1, 2, 3, 4, 5 or 9 ##STR00438## wherein, Z.sup.1, Z.sup.2, Z.sup.3, R, R.sup.1 and R.sup.2 are defined as claim 1, R.sup.3 is C.sub.1C.sub.6 alkyl or C.sub.1C.sub.6 alkoxy substituted C.sub.1C.sub.6 alkyl; M is a halogen; L is a halogen; preferably, the ##STR00439## may be ##STR00440## or may be ##STR00441## preferably, the ##STR00442## may be ##STR00443## or may be ##STR00444## preferably, the ##STR00445## can be ##STR00446## preferably, the ##STR00447## can be ##STR00448## or can be ##STR00449##

17. A method for prevent or treating inflammatory bowl diseases (IBD) in a subject in need thereof, comprising administering an effective amount of the compound represented by Formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 1 to the subject.

18. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 3, characterized in that each satisfies one or more of the following conditions: (1) in R.sup.1, when the 310-membered heterocycloalkyl group is a bicyclic heterocycloalkyl group, it is ##STR00450## (2) in R.sup.1, when the 310-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group, it is ##STR00451##

19. The compound represented by formula I, the solvate thereof, the pharmaceutically acceptable salt thereof or the solvate of the pharmaceutically acceptable salt thereof according to claim 7, characterized in that it satisfies one or more of the following conditions: (1) in the scenario 2, the R.sup.1-2 is located at the ortho position of the linker group in ##STR00452## (2) in the scenario 3, the R.sup.1-2 is located at the ortho position of the linker group in R.sup.1 ##STR00453##

20. The preparation method according to claim 12, wherein, the method 1 satisfies one or more of the following conditions: (1) in R.sup.3, the C.sub.1C.sub.6 alkyl group is CH.sub.3; the C.sub.1C.sub.6 alkoxy substituted C.sub.1C.sub.6 alkyl is CH.sub.2OCH.sub.2CH.sub.3; (2) the solvent is one or more of ester, alcohol and halogenated hydrocarbon; (3) the acid is inorganic acid and/or lewis acid; (4) the method 1 further include the following reaction: in a solvent, under the action of base, compound 2 reacts with compound 3 to obtained the compound 1; ##STR00454## wherein M is a halogen; the solvent is one or more of nitrogen-containing organic solvents, ether solvents or alcohol solvents; the base is diisopropyl ethylamine; or, the method 2 satisfies the following condition: (1) M is F, Cl, Br or I; (2) the solvent is N-methylpyrrolidone; (3) the base is diisopropyl ethylamine; or, the method 3 satisfies one or more of the following conditions: (1) L is F, Cl, Br or I; (2) the solvent is ether solvent and/or water; (3) the palladium catalyst is Pd(PPh.sub.3).sub.4; (4) the base is the carbonate of an alkali metal.

21. The preparation method according to claim 20, wherein, in the method 1, the ester solvent is ethyl acetate; the alcohol solvent is methanol; the halogenated hydrocarbon solvent is dichloromethane; or, in the method 1, when R.sup.3 is C.sub.1C.sub.6 alkyl group, the solvent is a halogenated hydrocarbon solvent, and the acid is lewis acid; or, in the method 1, when R.sup.3 is C.sub.1C.sub.6 alkoxy substituted C.sub.1C.sub.6 alkyl, the solvent is an ester solvent and/or an alcohol solvent, and the acid is an inorganic acid; or, in the method 2, the solvent is 1,4-dioxane and H.sub.2O; or, in the method 3, the base is cesium carbonate.

22. The preparation method according to claim 21, wherein, in the reaction that compound 2 reacts with compound 3 to obtain the compound 1, M is F, Cl, Br or I; or, the solvent is one or more of N-methylpyrrolidone, n-butanol and dioxane.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0152] Some embodiments are further disclosed in detail in the following exhibits, which are not in any way intended to limit the scope of the claims.

Embodiment 1

##STR00127##

(R)-3,5-Dimethyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[0153] The specific reaction Formula is as follows:

##STR00128##

Step A: 2-iodo-3,5-dimethylphenol (compound 1.1)

[0154] Dissolve 3,5-dimethylphenol (10.0 g, 81.86 mmol) into 400 mL toluene, cool to 0 C., add sodium hydride (6.55 g, 163.71 mmol) in batches, stir for 50 minutes at 0 C. and under the protection of nitrogen, raise to room temperature and continue the stirring for 15 minutes, cool to 0 C. again, add iodine (20.78 g, 81.86 mmol) in batches, and stir for 1 hour. 0.5 M aqueous solution of hydrochloric acid was added to the reaction solution to quench the reaction, extracted with ethyl acetate (400 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 1.1 (15 g, yield: 74%).

Step B: 1-(ethoxymethoxy)-2-iodo-3,5-xylene (compound 1.2)

[0155] Compound 1.1 (5.0 g, 20.16 mmol) was dissolved into 60 mL of NN-dimethylformamide (DMF), then cesium carbonate (6.57 g, 20.16 mmol) and chloromethyl ether (2.48 g, 26.20 mmol) were added, and the reaction was stirred for 16 hours at room temperature. The reaction was quenched with water, extracted with ethyl acetate (200 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 1.2 (5.0 g, yield: 81%).

Step C: 2-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (compound 1.3)

[0156] Compound 1.2 (3.65 g, 11.92 mmol) was added to 60 mL of 1,4-dioxane, followed by 4,4,5,5-tetramethyl-1,3,2-dioxaborane (3.05 g, 23.85 mmol), triethylamine (3.6 g, 35.77 mmol), Pd(OAc).sub.2 (267 mg, 1.19 mmol) and CyJohnphos (835 mg, 2.38 mmol), and let the reaction stir overnight at 95 C. and under nitrogen protection. The reaction solution was filtered, quenched with water, extracted with ethyl acetate (60 mL2), combined the organic phases, washed with brine solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 1.3 (1.74 g, yield: 48%). LCMS ESI(+)m/z: 307.2 (M+1).

Step D: 6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-amine (compound 1.4)

[0157] The compounds 6-bromo-1,2,4-triazin-3-amine (1.00 g, 5.71 mmol) and compound 1.3 (1.75 g, 5.71 mmol) were dissolved in 30 mL of dioxane and 5 mL of water, and cesium carbonate (5.57 g, 17.14 mmol) and PdCl.sub.2(dppf) (466 mg, 0.57 mmol) were added, the reaction solution was stirred at 100 C. and under nitrogen protection for 16 h. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 1.4 (390 mg, yield: 28%). LCMS ESI(+)m/z: 275.2 (M+1).

Step E: 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (compound 1.5)

[0158] The compound 1.4 (390 mg, 1.42 mmol) was dissolved in 30 mL of acetonitrile, and then, copper chloride (287 mg, 2.13 mmol) and tert-butyl nitrite (220 mg, 2.13 mmol) were added at 0 C. under the protection of nitrogen, and the reaction solution was stirred at 60 C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the product was purified by column chromatography to obtain 1.5 (158 mg, yield: 38%). LCMS ESI(+)m/z: 294.1 (M+1).

Step F: (R)-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (compound 1.6)

[0159] Compound 1.5 (44 mg, 0.15 mmol) was dissolved in 2 mL n-butanol, (R)-1-methylpiperidine-3-amine (43 mg, 0.37 mmol) and diisopropylethylamine (77 mg, 0.60 mmol) were added, and the reaction solution was stirred at 180 C. with microwave for 2 hours. The reaction solution was concentrated under reduced pressure, and the product was purified by column chromatography to obtain 1.6 (30 mg, yield: 54%). LCMS ESI(+)m/z: 372.2 (M+1).

Step G: (R)-3,5-dimethyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (compound 1)

[0160] Dissolve compound 1.6 (30 mg, 0.08 mmol) in 8 mL of hydrochloric acid/ethyl acetate (2 M (mol/L)) and stir for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure and purified by reversed-phase prep-HPLCHPLC to obtain compound 1 (20 mg, yield: 80%). LCMS ESI(+)m/z: 314.2 (M+1). 1H NMR (400 MHz, DMSO-d6) 10.89 (s, 1H), 8.28 (s, 1H), 7.94-7.64 (m, 1H), 6.67 (s, 1H), 6.62 (s, 1H), 4.39-4.37 (m, 1H), 3.62 (d, J=12.6 Hz, 1H), 3.39 (d, J=9.6 Hz, 1H), 3.09-2.81 (m, 2H), 2.80 (s, 3H), 2.26 (s, 3H), 2.10 (s, 4H), 1.90 (dd, J=41.2, 8.6 Hz, 2H), 1.69-1.50 (m, 1H).

Embodiment 2

##STR00129##

(R)-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3,5-dimethylphenol

[0161] The specific reaction Formula is as follows:

##STR00130##

Step A: (R)-tert-butyl(1-(2-hydroxyethyl)piperidin-3-yl)carbamate (compound 2.1)

[0162] Dissolve (R)-tert-butylpiperidin-3-ylcarbamate (1 g, 5 mmol) in 10 mL of acetonitrile solution, add bromoethanol (812 mg, 6.5 mmol), sodium carbonate (800 mg, 7.5 mmol), and stir at 60 C. for 6 hours. The reaction solution was filtered, the solvent was spun dry, and the compound was purified by column chromatography to obtain compound 2.1 (1.1 g, yield: 90%). LCMS ESI(+)m/z: 245.2(M+1).

Step B: (R)-2-(3-aminopiperidin-1-yl)ethanol (compound 3.2)

[0163] Dissolve compound 2.1 (1.1 g, 4.5 mmol) in 10 mL of dichloromethane solution, add 4 mL of trifluoroacetic acid, and stir for 2 hours at room temperature. Spin dry the solvent to obtain crude compound 2.2 (2 g, yield: 100%). LCMS ESI(+)m/z: 145.2(M+1).

Step C: (R)-2-(3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethanol (compound 2.3)

[0164] Compound 2.2 (110 mg, 0.43 mmol) was dissolved in 5 mL of n-butanol solution, and 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (50 mg, 0.17 mmol) and diisopropylethylamine (111 mg, 0.8 mmol) were added and stirred at 160 C. for 3 hours. Compound 2.3 (50 mg, yield: 80%) was obtained by spinning the solvent and column chromatography. LCMS ESI(+)m/z: 402.2(M+1).

Step D: (R)-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3,5-dimethylphenol (compound 2)

[0165] Compound 2.3 (50 mg, 0.13 mmol) was dissolved in 5 mL of ethyl acetate solution, 5 mL of ethyl acetate hydrochloride was added, and stirred for 2 h at room temperature. Compound 2 (25 mg, yield: 58%) was purified by spin-drying solvent and reversed-phase preparation. LCMS ESI(+)m/z: 344.2(M+1). .sup.1H NMR (400 MHz, DMSO) 10.57 (s, 1H), 8.28 (s, 1H), 6.68 (s, 1H), 6.62 (s, 1H), 4.50 (s, 1H), 3.85 (s, 2H), 3.70 (s, 2H), 3.54 (s, 2H), 3.23 (s, 2H), 2.93 (d, J=9.3 Hz, 2H), 2.26 (s, 3H), 2.10 (s, 3H), 1.96 (d, J=12.4 Hz, 2H), 1.63 (d, J=11.8 Hz, 1H).

Embodiment 3

##STR00131##

(R)-2-(3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetic acid

[0166] The specific reaction Formula is as follows:

##STR00132##

Step A: (R)-ethyl2-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)acetate (compound 3.1)

[0167] (R)-tert-butylpiperidine-3-ylcarbamate (500 mg, 2.5 mmol) was dissolved in 10 mL of acetonitrile solution, ethyl bromoacetate (406 mg, 3.25 mmol) and sodium carbonate (400 mg, 3.75 mmol) were added, and stirred at 60 C. for 6 hours. The reaction solution was filtered, the solvent was spun dry, and the compound was purified by column chromatography to obtain compound 3.1 (670 mg, yield: 93%). LCMS ESI(+)m/z: 287.2(M+1).

Step B: (R)-2-(3-aminopiperidin-1-yl)ethyl acetate (compound 3.2)

[0168] Dissolve compound 3.1 (670 mg, 2.34 mmol) in 10 mL of dichloromethane solution, add 4 mL of trifluoroacetic acid, and stir for 2 hours at room temperature. Spin dry the solvent to obtain crude compound 3.2 (1.5 g, yield: 100%). LCMS ESI(+)m/z: 187.1(M+1).

Step C: (R)-2-(3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)ethyl acetate (compound 3.3)

[0169] Compound 3.2 (60 mg, 0.20 mmol) was dissolved in 5 mL of n-butanol solution, and 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (68 mg, 0.23 mmol) and diisopropylethylamine (133 mg, 1.02 mmol) were added and stirred at 160 C. for 3 hours under microwave. The solvent was spun dry and the column chromatography was purified to obtain compound 3.3 (60 mg, yield: 66%). LCMS ESI(+)m/z: 444.3(M+1).

Step D: (R)-ethyl2-(3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetate (compound 3.4)

[0170] Compound 3.3 (60 mg, 0.14 mmol) was dissolved in 5 mL of ethyl acetate solution, 5 mL of ethyl acetate hydrochloride solution was added, and stirred for 2 h at room temperature. The solvent was spun dry and the column chromatography was purified to obtain compound 3.4 (100 mg, yield: 58%). LCMS ESI(+)m/z: 386.2(M+1).

Step E: (R)-2-(3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidine-1-yl)acetic acid (compound 3)

[0171] Compound 3.4 (100 mg, 0.26 mmol) was dissolved in 5 mL of ethanol and 1 mL of aqueous solution, sodium hydroxide (52 mg, 1.3 mmol) was added, and stirred for 1 h at room temperature. Compound 3 (20 mg, yield: 22%) was obtained by spinning the solvent and reversed-phase preparation. LCMS ESI(+)m/z: 358.2(M+1). .sup.1H NMR (400 MHz, DMSO) 9.44 (s, 1H), 8.21 (s, 1H), 7.56 (s, 1H), 6.60 (s, 2H), 4.06 (s, 1H), 3.21 (s, 2H), 3.08 (d, J=8.9 Hz, 1H), 2.83 (d, J=10.7 Hz, 1H), 2.39 (t, J=10.1 Hz, 2H), 2.23 (s, 3H), 2.06 (s, 3H), 1.88 (d, J=8.7 Hz, 1H), 1.74 (dd, J=9.3, 4.2 Hz, 1H), 1.60 (d, J=10.6 Hz, 1H), 1.42 (d, J=9.5 Hz, 1H).

Embodiment 4

##STR00133##

(R)-3,5-dimethyl-2-(9-((1,2,3,5,6,7,8,8a-octahydroindozine-9-yl)amino)-1,2,4-triazin-6-yl)phenol

##STR00134##

Step A: Methyl 4-(pyrrole-1-yl)butyrate (compound 4.1)

[0172] 2,5-dimethoxytetrahydrofuran (5.1 g, 38.7 mmol), methyl 4-aminobutyrate hydrochloride (6.0 g, 38.7 mmol) and sodium acetate (3.21 g, 38.7 mmol) were added to the mixture of 60 mL of water and 39 mL of acetic acid, and the reaction was heated to 80 C. for 2 hours. The reaction solution was extracted with 100 mL of dichloromethane, washed with water, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 4.1 (4.52 g, yield: 70%). LCMS ESI(+)m/z: 168.1 (M+1).

Step B: 6,7-Dihydro-8(5H)-indolazinone (compound 4.2)

[0173] Compound 4.1 (4.52 g, 27.1 mmol) was dissolved in 180 mL of methylene chloride, cooled to about 0 C. under nitrogen, phosphorus tribromide (7.8 g, 28.7 mmol) was slowly added dropwise to the reaction solution, and the mixture was stirred in an ice water bath for 30 minutes. The reaction was quenched by addition of the solution to 70 mL of ice water, sodium bicarbonate saturated solution was added to adjust PH to neutral, stratified, washed organic phase with water, dried the organic phase with anhydrous sodium sulfate, filtered, filtrate concentrated under reduced pressure, and purified by column chromatography to obtain a product of 4.2 (1.64 g, yield: 44.9%). LCMS ESI(+)m/z: 136.1 (M+1).

Step C: 1-Azabicyclo[4.3.0]azelaic acid-6,8-diene-5-oxime (compound 4.3)

[0174] Compound 4.2 (1.24 g, 9.18 mmol), hydroxylamine hydrochloride (1.27 g, 1.27 mmol) and sodium acetate (2.48 g, 30.2 mmol) were added to a mixture of 14 mL of water and 14 mL of ethanol, and the reaction was heated to 80 C. for 2 hours. The reaction solution was concentrated to dry under reduced pressure, dissolved with 50 mL ethyl acetate, washed with water, combined the organic phases, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated until the white solid product was 4.3 (1.1 g, yield: 79.7%). LCMS ESI(+)m/z: 151.1 (M+1).

Step D: 1,2,3,5,6,7,8,8a-Octahydroindolezine-8-ammonia (compound 4.4)

[0175] Compound 4.3 (300 mg, 2.2 mmol) and platinum dioxide (40 mg, 0.17 mmol) were added to 50 mL of methanol, hydrogenated at 0.1 Mpa pressure, and the reaction was completed by stirring for 2 hours at room temperature. The reaction solution was filtered, and the filtrate was concentrated to dry compound 4.4 (250 mg, yield: 81.1%) LCMS ESI(+)m/z: 141.1(M+1).

Step E: (R)-3,5-dimethyl-2-(9-((1,2,3,5,6,7,8,8a-octahydroindolazine-9-yl)amino)-1,2,4-triazin-6-yl)phenol (compound 4)

[0176] Compounds 4.4 (50 mg, 0.357 mmol), 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (40 mg, 0.136 mmol) and N,N-diisopropylethylamine (184.6 mg, 1.4 mmol) were added to 3 mL of dioxane, and the reaction was heated to 140 C. under microwave for 1 hour. The reaction solution was extracted with 20 mL of dichloromethane, washed with water, combined the organic phases, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified compound 4 (10 mg, yield: 21.7%) was prepared with reversed-phase. LCMS ESI(+)m/z: 340.2 (M+1). .sup.1H NMR (400 MHz, DMSO-d6) 9.44 (d, J=11.8 Hz, 1H), 8.22 (s, 1H), 8.17 (d, J=4.4 Hz, 1H), 6.60 (s, 2H), 3.10-2.96 (m, 4H), 2.23 (s, 3H), 2.06 (s, 3H), 1.96 (dd, J=29.5, 9.3 Hz, 4H), 1.70-1.46 (m, 6H).

Embodiment 5

##STR00135##

2-(3-((1S,2S)-2-aminocyclohexyl)amino)-1,2,4-triazin-6-yl)-3,5-dimethylphenol

[0177] The specific reaction Formula is as follows:

##STR00136##

Step A: (1S,2S)-N1-(6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)cyclohexane-1,2-diamine (compound 5.1)

[0178] (1S,2S)-cyclohexane-1,2-diamine (22.8 mg, 0.2 mmol), 3-chloro-6-(2-ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (29.3 mg, 0.1 mmol) and N,N-diisopropylethylamine (38.7 mg, 0.3 mmol) were dissolved in 3 mL of n-butanol and placed in the microwave at 160 C. for 2 hours. The reaction solution is concentrated to obtain a crude product of compound 5.1, which is directly used in the next step.

Step B: 2-(3-((1S,2S)-2-aminocyclohexyl)amino)-1,2,4-triazin-6-yl)-3,5-dimethylphenol (compound 5)

[0179] Dissolve compound 5.1 crude in 5 mL of ethyl acetate solution (2M) of hydrogen chloride and stir for 0.5 hours at room temperature. The reaction solution was concentrated under reduced pressure and purified by reversed-phase prep-HPLC to obtain compound 5 (25 mg, yield: 64.6%). LCMS ESI(+)m/z: 314.2 (M+1). .sup.1H NMR (400 MHz, DMSO) 9.76 (s, 1H), 8.42 (d, J=17.9 Hz, 1H), 8.31-8.05 (m, 3H), 6.68 (s, 1H), 6.61 (s, 1H), 4.08 (s, 1H), 3.38-2.99 (m, 1H), 2.24 (s, 3H), 2.16-2.06 (m, 4H), 2.02 (d, J=11.7 Hz, 1H), 1.74 (d, J=6.8 Hz, 2H), 1.58-1.35 (m, 2H), 1.34-1.20 (m, 2H).

Embodiment 6

##STR00137##

(R)-2-(3-((1-cyclopropylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3,5-dimethylphenol

[0180] The specific reaction Formula is as follows:

##STR00138##

Step A: Tert-butyl(R)-(1-cyclopropylpiperidin-3-yl)carbamate (compound 6.1)

[0181] Tert-butyl(R)-piperidin-3-ylcarbamate (300 mg, 1.5 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (522 mg, 3 mmol) were dissolved in 8 mL of tetrahydrofuran and 8 mL of methanol, and then sodium cyanoborohydride (141 mg, 2.25 mmol) was added sequentially at room temperature with nitrogen protection, Glacial acetic acid (450 mg, 7.5 mmol) and 4A active molecular sieve (0.5 g), the reaction solution was stirred at 60 C. for 7 h, using TLC to monitor the reaction to complete. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The residue was dissolved with ethyl acetate, washed with 1M sodium hydroxide (4 mL) and saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 6.1 (489 mg, yield: 100%).

Step B: (R)-1-cyclopropylpiperidin-3-amine (compound 6.2)

[0182] Dissolve compound 6.1 (489 mg, 2 mmol) in 4 mL of hydrochloric acid/ethyl acetate (2 M) and stir for 1 h at room temperature. Use TLC to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 6.2 (369 mg, yield: 100%).

Step C: (R)N-(1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-amine (compound 6.3)

[0183] The compound 6.2 (50 mg, 0.28 mmol) was dissolved in 2 mL of n-butanol, and 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (40 mg, 0.14 mmol) and diisopropylethylamine (90 mg, 0.70 mmol) were added, and the reaction solution was stirred at 150 C. under microwave for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 6.3 (60 mg, yield: 100%). LCMS ESI(+)m/z: 398.1 (M+1).

Step D: (R)-2-(3-((1-cyclopropylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3,5-dimethylphenol (Compound 6)

[0184] Dissolve compound 6.3 (60 mg, 0.15 mmol) in 3 mL of hydrogen chloride/ethyl acetate (2 M) and stir for 1 h at room temperature. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure and purified by reversed-phase prep-HPLC to obtain compound 6 (20 mg, yield: 39%). LCMS ESI(+)m/z: 340.1 (M+1). .sup.1H NMR (400 MHz, DMSO-d6) 10.45 (s, 1H), 8.33 (d, J=16.9 Hz, 1H), 8.14 (d, J=92.0 Hz, 2H), 6.62 (d, J=10.1 Hz, 3H), 4.64-4.10 (m, 2H), 3.04 (dd, J=22.3, 11.0 Hz, 2H), 2.89 (s, 1H), 2.23 (s, 4H), 2.07 (s, 5H), 1.88 (d, J=29.6 Hz, 3H), 1.58 (s, 1H), 1.24 (s, 1H), 1.12 (d, J=10.6 Hz, 2H), 0.81 (t, J=8.4 Hz, 2H).

Embodiment 7

##STR00139##

(R)-5-Chloro-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[0185] The specific reaction Formula is as follows:

##STR00140##

Step A: 6-(4-chloro-2-methoxyphenyl)-1,2,4-triazin-3,5(2H,4H)-dione (compound 7.1)

[0186] The compounds (4-chloro-2-methoxyphenyl)boric acid (1.00 g, 5.36 mmol) and 6-bromo-1,2,4-triazin-3,5(2H,4H)-dione (1.24 g, 6.44 mmol) were dissolved in 25 mL of dioxane and 3 mL of water, and potassium carbonate (2.22 g, 16.1 mmol) and PdCl.sub.2(dppf) (390 mg, 0.536 mmol) were added, the reaction solution was stirred at 100 C. under nitrogen for 16 h. 50 mL of water was added to the reaction solution, the pH was adjusted to 4 with citric acid solution, extracted with ethyl acetate (80 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 7.1 (1.27 g, yield: 94%). LCMS ESI(+)m/z: 254 (M+1).

Step B: 3,5-Dichloro-6-(4-chloro-2-methoxyphenyl)-1,2,4-triazine (compound 7.2)

[0187] Compound 7.1 (1.27 g, 5.01 mmol) was dissolved in 20 mL of phosphorus oxychloride, 2 mL of diisopropylyethylamine was added, and the reaction solution was stirred at 100 C. under nitrogen for 10 hours. The reaction solution was concentrated under reduced pressure, the residue was added dropwise to 100 mL of water, the pH was adjusted to 8 with sodium bicarbonate solution, extracted with ethyl acetate (100 mL3), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product was purified by column chromatography to obtain a product of 7.2 (780 mg, yield: 54%). LCMS ESI(+)m/z: 290 (M+1).

Step C: 3-Chloro-6-(4-chloro-2-methoxyphenyl)-5-methyl-1,2,4-triazine (compound 7.3)

[0188] Compound 7.2 (280 mg, 0.964 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, cooled to 60 C., under the protection of nitrogen, magnesium methyl bromide (1.93 mL, 1.93 mmol) was added dropwise, the reaction solution was stirred at 60 C. for 0.5 hours, and then gradually raised to 20 C., and the stirring continued for 1 hour. Ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate (100 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 7.3 (35 mg, yield: 14%). LCMS ESI(+)m/z: 270 (M+1).

Step D: (R)-6-(4-chloro-2-methoxyphenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (compound 7.4)

[0189] The compounds 7.3 (35 mg, 0.13 mmol) and (R)-1-methylpiperidine-3-amine hydrochloride (31 mg, 0.168 mmol) were dissolved in 3 mL of n-butanol, diisopropylethylamine (66.8 mg, 0.518 mmol) was added, and the reaction solution was microwaved at 150 C. under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a product of 7.4 (60 mg, yield: 100%). LCMS ESI(+)m/z: 348.2 (M+1).

Step E: (R)-5-chloro-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (compound 7)

[0190] Dissolve compound 7.4 (60 mg, 0.172 mmol) in 8 mL of dichloromethane, add boron tribromide (173 mg, 0.690 mmol) dropwise at 0 C. and nitrogen protection, stirring at 0 C. for 1 h. 5 mL of water was added dropwise to quench the reaction, the pH was adjusted to 8 with sodium bicarbonate solution, extracted with ethyl acetate (40 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 7 (15 mg, yield: 26%). LCMS ESI(+)m/z: 334.1 (M+1). .sup.1H NMR (400 MHz, DMSO-d6) 10.65-10.61 (m, 2H), 8.13-8.10 (m, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.2, 2.0 Hz, 1H), 4.35-4.30 (m, 1H), 3.69-3.48 (m, 1H), 3.36-3.30 (m, 1H), 3.04-2.73 (m, 5H), 2.24 (d, J=5.3 Hz, 3H), 2.04 (d, J=11.2 Hz, 1H), 1.98-1.73 (m, 2H), 1.59-1.42 (m, 1H).

Embodiment 8

##STR00141##

(R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0191] The specific reaction Formula is as follows:

##STR00142##

Step A: 6-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazin-3,5(2H,4H)-dione (compound 8.1)

[0192] (2-Methoxy-4-(trifluoromethyl)phenyl)boric acid (900 mg, 4.09 mmol) and 6-bromo-1,2,4-triazin-3,5(2H,4H)-dione (943 mg, 4.91 mmol) were dissolved in 10 mL of dioxane and 1 mL of water, and potassium carbonate (1.69 g, 12.28 mmol) and PdCl.sub.2(dppf) (297 mg, 0.40 mmol) were added, the reaction mixture was microwaved at 100 C. under nitrogen for 2 hours. 50 mL of water was added to the reaction solution, the pH was adjusted to 4 with citric acid solution, extracted with ethyl acetate (80 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 8.1 (1.08 g, yield: 91%). LCMS ESI(+)m/z: 288.1 (M+1).

Step B: 3,5-Dichloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine (compound 8.2)

[0193] Compound 8.1 (800 mg, 2.79 mmol) was dissolved in 10 mL of phosphorus oxychloride, 1 mL of diisopropylethylamine was added, and the reaction solution was stirred at 100 C. under nitrogen for 7 hours. The reaction solution was concentrated under reduced pressure, the residue was added dropwise to 100 mL of water, the pH was adjusted to 8 with sodium bicarbonate solution, extracted with ethyl acetate (40 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 8.2 (640 mg, yield: 71%). LCMS ESI(+)m/z: 324 (M+1).

Step C: 3-chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazine (compound 8.3)

[0194] Compound 8.2 (100 mg, 0.31 mmol) was dissolved in 6 mL of anhydrous tetrahydrofuran, cooled to 60 C., under the protection of nitrogen, magnesium methyl bromide (0.46 mL, 0.46 mmol) was added dropwise, and the reaction solution was stirred at 60 C. for 0.5 hours, and then gradually increased to 20 C., and continued to stir at 20 C. for 1 hour. Ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate (40 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 8.3 (15 mg, yield: 16%). LCMS ESI(+)m/z: 304 (M+1).

Step D: (R)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (compound 8.4)

[0195] The compounds 8.3 (15 mg, 0.05 mmol) and (R)-1-methylpiperidine-3-amine hydrochloride (10 mg, 0.05 mmol) were dissolved in 3 mL of n-butanol, diisopropylethylamine (32 mg, 0.247 mmol) was added, and the reaction solution was microwaved at 180 C. under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a product of 8.4 (30 mg, yield: 100%). LCMS ESI(+)m/z: 382.2 (M+1).

Step E: (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (Compound 8)

[0196] Dissolve compound 8.4 (30 mg, 0.08 mmol) in 8 mL of methylene chloride, add boron tribromide (59 mg, 0.23 mmol) dropwise at 0 C. under nitrogen, stirring at 0 C. for 1 h. 5 mL of water was added dropwise to quench the reaction, the pH was adjusted to 8 with sodium bicarbonate solution, extracted with ethyl acetate (40 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 8 (7 mg, yield: 31%). LCMS ESI(+)m/z: 368.2 (M+1). .sup.1H NMR (400 MHz, Methanol-d4) 8.50 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 4.34-4.30 (m, 1H), 3.50 (d, J=14.1 Hz, 1H), 3.23 (d, J=12.0 Hz, 1H), 2.91-2.75 (m, 2H), 2.74 (s, 3H), 2.32 (s, 3H), 2.18-2.00 (m, 2H), 1.97-1.79 (m, 1H), 1.72-1.66 (m, 1H).

Embodiment 9

##STR00143##

(R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)pyridin-3-ol

[0197] The specific reaction Formula is as follows:

##STR00144##

Step A: 3-Methoxy-5-(trifluoromethyl)picolinonitrile (compound 9.1)

[0198] 3-chloro-5-(trifluoromethyl)picolinonitrile (3.0 g, 14.56 mmol) was dissolved in 30 mL of methanol, sodium methoxide (1.18 g, 21.84 mmol) was added, and the reaction solution was stirred at 70 C. for 16 hours. The reaction solution was concentrated under reduced pressure, 50 mL of water was added to the residue, the solids were precipitated by pulping, the crude product was filtered and valuum dried to obtain compound 9.1 (2.52 g, yield: 86%). LCMS ESI(+)m/z: 203 (M+1).

Step B: 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-1-one (compound 9.2)

[0199] Compound 9.1 (1.58 g, 7.82 mmol) was dissolved in 20 mL THF, magnesium ethyl bromide (11.7 mL, 11.71 mmol) was added under nitrogen in an ice water bath, and the reaction was stirred for 2.5 hours at room temperature. 50 mL of saturated ammonium chloride was added to the reaction solution, extracted with ethyl acetate (50 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 9.2 (730 mg, yield: 40%). LCMS ESI(+)m/z: 234.1 (M+1).

Step C: 2-bromo-1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)propane-1-one (Compound 9.3)

[0200] Compound 9.2 (570 mg, 2.45 mmol) was dissolved with 20 mL of acetonitrile, NBS (522 mg, 2.94 mmol) and p-toluenesulfonic acid (93 mg, 0.49 mmol) were added, and the reaction solution was stirred at 60 C. for 4 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 9.3 (625 mg, yield: 82%). LCMS ESI(+)m/z: 312, 314 (M+1).

Step D: 6-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-5-methyl-1,2,4-triazin-3-amine (compound 9.4)

[0201] Compound 9.3 (280 mg, 0.87 mmol) was dissolved in 10 mL DMF, aminoguanidine hydrochloride (114 mg, 1.04 mmol), triethylamine (264 mg, 2.61 mmol) and sodium iodide (130 mg, 0.87 mmol) were added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, 50 mL of water was added to the residue, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain a product of 9.4 (70 mg, yield: 28%). LCMS ESI(+)m/z: 286.1 (M+1).

Step E: 3-chloro-6-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-5-methyl-1,2,4-triazine (compound 9.5)

[0202] Compound 9.4 (70 mg, 0.25 mmol) was dissolved in 4 mL THF, anhydrous copper chloride (50 mg, 0.37 mmol) and tert-butyl nitrite (38 mg, 0.37 mmol) were added, and the reaction solution was stirred at 60 C. for 1 hour. The reaction solution was concentrated under reduced pressure, 50 mL of water was added to the residue, the pH was adjusted to 7-8 with saturated sodium bicarbonate, extracted with dichloromethane (80 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 9.5 (13 mg, yield: 17%). LCMS ESI(+)m/z: 305 (M+1). [0203] Step F: (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)pyridin-3-ol (compound 9).

[0204] Compound 9.5 (13 mg, 0.04 mmol) was dissolved in 3 mL of NMP, (R)-1-methylpiperidine-3-amine (16 mg, 0.09 mmol) and diisopropylethylamine (31 mg, 0.24 mmol) were added, and the reaction solution was stirred at 160 C. for 3 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 9 (2.4 mg, yield: 16%). LCMS ESI(+)m/z: 369.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 8.46 (d, J=16.5 Hz, 2H), 7.59 (d, J=1.3 Hz, 1H), 4.26 (s, 1H), 3.52 (d, J=10.4 Hz, 1H), 3.22 (d, J=12.1 Hz, 1H), 2.93-2.78 (m, 2H), 2.74 (s, 3H), 2.65 (s, 3H), 2.16-2.01 (m, 2H), 1.85 (ddd, J=21.3, 10.6, 3.8 Hz, 1H), 1.75-1.62 (m, 1H).

Embodiment 10

##STR00145##

(R)-3-methyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0205] The specific reaction Formula is as follows:

##STR00146##

Step A: 2-Iodo-3-methyl-5-(trifluoromethyl)phenol (compound 10.1)

[0206] 3-methyl-5-(trifluoromethyl)phenol (500 mg, 2.84 mmol) was dissolved in 7 mL of toluene, sodium hydride (227 mg, 5.68 mmol) was added with an ice-water bath cooling and stirred for half an hour, then iodine (720 mg, 2.84 mmol) was added, stirred with an ice-water bath cooling for 3 hours, and then the reaction was quenched with an aqueous solution of hydrochloric acid, and extracted with ethyl acetate (30 mL2). The organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and reversed-phase prep-HPLC and purified to obtain a product of 10.1 (457 mg, yield: 53.2%). LCMS ESI(+)m/z: 303.1 (M+1).

Step B: 1-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene (compound 52.2)

[0207] Compound 10.1 (457 mg, 1.51 mmol) was dissolved in 4 mL of DMF, cesium carbonate (493 mg, 1.51 mmol) and (chloromethoxy)ethane (179 mg, 1.89 mmol) were added with an ice-water bath cooling and stirred for 3 hours, and then the reaction was quenched with water solution and extracted with ethyl acetate (30 mL2). The organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase prep-HPLC to obtain a product of 10.2 (160 mg, yield: 29.4%). LCMS ESI(+)m/z: 361.1 (M+1).

Step C: 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 10.3)

[0208] Compound 10.2 (160 mg, 0.444 mmol) was added to 3 mL of 1,4-dioxane, followed by pinaol biborate (284 mg, 2.22 mmol), triethylamine (328 mg, 3.24 mmol), CyJohnphos (Chinese full name 2-(dicyclohexylphosphine) biphenyl) (39 mg, 0.111 mmol) and Pd(OAc).sub.2 (15 mg, 0.066 mmol), let the reaction stir at 95 C. for 18 hours, quench the reaction with water, filter the reaction solution, and extract with ethyl acetate (60 mL3). The organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 10.3 (50 mg, yield: 31.3%). LCMS ESI(+)m/z: 361.1 (M+1).

Step D: 6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-1,2,4-triazin-3-amine (compound 10.4)

[0209] The compounds 10.3 (50 mg, 0.139 mmol) and 6-bromo-1,2,4-triazin-3-amine (25 mg, 0.139 mmol) were dissolved in 2 mL of dioxane and 0.2 mL of water, and cesium carbonate (91 mg, 0.278 mmol) and Pd(PPh.sub.3).sub.4 (32 mg, 0.028 mmol) were added, the reaction solution was stirred at 110 C. under nitrogen for 2 hours in a microwave environment. 10 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 10.4 (31 mg). LCMS ESI(+)m/z: 329.1 (M+1).

Step E: 3-chloro-6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-1,2,4-triazine (compound 10.5)

[0210] Compound 10.4 (31 mg, 0.095 mmol) was dissolved in 2 mL of acetonitrile, and then copper chloride (19 mg, 0.143 mmol) and tert-butyl nitrite (15 mg, 0.143 mmol) were added under nitrogen at 0 C., and the reaction solution was stirred at 60 C. for 1.5 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain a product of 10.5 (15 mg, yield: 45.3%). LCMS ESI(+)m/z: 348.1 (M+1).

Step F: (R)-6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (compound 10.6)

[0211] Compound 10.5 (15 mg, 0.043 mmol) was dissolved in 2 mL n-butanol, (R)-1-methylpiperidine-3-amine (10 mg, 0.052 mmol) and diisopropylethylamine (27 mg, 0.215 mmol) were added, and the reaction solution was stirred at 150 C. under microwave for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of 10.6 (15 mg). LCMS ESI(+)m/z: 425.1 (M+1).

Step G: (R)-3-methyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (compound 10)

[0212] Dissolve compound 10.6 (20 mg, 0.08 mmol) in 8 mL of hydrogen chloride/ethyl acetate (2 M) solution and stir for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure and purified with reversed-phase prep-HPLC to obtain compound 10 (3 mg). LCMS ESI(+)m/z: 367.1 (M+1). .sup.1H NMR (400 MHz, DMSO) 10.31 (s, 1H), 8.30 (s, 1H), 7.15 (d, J=1.7 Hz, 1H), 7.08 (d, J=1.8 Hz, 1H), 3.99 (s, 1H), 2.93 (s, 1H), 2.68 (d, J=12.1 Hz, 1H), 2.20 (d, J=16.1 Hz, 6H), 1.92 (dd, J=23.5, 11.8 Hz, 3H), 1.78-1.67 (m, 1H), 1.55 (d, J=12.5 Hz, 1H), 1.40-1.30 (m, 1H).

Embodiment 11

##STR00147##

(R)-5-chloro-3-methyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol

[0213] The specific reaction Formula is as follows:

##STR00148##

Step A: 5-chloro-2-iodo-3-methylphenol (compound 11.1)

[0214] 5-chloro-2-iodo-3-methylaniline (1 g, 3.74 mmol) is dissolved in 4.5 mL of HCl (1 M), and then sodium nitrite aqueous solution (310 mg, 4.49 mmol) is slowly added dropwise with an ice water bath cooling. After stirring at 0 C. for 15 minutes, concentrated sulfuric acid (1.8 mL) was added to the reaction solution and heated and refluxed for 1 hour. Use TLC to monitor the reaction to completion. The reaction was quenched by adding an aqueous solution to the reaction solution, extracted with ethyl acetate (150 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain a product of 11.1 (578 mg, yield: 57%/).

Step B: 5-chloro-1-(ethoxymethoxy)-2-iodo-3-toluene (compound 11.2)

[0215] 11.1 (578 mg, 2.15 mmol) and (chloromethoxy)ethane (407 mg, 4.3 mmol) were dissolved in 40 mL of DMF, and then at room temperature, cesium carbonate (1.4 g, 4.3 mmol) was added, and the reaction solution was stirred overnight at room temperature. Use TLC to monitor the reaction to completion. An aqueous solution was added to the reaction solution and quenched, extracted with ethyl acetate (100 mL2), the organic phases were combined, and washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain a product of 11.2 (416 mg, yield: 59%/).

Step C: 2-(4-chloro-2-(ethoxymethoxy)-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde (compound 11.3)

[0216] Compound 11.2 (416 mg, 1.27 mmol) is added to 5 mL of 1,4-dioxane, followed by 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (488 mg, 3.81 mmol), triethylamine (530 L, 3.81 mmol), Pd(OAc): (57 mg, 0.254 mmol) and CyJohnphos (2-(dicyclohexylphosphine)biphenyl) (134 mg, 0.381 mmol) and let the reaction stir overnight at 100 C. and under the protection of argon. Use TLC to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure, and the product was purified by column chromatography to obtain 11.3 (217 mg, yield: 53%).

Step D: 6-(4-chloro-2-(ethoxymethoxy)-6-methylphenyl)-1,2,4-triazin-3-amine (compound 11.4)

[0217] The compounds 11.3 (217 mg, 0.67 mmol) and 6-bromo-1,2,4-triazin-3-amine (98 mg, 0.56 mmol) were dissolved in 6 mL of dioxane and 1 mL of water, cesium carbonate (547 mg, 1.68 mmol) and PdCl2(dppf) (129 mg, 0.112 mmol) were added, and the reaction solution was stirred at 100 C. and under argon for 16 hours. Use LCMS to monitor the reaction to completion. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 11.4 (84 mg, yield: 43%). LCMS ESI(+)m/z: 295.1 (M+1).

Step E: 3-chloro-6-(4-chloro-2-(ethoxymethoxy)-6-methylphenyl)-1,2,4-triazine (compound 11.5)

[0218] Compound 11.4 (84 mg, 0.285 mmol) was dissolved in 5 mL of acetonitrile, and then copper chloride (58 mg, 0.428 mmol) and tert-butyl nitrite (44 mg, 0.428 mmol) were added under nitrogen with an ice water bath cooling. The reaction solution is then stirred at 60 C. for 2 h. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure, and the product was purified by column chromatography to obtain 11.5 (8 mg, yield: 9%). LCMS ESI(+)m/z: 315.1 (M+1).

Step F: (R)-6-(4-chloro-2-(ethoxymethoxy)-6-methylphenyl)-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-3-amine (compound 11.6)

[0219] Compound 11.5 (8 mg, 0.0256 mmol) was dissolved in 2 mL of n-butanol, (R)-1-methylpiperidine-3-amine (5 mg, 0.0282 mmol) and diisopropylethylamine (16 mg, 0.128 mmol) were added, and the reaction solution was stirred at 150 C. under microwave for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 11.6 (25 mg). LCMS ESI(+)m/z: 392.1 (M+1).

Step G: (R)-5-chloro-3-methyl-2-(3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)phenol (Compound 11)

[0220] Dissolve compound 11.6 (25 mg, 0.064 mmol) in 3 mL of 2 M hydrochloric acid/ethyl acetate and stir for 1 h at room temperature. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure and purified by reversed-phase prep-HPLC to obtain compound 11 (6.5 mg, yield: 76%). LCMS ESI(+)m/z: 334.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 6.83 (s, 1H), 6.76 (d, J=1.8 Hz, 1H), 5.45-5.32 (m, 1H), 4.29 (s, 1H), 4.11 (s, 1H), 3.79 (d, J=10.0 Hz, 1H), 3.69 (d, J=8.1 Hz, 1H), 3.53 (d, J=11.9 Hz, 1H), 2.99 (d, J=11.9 Hz, 1H), 2.94 (t, J=6.3 Hz, 3H), 2.30 (s, 3H), 2.22 (d, J=12.9 Hz, 1H), 2.11 (d, J=15.0 Hz, 1H), 2.02 (d, J=6.0 Hz, 1H), 1.66 (d, J=12.3 Hz, 1H).

Embodiment 12

##STR00149##

(R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pyridin-3-ol

[0221] The specific reaction Formula is as follows:

##STR00150##

Step A: 3-methoxy-5-(trifluoromethyl)picolinonitrile (compound 12.1)

[0222] 3-chloro-5-(trifluoromethyl)picolinonitrile (3.0 g, 14.56 mmol) was dissolved in 30 mL of methanol, sodium methoxide (1.18 g, 21.84 mmol) was added, and the reaction solution was stirred at 70 C. for 16 hours. The reaction solution was concentrated under reduced pressure, 50 mL of water was added to the residue, the solids were precipitated by beating, the crude product was filtered, and the compound was 12.1 (2.52 g, yield: 86%) was obtained by vacuum drying. LCMS ESI(+)m/z: 203 (M+1).

Step B: 1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)propyl-1-one (compound 12.2)

[0223] Compound 12.1 (1.58 g, 7.82 mmol) was dissolved in 20 mL THF, magnesium ethyl bromide (11.7 mL, 11.71 mmol) was added under nitrogen with an ice water bath cooling, and the reaction was then stirred for 2.5 hours at room temperature. 50 mL of saturated ammonium chloride was added to the reaction solution, extracted with ethyl acetate (50 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 12.2 (730 mg, yield: 40%). LCMS ESI(+)m/z: 234.1 (M+1).

Step C: 2-hydroxy-4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-3-methyl-4-oxobutyrate ethyl ester (Compound 12.3)

[0224] Compound 12.2(200 mg, 0.86 mmol) was dissolved with 10 mL of THF, LDA (0.65 mL, 1.29 mmol) was added dropwise at 78 C., stirred at 78 C. for 30 minutes, ethyl 2-oxoacetate (132 mg, 1.29 mmol) was added, and the reaction solution was stirred at 78 C. under nitrogen for 1 hour. 50 mL of saturated ammonium chloride was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 12.3 (306 mg). LCMS ESI(+)m/z: 318.1 (M+1).

Step D: 6-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-5-methylpyridazin-3(2H)-one (compound 12.4)

[0225] Compound 12.3 (306 mg, 0.97 mmol) was dissolved in 10 mL of absolute ethanol, hydrazine hydrate (485 mg, 9.70 mmol) was added, and the reaction solution was stirred at 90 C. for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude compound of 12.4 (282 mg), which was directly used in the next reaction. LCMS ESI(+)m/z: 286.1 (M+1).

Step E: 6-chloro-3-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-4-methylpyridazine (compound 12.5)

[0226] Compound 12.4 (282 mg, 0.99 mmol) was dissolved in 5 mL of phosphorus oxychloride and the reaction solution was stirred at 60 C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, 50 mL of water was added to the residue, the pH was adjusted to 7-8 with saturated sodium bicarbonate, extracted with dichloromethane (80 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product was purified by column chromatography to obtain 12.5 (110 mg, yield: 37%). LCMS ESI(+)m/z: 304 (M+1).

Step F: (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pyridin-3-ol (Compound 12)

[0227] Compound 12.5 (110 mg, 0.36 mmol) was dissolved in 3 mL of NMP, (R)-1-methylpiperidin-3-amine (101 mg, 0.55 mmol) and diisopropylethylamine (233 mg, 1.80 mmol) were added, and the reaction solution was stirred at 150 C. with microwave for 3 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 12 (10.4 mg, yield: 8%). LCMS ESI(+)m/z: 368.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 8.54 (s, 1H), 8.40 (d, J=0.9 Hz, 1H), 7.53 (d, J=1.7 Hz, 1H), 6.87 (d, J=0.8 Hz, 1H), 4.24 (ddd, J=13.0, 9.0, 3.8 Hz, 1H), 3.30 (s, 1H), 3.03-2.93 (m, 1H), 2.65-2.42 (m, 8H), 2.11-2.02 (m, 1H), 1.95 (ddt, J=12.9, 8.6, 4.5 Hz, 1H), 1.88-1.74 (m, 1H), 1.59-1.47 (m, 1H).

Embodiment 13

##STR00151##

(R)-2-(4-((1-methylpiperidin-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0228] The specific reaction Formula is as follows:

##STR00152##

Step A: 2-(((trifluoromethyl)sulfonyl)oxy)cyclopenta-1-en-1-carboxylate methyl ester (compound 13.1)

[0229] 2-oxocyclopentane-1-carboxylic acid methyl ester (5 g, 35.17 mmol) was dissolved in 70 mL of dichloromethane, diisopropylethylamine (6.82 g, 52.75 mmol) was added at 20 C., and then trifluoromethanesulfonic anhydride (10.4 g, 36.93 mmol) was slowly added dropwise, stirred for 1 hour, then heated to room temperature and stirred for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, spun dried, and purified by column chromatography to obtain a product of 13.1 (4.99 g, yield: 51.4%). LCMS ESI(+)m/z: 275.1 (M+1).

Step B: 2-(Methoxycarbonyl)cyclopenta-1-en-1-carboxylic acid (compound 13.2)

[0230] Compound 13.1 (5 g, 18.2 mmol) was dissolved in 100 mL of DMF, and sodium formate (3.7 g, 54 mmol), lithium chloride (2.3 g, 54 mmol), acetic anhydride (3.7 g, 36 mmol), diisopropylamine (3.6 g, 36 mmol) and palladium acetate (0.4 g, 1.8 mmol), stirred at room temperature for 3 hours, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with brine, derived with anhydrous sodium sulfate, and the product was 13.2 (1.32 g, yield: 42.6%) was obtained by spin drying. LCMS ESI(+)m/z: 171.1 (M+1).

Step C: Dimethyl cyclopenta-1-en-1,2-dicarboxylic acid (compound 13.3)

[0231] The compound 13.2 (1.32 g, 7.75 mmol) was dissolved in 50 mL of methanol, thionyl chloride (10 mL) was slowly added dropwise with an ice bath cooling, stirred at room temperature for 3 hours, the reaction solution was directly dried, and then quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, and spun dried to obtain a product of 13.3 (1.1 g, yield: 77.1%). LCMS ESI(+)m/z: 185.1 (M+1).

Step D: 2,3,6,7-tetrahydro-1H-cyclopentano[d]pyridazin-1,4(5H)-dione (compound 13.4)

[0232] Compound 13.3 (1.1 g, 5.98 mmol) was dissolved in 50 mL ethanol, hydrazine hydrate (3 g, 60.1 mmol) was added at room temperature, stirred at 90 C. for 3 hours, the reaction solution was directly dried, and then quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, spin dried, and column purified to obtain a product of 13.4 (230 mg, yield: 25%). LCMS ESI(+)m/z: 153.1 (M+1).

Step E: 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (compound 13.5)

[0233] The compound 13.4 (230 mg, 1.51 mmol) was dissolved in 5 mL of phosphorus oxychloride, heated to 90 C. and stirred for 1 hour, the reaction solution was directly dried, and then quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, washed with brine, derived with anhydrous sodium sulfate, spin dried, and the product was purified by column to obtain 13.5 (280 mg, yield: 98.1%). LCMS ESI(+)m/z: 189.1 (M+1).

Step F: (R)-4-chloro-N-(1-methylpiperidin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine (compound 13.6)

[0234] The compound 13.5 (80 mg, 0.422 mmol) was dissolved in 3 mL n-butanol, diisopropylethylamine (272 mg, 2.11 mmol) and (R)-1-methylpiperidin-3-amine (100 mg, 0.548 mmol) were added, microwave heated to 180 C. and stirred for 5 hours, the reaction solution was directly dried, and then extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, spun dried, and purified by column to obtain the product 13.6 (53 mg, yield: 47.1%). LCMS ESI(+)m/z: 267.1 (M+1).

Step G: (R)-2-(4-((1-methylpiperidin-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (compound 13)

[0235] Compounds 13.6 (53 mg, 0.198 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl) boronic acid (49 mg, 0.238 mmol) were added to a mixture of 3 mL of 1,4-dioxane and 0.5 mL of water, followed by cesium carbonate (161 mg, 0.495 mmol) and Pd (PPh.sub.3).sub.4 (45 mg, 0.037 mmol), under nitrogen, 110 C. reaction in microwave environment for 2 hours, quenching reaction with water, extraction with ethyl acetate (40 mL2), combined organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and reversed-phase prep-HPLC and purification to obtain compound 13 (13 mg, yield: 17.5%). LCMS ESI(+)m/z: 373.2 (M+1). .sup.1H NMR (400 MHz, DMSO) 11.10 (d-J=120.2 Hz, 1H), 8.39 (d, J=112.9 Hz, 1H), 7.62 (t, J=7.0 Hz, 1H), 7.43 (d, J=1.7 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 4.66-4.37 (m, 1H), 3.57 (d, J=12.3 Hz, 2H), 3.46-3.32 (m, 2H), 3.22 (t, J=7.6 Hz, 1H), 2.97 (dt, J=29.4, 7.4 Hz, 4H), 2.79 (dd, J=9.3, 4.6 Hz, 3H), 2.16 (p, J=9.9, 8.8 Hz, 2H), 2.02-1.52 (m, 3H).

Embodiment 14

##STR00153##

(R)-2-(4-((1-methylpiperidin-3-yl)amino)phthazin-1-yl)-5-(trifluoromethyl)phenol

[0236] The specific reaction Formula is as follows:

##STR00154##

Step A: (R)-4-chloro-N-(1-methylpiperidin-3-yl)phthazine-1-amine (compound 14.1)

[0237] 1,4-dichlorophthalazine (100 mg, 0.5 mmol) was dissolved in 2 mL of NMP, (R)-1-methylpiperidine-3-amine dihydrochloride (103 mg, 0.55 mmol) and diisopropylethylamine (323 mg, 2.5 mmol) were added, and the reaction solution was stirred at 180 C. with microwave for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was diluted with ethyl acetate (60 mL), washed with saturated saline (40 mL3), dried with anhydrous sodium sulfate, and concentrated by vacuum, and the obtained residue was purified by column chromatography to obtain a product of 14.1 (61 mg, yield: 46%). LCMS ESI(+)m/z: 277.1 (M+1).

Step B: (R)-2-(4-((1-methylpiperidin-3-yl)amino)phthazin-1-yl)-5-(trifluoromethyl)phenol (Compound 14)

[0238] Compound 14.1(61 mg, 0.22 mmol) was added to 2.2 mL of 1,4-dioxane/H2O (V:V=10:1), followed by (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (56 mg, 0.27 mmol), Pd(PPh.sub.3).sub.4 (51 mg, 0.044 mmol), and cesium carbonate (215 mg, 0.66 mmol), Allow the reaction to stir at 120 C. for 2 h under microwave. Use LCMS to monitor the reaction to completion. The reaction solution was quenched with water, extracted with ethyl acetate (30 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 14 (40 mg, yield: 45%). LCMS ESI(+)m/z: 403.1 (M+1). .sup.1H NMR (400 MHz, DMSO-d6) 11.28 (s, 1H), 11.11 (s, 2H), 10.77 (s, 1H), 9.76 (s, 2H), 9.44 (d, J=8.0 Hz, 1H), 9.09 (s, 1H), 8.24-8.15 (m, 2H), 8.11 (td, J=7.5, 3.4 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.63 (dd, J=7.6, 3.7 Hz, 2H), 7.48 (s, 2H), 7.40 (d, J=7.9 Hz, 2H), 4.84 (s, 1H), 4.65 (d, J=7.1 Hz, 1H), 3.71 (t, J=13.9 Hz, 3H), 3.28 (s, 2H), 3.09 (d, J=11.6 Hz, 1H), 2.95 (s, 2H), 2.84 (s, 7H), 2.21 (d, J=11.1 Hz, 2H), 2.09 (d, J=9.6 Hz, 1H), 1.99 (s, 2H), 1.84 (dd, J=24.3, 11.2 Hz, 3H).

Embodiment 15

##STR00155##

(R)-2-(4-((1-methylpiperidin-3-yl)amino)furo[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol

[0239] The specific reaction Formula is as follows:

##STR00156##

Step A: Dimethyl furan-2,3-dicarboxylic acid (compound 15.1)

[0240] Furan-2,3-dicarboxylic acid (4.43 g, 28.38 mmol) was dissolved in 80 mL of methanol, dichlorothionyl (13.51 g, 113.52 mmol) was added dropwise in an ice water bath, and the reaction solution was stirred at room temperature for 16 hours. 50 mL of water was added to the reaction solution, concentrated under reduced pressure, extracted with ethyl acetate (50 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 15.1 (5.3 g). LCMS ESI(+)m/z: 185 (M+1).

Step B: 5,6-dihydrofuro[2,3-d]pyridazin-4,7-dione (compound 15.2)

[0241] Compound 15.1(5.3 g, 28.80 mmol) was dissolved in 100 mL of absolute ethanol, hydrazine hydrate (14.4 g, 288 mmol) was added, and the reaction solution was stirred at 90 C. for 16 hours. 50 mL of water was added to the reaction solution, concentrated under reduced pressure, 2M HCl (15 mL) was added to the residue, stirred at 100 C. for 3 hours, filtered at room temperature, and the solid vacuum dried to obtain 15.2 (2.52 g, yield: 57%). LCMS ESI(+)m/z: 153 (M+1).

Step C: 4,7-Dichlorofuran [2,3-d]pyridazine (Compound 15.3)

[0242] Compound 15.2 (820 mg, 5.39 mmol) was dissolved with 15 mL of phosphorus oxychloride, pyridine (0.85 g, 10.79 mmol) was added, and the reaction solution was stirred at 100 C. for 1 hour. The reaction solution was spun dry, 50 mL of ice water was added to the residue, the pH was adjusted to 7-8 with saturated sodium bicarbonate, extracted with dichloromethane (80 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a product of 15.3 (500 mg, yield: 50%). LCMS ESI(+)m/z: 189,191 (M+1).

Step D: (R)-4-chloro-N-(1-methylpiperidin-3-yl)furo[2,3-d]pyridazin-7-amine (compound 15.4)

[0243] Compound 15.3 (500 mg, 2.67 mmol) was dissolved in 10 mL of n-butanol, (R)-1-methylpiperidin-3-amine (745 mg, 4.01 mmol) and diisopropylethylamine (1.72 g, 13.35 mmol) were added, and the reaction solution was stirred at 180 C. for 4 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 15.4 (100 mg, yield: 14%). LCMS ESI(+)m/z: 267.1 (M+1).

Step E: (R)-2-(4-((1-methylpiperidin-3-yl)amino)furo[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol (Compound 15)

[0244] The compounds 15.4 (100 mg, 0.38 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl) boronic acid (78 mg, 0.38 mmol) were dissolved in 4 mL of dioxane and 0.8 mL of water, and cesium carbonate (366 mg, 1.14 mmol) and Pd(PPh.sub.3).sub.4 (46 mg, 0.04 mmol) were added, the reaction solution was stirred at 120 C. and under nitrogen-protected microwave for 3 h. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 15 (8.9 mg, yield: 6%). LCMS ESI(+)m/z: 393.2 (M+1). .sup.1H NMR (400 MHz-MeOD) S 8.47 (d, J=2.1 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.35 (s, 1H), 4.65 (s, 1H), 4.57 (tt, J=11.6, 4.0 Hz, 1H), 3.92-3.85 (m, 1H), 3.58 (d, J=11.4 Hz, 1H), 3.47 (dd, J=13.4, 3.0 Hz, 1H), 3.21-3.03 (m, 3H), 2.98 (s, 3H), 2.93 (s, 1H), 2.33 (d, J=11.4 Hz, 1H), 2.24-2.13 (m, 2H), 2.12-1.98 (m, 2H), 1.84 (qd, J=12.7, 4.3 Hz, 1H).

Embodiment 16

##STR00157##

(R)-2-(8-((1-methylpiperidin-3-yl)amino)pyridine[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol

[0245] The specific reaction Formula is as follows:

##STR00158##

Step A: (R)-5-chloro-N-(1-methylpiperidine-3-yl)pyrido[2,3-d]pyridazin-8-amine (compound 16.1)

[0246] 5,8-dichloropyridine and [2,3-d]pyridazine (200 mg, 1.0 mmol) were dissolved in 2 mL of n-butanol, (R)-1-methylpiperidin-3-amine dihydrochloride (206 mg, 1.1 mmol) and diisopropylethylamine (645 mg, 5.0 mmol) were added, and the reaction solution was stirred at 150 C. with microwave for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure, and the product was purified by column chromatography to obtain 16.1(110 mg, yield: 40%). LCMS ESI(+)m/z: 278.1 (M+1). .sup.1H NMR (400 MHz, DMSO-d6) 9.22 (dd, J=4.5, 1.5 Hz, 1H), 8.49 (dd, J=8.3, 1.5 Hz, 1H), 8.06 (dd, J=8.3, 4.5 Hz, 1H), 7.66 (s, 1H), 4.48 (s, 1H), 3.60 (s, 1H), 3.11 (s, 2H), 1.76 (dd, J=27.1, 17.6 Hz, 4H), 1.30-1.14 (m, 3H).

Step B: ((R)-2-(8-((1-methylpiperidin-3-yl)amino)pyridin[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol (Compound 16)

[0247] Compound 16.1(69 mg, 0.25 mmol) was added to 2.2 mL of 1,4-dioxane/H.sub.2O (V:V=10:1), followed by (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (62 mg, 0.30 mmol), Pd(PPh.sub.3).sub.4 (58 mg, 0.050 mmol) and cesium carbonate (244 mg, 0.75 mmol) and stir the reaction at 120 C. with microwave for 2 hours. Use LCMS to monitor the reaction to completion. The reaction solution was quenched with water, extracted with ethyl acetate (30 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase prep-HPLC to obtain compound 16 (36 mg, yield: 36%). LCMS ESI(+)m/z: 404.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.45-9.18 (m, 1H), 8.33 (t, J=9.5 Hz, 1H), 8.20-8.00 (m, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 4.67 (d, J=32.3 Hz, 1H), 3.89 (dd, J=24.9, 10.4 Hz, 1H), 3.60 (d, J=11.0 Hz, 1H), 3.16 (dd, J=21.3, 7.6 Hz, 1H), 3.06 (t, J=12.0 Hz, 1H), 2.34 (d, J=12.4 Hz, 1H), 2.19 (d, J=14.8 Hz, 1H), 2.14-1.98 (m, 1H), 1.89 (dt, J=12.8, 9.7 Hz, 1H).

Embodiment 17

##STR00159##

(R)-2-(5-((1-methylpiperidin-3-yl)amino)pyridin[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol

[0248] The specific reaction Formula is as follows:

##STR00160##

Step A: (R)-8-chloro-N-(1-methylpiperidin-3-yl)pyrido[2,3-d]pyridazin-5-amine (compound 17.1)

[0249] 5,8-dichloropyridine and [2,3-d]pyridazine (200 mg, 1.0 mmol) were dissolved in 2 mL of n-butanol, (R)-1-methylpiperidin-3-amine dihydrochloride (206 mg, 1.1 mmol) and diisopropylethylamine (645 mg, 5.0 mmol) were added, and the reaction solution was stirred at 150 C. with microwave for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure, and the product was purified by column chromatography to obtain 17.1 (36 mg, yield: 13%). LCMS ESI(+)m/z: 278.1 (M+1). .sup.1H NMR (400 MHz, DMSO-d6) 9.22 (d, J=4.2 Hz, 1H), 8.90 (dd, J=8.5, 1.4 Hz, 1H), 7.99 (dd, J=8.4, 4.4 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 4.39-4.16 (m, 1H), 3.04 (d, J=7.6 Hz, 1H), 2.70 (d, J=11.0 Hz, 1H), 2.21 (s, 3H), 1.95 (ddd, J=30.1, 12.5, 6.6 Hz, 3H), 1.80-1.69 (m, 1H), 1.59 (td, J=12.2, 3.8 Hz, 1H), 1.42 (ddd, J=23.5, 12.0, 4.1 Hz, 1H), 1.24 (d, J=11.9 Hz, 1H).

Step B: (R)-2-(5-((1-methylpiperidin-3-yl)amino)pyridin[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol (Compound 17)

[0250] Compound 17.1(36 mg, 0.13 mmol) was added to 2.2 mL of 1,4-dioxane/H.sub.2O (V:V=10:1), followed by (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (32 mg, 0.16 mmol), Pd(PPh.sub.3).sub.4 (30 mg, 0.026 mmol), and cesium carbonate (127 mg, 0.39 mmol), Allow the reaction to stir at 120 C. with microwave for 3 h. Use LCMS to monitor the reaction to completion. The reaction solution was quenched with water, extracted with ethyl acetate (30 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 17 (5 mg, yield: 10%). LCMS ESI(+)m/z: 404.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.55 (d, J=8.3 Hz, 1H), 9.35-9.24 (m, 4H), 9.14 (d, J=8.1 Hz, 3H), 8.16 (dt, J=8.3, 4.1 Hz, 3H), 7.80-7.68 (m, 4H), 7.36 (d, J=8.1 Hz, 3H), 7.31 (s, 3H), 4.68 (t, J=11.5 Hz, 4H), 3.91 (d, J=11.8 Hz, 4H), 3.60 (d, J=12.0 Hz, 4H), 3.48 (dd, J=6.6, 4.9 Hz, 1H), 3.21-3.04 (m, 6H), 2.99 (s, 7H), 2.93 (s, 3H), 2.45-2.29 (m, 4H), 2.29-2.13 (m, 4H), 2.13-1.99 (m, 5H), 1.99-1.79 (m, 3H).

Embodiment 18

##STR00161##

(R)-2-(7-((1-methylpiperidin-3-yl)amino)furo[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[0251] The specific reaction Formula is as follows:

##STR00162##

Step A: (R)-4-chloro-N-(1-methylpiperidin-3-yl)furo[2,3-d]pyridazin-7-amine (compound 18.1)

[0252] Compound 15.3 (500 mg, 2.67 mmol) was dissolved in 10 mL of n-butanol, (R)-1-methylpiperidin-3-amine (745 mg, 4.01 mmol) and diisopropylethylamine (1.72 g, 13.35 mmol) were added, and the reaction solution was stirred at 180 C. with microwave for 4 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 18.1 (40 mg, yield: 6%). LCMS ESI(+)m/z: 267.1 (M+1).

Step B: (R)-2-(7-((1-methylpiperidin-3-yl)amino)furo[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (Compound 18)

[0253] Compounds 18.1(40 mg, 0.15 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl) boric acid (46 mg, 0.23 mmol) were dissolved in 4 mL of dioxane and 0.8 mL of water, and cesium carbonate (147 g, 0.45 mmol) and Pd(PPh.sub.3).sub.4 (23 mg, 0.02 mmol) were added, the reaction solution was stirred at 120 C. and under nitrogen-protected microwave for 3 h. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (80 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase prep-HPLC to obtain compound 18 (4.0 mg, yield: 7%). LCMS ESI(+)m/z: 393.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 8.23 (d, J=1.6 Hz, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.46 (d, J=1.9 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.26 (s, 1H), 4.62 (s, 1H), 3.94 (s, 1H), 3.58 (d, J=15.3 Hz, 1H), 2.95 (s, 5H), 2.24 (d, J=24.7 Hz, 2H), 2.02 (s, 1H), 1.81 (s, 1H).

Embodiment 19

##STR00163##

(R)-2-(4-((1-methylpiperidin-3-yl)amino)-2,3-dihydrofuro[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol

[0254] The specific reaction Formula is as follows:

##STR00164##

Step A: (R)-2-(4-((1-methylpiperidin-3-yl)amino)-2,3-dihydrofuro[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol (Compound 19)

[0255] (R)-2-(4-((1-methylpiperidin-3-yl)amino)furo[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol (55 mg, 0.14 mmol) was dissolved in 5 mL of methanol, palladium hydroxide carbon (110 mg) was added, and the reaction solution was stirred at room temperature for 24 hours under ambient pressure hydrogen. The reaction solution was filtered, concentrated under reduced pressure, 50 mL of water was added to the reaction solution, concentrated under reduced pressure, extracted with ethyl acetate (50 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase prep-HPLC to obtain compound 19 (17.2 mg, yield: 31%). LCMS ESI(+)m/z: 395.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 7.82 (t, J=7.3 Hz, 1H), 7.26 (d, J=10.0 Hz, 3H), 7.00-6.94 (m, 1H), 5.01 (t, J=9.4 Hz, 3H), 4.51 (s, 1H), 4.41 (t, J=11.6 Hz, 1H), 3.79 (t, J=11.5 Hz, 1H), 3.58 (dd, J=18.8, 8.5 Hz, 3H), 3.38 (t, J=9.4 Hz, 3H), 3.17-2.98 (m, 3H), 2.96 (s, 3H), 2.90 (s, 1H), 2.28 (t, J=16.5 Hz, 1H), 2.05 (ddd, J=27.9, 23.4, 8.9 Hz, 3H), 1.75 (qd, J=12.8, 4.1 Hz, 1H).

Embodiment 20

##STR00165##

(R)-2-(7-((1-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-d]pyrazin-4-yl)-5-(trifluoromethyl)phenol

[0256] The specific reaction Formula is as follows:

##STR00166##

Step A: Ethyl 4-(dibenzylamino)butyrate (compound 20.1)

[0257] Ethyl 4-bromobutyrate (10.0 g, 51.3 mmol) was dissolved into 100 mL of DMF, and then dibenzylamine (10.1 g, 51.3 mmol), potassium carbonate (14.2 g, 102.6 mmol) and potassium iodide (852 mg, 5.13 mmol) were added sequentially, and the reaction was stirred overnight at 80 C. Use TLC to monitor the reaction to completion. The reaction solution was quenched with water, extracted with ethyl acetate (200 mL3), combined the organic phases, washed with brine (4100 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 20.1 (11.4 g, yield: 72%).

Step B: 2-(2-(dibenzylamino)ethyl)-3-oxosuccinate diethyl ester (compound 20.2)

[0258] Compound 20.1 (11.4 g, 36.7 mmol) and diethyl oxalate (5.36 g, 36.7 mmol) were dissolved in 100 mL of toluene, potassium tert-butoxide (4.94 g, 44.07 mmol) was added at room temperature, and stirred overnight at room temperature. Use TLC to monitor the reaction to completion. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (200 mL3), combined the organic phases, washed with brine (200 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 20.2 (8.6 g, yield: 57%).

Step C: Pyrrolidin-2,3-diethyl dicarboxylate (compound 20.3)

[0259] Compound 20.2 (4.1 g, 10 mmol) was dissolved in 50 mL of ethanol, Pd/C (820 mg, 20%) was added at room temperature, and stirred overnight in a hydrogen atmosphere. Use TLC to monitor the reaction to completion. The reaction solution was passed through a suction funnel coated with diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 20.3 (1.5 g, yield: 70%).

Step D: 1H-pyrrole-2,3-dicarboxylic acid diethyl ester (compound 20.4)

[0260] Compound 20.3 (1.5 g, 6.97 mmol) was dissolved in 60 mL of anhydrous methylene chloride, active manganese dioxide (4.5 g) was added at room temperature, and stirred overnight at room temperature. Use TLC to monitor the reaction to completion. The reaction solution was passed through a suction funnel coated with diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 20.4 (333 mg, yield: 23%).

Step E: 1H-pyrrole-2,3-dicarboxylhydrazide (compound 20.5)

[0261] Compound 20.4 (333 mg, 1.58 mmol) was dissolved in 20 mL of ethanol, hydrazine hydrate (790 mg, 15.8 mmol) was added at room temperature, and stirred overnight at 80 C. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 20.5 (338 mg, yield: 100%).

Step F: 5,6-dihydro-1H-pyrrolo[2,3-d]pyrazine-4,7-dione (compound 20.6)

[0262] Dissolve compound 20.5 (338 mg, 1.58 mmol) in 20 mL of 2 M hydrochloric acid solution and stir overnight at 100 C. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 20.6 (358 mg, yield: 100%).

Step G: 4,7-dichloro-1H-pyrrolo[2,3-d]pyridazine (compound 20.7)

[0263] Dissolve compound 20.6 (358 mg, 1.58 mmol) in 8 mL of phosphorus oxychloride, add DIPEA (2 mL) at room temperature, and stir overnight at 100 C. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure, the residue was dissolved with ethyl acetate (30 mL), and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, the organic phase was washed with brine, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 20.7 (147 mg, yield: 49%).

Step H: (R)-4-chloro-N-(1-methylpiperidin-3-yl)-1H-pyrrolo[2,3-d]pyrazin-7-amine (compound 20.8)

[0264] Compound 20.7 (147 mg, 0.78 mmol) was dissolved in 4 mL of NMP, (R)-1-methylpiperidine-3-amine (98 mg, 0.86 mmol) and diisopropylethylamine (501 mg, 3.9 mmol) were added, and the reaction solution was stirred at 180 C. with microwave for 5 hours. Use LCMS to monitor the reaction to completion. The reaction solution was diluted with ethyl acetate (60 mL), washed with saturated saline (40 mL3), dried with anhydrous sodium sulfate, and concentrated in vacuum, and the obtained residue was purified by column chromatography to obtain a product of 20.8 (45 mg, yield: 22%). LCMS ESI(+)m/z: 266.1 (M+1).

Step I: (R)-2-(7-((1-methylpiperidin-3-yl)amino)-1H-pyrrole[2,3-d]pyrazin-4-yl)-5-(trifluoromethyl)phenol (Compound 20)

[0265] Compound 20.8 (45 mg, 0.17 mmol) was added to 2.2 mL of 1,4-dioxane/H.sub.2O (V:V=10:1), followed by (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (42 mg, 0.20 mmol), Pd(PPh.sub.3).sub.4 (39 mg, 0.034 mmol), and cesium carbonate (166 mg, 0.51 mmol) and allow the reaction to stir for 3 h at 120 C. with microwave. Use LCMS to monitor the reaction to completion. The reaction solution was quenched with water, extracted with ethyl acetate (30 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 20 (4 mg, yield: 6%). LCMS ESI(+)m/z: 392.1 (M+1). 1HMR (400 MHz, MeOD) 7.93-7.84 (m, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 6.95-6.89 (m, 1H), 4.65-4.46 (m, 1H), 4.10-3.85 (m, 1H), 3.65-3.52 (m, 1H), 3.09 (ddd, J=29.2, 13.8, 11.6 Hz, 2H), 2.97 (s, 2H), 2.89 (d, J=6.3 Hz, 1H), 2.35 (d, J=12.7 Hz, 1H), 2.18 (d, J=14.8 Hz, 1H), 2.10-1.93 (m, 2H), 1.87-1.68 (m, 1H).

Embodiment 21

##STR00167##

(R)-2-(4-((1-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-d]pyrazin-7-yl)-5-(trifluoromethyl)phenol

[0266] The specific reaction Formula is as follows:

##STR00168##

Step A: ((R)-7-chloro-N-(1-methylpiperidin-3-yl)-1H-pyrrolo[2,3-d]pyrazin-4-amine (compound 21.1)

[0267] 4,7-dichloro-1H-pyrrolo[2,3-d]pyrazine (147 mg, 0.78 mmol) was dissolved in 4 mL of NMP, (R)-1-methylpiperidin-3-amine (98 mg, 0.86 mmol) and diisopropylethylamine (501 mg, 3.9 mmol) were added, and the reaction solution was stirred at 180 C. with microwave for 5 hours. Use LCMS to monitor the reaction to completion. The reaction solution was diluted with ethyl acetate (60 mL), washed with saturated saline (40 mL3), dried with anhydrous sodium sulfate, and concentrated in vacuum, and the obtained residue was purified by column chromatography to obtain a product of 21.1 (45 mg, yield: 22%). LCMS ESI(+)m/z: 266.1 (M+1).

Step B: (R)-2-(4-((1-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-d]pyrazine-7-yl)-5-(trifluoromethyl)phenol (Compound 21)

[0268] Compound 21.1(45 mg, 0.17 mmol) was added to 2.2 mL of 1,4-dioxane/H.sub.2O (V:V=10:1), followed by (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (42 mg, 0.20 mmol), Pd(PPh3).sub.4 (39 mg, 0.034 mmol), and cesium carbonate (166 mg, 0.51 mmol) and allow the reaction to stir for 3 h at 120 C. with microwave. Use LCMS to monitor the reaction to completion. The reaction solution was quenched with water, extracted with ethyl acetate (30 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase prep-HPLC to obtain compound 21 (7 mg, yield: 11%). LCMS ESI(+)m/z: 392.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 7.93 (s, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.37 (s, 2H), 7.23 (s, 1H), 4.59 (d, J=39.9 Hz, 1H), 3.89 (d, J=10.9 Hz, 1H), 3.58 (d, J=12.5 Hz, 1H), 3.52-3.39 (m, 1H), 3.13 (dd, J=6.0, 4.3 Hz, 1H), 3.06 (t, J=13.0 Hz, 1H), 2.95 (d, J=19.1 Hz, 4H), 2.32 (d, J=9.8 Hz, 1H), 2.17 (d, J=14.3 Hz, 1H), 1.98 (d, J=32.6 Hz, 2H), 1.82 (tt, J=17.2, 8.6 Hz, 1H).

Embodiment 22

##STR00169##

2-(3-(((3R)-1-(1-hydroxypropyl-2-yl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3,5-dimethylphenol

[0269] The specific reaction Formula is as follows:

##STR00170##

Step A: ((3R)-1-(1-hydroxypropyl-2-yl)piperidin-3-yl)tert-butyl carbamate (compound 22.1)

[0270] Tert-butyl(R)-piperidin-3-yl carbamate (200 mg, 1 mmol) and 2-bromopropanol (138 mg, 1 mmol) were dissolved in 8 mL of DMF, then potassium carbonate (276 mg, 2 mmol) and potassium iodide (166 mg, 1 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. Use TLC to monitor the reaction to completion. The reaction solution was diluted with water, extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product was obtained by column chromatography 22.1 (230 mg, yield: 89.1%). LCMS ESI(+)m/z: 259.1 (M+1).

Step B: 2-((R)-3-aminopiperidin-1-yl)propyl-1-ol (compound 22.2)

[0271] Dissolve compound 22.1 (1.4 g, 5.4 mmol) in 15 mL of hydrogen chloride/ethyl acetate (2 M) and stir for 1 h at room temperature. Use TLC to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 22.2 (1.2 g, yield: 100%). LCMS ESI(+)m/z: 159.1 (M+1).

Step C: 2-((R)-3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)propane-1-ol (compound 22.3)

[0272] The compound 22.2 (30 mg, 0.102 mmol) was dissolved in 2 mL of n-butanol, and 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (62 mg, 0.204 mmol) and diisopropylethylamine (90 mg, 0.70 mmol) were added, and the reaction solution was stirred at 150 C. with microwave for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 22.3 (50 mg, yield: 100%). LCMS ESI(+)m/z: 415.2 (M+1).

Step D: 2-(3-(((3R)-1-(1-hydroxypropyl-2-yl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3,5-dimethylphenol (Compound 22)

[0273] Dissolve compound 22.3 (50 mg, 0.105 mmol) in 3 mL of 2 M hydrochloric acid/ethyl acetate and stir for 1 h at room temperature. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure and purified with reversed-phase prep-HPLC to obtain compound 22 (1.6 mg). LCMS ESI(+)m/z: 357.1 (M+1). .sup.1H NMR (400 MHz, DMSO) 9.89 (s, 1H), 9.54 (s, 1H), 9.01 (s, 1H), 8.37-8.19 (m, 1H), 7.88 (s, 1H), 6.72-6.52 (m, 2H), 4.48 (s, 1H), 4.24 (s, 1H), 3.41 (t, J=9.8 Hz, 3H), 3.20 (s, 1H), 3.11-2.74 (m, 2H), 2.23 (s, 3H), 2.07 (s, 4H), 1.92 (d, J=10.9 Hz, 2H), 1.84 (s, 1H), 1.60 (td, J=14.3, 11.8, 7.9 Hz, 2H), 1.25 (d, J=1.5 Hz, 3H).

Embodiment 23

##STR00171##

(R)-2-(3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetamide

[0274] The specific reaction Formula is as follows:

##STR00172##

Step A: (R)-(1-(2-amino-2-oxoethyl)piperidin-3-yl)tert-butyl carbamate (compound 23.1)

[0275] Tert-butyl(R)-piperidin-3-ylcarbamate (200 mg, 1 mmol) and 2-bromoacetamide (138 mg, 1 mmol) were dissolved in 8 mL of DMF, then potassium carbonate (276 mg, 2 mmol) and potassium iodide (166 mg, 1 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. Use TLC to monitor the reaction to completion. The reaction solution was diluted with water, extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product was obtained by column chromatography 23.1 (230 mg, yield: 89.1%). LCMS ESI(+)m/z: 258.1 (M+1).

Step B: (R)-2-(3-aminopiperidin-1-yl)acetamide (compound 23.2)

[0276] Dissolve compound 23.1 (1.4 g, 5.4 mmol) in 15 mL of 2 M hydrochloric acid/ethyl acetate and stir for 1 h at room temperature. Use TLC to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 23.2 (1.2 g, yield: 100%). LCMS ESI(+)m/z: 158.21 (M+1).

Step C: (R)-2-(3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetamide (compound 23.3)

[0277] The compound 23.2 (30 mg, 0.102 mmol) was dissolved in 2 mL of n-butanol, and 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (62 mg, 0.204 mmol) and diisopropylethylamine (90 mg, 0.70 mmol) were added, and the reaction solution was stirred at 150 C. for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 23.3 (50 mg, yield: 100%). LCMS ESI(+)m/z: 414.1 (M+1).

Step D: (R)-2-(3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetamide (Compound 23)

[0278] Compound 23.3 (50 mg, 0.105 mmol) is dissolved in 3 mL of hydrochloric acid/ethyl acetate (2 M) and stirred for 1 h at room temperature. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure and purified by reversed-phase prep-HPLC to obtain compound 23 (1.6 mg). LCMS ESI(+)m/z: 356.1 (M+1). .sup.1H NMR (400 MHz, DMSO) 10.30 (s, 1H), 9.62 (d, J=166.1 Hz, 1H), 8.33 (s, 1H), 8.09 (s, 2H), 7.68 (s, 1H), 6.67 (s, 1H), 6.61 (s, 1H), 4.44 (s, 1H), 3.97 (s, 3H), 3.47 (d, J=12.1 Hz, 2H), 3.01 (d, J=36.2 Hz, 2H), 2.23 (s, 4H), 2.08 (s, 4H), 1.97-1.81 (m, 3H), 1.63-1.46 (m, 1H).

Embodiment 24

##STR00173##

2-((R)-3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)-N((S)-1-hydroxypropyl-2-yl)acetamide

[0279] The specific reaction Formula is as follows:

##STR00174##

Step A: (R)-2-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)methyl acetate (compound 24.1)

[0280] Tert-butyl(R)-piperidin-3-ylcarbamate (1 g, 5 mmol) and methyl 2-bromoacetate (835 mg, 5 mmol) were dissolved in 10 mL of DMF, then potassium carbonate (1.38 g, 10 mmol) and potassium iodide (830 mg, 5 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. Use TLC to monitor the reaction to completion. The reaction solution was diluted with water, extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography obtained a product of 24.1 (1.6 g, yield: 100%). LCMS ESI(+)m/z: 273.1 (M+1).

[0281] Step B: ((R)-2-(3-(tert-butoxycarbonyl)amino)piperidin-1-yl)acetic acid (compound 24.2) dissolve compound 24.1 (1.6 g) in 5 mL of THF solution, add lithium hydroxide aqueous solution (30 mg) and stir for 12 hours at room temperature, and extract with ethyl acetate, combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 24.2 (1.5 g). LCMS ESI(+)m/z: 259.1 (M+1).

Step C: ((R)-1-(2-(((S)-1-hydroxypropyl-2-yl)amino)-2-oxethyl)piperidin-3-yl)tert-butyl carbamate (compound 24.3)

[0282] Compound 24.2 (200 mg, 0.775 mmol) was dissolved in 3 mL of DMF, and (S)-2-aminopropane-1-ol (70 mg, 0.93 mmol), diisopropylethylamine (295 mg, 2.32 mmol) and T.sub.3P solution in DMF (50 wt %, 739 mg, 1.16 mmol) were added with an ice bath cooling, then stir for 2 hours at room temperature. The reaction solution was diluted with water, extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, and obtained a crude compound of 24.3 (240 mg) after spin drying. LCMS ESI(+)m/z: 316.1 (M+1).

Step D: 2-((R)-3-aminopiperidin-1-yl)-N((S)-1-hydroxypropyl-2-yl)acetamide (compound 24.4)

[0283] Dissolve compound 24.3 (240 mg) in 15 mL of 2 M hydrochloric acid/ethyl acetate and stir for 1 h at room temperature. Use TLC to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 24.4 (120 mg, yield: 100%). LCMS ESI(+)m/z: 216.1 (M+1).

Step E: 2-((R)-3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)-N((S)-1-hydroxypropyl-2-yl)acetamide (compound 24.5)

[0284] Compound 24.4 (120 mg, 0.6 mmol) was dissolved in 2 mL of n-butanol, and 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (50 mg, 0.17 mmol) and diisopropylethylamine (132 mg, 1.02 mmol) were added, and the reaction solution was stirred at 150 C. with microwave for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 24.5 (70 mg). LCMS ESI(+)m/z: 472.1 (M+1).

Step F: 2-((R)-3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)-N((S)-1-hydroxypropyl-2-yl)acetamide (compound 24)

[0285] Dissolve compound 24.5 (70 mg) in 3 mL of hydrogen chloride/ethyl acetate (2 M) solution and stir for 1 h at room temperature. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure and purified with reversed-phase prep-HPLC to obtain compound 24 (6 mg). LCMS ESI(+)m/z: 414.1 (M+1). .sup.1H NMR (400 MHz, DMSO) 10.24 (s, 1H), 9.67 (d, J=90.1 Hz, 1H), 8.51 (d, J=7.9 Hz, 1H), 8.29 (s, 1H), 7.96 (s, 1H), 6.66-6.57 (m, 2H), 4.42 (s, 1H), 3.94 (s, 2H), 3.83 (p, J=6.3 Hz, 1H), 3.67 (d, J=11.3 Hz, 1H), 3.46 (d, J=12.2 Hz, 1H), 3.33 (qd, J=10.8, 5.6 Hz, 2H), 3.02 (s, 1H), 2.90 (dd, J=11.0, 7.0 Hz, 1H), 2.23 (s, 3H), 2.07 (s, 4H), 1.88 (d, J=32.1 Hz, 2H), 1.57 (q, J=10.4, 9.3 Hz, 1H), 1.04 (d, J=6.7 Hz, 3H).

Embodiment 25

##STR00175##

N-((1s,3S)-3-hydroxy-3-methylcyclobutyl)-2-((R)-3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazin)-3-yl)amino)piperidin-1-yl)acetamide

[0286] The specific reaction Formula is as follows:

##STR00176##

Step A: ((R)-1-(2-(((1s,3S)-3-hydroxy-3-methylcyclobutyl)amino)-2-oxoethyl)piperidin-3-yl)tert-butyl carbamate (compound 25.1)

[0287] (R)-2-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)acetic acid (200 mg, 0.775 mmol) was dissolved in 10 mL of DMF, added (1s,3s)-3-amino-1-methylcyclobutane-1-ol (162 mg, 0.929 mmol), diisopropylethylamine (500 mg, 3.1 mmol) and the 50% of DMF solution of T 3P was (739 mg, 0.929 mmol), then stir for 2 h at room temperature. The reaction solution was diluted with water, extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, and obtained a crude compound of 25.1 (250 mg) after spin drying. LCMS ESI(+)m/z: 342.1 (M+1).

Step B: 2-((R)-3-aminopiperidin-1-yl)-N-((1s,3S)-3-hydroxy-3-methylcyclobutyl)acetamide (compound 25.2)

[0288] Dissolve compound 25.1 (250 mg) in 15 mL of 2 M hydrochloride/ethyl acetate and stir for 1 h at room temperature. Use TLC to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 25.2 (120 mg, yield: 100%). LCMS ESI(+)m/z: 242.1 (M+1).

Step C: 2-((R)-3-((6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl)-N-((1s,3S)-3-hydroxy-3-methylcyclobutyl)acetamide (compound 25.3)

[0289] Compound 25.2 (120 mg, 0.25 mmol) was dissolved in 2 mL of n-butanol, and 3-chloro-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-1,2,4-triazine (50 mg, 0.17 mmol) and diisopropylethylamine (132 mg, 1.02 mmol) were added, and the reaction solution was stirred at 150 C. microwave for 1 hour. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product of 25.3 (85 mg). LCMS ESI(+)m/z: 498.1 (M+1).

Step D: N-((1s,3S)-3-hydroxy-3-methylcyclobutyl)-2-((R)-3-((6-(2-hydroxy-4,6-dimethylphenyl)-1,2,4-triazine)-3-yl)amino)piperidin-1-yl)acetamide (compound 25)

[0290] Dissolve compound 25.3 (85 mg, 0.09 mmol) in 3 mL of hydrogen chloride/ethyl acetate (2 M) and stir for 1 h at room temperature. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure and purified with reversed-phase prep-HPLC to obtain a product of 25 (36 mg). LCMS ESI(+)m/z: 440.1 (M+1). .sup.1H NMR (400 MHz, DMSO) 10.36 (s, 1H), 9.71 (d, J=113.8 Hz, 1H), 8.93 (d, J=7.0 Hz, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 6.73-6.51 (m, 2H), 4.39 (d, J=24.6 Hz, 1H), 3.95 (d, J=3.0 Hz, 2H), 3.78 (p, J=7.9 Hz, 1H), 3.73-3.55 (m, 1H), 3.44 (d, J=11.8 Hz, 1H), 3.13-2.82 (m, 2H), 2.33-2.17 (m, 5H), 2.07 (s, 4H), 2.00-1.75 (m, 4H), 1.67-1.44 (m, 1H), 1.22 (s, 3H).

Embodiment 26

##STR00177##

(R)-3,5-Dimethyl-2-(6-((1-methylpiperidin-3)amino)-1,2,4,5-tetraazin-3)phenol

[0291] The specific reaction Formula is as follows:

##STR00178##

Step A: (R)-6-chloro-N-(1-methylpiperidin-3-yl)-1,2,4,5-tetraazin-3-amine (compound 26.1)

[0292] 3,6-dichloro-1,2,4,5-tetrazine (250 mg, 1.66 mmol) was dissolved in 13 mL of methyl tert-butyl ether, and (R)-1-methylpiperidin-3-amine hydrochloride (467 mg, 2.5 mmol) and diisopropylethylamine (1.5 mL, 8.3 mmol) were added to the reaction overnight at room temperature. The reaction solution was quenched with sodium bicarbonate aqueous solution, extracted with ethyl acetate (10 mL5), combined the organic phases, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 26.1 (22.5 mg, yield: 5.9%). LCMS ESI(+)m/z: 229.1 (M+1).

Step B: (R)-6-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-N-(1-methylpiperidin-3-yl)-1,2,4,5-tetraazine-3-amine (compound 26.2)

[0293] The compounds 26.1 (12.5 mg, 0.055 mmol) and (2-ethoxymethoxy)-4,6-dimethylphenyl) boronic acid (18.4 mg, 0.08 mmol) were dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water, and cesium carbonate (45 mg, 0.14 mmol) was added BrettPhos-Pd-G4 (5 mg) under nitrogen, overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the product was purified by column chromatography to obtain 26.2 (8 mg, yield: 39%). LCMS ESI(+)m/z: 373.2 (M+1).

Step C: (R)-3,5-dimethyl-2-(6-((1-methylpiperidin-3yl)amino)-1,2,4,5-tetraazin-3yl)phenol (compound 26)

[0294] Compound 26.2 (8 mg, 0.022 mmol) was dissolved in 2 mL of methanol, 2 mL of methanol (4 M) of hydrogen chloride was added, and stirred for 0.5 hours at room temperature. The reaction solution was concentrated under reduced pressure and purified by reversed-phase prep-HPLC to obtain compound 26 (5.9 mg, yield: 76.5%). LCMS ESI(+)m/z: 315.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 6.69 (s, 1H), 6.64 (s, 1H), 4.52-4.31 (m, 1H), 3.98-3.79 (m, 1H), 3.61-3.47 (m, 1H), 3.02 (td, J=12.9, 3.1 Hz, 1H), 2.95 (s, 3H), 2.89 (s, 1H), 2.30 (s, 3H), 2.29-2.24 (m, 1H), 2.21-2.16 (m, 1H), 2.13 (s, 3H), 2.10-1.98 (m, 1H), 1.75 (ddd, J=25.4, 12.8, 3.9 Hz, 1H).

Embodiment 27

##STR00179##

(R)-5-methyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol

[0295] The specific reaction Formula is as follows:

##STR00180##

Step A: (R)-4-(2-(ethoxymethoxy)-4-methylphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (compound 27.1)

[0296] (R)-4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (100 mg, 0.36 mmol) and 2-(2-(ethoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde (127 mg, 0.432 mmol) were dissolved in 4 mL of dioxane and 0.4 mL of water, and cesium carbonate (352 mg, 1.08 mmol) was added PdCl.sub.2(dppf) (53 mg, 0.072 mmol), the reaction solution was stirred at 120 C. with microwave for 3 hours. Use LCMS to monitor the reaction to completion. 30 mL of water was added to the reaction solution and quenched, extracted with ethyl acetate (50 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 27.1 (103 mg, yield: 69%). LCMS ESI(+)m/z: 407.2 (M+1).

Step B: (R)-5-methyl-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 27)

[0297] Dissolve compound 27.1 (103 mg, 0.25 mmol) in 2 M hydrochloric acid/ethyl acetate 5 mL and stir for 1 h at room temperature. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure and purified by reversed-phase prep-HPLC to obtain compound 27 (30 mg, yield: 34%). LCMS ESI(+)m/z: 349.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.03 (s, 1H), 8.68 (d, J=7.0 Hz, 3H), 8.27 (t, J=7.6 Hz, 4H), 8.12 (t, J=7.7 Hz, 4H), 8.04 (d, J=8.0 Hz, 4H), 7.35 (d, J=7.7 Hz, 4H), 7.04-6.87 (m, 9H), 4.72 (d, J=23.8 Hz, 5H), 3.91 (d, J=11.8 Hz, 4H), 3.58 (d, J=12.0 Hz, 4H), 3.46 (dd, J=9.5, 7.8 Hz, 1H), 3.20-3.00 (m, 8H), 2.95 (d, J=19.2 Hz, 13H), 2.43 (s, 13H), 2.31 (t, J=13.6 Hz, 5H), 2.18 (d, J=14.6 Hz, 3H), 1.99 (dt, J=36.6, 8.6 Hz, 9H).

Embodiment 28

##STR00181##

(R)-5-chloro-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol

[0298] The specific reaction Formula is as follows:

##STR00182##

Step A: (R)-5-chloro-2-(4-((1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (compound 28)

[0299] (R)-4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (70 mg, 0.25 mmol) was added to 3.3 mL of 1,4-dioxane/H.sub.2O (V:V=10:1), followed by (4-chloro-2-hydroxyphenyl)boronic acid (52 mg, 0.30 mmol), Pd(PPh.sub.3).sub.4 (58 mg, 0.05 mmol) and cesium carbonate (244 mg, 0.75 mmol) and stir the reaction at 120 C. with microwave for 2 hours. Use LCMS to monitor the reaction to completion. The reaction solution was quenched with water, extracted with ethyl acetate (30 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with reversed-phase prep-HPLC to obtain compound 28 (14 mg, yield: 15%). LCMS ESI(+)m/z: 469.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.06 (s, 1H), 8.68 (d, J=4.3 Hz, 3H), 8.28 (t, J=7.8 Hz, 4H), 8.13 (t, J=7.7 Hz, 5H), 7.99 (d, J=8.2 Hz, 4H), 7.48 (d, J=8.1 Hz, 4H), 7.23-7.00 (m, 9H), 4.70 (d, J=27.6 Hz, 5H), 3.90 (d, J=11.7 Hz, 4H), 3.59 (d, J=12.1 Hz, 4H), 3.47 (dd, J=8.7, 7.1 Hz, 1H), 3.12 (ddd, J=31.7, 22.9, 12.5 Hz, 8H), 2.95 (d, J=19.0 Hz, 13H), 2.31 (t, J=17.9 Hz, 5H), 2.18 (d, J=14.4 Hz, 3H), 2.10-1.76 (m, 9H).

Embodiment 29

##STR00183##

5-Chloro-3-methyl-2-(4-((R)-1-methylpiperidin-3-yl)amino)phthazine-1-yl)phenol

[0300] The specific reaction Formula is as follows:

##STR00184##

Step A: (4-(4-chloro-2-(ethoxymethoxy)-6-methylphenyl)-N((R)-1-methylpiperidin-3-yl)phthalazin-1-amine (compound 29.1)

[0301] (R)-4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (100 mg, 0.36 mmol) and 2-(4-chloro-2-(ethoxymethoxy)-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde (141 mg, 0.432 mmol) was dissolved in 4 mL of dioxane and 0.4 mL of water, cesium carbonate (352 mg, 1.08 mmol) and PdCl.sub.2(dppf) (53 mg, 0.072 mmol) were added, and the reaction solution was stirred at 120 C. with microwave for 3 hours. Use LCMS to monitor the reaction to completion. 30 mL of water was added to the reaction solution and quenched, extracted with ethyl acetate (50 mL2), combined the organic phases, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a product of 29.1 (35 mg, yield: 22%). LCMS ESI(+)m/z: 441.1 (M+1).

Step B: 5-chloro-3-methyl-2-(4-((R)-1-methylpiperidin-3-yl)amino)phthalazin-1-yl)phenol (Compound 29)

[0302] Dissolve compound 29.1 (35 mg, 0.08 mmol) in 5 mL of hydrogen chloride/ethyl acetate (2 M) and stir for 1 h at room temperature. Use LCMS to monitor the reaction to completion. The reaction solution was concentrated under reduced pressure and purified by reversed-phase prep-HPLC to obtain compound 29 (12 mg, yield: 39%). LCMS ESI(+)m/z: 383.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.08 (s, 1H), 8.72 (s, 3H), 8.28 (d, J=7.7 Hz, 4H), 8.13 (t, J=7.7 Hz, 5H), 7.83 (d, J=8.0 Hz, 5H), 7.05 (s, 4H), 6.95 (d, J=1.3 Hz, 4H), 4.73 (d, J=25.8 Hz, 7H), 3.90 (d, J=11.5 Hz, 4H), 3.59 (d, J=11.7 Hz, 5H), 3.51-3.40 (m, 1H), 3.23-2.98 (m, 9H), 2.95 (d, J=16.6 Hz, 13H), 2.48-2.24 (m, 6H), 2.19 (d, J=15.1 Hz, 4H), 2.06 (s, 18H), 1.93 (d, J=4.9 Hz, 5H).

Embodiment 30

##STR00185##

(R)-2-(1-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[0303] The specific reaction Formula is as follows:

##STR00186##

Step A: (R)-4-chloro-N-(1-methylpiperidine-3-yl)pyrido[3,4-d]pyridazin-1-amine (compound 30.1)

[0304] 1,4-Dichloropyridine [3,4-d]pyridazine (100 mg, 0.5 mmol) was dissolved in 3 mL of n-butanol, and diisopropylethylamine (387 mg, 3 mmol) and (R)-1-methylpiperidine-3-amine (112 mg, 0.6 mmol) were added. After microwave heating to 180 C. and stirring for 2 hours, the reaction solution was directly dried, then extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, spun dry, and purified by column to obtain 30.1 (22 mg). LCMS ESI(+)m/z: 278.1 (M+1).

Step B: (R)-2-(1-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (compound 30)

[0305] Compounds 30.1 (40 mg, 0.144 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl) boronic acid (36 mg, 0.173 mmol) were added to a mixture of 3 mL of 1,4-dioxane and 0.5 mL of water, followed by cesium carbonate (118 mg, 0.36 mmol) and Pd (PPh.sub.3).sub.4 (33 mg, 0.028 mmol), under nitrogen, the reaction was carried out at 110 C. in a microwave environment for 2 hours, the reaction was quenched with water, extracted with ethyl acetate (40 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase prep-HPLC to obtain compound 30 (2.8 mg). LCMS ESI(+)m/z: 404.25 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.11 (t, J=3.0 Hz, 2H), 8.70-8.29 (m, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.47-7.38 (m, 1H), 7.34 (d, J=1.7 Hz, 1H), 4.66 (t, J=11.2 Hz, 1H), 3.97 (d, J=11.1 Hz, 1H), 3.60 (d, J=12.5 Hz, 1H), 3.18-2.85 (m, 5H), 2.26 (dd, J=55.7, 13.7 Hz, 2H), 2.13-1.77 (m, 2H).

Embodiment 31

##STR00187##

(R)-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0306] The specific reaction Formula is as follows:

##STR00188##

Step A: ((R)-1-chloro-N-(1-methylpiperidine-3-yl)pyrido[3,4-d]pyridazin-4-amine (compound 31.1)

[0307] 1,4-dichloropyridine [3,4-d]pyridazine (100 mg, 0.5 mmol) was dissolved in 3 mL n-butanol, diisopropylethylamine (387 mg, 3 mmol) and (R)-1-methylpiperidin-3-amine (112 mg, 0.6 mmol) were added, microwave heated to 180 C. and stirred for 2 hours, the reaction solution was directly dried, and then extracted with ethyl acetate, washed with brine, dried with anhydrous sodium sulfate, spun dried, and purified by column to obtain the product 31.1 (44 mg,). LCMS ESI(+)m/z: 278.1 (M+1).

Step B: (R)-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (compound 31)

[0308] Compounds 31.1 (40 mg, 0.144 mmol) and (2-hydroxy-4-(trifluoromethyl)phenyl) boronic acid (36 mg, 0.173 mmol) were added to a mixture of 3 mL of 1,4-dioxane and 0.5 mL of water, followed by cesium carbonate (118 mg, 0.36 mmol) and Pd (PPh.sub.3).sub.4 (33 mg, 0.028 mmol), under nitrogen, the reaction was 110 C. in a microwave environment for 2 hours, the reaction was quenched with water, extracted with ethyl acetate (40 mL2), the organic phase was combined, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reversed-phase prep-HPLC to obtain compound 31 (32 mg). LCMS ESI(+)m/z: 404.25 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.78 (s, 1H), 8.98 (d, J=5.6 Hz, 1H), 7.67-7.51 (m, 2H), 7.41-7.33 (m, 1H), 7.30 (d, J=1.7 Hz, 1H), 4.77-4.62 (m, 1H), 4.00 (d, J=12.1 Hz, 1H), 3.60 (d, J=12.7 Hz, 1H), 2.95 (d, J=18.3 Hz, 4H), 2.35 (d, J=12.6 Hz, 1H), 2.20 (d, J=15.2 Hz, 1H), 1.93 (dq, J=51.4, 13.4, 12.7 Hz, 2H).

Embodiment 32

##STR00189##

(R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-3-yl)phenol

[0309] The specific reaction Formula is as follows:

##STR00190##

Step A: 2-(4-chloro-2-methoxybenzoylamido)ethyl acetate) (compound 32.1)

[0310] 4-chloro-2-methoxybenzoic acid (10 g, 53.6 mmol) was dissolved in 200 mL of DMF solution, DIPEA (17.3 g, 134 mmol), HATU (30.5 g, 80 mmol), ethyl glycinate hydrochloride (9 g, 64.3 mmol) were added, and stirred for two hours at room temperature. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted in three times with 200 mL ethyl acetate, combined the organic phases, and dried with anhydrous sodium sulfate. Compound 32.1 (14 g, yield: 96%) was obtained by spinning and purification. LCMS ESI(+)m/z: 272.1(M+1).

Step B: Ethyl acetate (compound 32.2) of 2-(4-chloro-2-methoxyphenylthioamino)acetate

[0311] Compound 32.1 (14 g, 51.47 mmol) was dissolved in 150 mL of toluene solution, Lawson's reagent (10.4 g, 25.73 mmol) was added, and stirred at 100 C. for two hours. The reaction solution was cooled to 0 C., and the solids were collected by filtration, and a compound of 32.2 (10 g, yield: 67.5%) was obtained. LCMS ESI(+)m/z: 288(M+1).

Step C: 3-(4-chloro-2-methoxyphenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (compound 32.3)

[0312] Compound 32.2 (9.6 g, 33.45 mmol) was dissolved in 100 mL of n-butanol solution, hydrazine hydrate (99%) (8.4 g, 167 mmol) was added, and stirred overnight at 120 C. The solvent was spun dry and the compound was purified to obtain 32.3 (4 g, yield: 50%). LCMS ESI(+)m/z: 240.1(M+1).

Step D: 6-chloro-3-(4-chloro-2-methoxyphenyl)-4,5-dihydro-1,2,4-triazine (compound 32.4)

[0313] Compound 32.3 (1 g, 4.18 mmol) was added to 20 mL of phosphorus oxychloride solution, stirred at 100 C. for two hours, the solvent was spun dry, and the crude product was spun dried again with toluene solution, and the operation was repeated twice to obtain crude compound 32.4 (1 g, yield: 93%). LCMS ESI(+)m/z: 258(M+1).

Step E: 6-chloro-3-(4-chloro-2-methoxyphenyl)-1,2,4-triazine (compound 32.5)

[0314] Compound 32.4 (1 g, 3.88 mmol) was dissolved in 20 mL DMF solution, manganese dioxide (3.37 g, 38.8 mmol) was added in batches with an ice water bath cooling, and the reaction solution was stirred overnight at 50 C. Diatomaceous earth filtered the reaction solution, spun dry the solvent, and purified to obtain a compound of 32.5 (290 mg, yield: 29%). LCMS ESI(+)m/z: 256(M+1).

Step F: (R)-3-(4-chloro-2-methoxyphenyl)-N-(1-methylpiperidin-3-yl)-1,2,4-triazin-6-amine (compound 32.6)

[0315] Compound 32.5 (100 mg, 0.4 mmol) was dissolved in 5 mL of n-butanol solution, (R)-1-methylpiperidin-3-amine (63 mg, 0.55 mmol) and DIPAE (153 mg, 1.18 mmol) were added, and stirred at 150 C. in the microwave for 3 hours. The solvent was spun dry and the compound was purified to obtain 32.6 (50 mg, yield: 38%). LCMS ESI(+)m/z: 334.1(M+1).

Step G: (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-3-yl)phenol (compound 32)

[0316] Dissolve compound 32.6 (50 mg, 0.15 mmol) in 5 mL of dichloromethane solution, add 0.2 mL of boron tribromide solution dropwise with an ice-water bath cooling, and stir at 0 C. for 1 hour. 10 mL of aqueous solution was added to quench the reaction, and 10 mL of saturated sodium bicarbonate aqueous solution was added, and 20 mL of dichloromethane was used for extraction in three times, combined the organic phases, and dried with anhydrous sodium sulfate. Compound 32 (10 mg, yield: 21%) was obtained by spinning and purification. LCMS ESI(+)m/z: 320.1(M+1). .sup.1H NMR (400 MHz, DMSO) 13.00 (s, 1H), 8.46 (s, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 7.02 (dd, J=8.5, 2.1 Hz, 1H), 4.08-4.02 (m, 1H), 2.80 (d, J=9.4 Hz, 1H), 2.22 (s, 3H), 2.14 (dd, J=29.8, 2.5 Hz, 2H), 1.84-1.71 (m, 2H), 1.55 (dd, J=9.2, 3.8 Hz, 1H), 1.41 (d, J=8.8 Hz, 1H), 1.23 (s, 1H).

[0317] Referring to embodiment 7, embodiment 8 and embodiment 10, (2-methoxy-4-(trifluoromethyl)phenyl) boronic acid and (2-methoxy-4-chlorophenyl) boronic acid and intermediate 1.3 are used as raw materials, (R)-1-methylpiperidin-3-amine hydrochloride is replaced with (1R,2R)-2-aminocyclohexyl-1-ol, (cis)-3-amino-methylcyclobutyl-1-ol, (1R,3R)-3-aminocyclohexanol, and the intermediates 3.2, 4.2, 22.2, 23.2 after a five-step chemical reactions, respectively, to obtain the following embodiments 33-48.

Embodiment 33

##STR00191##

2-(3-((((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0318] LCMS ESI(+)m/z: 369.2 (M+1). .sup.1H NMR (400 MHz, Methanol-d4) 7.46 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 3.95-3.80 (m, 1H), 3.60-3.48 (m, 1H), 2.29 (s, 3H), 2.13-2.04 (m, 2H), 1.85-1.67 (m, 2H), 1.57-1.19 (m, 4H).

Embodiment 34

##STR00192##

5-Chloro-2-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)phenol

[0319] LCMS ESI(+)m/z: 335.1 (M+1).

Embodiment 35

##STR00193##

5-Chloro-2-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-1,2,4-triazin-6-yl)-3-methylphenol

[0320] LCMS ESI(+)m/z: 335.1 (M+1).

Embodiment 36

##STR00194##

2-(3-(((1R,3R)-3-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0321] LCMS ESI(+)m/z: 369.2 (M+1). .sup.1H NMR (400 MHz, Methanol-d4) 7.52 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.23 (s, 1H), 4.23-4.20 (m, 1H), 4.05-4.01 (m, 1H), 2.52 (s, 3H), 2.16-1.99 (m, 2H), 1.90 (q, J=12.5 Hz, 1H), 1.79-1.64 (m, 3H), 1.63-1.45 (m, 2H).

Embodiment 37

##STR00195##

2-(3-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0322] LCMS ESI(+)m/z: 355.1 (M+1). .sup.1H NMR (400 MHz, Methanol-d4) 7.51 (d, J=7.8 Hz, 1H), 7.34-7.27 (m, 1H), 7.24 (s, 1H), 4.10 (d, J=163.7 Hz, 1H), 2.66-2.62 (m, 2H), 2.53 (s, 3H), 2.28 (td, J=8.7, 2.4 Hz, 2H), 1.42 (s, 3H).

Embodiment 38

##STR00196##

2-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-1,2,4-triazin-6-yl)-3-methyl-5-(trifluoromethyl)phenol

[0323] LCMS ESI(+)m/z: 369.2 (M+1).

Embodiment 39

##STR00197##

2-(3-(1R,3R)-3-hydroxycyclohexyl)amino)-1,2,4-triazin-6-yl)-3-methyl-5-(trifluoromethyl)phenol

[0324] LCMS ESI(+)m/z: 369.2 (M+1). .sup.1H NMR (400 MHz, Methanol-d4) 7.09 (s, 1H), 6.98 (s, 1H), 5.35 (d, J=2.8 Hz, 1H), 4.15 (s, 1H), 3.89 (td, J=10.5, 4.1 Hz, 1H), 2.45-2.32 (m, 3H), 2.01 (d, J=13.9 Hz, 2H), 1.87 (q, J=11.8 Hz, 1H), 1.77-1.61 (m, 3H), 1.61-1.42 (m, 2H).

Embodiment 40

##STR00198##

2-(3-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-1,2,4-triazin-6-yl)-3-methyl-5-(trifluoromethyl)phenol

[0325] LCMS ESI(+)m/z: 355.1 (M+1). .sup.1H NMR (400 MHz, DMSO) 10.46 (s, 1H), 8.41 (d, J=18.9 Hz, 2H), 7.15 (d, J=1.8 Hz, 1H), 7.12 (d, J=1.8 Hz, 1H), 3.97 (s, 1H), 2.46-2.31 (m, 3H), 2.19 (s, 3H), 2.11 (td, J=8.8, 2.7 Hz, 2H), 1.28 (s, 3H).

Embodiment 41

##STR00199##

(R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl) acetic acid

[0326] LCMS ESI(+)m/z: 412.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 7.51 (d, J=7.8 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.23 (s, 1H), 4.58-4.48 (m, 1H), 4.18 (s, 2H), 3.96 (dd, J=9.9, 4.1 Hz, 1H), 3.69 (dd, J=17.8, 8.0 Hz, 1H), 3.22-2.97 (m, 2H), 2.48 (s, 3H), 2.22 (dd, J=10.0, 4.8 Hz, 2H), 2.04 (dd, J=7.7, 3.8 Hz, 2H).

Embodiment 42

##STR00200##

(R)-2-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl) acetamide

[0327] LCMS ESI(+)m/z: 411.2 (M+1). .sup.1H NMR (400 MHz, Methanol-d4) 7.54 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.25 (s, 1H), 4.68-4.63 (m, 1H), 4.08 (s, 2H), 3.94-3.90 (m, 1H), 3.68-3.63 (m, 1H), 3.17-3.12 (m, 2H), 2.59 (s, 3H), 2.34-1.75 (m, 4H).

Embodiment 43

##STR00201##

2-(3-(((3R)-1-(1-hydroxypropyl-2-yl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0328] LCMS ESI(+)m/z: 412.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 7.52 (d, J=7.9 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.24 (s, 1H), 4.59 (s, 1H), 3.92 (dd, J=12.6, 3.8 Hz, 1H), 3.87-3.69 (m, 2H), 3.65-3.48 (m, 2H), 3.25-2.99 (m, 2H), 2.67-2.41 (m, 3H), 2.27-2.01 (m, 3H), 1.82-1.74 (m, 1H), 1.39 (d, J=6.8 Hz, 3H).

Embodiment 44

##STR00202##

(R)-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0329] LCMS ESI(+)m/z: 398.2 (M+1).

Embodiment 45

##STR00203##

(R)-2-(3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl) acetic acid

[0330] LCMS ESI(+)m/z: 412.2 (M+1).

Embodiment 46

##STR00204##

(R)-2-(3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-1,2,4-triazin-3-yl)amino)piperidin-1-yl) acetamide

[0331] LCMS ESI(+)m/z: 411.2 (M+1).

Embodiment 47

##STR00205##

2-(3-(((3R)-1-(1-hydroxypropyl-2-yl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-methyl-5-(trifluoromethyl)phenol

[0332] LCMS ESI(+)m/z: 412.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 7.11 (d, J=13.5 Hz, 1H), 7.06-6.95 (m, 1H), 5.42 (dd, J=9.0, 1.2 Hz, 1H), 4.20 (d, J=18.7 Hz, 1H), 3.95 (dd, J=13.3, 4.3 Hz, 1H), 3.85-3.68 (m, 2H), 3.62-3.49 (m, 2H), 3.18 (dt, J=15.0, 7.3 Hz, 2H), 2.39 (s, 3H), 2.27 (d, J=10.3 Hz, 1H), 2.10 (d, J=16.6 Hz, 2H), 1.69 (dt, J=17.4, 12.2 Hz, 1H), 1.45-1.37 (m, 3H).

Embodiment 48

##STR00206##

(R)-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-triazin-6-yl)-3-methyl-5-(trifluoromethyl)phenol

[0333] LCMS ESI(+)m/z: 398.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 7.19-7.06 (m, 1H), 6.99 (d, J=1.7 Hz, 1H), 5.42 (d, J=8.9 Hz, 1H), 4.20 (d, J=13.2 Hz, 1H), 4.05-3.82 (m, 3H), 3.68 (d, J=12.7 Hz, 1H), 3.46-3.33 (m, 2H), 3.08 (td, J=12.1, 11.7, 3.3 Hz, 2H), 2.39 (s, 3H), 2.32-2.19 (m, 1H), 2.17-2.05 (m, 2H), 1.71 (d, J=12.7 Hz, 1H).

[0334] Referring to embodiment 9, 3-chloro-5-(trifluoromethyl)picolinonitrile, 3-chloro-5-(trifluoromethyl)picolinonitrile were used as raw materials, and (R)-1-methylpiperidin-3-amine hydrochloride was replaced with (1R,2R)-2-aminocyclohexyl-1-ol, (cis)-3-amino-methylcyclobutyl-1-ol, (1R,3R)-3-Aminocyclohexanol, and the intermediates 3.2, 4.2, 22.2 and 23.2, after six-step chemical reactions, the compounds of the following embodiment 4963 are synthesized respectively.

Embodiment 49

##STR00207##

2-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)pyridin-3-ol

[0335] LCMS ESI(+)m/z: 369.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 8.53 (d, J=0.9 Hz, 1H), 7.68 (d, J=1.4 Hz, 1H), 7.44 (s, 1H), 3.65 (td, J=10.6, 4.1 Hz, 1H), 3.52 (td, J=9.9, 4.4 Hz, 1H), 2.28 (d, J=0.6 Hz, 3H), 2.08 (dd, J=7.4, 5.1 Hz, 2H), 1.81 (d, J=8.8 Hz, 2H), 1.46 (ddd, J=23.6, 12.6, 6.7 Hz, 4H).

Embodiment 50

##STR00208##

2-(6-(1R,3R)-3-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)pyridin-3-ol

[0336] LCMS ESI(+)m/z: 369.2 (M+1).

Embodiment 51

##STR00209##

2-(6-(cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)pyridin-3-ol

[0337] LCMS ESI(+)m/z: 355.1(M+1). .sup.1H NMR (400 MHz, MeOD) 8.53 (d, J=0.9 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.44 (s, 1H), 3.92 (p, J=7.7 Hz, 1H), 2.76-2.62 (m, 2H), 2.29 (s, 3H), 2.23 (dd, J=14.7, 5.5 Hz, 2H), 1.42 (s, 3H).

Embodiment 52

##STR00210##

(R)-2-(3-((6-(3-hydroxy-5-(trifluoromethyl)pyridin-2-yl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidine-1-yl)acetic acid

[0338] LCMS ESI(+)m/z: 413.2 (M+1).

Embodiment 53

##STR00211##

(R)-2-(3-((6-(3-hydroxy-5-(trifluoromethyl)pyridin-2-yl)-5-methyl-1,2,4-triazin-3-yl)amino)piperidin-1-yl)acetamide

[0339] LCMS ESI(+)m/z: 412.2 (M+1).

Embodiment 54

##STR00212##

2-(3-(((3R)-1-(1-hydroxypropyl-2-yl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)pyridin-3-ol

[0340] LCMS ESI(+)m/z: 413.2 (M+1).

Embodiment 55

##STR00213##

(R)-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)pyridin-3-ol

[0341] LCMS ESI(+)m/z: 399.2 (M+1).

Embodiment 56

##STR00214##

5-Chloro-2-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)pyridin-3-ol

[0342] LCMS ESI(+)m/z: 335.1 (M+1).

Embodiment 57

##STR00215##

5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)pyridin-3-ol

[0343] LCMS ESI(+)m/z: 321.1 (M+1).

Embodiment 58

##STR00216##

2-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methylpyridazin-3-yl)-5-methylpyridin-3-ol

[0344] LCMS ESI(+)m/z: 315.2 (M+1).

Embodiment 59

##STR00217##

2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-methylpyridin-3-ol

[0345] LCMS ESI(+)m/z: 301.2 (M+1).

Embodiment 60

##STR00218##

(R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)pyridin-3-ol

[0346] LCMS ESI(+)m/z: 369.2 (M+1).

Embodiment 61

##STR00219##

2-(3-(((1R,2R)-2-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)pyridin-3-ol

[0347] LCMS ESI(+)m/z: 370.1 (M+1).

Embodiment 62

##STR00220##

2-(3-(((1R,3R)-3-hydroxycyclohexyl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)pyridin-3-ol

[0348] LCMS ESI(+)m/z: 370.1 (M+1).

Embodiment 63

##STR00221##

2-(3-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)pyridin-3-ol

[0349] LCMS ESI(+)m/z: 356.1 (M+1).

[0350] Referring to embodiment 14, with 1,4-dichlorophthalazine and its analogues as raw materials, (R)-1-methylpiperidin-3-amine hydrochloride is replaced with (1R,2R)-2-aminocyclohexyl-1-ol, (cis)-3-aminocyclobutyl-1-ol, (1R,3R)-3-aminocyclohexanol, and intermediates 3.2, 4.2, 22.2, 23.2 respectively, and the following embodiments 64-101 are synthesized after two step chemical reactions, respectively.

Embodiment 64

##STR00222##

2-(4-((1R,2R)-2-hydroxycyclohexyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0351] LCMS ESI(+)m/z: 404.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 8.73 (d, J=8.0 Hz, 1H), 8.09 (pd, J=7.3, 1.4 Hz, 2H), 7.78-7.69 (m, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.28 (s, 1H), 4.03-3.84 (m, 1H), 3.75 (td, J=10.3, 4.5 Hz, 1H), 2.15 (dd, J=9.7, 4.8 Hz, 2H), 1.86 (d, J=9.6 Hz, 2H), 1.68 (dt, J=12.6, 7.9 Hz, 1H), 1.62-1.37 (m, 3H).

Embodiment 65

##STR00223##

2-(4-((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0352] LCMS ESI(+)m/z: 390.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 8.85-8.58 (m, 1H), 8.24-7.87 (m, 2H), 7.81-7.67 (m, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.29 (s, 1H), 4.14 (p, J=7.8 Hz, 1H), 2.82-2.70 (m, 2H), 2.44 (t, J=10.1 Hz, 2H), 1.48 (s, 3H).

Embodiment 66

##STR00224##

(R)-2-(8-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridino[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol

[0353] LCMS ESI(+)m/z: 434.2 (M+1).

Embodiment 67

##STR00225##

(R)-2-(3-((5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)amino)piperidin-1-yl)acetic acid

[0354] LCMS ESI(+)m/z: 448.2 (M+1).

Embodiment 68

##STR00226##

(R)-2-(3-((5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridino[2,3-d]pyridazin-8-yl)amino)piperidin-1-yl)acetamide

[0355] LCMS ESI(+)m/z: 447.2 (M+1).

Embodiment 69

##STR00227##

2-(8-(((3R)-1-(1-hydroxypropyl-2-yl)piperidin-3-yl)amino)pyridino[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol

[0356] LCMS ESI(+)m/z: 448.2 (M+1).

Embodiment 70

##STR00228##

2-(8-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol

[0357] LCMS ESI(+)m/z: 405.2 (M+1). .sup.1H NMR (400 MHz, CD3OD) 9.25 (d, J=4.2 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.05 (dd, J=8.2, 4.3 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.31 (s, 1H), 4.03-3.89 (m, 1H), 3.78 (td, J=10.0, 4.3 Hz, 1H), 2.14 (d, J=12.8 Hz, 2H), 1.93-1.72 (m, 3H), 1.49 (m, 3H).

Embodiment 71

##STR00229##

2-(5-(1R,2R)-2-hydroxycyclohexyl)amino)pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol

[0358] LCMS ESI(+)m/z: 405.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.23 (dd, J=4.4, 1.2 Hz, 1H), 9.16 (dd, J=8.5, 1.2 Hz, 1H), 8.04 (dd, J=8.5, 4.5 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.28 (d, J=7.9 Hz, 1H), 7.22 (s, 1H), 3.97 (td, J=11.8, 4.0 Hz, 1H), 3.76 (td, J=10.4, 4.5 Hz, 1H), 2.24-2.06 (m, 2H), 1.96-1.82 (m, 2H), 1.70 (ddd, J=24.9, 12.7, 3.1 Hz, 1H), 1.60-1.40 (m, 3H).

Embodiment 72

##STR00230##

2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0359] LCMS ESI(+)m/z: 405.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 10.11 (s, 1H), 9.14 (d, J=5.5 Hz, 1H), 7.65 (d, J=5.5 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 4.05-3.94 (m, 1H), 3.79 (td, J=10.5, 4.5 Hz, 1H), 2.22-2.11 (m, 2H), 1.87 (d, J=2.7 Hz, 2H), 1.81-1.66 (m, 1H), 1.63-1.37 (m, 3H).

Embodiment 73

##STR00231##

2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[0360] LCMS ESI(+)m/z: 405.2 (M+1).

Embodiment 74

##STR00232##

5-Chloro-2-(8-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol

[0361] LCMS ESI(+)m/z: 371.1 (M+1).

Embodiment 75

##STR00233##

2-(8-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol

[0362] LCMS ESI(+)m/z: 391.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.25 (dd, J=4.4, 1.6 Hz, 1H), 8.16 (dd, J=8.3, 1.6 Hz, 1H), 8.04 (dd, J=8.4, 4.5 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.36 (dd, J=7.9, 0.9 Hz, 1H), 7.30 (s, 1H), 4.17 (p, J=7.9 Hz, 1H), 2.79-2.72 (m, 2H), 2.47 (td, J=8.7, 2.5 Hz, 2H), 1.48 (s, 3H).

Embodiment 76

##STR00234##

2-(5-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol

[0363] LCMS ESI(+)m/z: 391.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 9.23 (dd, J=4.5, 1.5 Hz, 1H), 9.11 (dd, J=8.5, 1.5 Hz, 1H), 8.04 (dd, J=8.5, 4.5 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.28 (dd, J=8.0, 0.9 Hz, 1H), 7.22 (s, 1H), 4.15 (p, J=8.0 Hz, 1H), 2.84-2.72 (m, 2H), 2.45 (td, J=8.8, 2.5 Hz, 2H), 1.48 (s, 3H).

Embodiment 77

##STR00235##

2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0364] LCMS ESI(+)m/z: 391.1 (M+1).

Embodiment 78

##STR00236##

2-(1-((((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[0365] LCMS ESI(+)m/z: 391.1 (M+1). .sup.1H NMR (400 MHz, MeOD) 10.05 (s, 1H), 9.13 (d, J=5.5 Hz, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 4.16 (t, J=7.7 Hz, 1H), 2.82-2.75 (m, 2H), 2.50 (dd, J=11.4, 8.7 Hz, 2H), 1.48 (s, 3H).

Embodiment 79

##STR00237##

2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)pyridin-3-ol

[0366] LCMS ESI(+)m/z: 405.2 (M+1).

Embodiment 80

##STR00238##

2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)pyridin-3-ol

[0367] LCMS ESI(+)m/z: 391.1 (M+1).

Embodiment 81

##STR00239##

2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0368] LCMS ESI(+)m/z: 394.2 (M+1). .sup.1H NMR (400 MHz, MeOD) 7.52 (d, J=7.9 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 3.78 (td, J=11.3, 4.2 Hz, 1H), 3.60 (td, J=10.0, 4.4 Hz, 1H), 3.13-2.94 (m, 4H), 2.27 (p, J=7.7 Hz, 2H), 2.15-1.95 (m, 2H), 1.89-1.76 (m, 2H), 1.62-1.21 (m, 4H).

Embodiment 82

##STR00240##

2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0369] LCMS ESI(+)m/z: 380.2 (M+1). .sup.1H NMR (400 MHz, Methanol-d4) 7.54 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 3.99 (p, J=8.0 Hz, 1H), 3.05 (q, J=8.2 Hz, 4H), 2.66 (dd, J=12.0, 7.4 Hz, 2H), 2.28 (t, J=7.7 Hz, 4H), 1.43 (s, 3H).

Embodiment 83

##STR00241##

(R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0370] LCMS ESI(+)m/z: 423.2 (M+1).

Embodiment 84

##STR00242##

(R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)amino)piperidin-1-yl)acetic acid

[0371] LCMS ESI(+)m/z: 437.2 (M+1).

Embodiment 85

##STR00243##

(R)-2-(3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)amino)piperidin-1-yl)acetamide

[0372] LCMS ESI(+)m/z: 436.2 (M+1).

Embodiment 86

##STR00244##

2-(4-(((3R)-1-(1-hydroxypropyl-2-yl)piperidin-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0373] LCMS ESI(+)m/z: 437.2 (M+1).

Embodiment 87

##STR00245##

2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)pyridin-3-ol

[0374] LCMS ESI(+)m/z: 395.2 (M+1).

Embodiment 88

##STR00246##

2-(4-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)pyridin-3-ol

[0375] LCMS ESI(+)m/z: 381.2 (M+1).

Embodiment 89

##STR00247##

2-(7-(1R,2R)-2-hydroxycyclohexyl)amino)-2,3-dihydrofuro[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)pyridin-3-ol

[0376] LCMS ESI(+)m/z: 397.1 (M+1).

Embodiment 90

##STR00248##

2-(4-(1R,2R)-2-hydroxycyclohexyl)amino)-5,7-dihydrofuro[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)pyridin-3-ol

[0377] LCMS ESI(+)m/z: 397.1 (M+1).

Embodiment 91

##STR00249##

2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-2,3-dihydrofuro[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)pyridin-3-ol

[0378] LCMS ESI(+)m/z: 397.1 (M+1).

Embodiment 92

##STR00250##

2-(7-(((1R,2R)-2-hydroxycyclohexyl)amino)furo[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)pyridin-3-ol

[0379] LCMS ESI(+)m/z: 395.1 (M+1).

Embodiment 93

##STR00251##

2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)furo[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)pyridin-3-ol

[0380] LCMS ESI(+)m/z: 395.1 (M+1).

Embodiment 94

##STR00252##

2-(7-(((1R,2R)-2-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-d]pyrazine-4-yl)-5-(trifluoromethyl)pyridin-3-ol

[0381] LCMS ESI(+)m/z: 394.1 (M+1).

Embodiment 95

##STR00253##

2-(7-(((1R,2R)-2-hydroxycyclohexyl)amino)-1-methyl-1H-pyrrolo[2,3-d]pyrazine-4-yl)-5-(trifluoromethyl)pyridin-3-ol

[0382] LCMS ESI(+)m/z: 408.2 (M+1).

Embodiment 96

##STR00254##

2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-1H-pyrrolo[2,3-d]pyrazine-7-yl)-5-(trifluoromethyl)pyridin-3-ol

[0383] LCMS ESI(+)m/z: 394.1 (M+1).

Embodiment 97

##STR00255##

2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-1-methyl-1H-pyrrolo[2,3-d]pyrazine-7-yl)-5-(trifluoromethyl)pyridin-3-ol

[0384] LCMS ESI(+)m/z: 408.2 (M+1).

Embodiment 98

##STR00256##

2-(7-(cis)-3-hydroxy-3-methylcyclobutyl)amino)-2,3-dihydrofuro[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)pyridin-3-ol

[0385] LCMS ESI(+)m/z: 383.1 (M+1).

Embodiment 99

##STR00257##

2-(7-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)furo[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)pyridin-3-ol

[0386] LCMS ESI(+)m/z: 381.1 (M+1).

Embodiment 100

##STR00258##

2-(7-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-1H-pyrrolo[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)pyridin-3-ol

[0387] LCMS ESI(+)m/z: 380.1 (M+1).

Embodiment 101

##STR00259##

2-(7-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-1-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)pyridin-3-ol

[0388] LCMS ESI(+)m/z: 394.1 (M+1).

[0389] Referring to embodiment 32, we obtain the compounds of the following embodiments 102-106.

Embodiment 102

##STR00260##

2-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-1,2,4-triazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0390] LCMS ESI(+)m/z: 369.2 (M+1).

Embodiment 103

##STR00261##

2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)-1,2,4-triazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0391] LCMS ESI(+)m/z: 369.2 (M+1).

Embodiment 104

##STR00262##

2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-1,2,4-triazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0392] LCMS ESI(+)m/z: 355.1 (M+1).

Embodiment 105

##STR00263##

5-Chloro-2-(6-(((1R,2R)-2-hydroxycyclohexyl)amino)-1,2,4-triazin-3-yl)-3-methylphenol

[0393] LCMS ESI(+)m/z: 335.1 (M+1).

Embodiment 106

##STR00264##

5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-1,2,4-triazin-3-yl)-3-methylphenol

[0394] LCMS ESI(+)m/z: 321.1 (M+1).

Embodiment 107-161

TABLE-US-00001 Synthesis methods and Embodiment structure characterization data 107 [00265] The synthesis method refers to embodiment 1 LCMS ESI(+)m/z: 388(M + 1). .sup.1HNMR(400 MHz, MeOD) 8.34 (s, 1H), 7.34 (s, 1H), 7.22 (s, 1H), 5.45 (d, J = 8.9 Hz, 1H), 4.07 (dd, J = 16.1, 6.7 Hz, 1H), 3.64-3.47 (m, 2H), 2.94 (s, 3H), 2.21 (d, J = 7.5 Hz, 2H), 2.03 (d, J = 4.5 Hz, 2H), 1.69 (d, J = 12.4 Hz, 2H). 108 [00266] The synthesis method refers to embodiment 1 LCMS ESI(+)m/z: 314 (M + 1). .sup.1H NMR (400 MHz, DMSO-d6) 10.89 (s, 1H), 8.28 (s, 1H), 7.94-7.64 (m, 1H), 6.67 (s, 1H), 6.62 (s, 1H), 4.39- 4.37 (m, 1H), 3.62 (d, J = 12.6 Hz, 1H), 3.39 (d, J = 9.6 Hz, 1H), 3.09- 2.81 (m, 2H), 2.80 (s, 3H), 2.26 (s, 3H), 2.10 (s, 4H), 1.90 (dd, J = 41.2, 8.6 Hz, 2H), 1.69-1.50 (m, 1H). 109 [00267] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 393(M + 1). .sup.1H NMR (400 MHz, DMSO) 10.46 (s, 1H), 9.45 (s, 1H), 8.90 (s, 1H), 7.79 (s, 1H), 7.41-7.28 (m, 2H), 4.65-4.47 (m, 1H), 3.72 (d, J = 11.3 Hz, 2H), 2.83 (s, 3H), 2.20 (s, 1H), 1.99 (d, J = 7.5 Hz, 2H), 1.87 (d, J = 11.0 Hz, 1H), 1.68 (d, J = 10.7 Hz, 1H), 1.54-1.42 (m, 1H), 1.36-1.28 (m, 1H). 110 [00268] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 395(M + 1). 111 [00269] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 395 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.70 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 6.6 Hz, 1H), 7.33 (s, 1H), 5.14 (t, J = 8.1 Hz, 2H), 4.46 (s, 1H), 3.82 (dd, J = 31.8, 11.8 Hz, 1H), 3.59-3.43 (m, 3H), 3.20-2.88 (m, 5H), 2.22 (d, J = 11.6 Hz, 1H), 2.12 (d, J = 13.9 Hz, 1H), 2.00 (t, J = 13.2 Hz, 1H), 1.73 (dd, J= 23.1, 10.8 Hz, 1H). 112 [00270] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 429 (M + 1). .sup.1H NMR (400 MHz, DMSO-d6) 10.75 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.85-4.69 (m, 1H), 3.58 (d, J = 11.4 Hz, 1H), 3.42 (d, J = 12.0 Hz, 1H), 3.02 (s, 3H), 2.88-2.76 (m, 4H), 2.72-2.56 (m, 2H), 2.03 (d, J = 10.3 Hz, 1H), 1.97- 1.80 (m, 2H), 1.71 (q, J = 16.8, 16.4 Hz, 1H). 113 [00271] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 406.1(M + 1). .sup.1H NMR (400 MHz, MeOD) 7.83- 7.73 (m, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 6.87 (d, J = 3.0 Hz, 1H), 4.60 (dd, J = 15.4, 3.5 Hz, 1H), 4.45 (d, J = 61.5 Hz, 2H), 3.94 (dd, J = 29.3, 12.2 Hz, 1H), 3.58 (d, J = 12.3 Hz, 1H), 3.09 (ddd, J = 29.0, 20.0, 12.8 Hz, 1H), 2.92 (d, J = 34.9 Hz, 2H), 2.31 (t, J = 13.8 Hz, 1H), 2.16 (d, J = 14.8 Hz, 1H), 2.04 (dd, J = 24.4, 14.9 Hz, 1H), 1.96-1.77 (m, 1H). 114 [00272] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 406.1(M + 1). .sup.1H NMR (400 MHz, MeOD) 7.91 (s, 1H), 7.71 (s, 2H), 7.42 (d, J = 6.0 Hz, 2H), 7.34 (s, 1H), 7.22 (s, 1H), 4.57 (d, J = 37.3 Hz, 1H), 3.87 (d, J = 10.2 Hz, 1H), 3.65 (s, 4H), 3.57 (d, J= 12.0 Hz, 1H), 3.19-3.01 (m, 2H), 2.96 (s, 3H), 2.91 (s, 1H), 2.30 (d, J = 9.6 Hz, 1H), 2.16 (d, J = 14.4 Hz, 1H), 2.02 (d, J = 10.7 Hz, 2H), 1.82 (t, J = 12.5 Hz, 1H). 115 [00273] The synthesis method refers to embodiment 1 LCMS ESI(+)m/z: 370.21 (M + 1). .sup.1H NMR (400 MHz, MeOD) 6.65- 6.50 (m, 2H), 5.42 (d, J = 9.1 Hz, 1H), 4.03 (hept, J = 11.7 Hz, 2H), 3.82- 3.63 (m, 1H), 3.53 (d, J = 12.4 Hz, 1H), 2.90-2.65 (m, 4H), 2.27 (d, J = 9.7 Hz, 8H), 2.16-1.88(m, 3H), 1.67 (ddt, J = 21.1, 13.4, 6.2 Hz, 1H). 116 [00274] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 383.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 9.08 (s, 1H), 8.72 (s, 3H), 8.28 (d, J = 7.7 Hz, 4H), 8.13 (t, J = 7.7 Hz, 5H), 7.83 (d, J = 8.0 Hz, 5H), 7.05 (s, 4H), 6.95 (d, J = 1.3 Hz, 4H), 4.73 (d, J = 25.8 Hz, 7H), 3.90 (d, J = 11.5 Hz, 4H), 3.59 (d, J = 11.7 Hz, 5H), 3.51-3.40 (m, 1H), 3.23-2.98 (m, 9H), 2.95 (d, J = 16.6 Hz, 13H), 2.48-2.24 (m, 6H), 2.19 (d, J = 15.1 Hz, 4H), 2.06 (s, 18H), 1.93 (d, J = 4.9 Hz, 5H). 117 [00275] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 433.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 8.68 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.43- 7.27 (m, 2H), 7.09 (s, 1H), 4.64 (d, J = 30.4 Hz, 1H), 3.88 (s, 4H), 3.70- 3.51 (m, 2H), 3.11 (d, J = 35.5 Hz, 2H), 2.95 (s, 3H), 2.30 (d, J = 10.3 Hz, 1H), 2.21-1.82 (m, 3H). 118 [00276] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 433.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 8.48 (s, 1H), 8.13 (s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 4.69 (s, 1H), 4.18 (d, J = 21.1 Hz, 3H), 3.90 (d, J = 6.7 Hz, 1H), 3.53 (d, J = 34.1 Hz, 1H), 3.21-3.04 (m, 2H), 2.95 (d, J = 19.5 Hz, 3H), 2.33 (d, J = 10.0 Hz, 1H), 2.18 (d, J = 12.9 Hz, 1H), 2.00 (dd, J = 26.1, 13.2 Hz, 2H). 119 [00277] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 421.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 8.18- 8.07 (m, 1H), 8.02 (dd, J = 12.5, 7.7 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 4.73 (s, 1H), 4.07- 3.78 (m, 1H), 3.59 (d, J = 11.5 Hz, 1H), 3.25-3.01 (m, 2H), 2.95 (d, J = 21.0 Hz, 3H), 2.53-1.75 (m, 4H). 120 [00278] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 421(M + 1). .sup.1H NMR (400 MHz, MeOD) 8.46 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 9.1, 5.3 Hz, 1H), 7.89 (dd, J = 8.3, 2.2 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 4.69 (d, J = 11.3 Hz, 1H), 3.92 (d, J = 9.2 Hz, 1H), 3.58 ( d, J = 10.3 Hz, 1H), 3.07 (d, J = 10.0 Hz, 2H), 2.97 (s, 3H), 2.33 (d, J = 11.6 Hz, 1H), 2.18 (d, J = 12.6 Hz, 1H), 2.09-1.89 (m, 2H). 121 [00279] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 421(M + 1). .sup.1H NMR (400 MHz,) 8.84 (d, J = 4.4 Hz, 1H), 8.01 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.7, 2.3 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.35 (s, 1H), 4.70 (d, J = 25.3 Hz, 1H), 3.90 (d, J = 9.5 Hz, 1H), 3.59 (d, J = 10.8 Hz, 1H), 3.23-3.03 (m, 2H), 2.98 (s, 3H), 2.34 (d, J = 11.3 Hz, 1H), 2.18 (d, J = 12.7 Hz, 1H), 2.02 (dd, J = 32.2, 17.8 Hz, 2H). 122 [00280] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 421.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 9.05- 8.41 (m, 1H), 8.27 (td, J = 8.2, 5.3 Hz, 1H), 7.86 (dd, J = 11.1, 8.2 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 4.77-4.52 (m, 1H), 3.90 (d, J = 11.9 Hz, 1H), 3.59 (d, J = 12.3 Hz, 1H), 3.53-3.03 (m, 2H), 2.95 (d, J = 18.6 Hz, 3H), 2.42-2.11 (m, 2H), 2.11-1.74 (m, 2H). 123 [00281] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 370.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 9.43- 9.33 (m, 1H), 8.37 (t, J = 9.9 Hz, 1H), 8.18-8.03 (m, 1H), 7.50 (t, J = 8.3 Hz, 1H), 7.21-7.06 (m, 2H), 4.66 (dd, J = 23.0, 11.3 Hz, 1H), 3.89 (dd, J = 30.6, 10.4 Hz, 1H), 3.71-3.43 (m, 1H), 3.26-3.11 (m, 1H), 3.07 (td, J = 12.7, 3.1 Hz, 1H), 2.97 ( d, J = 6.3 Hz, 3H), 2.32 (d, J = 12.3 Hz, 1H), 2.28- 2.13 (m, 1H), 2.06 (dd, J = 27.1, 13.6 Hz, 1H), 1.90 (qd, J = 12.6, 3.9 Hz, 1H). 124 [00282] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 370.1 (M + 1). .sup.1H NMR (400 MHz, DMSO) 11.00 (d, J = 129.0 Hz, 1H), 10.32-9.37 (m, 2H), 9.29 (td, J = 4.2, 1.3 Hz, 1H), 8.36-7.92 (m, 1H), 7.49 (t, J = 9.1 Hz, 1H), 7.12 (s, 1H), 7.05 (dd, J = 8.2, 2.0 Hz, 1H), 4.92-4.46 (m, 1H), 3.76-3.60 (m, 1H), 3.53-3.39 (m, 1H), 3.26 (dd, J = 22.7, 12.8 Hz, 1H), 3.17-2.87 (m, 1H), 2.83 (d, J = 4.5 Hz, 3H), 2.20 (d, J = 11.6 Hz, 1H), 2.13-1.66 (m, 3H). 125 [00283] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 384.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 9.41 (dd, J = 13.6, 4.0 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 8.3, 4.4 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J = 1.7 Hz, 1H), 4.68 (d, J = 25.6 Hz, 1H), 3.86 (d, J = 10.7 Hz, 1H), 3.68-3.42 (m, 1H), 3.22-3.01 (m, 2H), 2.98 (d, J = 2.5 Hz, 3H), 2.33 (d, J = 12.7 Hz, 1H), 2.24-1.99 (m, 5H), 1.98-1.78 (m, 1H). 126 [00284] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 448.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 10.07 (d, J = 3.2 Hz, 1H), 9.17 (d, J = 5.5 Hz, 1H), 7.76 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.45-7.37 (m, 1H), 7.35 (d, J = 1.6 Hz, 1H), 4.76 (d, J = 14.0 Hz, 1H), 4.04-3.86(m, 2H), 3.77 (dt, J = 12.7, 7.1 Hz, 1H), 3.70- 3.52 (m, 2H), 3.37 (dq, J = 11.5, 6.5, 4.7 Hz, 1H), 3.25 (dd, J = 13.8, 10.8 Hz, 1H), 2.39 (d, J = 12.8 Hz, 1H), 2.27-2.05 (m, 2H), 2.02-1.87 (m, 1H), 1.50-1.38 (m, 3H). 127 [00285] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 448.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 9.39- 9.11 (m, 2H), 8.56 (dd, J = 5.8, 3.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.0, 1.7 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 4.80 (s, 1H), 3.94 (dd, J = 12.6, 3.8 Hz, 2H), 3.75 (ddd, J = 12.6, 6.7, 4.2 Hz, 1H), 3.68- 3.50 (m, 2H), 3.30-3.15 (m, 2H), 2.36 (d, J = 12.6 Hz, 1H), 2.25-2.01 (m, 2H), 1.94 (qd, J = 12.4, 4.1 Hz, 1H), 1.49-1.37 (m, 3H). 128 [00286] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 370.1 (M + 1). .sup.1H NMR (400 MHz, DMSO) 9.79 (s, 1H), 8.85 (d, J = 5.6 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.66 (s, 1H), 7.40- 7.24 (m, 2H), 7.11-6.97 (m, 2H), 4.50 (s, 1H), 3.18 (dd, J = 11.1, 3.9 Hz, 1H), 2.82 (d, J = 10.3 Hz,1H), 2.32 (d, J = 1.4 Hz, 3H), 2.20-1.96 (m, 3H), 1.82 (dt, J = 13.2, 3.6 Hz, 1H), 1.75-1.42 (m, 2H). 129 [00287] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 370.1 (M + 1). .sup.1H NMR (400 MHz, DMSO) 10.36 (s, 1H), 8.93 (d, J = 5.7 Hz, 1H), 8.84 (d, J = 0.8 Hz, 1H), 8.30 (dd, J = 5.8, 1.0 Hz, 1H), 8.17 (d, J = 4.1 Hz, 1H), 7.41 (dd, J = 13.2, 8.1 Hz, 2H), 7.05 (dq, J = 3.7, 2.1 Hz, 2H), 4.43(d, J = 9.6 Hz, 1H), 3.14 (d, J = 10.5 Hz, 2H), 2.79 (d, J = 11.0 Hz, 1H), 2.29 (d, J = 3.4 Hz, 3H), 2.12-1.96 (m, 3H), 1.80 (d, J = 13.1 Hz, 1H), 1.63 (d, J = 12.5 Hz, 1H), 1.57-1.41 (m, 1H). 130 [00288] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 437.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 8.43 (s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.46- 7.36 (m, 2H), 7.32 (s, 1H), 4.75-4.71 (m, 1H), 4.00-3.83 (m, 2H), 3.82- 3.72 (m, 1H), 3.64-3.57 (m, 2H), 3.24-3.10 (m, 2H), 2.31 (d, J = 11.3 Hz, 1H), 2.21-2.02 (m, 2H), 1.96- 1.77 (m, 1H), 1.41 (d, J = 6.7 Hz, 3H). 131 [00289] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 437.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 8 8.47 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 4.71-4.60 (m, 1H), 4.02-3.84 (m, 2H), 3.81-3.72 (m, 1H), 3.64-3.53 (m, 2H), 3.26-3.15 (m, 2H), 2.34 (d, J = 11.1 Hz, 1H), 2.22-2.05 (m, 2H), 1.86 (qd, J = 12.4, 4.3 Hz, 1H), 1.43 (dd, J = 13.9, 6.3 Hz, 3H). 132 [00290] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 426.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.56 (d, J = 7.1 Hz, 1H), 7.36-7.23 (m, 2H), 4.78 (s, 1H), 3.89 (s, 1H), 3.77-3.63 (m, 3H), 3.10 (dd, J = 20.6, 9.9 Hz, 2H), 2.59 (s, 3H), 2.28-2.03 (m, 3H), 1.85 (s, 1H), 1.44 (s, 6H). 133 [00291] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 426.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.52 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H), 4.61 (s, 1H), 4.05 (d, J = 8.2 Hz, 1H), 3.81-3.71 (m, 1H), 3.45-3.34 (m, 1H), 3.25-3.20 (m, 2H), 3.11-2.98 (m, 1H), 2.51 (s, 3H), 2.26-2.07 (m, 3H), 1.93-1.69 (m, 1H), 1.38-1.36 (m, 6H). 134 [00292] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 424.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.51 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H), 4.58 (s, 1H), 4.02 (d, J = 8.9 Hz, 1H), 3.79 (d, J = 12.2 Hz, 1H), 3.34 (d, J = 4.1 Hz, 2H), 3.05 (ddd, J = 28.2, 18.6, 7.3 Hz, 2H), 2.47 (s, 3H), 2.26 (d, J = 12.4 Hz, 1H), 2.15 (d, J = 14.6 Hz, 1H), 2.06-1.99 (m, 1H), 1.76 (d, J = 9.9 Hz, 1H), 0.95- 0.90 (m, 2H), 0.83-0.74 (m, 2H). 135 [00293] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 422.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 8.09 (td, J = 8.2, 5.2 Hz, 1H), 7.89 (ddd, J = 12.9, 8.2, 0.7 Hz, 1H), 7.61-7.55 (m, 2H), 7.35 (dd, J = 7.9, 0.9 Hz, 1H), 7.28 (s, 1H), 3.95 (t, J = 10.1 Hz, 1H), 3.78 (td, J = 10.0, 4.5 Hz, 1H), 2.26-2.06 (m, 2H), 1.92-1.81 (m, 2H), 1.67 (qd, J = 12.5, 3.1 Hz, 1H), 1.61-1.33 (m, 3H) 136 [00294] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 422.2(M + 1). .sup.1H NMR (400 MHz, MeOD) 8.56 (dd, J = 9.5, 2.1 Hz, 1H), 7.86 (qd, J = 9.0, 3.9 Hz, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 3.97 (td, J = 11.6, 4.2 Hz, 1H), 3.74 (td, J = 10.3, 4.5 Hz, 1H), 2.19-2.10 (m, 2H), 1.86 (d, J = 9.5 Hz, 2H), 1.66 (dt, J = 12.6, 7.7 Hz, 1H), 1.54 (d, J = 11.3 Hz, 1H), 1.50-1.39 (m, 2H). 137 [00295] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 422.2(M + 1). .sup.1H NMR (400 MHz, MeOD) 8.86 (dd, J = 9.2, 4.8 Hz, 1H), 7.92 (ddd, J = 9.1, 8.1, 2.6 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.38-7.33 (m, 2H), 7.29 (s, 1H), 3.94 (ddd, J = 11.6, 9.5, 4.2 Hz, 1H), 3.80-3.72 (m, 1H), 2.18-2.09 (m, 2H), 1.90-1.81 (m, 2H), 1.70 (qd, J = 12.6, 3.3 Hz, 1H), 1.59-1.51 (m, 1H), 1.44 (dd, J = 16.9, 7.0 Hz, 2H). 138 [00296] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 408.1(M + 1). .sup.1H NMR (400 MHz, MeOD) 8.87 (dd, J = 9.1, 4.7 Hz, 1H), 7.96-7.89 (m, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 9.1, 2.4 Hz, 1H), 7.36 (d, J = 9.1 Hz, 1H), 7.31 (s, 1H), 4.13 (p, J = 7.7 Hz, 1H), 2.84-2.73 (m, 2H), 2.46 (t, J = 9.8 Hz, 2H), 1.48 (s, 3H). 139 [00297] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 408.1(M + 1). .sup.1H NMR (400 MHz, MeOD) 8.57- 8.52 (m, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 4.13 (p, J = 8.0 Hz, 1H), 2.76 (ddd, J = 7.4, 6.3, 2.8 Hz, 2H), 2.42 (td, J = 8.8, 2.5 Hz, 2H), 1.47 (s, 3H). 140 [00298] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 423.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 9.25 (dd, J = 4.4, 1.7 Hz, 1H), 8.08 (dd, J = 8.3, 1.1 Hz, 1H), 8.03 (dd, J = 8.3, 4.4 Hz, 1H), 7.17 (d, J = 9.1 Hz, 1H), 7.14 (s, 1H), 3.96 (ddd, J = 11.6, 9.5, 4.2 Hz, 1H), 3.76 (td, J = 9.9, 4.4 Hz, 1H), 2.26-2.08 (m, 2H), 1.85 (dd, J = 6.9, 2.1 Hz, 2H), 1.72 (ddd, J = 24.7, 12.5, 3.2 Hz, 1H), 1.60-1.37 (m, 3H). 141 [00299] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 394.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.53 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 4.74-4.44 (m, 1H), 3.90 (d, J = 9.3 Hz, 1H), 3.69 (d, J = 12.1 Hz, 1H), 3.24-3.14 (m, 1H), 2.93 (d, J = 4.5 Hz, 1H), 2.52 (s, 3H), 2.26-1.97 (m, 4H), 1.91-1.70 (m, 1H), 1.16 (s, 2H), 0.99 (d, J = 3.8 Hz, 2H). 142 [00300] The synthesis refers to Example 8 LCMS ESI(+)m/z: 408(M + 1). .sup.1H NMR (400 MHz, MeOD) 7.49 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H), 4.38 (s, 1H), 3.81- 3.65 (m, 2H), 3.51 (d, J = 11.5 Hz, 1H), 2.78 (t, J = 11.4 Hz, 1H), 2.67 (t, J = 11.6 Hz, 1H), 2.41 (s, 1H), 2.40 (d, J = 5.6 Hz, 3H), 2.36-2.32 (m, 2H), 2.28 (s, 1H), 2.24 (d, J = 10.6 Hz, 1H), 2.13 (s, 1H), 2.00 (dd, J = 28.4, 11.0 Hz, 1H), 1.88 (dd, J = 18.2, 10.5 Hz, 2H), 1.73 (dd, J = 12.6, 3.1 Hz, 1H). 143 [00301] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 382(M + 1). .sup.1H NMR (400 MHz, MeOD) 7.55 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H), 4.66 (d, J = 11.1 Hz, 1H), 4.01-3.67 (m, 2H), 3.63 (d, J = 11.5 Hz, 1H), 2.99 (t, J = 10.9 Hz, 2H), 2.60 (s, 3H), 2.27 (d, J = 8.7 Hz, 1H), 2.16 ( d, J = 14.0 Hz, 1H), 2.05 (dd, J = 23.0, 9.3 Hz, 2H), 1.83 (s, 1H), 1.41 (t, J = 7.2 Hz, 3H). 144 [00302] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 396(M + 1). .sup.1H NMR (400 MHz, MeOD) 7.53 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.24 (s, 1H), 4.67 (s, 1H), 3.72 (d, J = 9.6 Hz, 1H), 3.62 (dd, J = 12.8, 6.3 Hz, 1H), 3.51 (d, J = 12.2 Hz, 1H), 3.05 (dd, J = 28.0, 12.5 Hz, 2H), 2.55 (s, 3H), 2.26 (d, J = 10.8 Hz, 1H), 2.17 (d, J = 14.6 Hz, 1H), 2.04 (d, J = 9.1 Hz, 1H), 1.81 (s, 1H), 1.41 (t, J = 8.9 Hz, 6H). 145 [00303] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 432.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.51 (d, J = 7.9 Hz, 1H), 7.30 (dd, J = 7.9, 0.9 Hz, 1H), 7.23 (s, 1H), 4.24 (s, 1H), 3.76 (d, J = 10.3 Hz, 1H), 3.48 (s, 1H), 3.05 (d, J = 6.8 Hz, 2H), 2.89 (s, 3H), 2.52 (s, 3H), 2.14-1.93 (m, 2H), 1.83- 1.69 (m, 2H). 146 [00304] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 408.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.53 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 4.63 (s, 1H), 3.89 (dd, J = 30.0, 11.6 Hz, 1H), 3.69 (dd, J = 26.1, 12.6 Hz, 1H), 3.22-3.11 (m, 2H), 3.08-2.93 (m, 2H), 2.54 (s, 3H), 2.31-2.00 (m, 3H), 1.94-1.63 (m, 1H), 1.27-1.12 (m, 1H), 0.93-0.67 (m, 2H), 0.49 (q, J = 4.9 Hz, 2H). 147 [00305] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 412.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.54 (d, J = 7.9 Hz, 1H), 7.37-7.28 (m, 1H), 7.25 (s, 1H), 4.63 (s, 1H), 4.37-4.18 (m, 1H), 3.92 (d, J = 9.0 Hz, 1H), 3.72 (d, J = 11.5 Hz, 1H), 3.58-3.39 (m, 1H), 3.24 (dd, J = 13.1, 2.7 Hz, 1H), 3.05 (ddd, J = 24.4, 12.8, 6.9 Hz, 2H), 2.56 (d, J = 5.0 Hz, 3H), 2.25 (d, J = 10.8 Hz, 1H), 2.16 (d, J = 14.9 Hz, 1H), 2.07-1.89 (m, 1H), 1.81 (s, 1H), 1.25 (t, J = 7.3 Hz, 3H). 148 [00306] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 412.1 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.55 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.25 (s, 1H), 4.68 (s, 1H), 4.25 (s, 1H), 3.92 (d, J = 9.2 Hz, 1H), 3.69 (dt, J = 40.5, 17.3 Hz, 1H), 3.25 (d, J = 12.7 Hz, 1H), 3.18-2.96 (m, 3H), 2.59 (s, 3H), 2.25 (d, J = 10.1 Hz, 1H), 2.08 (d, J = 19.1 Hz, 2H), 1.83 (s, 1H), 1.25 (t, J = 6.5 Hz, 3H). 149 [00307] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 368 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.55 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 4.65 (s, 1H), 4.31- 4.24 (m, 1H) , 3.92 (d, J = 9.9 Hz, 1H), 3.72 (d, J = 12.1 Hz, 1H), 3.26 (dd, J = 13.0, 2.6 Hz, 1H), 3.16-3.01 (m, 3H), 2.56 (s, 3H), 2.26 (d, J = 11.4 Hz, 1H), 2.16 (d, J = 15.0 Hz, 1H), 2.02 (d, J = 14.6 Hz, 1H), 1.83 (s, 1H), 1.24 (d, J = 6.2 Hz, 3H). 150 [00308] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 412.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.54 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.25 (s, 1H), 4.63 (s, 1H), 4.24 (d, J = 6.3 Hz, 1H), 3.93 (d, J = 10.2 Hz, 1H), 3.77-3.63 (m, 1H), 3.27- 3.20 (m, 1H), 3.20-2.92 (m, 3H), 2.55 (s, 3H), 2.28-2.04 (m, 3H), 1.81 (d, J = 9.9 Hz, 1H), 1.24 (d, J = 6.2 Hz, 3H). 151 [00309] The synthesis method refers to embodiment 12 LCMS ESI(+)m/z: 398.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 8.58 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.57 (s, 1H), 4.46-4.34 (m, 1H), 3.94 (dd, J = 9.5, 4.5 Hz, 3H), 3.68 (d, J = 12.2 Hz, 1H), 3.40-3.33 (m, 2H), 3.13-3.04 (m, 1H), 2.98 (t, J = 11.7 Hz, 1H), 2.38 (s, 3H), 2.28 (d, J = 9.2 Hz, 1H), 2.12 (t, J = 13.5 Hz, 1H), 2.07-2.01 (m, 1H), 1.72 (qd, J = 12.6, 4.3 Hz, 1H). 152 [00310] The synthesis method refers to Example 8 LCMS ESI(+)m/z: 364.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 7.33 (d, J = 8.1 Hz, 1H), 7.13-6.95 (m, 2H), 4.64 (s, 1H), 4.04-3.86 (m, 3H), 3.69 (d, J = 12.4 Hz, 1H), 3.41-3.33 (m, 2H), 3.19-2.96 (m, 2H), 2.58 (s, 3H), 2.28-2.02 (m, 3H), 1.81 (d, J = 10.4 Hz, 1H). 153 [00311] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 417(M + 1). .sup.1H NMR (400 MHz, MeOD) 8.51 (dd, J = 9.4, 2.3 Hz, 1H), 8.11 (dd, J = 9.0, 5.3 Hz, 1H), 7.93 (td, J = 9.0, 2.3 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.17 (dt, J = 5.3, 1.8 Hz, 2H), 4.77-4.68 (m, 1H), 4.07-4.00 (m, 1H), 3.95 (dd, J = 12.9, 7.9 Hz, 2H), 3.71 (d, J = 12.4 Hz, 1H), 3.43-3.34 (m, 2H), 3.12 (dt, J = 19.2, 7.1 Hz, 2H), 2.33 (d, J = 9.6 Hz, 1H), 2.18 (d, J = 14.6 Hz, 1H), 2.13-2.01 (m, 1H), 2.00-1.88 (m, 1H). 154 [00312] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 417(M + 1). .sup.1H NMR (400 MHz, MeOD) 8.85 (dd, J = 9.0, 4.6 Hz, 1H), 8.06 (t, J = 7.5 Hz, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.4 Hz, 2H), 4.75 (d, J = 11.8 Hz, 1H), 4.02 (d, J = 11.3 Hz, 1H), 3.96 (t, J = 4.5 Hz, 2H), 3.72 (d, J = 12.1 Hz, 1H), 3.38 (s, 2H), 3.16 (dd, J = 16.3, 6.5 Hz, 2H), 2.34 (d, J = 10.2 Hz, 1H), 2.18 (d, J = 14.4 Hz, 1H), 2.12-1.88 (m, 2H). 155 [00313] The synthesis method refers to Embodiment 14 LCMS ESI(+)m/z: 399.2 (M + 1). .sup.1H NMR (400 MHz, MeOD) 8.68 (d, J = 8.2 Hz, 1H), 8.28 (t, J = 7.7 Hz, 1H), 8.13 (t, J = 7.4 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.20-7.11 (m, 2H), 4.78-4.69 (m, 1H), 4.09-3.90 (m, 3H), 3.67 (dd, J = 37.9, 10.7 Hz, 1H), 3.45-3.34 (m, 2H), 3.19-2.98 (m, 2H), 2.34 (d, J = 10.8 Hz, 1H), 2.21-1.89 (m, 3H).

Effect Example 1: Measuring IL-1 (interleukin-1) Secretion on the Products of Embodiments 1 to 155

1. Reagent Preparation

1.1 Medium Preparation

Cell Culture Medium

TABLE-US-00002 reagent concentration RPMI 1640 medium 89% FBS 10% Pen/Strep 1% 2-mercaptoethanol 0.05 mM

Cryopreservation Medium

TABLE-US-00003 reagent concentration DMSO 10% FBS 90%

1.2 Cell Preparation

1.2.1 Cells Thawing

[0395] Remove THP-1 cells from liquid nitrogen and place in a 37 C. water bath until ice melt. Add the cells to 5 mL of warm cell culture medium and centrifuge at 1,000 rpm for 5 min. Discard the supernatant and resuspend and culture in a new cell culture medium.

1.2.2 Cell Culturing and Passaging

[0396] THP-1 cells are cultured in the culture medium and passaged every 2-3 days. Cell is passaged every two days at concentration 5105 cells/mL, is passaged every three days at concentration 3105 cells/mL, and the cell density is maintained between 51051.5106 viable cells/mL (it is best to use cells that have been passaged less than 30 times to maintain high transfection efficiency).

1.2.3 Cell Cryopreservation

[0397] Resuspend the cells with fresh cell cryopreservation medium, adjust the cell density to 31066106/mL, add 1 mL of adjusted cell density medium to each cryovial, put it in a freezer containing methanol to freeze the cells at 80 C., and transfer to liquid nitrogen one day later.

1.3 Preparation of IFN- Solution

[0398] Dissolve IFN- in 1 mL of water to yield 100 g/mL mother liquor, store at 20 C. The mother liquor was further diluted to 25 ng/mL with cell culture medium.

1.4 LPS Solution Preparation

[0399] Dissolve LPS in 1 mL of PBS to obtain a 1 mg/mL stock solution, split into aliquots and store at 4 C. The stock solution was further diluted to 50 ng/mL with serum-free medium.

2 Compound Activity Assay

2.1 THP-1 Cells are Differentiated Under the Action of IFN-

[0400] 2.1.1 Cells are diluted to 100K cells/well with cell culture medium and IFN- (final concentration 25 ng/mL) is added to the cell suspension.

[0401] 2.1.1 Add 100 L of cell suspension per well to the cell plate and incubate the cell plate in a 37 C., 5% CO.sub.2 incubator for 24 hours.

2.2 LPS Induction

[0402] 2.2.1 Discard the supernatant of IFN- differentiation after differentiation treatment. Add 100 L of serum-free medium containing LPS (final concentration of 50 ng/mL) to the cell plate. The cell plates were incubated in a 37 C., 5% CO.sub.2 incubator for 4 h.

[0403] 2.2.2 According to the plate map, use Tecan to add 1% of the products of embodiments 1 to 155 into the cell plate as the sample treatment group and DMSO as the blank control group. Place the cell plate in an incubator at 37 C. and 5% CO.sub.2 for 1 hour.

[0404] 2.2.3 Add 20 L of 6ATP per well according to the plate map (final concentration 5 mM) and incubate the cell plate in a 37 C., 5% CO.sub.2 incubator for 1 h. Collect the supernatant (60 L) and store at 20 C.

2.3 Cell Plate Coating

[0405] The capture antibody mAb Mt175 is diluted to 2 g/mL with PBS (1:250) and added to the cell plate at 15 L per well. Keep the plate overnight at 4 C.

2.4 IL-1 Detection

[0406] 2.4.1 Discard the coated antibody and wash 4 times with PBST.

[0407] 2.4.2 Add 25 L of blocking buffer (Licor-927-40010) containing 0.1% Tween 20 per well to the cell plate and incubate for 1 h at room temperature.

[0408] 2.4.3 Discard the blocking buffer and wash 4 times with PBST.

[0409] 2.4.4 Add 25 L of 2.2.3 collected supernatant sample per well and incubate for 2 h at room temperature.

[0410] 2.4.5 Discard the samples and wash 4 times with PBST.

[0411] 2.4.6 Add mAb7P10-biotin (concentration 0.5 ug/mL) to blocking buffer, add 15 L per well to the cell plate, and incubate for 1 hour at room temperature.

[0412] 2.4.7 Discard the antibody and wash 4 times with PBST.

[0413] 2.4.8 Streptavidin-HRP was diluted 1:1000 in blocking buffer, 15 L per well was added to the cell plate, and incubated for 1 hour at room temperature.

[0414] 2.4.9 Discard streptavidin-HRP and wash 4 times with PBST.

[0415] 2.4.10 Add 25 L of HRP substrate (Surmodics-TMBW-0100-01) per well and incubate the cell plate until a blue product appears.

[0416] 2.4.11 Add 25 L of stop solution (Surmodics-LSTP-0100-01) per well, and the blue product turns yellow.

[0417] 2.4.12 Read the cell plate at 450 nm with a microplate reader.

3 Data Processing

[0418] The half inhibition rate IC50 value is obtained from the readings of the sample treatment group and the blank control group through a microplate reader, as shown in Table 1.

[0419] Among them, in addition to measuring the products of embodiment 1155, the IC50 values of

##STR00314##

were also measured.

TABLE-US-00004 TABLE 1 Half inhibition rate of NLRP3 of the product and positive control 1~4 (IC50) Embodiment IC50 (M) Embodiment IC50 (M) 1 0.0109 2 0.0402 3 0.0535 4 0.0321 6 0.0074 7 0.0012 8 0.0015 9 0.067 10 0.0155 11 0.004 12 0.0311 13 0.0024 14 0.001 15 0.028 16 0.0043 17 0.0155 18 0.0057 19 0.0852 20 0.0213 21 0.0494 22 0.024 23 0.376 24 0.193 25 0.317 26 0.446 27 0.0014 28 0.0011 29 0.0051 30 0.0029 31 0.0022 33 0.0058 35 0.0124 36 0.0542 37 0.0273 40 0.0124 42 0.0627 43 0.0065 44 0.0004 47 0.0046 48 0.0091 54 0.0464 64 0.0047 65 0.0104 70 0.0053 71 0.0928 72 0.343 76 0.0113 77 0.0194 78 0.0028 81 0.0348 82 0.0474 107 0.0292 108 0.0109 109 0.0406 110 0.003 111 0.0197 112 0.002 113 0.0161 114 0.031 116 0.0106 117 0.0047 118 0.0029 119 0.005 120 0.0041 121 0.0012 122 0.0029 123 0.00547 124 0.0206 125 0.0099 126 0.0039 127 0.0035 128 0.003 129 0.0038 130 0.0019 131 0.0073 132 0.0041 133 0.0066 134 0.014 135 0.0051 136 0.0044 137 0.002 138 0.0047 139 0.0019 140 0.0095 141 0.0015 142 0.0113 143 0.0009 144 0.0018 146 0.0074 147 0.009 148 0.0144 149 0.0248 150 0.0099 152 0.0104 153 0.0024 154 0.0032 155 0.0025 Reference 1 0.00916 Control 2 0.0014 Comparison 3 0.0014 Comparison 4 0.0224

[0420] The results show that the compound of the present invention can significantly inhibit pyroptosis of human cells THP-1.

Effect Example 2: Effect of the Compounds on the hERG Pathway Current

[0421] The fast-activating potassium channel encoded by the human ether-a-go-go-related gene (hERG) is an important ion channel involved in the formation of phase 3 repolarization of myocardial action potential. Drug blockade of the hERG channel can lead to prolonged cardiac repolarization, which is called long QT syndrome on ECG. Drug-induced delayed ventricular repolarization may cause a fatal arrhythmia-torsade de pointes in some cases.

[0422] In this study, a whole-cell patch-clamp technique was used to study the inhibitory effect of compounds on hERG potassium channels and to evaluate the risk of ventricular repolarization toxicity.

Cell Culture

[0423] The HEK293 cell line stably expressing the hERG potassium channel cells was purchased from Creacell, Inc. (Cat. No. A-0320).

[0424] The HEK293 cell line that can stably express the hERG potassium channel, was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at 37 C. and 5% carbon dioxide.

[0425] Cell passaging: Remove the old medium and wash once with PBS, then add 2 mL of TrypLE Express solution and incubate at 37 C. for about 1 min. When the cells are detached from the bottom of the dish, add approximately 5 mL of complete medium pre-warmed at 37 C. Gently pipette the cell suspension with a pipette to detach the clustered cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells. To expand or maintain the culture, cells are seeded in 10 cm cell culture dishes with a cell volume of 610.sup.5 cells per dish (final volume: 10 mL).

[0426] To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0427] Before the test, the cells were separated with TrypLET Express, centrifuged after adding medium to terminate digestion, resuspended the cell count, adjusted the cell density to 2-310.sup.6 cells/mL, and then lightly mixed the cells on a room temperature equilibration shaker for 15-20 min.

Patch-Clamp Testing

[0428] Electrophysiological assays were performed using a fully automated patch-clamp QPatch 48 X (Sophion) device. The prepared cells were placed on a centrifuge on the Qpatch bench, the cells were washed using multiple centrifugation/suspension methods, and the cell culture medium was replaced with extracellular fluid. Remove an MTP-96 plate and place it in the location of the MTP source. Remove the QPlate chip and subsequently place the QPlate at the Qplate source location. The robotic arm scans the MTP-96 board and the QPlate chip barcode and grabs it to the measuring station. Draw the intracellular and external fluid from the liquid pool and add them to the intracellular fluid pool, cell and test cell pool of the QPlate chip, respectively. At the measuring station, all measuring sites on the QPlate undergo initial quality control. The quality control process includes aspirating the cell suspension from the cell vessel of the centrifuge and positioning the cells to the chip wells via a pressure controller to establish a high-resistance seal and create a whole-cell recording pattern. Once a stable baseline of control currents has been obtained, the test substance can be aspirated from the TEST MTP-96 plate and applied to the cells in a concentration gradient.

[0429] The voltage stimulation protocol for whole-cell patch-clamp recording of whole-cell hERG potassium currents is as follows: the cell membrane voltage clamps at 80 mV when a whole-cell closure is formed. The clamping voltage is depolarized from 80 mV to 50 mV for 0.5 s (as a leakage current detection), then steps to 30 mV for 2.5 s, and then quickly recovers to 50 mV for 4 s to excite the tail current of the hERG channel. The data were collected repeatedly every 10 s to observe the effect of the drug on the hERG tail current. 50 mV stimulation at 0.5 s was used as the leakage current detection. The test data is collected by Qpatch and stored in the connected service station.

Data Analysis

[0430] First, the current after the effect of each drug concentration and the blank control current are normalized 0, and then the inhibition rate corresponding to each drug concentration is calculated.

[00001]$\frac{\mathrm{Peak}\mathrm{tail}\mathrm{current}\mathrm{compound}}{\mathrm{Peak}\mathrm{tail}\mathrm{current}\mathrm{vehicle}}\left(1-\frac{\mathrm{Peak}\mathrm{tail}\mathrm{current}\mathrm{compound}}{\mathrm{Peak}\mathrm{tail}\mathrm{current}\mathrm{vehicle}}\right)$

Calculate the mean and standard error for each concentration and calculate the semi-inhibitory concentration for each compound using the following Formula:

[0431] Y=Bottom+(TopBottom)/(1+10{circumflex over ()}((LogIC50X)*HillSlope)) The above Formula was used to fit the dose-dependent effect nonlinearly, where C represents the test substance concentration, IC50 is the semi-inhibitory concentration, and h represents the Hill coefficient. Curve fitting and IC50 calculations were performed using Graphpad software. The test results of some compounds are shown in Table 2

TABLE-US-00005 TABLE 2 Semi-inhibitory concentrations (IC50) of some embodiment compounds and control substances 1~4 on hERG current Embodiment IC50 (M) Embodiment IC50 (M) 2 >30 6 >30 33 >30 35 >30 37 >30 39 >30 40 >30 43 >30 44 >30 47 >30 48 >30 64 >30 70 >30 78 >30 126 >30 127 >30 130 >30 131 >30 132 >30 133 >30 135 >30 136 >30 137 >30 139 >30 147 >30 148 >30 150 >30 152 >30 153 >30 155 >30 Reference 1 <10 Control 2 <10 Comparison 3 <10 Comparison 4 23

[0432] The results show that the IC50 result of the compound of the present invention acting on the hERG current is >30 M, and the compound of the present invention has no inhibitory effect on the hERG channel according to the general standard judgment of hERG. The experimental results of the control compounds showed that there was a certain weak inhibitory effect, which had certain cardiac safety risks.

Effect Example 3: In Vivo Pharmacokinetic Evaluation of Some Compounds in Mice

[0433] CD-1 mice, after fasting overnight (free drinking), are divided into tail vein (IV) and gavage administration (PO) groups. The tail vein administration group collected 0.1 mL of blood from the orbital venous plexus before administration and 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration, and sample centrifugation at 4 C. for 5 minutes, and stored at 70 C. for testing. In the gavage administration group, 0.1 mL of blood was collected from the orbital venous plexus before administration and at 15 minutes 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after administration, and the treatment method was the same as that of the intravenous administration group. The plasma parent drug concentration was determined by LC-MS/MS. The results are shown in Table 3.

TABLE-US-00006 TABLE 3 Pharmacokinetic test results of some compounds in vivo route of Dosage Cmax AUC t1/2 Cl Vss Embodiment administration (mg/kg) (ng/ml) (ng .Math. h/mL) (h) (mL/h/kg) (L/kg) F % 33 IV 3 4595 4.89 0.653 2.60 PO 20 8517 30015 3.60 98.0 44 IV 3 2947 4.02 1.01 4.35 PO 20 4530 18777 3.62 95.3 132 IV 3 3159 2.81 0.948 3.56 PO 20 3067 18644 2.53 88.5 136 IV 3 3249 6.07 0.906 2.35 PO 20 6516 20312 5.67 93.8 147 IV 3 3286 3.28 0.913 3.39 PO 20 5710 17232 2.76 78.7 148 IV 3 4748 4.17 0.632 3.00 PO 20 7727 30128 3.68 95.2 Reference 1 IV 3 10174 4.00 0.29 1.62 PO 20 3957 36893 4.23 54.6 Comparison 4 IV 3 1590 4.76 2.43 5.89 PO 20 1709 5208 2.95 49.1

[0434] The results show that the pharmacokinetic parameters of the compound of the present invention in animals are significantly better than those of the reference substance.

Effect Example 4: Inhibitory Effect of Embodiment Compound 33 on Plasma II-1 and IL-18 Cytokines in LPS-Induced Sepsis Mouse Model

[0435] The purpose of this study was to investigate and evaluate the inhibitory effect of the test compound on IL-103 and IL-18 cytokine production in a mouse model of lipopolysaccharide (LPS)-induced sepsis.

Animal Study:

[0436] 6-8 weeks female C57BL/6J mice, randomized, 5 animals in the Nave group, and the rest of the groups (vehicle group, 15 mg/kg group with embodiment 33 compound, 50 mg/kg group with embodiment 33 compound and 150 mg/kg group with embodiment 33 compound, wherein 15 mg/kg, 50 mg/kg and 150 mg/kg is the dosage of embodiment 33, mg/kg is referred to as mpk) 10 animals per group. Among them, the Nave group was not stimulated with LPS, and the 10 mice in each group were intraperitoneally injected with LPS (10 mg/kg) to induce sepsis model in the mouse. The vehicle (corresponding to the vehicle group) and the test compound (corresponding to the 15mpk group of Example 33, the 50mpk group of Example 33 and the 150mpk group of Example 33 respectively) were administered 30 minutes before LPS stimulation. 2 hours after LPS stimulation, the mice were euthanized, and whole blood was collected from the heart and placed in EP tubes, left to stand at room temperature for 1 hour, and centrifuged at 8000 rpm for 10 minutes to collect serum for measurement of cytokines IL-10 and IL-18.

IL-1 Cytokine Assay:

[0437] For the standard pellet in the IL-10 cytokine CBA kit, put the IL-10 standard pellet into a 15 mL centrifuge tube, add 4 mL of Assay Diluent, and let it stand at room temperature for more than 15 minutes; [0438] After the supernatant sample is melted and mixed evenly, the supernatant is diluted 2 times; [0439] Preparation of standard reagent: Add the diluent Assay Diluent in advance to the 96-well V-shaped bottom plate, 100 L/well. Add 200 L of the standard that has been left to stand for 15 minutes into the well plate, and add 100 L each time to the diluent in sequence. Gradually dilute the standard to 11 gradients (double dilution each time). The 12th hole is used as Blank, 200 L/well; [0440] Preparation of Capture beads reagent: Take the capture beads in the IL-10 cytokine CBA kit and vortex for 30 seconds. Prepare the Beads as follows: 60 L IL-10 beads+2440 L capture beads diluent (60 wells); mix evenly, 50 L/well, add it to a %-well V-bottom plate; shake at 200 g for 5 minutes, and incubate at room temperature for 1 hour; [0441] Preparation of Detection reagent: Take the PE Detection from the IL-10 cytokine CBA kit and vortex for 30 seconds. Prepare the PE as follows: 60 L IL-10 Detection+2440 L PE detection diluent; mix evenly. Add 50 L/well of the standard and sample to be tested; shake at 200 g for 1 minute, and incubate at room temperature for 1 hour; [0442] Washing: Add 200 L of wash buffer/well, 400 g, and centrifuge for 5 minutes at 4 C.; [0443] Discard the supernatant, add wash buffer 150 L/well, and wait for detection on the machine; [0444] Fortessa testing.

IL-18 Cytokine Assay:

[0445] After the kit is taken out of the refrigerator, it should be equilibrated at room temperature (25-28 C.) for 20 minutes; the remaining reagents should be stored at 4 C. immediately after each test.

[0446] Prepare an appropriate amount of standard diluent: dilute the standard diluent (5) to 1 with double-distilled or deionized water. For example, add 10 mL of standard diluent (5) to 40 mL of water and mix well to obtain a 1 standard. Diluent.

[0447] Prepare an appropriate amount of washing liquid: Dilute the washing liquid (20) with double-distilled or deionized water to 1. For example, add 10 mL of washing liquid (20) to 190 mL of water and mix well to obtain a 1washing liquid.

[0448] Standard preparation: Add the standard diluent to one bottle of standard according to the volume (0.5 mL) marked on the standard label, incubate at room temperature for 15 minutes, then mix gently and pipet several times with a pipette to completely dissolve the standard. The final concentration of the standard reaches 1500 pg/mL. Take 5 clean 1.5 mL centrifuge tubes, add 250 L of standard diluent to each tube in advance, and perform dilutions of the standard to obtain a total of 1500, 750, 375, 187.5, 93.75, 46.875, and 23.4375 pg/mL. standard concentration, and finally add the diluted standard to the pre-coated plate wells in sequence, and add the standard diluent directly as a concentration of 0 pg/mL, for a total of 8 standard concentrations.

Procedure:

[0449] Calculate and determine the number of pre-coated strips required for an experiment, take out the required strips and place them in a %-well frame.

[0450] Add samples or standards of different concentrations into the corresponding wells at 100 L/well, seal the reaction wells with sealing film (transparent), and incubate at room temperature for 120 minutes.

[0451] Wash the plate 3 times and pat dry on thick absorbent paper for the last time.

[0452] Add 100 L/well of horseradish peroxidase-labeled antibody, seal the reaction well with sealing film (transparent), and incubate at room temperature for 60 minutes.

[0453] Wash the plate 3 times and pat dry on thick absorbent paper for the last time.

[0454] Add 100 L/well of chromogen TMB solution, seal the reaction well with sealing film (white), and incubate at room temperature in the dark for 15-20 minutes.

[0455] Add 50 L of stop solution/well, mix well and measure the A450 value immediately.

[0456] All data were first tested for homogeneity of variances. After passing the homogeneity of variances test, one-way analysis of variance (ANOVA) was used for intra-group significance analysis, and the Dunnet method was used to compare differences between groups. If the variances are not equal, the rank sum test in the non-parametric test is used for analysis. Among them, *P<0.05, **P<0.01, ***P<0.001.

[0457] The experimental results are shown in Table 4: Compared with Nave, the levels of IL-10 and IL-18 in the Vehicle group increased significantly; compared with the Vehicle group, the three dose groups of Embodiment 33 had a significant inhibitory effect on IL-1. Embodiment 33 has a significant inhibitory effect on IL-18 at two doses of 50 mg/kg and 150 mg/kg.

[0458] In summary, Embodiment 33 can dose-dependently inhibit LPS-induced levels of IL-10 and IL-18 in plasma.

TABLE-US-00007 TABLE 4 Experimental test results of PD in vivo in Embodiment 33 Embodiment Embodiment Embodiment Nave Vehicle 33 15 mpk 33 50 mpk 33 150 mpk Number 5 10 10 10 10 of animals IL-1 0.2684 1.278 769.7 128.4 310.1 32.88 213.4 25.66 19.36 5.166 IL-18 142.5 14.1 685.3 65.88 560.5 46.39 320.1 29.69 216.2 9.238

Effect Embodiment 5: Embodiment 33 Effect on DSS-Induced Acute Enteritis Mouse Model

[0459] Grouping and modeling: One day before the start of the experiment, all C57BL/6 mice were ear-labeled and recorded, and the animals with appropriate weight and normal status were selected for grouping (Sham group, vehicle group and embodiment 33 group). 10 animals per group; 3.5% dextran sulfate sodium salt (DSS, MP, molecular weight 36000-50000) prepared with sterile water is loaded into the drinking bottle in the vehicle and the 33 testing groups of rearing cages in the embodiment (100 mL per cage, replace the 3.5% DSS solution after 2-3 days with freshly prepared solution), and the animals in the vehicle and the 33 testing groups of the embodiment are free to drink for 10 consecutive days. The Sham group drank the normal water not containing DSS. Embodiment 33 compound is administered orally BID.

Evaluation Indicators:

[0460] 1) Body Weight Change (%)=BWi/BW0100%, BWi is the average body weight of mice in the group on a given day, BW0 is the average body weight of mice before the start of treatment. The results of the assessment are shown in Table 5.

TABLE-US-00008 TABLE 5 The average rate of change in body weight of each treatment group at day 11 (n = 10). Day 11 weight Rate of body P Group change (%) weight loss (%) Value Sham 102.27% 1 / Vehicle 78.73% 21.27% Embodiment 33 50 mpk P.O Bid 88.09% 11.91%** 0.004 Note: Compared with the G2 Vehicle group, the one-way ANOVA method test for each treatment group was: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

[0461] 2) DAI score: The Disease Activity Index (DAI) scoring criteria are as follows:

TABLE-US-00009 % of Body Score weight loss Stool characteristics Blood in the stool 0 0 Normal Negative 1 1-5% soft stool \ 2 6-10% Semi-loose stool Occult blood 3 11-15% Loose stool with residue \ 4 >15% Watery stool Visible bloody stool

[0462] The results of the assessment are shown in Table 6:

TABLE-US-00010 TABLE 6 DAI score data during treatment (n = 10). Group Day 3 Day 5 Day 7 Day 9 Day 11 Sham 0.20 0.13 0.20 0.13 0.00 0.00 0.00 Vehicle 0.30 0.15 3.60 0.37 6.50 0.31 9.60 0.62 11.00 0.37 Embodiment 33 50 mpk P.O 0.00 2.60 0.45 4.40 0.6* 6.20 0.68** 7.80 0.63** Bid Note: DAI scores compared with the G2 Vehicle group, the one-way ANOVA method test: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

[0463] 3) Colon length: After the last dose, all animals were euthanized with CO.sub.2 and dissected. The entire colon (anus-cecum section) was isolated, moistened with ice-cold saline, smoothed and laid flat. On the dissecting board, without applying external force to stretch, use a digital vernier caliper to measure the length of the colon and record it, and take photos for retention. The evaluation results are shown in Table 7.

TABLE-US-00011 TABLE 7 Colon length statistics (n = 10). Group Colon length(mm) P Value Sham 74.29 0.71 Vehicle 49.99 1.55 Embodiment 33 50 mpk P.O Bid 58.27 1.48 0.000316 Note: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, and the one-way ANOVA method test were all compared with the G2 Vehicle group.

[0464] 4) Detection of inflammatory factors: Blood was collected from all animals under their jaws, and serum was separated; serum and colon tissue IL-10 and IL-18 cytokines were detected according to the detection method in the Effect Embodiment 4.

[0465] The experimental results are shown in Table 8. Embodiment compound 33 (50mpk P.O Bid) has significant curative effect on animals with DSS-induced acute enteritis (IBD). It can significantly improve animal weight, reduce intestinal inflammation and bleeding, and improve intestinal inflammation. Reduce colon shortening, and inhibition of serum and colon tissue IL-10 and IL-18 cytokines, and there were statistically significant differences.

TABLE-US-00012 TABLE 8 Inflammatory factor test results of IBD experiment in vivo in example 33 animals Embodiment 33 Sham Vehicle 50 mpk, BID Number of animals 10 10 10 IL-1 in serum 32.07 9.439 1227 25.21 290.3 30.65 IL-1 in the colon 0.2737 0.113 12.22 1.658 6.018 0.9675

Effect Embodiment 6: Safety Investigation of the Compound of Embodiment 33 Administered Orally to SD Rats for 14 Consecutive Days

[0466] The purpose of this experiment was to study the reactions of SD rats after oral administration of different doses of the compound of Embodiment 33 and to examine the tolerance of the compound.

[0467] In this trial, low-dose and high-dose groups were administered orally with 50 and 100 mg/mL solutions respectively. The administration volume was 20 mL/kg, and the administration doses were 1000 and 2000 mg/kg respectively. Administer continuously for 14 days. Drink water freely during the experiment. The experimental results are shown in Table 9.

TABLE-US-00013 TABLE 9 Test dose and experimental design Dosage Dosing Number of administered concentration Frequency of volume animals/animal Groups (mg/kg) (mg /mL) administration (mL/kg) Low-dose 1000 50 1 time/day for 20 5 5 group 14 consecutive High-dose 2000 100 days 20 5 5 group

[0468] After administration, no obvious toxicity reactions were seen in the animals in each dose group. And there was no significant impact on the animal body weight. Gross anatomy showed no obvious pathological changes in the surface color, shape, size, texture, etc. of the heart, liver, spleen, lungs, kidneys, brain, and gastrointestinal tract of the animals in each dose group. Based on the above analysis, the compound of Embodiment 33 may not have any toxic effects at a dose of 2000 mg/kg, indicating that it is well tolerated.

[0469] Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only illustrations, and that various changes or modifications may be made to these embodiments without deviating from the principle and substance of the present invention. Accordingly, the scope of the present invention is defined by the appended claims.