COMPOUND SERVING AS NLRP3 INHIBITOR

Abstract

The present invention provides a compound serving as an NLRP3 inhibitor. Specifically, the present invention provides a compound having a structure shown in the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, and solvate thereof. The compound can be used for treating or preventing diseases or disorders associated with the activity or expression level of NLRP3.

##STR00001##

Claims

1. A compound of formula (I), or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof: ##STR00085## wherein: ring A is selected from the group consisting of substituted or unsubstituted 8-15 membered bicyclic or tricyclic fused ring systems; wherein, the substituted means the hydrogen atoms on the group are substituted by one or more R.sup.e; the bicyclic or tricyclic fused ring system comprises at least one aromatic ring and one or two saturated or unsaturated rings fused with the aromatic ring, and the connecting site of ring A and X locating on the aromatic ring; ring B is selected from the group consisting of none, substituted or unsubstituted aryl, substituted or unsubstituted 5-12 membered heterocycle (including partially unsaturated or saturated heterocycle), or substituted or unsubstituted heteroaryl; wherein, the substituted means the hydrogen atoms on the group are substituted by one or more R.sup.f; and when B is none, E and G are absent; X is selected from NR.sup.5, CR.sup.6R.sup.7; Y is selected from O, NR.sup.5-; T is selected from chemical bond, NR.sup.5, (CR.sup.aR.sup.b).sub.1-2-, C.sub.3-6cycloalkyl, 3-8 membered heterocyclyl, aryl, and heteroaryl; R is selected from the group consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.2-4 alkenyl, C.sub.2-4alkynyl, C.sub.3-8cycloalkyl, 3-8membered heterocyclyl, aryl, heteroaryl, and NR.sup.8R.sup.9; wherein, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.2-4haloalkenyl, C.sub.1-4alkoxy, C.sub.1-4 haloalkoxy, NR.sup.8R.sup.9, CN, NO.sub.2, SR.sup.h, C(O)R.sup.t, C(O)OR.sup.h, C(O)NR.sup.hR.sup.h, NR.sup.hC(O)R.sup.t, NR.sup.hS(O).sub.2R.sup.t, and S(O).sub.2R.sup.t; or the cycloalkyl or heterocyclic group is substituted by =M, where M is selected from O or CR.sup.10R.sup.11; E is selected from the group consisting of chemical bond, O, O(CR.sup.aR.sup.b).sub.1-2, (CR.sup.aR.sup.b).sub.1-20, S, S(CR.sup.aR.sup.b).sub.1-2, (CR.sup.aR.sup.b).sub.1-2S, NR.sup.5, (CR.sup.aR.sup.b).sub.1-2NR.sup.5, NR.sup.5 (CR.sup.aR.sup.b).sub.1-2-, C.sub.1-2alkylene, C?C, C?C-, and C.sub.3-6cycloalkyl; G is selected from the group consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, saturated C.sub.3-8 cycloalkyl, unsaturated C.sub.3-8 cycloalkyl, saturated 3-12 membered heterocyclyl, unsaturated 3-12 membered heterocyclyl, aryl, heteroaryl, and NR.sup.8R.sup.9; wherein, the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.2-4 haloalkenyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, NR.sup.8R.sup.9, CN, NO.sub.2, SR.sup.h, C(O)R.sup.1, C(O)OR.sup.h, C(O)NR.sup.hR.sup.h, NR.sup.hC(O)R.sup.t, NR.sup.hS(O).sub.2R.sup.t, and S(O).sub.2R.sup.t; R.sup.5 is selected from the group consisting of H, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl, and C.sub.3-6cycloalkyl; or R.sup.6 and R.sup.7 together with their connected carbon atoms form a C.sub.3-6cycloalkyl, or a 4-6 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, S; R.sup.8 and R.sup.9 are independently selected from the group consisting of hydrogen, C.sub.1-4 alkyl, C.sub.3-6cycloalkyl, and 4-8 membered heterocyclyl; the cycloalkyl or heterocyclyl is optionally substituted by =M, wherein M is selected from O or CR.sup.10R.sup.11; or R.sup.8 and R.sup.9 together with their connected nitrogen atoms form a 4-8 membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 N atoms and 0 or 1 heteroatom selected from O, S; and when ring A is a tricyclic fused ring system, and R is not an unsaturated C.sub.3-8 cycloalkyl (nonaromatic) or unsaturated 3-8 membered heterocyclyl (nonaromatic), R is a C.sub.3-8cycloalkyl or 3-8 membered heterocyclyl, and R is at least substituted by one =M; or R is a C.sub.3-8 cycloalkyl or 3-8 membered heterocyclyl, and T is NR.sup.5-, and R is at least substituted by one substituent selected from the group consisting of fluorine, C.sub.1-4 fluoroalkyl, and C.sub.2-4fluoroalkenyl; and when ring A is a bicyclic fused ring system, and G is not an unsaturated 3-12 membered heterocyclyl (nonaromatic), saturated 3-12 membered spiro-heterocyclyl, saturated 3-12 membered fused-heterocyclyl, and saturated 3-12 membered bridge-heterocyclyl, R is C.sub.3-8 cycloalkyl or 3-8 membered heterocyclyl, and R is at least substituted by one =M; or R is C.sub.3-8 cycloalkyl or 3-8 membered heterocyclyl, and T is NR.sup.5-, and R is at least substituted by one substituent selected from the group consisting of fluorine, C.sub.1-4 fluoroalkyl, and C.sub.2-4fluoroalkenyl; R.sup.10 and R.sup.11 are independently selected from the group consisting of hydrogen, deuterium, halogen, and C.sub.1-4 alkyl; wherein, the alkyl is optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, NR.sup.8R.sup.9, C.sub.3-8 cycloalkyl, 3-8 membered heterocyclyl, aryl, and heteroaryl; or R.sup.10 and R.sup.11 together with their connected carbon atoms form a 3-6 membered cycloalkyl, or a 4-8 membered heterocyclyl having 1 or 2 heteroatoms selected from N, O, and S; R.sup.a and R.sup.b are independently selected from the group consisting of H, halogen, C.sub.1-4 alkyl, or C.sub.3-6 cycloalkyl; R.sup.e and R.sup.f are independently selected from the group consisting of deuterium, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, 4-8 membered heterocyclyl, aryl, heteroaryl, CN, NO.sub.2, OR.sup.h, SR.sup.h, NR.sup.hR.sup.h, C(O)R.sup.t, C(O)NR.sup.hR.sup.h; R.sup.t is C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-8 cycloalkyl, 4-8 membered heterocyclyl, aryl, or heteroaryl; each R.sup.h is independently hydrogen or C.sub.1-4 alkyl; or two R.sup.h together with their connected nitrogen atoms form a 3-8 membered heterocyclyl having 1 or 2 N atoms and 0 or 1 heteroatom selected from O and S; wherein, each of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted by 1-3 substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.3-8 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, CN, NO.sub.2, OR.sup.h, SR.sup.h, NR.sup.hR.sup.h, C(O)R.sup.t, C(O)OR.sup.h, C(O)NR.sup.hR.sup.h, NR.sup.hC(O)R.sup.t, NR.sup.hS(O).sub.2R.sup.t, and S(O).sub.2R.sup.t, the premise is that the resulting chemical structure is stable and meaningful; wherein, R.sup.h and R.sup.t are as described above; unless otherwise specified, the aryl described above is aromatic group containing 6-12 carbon atoms; the heteroaryl is 5-15 membered (preferably 5-12 membered) heteroaromatic groups.

2. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, R is selected from C.sub.3-8cycloalkyl or 3-8 membered heterocyclyl; wherein, the cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-4haloalkenyl, C.sub.1-4alkoxy, C.sub.1-4haloalkoxy, NR.sup.8R.sup.9, and =M, wherein, M is selected from O or CR.sup.10R.sup.11; A, B, E, G, X, Y, T, R.sup.8, R.sup.9, R.sup.10, R.sup.11 are as described in claim 1.

3. The compound of claim 2, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, R is selected from C.sub.3-8cycloalkyl or 3-8 membered heterocyclyl; wherein, the cycloalkyl or heterocyclyl is at least substituted by one =M, wherein M is CR.sup.10R.sup.11; wherein, R.sup.10 and R.sup.11 are as described in claim 2.

4. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein ##STR00086## is selected from ##STR00087## represents the connecting site of the above structural fragments of formula (IIa) or (IIb) with the rest moiety of formula (I); R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, and C.sub.1-4haloalkoxy; each R.sup.3 is independently selected from the group consisting of hydrogen, deuterium, halogen, and C.sub.1-4alkyl; m is 0, 1, 2 or 3; ##STR00088## is pyridine, pyrimidine, or pyridazine; E is selected from the group consisting of chemical bond, O, O(CR.sup.aR.sup.b).sub.1-2, (CR.sup.aR.sup.b).sub.1-20, S, S(CR.sup.aR.sup.b).sub.1-2, (CR.sup.aR.sup.b).sub.1-2, NR.sup.5, (CR.sup.aR.sup.b).sub.1-2NR.sup.5, NR.sup.5 (CR.sup.aR.sup.b).sub.1-2-, C.sub.1-2alkylene, C?C-, and C?C-; wherein, R.sup.a and R.sup.b are independently selected from hydrogen and C.sub.1-4alkyl; G is selected from unsaturated C.sub.3-8 cycloalkyl or unsaturated 3-12 membered heterocyclyl; wherein the cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.2-4haloalkenyl, C.sub.1-4alkoxy, C.sub.1-4haloalkoxy, NR.sup.8R.sup.9, CN, NO.sub.2, SR.sup.h, C (O) R.sup.t, C(O)OR.sup.h, C(O)NR.sup.hR.sup.h, NR.sup.hC(O)R.sup.t, NR.sup.hS(O).sub.2R.sup.t, and S(O).sub.2R.sup.t; R.sup.5, R.sup.8, R.sup.9, R.sup.h and R.sup.t are as described in claim 1.

5. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (III): ##STR00089## R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, and C.sub.1-4haloalkoxy; each R.sup.3 is independently selected from the group consisting of hydrogen, deuterium, halogen, and C.sub.1-4alkyl; m is 0, 1 or 2; E is selected from the group consisting of chemical bond, O, O(CR.sup.aR.sup.b).sub.1-2, (CR.sup.aR.sup.b).sub.1-20, S, S (CR.sup.aR.sup.b).sub.1-2, (CR.sup.aR.sup.b).sub.1-2S, NR.sub.5, (CR.sup.aR.sup.b).sub.1-2NR.sup.5, NR.sup.5 (CR.sup.aR.sup.b).sub.1-2-, C.sub.1-2alkylene, C?C, C?C-; wherein, R.sup.a and R.sup.b are independently selected from hydrogen and C.sub.1-4alkyl; G is selected from unsaturated C.sub.3-8cycloalkyl or unsaturated 3-12 membered heterocyclyl; wherein, the cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.2-4haloalkenyl, C.sub.1-4alkoxy, C.sub.1-4haloalkoxy, NR.sup.8R.sup.9, CN, NO.sub.2, SR.sup.h, C(O)R.sup.t, C(O)OR.sup.h, C(O)NR.sup.hR.sup.h, NR.sup.hC(O)R.sup.t, NR.sup.hS(O).sub.2R.sup.t, and S(O).sub.2R.sup.t; X, Y, T, R, R.sup.5, R.sup.8, R.sup.9, R.sup.h and R.sup.t are as described in claim 1.

6. The compound of claim 5, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, E is selected from the group consisting of chemical bond, O, O(CR.sup.aR.sup.b).sub.1-2, (CR.sup.aR.sup.b).sub.1-20, NR.sup.b, (CR.sup.aR.sup.b).sub.1-2NR.sup.5, NR.sup.5 (CR.sup.aR.sup.b).sub.1-2-, and C?C-; wherein, R.sup.a and R.sup.b are independently selected from hydrogen and C.sub.1-4alkyl.

7. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (IV): ##STR00090## M is selected from CR.sup.10R.sup.11, wherein, R.sup.10 and R.sup.11 are as described in claim 1; U is selected from N or CR.sup.12; wherein, R.sup.12 is selected from hydrogen, halogen and C.sub.1-4alkyl; W is selected from chemical bond, NR.sup.13 (CR.sup.cR.sup.d).sub.1-2-, and O (CR.sup.cR.sup.d).sub.1-2-; wherein, R.sup.13 is selected from hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, 3-6 membered heterocyclyl, aryl, heteroaryl, C (O) R.sup.t, and S (O).sub.2R.sup.t; R.sup.c and R.sup.d are independently selected from hydrogen and C.sub.1-4alkyl; p and q are independently selected from 0, 1, 2, 3, 4, 5 and 6; the premise is that p and q are not 0 at the same time; A, B, E, G, X, Y, T and R.sup.t are as described in claim 1.

8. The compound of claim 7, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (Va) or formula (Vb): ##STR00091## T is selected from chemical bond, NR.sup.5-, aryl, and heteroaryl; M, U, W, p, q, E, G, and R.sup.5 are as described in claims 7; R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, and C.sub.1-4haloalkoxy; each R.sup.3 is independently selected from the group consisting of hydrogen, deuterium, halogen, and C.sub.1-4 alkyl; m is 0, 1, 2 or 3.

9. The compound of claim 7, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (VIa) or formula (VIb): ##STR00092## R.sup.5 is selected from hydrogen and C.sub.1-4alkyl; U is selected from CR.sup.12, wherein, R.sup.12 is selected from hydrogen, and C.sub.1-4alkyl; M, W, p, q, E, and G are as described in claims 7; R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; each R.sup.3 is independently selected from the group consisting of hydrogen, deuterium, halogen, and C.sub.1-4 alkyl; m is 0, 1, 2 or 3.

10. The compound of claim 7, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (VIIa) or formula (VIIb): ##STR00093## U is selected from CR.sup.12; wherein, R.sup.12 is selected from hydrogen, and C.sub.1-4alkyl; M, W, p, q, E, and G are as described in claims 7; R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, and C.sub.1-4haloalkoxy; each R.sup.3 is independently selected from the group consisting of hydrogen, deuterium, halogen, and C.sub.1-4 alkyl; m is 0, 1, 2 or 3.

11. The compound of claim 8, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (VIIIa) or formula (VIIIb): ##STR00094## M, U, W, R.sup.1, R.sup.2, R.sup.3, E, G, m, p, and q are as described in claim 8.

12. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (IXa) or formula (IXb): ##STR00095## k and j are independently 0, 1 or 2; R.sup.14 and R.sup.15 are independently selected from the group consisting of H, halogen, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl; and T, U, W, R.sup.1, R.sup.2, R.sup.3, E, G, m, and p are as described in claim 8.

13. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, and solvates thereof, wherein, formula (I) has the structure of formula (X): ##STR00096## Z is selected from N and CR.sup.16, wherein, R.sup.16 is selected from hydrogen, halogen and C.sub.1-4alkyl; p and q are independently selected from 0, 1, 2, 3, 4, 5, and 6; U is selected from CR.sup.12; wherein, R.sup.12 is selected from hydrogen, and C.sub.1-4alkyl; M is selected from CR.sup.10R.sup.11, wherein, R.sup.10 and R.sup.11 are as described in claim 1; and A, B, E and G are as described in claim 1.

14. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (XIa) or formula (XIb): ##STR00097## ##STR00098## is selected from pyridine, pyrimidine, and pyridazine; Z is selected from N and CR.sup.16, wherein, R.sup.16 is selected from hydrogen, halogen and C.sub.1-4alkyl; p and q are independently selected from 0, 1, 2, 3, 4, 5, and 6; U is selected from CR.sup.12; wherein, R.sup.12 is selected from hydrogen, and C.sub.1-4alkyl; M is selected from CR.sup.10R.sup.11, wherein, R.sup.10 and R.sup.11 are as described in claim 1; R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, and C.sub.1-4haloalkoxy; each R.sup.3 is independently selected from the group consisting of hydrogen, deuterium, halogen, and C.sub.1-4 alkyl; m is 0, 1, 2 or 3; and E, and G are as described in claim 1.

15. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, formula (I) has the structure of formula (XII): ##STR00099## p and q are independently selected from 0, 1, 2, 3, 4, 5, and 6; M is selected from CR.sup.10R.sup.11; wherein, R.sup.10 and R.sup.11 are independently selected from the group consisting of hydrogen, fluorine, and C.sub.1-2 alkyl; wherein, the alkyl is optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4 haloalkoxy, NR.sup.8R.sup.9, C.sub.3-8cycloalkyl, and 3-8 membered heterocyclyl; R.sup.1 and R.sup.2 are independently selected from hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, and C.sub.1-4haloalkoxy; each R.sup.3 is independently selected from hydrogen, halogen, and C.sub.1-4alkyl; m is 0, 1 or 2; E is selected from the group consisting of chemical bond, O, O (CR.sup.aR.sup.b).sub.1-2, (CR.sup.aR.sup.b).sub.1-2O, S, NR.sup.5, (CR.sup.aR.sup.b).sub.1-2NR.sup.5, NR.sup.5 (CR.sup.aR.sup.b).sub.1-2, C.sub.1-2alkylene, C?C-, and C.sub.3-6cycloalkyl; wherein, R.sup.a and R.sup.b are independently selected from group consisting hydrogen and C.sub.1-4 alkyl; R.sup.5 is selected from the group consisting of H, C.sub.1-4 alkyl, and C.sub.3-6cycloalkyl; G is selected from the group consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.2-4 alkenyl, C.sub.2-4alkynyl, saturated C.sub.3-8cycloalkyl, unsaturated C.sub.3-8cycloalkyl, saturated 3-12 membered heterocyclyl, unsaturated 3-12 membered heterocyclyl, aryl, heteroaryl, and NR.sup.8R.sup.9; wherein, the cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkoxy, NR.sup.8R.sup.9, CN, C (O) R.sup.t, and S (O).sub.2R.sup.t; wherein, R.sup.t is C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4alkynyl, C.sub.3-8cycloalkyl, 4-8-membered heterocyclyl, aryl, or heteroaryl; R.sup.8 and R.sup.9 are independently selected from the group consisting of H, C.sub.1-4 alkyl, C.sub.3-6cycloalkyl, and 4-8 membered heterocyclyl;

16. The compound of claim 1, wherein, the compound of formula (I) is selected from group consisting of ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## * represents chiral center.

17. The compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, wherein, the pharmaceutically acceptable salt is alkali metal salts, preferably, is the salt selected from the group consisting of sodium salt, potassium salt, and lithium salt.

18. A pharmaceutical composition, comprising a compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof, and pharmaceutically acceptable carriers.

19-20. (canceled)

21. A method for the treatment of diseases, disorders or symptoms associated with NLRP3 activity or expression, which comprises the step: adminstrating the compound of claim 1, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof to a subject in need thereof.

22. The method of claim 21, wherein, the disease, disorder or symptom is selected from the group consisting of inflammation, autoimmune disease, knee osteoarthritis, cancer, infection, central nervous system disease, metabolic disease, cardiovascular disease, respiratory disease, liver disease, kidney disease, ocular disease, skin disease, lymphatic condition, psychological disorder, graft versus host disease, allodynia, cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset of multisystem inflammatory disease (NOMID), familial mediterranean fever (FMF), septic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), systemic juvenile idiopathic arthritis, adult onset Still's disease (AOSD), relapsing polychondritis, schnitzler's syndrome, sweet syndrome, behcet's disease, anti synthetase syndrome, deficiency of interleukin-1 receptor antagonist (DIRA) and haploinsufficiency of A2o (HA2o).

Description

EXAMPLE 1

Preparation of Compound 1

[0171] ##STR00053##

[0172] Compound 1a and 1d were synthesized according to WO2020035465

[0173] To a solution of 1b (18 mg, 0.14 mmol) in DMF (1.5 mL) was added NaH (6 mg, 0.14 mmol) at 0 at. The reaction mixture was stirred 1 h under N.sub.2. Then a solution of 1a (14 mg, 0.06 mmol) in DMF (0.8 mL) was added. The reaction was stirred at 60? C. for about 2 h. The mixture was cooled to RT (room temperature) and quenched with water. Then the mixture was extracted with EA (ethyl acetate) (3?5 mL), and the collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to give the crude product 1c. The crude product was used to the next step without further purification. LCMS: m/z 350.5 [M+H].sup.+.

[0174] The crude product 1c (20 mg, 0.06 mmol) and 1d (14 mg, 0.06 mmol) was dissolved in MeCN (acetonitrile) (2.5 mL). The mixture was stirred at 60? C. for 1 h. The mixture was cooled to RT and concentrated to give the crude. The crude was purifired by Pre-TLC (thin layer chromatography) (DCM (dichloromethane): MeOH (methanol)=8:1, 2% NH.sub.3/H.sub.2O) to afford a white solid 1 (9 mg, 33% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.16 (d, J=5.0 Hz, 1H), 7.06 (s, 1H), 6.86 (d, J=5.0 Hz, 1H), 6.68 (s, 1H), 5.78 (s, 1H), 4.94 (d, J=13.5 Hz, 1H), 4.71 (d, J=13.5 Hz, 1H), 3.67-3.52 (m, 2H), 3.28-3.13 (m, 2H), 2.98-2.89 (m, 3H), 2.88-2.84 (m, 1H), 2.83 (s, 3H), 2.79 (s, 3H), 2.53-2.38 (m, 2H), 2.14-2.07 (m, 2H), 2.06 (s, 3H) ppm. LCMS: m/z 471.5 [M+H].sup.+.

EXAMPLE 2

Preparation of Compound 2

[0175] ##STR00054##

[0176] To a solution of (1-methyl-1,2,5,6-tetrahydropyridine-3-yl) methanol 2a (20 mg, 0.16 mmol) in DMF (2 mL) was added NaH (7 mg, 0.17 mmol) at 0? C. The reaction mixture was stirred 0.5 h. Then a solution of 1a (20 mg, 0.08 mmol) in DMF (1 mL) was added. The reaction was stirred at 60? C. for about 4 h under N.sub.2. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude was purifired by Pre-TLC (DCM: MeOH=15:1) to afford a white solid 2b (13 mg, 45%). LCMS: m/z 350.5 [M+H].sup.+.

[0177] The crude product 2b (13 mg, 0.04 mmol) and 1d (10 mg, 0.04 mmol) was dissolved in MeCN (5 mL). The mixture was stirred at 60? C. for 3 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC (DCM: MeOH: Ammonia=10:1:0.1) to afford a white solid 2 (3 mg, 17% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.14 (d, J=5.0 Hz, 1H), 7.08 (s, 1H), 6.84 (d, J=5.0 Hz, 1H), 6.70 (s, 1H), 6.05 (s, 1H), 5.00 (d, J=12.0 Hz, 1H), 4.70 (d, J=12.0 Hz, 1H), 3.66 (s, 2H), 3.22-3.08 (m, 2H), 2.99-2.74 (m, 10H), 2.51-2.41 (m, 2H), 2.12-2.00 (m, 5H) ppm. LCMS: m/z 471.4 [M+H].sup.+.

EXAMPLE 3

Preparation of Compound 3

[0178] ##STR00055##

[0179] Compound 3f was synthesized according to WO2020035465

[0180] To a solution of 4-Bromopyridine (1.12 g, 7.09 mmol) in DCM (5 mL) was added Mel (Methyl iodide) (2.01 g, 14.18 mmol) at 0? C. The reaction mixture was stirred 16 h at RT. Then the mixture was filterated and the solid was washed with PE (petroleum ether) to give a brown solid 3b (1.70 g, 80% yield). .sup.1H NMR (500 MHZ, D20) ? 8.59 (d, J=6.5 Hz, 2H), 8.24 (d, J=6.5 Hz, 2H), 4.28 (s, 3H) ppm.

[0181] The 3b (0.70 g, 2.33 mmol) and 4-Bromo-2-hydroxypyridine (0.40 g, 2.33 mmol) was dissolved in MeCN (10 mL). The mixture was added Cs.sub.2CO.sub.3 (1.14 g, 3.50 mmol) in portions with stirring at RT. Then the reaction mixture was stirred 3 h at RT. Then the reaction was filterated and the solid was washed with MeCN to give give the crude product 3c (2.0 g). LCMS: m/z 265.2 & 267.2 [M+H].sup.+.

[0182] The crude product 3c (2.0 g) was dissolved in MeOH (30 mL). The mixture was added NaBH.sub.4 (173 mg, 4.6 mmol) in portions with stirring at 0? C. Then the reaction mixture was stirred 1 h at 0? C. The reaction was adjusted to pH=8 with sat. NaHCO.sub.3 slowly and stirred for another 5 min. Then the mixture was diluted with EA (50 mL), dried with anhydrous sodium sulfate, filterated and concentrated to give the crude product. The crude product was purified by column chromatography (0-10% MeOH: DCM) to afford a brown solid 3d (0.3 g, 50% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 7.44 (d, J=7.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 6.60 (dd, J=7.0, 2.0 Hz, 1H), 5.93-5.80 (m, 1H), 3.19 (dd, J=6.0 Hz, J=3.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.54 (td, J=6.0 Hz, J=3.0 Hz, 2H), 2.44 (s, 3H) ppm.

[0183] To a mixture of 3d (120 mg, 0.445 mmol), Bisphenol borate (169 mg, 0.668 mmol), KOAc (131 mg, 1.34 mmol) and Pd (dppf) Cl.sub.2 (36 mg, 0.045 mmol) was added dioxane (1 mL). The mixture was stirred for 16 h at 90? C. under N.sub.2. The reaction was cooled and the mixture of 3e was used to the next step. To a solution of 3e was added 3f (50 mg, 0.22 mmol), K.sub.2CO.sub.3 (123 mg, 0.891 mmol), water (0.1 mL) and Pd (dppf) Cl.sub.2 (18 mg, 0.022 mmol) under N.sub.2. The mixture was stirred for 4 h at 80? C. Then the mixture was cooled to RT, diluted with EA (50 mL), washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to give the crude product. The crude product was purified by column chromatography (0-20% MeOH: DCM, 1% NH.sub.3/H.sub.2O) to afford a brown solid 3g (70 mg, 46% yield). 1H NMR (500 MHZ, CD.sub.3OD) ? 7.56 (d, J=7.0 Hz, 1H), 6.56 (s, 1H), 6.38 (d, J=1.5 Hz, 1H), 6.27 (dd, J=7.0 Hz, J=1.5 Hz, 1H), 5.98-5.87 (m, 1H), 3.25-3.23 (m, 2H), 2.86-2.82 (m, 4H), 2.76-2.68 (m, 2H), 2.66-2.60 (m, 2H), 2.47 (s, 3H), 2.11-2.04 (m, 2H), 2.04 (s, 3H) ppm. LCMS: m/z 336.4 [M+H].sup.+.

[0184] The 3g (25 mg, 0.07 mmol) and 1d (18 mg, 0.07 mmol) was dissolved in MeCN (5 mL). The mixture was stirred at 60? C. for 3 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC (DCM: MeOH: Ammonia=10:2:0.1) to afford a white solid 3 (5 mg, 15% yield).

[0185] To a solution of 3 (1.72 mg, 0.0038 mmoL) in MeCN (1 mL) was added 0.01 mol/L NaOH solution (0.38 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 3 (1.8 mg, 100% yield). MS m/z 457.5 [M+H].sup.+.

EXAMPLE 4

Preparation of Compound 4

[0186] ##STR00056## ##STR00057##

[0187] To a mixture of 4a (1.00 g, 4.22 mmol), 4b (1.31 g, 4.22 mmol), Na.sub.2CO.sub.3 (894 mg, 8.44 mmol) and Pd (PPh3) 4 (487 mg, 0.42 mmol) was added toluene/EtOH/water (8:4:2, v:v:v) (14 mL). The mixture was stirred for 2 h at 100? C. under N.sub.2. The reaction was cooled to RT and filterated through diatomite and concentrated to give the crude product. The crude product was purified by column chromatography (PE: EA=10:1) to afford a white solid 4c (815 mg, 57% yield). LCMS: m/z 340.2 [M+H].sup.+.

[0188] To a mixture of 4c (180 mg, 0.53 mmol), Bisphenol borate (139 mg, 0.55 mmol), KOAc (208 mg, 2.12 mmol) and Pd (dppf) Cl.sub.2 (41 mg, 0.05 mmol) was added dioxane (5 mL). The mixture was stirred for 1 h at 100? C. under N.sub.2. LCMS indicated the reaction was completed. The reaction was cooled and added the mixture of 3f (80 mg, 0.35 mmol) in dioxane (2 mL), K.sub.2CO.sub.3 (219 mg, 1.59 mmol) and water (1 mL). The mixture was stirred for overnight at 100? C. LCMS indicated the reaction was completed. The reaction was cooled to RT, filterated through diatomite and concentrated to give the crude product. The crude product was purified by Pre-TLC (DCM: MeOH=20:1) to afford a white solid 4e (27 mg, 19% yield). LCMS: m/z 406.5 [M+H].sup.+.

[0189] The 4e (27 mg, 0.07 mmol) and 1d (16 mg, 0.07 mmol) was dissolved in MeCN (5 mL). The mixture was stirred at 60? C. for 3 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude. The crude was purified by Pre-TLC (DCM: MeOH: Ammonia=15:1:0.1) to afford an off-white solid 4f (22 mg, 63% yield). LCMS: m/z 527.6 [M+H].sup.+.

[0190] To a solution of 4f (22 mg, 0.04 mmol) in MeOH (5 mL) was added 4 M HCl/MeOH solution (0.5 mL). The mixture was stirred at 50? C. for 2 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC (DCM: MeOH =10:1) to afford a white solid 4g (15 mg, 83% yield). LCMS: m/z 427.5 [M+H].sup.+.

[0191] To a solution of 4g (15 mg, 0.04 mmol) in MeOH (5 mL) was added paraformaldehyde (2 mg, 0.07mmol), ZnCl.sub.2 (14 mg, 0.11 mmol) and NaBH.sub.3CN (7 mg, 0.11 mmol). The mixture was stirred at 60? C. for 2 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC (DCM: MeOH: Ammonia=15:1:0.1) to afford a pale solid 4 (3 mg, 19% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.57 (d, J=5.0 Hz, 1H), 7.43 (s, 1H), 7.20 (dd, J=5.0, 1.5 Hz, 1H), 7.15 (s, 1H), 6.68-6.63 (m, 1H), 3.92 (s, 2H), 3.47 (t, J=6.0 Hz, 2H), 3.03 (s, 3H), 3.01-2.95 (m, 6H), 2.93-2.84 (m, 3H), 2.15-2.08 (m, 2H), 2.04 (s, 3H) ppm. LCMS: m/z 441.4 [M+H].sup.+.

EXAMPLE 5

Preparation of Compound 5

[0192] ##STR00058##

[0193] Using the method in Example 2, yellow solid compound 5b (15 mg, 26% yield) was obtained from compound la (30 mg, 0.12 mmol) and compound 5a (28 mg, 0.24 mmol).

[0194] Using the method in Example 2, white solid compound 5 (12 mg, 59% yield) was obtained from compound 5b (15 mg, 0.04 mmol) and 1d (11 mg, 0.04 mmol). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.14 (d, J=5.0 Hz, 1H), 7.10 (s, 1H), 6.81 (dd, J=5.0, 1.0 Hz, 1H), 6.68 (s, 1H), 5.87-5.83 (m, 1H), 4.79-4.69 (m, 2H), 4.16-4.12 (m, 2H), 3.84-3.80 (m, 2H), 2.98 (s, 3H), 2.94 (t, J=7.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.24-2.18 (m, 2H), 2.12-2.04 (m, 2H), 2.06 (s, 3H) ppm. LCMS: m/z 458.4 [M+H].sup.+.

EXAMPLE 6

Preparation of Compound 6

[0195] ##STR00059##

[0196] The cyclopropyl Sulfonamide 6a (2.00 g, 16.51 mmol) and 4-Dimethylaminopyridine (4.03 g, 33.02 mmol) was dissolved in MeCN (28 mL). The mixture was stirred at RT for 10 min. Then diphenyl carbonate (3.89 g, 18.16 mmol) was added. The mixture was stirred at RT for 48 h to obtain a solution of 6b, which was used to the next step directly.

[0197] The 2b (40 mg, 0.11 mmol) and 6b (0.5 mL) was dissolved in MeCN (5 mL). The mixture was stirred at 60? C. for 3 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purifired by Pre-TLC (DCM: MeOH: Ammonia=10:2:0.1) to afford a white solid 6 (17 mg, 30% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.14 (d, J=5.2 Hz, 1H), 7.07 (s, 1H), 6.83 (d, J=5.2 Hz, 1H), 6.69 (s, 1H), 6.01 (s, 1H), 4.94 (d, J=12.5 Hz, 1H), 4.69 (d, J=12.5 Hz, 1H), 3.53 (s, 2H), 3.03 (dd, J=10.9, 5.6 Hz, 2H), 2.94 (t, J=7.4 Hz, 2H), 2.90-2.84 (m, 2H), 2.73 (s, 3H), 2.65-2.59 (m, 1H), 2.48-2.39 (m, 2H), 2.13-2.06 (m, 2H), 2.05 (s, 3H), 1.04-0.97 (m, 2H), 0.91-0.84 (m, 2H) ppm. MS m/z 497.5 [M+H].sup.+.

[0198] To a solution of 6 (14.36 mg, 0.0289 mmol) in MeCN (2 mL) was added 0.01 mol/L NaOH solution (2.89 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 6 (15 mg, 100% yield). MS m/z 497.5 [M+H].sup.+.

EXAMPLE 7

Preparation of Compound 7

[0199] ##STR00060##

[0200] The N, N-dimethylamino Sulfonamide (2.00 g, 16.11 mmol) and 4-Dimethylaminopyridine (3.94 g, 32.22 mmol) was dissolved in MeCN (28 mL). The mixture was stirred at RT for 10 min. Then diphenyl carbonate (3.80 g, 17.72 mmol) was added. The mixture was stirred at RT for overnight and white solid precipitated. The reaction was filterated and the solid was washed with MTBE (methyl tert-butyl ether). The solid was dried to obtain compound 7b (1.20 g, 27% yield). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 8.80 (d, J=7.6 Hz, 2H), 6.98 (d, J=7.6 Hz, 2H), 3.25 (s, 6H), 2.66 (s, 6H) ppm.

[0201] Using the method in Example 2, white solid compound 7 (15 mg, 26% yield) was obtained from compound 2b (40 mg, 0.11 mmol) and 7b (63 mg, 0.23 mmol). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.16 (d, J=5.2 Hz, 1H), 7.09 (s, 1H), 6.81 (d, J=5.2 Hz, 1H), 6.67 (s, 1H), 6.00 (s, 1H), 4.89 (d, J=12.6 Hz, 1H), 4.72 (d, J=12.3 Hz, 1H), 3.49-3.39 (m, 2H), 2.98-2.90 (m, 4H), 2.87-2.82 (m, 2H), 2.70-2.63 (m, 9H), 2.46-2.34 (m, 2H), 2.12-2.06 (m, 2H), 2.05 (s, 3H) ppm. MS m/z 500.5 [M+H].sup.+.

[0202] To a solution of 7 (13.41 mg, 0.0268 mmol) in MeCN (2 mL) was added 0.01 mol/L NaOH solution (2.68 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 7 (15 mg, 100% yield). MS m/z 500.7 [M+H].sup.+.

EXAMPLE 8

Preparation of Compound 8

[0203] ##STR00061##

[0204] The compound 8a (1.00 g, 7.41mmol) and potassium thioacetate (1.69 g, 14.81 mmol) was dissolved in DMF (10 mL). The mixture was stirred at 60? C. for 4 h. TLC indicated the reaction was completed. The reaction was added sat. NaCl and extracted with EA (3?50 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to give the crude product. The crude product was purified by column chromatography (PE: EA=5:1) to afford yellow oil 8b (670 mg, 69%). .sup.1H NMR (500 MHZ, CDCl.sub.3) 8 4.15-4.06 (m, 1H), 2.49-2.38 (m, 2H), 2.27 (s, 3H), 2.11-1.93 (m, 4H) ppm.

[0205] To a solution of NCS (N-Chlorosuccinimide) (824 mg, 6.17 mmol) in MeCN (10 mL) was added Con. HCl (1.5 mL). The mixture was stirred at RT for 10 min. Then a solution of 8b (670 mg, 5.15 mmol) in MeCN (5 mL) was added to the reaction at 0? C. The mixture was stirred at 0? C. for 10 min. TLC indicated the reaction was completed. The reaction was quenched with sat. NaHCO3, extracted with MTBE (3?30 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to give the yellow oil 8c (548 mg, 69%), which was used to the next step directly.

[0206] To a solution of 8c (548 mg, 3.56 mmol) in DCM (5 mL) was added Con. ammonia (1.5 mL). The mixture was stirred at RT for 1 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude. The crude was purified by column chromatography c to give compound 8d (234 mg, 34%). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 6.72 (s, 2H), 3.75-3.70 (m, 1H), 2.34-2.16 (m, 4H), 1.97-1.82 (m, 2H) ppm.

[0207] The 8d (234 mg, 1.73mmol) and 4-Dimethylaminopyridine (423 mg, 3.46 mmol) was dissolved in MeCN (3 mL). The mixture was stirred at RT for 48 h. Then diphenyl carbonate (3.89 g, 18.16 mmol) was added. The mixture was stirred at RT for 48 h to obtain a solution of 8e, which was used to the next step directly.

[0208] The 2b (40 mg, 0.11 mmol) and 8e (0.5 mL) was dissolved in MeCN (5 mL). The mixture was stirred at 60? C. for 3 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC (DCM: MeOH: Ammonia=10:1:0.1) to afford white solid 8 (11 mg, 19% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.15 (d, J=5.2 Hz, 1H), 7.06 (s, 1H), 6.82 (d, J=5.1 Hz, 1H), 6.66 (s, 1H), 6.02 (s, 1H), 4.93 (d, J=12.5 Hz, 1H), 4.71 (d, J=12.1 Hz, 1H), 3.98-3.91 (m, 1H), 3.55 (s, 2H), 3.12-3.00 (m, 2H), 2.93 (t, J=7.4 Hz, 2H), 2.88-2.82 (m, 2H), 2.74 (s, 3H), 2.48-2.40 (m, 2H), 2.40-2.32 (m, 2H), 2.21-2.13 (m, 2H), 2.11-2.05 (m, 2H), 2.04 (s, 3H), 2.00-1.85 (m, 2H). MS m/z 511.6 [M+H].sup.+.

[0209] To a solution of 8 (9.59 mg, 0.0188 mmoL) in MeCN (2 mL) was added 0.01 mol/L NaOH solution (1.88 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 8 (10 mg, 100% yield). MS m/z 511.5 [M+H].sup.+.

EXAMPLE 9

Preparation of Compound 9

[0210] ##STR00062##

[0211] Using the method in Example 6, white solid compound 9 (11 mg, 19% yield) was obtained from compound 3g (40 mg, 0.12 mmol) and 6b (0.5 mL reaction solution). .sup.1H NMR (500 MHZ, CDCl.sub.3) ? 7.74 (brs, 1H), 7.29 (d, J=6.8 Hz, 1H), 7.02 (s, 1H), 6.32 (s, 1H), 6.13 (d, J=6.7 Hz, 1H), 5.77 (s, 1H), 4.80 (brs, 1H), 3.19-3.04 (m, 2H), 2.98-2.77 (m, 6H), 2.74-2.61 (m, 2H), 2.59-2.50 (m, 1H), 2.43 (s, 3H), 2.12 (s, 3H), 2.10-2.00 (m, 2H), 1.20-1.10 (m, 2H), 0.90-0.80 (m, 2H) ppm. MS m/z 483.5 [M+H].sup.+.

[0212] To a solution of 9 (10.52 mg, 0.0218 mmoL) in MeCN (2 mL) was added 0.01 mol/L NaOH solution (2.18 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 9 (11.0 mg, 100% yield). MS m/z 483.6 [M+H].sup.+

EXAMPLE 10

Preparation of Compound 10

[0213] ##STR00063##

[0214] Using the method in Example 1, compound 10b crude product (97 mg, 55% purity) was obtained from compound 1a (30 mg, 0.12 mmol) and 10a (66 mg, 0.31 mmol).

[0215] Using the method in Example 1, compound 10c (20 mg, 29% yield) was obtained from compound 10b crude product (97 mg, 55% purity) and 1d (30 mg, 0.12 mmol).

[0216] To a solution of 10c (20 mg, 0.04 mmol) in MeOH (3 mL) was added 4 M HCl/MeOH solution (0.5 mL). The mixture was stirred at 40? C. for 1 h. After cooling the reaction solution, ammonia water was added to adjust the pH to neutral. The mixture was concentrated to give the crude. The crude was purifired by Pre-TLC (DCM: MeOH: Ammonia=2:1:0.02) to afford a white solid 10 (7 mg, 43% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.15 (d, J=5.2 Hz, 1H), 7.12 (s, 1H), 6.83 (d, J=4.2 Hz, 1H), 6.60 (s, 1H), 5.07-5.01 (m, 1H), 4.16 (s, 2.Math.H), 4.10 (s, 2H), 3.05 (s, 3H), 2.95 (t, J=7.4 Hz, 2H), 2.90-2.82 (m, 4H), 2.46-2.36 (m, 2H), 2.13-2.07 (m, 2H), 2.06 (s, 3H) ppm. MS m/z 457.4 [M+H].sup.+.

[0217] To a solution of 10 (3.82 mg, 0.0084 mmoL) in MeCN (1 mL) was added 0.01 mol/L NaOH solution (0.84 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 10 (11.0 mg, 100% yield). MS m/z 483.6 [M+H].sup.+.

EXAMPLE 11

Preparation of Compound 11

[0218] ##STR00064## ##STR00065##

[0219] To a mixture of 11a (4.00 g, 29.39mmol) and iodophenyl diacetate (14.20 g, 44.09mmol) in DCM was added KBr (5.95 g, 49.96mmol). The mixture was stirred for 48 h at RT under 365 nm fluorescent lamp irradiation. Filtered the reaction mixture, distilled the filtrate at 70? C. under atmospheric pressure until there is no fraction, and then distilled at 60? C. under reduced pressure to obtain a light yellow liquid compound 11b (2.07 g, 41% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 4.28-4.13 (m, 1H), 3.38-3.19 (m, 2H), 3.06-2.89 (m, 2H) ppm

[0220] Using the method in Example 8, yellow oil compound 11c (150 mg, 15% yield) was obtained from compound 11b (1.00 g, 5.85 mmol) and potassium thioacetate (1.27 g, 7.41 mmol).

[0221] Using the method in Example 8, 11e (20 mg, 17% yield) was obtained from compound 11c (100 mg, 0.60mmol). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.11 (s, 2H), 3.76-3.66 (m, 1H), 3.02-2.83 (m, 4H)

[0222] The 11e (20 mg, 0.12 mmol) and 4-Dimethylaminopyridine (29 mg, 0.23 mmol) was dissolved in MeCN (1 mL). The mixture was stirred at RT for 10 min. Then diphenyl carbonate (28 mg, 0.13 mmol) was added. The mixture was stirred at RT for 48 h to obtain a solution of 11f, which was used to the next step directly.

[0223] Using the method in Example 6, white solid compound 11 (5 mg, 13% yield) was obtained from compound 2b (20 mg, 0.06 mmol) and 11f (1.0 mL, reaction solution). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.14 (d, J=5.1 Hz, 1H), 7.05 (s, 1H), 6.83 (dd, J=5.2, 1.1 Hz, 1H), 6.70 (s, 1H), 6.07 (s, 1H), 5.01 (d, J=12.7 Hz, 1H), 4.69 (d, J=11.2 Hz, 1H), 3.88-3.79 (m, 1H), 3.72 (m, 2H), 3.27-3.18 (m, 2H), 2.96-2.84 (m, 6H), 2.87 (s, 3H), 2.80-2.70 (m, 2H), 2.52-2.46 (m, 2H), 2.12-2.02 (m, 2H), 2.05 (s, 3H). MS m/z 547.6 [M+H].sup.+.

[0224] To a solution of 11 (4.58 mg, 0.0084 mmoL) in MeCN (1 mL) was added 0.01 mol/L NaOH solution (0.84 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 11 (11.0 mg, 100% yield). MS m/z 547.8 [M+H].sup.+.

EXAMPLE 12

Preparation of Compound 12

[0225] ##STR00066##

[0226] Compound 12a was synthesized according to WO2020104657

[0227] Using the method in Example 6, white solid compound 12 (30 mg, 90% yield) was obtained from compound 2b (21 mg, 0.06 mmol) and 12a (40 mg, 0.12 mmol). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.15 (d, J=4.5 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.11 (s, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.66 (s, 1H), 6.14 (s, 1H), 5.04 (d, J=12.8 Hz, 1H), 4.76 (d, J=12.3 Hz, 1H), 4.61 (dt, J=13.4, 6.7 Hz, 1H), 3.88 (s, 2H), 3.41-3.35 (m, 2H), 2.98 (s, 3H), 2.92 (t, J=7.4 Hz, 2H), 2.64-2.51 (m, 4H), 2.06 (s, 3H), 2.04-1.97 (m, 2H), 1.51 (d, J=6.7

[0228] Hz, 6H) ppm. MS m/z 565.8 [M+H].sup.+.

[0229] To a solution of 12 (24 mg, 0.0426 mmoL) in MeCN (2 mL) was added 0.01 mol/L NaOH solution (4.26 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 12 (25.0 mg, 100% yield). MS m/z 565.7 [M+H].sup.+.

EXAMPLE 13

Preparation of Compound 13

[0230] ##STR00067##

[0231] To a solution of 3a (100 mg, 0.59 mmol) in MeCN (1 mL) was added Con. ammonia (1.0 mL). The mixture was stirred at RT for 2 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by column chromatography to give a white solid compound 13b (71 mg, yield 80%). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 6.70 (s, 2H), 3.43-3.35 (m, 1H), 1.94-1.81 (m, 4H), 1.70-1.60 (m, 2H), 1.59-1.50 (m, 2H) ppm.

[0232] The 13b (70 mg, 0.47 mmol) and 4-Dimethylaminopyridine (115 mg, 0.94 mmol) was dissolved in MeCN (3 mL). The mixture was stirred at RT for 5 min. Then diphenyl carbonate (28 mg, 0.13 mmol) was added. The mixture was stirred at RT for 48 h to obtain a solution of 13c, which was used to the next step directly.

[0233] Using the method in Example 6, white solid compound 13 (2.8 mg, 32% yield) was obtained from compound 2b (6 mg, 0.02 mmol) and 13c (0.4 mL reaction solution). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 8.16 (d, J=5.2 Hz, 1H), 7.41 (s, 1H), 7.07 (s, 1H), 6.74 (d, J=5.1 Hz, 1H), 6.57 (s, 1H), 5.83 (s, 1H), 4.70 (s, 2H), 3.71-3.63 (m, 1H), 2.94-2.85 (m, 3H), 2.74 (t, J=7.3 Hz, 2H), 2.65-2.62 (m, 1H), 2.44 (t, J=5.6 Hz, 2H), 2.38-2.34 (m, 1H), 2.27 (s, 3H), 2.14 (s, 2H), 2.03-2.00 (m, 1H), 1.98 (s, 3H), 1.80-1.71 (m, 4H), 1.64-1.56 (m, 2H), 1.56-1.48 (m, 2H) ppm. MS m/z 525.7 [M+H].sup.+.

[0234] To a solution of 13 (1.27 mg, 0.0024 mmoL) in MeCN (0.2 mL) was added 0.01 mol/L NaOH solution (0.24 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 13 (1.32 mg, 100% yield). MS m/z 525.5 [M+H].sup.+.

EXAMPLE 14

Preparation of Compound 14

[0235] ##STR00068##

[0236] To a solution of sulfonamide (353 mg, 3.68 mmol) in dioxane (4 mL) was added 14a (200 mg, 3.50 mmol). The mixture was stirred at 90? C. for 24 h. TLC indicated the reaction was completed. The mixture was concentrated and dissolved in CHCl.sub.3. The mixture was concentrated to give the white crude product 14b, which was used to the next step directly.

[0237] The 14b (477 mg) and 4-Dimethylaminopyridine (855 mg, 7.00 mmol) was dissolved in MeCN (5 mL). The mixture was stirred at RT for 5 min. Then diphenyl carbonate (900 mg, 4.20 mmol) was added. The mixture was stirred at RT for 3 d to obtain a solution of 14c, which was used to the next step directly.

[0238] Using the method in Example 6, white solid compound 14 (6.37 mg, 35% yield) was obtained from compound 2b (12 mg, 0.03 mmol) and 14c (1.0 mL reaction solution).

[0239] To a solution of 14 (2.34 mg, 0.0046 mmoL) in MeCN (0.5 mL) was added 0.01 mol/L NaOH solution (0.24 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 14 (2.44 mg, 100% yield). MS m/z 512.6 [M+H].sup.+.

EXAMPLE 15

Preparation of Compound 15

[0240] ##STR00069##

[0241] To a solution of 15a (200 mg, 1.08 mmol) in DCM (5 mL) was added DAST (diethylaminosulphur trifluoride) 15b (261 mg, 1.62 mmol) slowly at 0? C. The reaction mixture was stirred overnight at RT. When the reaction was completed, the reaction was quenched with sat. NaHCO.sub.3, extracted with DCM (3?15 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to to give the crude product. The crude product was purified by column chromatography (PE: EA=8:1) to give a white solid compound 15c (45 mg, 20% yield). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 7.52 (s, 1H), 5.90 (t, J=57.1 Hz, 1H), 1.38 (s, 9H), 0.97-0.91 (m, 2H), 0.84-0.76 (m, 2H) ppm.

[0242] To a solution of 15c (45 mg, 0.22 mmol) in DCM (4 mL) was added 4 M HCl/dioxane solution (1 mL). The mixture was stirred overnight at RT. When the reaction was completed, the mixture was concentrated to give brown solid 15d (31 mg, 100% yield). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) 89.11 (brs, 3H), 5.96 (t, J=53.8 Hz, 1H), 1.21-1.14 (m, 2H), 1.04-1.00 (m, 2H) ppm.

[0243] Under ice water bath, Chlorosulfonyl isocyanate 15f (7 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL) and then compound 15e (8 mg, 0.05 mmol) was added. The reaction mixture was stirred in an ice water bath for 10 minutes. TLC indicated the reaction was completed. A mixture of dichloromethane (2 mL) of compound (13 mg, 0.09 mmol) and diisopropylethylamine (2 drops) was slowly added to the reaction solution. The reaction mixture was stirred at room temperature for 1 hour. After the reaction is completed, the reaction solution is concentrated to obtain the crude product. The crude product was purified by Pre-TLC (DCM: MeOH=15:1, 2% ammonia) to afford a white solid 15 (4 mg, 22% yield). 1H NMR (500 MHZ, DMSO-d.sub.6) ? 10.29 (s, 1H), 7.89 (s, 1H), 6.91 (s, 1H), 6.12 (t, J=57.6 Hz, 1H), 2.80 (t, J=7.3 Hz, 4H), 2.70 (t, J=7.3 Hz, 4H), 2.02-1.92 (m, 4H), 1.10-1.05 (m, 2H), 0.96-0.91 (m, 2H) ppm. MS m/z 386.5 [M+H].sup.+.

[0244] To a solution of 15 (2.89 mg, 0.0075 mmoL) in MeCN (1.0 mL) was added 0.01 mol/L NaOH solution (0.75 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 15 (3.05 mg, 100% yield). MS m/z 386.3 [M+H].sup.+.

EXAMPLE 16

Preparation of Compound 16

[0245] ##STR00070##

[0246] To a solution of tBuOK (549 mg, 4.89 mmol) in DMF (5 mL) was added 16a (503 mg, 2.72 mmol) and 16b (472 mg, 2.44 mmol) at ?50? C. under N.sub.2. The reaction mixture was stirred for 1 h at ?50? C. Then sat. NH.sub.4Cl (10.0 mL) and Con. HCl (5 mL) was added. The reaction was stirred for 3 h at RT. TLC indicated the reaction was completed. Water (30 mL) was added and extracted with EA (3?30 mL). The collected organic phase was washed with sat.NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to to give the crude product. The crude product was purified by column chromatography (PE: EA=20:1) to give a white solid 16c (353 mg, 59% yield). .sup.1H NMR (500 MHZ, CDCl.sub.3) ? 5.01 (s, 1H), 4.54 (d, J=24.5 Hz, 1H), 1.44 (s, 9H), 1.04-0.90 (m, 4H) ppm.

[0247] To a solution of 16c (353 mg, 1.61 mmol) in DCM (10 mL) was added 4 M HCl/dioxane solution (3 mL). The mixture was stirred overnight at 40? C. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product 16d, which was used to the next step directly.

[0248] To a solution of 16d (250 mg, 1.61 mmol) in ethylene glycol dimethyl ether (5 mL) was added diisopropylethylamine (5 drops) and sulfonamide (185 mg, 1.93 mmol). The reaction mixture was stirred overnight at 90? C. TLC indicated the reaction was completed. The reaction was concentrated to to give the crude product. The crude product was purified by column chromatography (PE: EA=2:1) to give a white solid 16e (82 mg, 26% yield). .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 7.30 (s, 1H), 6.63 (s, 2H), 4.90 (dd, J=25.9, 3.3 Hz, 1H), 1.12 (q, J=4.8 Hz, 2H), 0.78 (q, J=5.0 Hz, 2H) ppm.

[0249] The 16e (82 mg, 0.41 mmol) and 4-Dimethylaminopyridine (101 mg, 0.83 mmol) was dissolved in MeCN (2 mL). The mixture was stirred at RT for 5 min. Then diphenyl carbonate (98 mg, 0.46 mmol) was added. The mixture was stirred at RT for 48 h to obtain a solution of 16f, which was used to the next step directly.

[0250] Using the method in Example 6, white solid compound 16 (3.0 mg, 13% yield) was obtained from compound 15e (10 mg, 0.06 mmol) and 16f (1.0 mL reaction solution). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 6.98 (s, 1H), 4.82 (dd, J=24.8, 2.4 Hz, 1H), 2.87 (t, J=7.3 Hz, 4H), 2.79 (t, J=7.3 Hz, 4H), 2.11-2.02 (m, 4H), 1.24 (q, J=5.0 Hz, 2H), 0.94 (q, J=5.0 Hz, 2H) ppm. MS m/z 398.4 [M+H].sup.+.

[0251] To a solution of 16 (2.41 mg, 0.0061 mmoL) in MeCN (1 mL) was added 0.01 mol/L NaOH solution (0.61 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 16 (2.54 mg, 100% yield). MS m/z 398.3 [M+H].sup.+.

EXAMPLE 17

Preparation of Compound 17

[0252] ##STR00071## ##STR00072##

[0253] Using the method in Example 16, white solid compound 17b (384.0 mg, 32% yield) was obtained from compound 17a (1.00 g, 5.40 mmol), tBuOK (1.09 g, 9.72 mmol) and 16b (939 mg, 4.86 mmol). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 4.79 (brs, 1H), 4.23 (brs, 1H), 3.13-2.99 (m, 2H), 2.60-2.48 (m, 2H), 1.44 (s, 9H) ppm

[0254] Using the method in Example 16, crude compound 17c was obtained from compound 17b (148 mg, 0.68 mmol), which was used to the next step directly.

[0255] Using the method in Example 16, white solid compound 17d (50.0 mg, 37% yield) was obtained from compound 17c (105 mg, 0.67 mmol) and sulfonamide (78 mg, 0.81 mmol). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.16 (d, J=8.8 Hz, 1H), 6.62 (s, 2H), 3.92-3.76 (m, 1H), 3.03-2.91 (m, 2H), 2.74-2.62 (m, 2H) ppm.

[0256] The 17d (50 mg, 0.25 mmol) and 4-Dimethylaminopyridine (62 mg, 0.50 mmol) was dissolved in MeCN (2 mL). The mixture was stirred at RT for 5 min. Then diphenyl carbonate (59 mg, 0.28 mmol) was added. The mixture was stirred at RT for 48 h to obtain a solution of 17e, which was used to the next step directly.

[0257] Using the method in Example 6, white solid compound 17 (7 mg, 20% yield) was obtained from compound 15e (15 mg, 0.09 mmol) and 17e (1.0 mL reaction solution). .sup.1H NMR (500 MHz, CD.sub.3OD) ? 6.98 (s, 1H), 4.10-4.02 (m, 1H), 3.11-3.03 (m, 2H), 2.87 (t, J=7.4 Hz, 4H), 2.79 (t, J=7.4 Hz, 4H), 2.77-2.72 (m, 2H), 2.09-2.03 (m, 4H) ppm. MS m/z 398.4 [M+H].sup.+.

[0258] To a solution of 17 (6.4 mg, 0.0161 mmoL) in MeCN (1 mL) was added 0.01 mol/L NaOH solution (1.61 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 17 (6.74 mg, 100% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 6.88 (s, 1H), 3.99-3.90 (m, 1H), 3.05-2.94 (m, 2H), 2.88-2.74 (m, 8H), 2.74-2.61 (m, 2H), 2.11-1.95 (m, 4H) ppm MS m/z 398.3 [M+H].sup.+.

EXAMPLE 18

Preparation of Compound 18

[0259] ##STR00073##

[0260] The 18a (90 mg, 0.53 mmol) was dissolved in dioxane (1.5 mL), and diisopropylethylamine (2 drops) was added to adjust the pH of the mixture to alkaline. After this, sulfonamide (62 mg, 0.64 mmol) was added. The mixture was stirred overnight at 95? C. The mixture was cooled to room temperature, filtered and washed the reaction solution. The obtained filtrate is concentrated to obtain a white solid crude product 18b, which was used to the next step directly. The crude product 18b (111 mg) and 4-Dimethylaminopyridine (62 mg, 0.50 mmol) was dissolved in MeCN (3 mL). The mixture was stirred at RT for 5 min. Then diphenyl carbonate (123 mg, 0.58 mmol) was added. The mixture was stirred at RT for 2 d to obtain a solution of 18c, which was used to the next step directly.

[0261] Using the method in Example 6, white solid compound 18 (7.3 mg, 31% yield) was obtained from compound 15e (10 mg, 0.06 mmol) and 18c (0.5 mL reaction solution). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.00 (s, 1H), 3.41-3.22 (m, 4H), 2.93-2.81 (m, 4H), 2.81-2.68 (m, 4H), 2.39-2.19 (m, 4H), 2.13-1.96 (m, 4H) ppm. MS m/z 412.4 [M+H].sup.+.

[0262] To a solution of 18 (6.93 mg, 0.0168 mmoL) in MeCN (1 mL) was added 0.01 mol/L NaOH solution (1.68 mL) at RT. The reaction solution was stirred for 5 minutes and freeze dried to obtain a white solid sodium salt of compound 18 (7.30 mg, 100% yield). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 6.87 (s, 1H), 3.22 (t, J=5.5 Hz, 4H), 2.87-2.77 (m, 8H), 2.27 (t, J=5.5 Hz, 4H), 2.08-1.98 (m, 4H). MS m/z 412.4 [M+H].sup.+.

EXAMPLE 19

Preparation of Compound 19

[0263] ##STR00074## ##STR00075##

[0264] To a solution of NaH (642 mg, 60%, 16.06 mmol) in THF (25 mL) was added ethyl 2-(diethoxyphosphoryl) acetate (3.60 g, 16.06 mmol) at ?78? C. under N.sub.2. The reaction mixture was warmed to RT and stirred 0.5 h. Then 19a (2.50 g, 14.60 mmol) was added at 0? C. The mixture was stirred overnight at RT. TLC indicated the reaction was completed. The mixture was quenched with sat. NaHCO.sub.3 and extracted with EA (3?50 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated. The crude was purified by column chromatography to give the 19b (2.50 g, 71%).

[0265] To a solution of 19b (590 mg, 2.45 mmol) in THF (tetrahydrofuran) (10 mL) was added DIBAL-H (3.60 g, 16.06 mmol) at ?78? C. under N.sub.2. After this, the mixture was stirred for 1 h at ?78? C. TLC indicated the reaction was completed. Warmed the temperature of the reaction solution to 0? C., then water (0.2 mL), 15% sodium hydroxide aqueous solution (0.2 mL), and water (0.4 mL) was added successively. The reaction mixture was stirred at RT for 15 minutes. Anhydrous sodium sulfate was added and the reaction was stirred at RT for another 15 minutes. The mixture was filterated and concentrated. The crude product was purified by column chromatography to give the product 19c (372 mg, 76%).

[0266] To a solution of 19c (200 mg, 1.00 mmol) in DCM (5 mL) was added diisopropylethylamine (388 mg, 3.01 mmol) and methanesulfonyl chloride (185 mg, 1.93 mmol) at 0? C. The reaction mixture was stirred for 2 h at RT. TLC indicated the reaction was completed. A solution of sat. NaCl was added and extracted with DCM (3?20 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to give the crude product 19d (208 mg, 75%), which was used to the next step directly.

[0267] The compound 19d (100 mg, 0.36 mmol), Nal (5 mg, 0.04 mmol) and 1 M dimethylamine tetrahydrofuran solution (2 mL, 2.00 mmol) was dissolved in MeCN (2 mL). The mixture was stirred at 60? C. for 3 h under sealed tube. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by column chromatography to give the product 19e (51 mg, 63%). MS m/z 227.4 [M+H].sup.+.

[0268] To a solution of 19e (30 mg, 0.13 mmol) in DCM (1 mL) was added TFA (trifluoroacetic acid) (0.5 mL). The reaction mixture was stirred for 3 h at 40? C. TLC indicated the reaction was completed. The mixture was concentrated, dissolved in MeCN (1 mL) and con. HCl (0.1 mL). The mixture was freeze dried to obtain 19f (21 mg, 97%). MS m/z 127.2 [M+H].sup.+.

[0269] To a solution of chlorosulfonyl isocyanate (6 mg, 0.04 mmol) in DCM (1 mL) was added 19g (8 mg, 0.04 mmol) at 0? C. The reaction mixture was stirred for 10 min and 19f (11 mg, 0.09 mmol) was added. TLC indicated the reaction was completed. The mixture was quenched with water and extracted with DCM (3?5 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated. The crude product was purified by reverse column chromatography to give 19 (0.7 mg, 4%). MS m/z 405.4 [M+H].sup.+.

EXAMPLE 20

Preparation of Compound 20

[0270] ##STR00076## ##STR00077##

[0271] To a solution of tBuOK (163 mg, 1.46 mmol) in DMF (2 mL) was added 20a (150 mg, 0.81 mmol) and 20b (140 mg, 0.73 mmol) at ?50? C. under N.sub.2. The reaction mixture was stirred for 1 h at ?50? C. TLC indicated the reaction was completed. Then Con. HCl (1 mL) was added. The reaction was stirred for 2 h at RT. Water (20 mL) was added and extracted with EA (3?30 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to to give the crude product. The crude product was purified by column chromatography to give 20c (63 mg, 36%). .sup.1H NMR (500 MHZ, CDCl.sub.3) ? 5.01 (s, 1H), 4.54 (d, J=24.5 Hz, 1H), 1.44 (s, 9H), 1.02-0.96 (m, 2H), 0.94-0.89 (m, 2H) ppm.

[0272] To a solution of 20c (45 mg, 0.29 mmol) in DCM (2 mL) was added 4 M HCl/dioxane solution (1 mL). The mixture was stirred overnight at RT. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product 20d, which was used to the next step directly. .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 8.73 (s, 3H), 4.94 (dd, J=1.4 Hz, J=25.1 Hz, 1H), 1.22 (t, J=6.3 Hz, 2H), 0.94 (t, J=6.3 Hz, 2H) ppm.

[0273] To a solution of 20d (45 mg, 0.29 mmol) in DCM (2 mL) was added diisopropylethylamine (148 mg, 1.15 mmol) and sulfamyl chloride (40 mg, 0.35 mmol) at 0? C. The reaction mixture was stirred for 0.5 h at 0? C. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC to give the compound 20e (27 mg, 47%).

[0274] The 20e (27 mg, 0.14 mmol) and 4-Dimethylaminopyridine (33 mg, 0.27 mmol) was dissolved in MeCN (1 mL). The mixture was stirred at RT for 10 min. Then diphenyl carbonate (32 mg, 0.15 mmol) was added. The mixture was stirred at RT for 48 h to obtain a solution of 20f, which was used to the next step directly.

[0275] Compound 20g was synthesized according to WO20190211463

[0276] The compound 20g (14 mg, 0.06 mmol) and 20f (1 mL, reaction mixture) was dissolved in MeCN (1 mL). The mixture was stirred at 60? C. for 3 h. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC (DCM: MeOH: Ammonia=10:1:0.1) to give the compound 20 (3 mg, 11%). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.17 (d, J=5.2 Hz, 1H), 7.12 (s, 1H), 6.78 (dd, J=5.2, 1.3 Hz, 1H), 6.63 (s, 1H), 4.68 (dd, J=24.6, 2.4 Hz, 1H), 3.93 (s, 3H), 2.95 (t, J=7.4 Hz, 2H), 2.86-2.81 (m, 2H), 2.12-2.05 (m, 2H), 2.04 (s, 3H), 1.32-1.26 (m, 2H), 1.10-1.03 (m, 2H) ppm. MS m/z 479.5 [M+H].sup.+.

EXAMPLE 21

Preparation of Compound 21

[0277] ##STR00078## ##STR00079##

[0278] Compound 21a was synthesized according to WO2019034690

[0279] To a solution of 21a (700 mg, 1.81 mmol) in THF (14 mL) was added 3-bromo cyclobutanone (404 mg, 2.71 mmol) and K.sub.2CO.sub.3 (499 mg, 3.61 mmol). The reaction mixture was stirred for 3 h. TLC indicated the reaction was completed. Water (30 mL) was added and the mixture was extracted with EA (3?30 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to to give the crude product. The crude product was purified by column chromatography to give 21b (505 mg, 61%). .sup.1H NMR (500 MHz, CDCl.sub.3) ? 7.54 (d, J=2.0 Hz, 1H), 7.12-7.07 (m, 4H), 6.80-6.76 (m, 4H), 6.72 (d, J=1.9 Hz, 1H), 5.08-4.99 (m, 1H), 4.33 (s, 4H), 3.79 (s, 6H), 3.74-3.65 (m, 2H), 3.61-3.52 (m, 2H). MS m/z 456.3 [M+H].sup.+.

[0280] A solution of tBuOK (111 mg, 0.99 mmol) in DMF (3 mL) was cooled to ?50? C. under N.sub.2, to which was then added a solution of 21b (250 mg, 0.55 mmol) and 20b (95 mg, 0.49 mmol) in DMF (2 mL). The reaction mixture was stirred for 1 h at ?50? C. TLC indicated the reaction was completed. Then Con. HCl (1 mL) was added. The reaction was stirred for 2 h at RT. Water (20 mL) was added and the mixture was extracted with EA (3?30 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated to to give the crude product. The crude product was purified by column chromatography to give 21c (72 mg, 27%). MS m/z 490.4 [M+H].sup.+.

[0281] To a solution of 21c (72 mg, 0.15 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred overnight at RT. TLC indicated the reaction was completed. The mixture was concentrated to give the crudeproduct. The crude product was purifired by Pre-TLC to give the compound 21d (10 mg, 27%).

[0282] To a solution of 19g (15 mg, 0.09 mmol) in THF (1 mL) was added diisopropylethylamine (22 mg, 0.17 mmol) and triphosgene (13 mg, 0.04 mmol). The reaction mixture was stirred for 2.0 h at RT. TLC indicated the reaction was completed. The mixture was concentrated, Beated with petroleum ether, filter, and the filtrate was concentrated to give the crude product 21e, which was used to the next step directly.

[0283] To a solution of 21d (5 mg, 0.02 mmol) in THF (0.5 mL) was added tBuONa (2 mg, 0.02 mmol. The reaction mixture was stirred for 10 min at RT. Then 21e (4 mg, 0.02 mmol) was added. The reaction mixture was stirred for another 2 h at RT. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC to give the white solid 21 (8 mg, 89%). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 7.87 (d, J=2.3 Hz, 1H), 6.96 (s, 1H), 6.83 (d, J=2.3 Hz, 1H), 5.16-5.08 (m, 1H), 3.29-3.24 (m, 4H), 2.89-2.80 (m, 4H), 2.74-2.63 (m, 4H), 2.07-1.97 (m, 4H) ppm. MS m/z 449.3 [M+H].sup.+.

EXAMPLE 22

Preparation of Compound 22

[0284] ##STR00080##

[0285] To a solution of 20g (12 mg, 0.05 mmol) in THF (1 mL) was added diisopropylethylamine (12 mg, 0.10 mmol) and triphosgene (7 mg, 0.02 mmol). The reaction mixture was stirred for 2.0 h at RT. TLC indicated the reaction was completed. The mixture was concentrated, beated with petroleum ether, filtered, and the filtrate was concentrated to give the crude product 22a, which was used in the next step directly.

[0286] To a solution of 21d (6 mg, 0.02 mmol) in THF (0.5 mL) was added tBuONa (2 mg, 0.02 mmol. The reaction mixture was stirred for 10 min at RT. Then 22a (7 mg, 0.02 mmol) was added.

[0287] The reaction mixture was stirred for another 2 h at RT. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC to give the white solid 22 (6 mg, 51%). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.09 (d, J=5.1 Hz, 1H), 7.81 (d, J=1.2 Hz, 1H), 7.08 (s, 1H), 6.72 (d, J=5.2 Hz, 1H), 6.63 (d, J=1.4 Hz, 1H), 6.59 (s, 1H), 5.13-5.06 (m, 1H), 3.92 (s, 3H), 3.28-3.24 (m, 4H), 2.92 (t, J=7.4 Hz, 2H), 2.72-2.66 (m, 2H), 2.05-1.99 (m, 5H) ppm. MS m/z 530.5 [M+H].sup.+.

EXAMPLE 23

Preparation of Compound 23

[0288] ##STR00081## ##STR00082##

[0289] To a solution of NaH (26 mg, 60%, 0.64 mmol) in THF (2 mL) was added ethyl 2-(Diethoxyphosphoryl) acetate (143 mg, 0.64mmol) at ?78? C. under N.sub.2. The reaction mixture was warmed to RT and stirred 0.5 h. Then 21b (264 mg, 0.58 mmol) was added at 0? C. The mixture was stirred overnight at RT. TLC indicated the reaction was completed. The mixture was quenched with sat. NaHCO.sub.3 and extracted with EA (3?50 mL). The collected organic phase was washed with sat. NaCl, dried with anhydrous sodium sulfate, filterated and concentrated. The crude product was purified by column chromatography to give the 23a (179 mg, 59%). MS m/z 526.5 [M+H].sup.+.

[0290] To a solution of 23a (179 mg, 0.34 mmol) in THF (5 mL) was added DIBAL-H (0.85 mL, 0.85 mmol) at ?78? C. under N.sub.2. After this, the mixture was stirred for 1 h at ?78? C. TLC indicated the reaction was completed. Warmed the temperature of the reaction solution to 0? C., then water (0.05 mL), 15% sodium hydroxide aqueous solution (0.05 mL), and water (0.1 mL) was added successively. The reaction mixture was stirred at RT for 15 minutes. Anhydrous sodium sulfate was added and the reaction was stirred at RT for another 15 minutes. The mixture was filterated and concentrated. The crude product was purified by column chromatography to give the product 23b (116 mg, 70%).

[0291] To a solution of 23b (116 mg, 0.24 mmol) in DCM (3 mL) was added diisopropylethylamine (93 mg, 0.72 mmol) and methanesulfonyl chloride (55 mg, 0.48 mmol) at 0? C. The reaction mixture was stirred for 2 h at RT. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product 23c (134 mg), which was used to the next step directly.

[0292] The compound 23c (134 mg, 0.24 mmol), NaI (2 mg, 0.01mmol) and 1 M dimethylamine tetrahydrofuran solution (2 mL, 2.00 mmol) was dissolved in MeCN (2 mL). The mixture was stirred at 60? C. for 3 h under sealed tube. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by column chromatography to give the product 23d (54 mg, 44%). MS m/z 511.7 [M+H].sup.+.

[0293] To a solution of 23d (54 mg, 0.11mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred for overnight at RT. TLC indicated the reaction was completed. The mixture was concentrated to give the crude. The crude was purified by Pre-TLC to give the white solid 23e (16 mg, 56%). To a solution of 23e (8 mg, 0.03 mmol) in THF (1 mL) was added tBuONa (3 mg, 0.03 mmol). The reaction mixture was stirred for 10 min at RT. Then 21e (6 mg, 0.03 mmol) was added. The reaction mixture was stirred for another 2 h at RT. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC to give the white solid 23 (8 mg, 56%). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 7.84 (d, J=2.4 Hz, 1H), 6.93 (s, 1H), 6.79 (d, J=2.4 Hz, 1H), 5.54-5.48 (m, 1H), 5.10-5.04 (m, 1H), 3.62 (d, J=7.8 Hz, 2H), 3.43-3.33 (m, 4H), 2.86-2.81 (m, 10H), 2.67 (t, J=7.3 Hz, 4H), 2.01 (p, J=7.4 Hz, 4H) ppm. MS m/z 470.5 [M+H].sup.+.

EXAMPLE 24

Preparation of Compound 24

[0294] ##STR00083##

[0295] To a solution of 23e (8 mg, 0.03 mmol) in THF (1 mL) was added tBuONa (3 mg, 0.03 mmol). The reaction mixture was stirred for 10 min at RT. Then 22a (8 mg, 0.03 mmol) was added. The reaction mixture was stirred for another 2 h at RT. TLC indicated the reaction was completed. The mixture was concentrated to give the crude product. The crude product was purified by Pre-TLC to give the white solid 24 (8 mg, 52%). .sup.1H NMR (500 MHZ, CD.sub.3OD) ? 8.08 (d, J=5.0 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.09 (s, 1H), 6.71 (d, J=5.0 Hz, 1H), 6.61 (d, J =2.3 Hz, 1H), 6.58 (s, 1H), 5.55-5.49 (m, 1H), 5.11-5.04 (m, 1H), 3.92 (s, 3H), 3.65 (d, J =7.9 Hz, 2H), 3.43-3.30 (m, 4H), 2.92 (t, J=7.4 Hz, 2H), 2.86 (s, 6H), 2.72-2.65 (m, 2H), 2.07-1.99 (m, 5H) ppm. MS m/z 551.6 [M+H].sup.+.

EXAMPLE 25

Study of the Compound's Inhibitory Activity of NLRP3

Step 1: IL1 ? Induction

[0296] 60 ?L/well polylysine was added to 96-well cell culture plate and incubated at 37? C. for 30 min. Discard the solution in the plate and wash the cell culture plate twice with PBS. THP1 (50000 cells/well/95 ?L) was planted in cell culture plates, 5 ?L of PMA was added to each well (the final concentration was 50 ng/mL), and cultured overnight in a thermostat incubator at 37? C. The supernatant was gently sucked out, the cell culture plate was washed with PBS twice, and 80 ?L cell culture medium without FBS, followed by 5 ?L/well LPS (final concentration 500 ng/mL) was added to each well. The plate was cultured in a thermostat incubator at 37? C. for 3 hours. The compound (10 mM storage solution, DMSO dissolved) was diluted accordingly with 100% DMSO. Add 2 ?L diluted compound into 98 ?L medium and mix well. 5 ?L/well diluted compound was added into the cell plate and cultured in a thermostat incubator at 37? C. for 1 hour. Then 10 ?L/well nigericin (final concentration 10 ?g/mL) was added to the cell plate and cultured in a thermostat incubator at 37? C. for 0.5 hours. The cell supernatant was collected into a new cell plate and frozen at ?80? C. for future use.

Step 2: IL1 ? detection

[0297] IL1? antibody was diluted 60 times with coating buffer, and 100 ?L of diluted antibody was added to each well of ELISA plate, and incubated at 4? C. overnight. Discard the liquid in the ELISA plate and wash it 4 times with eluent. Add 300 ?L/well reagent diluent and incubate the ELISA plate at room temperature for 1.5 hours. Wash the plate with eluent for four times. Then 100 ?L/well samples were added to ELISA plate coated with IL1? and incubated at room temperature for 2 h. Wash the plate with eluent for four times. Each well was added with 100 ?L detection antibody and incubated at 37? C. for 2 h. Wash the plate with eluent for four times. Add 100 ?L of HRP labeled secondary antibody to each well. Incubate at 37? C. for 1 hour. Wash the plate with eluent for four times. Add 100 ?L of A+B substrate per well. Incubate at 37? C. for 30 minutes. Add 100 ?L STOP solution per well. Gently shake the plate for a few seconds. Read the absorption value at 450 nm on the EnVision multifunction reader and calculate the Inhibitory rate according to the following formula: Inhibition %=(Ave_H-Sample)/(Ave_H-Ave_L). Among them, Ave_H represents the average value of DMSO well, Sample represents the average value of compound well, and Ave_L represents the average value of 10 ?M positive control well. The log value of concentration was taken as the X-axis and the percentage inhibitory rate as the Y-axis. The dose-effect curve was fitted with log (inhibitor) vs. response-Variable slope from software GraphPad Prism 5 to obtain the IC50 value of each compound. Calculation formula: Y=Bottom+ (Top-Bottom)/(1+10{circumflex over ()} ((LogIC50-X)*HillSlope)).

TABLE-US-00001 TABLE 1 Inhibition of NLRP3 activity by compounds at 300 nM Compounds Inhibition at 300 nM IC.sub.50 (nM) 1 >50% 6 >50% 7* >50% 8* >50% 13* >50% 14* >50% 22 >50% <25 MCC950* >50% <100 *The representative compounds are sodium salt. [00084]

EXAMPLE 26

Pharmacokinetic Study in Rats

[0298] Instruments: XEVO TQ-S LC/MS instrument produced by Waters. All measurement data is collected and processed by Masslynx V4.1 software, and the data is calculated and processed by Microsoft Excel. Using WinNonLin 8.0 software, the statistical moment method was used to calculate the pharmacokinetic parameters. Mainly include kinetic parameters Tmax, T1/2, Cmax, AUClast etc. Column: ACQUITY UPLC BEH C18 (2.1 mm?50 mm, 1.7 ?m); column temperature 40? C.; mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, flow rate is 0.350 ml/min, gradient elution is adopted, the elution gradient is 0.50 min: 10% B; 1.50 min: 90% B; 2.50 min: 90% B; 2.51 min: 10% B; 3.50 min: stop. Injection volume: 1 ?L.

[0299] Animals: 3 male SD rats with a weight range of 200-220 g. After purchase, they will be kept in the laboratory of the Experimental Animal Center for 2 days and then used. They will be fasted for 12 hours predose and 4 hours after dosing. Drinking water is free during the test. After the rats were gavage, blood samples were taken according to the established time point.

[0300] Solvent: 0.4% ethanol+0.4% Tween80+99.2% (0.5% methylcellulose M450). Preparation of the solution for intragastrical administration: accurately weigh the compound, add it to the solvent, and use ultrasound at room temperature for 5 minutes to completely dissolve the drug, and prepare a 0.3 mg/mL medicinal solution.

[0301] Pharmaceutical samples: Generally, multiple samples with similar structures (with a molecular weight difference of more than 2 units) are taken, accurately weighed, and administered together (cassette PK). In this way, multiple compounds can be screened at the same time and their oral absorption rates can be compared. A single administration was also used to study the pharmacokinetics of the drug sample in rats.

[0302] After intragastrical administration, blood was taken from the orbit at 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours. Then take 50 ?L of the plasma sample, add 200 ?L of acetonitrile (including internal standard control verapamil 2 ng/mL), vortex for 3 min and centrifuge at 20000 ref, 4? C. for 10 min. The supernatant plasma was used for LC-MS/MS analysis.

[0303] Accurately weigh the compounds to prepare different concentrations, perform quantitative analysis on mass spectrometry to establish a standard curve, and then test the concentration of the above-mentioned compound in the plasma to obtain the compound concentration at different time points. All measurement data are collected and processed by relevant software, and the statistical moment method is used to calculate the pharmacokinetic parameters (mainly including kinetic parameters Tmax, T1/2, Cmax, AUClast etc). The kinetic parameters of some representative compounds are shown in Table 2.

TABLE-US-00002 TABLE 2 Pharmacokinetic parameters of the compounds in SD rats T.sub.max T.sub.1/2 C.sub.max AUC.sub.(0-24) Compound Oral dosage (h) (h) (ng/mL) (ng/mL*h) 22 3 mg/kg 1.00 5.60 1529.58 6708.67

[0304] All documents mentioned in the present application are hereby incorporated by reference in their entirety. In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.