EP-4735433-A2 - SUBSTITUTED PYRIDAZINE COMPOUNDS AS INHIBITORS OF NLRP3 ACTIVITY AND THERAPEUTIC USES THEREOF

Abstract

This application discloses novel substituted pyridazine compounds and analogues, their preparation, pharmaceutical compositions comprising them, and their therapeutic uses as medicaments for treating diseases or disorders associated with modulation of cytokines such as IL-1 β and IL-18, modulation of NLRP3, or inhibition of the activation of NLRP3 or related components of the inflammatory process.

Inventors

• SHEN, DONGMING
• WANG, HUI
• JIANG, FEI
• SUN, PEIHUA

Assignees

• Viva Star Biosciences (US) Inc.
• Viva Star Biosciences (Suzhou) Co., Ltd.

Dates

Publication Date

20260506

Application Date

20240627

Claims (1)

1. Docket No.: 358117.00008 CLAIMS What is claimed is: 1. A compound having the structure of Formula I: , or a stereoisomer, a acceptable salt or prodrug thereof, wherein: represents a single or double bond; X is NR 1 , CH 2 , O, S or a bond; R 1 is H, alkyl, cycloalkyl, alkyl-CO-, or heterocyclyl, wherein the alkyl, cycloalkyl, alkyl-CO, heterocyclyl are each optionally substituted with one to five groups independently selected from R 7 ; R 2 at each occurrence is independently selected from R 7 , or two R 2 groups and the intervening connecting atoms form a 3- to 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein said ring is optionally substituted with one to five groups independently selected from R7; or two nonadjacent R2 groups taken together form a 1- to 3-membered bridge optionally comprising one heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R 7 ; or alternatively, R 1 and an adjacent R 2 and the intervening connecting atoms form a 5- or 6- membered heterocyclyl optionally comprising one additional heteroatom independently selected from O, N, and S, wherein the heterocyclyl is optionally substituted with one to three groups independently selected from R 7 ; W1 and W2 are together selected from: (i) both nothing, (ii) both O, (iii) nothing and O, and (iv) NR 3 and O, wherein R 3 is H, alkyl, cycloalkyl, alkyl-CO-, CN, NO 2 , aryl, or heteroaryl, wherein alkyl, cycloalkyl, alkyl-CO-, aryl, and heteroaryl are each optionally substituted with 122 160112428.1 Docket No.: 358117.00008 one to five groups independently selected from R 8 ; or alternatively, R 3 and an R 2 together with their intervening connecting atoms form a 5- to 8- membered heterocyclic ring optionally comprising one additional heteroatom independently selected from O, N, and S and optionally substituted with 1 to 3 groups independently selected from R 7 ; Y is CR 4a , N, or C=O; Z is CR 4b , N, or N-R 9 , with the provisos that Y and Z are not both N; and if Y is C=O, then Z is N-R 9 ; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5- to 7-membered carbocylic, 5- to 7-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring fused to the existing ring containing N-N, each optionally substituted by one to three substituents independently selected from R 4a , R 4b , R 9 , R 10 , and R 11 ; R4a and R4b are independently selected from H, alkyl, cycloalkyl, CN, haloalkyl, phenyl, -C 1-6 alkyl-OR 9 , -C 1-6 alkyl-NHR 9 , and -C 1-6 alkyl-N(R 9 ) 2 ; R 5 is OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R 6 at each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, C 3-6 cycloalkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, halo, CN, SF 5 , NHR 9 , N(R 9 ) 2 , OR 9 , and SR 9 ; or alternatively, two adjacent R 6 groups together with their intervening connecting atoms form a 5- or 6-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R 7 at each occurrence is independently selected from H, C 1-6 alkyl, halo, CN, =O, OR 9 , SR 9 , NHR 9 , N(R 9 ) 2 , and CO 2 R 9 ; R 8 at each occurrence is independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1- 6 haloalkyl CN, phenyl, and halo; R 9 at each occurrence is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl; R 10 at each occurrence is independently H, C 1-6 alkyl, C 3-6 cycloalkyl, halo, or CF 3 ; R11 at each occurrence is independently H, C1-6 alkyl, C3-6 cycloalkyl, or =O; 123 160112428.1 Docket No.: 358117.00008 m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; i is 0, 1, 2, 3, 4; and j is 0, 1, 2, 3, 4. 2. The compound of claim 1, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is NR 1 , CH 2 , O, S or a bond; R 1 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl-CO-, 4-6 membered heterocyclyl, wherein the C 1-5 alkyl, C 3-6 cycloalkyl, C 1-4 alkyl-CO-, and 4-6 membered heterocyclyl are each optionally substituted with one to three groups independently selected from R 7 ; R2 at each occurrence is independently selected from R7, or two R2 groups and the intervening connecting atom(s) form a 3- to 6-membered ring optionally comprising a heteroatom selected from O, N, and S, and the ring is optionally substituted with one or two groups independently selected from R 7 ; or two nonadjacent R 2 groups taken together form a 1- to 3-membered bridge optionally comprising one heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R 7 ; or alternatively, R 1 and an adjacent R 2 and the intervening connecting atoms form a 5- or 6- membered heterocyclyl optionally comprising one additional heteroatom selected from O, N, and S, wherein the heterocyclyl is optionally substituted with one to three groups independently selected from R 7 ; W 1 and W 2 are together selected from: (i) both nothing, (ii) both O, (iii) nothing and O, and (iv) NR 3 and O, wherein R 3 is H, C 1-5 alkyl, C 3-6 cycloalkyl, C 1-4 alkyl-CO, CN, NO 2 , C 6 aryl, or 5- or 6-membered heteroaryl optionally substituted with one to three groups independently selected from R 8 ; or alternatively, R 3 and R 2 taken together with the intervening connecting atoms form a 5- to 8- membered heterocyclic ring optionally comprising one additional heteroatom selected from O, N, and S as part of this ring and optionally substituted with one or two groups independently selected from R 7 Y is CR 4a , N, or C=O; 124 160112428.1 Docket No.: 358117.00008 Z is CR 4b , N, or N-R 9 ; with the provisos that Y and Z are not both N, and if Y is C=O, then Z is N-R 9 ; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5- to 7-membered carbocyclic, 5- to 7-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring optionally substituted by one or two substituents independently selected from R 4a , R 4b , R 9 , R 10 , and R 11 ; R 4a and R 4b are independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, CN, CF 3 , or phenyl; R 5 is OH, OCHF 2 , OCF 3 , CHF 2 , CF 3 , CF 3 CH 2 , or OMe; R6 at each occurrence is independently selected from H, CF3, CF2CF3, OCF3, C3- 6 cycloalkyl, C 1-4 alkyl, CHF 2 , OCHF 2 , halo, CN, SF 5 , NHR 9 , N(R 9 ) 2 , OR 9 , and SR 9 ; or alternatively, two R 6 groups together with intervening connecting atoms form a 5- or 6-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R 7 at each occurrence is independently selected from H, C 1-4 alkyl, halo, CN, =O, OR 9 , SR9, NHR9, N(R9)2, and CO2R9; R 8 at each occurrence is independently selected from H, C 1-4 alkyl, cyclopropyl, CF 3 , CHF 2 , CN, phenyl, and halo; R 9 at each occurrence is independently H, C 1-4 alkyl, or cyclopropyl; R 10 at each occurrence is independently H, C 1-4 alkyl, cyclopropyl, halo, or CF 3 ; R 11 at each occurrence is independently H, C 1-4 alkyl, cyclopropyl or =O; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; i is 0, 1, 2, or 3; and j is 0, 1, or 2. 3. The compound of claim 1, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: 125 160112428.1 Docket No.: 358117.00008 X is NR 1 or O; R 1 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkyl-CO-, -C 1-6 alkyl-OR 9 , -C 1-6 alkyl- C(O)OR 9 , or 4- to 6-membered heterocyclyl, each, except hydrogen, optionally substituted with one to three groups independently selected from C 1-4 alkyl, halo, CN, =O, OR 9 , SR 9 , NHR 9 , and N(R 9 ) 2 ; R 2 at each occurrence is independently selected from C 1-6 alkyl, halo, CN, =O, OR 9 , SR 9 , NHR 9 , N(R 9 ) 2 , and CO 2 R 9 , or two adjacent R 2 groups and the intervening connecting atoms form a 5- or 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein said ring is optionally substituted with one to three groups independently selected from C 1-4 alkyl, halo, CN, =O, OR 9 , SR 9 , NHR 9 , N(R 9 ) 2 , and CO 2 R 9 ; or two nonadjacent R 2 groups taken together form a C 1-3 alkylene bridge optionally substituted by one or two substituents independently selected from C 1-4 alkyl, halo, CN, =O, OR 9 , SR 9 , NHR 9 , N(R 9 ) 2 , and CO 2 R 9 ; W1 and W2 together are selected from: (i) both nothing, (ii) both O, and (iii) nothing and O; Y is CR 4a or N; Z is CR 4b or N, provided that Y and Z are not both N; or alternatively, Y and Z taken together is part of a 5- or 6-membered carbocyclic, 5- or 6-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring, each fused to the existing ring containing N-N and each optionally substituted by one to three substituents independently selected from halo, CN, =O (excluding aromatic and heteroaromatic), C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, phenyl, -C 1-6 alkyl- OR 9 , -C 1-6 alkyl-NHR 9 , and -C 1-6 alkyl-N(R 9 ) 2 ; R 4a and R 4b are independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, CN, C 1-6 haloalkyl, phenyl, -C 1-6 alkyl-OR 9 , -C 1-6 alkyl-NHR 9 , and -C 1-6 alkyl-N(R 9 ) 2 ; R 5 is OH, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, or C 1-2 haloalkoxy; R 6 at each occurrence is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, halo, CN, NHR 9 , N(R 9 ) 2 , OR 9 , or SR 9 ; R 9 at each occurrence is independently H, C 1-4 alkyl, or C 1-4 haloalkyl, or C 3-6 cycloalkyl; 126 160112428.1 Docket No.: 358117.00008 m is 1, or 2; n is 1, 2, or 3; i is 0, 1, 2, 3; and j is 1, 2, 3. 4. The compound of any one of claims 1 to 3, having a structure of formula (I-a): , or a stereoisomer, a acceptable salt or prodrug thereof, wherein X, m, n, R2, Y, Z, R5, and R6 are as defined in any one of claims 1 to 3. 5. The compound of any one of claims 1 to 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein is selected from: Docket No.: 358117.00008 wherein: Z 1 , Z 2 , Z 3 , and Z 4 are independently selected from CR 10 and N, with the proviso that at most one of them is N; Z 5 is O, NR 9 , S, SO, or SO 2 ; Y 1 is a bond, CHR 11 , or SO 2 ; o and p are selected from the following combinations among the columns: o = 0 0 0 2 3 4 1 1 2 2 3 1 6. The compound according to claim 4 or 5, having a structure of formula (I-a-1): , or a stereoisomer, a acceptable salt or prodrug thereof, wherein: X is NR 1 or O; Y and Z are as defined in claim 5; R 5 is independently selected from OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, and C 1-2 haloalkoxy; R 6a is independently selected from halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C1-4 haloalkyl; R9 at each occurrence is independently H or C1-4 alkyl. 128 160112428.1 Docket No.: 358117.00008 7. The compound according to any one of claims 1 to 5, having a structure of formula (I-b): , or a stereoisomer, a acceptable salt or prodrug thereof, wherein n 1 =0, 1, or 2; and R 1 , R 2 , Y, Z, R 5 , and R 6 are as defined in any one of claims 1 to 5. 8. The compound according to claim 7, having a structure of formula (I-b-1): (R 2 ) i , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: Y and Z are as defined in claim 5; n 1 is 0 or 1; R 5 is independently selected from OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, and C 1-2 haloalkoxy; R 6a is independently selected from halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C 1-4 haloalkyl; R 9 at each occurrence is independently H or C 1-4 alkyl. 9. The compound according to any one of claims 1 to 5, having a structure of 129 160112428.1 Docket No.: 358117.00008 formula (I-c): R R 7 5 R 2 N N j or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0, 1, or 2; and Y, Z, R 1 , R 2 , j, R 6 , and R 7 are as defined in claim 4 or 5. 10. The compound according to claim 9, having a structure of formula (I-c-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0 or 1; Y and Z are as defined in claim 5; R 5 is independently selected from OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, and C 1-2 haloalkoxy; R 6a is independently selected from halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C 1-4 haloalkyl; and R 9 at each occurrence is independently H or C 1-4 alkyl. 11. The compound according to any one of claims 1 to 5, having a structure of formula (I-d): 130 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein X, R 2 , m, n, Y, Z, and R 6 are as defined in any one of claims 1 to 4. 12. The compound according to claim 11, having a structure of formula (I-d-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is NR 1 or O; Y and Z are as defined in claim 5; R6a is independently selected from halo, CN, OR9, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C 1-4 haloalkyl; and R 9 at each occurrence is independently H or C 1-4 alkyl. 13. The compound according to any one of claims 1 to 5, having a structure of formula (I-e): 131 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n 1 =0 or 1; and R 1 , R 2 , Y, Z, and R 6 are as defined in any one of claims 1 to 5. 14. The compound according to claim 13, having a structure of formula (I-e-1): , or a stereoisomer, a acceptable salt or prodrug thereof, wherein: n1=0 or 1; Y and Z are as defined in claim 5; R 6a is independently selected from halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C 1-4 haloalkyl; and R 9 at each occurrence is independently H or C 1-4 alkyl. 15. The compound according to any one of claims 1 to 5, having a structure of formula (I-f): 132 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n 1 =0 or 1; and R 1 , R 2 , i, j, R 4a , R 4b , and R 6 are as defined in any one of claims 1 to 5. 16. The compound according to claim 15, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n 1 is 1; i is 0, 1, or 2; j is 1 or 2; R 1 is hydrogen, C 1-6 alkyl, C 1-6 alkyl-CO-, -C 1-6 alkyl-OR 9 , or -C 1-6 alkyl-C(O)OR 9 ; R 2 at each occurrence is independently hydrogen, C 1-6 alkyl, or halo; or two nonadjacent R 2 groups taken together form a C 1-3 alkylene bridge optionally substituted by one or two substituents independently selected from R 7 ; R4a and R4b are independently selected from H, C1-6 alkyl, CN, C1-6 haloalkyl, -C1- 6 alkyl-OR 9 , -C 1-6 alkyl-NHR 9 , and -C 1-6 alkyl-N(R 9 ) 2 ; R 5 is OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, or C 1-2 haloalkoxy; R 6 at each occurrence is independently selected from hydrogen, halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5- membered heteroaryl; R 7 is hydrogen, C 1-4 alkyl, halo, or OR 9 ; and R 9 at each occurrence is independently H or C 1-4 alkyl. 17. The compound according to claim 15 or 16, having a structure of formula (I-f- 1): 133 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a acceptable salt or prodrug thereof, wherein: R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH 2 OH; R 2 is H or F; R 4a is H, CN, -CH 3 , -CH 2 OH, or -CH 2 NHCH 3 ; R 4b is H or -CH 3 ; R 5 is -OH, -CF 3 , or -OCHF 2 ; R 6 is H, F, Cl, -CF 3 , or -CH 3 ; and R 6a is -CF 3 , -CH 3 , . 18. The compound or 16, having a structure of formula (I-f- 2): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0, 1, or 2; R 1 is hydrogen, C 1-6 alkyl, C 1-6 alkyl-CO-, -C 1-6 alkyl-OR 9 , or -C 1-6 alkyl-C(O)OR 9 ; R 2 is hydrogen, C 1-6 alkyl, or halo; R 4a and R 4b are independently selected from H, C 1-6 alkyl, CN, C 1-6 haloalkyl, -C 1- 6 alkyl-OR 9 , -C 1-6 alkyl-NHR 9 , and -C 1-6 alkyl-N(R 9 ) 2 ; 134 160112428.1 Docket No.: 358117.00008 R 5 is OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, or C 1-2 haloalkoxy; R 6 at each occurrence is independently selected from hydrogen, halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5- membered heteroaryl; R 7 is C 1-4 alkyl, halo, and OR 9 ; and R 9 at each occurrence is independently H or C 1-4 alkyl. 19. The compound according to claim 18, having a structure of formula (I-f-2-a): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH 2 OH; R 4a is H, CN, -CH 3 , -CH 2 OH, or -CH 2 NHCH 3 ; R 4b is H or -CH 3 ; R 5 is -OH, -CF 3 , or -OCHF 2 ; R 6 is H, F, Cl, -CF 3 , or -CH 3 ; and R 6a is -CF 3 , -CH 3 , cyclopropyl, Cl, or . 20. The compound according to any one of claims 1 to 5, having a structure of formula (I-g): 135 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n 1 =0 or 1; R 1 , R 2 , R 5 , R 6 and R 10 are as defined in any one of claims 1 to 5; and Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 10 or N, with the proviso that no more than one of them are N. 21. The compound according to claim 20, having a structure of formula (I-g-1), (I- g-2), or (I-g-3): , or prodrug thereof, wherein: i is 0, 1, or 2; R 1 at each occurrence is independently hydrogen, C 1-6 alkyl, C 1-6 alkyl-CO-, -C 1-6 alkyl- OR 9 , or -C1-6alkyl-C(O)OR 9 ; R 2 at each occurrence is independently hydrogen, C 1-6 alkyl, or halo; R 5 at each occurrence is independently OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, or C 1-2 haloalkoxy; R 6a at each occurrence is independently selected from halo, CN, OR 9 , C 1-4 alkyl, C 1-4 136 160112428.1 Docket No.: 358117.00008 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C 1-4 haloalkyl; R 9 at each occurrence is independently H or C 1-4 alkyl; and R 10 at each occurrence is independently H, C 1-4 alkyl, cyclopropyl, halo, or CF 3 . 22. The compound according to claim 20 or 21, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH 2 OH; R 5 is -OH, -CF 3 , or -OCHF 2 ; R 6 is H, F, Cl, -CF 3 , or -CH 3 ; and R6a is -CF3, -CH3, cyclopropyl, Cl, or ; and R 10 is H. 23. The compound according to any one of claims 1 to 5, having a structure of formula (I-h), (I-i), or (I-j): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n 1 =0 or 1; and R 1 , R 2 , R 5 , R 6 , and R 10 are as defined in any one of claims 1 to 4. 24. The compound according to claim 23, having a structure of formula (I-h-1), (I- i-1), or (I-j-1): 137 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0, 1, or 2; R 1 at each occurrence is independently hydrogen, C 1-6 alkyl, C 1-6 alkyl-CO-, -C 1-6 alkyl- OR 9 , or -C 1-6 alkyl-C(O)OR 9 ; R 2 at each occurrence is independently hydrogen, C 1-6 alkyl, or halo; R 5 at each occurrence is independently OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, or C 1-2 haloalkoxy; R 6a at each occurrence is independently selected from halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C 1-4 haloalkyl; R 9 at each occurrence is independently H or C 1-4 alkyl; and R 10 at each occurrence is independently H, C 1-4 alkyl, cyclopropyl, halo, or CF 3 . 25. The compound according to claim 24, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH 2 OH; R 5 is -OH, -CF 3 , or -OCHF 2 ; R 6 is H, F, Cl, -CF 3 , or -CH 3 ; and R 6a is -CF 3 , -CH 3 , R 10 is H or -CH 3 . 138 160112428.1 Docket No.: 358117.00008 26. The compound according to any one of claims 1 to 5, having a structure of formula (I-k): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n 1 =0 or 1; i is 0, 1, or 2; q is 0 or 1; Y 1 is -CH 2 - or -S(O) 2 -; and R 1 , R 2 , R 5 , R 6 , and R 11 are as defined in any one of claims 1 to 5. 27. The compound according to claim 26, having a structure of formula (I-k-1), (I- k-2), (I-k-3): , salt or prodrug thereof, wherein: i is 0, 1, or 2; R 1 at each occurrence is independently hydrogen, C 1-6 alkyl, C 1-6 alkyl-CO-, -C 1-6 alkyl- OR 9 , or -C 1-6 alkyl-C(O)OR 9 ; 139 160112428.1 Docket No.: 358117.00008 R 2 at each occurrence is independently hydrogen, C 1-6 alkyl, or halo; R 5 at each occurrence is independently OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, or C 1-2 haloalkoxy; R 6a at each occurrence is independently selected from halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C 1-4 haloalkyl; R 9 at each occurrence is independently H or C 1-4 alkyl; and R 11 at each occurrence is independently H, C 1-4 alkyl, cyclopropyl, halo, or CF 3 . 28. The compound according to claim 27, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH 2 OH; R 5 is -OH, -CF 3 , or -OCHF 2 ; R 6 is H, F, Cl, -CF 3 , or -CH 3 ; and R 6a is -CF 3 , -CH 3 , R 11 at each occurrence is cyclopropyl, or =O. 29. The compound according to any one of claims 1 to 5, having a structure of formula (I-l): , 160112428.1 Docket No.: 358117.00008 or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n 1 =0 or 1; and R 1 , R 2 , R 4b , R 5 , and R 6 are as defined in any one of claims 1 to 5. 30. The compound according to claim 29, having a structure of formula (I-l-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0, 1, or 2; R 1 at each occurrence is independently hydrogen, C 1-6 alkyl, C 1-6 alkyl-CO-, -C 1-6 alkyl- OR 9 , or -C 1-6 alkyl-C(O)OR 9 ; R 2 at each occurrence is independently hydrogen, C 1-6 alkyl, or halo; R 4b is H, C 1-6 alkyl, CN, or C 1-6 haloalkyl, R 5 at each occurrence is independently OH, halo, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, or C 1-2 haloalkoxy; R 6a at each occurrence is independently selected from halo, CN, OR 9 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R 6 at each occurrence is independently selected from hydrogen, halo, OR 9 , C 1-4 alkyl, and C 1-4 haloalkyl; and R 9 at each occurrence is independently H or C 1-4 alkyl. 31. The compound according to claim 30, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; 141 160112428.1 Docket No.: 358117.00008 R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH 2 OH; R 4b is H or -CH 3 ; R 5 is -OH, -CF 3 , or -OCHF 2 ; R 6 is H, F, Cl, -CF 3 , or -CH 3 ; and R 6a is -CF 3 , -CH 3 , . 32. The compound 2, having a structure of formula (I-m): (R 2 ) i j , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n=0 or 1; and R 1 , R 2 , R 6 , and R 9 are as defined in claim 1 or 2. 33. The compound according to any one of claims 1 to 5, having a structure of formula (I-n): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein Y, Z, R 2 , m, n, i, and R 6 are as defined in any one of claims 1 to 5. 142 160112428.1 Docket No.: 358117.00008 34. The compound according to claim 33, having a structure of formula (I-n-1): , or a stereoisomer, a tautomer, acceptable salt or prodrug thereof, wherein: i is 0, 1, 2, or 3; R 2 is H, F, or -CH 3 ; R 4a is H, CN, -CH 3 , -CH 2 OH, or -CH 2 NHCH 3 ; R 4b is H or -CH 3 ; R 5 is -OH, -CF 3 , or -OCHF 2 ; R 6 is H, F, Cl, -CF 3 , or -CH 3 ; and R 6a is -CF 3 , -CH 3 , cyclopropyl, Cl, or . 35. The compound according to claim 1 or 2, or a stereoisomer, tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound is selected from Examples 1-40. 36. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 35, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers. 37. A method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1 to 35, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 36 to the subject. 143 160112428.1 Docket No.: 358117.00008 38. A method for treating or preventing a disease or condition in a subject in need thereof, comprising administering an effective amount of a compound of any one of Claims 1 to 35, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 36 to the subject, wherein the disease or condition is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease. 39. The method of claim 28, wherein the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease; the metabolic ailment is type 2 diabetes or atherosclerosis; the inflammatory disease is gout flares or osteoarthritis; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer; and the hereditary disease is Cryopyrin-associated periodic syndrome. 144 160112428.1

Description

Docket No.: 358117.00008 SUBSTITUTED PYRIDAZINE COMPOUNDS AS INHIBITORS OF NLRP3 ACTIVITY AND THERAPEUTIC USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority and benefits to International Patent Application No. PCT/CN2023/102566, filed on June 27, 2023, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE This application relates to pyridazine compounds and analogues as modulators of cytokines such as IL-1β and IL-18, or NLRP3, and their methods of preparation and therapeutic uses. BACKGROUND OF THE DISCLOSURE Nucleotide-binding oligomerization domain-like receptors (or NOD-like receptors, NLRs) are a family of pattern recognition receptors (PPRs), acting as intracellular sensors of pathogen-associated molecular patterns (PAMPs) and damage- or danger- associated molecular patterns (DAMPs). NLRP3 can be activated by a large assortment of stimuli. Accumulating evidences indicate that NLRs play important roles in innate immune responses against infection and cellular damages. Among numerous NOD-like receptors, Nucleotide-binding oligomerization domain, leucine-rich repeat receptor and pyrin-domain containing protein 3 (NLRP3) has been well characterized to form inflammasome involving its oligomers which recruits the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and the effector zymogen caspase-1. The formation of NLRP3 inflammasome activates caspase-1, which in turn catalyzes proteolytic reactions, releasing pro-inflammatory cytokines such as interleukin-1β (IL-lβ) and IL- 18 [Nat. Rev. Immunol. 2013 June;13(6):397-411]. NLRP3 inflammasome activation also leads to cleavage of Gasdermin D (GSDMD) which causes pyroptosis, a rapid and pro-inflammatory form of cell death resulting from membrane pore-forming fragments from GSDMD. It has been shown that dysregulated NLRP3 inflammasome activation contributes to the pathogenesis of several human diseases. Most notably, gain-of- function mutations in KNORP cause hereditary diseases such as Cryopyrin-associated periodic syndrome (CAPS). In addition, aberrant activation of NLRP3 1 160112428.1 Docket No.: 358117.00008 inf1ammasomes exacerbates chronic human diseases such as neurodegenerative disorders (multiple sclerosis, Alzheimer disease and Parkinson disease), metabolic ailments (atherosclerosis and type 2 diabetes), and inflammatory diseases (gout flares and osteoarthritis). More recently, roles of NLRP3 in the initiation and progression of cancers have been documented [Nat. Immunol. 2021 May;22(5):550- 559,doi:10.1038/s41590-021-00886-5]. A few biologic therapies targeting NLRP3/IL-1β innate immunity pathway have been approved. They include Anakinra (recombinant IL-1 receptor antagonist), Canakinumab (a human monoclonal antibody targeting IL-1β), and Rilonacept (a soluble decoy receptor that binds both IL-1β and IL-1α and prevents their interaction with cell surface receptors). Findings from the CANTOS study, where treatment with Canakinumab resulted in a significantly lower rate of recurrent cardiovascular events, demonstrating a clear benefit of targeting inflammation in high-risk patients with cardiovascular diseases. Targeting NLRP3 activation by small molecules is also feasible as exemplified by CRID3 (also known as MCC950). The direct binding of CRID3 with full-length NLRP3 and one of its analogs with NACHT domain of NLRP3 have been demonstrated by cryo-EM structures [Nature 2022; 604:184-189; J Mol Biol. 2021 Dec 3;433(24);167309]. Potential benefits of targeting NLRP3 using specific small molecule inhibitors instead of targeting IL-1β using biologics include sparing the other IL-1β producing inflammasomes with specific NLRP3 inhibitors and typically much shorter half-life of small molecule drugs compared to biologics (for example, the half-life of Canakinumab in humans is 28 days). The latter enables quick withdrawal when needed, for example, in the event of an infection. CRID3 (CP-456,773) was discovered by researchers at Pfizer in the late 1990s before its target was understood [US patent 6,166,064, 2000 Dec 26; J Pharmacol. Exp Ther 2001;299:187-197]. Its clinical studies were halted, and speculation was due to safety concerns. Since the identification of its biological target as NLRP3 in 2015 [Nat. Med.2015;21:248–255. doi: 10.1038/nm.3806], several largely peripherally distributed NLRP3 inhibitors have entered clinical trials. However, CRID3 and its derivative have proven to be far from brain penetrant as commonly defined in the field. Although a few NLRP3 inhibitors in early clinical trials were claimed to be CNS penetrant, the CNS penetration of the reported CNS penetrant NLRP3 inhibitors has not been independently confirmed. Thus, there is still a need to develop CNS penetrant, specific, and safe NLRP3 inhibitors for clinical development. 2 160112428.1 Docket No.: 358117.00008 Inhibition of the