Heterocyclic and heteroaryl compounds as inhibitors of nlrp3

Abstract

The present invention relates to novel compounds of Formula (I): wherein each ring A, R1, R2, X, Y, and Z are as defined herein, which inhibit NOD-like receptor protein 3 (NLRP3) inflammasome activity. The invention further relates to the process for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3.

Description

Heterocyclic and heteroaryl compounds as NLRP3 inhibitors This invention relates to novel compounds of formula (I): wherein each of rings A, R1, R2, X, Y, and Z is as defined herein, and the compound inhibits NOD-like receptor protein 3 (NLRP3) inflammasome activity. The invention also relates to methods for preparing the compound, pharmaceutical compositions and drugs comprising the compound, and their use in treating NLRP3-mediated diseases and conditions. Abstract

Claims

WHAT IS CLAIMED IS:

1. A compound having the structure of Formula (I):wherein:X and ¥ are independently selected from CR’, C(R’)(R’), N, NR”, 0 and S;Z is selected from N, C and CH; — is a single or double bond;R’ is independently selected from H, halogen, Cioalkyl, deutero-Ci-salkyl, OH, C.v 6cycloalkyl, C1-.4alkoxy, Q-scycloalkoxy, halo-C1-4 alkoxy, C1-.4alkyl-thio, SH and halo-C1- 4alkyl ,R” is independently selected from H, C1-.4alkyl, deutero-C1-.4alkyl, C3-6cycloalkyl, and halo-C1-4 alkyl;Ring A is selected from the group consisting of:Q1, Q2, Q3, Q4, Q5, Q6, and Q?are independently selected from CR8, C(R8) (R8), 0, N, NRy, and S;Rw is selected from OH, C1-.4alkyl, halo-C1-4 alkyl, C3-6cycloalkyl, C1-.4alkoxy and halo- C1-.4alkoxy;R1is selected from H, C1-4 alkyl, deutero-C1-.4alkyl, C1-.4alkyl-C3-6cycloalkyl, C1-.4alkyl-C3- eheterocycle, C3-6cycloalkyl optionally substituted with halogen orR3, C3-6heterocycle optionally substituted with halogen, C1-.4alkyl-amino, (C1-.4alkyl)2-amino, halo-C1-.4alkyl, Cn4alkyl-thio, C1-4 alkoxy, C3-6cycloalkoxy, and halo-C1.4alkoxy;R2is independently selected from C3-7 cycloalkyl, C1-4 alkyl-aryl, C1-.4alkyl-C3-7cycloalkyl, C1-4 alkyl-C3-7heterocycle, C3-7 heterocycle and aryl, wherein said C3-7 heterocycle is a saturated or partially unsaturated 4 to 8 membered monocyclic ring system having 1, 2, 3 heteroatom ring members independently selected from N, 0 and S, wherein said R2is optionally substituted with R3;R3is independently selected from C1-4 alkyl, deutero-C1-.4alkyl, halogen, OH, halo-C1- 4alkyl, CN, C3-6 cycloalkyl, C1-4 alkoxy, C3-6cycloalkoxy, halo- C1-.4alkoxy, and hydroxy- C1-.4alkyl;R4, R- and Rcare independently selected from H, C1-.4alkyl, deutero-Cn4alkyl, OH, C1- 4alkoxy, halo-C1-.4alkyl, halo-C1-4 alkoxy, halogen, C1-.4alkyl-thio,C3-6cycloalkyl, CN-ecycloalkoxy, C1-.4alkyl-amino, (C1-.4alkyl)2-amino, and CN, wherein R4is not H when R1is H;R7is independently selected from H, C1-.4alkyl, halo-C1-.4alkyl, C3-6cycloalkyl, C1-4 alkoxy, halo-C1-.4alkoxy, halogen and CN,Rsis selected from H, C1-4 alkyl, halogen and halo-C1-4 alkyl, C1-.4alkoxy and halo-Cn 4alkoxy;R9is selected from H, C1-4 alkyl, halo-C1-4 alkyl, C3-6cycloalkyl; and m is 0, 1 or 2; wherein a form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer, and isotope enriched form thereof.The compound of claim 1, wherein the compound is a compound of Formula (la)or a form thereof, wherein:X and Y are independently selected from CR’, C(R’)(R.’);R’ is independently selected from H, halogen, C1-4 alkyl, OH, C3-6cycloalkyl, C1-4 alkoxy, C1-.4alkyl-thio, CN, SH and halo-C1-4 alkyl; andR1is selected from H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3,3. The compound of claim 1, wherein the compound is a compound of Formula (lb)or a form thereof, wherein:R1is selected from H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3,4. The compound of claim 1, wherein the compound is a compound of Formula (Ic)or a form thereof wherein:Y is selected from CR’;R’ is independently selected from H, C Malkyl, and halo-C1-4 alkyl; andR1is selected from H, CH,3 CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3,The compound of claim 1, wherein the compound is a compound of Formula (Id)or form thereof, wherein:R1is selected from H, CH,3 CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3,6. The compound of claim 1, wherein the compound is a compound of Formula (le)or form thereof, wherein:X is CR’,R’ is selected from H and CH3; andR1is selected from H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3,7. The compound of claim 1, wherein the compound is a compound of Formula (If)or form thereof, wherein:Y is selected from CH and CH?;— is a single or double bond; andR1is selected from H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3,8. The compound of claim 1, wherein the compound is a compound of Formula (Ig)or form thereof, wherein:R1is selected from H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3,9. The compound of claim 1 , wherein the compound is a compound of Formula (Ih)or form thereof, wherein:R1is selected from H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3,10. The compound according to claim 1, wherein Ring A is selected from:Q1, Q2, Q3, Q4, Q5, Q6, and Q?are independently selected from CR8, C(R8) (R8), 0, N, NR9and S,Rw is selected from OH, Ci^alkyLhalo-Ci^kyLC^cycloalkyl, Ci-alkoxy and halo-Ct- alkoxy;R4, R5and R6are independently selected from H, CHs, CH2CH3, OH, OCHs, CF3, OCF3,CH2CF3, OCHI-2, F, Cl, Br, cyclopropyl, isopropyl, S CH,3 NfCHsh, CN and 0Rzis independently selected from H, OH, C1-4 alkyl, halo-C1-4 alkyl, Ca-ecycloalkyl, C1-4alkoxy and halo-C1-.4alkoxy, halogen and CN; Rsis selected from H, C1-4 alkyl, halogen and halo-C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy;R9is selected from H, C1-.4 alkyl, halo-C1-.4alkyl, C3-6cycloalkyl; and m is 0, 1 or 2.

11. The compound according to claim 1, wherein R2is selected from:wherein a form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer, and isotope enriched form thereof.

12. / X compound or form thereof, selected from the group consisting of2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl]-5-(trifluoromethyi)phenol;2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl]-5-methyl-phenol ;2-[4-isopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5 -(tri fluor om ethy l)ph enol ;5-cyclopropyl-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]phenol;2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazm-3-yl]-5-(trifluoromethy 1 jphenol ,2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- y 1] -3 -methyl -5 -(tri fl uoromethyl)ph enol;2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl] -3 -fl uoro- 5 -methyl -phenol ,2-[7-[(3R)-l-ethyl-3-piperidyl]-4-(1-methylcyclopropyl)-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;2-[4-cyclobutyl-7-[(3R)-l-ethyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethy Ijphenol ,2-[4-(3,3-difluorocyclobutyl)"7~[(3R)-1-ethyl-3-piperidyl]-5,6-dihydropyn’olo[2,3~ c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;2-[4-cyclobutyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;2-[4-cyclobutyl-7-[(3R,5R)-5-fluoro-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3- c]pyridazm-3-yl]-5-(trifluoromethyl)phenol;5-cyclopropyl-2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3- c]pyridazin-3 -yl ]phenol;2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yi]-5-methoxy -phenol ;5-chloro-2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3- c]pyiidazin-3 -y! Jphenol ,3,5-dimethyl-2-[7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl] phenol;3-methyl-2-[7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;3-methyl-2-[7-[(3R)-l-methy1pyn-olidin-3-yl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]- 5-(trifluoromethyl)phenol;3-methyl-2-[7-(1 -methy1-4-piperidyl)-5,6-dihydropyiTOlo[2,3-c]pyridazm-3-yl]-5- (trifluoromethyl)phenol;3-methyl-2-[5-methyl-7-[rac-(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;5-chloro-3-fluoro-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3- c]pyridazm-3-yl]phenol;5-chloro-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin- 3-yl]phenol;3-methyl-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin- 3 -yl ]- 5 -(tri fluoromethyl)phenol ;2-[4-cyclopropyl-7-[(3R)-l-(2-hydroxyethyl)-3-piperidyl]-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;2-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3- c] py ri dazin-3 -y 1 ] -5 -(trifluoromethy 1 )phenol ;2-[(7R)-4-cyclopropyl-7-tetrahydropyran-3-yl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]- 5-(trifluoromethyl)phenol;3-methoxy-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyirolo[2,3- c]pyridazin-3~yl]-5-(trifluoromethyl)phenol,2-(4-cy clopropyl -7-tetrahy drofuran -3 -y I -5,6-di hy dropyrrol o[2, 3 -cl pyridazi n-3 -yl)-5 - (trifl uororn ethyl)phen ol ;2-[4-cyxlopropyl-7-[(lR,2R.)-2-hydroxycyclohexyl]-5,6--dihydi'opyrrolo[2;3-c]pyridazin- 3 -y 1 ]-5 -(tri fl ijoromethyl)ph enol ;2-[4-cyclopropyl-7-(l H-pyrazol-3-yl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5- (trifluoroinethyl)phenol;2-[4"Cyclopropyl-7-[l~(3-hydroxyphenyl)ethyl]~5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl]-5-(trifluoromethyl)phenol;2-[(7R)-4-cyclopropyl-7-[(2S)-2-hydroxycyclohexyl]-5,6-dihydropyiTolo[2,3- c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;2-[4-cyclopropyl”7-[(lR,3S)”3"hydroxycyclohexyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)pheno] ,2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl]-5-ethyl-phenol;5-[4-cyclopropyl-7-[(3R)-l-methy1-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl]indan-4-ol;5-methyl-2-[7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazm-3-yl]-3-(trifluoromethy Ijphenoi ;5-[4-cyclopropyl-7-[(3R)-l-methy1-3-piperidyl]-5,6-dibydropyrrolo[2.3-c]pyridazm-3- yl]-2,3-dihydrobenzofuran-4-ol;3-methoxy-2-[7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethy Ijpheiiol ;3-methyl-2-[6-methyl-7-[(3R)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3 -y 1 ]-5-(tri fluoromethyl)phenol ;5-methyl-2-[6-methyl-7-[(3R)-l-methyl”3-piperidyl]-5,6-dihydropyirolo[2,3-c]pyridazin-3 -yl]-3 -(trifluoromethy 1 )phenol ;3~[2,4-bis(trifiuoromethyl)phenyl]-4~cyclopropyl-7-[(3R)-l~methyl”3-piperidyl]-5,6- dihydropyrrolo[2,3-c]pyridazine;3-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-4-(l-methylcyclopropyl)-7-[(3R)-l- methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazine;5-[7-[(3R,5R)-5-fluoro-l-methyl-3-piperidyl]-4-methyl-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]benzofuran-4-ol;5-[7-[(3S,4R)-4-fluoro-l-methyl-3-piperidyl]-4-methyl-5,6-dihydropyrrolo[2,3- c] py ri dazi n -3 -y I ] b enzofuran-4-ol ;5-[7-(3-hydroxy-3"methyl“Cyclobutyl)-4"methyl-5,6-dihydropyrrolo[2,3“C]pyridazin-3” yl]benzofuran-4-ol;5-[4-cyclopropyl-7-[(3R,5R)"5-fluorO"l-methyl-3-piperidyl]“5,6"dihydropyrrolo[2,3- c]pyridazin-3-yl]benzofuran-4~ol;5-[7-[(3R,5R)-5-fluoro-l-methy!-3-piperidyl]-4-methyl-5,6-dihydropyrrolo[2>3- c]pyridazin-3~yl]-2,3-dihydrobenzofuran-4-ol;5-[4-cyclopropyI-7-[(3R,5R)-5-fluoro-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yip2,3-dihydrobenzofuran-4-ol;5"[4"methyl~7-[(3R)-l~methyl"3~piperidyl]"5,6"dihydropyrrolo[2,3"C]pyridazm-3~yl]-2,3~ dihydrobenzofuran-4-ol;5-[4-methyl-7-[(3R.)-l-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yi]benzofuran-4-ol;5-[7-[(lR,2R)-2-hydroxycyclohexyS]-4-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3“ yl]benzofuran-4-ol;5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-4-methy!-5,6-dihydropyrrolo[2,3- c]pyridazin-3 -yl]benzofuran-4-ol ;5-[7-(3-hydroxy-3-methyl-cyc1obuty1)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6- methyl-benzofuran-4-ol;5-[7-[(lR,2R)-2-hydroxycyclohexyl]-5,6-dihydropyrro1o[2,3-c]pyridazin-3-yl]-6-methyl- benzofuran-4-ol;5-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]benzofuran-4-oi;5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methvl-benzofuran-4-ol:2-[7-(3-hydroxy-3-methyl-cyc1obuty])-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5- methyl-3-(trifluoromethyl)phenol;3-[(7R)-7-tetrahydrofuran-3-yl”5,6”dihydropyrrolo[2,3-c]pyridazin-3- yl]bicyclo[4.2.0]octa-l,3,5-trien-2-ol;(3S,4R)-4-[3-(2-hydroxy-3”bicyclo[4.2.0]octa-l,3,5-trienyl)~5,6-dihydropyrrolo[2,3- c]pyridazin-7-yl]tetrahydropyran-3-ol;5-[7-(3-hydroxy~3-methyl-cyclobutyl)-5”methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl ] -6-methy I -b enzofuran-4-ol ,(3S,4R)-4-[(5R)-3-[2-hydroxy-4-methyl-6-(trifluoromethyl)phenyl]-5-methyl-5,6- dihydropyrrolo[2,3-c]pyridazin-7-yl]tetrahydropyran-3-ol;(3S,4R)-4-[(5S)-3-[2-hydroxy-4-methyl-6-(trifluoromethyl)phenyl]-5-methyl-5,6- dihydropyrrolo[2,3-c]pyridazin-7-yl]tetrahydropyran-3-ol;2-[7-[(lR,2R)-2-hydroxycyclohexyl]-5-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]- 5-methyl~3 -(trifluoromethyl)phenol ;5-[7~[(lR,2R)-24iydroxycyciohexy!p5“methyl-5,6-dihydropyrrolo[2,3“C]pyridazin”3"yl]"6-methy I -benzofuran-4-ol ;5-[4-cyclopropyl-7-[(3R.)-l-methyl-3-piperidyl]-5,6-dihydropyTrolo[2,3-c]pyridazin-3- yl ] -7-fl uoro-benzofuran~4~ol ;5-[7-[(lR,2R)-2-hydroxycyclopentyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6- methyl-benzofuran-4-ol;5"[7-(3~hydroxy-3~methyl-cyclobutyl)~5,6-dihydropyrrolo[2,3-c]pyridazin-3"yl]-6- methyl-2,3-dihydrobenzofuran-4-ol;2-[7-(3-methoxy-3-methyl-cyclobuty])-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-3- methyl-5-(trifluoromethyl)phenol;2-[7-(3“methoxy“3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5- methyl -3 -(trifluoromethyl)phenol,5-[7-(3-methoxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6- m ethy 1 -b enzofuran-4-ol ;6-(difluoromethyl)-5-[7-(3-methoxy-3-methyl-cydobuty1)-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]benzofuran-4-ol;6-(difluoromethyl)-5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]benzofuran-4”Ol;6-methyl-5-[7-[rac-(1R,2S)-2-hydroxycyclobutyl]-5,6-dihydropyrro1o[2,3-c]pyridazin-3- yl]benzofuran-4-ol;6-methyl-5-[7-[rac-(lR,2R)-2-hydroxycyclobutyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3- yl ] b enzofuran-4-ol ;6-(difluoromethyl)-5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-5,6- dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol;3-[7-[(lR,2R)-2-hydroxycyclohexyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-4-methyl- bicyclo[4.2.0]octa-l,3,5"trieii-2-ol;3-(difluoroniethyl)-2-[7-(3-hydroxy”3-methyl~cyclobutyl)-5,6-dihydropyrrolo[2,3- c]pyridazin-3-yl]-5-methyl-phenol;5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-(2,2,2- tri fl uoroethyl)benzofuran -4-ol ;5"[7-[l-(3“hydroxyphenyl)ethyl]--5,6-dihydropyiTolo[2,3“C]pyridazin-3”y[]”6“methyl- benzofuran-4-ol ;2-[7-[(3R)-l-methyl-3-piperidyl]-4-(trifluoromethyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3 -y 11- 5 -(trifl uoromethy l)phenol ;5-chloro-2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3- yi] phenol;5-cyclopropyl“2-[4-cyclopropyl-7-[(3R)-l-methyl-3“piperidyl]pyrrolo[2,3-c]pyridazin-3- yljphenol;2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethy 1 )phenol ,2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidy!]pyn-olo[2,3-c]pyridazin-3-yl]-5-methyl- phenol;2-[4"Cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3~yip5-methoxy- phenol;2-[4-cyclopropyl-7-[(3R)-3-piperidyl]pyn-olo[2,3-c]pyridazin-3-yl]~5-methoxy-phenol;2-[4-cyclopropyl”7-[(3R)-l-ethyl-3-piperidyl]pyrrolo[2,3-c]pyridazin“3-yl]-5-methoxy- phenol;2-[4-cyclopropyl-7-[(3R)-l-(2-hydroxyethyl)-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]- 5-methoxy-phenol ;2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5- (trifluoromethyl)phenol;5-chloro-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]phenol;5-methoxy-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3- yl]phenol;5-[4-methyl-7-[(3R)-l-methyl-3"piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol;5-[4-methyl-7”[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzothiophen-4- ol,5“[4-methyl-7-[(3R)-l-methyl-3"piperidyl]pyrrolo[2,3"C]pyridazin-3-yl]indan“4-ol;5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2,3- dihydrobenzofuran-4-ol;5"[4-cyclopropyl’7-[(3R)"l~methyl’3-piperidyl]pyrroio[2,3"C]pyridazin"3-yl]benzofuran"4-ol;3-methyl-2-[6-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;5~methyl”2-[6~methyl”7-[(3R)-l-methyl~3-piperidyl]pyrrolo[2,3-c]pyridazin-3~yl]~3-(trifluorom et hy 1 )p henol ,2-[4-cyclopropyl-7-[(3 R)- 1 -methyl-3 -piped dyl]pyrrolo[2,3 -c]pyridazin-3 -yl]-4-fluoro-5- m ethyl -phenol;6-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2-fluoro-3- m ethyl -phenol,5-methyI-2-[7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-3-(trifl uorom ethyl)phen ol ;5-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-pyrrolo[2,3-c]pyridazin-3- yl]benzofuran-4-ol;3-methyl-2-[7"[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;5-[7-[(3S,4R)-4-fluoro-l-methyl-3-piperidyl]-4-melhyl-pyrrolo[2,3-c]pyridazin-3- yl ] b enzofuran-4-ol ;5-[7-[(3R,5R)-5-fluoro-l-methyl-3-piperidyl]-4-methyl-pyiTolo[2,3-c]pyridazin-3- yl]benzofuran-4-ol;5-[7”[(3S,4R)-l-ethyl-4-fluorO“3“piperidyl]“4-methyl-pyrrdo[2,3"C]pyridazin-3- yl]benzofuran-4-ol;3-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3- yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol;5-[7-(3-hydroxy-3-methyl-cyc1obuty1)-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl- benzofuran-4-ol;5-[7-[(lR,2R)-2-hydroxycyclohexyl]-4-methyl-pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol;5-[7-[(3S,4R)-3-hydroxy'tetrahydropyran-4-yl]-4-methyl-pyrrolo[2,3-c]pyridazin-3- yl]benzofuran-4-ol;5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-2,6- dimethyl-benzofuran-4-oi;6-methyl-5-[7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2,3- dihydrobenzofuran-4-ol;6-methyl-5-[7-[(3R)-l-mediyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol;5-[7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl- benzofuran-4-ol;5-[7-[(lR,2R)-2-hydroxycyclohexyl]pyrroio[2)3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol;5-[4,5-dimethyl-7-[(3R)-l-methy1-3~piperidyl]pyrrolo[2,3~c]pyridazin-3-yl]-2,3- dihydrobenzofuran-4-ol;5-[7-(3-hydroxy-3-methy1-cyclobutyl)-5-methyl-pyiTolo[2,3-c]pyridazin-3-yl]-6-methyl-2, 3 -di hydrobenzofuran-4-ol ;6-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-7-ol;6-[4-cyclopropyl-7-[(3R.)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-7-ol; ' ‘2-fluoro-5-[4-methyl-7-[(3R)~l-methyl~3-piperidy1]pyn’olo[2,3-c]pyridazin-3- yi]benzofuran-4-ol;5-[4-ethyl-7-[(3R)-l-methyl-3-piperidyl]pyn’olo[2,3-cJpyridazin-3-yl]benzof'uran-4-ol;2-[7~(3“hydroxy-3-methyl-cyclobutyl)“5-metiiy[--pyrrolo[2,3“C]pyridazin~3"yl]"5“methyi- 3 -(trifluoromethyl)phenol ;3-[4-ethyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]bicyclo[4.2.0]octa-L3,5-trien-2-ol: l,l-dimethyl-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pytTolo[2,3-c]pyridazin-3- yl]indan-4-ol;(3S,4R)“4-[3-[2-hydroxy-4-methyl-6-(trifluoromethyi)phenyl]“5-methyl-pyrrolo[2,3“ cjpyridazin -7 -y ! ]t.etrahy dropyran -3 -ol ,2-[7-[(lR,2R)-2-hydroxycyclohexyl]-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethy 1 jphenol ,5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl- benzofuran-4-ol;5-[4,5-dimethyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol;7-fluoro-5-[4-methyl-7-[(3R)-l-methyl-3-piperidy1]pyn’olo[2,3-c]pyridazin-3- yi]benzofuran-4-ol;5-[7-[(lR,2R)-2-hydroxycyclopentyl]pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol;5-[7-[(lR,2R)-2-hydroxycyclohexyl]-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl- benzofuran-4-ol;5-[7-(3-hydroxy~3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-2,3- dihydrobenzofuran-4-ol;6-(difluoromethyl)-5-[7-[(3R)-l-methyl-3-piperidyl]pyirolo[2,3-c]pyridazin-3- yl]benzofuran-4-ol;2-[7-[(lR,2R)-2-hydroxycyclopentyl]pyrrolo[2:)3-c]pyridazin-3-yl]-3-methyl-5- (trifluoromethyl)phenol;2-[7-(3-methoxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5- (trifluorom et hy 1 )p hen oS ;2-[7"(3-niethoxy“3-methyl"CyclobutyTl)pyrrolo[2,3-c]pyridazin“3-yip5-methyl"3“ (trifluoromethyl)phenol;6-(difluoromethyl)-5-[7-(3-methoxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3- yi]benzofuran-4-ol;6-(difluoromethyl)-5-[7-(3-hydroxy-3-methyl-cyclobutyr)pyrrolo[2,3-c]pyridazin-3- yl]benzofuran-4-ol;6-ethyl-5-[7-[(3R)-l-methyl-3-piperidyl]pyn-olo[2,3-c]pyridazin-3-yl]benzofuran-4-ol;6-methyI"5-[7-[rac-(lR,2S)“2“hydroxycyclobutyl]pyrrolo[2,3-c]pyridazin-3- yl ] b enzofuran-4-ol ;6-methyl-5-[7-[rac-(lR,2R)-2-hydroxycyclobutyl]pyrrolo[2,3-c]pyridazin-3- yl]benzofuran-4-o1 ,5-chloro-3-(difluoromethyl)-2-[7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3- c]py ridazin-3 -yl Jphenol ,2-[7-[(3R)-l-methyl“3-piperidyi]“4"(trifluoromethyl)pyrroio[2,3"C]pyridazin-3-yl]-5- (trifl uoromethyl)phen ol ;5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5^trifluoroinethyl)pyn-olo[2,3-c]pyridazin-3-yl]-6-rn ethyl -b enzofuran-4-ol ;2-[7-(3-hydroxy-3-methyl-cydobuty1)-5-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-3-yl]-5 -methyl - 3 -(triflu oromethy l)phenol ;5-[5-(dif!uoromethyl)-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol;3-(4-hydroxy-6-methyl-benzofuran-5-yl)-7-(3-hydroxy-3-methyl-cyclobutyl)pynolo[2,3- c] pyri dazine-5 -carbal dehy de ;2-[5-(difluoromethyl)-7-(3-hydroxy-3-methy]-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol;5-[5-(difluoromethyl)-7-(3-fluoro-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6- m ethyl -b enzoforan-4-ol ;6-(diiluoromethyl)-5-[5-(difluoromethyl)”7-(3-hydroxy-3-methyl”Cyclobutyl)pynolo[2,3- c]pyridazin-3-yl]benzofuran-4-ol;3-(4-hydroxy-6-methyl-benzofuran-5-yl)-7”(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3- c]pyridazine-5-carbomtrile;5-[5-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6- m ethyl -benzofuran -4-ol ;5-[5-fluoro-4-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3- yl]benzofuran-4-ol;5-[5-fluoro-4-methyl-7-[(3R)-l-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2,3- di hy drob en zofuran -4-ol ,5-[5-fluoro-7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-pyrrolo[2,3-c]pyridazin-3- yl]benzofuran-4-ol;5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5"iodO“pyrrolo[2,3-c]pyridazin"3-yl]-6-methyl- 2,3-dihydrobenzofuran-4-ol;2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethy 1 jphenol ,3-methyl-2-[7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazm-3-yl]-5- (trifluoromethyl)phenol;5-chloro-3-fluoro-2-[6-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl] phenol;5-chloro-2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl] phenol;2-[4”isopropyl-7-[(3R)-l-methyi"3-piperidyl]iinidazo[4,5-c]pyridazin-3-yl]-5- (trifi uoromethyl)phen ol ;3-methyl-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethy 1 jphenol ,2-[4-cyclopropyl-7-[(3R)-l-methy1-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3-methyl- 5-(trifluoromethyl)phenol;2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethy Ijphenoi ;2-[4-cyclopropyl-7-[(3R)-l-(2-hydroxyethyl)-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5~(trifluoromethyl)phenol:5-chloro-3-fluoro-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl] phenol;2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3,5- dimethyl-phenol;5-methoxy'-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]phenol;2-[4-cyclopropyl-7-[(3R)~l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3”yl]”5- m ethoxy -phenol;4-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3-hydroxy- benzonitrile,2-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-5- (trifluorom et hy 1 )p henol ;(3S,4R)-4-[4-cyclopropyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]imidazo[4,5- c] py ridazi n -7 -y I ]tetrahy dropyran-3 -ol ,2-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-3- methyl-5-(trifluoromethyi)phen.ol;(3S,4R)-3-[4“Cyclopropyl"3~[2-hydroxy-4-(trifluoromethyl)phenyl]iniidazo[4,5- c]pyridazin-7-yl]-l-methyl-piperidin-4-ol;(3S,4R)-3-[4-cyclopropyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]imidazo[4,5- c]pyridazin-7-yl]-l-ethyl-piperidin-4-ol;(3S,4R)-3-[4-cyc!opropyl-3-[2-hydroxy-4-(trifluoromethyl)phenyi]imida2o[4,5- c]pyridazin-7-yipi-(2-hydroxyethyl)piperidin"4-ol;5-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5~c]pyridazin-3-yl]indan-4-ol;5-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3- di hy drob en zofuran -4- ol ;3,5-dimethyl-2-[7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol;5-methyI-2“[7-[(3R)“l -methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3- (tri fl uoromethyl)phen ol ;5-[4-methyl-7-[(3R)-l-methyl-3-piperidy!]imidazo[4,5-c]pyridazin-3-yl]-2,3- dihydrobenzofuran-4-ol;5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazm-3-yl]indan-4-ol;3-methoxy-2-[7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5- (trifluorom et hy 1 )p henol ,5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol;5~[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3”yl]benzofuran-4-ol;5-[4-methyl-7-[(3R)~l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin~3-yl]benzothiophen~4-ol;5-[4-cyclopropyl-7-[(3R)“l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3" yl]benzothiophen-4-ol;5-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3- yl ] b enzothi ophen-4-ol ,2-[7-[(3R)-l-etliyi-3-piperidyl]-4-methyl-imidazo[4,5-c]pyridazin-3-yl]-5-methoxy- phenol;2-[4-cyclopropyl-7-[(lR,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]-5- (trifl uoromethyl)phen ol ;2-[4-cyclopropyl-7-[(2R)-2-hydroxypropyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl )phenol ,7-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]quinolin-8- ol;2-[4-cyclopropyl-7-[3-(hydroxymethyl)cyclobutyl]imidazo[4,5-c]pyridazin-3-yl]-5- (trifluoromethy Ijphenol ,2-[7~(3-hydroxy-3-Tnethyl~cyclobutyl)"4-methyl-imjdazo[4,5-c]pyridazin-3-yl]~5- (trifluoromethyl)phenol;7-[4-methyl-7-[(3R)-l-methy1-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]quinolin-8-ol;5-[4-cyclopropyl-7-[rac-(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin"3-yl]-2- methyl-l,3"benzoxazol-4-ol;3-methoxy-2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5- (trifluoromethy Ijphenol ;2-[(3R)-3-[3~[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-imidazo[4,5-c]pyridazin-7- yl]-l~piperidyl]acetonitrile;2-[(3R)“3”[3-(4-hydroxybenzofuran“5“yl)-4-methyMmidazo[4,5-c]pyridazin-7-yl]-l- piperi dyl Jacetoni trile,2- [(3 R)-3 -[4-cyclopropy 1-3 - [2-hy droxy-4-(trifluoromethy I )pheny I ]i midazo[4, 5 - c]pyridazin-7-yl]-l-piperidyl]acetonitrile;5-[4-cyclopropyl-7-[rac-(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2- methyl - 1 , 3 -b enzothi azol -4-ol ;2-methyl-5-[4-methyl-7-[rac-(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]- L3-benzoxazol-4-ol;2-methyl-5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-l,3- benzothiazol-4-ol;5-[4-cyclopropyl-7-[(3R)-I-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2-fluoro- benzothiophen-4 -ol ;2-[(3R)-3-[4-cyclopropyl-3-(4-hydroxybenzofuran-5-yl)imidazo[4,5-c]pyridazin-7-yl]-l- piperi dyl ] acetonitri 1 e;2-[7-[(3R)”l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)benzene- 1 , 3 -di ok2-fluoro-5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl ]b enzothi oph en-4-oi ;6-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzothiophen-7-ol;6"[4-metliyl"7“[(3R)-l-methyl-3-piperidyHimidazo[4,5"C]pyridazin-3“y[]"2,3“diliydro- l,4-benzodioxin-5-ol;2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-cJpyridazin-3-yl]-5-(trifl uoromethyl)benzene- 1 , 3 -di ol ;5-[4-methyl-7-[(3R)-l-(2,2,2-trifluoroethyl)-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol;2-[4-methyl-7"[(3R)-l-methyl-3-piperidyl]imidazo[4,5~c]pyridazin-3"yl]naphthalen-l"Ol;5-[4-methyl-7-[(3R)-l-(oxetan-3-yl)-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol;2-[4”Cyclopropyl”7-[(3R)-l”(oxetan-3”yl)”3“piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5” (trifluoromethyl)pbenol;6-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazm-3-yl]-2,3- dihydro-1 ,4-benzodioxm-5-ol;6-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]quinolin-5-ol;2-[4-ethyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5- (trifluoromethyl)phenol ;5-[7-[(3R)-l-methyl"3-piperidy[]-4"(3-thieny[)imidazo[4,5"C]pyridazin-3-yl^beiizofuraii"4-ol;5-[4,6-diniethyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3- dihydrobenzofuran-4-ol;5-[4,6-dimethyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol;6-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl ] b enzothi ophen-7-ol ;5-[4-ethyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazm-3-yl]indan-4-ol;3-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]bicyc]o[4.2.0]octa-1(6),2,4-trien-2-ol;5-[4-ethvl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazm-3-vl]beRzothiophen-4- ol,2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-4-fluoro-5- methyl-phenol;6-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2-fluoro-3- methyl-phenol;2-[7-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazjn-3-yl]-5-methyl-3- (trifluoromethy Ijphenol ;5-[4-ethyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofiiran-4-ol;5-[4-ethyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3- dihydrobenz.ofuran-4-ol;2.2-difluoro-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-1.3-benzodioxol-4-ol;5-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,2- difluoro- 1 ,3-benzodioxol-4-ol;3-[4,6-dimethyl~7-[(3R)~l~methyl-3-piperidyl]imidazo[4,5"C]pyridazin~3- yl]bicyclo[4.2.0]octa-L3,5-trien”2-ol;2-[4-cyclopropyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-4-fluoro-5- (trifluoromethyl)phenoi;6-methyl-5-[7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol;6-methyl-5-[7-[(3R)-l-methyl-3-piperidyl]iniidazo[4,5-c]pyridazin-3-yl]-2,3- dihydrobenzofuran-4-ol;3-[4-ethyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazm-3-yl]bicyclo[4.2.0]octa- l(6),2,4-trien-2-ol;5-[7-(3“hydroxy“3-methyl-cyclobutyl)imidazo[4,5“C]pyridazin-3“yl]“6-methyl- benz.ofuran-4-ol;5-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol ,3-[7-(3-hydroxy-3-methyl-cyc1obuty1)-4-methyl-imidazo[4,5-c]pyridazin-3- yl]bicyclo[4.2.0]octa-l(6),2,4-trien-2-ol;2-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-5-methyl-3- (trifluoromethy Ijphenoi ;2-[(3R)-3-[3~(4-hydroxy-6-methyl-benzofuran-5-yl)imidazo[4,5-c]pyridazin-7~yl]~l- piperidyl]acetonitriie;6-methyl-5-[7-[(3R)-l-(2,2,2-trifluoroethyl)-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl ] b enzofuran-4-ol ;7-fluoro-5-[4-methyl-7-[(3R)-l-methyl-3-piperidy1]imidazo[4,5-c]pyridazin-3-yl]-2,3- dihydrobenzofuran-4-ol;7-fluoro-5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol;6-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-7-ol;3-hydroxy-5-methyl-4-[7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yljbenzonitrile;2, 2 -di m ethyl-6-[4-methyl-7-[(3R)- 1 -methyl-3 -piperi dy 1] imi dazo[4, 5-c]pyridazin-3 -yl ] - 3H-benzofuran-7-ol1 , 1 -dimethyl -5-[4-m ethyl -7-[(3 R)~ 1 -methyl-3 -piperi dy 1 ]imidazo[4, 5 -c]py ridazin-3 - yl]indan-4-ol6-(difluoromethyl)-5-[7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol5-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-6-methyl-2,3- di hy drob en zofuran -4-ol ;2-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yip3-methyi-5-(trifluorom et hy l)p henol ,5-[7-[(3R)-l-methyl"3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]"6-(2,2,2” tri fl uoroethyl)benzofuran -4-ol ;6-(difluoromethyl)-5-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol ,3-(difluoromethyl)-5-methyl-2-[7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yljphenol;5-chloro-3-(difluoromethyl)-2-[7-[(3R)-l-methyl“3-piperidyl]imidazo[4,5-c]pyridazin-3“ yl]phenol;5-[7-(3,3 -dimethyltetrahydropyran-4-yl)imi dazo[4,5-c] pyridazin-3 -yl]-6-methy I - benzofuran-4-ol;3-[7-[(lR,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]-4-methyl- bicyclo[4.2.0]octa”l,3,5-trien-2-ol;6-(difluoromethyl)-5-[7-[(1R,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3- yl]benzofuran~4-ol;5-[7-[(lR,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]-6-(2,2,2- tri fl u oroethy 1 )b enz ofu ran-4-ol ;6-ethyl-5-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5~c]pyridazin-3-yl]benzofuran~4-ol;5-[7-[(lR,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol ;5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]imidazo[4,5-c]pyridazin-3-yl]-6-methyl- benzofuran-4-ol;(3S,4R)-4-[3-[2-hydroxy-6~metliyl-4-(trifluoromethyl)phenyl]imidazo[4,5-c]pyridazin-7- yl]tetrahydropyran-3 -ol ;5-[7-(2,2-dimethyltetrahydropyran~4-yl)imidazo[4,5-c]pyridazin-3-yl]-6-methyl- benzofuran-4-ol;6"ethyl"5-[7“[(lR,2R)“2-hydroxycyclohexyl]imidazo[4,5"C]pyridazin-3"y[]benzofuran“4" ok6-[4"methyl-7-[(3R)-l-methyl"3"piperidyl]iniidazo[4,5-c]pyridazin“3-yl]tetralin“5-ol;3.3-dimethyl-5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]indan-4-ok2.3-dimethyl-6-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]phenol;2-[4-methoxy-7”[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3”yl]”3-methyl-5-(trifluorom et hy l)p henol ,5-[4”(cyclopropoxy)-7-[(3R)-l-methyk3“piperidyl]imidazo[4,5-c]pyridazin-3- yl ] b enzofuran-4-ol ;5-[4-ethoxy-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol;5-[4-methoxy-7-[(3R)-l-methyl-3”piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4- ol;5-[4-(azetidin-l-yl)-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol;5-[4-(dimethylamino)“7-[(3R)"l-methyl-3"piperidyl]imidazo[4,5-c]pyridaziii"3- yl]benzofuran-4-ol;5-[4-(difluoromethyl)-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol ,2-[4-(difluoromethyl)-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5- (trifluoromethyl)phenol;2-[4-(l-hydroxyethyl)-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5- (trifluoromethy Ijphenol ;2-[4-(hydroxymethy1)-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5- (trifluoromethyl)phenol;5-chloro-3-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-imidazo[4,5-c]pyridazin-3- yl]bicyclo[4.2.0]octa-l(6),2,4-trien-2-ol;7-chloro-5-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol;7-chloro-5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3- yl]benzofuran-4-ol;2-[7-cyclopropyl-3-[(3R)-l-methyl-3-piperidyl]triazolo[4,5-c]pyridazin-6-yl]-5- (trifluoromethyl)phenol ;5-chloro-3-fluoro-2-[3-[(3R)-l”methyl-3-piperidyl]triazolo[4,5-c]pyridazin-6-yl]phenol;3-methyt-2-[3-[(3R)-l-methyl-3-piperidyl]triazolo[4,5-c]pyridazin-6-yl]-5- (trifluoromethyl)phenol ;3.5-dimethyl -2-[7-( 1 -methyl -3 -piperi dy 1 )-5 H-pyrrol o[3 ,2-c]py ri dazin-3 -yl]phenol ;5-[4-cyclopropyl-7-(l-methyl-3-piperidyl)-5H-pyn‘oio[3,2-c]pyridazir1-3-yl]indan-4-ol;2-[4-cyclopropyl-7-(l-methyl-3-piperidyl)“5H”pyrrolo[3,2-c]pyridazir1-3-y[]-5-( trifluoromethy 1 )phenol ,3.5-dimethyl-2-[7-(l-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]phenol;3.5-dimethyl-2-[7-(l-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3.2-c]pyridazin-3- yi]phenol;2-[4"methyl-7-[(3S)-l-methy[-3-piperidyl]thieno[3,2-c]pyridazin"3-yl]“5-(trifluoromethyl)phenol;2-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]-5-(trifluorom et hy 1 )p henol ,3-methyl-2-[7-[(3S)-l-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]-5-(trifl uoromethyl)phen ol ;3-methyI-2“[7-[(3R)“l-methyl-3“piperidyl]thieno[3,2“C]pyridazin-3-yi]“5“(tri fl uoromethyl)phen ol ;2-[4-methyl-7-(l-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethy 1 jphenol ,2-[4-cyclopropyl-7-(l-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol;3-methyl-2-[4-methyl-7-(l-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethy Ijphenoi ;5-[4-methyl-7-[(3 S)-l-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-y1]-2,3- dihvdrobenzofuran-4-ol;5-[4-methyl-7-[(3R)-l-methy]-3~piperidyl]t.bieno[3,2-c]pyridazin-3~yl]-2,3~ dihydrobenzofuran-4-ol;5-[4-methyl-7-(l-methy]-3-piperidy])t.bieno[3,2-c]pyridazin-3-yl]-2,3- dihydrobenzofuran-4-ol;6-methyl-5-[7-(l-methyl-3”piperidyl)thieno[3,2-c]pyridazin-3”yl]”2,3- dihydrobenzofuran-4-ol;5-[4-methyl-7-[(3R)-l-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]indan-4-ol;5-[4-methyl-7-[(3S)-l-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3~yljindan-4-ol;3-[4-niethyl-7-(l-methyl-3-piperidyr)thieno[3,2-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1 (6),2,4-trien-2-ok6-methyl-5-[7-(l-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol;5-[4-methyl-7"(l-methyl-3"piperidyl)thieno[3,2-c]pyridazin-3"yl]indan-4-ol;6-methyl-5-[7-[(3S)-l-me1hyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol;6-methyl-5-[7-[(3R)-l-methyl-3-piperidyi]thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol;5"[7-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-3"yl]-6-methyl“benzofuran-4"Ol;5-[7-(2-fluorophenyl)thieno[3,2-c]pyridazin-3-yl]-6-methyl~benzofuran-4-ol;6-methyl-5-[7-[2-(trifluoromethoxy)pheny1]thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol;6-methyI-5“[7-[2-(trifluoromethyl)phenyl]thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol;6-methyl”5-[7-(o-tolyl)thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol;5-[7-(2-chlorophenyl)thieno[3,2-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ok5-[7-(3,6-dihydro-2H-pyran-4-yl)thieno[3,2-c]pyridazin-3-yl]-6-methyl-benzoforan-4-ol;6-methyl-5-(7-tetrahydropyran-4-ylthieno[3,2-c]pyridazin-3-yl)benzofuran-4-ol;5-methyI-2-(7-tetrahydropyran-3 -ylthieno[3 ,2-c]pyridazin-3 -y I)-3 -(tri fl uoromethyl)phen ol ;6-methyl-5-(7-tetrahydrofurajn-3-ylthieno[3,2-c]pyridazin-3-yl)benzofuran-4-ol;5-[7-(2,5-dihydrofuran-3-yl)thieno[3,2-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol;6-methyl-5-(7-tetrahydropyran-3-ylthieno[3,2-cjpyridazin-3-yl)benzofuran-4-o1;3-methyl-2-[7-(l-methyl-3,6-dihydro-2H-pyridin-5-yl)furo[3,2-c]pyridazin-3-yl]-5- (trifluoromethy l)phenol ;3-methyl-2-[7-(l-methy]-3-piperidyl)furo[3,2-c]pyridazin-3-y]]-5-(trifluoromethyl)phenol;2-[4-methyl-7-(l-methyl-3-piperidyl)furo[3,2-c]pyridazin-3~yl]-5-(trifluoromethy Ijphenol ;5-[4-methyl-7-(l-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]indan-4-ol;5-[4-methyl-7-(l-methyl-3-piperidyl)foro[3,2-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol ;3-methyl-2-[4-methyl-7-(l-methy[-3-piperidyl)furo[3,2-c]pyridazin-3-yl]-5- (trifluoromethyl)phenol;3-methyl~2-[7-[(3R)-l-methy]-3~piperidy1]furo[3,2-c]pyridazin-3-y]]-5~(trifluoromethy Ijphenol ,3-methyl-2-[7~[(3S)-l -methyl-'3"piperidyl}furo[3,2-c]pyridazin-3-yl]"5- (trifluoromethyl)phenol;5-[4-methyl-7-(l-melhyl-3-p!peridyl)furo[3,2-c]pyridaziTi-3~yl]benzofuran-4-ol;6-methyl-5-[7-(l-methyl-3-piperidyr)furo[3,2-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol;6-niethyl-5-[7-(l-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]benzofuran-4-ol;2-[4"Cyclopropyl"l“(l-methyl”3“piperidyl)pyrazolo[3,4"C]pyridaziii”5“yip5-methyl" phenol;3-[4-cyclopropyl-l-(l-methyl-3-piperidyl)pyrazolo[3,4-c]pyridazin-5- yl]bicyclo[4.2.0]octa-1,3,5-trien-2~ol;5-[4-cyclopropyl-l-( l-methyl-3-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]benzofuran-4-ol; and2-[4-cyclopropyl-l-(l~methyl-3-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]-5-(trifluoromethyl)phenolwherein a form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer, and isotope enriched form thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or claim 12 wherein said compounds comprise a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

14. A method for treating or ameliorating a disease modulated by NLRP3 in a subject in need thereof comprising, administering to the subject an effective amount of the compound according to claim 1 or claim 12.

15. A method of treating or ameliorating a disease modulated by NLRP3 according to claim 14 wherein said disease is selected from Alzheimer disease, Frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, Perioperative neurocognitive disorders, Post-cardiac arrest cognitive impairment, Poststroke cognitive impairment, Sepsis, Sepsis associated encephalopathy, Subarachnoid hemorrhage, Macular Degeneration, Retinal neovascularization. Uveitis, Colitis, Endothelial dysfunction, Gout, Pseudogout, Graft- versus-host-disease (GvHD), Systemic lupus eiythematosus-lupus nephritis, Cryopyrin-associated periodic syndromes (CAPS), Cystic fibrosis, Sickle-cell disease, VCP-associated disease, Liver fibrosis, Nonalcoholic fatty liver disease (NASH), muscle atrophy, inherited and acquired myopathies, Duchenne Muscular Dystrophy (DMD), Hyperalgesia, Multiple sclerosis-associated neuropathic pain, Acute Kidney Injury, Chronic crystal nephropathy, Chronic Kidney Disease, asthma and allergic airway inflammation Diabetes-associated atherosclerosis, Diabetic encephalopathy, Diabetic kidney disease, Islet transplantation rejection, Obesity-associated renal disease, Oxalate-induced nephropathy, Renal fibrosis, Renal hypertension, Type I diabetes, Type II diabetes, Psoriasis, Hidradenitis suppurativa, Atherosclerosis and Cytokine Release Syndrome (CRS).

16. The method of claim 14, wherein the effective amount of the compound is in a range of from about 0.001 mg / kg / day to about 500 mg / kg / day.

17. A compound according to claim 1 or claim 12, wherein said pharmaceutically acceptable salt thereof, for use in treating or ameliorating a disease modulated by NLRP3 is selected from Alzheimer disease, Frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, Perioperative neurocognitive disorders, Post-cardiac arrest cognitive impairment, Poststroke cognitive impairment, Sepsis, Sepsis associated encephalopathy. Subarachnoid hemorrhage, Macular Degeneration, Retinal neovascularization, Uveitis, Colitis, Endothelial dysfunction, Gout, Pseudogout, Graft-versus- host-di sense (GvHD), Systemic lupus erythematosus-lupus nephritis, Cryopyrin-associated periodic syndromes (CAPS), Cystic fibrosis, Sickle-cell disease, VCP-associated disease, Liver fibrosis, Nonalcoholic fatty' liver disease (NASH), muscle atrophy, inherited and acquired myopathies, Hyperalgesia, Multiple sclerosis-associated neuropathic pain, Acute Kidney Injury, Chronic crystal nephropathy, Chronic Kidney Disease, asthma and allergic airway inflammation Diabetes-associated atherosclerosis, Diabetic encephalopathy, Diabetic kidney disease. Islet transplantation rejection. Obesity- associated renal disease. Oxalate -induced nephropathy, Renal fibrosis, Renal hypertension, Type I diabetes. Type II diabetes. Psoriasis, Hidradenitis suppurativa, Atherosclerosis and Cytokine Release Syndrome (CRS).

18. Use of a compound according to claim 17, wherein the effective amount of the compound is in a range of from about 0.001 mg / kg / day to about 500 mg / kg / day.

19. Use of a compound according to claim 1 or claim 12 in the preparation of a pharmaceutical composition for treating or ameliorating a disease modulated by NLRP3 in a subject in need thereof comprising, administering to the subject an effective amount of the compound or a form thereof in admixture with one or more of the pharmaceutically acceptable excipients