Inhibitors of NLRP3

Abstract

The present invention relates to novel compounds of formulas I-XI that inhibit NOD-like receptor protein 3 (NLRP3) inflammasome activity. JPEG2024534162000343.jpg3994 JPEG2024534162000344.jpg3992 (in the formula, each A, A', Q, Q', W, R w (wherein Y and Z, and -- are as defined herein) The present invention further relates to methods for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 237,049, filed August 25, 2021, and U.S. Provisional Patent Application No. 63 / 311,463, filed February 18, 2022, the contents of which are incorporated herein by reference in their entirety and for any purpose. FIELD OF THE INVENTION The present invention relates to compounds useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, methods of using the compounds and medicaments containing them in the treatment of various diseases and disorders, and their use in pathological conditions and disorders mediated by NLRP3. [Background technology]

[0002] The term inflammasome was coined by Martinon et al. to describe a molecular platform that triggers the activation of inflammatory caspases and the processing of interleukin-1 (IL-1) family cytokines (Fabio Martinon et al., Mol Cell 10(2):417-26, 2002). Inflammasomes are part of the innate immune system. Inflammasome activation is initiated by the assembly of a multiprotein complex containing nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), the adaptor apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, and the effector protease caspase-1. Complex assembly leads to the activation of caspase-1 and the release of mature proinflammatory cytokines, such as IL-1β and IL-18. Among inflammasomes, the NLR family NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome has been extensively studied and found to be activated by a wide range of stimuli. The regulatory mechanisms of NLRP3 activation are summarized in a recent review article (Seungwha Paik et al., Cell Mol Immunol 18(5):1141-1160, 2021).

[0003] NLRP3 activation is induced by various infectious and non-infectious molecules, including molecular by-products of aging, physical inactivity, and excessive nutrition. Its activation enhances downstream production of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function mutations in NLRP3 are associated with several genetic disorders, including cryopyrin-associated periodic fever syndrome (CAPS). Furthermore, NLRP3 has been implicated in numerous common I) autoimmune, II) autoinflammatory, III) neurodegenerative, IV) cardiovascular, and V) neuromuscular and myodegenerative diseases, for example (Matthew SJ Mangan et al., Nat Rev Drug Discov 17(8):588-606, 2018; Corcoran et al., Pharmacol Rev 73(3):968-1000, 2021; Dubuisson et al., Cells 10(11):3023, 2021). Inflammasome activation has also been observed in retinal pigment epithelial (RPE) cells and has been proposed to be a causative factor in RPE dysfunction and degeneration (Gao et al., Mediators Inflamm 2015:690243, 2015). Furthermore, NLRP3 activation is associated with severe COVID-19 cases and cytokine release syndrome (CRS) induced by cell-based therapeutics and biological treatments (Tracey L Freeman and Talia H Swartz Front Immunol 11:1518, 2020; Lin et al., PLoS Pathog 6;15(6):e1007795, 2019). Therefore, NLRP3 inflammasome inhibitors can be used as single or combined agents clinically as novel therapies for these diseases. Thus, these inflammasome-related diseases and disorders, such as autoinflammatory fever syndrome, cryopyrin-associated periodic fever syndrome (CAPS), sickle cell disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, pseudogout (chondrocalcinosis), type I / II diabetes and related complications (e.g., nephropathy, retinopathy), fibrosis, rheumatoid arthritis, inflammatory bowel disease, asthma and allergic airway inflammation, neuroinflammatory-related disorders (e.g., multiple sclerosis, brain infection, There is a need for inhibitors of the NLRP3 inflammasome pathway that provide new and / or alternative treatments for acute injury, Alzheimer's disease, Parkinson's disease, Huntington's disease), neuromuscular and muscular degenerative diseases, atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis). References: JPEG2024534162000002.jpg222166 Summary of the Invention

[0004] The present invention provides a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, wherein the compound inhibits the NLRP3 inflammasome pathway. The present invention further provides a method for treating or preventing a disease and / or disorder associated with NLRP3, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Various aspects of the present invention have been described herein.

[0005] The present application relates to a compound of formula Ia, Ib, Ic, or Id, wherein the compound is in a form selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, and tautomeric forms thereof, with the proviso that the compound is selected from the group consisting of phenol, 5-([1,1'-biphenyl]-4-yl-4-dibenzothienylamino)-2-[4-([1,1'-biphenyl]-4-yl-4-dibenzothienylamino)-1-naphthalenyl]; 5-[phenyl(6-phenyl-4-dibenzothienyl)amino]-2-[ 4-[phenyl(6-phenyl-4-dibenzothienyl)amino]-1-naphthalenyl]phenol;5-[2-dibenzothienyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-2-[4-[2-dibenzothienyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-1-naphthalenyl]phenol;5-[2-dibenzofuranyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-2-[4-[2-dibenzofuranyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-1-naphthalenyl]phenol phenyl]phenol;5-(4-dibenzofuranylphenylamino)-2-[4-(4-dibenzofuranylphenylamino)-1-naphthalenyl]phenol;5-(4-dibenzofuranyl-2-naphthalenylamino)-2-[4-(4-dibenzofuranyl-2-naphthalenylamino)-1-naphthalenyl]phenol;5-[phenyl(6-phenyl-4-dibenzofuranyl)amino]-2-[4-[phenyl(6-phenyl-4-dibenzofuranyl)amino]-1-naphthalenyl]phenol;5-([1,1'-biphenyl] -2-yl-4-dibenzofuranylamino)-2-[4-([1,1'-biphenyl]-2-yl-4-dibenzofuranylamino)-1-naphthalenyl]phenol; 4-[4-(4-dibenzofuranylphenylamino)-1-naphthalenyl]-2',3',5',6'-tetrafluoro-4'-(2-naphthalenylphenylamino)[1,1'-biphenyl]-3-ol; 2-[4-[[6-[[3-(2-amino-4-pyrimidinyl)-2-pyridinyl]oxy]-3-pyridinyl]amino]-1-phthalazinyl]phenol;or 2-[4-[[6-[[3-(2-amino-4-pyrimidinyl)-2-pyridinyl]oxy]-3-pyridinyl]amino]-1-phthalazinyl]-4-fluorophenol;

[0006] [ka] JPEG2024534162000004.jpg46116

[0007] (In the formula, R w is hydrogen, C 1-6 Alkyl (e.g., CH3), C 2-8 Alkynyl, halogen (e.g., F, Cl), C1-6 alkoxy (e.g., OCH3), halo-C 1-4 Alkyl (e.g., CHF2, CF3), halo-C 1-4 Alkoxy (e.g., OCHF2, OCF3), cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR 1a , N.R. 1b , S(=O)R 1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)NR 1b , ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2 or S(=O)2NR 1b and each C 1-6The alkyl, heterocycle (e.g., 2,5-dihydrofuran-3-yl), heteroaryl, and aryl are optionally substituted with 1 or 2 substituents each selected from R5; each W is independently CH, CR′, or N; each Q is independently N or CH; each Q' is independently N, C, or CH; Each A is independently CH, CH2, or CR a , CHR a , CR4, CHR4, N, NH, NR a , NR4, S or O; Each A' is independently absent, CH, CH2, CR a , CHR a , CR4, CHR4, N, NH, NR a , NR4, S or O;

[0008] Each R a are independently hydrogen, deuterium, halogen, -CN, -OH, -OR2, =O, =N-OR2, -SR2, -S(=O)R2, -S(=O)2R2, -N(R2)2, -NR2S(=O)(=NR2)R 2 , -NR2S(=O)2R2, -S(=O)2N(R2)2, -C(=O)R2, -OC(=O)R2, -C(=O)OR2, -OC(=O)O R2, -C(=O)N(R2)2, -OC(=O)N(R2)2, -NR2C(=O)R2, -P(=O)(R2)2, C1-4 alkyl, (C 1-4 alkyl), halo-C alkyl, C heteroalkyl, C cycloalkyl, C heterocycloalkyl, aryl, or monocyclic heteroaryl; Each --- represents an absent bond or a single or double bond; Y is C(R 1a )2, C=O, O, NR 1b or a bond, Each R 1a are independently hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4Alkyl, amino or hydroxy-C 1-4 Alkyl, C 3-10 cycloalkyl, C2-7 heterocycloalkyl or aryl; Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each R' is independently selected from heterocyclyl, heteroaryl, aryl, C 3-8 Cycloalkyl, C 1-4 Alkyl, C 1-4 Alkoxy, Deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl (e.g., trifluoromethyl, difluoromethyl), halo-C 1-4 Alkoxy (e.g., trifluoromethoxy), hydroxy-C 1-4 alkyl, halogen, hydroxy or cyano;

[0009] Each heterocyclyl (e.g., 1-methyl-2,5-dihydro-1H-pyrrol-3-yl, 2,5-dihydrofuran-3-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-2H-pyran-3-yl, N-methylpyrrol-3-yl, N-pyrrolidin-1-yl, pyrrolidin-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, N-methylpyridinon-4-yl) pyridinone-4-yl), heteroaryl (e.g., 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2-pyrazol-4-yl, 5-methyl-1,2,4-thiadiazol-2-yl, N-methylpyrrol-3-yl, N-methylpyridinon-4-yl, tetrazol-5-yl), C 3-8cycloalkyl (2-cyanocycloprop-1-yl, cyclopropyl) and aryl (e.g., phenyl, 4-chloro-2-cyanophenyl, 4-chloro-2-hydroxyphenyl) are optionally substituted with one or two substituents each selected from R3; Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-8 Alkyl, C 1-6 Alkoxy, NH(hydroxy-C 1-6 alkyl), NH(C 1-6 alkoxy), wherein each Z is optionally substituted with OH, NH, —COH, halogen, C alkyl, C haloalkyl, C hydroxyalkyl, C acyl, C alkanoic acid, C alkanoate ester, or heterocyclyl, and is optionally substituted with heterocyclyl, C 3-10 cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2;

[0010] R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-6 Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4Alkyl, (C 1-4 Alkyl-amino)2-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C1-4 alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy; Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O or S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S;

[0011] C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4independently selected from alkoxy; Each R4 is a halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl)

[0012] The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound according to the compound definitions of Formulas I-XI or subformulas thereof disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical compositions are useful for treating diseases and / or disorders associated with NLRP3 activity. In another aspect, the present invention provides combinations, particularly pharmaceutical combinations, comprising a therapeutically effective amount of a compound according to the compound definitions of Formulas I-XI or subformulas thereof disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents. In another aspect, the present invention provides combinations, particularly pharmaceutical combinations, disclosed herein for use as a medicament. In another aspect, the present invention provides a compound of Formulas I-XI or a subformula thereof disclosed herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms, and / or the progression of said disease or disorder. In another aspect, the present invention provides a method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms, and / or the progression of said disease or disorder, comprising administering a therapeutically effective amount of a compound of Formulas I-XI or a subformula thereof disclosed herein, or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method for inhibiting NLRP3 inflammasome activity in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formulas I-XI or a subformula thereof disclosed herein, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to the use of a compound of Formulas I-XI or a subformula thereof disclosed herein, or a pharmaceutically acceptable salt thereof, as a pharmaceutical.

[0013] Another aspect of the present invention relates to a compound of Formulas I-XI or a subformula thereof disclosed herein, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. Another aspect of the present invention also provides a compound of Formula I-XI or a subformula thereof disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from an inflammasome-associated disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, and an autoinflammatory disease. DETAILED DESCRIPTION OF THE INVENTION

[0014] An embodiment of the present invention is a compound having the structure of Formula Ia, Ib, Ic, or Id, wherein the compound is in a form selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers, and isotopically enriched forms thereof, with the proviso that the compound is selected from the group consisting of phenol, 5-([1,1'-biphenyl]-4-yl-4-dibenzothienylamino)-2-[4-([1,1'-biphenyl]-4-yl-4-dibenzothienylamino)-1-naphthalenyl]; 5-[phenyl(6-phenyl-4-dibenzothienyl)amino]-2-[4-([1,1'-biphenyl]-4-yl-4-dibenzothienylamino)-1-naphthalenyl]; 5-[2-Dibenzothienyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-2-[4-[2-dibenzothienyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-1-naphthalenyl]phenol;5-[2-Dibenzothienyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-2-[4-[2-dibenzothienyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-1-naphthalenyl]phenol;5-[2-Dibenzofuranyl(9,9-dimethyl-9H-fluoren-2-yl)amino]-2-[4-[2-dibenzofuranyl(9,9-dimethyl-9H-fluoren-2-yl)amino]- 5-(4-Dibenzofuranylphenylamino)-2-[4-(4-dibenzofuranylphenylamino)-1-naphthalenyl]phenol;5-(4-Dibenzofuranyl-2-naphthalenylamino)-2-[4-(4-dibenzofuranyl-2-naphthalenylamino)-1-naphthalenyl]phenol;5-[phenyl(6-phenyl-4-dibenzofuranyl)amino]-2-[4-[phenyl(6-phenyl-4-dibenzofuranyl)amino]-1-naphthalenyl]phenol;5-([1,1'-bifuranyl 4-[4-(4-dibenzofuranylphenylamino)-1-naphthalenyl]-2',3',5',6'-tetrafluoro-4'-(2-naphthalenylphenylamino)[1,1'-biphenyl]-3-ol;2-[4-[[6-[[3-(2-amino-4-pyrimidinyl)-2-pyridinyl]oxy]-3-pyridinyl]amino]-1-phthalazinyl]phenol;or 2-[4-[[6-[[3-(2-amino-4-pyrimidinyl)-2-pyridinyl]oxy]-3-pyridinyl]amino]-1-phthalazinyl]-4-fluorophenol;

[0015] [ka] JPEG2024534162000006.jpg3793 (in the formula, R w is hydrogen, C 1-6 Alkyl, C 2-8 Alkynyl, halogen, C1-6 alkoxy, halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR 1a , N(R 1b )2, S(=O)R 1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NHR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)N(R 1b )2, ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2R 1a or S(=O)2N(R 1b )2, and each C 1-6 The alkyl, heterocycle, heteroaryl and aryl are optionally substituted with 1 or 2 substituents each selected from R5;

[0016] each W is independently CH, CR′, or N; each Q is independently N or CH; each Q' is independently N, C, or CH; Each A is independently CH, CH2, or CR a , CHR a , CR4, CHR4, N, NH, NR a , NR4, S or O; Each A' is independently absent, CH, CH2, CR a , CHR a , CR4, CHR4, N, NH, NR a , NR4, S or O; Each R a are independently H, deuterium, halogen, -CN, -OH, -OR2, =O, =N-OR2, -SR2, -S(=O)R2, -S(=O)2R2, -N(R2)2, -NR2S(=O)(=NR2)R 2 , -NR2S(=O)2R2, -S(=O)2N(R2)2, -C(=O)R2, -OC(=O)R2, -C(=O)OR2, -OC(=O)O R2, -C(=O)N(R2)2, -OC(=O)N(R2)2, -NR2C(=O)R2, -P(=O)(R2)2, C1-4 alkyl, (C 1-4 Alkyl)2, Halo-C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 2-7 heterocycloalkyl, aryl, or monocyclic heteroaryl;

[0017] Each --- represents an absent bond or a single or double bond; Y is C(R 1a )2, C=O, O, NR 1b or a bond, Each R 1a are independently hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, amino or hydroxy-C 1-4 Alkyl, C 3-10Cycloalkyl, C 2-7 heterocycloalkyl or aryl; Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each R' is independently selected from heterocyclyl, heteroaryl, aryl, C 3-8 Cycloalkyl, C 1-4 Alkyl, C 1-4 Alkoxy, Deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 alkyl, halogen, hydroxy or cyano; Each heterocycle, heteroaryl, C 3-8 The cycloalkyl and aryl are optionally substituted with 1 or 2 substituents each selected from R3;

[0018] Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-8 Alkyl, C 1-6 Alkoxy, NH(hydroxy-C 1-6 alkyl), NH(C 1-6 alkoxy), and each Z is OH, NH2, -CO2H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Achill, C 2-6 Alkanoic acid, C 2-6 Optionally substituted with alkanoate ester or heterocyclyl, heterocyclyl, C 3-10cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2; R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-6 Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C 1-4 Alkyl-amino)2-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C1-4 alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy;

[0019] Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O and S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4 independently selected from alkoxy;

[0020] Each R4 is a halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl)

[0021] Another aspect of the present invention also provides a compound having the structure of Formula IIa, IIb, IIc, or IId, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] JPEG2024534162000008.jpg3895 (in the formula, R w is hydrogen, C 1-6 Alkyl, C 2-8 Alkynyl, halogen, C1-6 alkoxy, halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR 1a , N(R 1b )2, S(=O)R1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NHR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)N(R 1b )2, ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2R 1a or S(=O)2N(R 1b )2, and each C 1-6 The alkyl, heterocycle, heteroaryl and aryl are optionally substituted with 1 or 2 substituents each selected from R5;

[0022] each W is independently CH, CR', or N, and at least one Q' is N; each Q is independently N or CH; each Q' is independently N, C, or CH; Each A is independently CH, CH2, or CR a , CHR a , CR4, CHR4, N, NH, NR a , NR4, S or O; Each A' is independently absent, CH, CH2, CR a , CHR a , CR4, CHR4, N, NH, NR a , NR4, S or O; Each R a are independently H, deuterium, halogen, -CN, -OH, -OR2, =O, =N-OR2, -SR2, -S(=O)R2, -S(=O)2R2, -N(R2)2, -NR2S(=O)(=NR2)R 2, -NR2S(=O)2R2, -S(=O)2N(R2)2, -C(=O)R2, -OC(=O)R2, -C(=O)OR2, -OC(=O)OR2, -C(=O)N(R2)2, -OC(=O)N(R2)2, -NR2C(=O)R2, -P(=O)(R2)2, C 1-4 Alkyl, (C 1-4 Alkyl)2, Halo-C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 2-7 heterocycloalkyl, aryl, or monocyclic heteroaryl;

[0023] Each -- represents an absent bond or a single or double bond; Y is C(R 1a )2, C=O, O, NR 1b or a bond, Each R 1a are independently hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, amino or hydroxy-C 1-4 Alkyl, C 3-10 cycloalkyl, C2-7 heterocycloalkyl or aryl; Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each R' is independently selected from heterocyclyl, heteroaryl, aryl, C 3-8 Cycloalkyl, C 1-4 Alkyl, C 1-4 Alkoxy, Deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 alkyl, halogen, hydroxy or cyano;

[0024] Each heterocycle, heteroaryl, C 3-8 The cycloalkyl and aryl are optionally substituted with 1 or 2 substituents each selected from R3; Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-8 Alkyl, C 1-6 Alkoxy, NH(hydroxyl-C 1-6 alkyl), NH(C 1-6 alkoxy), wherein each Z is optionally substituted with OH, NH, —COH, halogen, C alkyl, C haloalkyl, C hydroxyalkyl, C acyl, C alkanoic acid, C alkanoate ester, or heterocyclyl, and is optionally substituted with heterocyclyl, C 3-10 cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2;

[0025] R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-6 Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C 1-4 Alkyl-amino)2-C 1-4Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C1-4 alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy; Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O and S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S;

[0026] C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4 independently selected from alkoxy; Each R' and R4 is a halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl)

[0027] Another aspect of the present invention also provides a compound having the structure of Formula IIIa, IIIb, IIIc, or IIId, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] JPEG2024534162000010.jpg46114 (in the formula, R w is hydrogen, C 1-6 Alkyl, C 2-8 Alkynyl, halogen, C1-6 alkoxy, halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR 1a , N(R 1b )2, S(=O)R 1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NHR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)N(R 1b )2, ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2R 1a or S(=O)2N(R 1b ) 2, wherein each heterocycle, heteroaryl, and aryl is optionally substituted with 1 or 2 substituents each selected from R5;

[0028] each W is independently CH, CR′, or N; each Q is independently N or CH; Y is C(R 1a )2, C=O, O, NR 1b or a bond, Each R 1a are independently hydrogen, halogen, hydroxyl, cyano, C1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, amino or hydroxy-C 1-4 is alkyl, Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each R4 is a halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl;

[0029] Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-8 Alkyl, NH(hydroxy-C 1-6 alkyl), NH(C 1-6alkoxy), wherein each Z is optionally substituted with OH, NH2, —CO2H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 acyl, C2-6 alkanoic acid, C2-6 alkanoate ester, or heterocyclyl, wherein the heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2;

[0030] R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-6 Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C 1-4 Alkyl-amino)2-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C1-4 Alkyl, heterocyclyl-C 1-4 Alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy;

[0031] Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O and S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4 independently selected from alkoxy;

[0032] Each R' and R4 is a halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl; n is 0, 1, 2 or 3

[0033] Another aspect of the present invention also provides a compound having the structure of Formula IVa, IVb, IVc, or IVd, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] JPEG2024534162000012.jpg49114 (in the formula, R w is hydrogen, C 1-6 Alkyl, C 2-8 Alkynyl, halogen, C1-6 alkoxy, halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR 1a , N(R 1b )2, S(=O)R 1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NHR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)N(R 1b )2, ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2R 1a or S(=O)2N(R 1b )2, wherein each heterocycle, heteroaryl, and aryl is optionally substituted with 1 or 2 substituents each selected from R5, and each A is independently NH, S, O, CH2, or CR4; A' is independently NH, S, O, CH2, CR4, or absent;

[0034] Each -- represents an absent bond or a single or double bond; Y is C(R 1a )2, C=O, O, NR 1b or a bond, R 1a is hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, amino or hydroxy-C 1-4 is alkyl, R 1b is hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-8 Alkyl, NH(hydroxy-C 1-6 alkyl), NH(C 1-6 alkoxy), and each Z is OH, NH2, -CO2H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Achill, C 2-6 Alkanoic acid, C 2-6 optionally substituted with an alkanoate ester or heterocyclyl, wherein the heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2;

[0035] R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-6 Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C 1-4 Alkyl-amino)2-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C 1-4 Alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy; Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O and S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S;

[0036] C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4 independently selected from alkoxy; Each R4 is a halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocycle, and phenyl;

[0037] Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3

[0038] Another aspect of the present invention also provides a compound having the structure of Formula Va, Vb, Vc, or Vd, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] (In the formula, R w is hydrogen, C 1-6 Alkyl, C 2-8 Alkynyl, halogen, C 1-6 Alkoxy, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR 1a , N(R 1b )2, S(=O)R 1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NHR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)N(R 1b )2, ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2R 1a or S(=O)2N(R 1b ) 2, wherein each heterocycle, heteroaryl, and aryl is optionally substituted with 1 or 2 substituents each selected from R5;

[0039] each W is independently CH, CR′, or N; Y is C(R 1a )2, C=O, O, NR 1b or a bond, R 1a is hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, amino or hydroxy-C 1-4 is alkyl, R 1b is hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-8 Alkyl, NH(hydroxy-C 1-6 alkyl), NH(C 1-6 alkoxy), and each Z is OH, NH2, -CO2H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Achill, C 2-6 Alkanoic acid, C 2-6 optionally substituted with an alkanoate ester or heterocyclyl, wherein the heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2;

[0040] R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-6 Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C1-4 Alkyl-amino)2-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C 1-4 Alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy; Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O or S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S;

[0041] C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4independently selected from alkoxy; Each R' or R4 is a halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl; n is 0, 1, 2 or 3

[0042] Another aspect of the present invention also provides a compound having the structure of Formula VIa, VIb, VIc, or VId, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] (In the formula, R w is hydrogen, C 1-6 Alkyl, C 2-8 Alkynyl, halogen, C 1-6 Alkoxy, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR 1a , N(R 1b )2, S(=O)R 1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NHR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)NHR 1b , ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2R 1a or S(=O)2N(R 1b ) 2, wherein each heterocycle, heteroaryl, and aryl is optionally substituted with 1 or 2 substituents each selected from R5;

[0043] each W is independently CH, CR′, or N; Y is C(R1a )2, C=O, O, NR 1b or a bond, Each R 1a are independently hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, amino or hydroxy-C 1-4 is alkyl, Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-8 Alkyl, NH(hydroxy-C 1-6 alkyl), NH(C 1-6 alkoxy), and each Z is OH, NH2, -CO2H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Achill, C 2-6 Alkanoic acid, C 2-6 an alkanoate ester or a heterocyclyl, wherein the heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2;

[0044] R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-6Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C 1-4 Alkyl-amino)2-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C 1-4 Alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy;

[0045] Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O and S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4 independently selected from alkoxy;

[0046] Each R' or R4 is a halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl; n is 0, 1, 2 or 3

[0047] Another aspect of the present invention also provides a compound having the structure of Formula VIIa, VIIb, VIIc, or VIId, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] (In the formula, R w is hydrogen, C 1-6 Alkyl, C 2-8 Alkynyl, halogen, C 1-6 Alkoxy, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR 1a , N(R 1b )2, S(=O)R 1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NHR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)N(R 1b )2, ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2R 1a or S(=O)2N(R1b ) 2, wherein each heterocycle, heteroaryl, and aryl is optionally substituted with 1 or 2 substituents each selected from R5;

[0048] each W is independently CH, CR′, or N; Each -- represents an absent bond or a single or double bond; each Z' is independently CH2 or absent; Y is C(R 1a )2, C=O, O, NR 1b or a bond, Each R 1a are independently hydrogen, halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, amino or hydroxy-C 1-4 is alkyl, Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl,

[0049] Each of Z1, R' and R4 is selected from the group consisting of halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl; n is 0, 1, 2 or 3

[0050] Another aspect of the present invention also provides a compound having the structure of Formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe, or VIIIf, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] (In the formula,

[0051] R w is hydrogen, C 1-6 Alkyl, C 2-8 Alkynyl, halogen, C 1-6 Alkoxy, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, cyano, -NH2, -N(C 1-6 alkyl), thiol, -SO2NH2, -SO2N(C 1-6 alkyl)2, -S(=O)(C 1-6 alkyl), cycloalkyl, CHR 1a , (C=O)R 1a , OR1a , N(R 1b )2, S(=O)R 1a , S(=O)2R 1a , O(C=O)R 1a , (C=O)OR 1a , N.R. 1b (C=O)R 1b , (C=O)NHR 1b , (C=O)N(R 1b )2, NR 1b (C=O)OR 1a , O(C=O)N(R 1b )2, ONR 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2R 1a or S(=O)2N(R 1b ) 2, wherein each heterocycle, heteroaryl, and aryl is optionally substituted with 1 or 2 substituents each selected from R5; each W is independently CH, CR′, or N; Each A is independently absent, CH, CH2, or CR a , CHRa, N, NH, NR a , S or O, and C and N are optionally substituted with R4; Each R a are independently H, deuterium, halogen, -CN, -OH, -OR2, =O, =N-OR2, -SR2, -S(=O)R2, -S(=O)2R2, -N(R2)2, -NR2S(=O)(=NR2)R 2 , -NR2S(=O)2R2, -S(=O)2N(R2)2, -C(=O)R2, -OC(=O)R2, -C(=O)OR2, -OC(=O)O R2, -C(=O)N(R2)2, -OC(=O)N(R2)2, -NR2C(=O)R2, -P(=O)(R2)2, C1-4 alkyl, (C 1-4 Alkyl)2, Halo-C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 2-7 heterocycloalkyl, aryl, or monocyclic heteroaryl;

[0052] Each -- represents an absent bond or a single or double bond; p is 0, 1, 2, 3 or 4; Each Z1, Z2, R2, R' or R4 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; Heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members selected from N, O and S; Heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S; each instance of phenyl, heteroaryl, or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5; R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkylamino, (C 1-4 Alkyl)2amino, Amino C 1-4 Alkyl, Hydroxyl C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl)

[0053] Another aspect of the present invention also provides a compound having the structure of Formula IXa, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof: [ka] (In the formula,

[0054] each W is independently CH, CR′, or N; each Q' is independently N or C, and at least one Q' is N; Each A is independently CH, CH2, or CR a , CR4, N, NH or NR4, Y is NR 1b or a bond, Each R wa is hydrogen, hydroxyl, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy or halo-C 1-4 is an alkoxy, Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-8 Alkyl, NH(hydroxy-C 1-6 alkyl), NH(C 1-6alkoxy), wherein each Z is optionally substituted with OH, NH2, —CO2H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 acyl, C2-6 alkanoic acid, C2-6 alkanoate ester, or heterocyclyl, wherein the heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2;

[0055] R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-6 Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C 1-4 Alkyl-amino)2-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, hydroxyl-Chydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C 1-4 Alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy;

[0056] Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O and S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4 independently selected from alkoxy;

[0057] R' is H, substituted or unsubstituted cycloalkyl, halo-C 1-4 Alkyl, haloalkoxy, halogen, C 1-6 Alkoxy, cyano, hydroxy-C 1-4 C optionally substituted by alkyl or aryl 1-4 alkyl, Each R a are independently H, deuterium, halogen, -CN, -OH, -OR2, =O, =N-OR2, -SR2, -S(=O)R2, -S(=O)2R2, -N(R2)2, -NR2S(=O)(=NR2)R 2, -NR2S(=O)2R2, -S(=O)2N(R2)2, -C(=O)R2, -OC(=O)R2, -C(=O)OR2, -OC(=O)OR2, -C(=O)N(R2)2, -OC(=O)N(R2)2, -NR2C(=O)R2, -P(=O)(R2)2, C 1-4 Alkyl, (C 1-4 Alkyl)2, Halo-C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 2-7 heterocycloalkyl, aryl, or monocyclic heteroaryl; R4 is halogen, hydroxyl, cyano or C 1-4 alkyl)

[0058] Another aspect of the present invention also provides a compound having the structure of Formula Xa, Xb, Xc, Xd, Xe, or Xf, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] (In the formula, Each R wa is hydrogen, hydroxyl, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy or halo-C 1-4 is an alkoxy,

[0059] R' is hydrogen, halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl; R4 is hydrogen, C 1-4 Alkyl, halogen, halo-C 1-4 alkyl, Y is NR 1b or a bond, Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, NH(hydroxy-C 1-6 alkyl), NH(C 1-6 alkoxy), and each Z is OH, NH2, -CO2H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Achill, C 2-6 Alkanoic acid, C 2-6 optionally substituted with an alkanoate ester or heterocyclyl, wherein the heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2;

[0060] R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C1-6 Alkyl) 2-amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 Alkyl) 2-amino, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C 1-4 Alkyl-amino)2-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 Alkoxy, Hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, Heteroaryl-C 1-4 Alkyl, Heteroaryl-amino, Heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C 1-4 Alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy;

[0061] Heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O and S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; C 3-10 Cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 each instance of cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R; R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and Halo-C 1-4 independently selected from alkoxy; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3

[0062] Another aspect of the present invention also provides compounds having the structure of Formula XIa, XIb, or XIc, wherein the compound is in a form selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof. [ka] (In the formula, the structure

[0063] [ka] The part having

[0064] [ka] is selected from R' is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, amino-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl; When Y and Z are taken together,

[0065] [ka] is selected from R4 is hydrogen, C 1-4 Alkyl, halogen, halo-C 1-4 alkyl, R8 is C 1-4 alkyl, CH2CH2OH, CH2CH2OCF3, CH2CH2OCHF2 and CH2CH2C(CH3)2OH; R9, R 9a , R 9b is hydrogen or C 1-4 Alkyl and C 3-6 cycloalkyl, C 9a and C 9b may be cyclized to form a 3- to 6-membered ring, m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; X is selected from O or NR8

[0066] Another aspect of the present invention also provides compounds having the structure of Formula XIa, XIb, XIc, wherein the compound is in a form selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers, and isotopically enriched forms thereof. (In the formula, the structure

[0067] [ka] The part having

[0068] [ka] (selected from Another embodiment includes compounds of Formulas I-XI, wherein the compound is in a form selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers, and isotopically enriched forms thereof. wherein Y and Z, when taken together,

[0069] [ka] (selected from

[0070] Another aspect of the present invention provides any one of the compounds selected from the following, wherein the compound is in a form selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, and tautomeric forms thereof: 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0071] 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}thieno[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol; 2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 2-{4-[(pyrrolidin-3-yl)amino]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(7-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(2H-1,2,3-triazol-2-yl)phenol;

[0072] 2-(4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 3-Fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)benzene-1,3-diol; 5-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol;

[0073] 4-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 4-fluoro-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]oxy}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-1-methylpiperidin-3-yl]oxy}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-methyl-4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 3-hydroxy-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)benzonitrile; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol;

[0074] 2-(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-methyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-fluoro-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]oxy}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(piperidin-3-yl)methyl]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0075] 5-(5-methyl-1,2,4-thiadiazol-3-yl)-2-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(1H-1,2,3-triazol-1-yl)phenol;

[0076] 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(5-methyl-1,2,4-thiadiazol-3-yl)phenol; 4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)[1,1'-biphenyl]-3-ol; 3-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)[1,1'-biphenyl]-4-ol; 4,5-dimethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2,3-dimethyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(1-methylpiperidin-3-yl)methyl]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-(7,7-dimethyl-4-{[(3R)-piperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0077] 2-(7,7-dimethyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{methyl[(3R)-1-methylpiperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-Fluoro-3-methyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol;

[0078] 5-(5,6-dihydro-2H-pyran-3-yl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; (3S,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-3-ol; 2-(1-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-(3,6-dihydro-2H-pyran-4-yl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-(2,5-dihydrofuran-3-yl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol;

[0079] 5-chloro-2-(1-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)phenol; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(oxolan-3-yl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; (3S,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)-1-methylpiperidin-3-ol; 1-[3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-1-yl]ethan-1-one; ethyl [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-1-yl]acetate, 2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol;

[0080] 2-[4-({[(2S)-pyrrolidin-2-yl]methyl}amino)phthalazin-1-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-Methoxy-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 4-hydroxy-5-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridine-2-carbonitrile; 3-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-6-(trifluoromethyl)pyridin-2-ol;

[0081] 2-chloro-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-Cyclopropyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 6-methyl-3-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)pyridin-2-ol; 5-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-2-(trifluoromethyl)pyridin-4-ol; 6-hydroxy-5-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridine-2-carbonitrile; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridin-3-ol; 2-methyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol;

[0082] (3R,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-3-ol; (3R,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)-1-methylpiperidin-3-ol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}furo[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol; 5-methyl-2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol; 2-[4-({[(2S)-1-methylpyrrolidin-2-yl]methyl}amino)phthalazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridin-3-ol; 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridin-3-ol; 3-hydroxy-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile;

[0083] 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(pyrrolidin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(1-methyl-1H-pyrrol-3-yl)phenol; 2-{4-[(1-methylazepan-3-yl)amino]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-1-methylpiperidin-3-yl]methyl}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]methyl}phthalazin-1-yl)-5-(trifluoromethyl)phenol; [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-1-yl]acetic acid,

[0084] 5-methyl-2-(1-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)phenol; 2-{1-[(piperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 2-(1-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol; 3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-chloro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0085] 3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(1-methylpyrrolidin-3-yl)phenol; 2-(4-{[2-(morpholin-4-yl)ethyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(azetidin-3-yl)amino]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-[1-({[(2S)-pyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-[4-({[(2S)-pyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-({[(2S)-1-methylpyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol;

[0086] 2-(4-{[2-(piperidin-1-yl)ethyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-[1-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-(4-methyl-5-{[(3R)-1-methylpiperidin-3-yl]amino}-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazin-8-yl)-5-(trifluoromethyl)phenol; 2-{1-[(1-methylpiperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 1-[2-Methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine;

[0087] 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine; 4-[2-amino-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; N-[2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenyl]methanesulfonamide; 4-[2-(methylamino)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; N-[2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenyl]acetamide;

[0088] 4-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-(4-chloro-2-fluorophenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzonitrile; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)benzonitrile; 1-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 1-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile;

[0089] 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(2H-1,2,3-triazol-2-yl)phenol; 1-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-chloro-2-(4-{[(3S)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 3-hydroxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 3,5-dimethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 5-chloro-3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol;

[0090] 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-Methoxy-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1H-pyrazolo[3,4-d]pyridazin-7-amine; 1-[2-(2,5-dihydrofuran-3-yl)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(1-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}-1H-pyrazolo[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 2-[4-({2-[(3R)-3-methylmorpholin-4-yl]ethyl}amino)phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-({2-[(3S)-3-methylmorpholin-4-yl]ethyl}amino)phthalazin-1-yl]-5-(trifluoromethyl)phenol;

[0091] 2-(4-{[2-(piperazin-1-yl)ethyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(azetidin-2-yl)methyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-{1-[3-(dimethylamino)piperidin-1-yl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 4-[2-Methoxy-4-(trifluoromethyl)phenyl]-1-(piperazin-1-yl)pyrido[3,4-d]pyridazine; 2-(1-methyl-8-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(1-methyl-8-{[(3S)-1-methylpiperidin-3-yl]amino}-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzene-1-sulfonamide;

[0092] 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 1-[4-cyclopropyl-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-methyl-5-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridin-4-ol; 4-(2-methoxy-6-methylpyridin-3-yl)-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 2-(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 1-{4-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-1-yl}-N,N-dimethylpiperidin-3-amine;

[0093] 2-amino-3-chloro-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3S,5S)-5-fluoro-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 4-(2,3-difluoro-4-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 3-(Difluoromethoxy)-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 1-[2-(difluoromethoxy)-3-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzene-1-sulfonamide; 5-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol;

[0094] 1-[2-(difluoromethoxy)-4-methoxyphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)pyridin-3-ol; 1-[2-(methoxymethoxy)-4-(1,3-oxazol-2-yl)phenyl]-N-[(3S)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-Methoxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3S)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(1,3-oxazol-2-yl)phenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine;

[0095] 1-[2-(difluoromethoxy)-5-fluoro-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-Fluoro-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-{4-[(1-methyl-1H-pyrazol-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-[4-Methoxy-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzamide; 5-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[2,3-d]pyridazin-8-amine;

[0096] 8-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[2,3-d]pyridazin-5-amine; 2-{1-[(1-methylazepan-3-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-1-methylazepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylazepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; N-[(3R)-1-methylpiperidin-3-yl]-1-{2-[(oxetan-3-yl)oxy]-4-(trifluoromethyl)phenyl}pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; [2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenyl]methanol; 1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine;

[0097] 1-[2-(methanesulfonyl)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)pyridin-3-ol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0098] 1-(4-chloro-2-fluoro-6-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(pyrimidin-2-yl)phenol; 1-{4-[2-methoxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}-N,N-dimethylpiperidin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}phthalazin-1-yl)-5-(trifluoromethyl)phenol;

[0099] 1-[2-(difluoromethoxy)-6-(trifluoromethyl)pyridin-3-yl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-(2,4,6-trimethylphenyl)pyrido[3,4-d]pyridazin-4-amine; 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2,4-di(propan-2-yl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-(3-cyclopropyl-6-fluoro-2-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 6-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 6-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 6-chloro-3-fluoro-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)phenol;

[0100] 2-{4-[(4-methyl-4-azaspiro[2.5]octan-7-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-[2-Methoxy-4-(trifluoromethyl)phenyl]-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-cyclobutylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-(2,4-dimethylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-methyl-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile;

[0101] 1-(4-chloro-2,6-dimethylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-cyclopropylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2,2,2-trifluoro-1-[3-hydroxy-4-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)phenyl]ethan-1-one; 1-(4-chloro-2,6-difluorophenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-fluoro-6-methyl-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-nitrophenol;

[0102] 2-{4-[(1-methylpiperidin-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 5-(cyclopropylethynyl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-ethynyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(prop-1-yn-1-yl)phenol; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(prop-1-yn-1-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-{1-[(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol;

[0103] 2-{1-[(1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-piperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(1-methyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-{4-[3-(dimethylamino)piperidin-1-yl]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-[4-(difluoromethyl)-2-methoxyphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 5-(cyclopropyloxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol;

[0104] 2-[(3R)-3-({4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[4-chloro-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 4-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 1-(2-cyclopropyl-4-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(1-methylpiperidin-2-yl)methyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0105] 4-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 4-[2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 4-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 1-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[4-(difluoromethyl)-2-fluorophenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine;

[0106] 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}thieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; N-[(3R)-azepan-3-yl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-{4-[(1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 2-{4-[(azepan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-(4-Methoxy-2-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(3-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}[1,2]oxazolo[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}-3-methyl[1,2]oxazolo[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol;

[0107] 2-[4-({(3R)-1-[3-(2,2-difluoroethyl)cyclobutyl]piperidin-3-yl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-[4-Methoxy-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 4-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 2-{1-[(4-methyl-1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-azepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(4-methyl-1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol;

[0108] 2-{4-[(1-methylazepan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 2-{4-[(1,4-dimethyl-1,4-diazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-5,5-difluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; ethyl (2S,5R)-5-({1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)piperidine-2-carboxylate, 3-Methoxy-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzene-1,3-diol;

[0109] 2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3R)-3-hydroxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(oxetan-3-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-(4-cyclopropyl-2-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 3-Cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[2-(dimethylamino)-2-methylpropyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0110] N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S,5S)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(oxan-4-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(oxolan-3-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0111] 5-chloro-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethyl)-4-methoxyphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine;

[0112] 2-[4-(cyclohexylamino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 1-[4-chloro-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-methyl-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-{2-[(propan-2-yl)oxy]-4-(trifluoromethyl)phenyl}pyrido[3,4-d]pyridazin-4-amine; 2-(4-{methyl[(3R)-piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-({(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol;

[0113] 2-(4-{[(3R)-1-(3-fluoropropyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-[4-Methoxy-2-(propan-2-yl)phenyl]-N-[(3S)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{methyl[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; N-[(3R)-1-methylpiperidin-3-yl]-1-[4-methyl-2-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-(difluoromethyl)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine;

[0114] 2-(4-{[(3R)-1-(1- 2H) cyclobutylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S,4R)-4-fluoropiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1-methylpiperidin-4-yl)methyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-({[1-(2-hydroxyethyl)piperidin-4-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-5-methyl-2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol; 2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0115] 5-ethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(1R,3S)-3-methoxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-oxan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-oxan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-piperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-cyclobutylpiperidin-3-yl]-1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}furo[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)phenol;

[0116] 2-(4-{[(3S,4R)-4-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1r,3r)-3-hydroxy-3-methylcyclobutyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)azepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; ethyl (2S,5R)-5-({1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)-1-methylpiperidine-2-carboxylate, 1-[2-(difluoromethyl)-4-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-(difluoromethyl)-5-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine;

[0117] 2-(8-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}-1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; N-[(3R)-Azocan-3-yl]-1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol;

[0118] 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-(oxan-4-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-cyclopropyl-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-Methoxy-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine;

[0119] 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(2-methyl-4-{[(3R)-piperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-7-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-Bromo-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0120] 2-(2-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-7-yl)-5-(trifluoromethyl)phenol; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-yl)-5-(trifluoromethyl)phenol; 5-Methoxy-2-(2-methyl-4-{[(3R)-piperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-7-yl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-(oxan-4-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol;

[0121] 3-Fluoro-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-(oxan-4-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-({(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluoro-5-methylphenol; 2-(4-{[(6S)-4-methyl-4-azaspiro[2.5]octan-6-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(2-cyclopropyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 2-(2-cyclopropyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-methoxyphenol;

[0122] 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-Methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-Methoxy-2-(2-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-7-yl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0123] 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-Methoxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol;

[0124] 3-Fluoro-5-methyl-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; (1S,3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)cyclohexan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(1R,3S)-3-methoxycyclohexyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-Fluoro-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0125] 2-(4-{[(3R)-piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-chloro-2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol;

[0126] 1-[4-Methoxy-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 4-[4-bromo-2-(trifluoromethoxy)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 2-[(3R)-3-({4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-yl}amino)piperidin-1-yl]ethan-1-ol;

[0127] 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-oxan-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; (1R,3S)-N 1 -{1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}cyclohexane-1,3-diamine; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 4-[4-Methoxy-2-(trifluoromethyl)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine;

[0128] 4-[2,4-bis(trifluoromethyl)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 1-(4-chloro-2-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; (3R,5R)-5-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylpiperidin-3-ol; 8-[2-Methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,2-d][1,2,4]triazin-5-amine; (3R,5R)-5-{[1-(4-cyclopropyl-2-fluoro-6-hydroxyphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl]amino}-1-methylpiperidin-3-ol;

[0129] 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-oxolan-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (2S)-1-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)propan-2-ol; 4-(4-bromo-2-methoxyphenyl)-N-[(3R)-piperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-Bromo-2-(7-{[(3R)-piperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; N-[(3R)-1-ethylpiperidin-3-yl]-1-[4-methoxy-2-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0130] 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoro-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-Fluoro-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-Methyl-N-[(3R)-1-methylpiperidin-3-yl]-4-[4-methyl-2-(trifluoromethoxy)phenyl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 2-(4-{[(3R)-oxan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,2-d][1,2,4]triazin-8-yl)-5-(trifluoromethyl)phenol;

[0131] 2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3S)-3-methoxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol;

[0132] 5-chloro-2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-Methoxy-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)benzonitrile; 2-(4-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol;

[0133] 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-(trifluoromethyl)phenol; 3-Fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol 3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0134] 3-fluoro-2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 4-[4-cyclopropyl-2-(trifluoromethoxy)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 2-Methyl-N-[(3R)-1-methylpiperidin-3-yl]-4-[2-(trifluoromethoxy)phenyl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 3-Fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-5-methyl-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol;

[0135] 3-Fluoro-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-Cyclopropyl-3-fluoro-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[2-(difluoromethyl)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (1s,3s)-3-({1-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol;

[0136] 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-cyclopropyl-3-fluoro-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-(oxan-4-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol;

[0137] 5-chloro-3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-{4-[(2-hydroxy-2-methylpropyl)amino]pyrrolo[1,2-d][1,2,4]triazin-1-yl}-5-(trifluoromethoxy)phenol;

[0138] 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoro-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (2R)-1-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)propan-2-ol; 2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 5-chloro-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 1-[4-chloro-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol;

[0139] 5-cyclopropyl-3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-(4-{[(3R)-1-(oxolan-3-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3S)-3-hydroxycyclopentyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3R)-3-hydroxycyclopentyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0140] 2-{4-[(3-hydroxy-3-methylcyclohexyl)amino]pyrrolo[1,2-d][1,2,4]triazin-1-yl}-5-(trifluoromethyl)phenol; 4-(4-bromo-2-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-Bromo-2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-Bromo-2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 2-[(3R)-3-({1-[4-methoxy-2-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 5-chloro-3-fluoro-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol;

[0141] 3-Fluoro-5-methoxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3S)-oxolan-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3S)-oxolan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methyl-1,2,3,6-tetrahydropyridin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}[1,2,3]triazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol;

[0142] 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R)-oxan-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (1s,3s)-3-({1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 3-Fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol;

[0143] 5-Cyclopropyl-3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[(3R)-3-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]-2-methylpropan-2-ol; 1-[2-(difluoromethoxy)-4-methoxyphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0144] (1r,3r)-3-({1-[2-(difluoromethoxy)-4-methoxyphenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 2-(4-{[(2S)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-oxolan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R)-1-(oxan-4-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[(3R)-3-({1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]-2-methylpropan-2-ol; 3,5-dimethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3S,4S)-4-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0145] 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0146] 5-Bromo-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3S,4R)-4-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R)-1-(oxolan-3-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0147] 3-fluoro-5-methyl-2-(4-{[(3R)-1-(oxolan-3-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-Bromo-2-(4-{[(3R)-piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-[(3R)-3-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; (2R)-1-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)propan-2-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-(propan-2-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0148] 5-cyclopropyl-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-Cyclopropyl-3-fluoro-2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-chloro-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol; 3-Fluoro-2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-Cyclopropyl-3-fluoro-2-(4-{[(2S)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-[( 2 H3) methyloxy]-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol;

[0149] 3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; 1-[4-bromo-2-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[4-chloro-2-(difluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[4-chloro-2-(difluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0150] 2-[(3R)-3-({1-[4-cyclopropyl-2-(difluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 5-cyclopropyl-2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol; 2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-5-[( 2 H3) methyloxy]-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol;

[0151] 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-[( 2 H3)methyloxy]phenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluoro-5-methylphenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-(oxan-4-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-(oxolan-3-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-chloro-2-(4-{[(3R)-oxan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0152] 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (1s,3s)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol;

[0153] (1S,3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)cyclohexan-1-ol; (1s,3s)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 2-(8-fluoro-4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0154] 5-bromo-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-(propan-2-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-2-methylpropan-2-ol; (1s,3s)-3-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; N-[(3R)-1-methylpiperidin-3-yl]-1-[4-methyl-2-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[4-cyclopropyl-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0155] 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-2-methylpropan-2-ol; (1s,3s)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-Fluoro-2-{4-[(2-hydroxy-2-methylpropyl)amino]pyrrolo[1,2-d][1,2,4]triazin-1-yl}-5-methylphenol;

[0156] 5-Cyclopropyl-3-fluoro-2-{4-[(2-hydroxy-2-methylpropyl)amino]pyrrolo[1,2-d][1,2,4]triazin-1-yl}phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(6-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-Bromo-2-(7-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol;

[0157] 4-[2-(benzyloxy)-4-bromophenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-Bromo-2-(7-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-Bromo-2-(7-{[(3R)-oxan-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-Bromo-2-(7-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-chloro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-methyl-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 3-Fluoro-5-methoxy-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol;

[0158] 5-bromo-2-(4-{[(3R)-1-(1-hydroxypropan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluorophenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluoro-5-methoxyphenol; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-amine;

[0159] 5-chloro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 3-methyl-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(4-{[(3R)-oxolan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 3-Fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol;

[0160] 5-ethyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-Bromo-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-{4-[(1-methylpiperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-(2-methoxy-2-methylpropyl)pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0161] 3-fluoro-5-methyl-2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-5-methyl-2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol; 2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; (1s,3s)-3-({1-[2,4-bis(difluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol;

[0162] 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 2-(4-{[(3R,5S)-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-cyclopropyl-2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-chloro-3-fluoro-2-(4-{[(2S)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluorophenol;

[0163] 5-chloro-2-(4-{[(3S)-oxolan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(1R,3S)-3-methoxycyclohexyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluoro-5-methylphenol; 5-cyclopropyl-2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluorophenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethoxy)phenol; 4-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-amine;

[0164] 5-Cyclopropyl-2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; 2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-{[(3S)-oxolan-3-yl]methyl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-{[(3R)-oxolan-3-yl]methyl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-7-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoro-N-[(3R)-1-(propan-2-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0165] 2-(8-fluoro-4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-fluoro-4-{[(2S)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-fluoro-4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; (3R,5R)-5-({8-fluoro-1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylpiperidin-3-ol;

[0166] 2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 5-cyclopropyl-2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-3-fluoro-2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol;

[0167] (3R,5R)-5-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-ethylpiperidin-3-ol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; (3R,5R)-1-ethyl-5-({8-fluoro-1-[2-hydroxy-4-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-3-ol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-fluoro-2-(7-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol;

[0168] 5-chloro-3-fluoro-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-{[(2S)-oxolan-2-yl]methyl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-{[(2R)-oxolan-2-yl]methyl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(difluoromethoxy)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine;

[0169] 2-[(3R)-3-({1-[2,4-bis(difluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2,4-bis(difluoromethoxy)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-(Difluoromethoxy)-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-(Difluoromethoxy)-3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-(Difluoromethoxy)-3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-(Difluoromethoxy)-2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol;

[0170] 5-chloro-2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-chloro-3-fluoro-2-(4-{[(oxolan-2-yl)methyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-Bromo-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine;

[0171] 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol; 5-Bromo-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-Bromo-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-ethoxy-3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-ethoxy-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-ethoxy-3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-methoxyphenol;

[0172] 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-methylphenol; 5-Methoxy-2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; (R)-2-(4-((1-ethylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3,5-dimethylphenol; (3S,5R)-5-((1-(2-fluoro-6-hydroxy-4-methylphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-methylpiperidin-3-ol; (3S,5R)-1-ethyl-5-((1-(2-fluoro-6-hydroxy-4-methylphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)piperidin-3-ol; (3S,5R)-5-((1-(4-cyclopropyl-2-fluoro-6-hydroxyphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-methylpiperidin-3-ol; and (3S,5R)-5-((1-(4-cyclopropyl-2-fluoro-6-hydroxyphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-ethylpiperidin-3-ol

[0173] Another aspect of the present invention provides any one of the compounds selected from the following, wherein the compound is in a form selected from the group consisting of a hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomeric form thereof: 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-{4-[(pyrrolidin-3-yl)amino]phthalazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol hydrochloride,

[0174] 2-(8-methyl-4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-{4-[(piperidin-3-yl)methyl]phthalazin-1-yl}-5-(trifluoromethyl)phenol hydrochloride, 2-(4-{[(3R)-piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol diformate, 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-{4-[(1-methylpiperidin-3-yl)methyl]phthalazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol formate, (3S,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-3-ol formate,

[0175] 2-(1-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol N-ethylethanamine, 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol diformate, (3S,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)-1-methylpiperidin-3-ol formate, 2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol formate, (3R,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-3-ol formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}furo[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol formate,

[0176] 5-methyl-2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol formate, [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-1-yl]acetic acid formate, 2-{1-[(piperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol hydrochloride, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(1-methylpyrrolidin-3-yl)phenol formate, 2-[1-({[(2S)-pyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol formate, 2-[4-({[(2S)-pyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate, 2-[4-({[(2S)-1-methylpyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate,

[0177] 2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate, 2-{1-[(1-methylpiperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol formate, 1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine formate,

[0178] 4-[2-amino-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, N-[2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenyl]methanesulfonamide formate, 4-[2-(methylamino)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, N-[2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenyl]acetamidoformate, 1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 1-(4-chloro-2-fluorophenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 1-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate,

[0179] 1-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1H-pyrazolo[3,4-d]pyridazin-7-amine formate, 2-(1-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}-1H-pyrazolo[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol formate, 2-(1-methyl-8-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol triformate,

[0180] 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile formate, 2-amino-3-chloro-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol formate, 4-(2,3-difluoro-4-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, 5-methoxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 1-[4-methoxy-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzamidoformate,

[0181] 5-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[2,3-d]pyridazin-8-amine formate, 8-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[2,3-d]pyridazin-5-amine formate, 2-{1-[(1-methylazepan-3-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-methylazepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate, [2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenyl]methanol formate,

[0182] N-[(3R)-1-methylpiperidin-3-yl]-1-(2,4,6-trimethylphenyl)pyrido[3,4-d]pyridazin-4-amine formate, 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)piperidin-1-yl]ethan-1-ol formate, 6-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 6-chloro-3-fluoro-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)phenol formate, N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate,

[0183] 3-methyl-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile formate, 1-(4-chloro-2,6-dimethylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 2,2,2-trifluoro-1-[3-hydroxy-4-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)phenyl]ethan-1-one formate, 5-(cyclopropylethynyl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(prop-1-yn-1-yl)phenol formate, N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(prop-1-yn-1-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate, 2-{1-[(1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol formate,

[0184] 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-piperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine formate, 5-(cyclopropyloxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 2-[(3R)-3-({4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]ethan-1-ol formate, 4-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine formate,

[0185] 4-[2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine formate, 4-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine formate, 1-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, N-[(3R)-azepan-3-yl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate, 2-{4-[(1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol formate,

[0186] 2-{4-[(azepan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-(3-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}[1,2]oxazolo[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}-3-methyl[1,2]oxazolo[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-azepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-{4-[(1-methylazepan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-{4-[(1,4-dimethyl-1,4-diazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol formate,

[0187] ethyl (2S,5R)-5-({1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)piperidine-2-carboxylate hydrochloride, 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzene-1,3-diol formate, 2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(1R,3R)-3-hydroxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol formate, 2-(4-{[2-(dimethylamino)-2-methylpropyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate,

[0188] 2-(4-{[(3S,5S)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 5-chloro-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate,

[0189] 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 2-[4-({(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 1-[2-(difluoromethyl)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 2-(4-{[(1-methylpiperidin-4-yl)methyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-[4-({[1-(2-hydroxyethyl)piperidin-4-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate,

[0190] 2-(4-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 5-ethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}-1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazine-4-amine formate, 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate,

[0191] 1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazine-4-amine formate, 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol hydrochloride, 1-(4-chloro-2-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazine-4-amine formate, 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, 8-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,2-d][1,2,4]triazine-5-amine formate, (3R,5R)-5-{[1-(4-cyclopropyl-2-fluoro-6-hydroxyphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl]amino}-1-methylpiperidin-3-ol formate,

[0192] 4-(4-bromo-2-methoxyphenyl)-N-[(3R)-piperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazine-7-amine formate, 2-(4-{[(3R)-oxan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,2-d][1,2,4]triazin-8-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol hydrochloride, 4-[4-cyclopropyl-2-(trifluoromethoxy)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazine-7-amine formate, 2-methyl-N-[(3R)-1-methylpiperidin-3-yl]-4-[2-(trifluoromethoxy)phenyl]pyrazolo[1,5-d][1,2,4]triazine-7-amine formate,

[0193] 2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol hydrochloride, 2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol hydrochloride, 5-chloro-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, 5-chloro-3-fluoro-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol formate, 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3S)-oxolan-3-yl]pyrrolo[1,2-d][1,2,4]triazine-4-amine formate,

[0194] 2-(4-{[(3R)-1-methyl-1,2,3,6-tetrahydropyridin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}[1,2,3]triazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3S,4S)-4-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate,

[0195] 1-[2-(difluoromethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazine-4-amine formate, 1-[4-chloro-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazine-4-amine formate, 5-cyclopropyl-2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol formate, 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol formate, 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate,

[0196] 2-(6-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 5-bromo-2-(4-{[(3R)-1-(1-hydroxypropan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol formate, 5-cyclopropyl-2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluorophenol formate, 5-chloro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, 5-ethyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol formate,

[0197] 5-bromo-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol formate, 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazine-4-amine formate, 2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluoro-5-methylphenol formate, 5-cyclopropyl-2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluorophenol formate, 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(8-fluoro-4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate,

[0198] (3R,5R)-5-({8-fluoro-1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylpiperidin-3-ol formate, 2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol formate, 5-bromo-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazine-4-amine formate, and 5-Bromo-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate

[0199] Another aspect of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formulas I-XI or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. Another aspect of the present invention provides a method for treating or ameliorating an NLRP3-modulated disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formulae I-XI. Another aspect of the invention is directed to the treatment of Alzheimer's disease, frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, perioperative neurocognitive impairment, post-cardiac arrest cognitive impairment, post-stroke 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 erythematosus-lupus nephritis, cryopyrin-associated periodic fever syndromes (CAPS), cystic fibrosis, sickle cell disease, VCP-related disease, liver fibrosis, non-alcoholic fatty liver disease (NASH), muscle atrophy, inherited and acquired myopathies, e.g. 16. The method of claim 15, wherein the disease is selected from 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, pancreatic islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

[0200] Another aspect of the present invention provides a method of administering a compound of Formulas I-XI, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day. Another aspect of the present invention is directed to the treatment of Alzheimer's disease, frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, perioperative neurocognitive impairment, post-cardiac arrest cognitive impairment, post-stroke 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 erythematosus-lupus nephritis, cryopyrin-associated periodic fever syndrome (CAPS), cystic fibrosis, sickle cell disease, VCP-related disease, liver fibrosis, non-alcoholic fatty liver disease (NASH), muscle atrophy, hereditary and acquired myopathies, pain, and the like. Provided are compounds of Formulas I-XI or pharmaceutically acceptable salts thereof for use in treating or ameliorating a disease modulated by NLRP3 selected from hypersensitivity, 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, pancreatic islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

[0201] Another aspect of the present invention provides the use of a compound of Formula I-XI, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day. Another aspect of the present invention provides the use of compounds of Formulas I-XI 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 admixed with one or more pharmaceutically acceptable excipients. Another aspect is R w But H, C 1-4 Alkyl, halogen, C 1-6 Alkoxy, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, C 3-6 The present invention includes compounds of formulas I-VIII, wherein the aryl group is selected from cycloalkyl, amino, or cyano. Another aspect is R wis hydrogen. Another aspect is R w C 1-6 Alkoxy or halo-C 1-4 Includes compounds of Formulas I-VIII where: Another aspect is R w is OCHF2 or OCF3. Another aspect is R w is OCH3.

[0202] Another aspect is R w But C 1-4 Alkyl or halo-C 1-4 Alkyl or C 3-6 Includes compounds of Formulas I-VIII that are cycloalkyl. Another aspect is R w is CH3. Another aspect is R w is c-Pr. Another aspect is R w is CF3 or CHF2. Another aspect is R w is a halogen selected from Br, Cl or F. Another aspect is R w is F. Another aspect is R w is Cl. Another aspect is R w is Br. Another aspect is R w is cyano. Another aspect is R wa But hydrogen, hydroxyl, C 1-4 Alkyl, halogen, C 1-6 Alkoxy, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, C 3-6The compounds of formula IX-XI include compounds of formula IX-XI, wherein the alkyl group is selected from cycloalkyl, amino, and cyano. Another aspect is R wa is hydrogen. Another aspect is R wa is OH.

[0203] Another aspect is R wa But C 1-6 Alkoxy or halo-C 1-4 Includes compounds of formulas IX-XI in which the aryl group is alkoxy. Another aspect is R wa is OCHF2 or OCF3. Another aspect is R wa is OCH3. Another aspect is R wa But C 1-4 Alkyl or halo-C 1-4 Alkyl or C 3-6 Included are compounds of formulas IX-XI which are cycloalkyl. Another aspect is R wa is CH3. Another aspect is R wa is c-Pr. Another aspect is R wa is CF3 or CHF2. Another embodiment includes compounds of Formulas IX-XI, where Rwa is a halogen selected from Br, Cl, or F. Another aspect is R wa is F. Another aspect is R wa is Cl.

[0204] Another aspect is R wa is Br. Another aspect is R wa is cyano. Another embodiment includes compounds of Formulas I-III and V-IX, wherein W is selected from CH, CR', and N. Another embodiment is where each R' is independently selected from heterocyclyl, heteroaryl, aryl, cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy, Deutero-C 1-4 Alkoxy or hydroxy-C 1-4 This includes compounds of formulas I-III and V-X in which: Another embodiment is where each R' is independently C 1-4 Alkyl or halo-C 1-4 This includes compounds of formulas I-III and V-X in which: Another embodiment includes compounds of Formulas I-III and V-X, where each R' is independently methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, CF3, or CHF2. Another embodiment is where each R' is independently C 1-4 Alkoxy or deutero-C 1-4 Includes compounds of formulas I-III and V-X that are alkoxy.

[0205] Another embodiment includes compounds of Formulas I-III and V-X, where each R' is independently OCH3, OCD3, OCHF2, OCF3, or OEt. Another embodiment includes compounds of Formulas I-III and V-X, where each R' is independently a halogen selected from F, Cl, or Br. Another embodiment includes compounds of Formulae I-III and V-X, wherein each R' is independently F. Another embodiment includes compounds of Formulae I-III and V-X, where each R' is independently Cl. Another embodiment includes compounds of Formulae I-III and V-X, where each R' is independently Br. Another embodiment includes compounds of Formulae I-III where Q is independently N or CH.

[0206] Another embodiment includes compounds of Formulas I-III and IX where Q' is independently N, C, or CH. Another aspect of the present invention is that the cores of formulas I and III-VIII above further comprise one or more R4: [ka] It indicates that the group may be any of the following structures, which may be substituted with:

[0207] Another aspect of the present invention is that the core of formula I, IV or VIII above may further comprise the following structure: [ka] indicates that it can be either of the following.

[0208] Another aspect of the invention is that the core of formulas IX-XI further comprises one or more R4: [ka] It is noted that the structure may be, but is not limited to, any of the following structures, optionally substituted with:

[0209] Another embodiment is where each A is independently absent, CH, CH, CRa, CHR a , CR4, CHR4, N, NH, NR4 or NR a This includes compounds of formulae I-II, IV and VIII-IX, Another embodiment is when A' is independently absent, CH, CH, CR a , CHR a , CHR4, CHR a , N, NH, NR4, NR a This includes compounds of formulae I-II, IV and VIII-IX, Another aspect is that each R a are independently halogen, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, HaloC 1-4 Alkyl, C 1-4 Alkoxy, HaloC 1-4Alkoxy, amino or C 1-4 Includes compounds of Formulas I-VII that are alkylamino. Another aspect is that each R a is independently a halogen selected from F, Cl, or Br. Another aspect is that each R a is independently cyano.

[0210] Another aspect is that each R a is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; 1-4

[0033] Includes compounds of Formulas I-VII where: Another aspect is that each R a is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl 3-6 Includes compounds of Formulas I-VII where: Another aspect is that each R a is independently cyclopropyl or cyclobutyl. Another aspect is that each R a is independently selected from methoxy, ethoxy, isopropoxy, cyclopropoxy, difluoromethoxy, and trifluoromethoxy; 1-4 Alkoxy or haloC 1-4 Includes compounds of Formulas I-VII where:

[0211] Another aspect is that each R a is independently amino. Another aspect is that each R a is independently selected from methylamino, ethylamino, N,N-dimethylamino, isopropylamino, or cyclopropylamino 1-4 Includes compounds of Formulas I-VII that are alkylamino. Another embodiment is where Y is NR 1b This includes compounds of formulae I-XI, Another aspect is R 1b is hydrogen. Another aspect is R 1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl or butyl 1-4 Including those which are alkyl. Further embodiments include those in which R1b is methyl. Another embodiment includes compounds of Formulas I-VII and IX-XI where Y is O.

[0212] Another embodiment is where Y is R 1a The present invention includes compounds of formulas I-VII and IX-XI, wherein R is an optionally substituted carbon atom. Another aspect is R 1a is hydrogen or C 1-4 alkyl. Another aspect is R 1a is hydrogen. Another aspect is R 1a is methyl. Another embodiment is a C11 group in which Z is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with R2. 3-6 Includes compounds of Formulas I-XI in which is cycloalkyl. Another embodiment is where Z is halogen, cyano, hydroxyl, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 3-6 The compounds of formulae I-XI include compounds of formula I-XI wherein R is cyclopropyl optionally substituted with R2 selected from cycloalkyl. Another embodiment includes compounds of Formulae I-XI where Z is cyclopropyl optionally substituted with R selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, CHF2, CF3, cPr, or cBu.

[0213] Another embodiment is where Z is halogen, cyano, hydroxyl, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 3-6 The compounds of formulae I-XI include compounds of formula I-XI wherein R is cyclobutyl optionally substituted with R2 selected from cycloalkyl. Another embodiment includes compounds of Formulae I-XI where Z is cyclobutyl optionally substituted with R selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, CHF2, CF3, cPr, or cBu. Another embodiment is where Z is halogen, cyano, hydroxyl, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 3-6 The compounds of formulae I-XI include compounds of formula I-XI wherein R is cyclopentyl optionally substituted with R2 selected from cycloalkyl. Another embodiment includes compounds of Formulae I-XI where Z is cyclopentyl optionally substituted with R selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, CHF2, CF3, cPr, or cBu. Another embodiment is where Z is halogen, cyano, hydroxyl, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 3-6 The compounds of formulae I-XI include compounds of formula I-XI wherein R is cyclohexyl optionally substituted with R2 selected from cycloalkyl.

[0214] Another embodiment includes compounds of Formulae I-XI where Z is cyclohexyl optionally substituted with R selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, CHF2, CF3, cPr, or cBu. Another embodiment is where Z is heterocyclyl, each of which is selected from halogen, cyano, hydroxyl, C1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 3-6 This includes compounds of formulae I-XI optionally substituted with R2 selected from cycloalkyl. Another embodiment is where Z is piperidinyl, tetrahydro-2H-pyran, tetrahydrofuran, or pyrrolidinyl, each of which is selected from halogen, cyano, hydroxyl, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 3-6 This includes compounds of formulae I-XI optionally substituted with R2 selected from cycloalkyl.

[0215] Another embodiment includes compounds of Formulae I-XI where Z is piperidinyl optionally substituted with R selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, iPr, CHF2, CF3, cPr, cBu, -CH2CH2OH, -CH2CH2OCHF2, -CH2CH2OCF3, tetrahydrofuranyl, or tetrahydropyranyl. Another embodiment includes compounds of Formulae I-XI where Z is pyrrolidinyl optionally substituted with R selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, iPr, CHF2, CF3, cPr, cBu, -CH2CH2OH, -CH2CH2OCHF2, -CH2CH2OCF3, tetrahydrofuranyl, or tetrahydropyranyl. Another embodiment includes compounds of Formulae I-XI where Z is tetrahydropyranyl optionally substituted with R2 selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, iPr, CHF2, CF3, cPr, cBu, -CH2CH2OH, -CH2CH2OCHF2, -CH2CH2OCF3, tetrahydrofuranyl, or tetrahydropyranyl.

[0216] Another embodiment includes compounds of Formulae I-XI where Z is tetrahydrofuranyl optionally substituted with R2 selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, iPr, CHF2, CF3, cPr, cBu, -CH2CH2OH, -CH2CH2OCHF2, -CH2CH2OCF3, tetrahydrofuranyl, or tetrahydropyranyl. Another embodiment is where Z is halogen, cyano, hydroxyl, C 1-4 Alkoxy, HaloC 1-4 Alkoxy, C 1-4 Alkyl, HaloC 1-4 Alkyl or C 3-6 C optionally substituted with R2 selected from cycloalkyl 1-4 This includes compounds of formulas I-XI in which: Another embodiment is a C-substituted aryl group in which Z is optionally substituted with R selected from F, CN, OH, MeO, EtO, iPrO, cPrO, ​​CHF2O, CF3O, Me, Et, CHF2, CF3, cPr, or cBu. 1-4 This includes compounds of formulas I-XI in which: Aspects of the present specification include methods for preventing, treating, or ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formulas I-XI or a form thereof. Another embodiment includes compounds of Formulae I-XI where R2 is a halogen selected from bromo, chloro, fluoro, and iodo.

[0217] Another embodiment includes compounds of Formulae I-XI where R2 is fluoro. Another embodiment includes compounds of Formulas I-XI where R2 is hydroxyl. Another embodiment is a C 1111111 wherein R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. 1-4 This includes compounds of formulas I-XI in which: Another embodiment is a C in which R is selected from methyl and ethyl.1-4 This includes compounds of formulas I-XI in which: Another embodiment includes compounds of Formulas I-XI where R2 is methyl. Another embodiment includes compounds of Formulas I-XI where R2 is ethyl. Another embodiment includes compounds of Formulas I-XI where R2 is amino. Another embodiment is where R2 is C 1-6 alkylamino, C 1-4 Includes compounds of formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, and 3-methylpentyl.

[0218] Another embodiment is where R2 is C 1-6 alkylamino, C 1-4 Includes compounds of formulae I-XI where alkyl is selected from methyl, ethyl, isopropyl, tert-butyl, 2-methylbutyl, and 3-methylpentyl. Another embodiment includes compounds of Formulas I-XI where R2 is methylamino. Another embodiment includes compounds of Formulas I-XI where R2 is ethylamino. Another embodiment includes compounds of Formulas I-XI where R2 is isopropylamino. Another embodiment includes compounds of Formulas I-XI where R2 is tert-butylamino. Another embodiment includes compounds of Formulas I-XI where R2 is 2-methylbutyl-2-amino. Another embodiment includes compounds of Formulas I-XI where R2 is 3-methylpentyl-3-amino. Another embodiment is when R2 is (C 1-6 alkyl)2amino, C 1-4 Includes compounds of Formulas I-XI where each alkyl is independently selected from methyl, ethyl, isopropyl, tert-butyl, 2-methylbutyl, and 3-methylpentyl. Another embodiment is when R2 is (C 1-6 alkyl)2amino, C 1-4Includes compounds of formulas I-XI where alkyl is methyl or ethyl.

[0219] Another embodiment includes compounds of Formulae I-XI where R2 is dimethylamino or diethylamino. Another embodiment includes compounds of Formulae I-XI where R2 is dimethylamino. Another embodiment includes compounds of Formulas I-XI where R2 is diethylamino. Another embodiment is where R2 is halo-C 1-4 alkylamino, C 1-4 Includes compounds of formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, partially or fully substituted with one or more halogen atoms, where allowed by available valences. Another embodiment is where R2 is halo-C 1-4 alkylamino, C 1-4 Alkyl includes compounds of formulae I-XI where alkyl is selected from isopropyl and tert-butyl, partially or fully substituted with one or more halogen atoms, where available valences allow. Another embodiment includes compounds of Formulae I-XI where R2 is 1-fluoro-2-methylpropane-2-amino or 1-fluoropropane-2-amino. Another embodiment is where R2 is hydroxy-C 1-4 alkylamino, C 1-4 Includes compounds of formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, which are partially or fully substituted, where available valences allow, with one or more hydroxy groups.

[0220] Another embodiment is where R2 is hydroxy-C 1-4 alkylamino, C 1-4 Includes compounds of formulae I-XI where alkyl is selected from ethyl and propyl, partially or fully substituted with one or more hydroxy groups, where available valences allow. Another embodiment includes compounds of Formulae I-XI where R2 is 2-hydroxyethylamino or 3-hydroxypropylamino. Another embodiment is where R2 is C 1-4 Alkoxy-C 1-4 alkyl-amino, C 1-4 Alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy; 1-4 Includes compounds of Formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Another embodiment is where R2 is C 1-4 Alkoxy-C 1-4 alkyl-amino, C 1-4 Alkoxy is methoxy, C 1-4 Includes compounds of Formulas I-XI where alkyl is selected from propyl, isopropyl, and tert-butyl.

[0221] Another embodiment includes compounds of Formulae I-XI where R2 is 1-methoxypropane-2-amino or 1-methoxy-2-methylpropane-2-amino. Another embodiment is where R2 is C 1-4 Alkylamino C 1-4 alkyl, and each C 1-4 Includes compounds of Formulas I-XI where alkyl is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Another embodiment is where R2 is C 1-4 Alkylamino C 1-4 alkyl, and each C 1-4 Includes compounds of Formulas I-XI where alkyl is independently selected from methyl, ethyl, isopropyl, and tert-butyl. Another embodiment includes compounds of Formulae I-XI where R2 is methylaminomethyl, propan-2-yl-aminomethyl, propan-2-yl-aminoethyl, or tert-butylaminomethyl. Another embodiment is when R2 is (C 1-4 Alkylamino)2C1-4 alkyl, and each C 1-4 Includes compounds of Formulas I-XI where alkyl is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Another embodiment is when R2 is (C 1-4 Alkylamino)2C 1-4 alkyl, and each C 1-4 Includes compounds of formulas I-XI where alkyl is methyl.

[0222] Another embodiment includes compounds of Formulas I-XI where R2 is dimethylaminomethyl. Another embodiment is a C 1111111 wherein R2 is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-4 Includes compounds of formulas I-XI in which: Another embodiment includes compounds of Formulae I-XI where R2 is methoxy. Another embodiment is where R2 is C 3-10 cycloalkyl-amino, C 3-10 Includes compounds of formulae I-XI where cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]hexanyl, and adamantyl. Another embodiment is where R2 is C 3-10 cycloalkyl-amino, C 3-10 Includes compounds of formulae I-XI where cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[2.2.1]hexanyl, and adamantyl. Another embodiment is where R2 is C 3-10 Cycloalkyl-amino-C 1-4 alkyl, C 3-10 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]hexanyl, and adamantyl; 1-4 Includes compounds of Formulas I-XI where alkyl is selected from methyl, ethyl, propyl, and butyl.

[0223] Another embodiment is where R2 is C 3-10 Cycloalkyl-amino-C 1-4 alkyl, C 3-10 cycloalkyl is selected from cyclopropyl, cyclobutyl, and cyclopentyl; 1-4 Includes compounds of formulas I-XI where alkyl is methyl. Another embodiment includes compounds of Formulae I-XI where R2 is cyclopropylaminomethyl, cyclobutylaminomethyl, or cyclopentylaminomethyl. Another embodiment is when R2 is heteroaryl-C 1-4 alkyl-amino, and heteroaryl is selected from thienyl, 1H pyrazolyl, 1H imidazolyl, 1,3 thiazolyl, oxazolyl, 1,2,4 oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,4 thiadiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, 1,2,4 triazinyl, 1,3,5-triazinyl, 1H indolyl, 1H indazolyl, 2H indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H benzimidazolyl, 1,3 benzoxazolyl, 1,3 benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 9H purinyl, quinolinyl, isoquinolinyl, and quinoxalinyl; 1-4 Includes compounds of Formulas I-XI where alkyl is selected from methyl, ethyl, propyl, and butyl.

[0224] Another embodiment is when R2 is heteroaryl-C 1-4 alkyl-amino, heteroaryl is pyridinyl, C 1-4 Includes compounds of formulas I-XI where alkyl is methyl. Another embodiment includes compounds of Formulas I-XI where R2 is pyridin-2-yl-methylamino. Another embodiment includes compounds of Formulae I-XI where R2 is heterocyclyl-amino, and heterocyclyl is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, 8-azabicyclo[3.2.1]octanyl, and 8-oxabicyclo[3.2.1]octanyl. Another embodiment includes compounds of Formulae I-XI where R2 is heterocyclyl-amino, where heterocyclyl is selected from oxetanyl and tetrahydropyranyl. Another embodiment includes compounds of Formulae I-XI where R2 is oxetanylamino or tetrahyropyranylamino. Another embodiment is where R2 is heterocyclyl-amino-C 1-4 alkyl and heterocyclyl is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxanyl, 8-azabicyclo[3.2.1]octanyl and 8-oxabicyclo[3.2.1]octanyl; C 1-4 Includes compounds of Formulas I-XI where alkyl is selected from methyl, ethyl, propyl, and butyl.

[0225] Another embodiment is where R2 is heterocyclyl-amino-C 1-4 alkyl and heterocyclyl is selected from tetrahydrofuranyl, oxanyl, and 8-oxabicyclo[3.2.1]octanyl; C 1-4 Includes compounds of formulas I-XI where alkyl is methyl. Another embodiment includes compounds of Formulae I-XI where R2 is oxanylaminomethyl, tetrahydrofuranylaminomethyl, and 8-oxabicyclo[3.2.1]octanylamino. Another embodiment is where R2 is heterocyclyl-amino-C 3-10 cycloalkyl and heterocyclyl is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxanyl, 8-azabicyclo[3.2.1]octanyl and 8-oxabicyclo[3.2.1]octanyl; C 3-10Includes compounds of formulae I-XI where cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Another embodiment is where R2 is heterocyclyl-amino-C 3-10 cycloalkyl, heterocyclyl is oxanyl, C 3-10 Includes compounds of Formulas I-XI where cycloalkyl is cyclopropyl.

[0226] Another embodiment includes compounds of Formulae I-XI where R2 is oxanylaminocyclopropyl. In one embodiment, R3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkoxy and HaloC 1-4 Includes compounds of formulas I-XI in which: Another embodiment is where R3 is selected from the group consisting of halogen and C 1-4 This includes compounds of formulas I-XI in which: Another embodiment includes compounds of Formulae I-XI where R3 is a halogen selected from bromo, chloro, fluoro, and iodo. Another embodiment includes compounds of Formulae I-XI where R3 is fluoro. Another embodiment is a C 1111111 wherein R3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. 1-4 This includes compounds of formulas I-XI in which:

[0227] Another embodiment includes compounds of Formulas I-XI where R3 is methyl. In one embodiment, R4 is selected from the group consisting of halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4 Alkylamino, (C 1-4 Alkyl)2amino, C 1-4 Alkoxy, Halo-C 1-4selected from alkoxy, heteroaryl, heterocyclyl, and phenyl; heteroaryl is a 5- to 6-membered monocyclic or 6- to 10-membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S; heterocyclyl is a saturated or partially unsaturated 3- to 6-membered monocyclic or 9- to 10-membered bicyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; Includes compounds of formulae I-XI wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1 or 2 substituents each selected from R5. Another embodiment is where R4 is halogen, C 1-4 The present invention includes compounds of formulas I-XI, wherein the aryl is selected from alkoxy, heteroaryl, and phenyl. Another embodiment includes compounds of Formulae I-XI where R4 is a halogen selected from bromo, chloro, fluoro, and iodo.

[0228] Another embodiment includes compounds of Formulae I-XI where R4 is fluoro. Another embodiment is a C 1111111 wherein R4 is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-4 Includes compounds of formulas I-XI in which: Another embodiment includes compounds of Formulae I-XI where R4 is methoxy. Another embodiment includes compounds of Formulae I-XI where R4 is heteroaryl, which is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S, and which are optionally substituted with 1 or 2 substituents each selected from R5. Another embodiment includes compounds of Formulae I-XI where R4 is phenyl, one or two substituents each selected from R5. In one embodiment, R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Halo-C 1-4 Alkyl, Amino, C 1-4Alkylamino, (C 1-4 Alkyl)2amino, Amino C 1-4 Alkyl, Hydroxyl C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl.

[0229] Another embodiment is where R5 is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, Amino, C 1-4 Alkylamino, Amino C 1-4 Alkyl, Hydroxyl C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio and C 3-10 cycloalkyl. Another embodiment includes compounds of Formulae I-XI where R5 is a halogen selected from bromo, chloro, fluoro, and iodo. Another embodiment includes compounds of Formulae I-XI where R5 is a halogen selected from bromo, chloro, and fluoro. Another embodiment includes compounds of Formulae I-XI where R5 is chloro. Another embodiment includes compounds of Formulae I-XI where R5 is fluoro. Another embodiment includes compounds of Formulae I-XI where R5 is hydroxy. Another embodiment includes compounds of Formulae I-XI where R5 is cyano. Another embodiment includes compounds of Formulae I-XI where R5 is nitro. Another embodiment is a C 1111111 wherein R5 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. 1-4 This includes compounds of formulas I-XI in which:

[0230] Another embodiment includes compounds of Formulae I-XI where R5 is methyl. Another embodiment is where R5 is deutero-C 1-4 alkyl, C 1-4 Includes compounds of formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, partially or fully substituted with one or more deuterium atoms, where available valences allow. Another embodiment is where R5 is ( 2 H3) methyl, including compounds of formulae I-XI. Another embodiment includes compounds of Formulas I-XI where R5 is amino. Another embodiment is where R5 is C 1-6 alkylamino, C 1-4 Includes compounds of formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, and 3-methylpentyl. Another embodiment is where R5 is C 1-4 alkylamino, C 1-4 Includes compounds of formulas I-XI where alkyl is methyl. Another embodiment includes compounds of Formulae I-XI where R5 is methylamino. Another embodiment is where R5 is amino C 1-4 alkyl, C 1-4 Includes compounds of Formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0231] Another embodiment is where R5 is amino C 1-4 alkyl, C 1-4 Includes compounds of formulas I-XI where alkyl is methyl. Another embodiment includes compounds of Formulae I-XI where R5 is aminomethyl. Another embodiment is where R5 is hydroxyl C 1-4 alkyl, C 1-4Includes compounds of formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, partially or fully substituted with one or more hydroxyl groups, where available valences allow. Another embodiment is where R5 is hydroxyl C 1-4 alkyl, C 1-4 Includes compounds of formulas I-XI where alkyl is methyl substituted with one hydroxyl group. Another embodiment includes compounds of Formulae I-XI where R5 is hydroxymethyl. Another embodiment is where R5 is C 1-4 Alkylcarbonyl, C 1-4 Includes compounds of Formulas I-XI where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Another embodiment is where R5 is C 1-4 Alkylcarbonyl, C 1-4 Includes compounds of formulas I-XI where alkyl is methyl.

[0232] Another embodiment includes compounds of Formulas I-XI where R5 is CH3C(O)-. Another embodiment is a C 1111111 wherein R5 is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-4 Includes compounds of formulas I-XI in which: Another embodiment includes compounds of Formulae I-XI where R5 is methoxy. Another embodiment is a C 1111111 wherein R5 is selected from methylthio, ethylthio, propylthio, isopropylthio, butylthio, and tert-butylthio. 1-4 Includes compounds of formulas I-XI that are alkylthio. Another embodiment includes compounds of Formulae I-XI where R5 is methylthio. Another embodiment is where R5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]hexanyl, and categorically 3-10Includes compounds of Formulas I-XI in which is cycloalkyl.

[0233] Another aspect of the invention is a method of treating or ameliorating a disease modulated by NLRP3 with a compound of Formulas I-XI, wherein the disease is Alzheimer's disease, frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, perioperative neurocognitive impairment, post-cardiac arrest cognitive impairment, post-stroke 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 erythematosus-lupus nephritis, cryopyrin-associated periodic fever syndrome (CAPS), cystic fibrosis, sickle cell disease, or VCP-related disease. , liver fibrosis, non-alcoholic fatty liver disease (NASH), muscle atrophy, inherited and acquired myopathies such as 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, pancreatic islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

[0234] Another aspect of the present invention provides a method of treating a subject with a compound of Formulas I-XI, wherein an effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day. Another aspect of the present invention is directed to the treatment of Alzheimer's disease, frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, perioperative neurocognitive impairment, post-cardiac arrest cognitive impairment, post-stroke 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 erythematosus-lupus nephritis, cryopyrin-associated periodic fever syndrome (CAPS), cystic fibrosis, sickle cell disease, VCP-related disease, liver fibrosis, non-alcoholic fatty liver disease (NASH), muscle atrophy, hereditary and acquired myopathies, pain, and the like. Provided are compounds of Formulas I-XI or pharmaceutically acceptable salts thereof for use in treating or ameliorating a disease modulated by NLRP3 selected from hypersensitivity, 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, pancreatic islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

[0235] Another aspect of the present invention provides the use of a compound of Formula I-XI, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day. Another aspect of the present invention provides use of a compound of Formulas I-XI 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 admixed with one or more pharmaceutically acceptable excipients. The present application further provides the compounds, compositions, uses or methods described herein.

[0236] Methods of using the present invention There is evidence for a role for NLRP3-induced IL-I and IL-18 in the inflammatory response associated with or resulting from a number of different disorders (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15; Strowig et al., Nature, 2012, 481, 278-286). NLRP3 mutations have been found to be responsible for a series of rare autoinflammatory diseases known as CAPS (Ozaki et al., J. Inflammation Research, 2015, 8, 15-27; Schroder et al., Cell, 2010, 140:821-832; Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15). CAPS is a genetic disorder characterized by relapsing fever and inflammation and consists of three autoinflammatory disorders that form a clinical continuum. These diseases, in descending order of severity, are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile-onset neurocutaneous and articular syndrome (CINCA; also known as neonatal-onset multisystem inflammatory disease, NOMID), all of which have been shown to be caused by gain-of-function mutations in the NLRP3 gene, which result in increased secretion of IL-1 beta. NLRP3 has also been implicated in several autoinflammatory diseases, including septic arthritis, pyoderma gangrenosum, and acne (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al., Eur J. Immunol., 2010, 40, 595-653). Specifically, it has been shown to be effective in multiple sclerosis, type 1 diabetes (TlD), psoriasis, rheumatoid arthritis (RA), Behçet's disease, Schnitzler syndrome, and macrophage activation syndrome (Braddock et al. Nat. Rev. Drug Disc. 2004, 3, 1-10; Inoue et al, Immunology, 2013, 139, 11-18, Coll et al, Nat. Med. 2015, 21(3), 248-55; Scott et al, Clin. Exp.Several autoimmune diseases have been shown to involve NLRP3, including systemic lupus erythematosus and its complications, such as lupus nephritis (Lu et al, J. Immunol., 2017, 198(3), 1119-29), and systemic sclerosis (Artlett et al, Arthritis Rheum. 2011, 63(11), 3563-74). NLRP3 has also been shown to play a role in several lung diseases, including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al, Am. J. Pathol., 2014, 184: 42-54; Kim et al. Am. J. Respir Crit Care Med, 2017, 196(3), 283-97). NLRP3 has also been suggested to have a role in several central nervous system conditions, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis (Walsh et al, Nature Reviews, 2014, 15, 84-97; and Dempsey et al. Brain. Behav. Immun. 2017, 61, 306-16), intracranial aneurysm (Zhang et al. J. Stroke and Cerebrovascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al. J. Neurotrauma., 2018, 35(11), 1294-1303). NRLP3 activity is a key factor in type 2 diabetes (T2D) and its oigan-specific complications, including atherosclerosis, obesity, gout, pseudogout, metabolic syndrome (Wen et al, Nature Immunology, 2012, 13, 352-357; Duewell et al, Nature, 2010, 464, 1357-1361; Strowig et al, Nature, 2014, 481, 278-286), and nonalcoholic steatohepatitis (Mridha et al. J.Hepatol. 2017, 66(5), 1037-46). NLRP3 has also been suggested to play an important pathological role in the development and progression of several skeletal muscle diseases, such as muscle atrophy, hereditary and acquired myopathies (Dubussion et al. Cells 2021, 10(11):3023). A role for NLRP3 via IL-I beta has also been suggested in atherosclerosis, myocardial infarction (van Hout et al. Eur Heart J. 2017, 38(11), 828-36), heart failure (Sano et al. J. Am. Coll. Cardiol. 2018, 71(8), 875-66), aortic aneurysm and dissection (Wu et al. Arterioscler Thromb. Vase. Biol., 2017, 37(4), 694-706), and other cardiovascular events (Ridker et al, N. Engl. J. Med, 2017, 377(12), 1119-31). Other diseases in which NLRP3 has been shown to be involved include eye diseases, including both wet and dry age-related macular degeneration (Doyle et al. Nature Medicine, 2012, 18, 791-798; Tarallo et al. Cell 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol., 2017, 95(8), 803-8), non-infectious uveitis and optic nerve damage (Puyang et al. Sci. Rep. 2016, 6, 20998); liver diseases, including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al. Nature, 2012, 482, 179-185); contact hypersensitivity disorders, such as bullous pemphigoid (Fang et al. J Dermatol. Sci. 2016, 83(2),116-23)), atopic dermatitis (Niebuhr et al. Allergy, 2014, 69(8), 1058-67), and hidradenitis suppurativa (Alikhan et al. J. Am. Acad. Dermatol., 2009, 60(4), 539-61) and sarcoidosis (Jager et al. Am. J. Respir Crit. Care Med., 2015, 191, A5816); inflammatory responses in the lungs and skin (Primiano et al. J. Immunol. 2016, 197(6), 2421-33); inflammatory responses in the joints (Braddock et al, Nat. Rev. Drug Disc, 2004, 3, 1-10); amyotrophic lateral sclerosis (Gugliandolo et al. Int. J. Mol. Sci., 2018, 19(7), E1992); cystic fibrosis (larmitti et al. Nat. Commun., 2016,7, 10791); stroke (Walsh et al, Nature Reviews, 2014, 15, 84-97); chronic kidney disease (Granata et al. PLoS One 2015, 10(3), eoi22272); and inflammatory bowel diseases, including ulcerative colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc, 2004, 3, 1-10; Neudecker et al. J. Exp. Med. 2017, 214(6), 1737-52; Lazaridis et al. Dig. Dis. Sci. 2017, 62(9), 2348-56). The NLRP3 inflammasome has been found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al., Inflammation, 2017, 40, 366-86). U.S. Patent US20200361898 is incorporated herein by reference.

[0237] definition The following specific examples are included to aid in understanding the scope of the compounds of Formulas I-XI, or forms thereof, described herein. Experimentation with the compounds of Formulas I-XI, or forms thereof, described herein, should, of course, not be construed as specifically limiting the scope of the compounds of Formulas I-XI, or forms thereof, described herein, and all such variations of the compounds of Formulas I-XI, or forms thereof, described herein, that are within the purview of one of ordinary skill in the art, now known, or later developed, are deemed to fall within the scope described herein and claimed hereinafter.

[0238] Except in the examples, all numbers expressing quantities of raw materials, reaction conditions, experimental data, and the like used in the specification and claims should be understood to be modified by the term "about" unless otherwise indicated. Accordingly, all such numbers represent approximations that may vary depending on the desired properties sought to be obtained by the reaction or as a result of varying experimental conditions. Thus, within the expected range of experimental reproducibility, the term "about" in reference to resulting data refers to a range for the data, provided that it may vary according to the standard deviation from the mean. Similarly, given experimental results obtained, resulting data may be rounded up or down consistently relative to the data without loss of significant figures. At the very least, and without attempting to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be construed in light of significant digits and ordinary rounding techniques.

[0239] Although the numerical ranges and parameters setting forth the characterization of the compounds of Formulas I-XI or forms thereof described herein are approximations, the numerical values ​​set forth in the examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The compounds of Formulas I-XI, or forms thereof, provided herein are described in more detail with reference to the following non-limiting examples, which are presented to more fully illustrate, but are not to be construed as limiting, the scope of the compounds of Formulas I-XI, or forms thereof, described herein. The examples illustrate the preparation of the compounds of Formulas I-XI, or forms thereof, described herein, and the in vitro and / or in vivo testing of these compounds of Formulas I-XI, or forms thereof. Those skilled in the art will appreciate that the synthetic techniques described in these examples represent techniques that are within the practice of one of ordinary skill in the chemical arts, and thus constitute preferred modes of practice. However, it should be appreciated that those skilled in the art, in light of the present disclosure, should recognize that many variations can be made in the specific methods disclosed herein and still obtain like or similar results without departing from the spirit and scope described herein.

[0240] In certain embodiments described herein, the compounds of Formulas I-XI or forms thereof are isolated for use. As used herein, the term "isolated" means a compound of Formulas I-XI or a physical state thereof that has been isolated and / or separated and / or purified from a synthetic process (e.g., from a reaction mixture), or from a natural source, or a combination thereof, in sufficient purity to be characterized by an isolation, separation, or purification process, or processes described herein or known to those of skill in the art (e.g., chromatography, recrystallization), or by standard analytical techniques described herein or known to those of skill in the art. As used herein, the term "protected" means that a functional group in a compound of Formula I-XI or its form is in a modified form to prevent undesired side reactions of the functional group when the compound is subjected to a reaction. Suitable protecting groups are known to those skilled in the art and by reference to standard textbooks, such as T.W. Greene et al., Protective Groups in Organic Synthesis (2007), Wiley, New York. Prodrugs and solvates of the compounds of Formulas I-XI or forms thereof described herein are also contemplated.

[0241] As used herein, the term "prodrug" means that a functional group on a compound of Formula I-XI is in a form that is converted in vivo (e.g., acts as an active or inactive drug precursor) to yield an active or more active compound of Formula I-XI or a form thereof. Conversion can occur by various mechanisms (e.g., by metabolic and / or non-metabolic chemical processes), for example, by hydrolysis and / or metabolism in the blood, liver, and / or other organs and tissues. A discussion of the use of prodrugs is provided by V. J. Stella, et. al., "Biotechnology: Pharmaceutical Aspects, Prodrugs: Challenges and Rewards," American Association of Pharmaceutical Scientists and Springer Press, 2007. In one example, when a compound of Formula I-XI or a form thereof contains a carboxylic acid functional group, prodrugs can include esters formed by substitution of the hydrogen atom of the acidic group with a functional group such as alkyl. In another example, when a compound of Formula I-XI or a form thereof contains an alcohol functional group, prodrugs can be formed by substitution of the hydrogen atom of the alcohol group with a functional group such as alkyl or carbonyloxy. In another example, when a compound of Formula I-XI or a form thereof contains an amine functional group, prodrugs can be formed by substitution of one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl.

[0242] Pharmaceutically acceptable prodrugs of compounds of Formulas I-XI or forms thereof include compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonic acid esters, amino acid esters, phosphonic acid esters (e.g., phosphoramidic acids used to derive phosphoramidic acids), and mono-, di-, or triphosphate esters, which may be further substituted with alkyl, as appropriate. As described herein, it will be understood by those skilled in the art that one or more of such substituents may be used to provide compounds of Formulas I-XI or forms thereof as prodrugs. The compounds of Formulas I-XI or their forms can form salts, which are intended to be included within the scope of this description. Reference herein to compounds of Formulas I-XI or their forms is understood to include reference to salts thereof, unless otherwise indicated. As used herein, the term "salt" refers to acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Furthermore, when compounds of Formulas I-XI or their forms contain both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed and are included within the term "salt" as used herein.

[0243] The term "pharmaceutically acceptable salt," as used herein, refers to salts of the compounds of Formulas I-XI or forms thereof described herein that are safe and effective for use in mammals (i.e., non-toxic, physiologically acceptable) and possess biological activity, although other salts are also useful. Salts of compounds of Formulas I-XI can be formed, for example, by reacting a compound of Formulas I-XI with an amount, e.g., an equivalent amount, of an acid or base in a medium, e.g., one in which the salt precipitates, or in an aqueous medium, followed by lyophilization. Pharmaceutically acceptable salts include salts of one or more of the acidic or basic groups present in the compounds of Formulae I-XI or forms thereof described herein. Embodiments of acid addition salts include, but are not limited to, acetate, superphosphate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucaronate, glutamate, hydrobromide, hydrochloride, dihydrochloride, hydroiodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, and the like. One or more embodiments of the acid addition salt include chloride salts, hydrochloride salts, dihydrochloride salts, trihydrochloride salts, hydrobromide salts, acetate salts, diacetate salts, methanesulfonate salts, sulfate salts, trifluoroacetate salts, trifluoroacetate salts, etc. More specific embodiments include chloride salts, hydrochloride salts, dihydrochloride salts, hydrobromide salts, methanesulfonate salts, sulfate salts, trifluoroacetate salts, trifluoroacetate salts, etc.

[0244] In certain embodiments of the compounds of Formulas I-XI or forms thereof described herein, the compounds are isolated as salt forms, and the compounds are conjugated with the salt in a ratio, in a non-limiting example, represented as "compound:salt (A:B)," where "A" and "B" represent the equivalents of the compound to the salt in its isolated form. Additionally, acids that may be suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on their website), the disclosures of which are incorporated herein by reference.

[0245] Suitable base salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. Certain compounds of Formulas I-XI described herein or forms thereof may also form pharmaceutically acceptable salts with organic bases (e.g., organic amines), such as, but not limited to, dicyclohexylamine and tert-butylamine, and with various amino acids, such as, but not limited to, arginine and lysine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long-chain halides (e.g., decyl chlorides, bromides, and iodides, lauryl, and stearyl), and aralkyl halides (e.g., benzyl and phenethyl bromides). All such acid and base salts are intended to be included within the scope of pharmaceutically acceptable salts described herein, and furthermore, all such acid and base salts are considered equivalent to the free form of the corresponding compound for purposes of this description. Compounds of Formulas I-XI and forms thereof may further exist in tautomeric forms, and all such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formulas I-XI and forms thereof described herein.

[0246] The compounds of Formulas I-XI or forms thereof may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present specification is intended to include all stereoisomers of the compounds of Formulas I-XI as well as mixtures thereof, including racemic mixtures. The compounds of Formulas I-XI, or forms thereof, described herein may contain one or more chiral centers and thus may exist as racemic mixtures (R / S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (if one chiral center is present). In one embodiment, the compounds of Formulas I-XI, or forms thereof, described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another embodiment, the compounds of Formulas I-XI, or forms thereof, described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will appreciate, when more than one chiral center is present, the compounds of Formulas I-XI, or forms thereof, described herein may also exist as (R,R), (R,S), (S,R), or (S,S) isomers, as defined by IUPAC nomenclature recommendations.

[0247] As used herein, the term "substantially pure" refers to a compound of Formula I-XI or a form thereof that consists essentially of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100% of a single isomer. In one described embodiment, a compound of Formulas I-XI or a form thereof is a substantially pure (S) enantiomer present in an amount of 90% or greater, 92% or greater, 95% or greater, 98% or greater, 99% or greater, or in an amount equal to 100%. In one described embodiment, a compound of Formulas I-XI or a form thereof is a substantially pure (R) enantiomer present in an amount of 90% or greater, 92% or greater, 95% or greater, 98% or greater, 99% or greater, or in an amount equal to 100%. As used herein, the term "racemate" refers to any mixture of isometric forms that is not "enantiomerically pure," including, for example, but not limited to, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20, about 85 / 15, or about 90 / 10. Furthermore, the compounds of Formulas I-XI or forms thereof described herein encompass all geometric and positional isomers. For example, if a compound of Formulas I-XI or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures thereof, are encompassed within the scope of the compounds of Formulas I-XI or forms thereof described herein.

[0248] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by use of a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary, e.g., a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). All stereoisomers (e.g., geometric isomers, optical isomers) of the present compounds of Formulas I-XI or forms thereof (including salts, solvates, esters and prodrugs, and converted prodrugs thereof) that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even without asymmetric carbons), rotamer forms, atropisomers, diastereomeric and positional isomeric forms, are contemplated within the scope of this description. Individual stereoisomers of the compounds of Formulas I-XI or forms thereof described herein may, for example, be substantially free of other isomers or may exist as racemic mixtures as described above.

[0249] Use of the terms "salts," "solvates," "esters," "prodrugs," and the like is intended to apply equally to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, isotopologues, or prodrugs of the present compounds. One or more compounds of Formulas I-XI or forms thereof described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and references herein are intended to encompass both solvated and unsolvated forms. As used herein, the term "solvate" means a physical association of a compound of Formulas I-XI or a form thereof described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, a solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. One or more compounds of Formulas I-XI or forms thereof described herein may be converted to a solvate. The preparation of solvates is generally known. A typical, non-limiting process involves dissolving a compound of Formulas I-XI or a form thereof in a desired amount of a desired solvent (organic or aqueous or a mixture thereof) at a temperature above ambient temperature and cooling the solution at a rate sufficient to form crystals, which are then isolated by standard methods. Analytical techniques, such as infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[0250] As used herein, the term "hydrate" means a solvate where the solvent molecule is water. As used herein, the term "isotopically enriched" refers to a compound of Formulas I-XI or a form thereof that is identical to that set forth herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into compounds of Formula (I) or forms thereof described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as H, ... 2 , H 3 , C 13 , C 14 , N 15 , O 18 , O 17 , P 31 , P 32 , S 35 , F 18 , Cl 35 and Cl 36 each of which is also within the scope of this description. Polymorphic crystalline and amorphous forms of the compounds of Formulas I-XI or forms thereof and salts, solvates, esters, and prodrugs of the compounds of Formulas I-XI or forms thereof are further intended to be included within the scope of the compounds of Formulas I-XI or forms thereof described herein.

[0251] Terminology It will be understood by those skilled in the art that the chemical terms used above and throughout the description herein have the following indicated meanings unless specifically defined otherwise. As used herein, "C 1-8 The term "alkyl" refers to a saturated hydrocarbon radical having from 1 to 8 carbon atoms in a straight or branched chain arrangement, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. In some embodiments, C 1-8 Alkyl is C 1-6 Alkyl, C 1-4 Contains alkyl, etc. C 1-8 Alkyl radicals may be optionally substituted where available valences allow.

[0252] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl (also called naphthalenyl), anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. The aryl radical may be optionally substituted where available valences allow.

[0253] As used herein, the term "heteroaryl" includes, where structural stability permits, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl (also referred to as 1H-pyrazolyl), imidazolyl (also referred to as 1H-imidazolyl), isoxazolyl (also referred to as 1,2-oxazolyl), isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl (also referred to as pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl (also referred to as 1H-indolyl), azaindolyl, indazolyl (also referred to as 2H-indazolyl), azaindolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl, aryl (also known as 1H-benzimidazolyl), benzothiazolyl, benzoxazolyl, imidazo[2,1-b][1,3]thiazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-c]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-imidazo[4,5-b]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[1

[0023] refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members are replaced by one or more heteroatoms, such as O, S, or N atoms, including, but not limited to, pyrimidinyl, 7H-purinyl, 9H-purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, acridinyl, etc., and their related homologs and positional isomers. Heteroaryl radicals may be substituted on carbon or nitrogen atom ring members where available valences allow.

[0254] As used herein, the term "heterocyclyl" includes, where structural stability permits, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl , triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, 1,3-dioxolanyl, dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl , dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl, tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl, dihydro-benzoxazolyl, tetrahydro-benzoxazolyl, di Hydro-benzoxazinyl, tetrahydro-benzoxazinyl, benzo[1,3]dioxolyl (also called 1,3-benzodioxolyl), benzo[1,4]dioxanyl (also called 1,4-benzodioxanyl or 2,3-dihydro-1,4-benzodioxinyl), benzo[1,4]dioxinyl (also called 1,4-benzodioxinyl), 4,5,6,7-tetrahydro-2H-indazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c] refers to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic carbon atom ring structure radicals in which one or more carbon atom ring members are replaced with heteroatoms, such as O, S, or N atoms, including, but not limited to, pyridinyl, dihydro-purinyl, tetrahydro-purinyl, dihydro-quinolinyl, tetrahydro-quinolinyl, dihydro-isoquinolinyl, tetrahydro-isoquinolinyl, dihydro-quinazolinyl, tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, and the like, and their related congeners. Heterocyclyl radicals may be substituted on carbon or nitrogen atom ring members, if available valences permit.

[0255] As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluoro, chloro, bromo, and iodo. As used herein, "C 1-4 Alkoxy-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Alkyl-OC 1-4 Refers to an alkyl radical. As used herein, "C 1-4 The term "alkoxy-carbonyl" refers to a group of the formula: -C(O)-OC 1-4 Refers to an alkyl radical. As used herein, "C 1-4 The term "alkoxy-carbonyl-amino" refers to a group of the formula: -NH-C(O)-OC 1-4 Refers to an alkyl radical. As used herein, "C 1-4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-4 Refers to an alkyl radical. As used herein, "(C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 It refers to the radical (alkyl)2.

[0256] As used herein, "C 1-4 Alkyl-amino-C1-4 The term "alkoxy" means a group of the formula: -OC 1-4 Alkyl-NH-C 1-4 Refers to an alkyl radical. As used herein, "(C 1-4 Alkyl)2-amino-C 1-4 The term "alkoxy" means a group of the formula: -OC 1-4 Alkyl-N(C 1-4 It refers to the radical (alkyl)2. As used herein, "C 1-4 Alkyl-amino-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Alkyl-NH-C 1-4 Refers to an alkyl radical. As used herein, "(C 1-4 Alkyl)2-amino-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Alkyl-N(C 1-4 It refers to the radical (alkyl)2. As used herein, "C 1-4 The term "alkyl-carbonyl" refers to a group of the formula: -C(O)-C 1-4 Refers to an alkyl radical. As used herein, "C 1-4 The term "alkyl-carbonyl-amino" refers to a group of the formula: -NH-C(O)-C 1-4 Refers to an alkyl radical. As used herein, "C 1-4 The term "alkyl-thio" refers to a group of the formula: -SC 1-4 Refers to an alkyl radical.

[0257] As used herein, "amino-C 2-8 The term "alkenyl" refers to an alkenyl group having the formula: -C 2-8 Refers to the radical alkenyl-NH2. As used herein, "amino-C 1-4 The term "alkoxy" means a group of the formula: -OC 1-4 Refers to the alkyl-NH2 radical. As used herein, "amino-C1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to the alkyl-NH2 radical. As used herein, "amino-C 1-4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-4 Refers to the alkyl-NH2 radical.

[0258] As used herein, "(amino-C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 Refers to the radical alkyl-NH2). As used herein, "(amino-C 1-4 Alkyl)(C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 Alkyl)(C 1-4 Refers to the radical alkyl-NH2). As used herein, "amino-C 2-8 The term "alkynyl" refers to a group of groups of the formula: -C 2-8 Refers to the radical alkynyl-NH2. As used herein, "aryl-C 1-4 The term "alkoxy-carbonyl" refers to a group of the formula: -C(O)-OC 1-4 Refers to the alkyl-aryl radical. As used herein, "aryl-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to the alkyl-aryl radical. As used herein, "aryl-C 1-4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-4 Refers to the alkyl-aryl radical. As used herein, "(aryl-C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 It refers to the radical alkyl-aryl. As used herein, the term "aryl-amino" refers to a radical of the formula: --NH-aryl.

[0259] As used herein, the term "aryl-amino-carbonyl" refers to a radical of the formula: --C(O)--NH-aryl. As used herein, the term "benzoxy-carbonyl" refers to a radical of the formula: -C(O)-O-CH2-phenyl. As used herein, "C 3-14 Cycloalkyl-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Alkyl-C 3-14 Refers to a cycloalkyl radical. As used herein, "C 3-14 The term "cycloalkyl-amino" refers to a group of the formula: -NH-C 3-14 Refers to a cycloalkyl radical. As used herein, "C 3-14 The term "cycloalkyl-oxy" refers to a group of the formula: -OC 3-14 Refers to a cycloalkyl radical. As used herein, "deutero-C" 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 refers to an alkyl-deutero radical, where C 1-4 Alkyl is partially or fully substituted with one or more deuterium atoms where available valences permit. As used herein, "halo-C" refers to 1-4 The term "alkoxy" means a group of the formula: -OC 1-4 Refers to alkyl-halo radicals, C 1-4 The alkyl may be partially or fully substituted with one or more halogen atoms, where available valences allow.

[0260] As used herein, "halo-C" refers to 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to alkyl-halo radicals, C 1-4 The alkyl may be partially or fully substituted with one or more halogen atoms, where available valences allow. As used herein, "halo-C" refers to 1-4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-4 Refers to the alkyl-halo radical. As used herein, "(halo-C 1-4 Alkyl)(C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 Alkyl)(C 1-4 It refers to the radical alkyl-halo. As used herein, "(halo-C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 Refers to the radical alkyl-halo2. As used herein, "heteroaryl-C 1-4 The term "alkoxy" means a group of the formula: -OC 1-4 Refers to alkyl-heteroaryl radicals. As used herein, "heteroaryl-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to alkyl-heteroaryl radicals.

[0261] As used herein, the term "heteroaryl-amino" refers to a radical of the formula: --NH-heteroaryl. As used herein, "heterocyclyl-C 1-4 The term "alkoxy" means a group of the formula: -OC 1-4 Refers to an alkyl-heterocyclyl radical. As used herein, "heterocyclyl-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to an alkyl-heterocyclyl radical. As used herein, "heterocyclyl-C 1-4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-4 Refers to an alkyl-heterocyclyl radical. As used herein, "(heterocyclyl-C 1-4 The term "amino" refers to a group of the formula: -N(C1-4 It refers to the radical alkyl-heterocyclyl). As used herein, the term "heterocyclyl-amino" refers to a radical of the formula: --NH-heterocyclyl. As used herein, "(heterocyclyl)(C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 It refers to the radical of (heterocyclyl) (alkyl). As used herein, "heterocyclyl-amino-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 refers to the radical alkyl-NH-heterocyclyl.

[0262] As used herein, the term "heterocyclyl-carbonyl" refers to a radical of the formula: --C(O)-heterocyclyl. As used herein, the term "heterocyclyl-carbonyl-oxy" refers to a radical of the formula: --OC(O)-heterocyclyl. As used herein, the term "heterocyclyl-oxy" refers to a radical of the formula: -O-heterocyclyl. As used herein, the term "hydroxy" refers to a radical of the formula: --OH. As used herein, "hydroxy-C 1-4 Alkoxy-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Alkyl-OC 1-4 Refers to the alkyl-OH radical. As used herein, "hydroxy-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 refers to the alkyl-OH radical, where C 1-4 The alkyl is partially or fully substituted, where available valences allow, with one or more hydroxy radicals. As used herein, "hydroxy-C 1-4 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-4Refers to the alkyl-OH radical.

[0263] As used herein, "(hydroxy-C 1-4 The term "amino" refers to a group of the formula: -N(C 1-4 Refers to the radical alkyl (-OH). As used herein, the term "substituent" refers to a positional variable on an atom of a core molecule that is substituted at the designated atom position, replacing one or more hydrogens on the designated atom, provided that the normal valence for the designated atom is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Those of skill in the art should note that, as described or depicted herein, any carbon and heteroatom with an apparently unsatisfied valence is assumed to have as many hydrogen atoms as possible to satisfy the valences described or depicted. In certain instances, one or more substituents having a double bond (e.g., "oxo" or "=O") are described, depicted, or listed herein as the point of attachment within a substituent, and structures may show only a single bond as the point of attachment to the core structure of Formulas I-XI. Those of skill in the art will understand that a double bond is intended for such substituents, even if only a single bond is depicted.

[0264] As used herein, the term "such as" in reference to the definitions of chemical terms set forth herein means that variations in chemical structure that might be anticipated by one of ordinary skill in the art include, but are not limited to, isomers (including chain, branched, or positional structural isomers), hydration of ring systems (including saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring structures), and all other variations that result in stable compounds, where available valences allow. As used herein, the term "substituent" refers to a positional variable on the atom of a core molecule to which it is attached at the specified atom, replacing one or more hydrogen atoms on the specified atom, provided that the atom to which it is attached does not exceed the available valence or covalence such that the substitution results in a stable compound. Thus, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. It should also be noted that, as described or shown herein, any carbon and heteroatom having an apparently unsatisfied valence level is assumed to have as many hydrogen atoms as necessary to satisfy the valences described or shown. For purposes of this description, when one or more variable substituents in a compound of Formulas I-XI include a functional group incorporated into a compound of Formulas I-XI, each functional group appearing at any site within the disclosed compound may be independently selected and, where appropriate, independently and / or optionally substituted.

[0265] As used herein, the term "independently selected" or "each selected" refers to a variable functional group in a list of substituents that may be attached more than once to the structure of a core molecule, and the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Furthermore, the use of a generic substituent on a core structure described herein is understood to include substitution of the generic substituent with specific substituents included within the particular genus, for example, aryl may be independently replaced with phenyl or naphthalenyl (also referred to as naphthyl), and the resulting compound is intended to be included within the scope of the compounds described herein. As used herein, the term "each instance" or "each variable independently" refers to, for example, "...aryl, aryl-C 1-8 Alkyl, heterocyclyl and heterocyclyl-C 1-8When used in the phrase "alkyl, and each instance of aryl and heterocyclyl may be substituted with 1 or 2 substituents...", the aryl and heterocyclyl rings each include 1 or 2 substituents, and the aryl-C 1-8 Alkyl and heterocyclyl-C 1-8 It is intended to include optional independent substitution on the aryl and heterocyclyl portions of an alkyl.

[0266] As used herein, the term "optionally substituted" means that the particular variable substituent, group, radical, or moiety represents a generic range and can be independently selected, as needed, to replace one or more hydrogen atoms at the specified atom of attachment of the core molecule. As used herein, the terms "stable compound" or "stable structure" mean a compound that is sufficiently robust to be isolated from a reaction mixture and preparation thereof to a degree of purity useful in an effective therapeutic agent. As used herein, the terms "subject" and "patient" are used interchangeably to refer to an animal or any living organism that has sensation and the power of voluntary movement and requires the presence of oxygen and organic food. Non-limiting examples include humans, horses, pigs, cows, rats, mice, dogs, and members of the cat species. In some embodiments, the subject is a mammal or warm-blooded vertebrate. In certain embodiments, the subject is a non-human animal. In specific embodiments, the subject is a human.

[0267] The names of compounds shown herein were obtained using ACD Labs Index Name software provided by ACD Labs and / or ChemDraw Ultra software provided by CambridgeSoft®. Where the name of a compound disclosed herein does not match the depicted structure, the depicted structure supersedes the use of the name to define the intended compound. The nomenclature of substituent radicals defined herein may differ slightly from the chemical names from which they are derived, and those skilled in the art will understand that the definitions of substituent radicals are intended to include the radicals found in the chemical names. Usage and dosage The compounds of the present invention can be formulated into a wide variety of oral dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, liquids, emulsions, syrups, or suspensions. The compounds of the present invention are effective when administered by other routes of administration, including continuous (intravenous drip), topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, nasal, inhalation, and suppository administration, among others. The preferred method of administration is generally oral, using a convenient daily dosage regimen, which can be adjusted according to the degree of discomfort and the patient's response to the active ingredient.

[0268] The compounds of the present invention, as well as their pharmaceutically acceptable salts, may be placed into the form of pharmaceutical compositions and unit dosages together with one or more conventional excipients, carriers, or diluents. Pharmaceutical compositions and unit dosage forms may consist of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient consistent with the daily dosage range for which it is intended to be used. Pharmaceutical compositions may be used as solids, such as tablets or filled capsules, semisolids, powders, sustained-release formulations, or liquids, such as solutions, suspensions, emulsions, elixirs, or filled capsules, for oral use; or as suppositories for rectal or vaginal administration; or as sterile injectable solutions for parenteral use. Typical preparations contain from about 5% to about 95% active compound (w / w). The terms "preparation" or "dosage form" are intended to encompass both solid and liquid formulations of the active compound, and those skilled in the art will recognize that the active ingredient may be present in different preparations depending on the target organ or tissue, as well as the desired dose and pharmacokinetic parameters. As used herein, the term "excipient" refers to a compound that is generally safe, non-toxic, and not biologically or otherwise undesirable, useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds of the invention can be administered alone, but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents, or carriers selected for the intended route of administration and standard pharmaceutical practice.

[0269] "Pharmaceutically acceptable" means generally safe, non-toxic, and not biologically or otherwise undesirable, useful in the preparation of pharmaceutical compositions, and includes those acceptable for veterinary and human pharmaceutical use. A "pharmaceutically acceptable salt" form of an active ingredient may initially impart desirable pharmacokinetic properties to the active ingredient not present in the non-salt form and may even favorably affect the pharmacodynamics of the active ingredient with respect to therapeutic activity in the body. The phrase "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the unchanged form. Such salts may be formed: (1) with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- These include acid addition salts formed with methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; or (2) salts formed when an acidic proton present in the unchanged compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or when coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine.

[0270] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is generally a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in suitable proportions and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. Solid form preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0271] Liquid preparations are also suitable for oral administration, including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These include solid-form preparations intended to be converted to liquid-forming preparations immediately before use. Emulsions can be prepared in solution, for example, in aqueous propylene glycol, or can contain emulsifiers such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. The compounds of the present invention can be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous injection), and can be presented in unit dosage form with added preservatives in ampoules, pre-filled syringes, small-volume injections, or multi-dose containers.The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, such as solutions in aqueous polyethylene glycol.Examples of oily or non-aqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate), and can contain formulation agents such as preservatives, wetting agents, emulsifying or suspending agents, stabilizing agents, and / or dispersing agents.Alternatively, the active ingredient can be in powder form, obtained by aseptic isolation of sterile solids or by lyophilization from a solution that is to be constituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0272] The compounds of the present invention can be formulated as ointments, creams, or lotions for topical administration to the epidermis, or as transdermal patches. Ointments and creams can be formulated with an aqueous or oily base, for example, with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier. The compounds of the present invention can be formulated for administration as suppositories. A low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and solidify.

[0273] The compounds of the present invention can be formulated for vaginal administration using pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. The compound of the present invention can be formulated for nasal administration.The solution or suspension is directly applied to the nasal cavity by conventional means, for example, by dropper, pipette or spray.The formulation can be provided in single or multiple dose form.In the latter case of dropper or pipette, this can be achieved by the patient administering an appropriate predetermined volume of the solution or suspension.In the case of spray, this can be achieved, for example, by a metering atomizing spray pump. The compounds of the present invention can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compounds generally have a small particle size, for example, of the order of 5 μm or less. Such a particle size can be obtained by means known in the art, for example, by micronization. The active ingredient can be delivered in a pressurized pack using a suitable propellant, for example, a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. The aerosol can conveniently also contain a surfactant, for example, lecithin. The dose of drug can be controlled by a metered valve. Alternatively, the active ingredient can be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base, such as lactose, starch, starch derivatives, for example, hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier forms a gel in the nasal cavity. Powder compositions can be presented in unit dose form, for example, in capsules or cartridges of, for example, gelatin or blister packs, from which the powder can be administered by inhaler.

[0274] If desired, formulations can be prepared with enteric coatings adapted for sustained or controlled-release administration of the active ingredient. For example, the compounds of the present invention can be formulated into transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is essential and when compliance with the treatment regimen is critical. In transdermal delivery systems, the compound is often attached to a skin-adhesive solid carrier. The compound of interest can also be combined with a permeation enhancer, such as Azone (1-dodecylaza-cycloheptan-2-one). Sustained-release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. Subdermal implants encapsulate the compound in a lipid-soluble membrane, such as silicone rubber or a biodegradable polymer, such as polylactic acid.

[0275] Suitable formulations, along with pharmaceutical carriers, diluents, and expcipients, are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Formulation scientists can modify the formulations within the teachings herein to obtain a multitude of formulations for specific routes of administration without destabilizing the compositions of the invention or compromising their therapeutic activity. Modifications to make the compounds more soluble in water or other vehicles can be readily accomplished, for example, by minor modifications (salt formulations, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill in the art to modify the route of administration and dosage regimen of a particular compound to manage the pharmacokinetics of the compound for maximum beneficial effect in the patient.

[0276] The term "therapeutically effective amount," as used herein, refers to the amount required to reduce the symptoms of a disease in an individual. Doses will be tailored to the individual requirements of each particular case. The dosage may vary within wide limits depending on numerous factors, such as the severity of the disease being treated, the age and general health of the patient, other medications the patient is being treated with, the route and form of administration, and the preference and experience of the physician involved. For oral administration, a daily dosage of about 0.01 to about 1,000 mg / kg body weight per day should be appropriate in monotherapy and / or combination therapy. A preferred daily dosage is about 0.1 to about 500 mg / kg body weight per day, with 0.1 to about 100 mg / kg body weight being more preferred, and 1.0 to about 10 mg / kg body weight being most preferred. Thus, for administration to a 70 kg human, the dosage range may be about 7 mg to 0.7 g per day. The daily dosage may be administered as a single dose or in divided doses, typically 1 to 5 doses per day. Generally, treatment is initiated with a smaller dosage that is less than the optimal dose of the compound.The dosage is then gradually increased until the optimal effect for each patient is reached.In treating the diseases described herein, those skilled in the art can determine the specific therapeutically effective amount of the compound of the present invention for a given disease and patient without undue experimentation and relying on their own knowledge, experience and the disclosure of this application.

[0277] Pharmaceutical preparations are preferably in unit dosage form.In such form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, the package containing discrete amounts of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form. In general, the nomenclature used in this application is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. In the event of a discrepancy between a depicted structure and a name given to that structure, greater weight should be given to the depicted structure. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated, e.g., with a bold or dashed line, the structure or portion of a structure should be interpreted as encompassing all stereoisomers thereof.

[0278] Reagents and solvents were used as purchased (from various vendors) except where noted. Where applicable, the term "Celite" is used as shown in the following examples to refer to the trade name CELITE® (a brand of diatomaceous earth). Where applicable, chromatographic separations were performed using commonly available techniques and equipment, for example, by using an ISCO CombiFlash® Rf system. Where applicable, NMR spectra were obtained using, for example, a Bruker Avance III 500 The compounds were obtained using commonly available techniques and equipment by using a spectrometer and deuterated solvents, e.g., DMSO-d6, or residual solvent as a standard. Where applicable, TLC analyses were performed using commonly available techniques and equipment by using, e.g., Aldrich 254 nm glass-backed plates (60 Å, 250 μm) visualized using UV and I2 staining. Where applicable, ESI mass spectra were obtained using, e.g., [M+H] unless otherwise indicated. + or [MH] - The structures were obtained using commonly available techniques and equipment by using an ACQUITY UPLC® system with the values ​​shown. Where applicable, the structures of the products were obtained by 2D NOESY (Nuclear Overhauser SpectroscopY) experiments.

[0279] chemical definition As used herein, "C 1-4The term "alkyl" generally refers to a saturated hydrocarbon radical having from 1 to 4 carbon atoms in a straight or branched chain arrangement, including, but not limited to, methyl, ethyl, n-propyl (also known as propyl or propanyl), isopropyl, n-butyl (also known as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, and the like. 1-4 Alkyl radicals may be optionally substituted, where available valences allow, with substituent types described herein.

[0280] As used herein, "C 2-4 The term "alkenyl" generally refers to a partially unsaturated hydrocarbon radical having from 2 to 4 carbon atoms in a straight or branched arrangement and one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also known as vinyl), allyl, propenyl, and the like. 2-4 Alkenyl radicals may be optionally substituted, where available valences allow, with the types of substituents described herein. As used herein, "C 2-8 The term "alkynyl" generally refers to a partially unsaturated hydrocarbon radical having from 2 to 8 carbon atoms in a straight or branched chain arrangement and one or more carbon-carbon triple bonds therein, including, but not limited to, ethynyl, propynyl, butynyl, and the like. In certain embodiments, C 2-8 Alkynyl is C 2-6 Alkynyl, C 2-4 Alkynyl and the like are included, but are not limited to. 2-8 Alkynyl radicals may be optionally substituted, where available valences allow, with the types of substituents described herein.

[0281] As used herein, "C 1-4 The term "alkoxy" generally refers to groups of the formula: -OC, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. 1-4Alkyl refers to a saturated hydrocarbon radical having 1 to 4 carbon atoms in a straight or branched chain arrangement. 1-4 Alkoxy radicals may be optionally substituted, where available valences allow, with substituent types described herein. As used herein, "C 3-10 The term "cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like. 3-10 Cycloalkyl radicals may be optionally substituted, where available valences allow, with the types of substituents described herein. As used herein, the term "aryl" generally refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. Aryl radicals may be optionally substituted, where available valences allow, with substituent types described herein.

[0282] As used herein, the term "heteroaryl" generally refers to any of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl ... ,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-diazanaphthalenyl, acridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2, 3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a

[0033] refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members, where structural stability permits, are replaced by one or more heteroatoms, such as O, S, or N atoms, including, but not limited to, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, and the like. Heteroaryl radicals may be optionally substituted on the carbon or nitrogen ring members, where available valences permit, with the types of substituents described herein.

[0283] In certain aspects, the nomenclature of heteroaryl radicals may differ, for example, in non-limiting examples, furanyl may also be referred to as furyl, thienyl may also be referred to as thiophenyl, pyridinyl may also be referred to as pyridyl, benzothienyl may also be referred to as benzothiophenyl, and 1,3-benzoxazolyl may also be referred to as 1,3-benzoxazolyl.

[0284] In certain other aspects, the term heteroaryl radicals include, for example, the term pyrrolyl can include 2H-pyrrolyl, 3H-pyrrolyl, etc., the term pyrazolyl can include 1H-pyrazolyl, etc., the term imidazolyl can include 1H-imidazolyl, etc., the term triazolyl can include 1H-1,2,3-triazolyl, etc., the term oxadiazolyl can include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc. The term benzoimidazolyl may also include 1H-benzoimidazolyl, 2H-benzoyl, etc., the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl, etc., the term indolyl may also include 1H-indolyl, etc., the term indazolyl may also include 1H-indazolyl, 2H-indazolyl, etc., the term benzimidazolyl may also include 1H-benzimidazolyl, the term purinyl may also include 9H-purinyl, etc., in non-limiting examples.

[0285] As used herein, the term "heterocyclyl" generally refers to any of oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl , tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3 aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-Hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-Hexahydropyrrolo[3,4-c]pyrrol-(1H) -yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8 -Azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, cyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 5,8- It refers to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic carbon atom ring structure radicals in which one or more carbon atom ring members, where structural stability permits, are replaced by heteroatoms, such as O, S, or N atoms, including, but not limited to, diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl, 7-azadispiro[5.1.58.36]hexadecanyl, and the like. Heterocyclyl radicals may be substituted on carbon or nitrogen atom ring members, where available valences permit, with the substituents described herein.

[0286] In certain embodiments, the nomenclature of heterocyclyl radicals may differ, for example, in non-limiting examples, 1,3-benzodioxolyl may also be referred to as benzo[d][1,3]dioxolyl, and 2,3-dihydro-1,4-benzodioxinyl may also be referred to as 2,3-dihydrobenzo[b][1,4]dioxinyl. As used herein, "deutero-C" 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 refers to an alkyl-deutero radical, where C 1-4 Alkyl is partially or fully substituted with one or more deuterium atoms where available valences permit. For purposes of this description, when a compound of Formulas I-XI, or one or more variable substituents therein, includes a functional group incorporated into a compound of Formulas I-XI, each functional group appearing at any site within the disclosed compound may be independently selected and, where appropriate, independently and / or optionally substituted.

[0287] As used herein, the terms "independently selected" or "each selected" refer to a variable functional group in a list of substituents that may occur more than once on the structures of Formulas I-XI, where the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Furthermore, the use of a generic variable substituent on any formula or structure of a compound described herein is understood to include substitution of the generic substituent with a species of substituent included within the particular genus; for example, aryl can be replaced with phenyl or naphthalenyl, etc., with the resulting compound being within the scope of the compounds described herein. As used herein, the terms "each instance" or "in each instance, if present" are used interchangeably, e.g., "...C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, heteroaryl, heteroaryl-C 1-4Alkyl, heterocyclyl and heterocyclyl-C 1-4 When used preceding the term "alkyl," each, when present alone or as a substituent, is a C 3-14 It is intended to refer to cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems. As used herein, the term "optionally substituted" means optional substitution with the specified variable substituents, groups, radicals or moieties.

[0288] Compound form As used herein, the term "form" means a compound of Formulas I-XI having a form selected from the group consisting of its free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereoisomer, stereoisomer, polymorph, and tautomeric form. In certain embodiments described herein, the compounds of Formulas I-XI are in the form of a free acid, a free base, or a salt thereof. In certain embodiments described herein, the compounds of Formulas I-XI are in the form of salts thereof. In certain embodiments described herein, the forms of the compounds of Formulas I-XI are isotopologues thereof. In certain embodiments described herein, the compounds of Formulas I-XI are in the form of a stereoisomer, racemate, enantiomer, or diastereoisomer thereof. In certain embodiments described herein, the forms of the compounds of Formulas I-XI are tautomers thereof.

[0289] In certain embodiments described herein, the compounds of Formulas I-XI are in a pharmaceutically acceptable form. In certain embodiments described herein, the compounds of Formulas I-XI or forms thereof are isolated for use. As used herein, the term "isolated" refers to the physical state of a compound of Formulas I-XI or a form thereof after isolation and / or purification from a synthetic process (e.g., from a reaction mixture), or from a natural source or combination thereof following an isolation or purification process (e.g., chromatography, recrystallization) described herein or known to one of ordinary skill in the art, to a sufficient purity to be characterized by standard analytical techniques described herein or known to one of ordinary skill in the art.

[0290] As used herein, the term "protected" means that a functional group in a compound of Formulas I-XI or its form is in a modified form to prevent undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups are known to those skilled in the art and by reference to standard textbooks, such as T.W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino, and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters. In certain instances, the protecting group may also be a polymer resin, such as a Wang resin or a 2-chlorotrityl-chloride resin. Protecting groups may be added or removed according to standard techniques well known to those of skill in the art and described herein. It will also be recognized by those skilled in the art that such protected derivatives of the compounds described herein may not themselves possess pharmacological activity, but may be administered to a subject and subsequently metabolized in the body to form the pharmacologically active compounds described herein. Such derivatives may therefore be described as "prodrugs." All prodrugs of the compounds described herein are included within the scope of the uses described herein.

[0291] As used herein, the term "prodrug" refers to a form of the compound (e.g., a drug precursor) that is converted in vivo to provide the active compound of Formulas I-XI or a form thereof. The conversion may occur by various mechanisms (e.g., by metabolic and / or non-metabolic chemical processes), for example, by hydrolysis and / or metabolism in the blood, liver, and / or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. In one example, when a compound of Formula I-XI or a form thereof contains a carboxylic acid functional group, prodrugs can include esters formed by replacing the hydrogen atom of the acidic group with a functional group such as alkyl. In another example, when a compound of Formula I-XI or a form thereof contains a hydroxyl functional group, prodrug forms can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl, or phosphonate ester. In another example, when a compound of Formula I-XI or a form thereof contains an amine functional group, prodrug forms can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of compounds of Formula I-XI or a form thereof include compounds substituted with one or more of the following groups: carboxylic acid ester, sulfonic acid ester, amino acid ester, phosphonic acid ester, and mono-, di-, or triphosphate ester, or alkyl substituents, as appropriate. It will be appreciated by those skilled in the art that one or more of such substituents, as described herein, may be used to obtain compounds of Formulas I-XI or forms thereof as prodrugs.

[0292] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the description herein is intended to encompass both solvated and unsolvated forms. As used herein, the term "solvate" refers to a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, a solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

[0293] The compounds of Formulas I-XI can form salts, which are intended to be included within the scope of this description. Reference herein to compounds of Formulas I-XI or their forms is understood to include reference to their salt forms, unless otherwise indicated. As used herein, the term "salt" refers to acid salts formed with inorganic and / or organic acids and basic salts formed with inorganic and / or organic bases. Furthermore, when compounds of Formulas I-XI or their forms contain both a basic moiety, such as, but not limited to, an amine moiety, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed and are included within the term "salt" as used herein.

[0294] The term "pharmaceutically acceptable salt," as used herein, refers to salts of compounds described herein that are safe and effective for use in mammals (i.e., non-toxic, physiologically acceptable) and possess biological activity, although other salts are also useful. Salts of compounds of Formulas I-XI can be formed, for example, by reacting a compound of Formulas I-XI or a form thereof with an amount, e.g., an equivalent amount, of acid or base in a medium, e.g., one in which the salt is precipitated or an aqueous medium, followed by lyophilization. Pharmaceutically acceptable salts include salts of one or more of the acidic or basic groups present in the compounds described herein. Specific embodiments of acid addition salts include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucuronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, and the like. Certain detailed embodiments of acid addition salts include chlorides or dichlorides.

[0295] Additionally, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on their website), the disclosures of which are incorporated herein by reference. Suitable base salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, and zinc salts. All such acid and base salts are intended to be included within the scope of pharmaceutically acceptable salts described herein, and further, all such acid and base salts are considered equivalent to the free form of the corresponding compound for purposes of this description. Compounds of Formulas I-XI and forms thereof may further exist in tautomeric forms, and all such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formulas I-XI and forms thereof described herein.

[0296] The compounds of Formulas I-XI or forms thereof may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. This specification is intended to include all stereoisomers of the compounds of Formulas I-XI as well as mixtures thereof, including racemic mixtures. The compounds described herein may contain one or more chiral centers and, as such, may exist as racemic mixtures (R / S) or as substantially pure enantiomers and diastereoisomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (if one chiral center is present). In one detailed aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions containing substantially only the (S) isomer. In another detailed aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions containing substantially only the (R) isomer. As one of ordinary skill in the art will appreciate, when more than one chiral center is present, the compounds described herein may also exist as (R,R), (R,S), (S,R), or (S,S) isomers, as defined by IUPAC nomenclature recommendations. As used herein, the term "substantially pure" refers to a compound that consists essentially of a single isomer in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100%.

[0297] In one described embodiment, the compound of Formula I-XI or a form thereof is a substantially pure (S) enantiomer form present in an amount of 90% or greater, 92% or greater, 95% or greater, 98% or greater, 99% or greater, or an amount equal to 100%. In one described embodiment, the compound of Formula I-XI or a form thereof is a substantially pure (R) enantiomer form present in an amount of 90% or greater, 92% or greater, 95% or greater, 98% or greater, 99% or greater, or an amount equal to 100%. As used herein, a "racemate" is any mixture of isometric forms that is not "enantiomerically pure," including, for example, but not limited to, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20. Furthermore, the present disclosure encompasses all geometric and positional isomers. For example, if a compound of Formulas I-XI or a form thereof incorporates a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are encompassed within the scope of the disclosure. Diastereomeric mixtures can be separated into their individual diastereoisomers based on their physical chemical differences by methods known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by using a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Additionally, some of the compounds of Formulas I-XI may be atropisomers (e.g., substituted biaryls) and are considered part of this disclosure.

[0298] All stereoisomers (e.g., geometric isomers, optical isomers) of the compounds (including salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of the prodrugs), including enantiomeric forms (which may exist without asymmetric carbons), rotamer forms, atropisomers, and diastereomeric forms, including those that may exist due to asymmetric carbons on various substituents, are contemplated within the scope of this description, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers or may exist as racemic mixtures as described above. Use of the terms "salts," "solvates," "esters," "prodrugs," and the like is intended to apply equally to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or isotopologues of the present compounds.

[0299] The term "isotopologue" refers to an isotopically enriched compound described herein that is identical to that listed herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 35 Cl and 36 Cl, each of which is also within the scope of this description. Certain isotopically enriched compounds described herein (e.g., 3 H and 14C) are useful for compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e. 2 H) may offer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability and may therefore be preferred in some circumstances. Polymorphic crystalline and amorphous forms of the compounds of Formulas I-XI, and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formulas I-XI, are further intended to be included herein.

[0300] Use of the compound In accordance with the scope contemplated herein, embodiments herein include compounds that have been identified and demonstrated to be useful in selectively preventing, treating, or ameliorating any disease mediated by NLRP3, and are provided for use in preventing, treating, or ameliorating any disease mediated by NLRP3. Aspects of the present specification include methods for preventing, treating, or ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formulas I-XI or a form thereof. Embodiments herein include methods for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formulas I-XI or a form thereof. Embodiments herein include methods for preventing any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formulas I-XI or a form thereof.

[0301] Embodiments herein include methods for treating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formulas I-XI or a form thereof. Embodiments herein include a method for ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formulas I-XI or a form thereof. Another aspect of the present specification includes a method for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of Formulas I-XI or a form thereof. Aspects herein include a method of using a compound of Formula I-XI, or a form thereof, or a composition, to treat or ameliorate any disease mediated by NLRP3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I-XI, or a form thereof, or a composition.

[0302] Another aspect herein includes a method of using a compound salt of Formulas I-XI, or a form thereof, or a composition to treat or ameliorate any disease mediated by NLRP3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound salt of Formulas I-XI, or a form thereof. Aspects of the present specification include the use of a compound of Formula I-XI or a form thereof for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I-XI or a form thereof.

[0303] Another aspect of the present specification includes the use of a salt of a compound of Formula I-XI or a form thereof for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of Formula I-XI or a form thereof. Aspects of the present specification include the use of a compound of Formulas I-XI or a form thereof in the manufacture of a medicament for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of the medicament. Another aspect of the present specification includes the use of a salt of a compound of Formula I-XI or a form thereof in the manufacture of a medicament for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of the medicament. Aspects of the present specification include the in vitro or in vivo use of compounds of Formulas I-XI or forms thereof that have activity against any disease mediated by NLRP3. Embodiments herein include the use of compounds of Formulas I-XI or forms thereof in combination therapy to provide additive or synergistic activity, thus enabling the development of combination products to treat or ameliorate any disease mediated by NLRP3.

[0304] Another aspect of the present specification includes combination therapies comprising a compound described herein in combination with one or more known drugs or one or more known therapies that can be used to treat any disease mediated by NLRP3, regardless of whether the disease is responsive to the known drugs. Aspects herein include the use of a compound of Formula I-XI or a form thereof in a combination product with one or more therapeutic agents to treat or ameliorate any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I-XI or a form thereof in combination with an effective amount of the one or more agents. Another aspect herein includes the use of a salt of a compound of Formula I-XI or a form thereof in a combination product with one or more therapeutic agents to treat or ameliorate any disease mediated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a salt of a compound of Formula I-XI or a form thereof in combination with an effective amount of the one or more agents.

[0305] In certain embodiments of the uses or methods described herein, a compound of Formulas I-XI or a form thereof used in combination with one or more additional agents can be administered to a subject or contacted with cells of a subject or patient prior to, simultaneously with, or subsequent to administration to the subject or patient or contacting the cells with the additional agent. A compound of Formulas I-XI or a form thereof and the additional agent(s) can be administered to a subject or contacted with cells in a single composition or in different compositions. In certain embodiments, a compound of Formulas I-XI or a form thereof is used in combination with gene therapy or administration of another small molecule Nlrp3 inhibitor (e.g., using a viral delivery vector) to inhibit NLRP3 expression. In another specific embodiment, a compound of Formulas I-XI or a form thereof is used in combination with cell replacement using differentiated, unmutated NLRP3 stem cells. In another specific embodiment, a compound of Formulas I-XI or a form thereof is used in combination with cell replacement using differentiated NLRP3 stem cells. In one aspect, provided herein is the use of a compound of Formula I-XI or a form thereof in combination with supportive standard of care therapy, including palliative care.

[0306] Aspects herein include the use of a compound of Formula I-XI or a form thereof in the preparation of a kit for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, the kit comprising a compound of Formula I-XI or a form thereof and instructions for administering an effective amount of the compound of Formula I-XI or a form thereof. Aspects herein include the use of a compound of Formula I-XI or a form thereof in the preparation of a kit for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, the kit comprising a compound of Formula I-XI or a form thereof and instructions for administering an effective amount of the compound of Formula I-XI or a form thereof, and optionally, for administering to the subject an effective amount of the compound of Formula I-XI or a form thereof in a combination product with an effective amount of one or more therapeutic agents.

[0307] Aspects herein include the use of a compound of Formula I-XI or a form thereof in the preparation of a kit for treating or ameliorating any disease mediated by NLRP3 in a subject in need thereof, the kit comprising a compound of Formula I-XI or a form thereof and an effective amount of the compound of Formula I-XI or a form thereof, and optionally instructions for administering to the subject an effective amount of the compound of Formula I-XI or a form thereof in a combination product with an effective amount of one or more therapeutic agents, and optionally in combination therapy with standard of care supportive care, where the standard of care supportive care is palliative care. In one respect, in each such embodiment, the subject is treatment naive. In another respect, in each such embodiment, the subject is not treatment naive. As used herein, the term "preventing" refers to keeping a disease, disorder, or condition from occurring in a subject who may be predisposed to the disease, disorder, and / or condition, but who has not yet been diagnosed with the disease, disorder, and / or condition. As used herein, the term "treating" refers to inhibiting the progression of a disease, disorder, or condition in a subject who already exhibits symptoms of the disease, disorder, and / or condition, i.e., halting the development of the disease, disorder, and / or condition in an already affected subject. As used herein, the term "ameliorating" refers to reducing the symptoms of a disease, disorder, or condition in a subject who already exhibits symptoms of the disease, disorder, and / or condition, i.e., causing regression of the disease, disorder, and / or condition that has already affected the subject.

[0308] As used herein, the term "subject" refers to an animal or any living organism that has sensation and the power of voluntary movement and requires oxygen and organic food. Non-limiting examples include humans, primates, horses, pigs, cows, mice, rats, dogs, and members of the cat species. In certain aspects, the subject is a mammal or warm-blooded vertebrate. In other aspects, the subject is a human. As used herein, the term "patient" may be used interchangeably with "subject" and "human." As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of Formulas I-XI or a form, composition, or medicament thereof that achieves a target plasma concentration effective to treat or ameliorate any disease mediated by NLRP3 described herein, and thus produces the desired therapeutic, ameliorative, inhibitory, or preventative effect in a subject in need thereof. In one aspect, an effective amount can be the amount required to treat any disease mediated by NLRP3 in a subject or patient, more particularly in a human.

[0309] In another aspect, the concentration-biological effect relationships observed for compounds of Formulas I-XI or forms thereof indicate target plasma concentrations ranging from about 0.001 μg / mL to about 50 μg / mL, from about 0.01 μg / mL to about 20 μg / mL, from about 0.05 μg / mL to about 10 μg / mL, or from about 0.1 μg / mL to about 5 μg / mL. To achieve such plasma concentrations, the compounds described herein may be administered at varying doses, including but not limited to, from 1.0 ng to 10,000 mg.

[0310] In one aspect, the dose administered to achieve an effective target plasma concentration can be based on subject or patient specific factors, and the dose administered on a weight basis can be: about 0.001 mg / kg / day to about 3500 mg / kg / day, or about 0.001 mg / kg / day to about 3000 mg / kg / day, or about 0.001 mg / kg / day to about 2500 mg / kg / day, or about 0.001 mg / kg / day to about 2000 mg / kg / day, or about 0.001 mg / kg / day to about 1500 mg / kg / day, or about 0.001 mg / kg / day to about 1000 mg / kg / day, or about 0.001 mg / kg / day to about 500 mg / kg / day, or about 0.001 mg / kg / day to about 250 mg / kg / day, or about 0.001 mg / kg / day to about 200 mg / kg / day kg / day, or about 0.001 mg / kg / day to about 150 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day, or about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 50 mg / kg / day, or about 0.001 mg / kg / day to about 25 mg / kg / day, or about 0.001 mg / kg / day to about 10 mg / kg / day, or about 0.001 mg / kg / day to about 5 mg / kg / day, or about 0.001 mg / kg / day to about 1 mg / kg / day, or about 0.001 mg / kg / day to about 0.5 mg / kg / day, or is from about 0.001 mg / kg / day to about 0.1 mg / kg / day, or from about 0.01 mg / kg / day to about 3500 mg / kg / day, or from about 0.01 mg / kg / day to about 3000 mg / kg / day, or from about 0.01 mg / kg / day to about 2500 mg / kg / day, or from about 0.01 mg / kg / day to about 2000 mg / kg / day, or from about 0.01 mg / kg / day to about 1500 mg / kg / day, or from about 0.01 mg / kg / day to about 1000 mg / kg / day, or from about 0.01 mg / kg / day to about 500 mg / kg / day, or from about 0.01 mg / kg / day to about 250 mg / kg / day, or About 0.01 mg / kg / day to about 200 mg / kg / day, or about 0.01 mg / kg / day to about 150 mg / kg / day, or about 0.01 mg / kg / day to about 100 mg / kg / day, or about 0.01 mg / kg / day to about 75 mg / kg / day, or about 0.01 mg / kg / day to about 50 mg / kg / day, or about 0.01 mg / kg / day to about 25 mg / kg / day, or about 0.01 mg / kg / day to about 10 mg / kg / day, or about 0.01 mg / kg / day to about 5 mg / kg / day, or about 0.01 mg / kg / day to about 1 mg / kg / day, or about 0.01 mg / kg / day to about 0.5 mg / kg / day, or about 0.01 mg / kg / day to about 0.1 mg / kg / day, or about 0.1 mg / kg / day to about 3500 mg / kg / day, or about 0.1 mg / kg / day to about 3000 mg / kg / day, or about 0.1 mg / kg / day to about 2500 mg / kg / day, or about 0.1 mg / kg / day to about 2000 mg / kg / day, or about 0.1 mg / kg / day to about 1500 mg / kg / day, or about 0.1 mg / kg / day to about 1000 mg / kg / day, or about 0.1 mg / kg / day to about 500 mg / kg / day, or about 0.1 mg / kg / day to about 250 mg / kg / day, or about 0. It may range from 1 mg / kg / day to about 200 mg / kg / day, or from about 0.1 mg / kg / day to about 150 mg / kg / day, or from about 0.1 mg / kg / day to about 100 mg / kg / day, or from about 0.1 mg / kg / day to about 75 mg / kg / day, or from about 0.1 mg / kg / day to about 50 mg / kg / day, or from about 0.1 mg / kg / day to about 25 mg / kg / day, or from about 0.1 mg / kg / day to about 10 mg / kg / day, or from about 0.1 mg / kg / day to about 5 mg / kg / day, or from about 0.1 mg / kg / day to about 1 mg / kg / day, or from about 0.1 mg / kg / day to about 0.5 mg / kg / day.

[0311] The effective amount for a given subject can be determined by routine experimentation within the skill and judgment of the clinician or skilled artisan, taking into account subject-related factors. Dosage regimens can be adjusted to provide sufficient levels of active agent or to maintain a desired effect. Factors that can be considered include genetic screening, severity of the disease state, status of disease progression, the subject's overall health, ethnicity, age, weight, sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, experience with other therapies, and tolerance / response to treatment. The dose administered to achieve an effective target plasma concentration may be administered orally once (approximately once every 24 hours; i.e., "qd"), twice (approximately once every 12 hours; i.e., "bid" or "q.12h"), three times (approximately once every 8 hours; i.e., "tid" or "q.8h"), or four times (approximately once every 6 hours; i.e., "qds", "qid" or "q.6h") daily. In certain embodiments, the dose administered to achieve an effective target plasma concentration may also be administered in single, divided, or continuous doses to patients or subjects having a weight ranging from about 40 kg to about 200 kg (doses may be adjusted for patients or subjects above or below this range, particularly children below 40 kg). A typical adult subject is expected to have a median weight in the range of about 70 kg. Long-acting pharmaceutical compositions may be administered every 2, 3, or 4 days, weekly, or biweekly, depending on the half-life and clearance rate of the particular formulation.

[0312] The compounds and compositions described herein can be administered to a subject via any drug delivery route known in the art, including, but not limited to, oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and injection), intracerebral, and pulmonary routes of administration. In another aspect, the administered dose can be adjusted based on a dosage form described herein formulated for delivery of about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000 or 4000 mg / day. For any compound, the effective dose can be estimated initially in cell culture assays or in relevant animal models, such as mice, guinea pigs, chimpanzees, marmosets, or tamarins. Relevant animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. The efficacy and toxicity of therapeutic agents can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50(the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and the LD 50 / ED 50 In certain embodiments, an effective amount is such that a high therapeutic index is achieved. In further detailed embodiments, the dosage is such that an ED 50 The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0313] In one aspect, provided herein is a method for modulating the amount of NLRP3, comprising contacting a human cell with a compound of Formulas I-XI or a form thereof. In a particular aspect, provided herein is a method for modulating the expression of NLRP3, comprising contacting a human cell with a compound of Formulas I-XI or a form thereof. The human cell can be contacted with a compound of Formulas I-XI or a form thereof in vitro or in vivo, e.g., in a non-human animal or in a human. In a particular aspect, the human cell is from or in a human. In another particular aspect, the human cell is from or in a human having any disease modulated by NLRP3. In another particular aspect, the human cell is from or in a human having any disease modulated by NLRP3 caused by a loss of NLRP3 expression and / or function. In another aspect, the human cell is from a human having any disease modulated by NLRP3. In another aspect, the human cell is in a human having any disease modulated by NLRP3. In one embodiment, the compound is in the form of a compound of Formula I-XI.

[0314] In certain aspects, provided herein are methods for improving inhibition of mutant NLRP3 transcribed from the NLRP3 gene, comprising contacting a human cell with a compound of Formulas I-XI or a form thereof. The human cell can be contacted with a compound of Formulas I-XI or a form thereof in vitro or in vivo, e.g., in a non-human animal or in a human. In certain aspects, the human cell is from or within a human. In another particular aspect, the human cell is from or within a human with any disease modulated by NLRP3. In another particular aspect, the human cell is from or within a human with HD caused by a CAG repeat in the NLRP3 gene resulting in the loss of wild-type "normal" NLRP3 expression and / or function. In another aspect, the human cell is from or within a human with any disease modulated by NLRP3. In another aspect, the human cell is from or within a human with any disease modulated by NLRP3. In one aspect, the compound is in the form of a compound of Formulas I-XI.

[0315] In another aspect, provided herein are methods for modulating the inhibition of mutant NLRP3 transcribed from the NLRP3 gene, comprising administering a compound of Formulas I-XI, or a form thereof, to a non-human animal model for any disease modulated by NLRP3. In certain aspects, provided herein are methods for modulating the inhibition of mutant NLRP3 transcribed from the HNLRP3 gene, comprising administering a compound of Formulas I-XI, or a form thereof, to a non-human animal model for any disease modulated by NLRP3. In certain aspects, the compound is in the form of a compound of Formulas I-XI.

[0316] In another aspect, provided herein are methods for reducing the amount of mutant NLRP3, comprising contacting a human cell with a compound of Formulas I-XI or a form thereof. In a particular aspect, provided herein are methods for reducing the amount of mutant NLRP3, comprising contacting a human cell with a compound of Formulas I-XI that inhibits transcription of mutant NLRP3 from the NLRP3 gene. In another particular aspect, provided herein are methods for reducing the amount of NLRP3, comprising contacting a human cell with a compound of Formulas I-XI that inhibits expression of mutant NLRP3 transcribed from the NLRP3 gene. The human cell can be contacted with a compound of Formulas I-XI or a form thereof in vitro or in vivo, for example, in a non-human animal or in a human. In a particular aspect, the human cell is from or in a human. In another particular aspect, the human cell is from or in a human having any disease modulated by NLRP3. In another particular aspect, the human cell is from or in a human having any disease modulated by NLRP3. In another embodiment, the human cell is from a human having any disease modulated by NLRP3. In another embodiment, the human cell is in a human having any disease modulated by NLRP3. In one embodiment, the compound is in the form of a compound of Formulas I-XI.

[0317] In certain embodiments, treating or ameliorating any disease modulated by NLRP3 with a compound of Formulas I-XI or a form thereof (alone or in combination with an additional agent) has a therapeutic and / or beneficial effect. In certain embodiments, treating any disease modulated by NLRP3 with a compound of Formulas I-XI or a form thereof (alone or in combination with an additional agent) can result in the following effects: (i) reducing or ameliorating the severity of any disease modulated by NLRP3, (ii) delaying the onset of any disease modulated by NLRP3, (iii) inhibiting the progression of any disease modulated by NLRP3, (iv) reducing the hospitalization of a subject, (v) reducing the length of hospitalization of a subject, (vi) increasing the survival rate of a subject, (vii) improving the quality of life of a subject, (viii ... (ix) reducing the number of symptoms associated with any disease modulated by NLRP3; (x) reducing the severity or amelioration of symptoms associated with any disease modulated by NLRP3; (xi) preventing the recurrence of symptoms associated with any disease modulated by NLRP3; (xii) inhibiting the onset or onset of symptoms of any disease modulated by NLRP3; and / or (xiii) inhibiting the progression of symptoms associated with any disease modulated by NLRP3.

[0318] Metabolites Another aspect included within the scope of this specification is the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, or esterification of the administered compound, primarily through enzymatic processes. Thus, the specification includes the use of compounds produced by a process comprising contacting a compound described herein with mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically include radiolabeled isotopologues of the compounds described herein (e.g., 14 C or3 The radiolabeled compounds are identified by preparing a radioactive isotope (H), administering a detectable dose (e.g., greater than about 0.5 mg / kg) of the radiolabeled compound to a mammal, such as a rat, mouse, guinea pig, dog, monkey, or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic transformation products from urine, bile, blood, or other biological samples. Because the transformation products are "radiolabeled" by virtue of being isotopically enriched, they are readily isolated (others are isolated by the use of antibodies capable of binding to antigenic determinants surviving on the metabolites). The structures of the metabolites are determined in conventional manner, for example, by MS or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The transformation products are useful in diagnostic assays for therapeutic administration of the compounds described herein, even if they do not themselves possess biological activity unless otherwise found in vivo.

[0319] Pharmaceutical Composition In accordance with the intended scope of the present specification, embodiments of the present specification include compounds that have been identified and demonstrated to be useful for selectively preventing, treating, or ameliorating any disease modulated by NLRP3, and obtained for use as one or more pharmaceutical compositions for preventing, treating, or ameliorating any disease modulated by NLRP3. Aspects herein include the use of a compound of Formula I-XI or a form thereof in the preparation of a pharmaceutical composition for treating or ameliorating any disease modulated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I-XI or a form thereof, in admixture with one or more pharmaceutically acceptable excipients. Aspects of the present specification include the use of a compound of Formula I-XI or a pharmaceutical composition in that form in the preparation of a kit for treating or ameliorating any disease modulated by NLRP3 in a subject in need thereof, the kit comprising a compound of Formula I-XI or a pharmaceutical composition in that form and instructions for administering the pharmaceutical composition.

[0320] As used herein, the term "composition" means a product that includes specified ingredients in specified amounts, as well as specified amounts of any products that are derived directly or indirectly from the combination of specified ingredients. Pharmaceutical compositions can be formulated to achieve a physiologically compatible pH ranging from about pH 3 to about pH 11. In certain embodiments, pharmaceutical compositions are formulated to achieve a pH of about pH 3 to about pH 7. In other embodiments, pharmaceutical compositions are formulated to achieve a pH of about pH 5 to about pH 8. The term "pharmaceutically acceptable excipient" refers to an excipient for administering a pharmaceutical agent, e.g., a compound described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. A pharmaceutically acceptable excipient may be determined in part by the particular composition to be administered, as well as by the particular mode of administration and / or dosage form. Non-limiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, and the like. Accordingly, there is a wide variety of formulations of pharmaceutical compositions suitable for the compounds described herein (see, e.g., Remington's Pharmaceutical Sciences).

[0321] Suitable excipients may be carrier molecules, including large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and ...

Claims

1. A compound or a form thereof having a structure of formula Xb or Xc, wherein the form of the compound is selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers and isotopically enriched forms thereof. 【Chemistry 9】 (In the formula, Y is NR 1b or a bond, Each R wa is hydroxyl, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkoxy or halo-C 1-4 is an alkoxy; Each R 1b are independently hydrogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, halo-C 1-4 Alkyl or hydroxy C 1-4 is alkyl, Each Z is heterocyclyl, heteroaryl, aryl, C 3-10 Cycloalkyl, C 1-4 Alkyl, deutero-C 1-4 Alkyl, halo-C 1-4 Alkyl, hydroxy-C 1-8 Alkyl, NH(hydroxy-C 1-6 alkyl), NH(C 1-6 alkoxy), and each Z is OH, NH 2 , -CO 2 H, halogen, C 1 - 6 Alkyl, C 1 - 6 Haloalkyl, C 1 - 6 Hydroxyalkyl, C 2 - 6 Acyl, C 2 - 6 Alkanoic acid, C 2 - 6 alkanoate ester or heterocyclyl, wherein the heterocyclyl is R 2 a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R 2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkyl-amino, (C 1-6 alkyl) 2 -amino, halo-C 1-4 Alkyl-amino, (halo-C 1-6 alkyl) 2 -amino, hydroxy-C 1-4 alkyl, hydroxy-C 1-4 Alkyl-amino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, amino-C 1-4 Alkyl, C 1-4 Alkyl-amino-C 1-4 Alkyl, (C 1-4 alkyl-amino) 2 -C 1-4 Alkyl, C 1-4 Alkoxy, halo-C 1-4 Alkoxy, hydroxy-C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl-amino-C 1-4 Alkyl, heteroaryl-C 1-4 Alkyl, heteroaryl-amino, heteroaryl-C 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C 1-4 Alkyl, heterocyclyl-amino, heterocyclyl-amino-C 1-4 Alkyl, heterocyclyl-C 1 - 4 Alkoxy, heterocyclyl-amino-C 3-10 Cycloalkyl, phenyl and phenyl-C 1-4 independently selected from alkoxy; heteroaryl is a 5-6 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3 or 4 heteroatom ring members independently selected from N, O or S; heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic, 6- to 10-membered bicyclic, or 13- to 16-membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S; C 3-10 cycloalkyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system; Phenyl, heteroaryl, heterocyclyl or C 3-10 Each instance of cycloalkyl is R 3 and optionally substituted with one or two substituents each selected from R 3 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkoxy and halo-C 1-4 independently selected from alkoxy; R' is H, substituted or unsubstituted cycloalkyl, hydroxyl, C 1-4 alkyl, deutero-C 1-4 alkyl, amino, C 1-4 alkyl-amino, (C 1-6 alkyl) 2 -amino, amino-C 1-4 alkyl, nitro, C 1-4 alkyl-carbonyl, C 1-4 alkylthio, halo-C 1-4 Alkyl, haloalkoxy, halogen, C 1-6 Alkoxy, cyano, hydroxy C 1-4 Alkyl or C 1-4 aryl optionally substituted by alkyl; R 4 is hydrogen, halogen, hydroxyl, cyano, halo-C 1-4 alkyl or C 1-4 independently selected from alkyl, m is 1, 2, 3, 4 or 5; n is 0, 1, 2 or 3.

2. Structure 【Chemistry 12】 The part having 【Chemistry 13】 is selected from R' is halogen, hydroxyl, cyano, nitro, C 1-4 Alkyl, deutero-C 1-4 Alkyl, halo-C 1-4 Alkyl, amino, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -amino, amino-C 1-4 Alkyl, hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, halo-C 1-4 Alkoxy and C 3-10 cycloalkyl; Y and Z, when taken together, are 【Chemistry 14】 is selected from R 4 is hydrogen, C 1-4 Alkyl, halogen and halo-C 1 - 4 alkyl, R 8 is C 1-4 Alkyl, CH 2 CH 2 OH, CH 2 CH 2 OCF 3 , C.H. 2 CH 2 OCHF 2 and CH 2 CH 2 C(CH 3 ) 2 OH, R 9 , R 9a , R 9b is hydrogen or C 1-4 Alkyl or C 3-6 cycloalkyl; 9a and C 9b may be cyclized to form a 3- to 6-membered ring m is 1, 2, 3, 4 or 5; n is 0, 1, 2 or 3; X is O or NR 8 2. The compound of claim 1, or a form thereof, wherein:

3. Structure 【Chemistry 15】 The part having 【Chemistry 16】 3. The compound or a form thereof according to claim 2, selected from:

4. When Y and Z are together, 【Chemistry 17】 4. The compound or a form thereof according to claim 3, selected from:

5. 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}thieno[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol; 2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 2-{4-[(pyrrolidin-3-yl)amino]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(7-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(2H-1,2,3-triazol-2-yl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)benzene-1,3-diol; 5-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 4-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 4-fluoro-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]oxy}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-1-methylpiperidin-3-yl]oxy}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-methyl-4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 3-hydroxy-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)benzonitrile; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-methyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-fluoro-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]oxy}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(piperidin-3-yl)methyl]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-(5-methyl-1,2,4-thiadiazol-3-yl)-2-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(1H-1,2,3-triazol-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(5-methyl-1,2,4-thiadiazol-3-yl)phenol; 4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)[1,1′-biphenyl]-3-ol; 3-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)[1,1′-biphenyl]-4-ol; 4,5-dimethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2,3-dimethyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(1-methylpiperidin-3-yl)methyl]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-(7,7-dimethyl-4-{[(3R)-piperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(7,7-dimethyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{methyl[(3R)-1-methylpiperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-fluoro-3-methyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-(5,6-dihydro-2H-pyran-3-yl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; (3S,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-3-ol; 2-(1-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-(3,6-dihydro-2H-pyran-4-yl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-(2,5-dihydrofuran-3-yl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-chloro-2-(1-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)phenol; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(oxolan-3-yl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol; (3S,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)-1-methylpiperidin-3-ol; 1-[3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-1-yl]ethan-1-one; ethyl [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-1-yl]acetate, 2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol; 2-[4-({[(2S)-pyrrolidin-2-yl]methyl}amino)phthalazin-1-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-Methoxy-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 4-hydroxy-5-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridine-2-carbonitrile; 3-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-6-(trifluoromethyl)pyridin-2-ol; 2-chloro-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-cyclopropyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 6-methyl-3-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)pyridin-2-ol; 5-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-2-(trifluoromethyl)pyridin-4-ol; 6-hydroxy-5-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridine-2-carbonitrile; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridin-3-ol; 2-methyl-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; (3R,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-3-ol; (3R,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)-1-methylpiperidin-3-ol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}furo[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol; 5-methyl-2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol; 2-[4-({[(2S)-1-methylpyrrolidin-2-yl]methyl}amino)phthalazin-1-yl]-5-(trifluoromethyl)phenol; 4-fluoro-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridin-3-ol; 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridin-3-ol; 3-hydroxy-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(pyrrolidin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(1-methyl-1H-pyrrol-3-yl)phenol; 2-{4-[(1-methylazepan-3-yl)amino]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-1-methylpiperidin-3-yl]methyl}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]methyl}phthalazin-1-yl)-5-(trifluoromethyl)phenol; [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-1-yl]acetic acid, 5-methyl-2-(1-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)phenol; 2-{1-[(piperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 2-(1-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol; 3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-chloro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(1-methylpyrrolidin-3-yl)phenol; 2-(4-{[2-(morpholin-4-yl)ethyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(azetidin-3-yl)amino]phthalazin-1-yl}-5-(trifluoromethyl)phenol; 2-[1-({[(2S)-pyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-[4-({[(2S)-pyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-({[(2S)-1-methylpyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-(4-{[2-(piperidin-1-yl)ethyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-[1-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-(4-methyl-5-{[(3R)-1-methylpiperidin-3-yl]amino}-3,4-dihydro-2H-pyridazino[4,5-b][1,4]oxazin-8-yl)-5-(trifluoromethyl)phenol; 2-{1-[(1-methylpiperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine; 4-[2-amino-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; N-[2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenyl]methanesulfonamide; 4-[2-(methylamino)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; N-[2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenyl]acetamide; 4-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-(4-chloro-2-fluorophenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzonitrile; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)benzonitrile; 1-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 1-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(2H-1,2,3-triazol-2-yl)phenol; 1-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-chloro-2-(4-{[(3S)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 3-hydroxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 3,5-dimethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 5-chloro-3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1H-pyrazolo[3,4-d]pyridazin-7-amine; 1-[2-(2,5-dihydrofuran-3-yl)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(1-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}-1H-pyrazolo[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 2-[4-({2-[(3R)-3-methylmorpholin-4-yl]ethyl}amino)phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-({2-[(3S)-3-methylmorpholin-4-yl]ethyl}amino)phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-(4-{[2-(piperazin-1-yl)ethyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(azetidin-2-yl)methyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-{1-[3-(dimethylamino)piperidin-1-yl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 4-[2-methoxy-4-(trifluoromethyl)phenyl]-1-(piperazin-1-yl)pyrido[3,4-d]pyridazine; 2-(1-methyl-8-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(1-methyl-8-{[(3S)-1-methylpiperidin-3-yl]amino}-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzene-1-sulfonamide; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 1-[4-cyclopropyl-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-methyl-5-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)pyridin-4-ol; 4-(2-methoxy-6-methylpyridin-3-yl)-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; 2-(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 1-{4-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-1-yl}-N,N-dimethylpiperidin-3-amine; 2-amino-3-chloro-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3S,5S)-5-fluoro-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 4-(2,3-difluoro-4-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 3-(difluoromethoxy)-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 1-[2-(difluoromethoxy)-3-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzene-1-sulfonamide; 5-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 1-[2-(difluoromethoxy)-4-methoxyphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)pyridin-3-ol; 1-[2-(methoxymethoxy)-4-(1,3-oxazol-2-yl)phenyl]-N-[(3S)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-methoxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3S)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(1,3-oxazol-2-yl)phenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-(difluoromethoxy)-5-fluoro-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-fluoro-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-{4-[(1-methyl-1H-pyrazol-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-[4-methoxy-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzamide; 5-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[2,3-d]pyridazin-8-amine; 8-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[2,3-d]pyridazin-5-amine; 2-{1-[(1-methylazepan-3-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-1-methylazepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylazepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; N-[(3R)-1-methylpiperidin-3-yl]-1-{2-[(oxetan-3-yl)oxy]-4-(trifluoromethyl)phenyl}pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; [2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenyl]methanol; 1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-(methanesulfonyl)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-cyclopropyl-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)pyridin-3-ol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-(4-chloro-2-fluoro-6-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(pyrimidin-2-yl)phenol; 1-{4-[2-methoxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}-N,N-dimethylpiperidin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[5-(trifluoromethyl)[1,1′-biphenyl]-2-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}phthalazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-6-(trifluoromethyl)pyridin-3-yl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-(2,4,6-trimethylphenyl)pyrido[3,4-d]pyridazin-4-amine; 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2,4-di(propan-2-yl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-(3-cyclopropyl-6-fluoro-2-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 6-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 6-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 6-chloro-3-fluoro-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)phenol; 2-{4-[(4-methyl-4-azaspiro[2.5]octan-7-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-cyclobutylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-(2,4-dimethylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-methyl-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile; 1-(4-chloro-2,6-dimethylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-cyclopropylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2,2,2-trifluoro-1-[3-hydroxy-4-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)phenyl]ethan-1-one; 1-(4-chloro-2,6-difluorophenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-fluoro-6-methyl-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-nitrophenol; 2-{4-[(1-methylpiperidin-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 5-(cyclopropylethynyl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 5-ethynyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(prop-1-yn-1-yl)phenol; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(prop-1-yn-1-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-{1-[(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 2-{1-[(1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-piperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(1-methyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-{4-[3-(dimethylamino)piperidin-1-yl]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-[4-(difluoromethyl)-2-methoxyphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 5-(cyclopropyloxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-[(3R)-3-({4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[4-chloro-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(pyridin-3-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 4-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 1-(2-cyclopropyl-4-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(1-methylpiperidin-2-yl)methyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 4-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 4-[2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 4-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 1-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[4-(difluoromethyl)-2-fluorophenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}thieno[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; N-[(3R)-azepan-3-yl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-{4-[(1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 2-{4-[(azepan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-(4-methoxy-2-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(3-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}[1,2]oxazolo[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}-3-methyl[1,2]oxazolo[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol; 2-[4-({(3R)-1-[3-(2,2-difluoroethyl)cyclobutyl]piperidin-3-yl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-[4-methoxy-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 4-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine; 2-{1-[(4-methyl-1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-azepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(4-methyl-1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 2-{4-[(1-methylazepan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 2-{4-[(1,4-dimethyl-1,4-diazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-5,5-difluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; ethyl (2S,5R)-5-({1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)piperidine-2-carboxylate, 3-Methoxy-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzene-1,3-diol; 2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3R)-3-hydroxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(oxetan-3-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-(4-cyclopropyl-2-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol; 3-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[2-(dimethylamino)-2-methylpropyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S,5S)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(oxan-4-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(oxolan-3-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethyl)-4-methoxyphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-[4-(cyclohexylamino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 1-[4-chloro-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-[2-methyl-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-methylpiperidin-3-yl]-1-{2-[(propan-2-yl)oxy]-4-(trifluoromethyl)phenyl}pyrido[3,4-d]pyridazin-4-amine; 2-(4-{methyl[(3R)-piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-({(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(3-fluoropropyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-[4-methoxy-2-(propan-2-yl)phenyl]-N-[(3S)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{methyl[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; N-[(3R)-1-methylpiperidin-3-yl]-1-[4-methyl-2-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-(difluoromethyl)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(4-{[(3R)-1-(1- 2 H) cyclobutylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S,4R)-4-fluoropiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1-methylpiperidin-4-yl)methyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-({[1-(2-hydroxyethyl)piperidin-4-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-fluoro-5-methyl-2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol; 2-(4-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-ethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol; 2-(4-{[(1R,3S)-3-methoxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-oxan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S)-oxan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-piperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; N-[(3R)-1-cyclobutylpiperidin-3-yl]-1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine; 2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}furo[2,3-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3S,4R)-4-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)azepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; ethyl (2S,5R)-5-({1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)-1-methylpiperidine-2-carboxylate, 1-[2-(difluoromethyl)-4-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 1-[2-(difluoromethyl)-5-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine; 2-(8-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}-1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; N-[(3R)-Azocan-3-yl]-1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-(oxan-4-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-cyclopropyl-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-methoxy-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-cyclopropyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(2-methyl-4-{[(3R)-piperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-7-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-bromo-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(2-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-7-yl)-5-(trifluoromethyl)phenol; 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-yl)-5-(trifluoromethyl)phenol; 5-methoxy-2-(2-methyl-4-{[(3R)-piperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-7-yl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-(oxan-4-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 3-fluoro-5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-(oxan-4-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-({(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluoro-5-methylphenol; 2-(4-{[(6S)-4-methyl-4-azaspiro[2.5]octan-6-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(2-cyclopropyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 2-(2-cyclopropyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-methoxyphenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-methoxy-2-(2-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-7-yl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-methoxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; 3-fluoro-5-methyl-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; (1S,3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)cyclohexan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(1R,3S)-3-methoxycyclohexyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-chloro-2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-methoxy-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 4-[4-bromo-2-(trifluoromethoxy)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 2-[(3R)-3-({4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-oxan-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; (1R,3S)-N 1 -{1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}cyclohexane-1,3-diamine; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 4-[4-methoxy-2-(trifluoromethyl)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 4-[2,4-bis(trifluoromethyl)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 1-(4-chloro-2-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; (3R,5R)-5-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylpiperidin-3-ol; 8-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,2-d][1,2,4]triazin-5-amine; (3R,5R)-5-{[1-(4-cyclopropyl-2-fluoro-6-hydroxyphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl]amino}-1-methylpiperidin-3-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-oxolan-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (2S)-1-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)propan-2-ol; 4-(4-bromo-2-methoxyphenyl)-N-[(3R)-piperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-bromo-2-(7-{[(3R)-piperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; N-[(3R)-1-ethylpiperidin-3-yl]-1-[4-methoxy-2-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoro-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-methyl-N-[(3R)-1-methylpiperidin-3-yl]-4-[4-methyl-2-(trifluoromethoxy)phenyl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 2-(4-{[(3R)-oxan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,2-d][1,2,4]triazin-8-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3S)-3-methoxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(1s,3s)-3-hydroxy-3-(trifluoromethyl)cyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-methoxy-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)benzonitrile; 2-(4-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-(trifluoromethyl)phenol; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol 3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 4-[4-cyclopropyl-2-(trifluoromethoxy)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 2-methyl-N-[(3R)-1-methylpiperidin-3-yl]-4-[2-(trifluoromethoxy)phenyl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-fluoro-5-methyl-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[2-(difluoromethyl)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (1s,3s)-3-({1-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-cyclopropyl-3-fluoro-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-(oxan-4-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-chloro-3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 2-{4-[(2-hydroxy-2-methylpropyl)amino]pyrrolo[1,2-d][1,2,4]triazin-1-yl}-5-(trifluoromethoxy)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoro-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (2R)-1-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)propan-2-ol; 2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 5-chloro-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 1-[4-chloro-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-(4-{[(3R)-1-(oxolan-3-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3S)-3-hydroxycyclopentyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1R,3R)-3-hydroxycyclopentyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-{4-[(3-hydroxy-3-methylcyclohexyl)amino]pyrrolo[1,2-d][1,2,4]triazin-1-yl}-5-(trifluoromethyl)phenol; 4-(4-bromo-2-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-bromo-2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-bromo-2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 2-[(3R)-3-({1-[4-methoxy-2-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 5-chloro-3-fluoro-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 3-fluoro-5-methoxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3S)-oxolan-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3S)-oxolan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-methyl-1,2,3,6-tetrahydropyridin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}[1,2,3]triazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R)-oxan-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (1s,3s)-3-({1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-cyclopropyl-3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[(3R)-3-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]-2-methylpropan-2-ol; 1-[2-(difluoromethoxy)-4-methoxyphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (1r,3r)-3-({1-[2-(difluoromethoxy)-4-methoxyphenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 2-(4-{[(2S)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-oxolan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R)-1-(oxan-4-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[(3R)-3-({1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]-2-methylpropan-2-ol; 3,5-dimethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3S,4S)-4-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-bromo-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3S,4R)-4-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-6-fluoro-4-methylphenyl]-N-[(3R)-1-(oxolan-3-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-5-methyl-2-(4-{[(3R)-1-(oxolan-3-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-bromo-2-(4-{[(3R)-piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-[(3R)-3-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; (2R)-1-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)propan-2-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-(propan-2-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-cyclopropyl-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-cyclopropyl-3-fluoro-2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[4-chloro-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol; 3-fluoro-2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methylphenol; 5-cyclopropyl-3-fluoro-2-(4-{[(2S)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-[( 2 H 3 )methyloxy]-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; 1-[4-bromo-2-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[4-chloro-2-(difluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[4-chloro-2-(difluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[4-cyclopropyl-2-(difluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 5-cyclopropyl-2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol; 2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 3-fluoro-5-[( 2 H 3 )methyloxy]-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-[( 2 H 3 ) methyloxy]phenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluoro-5-methylphenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-(oxan-4-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-(oxolan-3-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-chloro-2-(4-{[(3R)-oxan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; (1s,3s)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; (1S,3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)cyclohexan-1-ol; (1s,3s)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 2-(8-fluoro-4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-bromo-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-(propan-2-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-2-methylpropan-2-ol; (1s,3s)-3-({1-[2,4-bis(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; N-[(3R)-1-methylpiperidin-3-yl]-1-[4-methyl-2-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[4-cyclopropyl-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-2-methylpropan-2-ol; (1s,3s)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-2-{4-[(2-hydroxy-2-methylpropyl)amino]pyrrolo[1,2-d][1,2,4]triazin-1-yl}-5-methylphenol; 5-cyclopropyl-3-fluoro-2-{4-[(2-hydroxy-2-methylpropyl)amino]pyrrolo[1,2-d][1,2,4]triazin-1-yl}phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(6-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-bromo-2-(7-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 4-[2-(benzyloxy)-4-bromophenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-bromo-2-(7-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-bromo-2-(7-{[(3R)-oxan-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-bromo-2-(7-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-chloro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-methyl-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 3-fluoro-5-methoxy-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; 5-bromo-2-(4-{[(3R)-1-(1-hydroxypropan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluorophenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluoro-5-methoxyphenol; 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-chloro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 3-methyl-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(4-{[(3R)-oxolan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; 5-ethyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-bromo-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-{4-[(1-methylpiperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-(2-methoxy-2-methylpropyl)pyrrolo[1,2-d][1,2,4]triazin-4-amine; 3-fluoro-5-methyl-2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 3-fluoro-5-methyl-2-(4-{[(3R)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol; 2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; (1s,3s)-3-({1-[2,4-bis(difluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylcyclobutan-1-ol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 2-(4-{[(3R,5S)-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-cyclopropyl-2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-chloro-3-fluoro-2-(4-{[(2S)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluorophenol; 5-chloro-2-(4-{[(3S)-oxolan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-chloro-2-(4-{[(1R,3S)-3-methoxycyclohexyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluoro-5-methylphenol; 5-cyclopropyl-2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluorophenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethoxy)phenol; 4-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-amine; 5-cyclopropyl-2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-methoxyphenol; 2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 1-[2,4-bis(trifluoromethyl)phenyl]-N-{[(3S)-oxolan-3-yl]methyl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(trifluoromethyl)phenyl]-N-{[(3R)-oxolan-3-yl]methyl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-7-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoro-N-[(3R)-1-(propan-2-yl)piperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-(8-fluoro-4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-fluoro-4-{[(2S)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 2-(8-fluoro-4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; (3R,5R)-5-({8-fluoro-1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylpiperidin-3-ol; 2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 5-cyclopropyl-2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-3-fluoro-2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-cyclopropyl-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; (3R,5R)-5-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-8-fluoropyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-ethylpiperidin-3-ol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; (3R,5R)-1-ethyl-5-({8-fluoro-1-[2-hydroxy-4-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-3-ol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-fluoro-2-(7-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-(4-{[(3R)-oxan-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-{[(2S)-oxolan-2-yl]methyl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-{[(2R)-oxolan-2-yl]methyl}pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 1-[2,4-bis(difluoromethoxy)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 2-[(3R)-3-({1-[2,4-bis(difluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol; 1-[2,4-bis(difluoromethoxy)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazin-4-amine; 5-(difluoromethoxy)-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-(difluoromethoxy)-3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-(difluoromethoxy)-3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-(difluoromethoxy)-2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-chloro-2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol; 5-chloro-3-fluoro-2-(4-{[(oxolan-2-yl)methyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-bromo-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazin-4-amine; 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol; 5-bromo-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-bromo-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol; 5-ethoxy-3-fluoro-2-(4-{[(1s,3s)-3-hydroxy-3-methylcyclobutyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-ethoxy-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 5-ethoxy-3-fluoro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-methoxyphenol; 2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-methylphenol; 5-methoxy-2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol; (R)-2-(4-((1-ethylpiperidin-3-yl)amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3,5-dimethylphenol; (3S,5R)-5-((1-(2-fluoro-6-hydroxy-4-methylphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-methylpiperidin-3-ol; (3S,5R)-1-ethyl-5-((1-(2-fluoro-6-hydroxy-4-methylphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)piperidin-3-ol; (3S,5R)-5-((1-(4-cyclopropyl-2-fluoro-6-hydroxyphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-methylpiperidin-3-ol; and A compound or a form thereof selected from the group consisting of (3S,5R)-5-((1-(4-cyclopropyl-2-fluoro-6-hydroxyphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-ethylpiperidin-3-ol, wherein the compound or a form thereof is selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomeric form thereof.

6. 2-{4-[(pyrrolidin-3-yl)amino]phthalazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol hydrochloride, 2-(8-methyl-4-{[(3R)-piperidin-3-yl]amino}-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-{4-[(piperidin-3-yl)methyl]phthalazin-1-yl}-5-(trifluoromethyl)phenol hydrochloride, 2-(4-{[(3R)-piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol diformate, 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-{4-[(1-methylpiperidin-3-yl)methyl]phthalazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenol formate, (3S,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-3-ol formate, 2-(1-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol N-ethylethanamine, 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol diformate, (3S,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)-1-methylpiperidin-3-ol formate, 2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol formate, (3R,5R)-5-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-3-ol formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}furo[2,3-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol formate, 5-methyl-2-(8-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-5-yl)phenol formate, [(3R)-3-({4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl}amino)piperidin-1-yl]acetic acid formate, 2-{1-[(piperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol hydrochloride, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(1-methylpyrrolidin-3-yl)phenol formate, 2-[1-({[(2S)-pyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol formate, 2-[4-({[(2S)-pyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate, 2-[4-({[(2S)-1-methylpyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate, 2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate, 2-{1-[(1-methylpiperidin-3-yl)methyl]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol formate, 1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine formate, 4-[2-amino-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, N-[2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenyl]methanesulfonamidoformate, 4-[2-(methylamino)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, N-[2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(trifluoromethyl)phenyl]acetamidoformate, 1-[2-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 1-(4-chloro-2-fluorophenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 1-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[4-chloro-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, 1-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, 1-[2-chloro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 4-[2-methoxy-4-(trifluoromethyl)phenyl]-1-methyl-N-[(3R)-1-methylpiperidin-3-yl]-1H-pyrazolo[3,4-d]pyridazin-7-amine formate, 2-(1-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}-1H-pyrazolo[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol formate, 2-(1-methyl-8-{[(3R)-1-methylpiperidin-3-yl]amino}-1,2,3,4-tetrahydropyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol triformate, 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile formate, 2-amino-3-chloro-6-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol formate, 4-(2,3-difluoro-4-methylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]phthalazin-1-amine formate, 5-methoxy-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 1-[2,4-bis(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 1-[4-methoxy-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)benzamidoformate, 5-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[2,3-d]pyridazin-8-amine formate, 8-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[2,3-d]pyridazin-5-amine formate, 2-{1-[(1-methylazepan-3-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-methylazepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate, [2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenyl]methanol formate, N-[(3R)-1-methylpiperidin-3-yl]-1-(2,4,6-trimethylphenyl)pyrido[3,4-d]pyridazin-4-amine formate, 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)piperidin-1-yl]ethan-1-ol formate, 6-chloro-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 6-chloro-3-fluoro-2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[2,3-d]pyridazin-8-yl)phenol formate, N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate, 3-methyl-4-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzonitrile formate, 1-(4-chloro-2,6-dimethylphenyl)-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 2,2,2-trifluoro-1-[3-hydroxy-4-(4-{[(3R)-piperidin-3-yl]amino}phthalazin-1-yl)phenyl]ethan-1-one formate, 5-(cyclopropylethynyl)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)phenol formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}phthalazin-1-yl)-5-(prop-1-yn-1-yl)phenol formate, N-[(3R)-1-methylpiperidin-3-yl]-1-[2-(prop-1-yn-1-yl)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate, 2-{1-[(1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-4-yl}-5-(trifluoromethyl)phenol formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-piperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]pyrido[3,4-d]pyridazin-1-amine formate, 4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine formate, 5-(cyclopropyloxy)-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 2-[(3R)-3-({4-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-1-yl}amino)piperidin-1-yl]ethan-1-ol formate, 4-[2-(difluoromethoxy)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine formate, 4-[2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine formate, 4-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine formate, 1-[4-cyclopropyl-2-(difluoromethoxy)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 1-[4-cyclopropyl-2-(difluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, N-[(3R)-azepan-3-yl]-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate, 2-{4-[(1,4-oxazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-{4-[(azepan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-(3-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}[1,2]oxazolo[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}-3-methyl[1,2]oxazolo[4,5-d]pyridazin-7-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-azepan-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-{4-[(1-methylazepan-4-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol formate, 2-{4-[(1,4-dimethyl-1,4-diazepan-6-yl)amino]pyrido[3,4-d]pyridazin-1-yl}-5-(trifluoromethyl)phenol formate, ethyl (2S,5R)-5-({1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl}amino)piperidine-2-carboxylate hydrochloride, 5-methyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)benzene-1,3-diol formate, 2-(4-{[(1R,3S)-3-hydroxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(1R,3R)-3-hydroxycyclohexyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol formate, 2-(4-{[2-(dimethylamino)-2-methylpropyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-amine formate, 2-(4-{[(3S,5S)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 5-chloro-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 5-cyclopropyl-3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 3-fluoro-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, 2-[4-({(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 1-[2-(difluoromethyl)-4-methylphenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrido[3,4-d]pyridazin-4-amine formate, 2-(4-{[(1-methylpiperidin-4-yl)methyl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-[4-({[1-(2-hydroxyethyl)piperidin-4-yl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol formate, 5-ethyl-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol formate, N-{(3R)-1-[2-(difluoromethoxy)ethyl]piperidin-3-yl}-1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazine-4-amine formate, 2-[(3R)-3-({1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)piperidin-1-yl]ethan-1-ol formate, 2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 1-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazine-4-amine formate, 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol hydrochloride, 1-(4-chloro-2-methoxyphenyl)-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazine-4-amine formate, 5-chloro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, 8-[2-methoxy-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,2-d][1,2,4]triazine-5-amine formate, (3R,5R)-5-{[1-(4-cyclopropyl-2-fluoro-6-hydroxyphenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl]amino}-1-methylpiperidin-3-ol formate, 4-(4-bromo-2-methoxyphenyl)-N-[(3R)-piperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazine-7-amine formate, 2-(4-{[(3R)-oxan-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(5-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,2-d][1,2,4]triazin-8-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R,5R)-5-fluoropiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol hydrochloride, 4-[4-cyclopropyl-2-(trifluoromethoxy)phenyl]-2-methyl-N-[(3R)-1-methylpiperidin-3-yl]pyrazolo[1,5-d][1,2,4]triazine-7-amine formate, 2-methyl-N-[(3R)-1-methylpiperidin-3-yl]-4-[2-(trifluoromethoxy)phenyl]pyrazolo[1,5-d][1,2,4]triazine-7-amine formate, 2-(4-{[(2R)-2-hydroxypropyl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol hydrochloride, 2-(8-fluoro-4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol hydrochloride, 5-chloro-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, 5-chloro-3-fluoro-2-(2-methyl-7-{[(3R)-1-methylpiperidin-3-yl]amino}pyrazolo[1,5-d][1,2,4]triazin-4-yl)phenol formate, 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3S)-oxolan-3-yl]pyrrolo[1,2-d][1,2,4]triazine-4-amine formate, 2-(4-{[(3R)-1-methyl-1,2,3,6-tetrahydropyridin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(7-{[(3R)-1-methylpiperidin-3-yl]amino}[1,2,3]triazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3S,4S)-4-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(4-{[(3R)-1-(propan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 1-[2-(difluoromethoxy)-6-fluoro-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazine-4-amine formate, 1-[4-chloro-2-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]pyrrolo[1,2-d][1,2,4]triazine-4-amine formate, 5-cyclopropyl-2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluorophenol formate, 2-(4-{[(3R)-1-(2,2-difluoroethyl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-3-fluoro-5-methylphenol formate, 2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(6-methyl-4-{[(3R)-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 5-bromo-2-(4-{[(3R)-1-(1-hydroxypropan-2-yl)piperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol formate, 5-cyclopropyl-2-(7-{[(3R)-1-ethylpiperidin-3-yl]amino}-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-yl)-3-fluorophenol formate, 5-chloro-2-(4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, 5-ethyl-3-fluoro-2-(4-{[(3R)-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol formate, 5-bromo-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)phenol formate, 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-ethylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazine-4-amine formate, 2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluoro-5-methylphenol formate, 5-cyclopropyl-2-[4-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}amino)pyrrolo[1,2-d][1,2,4]triazin-1-yl]-3-fluorophenol formate, 2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, 2-(8-fluoro-4-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol formate, (3R,5R)-5-({8-fluoro-1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-yl}amino)-1-methylpiperidin-3-ol formate, 2-(4-{[(3R,5R)-1-ethyl-5-fluoropiperidin-3-yl]amino}-8-fluoropyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethoxy)phenol formate, 5-bromo-2-(4-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, 1-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-N-[(3R)-1-methylpiperidin-3-yl]imidazo[1,5-d][1,2,4]triazine-4-amine formate and 5-bromo-2-(4-{[(3R)-1-ethylpiperidin-3-yl]amino}imidazo[1,5-d][1,2,4]triazin-1-yl)phenol formate, or a form thereof, wherein the compound salt form is selected from the group consisting of a hydrate, a solvate, a racemate, an enantiomer, a diastereoisomer, a stereoisomer, and a tautomer thereof.

7. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1, 5 and 6 or a form thereof, and one or more pharmaceutically acceptable carriers, diluents and excipients.

8. 8. The pharmaceutical composition of claim 7 for treating or alleviating a disease modulated by NLRP3 in a subject in need thereof, wherein the treatment or alleviation comprises administering to the subject an effective amount of the compound.

9. The disease is Alzheimer's disease, frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, perioperative neurocognitive disorder, post-cardiac arrest cognitive impairment, post-stroke 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 erythematosus-lupus nephritis, cryopyrin-associated periodic fever syndrome (CAPS), cystic fibrosis, sickle cell disease, VCP-related disease, hepatic fibrosis, non-alcoholic fatty liver disease (NASH), muscle atrophy, genetic 9. The pharmaceutical composition of claim 8, wherein the disease is selected from hereditary and acquired myopathies, Duchenne muscular dystrophy (DMD), hyperalgesia, multiple sclerosis-associated neuropathic pain, acute kidney injury, chronic crystalline nephropathy, chronic kidney disease, asthma and allergic airway inflammation, diabetes-associated atherosclerosis, diabetic encephalopathy, diabetic kidney disease, pancreatic islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

10. 8. The pharmaceutical composition of claim 7, wherein the effective amount of the compound or a form thereof ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

11. 10. Use of a compound according to any one of claims 1 to 6 in the preparation of a pharmaceutical composition for treating or ameliorating a disease modulated by NLRP3 in a subject in need thereof, wherein treating or ameliorating comprises administering to the subject an effective amount of the compound or a form thereof in admixture with one or more pharmaceutically acceptable excipients.

12. The disease is Alzheimer's disease, frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, perioperative neurocognitive disorder, post-cardiac arrest cognitive impairment, post-stroke 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 erythematosus-lupus nephritis, cryopyrin-associated periodic fever syndrome (CAPS), cystic fibrosis, sickle cell disease, VCP-related disease, hepatic fibrosis, non-alcoholic fatty liver disease ( 12. The use of claim 11, wherein the condition is selected from NASH), muscle atrophy, hereditary and acquired myopathies, hyperalgesia, multiple sclerosis-associated neuropathic pain, acute kidney injury, chronic crystalline nephropathy, chronic kidney disease, asthma and allergic airway inflammation, diabetes-associated atherosclerosis, diabetic encephalopathy, diabetic kidney disease, pancreatic islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

13. The use of claim 11, wherein the effective amount of the compound is in the range of about 0.001 mg / kg / day to about 500 mg / kg / day.

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