Inhibitors of NLRP3

Abstract

The present invention relates to compounds useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway, methods for preparing said compounds, pharmaceutical compositions comprising said compounds, methods of using said compounds and medicaments containing them in the treatment of various diseases and disorders, and their use in diseases and disorders mediated by NLRP3.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to PCT Application No. PCT / US2022 / 075421, filed August 24, 2022, and U.S. Provisional Application No. 63 / 311,463, filed February 18, 2022, the contents of which are incorporated by reference in their entirety and for any purpose. 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 said compounds, pharmaceutical compositions containing said compounds, methods of using said compounds and medicaments containing them in the treatment of various diseases and disorders, and their use in diseases 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 that includes nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), the adaptor apoptosis-associated speck-like protein (ASC) that contains a caspase recruitment domain, and the effector protease caspase-1. Assembly of the complex 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 a variety of infectious and non-infectious molecules, including molecular by-products of aging, physical inactivity, and nutritional excess. When activated, it enhances downstream production of the inflammatory 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 is linked to a number of 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 identified 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, as well as 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 combination agents clinically as novel therapies for these diseases. Thus, these inflammasome-related diseases, 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 infections, There is a need for inhibitors of the NLRP3 inflammasome pathway to provide new and / or alternative treatments for acute injuries, Alzheimer's disease, Parkinson's disease, Huntington's disease), neuromuscular and musculo-degenerative diseases, atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis). References: JPEG2025509088000001.jpg120170 Summary of the Invention

[0004] The present invention provides a compound or a pharma- ceutically acceptable salt thereof, 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 pharma- ceutically acceptable salt thereof. Various aspects of the present invention have been described herein.

[0005] The present application discloses a compound of formula I, wherein the form of the compound is selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, and tautomeric forms thereof.

[0006] [ka]

[0007] (In the formula, R w is hydrogen, C 1-6 Alkyl (e.g., CH3), C 2-8 Alkynyl, halogen (e.g., F, Cl), C 1-6 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 , O.N.R. 1b (C=NR 1b )NR 1b , N.R. 1b S(=O)2 or S(=O)2NR 1b And each C 1-6 The 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, C, or CH; Each A is independently CH, CH2, CR a , C.H.R. a , CR4, CHR4, N, NH, NR a , NR4, S or O; Each A' is independently absent, CH, CH2, CR a , C.H.R. 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)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; Each -- represents an absence of a 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, C 2-7 heterocycloalkyl or aryl; Each R 1b are independently hydrogen, C1-4 Alkyl, deutero-C 1-4 Alkyl, halo-C 1-4 Alkyl or hydroxy-C 1-4 is alkyl, Each R' is independently 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 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), where 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 3-10 Cycloalkyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O and S, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents each selected from R2;

[0010] R2 is halogen, hydroxyl, cyano, C 1-4Alkyl, Hydroxy-C 1-4 Alkyl, Deuterium-C 1-4 Alkyl, halo-C 1-4 Alkyl, Amino, C 1-4 Alkylamino, (C 1- Alkyl)2amino, halo-C 1-4 Alkylamino, (Halo-C 1-6 Alkyl)2amino, hydroxy-C 1-4 Alkylamino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, Amino C 1-4 Alkyl, C 1-4 Alkylamino C 1-4 Alkyl, (C 1-4 Alkylamino)2C 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, Heteroarylamino, HeteroarylC 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;

[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 1-4 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 1-4 Alkylamino, (C 1-4 Alkyl)2amino, 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 Alkylamino, (C 1-4 Alkyl)2amino, Amino C 1-4 Alkyl, Hydroxy-C 1-4Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxy, C 1-4 Alkylthio, Halo-C 1-4 Alkoxy and C 3-10 cycloalkyl)

[0012] Another aspect of the present invention provides a compound having the structure of Formula II, wherein the compound is in a form selected from the group consisting of a pharma- ceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof.

[0013] [ka] (In the formula, each W is independently CH, CR', or N; Each A is independently CH, CH2, CR a , CR4, N, NH or NR4; Each -- represents a single or double bond; Y is NR 1b or a bond, Each R w is hydrogen, halogen, C 1-4 Alkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 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 1-8Alkyl, NH(hydroxy-C 1-6 alkyl), NH(C 1-6 alkoxy), where 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 alkanoate ester or heterocyclyl, which is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R2; R2 is halogen, hydroxyl, cyano, C 1-4 Alkyl, deutero-C 1-4 Alkyl, halo-C 1-4 Alkyl, Amino, C 1-4 Alkylamino, (C 1-6 Alkyl)2amino, halo-C 1-4 Alkylamino, (Halo-C 1-6 Alkyl)2amino, hydroxy-C 1-4 Alkylamino, C 1-4 Alkoxy-C 1-4 Alkyl-amino, Amino C 1-4 Alkyl, C 1-4 Alkylamino C 1-4 Alkyl, (C 1-4 Alkylamino)2C 1-4 Alkyl, C 1-4 Alkoxy, Halo-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, Heteroarylamino, HeteroarylC 1-4 Alkyl-amino, heterocyclyl, heterocyclyl-C1-4 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; 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, R' is H, substituted or unsubstituted cycloalkyl, C 1-4 Alkyl, halo-C 1-4 Alkyl, halo-C 1-6 Alkoxy, halogen, C 1-6 Alkoxy, cyano, hydroxy-C 1-4 Alkyl or C 1-4 aryl optionally substituted by alkyl; Each R aare independently H, deuterium, halogen, -CN, -OH, -OR2, =O, =N-OR2, -SR2, -S(=O)R2, -S(=O)2R2, -N(R2)2, -NR2S(=O)(=NR2)R2, -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)

[0014] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the compound definition of formula I disclosed herein, or a form thereof, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers. The pharmaceutical composition is useful for treating diseases and / or disorders associated with NLRP3 activity. In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to the compound definition of formula I or a subformula thereof disclosed herein, or a pharma- ceutically acceptable salt thereof, and one or more therapeutic agents. In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, disclosed herein for use as a medicament.

[0015] In another aspect, the present invention provides a compound of formula I or a subformula thereof disclosed herein, or a pharma- ceutically acceptable salt thereof, for use in treating a disease or disorder in which NLRP3 signaling contributes to a pathology and / or symptom, and / or the progression of said disease or disorder. In another aspect, the present invention provides a method of treating a disease or disorder in which NLRP3 signaling contributes to a pathology and / or symptom, and / or the progression of said disease or disorder, comprising administering a therapeutically effective amount of a compound of formula I or a subformula thereof disclosed herein, or a pharma- ceutically acceptable salt thereof. In another aspect, the present invention provides a method of 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 formula I disclosed herein, or a form thereof, or a pharma- ceutically acceptable salt thereof.

[0016] Another aspect of the present invention relates to the use of a compound of Formula I or a subformula thereof disclosed herein, or a pharma- ceutically acceptable salt thereof, as a medicine. Another aspect of the present invention relates to a compound of Formula I or a subformula thereof disclosed herein, or a pharma- ceutically acceptable salt thereof, for use as a medicament. Another aspect of the present invention also provides a compound of formula I or a subformula thereof disclosed herein, or a pharma- ceutically 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 PREFERRED EMBODIMENTS

[0017] The present invention provides a compound selected from the following, wherein the compound is in a form selected from the group consisting of a pharma- ceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof:

[0018] [ka] JPEG2025509088000005.jpg253170 JPEG2025509088000006.jpg243170 JPEG2025509088000007.jpg241170 JPEG2025509088000008.jpg246170 JPEG2025509088000009.jpg245158 JPEG2025509088000010.jpg244170 JPEG2025509088000011.jpg243158 JPEG2025509088000012.jpg249163 JPEG2025509088000013.jpg249164 JPEG2025509088000014.jpg245158 JPEG2025509088000015.jpg249163 JPEG2025509088000016.jpg217170

[0019] In embodiment 1, the present invention provides the compound described above or a pharma- ceutically acceptable salt thereof. In embodiment 2, the present invention provides a compound selected from the following, wherein the form of the compound is selected from the group consisting of a pharma- ceutically acceptable salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereoisomer, a stereoisomer, a tautomer, and an isotopically enriched form thereof:

[0020] [Table 1] JPEG2025509088000018.jpg243157 JPEG2025509088000019.jpg244155 JPEG2025509088000020.jpg246160 JPEG2025509088000021.jpg245153 JPEG2025509088000022.jpg242159 JPEG2025509088000023.jpg245156 JPEG2025509088000024.jpg245156 JPEG2025509088000025.jpg245157 JPEG2025509088000026.jpg242159 JPEG2025509088000027.jpg243157 JPEG2025509088000028.jpg244160 JPEG2025509088000029.jpg243160 JPEG2025509088000030.jpg243153 JPEG2025509088000031.jpg245153 JPEG2025509088000032.jpg244158 JPEG2025509088000033.jpg245161 JPEG2025509088000034.jpg245155 JPEG2025509088000035.jpg244154 JPEG2025509088000036.jpg245158 JPEG2025509088000037.jpg243159 JPEG2025509088000038.jpg242155 JPEG2025509088000039.jpg208167

[0021] In embodiment 3, the present invention provides a compound selected from the following, wherein the form of the compound is selected from the group consisting of a hydrate, a solvate, a racemate, an enantiomer, a diastereoisomer, a stereoisomer, a tautomer, a free base, and an isotopically enriched form thereof:

[0022] [Table 2] JPEG2025509088000041.jpg243158 JPEG2025509088000042.jpg125165

[0023] In embodiment 4, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers. In embodiment 5, 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 according to any one of embodiments 1-3.

[0024] In embodiment 6, the present invention relates to a method for treating 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, inherited and acquired myopathies, e.g. A method of treating or ameliorating a disease modulated by NLRP3 according to embodiment 5 is provided, for example, 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 mellitus-related atherosclerosis, diabetic encephalopathy, diabetic kidney disease, 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).

[0025] In embodiment 7, the present invention provides the method of any one of embodiments 5-6, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

[0026] In embodiment 8, the present invention relates to a method for treating Alzheimer's disease, frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, perioperative neurocognitive disorder, post-cardiac arrest cognitive disorder, post-stroke cognitive disorder, 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, inherited and acquired myopathies, hyperalgesia, Provided is a compound or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1-3 for use in treating or ameliorating a disease modulated by NLRP3 selected from multiple sclerosis-associated neuropathic pain, acute kidney injury, chronic crystal nephropathy, chronic kidney disease, asthma and allergic airway inflammation, diabetes mellitus-associated atherosclerosis, diabetic encephalopathy, diabetic kidney disease, islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, diabetes mellitus type I, diabetes mellitus type II, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

[0027] In embodiment 9, the present invention provides the use of a compound according to embodiment 8, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

[0028] In embodiment 10, the present invention provides the use of a compound according to any one of embodiments 1 to 3 in the preparation of a pharmaceutical composition for treating or ameliorating a disease modulated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of the compound or a form thereof in admixture with one or more pharma- ceutically acceptable excipients.

[0029] Methods of using the present invention There is evidence for a role for NLRP3-induced IL-1β 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 order of increasing 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 result from gain-of-function mutations in the NLRP3 gene that cause increased secretion of IL-I beta. NLRP3 has also been linked to 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 treating multiple sclerosis, type 1 diabetes (T1D), 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 aneurysms (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 has been implicated in type 2 diabetes (T2D) and its organ-specific complications, 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 non-alcoholic steatohepatitis (Mridha et al. J. Hepatol.NLRP3 has also been shown to be involved in various metabolic diseases, including skeletal muscle diseases, such as muscle atrophy, inherited 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), 828-3-6), 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 play a role 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. 2013, 11, 111-112); 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 disease 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 play a role in inflammatory hyperalgesia (Dolunay et al, Inflammation, 2017, 40, 3-66-86). United States Patent US202003-61898 is incorporated herein by reference.

[0030] definition The following specific examples are included to aid in understanding the scope of the compounds of formula I or forms thereof described herein. Experimentation with the compounds of formula I or forms thereof described herein should, of course, not be construed as specifically limiting the scope of the compounds of formula I or forms thereof described herein, and such variations of the compounds of formula I or forms thereof described herein that are within the scope 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.

[0031] 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. Thus, 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 variable experimental conditions. Thus, within the expected range of experimental reproducibility, the term "about" in relation to the resulting data refers to a range for the data, provided that it may vary according to the standard deviation from the mean. Similarly, in the experimental results obtained, the resulting data may be rounded up or down consistently with respect to the present data without loss of significant numbers. 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.

[0032] Notwithstanding that the numerical ranges and parameters setting forth the characterization of the compounds of Formula I 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 formula I or forms thereof provided herein are described in more detail with respect to the following non-limiting examples, which are presented to more fully illustrate the scope of the compounds of formula I or forms thereof described herein, but should not be construed as limiting the scope thereof. The examples illustrate the preparation of the compounds of formula I or forms thereof described herein, and the in vitro and / or in vivo testing of these compounds of formula I or forms thereof. Those skilled in the art will understand that the synthetic techniques described in these examples represent techniques that fall within the practice of those skilled in the chemical arts, and therefore constitute preferred modes of practice. However, it should be appreciated that those skilled in the art should recognize in light of this disclosure that many variations can be made in the specific methods disclosed herein while still obtaining similar or similar results without departing from the spirit and scope described herein.

[0033] In certain embodiments described herein, the compound of Formula I or a form thereof is isolated for use. As used herein, the term "isolated" refers to the physical state of a compound of formula I or a form 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), 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 the compound of formula I or in its form is in a modified form to preclude undesired side reactions of the functional group when the compound is subjected to a reaction. Suitable protecting groups are known by those skilled in the art and by reference to standard textbooks, for example, TW Greene et al, Protective Groups in Organic Synthesis (2007), Wiley, New York. Prodrugs and solvates of the compounds of Formula I or forms thereof described herein are also contemplated.

[0034] As used herein, the term "prodrug" refers to a compound of formula I or a functional group thereof that is converted in vivo (e.g., acts as an active or inactive drug precursor) to produce an active or more active compound of formula I 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 blood, liver and / or other organs and tissues. A discussion of the use of prodrugs is provided by VJ 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 or a form thereof contains a carboxylic acid functional group, the prodrug may include an ester formed by replacing the hydrogen atom of the acidic group with a functional group, such as an alkyl. In another example, when a compound of formula I or a form thereof contains an alcohol functional group, the prodrug may be formed by replacing the hydrogen atom of the alcohol group with a functional group, such as an alkyl or carbonyloxy. In another example, when a compound of formula I or a form thereof contains an amine functional group, the prodrug may be formed by replacing one or more of the amine hydrogen atoms with a functional group, such as an alkyl or substituted carbonyl.

[0035] Pharmaceutically acceptable prodrugs of the compound of formula I or a form thereof include compounds substituted with one or more of the following groups: carboxylate esters, sulfonate esters, amino acid esters, phosphonate esters (e.g., phosphoramidates used to derive phosphoramidates), and mono-, di-, or triphosphate esters, further substituted with alkyl, as appropriate. As described herein, it will be appreciated by those skilled in the art that one or more of such substituents may be used to provide the compound of formula I or a form thereof as a prodrug. The compound of formula I or a form thereof may form salts, which are intended to be included within the scope of this description. Reference to the compound of formula I or a form thereof is understood to include reference to its salts, unless otherwise indicated. The term "salt" as used herein refers to acid salts formed with inorganic and / or organic acids, and base salts formed with inorganic and / or organic bases. Furthermore, when the compound of formula I or a form thereof contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, carboxylic acid, zwitterions ("internal salts") may be formed, which are included within the term "salt" as used herein.

[0036] The term "pharmaceutically acceptable salts" as used herein means salts of compounds of formula I 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 formula I or forms thereof can be formed, for example, by reacting compounds of formula I or forms thereof and compounds described herein with an amount, for example an equivalent amount, of an acid or base in a medium, for example one in which the salt is precipitated or an aqueous medium, followed by lyophilization. Additionally, acids that may be suitable for forming medicamentously 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.

[0037] Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. Certain compounds of formula I described herein or forms thereof can also form pharma- ceutically acceptable salts with organic bases (e.g., organic amines), such as, but not limited to, dicyclohexylamine, tert-butylamine, and various amino acids, such as, but not limited to, arginine, lysine. Basic nitrogen-containing groups can 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), aralkyl halides (e.g., benzyl and phenethyl bromides). All such acid and base salts are intended to be included within the scope of pharma- ceutically acceptable salts described herein, and furthermore, all such acid and base salts are considered equivalent to the free form of the corresponding compounds for purposes of this description. Compounds of Formula I 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 Formula I or forms thereof described herein.

[0038] The compounds of formula I or forms thereof may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. This specification is intended to include all stereoisomers of the compounds of formula I or forms thereof, as well as mixtures thereof, including racemic mixtures. The compounds of formula I described herein or forms thereof may contain one or more chiral centers and thus 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 embodiment, the compounds of formula I described herein or forms thereof may be (S) isomers and may exist as enantiomerically pure compositions substantially containing only the (S) isomer. In another embodiment, the compounds of formula I described herein or forms thereof may be (R) isomers and may exist as enantiomerically pure compositions substantially containing only the (R) isomer. As one skilled in the art will appreciate, if more than one chiral center is present, the compounds of formula I described herein or forms thereof may also exist as (R,R), (R,S), (S,R) or (S,S) isomers as defined by the IUPAC nomenclature recommendations.

[0039] As used herein, the term "substantially pure" refers to a compound of formula I or a form thereof 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%. In one described embodiment, the compound of Formula I or a form thereof is a substantially pure (S) enantiomer, present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or in an amount equal to 100%. In one described embodiment, the compound of Formula I or a form thereof is a substantially pure (R) enantiomer present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, 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. Additionally, the compounds of formula I or forms thereof described herein encompass all geometric and positional isomers. For example, if a compound of formula I 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 formula I or forms thereof described herein.

[0040] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those of ordinary skill in the art, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by use of chiral HPLC columns or other chromatographic methods known to those of ordinary skill 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 compounds of formula I or forms thereof (including salts, solvates, esters and prodrugs, as well as converted prodrugs) that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist without asymmetric carbons), rotamer forms, atropisomers, diastereomeric forms and positional isomeric forms, are contemplated within the scope of the present disclosure. Individual stereoisomers of the compounds of formula I or forms thereof described herein may, for example, be substantially free of other isomers or may exist in racemic mixtures as described above.

[0041] Use of the terms "salts," "solvates," "esters," "prodrugs," and the like are intended to apply equally to salts, solvates, esters and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, isotopically enriched forms or prodrugs of the present compounds. One or more compounds of formula I or forms thereof described herein may exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents, e.g., 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 the compound of formula I or a form thereof described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonds, including hydrogen bonds. In certain instances, the 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 formula I or its forms described herein may be converted into solvates. The preparation of solvates is generally known. A typical non-limiting process involves dissolving the compound of formula I or its forms in a desired amount of a desired solvent (organic or water or their mixture) at a temperature higher than 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 solvates (or hydrates).

[0042] As used herein, the term "hydrate" refers to a solvate where the solvent molecule is water. Polymorphic crystalline and amorphous forms of the compounds of Formula I or forms thereof, and the salts, solvates, esters and prodrugs of the compounds of Formula I or forms thereof, are further intended to be included within the scope of the compounds of Formula I or forms thereof described herein. As used herein, the term "isotopically enriched" refers to a compound of formula I 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 within the scope of this description.

[0043] Usage and dosage The compounds of the present invention can be formulated into a wide variety of oral administration 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), local parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain a penetration enhancer), buccal, nasal, inhalation and suppository administration, among other routes of administration. 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.

[0044] The compounds of the present invention, as well as their pharma- ceutically usable salts, may be placed into the form of pharmaceutical compositions and unit doses together with one or more conventional excipients, carriers, or diluents. The pharmaceutical compositions and unit dose forms may consist of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dose forms may contain any suitable effective amount of the active ingredient consistent with the range of daily doses intended to be used. The 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 in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. A typical preparation contains about 5% to about 95% active compound (w / w). The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound, and one skilled in the art will recognize that the active ingredient may be present in different preparations depending on the target organ or tissue, and also depending on the desired dose and pharmacokinetic parameters. As used herein, the term "excipient" refers to compounds that are generally safe, non-toxic, and not biologically or otherwise undesirable, useful in the preparation of pharmaceutical compositions, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. The compounds of the invention may 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.

[0045] "Pharmaceutically acceptable" means that which is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in the preparation of pharmaceutical compositions, and includes those acceptable for veterinary as well as human pharmaceutical use. A "pharmaceutical acceptable salt" form of an active ingredient can initially impart desirable pharmacokinetic properties to the active ingredient not present in the non-salt form and can even favorably affect the pharmacodynamics of the active ingredient with respect to therapeutic activity in the body. The phrase "pharmaceutical acceptable salt" of a compound means a salt that is pharmaceutical acceptable and possesses the desirable 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- or (2) salts formed when an acidic proton present in the unchanged form is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine.

[0046] The solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that can 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 a mixture with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in a suitable ratio and compressed 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 wax, cocoa butter, and the like. The solid form preparations can contain, in addition to the active ingredient, colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0047] Liquid preparations are also suitable for oral administration, including liquid preparations including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These include solid form preparations that are 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 emulsifying agents, for example 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 viscous materials, 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, by bolus injection or continuous injection), and can be presented in unit dose form with added preservatives in ampoules, prefilled syringes, small volume injections or multiple 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 formulatory 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 for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0048] The compound 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. Preparations suitable for topical administration in the mouth include lozenges that contain the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles that contain the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia; and mouthwashes that contain the active ingredient in a suitable liquid carrier. The compounds of the present invention can be formulated for administration as suppositories. A mixture of a low melting wax, such as 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.

[0049] The compounds of the present invention may be formulated for vaginal administration: pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. The compounds 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, with a dropper, pipette or spray.The formulation can be provided in single or multiple dose form.In the latter case of a dropper or pipette, this can be achieved by the patient administering an appropriate predetermined volume of the solution or suspension.In the case of a spray, this can be achieved, for example, by a metering atomizing spray pump. The compounds of the present invention may 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 is obtained in a pressurized pack with a suitable propellant, for example a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant, for example lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredient is obtained in the form of a dry powder, for example a powder mix of the compound in a suitable powder base, for example lactose, starch, starch derivatives, for example hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier forms a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in gelatin or blister packs, for example in capsules or cartridges from which the powder can be administered by an inhaler.

[0050] If desired, the 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. Compounds in transdermal delivery systems are often attached to skin-adhesive solid carriers. 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 polyactic acid.

[0051] 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. Formulators can modify the formulations within the teachings of this specification to obtain a multitude of formulations for specific routes of administration without destabilizing the compositions of the invention or compromising their therapeutic activity. Modifications of the compounds to make them 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.

[0052] The term "therapeutically effective amount" as used herein means an amount required to reduce the symptoms of a disease in an individual. The dose is adjusted to the individual requirements in each detailed 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 medicines with which the patient is being treated, 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 1000 mg / kg body weight per day should be appropriate in monotherapy and / or in combination therapy. The preferred daily dosage is about 0.1 to about 500 mg / kg body weight per day, more preferably 0.1 to about 100 mg / kg body weight per day, and most preferably 1.0 to about 10 mg / kg body weight per day. 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 started with a smaller dosage that is less than the optimal dose of the compound.The dosage is then increased in small increments until the optimal effect for each patient is reached.In treating the diseases described herein, those skilled in the art can ascertain 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. 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.

[0053] Examples of representative compounds encompassed by and within the scope of the present invention are set forth in the following table. These examples and preparations which follow are presented to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely illustrative and representative thereof. 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, the depicted structure shall be given more weight. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated, for example, with a bold or dashed line, the structure or portion of a structure shall be interpreted as encompassing all stereoisomers thereof.

[0054] Reagents and solvents were used as purchased (from various vendors) except where noted. Where applicable, the term "Celite" is used as indicated 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 data were obtained using commonly available techniques and equipment by using a spectrometer and deuterated solvents, e.g., DMSO-d6 or residual solvents as standards. Where applicable, melting points were determined using commonly available techniques and equipment, e.g., by using an SRS OptiMelt® MPA100 (values ​​obtained without correction / calibration). Where applicable, TLC analyses were performed using commonly available techniques and equipment, e.g., by using Aldrich 254 nm glass-backed plates (60 Å, 250 μm) visualized using UV and I2 stain. Where applicable, ESI mass spectra were obtained using commonly available techniques and equipment, 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. When applicable, the structures of the products were obtained by 2D NOESY (Nuclear Overhauser SpectroscopY) experiments.

[0055] Compounds and Preparation Examples of representative compounds encompassed by and within the scope of the present invention are presented herein. These examples and preparations are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely illustrative and representative thereof.

[0056] experiment As disclosed herein, the general method for preparing the compounds of formula I or forms thereof described herein can be prepared using the methods summarized in Scheme AJ by suitable selection of reagents with appropriate substitution, and solvents, temperatures, pressures and other reaction conditions can be easily selected by those skilled in the art. Many of the starting materials are commercially available, or if not available, can be prepared by standard well-known synthetic methodologies or using the routes described below using techniques known to those skilled in the art. It is intended that the synthetic schemes shown herein include multiple reaction steps, each of which can be carried out independently and with or without any preceding or succeeding steps. In other words, each of the individual reaction steps of the synthetic schemes shown herein with respect to isolation is envisioned. Depending on the nature of the groups depicted in the schemes below, the final compounds or their precursors can be further elaborated using standard well-known synthetic methods, such as SN2 displacement reactions, metal-catalyzed coupling reactions such as Suzuki coupling, Negishi coupling and Buchwald coupling, reductive amination, etc., to give compounds of general formula I-II.

[0057] Scheme A: [ka] Compound A1 (wherein X1 and X2 are independently bromine, chlorine, etc.) is converted to compound A2 by nucleophilic substitution with a suitable amine in the presence of a suitable base (e.g. DIEPA) in a suitable solvent (e.g. NMP) or with a suitable alcohol in the presence of a suitable base (e.g. NaH) in a suitable solvent (e.g. anhydrous THF). Compound A2 is converted to compound A3 by Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boron ester) in the presence of a catalyst (e.g. Pd(dppf)Cl2) and a base (e.g. aqueous K2CO3) in a suitable solvent (e.g. 1,4-dioxane).

[0058] Scheme B: [ka] Compound B1 is converted to compound B2 by Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boron ester) in the presence of a catalyst (e.g. Pd(dppf)Cl2) and a base (e.g. aqueous K2CO3) in a suitable solvent (e.g. 1,4-dioxane). Compound B2 is converted to compound B2 by Suzuki coupling with a catalyst (e.g. Pd2(dba)3), a ligand (e.g. RuPhos) and a base (e.g. NaO2) in a suitable solvent (e.g. PhMe). t The compound B3 is converted to compound B4 by Buchwald-Hartwig coupling with an appropriate amine in the presence of 1,2-dichloro-2,4-tetrahydrofuran (Bu).

[0059] Scheme C: [ka]

[0060] Compound C1 is prepared from 1,2,4,5-tetrazine with a suitable amine in the presence of a suitable base (e.g., DIEPA) in a suitable solvent (e.g., DCM). Compound C1 is converted to compound C2 by inverse electron demand Diels-Alder reaction with a suitable enol ether or enamine in a suitable solvent (e.g., PhMe). Compound C2 was converted to compound C3 according to the conditions described in Scheme A - Step 2.

[0061] Scheme D: [ka]

[0062] Compound D1 is converted to compound D2 (wherein P is a protecting group, e.g., Me) by reaction with a suitable organometallic compound (e.g., Grignard reagent) in a suitable solvent (e.g., THF). Compound D2 is converted to compound D3 by a condensation / cyclization sequence in the presence of hydrazine in a suitable solvent (e.g., EtOH). Compound D3 is converted to compound D4 by treatment with a dehydrating halogenating agent (e.g., POCl3). Compound D4 is converted to compound D5 by treatment with a catalyst (e.g., Pd2(dba)3), a ligand (e.g., RuPhos) and a base (e.g., NaO) in a suitable solvent (e.g., PhMe). t Compound D5 is converted to compound D6 by Buchwald-Hartwig coupling with an appropriate amine in the presence of Me (Bu). Compound D5 is converted to compound D6 upon treatment with appropriate conditions to remove the protecting group (e.g., BBr3 in DCM for the Me protecting group in a suitable solvent, such as DCM).

[0063] Scheme F: [ka]

[0064] Compound F1 is converted to compound F2 by reaction with hydrazine in a suitable solvent (e.g., EtOH). Reaction of F2 with a chloroformate in the presence of a base (e.g., DIPEA) in a suitable solvent (e.g., DCM) gives F3, which is cyclized to F4 by treatment with a base (e.g., KOH) in a suitable solvent (e.g., EtOH) at elevated temperature (e.g., 80° C.). Compound F4 is converted to compound F5 by treatment with POX3 (X=Cl or Br) with or without a base (e.g., DIPEA). Treatment of F5 with a thiolation reagent, e.g., Lawesson's reagent (LR) or P2S5, at a suitable temperature, e.g., 100° C., followed by alkylation with MeI gives F6. Compound F6 is converted to F7 by Suzuki coupling with an aryl or heteroboronic acid or borate in the presence of a suitable catalyst (e.g., PdCl2dppf) and base (e.g., K2CO3) in a suitable solvent (e.g., dioxane). Alternatively, compound F5 can first be converted to compound F7 via Suzuki coupling followed by thiolation with LR or P2S5 and subsequent alkylation with MeI to give compound F9. SNAr reaction of F7 with a nucleophile in a suitable solvent (e.g., DMSO) at elevated temperature (e.g., 130° C.) affords compound F8.

[0065] Scheme G: [ka]

[0066] Compound G1 prepared according to step 1 in scheme F is converted to compound G2 by reaction with a tri-alkoxy orthoformate in a suitable solvent (e.g., EtOH) at elevated temperature (e.g., 100° C.). Reaction of G2 with a halogenating agent (e.g., NBS) in a suitable solvent (e.g., DMF) gives compound G3, which is reacted with a nucleophile to give compound G4. Compound G4 is converted to compound G5 by treatment with POX3 (X=Cl or Br) with or without a base (e.g., DIPEA) at elevated temperature (e.g., 100° C.). Suzuki coupling of compound G5 with an aryl or heteroaryl boronic acid or borate in a suitable solvent (e.g., dioxane) in the presence of a suitable catalyst (e.g., PdCl2dppf) and base (e.g., K2CO3) gives compound G6. Alternatively, compound G4 can be directly converted to compound G6 by BOP-mediated Suzuki coupling.

[0067] Scheme H: [ka]

[0068] Reaction of an organometallic compound with an aldehyde, H1 with H2 or H1' with H2' gives alcohol H3. Compound H3 is converted to H4 by treatment with an oxidizing agent (e.g. MnO2) in a suitable solvent (e.g. DCM). Alternatively, reaction of compound H1'' with H2'' gives H4 directly. Deprotection of compound H4 gives compound H5. Reaction of compound H5 with methylhydrazinecarbodithioate in a suitable solvent (e.g. EtOH) at elevated temperature (e.g. 80° C.) followed by alkylation with MeI in the presence of a base (e.g. K2CO3) gives compound H6. Alternatively, compound H5 is converted to compound H5' by reaction with hydrazine in a suitable solvent (e.g., EtOH), followed by reaction with a chloroformate in the presence of a base (e.g., DIPEA) in a suitable solvent (e.g., DCM) and cyclization by treatment with a base (e.g., KOH) in a suitable solvent (e.g., EtOH) at elevated temperature (e.g., 80° C.). SNAr reaction of H6 with a nucleophile in a suitable solvent (e.g., DMSO) at elevated temperature (e.g., 130° C.) provides compound H7.

[0069] Scheme I: [ka]

[0070] Compound I1 is converted to compound I3 by two coupling reactions with a boronic acid or borate in the presence of a suitable catalyst (e.g., PdCl2dppf) and base (e.g., K2CO3) in a suitable solvent (e.g., dioxane). Alternatively, compound I4 is converted to compound I5 by coupling with a boronic acid or borate, which is further converted to compound I3 by BOP-mediated Suzuki coupling with an aryl or heteroaryl boronic acid or borate.

[0071] Scheme J: [ka] Compound J1 is converted to compound J2 by ​​reaction with TosMIC in the presence of a suitable base (e.g., K2CO3, DBU) in a suitable solvent (e.g., DCE). Suzuki coupling of compound J2 with an aryl or heteroaryl boronic acid or borate in the presence of a suitable catalyst (e.g., PdCl2dppf) and base (e.g., K2CO3) in a suitable solvent (e.g., dioxane) gives J3. Alternatively, compound JI is converted to compound J5 by coupling with a boronic acid or borate, which is further converted to compound J3 by reaction with TosMIC in the presence of a suitable base (e.g., K2CO3, DBU) in a suitable solvent (e.g., DCE). SNAr reaction of J3 with a nucleophile in a suitable solvent (e.g., DMSO) at elevated temperature (e.g., 130° C.) gives J4.

[0072] Synthesis Example To more fully describe and aid in understanding, the following non-limiting examples are presented to more fully illustrate the scope of the compounds described herein and should not be construed as specifically limiting the scope thereof. Such variations of the compounds described herein that may be ascertained by one skilled in the art and may be currently known or may be developed later are considered to fall within the scope of the compounds described herein and claimed hereinafter. These examples illustrate the preparation of certain compounds. Those skilled in the art will appreciate that the techniques described in these examples represent techniques that work well in the practice of synthesis as described by those skilled in the art and thus constitute preferred modes for the practice. However, in light of the present disclosure, it should be appreciated that those skilled in the art should recognize that many variations can be made in the specific methods disclosed and still obtain similar or similar results without departing from the spirit and scope of the present specification.

[0073] Other than the following examples of embodied compounds, unless otherwise indicated, all numbers expressing amounts 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". Thus, 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 variable experimental conditions. Thus, within the expected range of experimental reproducibility, the term "about" in relation to the resulting data refers to a range for the data, provided that it may vary according to the standard deviation from the mean. Similarly, in the experimental results obtained, the resulting data may be rounded up or down consistently with respect to the present data without loss of significant numbers. At the very least, and without attempting to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be interpreted in light of significant numbers and rounding methods used by those skilled in the art.

[0074] Notwithstanding that the numerical ranges and parameters setting forth the broad ranges herein are approximations, the numerical values ​​set forth in the examples set forth below 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.

[0075] Compound Examples As used above, and throughout this description, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

[0076] [Table 3] JPEG2025509088000053.jpg250160 JPEG2025509088000054.jpg63170

[0077] Intermediate 1a: 1-chloro-7-methylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one [ka]

[0078] Step 1. Ethyl 4-methyl-1H-pyrrole-2-carboxylate A mixture of ethyl 4-formyl-1H-pyrrole-2-carboxylate (10.3 g, 61.6 mmol, 1.0 equiv) and Pd / C (10%, 2.0 g) in EtOH (150 mL) was stirred under hydrogen (balloon) at room temperature overnight. The mixture was filtered. The filtrate was concentrated under reduced pressure. The crude colorless oil (8.50 g, 90% yield) was used in the next step without further purification. MS m / z 154.2 [M+H] + . Step 2. 4-Methyl-1H-pyrrole-2-carbohydrazide A solution of ethyl 4-methyl-1H-pyrrole-2-carboxylate (8.50 g, 55.5 mmol) in N2H4H2O (80%, 28 mL) was heated at 70° C. for 45 min. After cooling to room temperature, the mixture was filtered. The filter cake was washed with EtOH and dried in vacuum to give 4-methyl-1H-pyrrole-2-carbohydrazide as a white solid (7.5 g, 97% yield). MS m / z 140.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.14 (s, 1H), 6.62 (s, 1H), 6.55 (s, 1H), 4.27 (s, 2H), 2.00 (s, 3H).

[0079] Step 3. Isobutyl 2-(4-methyl-1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate To a suspension of 4-methyl-1H-pyrrole-2-carbohydrazide (7.5 g, 53.9 mmol, 1.0 equiv.) and DIEA (20.9 g, 161 mmol, 3.0 equiv.) in DCM (540 mL) was added isobutyl carbonochloridate (11.1 g, 80.9 mmol, 1.5 equiv.) dropwise with an ice-water cooling bath. The mixture was stirred at room temperature overnight. Upon completion, the reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with 0-30% EtOAc in hexanes to give isobutyl 2-(4-methyl-1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate (12.0 g, 93%) as a white solid. MS m / z 240.2 [M+H] + .

[0080] Step 4. 7-Methyl-2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione To a solution of isobutyl 2-(4-methyl-1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate (12.0 g, 50.2 mmol, 1.0 equiv.) in EtOH (840 mL) was added KOH (8.40 g, 151 mmol, 3.0 equiv.). The mixture was stirred at 85° C. for 2 h. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with EtOH. The solid was dissolved in water and adjusted to pH=4 with 1M HCl. The precipitate was filtered. The filter cake was washed with water and dried in vacuum to give 7-methyl-2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (4.0 g, 48% yield) as a white solid. MS m / z 166.2[M+H] + .

[0081] Step 5. 1-Chloro-7-methylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one To a solution of 7-methyl-2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (4.0 g, 24.2 mmol, 1.0 equiv.) in POCl3 (1.0 M, 25 mL) was added DIEA (3.12 g, 24.2 mmol, 1.0 equiv.) dropwise in an ice-cooled bath. The mixture was stirred at 100° C. for 16 h, then cooled to room temperature and concentrated. The residue was carefully poured into ice water and adjusted to pH=8 with saturated aqueous NaHCO3. The mixture was extracted with DCM:MeOH (10:1, 100 mL × 3), dried over Na2SO4, concentrated, and purified by silica gel column chromatography eluting with 0-50% EtOAc in hexane to give 1-chloro-7-methylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (2.0 g, 45% yield) as a white solid. MS m / z 184.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.66 (s, 1H), 6.75 (s, 1H), 2.23 (s, 3H). Intermediate 1b: 8-Fluoro-2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione [ka]

[0082] Step 1. 3-Fluoro-1H-pyrrole-2-carbohydrazide A mixture of N2H4·H2O (80% in water, 18 mL) and methyl 3-fluoro-1H-pyrrole-2-carboxylate (3.14 g, 20.0 mmol) was stirred at 70 °C for 45 min. After cooling to room temperature, the precipitate was filtered, the filter cake was washed with water and dried under vacuum to give 3-fluoro-1H-pyrrole-2-carbohydrazide (2.30 g, 73%) as a white solid. MS m / z 144.1 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.55 (s, 1H), 6.74 (dd, J = 4.6, 3.0 Hz, 1H), 5.97 (d, J = 3.0 Hz, 1H), 4.39 (s, 2H).

[0083] Step 2. Isobutyl 2-(3-fluoro-1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate To a solution of 3-fluoro-1H-pyrrole-2-carbohydrazide (2.15 g, 15.0 mmol, 1.0 equiv) in DCM (60 mL) was added DIPEA (5.80 g, 45.0 mmol, 3.0 equiv). Isobutyl carbonochloridate (3.00 g, 22.5 mmol, 1.5 equiv) was slowly added to the mixture. The mixture was stirred at room temperature for 16 h. After concentration, the mixture was diluted with EtOAc (200 mL). The organic layer was washed with water and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with 0-50% EtOAc in hexanes to give isobutyl 2-(3-fluoro-1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate (2.44 g, 66.7% yield) as a yellow solid. MS m / z 244.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.18 (s, 1H), 9.09 (s, 1H),6.82 (d, J = 4.4 Hz, 1H), 6.01 (d, J = 2.5 Hz, 1H), 3.82 (d, J = 6.6 Hz, 2H), 2.02 - 1.67 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H).

[0084] Step 3. 8-Fluoro-2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione To a solution of isobutyl 2-(3-fluoro-1H-pyrrole-2-carbonyl)hydrazine-1-carboxylate (2.44 g, 10.0 mmol, 1.0 equiv.) in EtOH (60 mL) was added KOH (1.68 g, 30 mmol, 3 equiv.). The mixture was stirred at 85 °C for 2 h. After cooling to room temperature, the mixture was concentrated. The residue was diluted with water (50 mL) and adjusted to pH 6-7 with 1 M HCl. The precipitate was filtered, and the filter cake was washed with water and dried under vacuum to give 8-fluoro-2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (1.16 g, 68.7% yield) as a brown solid. MS m / z 168.0 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 2H), 7.57 (t, J = 4.1 Hz, 1H), 6.68 (d, J = 3.4 Hz, 1H).

[0085] Intermediate 1c: 1-chloro-4-(methylthio)pyrrolo[1,2-d][1,2,4]triazine [ka]

[0086] Step 1. 1-Chloropyrrolo[1,2-d][1,2,4]triazin-4-ol To a stirred solution of 2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (prepared as per procedure for intermediate 1b, 2 g, 13.2 mmol) in POCl3 (60 mL) was added DIEA (1.84 g, 14.2 mmol). The reaction mixture was heated at 100° C. for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was diluted with cold saturated sodium bicarbonate solution and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure. The crude was further triturated with DCM to give the title compound 1-chloropyrrolo[1,2-d][1,2,4]triazine-4-ol (0.867 g, 38.6% yield) as an off-white solid, which was used in the next step without further purification. MS m / z 169.6 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 7.88 - 7.87 (m, 1H), 6.92 - 6.89 (m, 2H).

[0087] Step 2. 1-Chloropyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione To a solution of 1-chloropyrrolo[1,2-d][1,2,4]triazine-4-ol (30.0 g, 177 mmol) in toluene (1200 mL) was added Lawesson's reagent (46.2 g, 114 mmol). The reaction was stirred at 120 °C for 16 h. The mixture was diluted with H2O (1.5 L), acidified with aqueous HCl (1 M) until pH = 3, and extracted with EA. The EA layer was washed with saturated aqueous NaHCO3 (1 L) and brine (1 L), then dried over anhydrous Na2SO4 and concentrated to give crude 1-chloro-3H-pyrrolo[1,2-d][1,2,4]triazine-4-thione (crude 35.0 g, excess mass), which was used in the next step without further purification. MS m / z 184.1 [MH] - .

[0088] Step 3. 1-Chloro-4-(methylthio)pyrrolo[1,2-d][1,2,4]triazine To a solution of 1-chloro-3H-pyrrolo[1,2-d][1,2,4]triazine-4-thione (crude 35.0 g, 189 mmol) in THF (600 mL) and water (300 mL) was added K2CO3 (65.2 g, 472 mmol) followed by iodomethane (68.6 g, 483 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, then diluted with water and extracted with EA (3 × 100 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give the title product 1-chloro-4-methylsulfanyl-pyrrolo[1,2-d][1,2,4]triazine (21.8 g, 57.9% yield over two steps) as a white solid. MS m / z 200.0 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ: 7.83 (dd, J = 2.8 Hz, 1.2 Hz, 1H), 7.16 (dd, J = 4.0 Hz, 2.8 Hz, 1H), 7.11 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 2.81 (s, 3H). The following intermediates were prepared following the procedure of Intermediate 1c by substituting the appropriate starting materials, reagents and reaction conditions.

[0089] [Table 4] Intermediate 1d: 1-Bromo-4-(methylthio)pyrrolo[1,2-d][1,2,4]triazine

[0090] [ka]

[0091] Step 1. 1-Bromopyrrolo[1,2-d][1,2,4]triazin-4(3H)-one A mixture of 2,3-dihydropyrrolo[1,2-d][1,2,4]triazine-1,4-dione (30.0 g, 0.199 mol, 1.0 equiv.) and POBr3 (570 g, 1.99 mol, 10 equiv.) was heated at 80° C. for 3 h. The hot reaction mixture was slowly poured into a stirred mixture of ice and saturated aqueous NaHCO3. The mixture was neutralized to pH 7 with solid NaHCO3 and extracted with a mixture of MeOH / DCM (1 L×2, 1:10). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was triturated with DCM, filtered, and washed with DCM. The solid was dried under vacuum to give 1-bromopyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (21.9 g, 51.8% yield) as a pink solid. MS m / z 214.0, 215.9 [M+H] + .

[0092] Step 2. 1-Bromopyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione To a solution of 1-bromopyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (10.0 g, 46.7 mmol, 1.0 equiv) in DMSO (472 mL) was added Lawesson's reagent (12.4 g, 30.7 mmol, 0.65 equiv). The reaction mixture was heated at 120 °C for 6 h. The reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3, and extracted with EtOAc (300 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with 0-30% EtOAc in hexane to give 1-bromopyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione as a white solid (1.56 g, 14.5% yield). MS m / z 228.0, 230.0 [MH] - ; 1 H NMR (400Hz, DMSO-d6) δ 14.15 (s, 1H), 8.23 ​​(dd, J = 2.9, 1.4 Hz, 1H), 7.10 (dd, J = 3.7, 3.1 Hz, 1H), 7.06 (dd, J = 3.9, 1.4 Hz, 1H).

[0093] Step 3. 1-Bromo-4-(methylthio)pyrrolo[1,2-d][1,2,4]triazine To a mixture of 1-bromopyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (2.00 g, 8.69 mmol, 1.0 equiv) and K2CO3 (3.00 g, 21.7 mmol, 2.5 equiv) in THF (43 mL) and water (21 mL) was added iodomethane (1.35 mL, 2.28 g / mL, 21.7 mmol, 2.5 equiv) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-30% EtOAc in hexane to give 1-bromo-4-(methylthio)pyrrolo[1,2-d][1,2,4]triazine (1.40 g, 66.1% yield) as a white solid. MS m / z 243.9, 246.0 [M+H] + ; 1 H NMR (400Hz, DMSO-d6) δ 7.83 (dd, J = 2.8, 1.0 Hz, 1H), 7.15 (dd, J = 4.0, 2.8 Hz, 1H), 7.03 (dd, J = 4.0, 1.0 Hz, 1H), 2.79 (s, 3H).

[0094] Intermediate 1e: 1-Bromo-4-(methylthio)imidazo[1,5-d][1,2,4]triazine [ka] To a solution of TsMIC (5.21 g, 26.69 mmol, 1.1 equiv) and DBU (4.43 mg, 29.12 mmol, 1.2 equiv) in DCE (50 mL) was added 6-bromo-3-(methylthio)-1,2,4-triazine (5 g, 24.26 mmol, 1.0 equiv) at room temperature. The reaction mixture was stirred for 20 min, then diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=15:1) to give 1-bromo-4-(methylthio)imidazo[1,5-d][1,2,4]triazine (3.71 g, 62.38% yield) as a yellow solid. MS m / z 244.9, 246.9 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.93 (s, 1H), 2.80 (s, 3H).

[0095] Intermediate 1f: 7-Bromo-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-ol [ka]

[0096] Step 1. 5-Methyl-1H-pyrazole-3-carbohydrazide Hydrazine hydrate (54 mL, 1.032 g / mL, 1.11 mol, 6.2 equiv) was added to a solution of methyl 5-methyl-1H-pyrazole-3-carboxylate (25.0 g, 0.178 mol, 1.0 equiv) in EtOH (250 mL). The mixture was sealed and heated at 80° C. for 60 h, then cooled to room temperature. The solvent was evaporated in vacuo. The crude product was treated with a 1 / 1 mixture of water / MeOH, filtered, and the filter cake was washed with water. The solid was dried under vacuum to give 5-methyl-1H-pyrazole-3-carbohydrazide (21.7 g, 87.0% yield) as a white solid. MS m / z 141.1 [M+H] + .

[0097] Step 2. 2-Methylpyrazolo[1,5-d][1,2,4]triazin-4-ol A mixture of 5-methyl-1H-pyrazole-3-carbohydrazide (3.00 g, 21.4 mmol, 1.0 equiv) and trimethoxymethane (2.57 mL, 0.970 g / mL, 23.5 mmol, 1.1 equiv) in DMF (10 mL) was sealed in a tube. The reaction mixture was stirred at 165° C. for 1 h in a microwave and then cooled to room temperature. The precipitate was collected by filtration, washed with EtOH, and dried under vacuum to give 2-methylpyrazolo[1,5-d][1,2,4]triazin-4-ol (1.70 g, 52.9% yield) as a white solid. MS m / z 149.2[MH] - .

[0098] Step 3. 7-Bromo-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-ol Benzyltrimethylammonium tribromide (26.5 g, 68.0 mmol, 1.5 equiv) was added in portions to a stirred solution of 2-methylpyrazolo[1,5-d][1,2,4]triazin-4-ol (6.80 g, 45.3 mmol, 1.0 equiv) and 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (18.3 mL, 0.85 g / mL, 90.6 mmol, 2.0 equiv) in 1,4-dioxane (290 mL) at 10° C. under N2. Upon complete addition, the mixture was warmed to 20° C. and stirred at this temperature for 16 h. The mixture was then quenched with a mixture of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3, then extracted with EtOAc (150 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was triturated with EtOAc, filtered and washed with EtOAc. The solid was dried under vacuum to give 7-bromo-2-methylpyrazolo[1,5-d][1,2,4]triazin-4-ol (7.60 g, 73.6% yield) as an off-white solid. MS m / z 229.0, 230.9 [M+H] + ; 1H NMR (400Hz, DMSO-d6) δ 12.60 (s, 1H), 7.15 (s, 1H), 2.42 (s, 3H).

[0099] Intermediate 2a: 2-(4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0100] Step 1: (2-Bromo-5-methoxy-phenyl)methanol To an ice-cooled solution of 2-bromo-5-methoxy-benzoic acid (9.95 g, 43.1 mmol) in THF (86 mL) was added borane-dimethylsulfide complex (6.01 mL, 64.6 mmol). The resulting mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with methanol and stirred for 5 min. The reaction was concentrated and the resulting yellow oil was dissolved in EtOAc (150 mL) and washed with 10% Na2CO3 (30 mL). The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and concentrated to give a colorless oil which was carried on to the next step without further purification.

[0101] Step 2: 1-Bromo-2-(bromomethyl)-4-methoxy-benzene The crude [2-bromo-5-(trifluoromethyl)phenyl]methanol in concentrated HBr (30 mL) was heated to reflux for 2 h. The reaction was cooled to room temperature and extracted with DCM. The combined organic extracts were washed with saturated NaHCO3, brine, dried (Na2SO4), filtered and concentrated to give a white solid. Purification by chromatography on SiO2 (EtOAc:Hexanes, 10-30%) gave a white solid (10.99 g, 91%, 2 steps). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J= 8.9 Hz, 1 H), 7.00 (d, J= 3.0 Hz, 1 H), 6.75 (dd, J= 8.9 Hz, 3.0 Hz, 1H), 4.57 (s, 2 H), 3.81 (s, 3 H).

[0102] Step 3: 1-Bromo-4-methoxy-2-(2,2,2-trifluoroethyl)benzene To a solution of 1-bromo-2-(bromomethyl)-4-methoxy-benzene (5.62 g, 20.1 mmol) in DMF (45 mL) was added CuI (9.56 g, 50.2 mmol) and the solution was sparged with Ar. To this solution was added difluoro-fluorosulfonyl-acetic acid methyl ester (6.4 mL, 50.2 mmol) and the resulting reaction mixture was heated at 120° C. for 4 h. The reaction mixture was cooled to 0° C., diluted with EtOAc (200 ml) and stirred for 10 min. Concentrated ammonium hydroxide (30 mL) was added dropwise and the mixture was stirred at 0° C. for 15 min before warming to room temperature. EtOAc (200 ml) and water (100 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 ml), dried (MgSO4), filtered and concentrated. Purification by chromatography on SiO2 (EtOAc:Hexanes, 0-10%) afforded a pale yellow oil (4.13 g, 77%). 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J= 8.9 Hz, 1 H), 6.93 (d, J= 2.8 Hz, 1 H), 6.78 (dd, J= 8.8 Hz, 3.1 Hz, 1H), 3.81 (s, 3 H), 3.60 (q, J= 10.5 Hz, 2H).

[0103] Intermediate 2b: 4,4,5,5-tetramethyl-2-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane [ka] Step 1. (2-Bromo-5-(trifluoromethyl)phenyl)methanol To a solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (30.0 g, 118.6 mmol, 1.0 equiv) in MeOH (300 mL) was added NaBH4 (13.5 g, 3 equiv) slowly at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The filtrate was concentrated in vacuo to give (2-bromo-5-(trifluoromethyl)phenyl)methanol (27 g, 78.4% yield) as a white solid. The crude product was used directly without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.44 - 7.39 (m, 1H), 4.81 (s, 2H).

[0104] Step 2. 1-Bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene 2-Bromo-5-(trifluoromethyl)phenyl)methanol (26.0 g, 102.0 mmol, 1.0 equiv) was added to aqueous HBr (156 mL). The reaction mixture was stirred at 120° C. for 2 h under N2 atmosphere. The reaction mixture was diluted with NaHCO3 (100 mL) and extracted with DCM (250 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=0%-10%) to give 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (25 g, 76.9% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 8.4, 2.1 Hz, 1H), 4.83 (s, 2H).

[0105] Step 3. 1-Bromo-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzene To a solution of 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (40.5 g, 127.4 mmol, 1.0 equiv) in DMF (280 mL) was added CuI (60.7 g, 2.5 equiv) and ethyl 2,2-difluoro-2-(fluorosulfonyl)acetate (65.7 g, 2.5 equiv) at room temperature under N2. The reaction mixture was stirred at 120° C. overnight under N2 atmosphere. The reaction mixture was cooled to 0° C., diluted with EtOAc (1200 mL) and stirred at 0° C. for 10 min. A solution of ammonium hydroxide (240 mL) was added dropwise. The mixture was stirred over 20 min while warming from 0° C. to room temperature. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (550 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=0%-10%) to give 1-bromo-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzene (16.8 g, 17.9% yield) as a yellow oil. 1 HNMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 15.1, 8.2 Hz, 2H), 7.70 (dd, J = 8.4, 2.1 Hz, 1H), 3.97 (q, J= 11.0 Hz, 2H).

[0106] Step 4. 4,4,5,5-Tetramethyl-2-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane To a solution of 1-bromo-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzene (16.8 g, 54.7 mmol, 1.0 equiv.) in 1,4-dioxane (160 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (27.8 g, 2 equiv.), Pd(dppf)Cl2 (4.0 g, 0.1 equiv.) and KOAc (16.1 g, 3 equiv.) were added at room temperature under N2 atmosphere. The reaction mixture was stirred at 100° C. under N2 for 12 h. The reaction mixture was diluted with water (90 mL) and extracted with EtOAc (150 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=0%-10%) to give 4,4,5,5-tetramethyl-2-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (10.5 g, 45.8% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 7.8 Hz, 1H), 7.79 - 7.73 (m, 2H), 4.08 (q, J = 11.2 Hz, 2H), 1.32 (s, 12H).

[0107] The following intermediates were prepared following the procedures for intermediates 2a and 2b by substituting the appropriate starting materials, reagents and reaction conditions. [Table 5]

[0108] Intermediate 2c: 2-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0109] Step 1. 1-Bromo-2-(difluoromethyl)-4-(trifluoromethyl)benzene DAST (10 equiv., 39.5 mmol) was added dropwise to a −78° C. solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (1 g, 3.9 mmol) in DCM (5 mL, 78.0 mmol). The reaction was stirred for 15 min and then warmed to room temperature. After 4 h, TLC indicated incomplete conversion, so the mixture was cooled back to −78° C. and additional DAST (1 equiv., 3.9 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight, then poured onto ice and dilute NH4OH and extracted twice with DCM. The combined organic extracts were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give a residue that was purified on a short plug of silica to give the crude product 1-bromo-2-(difluoromethyl)-4-(trifluoromethyl)benzene (350 mg, 1.2 mmol, 32.2% yield) as a colorless oil.

[0110] Step 2. 2-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-bromo-2-(difluoromethyl)-4-(trifluoromethyl)benzene (100 mg, 0.36 mmol) in 1,4-dioxane (2 mL) was added bis(pinacolato)diboron (1.5 equiv, 0.5 mmol), potassium acetate (2 equiv, 0.72 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (0.15 equiv, 0.05 mmol). The mixture was stirred at 100 °C under N2 atmosphere for 16 h and monitored by TLC and LCMS. After the reaction, the solvent was removed under vacuum, and the residue was purified by column chromatography (10-15% EA in PE) to give 2-[2-(difluoromethyl)-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30 mg, 0.09 mmol, yield 25.6%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J= 7.6 Hz, 1H),7.94 (d, J= 8.4 Hz, 1H),7.92 (s, 1H), 7.38 (t, J= 55.6 Hz, 1H),1.34 (s, 12H).

[0111] Intermediate 2d: 2-(4-chloro-2-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] The title compound was prepared in an analogous manner following the procedure of Intermediate 2c, using 2-bromo-5-chlorobenzaldehyde instead of 2-bromo-5-(trifluoromethyl)benzaldehyde in step 1. 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J= 2.0 Hz, 1H), 7.68 -7.63 (m, 2H), 7.32(t, J= 55.6Hz, 1H), 1.32 (s, 12H).

[0112] Intermediate 2e: 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0113] Step 1. 1-Bromo-2-(difluoromethoxy)-4(trifluoromethyl)benzene A mixture of 2-bromo-5-(trifluoromethyl)phenol (5.00 g, 20.7 mmol, 1.0 equiv), sodium 2-chloro-2,2-difluoroacetate (7.07 g, 51.9 mmol, 2.50 equiv) and cesium carbonate (11.5 g, 41.5 mmol, 2.0 equiv) in water (20 mL) and N,N-dimethylformamide (80 mL) was heated at 100 °C for 12 h. Upon completion, the reaction mixture was cooled to room temperature and diluted with EtOAc. The reaction mixture was washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in hexanes to give 1-bromo-2-difluoromethoxy)-4-(trifluoromethyl)benzene (2.8 g, 47% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.46 (t, J = 72.8 Hz, 1H), 7.5 (d, J = 8.4 Hz, 1H).

[0114] Step 2. 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-bromo-2-difluoromethoxy)-4(trifluoromethyl)benzene (2.80 g, 9.62 mmol) in 1,4-dioxane (30 mL) was added bis(pinacolato)diboron (36.6 g, 14.4 mmol, 1.50 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalldium(II) (704 mg, 0.96 mmol, 0.1 equiv), potassium acetate (2.82 g, 28.9 mmol, 3.0 equiv). The reaction mixture was heated at 100° C. under nitrogen for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with EA and washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with hexane to give 2-(2-(difluoromethoxy)-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a white solid (1.70 g, 52% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.24 (t, J = 74.0 Hz, 1H), 1.31 (s, 12H).

[0115] Intermediate 2f: 2-(2,4-bis(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0116] Step 1. 1-Bromo-2,4-bis(difluoromethoxy)benzene To a solution of 4-bromobenzene-1,3-diol (10.0 g, 53.4 mmol, 1.0 equiv) in ACN / H2O (1:1, 100 mL) was added KOH (60.0 g, 1.07 mol, 20 equiv) slowly at 0 °C. The mixture was stirred for 10 min and cooled to -10 °C. Diethyl (bromodifluoromethyl)phosphonate (42.70 g, 160.2 mmol, 3.0 equiv) was added slowly and the mixture was stirred for 10 min, warmed to room temperature, and stirred for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=0%-5%) to give 1-bromo-2,4-bis(difluoromethoxy)benzene (3.30 g, 21.3% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 72.0 Hz, 1H), 7.35 (t, J = 76.0 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.11 (dd, J = 8.8, 2.8 Hz, 1H).

[0117] Step 2. 2-(2,4-bis(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-bromo-2,4-bis(difluoromethoxy)benzene (3.30 g, 11.4 mmol, 1.0 equiv) in 1,4-dioxane was added KOAc (2.23 g, 22.8 mmol, 2.0 equiv), Pd(dppf)Cl2 (0.830 g, 1.10 mmol, 0.1 equiv) and bis(pinacolato)diboron (4.34 g, 17.1 mmol, 1.5 equiv). The reaction mixture was stirred at 100 °C under N2 for 16 h. The mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA = 0% to 10%) to give 2-(2,4-bis(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.0 g, 52% yield) as a yellow oil. 1 H NMR (400 MHz, methanol-d4) δ 7.72 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 73.2 Hz, 1H), 7.12 (t, J = 74.4 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.02 - 6.97 (m, 1H), 1.29 (s, 12H).

[0118] Intermediate 2g. 2-(4-bromo-2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0119] Step 1. 4-Bromo-2-(difluoromethoxy)-1-nitrobenzene To a solution of 5-bromo-2-nitrophenol (5.7 g, 26.15 mmol) in DMF (135 mL) / H2O (15 mL) was added Cs2CO3 (17.0 g, 52.29 mmol) and sodium 2-chloro-2,2-difluoroacetate (10.0 g, 65.37 mmol). The mixture was stirred at room temperature for 15 min and then heated to 100 °C for 16 h. The reaction mixture was cooled to room temperature and partitioned between water (500 mL) and EA (200 mL). The aqueous phase was extracted with EA (2 × 200 mL). The combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column (0-20% EA in PE) to give 4-bromo-2-(difluoromethoxy)-1-nitrobenzene as a yellow oil (4.0 g, 57% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 8.8, J = 1.6 Hz, 1H), 7.43 (t, J = 72.4 Hz, 1H).

[0120] Step 2. 4-Bromo-2-(difluoromethoxy)aniline To a solution of 4-bromo-2-(difluoromethoxy)-1-nitrobenzene (1.0 g, 3.73 mmol) in THF (10 mL) / HO (5 mL) was added a solution of NH4Cl (1.6 g, 29.85 mmol), Zn (1.95 g, 29.85 mmol) in HO (10 mL). The mixture was stirred at room temperature for 2 h, then filtered through a pad of Celite and rinsed with EA. The filtrate was extracted with EA (30 mL × 2). The organic extract was dried over Na2SO4, decanted, concentrated and purified by silica gel column (0-10% EA in PE) to give 4-bromo-2-(difluoromethoxy)aniline as a yellow oil (750 mg, 84% yield). MS m / z 236.0 [M-1] -; 1H NMR (400 MHz, DMSO-d6) δ 7.15 (s, 1H), 7.11 (dd, J = 8.8, 2.0 Hz, 1H), 7.09 (t, J = 74.0 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.28 (s, 2H).

[0121] Step 3. 2-(4-bromo-2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 4-bromo-2-(difluoromethoxy)aniline (13.0 g, 54.61 mmol) in MeCN (300 mL) was added t-BuNO2 (8.45 g, 81.92 mmol), (BPin)2 (15.26 g, 60.08 mmol) at 0° C. The mixture was stirred at 80° C. for 4 h, then concentrated and purified by silica gel column (0-5% EA in PE) to give 2-(4-bromo-2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oil (5.4 g, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.0, J= 1.6 Hz, 1H), 7.42 (s, 1H), 7.15 (t, J = 74.2 Hz, 1H), 1.29 (s, 12H).

[0122] The following intermediates were prepared following the procedures of Intermediates 2e-2g by substituting the appropriate starting materials, reagents and reaction conditions. [Table 6]

[0123] Intermediate 2h: 2-(2-cyclopropyl-6-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1. 3-Cyclopropyl-5-fluorophenol To a solution of 3-bromo-5-fluorophenol (5.0 g, 26.3 mmol, 1.0 equiv.) in dioxane (40 mL) and water (10 mL) was added cyclopropylboronic acid (4.5 g, 52.6 mmol, 2.0 equiv.), Pd(dppf)Cl2 (377 mg, 0.52 mmol, 0.2 equiv.) and cesium carbonate (25.7 g, 78.9 mmol, 3.0 equiv.). The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 16 h, then diluted with ethyl acetate (200 mL) and washed with water (200 mL). The aqueous phase was adjusted to pH 4 by addition of 6 M HCl and then extracted with ethyl acetate (3×100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether) to give 4-bromo-3-cyclopropyl-5-fluorophenol (3.1 g, 77.5% yield) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ 6.31 (t, J= 1.8 Hz, 1H), 6.28 - 6.25 (m, 1H), 6.25 - 6.22 (m, 1H), 1.85 -1.76 (m, 1H), 0.97 - 0.88 (m, 2H), 0.66 - 0.58 (m, 2H).

[0124] Step 2. 4-Bromo-3-cyclopropyl-5-fluorophenol To a solution of 4-bromo-3-cyclopropyl-5-fluorophenol (3 g, 19.7 mmol, 1.0 equiv.) in dichloromethane (15 mL) and methanol (15 mL) was added tetrabutylammonium tribromide (10.4 g, 21.7 mmol, 1.1 equiv.). The resulting mixture was stirred at room temperature for 2 h. Water (100 mL) was then added. The mixture was extracted with dichloromethane (3×50 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether) to give 4-bromo-3-cyclopropyl-5-fluorophenol (3.9 g, 85.7% yield) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ 6.50 - 6.42 (m, 1H), 6.27 -6.20 (m, 1H), 2.23 - 2.09 (m, 1H), 1.03 - 0.97 (m, 2H), 0.66 - 0.59 (m, 2H).

[0125] Step 3. 2-Bromo-1-cyclopropyl-3-fluoro-5-methoxybenzene To a solution of 4-bromo-3-cyclopropyl-5-fluorophenol (3.9 g, 16.9 mmol, 1.0 equiv.) in N,N-dimethylformamide (40 mL) was added methyl iodide (1.58 mL, 25.4 mmol, 1.5 equiv.) and potassium carbonate (4.67 g, 33.8 mmol, 2.0 equiv.). The resulting mixture was stirred at 70° C. for 2 h. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (3×100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (3% ethyl acetate in petroleum ether) to give 2-bromo-1-cyclopropyl-3-fluoro-5-methoxybenzene (3.1 g, 74.8% yield) as a pink oil. 1H NMR (400 MHz, methanol-d4) δ 6.69 -6.55 (m, 1H), 6.48 - 6.28 (m, 1H), 3.87 - 3.72 (m, 3H), 2.26 - 2.08 (m, 1H), 1.03 - 0.93 (m, 2H), 0.77 - 0.59 (m, 2H).

[0126] Step 4. 2-(2-cyclopropyl-6-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 2-bromo-1-cyclopropyl-3-fluoro-5-methoxybenzene (3.0 g, 12.2 mmol, 1.0 equiv.) in tetrahydrofuran (30 mL) was added n-butyllithium (6.3 mL, 15.9 mmol, 1.3 equiv., 2.5 M in hexanes) at −78° C. The resulting mixture was stirred at −78° C. for 30 min, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.97 mL, 14.6 mmol, 1.2 equiv.) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for an additional 2 h. The reaction was quenched with water (100 mL) and the mixture was extracted with ethyl acetate (4×50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (3% ethyl acetate in petroleum ether) to give 2-(2-cyclopropyl-6-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 g, 53.3% yield) as a pale yellow oil. MS m / z 293.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ 6.52 - 6.37 (m, 1H), 6.31 - 6.17 (m, 1H), 3.79 - 3.69 (m, 3H), 2.34 - 2.19 (m, 0.8H), 2.00 - 1.90 (m, 0.16H), 1.39 - 1.33 (m, 12H), 0.95 - 0.84 (m, 2H), 0.69 - 0.60 (m, 2H).

[0127] Intermediate 2i. 2-(4-Methoxy-2-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1. 1-Bromo-4-methoxy-2-(2,2,2-trifluoroethoxy)benzene To a solution of NaH (2.2 g, 53.6 mmol, 60% in oil, 2.2 equiv) in DMF (20 mL) was added 2,2,2-trifluoroethan-1-ol (4.9 g, 48.8 mmol, 2.0 equiv) dropwise under N2 at 0° C. The mixture was stirred at 0° C. under N2 for 0.5 h and 1-bromo-2-fluoro-4-methoxybenzene (5.0 g, 24.4 mmol, 1.0 equiv) was added. The mixture was warmed to 100° C. and stirred under N2 for 16 h, then poured into water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0–7% ethyl acetate in petroleum ether) to give 1-bromo-4-methoxy-2-(2,2,2-trifluoroethoxy)benzene (3.5 g, 12.3 mmol, 50.4% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.61 (dd, J = 8.8, 2.8 Hz, 1H), 4.86 (q, J = 8.8 Hz, 2H), 3.78 (s, 3H).

[0128] Step 2. 2-(4-Methoxy-2-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-bromo-4-methoxy-2-(2,2,2-trifluoroethoxy)benzene (3.50 g, 12.3 mmol, 1.0 equiv.) in dioxane (40 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.7 g, 14.7 mmol, 1.2 equiv.), Pd(dppf)Cl2 (898.4 mg, 1.2 mmol, 0.1 equiv.) and KOAc (3.6 g, 36.8 mmol, 3.0 equiv.). The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 16 h, then cooled, diluted with ethyl acetate (200 mL), washed with water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (0–10% ethyl acetate in petroleum ether) to give 2-(4-methoxy-2-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 4.5 mmol, 36.8% yield) as a white solid. MS m / z 333.1[M+H]+; 1H NMR (400 MHz, methanol - d4) δ 7.56 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.0, 2.0 Hz, 1H), 6.54 (d, J = 2.0Hz, 1H), 4.47 (q, J = 8.4 Hz, 2H), 3.81 (s, 3H), 1.32 (s, 12H).

[0129] Intermediate 2j. 2-(4-Methoxy-2-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step 1. 4-Iodo-2-(trifluoromethoxy)aniline To a solution of 2-(trifluoromethoxy)aniline (29 g, 163.73 mmol, 1.0 equiv) in acetic acid (80 mL) was added NIS (40.52 g, 180.10 mmol, 1.1 equiv) slowly at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated in vacuo to remove acetic acid, then the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (EA in PE = 0% - 20) to give 4-iodo-2-(trifluoromethoxy)aniline (40.6 g, 81.8% yield) as a red solid. MS m / z 303.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.32 (m, 2H), 6.66 (d, J = 8.4 Hz, 1H), 5.59 (s, 2H).

[0130] Step 2. 4-Methoxy-2-(trifluoromethoxy)aniline To a solution of 4-iodo-2-(trifluoromethoxy)aniline (23.8 g, 78.54 mmol, 1.0 equiv.) in MeOH (200 mL), 1,10-phenanthroline (1.42 g, 7.85 mmol, 0.1 equiv.), Cs2CO3 (51.18 g, 157.08 mmol, 2.0 equiv.) and CuI (0.748 g, 3.93 mmol, 0.05 equiv.) were added at room temperature under N2. The reaction mixture was stirred at 110 °C for 16 h in an autoclave reactor. The reaction solution was concentrated in vacuum to remove MeOH, then the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (EA in PE=0%-10%) to give 4-methoxy-2-(trifluoromethoxy)aniline (11 g, 67.61% yield) as a yellow oil. MS m / z 208.2 [M+1] + ; 1H NMR (400 MHz, methanol- d4) δ 6.91 - 6.67 (m, 3H), 3.71 (s, 3H).

[0131] Step 3. 2-(4-Methoxy-2-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 4-methoxy-2-(trifluoromethoxy)aniline (11 g, 53.10 mmol, 1.0 equiv) in ACN (25 mL) was added tBuNO2 (8.21 g, 79.65 mmol, 1.5 equiv) and (BPin)2 (16.18 g, 63.72 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirred at 80° C. under N2 atmosphere for 4 h, then cooled and concentrated in vacuo, followed by dilution with water (200 mL) and extraction with ethyl acetate (150 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (EA in PE=0%-2%) to give 2-(4-methoxy-2-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.6 g, 33.15% yield) as a yellow oil. MS m / z 319.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J= 8.4 Hz, 1H), 7.08 - 7.03 (m, 1H), 6.92 (s, 1H), 3.87 (s, 3H), 1.32 (s, 12H). Intermediate 3a: (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-3-amine [ka]

[0132] Step 1. tert-Butyl (3R)-3-(benzyloxycarbonylamino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-aminopiperidine-1-carboxylate (30 g, 0.15 mol) in THF (330 mL) and water (83 mL) was added Na2CO3 (43 g, 0.31 mol). Cbz-Cl (34, 0.199 mol) was then added dropwise to the mixture in an ice bath and monitored by TLC. After 5 h, the reaction mixture was extracted with EA, dried over Na2SO4, and evaporated in vacuum. The crude product was purified by flash chromatography (PE:EA=4:1) to give tert-butyl (3R)-3-(benzyloxycarbonylamino)piperidine-1-carboxylate (35 g, 84% yield). MS m / z 235.1 [M-Boc+H] +

[0133] Step 2. Benzyl N-[(3R)-3-piperidyl]carbamate To a solution of tert-butyl (3R)-3-(benzyloxycarbonylamino)piperidine-1-carboxylate (35 g, 0.104 mol) in 450 mL DCM, HCl (350 mL, 4 M in 1,4-dioxane) was added and monitored by TLC. After 2 h, the solvent was removed in vacuo to give crude benzyl N-[(3R)-3-piperidyl]carbamate (25 g, 100% yield), which was used in the next step without purification. MS m / z 234.1 [M+H] + .

[0134] Step 3. Benzyl N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]carbamate To a solution of benzyl N-[(3R)-3-piperidyl]carbamate (25 g, 0.106 mol) in CH3CN (680 mL) was added Cs2CO3 (175 g, 0.537 mol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (40 g, 0.167 mol). The reaction mixture was stirred at 90° C. for 16 h, then filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography to give the product benzyl N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]carbamate (22.5 g, 53% yield). MS m / z 393.2 [M+H] + .

[0135] Step 4. (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-3-amine To a solution of benzyl N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]carbamate (22.5 g, 0.057 mol) in MeOH (60 mL) was added Pd / C (4.5 g, 20%). The system was evacuated and backfilled with hydrogen. The mixture was then stirred at room temperature overnight. After the reaction, the mixture was filtered, the solvent was removed in vacuo, and the crude product was purified by flash chromatography to give the product (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-3-amine (12 g, 81% yield). MS m / z 259.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 3.68 (t, J = 6.6 Hz, 2H), 2.85 - 2.74 (m, 2H), 2.67 - 2.58 (m, 1H), 2.46 (t, J = 6.4 Hz, 2H), 2.11 - 2.01 (m, 1H), 1.94 - 1.83 (m, 1H), 1.83 - 1.71 (m, 4H), 1.68 - 1.58 (m, 1H), 1.56 - 1.43 (m, 1H), 1.09 - 0.96 (m, 1H), 0.88 - 0.79 (m, 9H), 0.04 - (-)0.04 (m, 6H).

[0136] Intermediate 3b: (R)-1-Ethylpiperidin-3-amine hydrochloride [ka] Step 1. tert-Butyl (R)-(1-ethylpiperidin-3-yl)carbamate To a solution of tert-butyl (R)-piperidin-3-ylcarbamate (4 g, 20 mmol) in MeCN (40 mL) was added K2CO3 (2.76 g, 20 mmol) and MeI (3.12 g, 20 mmol) under N2 at 20 °C. The mixture was stirred at 20 °C for 16 h. TLC showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated. Purification by column (DCM:MeOH = 0-10%) gave tert-butyl (R)-(1-ethylpiperidin-3-yl)carbamate (3.6 g, 15.8 mmol, 78.9% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 6.65 (d, J= 7.8 Hz, 1H), 3.32 (s, 1H), 2.70 (dd, J= 41.0, 9.7 Hz, 2H), 2.29 (q, J= 7.1 Hz, 2H), 1.83 - 1.53 (m, 4H), 1.48 - 1.40 (m, 1H), 1.37 (s, 9H), 1.11 (qd, J= 11.8, 3.7 Hz, 1H), 0.96 (t, J = 7.2 Hz, 3H).

[0137] Step 2. (R)-1-Ethylpiperidin-3-amine hydrochloride To a solution of tert-butyl (R)-(1-ethylpiperidin-3-yl)carbamate (3.6 g, 15.8 mmol) in MeOH (10 mL) was added HCl (30 mL, 3M in EA) at room temperature. The mixture was stirred at 20° C. for 16 h. TLC showed the reaction was complete. The reaction mixture was concentrated to give (R)-1-ethylpiperidin-3-amine hydrochloride (3.03 g, 15.0 mmol, 95.0% yield) as a yellow oil. MS m / z 129.2 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ 3.83 - 3.59 (m, 3H), 3.36 - 3.30 (m, 2H), 3.18 - 2.96 (m, 2H), 2.25 (d, J= 12.7 Hz, 1H), 2.15 (d, J = 14.9 Hz, 1H), 2.07 - 1.92 (m, 1H), 1.76-1.72 (m, 1H), 1.43 (t, J= 7.3 Hz, 3H).

[0138] Intermediate 9c: (R)-1-(3-aminopiperidin-1-yl)-2-methylpropan-2-ol [ka] Step-1: tert-Butyl (R)-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)carbamate A mixture of tert-butyl (R)-piperidin-3-ylcarbamate (700 mg, 3.5 mmol, 1.0 equiv.) and 2,2-dimethyloxirane (800 mg, 11.1 mmol, 3.2 equiv.) was stirred at 90° C. for 18 h. The crude reaction mixture was allowed to cool to room temperature and diluted with DCM (20 mL). The organic phase was washed with saturated aqueous NaHCO3 (4 mL×2), followed by water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude material was then used in the following step. MS m / z 273.3 [M+H] + .

[0139] Step-2: (R)-1-(3-aminopiperidin-1-yl)-2-methylpropan-2-ol The crude compound from the previous step was dissolved in DCM (5 mL) and then 2M HCl in ether solution (10 mL) was added slowly at room temperature while the mixture was stirred vigorously. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo to give a light brown solid (520 mg) of the HCl salt. The amine was used without further purification. MS m / z 173.2 [M+H] + . The following intermediates were prepared following the procedures of Intermediates 3b-c or c by substituting the appropriate starting materials, reagents and reaction conditions.

[0140] [Table 7]

[0141] Intermediate 3d: (R)-1-(2-(difluoromethoxy)ethyl)piperidin-3-amine hydrochloride [ka]

[0142] Step 1: 2-Hydroxyethyl 4-methylbenzenesulfonate A mixture of ethylene glycol (2.5 g, 40 mmol), TsCl (1.90 g, 10 mmol), pyridine (1.1 g, 12 mmol) and DMAP (12 mg, 0.1 mmol) was stirred at room temperature for 18 h. The reaction mixture was partitioned between DCM (20 mL) and 0.5 M hydrochloric acid. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by chromatography on SiO2 (EtOAc:hexanes, 0-60%) gave a colorless oil (1.32 g, 78%). 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.25 Hz, 2 H), 7.37 (d, J = 8.13 Hz, 2 H), 4.15 (t, J = 4.50 Hz, 2 H), 3.83 (t, J = 4.63 Hz, 2 H), 2.46 (s, 3 H), 2.00 (br s, 1 H).

[0143] Step 2. 2-(Difluoromethoxy)ethyl 4-methylbenzenesulfonate To a stirred solution of 2-hydroxyethyl 4-methylbenzenesulfonate (1.70 g, 7.86 mmol) in MeCN (13 mL) was added copper(I) iodide (0.300 g, 1.57 mmol). The resulting mixture was stirred at 70° C. and treated dropwise over 25 min with 2,2-difluoro-2-fluorosulfonyl-acetic acid (2.80 g, 15.7 mmol) as a solution in MeCN (10 mL). The resulting mixture was treated with anhydrous Na2SO4 (tsp) and stirring was continued for 1.5 h. The mixture was then cooled to room temperature, diluted with Et2O, and washed with brine, a 1:1 mixture of brine:water (2×), and brine. The organic phase was dried (Na2SO4), filtered, and concentrated. Purification by chromatography on SiO2 (EtOAc:hexanes, 0-25%) gave a pale yellow oil (0.759 g, 36%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.25 Hz, 2 H), 7.49 (d, J = 8.13 Hz, 2 H), 6.65 (t, J = 75.04 Hz, 1 H), 4.22 - 4.16 (m, 2 H), 4.04 - 3.98 (m, 2 H), 2.43 (s, 3 H)

[0144] Steps 3 and 4: (R)-1-(2-(difluoromethoxy)ethyl)piperidin-3-amine hydrochloride To t-butyl N-[(3R)-3-piperidyl]carbamate (0.500 g, 2.50 mmol) in DMF (10 mL) was added 2-(difluoromethoxy)ethyl 4-methylbenzenesulfonate (0.764 g, 2.87 mmol) and K2CO3 (0.690 g, 4.99 mmol). The mixture was stirred at 100 °C for 2 h, then diluted with DCM / iPrOH (9:1), washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by chromatography on SiO2 (EtOAc:Hexanes, 5-60%) gave a pale yellow oil (0.709 g). The oil was dissolved in MeOH (2.0 mL), treated with HCl / dioxane (4.0 M, 3 mL) and stirred for 4 h. The mixture was concentrated, resuspended in ether and filtered to give a white solid (0.371 g, 67%). 1 H NMR (400 MHz, D2O) δ 6.45 (t, J = 73.6 Hz, 1 H), 4.26 (t, J = 5.2 Hz, 2 H), 3.81 (d, J = 11.2 Hz, 1 H), 3.67 -3.58 (m, 2 H), 3.55 (t, J = 4.8 Hz, 2 H), 3.15 - 3.02 (m, 2 H), 2.21 (d, J = 12.4 Hz, 1 H), 2.11 (d, J = 15.2 Hz, 1 H), 1.90 - 1.79 (m, 1 H), 1.70 -1.60 (m, 1 H).

[0145] Intermediate 3f: (3R,5R)-5-fluoro-1-methylpiperidin-3-amine hydrochloride [ka]

[0146] Step 1. Methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate 1-(tert-Butyl) 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 40.8 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. TFA (10 mL, 132.3 mmol) was added slowly and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was concentrated in vacuo to give crude methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate as a yellow oil, which was used in the next step without further purification. MS m / z 146.1 [M+H] + .

[0147] Step 2. Methyl (2S,4S)-4-hydroxy-1-tritylpyrrolidine-2-carboxylate To a solution of the crude methyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate from above step in DCM (50 mL) was added TEA (12.4 g, 123 mmol) and Ph3CCl (11.4 g, 40.9 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with DCM (30 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by flash chromatography on silica gel (PE:EA = 10:1 to 5:1) to give methyl (2S,4S)-4-hydroxy-1-trityl-pyrrolidine-2-carboxylate (7.60 g, 48% yield for two steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.60 - 7.50 (m, 6H), 7.32 -7.23 (m, 6H), 7.21 - 7.13 (m, 3H), 3.92 - 3.80 (m, 3H), 3.65 (s, 3H), 3.46 (d, J= 11.5 Hz, 1H), 2.80 (dd, J= 11.5, 3.8 Hz, 1H), 1.62 (d, J= 13.8 Hz, 1H), 1.38 - 1.11 (m, 1H).

[0148] Step 3. Methyl (2S,4S)-4-((methylsulfonyl)oxy)-1-tritylpyrrolidine-2-carboxylate To a solution of methyl (2S,4S)-4-hydroxy-1-trityl-pyrrolidine-2-carboxylate (10.0 g, 25.8 mmol) in DCM (100 mL) was added TEA (7.90 g, 78.0 mmol) and MsCl (4.50 g, 39.0 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with DCM (80 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to give crude methyl (2S,4S)-4-methylsulfonyloxy-1-trityl-pyrrolidine-2-carboxylate as a yellow oil, which was used directly in the next step.

[0149] Step 4. Methyl (2S,4R)-4-azido-1-tritylpyrrolidine-2-carboxylate To a solution of methyl (2S,4S)-4-methylsulfonyloxy-1-trityl-pyrrolidine-2-carboxylate from the above step in DMF (140 mL) was added sodium azide (7.80 g, 120 mmol). The reaction mixture was stirred at 80 °C for 16 h, then diluted with water and extracted with EA (3 × 100 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA = 0% to 10%) to give methyl (2S,4R)-4-azido-1-trityl-pyrrolidine-2-carboxylate (8.00 g, 64.5% yield for two steps) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.58 - 7.51 (m, 6H), 7.33 - 7.24 (m, 6H), 7.18 (t, J= 7.3 Hz, 3H), 4.20 - 4.06 (m, 1H), 3.91 (d, J= 8.9 Hz, 1H), 3.72 (dd, J= 10.3, 7.6 Hz, 1H), 3.63 (s, 3H), 2.63 (dd, J= 10.3, 7.8 Hz, 1H), 1.90 - 1.79 (m, 1H), 0.94 - 0.88 (m, 1H).

[0150] Step 5. ((2S,4R)-4-amino-1-tritylpyrrolidin-2-yl)methanol To a stirred suspension of LiAlH4 (2.20 g, 58.0 mmol) in THF (80 mL) at 0° C. was added a solution of methyl (2S,4R)-4-azido-1-trityl-pyrrolidine-2-carboxylate (8.00 g, 19.4 mmol) in THF (10 mL). After the addition was complete, the reaction mixture was stirred at 0° C. for 1 h. The reaction was quenched with water (2.5 mL), 15% NaOH solution (2.5 mL) and water (6 mL). After stirring for 0.5 h, the mixture was dried over Na2SO4, filtered and concentrated to give the crude product [(2S,4R)-4-amino-1-trityl-pyrrolidin-2-yl]methanol as a yellow oil (7.00 g), which was carried on to the next step without purification.

[0151] Step 6. tert-Butyl ((3R,5S)-5-(hydroxymethyl)-1-tritylpyrrolidin-3-yl)carbamate To a solution of [(2S,4R)-4-amino-1-trityl-pyrrolidin-2-yl]methanol (7.00 g, 19.5 mmol) in 1,4-dioxane (70 mL) was added TEA (3.90 g, 39.0 mmol) and (Boc)2O (5.10 g, 23.0 mmol). The mixture was stirred at room temperature for 2 h, then diluted with water and extracted with EA (3×100 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE:EA=20:1) to give tert-butyl N-[(3R,5S)-5-(hydroxymethyl)-1-trityl-pyrrolidin-3-yl]carbamate (8.00 g, 89.3% yield) as a colorless oil. MS m / z 459.3 [M+H] + , 1 H NMR (400 MHz, CDCl3) δ 7.67 - 7.50 (m, 6H), 7.33 - 7.23 (m, 7H), 7.18 (t, J= 7.3 Hz, 3H), 4.27 - 4.18 (m, 1H), 3.77 - 3.64 (m, 2H), 3.58 - 3.51 (m, 1H), 3.50 - 3.32 (m, 2H), 2.60 - 2.48 (m, 1H), 2.03 - 1.94 (m, 1H), 1.90 - 1.81 (m, 1H), 1.36 (s, 9H).

[0152] Step 7. tert-Butyl ((3R,5R)-5-fluoro-1-tritylpiperidin-3-yl)carbamate DAST (2.80 mL, 21.0 mmol) was added dropwise to a stirred solution of tert-butyl N-[(3R,5S)-5-(hydroxymethyl)-1-trityl-pyrrolidin-3-yl]carbamate (6.80 g, 15.0 mmol) in THF (70 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 1 h, then cooled to 0° C. again. A saturated aqueous solution of Na2SO3 was added to adjust the pH to 12. The phases were separated and the aqueous phase was extracted with EtOAc (2×40 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, PE / EtOAc=20 / 1) to give tert-butyl N-[(3R,5R)-5-fluoro-1-trityl-3-piperidyl]carbamate (3.90 g, 57% yield) as a white solid. MS m / z 483.3 [M+Na] + .

[0153] Step 8. tert-Butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate To a solution of tert-butyl N-[(3R,5R)-5-fluoro-1-trityl-3-piperidyl]carbamate (3.90 g, 8.50 mmol) in MeOH (80 mL) was added AcOH (8 mL, 139.6 mmol). The mixture was stirred at 80 °C for 2 h and then concentrated under reduced pressure. The residue was diluted with EA (20 mL) and H2O (20 mL). The mixture was acidified with aqueous HCl until pH = 2-3 and extracted with EA (10 mL x 2). The aqueous layer was basified with aqueous K2CO3 until pH = 9-10 and extracted with DCM (50 mL x 3). The DCM layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (1.60 g, 87% yield) as a white solid. MS m / z 219.1 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 6.61 (s, 1H), 4.77 (d, J= 48.5 Hz, 1H), 3.60 (br s, 1H), 2.96 - 2.82 (m, 2H), 2.77 - 2.62 (m, 1H), 2.43 - 2.33 (m, 1H), 2.09 - 1.97 (m, 1H), 1.78 - 1.55 (m, 1H), 1.39 (s, 9H)

[0154] Step 9. tert-Butyl ((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)carbamate To a solution of tert-butyl N-[(3R,5R)-5-fluoro-3-piperidyl]carbamate (1.60 g, 7.30 mmol) in DCE (20 mL) was added formic acid (1.20 g, 26.0 mmol) and (HCHO)n (0.75 g, 25 mmol) and stirred at room temperature for 1 h. To the mixture was added NaBH(OAc)3 (5.4 g, 25.0 mmol) and stirred at room temperature for 16 h. The reaction mixture was quenched with water, basified with aqueous K2CO3 and extracted with DCM. The organic phases were combined and washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA=3 / 1) to give tert-butyl N-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]carbamate (1.00 g, 59.0% yield) as a white solid. MS m / z 233.1 [M+H] + ,

[0155] Step 10. (3R,5R)-5-Fluoro-1-methylpiperidin-3-amine hydrochloride To a solution of tert-butyl N-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]carbamate (1.00 g, 4.30 mmol) in EA (10 mL) was added HCl in 1,4-dioxane (14 mL, 56 mmol, 4 mol / L). The resulting mixture was stirred at room temperature for 2 h, then filtered, the solid was washed with EA (2 mL) and dried under vacuum to give (3R,5R)-5-fluoro-1-methyl-piperidin-3-amine hydrochloride (750 mg, 75% yield) as a white solid. MS m / z 133.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (d, J = 3.6 Hz, 1H), 8.94 (s, 3H), 5.25 (d, J = 44.4 Hz, 1H), 3.72 - 3.66 (m, 2H), 3.56 - 3.50 (m, 1H), 3.41 - 3.27 (m, 1H), 3.13 (t, J= 11.2 Hz, 1H), 2.85 (s, 3H), 2.47 -2.41 (m, 1H), 2.01 - 1.83 (m, 1H).

[0156] Intermediate 3g: (3R,5R)-5-fluoro-1-ethylpiperidin-3-amine hydrochloride [ka] The starting material, tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate, was prepared as per the procedure of steps 1-8 of intermediate 3f.

[0157] The title compound was prepared in a similar manner following the procedure of Intermediate 3b, using tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate instead of tert-butyl (R)-piperidin-3-ylcarbamate in step 1. MS m / z 147.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.94 (s, 3H), 5.27 (d, J = 44.8 Hz, 1H), 3.74 - 3.62 (m, 3H), 3.32 - 3.22 (m, 3H), 3.09 - 3.05 (m, 1H), 2.48-2.43 (m, 1H), 2.06-1.89 (m, 1H), 1.28 - 1.25 (t, J = 14.0 Hz, 3H).

[0158] Example 1 Preparation of Compound 1 (1s,3s)-3-((1-(4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-methylcyclobutan-1-ol

[0159] [ka] Step 1: 1-[4-Methoxy-2-(2,2,2-trifluoroethyl)phenyl]-4-methylsulfanyl-pyrrolo[1,2-d][1,2,4]triazine 1-Chloro-4-methylsulfanyl-pyrrolo[1,2-d][1,2,4]triazine (Intermediate 1c, 0.380 g, 1.90 mmol), 2-[4-Methoxy-2-(2,2,2-trifluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (Intermediate 2a, 0.842 g, 2.66 mmol) and XPhos Pd G3 (0.164 g, 0.190 mmol) were added to a vial, evacuated and backfilled with Ar, to which was added dioxane (9.5 mL) and K2CO3 (2M, 2.9 mL, 5.71 mmol). The mixture was sparged with Ar for 5 min and then heated to 95 °C for 3 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with brine, dried (MgSO4), filtered and concentrated. Purification by chromatography on SiO2 (EtOAc:Hexanes, 0-30%) afforded a pink solid (0.329 g, 49%). MS m / z 354.4 [M+H] + .

[0160] Step 2: (1s,3s)-3-((1-(4-methoxy-2-(2,2,2-trifluoroethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)amino)-1-methylcyclobutan-1-ol 1-[4-Methoxy-2-(2,2,2-trifluoroethyl)phenyl]-4-methylsulfanyl-pyrrolo[1,2-d][1,2,4]triazine (0.070 g, 0.18 mmol) and 3-amino-1-methyl-cyclobutanol hydrochloride (0.030 g, 0.22 mmol) in DMA (0.10 mL) and iPr2NEt (0.10 mL, 0.57 mmol) were heated to 135 °C for 4 h. The reaction was cooled to room temperature and diluted with DCM / iPrOH (9:1). The solution was washed with brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography on SiO2 (MeOH:DCM, 0-10%) followed by reverse phase chromatography (0.1% formic acid in MeCN:0.1% formic acid in H2O, 5-100%) gave a white solid (0.010 g, 28%). MS m / z 407.3 [M+H]+; 1H NMR (500 MHz, methanol-d4) δ 7.83 (d, J= 1.8 Hz, 1H), 7.47 (d, J= 8.5 Hz, 1H), 7.10 (s, 1H), 7.09 - 7.04 (m, 1H), 6.96 (t, J = 3.4 Hz, 1H), 6.53 (d, J= 3.8 Hz, 1H), 4.31 - 4.21 (m, 1H), 3.89 (s, 3H), 3.69 (q, J= 11.14 Hz, 2H), 2.69 - 2.62 (m, 2H), 2.31 - 2.22 (m, 2H), 1.44 (s, 3H). 2H is not observed (NH and OH). The following compounds were prepared following the procedure of Example 1 by substituting the appropriate starting materials, reagents and reaction conditions.

[0161] [Table 8] JPEG2025509088000083.jpg254170 JPEG2025509088000084.jpg250170 JPEG2025509088000085.jpg250158 JPEG2025509088000086.jpg251165 JPEG2025509088000087.jpg249162 JPEG2025509088000088.jpg249157 JPEG2025509088000089.jpg250160 JPEG2025509088000090.jpg250157 JPEG2025509088000091.jpg242169 JPEG2025509088000092.jpg229170 JPEG2025509088000093.jpg250170 JPEG2025509088000094.jpg248170 JPEG2025509088000095.jpg249161 JPEG2025509088000096.jpg253170 JPEG2025509088000097.jpg239170 JPEG2025509088000098.jpg250160 JPEG2025509088000099.jpg249160 JPEG2025509088000100.jpg245169 JPEG2025509088000101.jpg246170 JPEG2025509088000102.jpg239170 JPEG2025509088000103.jpg250160 JPEG2025509088000104.jpg250170 JPEG2025509088000105.jpg250170 JPEG2025509088000106.jpg250170 JPEG2025509088000107.jpg250170

[0162] Example 2 Preparation of compound 2 (R)-N-(1-methylpiperidin-3-yl)-1-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)imidazo[1,5-d][1,2,4]triazin-4-amine

[0163] [ka] Step 1. 3-(Methylthio)-6-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,2,4-triazine To a solution of 4,4,5,5-tetramethyl-2-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (Intermediate 2b, 2 g, 5.7 mmol, 1.0 equiv.) in 1,4-dioxane / HO (5:1, 24 mL), 6-bromo-3-(methylthio)-1,2,4-triazine (1.1 g, 5.1 mmol, 1 equiv.), Pd(dppf)Cl2 (372.6 mg, 0.1 equiv.) and K3PO4 (2.16 g, 2 equiv.) were added at room temperature under N2 atmosphere. The reaction mixture was stirred at 90 °C under N2 for 2 h, then diluted with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA=0%-10%) to give 3-(methylthio)-6-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,2,4-triazine (1.6 g, 81.1% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.03 - 7.97 (m, 2H), 7.89 (d, J = 8.0 Hz, 1H), 4.10 (q, J = 11.2 Hz, 2H), 2.70 (s, 3H).

[0164] Step 2. 4-(Methylthio)-1-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)imidazo[1,5-d][1,2,4]triazine To a solution of TosMIC (1.1 g, 5.4 mmol, 1.2 equiv.) and DBU (827.4 mg, 5.4 mmol, 1.2 equiv.) in DCE (20 mL) was added 3-(methylthio)-6-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,2,4-triazine (1.6 g, 4.5 mmol, 1.0 equiv.) at room temperature under N2. The reaction mixture was stirred at room temperature for 2 h, then diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA = 0%-25%) to give the title product (1.29 g, 44.9% yield) as a yellow oil. MS m / z 392.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.04 (s, 1H), 7.95 (dd, J = 19.0, 8.2 Hz, 2H), 7.71 (s, 1H), 4.13 - 4.04 (m, 2H), 2.89 (s, 3H).

[0165] Step 3. (R)-N-(1-methylpiperidin-3-yl)-1-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)imidazo[1,5-d][1,2,4]triazin-4-amine To a solution of 4-(methylthio)-1-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-imidazo[1,5-d][1,2,4]triazine (100 mg, 0.25 mmol, 1.0 equiv.) in DMA (1 mL) was added (R)-1-methylpiperidin-3-amine dihydrochloride (119 mg, 0.64 mmol, 2.5 equiv.) and DIEA (329.4 mg, 10.0 equiv.) slowly at room temperature under N2. The reaction mixture was stirred at 140 °C under N2 for 12 h, then filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (0.1% formic acid in MeCN:0.1% formic acid in HO, 5-100%) to give the title product (16.4 mg, 13.8% yield) as a pale yellow solid as the formate salt. MS m / z 459.0 [M+1] + ; 1 H NMR(400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.49 (s, 1H), 7.92 (s, 1H), 7.85 (dd, J = 19.2, 8.2 Hz, 2H), 7.50 (s, 1H), 4.63 - 4.36 (m, 1H), 3.92 (q, J = 10.9 Hz, 2H), 3.64 - 3.47 (m, 1H), 3.29 - 3.08 (m, 2H), 3.02 - 2.79 (m, 2H), 2.72 - 2.57 (m, 1H), 2.31 - 1.70 (m, 4H), 1.28 (t, J = 6.8 Hz, 3H). The following compounds were prepared following the procedure of Example 2 by substituting the appropriate starting materials, reagents and reaction conditions.

[0166] [Table 9] JPEG2025509088000110.jpg250170 JPEG2025509088000111.jpg250161 JPEG2025509088000112.jpg239170 JPEG2025509088000113.jpg249170 JPEG2025509088000114.jpg249162 JPEG2025509088000115.jpg249157 JPEG2025509088000116.jpg249160 JPEG2025509088000117.jpg247170 JPEG2025509088000118.jpg252170 JPEG2025509088000119.jpg246170 JPEG2025509088000120.jpg246170 JPEG2025509088000121.jpg246170 JPEG2025509088000122.jpg250164 JPEG2025509088000123.jpg249164 JPEG2025509088000124.jpg250162 JPEG2025509088000125.jpg251161 JPEG2025509088000126.jpg254170 JPEG2025509088000127.jpg248159 JPEG2025509088000128.jpg245170 JPEG2025509088000129.jpg245170 JPEG2025509088000130.jpg152170

[0167] Example 3 Preparation of Compound 3 (1s,3s)-1-Methyl-3-((2-methyl-4-(2-(trifluoromethoxy)-4-(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-yl)amino)cyclobutan-1-ol

[0168] [ka]

[0169] Step 1. 2-Methyl-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazin-4-ol A cold solution of 7-bromo-2-methyl-pyrazolo[1,5-d][1,2,4]triazin-4-ol (Intermediate 1f, 600.0 mg, 2.620 mmol) in dry DMF (2.6 mL) was treated with sodium thiomethoxide (386.6 mg, 5.239 mmol) at 0° C. The mixture was then stirred at room temperature for 30 min. Upon completion, the DMF was evaporated and the resulting oily residue was precipitated with water. The mixture was then cooled at 0° C. and the precipitate was filtered while still cold. The collected precipitate was washed with water and dried overnight to give 2-methyl-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazin-4-ol (476.0 mg, 93% yield) as a white solid. MS m / z 197.1 [M+H] + .

[0170] Step 2. 4-Chloro-2-methyl-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazine A mixture of 2-methyl-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazin-4-ol (476.0 mg, 2.426 mmol) and phosphoryloxy chloride (7.44 g, 4.51 mL, 48.51 mmol) was heated at 75° C. for 6 h, whereupon the solution became clear. Excess POCl3 was then evaporated and the resulting residue was precipitated with water. The pH of the aqueous solution was adjusted to neutral (pH approx. 7) using saturated NaHCO3 solution. The precipitate was filtered, washed with water and dried overnight to give 4-chloro-2-methyl-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazine (383 mg, 74% yield) as a white solid. MS m / z 215.1 [M+H] + .

[0171] Step 3. 2-Methyl-7-(methylthio)-4-(2-(trifluoromethoxy)-4-(trifluoromethyl)phenyl)-pyrazolo[1,5-d][1,2,4]triazine A mixture of 4-chloro-2-methyl-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazine (38.8 mg, 0.181 mmol), [2-(trifluoromethoxy)-4-(trifluoromethyl)phenyl]boronic acid (64.4 mg, 0.235 mmol), XPhos Pd G4 (16.4 mg, 0.0181 mmol) and potassium carbonate (74.9 mg, 0.542 mmol) was dissolved in dioxane (2.1 mL) and water (0.4 mL). The reaction vessel was evacuated and backflushed with nitrogen (3x) and the mixture was stirred under nitrogen atmosphere at 80°C for 4 h. Upon completion, the mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The resulting crude product was purified by flash column chromatography eluting with 0-80% EtOAc in hexanes to give 2-methyl-7-(methylthio)-4-(2-(trifluoromethoxy)-4-(trifluoromethyl)phenyl)-pyrazolo[1,5-d][1,2,4]triazine (25.5 mg, 35% yield) as a brown solid. MS m / z 409.1 [M+H] + .

[0172] Step 4. (1s,3s)-1-Methyl-3-((2-methyl-4-(2-(trifluoromethoxy)-4-(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-yl)amino)cyclobutan-1-ol To a solution of 2-ethyl-7-(methylthio)-4-(2-(trifluoromethoxy)-4-(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazine (25.5 mg, 0.0625 mmol) in NMP (0.50 mL) was added (1s,3s)-3-amino-1-methylcyclobutan-1-ol hydrochloride (25.8 mg, 0.187 mmol) and N,N-diisopropylethylamine (48.4 mg, 65.4 μL, 0.375 mmol). The mixture was heated at 130° C. under a nitrogen atmosphere for 24 hours, where partial conversion was achieved. Additional (1s,3s)-3-amino-1-methylcyclobutan-1-ol hydrochloride (25.8 mg, 0.187 mmol) was then added and the reaction was stirred and further heated at 140° C. for 24 hours. Upon complete conversion to the product, the solution was diluted with a small amount of water (0.50 mL). The black solution was purified by reverse phase chromatography (0.1% formic acid in MeCN:0.1% formic acid in HO, 5-100%) to give (1s,3s)-1-methyl-3-((2-methyl-4-(2-(trifluoromethoxy)-4-(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-yl)amino)cyclobutan-1-ol (18.2 mg, 63% yield) as a white solid. MS m / z 462.1 [M+H] + ; 1 H NMR (500 MHz, methanol-d4) δ 7.95 (d, J= 8.1 Hz, 1H), 7.89 (d, J= 8.1 Hz, 1H), 7.81 (s, 1H), 6.51 (s, 1H), 4.39 - 4.31 (m, 1H), 2.71 - 2.61 (m, 2H), 2.54 (s, 3H), 2.36 - 2.26 (m, 2H), 1.44 (s, 3H). The following compounds were prepared following the procedure of Example 3 by substituting the appropriate starting materials, reagents and reaction conditions.

[0173] [Table 10] JPEG2025509088000133.jpg243170 JPEG2025509088000134.jpg248164 JPEG2025509088000135.jpg247162 JPEG2025509088000136.jpg247170 JPEG2025509088000137.jpg89170

[0174] Example 4 Preparation of compound 4 (1s,3s)-3-((4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-yl)amino)-1-methylcyclobutan-1-ol

[0175] [ka]

[0176] Step 1. (2,4-Bis(trifluoromethyl)phenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (5.3 g, 35.0 mmol, 1.0 equiv) in tetrahydrofuran (170 mL) was added n-butyllithium (16.8 mL, 1.2 equiv, 2.5 M in hexanes) dropwise at -78°C. The reaction mixture was stirred at -78°C for 30 min, then 2,4-bis(trifluoromethyl)benzaldehyde (11.02 g, 1.3 equiv) was added. The mixture was then warmed to room temperature and stirred for 2 h before being quenched with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude (2,4-bis(trifluoromethyl)phenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol (15.0 g, crude) as a dark yellow oil, which was used in the next step without further purification.

[0177] Step 2. (2,4-Bis(trifluoromethyl)phenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanone To a solution of (2,4-bis(trifluoromethyl)phenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol (15.0 g, crude) in dichloromethane (170 mL) was added Dess-Martin periodinane (19.3 g, mmol, 1.3 equiv.) in small portions at 0° C. The reaction mixture was stirred at room temperature for 2 h and then washed with saturated Na2S2O3 solution (2×100 mL), saturated NaHCO3 solution (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give (2,4-bis(trifluoromethyl)phenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanone (15 g, crude) as a dark yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.23 ​​(d, J= 8.4 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.68 (d, J= 2.0 Hz, 1H), 6.66 (d, J= 2.0 Hz, 1H), 6.17 (dd, J= 10.0, 2.0 Hz, 1H), 3.95 (d, J = 11.6 Hz, 1H), 3.71 - 3.57 (m, 1H), 2.38 - 2.27 (m, 1H), 2.07 - 1.93 (m, 2H), 1.78 - 1.64 (m, 1H), 1.61 - 1.51 (m, 2H).

[0178] Step 3. (2,4-Bis(trifluoromethyl)phenyl)(1H-pyrazol-3-yl)methanone (2,4-Bis(trifluoromethyl)phenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanone (15 g, crude) was dissolved in a solution of dichloromethane (300 mL) and trifluoroacetic acid (30 mL). The resulting mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was adjusted to pH 7 by addition of saturated NaHCO3 solution. The organic phase was partitioned, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in hexanes to give (2,4-bis(trifluoromethyl)phenyl)(1H-pyrazol-3-yl)methanone (6.50 g, 60.2% yield over three steps) as a yellow solid. MS m / z 309.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.21 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 7.99 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 6.98 (s, 1H).

[0179] Step 4. 4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7(6H)-one A mixture of (2,4-bis(trifluoromethyl)phenyl)(1H-pyrazol-3-yl)methanone (3.0 g, 9.7 mmol, 1.0 equiv.) and ethyl hydrazine carboxylate (1.01 g, 1.0 equiv.) in mesitylene (100 mL) was heated at 165° C. for 4 h. Upon completion, the reaction mixture was cooled to room temperature and then directly purified by silica gel column chromatography eluting with 0-40% EtOAc in hexanes to give 4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7(6H)-one (1.50 g, 44.4% yield) as a pale yellow solid. MS m / z 349.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.21 (s, 1H), 8.18 (d, J= 8.0 Hz, 1H), 7.99 (dd, J= 2.8, 1.6 Hz, 1H), 7.88 (d, J= 8.0 Hz, 1H), 6.98 (dd, J= 2.4, 2.0 Hz, 1H).

[0180] Step 5. 4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazine-7(6H)-thione A mixture of 4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazine-7(6H)-one (1.50 g, 4.31 mmol, 1.0 equiv.) and Lawesson's reagent (3.49 g, 2.0 equiv.) in toluene (40 mL) was heated at 120° C. for 16 h. Upon completion, the reaction mixture was cooled to room temperature and then filtered through a pad of Celite. The filtrate was washed with water (80 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazine-7(6H)-thione (1.30 g, crude) as a light yellow solid, which was used in the next step without further purification.

[0181] Step 6. 4-(2,4-bis(trifluoromethyl)phenyl)-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazine To a mixture of 4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazine-7(6H)-thione (1.30 g, 1.0 equiv.) and K2CO3 (1.49 g, 2.5 equiv.) in THF (12 mL) and water (6 mL) was added iodomethane (0.4 mL, 1.5 equiv.) dropwise. The mixture was stirred at room temperature for 1 h, then diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-30% EtOAc in hexanes to give 4-(2,4-bis(trifluoromethyl)phenyl)-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazine (1.08 g, 66.2% yield over two steps) as a pale yellow solid. MS m / z 379.3[M+H] + .

[0182] Step 7. (1s,3s)-3-((4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-yl)amino)-1-methylcyclobutan-1-ol A mixture of 4-(2,4-bis(trifluoro-methyl)phenyl)-7-(methylthio)pyrazolo[1,5-d][1,2,4]triazine (200 mg, 0.53 mmol, 1.0 equiv), (1s,3s)-3-amino-1-methylcyclobutan-1-ol hydrochloride (180.9 mg, 2.5 equiv) and DIEA (1.20 mL, 13.0 equiv) in DMAc (0.75 mL) was heated at 140° C. for 4 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give (1s,3s)-3-((4-(2,4-bis(trifluoromethyl)phenyl)pyrazolo[1,5-d][1,2,4]triazin-7-yl)amino)-1-methylcyclobutan-1-ol (68.9 mg, 30.1% yield) as a white solid. MS m / z 432.1 [M+H] + .1 H NMR (400 MHz, methanol-d4) δ 8.21 - 8.18 (m, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 4.36 (quintet, J = 8.0 Hz, 1H), 2.71 - 2.62 (m, 2H), 2.37 - 2.29 (m, 2H), 1.44 (s, 3H). The following compounds were prepared following the procedure of Example 4 by substituting the appropriate starting materials, reagents and reaction conditions.

[0183] [Table 11]

[0184] Biological assays IL-1β secretion assay: Monocytic THP-1 cells (ATCC:TIB-202) were maintained in growth medium consisting of RPMI 1640 medium (ThermoFisher, Cat#11875-085), 10% FBS (ThermoFisher) and 0.05 mM β-mercaptoethanol (ThermoFisher, Cat#21985-023) according to the supplier's instructions. The cell concentration was 7.5 × 10 5Cells were adjusted to cells / mL and seeded in complete growth medium with a final concentration of 100ng / mL phorbol 12-myristate 13-acetate (PMA, Sigma #P8139). Cells were seeded in 96-well cell culture plates at 100μL / well (ThermoFisher Cat#165305) and differentiated for 24 hours at 37℃, 5%CO2 in a cell culture incubator. Cells were washed 1× with 100μl PBS and replaced with fresh RPMI+5%FBS. Compounds were serially diluted in DMSO and diluted 3-fold for a total of 7 concentrations. Diluted compounds were added to cells at a ratio of 1:200 and incubated for 20 hours. NLRP3 inflammasomes were activated by adding 2.5μM nigericin (Sigma: Cat#SML1779-1ml) for 3 hours. After incubation, 15 μL of conditioned media was removed and assayed for levels of IL-1β using an HTRF IL-1β assay kit (Cisbio: Cat#62HIL1BPEH) according to the manufacturer's instructions.

[0185] Once the compounds are produced and prepared according to the present invention, they can be evaluated in various assays to characterize their activity. For example, NLRP3-dependent IL1β secretion was evaluated in THP1 cells. IC50 values ​​for IL1β inhibition were calculated from plots of percentage inhibition versus inhibitor concentration by logistics fit. Table I depicts examples of compounds according to general formula I. Data that are <1 nM are listed as *****; data between 1 and 10 nM are listed as ****; data between 10 and 100 nM are listed as ***, data between 100 and 300 nM are listed as **, and data >= 300 nM are listed as *. Data obtained from the THP1 NLRP3-dependent IL-1β secretion assay demonstrate that the compounds of the present invention can be used to treat diseases mediated through NLRP3 activation.

[0186] [Table 12] JPEG2025509088000141.jpg250157 JPEG2025509088000142.jpg249156 JPEG2025509088000143.jpg47170 Regardless of whether the documents cited in this specification are specifically and individually indicated to be incorporated by reference, all documents mentioned in this specification are incorporated by reference into this application for any and all purposes to the same extent as if each individual reference was fully set forth herein.

[0187] Although certain embodiments have been described in detail above, those skilled in the art will clearly appreciate that many variations are possible in the embodiments without departing from the teachings thereof, and all such variations are intended to be encompassed within the scope of the claims presented herein.

Claims

1. A compound selected from the following, wherein the form of the compound is selected from the group consisting of pharma- ceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers, and isotopically enriched forms thereof: 【Chemistry 1】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

2. A compound selected from the following, wherein the form of the compound is selected from the group consisting of pharma- ceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers, and isotopically enriched forms thereof: 【Table 1】

3. A compound selected from the following, wherein the form of the compound is selected from the group consisting of a pharma- ceutically acceptable salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereoisomer, a stereoisomer, a tautomer, a free base, and an isotopically enriched form thereof: 【Table 2】

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, and one or more pharma- ceutically acceptable carriers.

5. A method for treating or ameliorating a disease modulated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 3.

6. 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, liver fibrosis, non-alcoholic fatty liver disease (NASH), muscle atrophy, hereditary and acquired myopathies, e.g. duodenal ulcer disease, glaucoma ...

6. The method of claim 5 for treating or ameliorating a disease modulated by NLRP3, selected from Schenne muscular dystrophy (DMD), hyperalgesia, multiple sclerosis-associated neuropathic pain, acute kidney injury, chronic crystal nephropathy, chronic kidney disease, asthma and allergic airway inflammation, diabetes mellitus-associated atherosclerosis, diabetic encephalopathy, diabetic kidney disease, 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).

7. The method of any one of claims 5 to 6, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

8. 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, liver fibrosis, nonalcoholic fatty liver disease (NASH), muscle atrophy, hereditary and acquired myopathies, hyperalgesia, multiple sclerosis 4. The compound according to claim 1, or a pharma- ceutical acceptable salt thereof, for use in treating or ameliorating a disease modulated by NLRP3, selected from obesity-associated neuropathic pain, acute kidney injury, chronic crystal nephropathy, chronic kidney disease, asthma and allergic airway inflammation, diabetes mellitus-associated atherosclerosis, diabetic encephalopathy, diabetic kidney disease, 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).

9. 9. The use of the compound according to claim 8, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

10. Use of a compound according to any one of claims 1 to 3 in the preparation of a pharmaceutical composition for treating or ameliorating a disease modulated by NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of the compound or a form thereof in admixture with one or more pharma- ceutical acceptable excipients.

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