Heterocyclic and heteroaryl compounds as inhibitors of NLRP3

Abstract

The present invention relates to novel compounds of formula (I) that inhibit NOD-like receptor protein 3 (NLRP3) inflammasome activity. [Formula 1] JPEG2026502905000208.jpg2760 (where each ring A, R 1 , R 2 , X, Y and Z are as defined herein) The present invention further relates to methods for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 477,864, filed December 30, 2022, and U.S. Provisional Patent Application No. 63 / 503,344, filed May 19, 2023, the contents of which are incorporated herein by reference in their entirety and for all purposes. The present invention relates to compounds useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, methods of using the compounds and medicaments containing them in the treatment of various diseases and disorders, and their use in 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 containing nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), the adaptor apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, and the effector protease caspase-1. Complex assembly leads to the activation of caspase-1 and the release of mature proinflammatory cytokines, such as IL-1β and IL-18. Among inflammasomes, the NLR family NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome has been extensively studied and found to be activated by a wide range of stimuli. The regulatory mechanisms of NLRP3 activation are summarized in a recent review article (Seungwha Paik et al., Cell Mol Immunol 18(5):1141-1160, 2021).

[0003] NLRP3 activation is induced by various infectious and non-infectious molecules, including molecular by-products of aging, physical inactivity, and excessive nutrition. Its activation enhances downstream production of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function mutations in NLRP3 are associated with several genetic disorders, including cryopyrin-associated periodic fever syndrome (CAPS). Furthermore, NLRP3 has been implicated in numerous common I) autoimmune, II) autoinflammatory, III) neurodegenerative, IV) cardiovascular, and V) neuromuscular and myodegenerative diseases, for example (Matthew SJ Mangan et al., Nat Rev Drug Discov 17(8):588-606, 2018; Corcoran et al., Pharmacol Rev 73(3):968-1000, 2021; Dubuisson et al., Cells 10(11):3023, 2021). Inflammasome activation has also been observed in retinal pigment epithelial (RPE) cells and has been proposed to be a causative factor in RPE dysfunction and degeneration (Gao et al., Mediators Inflamm 2015:690243, 2015). Furthermore, NLRP3 activation is associated with severe COVID-19 cases and cytokine release syndrome (CRS) induced by cell-based therapeutics and biological treatments (Tracey L Freeman and Talia H Swartz Front Immunol 11:1518, 2020; Lin et al., PLoS Pathog 6;15(6):e1007795, 2019). Therefore, NLRP3 inflammasome inhibitors can be used as single or combined agents clinically as novel therapies for these diseases. Thus, these inflammasome-related diseases and disorders, such as autoinflammatory fever syndrome, cryopyrin-associated periodic fever syndrome (CAPS), sickle cell disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, pseudogout (chondrocalcinosis), type I / II diabetes and related complications (e.g., nephropathy, retinopathy), fibrosis, rheumatoid arthritis, inflammatory bowel disease, asthma and allergic airway inflammation, neuroinflammatory-related disorders (e.g., multiple sclerosis, brain infection, There is a need for inhibitors of the NLRP3 inflammasome pathway that provide new and / or alternative treatments for acute injury, Alzheimer's disease, Parkinson's disease, Huntington's disease), neuromuscular and muscular degenerative diseases, atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis). References: JPEG2026502905000002.jpg22168 JPEG2026502905000003.jpg157170 Summary of the Invention

[0004] An aspect of the present application provides a compound of formula (I), wherein the form of the compound may be selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers, and isotopically enriched forms thereof.

[0005] [ka] (In the formula, X and Y are independently selected from CR', C(R')(R'), N, NR'', O, and S; Z is selected from N, C and CH;

[0006] [ka] is a single or double bond, R' is H, halogen, C 1-4 Alkyl, OH, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, Halo-C 1-4 Alkoxy, C 1-4 Alkyl-thio, SH and halo-C 1-4 independently selected from alkyl, R'' is H, C 1-4 Alkyl, C 3-6 Cycloalkyl and halo-C 1-4 independently selected from alkyl, Ring A is

[0007] [ka] is selected from the group consisting of Q1, Q2, Q3, Q4, Q5, Q6 and Q7 are CR 8 , C.R. 8 R 8 , O, N, NR 9 and S are independently selected, Rw is OH, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy and Halo-C 1-4 alkoxy; R 1 is H, C 1-4 Alkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Heterocycle, halogen or R 3 C optionally substituted with 3-6 Cycloalkyl, halogen or R 3 C optionally substituted with 3-6 Heterocycle, C1-4 Alkyl-amino, (C 1-4 Alkyl) 2-amino, halo-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, C 3-6 Cycloalkoxy and halo-C 1-4 alkoxy; R 2 is C 3-7 Cycloalkyl, C 1-4 Alkyl-aryl, C 1-4 Alkyl-C 3-7 Cycloalkyl, C 1-4 Alkyl-C 3-7 Heterocycle, C 3-7 heterocycle, wherein C 3-7 Heterocycles are saturated or partially unsaturated monocyclic ring systems having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, and R 2 is R 3 may be substituted with R 3 is C 1-4 Alkyl, deutero-C 1-4 Alkyl, halogen, OH, halo-C 1-4 Alkyl, CN, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, Halo-C 1-4 Alkoxy, oxo and hydroxy-C 1-4 alkyl, R 4 , R 5 and R 6 is H, C 1-4 Alkyl, deutero-C 1-4 Alkyl, OH, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, halogen, C 1-4 Alkyl-thio, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Alkyl-amino, (C 1-4R is independently selected from alkyl)2-amino and CN; 1 If is H, then R 4 But not H, R 7 is H, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, Halo-C 1-4 independently selected from alkoxy, halogen, and CN; R 8 is H, C 1-4 Alkyl, halogen and halo-C 1-4 Alkyl, C 1-4 Alkoxy and Halo-C 1-4 alkoxy; R 9 is H, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 cycloalkyl; m is 0, 1 or 2

[0008] An aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the definition of compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, the pharmaceutical composition being useful for treating diseases and / or disorders associated with NLRP3 activity.

[0009] In one aspect, the present invention provides a compound of formula (I) as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms, and / or the progression of said disease or disorder. In another aspect, the present invention provides a method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology and / or symptoms, and / or the progression of said disease or disorder, comprising administering a therapeutically effective amount of a compound of formula (I) or a subformula thereof as disclosed herein, or a pharmaceutically acceptable salt thereof. In an aspect, the present invention provides a method for inhibiting NLRP3 inflammasome activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt thereof. An aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. An aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from an inflammasome-associated disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention provides a compound of formula (I), wherein the form of the compound may be selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers and isotopically enriched forms thereof.

[0011] [ka] (In the formula, X and Y are independently selected from CR', C(R')(R'), N, NR'', O, and S; Z is selected from N, C and CH;

[0012] [ka] is a single or double bond, R' is H, halogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, OH, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, Halo-C 1-4 Alkoxy, C 1-4 Alkyl-thio, SH and halo-C1-4 independently selected from alkyl, R'' is H, C 1-4 Alkyl, deutero-C 1-4 Alkyl, C 3-6 Cycloalkyl and halo-C 1-4 independently selected from alkyl, Ring A is

[0013] [ka] is selected from the group consisting of Q1, Q2, Q3, Q4, Q5, Q6 and Q7 are CR 8 , C(R 8 )(R 8 ), O, N, NR 9 and S are independently selected, Rw is OH, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy and Halo-C 1-4 alkoxy; R 1 is H, C 1-4 Alkyl, deutero-C 1-4 Alkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Heterocycle, halogen or R 3 C optionally substituted with 3-6 Cycloalkyl, halogen or R 3 C optionally substituted with 3-6 Heterocycle, C 1-4 Alkyl-amino, (C 1-4 Alkyl) 2-amino, halo-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, C 3-6 Cycloalkoxy and halo-C 1-4 alkoxy; R 2 is C 3-7 Cycloalkyl, C1-4 Alkyl-aryl, C 1-4 Alkyl-C 3-7 Cycloalkyl, C 1-4 Alkyl-C 3-7 Heterocycle, C 3-7 wherein C is independently selected from heterocycle and aryl; 3-7 Heterocycles are saturated or partially unsaturated monocyclic ring systems having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, and R 2 is R 3 may be substituted with R 3 is C 1-4 Alkyl, deutero-C 1-4 Alkyl, halogen, OH, halo-C 1-4 Alkyl, CN, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, Halo-C 1-4 Alkoxy, oxo and hydroxy-C 1-4 alkyl, R 4 , R 5 and R 6 is H, C 1-4 Alkyl, deutero-C 1-4 Alkyl, OH, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, Halo-C 1-4 Alkoxy, halogen, C 1-4 Alkyl-thio, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, CN, C 3-7 Heteroaryl, the C having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S. 3-7 Heteroaryl ring systems, as well as C 1-4 independently selected from alkoxy-carbonyl; R 7 is H, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C1-4 Alkoxy and Halo-C 1-4 selected from alkoxy, halogen and CN; R 8 is H, C 1-4 Alkyl, halogen and halo-C 1-4 Alkyl, C 1-4 Alkoxy and Halo-C 1-4 alkoxy; R 9 is H, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 cycloalkyl; m is 0, 1 or 2

[0014] Various embodiments of the present invention are described herein, and it is understood that the features specified in each embodiment may be combined with other specified features to form further embodiments of the present invention.

[0015] In embodiment 1, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt thereof. In embodiment 2, the present invention provides a compound of formula (Ia) according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0016] [ka] (In the formula, X and Y are independently selected from C-R', C(R')(R'); R' is H, halogen, C 1-4 Alkyl, OH, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkyl-thio, SH and halo-C 1-4 independently selected from alkyl, R 1 is H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3, NHCH3, CHF2, SCH3, OCH3 and

[0017] [ka] (selected from In embodiment 3, the present invention provides a compound of formula (Ib) according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0018] [ka] (In the formula, R 1 is H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3, NHCH3, CHF2, SCH3, OCH3 and

[0019] [ka] (selected from In embodiment 4, the present invention provides a compound of formula (Ic) according to embodiment 1, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, Y is selected from CR'; R' is H, C 1-4 Alkyl and halo-C 1-4 independently selected from alkyl, R 1 is H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3, NHCH3, CHF2, SCH3, OCH3 and

[0020] [ka] (selected from In embodiment 5, the present invention provides a compound of formula (Id) according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0021] [ka] (In the formula, R 1 is H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3, NHCH3, CHF2, SCH3, OCH3 and

[0022] [ka] (selected from In embodiment 6, the present invention provides a compound of formula (Ie) according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0023] [ka] (In the formula, X is CR', R' is selected from H and CH3; R 1 is H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3, NHCH3, CHF2, SCH3, OCH3 and

[0024] [ka] (selected from In embodiment 7, the present invention provides a compound of formula (If) according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0025] [ka] (In the formula, Y is selected from CH and CH; [ka] is a single or double bond, R 1is H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3, NHCH3, CHF2, SCH3, OCH3 and

[0026] [ka] (selected from In embodiment 8, the present invention provides a compound of formula (Ig) according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0027] [ka] (In the formula, R 1 is H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3, NHCH3, CHF2, SCH3, OCH3 and

[0028] [ka] (selected from In embodiment 9, the present invention provides a compound of formula (Ih) according to embodiment 1, or a pharmaceutically acceptable salt thereof.

[0029] [ka] (In the formula, R 1 is H, CH3, CH3CH2, cyclopropyl, cyclobutyl, isopropyl, tertbutyl, CF3, NHCH3, CHF2, SCH3, OCH3 and

[0030] [ka] (selected from In embodiment 10, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: (In the formula, Ring A is

[0031] [ka] is selected from Q1, Q2, Q3, Q4, Q5, Q6 and Q7 are CR 8 , C(R 8 )(R 8 ), O, N, NR 9 and S are independently selected, Rw is OH, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy and Halo-C 1-4 alkoxy; R 4 , R 5 and R 6 are H, CH3, CH2CH3, OH, OCH3, CF3, OCF3, CH2CF3, OCHF2, F, Cl, Br, cyclopropyl, isopropyl, SCH3, N(CH3)2, CN and

[0032] [ka] are independently selected from R 7 is H, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy and Halo-C 1-4 independently selected from alkoxy, halogen and CN; R 8 is H, C 1-4 Alkyl, halogen and halo-C 1-4 Alkyl, C 1-4 Alkoxy, Halo-C 1-4 alkoxy; R 9 is H, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 3-6 cycloalkyl; m is 0, 1 or 2), and In embodiment 11, the present invention provides a compound of Formula (I) according to embodiment 1, wherein the form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof, or a pharmaceutically acceptable salt thereof. (In the formula, R 2 teeth,

[0033] [ka] (selected from

[0034] In embodiment 12, the present invention provides a compound of Formula (I) according to embodiment 1, wherein the form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof, or a pharmaceutically acceptable salt thereof.

[0035] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 [Table 1-44] [Table 1-45] [Table 1-46] [Table 1-47] [Table 1-48]

[0036] In embodiment 13, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In embodiment 14, 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 to 12.

[0037] In embodiment 15, the present invention provides 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 syndromes (CAPS), cystic fibrosis, sickle cell disease, VCP-related diseases, liver fibrosis, non-alcoholic fatty liver disease (NASH), muscle atrophy, inherited and acquired myopathies, e.g. 15. A method of treating or ameliorating a disease modulated by NLRP3 according to embodiment 14, 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-associated atherosclerosis, diabetic encephalopathy, diabetic kidney disease, pancreatic islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS), is provided.

[0038] In embodiment 16, the invention provides the method of any one of embodiments 14-15, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

[0039] In embodiment 17, the present invention provides 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, hereditary and acquired myopathies, hyperalgesia, 13. Provided is a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-12 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-associated atherosclerosis, diabetic encephalopathy, diabetic kidney disease, pancreatic islet transplant rejection, obesity-related kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

[0040] In embodiment 18, the present invention provides the use of a compound according to embodiment 17, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day. In embodiment 19, the present invention provides use of a compound according to any one of embodiments 1 to 12 in the preparation of a pharmaceutical composition for treating or ameliorating an NLRP3-modulated disease in a subject in need thereof, wherein treating or ameliorating comprises administering to the subject an effective amount of the compound or a form thereof in admixture with one or more pharmaceutically acceptable excipients.

[0041] Methods of using the present invention There is evidence for a role for NLRP3-induced IL-1 and IL-18 in the inflammatory response associated with or resulting from a number of different disorders (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15; Strowig et al., Nature, 2012, 481, 278-286). NLRP3 mutations have been found to be responsible for a series of rare autoinflammatory diseases known as CAPS (Ozaki et al., J. Inflammation Research, 2015, 8, 15-27; Schroder et al., Cell, 2010, 140:821-832; Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15). CAPS is a genetic disorder characterized by relapsing fever and inflammation and consists of three autoinflammatory disorders that form a clinical continuum. These diseases, in descending order of severity, are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile-onset neurocutaneous and articular syndrome (CINCA; also known as neonatal-onset multisystem inflammatory disease, NOMID), all of which have been shown to be caused by gain-of-function mutations in the NLRP3 gene, which result in increased secretion of IL-1 beta. NLRP3 has also been implicated in several autoinflammatory diseases, including septic arthritis, pyoderma gangrenosum, and acne (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al., Eur J. Immunol., 2010, 40, 595-653). Specifically, it has been shown to be effective in multiple sclerosis, type 1 diabetes (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 aneurysm (Zhang et al. J. Stroke and Cerebrovascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al. J. Neurotrauma., 2018, 35(11), 1294-1303). NRLP3 activity is a key regulator of type 2 diabetes (T2D) and its organ-specific complications, including atherosclerosis, obesity, gout, pseudogout, and metabolic syndrome (Wen et al., Nature Immunology, 2012, 13, 352-357; Duewell et al., Nature, 2010, 464, 1357-1361; Strowig et al., Nature, 2014, 481, 278-286), and nonalcoholic steatohepatitis (Mridha et al. J. Hepatol.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 be involved include eye diseases, including both wet and dry age-related macular degeneration (Doyle et al. Nature Medicine, 2012, 18, 791-798; Tarallo et al. Cell 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol., 2017, 95(8), 803-8), non-infectious uveitis and optic nerve damage (Puyang et al. Sci. Rep. 2016, 6, 20998); liver diseases, including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al. Nature, 2012, 482, 179-185); contact hypersensitivity disorders, such as bullous pemphigoid (Fang et al. J Dermatol. Sci. 2016, 83(2),116-23)), atopic dermatitis (Niebuhr et al. Allergy, 2014, 69(8), 1058-67), and hidradenitis suppurativa (Alikhan et al. J. Am. Acad. Dermatol., 2009, 60(4), 539-61) and sarcoidosis (Jager et al. Am. J. Respir Crit. Care Med., 2015, 191, A5816); inflammatory responses in the lungs and skin (Primiano et al. J. Immunol. 2016, 197(6), 2421-33); inflammatory responses in the joints (Braddock et al, Nat. Rev. Drug Disc, 2004, 3, 1-10); amyotrophic lateral sclerosis (Gugliandolo et al. Int. J. Mol. Sci., 2018, 19(7), E1992); cystic fibrosis (larmitti et al. Nat. Commun., 2016,7, 10791); stroke (Walsh et al, Nature Reviews, 2014, 15, 84-97); chronic kidney disease (Granata et al. PLoS One 2015, 10(3), eoi22272); and inflammatory bowel diseases, including ulcerative colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc, 2004, 3, 1-10; Neudecker et al. J. Exp. Med. 2017, 214(6), 1737-52; Lazaridis et al. Dig. Dis. Sci. 2017, 62(9), 2348-56). The NLRP3 inflammasome has been found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al., Inflammation, 2017, 40, 3-66-86). U.S. Patent US202003-61898 is incorporated herein by reference.

[0042] compound form 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 all such variations of the compounds of formula (I) or forms thereof described herein that are within the purview of one of ordinary skill in the art, now known, or later developed, are deemed to fall within the scope described herein and claimed hereinafter.

[0043] Except in the examples, all numbers expressing quantities of raw materials, reaction conditions, experimental data, and the like used in the specification and claims should be understood to be modified by the term "about" unless otherwise indicated. Accordingly, all such numbers represent approximations that may vary depending on the desired properties sought to be obtained by the reaction or as a result of varying experimental conditions. Thus, within the expected range of experimental reproducibility, the term "about" in reference to resulting data refers to a range for the data, provided that it may vary according to the standard deviation from the mean. Similarly, given experimental results obtained, resulting data may be rounded up or down consistently relative to the data without loss of significant figures. At the very least, and without attempting to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be construed in light of significant digits and ordinary rounding techniques.

[0044] Although 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 reference to the following non-limiting examples, which are presented to more fully illustrate, but should not be construed as limiting, the scope of the compounds of formula (I) or forms thereof described herein. 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 are within the practice of one of ordinary skill in the chemical arts and therefore constitute preferred modes of practice. However, it should be appreciated that those skilled in the art, in light of this disclosure, should recognize 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.

[0045] In certain embodiments described herein, the compound of formula (I) or a form thereof is isolated for use. As used herein, the term "isolated" means a compound of formula (I) or a physical state of 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), or by standard analytical techniques described herein or known to those of skill in the art. As used herein, the term "protected" means that a compound of formula (I) or a functional group thereon is in a modified form so as to prevent undesired side reactions of the functional group when the compound is subjected to a reaction. Suitable protecting groups are known to those skilled in the art and by reference to standard textbooks, such as T.W. Greene et al., Protective Groups in Organic Synthesis (2007), Wiley, New York. Prodrugs and solvates of the compounds of formula (I) or forms thereof described herein are also contemplated.

[0046] As used herein, the term "prodrug" means that a functional group on a compound of Formula (I) is in a form that is converted in vivo (e.g., acts as an active or inactive drug precursor) to yield an active or more active compound of Formula (I) or form thereof. The conversion can occur by various mechanisms (e.g., by metabolic and / or non-metabolic chemical processes), for example, by hydrolysis and / or metabolism in the blood, liver, and / or other organs and tissues. A discussion of the use of prodrugs is provided by V. J. Stella, et. al., "Biotechnology: Pharmaceutical Aspects, Prodrugs: Challenges and Rewards," American Association of Pharmaceutical Scientists and Springer Press, 2007. In one example, when a compound of formula (I) or a form thereof contains a carboxylic acid functional group, prodrugs may include esters formed by substitution of the hydrogen atom of the acidic group with a functional group such as alkyl. In another example, when a compound of formula (I) or a form thereof contains an alcohol functional group, prodrugs may be formed by substitution of the hydrogen atom of the alcohol group with a functional group such as alkyl or carbonyloxy. In another example, when a compound of formula (I) or a form thereof contains an amine functional group, prodrugs may be formed by substitution of one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl.

[0047] Pharmaceutically acceptable prodrugs of the compound of formula (I) or a form thereof include compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonic acid esters, amino acid esters, phosphonic acid esters (e.g., phosphoramidic acids used to derive phosphoramidic acids), and mono-, di-, or triphosphate esters, which may be further substituted with alkyl, as appropriate. As described herein, it will be understood by those skilled in the art that one or more of such substituents may be used to provide the compound of formula (I) or a form thereof as a prodrug. The compound of formula (I) or a form thereof can 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 herein is understood to include reference to its salts, unless otherwise specified. The term "salt" as used herein refers to acid salts formed with inorganic and / or organic acids, and basic 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, a carboxylic acid, zwitterions ("internal salts") may be formed and are included within the term "salt" as used herein.

[0048] The term "pharmaceutically acceptable salts," as used herein, refers to salts of the 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) can be formed, for example, by reacting a compound of formula (I) with an amount, e.g., an equivalent amount, of an acid or base in a medium, e.g., one in which the salt is precipitated or an aqueous medium, followed by lyophilization.

[0049] Pharmaceutically acceptable salts include salts of one or more acidic or basic groups present in the compounds of formula (I) or forms thereof described herein. Embodiments of acid addition salts include, but are not limited to, acetate, superphosphate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucuronate, glutamate, hydrobromide, hydrochloride, dihydrochloride, hydroiodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, trifluoroacetic acid salt, and the like. One or more embodiments of the acid addition salt include chloride salts, hydrochloride salts, dihydrochloride salts, trihydrochloride salts, hydrobromide salts, acetate salts, diacetate salts, methanesulfonate salts, sulfate salts, trifluoroacetate salts, trifluoroacetate salts, etc. More specific embodiments include chloride salts, hydrochloride salts, dihydrochloride salts, hydrobromide salts, methanesulfonate salts, sulfate salts, trifluoroacetate salts, trifluoroacetate salts, etc.

[0050] In certain embodiments of the compounds of Formula (I) or forms thereof described herein, the compound is isolated as a salt form, and the compound is conjugated to the salt in a ratio represented, in a non-limiting example, as "compound:salt (A:B)," where "A" and "B" represent equivalent amounts of the compound and the salt in isolated form. Additionally, acids that may be suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on their website), the disclosures of which are incorporated herein by reference.

[0051] 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 may also form pharmaceutically acceptable salts with organic bases (e.g., organic amines), such as, but not limited to, dicyclohexylamine and tert-butylamine, and various amino acids, such as, but not limited to, arginine and lysine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long-chain halides (e.g., decyl chlorides, bromides, and iodides, lauryl, and stearyl), and aralkyl halides (e.g., benzyl and phenethyl bromides). All such acid and base salts are intended to be included within the scope of pharmaceutically acceptable salts described herein, and furthermore, all such acid and base salts are considered equivalent to the free form of the corresponding compound for purposes of this description. Compounds of 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) and forms thereof described herein.

[0052] 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) and 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 diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (if one chiral center is present). In one embodiment, the compounds of formula (I) described herein, or forms thereof, are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another embodiment, the compounds of formula (I) described herein, or forms thereof, are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of ordinary skill in the art will appreciate, when 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 IUPAC nomenclature recommendations.

[0053] As used herein, the term "substantially pure" refers to a compound of formula (I) or a form thereof that consists essentially of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100% of a single isomer. In one described embodiment, the compound of formula (I) or a form thereof is a substantially pure (S) enantiomer present in an amount of 90% or greater, 92% or greater, 95% or greater, 98% or greater, 99% or greater, or in an amount equal to 100%. In one described embodiment, the compound of formula (I) or a form thereof is a substantially pure (R) enantiomer present in an amount of 90% or greater, 92% or greater, 95% or greater, 98% or greater, 99% or greater, or in an amount equal to 100%. As used herein, the term "racemate" refers to any mixture of isometric forms that is not "enantiomerically pure," including, for example, but not limited to, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20, about 85 / 15, or about 90 / 10. Furthermore, the compounds of 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.

[0054] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by use of a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary, e.g., a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis).

[0055] All stereoisomers (e.g., geometric isomers, optical isomers) of the present 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 even without asymmetric carbons), rotamer forms, atropisomers, diastereomeric forms and positional isomer forms, are contemplated within the scope of the present description. 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 as racemic mixtures as described above.

[0056] Use of the terms "salts," "solvates," "esters," "prodrugs," and the like is intended to apply equally to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, isotopologues, or prodrugs of the present compounds. One or more compounds of formula (I) or forms thereof described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and references herein are intended to encompass both solvated and unsolvated forms. As used herein, the term "solvate" refers to a physical association of a 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 bonding, including hydrogen bonding. In certain instances, a solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. One or more compounds of formula (I) or their forms described herein may be converted into solvates. The preparation of solvates is generally known. A typical, non-limiting process involves dissolving a compound of formula (I) or its form in a desired amount of a desired solvent (organic or aqueous or a mixture thereof) 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 a solvate (or hydrate).

[0057] As used herein, the term "hydrate" means a solvate where the solvent molecule is water. Polymorphic crystalline and amorphous forms of the compound of formula (I) or a form thereof, and the salts, solvates, esters and prodrugs of the compound of formula (I) or a form thereof, are further intended to be included within the scope of the compound of formula (I) or a form 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 also within the scope of this description.

[0058] definition The chemical terms used above and throughout the description herein shall be understood by those skilled in the art to have the following indicated meanings, unless specifically defined otherwise. As used herein, "C 1-4 The term "alkyl" refers to a saturated hydrocarbon radical having from 1 to 8 carbon atoms in a straight or branched chain arrangement, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like. In some embodiments, C 1-8 Alkyl is C 1-6 Alkyl, C 1-4 Contains alkyl, etc. C 1-8 Alkyl radicals may be optionally substituted where available valences allow.

[0059] As used herein, "C 1-4 The term "alkoxy" refers to groups of the formula: OC, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like. 1-8 Alkyl refers to a saturated hydrocarbon radical of 1 to 8 carbon atoms having a straight or branched chain arrangement. In some embodiments, C 1-8 Alkoxy is C 1-6 Alkoxy, C 1-4 Alkoxy etc. C 1-4 Alkoxy radicals may be optionally substituted where available valences allow.

[0060] As used herein, "C 3-6 Cycloalkyl" and "C 3-7 The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or polycyclic hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. 3-6 Cycloalkyl and C 3-7 Cycloalkyl radicals may be optionally substituted where available valences allow. As used herein, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members, where structural stability permits, are replaced by heteroatoms such as O, S, or N atoms, including, but not limited to, piperidinyl, tetrahydro-2H-pyran, or pyrrolidinyl. A heterocyclyl or heterocycle radical may be substituted on a carbon or nitrogen atom ring member, where available valences permit.

[0061] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl (also called naphthalenyl), anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. Aryl radicals may be optionally substituted where available valences allow. As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members, if structural stability permits, are replaced by one or more heteroatoms, such as O, S, or N atoms. Heteroaryl radicals may also be substituted on carbon or nitrogen atom ring members if available valences permit.

[0062] As used herein, the terms "halo" or "halogen" generally refer to halogen atom radicals, including fluoro, chloro, bromo, and iodo. As used herein, "C 1-4 Alkoxy-C 1-4 The term "alkyl" refers to a group of the formula: 1-4 Alkyl OC 1-4 Refers to an alkyl radical. As used herein, "C 1-4 The term "alkyl-amino" refers to a group of the formula: NHC 1-4 Refers to an alkyl radical. As used herein, "(C 1-4The term "amino" refers to a group of the formula: N(C 1-4 It refers to the radical (alkyl)2. As used herein, "C 1-4 The term "alkyl-thio" refers to a group of the formula: -SC 1-4 Refers to an alkyl radical.

[0063] As used herein, "amino-C 1-4 The term "alkoxy" means a group of the formula: OC 1-4 Refers to the alkyl NH2 radical. As used herein, "amino-C 1-4 The term "alkyl" refers to a group of the formula: 1-4 Refers to the alkyl NH2 radical. As used herein, "aryl-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Refers to alkyl-aryl radicals. As used herein, "aryl C 1-4 The term "alkylamino" refers to a radical of the formula: NHC1-4alkylaryl. As used herein, "C 3-6 Cycloalkyl-C 1-4 The term "alkyl" refers to a group of the formula: C1-4 alkylC 314 Refers to a cycloalkyl radical.

[0064] As used herein, "C 3-6 The term "cycloalkyl-amino" refers to a group of the formula: -NH-C 3-6 Refers to a cycloalkyl radical. As used herein, "C 1-4 The term "alkoxy-carbonyl" refers to a group of the formula -C(O)-C 1-4 Refers to the radical of alkoxy. As used herein, "deutero-C" 1-4 The term "alkyl" refers to a group of the formula: 1-4 Refers to the alkyldeutero radical. (In the formula, C 1-4Alkyl is partially or fully substituted with one or more deuterium atoms where available valences permit.

[0065] As used herein, "halo-C" refers to 1-4 The term "alkoxy" means a group of the formula: OC 1-4 Refers to an alkylhalo radical. (In the formula, C 1-4 The alkyl is partially or fully substituted with one or more halogen atoms where available valences allow. As used herein, "halo-C" refers to 1-4 The term "alkyl" refers to a group of the formula: 1-4 Refers to an alkylhalo radical. (In the formula, C 1-4 The alkyl is partially or fully substituted with one or more halogen atoms where available valences allow. As used herein, the term "hydroxy" refers to a radical of the formula: --OH. As used herein, "hydroxy-C 1-4 Alkoxy-C 1-4 The term "alkyl" refers to a group of the formula: -C 1-4 Alkyl-OC 1-4 Refers to the alkyl-OH radical. As used herein, "hydroxy-C 1-4 The term "alkyl" refers to a group of the formula: 1-4 Refers to the alkyl-OH radical. (In the formula, C 1-4 The alkyl is partially or fully substituted with one or more hydroxy radicals where available valences allow. As used herein, "oxo" refers to carbonyl, i.e., --C(O)--.

[0066] As used herein, the term "such as" means that variations in chemical structure that may be anticipated by one of ordinary skill in the art with respect to the definitions of chemical terms provided herein include, but are not limited to, isomers (including linear, branched, or positional structural isomers), hydration of ring systems (including saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ring structures), and all other variations that result in stable compounds, where allowed by available valences. As used herein, the term "substituent" refers to a positional variable on an atom of a core molecule attached at a specified atom that replaces one or more hydrogen atoms on the specified atom, provided that the attached atoms do not exceed the available valences or covalences such that the substitution results in a stable compound. Thus, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. It should also be noted that any carbon and heteroatoms described or shown herein that appear to have unsatisfied valence levels are assumed to have a sufficient number of hydrogen atoms to satisfy the valences described or shown.

[0067] For purposes of this description, when one or more substituent variables for compounds of formula (I) include functional groups that are incorporated into compounds of formulas I-VII, each functional group appearing anywhere within the disclosed compounds can be independently selected and, where appropriate, independently and / or optionally substituted. As used herein, the term "independently selected" or "each selected" refers to a functional group variable in a list of substituents that may be attached more than once on the core molecular structure, where the substitution pattern at each occurrence is independent of any other occurrence. Furthermore, the use of a generic substituent on the core structure in the compounds provided herein is understood to include substitution of the generic substituent with a species of substituent included within the particular genus, for example, aryl can be independently replaced with phenyl or naphthalenyl (also referred to as naphthyl), etc., with the resulting compound intended to be included within the scope of the compounds described herein.

[0068] As used herein, the term "each instance of" or "each variable independently" refers to, for example, "...aryl, aryl C 1-4 Alkyl, heterocycle and heterocyclyl-C 1-4 When used in the phrase "alkyl, and each instance of aryl and heterocycle may be substituted with one or two substituents...", the aryl and heterocycle may each be substituted with one or two substituents. 1-4 Alkyl and heterocyclyl-C 1-4 It is intended to include any independent substitution on the aryl and heterocycle portions of an alkyl. As used herein, the term "optionally substituted" means that the specified substituents (variables, groups, radicals, or moieties) represent a genus and can be independently selected, as needed, to replace one or more hydrogen atoms at the specified atom attached to the core molecule. As used herein, the terms "stable compound" or "stable structure" mean a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent. As used herein, the terms "subject" and "patient" are used interchangeably to refer to an animal or any living organism that has sensation and the power of voluntary movement and requires oxygen and organic food for its survival. Non-limiting examples include humans, horses, pigs, cattle, members of the Rattus, murine, canine, and feline species. In some embodiments, the subject is a mammal or warm-blooded vertebrate. In certain embodiments, the subject is a non-human animal. In specific embodiments, the subject is a human.

[0069] The names of the compounds provided herein were obtained using ACD Labs Index Name software provided by ACD Labs and / or ChemDraw Ultra software provided by CambridgeSoft®. If the name of a compound disclosed herein conflicts with a depicted structure, the depicted structure supercedes the use of the name to define the intended compound. The nomenclature of the substituent radicals defined herein may differ slightly from the chemical names from which they are derived, and those skilled in the art will understand that the definition of the substituent radical is intended to include the radical found in the chemical name.

[0070] Usage and dosage The compounds of the present invention can be formulated into a wide variety of oral dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, liquids, emulsions, syrups, or suspensions. The compounds of the present invention are effective when administered by other routes of administration, including continuous (intravenous drip), topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, nasal, inhalation, and suppository administration, among others. The preferred method of administration is generally oral, using a convenient daily dosage regimen, which can be adjusted according to the degree of discomfort and the patient's response to the active ingredient.

[0071] The compounds of the present invention, as well as their pharmaceutically acceptable salts, may be placed into the form of pharmaceutical compositions and unit dosages together with one or more conventional excipients, carriers, or diluents. Pharmaceutical compositions and unit dosage forms may consist of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient consistent with the daily dosage range for which it is intended to be used. Pharmaceutical compositions may be used as solids, such as tablets or filled capsules, semisolids, powders, sustained-release formulations, or liquids, such as solutions, suspensions, emulsions, elixirs, or filled capsules, for oral use; or as suppositories for rectal or vaginal administration; or as sterile injectable solutions for parenteral use. Typical preparations contain from about 5% to about 95% active compound (w / w). The terms "preparation" or "dosage form" are intended to encompass both solid and liquid formulations of the active compound, and those skilled in the art will recognize that the active ingredient may be present in different preparations depending on the target organ or tissue, as well as the desired dose and pharmacokinetic parameters. As used herein, the term "excipient" refers to a compound that is generally safe, non-toxic, and not biologically or otherwise undesirable, useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds of the invention can be administered alone, but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents, or carriers selected for the intended route of administration and standard pharmaceutical practice.

[0072] "Pharmaceutically acceptable" means generally safe, non-toxic, and not biologically or otherwise undesirable, useful in the preparation of pharmaceutical compositions, and includes those acceptable for veterinary and human pharmaceutical use. A "pharmaceutically acceptable salt" form of an active ingredient may initially impart desirable pharmacokinetic properties to the active ingredient not present in the non-salt form and may even favorably affect the pharmacodynamics of the active ingredient with respect to therapeutic activity in the body. The phrase "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the unchanged form. Such salts may be formed: (1) with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- These include acid addition salts formed with methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; or (2) salts formed when an acidic proton present in the unchanged compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or when coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine.

[0073] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is generally a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in suitable proportions and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. Solid form preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0074] Liquid preparations are also suitable for oral administration, including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These include solid-form preparations intended to be converted to liquid-forming preparations immediately before use. Emulsions can be prepared in solution, for example, in aqueous propylene glycol, or can contain emulsifiers such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active ingredient in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0075] The compounds of the present invention can be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion), and can be presented in unit dosage form with added preservatives in ampoules, prefilled syringes, small-volume injections, or multi-dose containers. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, such as solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and can contain 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 a sterile solid or by lyophilization from a solution that is then constituted with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0076] The compounds of the present invention can be formulated as ointments, creams, or lotions for topical administration to the epidermis, or as transdermal patches. Ointments and creams can be formulated with an aqueous or oily base, for example, with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier. The compounds of the present invention can be formulated for administration as suppositories. A low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and solidify.

[0077] The compounds of the present invention can be formulated for vaginal administration using pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. The compound of the present invention can be formulated for nasal administration.The solution or suspension is directly applied to the nasal cavity by conventional means, for example, by dropper, pipette or spray.The formulation can be provided in single or multiple dose form.In the latter case of dropper or pipette, this can be achieved by the patient administering an appropriate predetermined volume of the solution or suspension.In the case of spray, this can be achieved, for example, by a metering atomizing spray pump. The compounds of the present invention can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compounds generally have a small particle size, for example, of the order of 5 μm or less. Such a particle size can be obtained by means known in the art, for example, by micronization. The active ingredient can be delivered in a pressurized pack using a suitable propellant, for example, a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. The aerosol can conveniently also contain a surfactant, for example, lecithin. The dose of drug can be controlled by a metered valve. Alternatively, the active ingredient can be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base, such as lactose, starch, starch derivatives, for example, hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier forms a gel in the nasal cavity. Powder compositions can be presented in unit dose form, for example, in capsules or cartridges of, for example, gelatin or blister packs, from which the powder can be administered by inhaler.

[0078] If desired, formulations can be prepared with enteric coatings adapted for sustained or controlled-release administration of the active ingredient. For example, the compounds of the present invention can be formulated into transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is essential and when compliance with the treatment regimen is critical. In transdermal delivery systems, the compound is often attached to a skin-adhesive solid carrier. The compound of interest can also be combined with a permeation enhancer, such as Azone (1-dodecylaza-cycloheptan-2-one). Sustained-release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. Subdermal implants encapsulate the compound in a lipid-soluble membrane, such as silicone rubber or a biodegradable polymer, such as polylactic acid.

[0079] Suitable formulations, along with pharmaceutical carriers, diluents, and expcipients, are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Formulation scientists can modify the formulations within the teachings herein to obtain a multitude of formulations for specific routes of administration without destabilizing the compositions of the invention or compromising their therapeutic activity. Modifications to make the compounds more soluble in water or other vehicles can be readily accomplished, for example, by minor modifications (salt formulations, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill in the art to modify the route of administration and dosage regimen of a particular compound to manage the pharmacokinetics of the compound for maximum beneficial effect in the patient.

[0080] The term "therapeutically effective amount," as used herein, refers to the amount required to reduce the symptoms of a disease in an individual. Doses will be tailored to the individual requirements of each particular case. The dosage may vary within wide limits depending on numerous factors, such as the severity of the disease being treated, the age and general health of the patient, other medications the patient is being treated with, the route and form of administration, and the preference and experience of the physician involved. For oral administration, a daily dosage of about 0.01 to about 1,000 mg / kg body weight per day should be appropriate in monotherapy and / or combination therapy. A preferred daily dosage is about 0.1 to about 500 mg / kg body weight per day, with 0.1 to about 100 mg / kg body weight being more preferred, and 1.0 to about 10 mg / kg body weight being most preferred. Thus, for administration to a 70 kg human, the dosage range may be about 7 mg to 0.7 g per day. The daily dosage may be administered as a single dose or in divided doses, typically 1 to 5 doses per day. Generally, treatment is initiated with a smaller dosage that is less than the optimal dose of the compound.The dosage is then gradually increased until the optimal effect for each patient is reached.In treating the diseases described herein, those skilled in the art can determine the specific therapeutically effective amount of the compound of the present invention for a given disease and patient without undue experimentation and relying on their own knowledge, experience and the disclosure of this application. 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.

[0081] 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 given to enable those skilled in the art to more clearly understand and to practice the present invention. They do not limit the scope of the invention, but should be considered merely as 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, greater weight should be given to the depicted structure. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated, e.g., with a bold or dashed line, the structure or portion of a structure should be interpreted as encompassing all stereoisomers thereof.

[0082] Reagents and solvents were used as purchased (from various vendors) except where noted. Where applicable, the term "Celite" is used as shown in the following examples to refer to the trade name CELITE® (a brand of diatomaceous earth). Where applicable, chromatographic separations were performed using commonly available techniques and equipment, for example, by using an ISCO CombiFlash® Rf system. Where applicable, NMR spectra were obtained using, for example, a Bruker Avance III 500 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 analysis was 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. Where applicable, the structures of the products were obtained by 2D NOESY (Nuclear Overhauser SpectroscopY) experiments. The following abbreviations are provided to ensure that the terms used herein are clear to those of ordinary skill in the art.

[0083] [Table 2-1] [Table 2-2] [Table 2-3]

[0084] Compounds and Preparation experiment General synthesis method As disclosed herein, general methods for preparing compounds of Formula I described herein or forms thereof can be prepared using the methods summarized in Scheme AG by suitable selection of reagents with appropriate substitution, with solvents, temperatures, pressures, and other reaction conditions readily selected by one of ordinary skill in the art. Many of the starting materials are commercially available, or if unavailable, can be prepared by standard, well-known synthetic methodologies or using the routes described below using techniques known to those skilled in the art. The synthetic schemes shown herein include multiple reaction steps, each of which is intended to be independent and can be carried out with or without any preceding or succeeding step. In other words, isolation is contemplated for each of the individual reaction steps of the synthetic schemes shown herein.

[0085] 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 SNAr substitution reactions, metal-catalyzed coupling reactions such as Suzuki coupling, Negishi coupling and Buchwald coupling, reductive amination, etc., to give compounds of general formula I.

[0086] [ka]

[0087] Compound A1 is converted to compound A2 by Miniski reaction with an appropriate carboxylic acid in the presence of a silver salt and a suitable oxidizing agent (e.g., ammonium persulfate) in a suitable solvent (e.g., acetonitrile). Compound A2 is converted to compound A3 by reaction with vinylmagnesium bromide in a suitable solvent (e.g., THF). Alternatively, compound A2′ can be synthesized by reacting compound A1′ with iodine in the presence of a suitable base (e.g., TMPZn(OPiv)MgCl.LiCl) in a suitable solvent (e.g., THF). Suzuki coupling of compound A2′ with vinylboronic acid (or pinacol boron ester) in the presence of a catalyst (e.g., Pd(dppf)Cl) and a base (e.g., aqueous KCO) in a suitable solvent (e.g., 1,4-dioxane) provides compound A3. Compound A3 is cyclized to compound A4 by treatment with an optionally protected amine in a suitable solvent (e.g., acetonitrile) in the presence of a base (e.g., DIPEA) at elevated temperatures (e.g., 110°C). Suzuki coupling of compound A4 with an optionally protected aryl- or heteroaryl-boronic acid (or pinacol boron ester) in a suitable solvent (e.g., 1,4-dioxane) in the presence of a catalyst (e.g., Pd(dppf)Cl) and a base (e.g., aqueous KCO) provides compound A5. Removal of the protecting group provides compound A6.

[0088] Compound A5 can be oxidized to compound A7 with an oxidizing agent (e.g., MnO2) in a suitable solvent (e.g., toluene) at elevated temperatures (e.g., 110°C). Deprotection of compound A7 provides compound A8.

[0089] [ka]

[0090] Compound B1 is reacted with an optionally protected amine in a suitable solvent (e.g., dioxane) in the presence of a base (e.g., KCO) at elevated temperatures (e.g., 60°C) to give compound B2, which is further converted to compound B3 by reaction with NaN in a suitable solvent (e.g., DMSO) at elevated temperatures (e.g., 80°C). Compound B3 is reduced to compound B4 with a suitable reducing agent (e.g., zinc), which is cyclized to compound B5 upon treatment with an orthoester at elevated temperatures (e.g., 100°C). Suzuki coupling of compound B5 with an optionally protected aryl- or heteroaryl-boronic acid (or pinacol boron ester) in a suitable solvent (e.g., 1,4-dioxane) in the presence of a catalyst (e.g., Pd(dppf)Cl) and a base (e.g., aqueous KCO) gives compound B6. Removal of the protecting group gives compound B7.

[0091] [ka]

[0092] Compound C1 is converted to compound C2 by reacting with a 2-hydroxy or 2-mercaptoacetate in a suitable solvent (e.g., THF) in the presence of a base (e.g., EtN, NaH). Suzuki coupling of compound C2 with an optionally protected aryl- or heteroaryl-boronic acid (or pinacol boron ester) in a suitable solvent (e.g., 1,4-dioxane) in the presence of a catalyst (e.g., Pd(dppf)Cl) and a base (e.g., aqueous KCO) provides compound C3, which is further converted to compound C4 by reacting with a triflating reagent (e.g., triflic anhydride) in the presence of a base (e.g., DIPEA) in a suitable solvent (e.g., DCM). Compound C4 is converted to compound C5 by coupling with an appropriate coupling partner (e.g., boronic acid, organozinc reagent) in the presence of a catalyst (e.g., Pd(dppf)Cl). Hydrolysis of compound C5 with a suitable base (e.g., LiOH) in a suitable solvent (e.g., THF) gives compound C6, which is decarboxylated in a suitable solvent (e.g., DMSO) in the presence of a metal salt (e.g., AgCO) at elevated temperature to give compound C7. Removal of the protecting group gives compound C8.

[0093] [ka]

[0094] Compound D1, prepared by the method described in Scheme C, is hydrolyzed to compound D2 by reaction with a base (e.g., LiOH) in a suitable solvent (e.g., dioxane). Decarboxylation of compound D2 in a suitable solvent (e.g., DMSO) in the presence of a metal salt (e.g., AgCO) at elevated temperatures (e.g., 120°C) provides compound D3, which is reacted with a triflating reagent (e.g., triflic anhydride) in a suitable solvent (e.g., DCM) in the presence of a base (e.g., pyridine). Compound D4 is converted to compound D5 by coupling with an appropriate coupling partner (e.g., boronic acid, organozinc reagent) in the presence of a catalyst (e.g., Pd(dppf)Cl). Compound D5 is further coupled with an optionally protected aryl- or heteroaryl-boronic acid (or pinacol boron ester) in the presence of a catalyst (e.g., Pd(dppf)Cl) and a base (e.g., aqueous KCO) in a suitable solvent (e.g., 1,4-dioxane) to give compound D6. Removal of the protecting group gives compound D7.

[0095] [ka]

[0096] Compound E1 is converted to compound E2 by Sonogashira reaction with TMS-acetylene in the presence of a catalyst (e.g., Pd(PPh3)4) and a base (e.g., NEt3) in a suitable solvent (e.g., THF), which is then cyclized to compound E3 in the presence of a base (e.g., K2CO3) in a suitable solvent (e.g., DMF). Compound E3 is coupled with an optionally protected aryl- or heteroaryl-boronic acid (or pinacol boron ester) in the presence of a catalyst (e.g., XPhos-Pd-G3) and a base (e.g., aqueous K2CO3) in a suitable solvent (e.g., 1,4-dioxane) to give compound E4. Reaction of compound E4 with a halogenating reagent (e.g., NBS) in a suitable solvent (e.g., NBS) gives compound E5. Compound E5 is converted to compound E6 by coupling with an appropriate coupling partner (e.g., boronic acid, organozinc reagent) in the presence of a catalyst (e.g., Pd(dppf)Cl2). Removal of the protecting group gives compound E7.

[0097] [ka]

[0098] Compound F1 is converted to compound F2 by Miniski reaction with an appropriate carboxylic acid in the presence of a silver salt and a suitable oxidizing agent (e.g., ammonium persulfate) in a suitable solvent (e.g., acetonitrile). Suzuki coupling of compound F2 with vinyl pinacol borate in the presence of a catalyst (e.g., Pd(dppf)Cl) and a base (e.g., KCO) in a suitable solvent (e.g., THF) provides compound F3, which is oxidized with an oxidizing agent (e.g., sodium periodate) to provide compound F4. Condensation of compound F4 with a substituted hydrazine provides compound F5, which is subsequently cyclized to compound F6 at elevated temperatures (e.g., 150°C). Suzuki coupling of compound F6 with an optionally protected aryl- or heteroaryl-boronic acid (or pinacol boron ester) in the presence of a catalyst (e.g., XPhos-Pd-G3) and a base (e.g., aqueous KCO3) in a suitable solvent (e.g., 1,4-dioxane) provides compound F7. Removal of the protecting group provides compound F8.

[0099] [ka] Compound G1 is reacted with an optionally protected amine in a suitable solvent (e.g., THF) in the presence of a base (e.g., KCO) at elevated temperatures (e.g., 50°C) to give compound G2, which is converted to compound G3 by reaction with NaN in a suitable solvent (e.g., DMSO) at elevated temperatures (e.g., 80°C). Compound G3 is reduced to compound G4 with a suitable reducing agent (e.g., zinc), which is cyclized to compound G5 upon treatment with sodium nitrite in the presence of an acid (e.g., HOAc) in water. Compound G5 is converted to compound G6 by a Miniski reaction with an appropriate carboxylic acid in the presence of a silver salt and a suitable oxidizing agent (e.g., ammonium persulfate) in a suitable solvent (e.g., acetonitrile). Suzuki coupling of compound G6 with an optionally protected aryl- or heteroaryl-boronic acid (or pinacol boron ester) in the presence of a catalyst (e.g., Pd(dppf)Cl) and a base (e.g., aqueous KCO) in a suitable solvent (e.g., 1,4-dioxane) provides compound G7. Removal of the protecting group provides compound G8.

[0100] Compounds and Preparation Intermediate 1: Preparation of 2-(4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0101] [ka]

[0102] Step 1:A mixture of CuBr2 (58.7 g, 263 mmol) in anhydrous ethyl acetate (150 mL) was stirred at 80 °C for 10 minutes, followed by the addition of 6,7-dihydrobenzofuran-4(5H)-one (10.0 g, 65.7 mmol) in CHCl3 (25 mL). The mixture was continuously stirred at 80 °C for 16 hours. Upon completion, the reaction was cooled to room temperature and filtered to remove solids. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give 5,5-dibromo-6,7-dihydrobenzo-furan-4(5H)-one as a yellow solid (9.4 g, 46% yield). MS m / z 294.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 7.84 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 3.16 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 5.6 Hz, 2H).

[0103] Step 2: To a solution of 5,5-dibromo-6,7-dihydrobenzofuran-4(5H)-one (9.4 g, 32 mmol) in DMF (150 mL) was added LiCO (14.2 g, 192 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 2 h. Upon completion, the mixture was cooled to room temperature and filtered to remove solids. The filtrate was concentrated, and the residue was diluted with water (500 mL) and then extracted with ethyl acetate (300 mL). The organic layer was washed with water (500 mL × 2) and brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0–20% ethyl acetate in petroleum ether to give 5-bromobenzofuran-4-ol as a yellow solid (6.4 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.48 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H).

[0104] Step 3: To a solution of 5-bromobenzofuran-4-ol (7.8 g, 36.6 mmol) in THF (150 mL) was added NaH (2.2 g, 54.9 mmol, 60%) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, followed by the dropwise addition of bromomethyl methyl ether (6.86 g, 54.9 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Upon completion, the reaction was quenched with water (150 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (150 mL × 1) and brine (150 mL × 1), dried over Na SO , filtered, and concentrated to afford 5-bromo-4-(methoxymethoxy)benzofuran as a yellow oil (9.0 g, 96% yield), which was carried on to the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ: 8.02 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 0.8 Hz, J = 8.4 Hz, 1H), 7.12 (dd, J = 0.8 Hz, J = 2.0 Hz, 1H), 5.36 (s, 2H), 3.55 (s, 3H).

[0105] Step 4:To a solution of 5-bromo-4-(methoxymethoxy)benzofuran (8.0 g, 31.1 mmol) in 1,4-dioxane (150 mL) under Ar was added pinacolborane (15.9 g, 124 mmol), TEA (22.0 g, 218 mmol), Pd(OAc) (777 mg, 4.67 mmol), and CyJohnphos (1.73 g, 7.78 mmol). The reaction mixture was stirred at 80 °C under Ar for 16 h and then filtered through a pad of Celite and washed with EtOAc. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel eluting with 0–6% ethyl acetate in petroleum ether to give 2-(4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow solid (4.17 g, 44% yield). 1 H NMR (400 MHz, DMSO-d6) δ: 7.96 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 5.22 (s, 2H), 3.51 (s, 3H), 1.30 (s, 12H).

[0106] Intermediate 2: Preparation of 2-(4-(difluoromethoxy)-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0107] [ka]

[0108] Step 1:To a solution of 1,3-dimethoxybenzene (55.0 g, 398 mmol, 1.0 equiv) in dry THF (500 mL) was added tetramethylethylenediamine (55.5 g, 1.2 equiv). The mixture was stirred at 0 °C for 30 min, and n-butyllithium (25.50 g, 398 mmol, 1.0 equiv, 2.5 M) was added dropwise slowly. The mixture was stirred at 0 °C for 3 h. Ethylene oxide (35.1 g, 796 mmol, 2.0 equiv) was added dropwise slowly at 0 °C for 1 h. The mixture was allowed to warm to room temperature. The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow solid. The solid was washed with ether (100 mL×2) to give 2-(2,6-dimethoxyphenyl)ethan-1-ol (20.1 g, 28% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.16 (t, J = 8.3 Hz, 1H), 6.56 (d, J = 8.3 Hz, 2H), 3.82 (s, 6H), 3.80 - 3.73 (m, 2H), 2.99 (t, J = 6.4 Hz, 2H). Step 2: A solution of 2-(2,6-dimethoxyphenyl)ethan-1-ol (40.2 g, 220 mmol, 1.0 equiv) in 40% aqueous HBr (700 mL, HBr-HO) was stirred at 105 °C for 16 h. The reaction solution was diluted with water (1 L) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (EA in PE = 9.32%) to give 2,3-dihydrobenzofuran-4-ol (2.8 g, 9.3% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.01 - 6.95 (m, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 8.2 Hz, 1H), 4.60 (t, J = 8.6 Hz, 2H), 3.16 (t, J = 8.8 Hz, 2H).

[0109] Step 3: To a solution of 2,3-dihydrobenzofuran-4-ol (6.08 g, 44.63 mmol, 1.0 equiv) in acetonitrile (60 mL) was added NIS (10.04 g, 44.63 mmol, 1.0 equiv) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (SiO, EA in PE = 0.7%) to give 5-iodo-2,3-dihydrobenzofuran-4-ol (4.76 g, 41% yield) as a brown solid. MS m / z 262.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.89 (brs, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 4.62 (t, J = 8.8 Hz, 2H), 3.22 (t, J = 8.8 Hz, 2H).

[0110] Step 4:To a mixture of 5-iodo-2,3-dihydrobenzofuran-4-ol (4.60 g, 17.6 mmol, 1.00 equiv) in THF (50.0 mL) was added NaH (60%) (1.40 g, 35.11 mmol, 2.00 equiv) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then, MOMBr (3.29 g, 26.33 mmol, 1.5 equiv) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL), and the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organics were washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give 5-iodo-4-(methoxymethoxy)-2,3-dihydrobenzofuran (3.4 g, yield 63%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.49 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.13 (s, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.59 (s, 3H), 3.34 (t, J = 8.7 Hz, 2H).

[0111] Step 5:To a mixture of 5-iodo-4-(methoxymethoxy)-2,3-dihydrobenzofuran (2.90 g, 9.47 mmol, 1.00 equiv.) in THF (30 mL), n-BuLi (4.55 mL, 2.5 M, 11.37 mmol, 1.2 equiv.) was added dropwise at −78° C. under a N atmosphere, and the mixture was stirred at −78° C. for 0.5 h. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.64 g, 14.21 mmol, 1.5 equiv.) in THF (10 mL) was added dropwise under a N atmosphere, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give 2-(4-(methoxymethoxy)-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 76% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.58 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 5.11 (s, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.56 (s, 3H), 3.27 (t, J = 8.7 Hz, 2H), 1.32 (s, 12H). Intermediate 3: Preparation of 2-(4-(methoxymethoxy)-6-methylbenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0112] [ka]

[0113] Step 1:To a solution of sodium bicarbonate (79.9 g, 951.2 mmol, 1.2 equiv.) and chloroacetaldehyde (155.5 g, 792.6 mmol, 1.0 equiv.) in water (1380 mL) was added dropwise a solution of 4,4-dimethylcyclohexane-1,3-dione in THF (1100 mL) at 0 °C. The resulting mixture was stirred at room temperature for 18 h, and ethyl acetate (1000 mL) was added. The mixture was adjusted to pH = 1 with 50% H2SO4 and stirred vigorously for 3 h. The organic layer was collected, and the acidic layer was extracted with ethyl acetate (3 x 400 mL). The combined organic extracts were washed with water, saturated NaHCO3, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel (petroleum ether / ethyl acetate=20 / 1 to 1 / 1) to give 6-methyl-6,7-dihydrobenzofuran-4(5H)-one (54 g, 359.5 mmol, 45.3% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 2.1 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H), 2.97 (dd, J = 17.1, 4.8 Hz, 1H), 2.59 (dd, J = 17.0, 9.4 Hz, 1H), 2.41 (dt, J = 17.0, 2.1 Hz, 2H), 2.28 (dd, J = 13.5, 3.7 Hz, 1H), 1.09 (d, J = 6.3 Hz, 3H).

[0114] Step 2:CuBr2 (321.2 g, 1.44 mol, 4.0 equiv) was added to EA (770 mL). The reaction was stirred at 80 °C for 10 min. To this was added a solution of 6-methyl-6,7-dihydrobenzofuran-4(5H)-one (54 g, 359.5 mmol, 1.0 equiv) in CHCl3 (128 mL) in one portion at 80 °C. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction was cooled to room temperature and filtered to remove solids. The filtrate was concentrated and purified by silica gel column chromatography (PE:EA = 50:1 to 5:1) to give 5,5-dibromo-6-methyl-6,7-dihydrobenzofuran-4(5H)-one (33 g, 107.1 mmol, 29.8% yield) as a yellow solid.

[0115] Step 3: 5,5-Dibromo-6-methyl-6,7-dihydrobenzofuran-4(5H)-one (33 g, 107.1 mmol, 1.0 equiv) was dissolved in anhydrous DMF (535 mL). To this solution was added LiCO (47.5 g, 642.9 mmol, 6.0 equiv). The reaction was stirred at 100 °C for 2 h. Upon completion, the reaction was cooled to room temperature, filtered to remove solids, and concentrated. The residue was diluted with water (500 mL) and extracted with EA (200 mL). The organic layer was washed with water (500 mL × 2) and brine (500 mL × 1), dried over NaSO, decanted, and concentrated. The residue was purified by silica gel column chromatography (EA:PE=1:50) to give 5-bromo-6-methylbenzofuran-4-ol (19.5 g, 85.8 mmol, 80.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 10.38 (s, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.12 (d, J = 0.9 Hz, 1H), 7.09 (dd, J = 2.2, 1.0 Hz, 1H), 2.41 (d, J = 0.6 Hz, 3H).

[0116] Step 4.To a solution of 5-bromo-6-methylbenzofuran-4-ol (19.5 g, 85.8 mmol, 1.0 equiv) in THF (110 mL) was added NaH (6.8 g, 171.7 mmol, 2.0 equiv) in small portions at 0 °C. The reaction mixture was warmed to room temperature for 1 h, and then MOMBr (16.1 g, 128.8 mmol, 1.5 equiv) was added. The reaction was stirred at room temperature for 1 h. The mixture was quenched with HO (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to afford 5-bromo-4-(methoxymethoxy)-6-methylbenzofuran (21 g, 77.4 mmol, 90.1% yield) as a brown oil, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 2.3 Hz, 1H), 7.42 (t, J = 0.9 Hz, 1H), 7.06 (dd, J = 2.3, 1.0 Hz, 1H), 5.35 (s, 2H), 3.55 (s, 3H), 2.46 (d, J = 0.7 Hz, 3H).

[0117] Step 5. To a solution of 5-bromo-4-(methoxymethoxy)-6-methylbenzofuran (21 g, 77.4 mmol, 1.0 equiv) in dioxane (370 mL) was added HBPin (37.7 g, 295.0 mmol, 4.0 equiv), TEA (52.2 g, 516.4 mmol, 7.0 equiv), Pd(OAc) (2.4 g, 11.0 mmol, 0.15 equiv), and CyJohnphos (6.4 g, 18.4 mmol, 0.25 equiv). The mixture was then purged with N. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction was cooled to room temperature and filtered through a pad of Celite, rinsing with EA. The filtrate was concentrated to give a crude oil. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 80 / 1 to 10 / 1) to give 2-(4-(methoxymethoxy)-6-methylbenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10 g, 31.4 mmol, 42.6% yield) as a brown solid.1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 2.4Hz, 1H), 7.14 (s, 1H), 6.93 (dd, J = 2.0, 0.8Hz, 1H), 5.22 (s, 2H), 3.48 (s, 3H), 2.37 (s, 3H), 1.33 (s, 12H). Intermediate 4. Preparation of 2-(6-ethyl-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0118] [ka]

[0119] Step 1. To a solution of 1-(3,5-dihydroxyphenyl)ethan-1-one (50.0 g, 0.330 mol, 1.0 equiv.) in HCl (4% w / w) (3750 mL) was added Pd / C (12 g, 25% w / w). The mixture was stirred under H2 (4 MPa) at room temperature for 16 h. The reaction mixture was filtered through a pad of Celite and rinsed with EA. The filtrate was then extracted with tert-butyl methyl ether (1 L). The combined organic layers were washed with water (500 mL × 3) and brine (500 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:0 to 5:1) to give 5-ethylbenzene-1,3-diol (33.0 g, 0.240 mol, 72.7% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 6.27 - 6.27 (m, 1H), 6.21 - 6.20 (m, 2H), 2.51 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0120] Step 2.To a mixture of 5-ethylbenzene-1,3-diol (42.0 g, 0.300 mol, 1.0 equiv.) in HO (420 mL) was added Raney Ni (3.60 g, 8.5% w / w) and NaOH (14.6 g, 0.360 mol, 1.2 equiv.). The reaction was stirred under H (4 MPa) at 50 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature. The pH was adjusted to approximately 4–5 with 2 M HCl, and the mixture was extracted with EtOAc (500 mL × 3). The organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:0 to 1:1) to give 5-ethylcyclohexane-1,3-dione (22.0 g, 0.160 mol, 51.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 5.19 (s, 1H), 2.27 (dd, J = 16.4, 3.2 Hz, 2H), 2.03 (d, J = 11.2 Hz, 1H), 1.98 (s, 1H), 1.36 - 1.32 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H).

[0121] Step 3. To a solution of NaHCO3 (11.5 g, 0.140 mol, 1.2 equiv.) and 2-chloroacetaldehyde (22.4 g, 0.110 mol, 1.0 equiv.) in water (160 mL) was added a solution of 5-ethylcyclohexane-1,3-dione (16.0 g, 0.110 mol, 1.0 equiv.) in THF (20 mL) dropwise at 0 °C. The reaction was stirred at room temperature for 16 h and then diluted with ethyl acetate. The pH was adjusted to pH = 1 with H2SO4 (50% w / w in HO), and the mixture was stirred vigorously for 3 h. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with water, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate=1:0 to 3:1) to give 6-ethyl-6,7-dihydrobenzofuran-4(5H)-one (10.5 g, 0.060 mol, 56.2% yield) as a yellow oil.1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 1.6 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 3.03 - 2.98 (m, 1H), 2.62 - 2.51 (m, 2H), 2.29 - 2.22 (m, 2H), 1.61 (s, 2H), 0.99 (t, J = 7.6 Hz, 3H).

[0122] Step 4: A mixture of CuBr2 (57.1 g, 0.260 mol, 4 equiv.) in ethyl acetate (180 mL) was heated and stirred at 80 °C for 10 min. Then, a solution of 6-ethyl-6,7-dihydrobenzofuran-4(5H)-one (10.5 g, 0.060 mol, 1 equiv.) in CHCl3 (100 mL) was added to the mixture at 80 °C. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE:EA = 1:0 to 20:1) to give 5,5-dibromo-6-ethyl-6,7-dihydrobenzofuran-4(5H)-one (8.00 g, 24.8 mmol, 38.8% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 3.07 (dd, J = 17.6, 4.8 Hz, 1H), 2.67 (dd, J = 17.6, 9.6 Hz, 1H), 2.43 - 2.36 (m, 2H), 1.78 - 1.61 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H).

[0123] Step 5:To a mixture of 5,5-dibromo-6-ethyl-6,7-dihydrobenzofuran-4(5H)-one (8.00 g, 24.9 mmol, 1.0 equiv.) in DMF (80 mL) was added LiCO (11.0 g, 149 mmol, 4.0 equiv.). The reaction mixture was stirred at 100 °C for 2 h. Upon completion, the reaction was cooled to room temperature, filtered through a pad of Celite, and rinsed with EtOAc. The filtrate was diluted with water (800 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA = 1:0 to 20:1) to afford 5-bromo-6-ethylbenzofuran-4-ol (4.50 g, 18.7 mmol, 75.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 7.08 (s, 1H), 2.77 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H).

[0124] Step 6: To a solution of 5-bromo-6-ethylbenzofuran-4-ol (5.00 g, 20.7 mmol, 1.0 equiv) in THF (50 mL) was added NaH (1.24 g, 31.0 mmol, 1.5 equiv) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. Bromomethyl methyl ether (3.89 g, 31.0 mmol, 1.5 equiv) was then added slowly at 0 °C. The reaction was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched by the addition of water, diluted with water (500 mL), and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to afford 5-bromo-6-ethyl-4-(methoxymethoxy)benzofuran (5.50 g, 19.3 mmol, 93.0% yield) as a yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.4 Hz, 1H), 7.20 (s, 1H), 6.88 (d, J = 2.0 Hz, 1H), 5.31 (s, 2H), 3.67 (s, 3H), 2.88 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).

[0125] Step 7. To a solution of 5-bromo-6-ethyl-4-(methoxymethoxy)benzofuran (5.90 g, 20.7 mmol, 1.0 equiv) in 1,4-dioxane (60 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.6 g, 83.0 mmol, 4.0 equiv), Pd(OAc) (517 mg, 3.10 mmol, 0.15 equiv), EtN (20.1 mL, 145 mmol, 7.0 equiv), and 2-(dicyclohexylphosphino)biphenyl (1.80 g, 5.20 mmol, 0.25 equiv). The reaction was stirred at 80 °C under a N atmosphere for 16 h. Upon completion, the reaction was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was diluted with water (500 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA = 1:0 to 20:1) to afford 2-(6-ethyl-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.70 g, 14.2 mmol, 68.3% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.4 Hz, 1H), 7.08 (s, 1H), 6.86 (d, J = 2.0 Hz, 1H), 5.24 (s, 2H), 3.59 (s, 3H), 2.76 (dd, J = 15.2 Hz, 7.6 Hz, 2H), 1.40 (s, 12H), 1.25 (t, J = 7.6 Hz, 3H). Intermediate 5.Preparation of 2-(6-cyclopropyl-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0126] [ka]

[0127] Step 1: To a mixture of 4-bromo-2,6-dimethoxybenzaldehyde (25.0 g, 102 mmol, 1.0 equiv.) and NaI (30.6 g, 204 mmol, 2.0 equiv.) in MeCN (150 mL) and DCM (150 mL) was added AlCl (27.2 g, 204 mmol, 2.0 equiv.) at 0 °C. The reaction was stirred at room temperature for 16 h. Upon completion, the reaction was quenched with aqueous NH Cl (100 mL) and extracted with EtOAc (500 mL × 2). The organic phase was washed with brine (200 mL), dried over Na SO , filtered, and concentrated in vacuo to afford 2-hydroxy-4-iodo(bromo)-6-methoxybenzaldehyde as a yellow solid (23.0 g, 97.6% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 12.07 (s, 1H), 11.97 (s, 0.6 H), 10.28 (s, 0.6 H), 10.26 (s, 1H), 7.00 (s, 0.6 H), 6.76 (s, 1+0.6 H), 6.55 (d, J = 1.4 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 2H).

[0128] Step 2:To a solution of 2-hydroxy-4-iodo(bromo)-6-methoxybenzaldehyde (23.0 g, 100 mmol, 1.0 equiv.) in DMF (230 mL) was added 2-bromoethyl acetate (25.1 g, 150 mmol, 1.5 equiv.) and CsCO (65.4 g, 200 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 0.5 h and then at 120 °C under an Ar atmosphere for 3 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with HO (1000 mL), and extracted with EtOAc (400 mL × 2). The organic layer was washed with brine (500 mL), dried over NaSO, filtered, and concentrated in vacuo to afford ethyl 6-iodo(bromo)-4-methoxybenzofuran-2-carboxylate as a yellow solid (18.0 g, 59.9% yield), which was used in the next step without further purification. MS m / z 210.9 [M−H] -

[0129] Step 3: To a solution of ethyl 6-iodo(bromo)-4-methoxybenzofuran-2-carboxylate (18.0 g, 52.0 mmol, 1.0 equiv.) in THF (150 mL) and HO (50 mL) was added NaOH (3.12 g, 78.0 mmol, 1.5 equiv.). The reaction was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was poured into 4 N HCl until pH = 4 and extracted with EtOAc (200 mL × 3). The organic phase was washed with brine (200 mL), dried over NaSO, filtered, and evaporated under reduced pressure to give 6-iodo(bromo)-4-methoxybenzofuran-2-carboxylic acid as a white solid (17.0 g, 92.5% yield), which was used in the next step without further purification. MS m / z 225.0 [M−H] - .

[0130] Step 4:To a mixture of 6-iodo(bromo)-4-methoxybenzofuran-2-carboxylic acid (17.0 g, 53.5 mmol, 1.0 equiv.) and AgCO (2.9 g, 10.7 mmol, 0.2 equiv.) in DMSO (170 mL) was added AcOH (16.1 g, 267 mmol, 5.0 equiv.). The reaction was stirred at 120 °C for 2 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with HO (1000 mL), and extracted with EtOAc (300 mL × 2). The organic layer was washed with brine (500 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (100% PE) to afford 6-iodo(bromo)-4-methoxybenzofuran as a white solid (12.0 g, 95% purity, 77.8% yield).

[0131] Step 5: To a suspension of NaH (5.7 g, 91.2 mmol, 5.0 equiv) in DMF (50 mL) was added ethanethiol (3.7 g, 91.2 mmol, 5.0 equiv) at 0 °C. The mixture was stirred under N2 atmosphere at 0 °C for 30 min. 6-Iodo(bromo)benzofuran-4-ol (5.0 g, 18.2 mmol, 1.0 equiv) was added in EtSNa solution at 0 °C. The reaction was stirred under N2 atmosphere at 60 °C for 24 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with HO (500 mL), and extracted with EtOAc (200 mL × 3). The organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by reverse-phase flash chromatography (80 g flash column eluting with 0-100% MeCN in HO) to give 6-iodo(bromo)benzofuran-4-ol as a white solid (4.5 g, 94.9% yield). MS m / z 213.1 [M−H] - .

[0132] Step 6:To a solution of 6-iodo(bromo)benzofuran-4-ol (7.3 g, 34.2 mmol, 1.0 equiv) in THF (80 mL) was added NaH (2.1 g, 51.4 mmol, 1.5 equiv) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. Bromomethyl methyl ether (6.4 g, 51.4 mmol, 1.5 equiv) was then added at 0 °C. The reaction was warmed to room temperature and stirred for 0.5 h. The mixture was quenched with water and extracted with EtOAc (70 mL × 3). The organic phase was dried over Na SO , filtered, and concentrated under reduced pressure to afford 6-iodo(bromo)-4-(methoxymethoxy)benzofuran as a yellow oil (8.3 g, 94.2% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.57 (s, 0.4 H), 7.52 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 2.0 Hz, 0.4 H), 7.37 (s, 1H), 7.22 (s, 0.4 H), 7.07 (d, J = 1.2 Hz, 1H), 6.84 (s, 0.4 H), 6.84 (s, 1H), 5.28 (s, 2H), 5.27 (s, 1H), 3.52 (s, 5H).

[0133] Step 7: To a solution of 6-iodo(bromo)-4-(methoxymethoxy)benzofuran (5.0 g, 19.5 mmol, 1.0 equiv.) and cyclopropylboronic acid (5.0 g, 58.4 mmol, 3.0 equiv.) in Tol (80 mL) and HO (20 mL) was added KPO (12.4 g, 58.4 mmol, 3.0 equiv.), P(Cy) (1.1 g, 3.9 mmol, 0.2 equiv.), and Pd(OAc) (437 mg, 1.9 mmol, 0.1 equiv.). The reaction was stirred at 100 °C under N in a microwave reactor for 1 h. 。The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (300 mL × 3). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: EtOAc = 20:1) to give 6-cyclopropyl-4-(methoxymethoxy)benzofuran as a white solid (3.3 g, yield 77.7%). 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.4 Hz, 1H), 6.88 (s, 1H), 6.83 - 6.77 (m, 1H), 6.71 (s, 1H), 5.29 (s, 2H), 3.53 (s, 3H), 2.04 - 1.92 (m, 1H), 1.03 - 0.92 (m, 2H), 0.75 - 0.67 (m, 2H).

[0134] Step 8: A solution of 6-cyclopropyl-4-(methoxymethoxy)benzofuran (3.0 g, 13.7 mmol, 1.0 equiv) in 2.0 M HCl in EA (30 mL) was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (40 g flash column eluting with 0-100% MeCN in HO) to afford 6-cyclopropylbenzofuran-4-ol as a white solid (777 mg, 32.5% yield). MS m / z 175.2 [M+H] + . Step 9:To a solution of 6-cyclopropylbenzofuran-4-ol (777 mg, 4.5 mmol, 1.0 equiv) in DCM (20 mL) was added 1-bromopyrrolidine-2,5-dione (715 mg, 4.0 mmol, 0.9 equiv) and diisopropylamine (dropwise) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was chromatographed on silica gel eluting with petroleum ether to give 5-bromo-6-cyclopropylbenzofuran-4-ol as a yellow solid (708 mg, 62.7% yield). MS m / z 253.0 [M−H] - .

[0135] Step 10: To a solution of 5-bromo-6-cyclopropylbenzofuran-4-ol (708 mg, 2.8 mmol, 1.0 equiv) in DCM (10 mL) was added DIEA (1.1 g, 8.4 mmol, 3.0 equiv) and bromomethyl methyl ether (385 mg, 3.1 mmol, 1.1 equiv). The reaction was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc (30 mL × 3). The organic phase was dried over Na SO , filtered, and concentrated under reduced pressure to give 5-bromo-6-cyclopropyl-4-(methoxymethoxy)benzofuran as a yellow oil (800 mg, 96.2% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.4 Hz, 1H), 6.97 (s, 1H), 6.87 (d, J = 2.0 Hz, 1H), 5.32 (s, 2H), 3.68 (s, 3H), 2.04 - 1.92 (m, 1H), 1.10 - 1.01 (m, 2H), 0.69 (q, J = 5.4 Hz, 2H).

[0136] Step 11:To a solution of 5-bromo-6-cyclopropyl-4-(methoxymethoxy)benzofuran (980 mg, 3.3 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 13.2 mmol, 4.0 equiv.), Pd(OAc) (111 mg, 0.5 mmol, 0.15 equiv.), TEA (2.3 g, 23.1 mmol, 7.0 equiv.), and 2-(dicyclohexylphosphino)biphenyl (289 mg, 0.8 mmol, 0.25 equiv.). The reaction was stirred at 100 °C under a N atmosphere for 16 h. Upon completion, the reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (40 g flash column eluting with 0–12% EA in PE) to give 2-(6-cyclopropyl-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 44.1% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 2.0 Hz, 1H), 6.86 (s, 1H), 6.84 (d, J = 1.2 Hz, 1H), 5.24 (s, 2H), 3.59 (s, 3H), 2.18 - 2.09 (m, 1H), 1.41 (s, 12H), 0.92 - 0.87 (m, 2H), 0.76 - 0.68 (m, 2H). Intermediate 6. Preparation of 2-(4-(methoxymethoxy)-6-methylbenzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0137] [ka]

[0138] Step 1:To a solution of 2-(thiophen-2-yl)acetic acid (10.0 g, 70.3 mmol, 1.0 equiv.) in DMF (70 mL, 1 M) was added CDI (11.4 g, 70.3 mmol, 1.0 equiv.). After stirring at 40 °C for 30 min, N,O-dimethylhydroxylamine hydrochloride (7.6 g, 77.4 mmol, 1.1 equiv.) was added. The reaction mixture was stirred at room temperature for 0.5 h. Upon completion, the mixture was diluted with saturated NH4Cl (50 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate / hexane = 0% to 20%) to give N-methoxy-N-methyl-2-(thiophen-2-yl)acetamide (7.0 g, 37.8 mmol, 53% yield) as a colorless oil. MS m / z 186.2[M+H] + .

[0139] Step 2: To a solution of N-methoxy-N-methyl-2-(thiophen-2-yl)acetamide (7.0 g, 37.8 mmol, 1.0 equiv.) in EtO (70 mL) was added CHMgBr (3 M in EtO, 25.2 mL, 75.6 mmol, 2.0 equiv.) under a N atmosphere at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Upon completion, the reaction mixture was quenched with aqueous NHCl and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography eluting with 0–20% EtOAc in hexanes to afford 1-(thiophen-2-yl)propan-2-one (1.5 g, 10.7 mmol, 28% yield) as a brown solid. MS m / z 141.1 [M+H] + , 1 H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 6.96 (m, 1H), 6.87 (d, J = 3.2 Hz, 1H), 3.87 (s, 2H), 2.18 (s, 3H).

[0140] Step 3:To a mixture of NaH (471 mg, 11.8 mmol, 1.1 equiv) in THF (15 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (2.6 g, 11.8 mmol, 1.1 equiv) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 0.5 h. 1-(thiophen-2-yl)propan-2-one (1.5 g, 10.7 mmol, 1.0 equiv) was added to the mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 1 h. Upon completion, the mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate / hexane = 0% to 30%) to give ethyl (Z)-3-methyl-4-(thiophen-2-yl)but-2-enoate (1.4 g, 6.7 mmol, 62% yield) as a brown solid. MS m / z 211.2 [M+H] + .

[0141] Step 4: A mixture of ethyl (Z)-3-methyl-4-(thiophen-2-yl)but-2-enoate (1.4 g, 6.7 mmol, 1.0 equiv.), Raney-Ni (280 mg, 20% w / w) in MeOH (14 mL) was stirred under an H atmosphere at room temperature for 16 h. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated to give ethyl 3-methyl-4-(thiophen-2-yl)butanoate (0.9 g, 4.2 mmol, 62% yield) as a brown solid, which was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.13 - 7.11(m, 1H), 6.91 - 6.90 (m, 1H), 6.78 (d, J = 2.4 Hz, 1H), 4.15 - 4.09 (m, 2H), 2.86 - 2.81 (m, 1H), 2.77 - 2.72 (m, 1H), 2.43 - 2.33 (m, 1H), 2.40 - 2.35 (m, 1H), 2.34 - 2.26 (m, 1H), 2.16 - 2.09 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H).

[0142] Step 5: To a solution of ethyl 3-methyl-4-(thiophen-2-yl)butanoate (0.9 g, 4.2 mmol, 1.0 equiv.) in a mixture of tetrahydrofuran and methanol (16 mL, 1:1) was added NaOH (0.8 g, 21.2 mmol, 5.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 4 h, and then the solvent was evaporated. The residue was dissolved in water, acidified with hydrochloric acid (4 N), and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 3-methyl-4-(thiophen-2-yl)butanoic acid (0.7 g, 3.8 mmol, 90% yield) as a white solid, which was used in the next step without purification. MS m / z 185.3 [M+H] + . Step 6: To a solution of 3-methyl-4-(thiophen-2-yl)butanoic acid (0.7 g, 3.8 mmol, 1.0 equiv.) in DCM (7 mL) was added (COCl) (0.4 mL, 4.2 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was concentrated in vacuo to give crude 3-methyl-4-(thiophen-2-yl)butanoyl chloride (0.8 g) as a yellow oil, which was used in the next step without further purification.

[0143] Step 7:A mixture of 3-methyl-4-(thiophen-2-yl)butanoyl chloride (0.8 g, 4.0 mmol, 1.0 equiv.) in 1,1,1,3,3,3-hexafluoropropan-2-ol (8 mL) was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was concentrated to remove 1,1,1,3,3,3-hexafluoropropan-2-ol. The residue was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane to afford 6-methyl-6,7-dihydrobenzo[b]thiophen-4(5H)-one (250 mg, 1.5 mmol, 35% yield) as a white solid. MS m / z 167.0 [M+H] + .

[0144] Step 8: To a mixture of CuBr2 (1.3 g, 6.0 mmol, 4.0 equiv) in EtOAc (5 mL) was added a solution of 6-methyl-6,7-dihydrobenzo[b]thiophen-4(5H)-one (250 mg, 1.5 mmol, 1.0 equiv) in CHCl3 (1 mL) at 80 °C. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature, filtered, and the organic phase was collected. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-3% EtOAc in hexane to afford 5,5-dibromo-6-methyl-6,7-dihydrobenzo[b]thiophen-4(5H)-one (260 mg, 0.8 mmol, 53% yield) as a white solid. MS m / z 324.8 [M+H] + .

[0145] Step 9:To a mixture of 5,5-dibromo-6-methyl-6,7-dihydrobenzo[b]thiophen-4(5H)-one (260 mg, 0.8 mmol, 1.0 equiv.) in DMF (3 mL) was added LiCO (356 mg, 4.8 mmol, 6.0 equiv.). The reaction was stirred at 100 °C for 2 h. Upon completion, the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (10 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane to afford 5-bromo-6-methylbenzo[b]thiophen-4-ol (60 mg, 0.2 mmol, 31% yield) as a white solid. MS m / z 243.0 [MH] - .

[0146] Step 10: To a solution of 5-bromo-6-methylbenzo[b]thiophen-4-ol (60 mg, 0.200 mmol, 1.0 equiv) in THF (1 mL) was added NaH (17.0 mg, 0.400 mmol, 2.0 equiv) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 0.5 h. Bromo(methoxy)methane (39 mg, 0.300 mmol, 1.5 equiv) was added to the mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. Upon completion, the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give ethyl (Z)-3-methyl-4-(thiophen-2-yl)but-2-enoate (60 mg, 6.7 mmol, 62% yield) as a brown solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.45 (d, J = 4.0 Hz, 1H), 5.24 (s, 2H), 3.60 (s, 3H), 2.48 (s, 3H).

[0147] Step 11:To a mixture of ethyl (Z)-3-methyl-4-(thiophen-2-yl)but-2-enoate (60 mg, 6.70 mmol, 1.0 equiv.), CyJohnPhos (18 mg, 0.052 mmol, 0.25 equiv.), Pd(OAc) (7 mg, 0.031 mmol, 0.15 equiv.), and EtN (148 mg, 1.46 mmol, 7.0 equiv.) in anhydrous 1,4-dioxane (2 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (107 mg, 0.835 mmol, 4.0 equiv.) was added dropwise at room temperature under a N atmosphere. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc (5 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–10% EtOAc in hexane to give 2-(4-(methoxymethoxy)-6-methylbenzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30 mg, 0.089 mmol, 43% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 5.6 Hz, 1H), 7.56 (s, 1H), 7.42 - 7.40 (m, 1H), 5.12 (s, 2H), 3.52 (s, 3H), 2.41 (s, 3H), 1.34 (s, 12H). Intermediate 7. Preparation of 2-(2-methoxy-4-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0148] [ka]

[0149] Step 1:A mixture of 3-bromobicyclo[4.2.0]octa-1(6),2,4-triene (57.8 g, 315 mmol, 1.0 equiv.), NHBoc (44.4 g, 379 mmol, 1.2 equiv.), CsCO (154 g, 474 mmol, 1.5 equiv.), Xantphos (9.14 g, 15.8 mmol, 0.05 equiv.), Pd(dba) (4.34 g, 4.74 mmol, 0.01 equiv.), and 1,4-dioxane (525 mL) was stirred at 105 °C under a N atmosphere for 16 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (1000 mL), and extracted with EtOAc (1000 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–10% EtOAc in hexane to give tert-butyl bicyclo[4.2.0]octa-1(6),2,4-trien-3-ylcarbamate (69.0 g, 315 mmol, 99.7% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.39 (s, 1H), 3.12 (s, 4H), 1.51 (s, 9H). MS m / z 164.4 [Mt-Bu+H] + .

[0150] Step 2: To a solution of tert-butyl bicyclo[4.2.0]octa-1(6),2,4-trien-3-ylcarbamate (73.2 g, 334 mmol, 1.0 equiv) in DCM (700 mL) was added TFA (140 mL). The reaction was stirred at room temperature for 16 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (1000 mL), neutralized to pH = 8 with aqueous NaHCO3, and extracted with DCM (1000 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford bicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (36.6 g, 307 mmol, 92.0% yield) as a yellow oil, which was used in the next step without further purification. 1H NMR (400Hz, CDCl3) δ 6.82 (d, J = 8.0 Hz, 1H), 6.52 (dd, J = 7.6, 1.6 Hz, 1H), 6.46 (s, 1H), 3.50 (s, 2H), 3.07 (s, 4H). MS m / z 120.3 [M+H] + .

[0151] Step 3: To a solution of bicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (36.6 g, 307 mmol, 1.0 equiv) in MeCN (1400 mL) was added a solution of NBS (53.6 g, 301 mmol, 0.98 equiv) in MeCN (1000 mL) dropwise at -30 °C. The reaction was allowed to warm to room temperature and stirred for 2 h. Upon completion, the reaction mixture was diluted with water (1000 mL) and extracted with EtOAc (1000 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–12% EtOAc in hexane to give 4-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (17.0 g, 85.8 mmol, 28.0% yield) as a black solid. 1 H NMR (400 MHz, CDCl3) δ 7.08 (s, 1H), 6.53 (s, 1H), 3.96 (s, 2H), 3.10 - 3.06 (m, 2H), 3.06 - 3.03 (m, 2H). MS m / z 239.3 [M+Na+H2O+H] + , 241.3 [M+Na+H2O+H] + .

[0152] Step 4:A mixture of 4-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (12.0 g, 60.6 mmol, 1.0 equiv.), KCO (25.1 g, 182 mmol, 3.0 equiv.), Pd(dppf)Cl (4.40 g, 6.06 mmol, 0.1 equiv.), HO (50 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M in THF, 86.6 mL, 303 mmol, 5 equiv.), and 1,4-dioxane (250 mL) was stirred at 90 °C under a N atmosphere for 3 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (1000 mL), and extracted with EtOAc (2 x 1000 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–10% EtOAc in hexane to give 4-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (4.94 g, 37.1 mmol, 61.2% yield) as an orange solid. 1 H NMR (400 MHz, CDCl3) δ 6.74 (s, 1H), 6.44 (s, 1H), 3.49 (s, 2H), 3.07 (s, 4H), 2.15 (s, 3H). MS m / z 134.1 [M+H] + .

[0153] Step 5: To a solution of 4-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (4.94 g, 37.1 mmol, 1.0 equiv.) in MeCN (200 mL) was added a solution of NBS (6.60 g, 37.1 mmol, 1.0 equiv.) in MeCN (100 mL) dropwise at -30 °C. The reaction was allowed to warm to room temperature and stirred for 1 h. Upon completion, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–10% EtOAc in hexane to give 2-bromo-4-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (3.1 g, 14.6 mmol, 39.4% yield) as an off-white solid.1 H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 3.07 - 3.04 (m, 2H), 3.03 - 3.01 (m, 2H), 2.19 (s, 3H). MS m / z 212.2, 214.2 [M+H] + .

[0154] Step 6: Solid Na (1.84 g, 80.2 mmol, 5.0 equiv) was added in portions to MeOH (20 mL) at 0 °C, and the mixture was warmed to room temperature until the solid was completely consumed. A 50 mL autoclave was charged with a mixture of fresh MeONa solution, 2-bromo-4-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (3.40 g, 16.0 mmol, 1.0 equiv), and CuI (3.36 g, 17.6 mmol, 1.1 equiv). The reaction was sealed and stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–10% EtOAc in hexanes to give 2-methoxy-4-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (700 mg, 4.29 mmol, 26.8% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 3.94 (s, 3H), 3.57 (s, 2H), 3.37 - 3.31 (m, 2H), 3.12 - 3.08 (m, 2H), 2.15 (s, 3H). MS m / z 164.4 [M+H] + .

[0155] Step 7:To a suspension of 2-methoxy-4-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-amine (1.00 g, 6.13 mmol, 1.0 equiv) in concentrated HCl (37% w / w, 10 mL) was added a solution of NaNO (845 mg, 12.3 mmol, 2.0 equiv) in water (10 mL) at 0 °C. After stirring for 10 min at 0 °C, an orange suspension was obtained, forming the diazonium salt compound. A solution of KI (4.07 g, 24.5 mmol, 4.0 equiv) in water (20 mL) was added to the diazonium salt. During the addition, a lot of solid matter formed. The reaction was then stirred at room temperature for 16 h, overnight. The reaction mixture was extracted with EtOAc (30 mL × 3). The organic layer was washed with aqueous NaSO (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane to give 3-iodo-2-methoxy-4-methylbicyclo[4.2.0]octa-1(6),2,4-triene (277 mg, 1.01 mmol, 16.5% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 6.55 (s, 1H), 3.92 (s, 3H), 3.40 - 3.30 (m, 2H), 3.09 - 3.03 (m, 2H), 2.37 (s, 4H).

[0156] Step 8:To a mixture of 3-iodo-2-methoxy-4-methylbicyclo[4.2.0]octa-1(6),2,4-triene (277 mg, 1.01 mmol, 1.0 equiv.), CyJohnPhos (88.6 mg, 0.253 mmol, 0.25 equiv.), Pd(OAc) (34.0 mg, 0.152 mmol, 0.15 equiv.), and EtN (716 mg, 7.07 mmol, 7.0 equiv.) in anhydrous 1,4-dioxane (4 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (647 mg, 5.05 mmol, 5.0 equiv.) was added dropwise at room temperature under a N atmosphere. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (20 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–10% EtOAc in hexanes to afford 2-(2-methoxy-4-methylbicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.500 mmol, 49.5% yield) as an orange solid. 1 H NMR (400 MHz, CDCl3) δ 6.46 (s, 1H), 3.85 (s, 3H), 3.37 - 3.29 (m, 2H), 3.14 - 3.06 (m, 2H), 2.30 (s, 3H), 1.36 (s, 12H). Intermediate 8. Preparation of 2-(6-(difluoromethyl)-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0157] [ka]

[0158] Step 1.To a stirred solution of furan-2-carbaldehyde (63.2 mL, 763 mmol, 1.0 equiv.) and diethyl butanedioate (190 mL, 1.14 mol, 1.5 equiv.) in absolute ethanol (1280 mL) was added NaOEt (130 g, 1.91 mol, 2.5 equiv.). The resulting mixture was refluxed at 90 °C for 16 h. After cooling to room temperature, the reaction solvent was evaporated under reduced pressure. The crude residue was then dissolved in water, and the pH of the solution was acidified to pH = 1 with concentrated HCl. The acidic solution was then extracted with EtOAc (3 × 1000 mL). The combined organic layers were extracted with 10% NaCO solution (3 × 500 mL). The basic aqueous solutions were collected, combined, washed with EtO (2 × 1000 mL), and then acidified to pH = 1 with concentrated HCl. The resulting acidic solution was back-extracted with EtOAc (3 × 500 mL). The combined EtOAc solution was then washed with water (2×500 mL) and brine, dried over NaSO, filtered, and evaporated under reduced pressure to give (Z)-3-(ethoxycarbonyl)-4-(furan-2-yl)but-3-enoic acid as a black oil (178 g, 104% yield).

[0159] Step 2. The resulting crude 3-ethoxycarbonyl-4-(2-furyl)but-3-enoic acid (178 g, 794 mmol, 1.0 equiv.) was dissolved in acetic anhydride (750 mL) and treated with sodium acetate (78.2 g, 953 mmol, 1.2 equiv.). The resulting mixture was refluxed at 160° C. for 5 hours. Upon completion, the reaction was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over NaSO, filtered, and evaporated under reduced pressure to give ethyl 4-acetoxybenzofuran-6-carboxylate as a black oil (137 g, 69.5% yield).

[0160] Step 3.To a solution of the resulting crude ethyl 4-acetoxybenzofuran-6-carboxylate (137 g, 552 mmol, 1.0 equiv.) in methanol (400 mL) was added potassium carbonate (114 g, 828 mmol, 1.5 equiv.). The mixture was refluxed at 60 °C for 1 h. After complete consumption of the starting material, the solvent was evaporated and the residue was diluted with water. The aqueous solution was acidified to pH = 3 with solid citric acid and then extracted with EtOAc (3 × 300 mL). The combined organic solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (gradient elution, petroleum ether: EtOAc = 4:1 to 2:3) to give ethyl 4-hydroxybenzofuran-6-carboxylate (48.5 g, 42.6% yield) as a yellow solid. MS m / z 207.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.62 (t, J = 1.1 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H), 7.03 (dd, J = 2.3, 1.0 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).

[0161] Step 4. To a mixture of ethyl 4-hydroxybenzofuran-6-carboxylate (50.0 g, 243 mmol, 1.0 equiv.) and DIPA (3.4 mL, 24.3 mmol, 0.1 equiv.) in DCM (500 mL) was added NBS (43.2 g, 243 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with DCM (400 mL × 3). The organic layer was dried over Na2SO4, decanted, and concentrated. The crude product was chromatographed on silica gel (gradient elution, petroleum ether: EtOAc = 20:1 → 10:1 → 5:1) to give ethyl 5-bromo-4-hydroxybenzofuran-6-carboxylate as a yellow oil (37.0 g, 53.5% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.48 (s, 1H), 7.31 -7.11 (m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0162] Step 5. To a solution of ethyl 5-bromo-4-hydroxybenzofuran-6-carboxylate (37.0 g, 130 mmol, 1.0 equiv) in anhydrous THF (370 mL) was added NaH (10.4 g, 260 mmol, 2.0 equiv) in small portions at 0 °C. The reaction was stirred at room temperature for 1 h. Bromomethyl methyl ether (24.3 g, 195 mmol, 1.5 equiv) was added to the mixture at 0 °C. The reaction was stirred at room temperature for 1 h. The mixture was diluted with HO (350 mL) and extracted with EtOAc (300 mL × 3). The organic phase was dried over NaSO, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (gradient elution, petroleum ether: EtOAc = 10:1) to give ethyl 5-bromo-4-(methoxymethoxy)benzofuran-6-carboxylate as a yellow oil (38.9 g, 91.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 4.0 Hz, 1H), 7.76 (s, 1H), 7.26 - 7.12 (m, 1H), 5.40 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.57 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H).

[0163] Step 6.To a mixture of LiAlH (5.19 g, 137 mmol, 3.0 equiv.) in THF (840 mL) was added ethyl 5-bromo-4-(methoxymethoxy)benzo[b]thiophene-6-carboxylate (15.0 g, 45.6 mmol, 1.0 equiv.) under a N atmosphere at −20 °C, and the mixture was stirred for 20 min. Upon completion, the reaction mixture was warmed to room temperature, treated with NaSO·10H O, and stirred for 5 min. The mixture was filtered through a Celite pad and rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–5% EtOAc in petroleum ether to give (5-bromo-4-(methoxymethoxy)benzo[b]thiophen-6-yl)methanol (12.0 g, 41.8 mmol, 92.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 2.0 Hz, 1H), 7.49 (s, 1H), 7.23 - 6.70 (m, 1H), 5.56 - 5.53 (t, J = 5.4 Hz, 1H), 5.35 (d, J = 0.4 Hz, 2H), 4.59 (d, J = 5.6 Hz, 2H), 3.54 (d, J = 0.4 Hz, 3H).

[0164] Step 7. To a mixture of (5-bromo-4-(methoxymethoxy)benzo[b]thiophen-6-yl)methanol (12.0 g, 41.8 mmol, 1.0 equiv.) in DCM (120 mL) was added MnO (21.8 g, 251 mmol, 6.0 equiv.). The reaction was stirred at 38 °C for 4 h. Upon completion, the reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with DCM. The filtrate was concentrated under reduced pressure to give 5-bromo-4-(methoxymethoxy)benzofuran-6-carbaldehyde (10.1 g, 35.4 mmol, 85% yield) as a white solid. MS m / z 284.9 [M+H] + . Step 8.To a solution of 5-bromo-4-(methoxymethoxy)benzofuran-6-carbaldehyde (10.1 g, 35.4 mmol, 1.0 equiv) in DCM (70 mL) was added DAST (23.4 mL, 177 mmol, 5.0 equiv) at -60 °C. The reaction mixture was warmed to room temperature and stirred for 4 h. Upon completion, the mixture was added dropwise to saturated NaHCO (50 mL), and the mixture was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The crude product was purified by column chromatography eluting with 0–10% EtOAc in petroleum ether to afford 5-bromo-6-(difluoromethyl)-4-(methoxymethoxy)benzo[b]thiophene (9.5 g, 30.9 mmol, 87% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 2.0 Hz, 1H), 7.72 (s, 1H), 7.38 - 7.1 (t, J = 54.8 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 5.41 (s, 2H), 3.55 (s, 3H).

[0165] Step 9.To a mixture of 5-bromo-6-(difluoromethyl)-4-(methoxymethoxy)benzo[b]thiophene (9.5 g, 30.9 mmol, 1.0 equiv.), CyJohnPhos (2.7 g, 7.7 mmol, 0.25 equiv.), Pd(OAc) (1.0 g, 4.6 mmol, 0.15 equiv.), and EtN (30.1 mL, 216.5 mmol, 7.0 equiv.) in anhydrous 1,4-dioxane (95 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.8 mg, 123.7 mmol, 4.0 equiv.) was added dropwise at room temperature under a N atmosphere. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-10% EtOAc in petroleum ether to give 2-(6-(difluoromethyl)-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.2 g, 14.7 mmol, 47% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.09 (d, J = 1.6 Hz, 1H), 7.20 - 6.92(t, J = 56.4 Hz, 1H) 5.30 (s, 2H), 3.50 (s, 3H), 1.32 (s, 12H). Intermediate 9. Preparation of 2-(4-(methoxymethoxy)-6-(2,2,2-trifluoroethyl)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0166] [ka]

[0167] Step 1.A 20 mL microwave tube was charged with a mixture of 5-bromo-4-(methoxymethoxy)benzofuran-6-carbaldehyde (1.0 g, 3.51 mmol, 1.0 equiv.) and 2,2-difluoro-2-(triphenylphosphonio)acetate (2.50 g, 7.02 mmol, 2.0 equiv.) in anhydrous DMF (6 mL) at room temperature under a N atmosphere. The vessel was sealed and stirred at 60 °C for 2 h. The reaction was repeated four more times simultaneously. Upon complete consumption of the starting material, as monitored by TLC, the reaction mixture was cooled to room temperature and poured into a 250 mL round-bottom flask. A solution of TBAF (1.0 M, 52.6 mL, 52.6 mmol, 3.0 equiv.) was added to the mixture. The reaction was stirred at 60 °C for 1 h under a N atmosphere. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The organic layer was washed with water (100 mL × 2) and brine (100 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0 to 10% EtOAc in hexane to give 5-bromo-4-(methoxymethoxy)-6-(2,2,2-trifluoroethyl)benzofuran (1.6 g, 4.72 mmol, 26.9% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 2.0 Hz, 1H), 7.35 (s, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.32 (s, 2H), 3.78 (q, J = 10.4 Hz, 2H), 3.67 (s, 3H).

[0168] Step 2.To a mixture of 5-bromo-4-(methoxymethoxy)-6-(2,2,2-trifluoroethyl)benzofuran (1.64 g, 4.84 mmol, 1.0 equiv.), CyJohnPhos (424 mg, 1.21 mmol, 0.25 equiv.), Pd(OAc) (163 mg, 0.725 mmol, 0.15 equiv.), and EtN (4.71 mL, 33.9 mmol, 7.0 equiv.) in anhydrous 1,4-dioxane (20 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.51 mL, 0.882 g / mL, 24.2 mmol, 5.0 equiv.) was added dropwise at room temperature under a N atmosphere. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–10% EtOAc in hexanes to afford 2-(4-(methoxymethoxy)-6-(2,2,2-trifluoroethyl)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.18 g, 3.06 mmol, 63.2% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 2.4 Hz, 1H), 7.23 (s, 1H), 6.95 - 6.88 (m, 1H), 5.23 (s, 2H), 3.68 (q, J = 10.8 Hz, 2H), 3.60 (s, 3H), 1.39 (s, 12H). Intermediate 10. Preparation of 2-(6-ethyl-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0169] [ka]

[0170] Step 1.To a solution of 1-(3,5-dihydroxyphenyl)ethan-1-one (50.0 g, 0.330 mol, 1.0 equiv.) in HCl (4% w / w) (3750 mL) was added Pd / C (12 g, 25% w / w). The mixture was stirred under H2 (4 MPa) at room temperature for 16 h. The reaction mixture was filtered through a pad of Celite and rinsed with EA. The filtrate was then extracted with tert-butyl methyl ether (1 L). The combined organic layers were washed with water (500 mL × 3) and brine (500 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:0 to 5:1) to give 5-ethylbenzene-1,3-diol (33.0 g, 0.240 mol, 72.7% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 6.27 - 6.27 (m, 1H), 6.21 - 6.20 (m, 2H), 2.51 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0171] Step 2. To a mixture of 5-ethylbenzene-1,3-diol (42.0 g, 0.300 mol, 1.0 equiv.) in HO (420 mL) was added Raney Ni (3.60 g, 8.5% w / w) and NaOH (14.6 g, 0.360 mol, 1.2 equiv.). The reaction was stirred under H (4 MPa) at 50 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature. The pH was adjusted to approximately 4–5 with 2 M HCl, and the mixture was extracted with EtOAc (500 mL × 3). The organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:0 to 1:1) to give 5-ethylcyclohexane-1,3-dione (22.0 g, 0.160 mol, 51.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 5.19 (s, 1H), 2.27 (dd, J = 16.4, 3.2 Hz, 2H), 2.03 (d, J = 11.2 Hz, 1H), 1.98 (s, 1H), 1.36 - 1.32 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H).

[0172] Step 3. To a solution of NaHCO3 (11.5 g, 0.140 mol, 1.2 equiv.) and 2-chloroacetaldehyde (22.4 g, 0.110 mol, 1.0 equiv.) in water (160 mL) was added a solution of 5-ethylcyclohexane-1,3-dione (16.0 g, 0.110 mol, 1.0 equiv.) in THF (20 mL) dropwise at 0 °C. The reaction was stirred at room temperature for 16 h and then diluted with ethyl acetate. The pH was adjusted to pH = 1 with H2SO4 (50% w / w in HO), and the mixture was stirred vigorously for 3 h. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with water, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate=1:0 to 3:1) to give 6-ethyl-6,7-dihydrobenzofuran-4(5H)-one (10.5 g, 0.060 mol, 56.2% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 1.6 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 3.03 - 2.98 (m, 1H), 2.62 - 2.51 (m, 2H), 2.29 - 2.22 (m, 2H), 1.61 (s, 2H), 0.99 (t, J = 7.6 Hz, 3H).

[0173] Step 4.A mixture of CuBr2 (57.1 g, 0.260 mol, 4 equiv.) in ethyl acetate (180 mL) was heated and stirred at 80 °C for 10 min. Then, a solution of 6-ethyl-6,7-dihydrobenzofuran-4(5H)-one (10.5 g, 0.060 mol, 1 equiv.) in CHCl3 (100 mL) was added to the mixture at 80 °C. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE:EA = 1:0 to 20:1) to give 5,5-dibromo-6-ethyl-6,7-dihydrobenzofuran-4(5H)-one (8.00 g, 24.8 mmol, 38.8% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 3.07 (dd, J = 17.6, 4.8 Hz, 1H), 2.67 (dd, J = 17.6, 9.6 Hz, 1H), 2.43 - 2.36 (m, 2H), 1.78 - 1.61 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H).

[0174] Step 5. To a mixture of 5,5-dibromo-6-ethyl-6,7-dihydrobenzofuran-4(5H)-one (8.00 g, 24.9 mmol, 1.0 equiv.) in DMF (80 mL) was added LiCO (11.0 g, 149 mmol, 4.0 equiv.). The reaction mixture was stirred at 100 °C for 2 h. Upon completion, the reaction was cooled to room temperature, filtered through a pad of Celite, and rinsed with EtOAc. The filtrate was diluted with water (800 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA = 1:0 to 20:1) to afford 5-bromo-6-ethylbenzofuran-4-ol (4.50 g, 18.7 mmol, 75.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 7.08 (s, 1H), 2.77 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H).

[0175] Step 6. To a solution of 5-bromo-6-ethylbenzofuran-4-ol (5.00 g, 20.7 mmol, 1.0 equiv) in THF (50 mL) was added NaH (1.24 g, 31.0 mmol, 1.5 equiv) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. Bromomethyl methyl ether (3.89 g, 31.0 mmol, 1.5 equiv) was then added slowly at 0 °C. The reaction was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched by the addition of water, diluted with water (500 mL), and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to afford 5-bromo-6-ethyl-4-(methoxymethoxy)benzofuran (5.50 g, 19.3 mmol, 93.0% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.4 Hz, 1H), 7.20 (s, 1H), 6.88 (d, J = 2.0 Hz, 1H), 5.31 (s, 2H), 3.67 (s, 3H), 2.88 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).

[0176] Step 7.To a solution of 5-bromo-6-ethyl-4-(methoxymethoxy)benzofuran (5.90 g, 20.7 mmol, 1.0 equiv) in 1,4-dioxane (60 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.6 g, 83.0 mmol, 4.0 equiv), Pd(OAc) (517 mg, 3.10 mmol, 0.15 equiv), EtN (20.1 mL, 145 mmol, 7.0 equiv), and 2-(dicyclohexylphosphino)biphenyl (1.80 g, 5.20 mmol, 0.25 equiv). The reaction was stirred at 80 °C under a N atmosphere for 16 h. Upon completion, the reaction was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was diluted with water (500 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE:EA = 1:0 to 20:1) to afford 2-(6-ethyl-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.70 g, 14.2 mmol, 68.3% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.4 Hz, 1H), 7.08 (s, 1H), 6.86 (d, J = 2.0 Hz, 1H), 5.24 (s, 2H), 3.59 (s, 3H), 2.76 (dd, J = 15.2 Hz, 7.6 Hz, 2H), 1.40 (s, 12H), 1.25 (t, J = 7.6 Hz, 3H). Intermediate 11. Preparation of (1s,3s)-1-methyl-3-((1-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)imidazo[1,5-d][1,2,4]triazin-4-yl)amino)cyclobutan-1-ol

[0177] [ka]

[0178] Step 1. A solution of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (700 mg, 2.95 mmol, 1.0 equiv) in THF (10 mL) was slowly added to LDA (2.5 M in hexanes, 1.8 mL, 4.43 mmol, 1.5 equiv) at −70 °C and stirred at −70 °C for 2 h. The mixture was added to trimethylborate (460 mg, 4.43 mmol, 1.5 equiv) at −70 °C and stirred at −70 °C for 2 h under N. The mixture was warmed to −30 °C while adding H2O dropwise and stirred at −30 °C for 0.5 h. The mixture was warmed to 5 °C, quenched with aqueous Na2SO3, and extracted with EtOAc (30 mL × 3). The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (12 g flash column eluted with 0–100% MeCN in HO) to afford 5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-ol (200 mg, 0.80 mmol, 26.8% yield) as a yellow oil. MS m / z 250.9 [M−H] - .

[0179] Step 2.5-Bromo-2,2-difluorobenzo[d][1,3]dioxol-4-ol (1 g, 3.95 mmol, 1.0 equiv) was dissolved in THF (anhydrous SDS) (10 mL) and cooled to 0 °C. To this, NaH (237 mg, 5.93 mmol, 1.5 equiv) was added portionwise at 0 °C. The reaction was stirred at 0 °C for 0.5 h. To this, MOMBr (749 mg, 5.93 mmol, 1.5 equiv) was added. The reaction was stirred at room temperature for 0.5 h and monitored by TLC. Upon completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (150 mL × 1) and brine (150 mL × 1). The organic layer was dried over NaSO, decanted, and concentrated to give 5-bromo-2,2-difluoro-4-(methoxymethoxy)benzo[d][1,3]dioxole (1 g, 3.37 mmol, 85.2% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.38 (s, 2H), 3.56 (s, 3H).

[0180] Step 3.To a solution of 5-bromo-2,2-difluoro-4-(methoxymethoxy)benzo[d][1,3]dioxole (1.1 g, 3.70 mmol, 1.0 equiv) in 1,4-dioxane (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 g, 14.81 mmol, 4.0 equiv), Pd(OAc) (92.5 mg, 0.55 mmol, 0.15 equiv), TEA (2.62 g, 25.92 mmol, 7.0 equiv), and 2-(dicyclohexylphosphino)biphenyl (324 mg, 0.92 mmol, 0.25 equiv). The reaction was stirred at 100 °C under N for 16 h and monitored by TLC. The reaction mixture was cooled to 25 °C and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to give 2-(2,2-difluoro-4-(methoxymethoxy)benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.58 mmol, 15.7% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.25 (s, 2H), 3.59 (s, 3H), 1.34 (s, 12H). Intermediate 12. Preparation of 2-(2-(difluoromethyl)-6-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0181] [ka]

[0182] Step 1.To a solution of N,N,N'-trimethylethylenediamine (27.60 g, 270.08 mmol, 1.3 equiv) in anhydrous THF was added n-BuLi (2.5 M, 108 mL, 270.08 mmol, 1.3 equiv) dropwise at 0°C under an argon atmosphere. The reaction mixture was stirred at 0°C for 30 minutes. A solution of 3-methoxy-5-methylbenzaldehyde (31.2 g, 207.75 mmol, 1.0 equiv) in anhydrous THF was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. n-BuLi (2.5 M, 166 mL, 415.51 mmol, 2.0 equiv) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. A solution of CBr4 (137.79 g, 415.51 mmol, 2 equiv.) in anhydrous THF was added dropwise at −78 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with NH4Cl and extracted with EtOAc (1000 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with PE / EtOAc (100:1, 50:1, 20:1) and reverse-phase flash chromatography (330 g flash column eluting with 0–100% MeCN in HO) to give 2-bromo-3-methoxy-5-methylbenzaldehyde (8.3 g, 36.23 mmol, 17.44% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 7.34 (d, J = 1.1 Hz, 1H), 6.95 (d, J = 1.3 Hz, 1H), 3.94 (s, 3H), 2.38 (s, 3H).

[0183] Step 2.DAST (29.20 g, 181.16 mmol, 5.0 equiv.) was added dropwise to a round-bottom flask containing 2-bromo-3-methoxy-5-methylbenzaldehyde (8.3 g, 36.23 mmol, 1.0 equiv.) in DCM at −78° C. under an inert atmosphere. The reaction was stirred at room temperature for 16 hours. The mixture was added dropwise to saturated aqueous NaHCO at 0° C. The resulting mixture was extracted with DCM (200 mL × 3). The organic phase was dried over NaSO, decanted, and concentrated to give 2-bromo-1-(difluoromethyl)-3-methoxy-5-methylbenzene (6.4 g, 25.73 mmol, 71.01% yield) as a brown oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), δ 6.93 (t, J = 55.2 Hz, 1H) 6.82 (s, 1H), 3.91 (s, 3H), 2.38 (s, 3H).

[0184] Step 3. A mixture of 2-bromo-1-(difluoromethyl)-3-methoxy-5-methylbenzene (2.3 g, 9.16 mmol, 1.0 equiv.), B2PIN2 (2.44 g, 9.62 mmol, 1.05 equiv.), KOAc (2.7 g, 27.48 mmol, 3 equiv.), and Pd(dppf)Cl2 (742.56 mg, 0.916 mmol, 0.1 equiv.) in anhydrous 1,4-dioxane was stirred at 100 °C for 16 h under an Ar atmosphere. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc (50 mL). The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (40 g flash column eluting with 0–10% EtOAc in PE) to afford 2-(2-(difluoromethyl)-6-methoxy-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 g, 3.69 mmol, 40.28% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.79 (t, J=56.8, 1H), 6.79 (s, 1H), 6.73 (s, 1H), 6.65 (s, 1H), 3.79 (s, 3H), 2.37 (s, 3H), 1.37 (s, 12H). Intermediate 13. Preparation of 2-(4-chloro-2-(difluoromethyl)-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0185] [ka]

[0186] Step 1. To a solution of 5-chloro-2-hydroxy-3-methoxybenzaldehyde (10.0 g, 53.6 mmol, 1.0 equiv) in THF (100 mL) was added NaH (4.29 g, 107.2 mmol, 2.0 equiv) at 0 °C. The mixture was stirred at room temperature for 0.5 h. Then MOMBr (10.1 g, 80.4 mmol, 1.5 equiv) was added slowly at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated to give 5-chloro-3-methoxy-2-(methoxymethoxy)benzaldehyde (10.0 g, 43.4 mmol, 81% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.46 (s, 1H), 7.24 (d, J = 2.4 Hz, 1H), 5.17 (s, 2H), 3.89 (s, 3H), 3.47 (s, 3H).

[0187] Step 2.To a solution of 5-chloro-3-methoxy-2-(methoxymethoxy)benzaldehyde (10.0 g, 43.4 mmol, 1.0 equiv.) in DCM (70 mL) was added DAST (28.6 mL, 216.8 mmol, 5.0 equiv.) at -60 °C. The reaction mixture was warmed to room temperature and stirred for 4 h. Upon completion, the mixture was added to saturated NaHCO (50 mL) and extracted with DCM (50 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The crude product was purified by column chromatography (ethyl acetate / hexane = 0% to 10%) to afford 5-chloro-1-(difluoromethyl)-3-methoxy-2-(methoxymethoxy)benzene (6.0 g, 23.8 mmol, 55% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.10 (t, J = 54.8 Hz, 1H), 5.11 (s, 2H), 3.87 (s, 3H).

[0188] Step 3. A solution of 5-chloro-1-(difluoromethyl)-3-methoxy-2-(methoxymethoxy)benzene (6.0 g, 23.8 mmol, 1.0 equiv) in HCl in EA (60 mL) was stirred with LCMS monitoring at 25° C. for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford 4-chloro-2-(difluoromethyl)-6-methoxyphenol as a yellow oil (5.7 g), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.17 (d, J = 2.0 Hz, 2H), 7.06 (t, J = 55.2 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 3.86 (s, 3H).

[0189] Step 4.To a solution of 4-chloro-2-(difluoromethyl)-6-methoxyphenol (5.7 g, 27.3 mmol, 1.0 equiv.) in DCM (60 mL) was added pyridine (5.5 mL, 68.3 mmol, 2.5 equiv.) and TfO (5.1 mL, 30.1 mmol, 1.1 equiv.) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 4 h. Upon completion, the mixture was quenched with water (30 mL) and extracted with DCM (50 mL × 3). The organic layer was washed with brine, dried over NaSO, and concentrated. The crude product was purified by column chromatography (ethyl acetate / hexane = 0% to 10%) to afford 4-chloro-2-(difluoromethyl)-6-methoxyphenyl trifluoromethanesulfonate (5.9 g, 17.3 mmol, 63% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.13 (t, J = 53.6 Hz, 1H), 3.97 (s, 3H).

[0190] Step 5.To a solution of 4-chloro-2-(difluoromethyl)-6-methoxyphenyl trifluoromethanesulfonate (3.0 g, 8.8 mmol, 1.0 equiv.) in 1,4-dioxane was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.4 g, 13.2 mmol, 1.5 equiv.), Pd(dppf)Cl2 (639.1 mg, 0.9 mmol, 0.1 equiv.), and KOAc (2.6 g, 26.4 mmol, 3.0 equiv.). The reaction was stirred at 100 °C under N2 for 16 h. Upon completion, the reaction was cooled to room temperature, filtered through a pad of Celite, and rinsed with EtOAc. The filtrate was 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 = 1:0 to 20:1) to give 2-(4-chloro-2-(difluoromethyl)-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 4.1 mmol, 46% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.22 (s, 1H), 7.18 (s, 1H), 6.94(t, J = 55.6 Hz, 1H), 3.80 (s, 3H), 1.25 (s, 12H). Intermediate 14. Preparation of 2-(2-(methoxymethoxy)-4-methyl-6-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and Intermediate 15: 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0191] [ka]

[0192] Step 1.A mixture of 1-bromo-3-methyl-5-(trifluoromethyl)benzene (51.0 g, 213.0 mmol, 1.0 equiv.), LiOH.HO (17.9 g, 426.7 mmol, 2 equiv.), BippyPhos (4.3 g, 8.5 mmol, 0.04 equiv.), and Pd(dba) (9.7 g, 10.7 mmol, 0.05 equiv.) in dioxane (500 mL) was stirred at 100 °C under N for 16 h. Upon completion, the reaction mixture was cooled to room temperature. The reaction mixture was filtered through a pad of Celite and rinsed with EtOAc (1000 mL). The filtrate was concentrated and purified by reverse-phase column (0.1% TFA, 35%-40% ACN) to give a pale yellow oil (32 g, 181.6 mmol, 85.1% yield). MS m / z 175.1 [M−H] - . 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 2.28 (s, 3H)

[0193] Step 2. To a solution of 3-methyl-5-(trifluoromethyl)phenol (32.0 g, 181.7 mmol, 1.0 equiv) in anhydrous Tol (500 mL) was added NaH (8.72 g, 363.3 mmol, 2 equiv) at 0 °C, and the mixture was stirred at 0 °C for 1 h. I2 (34.6 g, 136.3 mmol, 0.75 equiv) was added to the reaction at 0 °C, and the mixture was stirred for an additional 4 h. Upon completion, the reaction was poured into water, acidified to pH 5-6 with 1 M HCl, and diluted with EtOAc (100 mL). The organic phase was separated, dried over Na2SO4, filtered, concentrated, and purified by reverse-phase column chromatography (0.1% TFA, 40%-45% ACN) to give a mixture of 2-iodo-3-methyl-5-(trifluoromethyl)phenol and 2-iodo-5-methyl-3-(trifluoromethyl)phenol (33 g, 109.3 mmol, 60.1% yield) as a yellow oil, which was used in the next step without further purification. MS m / z 301.0 [MH] - .

[0194] Step 3.The mixture of 2-iodo-3-methyl-5-(trifluoromethyl)phenol and 2-iodo-5-methyl-3-(trifluoromethyl)phenol (33 g, 109.3 mmol, 1.0 equiv.) obtained above was dissolved in anhydrous THF (300 mL) at 0 °C. NaH (3.9 g, 163.9 mmol, 1.5 equiv.) was slowly added at 0 °C, and the mixture was stirred for 1 h. MOMBr (20.5 g, 163.9 mmol, 1.5 equiv.) was then added at 0 °C and stirred for an additional 1 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with EtOAc (200 mL), and quenched with water. The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with 0-10% EA in hexane to give 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (17 g, 49.1 mmol, 44.9% yield), 1 H NMR (400 MHz, DMSO-d): δ 7.36 (s, 1H), 7.18 (s, 1H), 5.39 (s, 2H), 3.39 (s, 3H), 2.49 (s, 3H); also obtained was 2-iodo-1-(methoxymethoxy)-5-methyl-3-(trifluoromethyl)benzene (5.5 g, 15.89 mmol, 14.5% yield). 1 H NMR (400 MHz, DMSO-d6): δ 7.24 (s, 1H), 7.22 (s, 1H), 5.33 (s, 2H), 3.43 (s, 3H), 2.34 (s, 3H).

[0195] Step 4.2-Iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (17 g, 49.1 mmol, 1.0 equiv.) was dissolved in anhydrous THF (200 mL) under N at −78 °C. To this was added n-BuLi (46.0 mL, 73.7 mmol, 1.5 equiv.) dropwise at −78 °C, and the mixture was stirred for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.7 g, 73.6 mmol, 1.5 equiv.) was then added at −78 °C, and the reaction mixture was stirred for an additional 1 h. Upon completion, the reaction mixture was diluted with EtOAc (200 mL) and quenched with saturated NH Cl (40 mL). The organic phase was separated, dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with 0-10% EA in hexane to give 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10 g, 28.9 mmol, 58.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 7.12 (s, 1H), 5.24 (s, 2H), 3.38 (s, 3H), 2.33 (s, 3H), 1.33 (s, 12H).

[0196] Step 5.2-Iodo-1-(methoxymethoxy)-5-methyl-3-(trifluoromethyl)benzene (5.5 g, 15.9 mmol, 1.0 equiv.) was dissolved in anhydrous THF (60 mL) under N at −78 °C. To this was added n-BuLi (14.9 mL, 23.8 mmol, 1.5 equiv.) dropwise at −78 °C, and the mixture was stirred for 1 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.4 g, 23.8 mmol, 1.5 equiv.) was then added at −78 °C and stirred for 1 h. Upon completion, the reaction mixture was diluted with EtOAc (100 mL) and quenched with saturated NH Cl (20 mL). The organic phase was dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with 0-10% EA in hexane to give 2-(2-(methoxymethoxy)-4-methyl-6-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.9 g, 8.4 mmol, 52.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 7.14 (s, 2H), 5.22 (s, 2H), 3.37 (s, 3H), 2.36 (s, 3H), 1.29 (s, 12H).

[0197] Intermediate 16. Preparation of 2-(4-(methoxymethoxy)-6-methyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0198] [ka] Step 1.A mixture of 2-(4-(methoxymethoxy)-6-methylbenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 15.7 mmol, 1.0 equiv.) and Pd / C (10%, 0.5 g) in MeOH (100 mL) was stirred under hydrogen (balloon) at 40° C. for 48 h. The mixture was filtered. The filtrate was concentrated under reduced pressure to give 2-(4-(methoxymethoxy)-6-methyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a white solid (3.0 g, 9.3 mmol, 59.6% yield). 1 H NMR (400 MHz, CDCl3) δ 6.39 (s, 1H), 5.07 (s, 2H), 4.52 (t, J = 8.4 Hz, 2H), 3.52 (s, 3H), 3.24 (t, J = 8.8 Hz, 2H), 2.34 (s, 3H), 1.36 (s, 12H).

[0199] Intermediate 17. Preparation of 2-(4-(methoxymethoxy)-6-methylbenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0200] [ka] Step 1.To a solution of sodium bicarbonate (79.9 g, 951.2 mmol, 1.2 equiv.) and chloroacetaldehyde (155.5 g, 792.6 mmol, 1.0 equiv.) in water (1380 mL) was added dropwise a solution of 4,4-dimethylcyclohexane-1,3-dione in THF (1100 mL) at 0 °C. The resulting mixture was stirred at room temperature for 18 h, and ethyl acetate (1000 mL) was added. The mixture was adjusted to pH = 1 with 50% H2SO4 and stirred vigorously for 3 h. The organic layer was collected, and the acidic layer was extracted with ethyl acetate (3 x 400 mL). The combined organic extracts were washed with water, saturated NaHCO3, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel (petroleum ether / ethyl acetate=20 / 1 to 1 / 1) to give 6-methyl-6,7-dihydrobenzofuran-4(5H)-one (54 g, 359.5 mmol, 45.3% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 2.1 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H), 2.97 (dd, J = 17.1, 4.8 Hz, 1H), 2.59 (dd, J = 17.0, 9.4 Hz, 1H), 2.41 (dt, J = 17.0, 2.1 Hz, 2H), 2.28 (dd, J = 13.5, 3.7 Hz, 1H), 1.09 (d, J = 6.3 Hz, 3H).

[0201] Step 2.CuBr2 (321.2 g, 1.44 mol, 4.0 equiv) was added to EA (770 mL). The reaction was stirred at 80 °C for 10 min. To this was added a solution of 6-methyl-6,7-dihydrobenzofuran-4(5H)-one (54 g, 359.5 mmol, 1.0 equiv) in CHCl3 (128 mL) in one portion at 80 °C. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction was cooled to room temperature and filtered to remove solids. The filtrate was concentrated and purified by silica gel column chromatography (PE:EA = 50:1 to 5:1) to give 5,5-dibromo-6-methyl-6,7-dihydrobenzofuran-4(5H)-one (33 g, 107.1 mmol, 29.8% yield) as a yellow solid.

[0202] Step 3. 5,5-Dibromo-6-methyl-6,7-dihydrobenzofuran-4(5H)-one (33 g, 107.1 mmol, 1.0 equiv) was dissolved in anhydrous DMF (535 mL). To this solution was added LiCO (47.5 g, 642.9 mmol, 6.0 equiv). The reaction was stirred at 100 °C for 2 h. Upon completion, the reaction was cooled to room temperature, filtered to remove solids, and concentrated. The residue was diluted with water (500 mL) and extracted with EA (200 mL). The organic layer was washed with water (500 mL × 2) and brine (500 mL × 1), dried over NaSO, decanted, and concentrated. The residue was purified by silica gel column chromatography (EA:PE=1:50) to give 5-bromo-6-methylbenzofuran-4-ol (19.5 g, 85.8 mmol, 80.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.12 (d, J = 0.9 Hz, 1H), 7.09 (dd, J = 2.2, 1.0 Hz, 1H), 2.41 (d, J = 0.6 Hz, 3H).

[0203] Step 4.To a solution of 5-bromo-6-methylbenzofuran-4-ol (19.5 g, 85.8 mmol, 1.0 equiv) in THF (110 mL) was added NaH (6.8 g, 171.7 mmol, 2.0 equiv) in small portions at 0 °C. The reaction mixture was warmed to room temperature for 1 h, and then MOMBr (16.1 g, 128.8 mmol, 1.5 equiv) was added. The reaction was stirred at room temperature for 1 h. The mixture was quenched with HO (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to afford 5-bromo-4-(methoxymethoxy)-6-methylbenzofuran (21 g, 77.4 mmol, 90.1% yield) as a brown oil, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 2.3 Hz, 1H), 7.42 (t, J = 0.9 Hz, 1H), 7.06 (dd, J = 2.3, 1.0 Hz, 1H), 5.35 (s, 2H), 3.55 (s, 3H), 2.46 (d, J = 0.7 Hz, 3H).

[0204] Step 5. To a solution of 5-bromo-4-(methoxymethoxy)-6-methylbenzofuran (21 g, 77.4 mmol, 1.0 equiv) in dioxane (370 mL) was added HBPin (37.7 g, 295.0 mmol, 4.0 equiv), TEA (52.2 g, 516.4 mmol, 7.0 equiv), Pd(OAc) (2.4 g, 11.0 mmol, 0.15 equiv), and CyJohnphos (6.4 g, 18.4 mmol, 0.25 equiv). The mixture was then purged with N. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction was cooled to room temperature and filtered through a pad of Celite, rinsing with EA. The filtrate was concentrated to give a crude oil. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 80 / 1 to 10 / 1) to give 2-(4-(methoxymethoxy)-6-methylbenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10 g, 31.4 mmol, 42.6% yield) as a brown solid.1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 2.4Hz, 1H), 7.14 (s, 1H), 6.93 (dd, J = 2.0, 0.8Hz, 1H), 5.22 (s, 2H), 3.48 (s, 3H), 2.37 (s, 3H), 1.33 (s, 12H).

[0205] Intermediate 18. Preparation of 2-(2-(methoxymethoxy)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0206] [ka] Step 1. To a solution of 1-(benzyloxy)-2-bromobenzene (30.0 g, 114.01 mmol) in THF (600 mL) was added 1,1-diethoxyethene (26.49 g, 228.02 mmol) and NaNH (22.24 g, 570.05 mmol). The reaction was stirred at 70 °C for 6 h. Upon completion, the reaction mixture was cooled to room temperature and poured into ice water. The pH of the reaction mixture was adjusted to pH = 2 with 4 N HCl. The reaction mixture was extracted with EA (500 mL × 3). The organic phase was dried over NaSO, filtered, concentrated, and purified by silica gel column chromatography (0–6% EA / PE) to give a yellow solid, 5-(benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one (8.0 g, 31.3% yield). MS m / z 225.1[M+H] + .

[0207] Step 2.To a solution of 5-(benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one (16.1 g, 71.79 mmol) in anhydrous MeOH (300 mL) was added NaBH (5.43 g, 143.58 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. Upon completion, the reaction mixture was quenched with water (300 mL) and extracted with EA (300 mL × 2). The organic layer was dried over anhydrous NaSO, filtered, concentrated, and purified by silica gel column chromatography (0–10% EA / PE) to give a yellow solid, 5-(benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol (12.2 g, 75.1% yield). MS m / z 225.2 [M−H] - .

[0208] Step 3. To a solution of 5-(benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol (14.0 g, 61.8 mmol, 1.0 equiv) in anhydrous DCM (300 mL) was added BF EtO (43.9 g, 309.3 mmol, 5.0 equiv) and EtSiH (35.97 g, 309.3 mmol, 5.0 equiv) under Ar at −78 °C. The reaction was stirred at −78 °C for 4 h. Upon completion, the reaction mixture was quenched with saturated aqueous NaHCO (300 mL) and extracted with DCM (500 mL × 2). The organic layer was dried over NaSO, decanted, concentrated, and purified by silica gel column chromatography (100% PE) to give a yellow solid 2-(benzyloxy)bicyclo[4.2.0]octa-1,3,5-triene (2.1 g, 61.8 mmol, 16.1% yield). 1 H NMR (400 MHz, CDCl3) δ 7.42-7.28 (m, 6H), 7.14-7.10 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 5.16 (s, 2H), 3.28 (t, J = 4.0 Hz, 2H), 3.14 (t, J = 4.0 Hz, 2H).

[0209] Step 4.A mixture of 2-(benzyloxy)bicyclo[4.2.0]octa-1,3,5-triene (2.1 g, 9.9 mmol, 1 equiv.) and Pd / C (10%, 0.2 g) in MeOH (20 mL) was stirred under hydrogen (balloon) at 60 °C for 8 h. The mixture was filtered. The filtrate was concentrated under reduced pressure. The crude yellow oil (1.2 g, 9.9 mmol, 100.0% yield) was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 8.0 Hz, 1H), 6.65 (dd, J = 10.8 Hz, 7.2 Hz, 2H), 3.12 (s, 4H).

[0210] Step 5. To a solution of bicyclo[4.2.0]octa-1,3,5-trien-2-ol (1.2 g, 9.9 mmol, 1.0 equiv) in anhydrous DCM (20 mL) was added NBS (1.78 g, 9.9 mmol, 1.0 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched with water (30 mL) and extracted with DCM (20 mL × 2). The organic layer was dried over NaSO, decanted, concentrated, and purified by silica gel column chromatography (100% PE) to give a yellow solid, 3-bromobicyclo[4.2.0]octa-1,3,5-trien-2-ol (1.1 g, 5.5 mmol, 55.3% yield). 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.6 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 5.44 (s, 1H), 3.16 (dd, J = 6.0 Hz, 3.6 Hz, 2H), 3.09 (dd, J = 5.2 Hz, 2.8 Hz, 2H).

[0211] Step 6.To a solution of 3-bromobicyclo[4.2.0]octa-1,3,5-trien-2-ol (1.1 g, 5.5 mmol, 1.0 equiv) in THF (20 mL) was added NaH (0.2 g, 8.3 mmol, 1.5 equiv) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Then MOMBr (1.04 g, 8.3 mmol, 1.5 equiv) was added. The reaction mixture was stirred at room temperature for 0.5 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (20 mL × 1) and brine (20 mL × 1). The organic layer was dried over Na2SO4, decanted, and concentrated to give a yellow oil, 3-bromo-2-(methoxymethoxy)bicyclo[4.2.0]octa-1,3,5-triene (1.2 g, 4.9 mmol, 89.3% yield) without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 3.49 (s, 3H), 3.30 (t, J = 4.0 Hz, 2H), 3.10 (t, J = 4.0 Hz, 2H).

[0212] Step 7. To a solution of 3-bromo-2-(methoxymethoxy)bicyclo[4.2.0]octa-1,3,5-triene (1.3 g, 5.3 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) was added (Bpin) (1.49 g, 5.8 mmol, 1.1 equiv), Pd(dppf)Cl (0.39 g, 0.5 mmol, 0.1 equiv), and AcOK (1.57 g, 16.0 mmol, 3.0 equiv). The reaction mixture was stirred at 80 °C under Ar for 16 h. The reaction mixture was filtered through a pad of Celite and rinsed with EA. The organic phase was concentrated and purified by silica gel column chromatography (0–6% PE / EA) to give a white solid, 2-(2-(methoxymethoxy)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.7 g, 2.4 mmol, 45.1% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H), 3.32 - 3.24 (m, 2H), 3.18 - 3.09 (m, 2H), 1.33 (s, 12H). Intermediate 19. Preparation of 2-(2-methoxy-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0213] [ka] Step 1. To a solution of 3-methoxy-5-(trifluoromethyl)aniline (5.0 g, 26.16 mmol) in 20% aqueous HCl (200 mL) was added NaNO (2.17 g, 31.39 mmol) at 0 °C. The reaction was stirred at 0 °C for 0.5 h. The reaction mixture was then added to water (200 mL) at 100 °C. The reaction was stirred at 110 °C for 15 min. Upon completion, the reaction mixture was cooled to room temperature. It was dissolved in EtOAc (200 mL) and washed with water (200 mL × 2) and brine (200 mL × 1). The organic phase was dried over NaSO, filtered, concentrated, and purified by silica gel column chromatography (0-10% EA / PE) to give a yellow oil, 3-methoxy-5-(trifluoromethyl)phenol (3.0 g, 59.7% yield). MS m / z 191.1 [M+H] - .

[0214] Step 2.To a solution of 3-methoxy-5-(trifluoromethyl)phenol (3.0 g, 15.61 mmol) in anhydrous THF (60 mL) was added NaH (937 mg, 23.42 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Then MOMBr (2.93 g, 23.42 mmol) was added. The reaction mixture was stirred at room temperature for an additional 0.5 h. Upon completion, the reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by silica gel column chromatography (100% PE) to give a yellow oil, 1-methoxy-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (2.8 g, 75.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 6.91 (s, 1H), 6.88 - 6.87 (m, 2H), 5.26 (s, 2H), 3.81 (s, 3H), 3.39(s, 3H).

[0215] Step 3. To a solution of 1-methoxy-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (1.0 g, 4.23 mmol) in anhydrous THF (10 mL) was added n-BuLi (2.65 mL, 4.23 mmol, 1.6 M) under Ar at −78° C. The reaction mixture was stirred at −78° C. for 1 h. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.58 g, 8.47 mmol) was added at −78° C. The reaction mixture was stirred at −78° C. for an additional 1 h. Upon completion, the reaction was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with water (30 mL × 2) and brine (30 mL × 1), dried over Na2SO4, decanted, concentrated, and purified by silica gel column chromatography (100% PE) to give a yellow solid 2-(2-methoxy-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (861 mg, 56.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 1H), 6.89 (s, 1H), 5.22 (s, 2H), 3.79 (s, 3H), 3.37 (s, 3H), 1.29 (s, 12H). Intermediate 20. Preparation of 2-(7-(methoxymethoxy)benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0216] [ka] Step 1. To a solution of thiophene-3-carbaldehyde (20 g, 178.3 mmol, 1 equiv.) in DCM (200 mL) was added (2-carboxyethyl)triphenylphosphonium bromide (88.8 g, 214.0 mmol, 1.2 equiv.) and t-BuOK (50.0 g, 445.8 mmol, 2.5 equiv.). The reaction was stirred at room temperature for 8 h. The reaction was quenched with water (300 mL) and extracted with DCM (300 mL). The organic layer was washed with water (200 mL × 2) and brine (300 mL × 1), dried over Na2SO4, decanted, concentrated, and purified by silica gel column chromatography (0–50% PE / EA) to give a yellow solid (E)-4-(thiophen-3-yl)but-3-enoic acid (14 g, 83.2 mmol, 46.7% yield). MS m / z 167.1 [M−H] - .

[0217] Step 2. A mixture of (£)-4-(thiophen-3-yl)but-3-enoic acid (14 g, 83.2 mmol, 1.0 equiv.) and Pd / C (10%, 1.4 g) in MeOH (100 mL) was stirred under hydrogen (balloon) at room temperature for 2 h. The mixture was filtered. The filtrate was concentrated under reduced pressure. The crude yellow solid (11.3 g, 59.9 mmol, 101.9% yield) was used in the next step without further purification. MS m / z 169.2 [M+H] + .

[0218] Step 3.A mixture of 4-(thiophen-3-yl)butanoic acid (10 g, 58.7 mmol, 1.0 equiv.), (COCl) (7.4 g, 58.7 mmol, 1.0 equiv.) and DMF (1 mL) in DCM (100 mL) was stirred under N at room temperature for 0.5 h. The mixture was concentrated under reduced pressure. The crude yellow oil (10.0 g, 58.7 mmol, 70.6% yield) was used in the next step without further purification. MS m / z 240.1 [M+H] + .

[0219] Step 4. A solution of 4-(thiophen-3-yl)butanoyl chloride (11.3 g, 59.9 mmol, 1 equiv.) in 1,1,1,3,3,3-hexafluoro-2-propanol (100 mL) was stirred at room temperature under N for 5 h. The reaction was quenched with water (300 mL) and extracted with DCM (300 mL). The organic layer was washed with water (200 mL × 2) and brine (300 mL × 1). The organic layer was dried over NaSO, decanted, concentrated, and purified by silica gel column chromatography (0-30% PE / EA) to give 5,6-dihydrobenzo[b]thiophen-7(4H)-one (7.6 g, 49.9 mmol, 83.4% yield) as a yellow oil. MS m / z 153.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 4.8 Hz, 1H), 2.85 (t, J = 6.0 Hz, 2H), 2.53 (t, J = 5.6 Hz, 2H), 2.06-2.11(m, 2H).

[0220] Step 5.A mixture of CuBr2 (44.6 g, 199.7 mmol, 4.0 equiv) in anhydrous EA (200 mL) was stirred at 80 °C for 10 min. Then, a solution of 5,6-dihydrobenzo[b]thiophen-7(4H)-one (7.6 g, 49.9 mmol, 1.0 equiv) in CHCl3 (40 mL) was added at 80 °C. The reaction was stirred at 80 °C for 16 h. Upon completion, the reaction was cooled to room temperature. The reaction mixture was filtered to remove solids, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-10% PE / EA) to give a black solid, 6,6-dibromo-5,6-dihydrobenzo[b]thiophen-7(4H)-one (13 g, 41.9 mmol, 84.0% yield). MS m / z 310.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 5.2 Hz, 1H), 6.84 (d, J = 4.8 Hz, 1H), 3.13 (t, J = 5.6 Hz, 2H), 2.96 (t, J = 5.6 Hz, 2H).

[0221] Step 6. To a solution of 6,6-dibromo-5,6-dihydrobenzo[b]thiophen-7(4H)-one (13.4 g, 43.23 mmol, 1.0 equiv.) in DMF (216 mL) was added LiCO (19.2 g, 259.3 mmol, 6.0 equiv.). The reaction mixture was stirred at 100 °C for 2 h. Upon completion, the reaction was cooled to room temperature and filtered to remove solids. The filtrate was concentrated. The residue was diluted with water (500 mL) and extracted with EA (300 mL). The organic layer was washed with water (500 mL × 2) and brine (500 mL × 1), dried over anhydrous NaSO, decanted, concentrated, and purified by silica gel column chromatography (0–2% PE / EA) to give a yellow solid, 6-bromobenzo[b]thiophen-7-ol (4.4 g, 19.21 mmol, 44.4% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H).

[0222] Step 7. To a solution of 6-bromobenzo[b]thiophen-7-ol (4.5 g, 19.6 mmol, 1.0 equiv) in THF (50 mL) was added NaH (0.7 g, 29.5 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then MOMBr (3.68 g, 29.5 mmol, 1.5 equiv) was added. The reaction mixture was stirred at room temperature for an additional 0.5 h. The reaction was quenched with water (150 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (150 mL × 1) and brine (150 mL × 1), dried over NaSO, decanted, and concentrated to give a yellow oil, 6-bromo-7-(methoxymethoxy)benzo[b]thiophene (4.7 g, 17.2 mmol, 87.6% yield), without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 5.2 Hz, 1H), 7.64-7.59(m, 2H), 7.49 (d, J = 5.6 Hz, 1H), 5.31 (s, 2H), 3.62 (s, 3H).

[0223] Step 8.To a solution of 6-bromo-7-(methoxymethoxy)benzo[b]thiophene (4.7 g, 17.2 mmol, 1.0 equiv) in 1,4-dioxane (50 mL) was added (Bpin)2 (6.55 g, 25.8 mmol, 1.5 equiv), Pd(dppf)Cl2 (1.25 g, 1.72 mmol, 0.1 equiv), and AcOK (5.07 g, 51.6 mmol, 3.0 equiv). The reaction mixture was stirred at 100 °C under Ar for 16 h. The reaction mixture was filtered through a pad of Celite and rinsed with EA. The filtrate was concentrated and purified by silica gel column chromatography (0–6% PE / EA) to give a yellow solid, 2-(7-(methoxymethoxy)benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 6.6 mmol, 38.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 5.2 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.48 (d, J = 5.2 Hz, 1H), 5.23 (s, 2H), 3.54 (s, 3H), 1.32 (s, 12H). Intermediate 21. Preparation of 2-(7-methoxybenzofuran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0224] [ka]

[0225] Step 1.To a mixture of 3-bromo-2-methoxyphenol (5 g, 24.63 mmol, 1 equiv.) and 2-bromo-1,1-diethoxyethane (7.25 g, 36.94 mmol, 1.5 equiv.) in DMF was added K2CO3 (6.81 g, 49.25 mmol, 2.0 equiv.) at room temperature. After the addition was complete, the mixture was heated at 100 °C for 16 h. Upon completion, the reaction was cooled to room temperature. The mixture was diluted with HO (50 mL) and extracted with EA (10 mL × 3). The organic layer was washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with (PE / EA=1:0 to 10:1) to give 1-bromo-3-(2,2-diethoxyethoxy)-2-methoxybenzene (8.5 g, 24.44 mmol, 99.2% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (dd, J = 8.0, 1.2 Hz, 1H), 7.10 (dd, J = 8.4, 1.2 Hz, 1H), 6.99 (t, J = 8.2 Hz, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.00 (d, J = 5.2 Hz, 2H), 3.77 (s, 3H), 3.73 - 3.65 (m, 2H), 3.63 - 3.56 (m, 2H), 1.14 (t, J = 7.2 Hz, 6H).

[0226] Step 2.To a mixture of 1-bromo-3-(2,2-diethoxyethoxy)-2-methoxybenzene (8.5 g, 26.63 mmol, 1.0 equiv.) in chlorobenzene (85 mL) was added PPA (7.83 g, 79.89 mmol, 3.0 equiv.). After the addition was complete, the mixture was heated at 120 °C for 16 h. Upon completion, the reaction was cooled to room temperature, and the mixture was diluted with HO (500 mL) and extracted with EA (300 mL × 3). The organic layer was washed with brine (100 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with PE / EA (1:0 to 10:1) to give 6-bromo-7-methoxybenzofuran (3.5 g, 15.41 mmol, 57.89% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 4.22 (s, 3H).

[0227] Step 3. A flask was charged with a mixture of 6-bromo-7-methoxybenzofuran (3.5 g, 15.41 mmol, 1 equiv.), B2Pin2 (4.31 g, 16.96 mmol, 1.1 equiv.), KOAc (4.54 g, 46.24 mmol, 3 equiv.), and Pd(dppf)Cl2 (1.12 g, 1.54 mmol, 0.1 equiv.) in anhydrous 1,4-dioxane (35 mL) at room temperature. The mixture was then degassed / purged with N2. The reaction was heated to 100 °C and stirred for 2 h. Upon completion, the reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with (PE / EA=1:0 to 10:1) to give 2-(7-methoxybenzofuran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 9.12 mmol, 59.16% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 4.09 (s, 3H), 1.30 (s, 12H). Intermediate 22. Preparation of 2-(7-fluoro-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0228] [ka]

[0229] Step 1. To a solution of 2-fluoro-5-methoxyphenol (9.0 g, 63.4 mmol, 1.0 equiv.) in hexafluoroisopropanol (100 mL), NBS (12.4 g, 69.7 mmol, 1.1 equiv.) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with aqueous NaHCO (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, concentrated in vacuo, and purified on a silica gel column eluted with PE / EtOAc = 20 / 1 to give 4-bromo-2-fluoro-5-methoxyphenol (12.8 g, 57.76 mol, 91.1% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 9.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 6.14 (d, J = 3.2 Hz, 1H), 3.83 (s, 3H).

[0230] Step 2.A mixture of 4-bromo-2-fluoro-5-methoxyphenol (10.0 g, 45.2 mmol, 1.0 equiv), 2-bromo-1,1-diethoxyethane (9.3 g, 47.5 mmol, 1.05 equiv), and KCO (12.5 g, 90.4 mmol, 2.0 equiv) in DMF (200 mL) was stirred at 100° C. for 16 h. Upon completion, the reaction was cooled to room temperature, diluted with EtOAc (200 mL), washed with water (500 mL × 3), dried over anhydrous NaSO, and concentrated to afford 1-bromo-4-(2,2-diethoxyethoxy)-5-fluoro-2-methoxybenzene (15.0 g, 44.49 mmol, 98.3% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 10.4 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 4.83 (t, J = 5.2 Hz, 1H), 4.08 (t, J = 4.4 Hz, 2H), 3.84 (s, 3H), 3.81-3.77 (m, 2H), 3.66-3.62 (m, 2H), 1.26-1.24 (m, 9H).

[0231] Step 3. To a solution of 1-bromo-4-(2,2-diethoxyethoxy)-5-fluoro-2-methoxybenzene (15.0 g, 44.49 mmol, 1.0 equiv.) in chlorobenzene (200 mL) was added PPA (15.0 g, 182.94 mmol, 4.1 equiv.). The reaction mixture was stirred at 100 °C for 16 h. Upon completion, the reaction was cooled to room temperature, diluted with HO (500 mL), and extracted with EtOAc (300 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, concentrated, and purified on a silica gel column eluted with PE / EtOAc = 20 / 1 to give 5-bromo-7-fluoro-4-methoxybenzofuran (6.5 g, 26.53 mmol, 59.6% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 9.6 Hz, 1H), 6.94 (t, J = 2.4 Hz, 1H), 4.01 (s, 3H).

[0232] Step 4. To a solution of 5-bromo-7-fluoro-4-methoxybenzofuran (5.0 g, 20.5 mmol, 1.0 equiv) in DCM (50 mL) was added BBr3 (51.1 g, 2.0 M, 204.04 mmol, 10.0 equiv) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with MeOH (30 mL) at 0 °C, and the pH was adjusted to approximately 7–8 by slow addition of NaHCO3. The reaction mixture was extracted with EtOAc (200 mL × 2) and washed with brine (300 mL). The organic phase was dried over Na2SO4, filtered, concentrated in vacuo, and purified on a silica gel column eluted with PE / EtOAc = 20 / 1 to give 5-bromo-7-fluorobenzofuran-4-ol (1.4 g, 6.06 mmol, 29.7% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 9.6 Hz, 1H), 6.92 (t, J = 2.8 Hz, 1H), 5.63 (s, 1H).

[0233] Step 5. To a solution of 5-bromo-7-fluorobenzofuran-4-ol (1.4 g, 6.09 mmol, 1.0 equiv) in THF (20 mL) was added NaH (0.365 g, 9.13 mmol, 1.5 equiv) at 0 °C and stirred at 0 °C for 0.5 h. MOMBr (1.14 g, 9.13 mmol, 1.5 equiv) was added to the mixture at 0 °C and stirred at 0 °C for an additional 1 h. The reaction mixture was quenched with aqueous NH Cl (10 mL), extracted with EtOAc (100 mL), washed with brine (50 mL), dried over anhydrous Na SO , and concentrated to give 5-bromo-7-fluoro-4-(methoxymethoxy)benzofuran (1.2 g, 4.36 mmol, 72.0% yield) as a yellow oil.1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 9.6 Hz, 1H), 6.96 (t, J = 2.4 Hz, 1H), 5.64 (s, 2H), 3.66 (s, 3H).

[0234] Step 6. A mixture of 5-bromo-7-fluoro-4-(methoxymethoxy)benzofuran (1.2 g, 4.36 mmol, 1.0 equiv), HBPin (2.2 g, 17.52 mmol, 4.0 equiv), TEA (3.1 g, 30.66 mmol, 7.0 equiv), Pd(OAc) (0.148 g, 0.66 mmol, 0.15 equiv), and CyJohnphos (0.383 g, 1.10 mmol, 0.25 equiv) in dioxane (10 mL) was stirred for 16 h at 80° C. Upon completion, the reaction was cooled to room temperature, diluted with EtOAc (50 mL), and filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified on a silica gel column eluted with PE / EtOAc=10 / 1 to give 2-(7-fluoro-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.5 g, 1.55 mmol, 35.6% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 10.8 Hz, 1H), 6.92 (t, J = 2.4 Hz, 1H), 5.19 (s, 2H), 3.62 (s, 3H), 1.36 (s, 12H).

[0235] Intermediate 23. Preparation of 2-(7-fluoro-4-(methoxymethoxy)-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0236] [ka] Step 1.To a solution of 2-(7-fluoro-4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2 g, 0.62 mmol, 1.0 equiv.) in MeOH (5 mL) was added dry Pd / C (0.02 g). The mixture was stirred under H at 50 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford 2-(7-fluoro-4-(methoxymethoxy)-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.14 g, 50% purity, 0.22 mol, 34.8% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 10.8 Hz, 1H), 5.05 (s, 2H), 3.59 (s, 3H), 3.34 (t, J = 8.8 Hz, 1H), 3.22 (t, J = 8.8 Hz, 1H), 1.35 (s, 12H). Intermediate 24. Preparation of 2-(2-fluoro-4-(methoxymethoxy)benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0237] [ka] Step 1.A suspension of CuBr2 (58.8 g, 263.16 mmol, 4.0 equiv) in EtOAc (200 mL) was stirred at 80 °C for 10 min. A solution of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (10.0 g, 65.79 mmol, 1.0 equiv) in CHCl3 (40 mL) was added to the suspension. The mixture was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, washed with PE / EtOAc = 10 / 1, and filtered again. The solid was dried in vacuo to give 5,5-dibromo-6,7-dihydrobenzo[b]thiophen-4(5H)-one (17.6 g, 56.77 mmol, 86.4% yield) as a yellow solid. MS m / z 310.9 [M+H] + .

[0238] Step 2. To a solution of 5,5-dibromo-6,7-dihydrobenzo[b]thiophen-4(5H)-one (17.6 g, 56.77 mmol, 1.0 equiv.) in DMF (300 mL) was added LiCO (25.2 g, 340.64 mmol, 6.0 equiv.). The reaction mixture was stirred at 100 °C for 6 h. Upon completion, the reaction mixture was cooled to room temperature, diluted with EtOAc (300 mL), and washed with HO (500 mL × 3). The organic phase was dried over anhydrous NaSO and concentrated. The residue was purified on a silica gel column eluted with PE / EtOAc = 50 / 1 to give 5-bromobenzo[b]thiophen-4-ol (8.3 g, 36.23 mmol, 63.81% yield) as a white solid. MS m / z 226.9 [MH] - .

[0239] Step 3.To a solution of 5-bromobenzo[b]thiophen-4-ol (8.3 g, 36.23 mmol, 1.0 equiv) in THF (150 mL) was added NaH (2.2 g, 54.37 mmol, 1.5 equiv) at 0 °C and stirred at 0 °C for 0.5 h. MOMBr (6.8 g, 54.37 mmol, 1.5 equiv) was added to the mixture at 0 °C and stirred at 0 °C for an additional 1 h. The reaction mixture was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (300 mL). The organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated to give 5-bromo-4-(methoxymethoxy)benzo[b]thiophene (10.9 g, 90% purity, 35.91 mmol, 99.1% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 5.6 Hz, 1H), 5.26 (s, 2H), 3.60 (s, 3H).

[0240] Step 4. To a solution of LDA (12.8 mL, 2.0 M, 25.6 mmol, 1.4 equiv) in THF (100 mL) was added a solution of 5-bromo-4-(methoxymethoxy)benzo[b]thiophene (5.0 g, 18.3 mmol, 1.0 equiv) in THF (50 mL) at −78° C. The mixture was stirred under Ar atmosphere at 0° C. for 1 h. NFSI (5.76 g, 18.3 mmol, 1.0 equiv) in THF (50 mL) was added to the solution at 0° C. The mixture was stirred under Ar atmosphere at 0° C. for an additional 1 h, then warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (300 mL). The organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column eluting with 100% PE to give 5-bromo-2-fluoro-4-(methoxymethoxy)benzo[b]thiophene (0.88 g, 3.02 mmol, 16.5% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 5.21 (s, 2H), 3.59 (s, 3H).

[0241] Step 5. A mixture of 5-bromo-2-fluoro-4-(methoxymethoxy)benzo[b]thiophene (0.2 g, 0.69 mmol, 1.0 equiv.), HBPin (0.352 g, 2.75 mmol, 4.0 equiv.), TEA (0.486 g, 4.81 mmol, 7.0 equiv.), Pd(OAc) (0.023 g, 0.10 mmol, 0.15 equiv.), and CyJohnphos (0.06 g, 0.17 mmol, 0.25 equiv.) in dioxane (2 mL) was stirred at 80 °C for 16 h. Upon completion, the reaction was cooled to room temperature, diluted with EtOAc (10 mL), and filtered through a pad of Celite. The filtrate was concentrated. The residue was purified by silica gel column eluting with PE / EtOAc=20 / 1 to give 2-(2-fluoro-4-(methoxymethoxy)benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.035 g, 0.10 mmol, 15.1% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 2.8 Hz, 1H), 5.14 (s, 2H), 3.51 (s, 3H), 1.32 (s, 12H). Intermediate 25. Preparation of (1s,3s)-3-methoxy-3-methylcyclobutan-1-amine

[0242] [ka]

[0243] Step 1.To a solution of 3-oxocyclobutane-1-carboxylic acid (38.80 g, 340.05 mmol, 1.0 equiv.) in dry THF (750 mL) under N2, MeMgCl (250 mL, 3.00 M, 2.2 equiv.) was added dropwise at a rate such that the temperature did not rise above -40 °C. The resulting mixture was stirred at room temperature under N2 for 16 h. The mixture was cooled to an internal temperature of 5 °C, and phosphoric acid (750 mL, 1 M) was slowly added to the mixture under N2 (maintaining the temperature below 15 °C). Upon completion of the phosphoric acid addition, the mixture was stirred at room temperature for 1 h. The mixture was diluted with HO (300 mL) and extracted with EA (300 mL × 3). The organic phase was washed with brine (300 mL × 3), dried over anhydrous Na2SO4, and concentrated. tert-Butyl methyl ether (80 mL) was added to the residue to precipitate a solid. The suspension was filtered and the solid was dried under vacuum to give (1s,3s)-3-hydroxy-3-methylcyclobutane-1-carboxylic acid (26.30 g, 202.09 mmol, 59.43% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 5.03 (s, 1H), 2.61 - 2.52 (m, 1H), 2.17 - 2.04 (m, 4H), 1.22 (s, 3H).

[0244] Step 2. To a solution of (1s,3s)-3-hydroxy-3-methylcyclobutane-1-carboxylic acid (15.00 g, 115.26 mmol, 1.0 equiv) in MeOH (255 mL) was added H2SO4 (2.34 mL, 16 M) at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The mixture was concentrated to give a residue. The residue was diluted with H2O (100 mL) and extracted with EA (100 mL × 3). The organic phase was washed with saturated NaHCO3 (100 mL × 2) and brine (100 mL × 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 23) to give methyl (1s,3s)-3-hydroxy-3-methylcyclobutane-1-carboxylate (14.3 g, 99.19 mmol, 86.06% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 5.08 (s, 1H), 3.59 (s, 3H), 2.67 (p, J = 8.9 Hz, 1H), 2.19 - 2.06 (m, 4H), 1.23 (s, 3H).

[0245] Step 3. To a solution of methyl (1s,3s)-3-hydroxy-3-methylcyclobutane-1-carboxylate (15.00 g, 104.04 mmol, 1.0 equiv) in DMF (250 mL) was added NaH (60%, 12.48 g, 312.13 mmol, 3.0 equiv) at 0 °C. The mixture was stirred at room temperature for 1 h. Then MeI (58.29 mL, 936.39 mmol, 9.0 equiv) was added to the mixture at 0 °C. The mixture was stirred at room temperature for 3 days. The mixture was quenched with HO (200 mL) and extracted with EA (200 mL × 3). The organic phase was washed with brine (200 mL × 3), dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 5) to give methyl (1s,3s)-3-methoxy-3-methylcyclobutane-1-carboxylate (10.80 g, 68.27 mmol, 65.62% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 3.60 (s, 3H), 3.05 (s, 3H), 2.80 (p, J = 8.8 Hz, 1H), 2.25 - 2.11 (m, 2H), 2.10 - 1.99 (m, 2H), 1.27 (s, 3H).

[0246] Step 4.To a solution of methyl (1s,3s)-3-methoxy-3-methylcyclobutane-1-carboxylate (6.20 g, 39.19 mmol, 1.0 equiv) in THF / EtOH / HO (25 mL / 25 mL / 10 mL) was added NaOH (6.27 g, 156.77 mmol, 4.0 equiv) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and washed with EtOAc (100 mL × 2). The aqueous phase was adjusted to pH = 5-6 with citric acid (1 M) and then extracted with EtOAc (100 mL × 3). The organic phase was washed with brine (80 mL × 3), dried over anhydrous NaSO and concentrated to give (1s,3s)-3-methoxy-3-methylcyclobutane-1-carboxylic acid (5.5 g, 38.15 mmol, 97.34% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 3.05 (s, 3H), 2.73 - 2.62 (m, 1H), 2.21 - 2.12 (m, 2H), 2.06 - 1.98 (m, 2H), 1.26 (s, 3H).

[0247] Step 5. To a solution of (1s,3s)-3-methoxy-3-methylcyclobutane-1-carboxylic acid (5.50 g, 38.15 mmol, 1.0 equiv) in cyclohexane (5 mL) was added DPPA (11.13 g, 45.78 mmol, 1.2 equiv), t-BuOH (145.95 mL, 1.53 mol, 40.0 equiv), and TEA (6.36 mL, 45.78 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred at 90 °C for 16 h. The mixture was diluted with HO (100 mL) and extracted with EA (100 mL × 3). The organic phase was washed with brine (100 mL × 3), dried over anhydrous NaSO, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 8) to give tert-butyl ((1s,3s)-3-methoxy-3-methylcyclobutyl)carbamate (3.20 g, 14.86 mmol, 38.96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 7.7 Hz, 1H), 3.69 - 3.51 (m, 1H), 3.03 (s, 3H), 2.19 - 2.05 (m, 2H), 2.02 - 1.86 (m, 2H), 1.36 (s, 9H), 1.20 (s, 3H).

[0248] Step 6. To a solution of tert-butyl ((1s,3s)-3-methoxy-3-methylcyclobutyl)carbamate (5.50 g, 38.15 mmol, 1.0 equiv) in EA (6 mL) was added HCl-EtOAc (20 mL, 4 M). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to give (1s,3s)-3-methoxy-3-methylcyclobutan-1-amine (3.20 g, 14.86 mmol, 38.96% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 3H), 3.43 - 3.37 (m, 1H), 3.08 (s, 3H), 2.19 (s, 2H), 2.17 (s, 2H), 1.24 (s, 3H). Intermediate 26. Preparation of 3,6-dichloro-4-vinylpyridazine

[0249] [ka] To a degassed solution of 4-bromo-3,6-dichloro-pyridazine (1.08 g, 4.74 mmol) in 1,4-dioxane (21 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) (347 mg, 0.474 mmol), vinylboronic acid pinacol ester (0.88 mL, 5.21 mmol), and 2 M aqueous potassium carbonate (7.1 mL, 14.2 mmol). The reaction was stirred at 70 °C for 2 h. Upon completion, the mixture was diluted with water, extracted with ethyl acetate, and the combined organics were evaporated under reduced pressure. The crude residue was purified by flash chromatography, eluting with 0 to 100% EtOAc / Hexanes, to give 3,6-dichloro-4-vinylpyridazine (574 mg, 69% yield). MS m / z 176.9, 178.9 [M+H] + .

[0250] Example 1. Preparation of (R)-2-(4-cyclopropyl-7-(1-methylpiperidin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (I-1)

[0251] [ka]

[0252] Step 1:To a flask containing 3,6-dichloro-4-(phenylsulfonyl)pyridazine (20.0 g, 69.1 mmol), acetonitrile (200 mL) was added, followed by silver nitrate (14.1 g, 82.9 mmol) and cyclopropanecarboxylic acid (17.8 g, 207.3 mmol). The resulting mixture was heated to 80° C., and then ammonium persulfate (78.8 g, 345.5 mmol) in water (150 mL) was added dropwise over 5 minutes. The reaction mixture was stirred at 80° C. for an additional 15 minutes. TLC (10% ethyl acetate in petroleum ether) showed that the starting material had been consumed and a new spot had appeared. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with gradient EtOAc / petroleum ether (0-4% EtOAc) to give 3,6-dichloro-4-cyclopropyl-5-(phenylsulfonyl)pyridazine (7.0 g, 31% yield, 21.3 mmol) as a white solid. MS m / z 328.9 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.95 - 7.84 (m, 2H), 7.77 - 7.67 (m, 1H), 7.62 - 7.56 (m, 2H), 2.33 - 2.18 (m, 1H), 1.52 - 1.39 (m, 2H), 0.93 (q, J = 6.0 Hz, 2H).

[0253] Step 2:To an oven-dried three-neck flask was added 3,6-dichloro-4-cyclopropyl-5-(phenylsulfonyl)pyridazine (4.0 g, 12.1 mmol) and anhydrous tetrahydrofuran (8 mL). The resulting mixture was cooled to -10 °C, and then vinylmagnesium bromide (1 M in THF, 24 mL, 24.0 mmol) was added dropwise. The resulting mixture was stirred at -10 °C for 1 h. TLC (10% EtOAc in petroleum ether) showed that the starting material was consumed. The reaction was quenched by the addition of saturated aqueous ammonium chloride (5 mL), and the mixture was extracted with EtOAc (3 × 20 mL). The organic phase was washed with water (2 × 20 mL) and brine (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient of EtOAc / petroleum ether (0-10% EtOAc) to give 3,6-dichloro-4-cyclopropyl-5-vinylpyridazine (700 mg, 27% yield, 3.25 mmol) as a yellow solid. MS m / z 215.0 [M+H] + .

[0254] Step 3: To a sealed tube was added 3,6-dichloro-4-cyclopropyl-5-vinylpyridazine (700 mg, 3.22 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (4.73 g, 1.84 mmol), acetonitrile (10 mL), and diisopropylethylamine (1.68 mL, 9.66 mmol). The resulting solution was heated at 110 °C for 16 h under N. TLC (30% EtOAc in petroleum ether) showed complete consumption of the starting material. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient of EtOAc / petroleum ether (0-30% EtOAc) to give tert-butyl (R)-3-(3-chloro-4-cyclopropyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (1.1 g, 90% yield, 2.90 mmol) as a white solid. MS m / z 379.3 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ: 4.16 - 3.88 (m, 3H), 3.66 - 3.52 (m, 2H), 3.05 (t, J = 8.0 Hz, 3H), 2.84 - 2.68 (m, 1H), 1.98 - 1.88 (m, 1H), 1.85 - 1.80 (m, 1H), 1.80 - 1.68 (m, 2H), 1.66 - 1.54 (m, 1H), 1.45 (s, 9H), 1.08 - 1.00 (m, 2H), 0.82 - 0.72 (m, 2H).

[0255] Step 4: To a screw-cap vial was added tert-butyl (R)-3-(3-chloro-4-cyclopropyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (165 mg, 0.44 mmol), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (175 mg, 0.5 mmol), and XPhos Pd G3 (38 mg, 0.04 mmol). The tube was degassed with Ar for 15 minutes, and then 1,4-dioxane (1 mL) and potassium carbonate (2 M aqueous solution, 0.66 mL, 1.32 mmol) were added. The resulting mixture was heated to 90° C. for 2 hours. Upon completion, the reaction mixture was loaded directly onto a precolumn and purified by flash chromatography eluting with a gradient of CHCl / MeOH / NHOH (0-30% MeOH / NHOH) to afford tert-butyl (R)-3-(4-cyclopropyl-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (155 mg, 64% yield) as a yellow oil. MS m / z 549.3 [M+H] + .

[0256] Step 5:A solution of tert-butyl (R)-3-(4-cyclopropyl-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (155 mg, 0.3 mmol) in trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3 hours. Upon completion, the trifluoroacetic acid was evaporated by blowing air through, and the crude material was used in the next step without further purification. MS m / z 405.3 [M+H] + .

[0257] Step 6: The crude residue from Step 5 was dissolved in CHCl (1.5 mL) and MeOH (0.5 mL), and triethylamine (276 μL, 1.98 mmol) was then added. The mixture was stirred for 5 min, then cooled to 0° C., and sodium triacetoxyborohydride (254 mg, 1.2 mmol) and formaldehyde (37% in water, 80 μL, 1.2 mmol) were added. The solution was stirred at 0° C. for 5 min before being quenched with sodium bicarbonate (10 mL) and extracted with CHCl. ​​The combined organic phases were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash eluting with a gradient of CHCl / MeOH / NHOH (0-30% MeOH / NHOH) to give ( R)-2-(4-cyclopropyl-7-(1-methylpiperidin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (85 mg, 71% yield over two steps). MS m / z 419.5 [M+H] + ; 1H NMR (500 MHz, methanol-d4) δ: 7.43 (d, J = 7.9 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.14 (d, J = 1.8 Hz, 1H), 4.21 (tt, J = 11.2, 4.1 Hz, 1H), 3.75 - 3.62 (m, 2H), 3.22 - 3.12 (m, 2H), 3.12 - 3.02 (m, 1H), 2.88 (d, J = 11.9 Hz, 1H), 2.36 (s, 3H), 2.31 (d, J = 8.4 Hz, 1H), 2.07 (s, 1H), 1.97 - 1.89 (m, 1H), 1.83 (tdd, J = 14.6, 7.7, 4.7 Hz, 2H), 1.77 - 1.69 (m, 1H), 1.63 (qd, J = 12.0, 3.9 Hz, 1H), 0.69 (dt, J = 9.4, 3.1 Hz, 2H), 0.48 (td, J = 6.0, 4.3 Hz, 2H); 1H not observed (OH).

[0258] Using the procedures described for Example 1 above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0259] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

[0260] Example 1A. Preparation of (R)-2-(7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (IA-1)

[0261] [ka]

[0262] Steps 1 and 2A solution of 3,6-dichloro-4-(trifluoromethyl)pyridazine (1.50 g, 6.91 mmol) in dry THF (10.0 mL) was cooled to −40 °C under an argon atmosphere. A 0.81 M solution of TMPZn(OPiv)2MgClLiCl (10 mL, 8.30 mmol) in THF was then added. The resulting mixture was stirred at −40 °C for 1 h, after which iodine (3.51 g, 13.8 mmol) was added to the mixture, and the solution was stirred at room temperature for 30 min. Upon completion, the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (3 × 20 mL). The combined organic portions were washed with saturated Na2S2O3 solution (2 × 5 mL), water, and brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel flash column chromatography eluting with a gradient of hexane / EtOAc (10-20% EtOAc) to give the crude product, which was recrystallized from hot hexane to give 3,6-dichloro-4-iodo-5-(trifluoromethyl)pyridazine (1.11 g, 47% yield) as a UV-sensitive pale yellow solid. MS m / z 342.8 [M+H] + .

[0263] Step 3.To a dry screw-cap vial was added 3,6-dichloro-4-iodo-5-(trifluoromethyl)pyridazine (0.100 g, 0.292 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.045 g, 0.05 mL, 0.29 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride (0.021 g, 0.029 mmol), and potassium carbonate (0.121 g, 0.875 mmol). The mixture was degassed by purging with nitrogen for 15 minutes, after which 1,4-dioxane (2.1 mL) and water (0.7 mL) were added. The reaction vessel was evacuated and backflushed with nitrogen (3x), and the mixture was heated at 60 °C for 2 h. Upon completion, the mixture was partitioned between EtOAc and water. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of hexanes / EtOAc (0-20% EtOAc) to afford 3,6-dichloro-4-(trifluoromethyl)-5-vinyl-pyridazine (0.017 g, 24.0% yield) as a brown oil. MS m / z 243.1, 245.1 [M+H] + .

[0264] Step 4.To a solution of 3,6-dichloro-4-(trifluoromethyl)-5-vinyl-pyridazine (75.0 mg, 0.31 mmol) in anhydrous acetonitrile (1.5 mL) was added (R)-1-methylpiperidin-3-amine dihydrochloride (64.0 mg, 0.339 mmol) and N,N-diisopropylethylamine (0.160 mL, 0.926 mmol). The resulting mixture was then heated at 60° C. for 15 minutes, at which point all starting material was consumed. The solvent was evaporated and the residue purified by flash column chromatography eluting with a gradient of CHCl / MeOH (5-20% MeOH) to give (R)-3-chloro-7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (75.1 mg, 76% yield) as a yellow oil that solidified over time. MS m / z 321.1, 323.1 [M+H] + .

[0265] Step 5.To a dry screw-cap vial was added (R)-3-chloro-7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (75.1 mg, 0.23 mmol), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (156 mg, 0.47 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (19.8 mg, 0.023 mmol), and potassium carbonate (97.1 mg, 0.70 mmol). The mixture was degassed by purging with nitrogen for 15 minutes, after which 1,4-dioxane (1.5 mL) and water (0.5 mL) were added. The reaction vessel was evacuated and backflushed with nitrogen (three times), and the mixture was heated at 90 °C for 1 hour. Upon completion, the mixture was partitioned between EtOAc and water. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-20% MeOH) to afford (R)-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (87.7 mg, 76% yield) as a brown foam. MS m / z 491.2 [M+H] + .

[0266] Step 6.A solution of (R)-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (87.7 mg, 0.179 mmol) in MeOH (1.0 mL) was treated with 12 N HCl solution (1.0 mL). The mixture was stirred at room temperature for 3 h. After all starting material was consumed, the acidic solution was neutralized with solid NaHCO. The aqueous solution was then extracted with CHCl (3 × 20 mL). The combined organic portions were washed with water, dried over NaSO, and evaporated to dryness. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-20% MeOH) to afford (R)-2-(7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (53.0 mg, 66% yield) as a yellow solid. MS m / z 447.2 [M+H] + ; 1 H NMR (500 MHz, methanol-d4) δ: 8.48 (br s, 1H, formic acid CH), 7.34 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.13 (s, 1H), 4.41 - 4.27 (m, 1H), 3.91 - 3.74 (m, 2H), 3.42 - 3.35 (m, 2H), 3.13 (d, J = 11.8 Hz, 1H), 2.83 - 2.68 (m, 1H), 2.60 (s, 3H), 2.55 - 2.41 (m, 1H), 2.08 - 1.93 (m, 2H), 1.90 - 1.76 (m, 2H); two Hs are not observed (OH and one of the CHs overlap with the solvent peak).

[0267] Example 2. Preparation of (R)-5-chloro-2-(4-cyclopropyl-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol (II-1)

[0268] [ka] Step 1: To a screw-cap vial was added tert-butyl (3R)-3-(3-chloro-4-cyclopropyl-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (prepared according to Example 1, 150 mg, 0.4 mmol), 2-[4-chloro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (142 mg, 0.48 mmol), Pd(dppf)Cl (29 mg, 0.04 mmol), and potassium carbonate (142 mg, 1.0 mmol). The vial was purged with Ar for 15 minutes, followed by the addition of water (0.5 mL) and 1,4-dioxane (1.3 mL). The mixture was heated at 90° C. for 2 hours. Upon completion, the reaction was concentrated, loaded directly onto a precolumn, and purified by flash column chromatography eluting with a gradient of CHCl / MeOH / NHOH (0-30% MeOH / NHOH) to give tert-butyl (3R)-3-[3-[4-chloro-2-(methoxymethoxy)phenyl]-4-cyclopropyl-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl]piperidine-1-carboxylate (110.1 mg, 54% yield). MS m / z 515.4, 517.4 [M+H] + .

[0269] Step 2:To a screw-cap vial was added tert-butyl (3R)-3-[3-[4-chloro-2-(methoxymethoxy)phenyl]-4-cyclopropyl-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl]piperidine-1-carboxylate (55 mg, 0.11 mmol), manganese(II) oxide (178 mg, 2.1 mmol), and toluene (0.2 mL). The suspension was heated at 110 °C for 16 hours. Upon completion, the reaction was filtered through a pad of Celite and concentrated under reduced pressure to give crude tert-butyl (3R)-3-[3-[4-chloro-2-(methoxymethoxy)phenyl]-4-cyclopropyl-pyrrolo[2,3-c]pyridazin-7-yl]piperidine-1-carboxylate. The crude product was used directly in the next step without further purification.

[0270] Step 3: To a vial containing tert-butyl (3R)-3-[3-[4-chloro-2-(methoxymethoxy)phenyl]-4-cyclopropyl-pyrrolo[2,3-c]pyridazin-7-yl]piperidine-1-carboxylate (crude from Step 2) was added TFA (1.0 mL). The mixture was stirred at room temperature for 1 h. Upon completion, the solvent was removed and the mixture was purified by silica flash column chromatography eluting with a gradient of CHCl / MeOH / NHOH (0-30% MeOH / NHOH) to give 5-chloro-2-[4-cyclopropyl-7-[(3R)-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]phenol (36 mg, 99% yield). MS m / z 369.3, 371.3 [M+H] + .

[0271] Step 4:A solution of 5-chloro-2-[4-cyclopropyl-7-[(3R)-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]phenol (36 mg, 0.1 mmol) in CHCl (1.0 mL) was cooled to 0°C, and formaldehyde (37% in water) (0.011 mL, 0.15 mmol) was added. Sodium triacetoxyborohydride (62 mg, 0.3 mmol) was then added. The mixture was stirred at 0°C for 20 minutes. Upon completion, the reaction was quenched with water, neutralized with saturated aqueous NaHCO, and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to give the crude material, which was purified using a C18 EZ-Prep with formic acid as a modifier to give 5-chloro-2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]phenol (13.9 mg, 37% yield) as the formate salt. MS m / z 383.3, 385.2 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ: 8.35 (s, 1H, formic acid peak), 7.93 (d, J = 3.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.74 (d, J = 3.5 Hz, 1H), 5.67 - 5.46 (m, 1H), 3.93 - 3.70 (m, 1H), 3.58 - 3.45 (m, 1H), 3.45 - 3.36 (m, 1H), 3.14 - 2.93 (m, 1H), 2.79 (s, 3H), 2.40 - 2.21 (m, 2H), 2.20 - 1.88 (m, 3H), 1.20 - 0.95 (m, 4H); 1H not observed (OH).

[0272] Using the procedures described in Example 2 above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0273] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8]

[0274] Example 2A. Preparation of (R)-2-(7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (IIA-1)

[0275] [ka]

[0276] Steps 1 and 2A solution of 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (1.0 mol / L) in THF / toluene (10.0 mL, 1:1) was cooled to 0 °C. Dry zinc pivalate (2.9 g, 11.0 mmol) was then added to the solution in one portion under a stream of nitrogen. The ice bath was removed, and the solution was stirred at room temperature for 1 h, resulting in a 0.73 M solution of TMPZn(OPiv)2MgClLiCl, as determined by titration with diphenylacetic acid. In a separate round-bottom flask, a solution of 3,6-dichloro-4-(trifluoromethyl)pyridazine (0.500 g, 2.30 mmol) in dry THF (4.60 mL) was cooled to -20 °C. A 0.73 M solution of TMP-Zn(OPiv)2-MgCl-LiCl (4.70 mL, 3.46 mmol) in THF / toluene (prepared as described above) was added dropwise. The reaction was stirred at -20 °C for 1 h, at which point the zincation was complete (as indicated by LCMS analysis of an aliquot sample quenched with I). A solution of 2.1 M copper(I) cyanide di(lithium chloride) complex solution in THF (0.11 mL, 0.230 mmol) was then added to the reaction mixture, followed by 3-bromoprop-1-ene (0.418 g, 0.299 mL, 3.46 mmol). The mixture was gradually warmed to 0 °C and stirred at this temperature for 1 h. Upon completion, the reaction was quenched with saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic portions were washed with water, brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography eluting with a gradient of hexane / EtOAc (0-10% EtOAc) to afford 4-allyl-3,6-dichloro-5-(trifluoromethyl)pyridazine (0.236 g, 40% yield over two steps) as a pale yellow oil. MS m / z 257.0, 259.0, 261.0 [M+H] + .

[0277] Step 3.To a solution of 4-allyl-3,6-dichloro-5-(trifluoromethyl)pyridazine (0.30 g, 1.17 mmol) in THF (6.0 mL) and water (2.0 mL) was added 2,4,6-trimethylpyridine (0.283 g, 0.31 mL, 2.33 mmol), osmium tetroxide (4%) in water (0.36 mL, 0.059 mmol), and sodium periodate (1.25 g, 5.84 mmol). After the addition, the reaction mixture changed color from transparent yellow to dark to milky white. The reaction mixture was stirred at room temperature for 6 hours. Upon completion, the reaction was quenched with water (10 mL). The aqueous solution was then extracted with CHCl (3 × 10 mL). The combined organic portions were washed with water, brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography eluting with a gradient of hexane / EtOAc (0-10% EtOAc) to give 3-[3,6-dichloro-5-(trifluoromethyl)pyridazin-4-yl]propane-1,2-diol (0.199 g, 59% yield) as a light brown oil. MS m / z 291.0, 293.0, 295.0 [M+H] + .

[0278] Step 4.A solution of 3-[3,6-dichloro-5-(trifluoromethyl)pyridazin-4-yl]propane-1,2-diol (0.199 g, 0.683 mmol) in MeOH (3.0 mL) was cooled to 0 °C, and a solution of sodium periodate (0.161 g, 0.751 mmol) in water (3.0 mL) was added dropwise. The mixture was stirred at room temperature for 2 h (formation of a precipitate was observed), then partitioned between water and EtOAc (3 × 10 mL). The combined organic portions were washed with water, brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography eluting with a gradient of hexane / EtOAc (10–20% EtOAc) to afford 2-(3,6-dichloro-5-(trifluoromethyl)pyridazin-4-yl)acetaldehyde (0.083 g, 47% yield) as a pale yellow solid. MS m / z 257.0, 259.0, 260.9 [MH] - .

[0279] Step 5. To a solution of 2-(3,6-dichloro-5-(trifluoromethyl)pyridazin-4-yl)acetaldehyde (0.083 g, 0.321 mmol) in CHCl (3.0 mL) was added acetic acid (0.0386 g, 0.0368 mL, 0.642 mmol), (R)-1-methylpiperidin-3-amine (0.0440 g, 0.385 mmol), and sodium triacetoxyborohydride (0.102 g, 0.482 mmol). The mixture was stirred at room temperature for 15 minutes, at which point the starting material was consumed. The solution was then partitioned between CHCl and water. The combined organic portions were washed with water, brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give crude (R,E)-N-(2-(3,6-dichloro-5-(trifluoromethyl)pyridazin-4-yl)vinyl)-1-methylpiperidin-3-amine, which was used in the next step without further purification. MS m / z 355.1, 357.1, 359.1 [M+H] + .

[0280] Step 6.(R,E)-N-(2-(3,6-dichloro-5-(trifluoromethyl)pyridazin-4-yl)vinyl)-1-methylpiperidin-3-amine from the previous step was dissolved in CHCl (1.0 mL) and MeOH (1.0 mL). Silica gel (5.0 g) was then added to the solution. The mixture was stirred at room temperature for 48 h, at which point LCMS indicated complete consumption of the starting material. The solvent was evaporated, and the residue was purified by flash column chromatography eluting with a gradient of CHCl / MeOH (0-20% MeOH) to afford (R)-3-chloro-7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-7H-pyrrolo[2,3-c]pyridazine (19.2 mg, 19% yield over two steps) as a yellow solid. M / S m / z 319.1, 321.1 [M+H] + .

[0281] Step 7.To a screw-cap vial was added (R)-3-chloro-7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-7H-pyrrolo[2,3-c]pyridazine (19.2 mg, 0.06 mmol), 2-[2-(methoxymethoxy)-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (39.6 g, 0.119 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (4.9 mg, 0.0060 mmol), and potassium carbonate (24.7 mg, 0.179 mmol). The mixture was degassed by purging with nitrogen for 15 minutes, followed by the addition of 1,4-dioxane (2.1 mL) and water (0.7 mL). The reaction vessel was evacuated and backflushed with nitrogen, and the mixture was stirred at 90° C. for 16 hours. Upon completion, the mixture was partitioned between EtOAc and water. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under pressure to provide (R)-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-7H-pyrrolo[2,3-c]pyridazine as a brown oil. The crude material was used in the next step without further purification. MS m / z 489.1 [M+H] + .

[0282] Step 8. The crude product from the previous step was then dissolved in MeOH (1.0 mL) and 12.0 N HCl (a few drops) was added. After 2 h of stirring, the reaction was quenched with saturated aqueous NaHCO3. The aqueous solution was then extracted with EtOAc (3 x 20 mL). The combined organic portions were washed with water, brine, dried over Na2SO4, and the solvent was evaporated. The residue was purified by reverse-phase column chromatography eluting with a gradient of ACN (0.1% formic acid) / water (0.1% formic acid) (5-10% ACN) to afford (R)-2-(7-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (4.6 mg, 17% yield over two steps) as a pale yellow solid. MS m / z 445.1 [M+H]+ ; 1 H NMR (500 MHz, methanol-d4) δ: 8.31 (s, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.20 (s, 1H), 6.82 (s, 1H), 5.34 - 5.22 (m, 1H), 3.01 - 2.92 (m, 1H), 2.81 - 2.68 (m, 1H), 2.45 (s, 3H), 2.40 - 2.30 (m, 1H), 2.30 - 2.08 (m, 2H), 2.05 - 1.95 (m, 1H), 1.95 - 1.82 (m, 1H); two hydrogens not observed. (NH and OH).

[0283] Example 2B. Preparation of 5-(7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-6-methylbenzofuran-4-ol (IIB-1)

[0284] [ka] Step 1:To a degassed solution of 4-bromo-3,6-dichloro-pyridazine (115 mg, 0.50 mmol) in 1,4-dioxane (3 mL) was added a 2 M aqueous solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl) (37 mg, 0.05 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (168 mg, 0.76 mmol), and potassium carbonate (0.76 mL, 1.5 mmol) under nitrogen. The mixture was heated to 50 °C for 30 min. Upon completion, the reaction was diluted with water, extracted with DCM, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography eluting with 0 to 100% EtOAc in hexanes to give 3,6-dichloro-4-[1-(trifluoromethyl)vinyl]pyridazine (80 mg, 65% yield). MS m / z 243.0 [M+H] + .

[0285] Step 2: To a solution of 3,6-dichloro-4-[1-(trifluoromethyl)vinyl]pyridazine (350 mg, 1.44 mmol) and cis-3-amino-1-methylcyclobutanol hydrochloride (238 mg, 1.73 mmol) in acetonitrile (4.80 mL) was added N,N-diisopropylethylamine (0.75 mL, 4.32 mmol). The mixture was stirred at 90 °C for 4 h. Upon completion, the reaction was diluted with DCM (5 mL) and washed with saturated ammonium chloride, water, and brine. The combined organics were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography eluting with 0–30% MeOH in DCM to give cis-3-[3-chloro-5-(trifluoromethyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl]-1-methyl-cyclobutanol (100 mg, 22% yield). MS m / z 308.0[M+H] + .

[0286] Step 3:To a solution of cis-3-[3-chloro-5-(trifluoromethyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl]-1-methyl-cyclobutanol (50 mg, 0.162 mmol) in 1,4-dioxane (0.54 mL) was added manganese(IV) oxide (0.028 mL, 1.62 mmol). The reaction was stirred at 110 °C for 2 h until TLC indicated the disappearance of the starting material. The reaction was then filtered through a pad of Celite. The Celite pad was washed with ethyl acetate, and the filtrate was evaporated under reduced pressure. The residue was further purified by flash chromatography eluting with 0–30% MeOH in DCM to give cis-3-[3-chloro-5-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-7-yl]-1-methyl-cyclobutanol (34 mg, 68% yield). MS m / z 306.0 [M+H] + ; 1 H NMR (500 MHz, MeOD) δ: 8.62 (d, J = 1.3 Hz, 1H), 7.99 (s, 1H), 5.10 (p, J = 8.3 Hz, 1H), 2.82 (ddt, J = 10.2, 5.2, 2.6 Hz, 2H), 2.69 (td, J = 9.3, 2.8 Hz, 2H), 1.51 (s, 3H).

[0287] Step 4:To a solution of cis-3-[3-chloro-5-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-7-yl]-1-methyl-cyclobutanol (110 mg, 0.360 mmol) in dioxane was added XPhos Pd G3 (30 mg, 0.0360 mmol), 2-[4-(methoxymethoxy)-6-methyl-benzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (229 mg, 0.720 mmol), and 2 M aqueous potassium carbonate (0.54 mL, 1.08 mmol). The reaction was stirred at 90 °C for 4 h. Upon completion, the organics were separated and the solvent was evaporated under reduced pressure. The crude residue was purified by flash chromatography eluting with 0-30% MeOH in DCM to give cis-3-[3-[4-(methoxymethoxy)-6-methyl-benzofuran-5-yl]-5-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-7-yl]-1-methyl-cyclobutanol (100 mg, 60% yield). MS m / z 462.2 [M+H] + .

[0288] Step 5:To a solution of cis-3-[3-[4-(methoxymethoxy)-6-methyl-benzofuran-5-yl]-5-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-7-yl]-1-methyl-cyclobutanol in 1,4-dioxane (1.25 mL) was added a 4 M solution of HCl in 1,4-dioxane (0.13 mL, 0.54 mmol). The reaction was stirred at room temperature for 1 h. Upon completion, the mixture was diluted with DCM and quenched with 10% aqueous sodium bicarbonate solution. The organics were washed with water, brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography eluting with 0–30% MeOH in DCM. The product fractions were collected, evaporated under reduced pressure, and repurified by flash chromatography eluting with 0-100% CH3CN in water to give 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol (4 mg, 10% yield). MS m / z 418.0 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ: 8.58 (s, 1H), 7.91 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.06 (s, 1H), 7.02 - 6.89 (m, 1H), 5.22 (p, J = 8.3 Hz, 1H), 2.92-2.83 (m, 2H), 2.81 - 2.64 (m, 2H), 2.13 (s, 3H), 1.54 (s, 3H). Using the procedure described in Example 2B above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0289] [Table 5]

[0290] Example 2C. Preparation of 5-(5-(difluoromethyl)-7-((cis)-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-6-methylbenzofuran-4-ol (IIC-1)

[0291] [ka]

[0292] Step 1. N,N-Diisopropylethylamine (2.6 mL, 15.0 mmol) was added to a solution of 3,6-dichloro-4-vinyl-pyridazine (875 mg, 5.00 mmol, prepared according to the procedure in Example 2B) and cis-3-amino-1-methyl-cyclobutanol hydrochloride (826 mg, 6.00 mmol) in ACN (12.5 mL) and stirred at 100 °C for 3 h. Upon completion of the reaction, the mixture was concentrated. The crude residue was purified by silica gel column chromatography eluting with 0:100 to 30:70 MeOH:DCM to give cis-3-(3-chloro-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl)-1-methyl-cyclobutanol (1.110 g, 4.64 mmol, 93% yield). MS m / z 240.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.13–7.08 (m, 1H), 4.17 (p, J = 8.4 Hz, 1H), 3.79–3.69 (m, 2H), 3.14–3.06 (m, 2H), 2.40–2.31 (m, 4H), 1.39 (s, 3H).

[0293] Step 2.cis-3-(3-chloro-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl)-1-methyl-cyclobutanol (1.007 g, 4.20 mmol), tert-butyldimethylchlorosilane (0.950 g, 6.30 mmol), and imidazole (857.8 mg, 12.6 mmol) were dissolved in DMF (10.5 mL) and stirred at room temperature for 4 hours. Upon completion, the reaction was diluted with EtOAc and NaHCO (saturated aqueous solution). The product was extracted several times with EtOAc, and the combined organic extracts were dried over NaSO and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 0:100 to 20:80 EtOAc:DCM to give 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (1.281 g, 3.62 mmol, 86% yield). MS m / z 354.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.14–7.07 (m, 1H), 4.17 (p, J = 8.4 Hz, 1H), 3.79–3.66 (m, 2H), 3.16–3.03 (m, 2H), 2.46–2.32 (m, 4H), 1.44 (s, 3H), 0.90 (s, 9H), 0.12 (s, 6H).

[0294] Step 3.Manganese(IV) oxide (5.216 g, 60.0 mmol) was added to a solution of 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (1.062 g, 3.00 mmol) in 1,4-dioxane (15 mL) and heated to 110° C. for 8 hours. After the reaction was cooled to ambient temperature, the crude reaction mixture was diluted with ethyl acetate and then filtered through Celite. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel column chromatography eluting with 0:100 to 40:60 EtOAc:(40% DCM in hexanes) to give 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazine (640 mg, 1.81 mmol, 61% yield). MS m / z 352.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.99 (d, J = 3.5 Hz, 1H), 7.92 (s, 1H), 6.62 (d, J = 3.5 Hz, 1H), 5.02 (p, J = 8.4 Hz, 1H), 2.84 - 2.63 (m, 4H), 1.56 (s, 3H), 0.93 (s, 9H), 0.15 (s, 6H).

[0295] Step 4.N-Iodosuccinimide (405 mg, 1.80 mmol) was added to a solution of 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazine (528 mg, 1.50 mmol) in ACN (10 mL) at 0 °C. After 30 min, the mixture was allowed to warm to room temperature and stirred for 3 h. Upon completion of the reaction, the mixture was poured into ice-cold NaHCO (saturated, aq.) and extracted with EtOAc. The product was extracted several times with EtOAc, and the combined organic extracts were dried over NaSO and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 5:95 to 30:70 EtOAc:hexanes to give 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (654 mg, 1.37 mmol, 91% yield). MS m / z 478.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.15 (s, 1H), 7.68 (s, 1H), 5.00 (p, J = 8.3 Hz, 1H), 2.87–2.67 (m, 4H), 1.55 (s, 3H), 0.93 (s, 9H), 0.15 (s, 6H).

[0296] Step 5.n-BuLi (1.25 M in hexane / EtO, 0.88 mL, 1.1 mmol) was added dropwise to a solution of 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-5-iodo-7H-pyrrolo[2,3-c]pyridazine (477.8 mg, 1.00 mmol) in THF (5 mL) cooled to −78 °C. After 45 min, DMF (4 M in EtO, 0.325 mL, 1.3 mmol) was added dropwise to the reaction mixture at −78 °C. After 1 h, the cooling bath was removed and the reaction mixture was stirred for 30 min. The reaction mixture was transferred to an ice bath and quenched with water. The product was extracted several times with EtOAc, and the combined organic extracts were dried over NaSO and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 1:99 to 40:60 EtOAc:hexanes to give 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazine-5-carbaldehyde (266 mg, 0.700 mmol, 70% yield). MS m / z 380.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.98 (s, 1H), 8.87 (s, 1H), 8.35 (s, 1H), 5.11–4.96 (m, 1H), 2.93–2.72 (m, 4H), 1.59 (s, 3H), 0.94 (s, 9H), 0.17 (s, 6H).

[0297] Step 6.DAST (483.6 mg, 3.00 mmol) was added to a solution of 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-7H-pyrrolo[2,3-c]pyridazine-5-carbaldehyde (228 mg, 0.600 mmol) in DCM (4 mL) at 0 °C. After 20 min, the ice bath was removed and the mixture was stirred at room temperature for 2 h. After 2 h, the temperature was raised to 40 °C and the reaction was stirred for 24 h. Upon completion of the reaction, the mixture was slowly quenched with cold NaHCO (saturated, aq.) while cooling in an ice bath. The product was extracted with DCM, and the combined organic extracts were dried over NaSO and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 1:99 to 50:50 EtOAc:hexanes to give 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-5-(difluoromethyl)-7H-pyrrolo[2,3-c]pyridazine (175 mg, 0.435 mmol, 73% yield). MS m / z 402.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.34–8.28 (m, 1H), 8.02 (s, 1H), 7.06 (t, J = 55.5 Hz, 1H), 5.01 (p, J = 8.5 Hz, 1H), 2.87–2.67 (m, 4H), 1.56 (s, 3H), 0.92 (s, 9H), 0.15 (s, 6H).

[0298] Step 7.A mixture of 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-5-(difluoromethyl)-7H-pyrrolo[2,3-c]pyridazine (60 mg, 0.150 mmol), 2-[4-(methoxymethoxy)-6-methyl-benzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57 mg, 0.180 mmol), KCO (2 M, 0.23 mL, 0.450 mmol), and XPhos Pd G (7.6 mg, 0.009 mmol) in 1,4-dioxane (0.75 mL) was sparged with argon and then heated to 95 °C for 2 h. After cooling to room temperature, the reaction was diluted with NaHCO (sat., aq.) and the product was extracted several times with EtOAc. The combined organic extracts were dried over NaSO and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 0:100 to 100:0 EtOAc:hexanes to give 7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-(difluoromethyl)-3-(4-(methoxymethoxy)-6-methylbenzofuran-5-yl)-7H-pyrrolo[2,3-c]pyridazine (75 mg, 0.134 mmol, 89% yield). 1 H NMR (400 MHz, methanol-d4) δ 8.30 (s, 1H), 7.95 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.29 (s, 1H), 7.10 (t, J = 55.5 Hz, 1H), 7.04 - 7.01 (m, 1H), 5.14 (p, J = 7.7 Hz, 1H), 3.13 (s, 3H), 2.94 - 2.69 (m, 4H), 2.14 (s, 3H), 1.59 (s, 3H), 0.94 (s, 9H), 0.17 (s, 6H).

[0299] Step 8.7-((cis)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-chloro-5-(difluoromethyl)-7H-pyrrolo[2,3-c]pyridazine (72 mg, 0.129 mmol) was dissolved in 1:2 HCl (12 M, aq):MeOH and stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, and the crude residue was purified by C18 reverse-phase preparative HPLC eluting with ACN:water using formic acid as a modifier. After reverse-phase purification, the solvent was removed to give 5-(5-(difluoromethyl)-7-((cis)-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-6-methylbenzofuran-4-ol (22 mg, 0.055 mmol, 43%). MS m / z 400.1 [M+H] + . 1 H NMR (400 MHz, methanol-d₄) δ: 8.35 (s, 1H), 7.94 (s, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.31 - 6.94 (m, 3H), 5.27 - 5.13 (m, 1H), 2.90 - 2.78 (m, 2H), 2.77 - 2.66 (m, 2H), 2.13 (s, 3H), 1.54 (s, 3H). No OH peak was observed. Using the procedure described in Example 2C above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0300] [Table 6]

[0301] Example 2D. Preparation of 7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-3-(4-hydroxy-6-methylbenzofuran-5-yl)-7H-pyrrolo[2,3-c]pyridazine-5-carbonitrile (IID-1)

[0302] [ka]

[0303] Step 1: 3-(3-Chloro-5-iodo-pyrrolo[2,3-c]pyridazin-7-yl)-1-methyl-cyclobutanol (0.150 g, 0.412 mmol), CuCN (0.110 g, 1.24 mmol), Pd(dba) (0.037 g, 0.041 mmol), and dppf (0.091 g, 0.165 mmol) were dissolved in dioxane (4.1 mL). The reaction mixture was heated at 90 °C for 16 h, then diluted with EtOAc and washed with water and brine. The organic phase was dried (MgSO), filtered, and concentrated. Purification by chromatography on SiO (EtOAc:hexanes, 0–100%) afforded a yellow foam (0.095 g, 87%). MS m / z 263.0, 264.9 [M+H] + .

[0304] Steps 2 and 3: 3-Chloro-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazine-5-carbonitrile (0.025 g, 0.091 mmol), 2-[4-(methoxymethoxy)-6-methyl-benzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.036 g, 0.114 mmol), XPhos Pd-G (0.008 g, 0.009 mmol), and KCO (0.14 mL, 0.285 mmol, 2 M) were dissolved in dioxane (0.6 mL). The reaction was heated at 95 °C for 14 h. The reaction was diluted with EtOAc and washed with water and brine. The organic phase was dried (MgSO), filtered, and concentrated. Purification by chromatography on SiO (EtOAc:hexanes, 0–80%) afforded a yellow film. MS m / z 419.1[M+H] +The material was dissolved in MeOH (1 mL), to which HCl (0.2 mL, 4.0 M in dioxane) was added, and the mixture was stirred at room temperature. Upon completion of the reaction, the mixture was concentrated, and the resulting residue was dissolved in DCM and washed with saturated NaHCO3 and brine. The organic phase was dried (Na2SO4), filtered, and concentrated. Purification by reverse-phase chromatography (1% formic acid in MeCN:1% formic acid in water, 0-80%) afforded a white solid (0.006 g, 17%, 2 steps). MS m / z 375.1 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ: 8.77 (s, 1H), 8.00 (s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.06 (s, 1H), 7.00 - 6.96 (m, 1H), 5.20 (quintet, J = 8.3 Hz, 1H), 2.91 - 2.83 (m, 2H), 2.82 - 2.68 (m, 2H), 2.14 (s, 3H), 1.54 (s, 3H). (2H not observed, 2OH).

[0305] Example 2E. Preparation of 5-(5-cyclopropyl-7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)-6-methylbenzofuran-4-ol (IIE-1)

[0306] [ka] Step 1:3-(3-Chloro-5-iodo-pyrrolo[2,3-c]pyridazin-7-yl)-1-methyl-cyclobutanol (0.60 g, 0.165 mmol), cyclopropylboronic acid (0.028 g, 0.330 mmol), Pd(OAc) (0.009 g, 0.040 mmol), PCy (0.018 g, 0.066 mmol), and KPO (0.116 g, 0.545 mmol) were dissolved in PhMe / HO (8:1, 0.9 mL). The reaction was heated at 90 °C for 16 h. The reaction was diluted with EtOAc and washed with water and brine. The organic phase was dried (MgSO), filtered, and concentrated. Purification by chromatography on SiO (EtOAc:hexanes, 0–80%) afforded a yellow solid (0.020 g, 44%). MS m / z 278.0, 279.9 [M+H] + .

[0307] Step 2: 3-(3-Chloro-5-cyclopropyl-pyrrolo[2,3-c]pyridazin-7-yl)-1-methyl-cyclobutanol (0.020 g, 0.072 mmol), 2-[4-(methoxymethoxy)-6-methyl-benzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.027 g, 0.086 mmol), XPhos Pd-G (0.006 g, 0.007 mmol), and KCO (0.11 mL, 0.216 mmol, 2 M solution) were dissolved in dioxane (0.36 mL). The reaction was heated at 95 °C for 14 h, then diluted with EtOAc and washed with water and brine. The organic phase was dried over MgSO, filtered, and concentrated. Purification by chromatography on SiO (EtOAc:hexanes, 0–80%) afforded a yellow film. MS m / z 419.1[M+H] + .

[0308] Step 3:The material from Step 2 was dissolved in MeOH (1 mL) and HCl (0.2 mL, 4.0 M in dioxane) was added and stirred at room temperature. Upon completion, the reaction was concentrated, and the resulting residue was dissolved in DCM and washed with saturated NaHCO3 and brine. The organic phase was dried (Na2SO4), filtered, and concentrated. Purification by reverse-phase chromatography (1% formic acid in MeCN:1% formic acid in water, 0-80%) afforded a white solid (0.008 g, 29%, 2 steps). MS m / z 390.1 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ: 8.21 (s, 1H, formic acid), 7.99 (s, 1H), 7.86 (s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J = 1.9 Hz, 1H), 5.12 (quintet, J = 8.4 Hz, 1H), 2.80 - 2.73 (m, 2H), 2.73 - 2.65 (m, 2H), 2.15 (s, 3H), 2.06 - 1.98 (m, 1H), 1.51 (s, 3H), 1.03 - 0.93 (m, 2H), 0.79 - 0.73 (m, 2H). (2H is not accepted, 2 OH).

[0309] Example 2F. Preparation of (R)-5-(5-fluoro-4-methyl-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)benzofuran-4-ol (IIF-1)

[0310] [ka] Step 1.A 20 mL tube was charged with a mixture of tert-butyl (R)-3-(3-chloro-4-methyl-5,6-dihydro-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (100 mg, 0.283 mmol, 1.0 equiv., prepared according to Example 1) and MnO (493 mg, 5.67 mmol, 20.0 equiv.) in 1,4-dioxane (6 mL). The reaction was stirred at 135 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–50% EtOAc in hexanes to give tert-butyl (R)-3-(3-chloro-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (35 mg, 0.998 mmol, 35.2% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 3.6 Hz, 1H), 6.48 (d, J = 3.6 Hz, 1H), 5.04 - 4.80 (m, 1H), 4.33 - 4.15 (m, 1H), 4.06 - 3.86 (m, 1H), 3.56 - 3.35 (m, 1H), 3.14 - 2.96 (m, 1H), 2.58 (s, 3H), 2.35 - 2.09 (m, 2H), 1.89 - 1.76 (m, 1H), 1.76 - 1.66 (m, 1H), 1.61 (s, 3H), 1.45 (s, 9H). MS m / z 351.4 [M+H] + .

[0311] Step 2.To a solution of tert-butyl (R)-3-(3-chloro-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (500 mg, 1.43 mmol, 1.0 equiv.) and AcOH (2 mL) in MeCN (10 mL) was added Selectfluor (757 mg, 2.14 mmol, 1.5 equiv.). The reaction was stirred at 50 °C under a N atmosphere for 16 h. Upon completion, the reaction mixture was cooled to room temperature, neutralized to pH = 8 with saturated aqueous NaHCO3, and extracted with EtOAc (20 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 0-30% EtOAc in hexane to give tert-butyl (R)-3-(3-chloro-5-fluoro-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (44 mg, 0.119 mmol, 8.37% yield) as a yellow oil. MS m / z 369.4 [M+H] + .

[0312] Step 3. A mixture of tert-butyl (R)-3-(3-chloro-5-fluoro-4-methyl-7H-pyrrolo[2,3-c]pyridazin-7-yl)piperidine-1-carboxylate (45 mg, 0.122 mmol, 1.0 equivalent) in HCl (25% w / w in MeOH, 1 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give (R)-3-chloro-5-fluoro-4-methyl-7-(piperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazine hydrochloride as a yellow solid (37 mg, 0.121 mmol, 99.4% yield), which was used directly in the next step without further purification. MS m / z 269.4 [M+H] + .

[0313] Step 4.To a solution of (R)-3-chloro-5-fluoro-4-methyl-7-(piperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazine hydrochloride (37 mg, 0.121 mmol, 1.0 equiv.) in MeOH (2 mL) was added EtN (12 mg, 0.121 mmol, 1 equiv.), HCHO (37% w / w in HO) (49 mg, 0.606 mmol, 5 equiv.), and AcOH (7 mg, 0.121 mmol, 1.0 equiv.). The reaction was stirred at room temperature under a N atmosphere for 1 hour, and NaBHCN (15 mg, 0.242 mmol, 2.0 equiv.) was added to the mixture. The reaction was stirred at room temperature under a N atmosphere for 2 hours. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with 50% EtOAc in hexane to give (R)-3-chloro-5-fluoro-4-methyl-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazine (25 mg, 0.088 mmol, 72.9% yield) as a white solid. MS m / z 283.4 [M+H] + .

[0314] Step 5.A 5 mL tube was charged with a mixture of (R)-3-chloro-5-fluoro-4-methyl-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazine (25 mg, 0.088 mmol, 1.0 equiv.), 2-(4-(methoxymethoxy)benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 mg, 0.177 mmol, 2.0 equiv.), KCO (37 mg, 0.265 mmol, 3.0 equiv.), and XPhos Pd G (8 mg, 0.009 mmol, 0.1 equiv.) in HO (0.2 mL) and 1,4-dioxane (1 mL). The reaction was sealed under a N atmosphere and stirred at 100 °C for 2 h. Upon completion, the reaction was cooled to room temperature, diluted with (10 mL), and extracted with EtOAc (10 mL x 3). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC eluting with 10% MeOH in DCM to give (R)-5-fluoro-3-(4-(methoxymethoxy)benzofuran-5-yl)-4-methyl-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazine (25 mg, 0.059 mmol, 66.6% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 6.65 (dd, J = 18.0, 12.0 Hz, 1H), 5.94 (dd, J = 12.0, 0.8 Hz, 1H), 5.67 (dd, J = 18.0, 0.8 Hz, 1H). MS m / z 425.1 [M+H] + .

[0315] Step 6.A mixture of (R)-5-fluoro-3-(4-(methoxymethoxy)benzofuran-5-yl)-4-methyl-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazine (25 mg, 0.058 mmol, 1.0 equiv.) in HCl (25% w / w in MeOH, 1 mL) was stirred at room temperature for 16 hours. The reaction mixture was neutralized to pH = 8 with saturated aqueous NaHCO3 and extracted with EtOAc (10 mL x 3). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC eluting with 10% MeOH in DCM to give (R)-5-(5-fluoro-4-methyl-7-(1-methylpiperidin-3-yl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)benzofuran-4-ol (20 mg, 0.053 mmol, 91.0% yield) as a white solid. MS m / z 381.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.88 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.03 (dd, J = 2.4, 0.8 Hz, 1H), 5.24 - 5.14 (m, 1H), 3.23 - 3.14 (m, 1H), 2.93 - 2.83 (m, 1H), 2.60 - 2.53 (m, 1H), 2.52 (s, 3H), 2.38 (s, 3H), 2.28 - 2.20 (m, 1H), 2.18 - 2.10 (m, 1H), 2.06 - 1.97 (m, 1H), 1.96 - 1.89 (m, 1H), 1.90 - 1.79 (m, 1H).

[0316] Using the procedures described in Example 2F above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0317] [Table 7]

[0318] Example 2G. Preparation of 5-(7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-c]pyridazin-3-yl)-6-methylbenzofuran-4-ol (IIG-1)

[0319] [ka] Step 1. N-Iodosuccinimide (27 mg, 0.12 mmol) was added to a solution of 7-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-(4-(methoxymethoxy)-6-methyl-2,3-dihydrobenzofuran-5-yl)-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine (51.2 mg, 0.100 mmol) in ACN (10 mL) at 0 °C. After 30 min, the mixture was allowed to warm to room temperature and stirred overnight. Upon completion of the reaction, the mixture was poured into ice-cold NaHCO (saturated, aq.) and extracted with EtOAc. The product was extracted several times with EtOAc, and the combined organic extracts were dried over NaSO and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with 0:100 to 100:00 EtOAc:DCM to give 7-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-iodo-3-(4-(methoxymethoxy)-6-methyl-2,3-dihydrobenzofuran-5-yl)-7H-pyrrolo[2,3-c]pyridazine (11.2 mg, 0.018 mmol, 18% yield). MS m / z 636.4 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.89 (s, 1H), 7.29 (s, 1H), 6.33 (s, 1H), 4.90 (p, J = 8.7 Hz, 1H), 4.62 (s, 2H), 4.44 - 4.33 (m, 2H), 3.19 - 3.11 (m, 2H), 2.86 (s, 3H), 2.71 - 2.47 (m, 4H), 1.77 (s, 3H), 1.36 (s, 3H), 1.07 - 0.91 (m, 2H), 0.73 (s, 9H), -0.05 (s, 6H).

[0320] Step 2. 7-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-5-iodo-3-(4-(methoxymethoxy)-6-methyl-2,3-dihydrobenzofuran-5-yl)-7H-pyrrolo[2,3-c]pyridazine (11.2 mg, 0.018 mmol) was dissolved in 1:2 HCl (12 M, aq.):MeOH and stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the crude residue was purified by C18 reverse-phase preparative HPLC using formic acid as a modifier and eluting with ACN:water. After reverse phase purification, the solvent was removed to give 5-(7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-c]pyridazin-3-yl)-6-methylbenzofuran-4-ol (7.9 mg, 0.0166 mmol, 94%). MS m / z 478.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.83 (s, 1H), 8.21 (s, 1H), 6.43 (s, 1H), 5.16 - 5.01 (m, 1H), 4.72 - 4.59 (m, 2H), 3.24 - 3.15 (m, 2H), 2.91 - 2.80 (m, 2H), 2.80 - 2.71 (m, 2H), 2.10 (s, 3H), 1.52 (s, 3H). No OH peak was observed.

[0321] Example 3. Preparation of (R)-2-(4-cyclopropyl-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (III-1)

[0322] [ka] Step 1: To a solution of 3,6-dichloro-4-cyclopropyl-5-(phenylsulfonyl)pyridazine (410 mg, 1.5 mmol) in dioxane (6.0 mL) was added (R)-1-methylpiperidin-3-amine (209 mg, 1.83 mmol) and potassium carbonate (274 mg, 2 mmol). The reaction mixture was stirred at 60° C. for 2 hours. Upon completion, the mixture was filtered, and the filtrate was diluted with water (20 mL) and extracted with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and reduced under reduced pressure to give (R)-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)-4-(phenylsulfonyl)pyridazin-3-amine (415 mg, 80% yield) as an orange oil. The crude material was used in the next step without further purification. MS m / z 345.0, 347.0 [M+H] + .

[0323] Step 2: To a solution of (R)-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)-4-(phenylsulfonyl)pyridazin-3-amine (415 mg, 1.2 mmol) in DMSO (0.5 mL) was added sodium azide (140 mg, 2.2 mmol). The reaction was stirred at 80° C. for 2 hours. Upon completion, the reaction was diluted with water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (R)-4-azido-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (200 mg, 58% yield) as a brown oil. The crude material was used in the next step without further purification. MS m / z 308.0, 310.0 [M+H]+ .

[0324] Step 3: To a solution of (R)-4-azido-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (100 mg, 0.32 mmol) in CHCl (0.8 mL) and AcOH (0.2 mL) was added zinc (60 mg, 0.92 mmol) at 0° C. The reaction was stirred at this temperature for 2 h. Upon completion, the mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give (R)-4-azido-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (60 mg, 63% yield) as a yellow oil. The crude material was used in the next step without further purification. MS m / z 282.1, 284.1 [M+H] + .

[0325] Step 4: To a solution of (R)-4-azido-6-chloro-5-cyclopropyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (60 mg, 0.21 mmol) in triethyl orthoformate (700 μL, 4.2 mmol) was added hydrochloric acid (100 μL, 0.02 mmol). The mixture was heated at 100 °C for 24 h. Upon completion, the reaction was diluted with dichloromethane, washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography eluting with a gradient of CHCl / MeOH / NHOH (0–30% MeOH / NHOH) to afford 3-chloro-4-cyclopropyl-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine as a yellow solid (60 mg, 95% yield). MS m / z 292.1, 294.1 [M+H] + .

[0326] Step 5:To a screw-cap vial was added 3-chloro-4-cyclopropyl-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine (30 mg, 0.1 mmol), XPhos Pd-G3 (9 mg, 0.01 mmol), and 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (40 mg, 0.12 mmol). The mixture was degassed by purging with Ar for 15 minutes, after which 1,4-dioxane (0.5 mL) and a 2 M solution of potassium carbonate (150 μL, 0.3 mmol) were added. The mixture was stirred at 110° C. for 2 hours. Upon completion, the reaction was concentrated, loaded directly onto a precolumn, and purified by flash silica gel column chromatography eluting with a gradient of CHCl / MeOH / NHOH (0-30% MeOH / NHOH) to afford 4-cyclopropyl-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine (28 mg, 51% yield) as a yellow oil. MS m / z 462.3 [M+H] + .

[0327] Step 6:4-Cyclopropyl-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine (28 mg, 0.06 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (0.5 mL) and stirred for 2 hours at room temperature. Upon completion, the reaction was diluted with dichloromethane and sodium bicarbonate was added. The solution was stirred for 10 minutes before being extracted with dichloromethane. The combined organic portions were washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH / NHOH (0-30% MeOH / NHOH) to give (R)-2-(4-cyclopropyl-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (12 mg, 53% yield). MS m / z 418.1 [M+H] + ; 1 H NMR (500 MHz, methanol-d₄) δ: 8.81 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.29 (s, 1H), 5.17 (m, 1H), 3.96 (m, 1H), 3.68 (m, 2H), 3.17 (m, 1H), 3.01 (s, 3H), 2.59–2.35 (m, 2H), 2.27 (m, 1H), 2.07 (m, 1H), 1.87 (d, J = 4.7 Hz, 3H), 1.21 (h, J = 4.8 Hz, 2H); 1H absent (OH).

[0328] Using the procedures described in Example 3 above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0329] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12] [Table 8-13]

[0330] Example 3A. Preparation of 2-(4-methoxy-7-((R)-1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (IIIA-1)

[0331] [ka]

[0332] Step 1:To a solution of 6-chloro-N3-[(3R)-1-methyl-3-piperidyl]pyridazine-3,4-diamine (483 mg, 2.00 mmol) in acetonitrile (2.0 mL) was added sodium acetate (246 mg, 3.0 mmol) and bromine (0.10 mL, 2.0 mmol) dropwise with stirring. The mixture was heated to 80 °C for 1 h until LCMS analysis indicated completion. The reaction was cooled to room temperature, diluted with dichloromethane, and washed with sodium bicarbonate and water. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Diethyl ether (10 mL) was added to the brown oily residue and stirred until a precipitate formed. The solid was filtered, washed with diethyl ether, and dried to give (R)-5-bromo-6-chloro-N3-(1-methylpiperidin-3-yl)pyridazine-3,4-diamine as a light brown solid (123 mg, 19% yield). MS m / z 322.0, 323.9 [M+H] + .

[0333] Step 2: A solution of 5-bromo-6-chloro-N3-[(3R)-1-methyl-3-piperidyl]pyridazine-3,4-diamine (123 mg, 0.384 mmol) in triethyl orthoformate (1.3 mL, 7.67 mmol) was stirred at 120 °C for 24 h. Upon completion, the reaction was cooled to room temperature, loaded directly onto a silica gel precolumn, and purified by flash column chromatography eluting with a gradient of CHCl / MeOH (0 to 30% MeOH) to afford (R)-4-bromo-3-chloro-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine as a brown solid (35 mg, 27% yield). MS m / z 331.9, 333.9 [M+H] + .

[0334] Step 3:To a solution of 4-bromo-3-chloro-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazine (34 mg, 0.1 mmol) in 1,4-dioxane was added RuPhos-Pd-G3 (1.6 mg, 0.002 mmol), sodium tert-butoxide (14 mg, 0.14 mmol), and methanol (8 μL, 0.20 mmol). The reaction was degassed by purging with argon and heated to 60° C. for 4 h until LCMS indicated completion. The mixture was loaded directly onto a solid silica precolumn and purified by flash column chromatography eluting with a gradient of CHCl / MeOH (0-30% MeOH) to give (R)-3-chloro-4-methoxy-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine as a light brown solid (17 mg, 58% yield). MS m / z 282.1, 284.0 [M+H + .

[0335] Step 4: To a screw-cap vial was added 3-chloro-4-methoxy-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazine (17 mg, 0.06 mmol), XPhos-Pd-G3 (5.1 mg, 0.006 mmol), and 2-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 mg, 0.07 mmol). The vial was degassed with Ar purging for 15 min. 1,4-Dioxane (0.5 mL) and potassium carbonate (2.0 M in water, 0.4 mL, 0.2 mmol) were added, and the mixture was heated to 90 °C for 1 h. Upon completion, the reaction was cooled to room temperature, loaded directly onto a solid silica precolumn cartridge, and purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-30% MeOH) to give 4-methoxy-3-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7-((R)-1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine (15 mg, 53% yield). MS m / z 466.7 [M+H] + .

[0336] Step 5: To a solution of 4-methoxy-3-[2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl]-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazine (15 mg, 0.032 mmol) in 1,4-dioxane (0.5 mL) was added HCl (0.081 mL, 0.32 mmol, 4.0 M in dioxane). The reaction was stirred at room temperature for 1 hour. Upon completion, the reaction was diluted with CHCl, quenched with aqueous sodium bicarbonate (10 mL), and extracted with CHCl (3 × 10 mL). The combined organic portions were washed with water, brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-30% MeOH) to afford 2-(4-methoxy-7-((R)-1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol as a yellow solid (7 mg, 52% yield). MS m / z 422.3 [M+H] + ; 1 H NMR (500 MHz, methanol-d4) δ: 8.65 (s, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 5.18 (d, J = 10.2 Hz, 1H), 4.54 (s, 3H), 3.78 - 3.70 (m, 1H), 3.58 (d, J = 14.6 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.06 - 2.93 (m, 1H), 2.82 (s, 3H), 2.46 (qd, J = 11.9, 3.3 Hz, 1H), 2.40 - 2.29 (m, 1H), 2.15 (d, J = 15.1 Hz, 2H), 2.06 (s, 3H); 1H not recognized (OH).

[0337] Using the procedure described in Example 3A above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0338] [Table 9]

[0339] Example 3B. Preparation of (R)-5-(4-(difluoromethyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)benzofuran-4-ol (IIIB-1)

[0340] [ka]

[0341] Steps 1 and 2.A solution of tert-butyl (R)-3-(3-chloro-4-methyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (50.0 mg, 0.142 mmol) in N,N-dimethylformamide dimethyl acetal (1.0 mL) was heated at 120 °C for 24 h. Upon completion, the reaction mixture was cooled to room temperature and partitioned between water and CHCl. ​​The combined organic portions were dried over NaSO and evaporated to dryness. The resulting crude (R,E)-2-(3-chloro-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-4-yl)-N,N-dimethylethen-1-amine was dissolved in THF (1.0 mL) and a solution of sodium periodate (91.2 mg, 0.43 mmol) in water (1.0 mL) was then added. The reaction mixture was stirred at room temperature for 2 hours. Upon completion, the reaction was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-20% MeOH) to give tert-butyl (R)-3-(3-chloro-4-formyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (43.1 mg, 83% yield over two steps). MS m / z 384.2, 386.1 [M+HO] + .

[0342] Step 3.A solution of tert-butyl (R)-3-(3-chloro-4-formyl-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (43.1 mg, 0.118 mmol) in dichloromethane (1.2 mL) was cooled down to 0 °C, and diethylaminosulfur trifluoride (47.5 mg, 0.039 mL, 0.295 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes. After all starting material was consumed, the solution was loaded directly onto a silica gel precolumn and purified by silica gel flash column chromatography eluting with a gradient of hexane / EtOAc (50-100% EtOAc) to give tert-butyl (R)-3-(3-chloro-4-(difluoromethyl)-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (20.3 mg, 44% yield) as a clear oil. MS m / z 388.1, 390.0 [M+H] + .

[0343] Step 4.To a dry crew-cap vial was added tert-butyl (R)-3-(3-chloro-4-(difluoromethyl)-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (20.3 mg, 0.052 mmol), 2-[4-(methoxymethoxy)benzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23.5 mg, 0.077 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (4.4 mg, 0.0052 mmol), and potassium carbonate (21.4 mg, 0.16 mmol). The mixture was degassed by purging with nitrogen for 15 minutes before adding 1,4 dioxane (0.75 mL) and water (0.25 mL). The reaction vessel was evacuated and backflushed with nitrogen (three times), and the mixture was heated at 80 °C for 16 hours. Upon completion, the mixture was partitioned between EtOAc and water. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-10% MeOH) to give tert-butyl (R)-3-(4-(difluoromethyl)-3-(4-(methoxymethoxy)benzofuran-5-yl)-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (27.0 mg, 99% yield). M / S m / z 530.2 [M+H] + .

[0344] Steps 5 and 6To a vial containing tert-butyl (R)-3-(4-(difluoromethyl)-3-(4-(methoxymethoxy)benzofuran-5-yl)-7H-imidazo[4,5-c]pyridazin-7-yl)piperidine-1-carboxylate (27.0 mg, 0.0525 mmol) was added 4 N HCl in dioxane (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was partitioned between CHCl and aqueous NaHCO. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under pressure to give crude (R)-5-(4-(difluoromethyl)-7-(piperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)benzofuran-4-ol as a brown oil. The crude product was then dissolved in CHCl (1.0 mL) and MeOH (0.25 mL), and the reaction mixture was cooled to 0° C. 37% aqueous formaldehyde (0.12 mL, 1.57 mmol) was then added. The mixture was stirred for 3 minutes before sodium triacetoxyborohydride (22.3 mg, 0.105 mmol) was added in one portion. The mixture was stirred at room temperature for 10 minutes. Upon completion, the reaction was quenched with saturated aqueous NaHCO (5.0 mL). The resulting mixture was extracted with CHCl (3×20 mL). The organic portions were combined, dried over NaSO, and evaporated to dryness. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-10% MeOH) to give (R)-5-(4-(difluoromethyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)benzofuran-4-ol (6.7 mg, 32% yield over two steps) as a pale yellow solid. MS m / z 400.2 [M+H] + ; 1H NMR (500 MHz, methanol-d4) δ: 9.05 (s, 1H), 7.76 (s, 1H), 7.30 (dd, J = 8.5, 2.6 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.07 (s, 1H), 6.86 (t, J = 52.8 Hz, 1H), 5.16 - 5.04 (m, 1H), 3.25 - 3.20 (m, 1H), 2.93 - 2.76 (m, 2H), 2.46 - 2.35 (m, 4H), 2.32 - 2.20 (m, 2H), 2.00 - 1.90 (m, 1H), 1.90 - 1.79 (m, 1H); 1H is not recognized (OH).

[0345] Using the procedure described in Example 3B above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0346] [Table 10]

[0347] Example 3C. Preparation of 2-(4-(1-hydroxyethyl)-7-((R)-1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (IIIC-1)

[0348] [ka] Step 1.To a screw-cap vial was added 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (281 mg, 0.85 mmol), (R)-3-chloro-4-methyl-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine (150 mg, 0.56 mmol), XPhos Pd G3 (48 mg, 0.056 mmol), and potassium carbonate (234 mg, 1.7 mmol). The vial was evacuated and backfilled with argon three times. 1,4-Dioxane (3.0 mL) and water (1.0 mL) were added, and the reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature and partitioned between water and EtOAc. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-20% MeOH) to give (R)-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methyl-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine (229 mg, 93% yield) as a light brown foam. MS m / z 436.2 [M+H] + .

[0349] Step 2.A solution of (R)-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methyl-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine (229 mg, 0.53 mmol) and N,N-dimethylformamide dimethyl acetal (0.35 mL, 2.63 mmol) in N,N-dimethylformamide (DMF) (0.50 mL) was heated at 135° C. for 48 h. Upon completion, the solvent was evaporated. The residue was partitioned between water and EtOAc. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide crude (R,E)-2-(3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-4-yl)-N,N-dimethylethen-1-amine, which was used in the next step without further purification.

[0350] Step 3. The crude product from Step 2 was dissolved in MeOH (2.0 mL) and water (1.0 mL). Sodium periodate (338 mg, 1.58 mmol) was added, and the solution was stirred at room temperature for 5 h, at which point the formation of a precipitate was observed. The solution was diluted with water, and the resulting aqueous solution was extracted with CHCl (3 × 20 mL). The combined organic portions were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0–20% MeOH) to afford (R)-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine-4-carbaldehyde (104 mg, 44% yield) as a brown solid. MS m / z 482.2 [M+CHOH+H] + .

[0351] Steps 4 and 5.A solution of (R)-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine-4-carbaldehyde (15.0 mg, 0.0334 mmol) in anhydrous tetrahydrofuran (0.33 mL) was stirred at −78° C. under a nitrogen atmosphere. A solution of 3.0 M methylmagnesium bromide (0.012 mL, 0.0367 mmol) in diethyl ether was then added dropwise. The mixture was stirred at room temperature for 30 minutes. After all starting material was consumed, 12 N aqueous HCl (1.0 mL, 12.0 mmol) was added. After stirring the mixture for an additional 30 minutes, water was added to dilute the mixture. The resulting aqueous solution was neutralized with solid NaHCO and subsequently extracted with CHCl (3×15 mL). The combined organic layers were dried over NaSO and evaporated to dryness under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-20% MeOH) to give 2-(4-(1-hydroxyethyl)-7-((R)-1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (8 mg, 56% yield) as a light brown solid. MS m / z 422.2 [M+H] + ; 1 H NMR (500 MHz, methanol-d4) δ: 8.91 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.25 (s, 1H), 5.10 - 5.00 (m, 1H), 4.94 (q, J = 6.9 Hz, 1H), 3.24 (s, 1H), 2.93 - 2.79 (m, 2H), 2.49 - 2.35 (m, 4H), 2.32 - 2.20 (m, 2H), 2.02 - 1.92 (m, 1H), 1.92 - 1.81 (m, 1H), 1.69 (d, J = 6.6 Hz, 3H); two H's are not allowed (two OH's). Example 3D. Preparation of (R)-2-(4-(hydroxymethyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (IIID-1)

[0352] [ka] Steps 1 and 2. To a solution of (R)-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine-4-carbaldehyde (9.0 mg, 0.0200 mmol, prepared according to Example 3c) in MeOH (1.0 mL) was added sodium borohydride (0.76 mg, 0.02 mmol). The mixture was stirred for 30 minutes, after which a 12 N solution of hydrochloric acid (1.0 mL) was added. After stirring for an additional 30 minutes, the aqueous solution was neutralized with saturated NaHCO solution. The resulting solution was extracted with CHCl (3×15 mL). The combined organic portions were dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-20% MeOH) to give (R)-2-(4-(hydroxymethyl)-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol (4.5 mg, 55% yield) as a light brown solid. MS m / z 408.2 [M+H] + ; 1H NMR (500 MHz, methanol-d₄) δ: 8.85 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 5.20–5.08 (m, 1H), 4.94 (s, 2H), 3.82–3.58 (m, 1H), 2.79 (s, 3H), 2.56–2.41 (m, 1H), 2.41–2.31 (m, 1H), 2.22–2.07 (m, 1H), 2.06–1.91 (m, 1H); five Hs absent (three CH signals overlapping with the solvent peak and two OH). Example 3E. Preparation of 5-chloro-3-(7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (IIIE-1)

[0353] [ka]

[0354] Step 1.To a solution of 2-(2-(methoxymethoxy)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (166.0 mg, 0.572 mmol, 1.5 equiv.) in 1,4-dioxane and HO was added (R)-3-chloro-4-methyl-7-(1-methylpiperidin-3-yl)-7H-imidazo[4,5-c]pyridazine (140.0 mg, 0.381 mmol, 1.0 equiv.), XPhos Pd G (32.83 mg, 0.038 mmol, 0.1 equiv.), and KCO (158.2 mg, 1.14 mmol, 1.0 equiv.) at room temperature. N was bubbled through the mixture. The sealed vial was irradiated in the microwave at 80°C for 2 h. Upon completion, the reaction was cooled to room temperature, filtered through a pad of Celite, and rinsed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE:EA = 1:0 to 20:1) to afford 7-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-(2-(methoxymethoxy)bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazine (170 mg, 0.344 mmol, 90.07% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 4.94 (s, 2H), 4.85 (t, J = 8.4 Hz, 1H), 3.25 (d, J = 3.6 Hz, 2H), 3.17 (s, 3H), 3.10 (t, J = 4.0 Hz, 2H), 2.81 - 2.75 (m, 2H), 2.56 (d, J = 8.8 Hz, 3H), 2.39 (s, 3H), 1.43 (s, 3H), 0.78 (s, 9H), 0.00 (s, 6H).

[0355] Step 2.A solution of 7-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-3-(2-(methoxymethoxy)bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-4-methyl-7H-imidazo[4,5-c]pyridazine (180 mg, 0.363 mmol, 1.0 equiv) in 2 N HCl in EtOAc was stirred at room temperature for 1 h. Upon completion, the resulting precipitate was filtered off and rinsed with EtOAc (5 mL). The solid was dried in vacuo to give 3-(7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (120 mg, 0.356 mmol, 98.07% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 14.33 (s, 1H), 13.57 (s, 1H), 11.81 (d, J = 7.2 Hz, 1H), 11.45 (d, J = 7.2 Hz, 1H), 10.11 (s, 1H), 7.87 (d, J = 8.0 Hz, 4H), 7.48 (dd, J = 22.0, 9.6 Hz, 4H), 6.17 (s, 3H), 5.82 (s, 1H), 5.60 (d, J = 4.8 Hz, 2H).

[0356] Step 3.To a solution of 3-(7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (70 mg, 0.28 mmol, 1.0 equiv.) in DCM was added NCS (28 mg, 0.21 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 30 min, then quenched with HO and extracted with DCM. The organic layer was washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with (PE / EA = 100:0 to 20:1) to give 5-chloro-3-(7-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-4-methyl-7H-imidazo[4,5-c]pyridazin-3-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (5.0 mg, 0.013 mmol, 6.8% yield) as a white solid. 1 H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 7.08 (s, 1H), 4.97 - 4.95 (m, 1H), 3.17 (s, 4H), 2.89 - 2.84 (m, 4H), 2.52 (s, 3H), 1.51 (s, 3H).

[0357] Using the procedures described in Example 3E above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0358] [Table 11]

[0359] Example 4. Preparation of (R)-2-(3-(1-methylpiperidin-3-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)-5-(trifluoromethyl)phenol (IV-1)

[0360] [ka] Step 1: To a solution of 3,6-dichloro-4-(methylsulfonyl)pyridazine (700 mg, 3.0 mmol) in THF (6 mL) was added tert-butyl(3R)-1-methylpiperidin-3-amine (451 mg, 3.95 mmol) and potassium carbonate (592 mg, 9.1 mmol). The reaction mixture was stirred at 50 °C for 2 h. Upon completion, it was filtered, and the filtrate was diluted with water (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient of CHCl / MeOH (0 to 30% MeOH) to afford (R)-6-chloro-N-(1-methylpiperidin-3-yl)-4-(methylsulfonyl)pyridazin-3-amine (734 mg, 80% yield) as a yellow oil. MS m / z 305.3, 307.1 [M+H] + .

[0361] Step 2: To a solution of (R)-6-chloro-N-(1-methylpiperidin-3-yl)-4-(methylsulfonyl)pyridazin-3-amine (734 mg, 2.4 mmol) in dimethyl sulfoxide (5 mL) was added sodium azide (250 mg, 3.8 mmol). The reaction mixture was stirred at 80° C. for 2 hours. The mixture was filtered, and the filtrate was diluted with water (20 mL) and extracted with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give (R)-4-azido-6-chloro-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (290 mg, 42% yield) as a yellow oil. The crude material was used in the next step without further purification. MS m / z 268.3, 270.3 [M+H] + .

[0362] Step 3:To a solution of (R)-4-azido-6-chloro-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (250 mg, 0.93 mmol) in CHCl (3 mL) and AcOH (1 mL) was added zinc (195 mg, 3 mmol) at 0° C. The reaction was stirred at this temperature for 2 h. Upon completion, the mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give (R)-6-chloro-N-(1-methylpiperidin-3-yl)pyridazine-3,4-diamine (120 mg, 55% yield) as a yellow oil. The crude material was used in the next step without further purification. MS m / z 242.2, 244.2 [M+H] + .

[0363] Step 4: To a solution of (R)-6-chloro-N3-(1-methylpiperidin-3-yl)pyridazine-3,4-diamine (170 mg, 0.7 mmol) in acetic acid (0.5 mL) and water (1 mL) was added sodium nitrite (68 mg, 1 mmol, 1.5 equiv.) at 0° C. The reaction was allowed to warm to room temperature and stirred for 2 hours. Upon completion, the reaction was quenched with sodium bicarbonate and extracted with dichloromethane. The combined organic portions were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of CHCl / MeOH / NHOH (0 to 30% MeOH / NHOH) to give (R)-6-chloro-3-(1-methylpiperidin-3-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (60 mg, 34% yield) as a yellow solid. MS m / z 253.2, 255.2 [M+H] + .

[0364] Step 5:To a solution of (R)-6-chloro-3-(1-methylpiperidin-3-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (170 mg, 0.76 mmol) in acetonitrile (1.5 mL) was added silver nitrate (60 mg, 0.35 mmol), cyclopropanecarboxylic acid (301 μL, 3.8 mmol), and sulfuric acid (176 μL, 2 mmol). The resulting mixture was heated to 70° C., and then an aqueous solution of ammonium persulfate (638 mg, 2.8 mmol) in water (5 mL) was added dropwise over 5 minutes. The reaction was cooled to room temperature and stirred for 1 hour. Upon completion, the reaction was diluted with water and sodium bicarbonate was added dropwise until a pH of 7 was achieved. The aqueous solution was extracted with ethyl acetate (3 × 20 mL), and the combined organic portions were washed with water, brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH / NHOH (0–30% MeOH / NHOH) to afford (R)-6-chloro-7-cyclopropyl-3-(1-methylpiperidin-3-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (80 mg, 40% yield) as a yellow oil. MS m / z 293.2, 295.2 [M+H] + .

[0365] Step 6:To a screw-cap vial was added (R)-6-chloro-7-cyclopropyl-3-(1-methylpiperidin-3-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (80 mg, 0.26 mmol), XPhos Pd G3 (25 mg, 0.028 mmol), and 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (107 mg, 0.32 mmol). The vial was degassed with Ar purging for 15 min. 1,4-Dioxane (1 mL) and potassium carbonate (2.0 M aqueous solution, 0.4 mL, 0.2 mmol) were added, and the mixture was heated at 90 °C for 4 h. Upon completion, the reaction was loaded directly onto a precolumn and purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-30% MeOH) to afford (R)-7-cyclopropyl-6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-3-(1-methylpiperidin-3-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (62 mg, 48% yield) as a yellow oil. MS m / z 463.6 [M+H] + .

[0366] Step 7:A solution of (R)-6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-3-(1-methylpiperidin-3-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine (62 mg, 0.13 mmol) in trifluoroacetic acid (0.5 mL) was stirred at room temperature for 1 hour. Upon completion, the reaction was diluted with dichloromethane, sodium bicarbonate (10 mL) was added, and the resulting mixture was stirred for 10 minutes before the aqueous layer was extracted with dichloromethane. The combined organic portions were washed with water, brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-30% MeOH) to give (R)-2-(3-(1-methylpiperidin-3-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)-5-(trifluoromethyl)phenol (25 mg, 50% yield) as a white solid. MS m / z 419.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 7.57 (dd, J = 11.4, 7.7 Hz, 1H), 7.33 (dd, J = 8.0, 1.8 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 5.24 (tt, J = 10.5, 4.2 Hz, 1H), 3.24 - 3.15 (m, 1H), 3.17 - 3.06 (m, 1H), 2.81 (d, J = 10.8 Hz, 1H), 2.66 (t, J = 10.4 Hz, 1H), 2.27 (d, J = 7.0 Hz, 4H), 2.21 (dd, J = 9.9, 5.6 Hz, 1H), 2.09 (td, J = 11.3, 2.9 Hz, 1H), 1.92 (dq, J = 13.9, 3.7 Hz, 1H), 1.84 - 1.69 (m, 3H), 1.36 - 1.22 (m, 2H).

[0367] Using the procedures described in Example 4 above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0368] [Table 12] Example 5. Preparation of 3,5-dimethyl-2-(7-(1-methylpiperidin-3-yl)-5H-pyrrolo[3,2-c]pyridazin-3-yl)phenol (V-1)

[0369] [ka]

[0370] Step 1: To a screw-cap vial was added tert-butyl (3,6-dichloropyridazin-4-yl)carbamate (5.0 g, 18.9 mmol), CuI (180 mg, 0.94 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.8 g, 1.51 mmol). The reaction was degassed with Ar purging for 15 minutes. EtN (25 mL) and THF (75 mL) were added, followed by trimethylsilylacetylene (5.5 mL, 37.8 mmol). The reaction was stirred at room temperature for 1.5 hours. Upon completion, it was concentrated, dissolved in EtOAc, and washed with water and brine. The combined organic portions were dried over sodium sulfate, concentrated, and purified by flash column chromatography eluting with a gradient of EtOAc / hexanes (0-30% EtOAc) to give tert-butyl n-[6-chloro-3-(2-trimethylsilylethynyl)pyridazin-4-yl]carbamate (3.4 g, 55% yield). MS m / z 326.2, 328.2 [M+H] + .

[0371] Step 2:To a solution of tert-butyl N-[6-chloro-3-(2-trimethylsilylethynyl)pyridazin-4-yl]carbamate (3.95 g, 12.1 mmol) in DMF (30 mL) was added potassium carbonate (3.35 g, 24.2 mmol), and the mixture was stirred at 60 °C for 45 min. Upon completion, the reaction was quenched with brine and extracted with EtOAc. The combined organic portions were washed with brine, dried over sodium sulfate, concentrated, and purified by flash column chromatography eluting with a gradient of EtOAc / hexanes (0-30% EtOAc) to give tert-butyl 3-chloropyrrolo[3,2-c]pyridazine-5-carboxylate (990 mg, 32.2% yield). MS m / z 254.1, 256.1 [M+H] + .

[0372] Step 3: To a screw-cap vial was added tert-butyl 3-chloropyrrolo[3,2-c]pyridazine-5-carboxylate (0.99 g, 3.9 mmol), (2-methoxy-4,6-dimethyl-phenyl)boronic acid (0.91 g, 5.1 mmol), K2CO3 (1.61 g, 11.7 mmol), and XPhos Pd G3 (0.33 g, 0.39 mmol). The reaction was degassed with an Ar purge for 15 minutes, and dioxane (10 mL) and water (2 mL) were added. The reaction mixture was stirred at 90 °C for 6 hours. Upon completion, the reaction was cooled to room temperature and partitioned between EtOAc and brine. The combined organic portions were washed with brine, dried over sodium sulfate, concentrated, and purified by flash column chromatography eluting with a gradient of EtOAc / hexanes (0-100% EtOAc) to give tert-butyl 3-(2-methoxy-4,6-dimethyl-phenyl)pyrrolo[3,2-c]pyridazine-5-carboxylate (1.11 g, 80.5% yield). MS m / z 354.4 [M+H] + .

[0373] Step 4:To a solution of tert-butyl 3-(2-methoxy-4,6-dimethyl-phenyl)pyrrolo[3,2-c]pyridazine-5-carboxylate (1.11 g, 3.14 mmol) in CHCl (2 mL) was added 4.0 M HCl in dioxane (31.4 mL), and the resulting mixture was stirred at 50° C. for 4 h. The crude material was dissolved in MeOH, and NaHCO was added to neutralize the mixture to pH 7. The solid was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude 3-(2-methoxy-4,6-dimethyl-phenyl)-5H-pyrrolo[3,2-c]pyridazine (790 mg, 3.1 mmol) was dissolved in DMF (15 mL), and the solution was cooled to 0° C. NBS (0.61 g, 3.43 mmol) was added portionwise, and the resulting mixture was stirred for 10 min. DIPEA (5.4 mL, 31.0 mmol) and tert-butoxycarbonyl tert-butyl carbonate (2.70 g, 12.4 mmol) were then added. The resulting mixture was stirred at 0 °C for 30 minutes. Upon completion, the reaction mixture was partitioned between EtOAc and brine. The combined organic portions were washed with brine, dried over sodium sulfate, concentrated, and purified by flash column chromatography eluting with a gradient of EtOAc / hexanes (0 to 100% EtOAc) to give tert-butyl 7-bromo-3-(2-methoxy-4,6-dimethyl-phenyl)pyrrolo[3,2-c]pyridazine-5-carboxylate (185 mg, 13.8% yield). MS m / z 432.1, 434.1 [M+H] + .

[0374] Step 5:To a screw-cap vial was added tert-butyl 7-bromo-3-(2-methoxy-4,6-dimethyl-phenyl)pyrrolo[3,2-c]pyridazine-5-carboxylate (240 mg, 0.55 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (0.16 g, 0.72 mmol), KCO (0.23 g, 1.66 mmol), and XPhos Pd G (47 mg, 0.055 mmol). The reaction was degassed with an Ar purge for 15 minutes, and dioxane (4 mL) and water (1 mL) were added. The reaction mixture was stirred at 90 °C for 6 hours. Upon completion, the reaction was cooled to room temperature and partitioned between EtOAc and brine. The combined organic portions were washed with brine, dried over sodium sulfate, concentrated, and purified by flash column chromatography eluting with a gradient of CHCl / MeOH (0-20% MeOH) to give tert-butyl 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)pyrrolo[3,2-c]pyridazine-5-carboxylate (220 mg, 88% yield). MS m / z 449.4 [M+H] + .

[0375] Step 6:To a solution of tert-butyl 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)pyrrolo[3,2-c]pyridazine-5-carboxylate (240 mg, 0.53 mmol) in methanol (11 mL) and EtOAc (1.0 mL) was added Pd / C (0.056 g, 0.053 mmol) and Pd(OH) / C (0.038 g, 0.053 mmol). The resulting mixture was subjected to 1 atm of H (balloon) and stirred at 55 °C for 5 h. Upon completion, the solid was filtered through Celite and rinsed with EtOAc and MeOH. The solvent was removed under reduced pressure to give crude tert-butyl 3-(2-methoxy-4,6-dimethylphenyl)-7-(1-methylpiperidin-3-yl)-5H-pyrrolo[3,2-c]pyridazine-5-carboxylate (240 mg, 100% yield) as an orange oil. The crude material was used in the next step without further purification. MS m / z 451.3 [M+H] + .

[0376] Step 7: tert-Butyl 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl)pyrrolo[3,2-c]pyridazine-5-carboxylate (240 mg, 0.53 mmol) was dissolved in TFA (5.0 mL) and the mixture was heated at 40° C. for 20 minutes. The solvent was removed under reduced pressure to give crude 3-(2-methoxy-4,6-dimethylphenyl)-7-(1-methylpiperidin-3-yl)-5H-pyrrolo[3,2-c]pyridazine (180 mg, 97% yield). The crude material was used in the next step without further purification. MS m / z 351.4 [M+H] + .

[0377] Step 8:A mixture of 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl)-5H-pyrrolo[3,2-c]pyridazine (180 mg, 0.52 mmol), ethanethiol sodium salt (0.39 g, 4.19 mmol), and DMF (1.1 mL) was stirred at 130 °C for 4 h. Upon completion, the reaction was cooled to room temperature, concentrated, and purified by flash elution with a gradient of CHCl / MeOH / NHOH (0 to 30% MeOH / NHOH) to give 3,5-dimethyl-2-[7-(1-methyl-3-piperidyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]phenol (110 mg, 55% yield). MS m / z 337.1 [M+H] + ; 1 H NMR (methanol-d₄) δ: 8.48 (s, 1H, formic acid), 7.54-7.67 (m, 1H), 7.49 (s, 1H), 6.59 (s, 1H), 6.54 (s, 1H), 3.46-3.70 (m, 2H), 2.92-3.07 (m, 1H), 2.72-2.84 (m, 1H), 2.65 (s, 3H), 2.50-2.56 (m, 3H), 2.10-2.20 (m, 1H), 1.95 (s, 3H), 1.80-1.90 (m, 2H); four Hs absent (NH, OH, and two CH overlap with solvent peaks).

[0378] Using the procedures described in Example 5 above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0379] [Table 13] Example 6. Preparation of 3,5-dimethyl-2-(7-(1-methylpiperidin-3-yl)thieno[3,2-c]pyridazin-3-yl)phenol (VI-1)

[0380] [ka]

[0381] Step 1: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (10 g, 48.3 mmol) in ACN (96 mL) was added dropwise a solution of methyl 2-sulfanylacetate (5.2 g, 49.2 mmol) in ACN (96 mL) at 0 °C, followed by the slow addition of EtN (6.73 mL, 48.3 mmol) at the same temperature. The reaction was stirred at 0 °C for 15 min. An additional amount of EtN (6.73 mL, 48.3 mmol) was added, and the mixture was allowed to warm to room temperature and stirred at room temperature for 3 h. Upon completion, the reaction was quenched with water, and the ACN was evaporated under reduced pressure. The mixture was acidified to pH ∼2 with 1.0 M HCl. During the pH adjustment, the bright yellow solution became colorless, and a white precipitate formed. The precipitate was collected by filtration, washed with water, and dried to give methyl 3-chloro-7-hydroxy-thieno[3,2-c]pyridazine-6-carboxylate (11.6 g, 98% yield). The crude material was used in the next step without further purification. MS m / z 245.0, 247.0 [M+H] + .

[0382] Step 2:To a dry round-bottom flask was added methyl 3-chloro-7-hydroxy-thieno[3,2-c]pyridazine-6-carboxylate (2.0 g, 8.17 mmol), (2-methoxy-4,6-dimethyl-phenyl)boronic acid (1.76 g, 9.80 mmol), K2CO3 (3.38 g, 24.5 mmol), and Pd(dppf)Cl2 (0.63 g, 0.81 mmol). The reaction mixture was degassed with Ar purging for 15 minutes, and then dioxane (60 mL) and water (15 mL) were added. The mixture was heated at 90 °C for 16 hours. Upon completion, the reaction was cooled to room temperature and partitioned between EtOAc and brine. The aqueous portion was extracted with EtOAc (3 times). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with gradient EtOAc / hexane (0-100% EtOAc) to give methyl 7-hydroxy-3-(2-methoxy-4,6-dimethyl-phenyl)thieno[3,2-c]pyridazine-6-carboxylate (1.1 g, 39% yield). MS m / z 345.4 [M+H] + .

[0383] Step 3: A solution of methyl 7-hydroxy-3-(2-methoxy-4,6-dimethyl-phenyl)thieno[3,2-c]pyridazine-6-carboxylate (500 mg, 1.45 mmol) and DIPEA (0.50 mL, 2.90 mmol) in CHCl (14.5 mL) was cooled to 0 °C, and TfO (11.74 mL, 1.0 M in CHCl, 1.74 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 20 min, then warmed to room temperature and partitioned between CHCl and brine. The aqueous portion was extracted with CHCl (3 times). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude methyl 3-(2-methoxy-4,6-dimethylphenyl)-7-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridazine-6-carboxylate (680 mg, 98% yield). The crude material was used in the next step without further purification. MS m / z 477.5 [M+H] + .

[0384] Step 4: To a dry crew-capped vial was added methyl 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(trifluoromethylsulfonyloxy)thieno[3,2-c]pyridazine-6-carboxylate (680 mg, 1.42 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (0.35 g, 1.59 mmol), KCO (0.60 g, 4.34 mmol), and Pd XPhos G3 (0.12 g, 0.14 mmol). The reaction mixture was degassed with an Ar purge for 15 minutes, and then dioxane (10 mL) and water (2.5 mL) were added. The mixture was heated at 90 °C for 16 hours. Upon completion, the reaction was cooled to room temperature and partitioned between EtOAc and brine. The aqueous portion was extracted with EtOAc (3 times). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of EtOAc / hexanes (0-100% EtOAc) to give methyl 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazine-6-carboxylate (500 mg, 81.5% yield). MS m / z 424.5 [M+H] + .

[0385] Step 5:To a solution of methyl 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazine-6-carboxylate (311 mg, 0.73 mmol) in THF (12 mL) and water (1.5 mL) was added LiOH (0.35 g, 14.6 mmol), and the resulting mixture was stirred at room temperature for 72 hours. The THF was evaporated under reduced pressure, and the aqueous portion was extracted with CHCl (3 times). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0-30% MeOH) to give 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazine-6-carboxylic acid (130 mg, 43% yield). MS m / z 410.2 [M+H] + .

[0386] Step 6: To a solution of 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazine-6-carboxylic acid (130 mg, 0.31 mmol) in DMSO (1.5 mL) was added AgCO (0.018 g, 0.063 mmol) and 2 drops of AcOH. The reaction was heated at 120 °C for 4 h, then cooled to room temperature and purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0 to 30% MeOH) to give 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazine (110 mg, 96% yield). MS m / z 366.6[M+H] + .

[0387] Step 7:To a solution of 3-(2-methoxy-4,6-dimethylphenyl)-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazine (110 mg, 0.30 mmol) in methanol (8.0 mL) and EtOAc (1.0 mL) was added Pd / C (0.043 g, 0.041 mmol) and Pd(OH) / C (0.028 g, 0.041 mmol). The resulting mixture was subjected to 55 psi of H (Parr shaker) and stirred for 72 h. Upon completion, the solid was filtered through Celite and rinsed with EtOAc and MeOH. The solvent was removed under reduced pressure to give crude 3-(2-methoxy-4,6-dimethylphenyl)-7-(1-methylpiperidin-3-yl)thieno[3,2-c]pyridazine (100 mg, 90% yield). The crude material was used in the next step without further purification. MS m / z 368.5 [M+H] + .

[0388] Step 8: To a solution of 3-(2-methoxy-4,6-dimethyl-phenyl)-7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazine (100 mg, 0.27 mmol) in DMF (2.7 mL) was added ethanethiol sodium salt (0.38 g, 4.08 mmol), and the resulting mixture was stirred at 130 °C for 4 h. Upon completion, the reaction was cooled to room temperature, and the crude material was loaded directly onto a precolumn and purified by silica gel flash column chromatography eluting with a gradient of CHCl / MeOH (0–30% MeOH) to afford 3,5-dimethyl-2-[7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]phenol (45 mg, 47% yield) as a tan solid. MS m / z 354.1 [M+H] + ; 1H NMR (methanol-d₄) δ: 8.56 (br s, 1H, formic acid), 8.44 (s, 1H), 7.82 (s, 1H), 6.60 (s, 1H), 6.55 (s, 1H), 3.64-3.79 (m, 1H), 3.44-3.59 (m, 1H), 3.09-3.16 (m, 1H), 2.60-2.76 (m, 2H), 2.51 (s, 3H), 2.25-2.21 (m, 1H), 2.21 (s, 3H), 1.96 (s, 3H), 1.87-1.93 (m, 1H), 1.71-1.86 (m, 2H); 1H not observed (OH).

[0389] Using the procedures described in Example 6 above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents and reaction conditions to provide a compound, for example, one selected from the following:

[0390] [Table 14-1] [Table 14-2] [Table 14-3] Example 6A: Preparation of 5-(7-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-3-yl)-6-methylbenzofuran-4-ol (VIA-1)

[0391] [ka]

[0392] Step 1:To a solution of methyl 3-chloro-7-hydroxy-thieno[3,2-c]pyridazine-6-carboxylate (11.84 g, 48.39 mmol, prepared according to Example 6) in dioxane / HO (5:1, 95 mL) was added LiOH—HO (12.18 g, 290.37 mmol). The mixture was stirred at 60° C. for 30 hours, then concentrated, and the resulting red mixture was acidified with 3 M HCl to give a tan slurry. The mixture was filtered, and the filtrate was extracted with EtOAc (3×). The combined organic extracts were dried (MgSO), filtered, and the filter cakes were combined. The mixture was concentrated to give a pale yellow solid. MS m / z 230.9, 232.8 [M+H] + .

[0393] Step 2: To a solution of 3-chloro-7-hydroxy-thieno[3,2-c]pyridazine-6-carboxylic acid (10.15 g, 44.01 mmol) in DMSO (88 mL) was added AgCO (2.43 g, 8.80 mmol) and acetic acid (12.6 mL, 220.1 mmol). The reaction was heated to 120 °C for 50 min. After cooling to room temperature, the reaction was poured onto EtOAc / water (4:1), and the mixture was stirred for 10 min and filtered through Celite. The layers of the filtrate were separated, and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO), filtered, and concentrated. The red oil was azeotroped with PhMe to remove AcOH. Purification by chromatography on SiO (EtOAc:hexanes, 5–80%) afforded a yellow solid (3.8 g, 46%, 3 steps). MS m / z 186.9, 188.8 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 10.92 (s, 1H), 8.59 (s, 1H), 7.02 (s, 1H).

[0394] Step 3:3-Chlorothieno[3,2-c]pyridazin-7-ol (2.0 g, 10.72 mmol) in DCM (48 mL) was cooled to 0 °C, and DIPEA (3.71 mL, 21.44 mmol) was added, followed by the dropwise addition of trifluoromethylsulfonyl trifluoromethanesulfonate (11.48 mL, 16.08 mmol, 1.4 M in DCM). The reaction was stirred at 0 °C for 1 h. The reaction was diluted with DCM and washed with cold water and brine. The organic phase was dried (Na SO ), filtered, and concentrated. Purification by chromatography on SiO (EtOAc:hexanes, 5-50%) afforded a gray solid (2.11 g, 62%). MS m / z 318.8, 320.7 [M+H] + .

[0395] Step 4: 3-Chlorothieno[3,2-c]pyridazin-7-yl)trifluoromethanesulfonate (0.15 g, 0.471 mmol), (2-hydroxyphenyl)boronic acid (78 mg, 0.565 mmol), Pd(dppf)Cl2 (34 mg, 0.0471 mmol), and K2CO3 (163 mg, 1.18 mmol) were dissolved in dioxane / HO (5:1, 2.4 mL). The reaction was heated at 90 °C for 1 h, then diluted with EtOAc and washed with water and brine. The organic phase was dried (MgSO4), filtered, and concentrated. Purification by chromatography on SiO2 (EtOAc:hexanes, 0-55%) afforded a yellow solid (0.048 g, 39%). MS m / z 262.9, 264.9 [M+H] + .

[0396] Steps 5 and 6:2-(3-Chlorothieno[3,2-c]pyridazin-7-yl)phenol (0.045 g, 0.171 mmol), 2-[4-(methoxymethoxy)-6-methyl-benzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.082 g, 0.257 mmol), XPhos Pd-G (0.015 g, 0.017 mmol), and KCO (0.21 mL, 0.428 mmol, 2 M solution) were dissolved in dioxane (0.85 mL). The reaction was heated at 90 °C for 1 h. The reaction was diluted with EtOAc and washed with water and brine. The organic phase was dried (MgSO), filtered, and concentrated. Purification by chromatography on SiO (EtOAc:hexanes, 0–50%) afforded a yellow film. MS m / z 419.1[M+H] + The material was dissolved in DCM (1 mL), TFA (0.2 mL) was added, and stirred at room temperature. Upon completion, the reaction was ...

Claims

1. A compound having the structure of formula (I), wherein the form of the compound may be selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers, and isotopically enriched forms thereof. 【Chemistry 1】 (In the formula, X and Y are independently selected from CR′, C(R′)(R′), N, NR″, O, and S; Z is selected from N, C and CH; 【Chemistry 2】 is a single or double bond, R' is H, halogen, C 1-4 Alkyl, deutero-C 1-4 Alkyl, OH, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, halo-C 1-4 Alkoxy, C 1-4 Alkyl-thio, SH and halo-C 1-4 independently selected from alkyl, R'' is H, C 1-4 Alkyl, deutero-C 1-4 Alkyl, C 3-6 Cycloalkyl and halo-C 1-4 independently selected from alkyl, Ring A is 【Transformation 3】 is selected from the group consisting of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 is CR 8 , C(R 8 ) (R 8 ), O, N, NR 9 and S, Rw is OH, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy and halo-C 1-4 alkoxy; R 1 is H, C 1-4 Alkyl, deutero-C 1-4 Alkyl, C 1-4 Alkyl-C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 Heterocycle, halogen or R 3 C optionally substituted with 3-6 cycloalkyl, optionally substituted with halogen 3-6 Heterocycle, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -amino, halo-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, C 3-6 Cycloalkoxy and halo-C 1-4 alkoxy; R 2 is C 3-7 Cycloalkyl, C 1-4 Alkyl-aryl, C 1-4 Alkyl-C 3-7 Cycloalkyl, C 1-4 Alkyl-C 3-7 Heterocycle, C 3-7 heterocycle and aryl, 3-7 The heterocycle is a saturated or partially unsaturated 4- to 8-membered monocyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, and S, and 2 But, R 3 may be substituted with R 3 is C 1-4 Alkyl, deutero-C 1-4 Alkyl, halogen, OH, halo-C 1-4 Alkyl, C-N, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, halo-C 1-4 Alkoxy and hydroxy-C 1-4 independently selected from alkyl, R 4 , R 5 and R 6 is H, C 1-4 Alkyl, deutero-C 1-4 Alkyl, OH, C 1-4 Alkoxy, halo-C 1-4 Alkyl, halo-C 1-4 Alkoxy, halogen, C 1-4 Alkyl-thio, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C 1-4 Alkyl-amino, (C 1-4 alkyl) 2 -amino and CN; R 1 is H, then R 4 But not H, R 7 is H, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, halo-C 1-4 independently selected from alkoxy, halogen, and CN; R 8 is H, C 1-4 Alkyl, halogen and halo-C 1-4 Alkyl, C 1-4 Alkoxy and halo-C 1-4 alkoxy; R 9 is H, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 3-6 cycloalkyl; m is 0, 1 or 2.

2. 2. The compound of claim 1, wherein the compound is a compound of formula (Ia) or a form thereof: 【Chemistry 4】 (In the formula, X and Y are independently selected from CR′, C(R′)(R′); R' is H, halogen, C 1-4 Alkyl, OH, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkyl-thio, CN, SH and halo-C 1-4 independently selected from alkyl, R 1 But H, CH 3 , C.H. 3 CH 2 , cyclopropyl, cyclobutyl, isopropyl, tert-butyl, CF 3 , NHCH 3 , CHF 2 , S.C.H. 3 , OCH 3 and 【Transformation 5】 (selected from

3. 2. The compound of claim 1, wherein the compound is a compound of formula (Ib) or a form thereof: 【Transformation 6】 (In the formula, R 1 But H, CH 3 , C.H. 3 CH 2 , cyclopropyl, cyclobutyl, isopropyl, tert-butyl, CF 3 , NHCH 3 , CHF 2 , S.C.H. 3 , OCH 3 and 【Transformation 7】 (selected from

4. 10. The compound of claim 1, wherein the compound is a compound of formula (Ic) or a form thereof: 【Transformation 8】 (In the formula, Y is selected from CR'; R' is H, C 1-4 Alkyl and halo-C 1-4 independently selected from alkyl, R 1 But H, CH 3 , C.H. 3 CH 2 , cyclopropyl, cyclobutyl, isopropyl, tert-butyl, CF 3 , NHCH 3 , CHF 2 , S.C.H. 3 , OCH 3 and 【Chemistry 9】 (selected from

5. 2. The compound of claim 1, wherein the compound is a compound of formula (Id) or a form thereof: 【Chemistry 10】 (In the formula, R 1 But H, CH 3 , C.H. 3 CH 2 , cyclopropyl, cyclobutyl, isopropyl, tert-butyl, CF 3 , NHCH 3 , CHF 2 , S.C.H. 3 , OCH 3 and 【Chemistry 11】 (selected from

6. 2. The compound of claim 1, wherein the compound is a compound of formula (Ie) or a form thereof: 【Chemistry 12】 (In the formula, X is CR'; R' is H and CH 3 is selected from R 1 But H, CH 3 , C.H. 3 CH 2 , cyclopropyl, cyclobutyl, isopropyl, tert-butyl, CF 3 , NHCH 3 , CHF 2 , S.C.H. 3 , OCH 3 and 【Chemistry 13】 (selected from

7. 2. The compound of claim 1, wherein the compound is a compound of formula (If) or a form thereof: 【Chemistry 14】 (In the formula, Y is CH and CH 2 is selected from 【Chemistry 15】 is a single or double bond, R 1 But H, CH 3 , C.H. 3 CH 2 , cyclopropyl, cyclobutyl, isopropyl, tert-butyl, CF 3 , NHCH 3 , CHF 2 , S.C.H. 3 , OCH 3 and 【Chemistry 16】 (selected from

8. 10. The compound of claim 1, wherein the compound is a compound of formula (Ig) or a form thereof: 【Chemistry 17】 (In the formula, R 1 But H, CH 3 , C.H. 3 CH 2 , cyclopropyl, cyclobutyl, isopropyl, tert-butyl, CF 3 , NHCH 3 , CHF 2 , S.C.H. 3 , OCH 3 and [Chemistry 18] (selected from

9. 10. The compound of claim 1, wherein the compound is a compound of formula (Ih) or a form thereof: 【Chemistry 19】 (In the formula, R 1 But H, CH 3 , C.H. 3 CH 2 , cyclopropyl, cyclobutyl, isopropyl, tert-butyl, CF 3 , NHCH 3 , CHF 2 , S.C.H. 3 , OCH 3 and 【Chemistry 20】 (selected from

10. Ring A is 【Chemistry 21】 is selected from Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 But, CR 8 , C(R 8 ) (R 8 ), O, N, NR 9 and S, Rw is OH, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy and halo-C 1-4 alkoxy; R 4 , R 5 and R 6 But H, CH 3 , C.H. 2 CH 3 , OH, OCH 3 , C.F. 3 , OCF 3 , C.H. 2 CF 3 , OCHF 2 , F, Cl, Br, cyclopropyl, isopropyl, SCH 3 , N(CH 3 ) 2 , CN and 【Chemistry 22】 are independently selected from R 7 But H, OH, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy and halo-C 1-4 independently selected from alkoxy, halogen and CN; R 8 But H, C 1-4 Alkyl, halogen and halo-C 1-4 Alkyl, C 1-4 Alkoxy, halo-C 1-4 alkoxy; R 9 But H, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 3-6 cycloalkyl; 2. The compound of claim 1, wherein m is 0, 1, or 2.

11. R 2 but, 【Chemistry 23】 and the form of the compound may be selected from the group consisting of pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereoisomers, stereoisomers, tautomers and isotopically enriched forms thereof.

12. 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-phenol; 2-[4-isopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-cyclopropyl-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]phenol; 2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-3-fluoro-5-methyl-phenol; 2-[7-[(3R)-1-ethyl-3-piperidyl]-4-(1-methylcyclopropyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclobutyl-7-[(3R)-1-ethyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-(3,3-difluorocyclobutyl)-7-[(3R)-1-ethyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclobutyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclobutyl-7-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-cyclopropyl-2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-methoxy-phenol; 5-chloro-2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]phenol; 3,5-dimethyl-2-[7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]phenol; 3-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-[(3R)-1-methylpyrrolidin-3-yl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-(1-methyl-4-piperidyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[5-methyl-7-[rac-(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]phenol; 5-chloro-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]phenol; 3-methyl-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[(7R)-4-cyclopropyl-7-tetrahydropyran-3-yl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-Methoxy-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-(4-cyclopropyl-7-tetrahydrofuran-3-yl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(1R,2R)-2-hydroxycyclohexyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-(1H-pyrazol-3-yl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[1-(3-hydroxyphenyl)ethyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[(7R)-4-cyclopropyl-7-[(2S)-2-hydroxycyclohexyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(1R,3S)-3-hydroxycyclohexyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-ethyl-phenol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]indan-4-ol; 5-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-3-(trifluoromethyl)phenol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 3-Methoxy-2-[7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[6-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-methyl-2-[6-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-3-(trifluoromethyl)phenol; 3-[2,4-bis(trifluoromethyl)phenyl]-4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazine; 3-[2-(difluoromethoxy)-4-(trifluoromethyl)phenyl]-4-(1-methylcyclopropyl)-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazine; 5-[7-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]-4-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(3S,4R)-4-fluoro-1-methyl-3-piperidyl]-4-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-cyclopropyl-7-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]-4-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4-cyclopropyl-7-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-4-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclohexyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 2-[7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 3-[(7R)-7-tetrahydrofuran-3-yl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1,3,5-trien-2-ol; (3S,4R)-4-[3-(2-hydroxy-3-bicyclo[4.2.0]octa-1,3,5-trienyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl]tetrahydropyran-3-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; (3S,4R)-4-[(5R)-3-[2-hydroxy-4-methyl-6-(trifluoromethyl)phenyl]-5-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl]tetrahydropyran-3-ol; (3S,4R)-4-[(5S)-3-[2-hydroxy-4-methyl-6-(trifluoromethyl)phenyl]-5-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-7-yl]tetrahydropyran-3-ol; 2-[7-[(1R,2R)-2-hydroxycyclohexyl]-5-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 5-[7-[(1R,2R)-2-hydroxycyclohexyl]-5-methyl-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-7-fluoro-benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclopentyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 2-[7-(3-methoxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[7-(3-methoxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 5-[7-(3-methoxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 6-(difluoromethyl)-5-[7-(3-methoxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 6-(difluoromethyl)-5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-[rac-(1R,2S)-2-hydroxycyclobutyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-[rac-(1R,2R)-2-hydroxycyclobutyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 6-(difluoromethyl)-5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 3-[7-[(1R,2R)-2-hydroxycyclohexyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-4-methyl-bicyclo[4.2.0]octa-1,3,5-trien-2-ol; 3-(Difluoromethyl)-2-[7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-phenol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-(2,2,2-trifluoroethyl)benzofuran-4-ol; 5-[7-[1-(3-hydroxyphenyl)ethyl]-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 2-[7-[(3R)-1-methyl-3-piperidyl]-4-(trifluoromethyl)-5,6-dihydropyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]phenol; 5-cyclopropyl-2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-methoxy-phenol; 2-[4-cyclopropyl-7-[(3R)-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-methoxy-phenol; 2-[4-cyclopropyl-7-[(3R)-1-ethyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-methoxy-phenol; 2-[4-cyclopropyl-7-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-methoxy-phenol; 2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]phenol; 5-methoxy-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]phenol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzothiophen-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]indan-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 3-methyl-2-[6-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-methyl-2-[6-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-3-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-4-fluoro-5-methyl-phenol; 6-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2-fluoro-3-methyl-phenol; 5-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-3-(trifluoromethyl)phenol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 3-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-[7-[(3S,4R)-4-fluoro-1-methyl-3-piperidyl]-4-methyl-pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]-4-methyl-pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(3S,4R)-1-ethyl-4-fluoro-3-piperidyl]-4-methyl-pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 3-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclohexyl]-4-methyl-pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]-4-methyl-pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-2,6-dimethyl-benzofuran-4-ol; 6-methyl-5-[7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 6-methyl-5-[7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclohexyl]pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[4,5-dimethyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 6-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-7-ol; 6-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-7-ol; 2-fluoro-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-ethyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 2-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 3-[4-ethyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1,3,5-trien-2-ol; 1,1-dimethyl-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]indan-4-ol; (3S,4R)-4-[3-[2-hydroxy-4-methyl-6-(trifluoromethyl)phenyl]-5-methyl-pyrrolo[2,3-c]pyridazin-7-yl]tetrahydropyran-3-ol; 2-[7-[(1R,2R)-2-hydroxycyclohexyl]-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[4,5-dimethyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 7-fluoro-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclopentyl]pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclohexyl]-5-methyl-pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 6-(difluoromethyl)-5-[7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 2-[7-[(1R,2R)-2-hydroxycyclopentyl]pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[7-(3-methoxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[7-(3-methoxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 6-(difluoromethyl)-5-[7-(3-methoxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 6-(difluoromethyl)-5-[7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 6-ethyl-5-[7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-[rac-(1R,2S)-2-hydroxycyclobutyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-[rac-(1R,2R)-2-hydroxycyclobutyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-chloro-3-(difluoromethyl)-2-[7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]phenol; 2-[7-[(3R)-1-methyl-3-piperidyl]-4-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 2-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-(trifluoromethyl)pyrrolo[2,3-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 5-[5-(difluoromethyl)-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 3-(4-hydroxy-6-methyl-benzofuran-5-yl)-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazine-5-carbaldehyde; 2-[5-(difluoromethyl)-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-[5-(difluoromethyl)-7-(3-fluoro-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 6-(difluoromethyl)-5-[5-(difluoromethyl)-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 3-(4-hydroxy-6-methyl-benzofuran-5-yl)-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazine-5-carbonitrile; 5-[5-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[5-fluoro-4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[5-fluoro-4-methyl-7-[(3R)-1-methyl-3-piperidyl]pyrrolo[2,3-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[5-fluoro-7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-pyrrolo[2,3-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-5-iodo-pyrrolo[2,3-c]pyridazin-3-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-[6-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol; 5-chloro-2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol; 2-[4-isopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; 2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3,5-dimethyl-phenol; 5-Methoxy-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-methoxy-phenol; 4-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3-hydroxy-benzonitrile; 2-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; (3S,4R)-4-[4-cyclopropyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]imidazo[4,5-c]pyridazin-7-yl]tetrahydropyran-3-ol; 2-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; (3S,4R)-3-[4-cyclopropyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]imidazo[4,5-c]pyridazin-7-yl]-1-methyl-piperidin-4-ol; (3S,4R)-3-[4-cyclopropyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]imidazo[4,5-c]pyridazin-7-yl]-1-ethyl-piperidin-4-ol; (3S,4R)-3-[4-cyclopropyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]imidazo[4,5-c]pyridazin-7-yl]-1-(2-hydroxyethyl)piperidin-4-ol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]indan-4-ol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 3,5-dimethyl-2-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol; 5-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3-(trifluoromethyl)phenol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]indan-4-ol; 3-Methoxy-2-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzothiophen-4-ol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzothiophen-4-ol; 5-[4-cyclopropyl-7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]benzothiophen-4-ol; 2-[7-[(3R)-1-ethyl-3-piperidyl]-4-methyl-imidazo[4,5-c]pyridazin-3-yl]-5-methoxy-phenol; 2-[4-cyclopropyl-7-[(1R,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-[(2R)-2-hydroxypropyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 7-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]quinolin-8-ol; 2-[4-cyclopropyl-7-[3-(hydroxymethyl)cyclobutyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 7-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]quinolin-8-ol; 5-[4-cyclopropyl-7-[rac-(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2-methyl-1,3-benzoxazol-4-ol; 3-Methoxy-2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[(3R)-3-[3-[2-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-imidazo[4,5-c]pyridazin-7-yl]-1-piperidyl]acetonitrile; 2-[(3R)-3-[3-(4-hydroxybenzofuran-5-yl)-4-methyl-imidazo[4,5-c]pyridazin-7-yl]-1-piperidyl]acetonitrile; 2-[(3R)-3-[4-cyclopropyl-3-[2-hydroxy-4-(trifluoromethyl)phenyl]imidazo[4,5-c]pyridazin-7-yl]-1-piperidyl]acetonitrile; 5-[4-cyclopropyl-7-[rac-(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2-methyl-1,3-benzothiazol-4-ol; 2-methyl-5-[4-methyl-7-[rac-(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-1,3-benzoxazol-4-ol; 2-methyl-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-1,3-benzothiazol-4-ol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2-fluoro-benzothiophen-4-ol; 2-[(3R)-3-[4-cyclopropyl-3-(4-hydroxybenzofuran-5-yl)imidazo[4,5-c]pyridazin-7-yl]-1-piperidyl]acetonitrile; 2-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)benzene-1,3-diol; 2-fluoro-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzothiophen-4-ol; 6-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzothiophen-7-ol; 6-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3-dihydro-1,4-benzodioxin-5-ol; 2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)benzene-1,3-diol; 5-[4-methyl-7-[(3R)-1-(2,2,2-trifluoroethyl)-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]naphthalen-1-ol; 5-[4-methyl-7-[(3R)-1-(oxetan-3-yl)-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 2-[4-cyclopropyl-7-[(3R)-1-(oxetan-3-yl)-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 6-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3-dihydro-1,4-benzodioxin-5-ol; 6-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]quinolin-5-ol; 2-[4-ethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-[7-[(3R)-1-methyl-3-piperidyl]-4-(3-thienyl)imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4,6-dimethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4,6-dimethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 6-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzothiophen-7-ol; 5-[4-ethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]indan-4-ol; 3-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 5-[4-ethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzothiophen-4-ol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-4-fluoro-5-methyl-phenol; 6-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2-fluoro-3-methyl-phenol; 2-[7-[(3R,5R)-5-fluoro-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 5-[4-ethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-ethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 2,2-difluoro-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-1,3-benzodioxol-4-ol; 5-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,2-difluoro-1,3-benzodioxol-4-ol; 3-[4,6-dimethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1,3,5-trien-2-ol; 2-[4-cyclopropyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-4-fluoro-5-(trifluoromethyl)phenol; 6-methyl-5-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 3-[4-ethyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 3-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-imidazo[4,5-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 2-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-5-methyl-3-(trifluoromethyl)phenol; 2-[(3R)-3-[3-(4-hydroxy-6-methyl-benzofuran-5-yl)imidazo[4,5-c]pyridazin-7-yl]-1-piperidyl]acetonitrile; 6-methyl-5-[7-[(3R)-1-(2,2,2-trifluoroethyl)-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 7-fluoro-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 7-fluoro-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 6-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-7-ol; 3-hydroxy-5-methyl-4-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzonitrile; 2,2-dimethyl-6-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3H-benzofuran-7-ol 1,1-dimethyl-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]indan-4-ol 6-(difluoromethyl)-5-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol 5-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 2-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-6-(2,2,2-trifluoroethyl)benzofuran-4-ol; 6-(difluoromethyl)-5-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 3-(difluoromethyl)-5-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol; 5-chloro-3-(difluoromethyl)-2-[7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol; 5-[7-(3,3-dimethyltetrahydropyran-4-yl)imidazo[4,5-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 3-[7-[(1R,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]-4-methyl-bicyclo[4.2.0]octa-1,3,5-trien-2-ol; 6-(difluoromethyl)-5-[7-[(1R,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]-6-(2,2,2-trifluoroethyl)benzofuran-4-ol; 6-ethyl-5-[7-(3-hydroxy-3-methyl-cyclobutyl)imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-[(1R,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-[(3S,4R)-3-hydroxytetrahydropyran-4-yl]imidazo[4,5-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; (3S,4R)-4-[3-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]imidazo[4,5-c]pyridazin-7-yl]tetrahydropyran-3-ol; 5-[7-(2,2-dimethyltetrahydropyran-4-yl)imidazo[4,5-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 6-ethyl-5-[7-[(1R,2R)-2-hydroxycyclohexyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 6-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]tetralin-5-ol; 3,3-dimethyl-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]indan-4-ol; 2,3-dimethyl-6-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]phenol; 2-[4-methoxy-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-3-methyl-5-(trifluoromethyl)phenol; 5-[4-(cyclopropoxy)-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-ethoxy-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-methoxy-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-(azetidin-1-yl)-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-(dimethylamino)-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-(difluoromethyl)-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 2-[4-(difluoromethyl)-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-(1-hydroxyethyl)-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-(hydroxymethyl)-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-imidazo[4,5-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 7-chloro-5-[7-(3-hydroxy-3-methyl-cyclobutyl)-4-methyl-imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 7-chloro-5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]imidazo[4,5-c]pyridazin-3-yl]benzofuran-4-ol; 2-[7-cyclopropyl-3-[(3R)-1-methyl-3-piperidyl]triazolo[4,5-c]pyridazin-6-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-[3-[(3R)-1-methyl-3-piperidyl]triazolo[4,5-c]pyridazin-6-yl]phenol; 3-methyl-2-[3-[(3R)-1-methyl-3-piperidyl]triazolo[4,5-c]pyridazin-6-yl]-5-(trifluoromethyl)phenol; 3,5-dimethyl-2-[7-(1-methyl-3-piperidyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]phenol; 5-[4-cyclopropyl-7-(1-methyl-3-piperidyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]indan-4-ol; 2-[4-cyclopropyl-7-(1-methyl-3-piperidyl)-5H-pyrrolo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3,5-dimethyl-2-[7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]phenol; 3,5-dimethyl-2-[7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazin-3-yl]phenol; 2-[4-methyl-7-[(3S)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-[(3S)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-methyl-7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-cyclopropyl-7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[4-methyl-7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-[4-methyl-7-[(3S)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4-methyl-7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 6-methyl-5-[7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 5-[4-methyl-7-[(3R)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]indan-4-ol; 5-[4-methyl-7-[(3S)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]indan-4-ol; 3-[4-methyl-7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol; 6-methyl-5-[7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol; 5-[4-methyl-7-(1-methyl-3-piperidyl)thieno[3,2-c]pyridazin-3-yl]indan-4-ol; 6-methyl-5-[7-[(3S)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-[(3R)-1-methyl-3-piperidyl]thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-(2-hydroxyphenyl)thieno[3,2-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-(2-fluorophenyl)thieno[3,2-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 6-methyl-5-[7-[2-(trifluoromethoxy)phenyl]thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-[2-(trifluoromethyl)phenyl]thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-(o-tolyl)thieno[3,2-c]pyridazin-3-yl]benzofuran-4-ol; 5-[7-(2-chlorophenyl)thieno[3,2-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 5-[7-(3,6-dihydro-2H-pyran-4-yl)thieno[3,2-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 6-methyl-5-(7-tetrahydropyran-4-ylthieno[3,2-c]pyridazin-3-yl)benzofuran-4-ol; 5-methyl-2-(7-tetrahydropyran-3-ylthieno[3,2-c]pyridazin-3-yl)-3-(trifluoromethyl)phenol; 6-methyl-5-(7-tetrahydrofuran-3-ylthieno[3,2-c]pyridazin-3-yl)benzofuran-4-ol; 5-[7-(2,5-dihydrofuran-3-yl)thieno[3,2-c]pyridazin-3-yl]-6-methyl-benzofuran-4-ol; 6-methyl-5-(7-tetrahydropyran-3-ylthieno[3,2-c]pyridazin-3-yl)benzofuran-4-ol; 3-methyl-2-[7-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)furo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-(1-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 2-[4-methyl-7-(1-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-[4-methyl-7-(1-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]indan-4-ol; 5-[4-methyl-7-(1-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 3-methyl-2-[4-methyl-7-(1-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-[(3R)-1-methyl-3-piperidyl]furo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 3-methyl-2-[7-[(3S)-1-methyl-3-piperidyl]furo[3,2-c]pyridazin-3-yl]-5-(trifluoromethyl)phenol; 5-[4-methyl-7-(1-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]benzofuran-4-ol; 6-methyl-5-[7-(1-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]-2,3-dihydrobenzofuran-4-ol; 6-methyl-5-[7-(1-methyl-3-piperidyl)furo[3,2-c]pyridazin-3-yl]benzofuran-4-ol; 2-[4-cyclopropyl-1-(1-methyl-3-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]-5-methyl-phenol; 3-[4-cyclopropyl-1-(1-methyl-3-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]bicyclo[4.2.0]octa-1,3,5-trien-2-ol; 5-[4-cyclopropyl-1-(1-methyl-3-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]benzofuran-4-ol; and 2-[4-cyclopropyl-1-(1-methyl-3-piperidyl)pyrazolo[3,4-c]pyridazin-5-yl]-5-(trifluoromethyl)phenol or a form thereof selected from the group consisting of: wherein the form of the compound may be selected from the group consisting of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, tautomer, and isotopically enriched form thereof.

13. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or claim 12 and one or more pharmaceutically acceptable carriers, wherein the compound includes a pharmaceutically acceptable salt thereof.

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

15. The diseases include 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 myopathy, degeneration, and the like.

15. The method of claim 14 for treating or ameliorating a disease modulated by NLRP3, selected from: Hechenne muscular dystrophy (DMD), hyperalgesia, multiple sclerosis-associated neuropathic pain, acute kidney injury, chronic crystalline nephropathy, chronic kidney disease, asthma and allergic airway inflammation, diabetes-associated atherosclerosis, diabetic encephalopathy, diabetic kidney disease, pancreatic islet transplant rejection, obesity-associated kidney disease, oxalate-induced nephropathy, renal fibrosis, renal hypertension, type I diabetes, type II diabetes, psoriasis, hidradenitis suppurativa, atherosclerosis, and cytokine release syndrome (CRS).

16. 15. The method of claim 14, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

17. and a pharmaceutically acceptable salt thereof for use in treating or ameliorating a disease modulated by NLRP3, including 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-associated disease, and the like.

13. The compound of claim 1 or claim 12, wherein the compound is selected from the group consisting of steroid hormone receptor agonists, ...

18. 18. The use of the compound of claim 17, wherein the effective amount of the compound ranges from about 0.001 mg / kg / day to about 500 mg / kg / day.

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

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