WO2020257487A1 - Glycolate oxidase inhibitors for the treatment of disease - Google Patents

Glycolate oxidase inhibitors for the treatment of disease Download PDF

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Publication number
WO2020257487A1
WO2020257487A1 PCT/US2020/038480 US2020038480W WO2020257487A1 WO 2020257487 A1 WO2020257487 A1 WO 2020257487A1 US 2020038480 W US2020038480 W US 2020038480W WO 2020257487 A1 WO2020257487 A1 WO 2020257487A1
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Prior art keywords
ring
alkyl
cycloalkyl
phenyl
halo
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PCT/US2020/038480
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French (fr)
Inventor
Bing Wang
Brett E. Crawford
Shripad Bhagwat
Xiaomei Bai
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Biomarin Pharmaceutical Inc.
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Priority to MX2021015874A priority Critical patent/MX2021015874A/en
Priority to KR1020227000835A priority patent/KR20220048489A/en
Priority to CA3143334A priority patent/CA3143334A1/en
Priority to BR112021025781A priority patent/BR112021025781A2/en
Priority to US17/619,818 priority patent/US20230088214A1/en
Priority to JP2021575417A priority patent/JP2022536969A/en
Application filed by Biomarin Pharmaceutical Inc. filed Critical Biomarin Pharmaceutical Inc.
Priority to PE2021002115A priority patent/PE20220901A1/en
Priority to CN202080058790.2A priority patent/CN114258390A/en
Priority to AU2020298238A priority patent/AU2020298238A1/en
Priority to EP20827629.5A priority patent/EP3986863A4/en
Publication of WO2020257487A1 publication Critical patent/WO2020257487A1/en
Priority to IL288920A priority patent/IL288920A/en

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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
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    • A61P13/00—Drugs for disorders of the urinary system
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    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods to treat or prevent diseases or disorders associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Also described herein is that such compounds are for use in said methods for treating or preventing diseases or disorders.
  • diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.
  • PH Primary hyperoxaluria
  • PH type I PHI
  • AGTT glyoxylate aminotransferase
  • AGT detoxifies glyoxylate to glycine.
  • LDH lactate dehydrogenase
  • Glycolate oxidase is a key enzyme involved in the oxalate metabolic pathway. Glycolate from internal metabolism and from diet will be oxidized by GO to glyoxylate. This oxidation only occurs in the liver peroxisome (Holmes et al, J
  • HAO1 HAO1
  • GO deficiency can correct overproduction of urine oxalate over production in AGXT -/- mouse (Martin-Higueras et al., Mol Ther.24(4): 719-725 (2016)).
  • the HAO1 -/- deficiency appears clinically/phenotypically normal except for the increased urine glycolate secretion (Martin- Higueras et al., Mol Ther.24(4): 719-725 (2016)).
  • oxalate Accumulation of oxalate is implicated in primary hyperoxaluria type II (“PH2) and primary hyperoxaluria type III (“PH3”). Similar to PH1, mutations in a gene results in decreased production or activity of the corresponding enzymes that are produced. Such disruptions to the enzymes adversely affects the normal breakdown of glyoxylate. In healthy subjects, glyoxylate is converted to glycine, which is readily secreted. In diseased subjects, there is a build-up of glyoxylate, which gets converted to oxalate. When the buildup of oxalate exceeds the capacity of the kidney to excrete it, the oxalate starts to deposit in various organ systems in a process called systemic oxalosis.
  • PH3 is a third type of PH, and is identified in patients with previously unclassified forms of PH. PH3 is caused by mutations in the HOGA gene (formerly known as the DHDPSL gene). This enzyme functions in the final step of 4-hydroxyproline (Hyp) catabolic pathway. Overactivity of the enzyme leads to excess conversion of hydroxyproline to glyoxylate, which yields high levels of oxalate.
  • the genetic mutations that cause PH are inherited as autosomal recessive traits.
  • Hyperoxaluria is characterized by an increased urinary excretion of oxalate.
  • Dietary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora.
  • a high intake of oxalate-rich foods eg, chocolate, nuts, spinach
  • a diet rich in animal protein can result in hyperoxaluria.
  • Low dietary calcium intake can also result in hyperoxaluria via decreased intestinal binding of oxalate and the resulting increased absorption.
  • Ascorbic acid can be converted into oxalate, resulting in increased urinary oxalate levels.
  • Patients with abnormal or altered cellular membrane oxalate transport mechanism have abnormally high absorption of dietary oxalate.
  • Enteric hyperoxaluria results from a chronic underlying gastrointestinal disorder associated with malabsorption of fat, bile acids, decreased enteric secretion of oxalate by the membrane protein anion transporter (slc26a6) due to the abnormal glycosylation of brush border, or triggered by obesity which influenced paracellular and transcellular transporting.
  • slc26a6 membrane protein anion transporter
  • steatorrhea inflammatory bowel disease (“IBD”), biliary cirrhosis, short-bowel syndrome, celiac disease, pancreatic insufficiency, Crohn’s disease, ulcerative colitis, bariatric surgery, jejunoileal bypass, ileal dysfunction, absence of gastrointestinal tract-dwelling bacterium oxalobacter formigenes, and Roux-en-Y gastric bypass (“RYGB”).
  • IBD inflammatory bowel disease
  • biliary cirrhosis short-bowel syndrome
  • celiac disease pancreatic insufficiency
  • Crohn’s disease ulcerative colitis
  • bariatric surgery jejunoileal bypass
  • ileal dysfunction absence of gastrointestinal tract-dwelling bacterium oxalobacter formigenes
  • Roux-en-Y gastric bypass Roux-en-Y gastric bypass
  • oxalate crystals are associated with renal inflammation, fibrosis and progressive renal failure. Studies also show high oxalate levels can be an activator of inflammatory pathways, and in particular, with inflammasome activation and the progression of kidney disease, and NALP3-mediated inflammation (see Ermer, T; et al., Curr Opin Nephrol Hypertens, 25(4):363-371 (2016 July); and Knauf, F., et al., Kidney Int., 84(5):895-901 (2013 Nov.)).
  • Elevation of plasma oxalate in CKD may promote renal inflammation and more rapid progression of CKD independent of primary etiology.
  • Higher urinary oxalate excretion among CKD patients is also associated with an elevated risk of end- stage renal disease (ESRD; also known as end-stage kidney disease,“ESKD”).
  • ESRD end-stage renal disease
  • Hyperoxaluria has been implicated as a complication or undesired side effect of various diseases, such as Hirschsprung’s disease, cystic fibrosis, chronic biliary pathology, pancreatic pathology, high blood pressure, diabetes, and obesity.
  • Hyperoxaluria can also be related to genetic or environmental vitamin B6 deficiency, genetic or environmental abnormal calcium metabolism such as, hypercalciuria and hyperparathyroidism and abnormal collagen metabolism, abnormal oxalate or oxalate precursor transporters. Reduction of oxalate levels would also have therapeutic benefit in the management of the complications from these diseases and conditions.
  • molecules that inhibit the activity of GO may be used to treat disorders of glyoxylate metabolism, including PH1, that are associated with production of excessive amounts of oxalate.
  • Other diseases and conditions impacted by excessive oxalate formation may benefit from treatment with a GO inhibitor, such as PH2, PH3, enteric hyperoxaluria, dietary hyperoxaluria, idiopathic hyperoxaluria, urolithiasis, nephrolithiasis, nephrocalcinosis, chronic kidney disease, end stage renal disease, or systemic oxalosis.
  • a GO inhibitor such as PH2, PH3, enteric hyperoxaluria, dietary hyperoxaluria, idiopathic hyperoxaluria, urolithiasis, nephrolithiasis, nephrocalcinosis, chronic kidney disease, end stage renal disease, or systemic oxalosis.
  • ring C is selected from:
  • R L is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, or benzyl; wherein the C 1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C3-8 cycloalkyl, C8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two groups
  • Ring A is substituted with:
  • Ring A is substituted with one or two R AB groups or
  • Ring A is unsubstituted, wherein:
  • Ring A is unsubstituted spirocycloalkyl, then L is O, S, or CH 2 S;
  • each R AA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo groups; or
  • each R AB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 R B groups;
  • each R B is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl;
  • alkylaminosulfonyl dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy;
  • alkylaminoalkoxy dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl;
  • alkylcarbonylaminoalkoxy cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy;
  • hydroxyalkyl cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered
  • heterocycloalkyl-one (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
  • R 1A , R 1B , and R 1C are each independently hydrogen or C 1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl
  • R AA when L is O, Ring A is phenyl, and Ring B is not present, then R AA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 R AA , and Ring B is not present, then R AA cannot be meta-substituted trifluoromethyl; iv. when L is O, Ring A is phenyl, Ring B is not present, and R 1 is ethyl, then R AA cannot be trifluoromethoxy;
  • ring C is selected from:
  • Y is hydrogen or W
  • R L is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, or benzyl; wherein the C 1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
  • Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with 1 or 2 R A1 groups;
  • each R A1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
  • Ring B when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 R A2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R A2 and R B is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
  • aminosulfonyl alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
  • dialkylaminocarbonyl alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
  • cycloalkyloxy ; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
  • heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
  • each R 2 and R 3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • R 4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
  • heterocycloalkylcarbonyloxy aminocarbonyloxy, alkylaminocarbonyloxy,
  • heterocycloalkyl or heteroaryl
  • each R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl;
  • n 1, 2, or 3;
  • Ring A is cyclopropyl, phenyl, indole, or thiophene, then Ring B is present;
  • a pharmaceutical composition comprising a compound disclosed herein, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as disclosed herein, and a pharmaceutically acceptable excipient.
  • a method of treating a disease or disorder associated with a defect in glyoxylate metabolism with a compound disclosed herein is for use in a method of treating a disease or disorder associated with a defect in glyoxylate metabolism, such as diseases or disorders associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism.
  • a disease or disorder associated with a defect in glyoxylate metabolism such as diseases or disorders associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism.
  • GO glycolate oxidase
  • Such a compound is, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
  • the disease or disorder is a primary hyperoxaluria. In certain embodiments, the disease or disorder is primary hyperoxaluria type I. In certain embodiments, the disease or disorder is PH2. In certain embodiments, the disease or disorder is PH3. In certain embodiments, the disease or disorder is an enteric hyperoxaluria. In certain embodiments, the disease or disorder is a dietary hyperoxaluria, In certain embodiments, the disease or disorder is an idiopathic hyperoxaluria. In certain embodiments, the disease or disorder is urolithiasis. In certain embodiments, the disease or disorder is nephrolithiasis. In certain embodiments, the disease or disorder is nephrocalcinosis. In certain embodiments, the disease or disorder is chronic kidney disease. In certain embodiments, the disease or disorder is end stage renal disease. In certain embodiments, the disease or disorder is systemic oxalosis.
  • “Acceptable” with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated.
  • alkoxy means a group of the formula–OR, wherein R is alkyl.
  • alkoxy includes methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy.
  • Alkoxyalkoxy means a group of the formula–OR-OR ⁇ , wherein R is alkylene as defined herein, and R ⁇ is alkyl as defined herein.
  • Alkoxycarbonyl means a group of the formula–C(O)R, wherein R is alkoxy, as defined herein.
  • Alkoxycarbonyloxy means a group of the formula–OC(O)R, wherein R is alkoxy, as defined herein.
  • Alkylcarbonylaminoalkoxy means a group of the formula–OR-NH-C(O)R’, wherein R is alkylene, as defined herein, and R’ is alkyl, as defined herein.
  • Alkyl means a straight or branched saturated hydrocarbon group containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms. In certain embodiments, alkyl includes 1-4 carbon atoms (“C1-4 alkyl”). In certain embodiments alkyl includes 1-3 carbon atoms (“C1-3 alkyl”).
  • alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.
  • Alkylene means a straight or branched saturated divalent hydrocarbon group containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms.
  • Alkylcarbonylamino means a group of the formula–NHC(O)R, wherein R is alkyl, as defined herein.
  • Amino means an–NH 2 group.
  • aminoalkoxy means a group of the formula–O-R-NH 2 , wherein R is alkyl as defined herein. In one embodiment, (amino)alkoxy includes (amino)propyloxy.
  • Alkylaminoalkoxy means an–O-R-NHR’ group, wherein R and R’ are independently alkyl as defined herein.
  • (dialkylamino)alkoxy includes (methylamino)propyloxy.
  • Aminocarbonyl means an–C(O)NH 2 group.
  • Aminocarbonyloxy means a group of the formula–OC(O)R, wherein R is amino, as defined herein.
  • Alkylaminocarbonyloxy means a group of the formula–OC(O)R, wherein R is alkylamino, as defined herein.
  • alkylamino means a group of the formula–NHR, wherein R is alkyl as defined herein.
  • alkylamino includes methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, iso-butylamino, or tert-butylamino.
  • Alkylcarbonyl means a group of the formula–C(O)R, wherein R is alkyl, as defined herein.
  • Alkylcarbonyloxy means a group of the formula–OC(O)R, wherein R is alkyl, as defined herein.
  • Alkylsulfonyl means a group of the formula–SO 2 R, wherein R is alkyl, as defined herein.
  • Aminosulfonyl means a group of the formula–SO2NH 2 .
  • Alkylaminosulfonyl means a group of the formula–SO 2 NHR, wherein R is alkyl, as defined herein.
  • Dialkylaminoalkoxy means an–O-R-NR’R” group, wherein R, R’, and R” are independently alkyl as defined herein.
  • (dialkylamino)alkoxy includes (dimethylamino)propyloxy.
  • Dialkylaminosulfonyl means a group of the formula–SO2NRR’, wherein R and R’ are independently alkyl, as defined herein.
  • Aryl means a monovalent six- to fourteen-membered, mono-, bi-, or tri- carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic or tricyclic ring is aromatic.
  • aryl includes phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indanyl, or anthracenyl.
  • Carboxyl means an–C(O)OH group.
  • Cycloalkyl means a monocyclic or bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon ring of three to ten carbon ring atoms. Cycloalkyl groups include fused and bridged bicyclic rings. For example, when fused, the cycloalkyl group may comprise two rings that share adjacent atoms (e.g., one covalent bond). When bridged, the cycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom.
  • cycloalkyl When a cycloalkyl group contains from x-y ring carbon atoms, it may be referred to herein as C x-y cycloalkyl.
  • cycloalkyl is C3-10 cycloalkyl, or is C5-7 cycloalkyl, or is C5-6 cycloalkyl, or is C3-6 cycloalkyl, or is C3-7 cycloalkyl.
  • cycloalkyl is C3-8 cycloalkyl.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the cycloalkyl group is
  • (Cycloalkyl)alkyl means an alkyl group, as defined herein, substituted with at least one cycloalkyl groups as defined herein. In certain embodiments, alkyl is substituted with 1 cycloalkyl group. In certain embodiments, alkyl is substituted with 1 or 2 cycloalkyl groups. In certain embodiments, (cycloalkyl)alkyl includes cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
  • (Cycloalkyl)alkoxy means a group of the formula–OR, wherein R is a
  • (cycloalkyl)alkyl group as defined herein.
  • (cycloalkyl)alkoxy includes cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy.
  • Cycloalkyloxy means a group of the formula–OR, wherein R is cycloalkyl, as defined herein.
  • cycloalkyloxy includes cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
  • Cycloalkylcarbonyl means a group of the formula–C(O)R, wherein R is cycloalkyl, as defined herein.
  • Cycloalkylcarbonyloxy means a group of the formula–OC(O)R, wherein R is cycloalkyl, as defined herein.
  • Dialkylamino means a group of the formula–NRR ⁇ , wherein R and R ⁇ are independently alkyl as defined herein.
  • dialkylamino includes dimethylamino, diethylamino, N,N-methylpropylamino or N,N-methylethylamino.
  • Dialkylaminocarbonyl means a group of the formula–C(O)R, wherein R is dialkylamino, as defined herein.
  • Dialkylaminocarbonyloxy means a group of the formula–OC(O)R, wherein R is dialkylamino, as defined herein.
  • Halo means a fluoro, chloro, bromo, or iodo group.
  • Haloalkoxy means an alkoxy group, substituted with one or more halo atoms. In certain embodiments, all hydrogen atoms of the alkoxy group are replaced with halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, or 3 halo atoms. In certain other embodiments, the alkoxy is substituted with 2 halo atoms. In certain embodiments, the alkoxy is substituted with 1 halo atom. Certain embodiments of haloalkoxy include difluoromethoxy,
  • Haloalkyl means an alkyl group substituted with one or more halo atoms. In certain embodiments, all hydrogen atoms of the alkyl group are substituted with halo atoms. In certain embodiments, the alkyl group is substituted by 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, the alkyl group is substituted by 1, 2, or 3 halo atoms. In certain other words,
  • the alkyl group is substituted with 2 halo atoms. In certain embodiments, the alkyl group is substituted with 1 halo atom. In certain embodiments, haloalkyl includes
  • haloalkyl include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,1,1- trifluoroethanyl.
  • monocyclic ring is aromatic and wherein at least one of the rings in the bicyclic or tricyclic rings is aromatic (but does not have to be a ring which contains a heteroatom, e.g.;
  • heteroaryl is a monocylic ring of 5 to 6 rings atoms. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting.
  • heteroaryl includes, but is not limited to, triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indolinyl, isoindolinyl, indazolyl, benzimidazolyl,
  • benzoxazolyl benzofuranyl, benzothienyl, benzopyranyl, benzothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
  • Heterocycloalkyl means a saturated or partially unsaturated (but not aromatic) monocyclic ring of 3 to 9 ring atoms, or a saturated or partially unsaturated (but not aromatic) bicyclic ring of 5 to 12 ring atoms in which one or more ring atoms is a heteroatom
  • heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 4 to 7 rings atoms, or a saturated or partially unsaturated bicyclic group of 7 to 9 ring atoms. In certain embodiments, heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 5 to 6 rings atoms or a saturated or partially unsaturated bicyclic group of 6 to 8 ring atoms.
  • the heterocycloalkyl group contains only one or two nitrogen atoms, and the remaining ring atoms are carbon.
  • heterocycloalkyl group contains from x to y ring atoms, it may be referred to herein as“a x-y membered heterocycloalkyl”.
  • the heterocycloalkyl is a 4-7 membered heterocycloalkyl, or is a 5-6 membered heterocycloalkyl, or is a 7-9 membered heterocycloalkyl.
  • the heterocycloalkyl is a 5-8 membered heterocycloalkyl.
  • Heterocycloalkyl groups include fused or bridged heterocycloalkyl bicyclic rings.
  • a fused heterocycloalkyl group may comprise two rings that share adjacent atoms (e.g., one covalent bond).
  • the heterocycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at
  • the heterocycloalkyl group is or .
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thi
  • (Heterocycloalkyl)alkyl means an alkyl group, as defined herein, substituted with at least one, in another example 1 or 2, heterocycloalkyl groups as defined herein. In certain embodiments, the alkyl is substituted with one heterocycloalkyl group.
  • Heterocycloalkylcarbonyl means a group of the formula–C(O)R, wherein R is heterocycloalkyl, as defined herein.
  • Heterocycloalkylcarbonyloxy means a group of the formula–OC(O)R, wherein R is heterocycloalkyl, as defined herein.
  • Heterocycloalkyl-one means a heterocycloalkyl group as defined herein and wherein one ring carbon atom of the heterocycloalkyl group forms a double bond with oxygen
  • heterocycloalkyl-one group is
  • “Hydroxy” means an–OH group.
  • the terms“hydroxy” and“hydroxyl” are used interchangeably and mean an–OH group.
  • “Hydroxyalkyl” means a group of formula–R-(OH)z, where R is an alkyl as defined herein and z is 1 or 2.
  • hydroxyalkyl is -ROH.
  • hydroxyalkyl includes -CH 2 OH.
  • hydroxyalkyl is -R(OH) 2 .
  • “Hydroxyalkoxy” means a group of formula–O-R-(OH)z, where R is an alkyl as defined herein and z is 1 or 2. In one embodiment, hydroxyalkoxy is–OR-(OH). In one embodiment, hydroxyalkoxy is–OR-(OH) 2 . In one embodiment (hydroxy)alkoxy includes (hydroxy)propyloxy.
  • Hydrocarbonyl means an–C(O)OH group.
  • hydroxycarbonyl and“carboxyl” are used interchangeably and refer to the same group.
  • Haldroxycarbonylalkyl means a group of the formula–RC(O)OH, wherein R is alkylene as defined herein.
  • Hydrocycloalkyl means a group of the formul–ROH, wherein R is
  • cycloalkyl as defined herein.
  • hydroxycycloalkyl is .
  • (Hydroxycycloalkyl)alkyl means a group of formula–RR’ wherein R is alkyl and R’ is hydroxycycloalkyl as defined herein. In certain embodiments (hydroxycycloalkyl)alkyl
  • (Phenyl)alkyl means an alkyl group, as defined herein, substituted with at least one phenyl group. In certain embodiments, the alkyl is substituted with one phenyl group. In certain embodiments, (phenyl)alkyl is benzyl.
  • (Phenyl)alkoxy means a group of the formula–OR, wherein R is (phenyl)alkyl as defined herein.
  • Phenylcarbonyloxy means a group of the formula–OC(O)R, wherein R is phenyl.
  • “Spirocycloalkyl” means a bicyclic cycloalkyl ring of 5 to 12 carbon ring atoms having one quaternary carbon ring atom common to both rings. In certain embodiments, the spirocycloalkyl is a C 5-12 spirocycloalkyl, or is a C 8-11 siprocycloalkyl.
  • spirocycloalkyl groups include spiro[2.5]octane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane , spiro[4.5]decane, or spiro[5.5]undecane.
  • the spirocycloalkyl group is .
  • compounds of the described herein exist as stereoisomers, wherein asymmetric or chiral centers are present.
  • the term (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45:13-30, hereby incorporated by reference.
  • the embodiments described herein specifically includes the various stereoisomers and mixtures thereof.
  • Stepoisomers include (but are not limited to) geometric isomers, enantiomers, diastereomers, and mixtures of geometric isomers, enantiomers or diastereomers.
  • individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column.
  • “Amelioration” of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
  • an“effective amount” or“therapeutically effective amount,” refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • Excipient or“pharmaceutically acceptable excipient” means a
  • each component is“pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response,
  • “Pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or salicylic acid.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, or lysine, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, or lysine, or by other methods previously determined.
  • a salt such as an ammoni
  • composition refers to a mixture of a compound described herein with other chemical components, such as an excipient.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
  • Subject refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g., human
  • monkey e.g., monkey
  • cow, pig sheep, goat
  • horse dog
  • cat rabbit
  • rat rat
  • human a primate
  • patient e.g., human
  • the subject is a mammal.
  • the subject is a human.
  • the subject is an adult human.
  • the subject is a human child.
  • the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain
  • the subject is a human child.
  • Treatment in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.
  • the term“disease or disorder characterized by high oxalate content in the urine” refers to an oxylate content that is at least 10% higher than a reference level observed in a healthy patient.
  • the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is at least 20% higher than a reference level observed in a healthy patient, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 200%, higher than a reference level observed in a healthy patient.
  • the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is about 10% higher than a reference level observed in a healthy patient, such as about 20%, about 30%, about 40%, about 50%, about 100%, about 200%, or more than 200%, higher than a reference level observed in a healthy patient.
  • the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is about 1.25 times higher than a reference level observed in a healthy patient, such as about 1.25 times, about 1.5 times, about 1.75 times, about 2 times, about 3 times, or more than 3 times, higher than a reference level observed in a healthy patient.
  • Ring C is selected from:
  • R L is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, or benzyl; wherein the C 1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C3-8 cycloalkyl, C8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two groups
  • Ring A is substituted with:
  • Ring A is substituted with one or two R AB groups or
  • Ring A is unsubstituted, wherein:
  • Ring A is unsubstituted spirocycloalkyl, then L is O, S, or CH 2 S;
  • each R AA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo groups; or
  • each R AB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl;
  • alkylaminosulfonyl dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy;
  • alkylaminoalkoxy dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl;
  • alkylcarbonylaminoalkoxy cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy;
  • cycloalkyl alkoxy wherein cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6- membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl,
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
  • R 1A , R 1B , and R 1C are each independently hydrogen or C1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl
  • R AA when L is O, Ring A is phenyl, and Ring B is not present, then R AA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 R AA , and Ring B is not present, then R AA cannot be meta-substituted trifluoromethyl;
  • Ring B cannot be mono or di-substituted halo.
  • Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.
  • Ring A cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl
  • Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.
  • Ring B when L is S or CH 2 , Ring B cannot be mono or di-substituted halo.
  • Ring B when L is S or CH 2 , Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.
  • Ring A cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl
  • Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.
  • ring C is selected from:
  • R L is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, or benzyl; wherein the C 1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is
  • Ring A is optionally substituted with 1 or 2 R AA groups; when Ring B is present, then Ring A is optionally substuted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
  • each R AA is independently alkyl; halo; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
  • aminocarbonyl alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
  • cycloalkylcarbonyloxy optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
  • heterocycloalkylcarbonyl or 5-6 membered heteroaryl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R 1A )C(O)R 1B , -N(R 1A )C(O)OR 1B , or -N(R 1A )C(O)NR 1B R 1C ; wherein R 1A , R 1B , and R 1C are each independently hydrogen or C1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • ring C is selected from:
  • R L is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 R AA groups;
  • each R AA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, alkylcarbonylaminoalkoxy, or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
  • the compound of Formula (I) is that wherein:
  • R L is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is optionally substuted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
  • Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is
  • each R AA is independently alkyl; halo; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
  • aminocarbonyl alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
  • cycloalkylcarbonyloxy optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
  • heterocycloalkylcarbonyl or 5-6 membered heteroaryl
  • R 1 is W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino,
  • alkylcarbonyloxy alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R 1A )C(O)R 1B , -N(R 1A )C(O)OR 1B , or -N(R 1A )C(O)NR 1B R 1C ; wherein R 1A , R 1B , and R 1C are each independently hydrogen or C 1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • the compound of Formula (I) is that wherein:
  • R L is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
  • Ring B is present or not present; wherein:
  • Ring A is optionally substuted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
  • Ring A is substituted with:
  • each R AA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; alkylcarbonylaminoalkoxy; or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
  • aminocarbonyl alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
  • cycloalkylcarbonyloxy optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
  • heterocycloalkylcarbonyl or 5-6 membered heteroaryl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
  • R 1A , R 1B , and R 1C are each independently hydrogen or C1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted
  • R AA when L is O, Ring A is phenyl, and Ring B is not present, then R AA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 R AA , and Ring B is not present, then R AA cannot be meta-substituted trifluoromethyl;
  • the compound of Formula (I) is that wherein:
  • alkylcarbonyloxy and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
  • Ring B is present or not present; wherein:
  • Ring A is optionally substuted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
  • Ring A is substituted with:
  • Ring A is substituted with one or two R AB groups or
  • Ring A is unsubstituted, wherein:
  • Ring A is unsubstituted spirocycloalkyl, then L is O or S;
  • each R AA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy;
  • each R AB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
  • aminocarbonyl alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
  • cycloalkylcarbonyloxy optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
  • heterocycloalkylcarbonyl or 5-6 membered heteroaryl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with
  • R 1A , R 1B , and R 1C are each independently hydrogen or C1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycl
  • Ring B cannot be halo-substituted phenyl
  • the compound of Formula (I) is that wherein:
  • R L is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, or benzyl; wherein the C 1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C 3-7 cycloalkyl, C 8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
  • Ring B is present or not present; wherein: when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
  • Ring A is substituted with:
  • halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
  • Ring A is substituted with one or two R AB groups or
  • Ring A is unsubstituted, wherein:
  • Ring A is unsubstituted spirocycloalkyl, then L is O or S; each R AA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy;
  • each R AB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
  • aminocarbonyl alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
  • cycloalkylcarbonyloxy optionally substituted with 1 or 2 groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
  • heterocycloalkylcarbonyl or 5-6 membered heteroaryl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
  • R 1A , R 1B , and R 1C are each independently hydrogen or C1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl
  • the compound of Formula (I) is that wherein: R L is hydrogen, C1-4 alkyl, or benzyl; and the benzyl group is optionally substituted with one or two haloalkoxy groups; and Ring A is C 3-7 cycloalkyl, C 8-11
  • spirocycloalkyl 5-8 membered heterocycloalkyl, phenyl, naphthyl, indanyl, tetrahydronaphthnyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl.
  • the compound of Formula (I) is that wherein: R L is hydrogen, C 1-4 alkyl, or benzyl; and the benzyl group is optionally substituted with one or two haloalkoxy groups; and Ring B, when present, is cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl.
  • the compound of Formula (I) is that wherein:
  • R L is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
  • Ring A is substituted with:
  • halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
  • Ring B when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two R AB groups;
  • each R AA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy; each R AB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
  • aminocarbonyl alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
  • cycloalkylcarbonyloxy optionally substituted with 1 or 2 groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
  • heterocycloalkylcarbonyl or 5-6 membered heteroaryl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
  • R 1A , R 1B , and R 1C are each independently hydrogen or C1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl
  • the compound of Formula (I) is that wherein:
  • Ring A is C5-6 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, phenyl,
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is substituted with:
  • halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
  • Ring A is substituted with one or two R AB groups;
  • Ring A is unsubstituted, wherein:
  • each R AA is independently haloalkyl; cycloalkyloxy; (cycloalkyl)alkoxy;
  • each R AB is independently halo, alkyl, haloalkyl, or haloalkoxy;
  • Ring B when present, cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl,
  • each Ring B is optionally substituted with one or two R B groups;
  • each R B is independently halo; cyano; alkyl; haloalkyl; haloalkoxy; alkoxyalkoxy;
  • heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6- membered heterocycloalkyl-one)alkyl;
  • R 1 is hydrogen, alkyl or W; wherein W is alkyl substituted with alkylcarbonyloxy,
  • R 2 and R 3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
  • heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl
  • alkylcarbonyloxy and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl;
  • alkoxyalkoxy aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
  • heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6- membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R 1A )C(O)R 1B , -N(R 1A )C(O)OR 1B , or -N(R 1A )C(O)NR 1B R 1C ; wherein
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B is not halo-substituted phenyl
  • the compound of Formula (I) is that wherein:
  • Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each is optionally substituted with one or two R B groups;
  • each R B is independently halo; cyano; alkyl, haloalkyl; haloalkoxy; alkoxyalkoxy;
  • R 1 is hydrogen, alkyl or W; wherein W is alkyl substituted with alkylcarbonyloxy,
  • R 2 and R 3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
  • heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl
  • Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is that wherein:
  • R L is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 R AA groups;
  • each R AA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, alkylcarbonylaminoalkoxy, or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl,
  • heterocycloalkyl alkyl, or heterocycloalkylcarbonyl
  • R 1 is W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • the compound of Formula (I) is that wherein:
  • R L is hydrogen or C 1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
  • Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl,
  • Ring A is optionally substituted with one or two halo, alkyl,
  • Ring A is substituted with:
  • Ring A is optionally
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl
  • R AA cannot be alkyl or trifluoromethyl
  • R AB cannot be alkyl
  • the compound of Formula (I) is that wherein:
  • R L is hydrogen or C 1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
  • Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two halo, alkyl,
  • Ring A is substituted with:
  • Ring B when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two R AB groups;
  • each R AA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • the compound of Formula (I) is that wherein: Ring B is present; wherein Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R B groups;
  • each R B is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
  • the compound of Formula (I) is that wherein:
  • Ring A is C 3-7 cycloalkyl, C 8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
  • Ring A is substituted with one or two R AB groups or
  • Ring A is unsubstituted, wherein:
  • Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R 1 is not hydrogen or ethyl;
  • Ring A is unsubstituted spirocycloalkyl, then L is O or S;
  • each R B is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered
  • heterocycloalkyl-one alkyl
  • 5-6-membered heterocycloalkyl-one
  • heterocycloalkyl alkyl
  • heterocycloalkylcarbonyl or 5-6 membered heteroaryl
  • the compound of Formula (I) is that wherein:
  • ring B is not present
  • R L is hydrogen or C 1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy;
  • Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;
  • Ring A is phenyl, then Ring A is substituted with:
  • Ring A when Ring A is other than phenyl, then Ring A is substituted with one or two R AB groups; each R AA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
  • the compound of Formula (I) is that wherein:
  • Ring A is phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl;
  • Ring A is phenyl, then Ring A is substituted with:
  • Ring A is other than phenyl, then Ring A is substituted with one or two R AB groups;
  • each R AA is independently haloalkoxy, cycloalkyloxy, or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo, alkyl, alkoxy, or haloalkoxy
  • R 1 is hydrogen, alkyl, cycloalkyl, or W; where W is alkyl substituted with alkylcarbonyloxy; and R 2 and R 3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with alkylcarbonyloxy; and
  • the compound of Formula (I) is that wherein:
  • ring B is not present
  • Ring A is C 3-7 cycloalkyl, C 8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl,
  • Ring A is phenyl, then Ring A is substituted with:
  • halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
  • Ring A is substituted with one or two R AB groups;
  • Ring A is unsubstituted, wherein:
  • Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R 1 is not hydrogen or ethyl;
  • Ring A is unsubstituted spirocycloalkyl, then L is O or S;
  • the compound of Formula (I) is that wherein:
  • Ring A is piperidinyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolynyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, spiro[2.5]octane, spiro[4.5]decane, or spiro[5.5]undecane;
  • Ring A is phenyl, then Ring A is substituted with:
  • each R AA is independently haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, or
  • each R AB is independently halo, alkyl, haloalkyl, or haloalkoxy
  • R 1 is hydrogen, alkyl or W; wherein W is alkyl substituted with alkylcarbonyloxy; R 2 and R 3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
  • heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl
  • the compound of Formula (I) is that wherein:
  • Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl; wherein Ring A is optionally substituted with one or two groups selected from halo, alkyl,
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R B groups;
  • each R B is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
  • heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or a halo; (5-6- membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or
  • the compound of Formula (I) is that wherein:
  • L is bond, CH 2 , CF 2 , O, NR L , S, CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S;
  • R L is hydrogen, C1-4 alkyl, or benzyl, wherein the phenyl, as part of the benzyl group, is
  • Ring A is C 3-7 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, or naphthyl, wherein Ring A is optionally substituted with halo or haloalkoxy;
  • Ring B is cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl, tetrahydroquinolinyl, quinolinyl, or, isoquinolinyl; wherein each Ring B is optionally substituted with one or two R B groups;
  • each R B is independently halo; cyano; haloalkyl; haloalkoxy; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkoxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6-membered heterocycloalkyl- one)alkyl; and
  • R 1 is hydrogen or W; wherein W is alkyl substituted with alkylcarbonyloxy,
  • the compound of Formula (I) is that wherein L is bond, O, S, NR L , CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S, and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is that wherein L is O or S, and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is that wherein:
  • ring C is selected from:
  • the compound or Formula (I) is that wherein:
  • Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two R B groups;
  • each R B is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl;
  • alkoxyalkoxy aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
  • heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6- membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl;
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
  • R 1A , R 1B , and R 1C are each independently hydrogen or C 1- 6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl
  • the compound of Formula (I) is that wherein:
  • L is bond, CH 2 , CF2, O, NR L , S, CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S; R L is hydrogen, C1-4 alkyl, or benzyl, wherein the phenyl in the benzyl group is optionally substituted with haloalkoxy group;
  • Ring A is C 3-7 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, or naphthyl, wherein Ring A is optionally substituted with halo or haloalkoxy;
  • Ring B is cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl, tetrahydroquinolinyl,
  • each R B is independently halo; cyano; haloalkyl; haloalkoxy; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkoxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6-membered heterocycloalkyl- one)alkyl; and
  • R 1 is hydrogen or W; wherein W is alkyl substituted with alkylcarbonyloxy,
  • Ring B cannot be halo-substituted phenyl
  • the compound of Formula (I) is that wherein:
  • R L is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
  • Ring A is C 5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl,
  • Ring A is optionally substituted with one or two halo, alkyl,
  • Ring A is substituted with:
  • each R AA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
  • alkylcarbonyloxy cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl
  • R AA cannot be alkyl or trifluoromethyl
  • R AB cannot be alkyl
  • R L is H or C 1-4 alkyl optionally substituted with hydroxycarbonylalkyl
  • Ring A is 5-6 membered heterocycloalkyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl;
  • Ring A is optionally substituted with one or two halo, alkyl, alkoxy, or haloalkoxy;
  • Ring A is substituted with:
  • Ring A is substituted
  • each R AA is independently haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy
  • each R AB is independently halo, alkyl, alkoxy, haloalkoxy, or phenoxy optionally substituted with one or two halo;
  • Ring B when present, is heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally
  • each R B is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy,
  • heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl; ii. when L is S and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; ii. when L is O, Ring A is phenyl, and Ring B is not present, then R AA cannot be alkyl or trifluoromethyl; iii. when L is O, Ring A is phenyl, Ring B is not present, and R 1 is ethyl, then R AA cannot be trifluoromethoxy;
  • R AB cannot be alkyl
  • the compound of Formula (I) is that wherein:
  • R L is H or C 1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
  • Ring A is heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
  • heterocycloalkyl alkyl, or heterocycloalkylcarbonyl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is that wherein:
  • R L is H or C1-4 alkyl optionally substituted with hydroxycarbonylalkyl; Ring A is heterocycloalkyl, phenyl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
  • Ring B when present, is heterocycloalkyl, phenyl, or heteroaryl; wherein each is optionally substituted with one or two R B groups;
  • each R B is independently halo, alkyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocycloalkyl,
  • heterocycloalkyl alkyl, or heterocycloalkylcarbonyl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, or alkylcarbonyloxy;
  • R 2 and R 3 are each hydrogen or alkyl optionally substituted with alkylcarbonyloxy;
  • Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is that wherein:
  • R L is H or C1-4 alkyl
  • Ring A is phenyl or heteroaryl; wherein each is optionally substituted with one halo or alkyl; Ring B, when present, is phenyl or heteroaryl; wherein each is optionally substituted with one or two R B groups;
  • each R B is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, or
  • heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, or alkylcarbonyloxy;
  • R 2 and R 3 are independently hydrogen or alkyl
  • Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is according to
  • ring C is selected from:
  • the compound of Formula (II) is that wherein:
  • alkylcarbonyloxy and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R 1A )C(O)R 1B , -N(R 1A )C(O)OR 1B , or -N(R 1A )C(O)NR 1B R 1C ; wherein R 1A , R 1B , and R 1C are each independently hydrogen or C 1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is that wherein:
  • alkylcarbonyloxy and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C 3-7 cycloalkyl, C 8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl,
  • Ring A is phenyl, then Ring A is substituted with:
  • halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
  • Ring A is substituted with one or two R AB groups;
  • Ring A is unsubstituted, wherein:
  • each R AA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, phenoxy optionally substituted with one or two halo, or alkylcarbonylaminoalkoxy;
  • each R AB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R 1A )C(O)R 1B , -N(R 1A )C(O)OR 1B , or -N(R 1A )C(O)NR 1B R 1C ; wherein R 1A , R 1B , and R 1C are each independently hydrogen or C 1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • R AB when L is NH, Ring A is pyridyl, indolyl, or indolinyl, then R AB cannot be alkyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is that wherein:
  • alkylcarbonyloxy and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, tetrahydronaphthyl, dihydronaphthyl,
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R 1A )C(O)R 1B , -N(R 1A )C(O)OR 1B , or -N(R 1A )C(O)NR 1B R 1C ; wherein R 1A , R 1B , and R 1C are each independently hydrogen or C1-6 alkyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
  • the compound of Formula (II) is that wherein:
  • Ring A is piperidinyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, spiro[2.5]octane, spiro[4.5]decane, or spiro[5.5]undecane;
  • Ring A is phenyl, then Ring A is substituted with:
  • Ring A is substituted with one or two R AB groups;
  • Ring A is unsubstituted, wherein:
  • Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R 1 is not hydrogen or ethyl, or
  • Ring A is unsubstituted spirocycloalkyl, then L is O or S; each R AA is independently haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, or
  • each R AB is independently halo, alkyl, haloalkyl, or haloalkoxy
  • R 1 is hydrogen, alkyl, or W; wherein W is alkyl substituted with alkylcarbonyloxy;
  • R 2 and R 3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
  • heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl
  • the compound of Formula (I) is according to
  • ring C is selected from:
  • the compound of Formula (II) is that wherein:
  • R L is H or C 1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
  • Ring A is heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
  • heterocycloalkyl alkyl, or heterocycloalkylcarbonyl
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is that wherein:
  • Ring A is C 5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl,
  • Ring A is phenyl, then Ring A is substituted with:
  • Ring A when Ring A is other than phenyl, then Ring A is substituted with one or two R AB groups; each R AA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • R AA when L is O and Ring A is phenyl, then R AA cannot be alkyl or trifluoromethyl; ii. when L is O, Ring A is phenyl, and R 1 is ethyl, then R AB cannot be trifluoromethoxy; iii. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, then R AB cannot be alkyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is that wherein:
  • R L is H or C 1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
  • Ring A is C5-7 cycloalkyl, tetrahydronaphthalinyl, dihydronaphthalinyl, benzothiazolyl, isoquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro- methanonaphthalenyl; provided that when L is NR L or O, then Ring A cannot be
  • R 1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
  • the compound of Formula (II) is that wherein:
  • Ring A is phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl;
  • Ring A is phenyl, then Ring A is substituted with:
  • Ring A when Ring A is other than phenyl, then Ring A is substituted with one or two R AB groups; each R AA is independently haloalkoxy, cycloalkyloxy, or phenoxy optionally substituted with one or two halo;
  • each R AB is independently halo, alkyl, alkoxy, or haloalkoxy
  • R 1 is hydrogen, alkyl, cycloalkyl, or W; where W is alkyl substituted with alkylcarbonyloxy; R 2 and R 3 are independently hydrogen or alkyl;
  • alkyl is optionally substituted with alkylcarbonyloxy
  • R AB when L is O, Ring A is phenyl, and R 1 is ethyl, then R AB cannot be trifluoromethoxy; ii. when L is NH, Ring A is pyridyl or indolinyl, then R AB cannot be alkyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is according to
  • ring C is selected from:
  • the compound of Formula (III) is that wherein:
  • alkylcarbonyloxy and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl,
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, and haloalkoxy;
  • Ring A is substituted with:
  • halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
  • Ring A is substituted with one or two R AB groups or
  • Ring A is unsubstituted, wherein:
  • each R AA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy;
  • each R AB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
  • heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl halo, (5-6-membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl;
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, or benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl; ii. when L is S or CH 2 , and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; ii. when L is O, Ring A is phenyl, and Ring B is not present, then R AA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 R AA , and Ring B is not present, then R AA cannot be meta-substituted trifluoromethyl;
  • the compound of Formula (III) is that wherein:
  • Ring A is C5-6 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, phenyl,
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two groups selected from halo and haloalkoxy;
  • Ring A is substituted with:
  • halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
  • Ring A is substituted with one or two R AB groups;
  • Ring A is unsubstituted, wherein:
  • Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R 1 is not hydrogen or ethyl;
  • Ring A is unsubstituted spirocycloalkyl, then L is O or S; each R AA is independently haloalkyl; cycloalkyloxy; (cycloalkyl)alkoxy;
  • each R AB is independently halo, alkyl, haloalkyl, or haloalkoxy;
  • Ring B when present, cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl,
  • each Ring B is optionally substituted with one or two R B groups;
  • each R B is independently halo; cyano; alkyl; haloalkyl; haloalkoxy; alkoxyalkoxy;
  • heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6- membered heterocycloalkyl-one)alkyl;
  • R 2 and R 3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
  • heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl
  • the compound of Formula (I) is according to
  • ring C is selected from:
  • the compound of Formula (III) is that wherein:
  • Ring A is C 5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl,
  • Ring B is present or not present; wherein:
  • Ring A is optionally substituted with one or two halo, alkyl, alkoxy, or haloalkoxy;
  • Ring A is substituted with:
  • Ring B when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two R AB groups;
  • Ring B when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
  • each R B is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
  • heterocycloalkyl alkyl, or heterocycloalkylcarbonyl
  • R 2 and R 3 are independently hydrogen, alkyl, phenyl, or benzyl;
  • alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
  • Ring B cannot be halo-substituted phenyl; ii. when L is S and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; ii. when L is O, Ring A is phenyl, and Ring B is not present, then R AA cannot be alkyl or trifluoromethyl;
  • R AB cannot be alkyl
  • Ring A cannot be thienyl
  • L is CH 2 , CF2, O, NR L , or S.
  • L is CF2, O, NR L , or S.
  • L is CF 2 , O, or NR L .
  • L is CH 2 , O, NR L , or S.
  • L is O, NR L , or S.
  • L is CH 2 , CF2, CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S.
  • L is CH 2 -Q, or Q-CH 2 ; wherein Q is O, NR L , or S.
  • L is CH 2 -Q; wherein Q is O, NR L , or S.
  • L is CH 2 -O, or L is CH 2 -S, or L is CH 2 - NR L , or L is O-CH 2 , or L is NR L -CH 2 .

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Abstract

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with a defect in glyoxylate metabolism, for example a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.

Description

GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional Patent Application
No. 62/863,786, filed June 19, 2019, the content of which is incorporated herein by reference in its entirety.
FIELD
[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods to treat or prevent diseases or disorders associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Also described herein is that such compounds are for use in said methods for treating or preventing diseases or disorders. Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.
BACKGROUND
[0003] Primary hyperoxaluria (“PH”) is an autosomal-recessive disorder of glyoxylate metabolism. PH type I (PHI) is caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine : glyoxylate aminotransferase (AGT) which is deficient or mistargeted to mitochondria (Danpure et al ., FEBS Lett. 201(l):20-24 (1986)). AGT detoxifies glyoxylate to glycine. When AGT activity is deficient or mistargeted, excessive glyoxylate cannot be detoxified and is oxidized by intracellular lactate dehydrogenase (“LDH”) to oxalate. Excessive amounts of oxalate lead to urolithiasis and nephrocalcinosis, and can result in renal failure, end stage renal disease and systemic oxalosis.
[0004] Glycolate oxidase (GO) is a key enzyme involved in the oxalate metabolic pathway. Glycolate from internal metabolism and from diet will be oxidized by GO to glyoxylate. This oxidation only occurs in the liver peroxisome (Holmes et al, J
Urol. 160(5): 1617-1624 (1998 Nov.)). Under normal conditions, the glyoxylate generated by GO will be detoxified by AGT to glycine. However, in PHI patients, where the glyoxylate to glycine pathway is blocked, the glyoxylate generated by GO is oxidized by LDH to produce excessive amounts of oxalate. [0005] An approach to treatment of PH1 is to inhibit the GO enzyme to reduce the production of glyoxylate and ultimately reduce the production of excessive amounts of oxalate. It has been shown in HAO1 (GO)-/- /AGXT-/- double knockout mouse that GO deficiency can correct overproduction of urine oxalate over production in AGXT-/- mouse (Martin-Higueras et al., Mol Ther.24(4): 719-725 (2016)). In both humans and mice, the HAO1-/- deficiency appears clinically/phenotypically normal except for the increased urine glycolate secretion (Martin- Higueras et al., Mol Ther.24(4): 719-725 (2016)). Inhibition of GO with Dicer-substrate siRNA has also been shown to reduce urine oxalate secretion and reduce kidney calcium oxylate deposition in the PH1 mouse model (Dutta et al., Mol Ther.24(4): 770-778 (2016 Apr.)).
[0006] The most commonly observed effect of high levels of oxalate is the formation of crystals in various tissues. Crystal oxalate formation in the kidney results in nephrolithiasis, or kidney stones. Similarly, increased urinary oxalates can also lead to nephrocalcinosis.
[0007] Accumulation of oxalate is implicated in primary hyperoxaluria type II (“PH2) and primary hyperoxaluria type III (“PH3”). Similar to PH1, mutations in a gene results in decreased production or activity of the corresponding enzymes that are produced. Such disruptions to the enzymes adversely affects the normal breakdown of glyoxylate. In healthy subjects, glyoxylate is converted to glycine, which is readily secreted. In diseased subjects, there is a build-up of glyoxylate, which gets converted to oxalate. When the buildup of oxalate exceeds the capacity of the kidney to excrete it, the oxalate starts to deposit in various organ systems in a process called systemic oxalosis. In PH2 patients, a decrease in the breakdown of glyoxylate is caused by mutations in the GRHPR gene, which normally reduces glyoxylate to glycolate. PH3 is a third type of PH, and is identified in patients with previously unclassified forms of PH. PH3 is caused by mutations in the HOGA gene (formerly known as the DHDPSL gene). This enzyme functions in the final step of 4-hydroxyproline (Hyp) catabolic pathway. Overactivity of the enzyme leads to excess conversion of hydroxyproline to glyoxylate, which yields high levels of oxalate. The genetic mutations that cause PH are inherited as autosomal recessive traits.
[0008] Build-up of oxalate and deficiencies in processes involving urinary excretion of oxalate is further implicated in a variety of diseases and disorders, such as progressive kidney failure, recurrent kidney stones, nephrocalcinosis, urinary tract infections, chronic kidney disease, and end stage renal disease. Reducing urinary oxalate levels and plasma oxalate levels can helpful in treating or ameliorating these diseases and conditions.
[0009] Hyperoxaluria is characterized by an increased urinary excretion of oxalate.
Excess urinary oxalate, whether from primary or enteric hyperoxaluria, can lead to oxalate deposits in the kidney. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria, as discussed above, is caused by genetic mutations which increases oxalate production. Secondary hyperoxaluria includes dietary hyperoxaluria, enteric hyperoxaluria and idiopathic hyperoxaluria. In addition to these types of hyperoxaluria, there are pharmacologically induced hyperoxalurias that are caused by the ingestion of compounds that can be metabolized to oxalate, such as ethylene glycol or other precursors such as hydroxyproline.
[0010] Dietary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. A high intake of oxalate-rich foods (eg, chocolate, nuts, spinach) and a diet rich in animal protein can result in hyperoxaluria. Low dietary calcium intake can also result in hyperoxaluria via decreased intestinal binding of oxalate and the resulting increased absorption. Ascorbic acid can be converted into oxalate, resulting in increased urinary oxalate levels. Patients with abnormal or altered cellular membrane oxalate transport mechanism have abnormally high absorption of dietary oxalate. Patients with a deficiency of oxalobacter formigenes, an intestinal oxalate degrading bacterial, will also have the increased oxalate absorption. Diets that are high in any metabolic precursor of oxalate can lead to elevated oxalate levels that could be reduced by inhibition of GO.
[0011] Enteric hyperoxaluria results from a chronic underlying gastrointestinal disorder associated with malabsorption of fat, bile acids, decreased enteric secretion of oxalate by the membrane protein anion transporter (slc26a6) due to the abnormal glycosylation of brush border, or triggered by obesity which influenced paracellular and transcellular transporting. Related diseases include steatorrhea, inflammatory bowel disease (“IBD”), biliary cirrhosis, short-bowel syndrome, celiac disease, pancreatic insufficiency, Crohn’s disease, ulcerative colitis, bariatric surgery, jejunoileal bypass, ileal dysfunction, absence of gastrointestinal tract-dwelling bacterium oxalobacter formigenes, and Roux-en-Y gastric bypass (“RYGB”). In addition, cystic fibrosis, high blood pressure, and diabetes can lead to metabolic changes which can result in increased oxalate (see Nazzal, L., et al., Nephrology Dialysis Transplantation, 31(3):375–382 (2016 Mar.).
[0012] There is an increased risk of urolithiasis and loss of kidney function from oxalate nephropathy. With idiopathic hyperoxaluria, the causes are unknown.
[0013] Formation of oxalate crystals are associated with renal inflammation, fibrosis and progressive renal failure. Studies also show high oxalate levels can be an activator of inflammatory pathways, and in particular, with inflammasome activation and the progression of kidney disease, and NALP3-mediated inflammation (see Ermer, T; et al., Curr Opin Nephrol Hypertens, 25(4):363-371 (2016 July); and Knauf, F., et al., Kidney Int., 84(5):895-901 (2013 Nov.)).
[0014] There is a known association of high urinary oxalate with acute kidney injury and chronic kidney disease (“CKD”). Studies show a correlation of higher urinary oxalate concentrations with a higher risk of CKD (Waikar, Sushru S., et al., JAMA Intern Med.,
179(4):542-551 (2019)). These studies have shown that patients with chronic kidney disease that also have high normal urine oxalate levels have a more rapid disease progression rate than those similar patients with low normal urine oxalate levels. Therapeutic approaches to reduce the oxalate burden in these patients has the potential to slow the progression of disease. If any of the multiple sources of oxalate can be reduced, there could be benefits to these patients. For example, inhibition of GO or LDH (or any other metabolic step that contributes to the generation or absorption of oxalate) could reduce oxalate levels and slow the progression of disease. It has long been known that as glomerular filtration rate (GFR) becomes reduced in CKD, there is an elevation of plasma oxalate. Elevation of plasma oxalate in CKD may promote renal inflammation and more rapid progression of CKD independent of primary etiology. Higher urinary oxalate excretion among CKD patients is also associated with an elevated risk of end- stage renal disease (ESRD; also known as end-stage kidney disease,“ESKD”).
[0015] Hyperoxaluria has been implicated as a complication or undesired side effect of various diseases, such as Hirschsprung’s disease, cystic fibrosis, chronic biliary pathology, pancreatic pathology, high blood pressure, diabetes, and obesity. Hyperoxaluria can also be related to genetic or environmental vitamin B6 deficiency, genetic or environmental abnormal calcium metabolism such as, hypercalciuria and hyperparathyroidism and abnormal collagen metabolism, abnormal oxalate or oxalate precursor transporters. Reduction of oxalate levels would also have therapeutic benefit in the management of the complications from these diseases and conditions.
[0016] Accordingly, molecules that inhibit the activity of GO may be used to treat disorders of glyoxylate metabolism, including PH1, that are associated with production of excessive amounts of oxalate. Other diseases and conditions impacted by excessive oxalate formation may benefit from treatment with a GO inhibitor, such as PH2, PH3, enteric hyperoxaluria, dietary hyperoxaluria, idiopathic hyperoxaluria, urolithiasis, nephrolithiasis, nephrocalcinosis, chronic kidney disease, end stage renal disease, or systemic oxalosis. SUMMARY
[0017] In one aspect, provided herein is a compound of Formula (I):
wherein:
Figure imgf000006_0001
ring C is selected from:
Figure imgf000006_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to L;
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-8 cycloalkyl, C8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups
independently selected from halo, alkyl, alkoxy, cyano, hydroxy, haloalkoxy,
(cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups;
(ii) 2 halo groups when L is other than O;
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl;
(iv) one halo group when L is CH2NRL;
(v) one halo group and one group selected from the group consisting of haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O, S, or S(=O), wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy; or
(vi) one cyano group and one (phenyl)alkoxy group, when L is bond or O, wherein the phenyl as part of the (phenyl)alkoxy group is optionally substituted with halo or haloalkoxy;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is a bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O, S, or CH2S;
each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo groups; or
alkylcarbonylaminoalkoxy;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl;
alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy;
alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl;
alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy;
(cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with
hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered
heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or - N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S or CH2, and Ring A is phenyl other than phenyl substituted with
(cycloalkyl)alkoxy, then Ring B cannot be halo-substituted phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl; iv. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl, and
vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[0018] In another aspect, provided herein is a compound of Formula (XII):
Figure imgf000009_0001
wherein:
ring C is selected from:
Figure imgf000009_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy; Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-; each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
provided:
i. the compound represented by Formula (XII) is exclusive of:
a. 4-(phenylamino)-1H-1,2,3-triazole-5-carbaldehyde;
b. 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-5-carbaldehyde; c. ethyl hydrogen (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate;
d. diethyl (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-1H- 1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; and
e. 1-((4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methyl)-5-methylpyrimidine- 2,4(1H,3H)-dione;
ii. when Z is -C(=O)H, L is NRL, RL is hydrogen, and Ring A is phenyl, then Ring B is present and/or the phenyl Ring A is substituted with 1, 2, or 3 RA2 groups;
iii. when Z is -C(=O)H, L is CH2, and Ring A is cyclopropyl, phenyl, indole, or thiophene, then Ring B is present;
iv. when Z is -C(=O)H, L is CH2-O, and Ring A is phenyl, then Ring B is present;
v. when Z is -CH2OY, Y is W, W is -P(=O)(OR7)2 or -P(=O)(OR7)(O-), R7 is ethyl, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine- 2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
vi. when Z is -CH2OY, Y is hydrogen, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [0019] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as disclosed herein, and a pharmaceutically acceptable excipient.
[0020] In a further aspect, provided herein is a method of treating a disease or disorder associated with a defect in glyoxylate metabolism with a compound disclosed herein. Thus, a compound disclosed herein is for use in a method of treating a disease or disorder associated with a defect in glyoxylate metabolism, such as diseases or disorders associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Such a compound is, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), as disclosed herein, or a pharmaceutical composition comprising the compound disclosed herein, and a pharmaceutically acceptable excipient, as disclosed herein.
[0021] In certain embodiments, the disease or disorder is a primary hyperoxaluria. In certain embodiments, the disease or disorder is primary hyperoxaluria type I. In certain embodiments, the disease or disorder is PH2. In certain embodiments, the disease or disorder is PH3. In certain embodiments, the disease or disorder is an enteric hyperoxaluria. In certain embodiments, the disease or disorder is a dietary hyperoxaluria, In certain embodiments, the disease or disorder is an idiopathic hyperoxaluria. In certain embodiments, the disease or disorder is urolithiasis. In certain embodiments, the disease or disorder is nephrolithiasis. In certain embodiments, the disease or disorder is nephrocalcinosis. In certain embodiments, the disease or disorder is chronic kidney disease. In certain embodiments, the disease or disorder is end stage renal disease. In certain embodiments, the disease or disorder is systemic oxalosis.
DETAILED DESCRIPTION
Abbreviations
Figure imgf000013_0001
Definitions
[0022] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well- known and commonly employed in the art.
[0023] “About” preceding a numerical value refers to a range of values ±10% of the value specified.
[0024] “Acceptable” with respect to a formulation, composition or ingredient, means having no persistent detrimental effect on the general health of the subject being treated.
[0025] Whenever a group is described as being“optionally substituted,” it is meant that the referenced group can be“unsubstituted or substituted.”
[0026] “Alkoxy” means a group of the formula–OR, wherein R is alkyl. In certain embodiments, alkoxy includes methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy.
[0027] “Alkoxyalkoxy” means a group of the formula–OR-OR¢, wherein R is alkylene as defined herein, and R¢ is alkyl as defined herein.
[0028] “Alkoxycarbonyl” means a group of the formula–C(O)R, wherein R is alkoxy, as defined herein. [0029] “Alkoxycarbonyloxy” means a group of the formula–OC(O)R, wherein R is alkoxy, as defined herein.
[0030] “Alkylcarbonylaminoalkoxy” means a group of the formula–OR-NH-C(O)R’, wherein R is alkylene, as defined herein, and R’ is alkyl, as defined herein.
[0031] “Alkyl” means a straight or branched saturated hydrocarbon group containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms. In certain embodiments, alkyl includes 1-4 carbon atoms (“C1-4 alkyl”). In certain embodiments alkyl includes 1-3 carbon atoms (“C1-3 alkyl”). In certain embodiments, alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.
[0032] “Alkylene” means a straight or branched saturated divalent hydrocarbon group containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms.
[0033] “Alkylcarbonylamino” means a group of the formula–NHC(O)R, wherein R is alkyl, as defined herein.
[0034] “Amino” means an–NH2 group.
[0035] “Aminoalkoxy” means a group of the formula–O-R-NH2, wherein R is alkyl as defined herein. In one embodiment, (amino)alkoxy includes (amino)propyloxy.
[0036] “Alkylaminoalkoxy” means an–O-R-NHR’ group, wherein R and R’ are independently alkyl as defined herein. In one embodiment (dialkylamino)alkoxy includes (methylamino)propyloxy.
[0037] “Aminocarbonyl” means an–C(O)NH2 group.
[0038] “Aminocarbonyloxy” means a group of the formula–OC(O)R, wherein R is amino, as defined herein.
[0039] “Alkylaminocarbonyloxy” means a group of the formula–OC(O)R, wherein R is alkylamino, as defined herein.
[0040] “Alkylamino” means a group of the formula–NHR, wherein R is alkyl as defined herein. In certain embodiments, alkylamino includes methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, iso-butylamino, or tert-butylamino.
[0041] “Alkylcarbonyl” means a group of the formula–C(O)R, wherein R is alkyl, as defined herein. [0042] “Alkylcarbonyloxy” means a group of the formula–OC(O)R, wherein R is alkyl, as defined herein.
[0043] “Alkylsulfonyl” means a group of the formula–SO2R, wherein R is alkyl, as defined herein.
[0044] “Aminosulfonyl” means a group of the formula–SO2NH2.
[0045] “Alkylaminosulfonyl” means a group of the formula–SO2NHR, wherein R is alkyl, as defined herein.
[0046] “Dialkylaminoalkoxy” means an–O-R-NR’R” group, wherein R, R’, and R” are independently alkyl as defined herein. In one embodiment (dialkylamino)alkoxy includes (dimethylamino)propyloxy.
[0047] “Dialkylaminosulfonyl” means a group of the formula–SO2NRR’, wherein R and R’ are independently alkyl, as defined herein.
[0048] “Aryl” means a monovalent six- to fourteen-membered, mono-, bi-, or tri- carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic or tricyclic ring is aromatic. In certain embodiments, aryl includes phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indanyl, or anthracenyl.
[0049] “Carbonyl” means an–C=(O) group.
[0050] “Carboxyl” means an–C(O)OH group.
[0051] “Cyano” means an–CN group.
[0052] “Cycloalkyl” means a monocyclic or bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon ring of three to ten carbon ring atoms. Cycloalkyl groups include fused and bridged bicyclic rings. For example, when fused, the cycloalkyl group may comprise two rings that share adjacent atoms (e.g., one covalent bond). When bridged, the cycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. When a cycloalkyl group contains from x-y ring carbon atoms, it may be referred to herein as Cx-y cycloalkyl. In certain embodiments, cycloalkyl is C3-10 cycloalkyl, or is C5-7 cycloalkyl, or is C5-6 cycloalkyl, or is C3-6 cycloalkyl, or is C3-7 cycloalkyl. In certain embodiments, cycloalkyl is C3-8 cycloalkyl. In certain embodiments, cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In
certain embodiments, the cycloalkyl group is
Figure imgf000016_0001
[0053] “(Cycloalkyl)alkyl” means an alkyl group, as defined herein, substituted with at least one cycloalkyl groups as defined herein. In certain embodiments, alkyl is substituted with 1 cycloalkyl group. In certain embodiments, alkyl is substituted with 1 or 2 cycloalkyl groups. In certain embodiments, (cycloalkyl)alkyl includes cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
[0054] “(Cycloalkyl)alkoxy” means a group of the formula–OR, wherein R is a
(cycloalkyl)alkyl group as defined herein. In certain embodiments, (cycloalkyl)alkoxy includes cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy.
[0055] “Cycloalkyloxy” means a group of the formula–OR, wherein R is cycloalkyl, as defined herein. In certain embodiments, cycloalkyloxy includes cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
[0056] “Cycloalkylcarbonyl” means a group of the formula–C(O)R, wherein R is cycloalkyl, as defined herein.
[0057] “Cycloalkylcarbonyloxy” means a group of the formula–OC(O)R, wherein R is cycloalkyl, as defined herein.
[0058] “Dialkylamino” means a group of the formula–NRR¢, wherein R and R¢ are independently alkyl as defined herein. In certain embodiments, dialkylamino includes dimethylamino, diethylamino, N,N-methylpropylamino or N,N-methylethylamino.
[0059] “Dialkylaminocarbonyl” means a group of the formula–C(O)R, wherein R is dialkylamino, as defined herein.
[0060] “Dialkylaminocarbonyloxy” means a group of the formula–OC(O)R, wherein R is dialkylamino, as defined herein.
[0061] “Halo” means a fluoro, chloro, bromo, or iodo group.
[0062] “Haloalkoxy” means an alkoxy group, substituted with one or more halo atoms. In certain embodiments, all hydrogen atoms of the alkoxy group are replaced with halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, or 3 halo atoms. In certain other embodiments, the alkoxy is substituted with 2 halo atoms. In certain embodiments, the alkoxy is substituted with 1 halo atom. Certain embodiments of haloalkoxy include difluoromethoxy,
trifluoromethoxy, or 1,1,1-trifluoroethoxy.
[0063] “Haloalkyl” means an alkyl group substituted with one or more halo atoms. In certain embodiments, all hydrogen atoms of the alkyl group are substituted with halo atoms. In certain embodiments, the alkyl group is substituted by 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, the alkyl group is substituted by 1, 2, or 3 halo atoms. In certain other
embodiments, the alkyl group is substituted with 2 halo atoms. In certain embodiments, the alkyl group is substituted with 1 halo atom. In certain embodiments, haloalkyl includes
trifluoromethyl, fluoromethyl, perfluoroethyl, or chloromethyl. Certain other embodiments of haloalkyl include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,1,1- trifluoroethanyl.
[0064] “Heteroaryl” means a monocyclic, bicyclic, or tricyclic ring of 5 to 14 ring atoms containing one or more ring heteroatoms independently selected from -O-, -S-, -N= (trivalent nitrogen), and -N(H)-, and the remaining ring atoms being carbon atoms, wherein the
monocyclic ring is aromatic and wherein at least one of the rings in the bicyclic or tricyclic rings is aromatic (but does not have to be a ring which contains a heteroatom, e.g.;
tetrahydroquinolinyl, dihydroisoquinolinyl, dihydrobenzodioxinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, and the like). In certain embodiments, heteroaryl is a monocylic ring of 5 to 6 rings atoms. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting.
[0065] In certain embodiments, heteroaryl includes, but is not limited to, triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, indolyl, indolinyl, isoindolinyl, indazolyl, benzimidazolyl,
benzoxazolyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
dihydroisoquinolinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2- a]pyridinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, furo[2,3-d]thiazolyl, thieno[2,3-d]oxazolyl, thieno[3,2-b]furanyl, furo[2,3-d]pyrimidinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 7,8-dihydro-6H- cyclopenta[g]quinoxalinyl, dihydrobenzodioxinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl. [0066]“Heterocycloalkyl” means a saturated or partially unsaturated (but not aromatic) monocyclic ring of 3 to 9 ring atoms, or a saturated or partially unsaturated (but not aromatic) bicyclic ring of 5 to 12 ring atoms in which one or more ring atoms is a heteroatom
independently selected from -O-, -S-, -N= (trivalent nitrogen), or -NH-, and the remaining ring atoms are carbon. In certain embodiments, heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 4 to 7 rings atoms, or a saturated or partially unsaturated bicyclic group of 7 to 9 ring atoms. In certain embodiments, heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 5 to 6 rings atoms or a saturated or partially unsaturated bicyclic group of 6 to 8 ring atoms.
[0067] In certain embodiments, the heterocycloalkyl group comprises one, two, three, or four ring heteroatoms, independently selected from -O-, -S-, -N= (trivalent nitrogen), or -NH-, and the remaining ring atoms are carbon. In certain embodiments, the heterocycloalkyl group contains only one or two nitrogen atoms, and the remaining ring atoms are carbon. When a
heterocycloalkyl group contains from x to y ring atoms, it may be referred to herein as“a x-y membered heterocycloalkyl”. In certain embodiments, the heterocycloalkyl is a 4-7 membered heterocycloalkyl, or is a 5-6 membered heterocycloalkyl, or is a 7-9 membered heterocycloalkyl. In certain embodiments, the heterocycloalkyl is a 5-8 membered heterocycloalkyl.
[0068] Heterocycloalkyl groups include fused or bridged heterocycloalkyl bicyclic rings. For example, a fused heterocycloalkyl group may comprise two rings that share adjacent atoms (e.g., one covalent bond). When bridged, the heterocycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at
least one atom. In certain embodiments, the heterocycloalkyl group is
Figure imgf000018_0001
or
Figure imgf000018_0002
.
[0069] In certain embodiments, heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, octahydropyrrolo[3,4-c]pyrrolinyl, decahydroisoquinolyl, tetrahydrofuryl, 2-azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 1,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, and 8-azabicyclo[3.2.1]octanyl.
[0070] “(Heterocycloalkyl)alkyl” means an alkyl group, as defined herein, substituted with at least one, in another example 1 or 2, heterocycloalkyl groups as defined herein. In certain embodiments, the alkyl is substituted with one heterocycloalkyl group.
[0071] “Heterocycloalkylcarbonyl” means a group of the formula–C(O)R, wherein R is heterocycloalkyl, as defined herein.
[0072] “Heterocycloalkylcarbonyloxy” means a group of the formula–OC(O)R, wherein R is heterocycloalkyl, as defined herein.
[0073] “Heterocycloalkyl-one” means a heterocycloalkyl group as defined herein and wherein one ring carbon atom of the heterocycloalkyl group forms a double bond with oxygen
atom. In certain embodiments heterocycloalkyl-one group is
Figure imgf000019_0001
[0074] “Hydroxy” means an–OH group. The terms“hydroxy” and“hydroxyl” are used interchangeably and mean an–OH group.
[0075] “Hydroxyalkyl” means a group of formula–R-(OH)z, where R is an alkyl as defined herein and z is 1 or 2. In one embodiment, hydroxyalkyl is -ROH. In one embodiment, hydroxyalkyl includes -CH2OH. In one embodiment, hydroxyalkyl is -R(OH)2.
[0076] “Hydroxyalkoxy” means a group of formula–O-R-(OH)z, where R is an alkyl as defined herein and z is 1 or 2. In one embodiment, hydroxyalkoxy is–OR-(OH). In one embodiment, hydroxyalkoxy is–OR-(OH)2. In one embodiment (hydroxy)alkoxy includes (hydroxy)propyloxy.
[0077] “Hydroxycarbonyl” means an–C(O)OH group. As used herein, the terms “hydroxycarbonyl” and“carboxyl” are used interchangeably and refer to the same group.
[0078] “Hydroxycarbonylalkyl” means a group of the formula–RC(O)OH, wherein R is alkylene as defined herein. [0079] “Hydroxycycloalkyl” means a group of the formul–ROH, wherein R is
cycloalkyl as defined herein. In certain embodiments, hydroxycycloalkyl is
Figure imgf000020_0001
.
[0080] “(Hydroxycycloalkyl)alkyl” means a group of formula–RR’ wherein R is alkyl and R’ is hydroxycycloalkyl as defined herein. In certain embodiments (hydroxycycloalkyl)alkyl
Figure imgf000020_0002
[0081] “(Phenyl)alkyl” means an alkyl group, as defined herein, substituted with at least one phenyl group. In certain embodiments, the alkyl is substituted with one phenyl group. In certain embodiments, (phenyl)alkyl is benzyl.
[0082] “(Phenyl)alkoxy” means a group of the formula–OR, wherein R is (phenyl)alkyl as defined herein.
[0083] “Phenylcarbonyloxy” means a group of the formula–OC(O)R, wherein R is phenyl.
[0084] “Spirocycloalkyl” means a bicyclic cycloalkyl ring of 5 to 12 carbon ring atoms having one quaternary carbon ring atom common to both rings. In certain embodiments, the spirocycloalkyl is a C5-12 spirocycloalkyl, or is a C8-11 siprocycloalkyl.
[0085] In certain embodiments, spirocycloalkyl groups include spiro[2.5]octane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane , spiro[4.5]decane, or spiro[5.5]undecane.
In certain embodiments, the spirocycloalkyl group is
Figure imgf000020_0003
Figure imgf000020_0004
.
[0086] In some embodiments, compounds of the described herein exist as stereoisomers, wherein asymmetric or chiral centers are present. The term (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45:13-30, hereby incorporated by reference. The embodiments described herein specifically includes the various stereoisomers and mixtures thereof.
[0087] “Stereoisomers” include (but are not limited to) geometric isomers, enantiomers, diastereomers, and mixtures of geometric isomers, enantiomers or diastereomers. In some embodiments, individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column.
[0088] “Amelioration” of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
[0089] The terms“effective amount” or“therapeutically effective amount,” refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
[0090] “Excipient” or“pharmaceutically acceptable excipient” means a
pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response,
immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.;
Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical
Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American
Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.
[0091] “Pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or salicylic acid. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, or lysine, or by other methods previously determined. The pharmacologically acceptable salts are not specifically limited as far as it can be used in medicaments.
[0092] The term“pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components, such as an excipient. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
[0093] “Subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and“patient” are used interchangeably. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a human child.
[0094] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain
embodiments, the subject is a human child.
[0095] “Treat,”“treating,” and“treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.
[0096] The term“disease or disorder characterized by high oxalate content in the urine” refers to an oxylate content that is at least 10% higher than a reference level observed in a healthy patient. For example, in certain embodiments, the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is at least 20% higher than a reference level observed in a healthy patient, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 100%, or at least 200%, higher than a reference level observed in a healthy patient. In certain embodiments, the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is about 10% higher than a reference level observed in a healthy patient, such as about 20%, about 30%, about 40%, about 50%, about 100%, about 200%, or more than 200%, higher than a reference level observed in a healthy patient. In certain embodiments, the disease or disorder characterized by high oxalate content in the urine refers to an oxylate content that is about 1.25 times higher than a reference level observed in a healthy patient, such as about 1.25 times, about 1.5 times, about 1.75 times, about 2 times, about 3 times, or more than 3 times, higher than a reference level observed in a healthy patient.
Embodiments
[0097] The following paragraphs present a number of embodiments of the compounds disclosed herein. In each instance the embodiment includes both the recited compound(s) as well as a single stereoisomer or mixture of stereoisomers thereof, as well as a pharmaceutically acceptable salt thereof.
[0098] In one aspect, provided herein is a compound of Formula (I):
Figure imgf000024_0001
wherein:
Ring C is selected from:
Figure imgf000024_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to L;
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-8 cycloalkyl, C8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups
independently selected from halo, alkyl, alkoxy, cyano, hydroxy, haloalkoxy,
(cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups;
(ii) 2 halo groups when L is other than O;
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl;
(iv) one halo group when L is CH2NRL; (v) one halo group and one group selected from the group consisting of haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O, S, or S(=O), wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy; or
(vi) one cyano group and one (phenyl)alkoxy group, when L is bond or O, wherein the phenyl as part of the (phenyl)alkoxy group is optionally substituted with halo or haloalkoxy;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O, S, or CH2S;
each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo groups; or
alkylcarbonylaminoalkoxy;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo groups;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl;
alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy;
alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl;
alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy;
(cycloalkyl)alkoxy wherein cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6- membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl,
(hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or - N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S or CH2, and Ring A is phenyl other than phenyl substituted with
(cycloalkyl)alkoxy, then Ring B cannot be halo-substituted phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
iv. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA
cannot be trifluoromethoxy;
v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl, and
vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[0099] In certain embodiments, Ring B cannot be mono or di-substituted halo.
[00100] In certain embodiments, Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl. [00101] In certain embodiments, Ring A cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl, and Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.
[00102] In certain embodiments, when L is S or CH2, Ring B cannot be mono or di-substituted halo.
[00103] In certain embodiments, when L is S or CH2, Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.
[00104] In certain embodiments, when L is S or CH2, Ring A cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl, and Ring B cannot be unsubstituted phenyl or phenyl substituted with one or two groups independently selected from alkyl, halo, or haloalkyl.
[00105] In certain embodiments, the compound of Formula (I):
Figure imgf000027_0001
is that wherein:
ring C is selected from:
Figure imgf000027_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to L;
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is
optionally substituted with 1 or 2 RAA groups; when Ring B is present, then Ring A is optionally substuted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
each RAA is independently alkyl; halo; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; alkylcarbonylaminoalkoxy; phenoxy optionally substituted with one or two halo; or (phenyl)alkoxy wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00106] In certain embodiments, the compound of Formula (I):
Figure imgf000029_0001
is that wherein:
ring C is selected from:
Figure imgf000029_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to L;
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups;
each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, alkylcarbonylaminoalkoxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00107] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
when Ring B is present, then Ring A is optionally substuted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is
optionally substituted with 1 or 2 RAA groups;
each RAA is independently alkyl; halo; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; alkylcarbonylaminoalkoxy; phenoxy optionally substituted with one or two halo; or (phenyl)alkoxy wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;
R1 is W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino,
alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy,
alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00108] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substuted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O,
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo; when Ring B is not present and Ring A is other than phenyl, then Ring A is optionally substituted with one or two RAB groups;
each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; alkylcarbonylaminoalkoxy; or phenoxy optionally substituted with one or two halo;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or - N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo-substituted
phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
iv. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl, and
vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00109] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substuted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O,
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or (v) one halo group and one group selected from the group consisting of haloalkoxy,
(cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S;
each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with
amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl;
iii. when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
iv. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl, and
vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00110] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein: when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O,
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S; each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with 1 or 2 groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or - N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl;
iii. when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
iv. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl, and
vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. In a further embodiment, the compound of Formula (I) is that wherein: RL is hydrogen, C1-4 alkyl, or benzyl; and the benzyl group is optionally substituted with one or two haloalkoxy groups; and Ring A is C3-7 cycloalkyl, C8-11
spirocycloalkyl, 5-8 membered heterocycloalkyl, phenyl, naphthyl, indanyl, tetrahydronaphthnyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl. In a further embodiment, the compound of Formula (I) is that wherein: RL is hydrogen, C1-4 alkyl, or benzyl; and the benzyl group is optionally substituted with one or two haloalkoxy groups; and Ring B, when present, is cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl.
[00111] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O,
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups;
each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy; each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy;
aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with 1 or 2 groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or - N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl;
iii. when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
iv. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy; v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl, and
vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00112] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, or benzyl; and the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C5-6 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, phenyl,
naphthyl, indanyl, tetrahydronaphthyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo and haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O,
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups; or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or 4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S; each RAA is independently haloalkyl; cycloalkyloxy; (cycloalkyl)alkoxy;
alkylcarbonylaminoalkoxy; or phenoxy optionally substituted with one or two halo; each RAB is independently halo, alkyl, haloalkyl, or haloalkoxy;
Ring B, when present, cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl,
tetrahydroquinolinyl, quinolinyl, or isoquinolinyl; wherein each Ring B is optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; haloalkoxy; alkoxyalkoxy;
aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkoxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6- membered heterocycloalkyl-one)alkyl;
R1 is hydrogen, alkyl or W; wherein W is alkyl substituted with alkylcarbonyloxy,
dialkylaminocarbonyloxy cycloalkylcarbonyloxy, or phenylcarbonyloxy;
R2 and R3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
(i) when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo substituted phenyl;
(ii) when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl;
(iii) when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
(iv) when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
(v) when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl, and
(vi) when L is NH, Ring A is pyridyl and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [00113] In certain embodiments, the compound of Formula (I) is that wherein: L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is H, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally
substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl;
alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6- membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl; R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when L is S or CH2, and Ring A is phenyl, then Ring B is not halo-substituted phenyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00114] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, O, CF2, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is H, C1-4 alkyl, or benzyl; and the phenyl in the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
Ring B, when present, is cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; wherein each is optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl, haloalkyl; haloalkoxy; alkoxyalkoxy;
aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkoxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6-membered
heterocycloalkyl-one)alkyl;
R1 is hydrogen, alkyl or W; wherein W is alkyl substituted with alkylcarbonyloxy,
dialkylaminocarbonyloxy cycloalkylcarbonyloxy, or phenylcarbonyloxy;
R2 and R3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when L is S and Ring A is phenyl, then Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00115] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, or alkylcarbonyloxy;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups;
each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, alkylcarbonylaminoalkoxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups; each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl,
(heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00116] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl,
thiazolyl, thiophenyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl,
dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, dihydrobenzodioxinyl, or tetrahydro-methanonaphthalenyl;Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl,
alkoxy, or haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O;
when Ring B is not present and Ring A is other than phenyl, then Ring A is optionally
substituted with one or two RAB groups;
each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo; each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl- one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
phenylcarbonyloxy;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl or trifluoromethyl;
iii. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
iv. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00117] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl,
alkoxy, or haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O;
when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups;
each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl- one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
phenylcarbonyloxy; and
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [00118] In certain embodiments, the compound of Formula (I) is that wherein: Ring B is present; wherein Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl- one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl; provided when L is S and Ring A is phenyl, then Ring B is not halo-substituted phenyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00119] In certain embodiments, the compound of Formula (I) is that wherein:
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O;
3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S;
each RB is independently halo; cyano; alkyl; alkylsulfonyl; aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered
heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one;
(heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;
and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally
optionally a pharmaceutically acceptable salt thereof.
[00120] In certain embodiments, the compound of Formula (I) is that wherein:
ring B is not present;
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;
wherein:
when Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O;
when Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups; each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
phenylcarbonyloxy; and
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00121] In certain embodiments, the compound of Formula (I) is that wherein:
Ring A is phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl;
wherein:
when Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O;
when Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups;
each RAA is independently haloalkoxy, cycloalkyloxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, alkoxy, or haloalkoxy;
R1 is hydrogen, alkyl, cycloalkyl, or W; where W is alkyl substituted with alkylcarbonyloxy; and R2 and R3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with alkylcarbonyloxy; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00122] In certain embodiments, the compound of Formula (I) is that wherein:
ring B is not present;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl,
dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
wherein:
when Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O; (iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl, (iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
when Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups; or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O;
3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S;
and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00123] In certain embodiments, the compound of Formula (I) is that wherein:
Ring A is piperidinyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolynyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, spiro[2.5]octane, spiro[4.5]decane, or spiro[5.5]undecane;
when Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O;
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy and (cycloalkyl)alkoxy, when L is bond, O or S;
each RAA is independently haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, or
alkylcarbonylaminoalkoxy;
each RAB is independently halo, alkyl, haloalkyl, or haloalkoxy;
R1 is hydrogen, alkyl or W; wherein W is alkyl substituted with alkylcarbonyloxy; R2 and R3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00124] In certain embodiments, the compound of Formula (I) is that wherein:
ring B is present;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl; wherein Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, and haloalkoxy;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or a halo; (5-6- membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or
heterocycloalkylcarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00125] In certain embodiments, the compound of Formula (I) is that wherein:
L is bond, CH2, CF2, O, NRL, S, CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is hydrogen, C1-4 alkyl, or benzyl, wherein the phenyl, as part of the benzyl group, is
optionally substituted with haloalkoxy group;
Ring A is C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, or naphthyl, wherein Ring A is optionally substituted with halo or haloalkoxy; Ring B is cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl, tetrahydroquinolinyl, quinolinyl, or, isoquinolinyl; wherein each Ring B is optionally substituted with one or two RB groups;
each RB is independently halo; cyano; haloalkyl; haloalkoxy; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkoxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6-membered heterocycloalkyl- one)alkyl; and
R1 is hydrogen or W; wherein W is alkyl substituted with alkylcarbonyloxy,
dialkylaminocarbonyloxy cycloalkylcarbonyloxy, or phenylcarbonyloxy; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00126] In certain embodiments, the compound of Formula (I) is that wherein L is bond, O, S, NRL, CH2-Q, or Q-CH2; wherein Q is O, NRL, or S, and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00127] In certain embodiments, the compound of Formula (I) is that wherein L is O or S, and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00128] In certain embodiments, the compound of Formula (I) is that wherein:
ring C is selected from:
Figure imgf000052_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the carbonyl of C(O)-OR1, and the C2 carbon to L; and Ring B is present.
[00129] In certain embodiments, the compound or Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy; Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl; wherein Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, or haloalkoxy;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl;
alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6- membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl; R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1- 6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00130] In certain embodiments, the compound of Formula (I) is that wherein:
L is bond, CH2, CF2, O, NRL, S, CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, or benzyl, wherein the phenyl in the benzyl group is optionally substituted with haloalkoxy group;
Ring A is C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, or naphthyl, wherein Ring A is optionally substituted with halo or haloalkoxy;
Ring B is cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl, tetrahydroquinolinyl,
quinolinyl, or isoquinolinyl; wherein each Ring B is optionally substituted with one or two RB groups;
each RB is independently halo; cyano; haloalkyl; haloalkoxy; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkoxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6-membered heterocycloalkyl- one)alkyl; and
R1 is hydrogen or W; wherein W is alkyl substituted with alkylcarbonyloxy,
dialkylaminocarbonyloxy cycloalkylcarbonyloxy, or phenylcarbonyloxy;
provided that when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00131] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl,
thiazolyl, thiophenyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl,
dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, dihydrobenzodioxinyl, or tetrahydro-methanonaphthalenyl;Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl,
alkoxy, or haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O; when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups;
each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl- one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
phenylcarbonyloxy;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl or trifluoromethyl;
iii. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
iv. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00132] In certain embodiments, the compound of Formula (I) is that wherein: L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is H or C1-4 alkyl optionally substituted with hydroxycarbonylalkyl;
Ring A is 5-6 membered heterocycloalkyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl;
wherein:
when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl, alkoxy, or haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O;
when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted
with one or two RAB groups;
each RAA is independently haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy
substituted with one or two halo;
each RAB is independently halo, alkyl, alkoxy, haloalkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally
substituted with one or two RB groups;
each RB is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy,
heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl or trifluoromethyl; iii. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
iv. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00133] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is H or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl,
(heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when L is S and Ring A is phenyl, then Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00134] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is H or C1-4 alkyl optionally substituted with hydroxycarbonylalkyl; Ring A is heterocycloalkyl, phenyl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
Ring B, when present, is heterocycloalkyl, phenyl, or heteroaryl; wherein each is optionally substituted with one or two RB groups;
each RB is independently halo, alkyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocycloalkyl,
(heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, or alkylcarbonyloxy;
R2 and R3 are each hydrogen or alkyl optionally substituted with alkylcarbonyloxy;
provided that when L is S and Ring A is phenyl, then Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00135] In certain embodiments, the compound of Formula (I) is that wherein:
L is a bond, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is H or C1-4 alkyl;
Ring A is phenyl or heteroaryl; wherein each is optionally substituted with one halo or alkyl; Ring B, when present, is phenyl or heteroaryl; wherein each is optionally substituted with one or two RB groups;
each RB is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, or
heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, or alkylcarbonyloxy;
R2 and R3 are independently hydrogen or alkyl;
provided that when L is S and Ring A is phenyl, then Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00136] In certain embodiments, the compound of Formula (I) is according to
Formula (II):
Figure imgf000059_0001
wherein:
ring C is selected from:
Figure imgf000059_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to L.
[00137] In certain embodiments, the compound of Formula (II) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is H, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally
substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when L is S or CH2, and Ring A is phenyl, then Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00138] In certain embodiments, the compound of Formula (II) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl,
dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
wherein:
when Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O;
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
when Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups; or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl, or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S; each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, phenoxy optionally substituted with one or two halo, or alkylcarbonylaminoalkoxy;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is O and Ring A is phenyl, then RAA cannot be alkyl;
ii. when L is O, Ring A is phenyl, and R1 is ethyl, then RAB cannot be trifluoromethoxy; ii. when L is O, Ring A is phenyl substituted with 1 RAA, then RAA cannot be meta- substituted trifluoromethyl;
iv. when L is bond, Ring A is other than phenyl, and R1 is H, then RAB cannot be methyl, and
v. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, then RAB cannot be alkyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00139] In certain embodiments, the compound of Formula (II) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is H, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally
substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, tetrahydronaphthyl, dihydronaphthyl,
benzothiazolyl, isoquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro- methanonaphthalenyl; provided that when L is NRL or O, then Ring A cannot be
tetrahydronaphthyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00140] In certain embodiments, the compound of Formula (II) is that wherein:
L is a bond, CH2, O, NH, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NH, or S;
Ring A is piperidinyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, spiro[2.5]octane, spiro[4.5]decane, or spiro[5.5]undecane;
wherein:
when Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O;
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy and (cycloalkyl)alkoxy, when L is bond, O or S;
when Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups; or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond; 2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O;
3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl, or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S; each RAA is independently haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, or
alkylcarbonylaminoalkoxy;
each RAB is independently halo, alkyl, haloalkyl, or haloalkoxy;
R1 is hydrogen, alkyl, or W; wherein W is alkyl substituted with alkylcarbonyloxy;
R2 and R3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is O, Ring A is phenyl, and R1 is ethyl, then RAB cannot be trifluoromethoxy; ii. when L is O, Ring A is phenyl substituted with 1 RAA, then RAA cannot be meta- substituted trifluoromethyl;
iii. when L is O, Ring A is phenyl substituted with 1 RAA, then RAA cannot be meta- substituted trifluoromethyl;
iv. when L is bond, Ring A is other than phenyl, and R1 is H, then RAB cannot be methyl, and
v. when L is NH, Ring A is pyridyl, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00141] In certain embodiments, the compound of Formula (I) is according to
Formula (II):
Figure imgf000063_0001
wherein:
ring C is selected from:
Figure imgf000064_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the carbonyl of C(O)-OR1, and the C2 carbon to L.
[00142] In certain embodiments, the compound of Formula (II) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is H or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one halo or alkyl;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl,
(heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with
amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when L is S and Ring A is phenyl, then Ring B is not halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00143] In certain embodiments, the compound of Formula (II) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl,
tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;
wherein:
when Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O;
when Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups; each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is O and Ring A is phenyl, then RAA cannot be alkyl or trifluoromethyl; ii. when L is O, Ring A is phenyl, and R1 is ethyl, then RAB cannot be trifluoromethoxy; iii. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, then RAB cannot be alkyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00144] In certain embodiments, the compound of Formula (II) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
RL is H or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; Ring A is C5-7 cycloalkyl, tetrahydronaphthalinyl, dihydronaphthalinyl, benzothiazolyl, isoquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro- methanonaphthalenyl; provided that when L is NRL or O, then Ring A cannot be
tetrahydronaphthalinyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00145] In certain embodiments, the compound of Formula (II) is that wherein:
L is a bond, CH2, O, NH, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NH, or S;
Ring A is phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl;
wherein:
when Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O;
when Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups; each RAA is independently haloalkoxy, cycloalkyloxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, alkoxy, or haloalkoxy;
R1 is hydrogen, alkyl, cycloalkyl, or W; where W is alkyl substituted with alkylcarbonyloxy; R2 and R3 are independently hydrogen or alkyl;
wherein the alkyl is optionally substituted with alkylcarbonyloxy;
provided:
i. when L is O, Ring A is phenyl, and R1 is ethyl, then RAB cannot be trifluoromethoxy; ii. when L is NH, Ring A is pyridyl or indolinyl, then RAB cannot be alkyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00146] In certain embodiments, the compound of Formula (I) is according to
Formula (III):
Figure imgf000067_0001
wherein:
ring C is selected from:
Figure imgf000067_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to L.
[00147] In certain embodiments, the compound of Formula (III) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl,
dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, , tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, and haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, (ii) 2 halo groups when L is other than O,
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is not O; or 4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S; each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl halo, (5-6-membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, or benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
iv. when L is bond, Ring A is other than phenyl and Ring B is not present, then RAB cannot be methyl, and
v. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00148] In certain embodiments, the compound of Formula (III) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, or benzyl; and the phenyl in the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C5-6 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, phenyl,
naphthyl, indanyl, tetrahydronaphthyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo and haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups,
(ii) 2 halo groups when L is other than O,
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl,
(iv) one halo group when L is CH2NRL, or
(v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups; or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is bond; 2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O;
3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O or S; each RAA is independently haloalkyl; cycloalkyloxy; (cycloalkyl)alkoxy;
alkylcarbonylaminoalkoxy; or phenoxy optionally substituted with one or two halo; each RAB is independently halo, alkyl, haloalkyl, or haloalkoxy;
Ring B, when present, cycloalkyl, heterocycloalkyl, phenyl, tetrahydronaphthyl,
tetrahydroquinolinyl, quinolinyl, or isoquinolinyl; wherein each Ring B is optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; haloalkoxy; alkoxyalkoxy;
aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkoxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; or (5-6- membered heterocycloalkyl-one)alkyl;
R2 and R3 are independently hydrogen or alkyl; wherein the alkyl is optionally substituted with cycloalkylcarbonyloxy or heterocycloalkylcarbonyloxy, wherein the
heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
(i) when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo substituted phenyl;
(ii) when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl;
(iii) when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
(iv) when L is bond, Ring A is other than phenyl, Ring B is not present, then RAB cannot be methyl, and
(v) when L is NH, Ring A is pyridyl and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [00149] In certain embodiments, the compound of Formula (I) is according to
Formula (III):
Figure imgf000071_0001
wherein:
ring C is selected from:
Figure imgf000071_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the carbonyl of C(O)-OR1, and the C2 carbon to L.
[00150] In certain embodiments, the compound of Formula (III) is that wherein:
L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl,
tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl, alkoxy, or haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups when L is other than O;
when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups;
each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo; each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl,
(heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, or benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl or trifluoromethyl;
iii. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl;
iv. when L is S and Ring B is not present, then Ring A cannot be thienyl or
benzothiophenyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00151] In certain embodiments provided herein of the compound according to any one Formula (I), (II) or (III), or single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt thereof, wherein L is a bond, CH2, CF2, O, NRL, S, S(=O), or C(=O). In certain embodiments, L is CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S. In certain embodiments, L is CH2, CF2, O, NRL, or S. In certain embodiments, L is CF2, O, NRL, or S. In certain embodiments, L is CF2, O, or NRL. In certain embodiments, L is CH2, O, NRL, or S. In certain embodiments, L is O, NRL, or S. In certain embodiments, L is CH2, CF2, or C(=O). In certain embodiments, L is CH2, CF2, CH2-Q, or Q-CH2; wherein Q is O, NRL, or S. In certain embodiments, L is CH2-Q, or Q-CH2; wherein Q is O, NRL, or S. In certain embodiments, L is bond, CF2, O, NRL, S, or S(=O). In certain embodiments, L is a bond, or L is CH2, or L is CF2. In certain embodiments, L is O. In certain embodiments, L is NRL. In certain embodiments, L is S. In certain embodiments, L is S(=O). In certain embodiments, L is C(=O). In certain
embodiments, L is CH2-Q; wherein Q is O, NRL, or S. In certain embodiments, L is CH2-O, or L is CH2-S, or L is CH2- NRL, or L is O-CH2, or L is NRL-CH2.
[00152] In certain embodiments, RL is H. In certain embodiments, RL is C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy. In certain embodiments, RL is H or C1-4 alkyl optionally substituted with hydroxycarbonyl. In certain embodiments, RL is C1-4 alkyl optionally substituted with
hydroxycarbonyl. In certain embodiments, RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is substituted with one or two groups selected from halo and haloalkoxy. In certain embodiments, RL is C3-6 cycloalkyl. In certain embodiments, RL is phenyl or benzyl; wherein the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo haloalkoxy. In certain embodiments, RL is benzyl optionally substituted with one or two groups selected from halo and haloalkoxy.
[00153] In certain embodiments, Ring A is cycloalkyl, spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups.
[00154] In certain embodiments, Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, pyridyl, phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indanyl, indolyl, indolinyl, isoindolinyl, benzothiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl.
[00155] In certain embodiments, Ring A is C3-7 cycloalkyl, 5-6 membered
heterocycloalkyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or
tetrahydroisoquinolinyl.
[00156] In certain embodiments, Ring A is cyclopentyl, cyclohexyl, spiro[2.5]octanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, piperidinyl, piperazinyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinolinyl, isoquinolinyl, pyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or 3-azabicyclo[3.1.0]hexanyl.
[00157] In certain embodiments, Ring A is cyclopentyl, cyclohexyl, bicycloheptanyl, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolyl, imidazolyl, triazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl,
dihydrobenzodioxiny, or 3-azabicyclo[3.1.0]hexanyl.
[00158] In certain embodiments, Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, phenyl, or naphthyl.
[00159] In certain embodiments, Ring A is cyclopentyl, cyclohexyl, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl, piperidinyl, piperazinyl, phenyl, or naphthyl.
[00160] In certain embodiments, Ring A is aryl. In certain embodiments, ring A is phenyl or naphthyl. In certain embodiments, ring A is phenyl.
[00161] In certain embodiments, Ring A is spirocycloalkyl, or is C8-11 spirocycloalkyl. In certain embodiments, ring A is spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.
[00162] In certain embodiments, Ring A is C3-7 cycloalkyl. In certain embodiments, Ring A is C5-6 cycloalkyl. In certain embodiments, Ring A is cyclopentyl or cyclohexyl.
[00163] In certain embodiments, Ring A is 5-6 membered heterocycloalkyl. In certain embodiments, Ring A is piperidinyl or piperazinyl.
[00164] In certain embodiments, Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is C3-7 cycloalkyl or C8-11 spirocycloalkyl, where each is optionally substituted with 1 or 2 RAB groups. In certain embodiments, Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, or 5-6 membered heterocycloalkyl, where each is optionally substituted with 1 or 2 RAB groups. In certain embodiments, Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, or aryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is aryl or heteroaryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, phenyl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, phenyl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is phenyl or heteroaryl, where each is optionally substituted with 1 or 2 RAA or RAB groups. In certain embodiments, Ring A is C3-7 cycloalkyl or C8-11 spirocycloalkyl, where each is optionally substituted with 1 or 2 RAB groups. In certain embodiments, Ring A is C3-7 cycloalkyl optionally substituted with 1 or 2 RAB groups. In certain embodiments, Ring A does not include thienyl. In certain embodiments, Ring A does not include indolyl.
[00165] In certain embodiments, when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, or haloalkoxy.
[00166] In certain embodiments, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with: (i) one or two RAA groups, or (ii) 2 halo groups when L is other than O.
[00167] In certain embodiments, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with: (i) one or two RAA groups, (ii) 2 halo groups when L is other than O, (iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl, (iv), one halo group when L is CH2NRL, or (v) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo.
[00168] In certain embodiments, each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, phenoxy optionally substituted with one or two groups selected from halo and alkylcarbonylaminoalkoxy. In certain embodiments, each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or
alkylcarbonylaminoalkoxy. In certain embodiments, each RAA is independently haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or alkylcarbonylaminoalkoxy. In certain embodiments, each RAA is independently haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, alkylcarbonylaminoalkoxy, (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo, or alkylcarbonylaminoalkoxy. In certain embodiments, each RAA is independently haloalkyl or cycloalkyloxy, or is haloalkyl or (cycloalkyl)alkoxy, or is haloalkyl or (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo.
[00169] In certain embodiments, each RAA is independently isopropyl, trifluoromethyl, propoxy, pentyloxy, trifluoromethoxy, cyclopropylmethoxy, cyclopentylmethoxy, or
cyclohexylmethoxy. In certain embodiments, each RAA is independently isopropyl,
trifluoromethyl, propoxy, pentyloxy, trifluoromethoxy, cyclopropylmethoxy,
cyclopentylmethoxy, cyclohexylmethoxy, or halobenzyloxy.
[00170] In certain embodiments, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo. In certain embodiments, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with one halo and one haloalkoxy, or with one halo and one (cycloalkyl)alkoxy, or with one halo and one (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo.
[00171] In certain embodiments, when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups. In certain embodiments, when Ring B is not present and Ring A is other than phenyl, then Ring A is unsubstituted: 1) when L is bond and Ring A is tetrahydroquinolinyl, 2) when L is O and Ring A is
dihydroxybenzodioxynyl, 3) when L is O, Ring A is tetrahydronapthalene, and R1 is not hydrogen or ethyl, or 4) when L is O or S, and ring A is spirocycloalkyl.
[00172] In certain embodiments, each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo. In certain embodiments, each RAB is independently halo, alkyl, haloalkyl, or haloalkoxy. In certain embodiments, each RAB is independently chloro, bromo, fluoro, methyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoromethoxy.
[00173] In certain embodiments, when Ring B is not present and Ring A is
spiro[2.5]octanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, phenyl, naphthyl, indanyl,
tetrahydronaphthyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridyl, quinolinyl, isoquinolinyl, pyridyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl; then ring A is substituted with one or two groups independently selected from the group consisting of haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, alkylcarbonylaminoalkoxy, and (phenyl)alkoxy, wherein the phenyl as part of (phenyl)alkoxy is optionally substituted with halo, or with one or two groups independently selected from the group consisting of halo, alkyl, alkoxy, and haloalkoxy, or with
difluoromethane, trifluoromethyl, cyclopropoxy, cyclopentyloxy, propylmethoxy,
pentylmethoxy, hexylmethoxy, and fluorobenzyloxy, or with fluoro, chloro, bromo, methyl, isopropyl, and trifluoromethoxy.
[00174] In certain embodiments, Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two RB groups. In certain embodiments, Ring B, when present, is cycloalkyl optionally substituted with one or two RB groups. In certain embodiments, Ring B, when present, is heterocycloalkyl optionally substituted with one or two RB groups. In certain embodiments, Ring B, when present, is aryl optionally substituted with one or two RB groups. In certain embodiments, Ring B, when present, is heteroaryl optionally substituted with one or two RB groups.
[00175] In certain embodiments, Ring B is C4-6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, Ring B is C4-6 cycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, Ring B is C4-6 cycloalkyl, 5-6 membered
heterocycloalkyl, phenyl, or heteroaryl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, tetrahydronaphthyl, tetrahydroquinolinyl, quinolinyl, or isoquinolinyl, tetrahydro-2H-pyranyl, cyclobutyl, cyclopentyl, cyclohexyl, or pyridyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, tetrahydronaphthyl, tetrahydroquinolinyl, quinolinyl, or isoquinolinyl, tetrahydro-2H-pyranyl, cyclobutyl, cyclopentyl, cyclohexyl, or pyridyl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, or quinolinyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, or heteroaryl. In certain embodiments, Ring B is cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, or quinolinyl. In certain embodiments, Ring B is phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is phenyl or quinolinyl. In certain
embodiments, Ring B is phenyl.
[00176] In certain embodiments, Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or two RB groups, wherein each RB is independently halo, cyano, alkyl, haloalkyl, haloalkoxy, alkoxyalkoxy, aminocarbonyl, alkylcarbonylaminoalkoxy, cycloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, heterocycloalkyl optionally substituted with alkyl, alkylcarbonyl or a halo, or (5-6-membered heterocycloalkyl- one)alkyl.
[00177] In certain embodiments, Ring B is cyclobutyl, cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, or tetrahydroquinolinyl; each substituted with one or two RB groups, wherein each RB is independently halo, cyano, alkyl, haloalkyl, haloalkoxy, alkoxyalkoxy, aminocarbonyl, alkylcarbonylaminoalkoxy, cycloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, (5-6-membered heterocycloalkyl-one)alkyl, or
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo.
[00178] In certain embodiments, Ring B is cyclobutyl, cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, or tetrahydroquinolinyl; each substituted with one or two RB groups, wherein each RB is independently aminocarbonyl, cyano, chloro, bromo, fluoro, methyl, trifluoromethyl, trifluoromethoxy, methoxyethoxy, acetamidoethoxy, cyclopropoxy, cyclopropylmethoxy, cyclobutyl, cyclohexyl,
tetrahydropyranyl, pyrrolidinyl, piperidinyl, methylpiperidinyl, difluoropiperidinyl,
methylpiperazinyl, acetylpiperazinyl, o
Figure imgf000078_0001
[00179] In certain embodiments, Ring B is phenyl optionally substituted with one or two RB groups, wherein each RB is independently aminocarbonyl, cyano, chloro, bromo, fluoro, trifluoromethyl, trifluoromethoxy, methoxyethoxy, acetamidoethoxy, cyclopropoxy,
cyclopropylmethoxy, cyclobutyl, cyclohexyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,
methylpiperidinyl, difluoropiperidinyl, methylpiperazinyl, acetylpiperazinyl, or
Figure imgf000078_0002
.
[00180] In certain embodiments, Ring B is cyclobutyl, cyclohexyl, piperidinyl, tetrahydropyranyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, or tetrahydroquinolinyl; each substituted with one or two RB groups, wherein each RB is independently chloro, bromo, fluoro, methyl, or piperidinyl.
[00181] In certain embodiments, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with one or two RAA groups. In certain embodiments, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with 2 halo groups when L is other than O. In certain embodiments, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with one halo group when L is CH2NRL. In certain embodiments, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O or S, wherein the phenyl is optionally substituted with halo.
[00182] In certain embodiments, when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups. In certain embodiments, when Ring B is not present and Ring A is other than phenyl, then Ring A is unsubstituted
tetrahydroquinolinyl when L is bond. In certain embodiments, when Ring B is not present and Ring A is other than phenyl, then Ring A is unsubstituted dihydroxybenzodioxynyl when L is O. In certain embodiments, when Ring B is not present and Ring A is other than phenyl, then Ring A is unsubstituted tetrahydronapthalene when L is O and R1 is not hydrogen or ethyl. In certain embodiments, when Ring B is not present and Ring A is other than phenyl, then Ring A is unsubstituted spirocycloalkyl when L is O or S.
[00183] In certain embodiments, when L is S and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl.
[00184] In certain embodiments, when L is S or CH2, and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl.
[00185] In certain embodiments, when L is CH2 and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl.
[00186] In certain embodiments, when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl or trifluoromethyl;
[00187] In certain embodiments, when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl.
[00188] In certain embodiments, when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be trifluoromethyl.
[00189] In certain embodiments, when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl.
[00190] In certain embodiments, when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy. [00191] In certain embodiments, when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl.
[00192] In certain embodiments, when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl.
[00193] In certain embodiments, R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy. In certain embodiments, R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy,
cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl.
[00194] In certain embodiments, R1 is hydrogen, alkyl, cycloalkyl, or heterocycloalkyl. In certain embodiments, R1 is hydrogen or alkyl. In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is alkyl. In certain embodiments, R1 is hydrogen or W. In certain embodiments, R1 is W. In certain embodiments, R1 is W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy, or W is substituted with dialkylamino or alkylcarbonyloxy, or W is substituted with
alkylcarbonyloxy, dialkylaminocarbonyloxy cycloalkylcarbonyloxy, or phenylcarbonyloxy.
[00195] In certain embodiments, the compound of Formula (I) is according to
Formula (IV):
Figure imgf000080_0001
wherein:
ring C is selected from:
Figure imgf000080_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the carbonyl of C(O)-OR1, and the C2 carbon to N of NRL;
RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl,
alkoxy, or haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups;
when Ring B is not present and Ring A is 5-6 membered heterocycloalkyl, pyrazolyl,
imidazolyl, triazolyl, thiazolyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, benzothiazolyl, quinolinyl, isoquinolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl, then Ring A is substituted with one or two RAB groups;
when Ring B is not present and Ring A is pyridyl, indolyl, or indolinyl, then Ring A is
substituted with one or two RAC groups;
each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAC is independently halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy,
(cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl- one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
phenylcarbonyloxy;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00196] In certain embodiments, the compound of Formula (IV) is that wherein:
ring C is selected from:
Figure imgf000082_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to N of NRL;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, and haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with: (i) one or two RAA groups, or
(ii) 2 halo groups;
when Ring B is not present and Ring A is 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl,
benzothiazolyl, quinolinyl, isoquinolinyl, isoindolinyl, tetrahydroquinolinyl,
dihydroisoquinolinyl, tetrahydroisoquinolinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl, then Ring A is substituted with one or two RAB groups;
when Ring B is not present and Ring A is C3-7 cycloalkyl or C8-11 spirocycloalkyl, then Ring A is optionally substituted with one or two RAB groups;
when Ring B is not present and Ring A is pyridyl, indolyl, or indolinyl, then Ring A is
substituted with one or two RAC groups;
each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy;
phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
each RAC is independently halo; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl;
alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6- membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or
heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1- 6 alkyl; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00197] In certain embodiments, the compound of Formula (IV) is that wherein RL is hydrogen or C1-4 alkyl, and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00198] In certain embodiments, the compound of Formula (IV) is that wherein RL is hydrogen, and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00199] In certain embodiments, the compound of Formula (I) is according to
Formula (IV):
Figure imgf000084_0001
wherein:
ring C is selected from:
Figure imgf000084_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to N of NRL;
[00200] In certain embodiments, the compound of Formula (IV) is that wherein:
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy; Ring A is C3-7 cycloalkyl, C8-11 spirocycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl,
dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups selected from halo, alkyl, alkoxy, or haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups;
when Ring B is not present and Ring A is 5-6 membered heterocycloalkyl, pyrazolyl,
imidazolyl, triazolyl, thiazolyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, benzothiazolyl, quinolinyl, isoquinolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl, then Ring A is substituted with one or two RAB groups;
when Ring B is not present and Ring A is C3-7 cycloalkyl or C8-11 spirocycloalkyl, then Ring A is optionally substituted with one or two RAB groups;
when Ring B is not present and Ring A is pyridyl, indolyl, or indolinyl, then Ring A is
substituted with one or two RAC groups;
each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or alkylcarbonylaminoalkoxy;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
each RAC is independently halo; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy,;aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6- membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl; R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00201] In certain embodiments, the compound of Formula (I) is according to
Formula (IV):
Figure imgf000086_0001
wherein:
ring C is selected from:
Figure imgf000086_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to N of NRL;.
[00202] In certain embodiments, the compound of Formula (IV) is that wherein:
RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy;
Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl,
tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl, alkoxy, or haloalkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups, or (ii) 2 halo groups;
when Ring B is not present and Ring A is 5-6 membered heterocycloalkyl, pyrazolyl,
imidazolyl, triazolyl, thiazolyl, naphthyl, indanyl, tetrahydronaphthalinyl,
dihydronaphthalinyl, benzothiazolyl, quinolinyl, isoquinolinyl, isoindolinyl,
tetrahydroquinolinyl, or dihydroisoquinolinyl, then Ring A is substituted with one or two RAB groups;
when Ring B is not present and Ring A is pyridyl, indolyl, or indolinyl, then Ring A is
substituted with one or two RAC groups;
each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAC is independently halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy,
(cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[
Figure imgf000088_0001
wherein:
ring C is selected from:
Figure imgf000088_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to O;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each is substituted with one or two RAB groups; provided
when Ring B is present, then Ring A is optionally substituted with one halo or alkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAD groups, or (ii) two groups selected from chloro or bromo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAD is independently hydroxy, alkoxy, haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B is present or not present; wherein:
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl- one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
phenylcarbonyloxy;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when Ring A is phenyl, Ring B is not present, and R1 is ethyl, then Ring A cannot be substituted with trifluoromethoxy; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00204] In certain embodiments, the compound of Formula (V) is that wherein:
ring C is selected from:
Figure imgf000089_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to O;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each is
substituted with one or two RAB groups;
Ring B is present or not present; wherein
when Ring B is present, then Ring A is optionally substituted with a group selected from halo, alkyl, alkoxy, cyano, hydroxy, and (cycloalkyl)alkoxy;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAD groups;
(ii) two groups selected from chloro or bromo; or (iii) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo;
(iv) one cyano group and one (phenyl)alkoxy group, wherein the phenyl as part of the (phenyl)alkoxy group is optionally substituted with halo or haloalkoxy;
or Ring A is unsubstituted C8-11 spirocycloalkyl; unsubstituted dihydroxybenzodioxynyl; or unsubstituted tetrahydronaphthalene when R1 is not hydrogen or ethyl;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or
(phenyl)alkoxy, wherein the phenyl is optionally substituted with halo;
each RAD is independently hydroxy; alkoxy; haloalkyl; cycloalkyloxy; (cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl;
alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy;
alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6-membered
heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl; or 5-6 membered heteroaryl optionally substituted with alkyl wherein alkyl is optionally substituted with 1 or 2 groups independently selected from cycloalkyl and hydroxy;
alkoxyalkyl; hydroxyalkyl; or hydroxycycloalkyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or - N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
(i) when Ring A is phenyl, Ring B is not present, and R1 is ethyl, then Ring A cannot be substituted with trifluoromethoxy; and
(ii) when Ring A is phenyl substituted with 1 RAD, then RAD cannot be meta-substituted trifluoromethyl;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00205] In certain embodiments, the compound of Formula (I) is according to
Formula (V):
Figure imgf000091_0001
wherein:
ring C is selected from:
Figure imgf000091_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to O.
[00206] In certain embodiments, the compound of Formula (V) is that wherein:
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each is substituted with one or two RAB groups; provided:
when Ring B is present, then Ring A is optionally substituted with one halo or alkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAD groups, (ii) two groups selected from chloro or bromo, or (iii) one halo group and one group selected from the group consisting of haloalkoxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo;
or Ring A is unsubstituted C8-11 spirocycloalkyl; unsubstituted dihydroxybenzodioxynyl; or unsubstituted tetrahydronaphthalene when R1 is not hydrogen or ethyl;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo;
each RAD is independently hydroxy, alkoxy, haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B is present or not present; wherein:
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6- membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl; R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided
(i) when Ring A is phenyl, Ring B is not present, and R1 is ethyl, then Ring A cannot be substituted with trifluoromethoxy; and
(ii) when Ring A is phenyl substituted with 1 RAD, then RAD cannot be meta-substituted trifluoromethyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00207] In certain embodiments, the compound of Formula (I) is according to
Formula (V):
Figure imgf000093_0001
wherein:
ring C is selected from:
Figure imgf000093_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to O.
[00208] In certain embodiments, the compound of Formula (V) is that wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each is substituted with one or two RAB groups; provided:
when Ring B is present, then Ring A is optionally substituted with one halo or alkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAD groups, or (ii) two groups selected from chloro or bromo;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAD is independently hydroxy, alkoxy, haloalkyl, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
Ring B is present or not present; wherein:
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl,
(heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when Ring A is phenyl, Ring B is not present, and R1 is ethyl, then Ring A cannot be substituted with trifluoromethoxy; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00209] In certain embodiments, the compound of Formula (I) is according to
Formula (VI):
Figure imgf000094_0001
wherein:
ring C is selected from:
Figure imgf000094_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to S;
wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl other than thienyl or benzothiophenyl; each is substituted with one or two RAB groups;
provided when Ring A is phenyl and Ring B is not present, then Ring A is substituted with one or two RAE; each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo;
each RAE is independently halo, alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, or
(cycloalkyl)alkoxy;
Ring B is present or not present; wherein:
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl- one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
phenylcarbonyloxy;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00210] In certain embodiments, the compound of Formula (VI) is that wherein:
ring C is selected from:
Figure imgf000095_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to S;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl other than
thienyl or benzothiophenyl; each is substituted with one or two RAB groups; provided when Ring A is phenyl and Ring B is not present, then Ring A is substituted with one or two RAE;
Ring B is present or not present; wherein:
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; or
(phenyl)alkoxy, wherein the phenyl is optionally substituted with halo;
each RAE is independently halo; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; alkylsulfonyl; haloalkyl; alkoxy; haloalkoxy;
alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl;
cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6-membered heterocycloalkyl-one)alkyl;
(heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6 membered heteroaryl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or - N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided when Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00211] In certain embodiments, the compound of Formula (I) is according to
Formula (VI):
Figure imgf000097_0001
wherein:
ring C is selected from:
Figure imgf000097_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to S.
[00212] In certain embodiments, the compound of Formula (VI) is that wherein:
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl other than
thienyl or benzothiophenyl; each is substituted with one or two RAB groups;
provided when Ring A is phenyl and Ring B is not present, then Ring A is substituted
with one or two RAE;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo; (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo;
each RAE is independently halo; alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; or (phenyl)alkoxy, wherein the phenyl is optionally substituted with halo;
Ring B is present or not present; wherein:
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo; cyano; alkyl; haloalkyl; alkoxy; haloalkoxy; alkylcarbonyl;
alkoxyalkoxy; aminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with 1 or 2 alkyl, alkylcarbonyl or halo; (5-6- membered heterocycloalkyl-one)alkyl; (heterocycloalkyl)alkyl; or heterocycloalkylcarbonyl; R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00213] In certain embodiments, the compound of Formula (I) is according to
Formula (VI):
Figure imgf000098_0001
wherein:
ring C is selected from:
Figure imgf000098_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to S.
[00214] In certain embodiments, the compound of Formula (VI) is that wherein:
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl other than thienyl or benzothiophenyl; each is substituted with one or two RAB groups;
provided when Ring A is phenyl and Ring B is not present, then Ring A is substituted
with one or two RAE;
each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo; each RAE is independently halo, alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, or
(cycloalkyl)alkoxy;
Ring B is present or not present; wherein:
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with one or two RB groups;
each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,
alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl,
(heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy; R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided that when Ring A is phenyl, then Ring B cannot be halo-substituted phenyl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00215] In another aspect, provided herein is a compound of Formula (VII):
Figure imgf000099_0001
wherein:
ring C is selected from:
Figure imgf000099_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the carbonyl of C(O)-OR1, and the C2 carbon to L;
R1, R2 and R3 are as defined above.
L is a bond, CH2, CH2CH2, O, or CH2O;
X is N or CH;
m is 1, 2, or 3;
n is 0, 1, 2, or 3;
Ring A and Ring B are each independently C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl or heteroaryl, optionally substituted with halo, haloalkyl or phenyl; wherein phenyl is optionally substituted with halo, haloalkyl, or haloalkoxy; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00216] In certain embodiments, the compound of Formula (VII) is that wherein:
L is a bond, CH2, CH2CH2, O, or CH2O;
X is N or CH;
m is 1, 2, or 3;
n is 0, 1, 2, or 3;
Ring A and Ring B are each independently aryl, optionally substituted with halo, haloalkyl or phenyl; wherein phenyl is optionally substituted with halo, haloalkyl, or haloalkoxy; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally
optionally a pharmaceutically acceptable salt thereof.
[00217] In certain embodiments, the compound of Formula (VII) is that wherein:
L is a bond, CH2, CH2CH2, O, or CH2O;
X is N or CH;
m is 1 or 2;
n is 0, 1, or 2;
Ring A and Ring B are each independently phenyl, optionally substituted with halo, or phenyl substituted with halo or haloalkoxy; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally
optionally a pharmaceutically acceptable salt thereof. [00218] In certain embodiments, the compound of Formula (I) is according to Formula (VIII):
Figure imgf000101_0001
wherein:
ring C is selected from:
Figure imgf000101_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to L;
R1, R2 and R3 are as defined above;
L is a bond, CH2, CH2CH2, O, or CH2O;
X is N or CH;
R1D and R1E are each independently H or hydroxy;
m is 1, 2, or 3;
n is 0, 1, 2, or 3;
Ring A and Ring B are each independently C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl or heteroaryl, optionally substituted with halo, haloalkyl or phenyl; wherein phenyl is optionally substituted with halo, haloalkyl, or haloalkoxy; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00219] In certain embodiments of any of the above formulas, Ring A is C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl. In certain embodiments, Ring A is C3-7 cycloalkyl. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl. In certain embodiments, Ring A is phenyl.
[00220] In certain embodiments of any of the above formulas, R1 is hydrogen or W. In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is W.
[00221] In certain embodiments of any of the above formulas, R2 and R3 are
independently hydrogen. In certain embodiments, R2 is hydrogen. In certain embodiments, R3 is hydrogen.
[00222] In certain embodiments of any of the above formulas, Ring C is:
Figure imgf000102_0001
.
[00223] In certain embodiments of any of the above formulas, Ring C is:
Figure imgf000102_0002
.
[00224] In certain embodiments of any of the above formulas where L is present, L is a bond, CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S.
[00225] In certain embodiments, L is CH2, CF2, O, NRL, S, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S. In certain embodiments, L is CH2, CF2, O, NRL, or S. In certain embodiments, L is CH2, O, NRL, or S. In certain embodiments, L is O, NRL, or S. In certain embodiments, L is CH2, CF2, C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S. In certain embodiments, L is CH2, CF2, or C(=O). In certain embodiments, L is CH2, CF2, CH2-Q, or Q- CH2; wherein Q is O, NRL, or S. In certain embodiments, L is CH2-Q, or Q-CH2; wherein Q is O, NRL, or S.
[00226] In certain embodiments of any of the above formulas where RL is present, RL is H. In certain embodiments, RL is C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy. In certain embodiments, RL is H or C1-4 alkyl optionally substituted with hydroxycarbonyl. In certain embodiments, RL is C1-4 alkyl optionally substituted with hydroxycarbonyl. In certain embodiments, RL is H or C1-4 alkyl substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy. In certain embodiments, RL is C1-4 alkyl substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy. In certain embodiments, RL is H or C1-4 alkyl substituted with hydroxycarbonyl.
[00227] In certain embodiments of any of the above formulas, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups;
[00228] In certain embodiments of any of the above formulas, Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiophenyl, pyridyl, phenyl, naphthyl, tetrahydronaphthalinyl, dihydronaphthalinyl, indanyl, indolyl, indolinyl, isoindolinyl, benzothiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
dihydroisoquinolinyl, dihydrobenzodioxinyl, or tetrahydro-methanonaphthalenyl.
[00229] In certain embodiments of any of the above formulas, Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl.
[00230] In certain embodiments of any of the above formulas, Ring A is heterocycloalkyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, phenyl, naphthyl, tetrahydronaphthalinyl,
dihydronaphthalinyl, indanyl, indolyl, isoindolinyl, benzothiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or dihydrobenzodioxinyl.
[00231] In certain embodiments of any of the above formulas, Ring A is heterocycloalkyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl,
dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl.
[00232] In certain embodiments of any of the above formulas, Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups. In certain embodiments, Ring A is heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups. In certain embodiments, Ring A is aryl or heteroaryl, where each is
optionallysubstituted with 1 or 2 RAA groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, phenyl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups. In certain embodiments, Ring A is heterocycloalkyl, phenyl, or heteroaryl, where each is optionally substituted with 1 or 2 RAA groups. In certain embodiments, Ring A is phenyl or heteroaryl, where each is optionallysubstituted with 1 or 2 RAA groups. In certain embodiments, Ring A does not include theinyl. In certain embodiments, Ring A does not include indolyl.
[00233] In certain embodiments, Ring A is C5-7 cycloalkyl, 5-6 membered
heterocycloalkyl, pyrazolyl, thienyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro- methanonaphthalenyl. In certain embodiments, Ring A is pyrazolyl, thienyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl,
tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl.
[00234] In certain embodiments, Ring A is cyclohexyl, bicycloheptanyl, pyrrolidinyl, piperidinyl, pyrazolyl, thienyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro- methanonaphthalenyl.
[00235] In certain embodiments, Ring A is C5-7 cycloalkyl, 5-6 membered
heterocycloalkyl, pyrazolyl, thienyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl. In certain embodiments, Ring A is cyclohexyl, bicycloheptanyl, pyrrolidinyl, piperidinyl, pyrazolyl, thienyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl.
[00236] In certain embodiments, Ring A is cyclohexyl, bicycloheptanyl, pyrrolidinyl, piperidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl,
tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro- methanonaphthalenyl. [00237] In certain embodiments, Ring A is cyclohexyl, bicycloheptanyl, pyrrolidinyl, piperidinyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl,
tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro- methanonaphthalenyl.
[00238] In certain embodiments, Ring A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl. In certain embodiments, Ring A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl.
[00239] In certain embodiments, Ring A is pyrrolidinyl, piperidinyl, imidazolyl, triazolyl, thiazolyl, phenyl, pyridyl, or thienyl. In certain embodiments, Ring A is pyrrolidinyl, piperidinyl, imidazolyl, triazolyl, thiazolyl, phenyl, or pyridyl. In certain embodiments, Ring A is thiazolyl, phenyl, or pyridyl. In certain embodiments, Ring A is thiazolyl or phenyl. In certain
embodiments, Ring A is phenyl.
[00240] In certain embodiments, Ring A is phenyl, naphthyl, indanyl,
tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl. In certain embodiments, Ring A is phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, indolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl. In certain embodiments, Ring A is tetrahydronaphthalinyl, dihydronaphthalinyl, benzothiazolyl, quinolinyl, isoquinolinyl, or tetrahydroquinolinyl.
[00241] In certain embodiments, Ring A is C5-7 cycloalkyl, 5-6 membered
heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, dihydronaphthalinyl, benzothiazolyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl. In certain embodiments, Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl,
dihydronaphthalinyl, benzothiazolyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl. In certain embodiments, Ring A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, dihydronaphthalinyl, benzothiazolyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl. In certain embodiments, Ring A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, benzothiazolyl, or isoquinolinyl.
[00242] In certain embodiments of any of the above formulas, when Ring B is present, then Ring A is optionally substituted with one or two halo, alkyl, alkoxy, or haloalkoxy;
[00243] In certain embodiments of any of the above formulas, when Ring B is not present and Ring A is phenyl, then Ring A is substituted with: (i) one or two RAA groups, or (ii) 2 halo groups when L is other than O.
[00244] In certain embodiments, each RAA is independently alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo.In certain embodiments, when Ring B is not present and Ring A is other than phenyl, then Ring A is optionally substituted with one or two RAB groups.
[00245] In certain embodiments of any of the above formulas, when Ring B is not present and Ring A is other than phenyl, then Ring A is substituted with one or two RAB groups.
[00246] In certain embodiments, each RAB is independently halo, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, or phenoxy optionally substituted with one or two halo.
[00247] In certain embodiments of any of the above formulas, when Ring B is not present, Ring A is pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl,
tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro- methanonaphthalenyl; wherein Ring A is substituted with one or two groups independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and phenoxy substituted with one or two chloro groups. In certain embodiments, when Ring B is not present, Ring A is phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl; wherein Ring A is substituted with one or two groups independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and phenoxy substituted with one or two chloro groups. In certain embodiments, when Ring B is not present, Ring A is phenyl, naphthyl, pyridyl, benzothiazolyl, quinolinyl, or isoquinolinyl; wherein Ring A is substituted with one or two groups independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and phenoxy substituted with one or two chloro groups. In certain embodiments, when Ring B is not present, Ring A is phenyl substituted with one or two groups independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and phenoxy substituted with one or two chloro groups. In certain embodiments, when Ring B is not present, Ring A is phenyl substituted with one or two groups independently selected from chloro, fluoro, trifluoromethoxy, cyclopentyloxy, and phenoxy substituted with one or two chloro groups.
[00248] In certain embodiments of any of the above formulas, Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with one or two RB groups.
[00249] In certain embodiments, each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl,
cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6- membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl.
[00250] In certain embodiments of any of the above formulas, Ring B is heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, or heteroaryl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, or quinolinyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, or heteroaryl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, or quinolinyl. In certain embodiments, Ring B is phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is phenyl or quinolinyl. In certain embodiments, Ring B is phenyl.
[00251] In certain embodiments, Ring B is heterocycloalkyl, aryl, or heteroaryl; each substituted with one or two RB groups, where each RB is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocycloalkyl, (heterocycloalkyl)alkyl, or
heterocycloalkylcarbonyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, or quinolinyl; each substituted with one or two RB groups, where each RB is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocycloalkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl.
[00252] In certain embodiments of any of the above formulas, Ring B is piperidinyl, piperazinyl, phenyl, or quinolinyl; each substituted with one or two RB groups, where each RB is independently chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, isopropoxy,
trifluoromethoxy, cyclopropoxy, cyclopentoxy, piperidinyl, piperidinylalkyl, or
piperidinylcarbonyl. In certain embodiments, Ring B is phenyl or quinolinyl; each substituted with one or two RB groups, where each RB is independently chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, cyclopentoxy, piperidinyl, piperidinylalkyl, or piperidinylcarbonyl. In certain embodiments, Ring B is phenyl substituted with one or two RB groups, where each RB is independently chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, cyclopentoxy, piperidinyl, piperidinylalkyl, or piperidinylcarbonyl. In certain embodiments, Ring B is phenyl substituted with one or two RB groups, where each RB is independently chloro, bromo, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, or cyclopropoxy. In certain
embodiments, Ring B is phenyl substituted with one or two RB groups, where each RB is independently chloro, trifluoromethyl, methoxy, or trifluoromethoxy.
[00253] In certain embodiments, when L is S and Ring A is phenyl, then Ring B cannot be halo-substituted phenyl.
[00254] In certain embodiments, when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl or trifluoromethyl;
[00255] In certain embodiments, when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy.
[00256] In certain embodiments, when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl.
[00257] In certain embodiments, R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or phenylcarbonyloxy.
[00258] In certain embodiments, R1 is hydrogen, alkyl, cycloalkyl, or heterocycloalkyl. In certain embodiments, R1 is hydrogen or alkyl. In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is alkyl. In certain embodiments, R1 is W; where W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, or
phenylcarbonyloxy. In certain embodiments, R1 is W; where W is alkyl substituted with dialkylamino or alkylcarbonyloxy.
[00259] In some embodiments provided herein is a compound or pharmaceutically acceptable salt thereof where the compound has Formula (IX), (X) or (XI):
Figure imgf000109_0001
wherein
R1 and RB are as defined in any of the above formulas;
L is S, O, NH or NRL;;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is
optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy; and
subscript x is 0, 1, 2 or 3.
[00260] In another aspect, provided herein is a compound of Formula (XII):
Figure imgf000109_0002
wherein:
ring C is selected from:
Figure imgf000110_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-),
or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
provided:
i. the compound represented by Formula (XII) is exclusive of:
a. 4-(phenylamino)-1H-1,2,3-triazole-5-carbaldehyde;
b. 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-5-carbaldehyde; c. ethyl hydrogen (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; d. diethyl (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-1H- 1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; and
e. 1-((4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methyl)-5-methylpyrimidine- 2,4(1H,3H)-dione;
ii. when Z is -C(=O)H, L is NRL, RL is hydrogen, and Ring A is phenyl, then Ring B is present and/or the phenyl Ring A is substituted with 1, 2, or 3 RA2 groups;
iii. when Z is -C(=O)H, L is CH2, and Ring A is cyclopropyl, phenyl, indole, or thiophene, then Ring B is present;
iv. when Z is -C(=O)H, L is CH2-O, and Ring A is phenyl, then Ring B is present;
v. when Z is -CH2OY, Y is W, W is -P(=O)(OR7)2 or -P(=O)(OR7)(O-), R7 is ethyl, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine- 2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
vi. when Z is -CH2OY, Y is hydrogen, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00261] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups; each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl; each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
provided:
i. the compound represented by Formula (XII) is exclusive of:
a. 4-(phenylamino)-1H-1,2,3-triazole-5-carbaldehyde;
b. 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-5-carbaldehyde; c. ethyl hydrogen (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate;
d. diethyl (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-1H- 1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; and
e. 1-((4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methyl)-5-methylpyrimidine- 2,4(1H,3H)-dione;
ii. when Z is -C(=O)H, L is NRL, RL is hydrogen, and Ring A is phenyl, then Ring B is present and/or the phenyl Ring A is substituted with 1, 2, or 3 RA2 groups;
iii. when Z is -C(=O)H, L is CH2, and Ring A is cyclopropyl, phenyl, indole, or thiophene, then Ring B is present;
iv. when Z is -C(=O)H, L is CH2-O, and Ring A is phenyl, then Ring B is present;
v. when Z is -CH2OY, Y is W, W is -P(=O)(OR7)2 or -P(=O)(OR7)(O-), R7 is ethyl, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine- 2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
vi. when Z is -CH2OY, Y is hydrogen, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00262] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CF2, O, S, S(=O), C(=O), CH2-NRL, CH2-S, or Q-CH2; wherein Q is O, NRL, or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W; W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-),
or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00263] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
Z is -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups; each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl; each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00264] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
Z is -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-),
or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
provided:
i. the compound represented by Formula (XII) is exclusive of:
a. ethyl hydrogen (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate;
b. diethyl (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-1H- 1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; and
c. 1-((4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methyl)-5-methylpyrimidine- 2,4(1H,3H)-dione; ii. when Z is -CH2OY, Y is W, W is -P(=O)(OR7)2 or -P(=O)(OR7)(O-), R7 is ethyl, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine- 2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
iii. when Z is -CH2OY, Y is hydrogen, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00265] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
Z is -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-),
or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00266] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CF2, O, S, S(=O), C(=O), CH2-NRL, CH2-S, or Q-CH2; wherein Q is O, NRL, or S;
Z is -C(=O)H; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [00267] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CF2, O, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-),
or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
provided:
i. the compound represented by Formula (XII) is exclusive of 4-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1H-1,2,3-triazole-5-carbaldehyde; and
ii. when Z is -C(=O)H, L is CH2-O, and Ring A is phenyl, then Ring B is present;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00268] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CF2, O, S, S(=O), or C(=O);
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-),
or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00269] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a O or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or
alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-),
or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00270] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a O;
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-),
or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00271] In certain embodiments, the compound of Formula (XII) is that wherein:
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); - SO2NR5R6; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy;
aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl;
dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl;
cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, - N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-; each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl,
heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00272] In certain embodiments, the compound of Formula (XII) is that wherein:
ring C is:
Figure imgf000131_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is O or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen;
Ring A is C5-7 cycloalkyl, 7-9 membered heterocycloalkyl, aryl, or heteroaryl; wherein Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
Ring B is C5-7 cycloalkyl, 7-9 membered heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; C1-4 alkyl; C1-4 hydroxyalkyl; C1-4 haloalkyl; C1-4 alkoxy; C1-4 aminoalkoxy; C1-4 hydroxyalkoxy; C1-4 haloalkoxy; C1-4 alkylcarbonyl; C1-4 alkoxyalkoxy; C1-4 aminocarbonyl; C3-6 cycloalkyl; 7-9 membered heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; and R2 is independently hydrogen;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00273] In certain embodiments, the compound of Formula (XII) is that wherein:
ring C is:
Figure imgf000132_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is O or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen;
Ring A is C5-7 cycloalkyl, piperidinyl, or phenyl; wherein Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
Ring B is C5-7 cycloalkyl, 7-9 membered heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; C1-4 alkyl; C1-4 hydroxyalkyl; C1-4 haloalkyl;
C1-4 alkoxy; C1-4 hydroxyalkoxy; C1-4 haloalkoxy; C3-6 cycloalkyl; 7-9 membered heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; and
R2 is independently hydrogen;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00274] In certain embodiments, the compound of Formula (XII) is that wherein:
ring C is:
Figure imgf000133_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is O or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen;
Ring A is C5-7 cycloalkyl, piperidinyl, or phenyl;
Ring B is C5-7 cycloalkyl, piperidynly, phenyl, or heteroaryl; wherein each is optionally
substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently fluoro, chloro; cyano; C1-4 alkyl; C1-4 hydroxyalkyl;
C1-4 haloalkyl; C1-4 alkoxy; C1-4 hydroxyalkoxy; C1-4 haloalkoxy; C3-6 cycloalkyl; 7-9 membered heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; and
R2 is independently hydrogen;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00275] In certain embodiments, the compound of Formula (XII) is that wherein:
ring C is:
Figure imgf000133_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is O or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen;
Ring A is C5-7 cycloalkyl, piperidinyl, or phenyl;
Ring B is phenyl, optionally substituted with 1, 2, or 3 RB groups; each RA2 and RB is independently halo; C1-4 haloalkyl; C1-4 alkoxy; C1-4 haloalkoxy; C3-6 cycloalkyl; 7-9 membered heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; and
R2 is independently hydrogen;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00276] In certain embodiments, the compound of Formula (XII) is that wherein Ring A is C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl. In certain embodiments, Ring A is C3-7 cycloalkyl. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl. In certain embodiments, Ring A is phenyl.
[00277] In certain embodiments, the compound of Formula (XII) is that wherein Ring C is:
Figure imgf000134_0001
.
[00278] In certain embodiments, the compound of Formula (XII) is that wherein Ring C is:
Figure imgf000134_0002
.
[00279] In certain embodiments, the compound of Formula (XII) is that wherein R2 and R3 are independently hydrogen. In certain embodiments, R2 is hydrogen. In certain embodiments, R3 is hydrogen.
[00280] In certain embodiments, the compound of Formula (XII) is that wherein L is a CF2, O, NRL, S, S(=O), C(=O), CH2-O, or O- CH2. In certain embodiments, L is a CF2, O, NRL, or S. In certain embodiments, L is a CF2, O, S, S(=O), or C(=O). In certain embodiments, L is a CF2, O, or S. In certain embodiments, L is CF2. In certain embodiments, L is O. In certain embodiments, L is S. In certain embodiments, L is a CH2-O. In certain embodiments, L is O-CH2. [00281] In certain embodiments, the compound of Formula (XII) is that wherein Z is - C(=O)H.
[00282] In certain embodiments, the compound of Formula (XII) is that wherein Z is - CH2OY. In certain embodiments, Y is hydrogen. In certain embodiments, Y is W. In certain embodiments, W is methylene substituted with
R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5; -S(O)R5; -S(O)2R5; -S(O)(OR5);
-S(O)2(OR5); or -SO2NR5R6. In certain embodiments, W is -C(=O)R5 or -C(=O)OR5. In certain embodiments, W is -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-. In certain embodiments, W is -P(=O)(OR7)2, wherein R7 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl. In certain embodiments, W is -P(=O)(OR7)2, wherein R7 is independently hydrogen or alkyl, for example, wherein R7 is independently hydrogen or C1-4 alkyl, such as wherein W
is -P(=O)(OH)2, -P(=O)(OH)(O-C1-4 alkyl), or -P(=O)(O-C1-4 alkyl)2. In certain embodiments, W is -P(=O)(OR7)(O-), wherein R7 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl. In certain embodiments, W is -P(=O)(OR7)(O-), wherein R7 is independently hydrogen or alkyl, for example, wherein R7 is independently hydrogen or C1-4 alkyl, such as wherein W is -P(=O)(OH)(O-) or -P(=O)(O-C1-4 alkyl)(O-). In certain
embodiments, W is methylene substituted with R4. In certain embodiments, W is methylene substituted with R4, wherein R4 is -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-. For example, in certain embodiments, W is methylene substituted with -O-P(=O)(OR7)(O-), wherein R7 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl. In certain embodiments, W is methylene substituted with–O-P(=O)(OR7)(O-), wherein R7 is independently hydrogen or alkyl, for example, wherein R7 is independently hydrogen or C1-4 alkyl, such as wherein W is methylene substituted with -O-P(=O)(OH)(O-) or–O-P(=O)(O-C1-4 alkyl)(O-). It will be understood that phosphoric acids and phosphate esters, such as, e.g., -O-P(=O)(OH)2 and–O-P(=O)(OR)(OH), where R is alkyl, aryl, etc., are ionizable groups, and can exist in equilibrium with their negatively charged or anionic forms, such as, e.g., -O-P(=O)(O-)2 and–O-P(=O)(OR)(O-), respectively.
[00283] In certain embodiments, the compound of Formula (XII) is that wherein R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy, heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, or alkoxycarbonyloxy. For example, in certain embodiments, R4 is C1-4 alkylcarbonyloxy, phenylcarbonyloxy,
C5-7 cycloalkylcarbonyloxy, 5-7 membered heterocycloalkylcarbonyloxy, aminocarbonyloxy, C1-4 alkylaminocarbonyloxy, C1-4 dialkylaminocarbonyloxy, or C1-4 alkoxycarbonyloxy. For example, in certain embodiments, R4 is C1-4 alkylcarbonyloxy, phenylcarbonyloxy,
C5-7 cycloalkylcarbonyloxy, or C1-4 alkoxycarbonyloxy. For example, in certain embodiments, R4 is 5-7 membered heterocycloalkylcarbonyloxy, aminocarbonyloxy,
C1-4 alkylaminocarbonyloxy, or C1-4 dialkylaminocarbonyloxy. In certain embodiments, R4 is -N(R10)C(O)R11, -N(R10)C(O)OR11, or -N(R10)C(O)NR12R13. For example, in certain embodiments, R4 is -N(R10)C(O)R11, -N(R10)C(O)OR11, or -N(R10)C(O)NR12R13. For example, in certain embodiments, R4 is -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-.
[00284] In certain embodiments, the compound of Formula (XII) is that wherein R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14,
-N(R9)C(=O)OR14, -SO2N(R9)2, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. For example, in certain embodiments, R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, -C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), C1-4 alkyl, phenyl, C5-7 cycloalkyl, 5-7 membered heterocycloalkyl, or heteroaryl. For example, in certain embodiments, R8 is independently hydrogen, fluoro, chloro, -CN, -OR9, -OC(=O)R9,
-OC(=O)OR9, C1-4 alkyl, phenyl, C5-7 cycloalkyl, 5-7 membered heterocycloalkyl, or heteroaryl. For example, in certain embodiments, R8 is independently hydrogen, fluoro, chloro, -CN, -OR9, -OC(=O)R9, or -OC(=O)OR9.
[00285] In certain embodiments, the compound of Formula (XII) is that wherein each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl. For example, in certain embodiments, each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, C1-4 alkyl, C5-7 cycloalkyl, phenyl, arylalkyl, 5-7 membered heterocycloalkyl, or heteroaryl. For example, in certain embodiments, each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, C1-4 alkyl,
C5-7 cycloalkyl, phenyl, or 5-7 membered heterocycloalkyl.
[00286] In certain embodiments, the compound of Formula (XII) is that wherein RL is hydrogen. In certain embodiments, RL is C1-4 alkyl optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy. In certain embodiments, RL is hydrogen or C1-4 alkyl optionally substituted with hydroxycarbonyl. In certain embodiments, RL is C1-4 alkyl optionally substituted with hydroxycarbonyl. In certain embodiments, RL is hydrogen or C1-4 alkyl substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy. In certain embodiments, RL is C1-4 alkyl substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy. In certain embodiments, RL is hydrogen or C1-4 alkyl substituted with hydroxycarbonyl.
[00287] In certain embodiments, the compound of Formula (XII) is that wherein Ring A is C3-10 cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
[00288] In certain embodiments, the compound of Formula (XII) is that wherein Ring A is C3-8 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiophenyl, pyridyl, phenyl, naphthyl, tetrahydronaphthalinyl, dihydronaphthalinyl, indanyl, indolyl, indolinyl, isoindolinyl, benzothiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, dihydrobenzodioxinyl, or tetrahydro-methanonaphthalenyl.
[00289] In certain embodiments, the compound of Formula (XII) is that wherein Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl. In certain embodiments, the compound of Formula (XII) is that wherein Ring A is C5-7 cycloalkyl. In certain embodiments, the compound of Formula (XII) is that wherein Ring A is cyclopentyl or cyclohexyl.
[00290] In certain embodiments, the compound of Formula (XII) is that wherein Ring A is heterocycloalkyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, phenyl, naphthyl,
tetrahydronaphthalinyl, dihydronaphthalinyl, indanyl, indolyl, isoindolinyl, benzothiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or dihydrobenzodioxinyl.
[00291] In certain embodiments, the compound of Formula (XII) is that wherein Ring A is heterocycloalkyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl,
tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, or dihydroisoquinolinyl.
[00292] In certain embodiments, the compound of Formula (XII) is that wherein Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, pyrazolyl, thienyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl, tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro-methanonaphthalenyl. In certain embodiments, Ring A is pyrazolyl, thienyl, imidazolyl, triazolyl, thiazolyl, phenyl, naphthyl, indanyl,
tetrahydronaphthalinyl, dihydronaphthalinyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, or tetrahydro- methanonaphthalenyl. In certain embodiments, Ring A is cyclohexyl or phenyl,
[00293] In certain embodiments, the compound of Formula (XII) is that wherein Ring A is pyrrolidinyl, piperidinyl, imidazolyl, triazolyl, thiazolyl, phenyl, pyridyl, or thienyl. In certain embodiments, Ring A is pyrrolidinyl, piperidinyl, imidazolyl, triazolyl, thiazolyl, phenyl, or pyridyl. In certain embodiments, Ring A is thiazolyl, phenyl, or pyridyl. In certain
embodiments, Ring A is thiazolyl or phenyl. In certain embodiments, Ring A is phenyl.
[00294] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present.
[00295] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RA1 groups. In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and Ring A is C5-7 cycloalkyl, or aryl, where each is optionally substituted with 1 or 2 RA1 groups. In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and Ring A is C5-7 cycloalkyl optionally substituted with 1 or 2 RA1 groups. In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and Ring A is aryl optionally substituted with 1 or 2 RA1 groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RA1 groups. In certain embodiments, Ring A is heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1 or 2 RA1 groups. In certain embodiments, Ring A is aryl or heteroaryl, where each is optionally substituted with 1 or 2 RA1 groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, phenyl, or heteroaryl, where each is optionally substituted with 1 or 2 RA1 groups. In certain embodiments, Ring A is heterocycloalkyl, phenyl, or heteroaryl, where each is optionally substituted with 1 or 2 RA1 groups. In certain embodiments, Ring A is phenyl or heteroaryl, where each is optionally substituted with 1 or 2 RA1 groups. In certain embodiments, the compound of Formula (XII), Ring A is unsubstituted. In certain embodiments, the compound of Formula (XII), Ring A is monosubstituted with 1 RA1 group. In certain embodiments, the compound of Formula (XII), Ring A is disubstituted with 2 RA1 groups.
[00296] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and Ring A is optionally substituted with 1 or 2 RA1 groups, wherein each RA1 is independently selected from fluoro, chloro, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, hydroxy, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, and C3-4 cycloalkyl. In certain embodiments, each RA1 is independently selected from fluoro, chloro, C1-4 alkyl, C1-4 alkoxy, cyano, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 haloalkoxy, and C3-4 cycloalkyl.
[00297] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is not present.
[00298] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is not present and Ring A is C5-7 cycloalkyl, 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1, 2, or 3 RA2 groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1, 2, or 3 RA2 groups. In certain embodiments, Ring A is heterocycloalkyl, aryl, or heteroaryl, where each is optionally substituted with 1, 2, or 3 RA2 groups. In certain embodiments, Ring A is aryl or heteroaryl, where each is optionallysubstituted with 1, 2, or 3 RA2 groups. In certain embodiments, Ring A is 5-6 membered heterocycloalkyl, phenyl, or heteroaryl, where each is optionally substituted with 1, 2, or 3 RA2 groups. In certain embodiments, Ring A is
heterocycloalkyl, phenyl, or heteroaryl, where each is optionally substituted with 1, 2, or 3 RA2 groups. In certain embodiments, Ring A is phenyl or heteroaryl, where each is optionally substituted with 1, 2, or 3 RA2 groups. In certain embodiments, the compound of Formula (XII), Ring A is unsubstituted. In certain embodiments, the compound of Formula (XII), Ring A is monosubstituted with 1 RA2 group. In certain embodiments, the compound of Formula (XII), Ring A is disubstituted with 2 RA2 groups. In certain embodiments, the compound of Formula (XII), Ring A is trisubstituted with 3 RA2 groups.
[00299] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and Ring A is unsubstituted. In certain embodiments, the compound of Formula (XII) is that wherein Ring A is unsubstituted and Ring B is unsubstituted. In certain embodiments, the compound of Formula (XII) is that wherein Ring A is unsubstituted and Ring B is substituted. In certain embodiments, the compound of Formula (XII) is that wherein Ring A is substituted and Ring B is unsubstituted. In certain embodiments, the compound of Formula (XII) is that wherein Ring A is substituted and Ring B is substituted. For example, in certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and Ring A is optionally substituted with 1, 2, or 3 RA2 groups, wherein each RA2 is independently selected from halo; cyano; C1-4 alkyl; C1-4 hydroxyalkyl; C1-4 haloalkyl; C1-4 alkoxy; C1-4 hydroxyalkoxy; C1-4 haloalkoxy; C1-4 alkylcarbonyl; C1-4 alkoxyalkoxy; C3-5 cycloalkyl; C5-6 heterocycloalkyl optionally substituted with one or two groups independently selected from halo, C1-4 alkyl, and C1-4 alkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxyalkyl, and C1-4 hydroxycycloalkyl. In certain embodiments, the RA2 is independently selected from halo; cyano; C1-4 alkyl; C1-4 hydroxyalkyl; C1-4 haloalkyl; C1-4 alkoxy; C1-4 hydroxyalkoxy; C1-4 haloalkoxy; C1-4 alkylcarbonyl; C5-6 heterocycloalkyl optionally substituted with one or two groups independently selected from halo, C1-4 alkyl, and C1-4 alkylcarbonyl. In certain embodiments, the RA2 is independently selected from fluoro; chloro; cyano; trifluoromethoxy; piperidinyl optionally substituted with one or two groups independently selected from halo, C1-4 alkyl, and C1-4 alkylcarbonyl.
[00300] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and is C3-8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups. In certain embodiments, Ring B is heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, or heteroaryl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is 5-6 membered heterocycloalkyl, phenyl, or quinolinyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, or heteroaryl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, or quinolinyl. In certain embodiments, Ring B is phenyl, pyridyl, quinolinyl, or isoquinolinyl. In certain embodiments, Ring B is phenyl or quinolinyl. In certain embodiments, Ring B is phenyl.
[00301] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and is heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups, wherein each RB is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocycloalkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl. In certain embodiments, Ring B is piperidinyl, piperazinyl, phenyl, or quinolinyl; each substituted with one or two RB groups, where each RB is independently halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocycloalkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl. In certain embodiments, each RB is independently halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxyalkoxy, alkylcarbonylaminoalkoxy, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, cycloalkylcarbonyl, cycloalkylcarbonyloxy, heterocycloalkyl optionally substituted with alkyl or alkylcarbonyl, (5-6-membered heterocycloalkyl-one)alkyl, (heterocycloalkyl)alkyl, or heterocycloalkylcarbonyl.
[00302] In certain embodiments, the compound of Formula (XII) is that wherein Ring B is present and is piperidinyl, piperazinyl, phenyl, or quinolinyl; wherein each is optionally substituted with 1, 2, or 3 RB groups, wherein each RB is independently chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, cyclopentoxy, piperidinyl, piperidinylalkyl, or piperidinylcarbonyl. In certain embodiments, Ring B is unsubstituted. In certain embodiments, Ring B is independently substituted with 1 RB group. In certain embodiments, Ring B is independently substituted with 2 RB groups. In certain embodiments, Ring B is independently substituted with 3 RB groups. In certain embodiments, Ring B is phenyl or quinolinyl; each substituted with one or two RB groups, where each RB is independently chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, isopropoxy,
trifluoromethoxy, cyclopropoxy, cyclopentoxy, piperidinyl, piperidinylalkyl, or
piperidinylcarbonyl. In certain embodiments, Ring B is phenyl substituted with one or two RB groups, where each RB is independently chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, cyclopentoxy, piperidinyl, piperidinylalkyl, or piperidinylcarbonyl. In certain embodiments, Ring B is phenyl substituted with one or two RB groups, where each RB is independently fluoro, chloro, bromo, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, or piperidinyl. In certain embodiments, Ring B is phenyl substituted with one or two RB groups, where each RB is independently fluoro, chloro, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, or piperidinyl. In certain embodiments, Ring B is phenyl substituted with one or two RB groups, where each RB is independently chloro, trifluoromethyl, methoxy, trifluoromethoxy, or piperidinyl. In certain embodiments, Ring B is phenyl substituted with one or two RB groups, where each RB is independently chloro, trifluoromethyl, methoxy, trifluoromethoxy, or piperidinyl.
[00303] In certain embodiments, the compound of Formula (XII) is selected from the group consisting of:
(4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol; (4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazol-5- yl)methanol;
(4-(((cis)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)thio)-1H-1,2,3-triazol-5- yl)methanol;
4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5- carbaldehyde;
4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5-carbaldehyde; (4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazol-5-yl)methanol;
(4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol;
(4-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol;
(4-((1-(3,5-dichlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol;
(4-((1-(3,5-dichlorophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazol-5-yl)methanol;
(4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol; and (4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazol-5-yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[00304] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol- 5-yl)methanol.
[00305] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazol-5-yl)methanol.
[00306] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-(((cis)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)thio)-1H-1,2,3- triazol-5-yl)methanol. [00307] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is 4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carbaldehyde.
[00308] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole- 5-carbaldehyde.
[00309] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazol-5- yl)methanol.
[00310] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5- yl)methanol.
[00311] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5- yl)methanol.
[00312] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-((1-(3,5-dichlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazol-5- yl)methanol.
[00313] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-((1-(3,5-dichlorophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazol-5- yl)methanol.
[00314] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5- yl)methanol.
[00315] In certain embodiments, the compound or pharmaceutically acceptable salt thereof of Formula (XII) is (4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazol- 5-yl)methanol.
[00316] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound from Table 1. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1-168, or a single stereoisomer or mixture of stereoisomers thereof. [00317] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58-1, 58-2, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 111-1, 111-2, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 152, 153, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166, 167, and 168, or a single stereoisomer or mixture of stereoisomers thereof.
[00318] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 4849, 50, 51, 52, 53, 54, 55, 56, 57, 58-1, 58-2, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 111-1, 111-2, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, and 168, or a single stereoisomer or mixture of stereoisomers thereof.
[00319] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 4849, 50, 51, 52, 53, 54, 55, 56, 57, 58-1, 58-2, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 111-1, 111-2, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, and 168, or a single stereoisomer or mixture of stereoisomers thereof. [00320] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58-1, 58-2, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 111-1, 111-2, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, and 168, or a single stereoisomer or mixture of stereoisomers thereof.
[00321] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 4-5, 14, 16, 21, 22, 30-33, 37, 38, 42, 45, 47, 51, 52, 54, 55, 58, 60, 62, 65-68, 72, 75, 81, 86, 87, 119, 126, 128-130, 139, 155-157, and 160-165, or a single stereoisomer or mixture of stereoisomers thereof.
[00322] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1-3, 8, 9, 11, 15, 17-19, 23-27, 29, 34, 39, 40, 43, 44, 53, 59, 61, 63, 64, and 124, or a single stereoisomer or mixture of stereoisomers thereof.
[00323] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 12, 20, and 145, or a single stereoisomer or mixture of stereoisomers thereof.
[00324] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 73, 90, 146, 149, and 150, or a single stereoisomer or mixture of stereoisomers thereof.
[00325] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 70, 71, and 74, or a single stereoisomer or mixture of stereoisomers thereof.
[00326] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 9, 11, 17, 19, 33, 37, 38, 40, 44, 45, 54, 55, 65, 72, 81, 93, 98, 107-110, 112, and 116, or a single stereoisomer or mixture of
stereoisomers thereof. [00327] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 54, 55, 37, 38, 81, and 107-109, or a single stereoisomer or mixture of stereoisomers thereof.
[00328] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 88, 91, 94, 95, 98, 100, 102-104, 112, and 131, or a single stereoisomer or mixture of stereoisomers thereof.
[00329] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound from Table 2. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 169-375, or a single stereoisomer or mixture of stereoisomers thereof.
[00330] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound from Table 3. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 294, 296, 366, 372 and 374, or a single stereoisomer or mixture of stereoisomers thereof.
[00331] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 185, 186, 187, 188, 189, 190, 194, 195, 196, 197, 198, 199, 200, 201, 203, 204, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272-1, 272-2, 273, 274, 275, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 295, 297, 298, 299, 300, 301, 303, 304, 305, 306, 307, 308-1, 308-2, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 367, 368, 369, 370, 373, and 375, or a single stereoisomer or mixture of stereoisomers thereof.
[00332] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 169, 170, 171, 172, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 197, 198, 199, 200, 201, 203, 216, 217, 220, 221, 222, 223, 224, 225, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 241, 242, 243, 247, 250, 253, 254, 255, 257, 259, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272-1, 272- 2, 273, 274, 275, 277, 279, 280, 282, 283, 284, 285, 286, 287, 289, 290, 291, 292, 293, 295, 297, 298, 299, 300, 304, 308-1, 308-2, 309, 310, 311, 312, 314, 315, 316, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 367, 368, 369, 373, and 375, or a single stereoisomer or mixture of stereoisomers thereof.
[00333] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 169, 170, 172, 173, 175, 244, 247, 277, 278, 311, 313, 314, 315, 317, 318, 319, 320, 321, 323, 324, 325, 326, 327, 330, 331, 332, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 351, and 352, or a single stereoisomer or mixture of stereoisomers thereof.
[00334] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 98, 110, 123, 142, 151, 159, 184, 191, 192, 193, 302, and 371, or a single stereoisomer or mixture of stereoisomers thereof.
[00335] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is compound 335, or a single stereoisomer or mixture of stereoisomers thereof.
[00336] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 171, 243, 312, 322, 328, 329, and 350, or a single stereoisomer or mixture of stereoisomers thereof.
[00337] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 174, 176, 177, 316, and 373, or a single stereoisomer or mixture of stereoisomers thereof.
[00338] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 220, 221, 222, 223, 224, 225, 226, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 245, 246, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 267, 268, 270, 271, 272-1, 272-2, 273, 275, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 295, 297, 301, 302, 303, 304, 305, 306, 307, 308-1, 308-2, 309, 310, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 367, 368, 370, 371, and 375, or a single
stereoisomer or mixture of stereoisomers thereof. [00339] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 227, 269, 274, 298, and 369, or a single stereoisomer or mixture of stereoisomers thereof.
[00340] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 264, 265, 266, 299, and 300, or a single stereoisomer or mixture of stereoisomers thereof.
[00341] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 181, 183, 186, and 190, or a single stereoisomer or mixture of stereoisomers thereof.
[00342] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 178, 179, 180, 184, 185, 187, 189, 193, 194, 195, 196, and 333, or a single stereoisomer or mixture of stereoisomers thereof.
[00343] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 178, 179, 180, and 333, or a single stereoisomer or mixture of stereoisomers thereof.
[00344] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound 182, or a single stereoisomer or mixture of stereoisomers thereof.
[00345] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 197, 198, 199, 200, and 201, or a single stereoisomer or mixture of stereoisomers thereof.
[00346] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 203, 204, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, and 334, or a single stereoisomer or mixture of stereoisomers thereof.
[00347] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compound 188, 191, and 192, or a single stereoisomer or mixture of stereoisomers thereof.
[00348] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound from Table 4 or 5. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 376-486, or a single stereoisomer or mixture of stereoisomers thereof.
[00349] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 376, 377, 379, 380, 381, 382, 383, 384, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442-1, 442-2, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, and 486, or a single stereoisomer or mixture of stereoisomers thereof.
[00350] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 294, 296, 366, 372, 374, 378, and 385.
[00351] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds 4, 5, 21, 22, 30, 31, 47, 48, 276, and 376.
[00352] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound from Table 7. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 487-497, or a single stereoisomer or mixture of stereoisomers thereof.
[00353] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 487, 488, 489, 490, 491, 492, 493-1, 493-2, 494, 495, 496, and 497, or a single stereoisomer or mixture of stereoisomers thereof.
[00354] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 490 and 491, or a single stereoisomer or mixture of stereoisomers thereof.
[00355] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 487, 488, 489, 492, 493-1, 493-2, 494, 495, 496, and 497, or a single stereoisomer or mixture of stereoisomers thereof. [00356] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 487, 491, 492, 493-1, 493-2, 496, and 497, or a single stereoisomer or mixture of stereoisomers thereof.
[00357] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 488, 489, and 490, or a single stereoisomer or mixture of stereoisomers thereof.
[00358] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 487, 488, 490, 491, 493-1, 493-2, 494, and 496, or a single stereoisomer or mixture of stereoisomers thereof.
[00359] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 489, 492, 495, and 497, or a single stereoisomer or mixture of stereoisomers thereof.
[00360] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 487, 488, 489, 490, 491, and 497, or a single stereoisomer or mixture of stereoisomers thereof.
[00361] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 493-1, 493-2, 494, and 495, or a single stereoisomer or mixture of stereoisomers thereof.
[00362] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 492 and 496, or a single stereoisomer or mixture of stereoisomers thereof. Pharmaceutical Compositions
[00363] In certain embodiments, optionally in combination with any or all of the above various embodiments, provided herein is a pharmaceutical composition comprising of a compound disclosed herein, for example, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
[00364] In certain embodiments, the pharmaceutical composition comprises a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
[00365] Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
[00366] Suitable excipients are well known to those skilled in the art. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
Formulation and Administration
[00367] In another aspect, provided herein, a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, as disclosed herein, and a pharmaceutical composition comprising the same and a pharmaceutically acceptable excipient, may be used in the methods of use provided herein, such as used in the methods for treatment of the diseases or disorders provided herein, or such as used in the methods for preventing the diseases or disorders provided herein. In certain embodiments, the compounds and pharmaceutical compositions provided herein are for use as a medicament for the treatment or prevention of the diseases or disorders provided herein. For example, in certain embodiments, the compounds and pharmaceutical compositions provided herein are for use in a method for the treatment or prevention of a disease or disorder associated with a defect in glyoxylate metabolism. For example, in certain embodiments, the compounds and pharmaceutical compositions provided herein are for use in a method for the treatment or prevention of a disease or disorder that is mediated by the enzyme GO or associated with alterations in oxalate metabolism. For example, a disease or disorder that is mediated by the enzyme GO or associated with alterations in oxalate metabolism include those disclosed in: Lorenzo, V., et al., Nefrologia, 34:398-412 (2014); Rumsby, G., et al., N Engl J Med., 369:2163 (2013); Cramer, S.D., et al., Hum Mol Genet., 8:2063–2069 (1999); Cregeen, D.P., et al., Hum Mutat., 22:497 (2003); Belostotsky, R., et al., Am J Hum Genet., 87:392–399 (2010); Liebow, A., et al., J. Am. Soc. Nephrol., 28(2):494–503 (2017); Dutta, C., et al., Mol. Ther., 24(4):770–778 (2016 Apr.); Selvam, R, et al., Indian J Exp Biol., 31(11):882-7 (1993 Nov); Lindsjö, M, et al., Scand J Urol Nephrol., 23(4):283-9 (1989); Worcester, E.M.,
Endocrinol Metab Clin North Am., 31:979–999 (2002); Lemann, J., et al., Kidney Int., 49:200– 208 (1996); Mittal, R.D., et al., J Endourol., 18:418–424 (2004); Sidhu, H., et al., J Am Soc Nephrol., 10 Suppl 14:S334–S340 (1999); Stapenhorst, L., et al., Pediatr Nephrol., 23:2277– 2279 (2008); Kraut, J.A., et al., Clin J Am Soc Nephrol., 3:208–225 (2008); Nasr, S.H., et al., Kidney Int., 70:1672 (2006); Canavese, C., et al., Am J Kidney Dis., 45:540–549 (2005);
Terribile, M, et al., Nephrol Dial Transplant., 21:1870–1875 (2006); Hueppelshaeuser, R., et al., Pediatr Nephrol., 27:1103–1109 (2012); Holmes, R.P., et al., Kidney Int., 59:270–276 (2001); Holmes, R.P., et al., J Urol., 174(3):943-947 (2005); Scales Jr., Charles, D., et al., European Urology, 62(1):160-165 (2012); Chadwick, V.S., et al., N Engl J Med., 289:172–176 (1973); Demoulin, Nathalie, et al., Medicine, 96(19):e6758 (2017 May); Amin, R., et al., Kidney Int., 93(5):1098-1107 (2018 May); Powell, C.R., et al., Urology, 55(6):825-30 (2000 Jun); Pini Prato, A, et al., Medicine (Baltimore), 88(2):83-90 (2009 Mar); Nazzal, L., et al., Nephrology Dialysis Transplantation, 31(3):375–382 (2016 Mar); Robijn, S., et al., Kidney Int., 80:1146–1158 (2011); Asplin, J.R., et al., J Urol., 177(2):565-9 (2007 Feb); Whitson, J.M., et al., Int Urol Nephrol., 42(2):369-74 (2010 Jun); Duffey, B.G., et al., J Am Coll Surg., 211(1):8-15 (2010); Isakova, T., et al., Nephrol Dial Transplant., 26(4):1258-1265 (2011); Eisner, B.H., et al., J Urol., 183(6):2244-2248 (2010); Massey, L.K., et al., J Am Diet Assoc., 93(8):901-906 (1993); Pak, C.Y., et al., Kidney Int., 68(5):2264-2273 (2005); Jiang, Z., et al., Nat Genet., 38:474–478 (2006); Freel, R.W., et al., Am J Physiol Gastrointest Liver Physiol., 290:G719–G728 (2006); Knight, T.F., et al., Am J Physiol., 240:F295–F298 (1981); Bergsland, K.J., et al., Am J Physiol Renal Physiol., 300:F311–F318 (2011); Sikora, P., et al., Kidney Int., 73:1181–1186 (2008); and Waikar, Sushru S., et al., JAMA Intern Med., 179(4):542-551 (2019); each of which is incorporated by reference in its entirety. In certain embodiments, the compounds and pharmaceutical compositions provided herein are for use in a method for the treatment of a disease or disorder in which inhibition of the enzyme GO ameliorates or treats the disease or disorder. In certain embodiments, a compound provided herein is a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof. In certain embodiments, provided is a method for treating any of the diseases or disorders described herein comprising administering to a subject in need of treatment thereof a compound according to any of the various embodiments described herein or a pharmaceutical composition according to any of the various embodiments described herein. The compounds and pharmaceutical compositions provided herein are for use in a method for the treatment of a disease or disorder that is mediated by the enzyme GO or associated with alterations in oxalate metabolism, or in which inhibition of the enzyme GO ameliorates or treats the disease or disorder. In certain embodiments, the compounds and pharmaceutical compositions provided herein are used in the preparation or manufacture of medicaments for the treatment of a disease or disorder that is mediated by the enzyme GO or associated with alterations in oxalate metabolism or in which inhibition of the enzyme GO ameliorates or treats the disease or disorder.
[00368] In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
[00369] In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Table 1, or stereoisomers thereof, and additionally optionally a
pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Table 2, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Table 4, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
[00370] In certain embodiments, provided herein is a method of treating a disease or disorder associated with a defect in glyoxylate metabolism, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a
pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the disease or disorder is associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. In certain embodiments, the disease or disorder is associated with the enzyme glycolate oxidase (GO). In certain embodiments, the disease or disorder is associated with alterations in oxalate metabolism. In certain embodiments, the disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism is characterized by high oxalate content in the urine. In certain
embodiments, the disease or disorder associated with the enzyme glycolate oxidase (GO) is characterized by high oxalate content in the urine. In certain embodiments, the disease or disorder associated with alterations in oxalate metabolism is characterized by high oxalate content in the urine. In certain embodiments, the disease or disorder is characterized by high oxalate content in the urine. In certain embodiments, the disease or disorder is a disease or disorder associated with the enzyme GO misregulation. In certain embodiments, the disease or disorder is treated or prevented by inhibition of the enzyme GO. In certain embodiments, the disease or disorder is treated by inhibition of the enzyme GO. In certain embodiments, the disease or disorder is prevented by inhibition of the enzyme GO. In certain embodiments, the disease or disorder is characterized by a deficiency in the enzyme alanine: glyoxylate
aminotransferase (AGT). In certain embodiments, the disease or disorder is characterized by a disruption of oxalate metabolic pathway. In certain embodiments, the disease or disorder is an enteric hyperoxaluria. In certain embodiments, the disease or disorder is a dietary hyperoxaluria. In certain embodiments, the disease or disorder is an idiopathic hyperoxaluria. In certain embodiments, the disease or disorder is a pharmacologically induced hyperoxaluria. In certain embodiments, the disease or disorder is a kidney disease.
[00371] In certain embodiments, provided herein is a method of treating a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the disease or disorder is characterized by high oxalate content in the urine. In certain embodiments, the disease or disorder results from a disruption of the oxalate metabolic pathway. In certain embodiments, the disease or disorder is selected from the group consisting of: hyperoxaluria, genetic or environmental vitamin B6 deficiency, genetic or environmental abnormal calcium metabolism, abnormal collagen metabolism, abnormal function of oxalate transporters, and genetic kidney disease. In certain embodiments, the disease or disorder is hyperoxaluria. In certain
embodiments, the disease or disorder hyperoxaluria is a primary hyperoxaluria (“PH”) or is a secondary hyperoxaluria. In specific embodiments, the disease or disorder is a primary hyperoxaluria (“PH”). In certain embodiments, the disease or disorder is a primary
hyperoxaluria selected from the group consisting of: Primary hyperoxaluria type 1 (“PH1”), Primary hyperoxaluria type 2 (“PH2”), and Primary hyperoxaluria type 3 (“PH3”). In a specific embodiment, the primary hyperoxaluria is Primary hyperoxaluria type 1 (“PH1”). In a specific embodiment, the primary hyperoxaluria is Primary hyperoxaluria type 2 (“PH2”). In a specific embodiment, the primary hyperoxaluria is Primary hyperoxaluria type 3 (“PH3”). In a specific embodiment, the hyperoxaluria is secondary hyperoxaluria. In a specific embodiment, the disease or disorder is a genetic or environmental vitamin B6 deficiency. In certain embodiments, the disease or disorder is a genetic or environmental abnormal calcium metabolism. In certain embodiments, the genetic or environmental abnormal calcium metabolism is hypercalciuria or hyperparathyroidism. In a specific embodiment, the genetic or environmental abnormal calcium metabolism is hypercalciuria. In a specific embodiment, the genetic or environmental abnormal calcium metabolism is hyperparathyroidism. In a specific embodiment, the disease or disorder is an abnormal collagen metabolism. In a specific embodiment, the disease or disorder is an abnormal function of oxalate transporters. In a specific embodiment, the disease or disorder is a genetic kidney disease. In a specific embodiment, the genetic kidney disease is Hirschsprung’s disease.
[00372] In certain embodiments, provided herein is a method of treating a disease or disorder characterized by high oxalate content in the urine is an enteric hyperoxaluria, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients. In certain embodiments, the disease or disorder is an enteric hyperoxaluria selected from the group consisting of: fat malabsorption, steatorrhea, inflammatory bowel disease (“IBD”), pancreatic insufficiency, biliary cirrhosis, short-bowel syndrome, bariatric surgery, jejunoileal bypass, Crohn’s disease, ulcerative colitis, cystic fibrosis, high blood pressure, diabetes, obesity, absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes, and ileal dysfunction. In a specific embodiment, the enteric hyperoxaluria is fat malabsorption. In a specific embodiment, the enteric hyperoxaluria is steatorrhea. In a specific embodiment, the enteric hyperoxaluria is inflammatory bowel disease (“IBD”). In a specific embodiment, the enteric hyperoxaluria is pancreatic insufficiency. In a specific embodiment, the enteric hyperoxaluria is biliary cirrhosis. In a specific embodiment, the enteric hyperoxaluria is short-bowel syndrome. In a specific embodiment, the enteric hyperoxaluria is bariatric surgery. In a specific embodiment, the enteric hyperoxaluria is jejunoileal bypass. In a specific embodiment, the enteric hyperoxaluria is Crohn’s disease. In a specific embodiment, the enteric hyperoxaluria is ulcerative colitis. In a specific embodiment, the enteric hyperoxaluria is cystic fibrosis. In a specific embodiment, the enteric hyperoxaluria is high blood pressure. In a specific embodiment, the enteric hyperoxaluria is diabetes. In a specific embodiment, the enteric hyperoxaluria is obesity. In a specific embodiment, the enteric hyperoxaluria is an absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes. In a specific embodiment, the enteric hyperoxaluria is an ileal dysfunction.
[00373] In certain embodiments, provided herein is a method of treating a disease or disorder characterized by high oxalate content in the urine is a dietary hyperoxaluria, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients. In certain embodiments, the dietary hyperoxaluria is associated with and/or the result of one or more of a high oxalate diet, a high protein diet, a high oxalate precursor diet, and a low calcium diet. In a specific embodiment, the dietary hyperoxaluria is associated with and/or the result of a high oxalate diet. In a specific embodiment, the dietary hyperoxaluria is associated with and/or the result of a high protein diet. In a specific embodiment, the dietary hyperoxaluria is associated with and/or the result of a high oxalate precursor diet. In a specific embodiment, the dietary hyperoxaluria is associated with and/or the result of a low calcium diet.
[00374] In certain embodiments, provided herein is a method of treating a disease or disorder characterized by high oxalate content in the urine is an idiopathic hyperoxaluria, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients. In certain embodiments, the idiopathic hyperoxaluria is undefined elevated hyperoxaluria. [00375] In certain embodiments, provided herein is a method of treating a disease or disorder characterized by high oxalate content in the urine is a pharmacologically induced hyperoxaluria, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the
pharmacologically induced hyperoxaluria is associated with and/or the result of ingestion of compounds that metabolize to oxylate. In certain embodiments, the pharmacologically induced hyperoxaluria is the result of ingestion of ethylene glycol or hydroxylproline. In certain embodiments, the pharmacologically induced hyperoxaluria is the result of ingestion of ethylene glycol. In certain embodiments, the pharmacologically induced hyperoxaluria is the result of ingestion of hydroxylproline.
[00376] In certain embodiments, provided herein is a method of treating a disease or disorder associated with a defect in glyoxylate metabolism, associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism, and/or characterized by high oxalate content in the urine, is a kidney disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the kidney disease is selected from the group consisting of: primary
hyperoxaluria, dietary hyperoxaluria, kidney stones (nephrolithiasis), recurrent kidney stones, progressive kidney failure, nephrocalcinosis, urinary tract infections, end stage renal disease, chronic kidney disease (“CKD”), end-stage kidney disease (“ESKD”), hypertension, diabetes, urolithiasis, and systemic oxalosis. In a specific embodiment, the kidney disease is primary hyperoxaluria. In a specific embodiment, the kidney disease is a dietary hyperoxaluria. In a specific embodiment, the kidney disease is kidney stones (nephrolithiasis). In a specific embodiment, the kidney disease is recurrent kidney stones. In a specific embodiment, the kidney disease is progressive kidney failure. In a specific embodiment, the kidney disease is nephrocalcinosis. In a specific embodiment, the kidney disease is urinary tract infections. In a specific embodiment, the kidney disease is end stage renal disease. In a specific embodiment, the kidney disease is chronic kidney disease (“CKD”). In a specific embodiment, the disease or disorder is end-stage kidney disease (“ESKD”). In a specific embodiment, the kidney disease is hypertension. In a specific embodiment, the kidney disease is diabetes. In a specific
embodiment, the kidney disease is urolithiasis. In a specific embodiment, the kidney disease is systemic oxalosis. In certain embodiments, the disease or disorder is nephropathy. In a specific embodiment, the nephropathy is oxalate nephropathy. In a specific embodiment, the
nephropathy is chronic calcium-oxalate nephropathy. In a specific embodiment, the disease or disorder is systemic oxalosis. In a specific embodiment, the disease or disorder is urolithiasis. In a specific embodiment, the disease or disorder is nephrocalcinosis. In a specific embodiment, the disease or disorder is calcium oxalate (CaOx) stone disease. In a specific embodiment, the disease or disorder is nephrolithiasis. In a specific embodiment, the nephrolithiasis is calcium oxalate (CaOx) nephrolithiasis. In a specific embodiment, the disease or disorder is renal failure.
[00377] In certain embodiments, provided herein is a method of treating a disease or disorder associated with a defect in glyoxylate metabolism, associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism, and/or characterized by high oxalate content in the urine, is selected from the group consisting of hyperoxaluria, chronic kidney disease (“CKD”), end-stage kidney disease (“ESKD”), nephropathy, systemic oxalosis, urolithiasis, nephrocalcinosis, calcium oxalate (CaOx) stone disease, nephrolithiasis, and renal failure, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients. In a specific embodiment, the disease or disorder is hyperoxaluria. In a specific embodiment, the hyperoxaluria is a primary hyperoxaluria. In a specific embodiment, the hyperoxaluria is PH1. In a specific embodiment, the hyperoxaluria is PH2. In a specific embodiment, the hyperoxaluria is PH3. In a specific embodiment, the hyperoxaluria is a secondary hyperoxaluria. In a specific embodiment, the disease or disorder is chronic kidney disease (“CKD”). In a specific embodiment, the disease or disorder is end-stage kidney disease (“ESKD”). In a specific embodiment, the disease or disorder is nephropathy. In a specific embodiment, the disease or disorder is systemic oxalosis. In a specific embodiment, the disease or disorder is urolithiasis. In a specific embodiment, the disease or disorder is nephrocalcinosis. In a specific embodiment, the disease or disorder is calcium oxalate (CaOx) stone disease. In a specific embodiment, the disease or disorder is nephrolithiasis. In a specific embodiment, the disease or disorder is renal failure.
[00378] In certain embodiments, provided herein is a method of treating a disease or disorder associated with a defect in glyoxylate metabolism, associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism, and/or characterized by high oxalate content in the urine, is selected from the group consisting of idiopathic hyperoxaluria, primary hyperoxaluria (“PH”), secondary hyperoxaluria, idiopathic hyperoxaluria, enteric hyperoxaluria, chronic kidney disease (“CKD”), end-stage kidney disease (“ESKD”), oxalate nephropathy, chronic calcium-oxalate nephropathy, systemic oxalosis, urolithiasis, nephrocalcinosis, calcium oxalate (CaOx) stone disease, calcium oxalate (CaOx) nephrolithiasis, and renal failure, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients. In a specific embodiment, the disease or disorder is idiopathic hyperoxaluria. In a specific embodiment, the disease or disorder is primary hyperoxaluria (“PH”). In a specific embodiment, the primary hyperoxaluria is PH1. In a specific embodiment, the primary hyperoxaluria is PH2. In a specific embodiment, the primary hyperoxaluria is PH3. In a specific embodiment, the disease or disorder is secondary hyperoxaluria. In a specific embodiment, the disease or disorder is idiopathic hyperoxaluria. In a specific embodiment, the disease or disorder is enteric hyperoxaluria. In a specific
embodiment, the disease or disorder is chronic kidney disease (“CKD”). In a specific embodiment, the disease or disorder is end-stage kidney disease (“ESKD”). In a specific embodiment, the disease or disorder is oxalate nephropathy. In a specific embodiment, the disease or disorder is chronic calcium-oxalate nephropathy. In a specific embodiment, the disease or disorder is systemic oxalosis. In a specific embodiment, the disease or disorder is urolithiasis. In a specific embodiment, the disease or disorder is nephrocalcinosis. In a specific embodiment, the disease or disorder is calcium oxalate (CaOx) stone disease. In a specific embodiment, the disease or disorder is calcium oxalate (CaOx) nephrolithiasis. In a specific embodiment, the disease or disorder is renal failure.
[00379] In another aspect, provided herein is a method of inhibiting the enzyme GO comprising administering to a subject in need thereof a therapeutically effective amount of the compounds and pharmaceutical compositions described herein.
[00380] The compounds or compositions disclosed herein can be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. The compounds are typically administered as pharmaceutical compositions by any route which makes the compound bioavailable. In certain embodiments, the composition is a solid formulation adapted for oral administration. In certain embodiments, the composition is a tablet, powder, or capsule; or the composition is a tablet. In certain embodiments, the composition is a liquid formulation adapted for oral administration. In certain embodiments, the composition is a liquid formulation adapted for parenteral administration. In certain embodiments, the composition is a solution, suspension, or emulsion; or the composition is a solution. In certain embodiments, solid form compositions can be converted, shortly before use, to liquid form compositions for either oral or parenteral administration. These particular solid form compositions are provided in unit dose form and as such are used to provide a single liquid dosage unit. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Marcel Dekker, Inc.: New York, NY, 2008).
[00381] The dosages may be varied depending on the requirement of the patient, the severity of the disease or disorder being treating and the particular compound and/or composition being employed. Determination of the proper dosage can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery. In certain embodiments, the compounds are administered to a subject at a daily dosage of between 0.01 to about 50 mg/kg of body weight. In other embodiments, the dose is from 1 to 1000 mg/day. In certain embodiments, the daily dose is from 1 to 750 mg/day; or from 10 to 500 mg/day.
[00382] In certain embodiments, the pharmaceutical composition is in unit dosage form. The composition can be subdivided into unit doses containing appropriate quantities of the active component(s). The unit dosage form can be a tablet, capsule, or powder in a vial or ampule, or it may be the appropriate number of any of these in a packaged form. The unit dosage form can be a packaged form, the package containing discrete quantities of composition such as packeted tablets, capsules, or powders in vials or ampules. The quantity of active compound(s) in a unit dose of the composition may be varied or adjusted from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or from about 1 mg to about 25 mg.
[00383] The compounds or pharmaceutical compositions disclosed herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. PREPARATION OF COMPOUNDS
[00384] The following are illustrative schemes and examples of how the compounds described herein can be prepared and tested. Although the examples can represent only some embodiments, it should be understood that the following examples are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein. [00385] General Scheme 1
Figure imgf000163_0001
[00386] A compound of Formula (I) can be prepared according to General Scheme 1, wherein R1 can be, for example, alkyl or cycloalkyl group. In certain embodiments, R1 is methyl, or ethyl.
[00387] Compound I-2 can be prepared from Compound I-1 using standard azide substitution conditions. More specifically, Compound I-1 can react with NaN3 in a solvent such as DMF, or THF, and at ambient temperature or up to 50 ^C.
[00388] Compound I-4 can be prepared from corresponding unsubstituted acetylene I-3 using standard halogenation conditions, wherein X is, for example, Cl, Br or I. More specifically, Compound I-3 can reaction with a halogenation reagent, such as NBS (N- Bromosuccinimide) or NIS (N-iodosuccinimide), in a solvent such as acetone or THF, in the presence of a silver salt such as AgNO3, to yield Compound I-4.
[00389] Intermediate I-5 can be prepared from Compounds I-2 and I-4 using standard click reaction conditions. More specifically, Compound I-2 can reaction with Compound I-4 optionally in the presence of copper salts, for example, a mixture of Cu(I) and Cu(II) salts such as CuI and Cu(OAc)2 in a solvent such as THF, to yield Intermediate I-5. [00390] Compound I-7 can be prepared using standard substitution conditions. More specifically, Compound I-5 can reacted with Compound I-6, in a solvent such as DMF or THF, in the presence of a base such as Na2CO3 or K2CO3, to yield Compound I-7.
[00391] Compound I can be prepared using standard PMB (p-Methoxybenzyl) deprotection conditions. More specifically, Compound I-7 can be treated in acidic conditions, such as in TFA (trifluoroacetic acid) as the solvent, at ambient temperature or up to 50 ^C to afford Compound I. [00392] General Scheme 2
Figure imgf000164_0001
[00393] Compound I or II of Formula (I) can be also prepared using General Scheme 2.
[00394] Compound II-2 can be prepared using standard substitution conditions. More specifically, Intermediate I-5 can reacted with Compound II-1, in a solvent such as DMF or THF, in the presence of a base such as Na2CO3 or K2CO3, to yield Compound II-2.
[00395] Compound II-3 can be prepared using standard coupling conditions. More specifically, Intermediate I-5 can reacted with methyl 3-mercaptopropanoate, in a solvent such as 1,4-dioxane or THF, in the presence of a base such as DIPEA (N,N-diisopropylethylamine), a palladium salt such as Pd2(dba)3, and a phosphine such as Xantphos, and to yield
Compound II-3.
[00396] Compound II-3 can be treated in basic condition to afford Compound II-4. More specification, Compound II-3 can reacted with potassium tert-butoxide, in a solvent such as THF at -78 o C and warmed up to ambient temperature, and to yield Compound II-4. [00397] Compound II-2 can also be prepared using standard substitution conditions. More specifically, Compound II-4 can reacted with Compound II-5, in a solvent such as DMF or THF, in the presence of a base such as Na2CO3 or K2CO3, to yield Compound II-2.
[00398] Compound II can be prepared using standard PMB (p-Methoxybenzyl) deprotection conditions. More specifically, Compound II-2 can be treated in acidic conditions, such as in TFA (trifluoroacetic acid) as the solvent, at ambient temperature or up to 50 ^C to afford Compound II. [00399] General Scheme 3
Figure imgf000165_0001
[00400] Compound III of Formula (I) can be also prepared using General Scheme 3.
[00401] Compound III-2 can be prepared using standard substitution conditions. More specifically, Intermediate I-5 can reacted with Compound III-1, in a solvent such as DMF or THF, in the presence of a base such as Na2CO3 or K2CO3, to yield Compound III-2.
[00402] Compound III-3 can be prepared using standard click reaction conditions. More specifically, Compound I-2 can reacted with dialkyl malonate, in a solvent such as 1,4-dioxane or THF, optionally in the presence of copper salts, for example, a mixture of Cu(I) and Cu(II) salts such as CuI and Cu(OAc)2 in a solvent such as THF, to yield Intermediate III-3.
[00403] Compound III-2 can also be prepared using standard substitution conditions. More specifically, Compound III-3 can reacted with Compound II-5, in a solvent such as DMF or THF, in the presence of a base such as Na2CO3 or K2CO3, to yield Compound III-2.
[00404] Compound III can be prepared using standard PMB (p-Methoxybenzyl) deprotection conditions. More specifically, Compound III-2 can be treated in acidic conditions, such as in TFA (trifluoroacetic acid) as the solvent, at ambient temperature or up to 50 ^C to afford Compound III.
[00405] General Scheme 4
Figure imgf000166_0001
[00406] Compound IV of Formula (I) can be also prepared using General Scheme 4.
[00407] Compound IV-2 can be prepared using standard substitution conditions. More specifically, Intermediate I-5 can reacted with Compound IV-1, in a solvent such as DMF or THF, in the presence of a base such as Na2CO3 or K2CO3, to yield Compound IV-2.
[00408] Compound IV-3 can be prepared using standard click reaction conditions. More specifically, Compound I-2 can reacted with ethyl 2-cyanoacetate, in a solvent such as 1,4- dioxane or THF, optionally in the presence of copper salts, for example, a mixture of Cu(I) and Cu(II) salts such as CuI and Cu(OAc)2 in a solvent such as THF, to yield Intermediate IV-3.
[00409] Compound IV-2 can also be prepared using standard substitution conditions. More specifically, Compound IV-3 can reacted with Compound II-5, in a solvent such as DMF or THF, in the presence of a base such as Na2CO3 or K2CO3, to yield Compound IV-2.
[00410] Compound IV can be prepared using standard PMB (p-Methoxybenzyl) deprotection conditions. More specifically, Compound IV-2 can be treated in acidic conditions, such as in TFA (trifluoroacetic acid) as the solvent, at ambient temperature or up to 50 ^C to afford Compound IV. [00411] General Scheme 5
Figure imgf000167_0001
[00412] Compound V of Formula (I) can be also prepared using General Scheme 5, wherein Y is a halo group for example, Cl, Br, or I.
[00413] Compound V-2 can be prepared using standard substitution conditions. More specifically, Intermediate I-5 can reacted with Compound V-1, in a solvent such as DMF or THF, in the presence of a base such as Na2CO3 or K2CO3, to yield Compound V-2.
[00414] Compound V-4 can be prepared using standard Suzuki-Miyaura coupling reaction conditions. More specifically, Compound V-2 can reacted with boronic acid Compound V-3, in a solvent such as toluene/EtOH/H2O or toluene/H2O, in the presence of a palladium salt such as Pd(PPh3)4 and a base such as Na2CO3 or K3PO4·7H2O, to yield Intermediate V-4.
[00415] Compound V can be prepared using standard PMB (p-Methoxybenzyl) deprotection conditions. More specifically, Compound V-4 can be treated in acidic conditions, such as in TFA (trifluoroacetic acid) as the solvent, at ambient temperature or up to 50 ^C to afford Compound V.
[00416] General Scheme 6
Figure imgf000168_0001
[00417] Compounds of Formula (I) can be also prepared using General Scheme 6.
Compounds I, II, III, IV, or V can be prepared using standard hydrolysis conditions. More specifically, Compounds I, II, III, IV, or V, respectively, can be treated in baisc conditions, such as in the presence of NaOH or LiOH.H2O in a solvent such as THF, at ambient temperature to afford the corresponding hydrolyzed Compound I, II, III, IV, or V, respectively.
[00418] Intermediate A
[00419] Synthesis of ethyl 5-bromo-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4- carboxylate
Figure imgf000169_0001
[00420] To a solution of NaN3 (25.0 g, 0.38 mol) in DMF (300 mL) was slowly added 1- (chloromethyl)-4-methoxybenzene (A-1) (49.7 mL, 0.37 mol) and stirred at 50 oC overnight. After cooling down to room temperature, the mixture was diluted with water (1000 mL) and extracted with ethyl acetate (500 mL x 3). The combined extracts were washed with water (500 mL x 4) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford Intermediate A-2. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.82 (s, 3H), 4.27 (s, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H).
[00421] To a solution of ethyl propionate (A-3) (26.3 g, 0.268 mol) and AgNO3 (4.56 g, 26.8 mmol) in anhydrous acetone (300 mL) was added NBS (52.6 g, 0.295 mol) in several small portions at 0 oC and stirred at room temperature overnight. The mixture was filtered. The filtrate was diluted with H2O (500 mL) and extracted with n-hexane (500 mL x 3). The combined extracts were washed with an aqueous HCl solution (10%, 500 mL x 2) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at room temperature (< 20 oC) to furnish Intermediate A-4 as a white solid. LC-MS (ESI) m/z: non- ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.32 (t, J = 7.2 Hz, 3H), 4.25 (q, J = 7.2 Hz, 2H).
[00422] A mixture of Intermediate A-2 (23.0 g, 0.14 mol), Intermediate A-4 (27.4 g, 0.155 mol), CuI (1.34 g, 7 mmol), and Cu(OAc)2 (1.27 g, 7 mmol) in anhydrous THF (500 mL) was stirred at 50 oC for 16 hours. After cooling down to room temperature, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with H2O (500 mL) and extracted with dichloromethane (500 mL x 2). The combined extracts were washed with saturated aqueous NaHCO3 solution (500 mL x 2) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a product. The product was slurred in petroleum ether (300 mL), filtered, and dried under vacuum to afford Intermediate A. LC-MS (ESI) m/z: 701 [2M+Na]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 5.55 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H).
[00423] Intermediate B
[00424] Synthesis of ethyl 5-iodo-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4- carboxylate
Figure imgf000170_0001
[00425] A mixture of Intermediate A-2 (840 mg, 5.1mmol), ethyl propiolate (A-3) (402 mg, 5.1 mmol), CuI (970 mg, 5.1 mmol), NIS (908 mg, 5.1 mmol), and N,N- diisopropylethylamine (658 mg, 5.1 mmol) in THF (10 mL) was stirred at room temperature for 16 hours. The mixture was concentrated and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 17% v/v) to afford Intermediate B. LC-MS (ESI) m/z: 388 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.43 (t, J = 6.8 Hz, 3H), 3.79 (s, 3H), 4.43 (q, J = 6.8 Hz, 2H), 5.60 (s, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H).
[00426] Intermediate C
[00427] Synthesis of mthyl 5-iodo-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4- carboxylate
Figure imgf000170_0002
[00428] Intermediate C was synthesized by employing the procedure described for Intermediate B using Intermediate C-1 in lieu of Intermediate A-3, LC-MS (ESI) m/z: 374
[M+H]+. [00429] Intermediate D
[00430] Synthesis of ethyl 5-mercapto-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4- carboxylate
Figure imgf000171_0002
[00431] To a solution of Intermediate A (1 g, 2.9 mmol) and methyl 3- mercaptopropanoate (418 mg, 3.48 mmol) in 1,4-dioxane (8 mL) was added N,N- diisopropylethylamine (748 mg, 5.8 mmol), Pd2(dba)3 (133 mg, 0.145 mmol), and Xantphos (168 mg, 0.29 mmol). The mixture was purged with nitrogen for 2 minutes and heated in a microwave oven at 120 oC for 30 minutes. The reaction mixture was concentrated and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 60% v/v) to yield Intermediate D-1. LC-MS (ESI) m/z: 380 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 2.43 (t, J = 7.2 Hz, 2H), 3.17 (t, J = 6.8 Hz, 2H), 3.65 (s, 3H), 3.77 (s, 3H), 4.34 (q, J = 7.2 Hz, 2H), 5.59 (s, 2H), 6.84 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H).
[00432] To a solution of Intermediate D-1 (0.8 g, 2.1 mmol) in dry THF (10 mL) was added potassium tert-butoxide (235 mg, 2.1 mmol) at -78 oC. The mixture was stirred at -78 oC under nitrogen for 30 minutes. After slowly warming to room temperature, the mixture was diluted with water (4 mL), acidified to pH 6 with a concentrated HCl solution, and concentrated under reduced pressure. The residue was purified with reverse phase chromatography using eluents (methanol in H2O, from 0% to 60% v/v) to afford Intermediate D. LC-MS (ESI) m/z: 294 [M+H]+.
[00433] Intermediate E
[00434] Synthesis of methyl 5-((4-bromophenyl)thio)-1-(4-methoxybenzyl)-1H-1,2,3- triazole-4-carboxylate
Figure imgf000171_0001
[00435] Intermediate E was synthesized by employing the procedure described for Compound 1E using 4-bromobenzenethiol and Intermediate C in lieu of Compound 1D and Intermediate B, LC-MS (ESI) m/z: 434 [M+H]+.
[00436] Intermediate F
[00437] Synthesis of ethyl 5-((4-bromophenyl)thio)-1-(4-methoxybenzyl)-1H-1,2,3- triazole-4-carboxylate
Figure imgf000172_0001
[00438] Intermediate F was synthesized by employing the procedure described for Compound 1E using 4-bromobenzenethiol and Intermediate A in lieu of Compound 1D and Intermediate B, LC-MS (ESI) m/z: 448 [M+H]+.
[00439] Intermediate G
[00440] Synthesis of ethyl 5-amino-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4- carboxylate
Figure imgf000172_0002
22.3 mmol), and EtONa (1.5 g, 22.3 mmol) in EtOH (50 mL) was stirred at 80 oC for 5.5 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL) and filtered. The cake was washed with water (100 mL x 2) and slurred in petroleum ether (20 mL) for 15 minutes. The resulting solid was collected and dried under vacuum to afford Intermediate G. LC-MS (ESI) m/z: 277 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.27 (t, J = 7.2 Hz, 3H), 3.72 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 5.35 (s, 2H), 6.57 (s, 2H), 6.91 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H). [00442] Intermediate H
[00443] Synthesis of ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4- carboxylate
[
Figure imgf000173_0001
mmol) in small pieces and stirred at room temperature until sodium was dissolved. To the solution was added diethyl malonate (2.08 g, 1.98 mL, 13 mmol) and stirred at room temperature for 30 minutes. To the mixture was dropped a solution of Intermediate A-2 (2.12 g, 13 mmol) in EtOH (5 mL) and heated at reflux for 18 hours. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was diluted with H2O (100 mL) and washed with ethyl acetate (50 mL x 2). The aqueous layer was adjusted to pH 3-4 with a diluted HCl solution (2 N) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated to afford Intermediate H. LC-MS (ESI) m/z: 278 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40 (t, J = 7.2 Hz, 3H), 3.79 (s, 3H), 4.42 (q, J = 7.2 Hz, 2H), 5.31 (s, 2H), 6.85- 6.88 (m, 2H), 7.29-7.31 (m, 2H).
[00445] Intermediate I
[00446] Synthesis of ethyl 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3- triazole-4-carboxylate
Figure imgf000173_0002
[00447] A mixture of 4-bromophenol (610 mg, 3.53 mmol), Intermediate A (1 g, 2.94 mmol), and K2CO3 (608 mg, 4.41 mmol) in DMF (20 mL) was stirred at 90 oC for 4 hours. The reaction mixture was cooled down to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined extracts were washed with water (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 40% v/v) to afford Intermediate I LC-MS (ESI) m/z: 432 [M+H]+.
[00448] Intermediate J
[00449] Synthesis of a mixture of 4-(ethoxycarbonyl)-1-(4-methoxybenzyl)-1H-1,2,3- triazole-5-carboxylic acid and 5-(ethoxycarbonyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4- carboxylic acid
Figure imgf000174_0001
[00450] A mixture of Intermediate J-1, diethyl but-2-ynedioate, (1.0 g, 5.9 mmol), CuI (2.25 g, 11.8 mmol), and Intermediate A-2 (963 mg, 5.9 mmol) in DMSO (20 mL) was stirred at room temperature under nitrogen overnight. The mixture was diluted with EtOAc (50 mL), washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Intermediate J-2. LC-MS (ESI) m/z: 334 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.31 (t, J = 7.2 Hz, 3H), 1.60 (t, J = 7.2 Hz, 3H), 3.79 (s, 3H), 4.33 (q, J = 7.2 Hz, 2H), 4.42 (q, J = 7.2 Hz, 2H), 5.73 (s, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H).
[00451] A mixture of Intermediate J-2 (5 g, 15 mmol) and potassium hydroxide (840 mg, 15 mmol) in water (25 mL) and EtOH (25 mL) was stirred at room temperature for16 hours. The mixture was adjusted to pH 6 with a diluted aqueous HCl solution (1 N) and a solid was precipitated. The solid was collected by filtration and dried under vacuum to give Intermediate J. LC-MS (ESI) m/z: 328 [M+Na]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.49 (t, J = 7.2 Hz, 3H), 3.76 (s, 3H), 4.57-4.59 (m, 2H), 6.00 (s, 2H), 6.82 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H). [00452] Intermediate K
Figure imgf000175_0001
[00453] Intermediates K-2 and K-3 were synthesized by employing the procedures described for Intermediates A-4 and A using Intermediates K-1 and K-2 in lieu of Intermediates A-3 and A-4. Intermediate K-2: LC-MS (m/z): Non-ionzable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.05 (s, 6H), 0.84 (s 9H), 4.27 (s, 2H). Intermediate K-3: LC-MS (m/z): 412 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.09 (s, 6H), 0.89 (s 9H), 3.79 (s, 3H), 4.74 (s, 2H), 5.47 (s, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H).
[00454] To a solution of Intermediate K-3 (14.02 g, 33.4 mmol) in dry THF (250 mL) at - 78 oC under nitrogen was dropped a solution of n-BuLi in n-hexane (2.5 N, 15 mL, 37.4 mmol) and stirred at -78 oC for 0.5 hour, followed by addition of ethyl carbonochloridate (11 mL, 112.2 mmol). The mixture was stirred at -78 oC for 0.5 hour, quenched with saturated aqueous NH4Cl solution (150 mL), and extracted with ethyl acetate (250 mL x 2). The combined organic layers was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to furnish Intermediate K-4. LC-MS (m/z): 406 [M+H]+.
[00455] To a solution of Intermediate K-4 (13.5 g, 33.4 mmol) in dry THF (20 mL) was dropped a solution of Bu4NF in THF (1 N, 16.7 mL, 16.7 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50% v/v) to give Intermediate K-5. LC-MS (m/z): 292 [M+H]+; 1H-NMR (CDCl3, 500 MHz): d (ppm) 1.38 (t, J = 7.0 Hz, 3H), 3.78 (s, 3H), 4.39 (q, J = 7.0 Hz, 2H), 4.91 (s, 2H), 5.82 (s, 2H), 6.84 (d, J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H).
[00456] To a solution of Intermediate K-5 (1.0 g, 3.44 mmol) in THF (40 mL) was added PBr3 (1.38 g, 5.16 mmol). The mixture was stirred at room temperature for 4 hours, quenched with water (10 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Intermediate K. LC-MS (ESI) m/z: 354 [M+H]+.
[00457] Example 1
[00458] Synthesis of ethyl 4-((4-(3,4-dichlorophenyl)thiazol-2-yl)thio)-1H-1,2,3- triazole-5-carboxylate (1)
Figure imgf000176_0001
[00459] A mixture of 2-bromo-1-(3,4-dichlorophenyl)ethanone (Compound 1A) (1.5 g , 5.6 mmol) and carbamodithioic acid ammonia salt (677 mg, 6.1 mmol) in EtOH (5 mL) was stirred at 60 oC for 10 minutes. The reaction mixture was concentrated. The residue was washed with water (20 mL) and dried under vacuum to give Compound 1B. LC-MS (ESI) m/z: 246 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.66 (s, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.75-7.78 (m, 1H), 8.03 (d, J = 2.0 Hz, 1H).
[00460] A mixture of Compound 1B (1150 mg, 4.7 mmol) and POCl3 (5 mL) was stirred at 100 °C for 1 hour. The mixture was concentrated to give Compound 1C. LC-MS (ESI) m/z: 264 [M+H]+.
[00461] A mixture of Compound 1C (1.2 g, 4.5mmol) and thiourea (686 mg, 9.0 mmol) in EtOH (10 mL) was stirred at 80 oC for 16 hours. After cooling down to room temperature, the mixture was diluted with water (60 mL) and filtered. The cake was dried under vacuum to afford Compound 1D. LC-MS (ESI) m/z: 262 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.63(s, 1H), 7.69-7.78 (m, 2H), 8.11 (s, 1H), 13.75 (brs, 1H).
[00462] A mixture of Compound 1D (300 mg, 0.77 mmol), Intermediate B (407 mg, 1.55 mmol), and K2CO3 (214 mg, 1.55 mmol) or Na2CO3 in DMF (5 mL) was stirred at 50 °C for 16 hours. The mixture was concentrated and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 17% v/v) to afford Compound 1E. LC-MS (ESI) m/z: 521 [M+H]+.
[00463] A mixture of Compound 1E (300 mg, 0.58 mmol) in TFA (5 mL) was stirred at 50 °C for 16 hours. The mixture was concentrated and purified with flash column
chromatography on silica gel (ethyl acetate in petroleum ether, 33% v/v) to afford Compound 1. LC-MS (ESI) m/z: 401 [M+H]+.
[00464] Example 2
[00465] Synthesis of 4-((4-(3,4-dichlorophenyl)thiazol-2-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (2)
Figure imgf000177_0001
[00466] A mixture of Compound 1 (100 mg, 0.25 mmol) and NaOH (100 mg, 2.5 mmol) in THF (20 mL) and H2O (2 mL) was stirred at room temperature for 16 hours. The mixture was concentrated and the residue was purified with preparative HPLC to afford Compound 2. LC-MS (ESI) m/z: 373 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.14 (brs, 2H), 7.68-7.71 (m, 1H), 7.89-7.92 (m, 1H), 8.15-8.18 (m, 2H).
[00467] Example 3
[00468] Synthesis of 4-((5-(3,4-dichlorophenyl)thiazol-2-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (3)
Figure imgf000177_0002
[00469] To a solution of 5-(3,4-dichlorophenyl)thiazole (Compound 3A) (2.3 g , 10 mmol) in anhydrous THF (20 mL) was dropped n-BuLi solution (2.5 M in n-hexane, 12 mL, 30 mmol) at -78 oC under nitrogen. After stirring at -78 oC for 30 minutes, to the mixture was added Br2 (3.2 g, 20 mmol) and stirred at -78 oC for 30 minutes. The reaction mixture was quenched with water (2 mL), concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 17% v/v) to give Compound 3B. LC-MS (ESI) m/z: 308 [M+H]+.
[00470] Compounds 3C, 3D, 3E, and 3 were synthesized by employing the procedures described for Compounds 1D, 1E, 1, and 2 using Compounds 3B, 3C, 3D, and 3E in lieu of Compounds 1C, 1D, 1E, and 1. Compound 3C: LC-MS (ESI) m/z: 262 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.43-7.46 (m, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 13.50 (brs, 1H). Compound 3D: LC-MS (ESI) m/z: 521 [M+H]+. Compound 3E: LC-MS (ESI) m/z: 401 [M+H]+. Compound 3: LC-MS (ESI) m/z: 373 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.13 (brs, 2H), 7.51-7.55 (m, 1H), 7.62-7.64 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H).
[00471] Reference Example 4
[00472] Synthesis of 4-((4'-bromo-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (4)
Figure imgf000178_0001
[00473] A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CO3 (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H2O (20/10/4 mL) was stirred at 80 oC under nitrogen overnight. The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H- NMR (CDCl3, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H).
[00474] To a solution of Compound 4B (278 mg, 1 mmol) in dichloromethane (10 mL) was added m-CPBA (258 mg, 1.5 mmol) at 0 oC, After the mixture was stirred at room temperature for 30 minutes, Ca(OH)2 (238 mg, 1.7 mmol) was added. The mixture was stirred at room temperature for 5 minutes and filtered. To the filtrate was added trifluoroacetoanhydride (440 mg, 2.1 mmol) and heated at reflux for 1 hour. The mixture was evaporated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4C. LC-MS (ESI) m/z: 263 [M-H]-; 1H-NMR (CDCl3, 400 MHz): d (ppm) 5.64 (s, 1H), 7.41-7.55 (m, 8H).
[00475] Compounds 4D, 4E, and 4 were synthesized by employing the procedures described for Compounds 1E, 1, and 2 using Compounds 4C, 4D, and 4E in lieu of Compounds 1D, 1E, and 1. Compound 4D: LC-MS (ESI) m/z: 524 [M+H]+. Compound 4E: LC-MS (ESI) m/z: 404 [M+H]+. Compound 4: LC-MS (ESI) m/z: 376 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.18-7.50 (m, 2H), 7.56-7.60 (m, 6H).
[00476] Example 5
[00477] Synthesis of 4-((4'-chloro-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (5)
Figure imgf000179_0001
[00478] Compounds 5A, 5B, 5C, 5D, and 5 were synthesized by employing the procedures described for Compounds 4B, 4C, 1E, 1, and 2 using 4-chlorophenylboronic acid, Compounds 5A, 5B, Intermediate C, 5C, and 5D in lieu of 4-bromophenylboronic acid, Compounds 4B, 1D, Intermediate B, 1E, and 1. Compound 5A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 2.52 (s, 3H), 7.31-7.33 (m, 2H), 7.38-7.40 (m, 2H), 7.47-7.50 (m, 4H). Compound 5B: LC-MS (ESI) m/z: 219 [M-H]-; 1H-NMR (DMSO-d6, 500 MHz): d (ppm) 5.96 (s, 1H), 7.58-7.73 (m, 8H). Compound 5C: LC-MS (ESI) m/z: 466 [M+H]+. Compound 5D: LC-MS (ESI) m/z: 346 [M+H]+.
Compound 5: LC-MS (ESI) m/z: 332 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.42-7.48 (m, 4H), 7.56-7.62 (m, 4H).
[00479] Example 6
[00480] Synthesis of 5-((3-(4-methylpiperazin-1-yl)phenyl)thio)-1H-1,2,3-triazole-4- carboxylic acid 2,2,2-trifluoroacetate (6)
Figure imgf000180_0001
[00481] Compound 6A was synthesized by employing the procedure described for Compound 1E using 3-bromobenzenethiol and Intermediate C in lieu of Compound 1D and Intermediate B, LC-MS (ESI) m/z: 434 [M+H]+.
[00482] To a solution of Compound 6A (138 mg, 0.32 mmol) in tolunen (4 mL) was added N-methylpiperazine (160 mg, 1.6 mmol), t-BuONa (61 mg, 0.64 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), and Xantphos (37 mg, 0.064 mmol) and heated in a microwave oven at 120 oC for 2 hours. The mixture was concentrated and purified by reverse phase column
chromatography to afford Compound 6B. LC-MS (ESI) m/z: 440 [M+H]+.
[00483] Compound 6 was synthesized by employing the procedure described for
Compound 1 using Compound 6B in lieu of Compound 1E, LC-MS (ESI) m/z: 320 [M+H]+; 1H- NMR (CD3OD, 400 MHz): d (ppm) 2.85 (s, 3H), 3.00-3.20 (br, 2H), 3.24-3.95 (br, 6H), 6.92- 6.94 (m, 2H), 7.07 (s, 1H), 7.17-7.21 (m, 1H).
[00484] Example 7 [00485] Synthesis of 4-((4-(piperidin-1-yl)phenyl)thio)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (7)
Figure imgf000181_0001
[00486] Compounds 7A and 7 were synthesized by employing the procedures described for Compounds 6B and 1 using Intermediate E, piperidine, and Compound 7A in lieu of Compounds 6A, 1-methylpiperazine, and 1E. Compound 7A: LC-MS (ESI) m/z: 425 [M+H]+. Compound 7: LC-MS (ESI) m/z: 305 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.75-1.76 (m, 2H), 1.91-1.94 (m, 4H), 3.49-3.52 (m, 4H), 7.40-7.42 (m, 2H), 7.57-7.59 (m, 2H).
[00487] Example 8
[00488] Synthesis of 4-((2-(3,4-dichlorophenyl)thiazol-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (8)
Figure imgf000181_0002
[00489] A mixture of 2,4-dibromothiazole (Compound 8A) (3.9 g, 16 mmol), 3,4- dichlorophenylboronic acid (3.05 g, 16 mol), Pd(dppf)Cl2 (0.7 g, 0.87 mmol), and cesium carbonate (15 g, 46 mmol) in DME (120 mL) and water (10 mL) was heated at reflux under nitrogen overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 8B. LC-MS (ESI) m/z: 308 [M+H]+.
[00490] Compounds 8C, 8D, and 8E were synthesized by employing the procedures described for Intermediates D-1, D, and Compound 1E using Compounds 8B, 8C, and 8D in lieu of Intermediates A, D-1, and Compound 1D. Compound 8C: LC-MS (ESI) m/z: 348 [M+H]+. Compound 8D: LC-MS (ESI) m/z: 262 [M+H]+. Compound 8E: LC-MS (ESI) m/z: 521 [M+H]+.
[00491] To a solution of Compound 8E (220 mg, 0.42 mmol) in THF (40 mL) and water (8 mL) was added LiOH.H2O (110 mg, 2.62 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to furnish Compound 8F, which was used directly for next step without further purification. LC-MS (ESI) m/z: 493.
[00492] Compound 8 was synthesized by employing the procedure described for
Compound 1 using Compound 8F in lieu of Compound 1E, LC-MS (ESI) m/z: 373 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 7.65 (d, J = 8.4 Hz, 1H), 7.85-7.88(m, 2H).8.13 (d, J = 2.0 Hz, 1H).
[00493] Example 9
[00494] Synthesis of cyclobutyl 4-((4-(3,4-dichlorophenyl)thiazol-2-yl)thio)-1H-1,2,3- triazole-5-carboxylate (9)
Figure imgf000182_0001
[00495] Compound 9A was synthesized by employing the procedure described for Compound 2 using Compound 1E in lieu of Compound 1, LC-MS (ESI) m/z: 493 [M+H]+.
[00496] A mixture of Compound 9A (200 mg, 0.4 mmol), cyclobutanol (86 mg, 1.2 mmol), and HBTU (456 mg, 1.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 hours. The mixture was evaporated under reduced pressure and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to afford Compound 9B. LC-MS (ESI) m/z: 547 [M+H]+.
[00497] Compound 9 was synthesized by employing the procedure described for
Compound 1 using Compound 9B in lieu of Compound 1E, LC-MS (ESI) m/z: 427 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.59-1.73 (m, 2H), 1.99-2.05 (m, 2H), 2.26-2.33 (m, 2H), 50.3-5.07 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.89-7.92 (m, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H).
[00498] Example 10
[00499] Synthesis of 4-((4-(4-methylpiperazin-1-yl)phenyl)thio)-1H-1,2,3-triazole-5- carboxylic acid (10)
Figure imgf000183_0001
[00500] Compounds 10A and 10 were synthesized by employing the procedures described for Compounds 6B and 1 using N-methylpiperazine, Intermediate E, and Compound 10A in lieu of 1-methylpiperazine, Compounds 6A, and 1E. Compound 10A: LC-MS (ESI) m/z: 440
[M+H]+. Compound 10: LC-MS (ESI) m/z: 320 [M+H]+; 1H-NMR (400 MHz, DMSO-d6): d (ppm) 2.27 (s, 3H), 2.48-2.50 (m, 4H), 3.17-3.19 (m, 4H), 6.92 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H).
[00501] Example 11
[00502] Synthesis of isopropyl 4-((4-(3,4-dichlorophenyl)thiazol-2-yl)thio)-1H-1,2,3- triazole-5-carboxylate (11)
Figure imgf000184_0001
[00503] A mixture of Compound 9A (400 mg, 0.8 mmol) and SOCl2 (960 mg, 8.0 mmol) in propan-2-ol (5 mL) was stirred at 60 oC for 16 hours. The mixture was concentrated and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to afford Compound 11A. LC-MS (ESI) m/z: 535 [M+H]+.
[00504] Compound 11 was synthesized by employing the procedure described for Compound 1 using Compound 11A in lieu of Compound 1E, LC-MS (ESI) m/z: 415 [M+H]+; 1H-NMR (DMSO-d6, 500 MHz): d (ppm) 1.18 (d, J = 6.0 Hz, 6H), 4.97-5.00 (m, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.89-7.91 (m, 1H), 8.09 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H).
[00505] Example 12
[00506] Synthesis of 4-((5-(4-bromophenyl)pyridin-2-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (12)
Figure imgf000184_0002
[00507] To a solution of Compound 12A (1.92 g, 10 mmol) in DMF (20 mL) was added NaHS (560 mg, 10.0 mmol). The reaction mixture was stirred at 70 oC under nitrogen for 14 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 12B. LC-MS (ESI) m/z: 190 [M+H]+.
[00508] Compounds 12C, 12D, 12E, and 12 were synthesized by employing the procedures described for Compounds 1E, 4B, 8F, and 1 using Compounds 12B, 12C, 12D, and 12E in lieu of Compounds 1D, 4A, 8E, and 1E. Compound 12C: LC-MS (ESI) m/z: 449
[M+H]+. Compound 12D: LC-MS (ESI) m/z: 525 [M+H]+. Compound 12E: LC-MS (ESI) m/z: 497 [M+H]+. Compound 12: LC-MS (ESI) m/z: 377 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.36 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.97 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H).
[00509] Example 13
[00510] Synthesis of 4-((5-(3,4-dichlorophenyl)-4H-1,2,4-triazol-3-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (13)
Figure imgf000185_0001
[00511] A mixture of 3,4-dichlorobenzoyl chloride (Compound 13A) (832 mg, 4 mmol) and hydrazinecarbothioamide (910 mg, 10 mmol) in THF (50 mL) was stirred at room temperature overnight. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 13B. LC-MS (ESI) m/z: 264 [M+H]+.
[00512] To a mixture of Compound 13B (526 mg, 2 mmol) in ethanol (10 mL) was added aqueous NaOH solution (4 N, 10 mL). The mixture was stirred at 80 oC overnight. The mixture was adjusted to pH 4 with acetic acid (20 mL) and a solid was precipitated. The resulting solid was filtered and dried under vacuum to afford Compound 13C. LC-MS (ESI) m/z: 246 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.79-7.89 (m, 2H), 8.14-8.15 (m, 1H), 13.84 (brs, 1H).
[00513] A mixture of Compound 13C (369 mg, 1.5 mmol), Intermediate B (388 mg, 1 mmol), t-BuONa (144 mg, 1.5 mmol), 2,9-dimethyl-1,10-phenanthroline (21 mg, 0.1 mmol), and CuI (20 mg, 0.1 mmol) in DMF (20 mL) was stirred at 110 oC under nitrogen overnight. The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to afford Compound 13D. LC-MS (ESI) m/z: 505 [M+H]+.
[00514] Compounds 13E and 13 were synthesized by employing the procedures described for Compounds 2 and 1 using Compounds 13D and 13E in lieu of Compounds 1 and 1E.
Compound 13E: LC-MS (ESI) m/z: 477 [M+H]+. Compound 13: LC-MS (ESI) m/z: 357
[M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.66 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.8, 2.0 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H).
[00515] Example 14
[00516] Synthesis of 4-((4'-methoxy-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (14)
Figure imgf000186_0001
[00517] Compounds 14A, 14B, and 14 were synthesized by employing the procedures described for Compounds 4B, 1, and 8F using 4-methoxyphenylboronic acid, Intermediate E, Compounds 14A, and 14B in lieu of (4-bromophenyl)boronic acid, Compounds 4A, 1E, and 8E. Compound 14A: LC-MS (ESI) m/z: 462 [M+H]+. Compound 14B: LC-MS (ESI) m/z: 342
[M+H]+. Compound 14: LC-MS (ESI) m/z: 328 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.80 (s, 3H), 7.01-7.06 (m, 2H), 7.48-7.52 (m, 2H), 7.61-7.66 (m, 4H).
[00518] Example 15
[00519] Synthesis of 4-((4-(3-chloro-4-methoxyphenyl)thiazol-2-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (15)
Figure imgf000187_0001
[00520] To a solution of 1-(3-chloro-4-methoxyphenyl)ethanone (Compound 15A) (500 mg, 2.7 mmol) and N-bromosuccinimide (482 mg, 2.7 mmol) in acetonitrile (10 mL) was added trimethylsilyl trifluoromethanesulfonate (600 mg, 2.7 mmol). The mixture was stirred at 40 °C overnight, diluted with ethyl acetate (30 mL), washed with H2O (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 15B, which was used directly in the next step without further purification. LC-MS (ESI) m/z: 263 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.00 (s, 3H), 4.39 (s, 2H), 7.01 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H).
[00521] A mixture of Compound 15B (700 mg, 1.90 mmol) and ammonium
carbamodithioate (209 mg, 1.90 mmol) in ethanol (20 mL) was stirred at 80 oC for 3 hours. The mixture was concentrated under reduced pressure. The residue was slurred in mixed solvents (petroleum ether/EtOAc, 1/2, v/v, 15 mL) and filtered. The solid was dried under vacuum to give Compound 15C. LC-MS (ESI) m/z: 258 [M+H]+.
[00522] Compounds 15D, 15E, and 15 were synthesized by employing the procedures described for Compounds 1E, 1, and 8F using Compounds 15C, 15D, and 15E in lieu of Compounds 1D, 1E, and 8E. Compound 15D: LC-MS (ESI) m/z: 517 [M+H]+; 1H-NMR
(CDCl3, 400 MHz): d (ppm) 1.36 (t, J = 6.8 Hz, 3H), 3.70 (s, 3H), 3.95 (s, 3H), 4.41 (q, J = 6.8 Hz, 2H), 5.72 (s, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 5.6 Hz, 3H), 7.63 (dd, J = 5.6, 2.0 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H). Compound 15E: LC-MS (ESI) m/z: 397 [M+H]+. Compound 15: LC-MS (ESI) m/z: 369 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 3.92 (s, 3H), 7.13 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H).
[00523] Example 16 [00524] Synthesis of 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (16)
Figure imgf000188_0001
[00525] Compounds 16A, 16B, and 16 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using 4-(trifluoromethoxy)phenylboronic acid,
Intermediate E, Compounds 16A, and 16B in lieu of (4-bromophenyl)boronic acid, Compounds 4A, 8E, and 1E. Compound 16A: LC-MS (ESI) m/z: 516 [M+H]+. Compound 16B: LC-MS (ESI) m/z: 502. Compound 16: LC-MS (ESI) m/z: 382 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.35 (s, 1H), 7.38 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.75 (s, 1H).
[00526] Example 17
[00527] Synthesis of methyl 4-((4-(3,4-dichlorophenyl)thiazol-2-yl)thio)-1H-1,2,3- t
Figure imgf000188_0002
[00528] Compounds 17A and 17 were synthesized by employing the procedures described for Compounds 11A and 1 using methanol and Compound 17A in lieu of isopropanol and Compound 1E. Compound 17A: LC-MS (ESI) m/z: 507 [M+H]+. Compound 17: LC-MS (ESI) m/z: 387 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.85 (s, 3H), 7.72 (d, J = 8.0 Hz, 1H), 7.91(d, J = 8.0 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H).
[00529] Example 18 [00530] Synthesis of 4-((4-(3-chloro-4-cyclopropoxyphenyl)thiazol-2-yl)thio)-1H- 1
Figure imgf000189_0001
Figure imgf000189_0002
[00531] To a solution of 4-bromo-2-chloro-1-cyclopropoxybenzene (Compound 18A) (7.42 g, 30 mmol) in anhydrous THF (50 mL) was dropped a solution of n-BuLi in n-hexane (2.5 M, 13.2 mL, 33 mmol) over 15 minutes at -78 oC under nitrogen and stirred at -78 oC for 30 minutes. To the mixture was added anhydrous DMF (2.78 mL, 36 mmol), stirred at -78 oC for 30 minutes, quenched with saturated NH4Cl solution (50 mL), and extracted with ethyl acetate (100 mL). The extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 18B. LC-MS (ESI) m/z: 197
[M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.90-0.92 (m, 4H), 3.88-3.92 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.4, 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 9.87 (s, 1H).
[00532] To a solution of Compound 18B (5.21 g, 26.5 mmol) in anhydrous THF (50 mL) was dropped a MeMgBr solution (3 M in ether, 9.72 mL, 29.2 mmol) over 10 minutes at -20 oC and stirred at -20 oC for 30 minutes and at room temperature for 3 hours. The reaction mixture was quenched with a saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 18C. LC-MS (ESI) m/z: 195 [M-OH]+.
[00533] To a solution of Compound 18C (5.52 g, 26.0 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (13.2 g, 31.2 mmol) in several portions at 0 oC and stirred at room temperature for 30 minutes. The mixture was quenched with a saturated Na2S2O3 aqueous solution (150 mL), stirred at room temperature for 15 minutes, and extracted with dichloromethane (100 mL x 2). The combined extracts were washed with saturated NaHCO3 solution (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 18D. LC-MS (ESI) m/z: 211 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.88-0.89 (m, 4H), 2.56 (s, 3H), 3.85-3.89 (m, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 8.4, 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H).
[00534] Compounds 18E, 18F, 18G, 18H, and 18 were synthesized by employing the procedures described for Compounds 15B, 15C, 1E, 1, and 8F using Compounds 18D, 18E, 18F, 18G, and 18H in lieu of Compounds 15A, 15B, 1D, 1E, and 8E. Compound 18E: LC-MS (ESI) m/z: 289 [M+H]+. Compound 18F: LC-MS (ESI) m/z: 284 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.71-0.75 (m, 2H), 0.83-0.89 (m, 2H), 4.00-4.03 (m, 1H), 7.31 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.73-7.76 (m, 1H), 7.89 (s, 1H), 13.61 (s, 1H). Compound 18G: LC-MS (ESI) m/z: 543 [M+H]+. Compound 18H: LC-MS (ESI) m/z: 423 [M+H]+. Compound 18: LC- MS (ESI) m/z: 395 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.77-0.80 (m, 2H), 0.82- 0.87 (m, 2H), 3.91-3.92 (m, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.81 (dd, J = 8.8, 2.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H).
[00535] Example 19
[00536] Synthesis of cyclopropyl 4-((4-(3,4-dichlorophenyl)thiazol-2-yl)thio)-1H- 1,2,3-triazole-5-carboxylate (19)
Figure imgf000190_0001
[00537] A mixture of Compound 9A (20 mg, 0.04 mmol), cyclopropanol (23 mg, 0.4 mmol), HATU (23 mg, 0.06 mmol), and DIPEA (10 mg, 0.08 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with water (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 19A. LC-MS (ESI) m/z: 533 [M+H]+. [00538] Compound 19 was synthesized by employing the procedure described for Compound 1 using Compound 19A in lieu of Compound 1E, LC-MS (ESI) m/z: 413 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.75-0.79 (m, 4H), 4.35-4.40 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.99 (s, 1H), 8.08(s, 1H).
[00539] Example 20
[00540] Synthesis of 4-((6-(3,4-dichlorophenyl)pyridin-2-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (20)
Figure imgf000191_0001
[00541] Compound 20B was synthesized by employing the procedure described for Compound 4B using (3,4-dichlorophenyl)boronic acid and Compound 20A in lieu of (4- bromophenyl)boronic acid and Compound 4A, LC-MS (ESI) m/z: 224 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 7.25-7.29 (m, 1H), 7.51-7.54 (m, 1H), 7.67-7.70 (m, 1H), 7.74-7.79 (m, 1H), 7.81-7.84 (m, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 4.4 Hz, 1H).
[00542] A mixture of Compound 20B (1.12 g, 5 mmol) and m-CPBA (1.3 g, 6.5 mmol) in dichloromethane (15 mL) was stirred at 20 °C for 5 hours. The mixture was poured into a saturated NaHCO3 solution (100 mL) and extracted with dichloromethane (50 mL x 2). The combined extracts were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 20C. LC-MS (ESI) m/z: 240
[M+H]+.
[00543] A mixture of Compound 20C (840 mg, 3.5 mmol) and POCl3 (9 mL) was stirred at 80 °C for 15 hour. The mixture was concentrated under reduced pressure. The residue was diluted with NaOH solution (6 N, 100 mL) and extracted with dichloromethane (50 mL x 2). The combined extracts were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 17% v/v) to afford Compound 20D. LC-MS (ESI) m/z: 258 [M+H]+.
[00544] Compounds 20E, 20F, 20G, and 20 were synthesized by employing the procedures described for Compounds 12B, 1E, 8F, and 1 using Compounds 20D, 20E, 20F, and 20G in lieu of Compounds 12A, 1D, 8E, and 1E. Compound 20E: LC-MS (ESI) m/z: 256
[M+H]+. Compound 20F: LC-MS (ESI) m/z: 515 [M+H]+. Compound 20G: LC-MS (ESI) m/z: 487 [M+H]+. Compound 20: LC-MS (ESI) m/z: 367 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.17 (brs, 1H), 7.75 (d, J = 8.8 Hz, 1H), 8.05-8.08 (m, 2H), 8.32 (d, J = 2 Hz, 1H), 8.53 (d, J = 5.2 Hz, 1H).
[00545] Example 21
[00546] Synthesis of 4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (21)
Figure imgf000192_0001
[00547] To a degassed solution of Compound 21A (1.89 g, 10 mmol) in DMF (15 mL) was added K2CO3 (1.38 g, 10 mmol). The mixture was stirred under nitrogen for 10 minutes, followed by addition of 1-(chloromethyl)-4-methoxybenzene (1.56 g, 10 mmol) dropwise. The mixture was stirred at room temperature for 12 hours and at 100 oC for 1 hour. The reaction was slowly quenched with water (25 mL) and a solid precipitated gradually. The solid was collected by filtration and recrystallized from methanol to give Compound 21B. LC-MS (ESI) m/z: non- ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.78 (s, 3H), 4.04 (s, 2H), 6.80-6.83 (m, 2H), 7.13-7.15 (m, 2H), 7.17-7.19 (m, 2H), 7.35-7.37 (m, 2H).
[00548] Compound 21C was synthesized by employing the procedure described for Compound 4B using (3,4-dichlorophenyl)boronic acid and Compound 21B in lieu of (4- bromophenyl)boronic acid and Compound 4A, LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.79 (s, 3H), 4.12 (s, 2H), 6.82-6.84 (m, 2H), 7.23-7.25 (m, 2H), 7.34-7.38 (m, 3H), 7.42-7.44 (m, 2H), 7.47-7.50 (m, 1H), 7.64 (d, J = 2.4 Hz, 1H).
[00549] A mixture of compound 21C (188 mg, 0.5 mmol) and TFA (3 mL) was stirred at 80 oC for 4 hours and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (5 mL) and water (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to furnish compound 21D. LC-MS (ESI) m/z: 253 [M-H]-.
[00550] Compounds 21E, 21F, and 21 were synthesized by employing the procedures described for Compounds 13D, 8F, and 1 using Compounds 21D, 21E, and 21F in lieu of Compounds 13C, 8E, and 1E. Compound 21E: LC-MS (ESI) m/z: 514 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.32 (t, J = 5.6 Hz, 3H), 3.79 (s, 3H), 4.37 (q, J = 5.6 Hz, 2H), 5.58 (s, 2H), 6.71-6.73 (m, 2H), 7.00-7.02 (m, 2H), 7.13-7.15 (m, 2H), 7.31-7.33 (m, 3H), 7.49 (d, J = 6.8 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H). Compound 21F: LC-MS (ESI) m/z: 486 [M+H]+.
Compound 21: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 7.45- 7.47 (m, 2H), 7.56-7.59 (m, 4H), 7.79 (d, J = 1.2 Hz, 1H).
[00551] Example 22
[00552] Synthesis of 4-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (22)
Figure imgf000194_0001
[00553] Compounds 22A, 22B, and 22 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using Intermediate F, 2,4-dichlorophenylboronic acid, Compounds 22A, and 22B in lieu of Compounds 4A, (4-bromophenyl)boronic acid, 8E, and 1E. Compound 22A: LC-MS (ESI) m/z: 514 [M+H]+. Compound 22B: LC-MS (ESI) m/z: 486
[M+H]+. Compound 22: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.43-7.47 (m, 3H), 7.52 (d, J = 8.4 Hz, 3H), 7.75 (s, 1H).
[00554] Example 23
[00555] Synthesis of 4-((2-(4-chloro-3-methoxyphenyl)thiazol-4-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (23)
Figure imgf000194_0002
[00556] Compounds 23A, 23B, 23C, 23D, 23E, and 23 were synthesized by employing the procedures described for Compounds 8B, Intermediates D-1, D, 1E, 8F, and 1 using 4- chloro-3-methoxyphenylboronic acid, Compounds 23A, 23B, 23C, Intermediate A, 23D, and 23E in lieu of (3,4-dichlorophenyl)boronic acid, Intermediates A, D-1, Compounds 1D, Intermediate B, 8E, and 1E. Compound 23A: LC-MS (ESI) m/z: 304 [M+H]+. Compound 23B: LC-MS (ESI) m/z: 344 [M+H]+. Compound 23C: LC-MS (ESI) m/z: 258 [M+H]+. Compound 23D: LC-MS (ESI) m/z: 517 [M+H]+. Compound 23E: LC-MS (ESI) m/z: 489 [M+H]+.
Compound 23: LC-MS (ESI) m/z: 369 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 3.97 (s, 3H), 7.48 (s, 2H), 7.67 (s, 1H), 7.86 (s, 1H).
[00557] Example 24
[00558] Synthesis of 4-((2-(4-chloro-3-isopropoxyphenyl)thiazol-4-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (24)
Figure imgf000195_0001
[00559] Compounds 24A, 24B, 24C, 24D, 24E, and 24 were synthesized by employing the procedures described for Compounds 8B, Intermediates D-1, D, 1E, 8F, and 1 using 4- chloro-3-methoxyphenylboronic acid, Compounds 24A, 24B, 24C, Intermediate A, 24D, and 24E in lieu of (3,4-dichlorophenyl)boronic acid, Intermediates A, D-1, Compounds 1D, Intermediate B, 8E, and 1E. Compound 24A: LC-MS (ESI) m/z: 332 [M+H]+. Compound 24B: LC-MS (ESI) m/z: 372 [M+H]+. Compound 24C: LC-MS (ESI) m/z: 286 [M+H]+. Compound 24D: LC-MS (ESI) m/z: 545 [M+H]+. Compound 24E: LC-MS (ESI) m/z: 517 [M+H]+.
Compound 24: LC-MS (ESI) m/z: 397 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.38 (d, J = 6.4 Hz, 6H), 4.75 (m, 1H), 7.47 (m, 2H), 7.66 (s, 1H), 7.85 (s, 1H).
[00560] Example 25
[00561] Synthesis of 5-((2-(3-chloro-4-methoxyphenyl)thiazol-4-yl)thio)-1-(4- methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid (25-1) and 4-((2-(3-chloro-4- methoxyphenyl)thiazol-4-yl)thio)-1H-1,2,3-triazole-5-carboxylic acid (25-2)
Figure imgf000196_0001
[00562] Compounds 25A, 25B, 25C, 25D, 25-1, and 25-2 were synthesized by employing the procedures described for Compounds 8B, Intermediates D-1, D, 1E, 8F, and 1 using 4- chloro-3-methoxyphenylboronic acid, Compounds 25A, 25B, 25C, Intermediate A, 25D, and 25- 1 in lieu of (3,4-dichlorophenyl)boronic acid, Intermediates A, D-1, Compounds 1D,
Intermediate B, 8E, and 1E. Compound 25A: LC-MS (ESI) m/z: 304 [M+H]; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 3.96 (s, 3H), 6.97 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 7.80 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H). Compound 25B: LC-MS (ESI) m/z: 344 [M+H]+; 1H- NMR (CDCl3, 400 MHz,): d (ppm) 2.77 (t, J = 7.2 Hz, 2H), 3.33 (t, J = 7.2 Hz, 2H), 3.71 (s, 3H), 3.97 (s, 3H), 6.98 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 7.81 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H). Compound 25C: LC-MS (ESI) m/z: 258 [M+H]+. Compound 25D: LC- MS (ESI) m/z: 517 [M+H]+. Compound 25-1: LC-MS (ESI) m/z: 489 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 3.76 (s, 3H), 3.97 (s, 3H), 5.76 (s, 2H), 6.80-6.82 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.69 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H). Compound 25-2: LC-MS (ESI) m/z: 369 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 3.92 (s, 3H), 7.27 (d, J = 8.8 Hz, 1H), 7.86 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.94 (s, 1H).
[00563] Example 26
[00564] Synthesis of 4-((2-(2,4-dichlorophenyl)thiazol-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (26)
Figure imgf000197_0001
[00565] Compounds 26A, 26B, 26C, 26D, 26E, and 26 were synthesized by employing the procedures described for Compounds 8B, Intermediates D-1, D, 1E, 8F, and 1 using 4- chloro-3-methoxyphenylboronic acid, Compounds 26A, 26B, 26C, Intermediate A, 26D, and 26E in lieu of (3,4-dichlorophenyl)boronic acid, Intermediates A, D-1, Compounds 1D, Intermediate B, 8E, and 1E. Compound 26A: LC-MS (ESI) m/z: 308 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 7.35-7.39 (m, 2H), 7.51 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H).
Compound 26B: LC-MS (ESI) m/z: 348 [M+H]+.1H-NMR (CDCl3, 400 MHz): d 2.77 (t, J = 7.2 Hz, 2H), 3.35 (t, J = 7.2 Hz, 2H), 3.70 (s, 3H), 7.26 (s, 1H), 7.36 (dd, J = 2.0, 8.8 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H). Compound 26C: LC-MS (ESI) m/z: 262 [M+H]+. Compound 26D: LC-MS (ESI) m/z: 521.1H-NMR (CDCl3, 400 MHz): d 1.35 (t, J = 7.2 Hz, 3H), 3.72 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 5.73 (s, 2H), 6.74 (d, J = 8.8 Hz, 2H), 7.18 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.31 (dd, J = 2.0, 8.8 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H). Compound 26E: LC-MS (ESI) m/z: 493 [M+H]+. Compound 26: LC-MS (ESI) m/z: 373 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.60 (dd, J = 2.0, 8.4 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 8.16-8.18 (m, 2H).
[00566] Example 27
[00567] Synthesis of 4-((2-(3-chloro-4-isopropoxyphenyl)thiazol-4-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (27)
Figure imgf000198_0001
[00568] To a solution of 4-bromo-2-chlorophenol (Compound 27A) (5.0 g, 24.1 mmol) in DMF (100 mL) was added K2CO3 (10.0 g, 72.5 mmol) and 2-bromopropane (7.5 g, 61.5 mmol) and stirred at 100 oC for 16 hours. The mixture was diluted with water (400 mL) and extracted with a mixture of ethyl acetate in petroleum ether (15% v/v, 300 mL x 3). The combined extracts were washed with bine (300 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel
(petroleum ether) to furnish Compound 27B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[00569] A mixture of Compound 27B (1.35 g, 5.4mmol), Pd(dppf)Cl2 (0.35 g, 0.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.09 g, 8.22 mmol), and potassium acetate (1.62 g, 16.5 mmol) in 1,4-dioxane (50 ml) was heated at 80 o C for 16 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to furnish Compound 27C. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[00570] Compounds 27D, 27E, 27F, 27G, 27H, and 27 were synthesized by employing the procedures described for Compounds 8B, Intermediates D-1, D, 1E, 8F, and 1 using
Compounds 27C, 27D, 27E, 27F, Intermediate A, 27G, and 27H in lieu of (3,4- dichlorophenyl)boronic acid, Intermediates A, D-1, Compounds 1D, Intermediate B, 8E, and 1E. Compound 27D: LC-MS (ESI) m/z: 332. Compound 27E: LC-MS (ESI) m/z: 372 [M+H]+. Compound 27F: LC-MS (ESI) m/z: 286 [M+H]+. Compound 27G: LC-MS (ESI) m/z: 545
[M+H]+. Compound 27H: LC-MS (ESI) m/z: 517 [M+H]+. Compound 27: LC-MS (ESI) m/z: 397 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.33 (d, J = 6.0 Hz, 6H), 4.77-4.80 (m, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.82 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 7.92-7.94 (m, 2H).
[00571] Example 28
[00572] Synthesis of 4-((5-(3,4-dichlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)thio)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (28)
Figure imgf000199_0001
[00573] To a solution of 3,4-dichlorobenzoic acid (28A) (500 mg, 2.62 mmol), N- methylhydrazinecarbothioamide (302 mg, 2.88 mmoL), and DIPEA (606 mg, 4.7 mmoL) in DMF (5 mL) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P, 1.25 g, 3.93 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were concentrated under reduced pressure. The residue was diluted with a mixture of water (10 mL) and DMF (2 mL), adjusted to pH 8 with aqueous NaOH solution (4 M) and heated to 70 oC for 16 hours. The mixture was acidified to pH 5 with concentrated HCl solution. The resulting solid was collected and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 100% v/v) to furnish Compound 28B. LC-MS (ESI) m/z: 260
[M+H]+.
[00574] Compounds 28C, 28D, and 28 were synthesized by employing the procedures described for Compounds 1E, 8F, and 1 using Intermediate A, Compounds 28B, 28C, and 28D in lieu of Intermediate B, Compounds 1D, 8E, and 1E. Compound 28C: LC-MS (ESI) m/z: 519 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.35 (t, J = 7.2 Hz, 3H), 3.70 (s, 3H), 3.72 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H), 5.84 (s, 2H), 6.84 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.55 (dd, J = 8.0, 2.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H). Compound 28D: LC-MS (ESI) m/z: 491 [M+H]+. Compound 28: LC-MS (ESI) m/z: 371 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.70 (s, 3H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 8.05 (d J = 2.0 Hz, 1H).
[00575] Example 29
[00576] Synthesis of 4-((5-ethoxybenzo[d]thiazol-2-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (29)
Figure imgf000200_0001
[00577] A mixture of 2-methylbenzo[d]thiazol-5-ol (Compound 29A) (2 g, 12.1 mmol), iodoethane (2.8 g, 18.2mmol), and potassium carbonate (3.4 g, 24.2mmol) in acetonitrile (40 mL) was stirred at 70 °C overnight. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with H2O (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 9% v/v) to give Compound 29B. LC-MS (ESI) m/z: 194 [M+H]+. [00578] To a solution of Compound 29B (500 mg, 2.59 mmol) in ethylene glycol (3 mL) was added an aqueous sodium hydroxide solution (50% w/w, 6 g, 75 mmol) and stirred at 140 °C for 3 hours. The mixture was poured into ice-water (50 mL), acidified to pH 3 with an aqueous hydrochloric acid solution (2 N), and extracted with dichloromethane (20 mL x 4). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give Compound 29C, which was used directly in next step without further purification. LC-MS (ESI) m/z: 170 [M +H]+.
[00579] A mixture of Compound 29C (400 mg, 2.36 mmol), carbon disulfide (450 mg, 5.9 mmol), and sodium hydroxide (236 mg, 5.9 mmol) in ethanol (10 mL) was heated at reflux for 2 hours. After cooled to room temperature, the mixture was filtered. The filtrate was diluted with ice-water (30 mL) and acidified to pH 3 with an aqueous hydrochloric acid solution (2 N). The resulting solid was collected and dried under vacuum to give Compound 29D. LC-MS (ESI) m/z: 212 [M +H]+.
[00580] Compounds 29E, 29F, and 29 were synthesized by employing the procedures described for Compounds 1E, 1, and 8F using Intermediate A, Compounds 29D, 29E, and 29F in lieu of Intermediate B, Compounds 1D, 1E, and 8E. Compound 29E: LC-MS (ESI) m/z: 471 [M +H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 1.47 (t, J = 7.2 Hz, 3H), 3.63 (s, 3H), 4.09 (q, J = 7.2 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H), 5.67 (s, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.97 (dd, J = 8.8, 2.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H). Compound 29F: LC-MS (ESI) m/z: 351 [M+H]+. Compound 29: LC-MS (ESI) m/z: 323 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.34 (t, J = 7.2 Hz, 3H), 4.08 (q, J = 7.2 Hz, 2H), 7.01 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H).
[00581] Example 30
[00582] Synthesis of 4-((4'-chloro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (30)
Figure imgf000202_0001
[00583] A mixture of isoamyl nitrite (4 mL, 30 mmol), copper (II) chloride (3.22 g, 24 mmol) and 4-bromo-2-(trifluoromethoxy)aniline (Compound 30A) (5.1 g, 20 mmol) in acetonitrile (80 mL) was heated at 70 oC for 3 hours. The mixture was poured into an aqueous HCl solution (0.5 M, 50 mL) and extracted with ethyl acetate (50 mL x 2). The combined extracts were washed with water (50 mL x 4) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (petroleum ether) to afford Compound 30B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.33-7.35 (m, 1H), 7.37-7.40 (m, 1H), 7.48 (t, J = 1.6 Hz, 1H).
[00584] To Compound 30B (1.7 g, 6.2 mmol) in anhydrous THF (30 mL) at -78 oC was dripped n-BuLi solution (2.5 M in hexanes, 3.15 mL, 6.25 mmol) and stirred at -78 oC for 30 minutes. To the mixture was added triisopropyl borate (1.44 mL, 6.25 mmol) and was gradually allowed to warm to room temperature and stirred at room temperature for 2 hours. The mixture was poured into water (100 mL), acidified to pH 4 with aqueous HCl solution (1 M), and extracted with ethyl acetate (100 mL x 2). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a mixture of Compound 30C-1 and 30C-2. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[00585] Mixture of 30D-1 and 30D-2, Compounds 30E-1, 30E-2, and 30 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using Intermediate F, Mixtures of 30C-1 and 30C-2, 30D-1 and 30D-2, and Compound 30E-1 in lieu of Intermediate B, Compounds 4A, 8E, and 1E. Mixture of 30D-1 and 30D-2: LC-MS (ESI) m/z: 564 [M+H]+. Compound 30E-1: LC-MS (ESI) m/z: 536 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.62 (s, 3H), 5.62 (s, 2H), 6.78 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.4 Hz, 4H), 7.58 (d, J = 8.8 Hz, 2H), 7.69-7.78 (m, 3H), 13.36 (s, 1H). Compound 30E-2: LC-MS (ESI) m/z: 536 [M+H]+.1H- NMR (DMSO-d6, 400 MHz): d (ppm) 3.66 (s, 3H), 5.63 (d, J = 14 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 7.10-7.16 (m, 4H), 7.32-7.71 (m, 5H), 13.39 (s, 1H). Compound 30: LC-MS (ESI) m/z: 416 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.53 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.79 (s, 2H), 7.86 (s, 1H).
[00586] Example 31
[00587] Synthesis of 4-((2'-chloro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (31)
Figure imgf000203_0001
[00588] Compound 31 was synthesized by employing the procedure described for Compound 1 using Compound 30E-2 in lieu of Compound 1E, LC-MS (ESI) m/z: 416 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)7.45-7.71 (m, 7H).
[00589] Example 32 [00590] Synthesis of 4-((3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (32)
Figure imgf000204_0001
[00591] Compound 32B was synthesized by employing the procedure described for Compound 30C-1 using Compound 32A in lieu of Compound 30B, LC-MS: (ESI) m/z: 239 [M- H]-; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.47-7.49 (m, 1H), 8.11-8.14 (m, 1H), 8.26 (d, J = 1.6 Hz, 1H).
[00592] A mixture of Compound 32B (150 mg, 0.34 mmol), Intermediate F (129 mg, 0.54 mmol), Pd(PPh3)4 (39 mg, 0.03 mmol), and K2CO3 (187 mg, 1.36 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was stirred at 90 oC under nitrogen for 4 hours. After the mixture was cooled down to room temperature, a solution of LiOH.H2O (21 mg, 053 mmol) in H2O (1 mL) was added and stirred at 40 oC for 2 hours. The reaction mixture was concentrated and purified with reverse phase chromatography using eluents (acetonitrile in water, form 0% to 90% v/v) to furnish Compound 32C. LC-MS: (ESI) m/z: 536 [M+H]+.
[00593] Compound 32 was synthesized by employing the procedure described for Compound 1 using Compound 32C in lieu of Compound 1E, LC-MS (ESI) m/z: 416 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 77.53 (d, J = 8.4 Hz, 2H), 7.64-7.67 (m, 1H), 7.74- 7.78 (m, 2H), 7.79-7.81 (m, 1H), 8.02 (d, J = 2.4 Hz, 1H).
[00594] Example 33
[00595] Synthesis of methyl 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H- 1,2,3-triazole-5-carboxylate (33)
Figure imgf000205_0001
[00596] Compound 33 was synthesized by employing the procedure described for Compound 1 using Compound 16A in lieu of Compound 1E, LC-MS (ESI) m/z: 396 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.85 (s, 3H), 7.47 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H).
[00597] Example 34
[00598] Synthesis of 4-((5-butoxybenzo[d]thiazol-2-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (34)
Figure imgf000205_0002
[00599] Compounds 34A, 34B, 34C, 34D, 34E, and 34 were synthesized by employing the procedures described for Compounds 29B, 29C, 29D, 1E, 1, and 8F using 1-iodobutane, Compounds 34A, 34B, Intermediate A, 34C, 34D, and 34E in lieu of iodoethane, Compounds 29B, 29C, Intermediate B, Compounds 1D, 1E, and 8E. Compound 34A: LC-MS (ESI) m/z: 222 [M +H]+. Compound 34B: LC-MS (ESI) m/z: 198 [M+H]+. Compound 34C: LC-MS (ESI) m/z: 240 [M+H]+. Compound 34D: LC-MS (ESI) m/z: 499 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.00 (t, J = 7.6 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H),1.50-1.56 (m, 2H), 1.79-1.84 (m, 2H), 3.63 (s, 3H), 4.01 (q, J = 7.2 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H), 5.67 (s, 2H), 6.67 (dd, J = 6.8, 2.0 Hz, 2H), 6.97 (dd, J = 8.8, 2.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H). Compound 34E: LC-MS (ESI) m/z: 379 [M+H]+. Compound 34: LC- MS (ESI) m/z: 351 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.93 (t, J = 7.6 Hz, 3H), 1.44 (m, 2H), 1.71 (m, 2H), 4.03 (t, J = 6.4 Hz, 2H), 7.01 (dd, J = 8.8, J = 2.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H).
[00600] Example 35
[00601] Synthesis of 4-((2-(3,4-dichlorophenyl)-1-methyl-1H-imidazol-5-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (35)
Figure imgf000206_0001
[00602] To a solution of 2-bromo-1-methyl-1H-imidazole 35A (5 g, 31.05 mmol) in chloroform (50 mL) was added NBS (5.53 g, 31.05 mmol) in several portions at 65 oC and stirred for 2 hours. The mixture was cooled down to room temperature, diluted with water (50 mL), and extracted with dichloromethane (30 mL). The organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a product, which was slurred in dichloromethane/petroleum (50 mL, 2:3 in volume) to furnish Compound 35B. LC-MS (ESI) m/z: 239 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.60 (s, 3H), 7.00 (s, 1H).
[00603] Compound 35C was synthesized by employing the procedure described for Compound 8B using Compound 35B in lieu of Compound 8A, LC-MS (ESI) m/z: 305 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 3.72 (s, 3H), 7.13 (s, 1H), 7.56 (dd, J = 8.4, 1.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H).
[00604] To a solution of Intermediate D (380 mg, 1.29 mmol) and Compound 35C (395 mg, 1.29 mmol) in 1,4-dioxane (6 mL) was added N,N-diisopropylethylamine (333 mg, 2.58 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), and Xantphos (133 mg, 0.23 mmol). The mixture was purged with nitrogen for 2 minutes and heated in a microwave oven at 120 oC for 70 minutes. After cooling down to room temperature, the mixture was filtered. The filtrate was concentrated and purified with reverse phase chromatography using eluents (methanol in H2O, from 20% to 100% v/v) to yield Compound 35D. LC-MS (ESI) m/z: 518 [M+H]+.
[00605] Compounds 35E and 35 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 35D and 35E in lieu of Compounds 8E and 1E. Compound 35E: LC-MS (ESI) m/z: 490 [M+H]+. Compound 35: LC-MS (ESI) m/z: 370
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.70 (s, 3H), 7.77-7.79 (m, 2H), 7.85 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H).
[00606] Example 36
[00607] Synthesis of 4-((5-(3,4-dichlorophenyl)thiophen-3-yl)thio)-1H-1,2,3-triazole- 5-carboxylic acid (36)
Figure imgf000207_0001
[00608] Compounds 36B, 36C, 36D, 36E, 36F, and 36 were synthesized by employing the procedures described for Compounds 8B, Intermediates D-1, D, 1E, 2, and 1 using
Compounds 36A, 36B, 36C, Intermediate A, 36D, 36E, and 36F in lieu of Compounds 8A, Intermediates A, D-1, B, 1D, 1, and 1E. Compound 36B: LC-MS (ESI) m/z: no ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 7.21-7.23 (m, 2H), 7.36-7.39 (m, 1H), 7.45-7.47 (m, 1H), 7.62-7.64 (m, 1H). Compound 36C: LC-MS (ESI) m/z: 347 [M+H]+. Compound 36D: LC-MS (ESI) m/z: no ionizable compound under routine conditions used. Compound 36E: LC-MS (ESI) m/z: 520 [M+H]+. Compound 36F: LC-MS (ESI) m/z: 492 [M+H]+. Compound 36: LC-MS (ESI) m/z: 372 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.55-7.60 (m, 3H), 7.74 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H).
[00609] Example 37
[00610] Synthesis of 2-(dimethylamino)ethyl 4-((4'-(trifluoromethoxy)-[1,1'- biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5-carboxylate (37)
Figure imgf000208_0001
[00611] Compounds 37A and 37 were synthesized by employing the procedures described for Compounds 19A and 1 using 2-(dimethylamino)ethanol, Compounds 16B using TEA as base and dichloromethane as solvent, and 37A in lieu of cyclopropanol, Compounds 9A using DIPEA as base and DMF as solvent, and 1E. Compound 37A: LC-MS (ESI) m/z: 573 [M+H]+.
Compound 37: LC-MS (ESI) m/z: 453 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.87 (s, 6H), 3.50 (t, J = 4.8 Hz, 2H), 4.62 (t, J = 4.8 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H).
[00612] Example 38
[00613] Synthesis of N,N,N-trimethyl-2-((4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)thio)-1H-1,2,3-triazole-5-carbonyl)oxy)ethan-1-aminium iodide (38)
Figure imgf000209_0001
[00614] A mixture of Compound 37A (200 mg, 0.349 mmol) and iodomethane (495 mg, 3.49 mmol) in acetonitrile (5 mL) was stirred at 50 oC for 4 hours. The mixture was concentrated under reduced pressure to furnish Compound 38A. LC-MS (ESI) m/z: 587 [M]+.
[00615] Compound 38 was synthesized by employing the procedure described for Compound 1 using Compound 38A in lieu of Compound 1E, LC-MS (ESI) m/z: 467 [M]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 3.14 (s, 9H), 3.67-3.69 (m, 2H), 4.56-4.57 (m, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H).
[00616] Example 39
[00617] Synthesis of 4-((2-(3-chloro-4-(trifluoromethoxy)phenyl)thiazol-4-yl)thio)- 1H-1,2,3-triazole-5-carboxylic acid (39)
Figure imgf000210_0001
[00618] Compounds 39A, 39B, 39C, 39D, 39E, and 39 were synthesized by employing the procedures described for Compounds 8B, Intermediates D-1, D, 1E, 8F, and 1 using
Compounds 32B, 39A, 39B, Intermediate A, 39C, 39D, and 39E in lieu of (3,4- dichlorophenyl)boronic acid, Intermediates A, D-1, B, Compounds 1D, 8E, and 1E. Compound 39A: LC-MS (ESI) m/z: 358 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.28 (s, 1H), 7.38- 7.42 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H). Compound 39B: LC-MS (ESI) m/z: 398 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.78 (t, J = 6.8 Hz, 2H), 3.35 (t, J = 6.8 Hz, 2H), 3.71 (s, 3H), 7.15 (s, 1H), 7.37-7.40 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H). Compound 39C: LC-MS (ESI) m/z: 312 [M+H]+. Compound 39D: LC-MS (ESI) m/z: 571 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.36 (t, J = 7.2 Hz, 3H), 3.70 (s, 3H), 4.36- 4.42 (m, 2H), 5.75 (s, 2H), 6.74 (d, J = 9.2 Hz, 2H), 7.10 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 10.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H). Compound 39E: LC-MS (ESI) m/z: 543 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.55 (s, 3H), 5.53 (s, 2H), 6.59 (brs, 2H), 7.16 (brs, 2H), 7.19 (s, 1H), 7.34 (brs, 1H), 7.70 (brs, 2H). Compound 39: LC-MS (ESI) m/z: 423 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 7.70 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H).
[00619] Example 40 [00620] Synthesis of methyl 4-((2-(3-chloro-4-(trifluoromethoxy)phenyl)thiazol-4- yl)thio)-1H-1,2,3-triazole-5-carboxylate (40)
Figure imgf000211_0001
[00621] A solution of Compound 39D (110 mg, 0.19 mmol) and concentrated H2SO4 (0.1 mL) in MeOH (5 mL) was stirred at 60 oC for 16 hours. The mixture was cooled down to room temperature, concentrated, and purified with reverse phase chromatography using eluents (acetonitrile in water, from 0% to 100% v/v) to afford Compound 40A. LC-MS (ESI) m/z: 557 [M+H]+.
[00622] Compound 40 was synthesized by employing the procedure described for Compound 1 using Compound 40A in lieu of Compound 1E, LC-MS (ESI) m/z: 437 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 3.86 (s, 3H), 7.70 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H).
[00623] Example 41
[00624] Synthesis of 4-((3,4-dichlorophenyl)thio)-1H-1,2,3-triazole-5-carboxylic acid (41)
Figure imgf000211_0002
[00625] Compounds 41B, 41C, and 41 were synthesized by employing the procedures described for Compounds 1E, 1, and 8F using Intermediate A, Compounds 41A using NMP as solvent at 100 °C, 41B, and 41C in lieu of Intermediates B, Compounds 1D using DMF as solvent at 50 °C, 1E, and 8E. Compound 41B: LC-MS (ESI) m/z: 438 [M+H]+. Compound 41C: LC-MS (ESI) m/z: 318 [M+H]+. Compound 41: LC-MS (ESI) m/z: 290 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H).
[00626] Example 42 [00627] Synthesis of 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (42)
Figure imgf000212_0001
[00628] Compounds 42B, 42C, and 42 were synthesized by employing the procedures described for Compounds 1E, 8B, and 1 using Intermediate A, Compounds 42A using NMP as solvent at 100 °C, 42B, 4-(trifluoromethoxy)phenylboronic acid, and 42C in lieu of
Intermediates B, Compounds 1D using DMF as solvent at 50 °C, 8A, (3,4- dichlorophenyl)boronic acid, and 8E. Compound 42B: LC-MS (ESI) m/z: 448 [M+H]+.
Compound 42C: LC-MS (ESI) m/z: 502 [M+H]+. Compound 42: LC-MS (ESI) m/z: 382
[M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.37 (d, J = 8.4 Hz, 2H), 7.51-7.80 (m, 6H).
[00629] Example 43
[00630] Synthesis of 4-((4-(3-chloro-4-(trifluoromethoxy)phenyl)thiazol-2-yl)thio)- 1H-1,2,3-triazole-5-carboxylic acid (43)
Figure imgf000213_0001
[00631] To a solution of Compound 43A (2.38 g, 10.0 mmol) in Et2O (15 mL) was dropped Br2 (1.60 g, 10.0 mmol) and stirred at room temperature for 2 hours. The mixture was washed with saturated NaHSO3 solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 43B. LC-MS (ESI) m/z: 317
[M+H]+.
[00632] To a solution of Compound 43B (3.17 g, 10.0 mmol) in EtOH (50 mL) was added KSCN (970 mg, 10.0 mmol). After the mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with H2O (30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give Compound 43C. LC-MS (ESI) m/z: 296 [M+H]+.
[00633] To a solution of Compound 43C (1.9 g, 6.4 mmol) in EtOH (30%, 60 mL) was added thiourea (975 mg, 12.8 mmol) and concentrated HCl solution (10 mL). The mixture was stirred at 90 oC under nitrogen overnight. After cooling down to room temperature, the reaction mixture was concentrated and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 12% v/v) to furnish Compound 43D. LC-MS (ESI) m/z: 312 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 6.77 (s, 1H), 7.45-7.48 (m, 2H), 7.68 (d, J = 2.4 Hz, 1H), 11.6 (br, 1H).
[00634] Compounds 43E, 43F, and 43 were synthesized by employing the procedures described for Compounds 1E, 8F, and 1 using Intermediate A, Compounds 43D using NMP as solvent at 90 °C, 43E, and 43F in lieu of Intermediates B, Compounds 1D using DMF as solvent at 50 °C, 8E, and 1E. Compound 43E: LC-MS (ESI) m/z: 571 [M+H]+. Compound 43F: LC-MS (ESI) m/z: 543 [M+H]+. Compound 43: LC-MS (ESI) m/z: 423 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 7.64 (dd, J1 = 8.8 Hz, J2 = 1.2 Hz, 1H), 8.01 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.37 (s, 1H).
[00635] Example 44
[00636] Synthesis of methyl 4-((4-(3-chloro-4-(trifluoromethoxy)phenyl)thiazol-2- yl)thio)-1H-1,2,3-triazole-5-carboxylate (44)
Figure imgf000214_0001
[00637] Compounds 44A and 44 were synthesized by employing the procedures described for Compounds 11A and 1 using methanol, Compounds 43F, and 44A in lieu of propan-2-ol, Compounds 9A, and 1E. Compound 44A: LC-MS (ESI) m/z: 557 [M+H]+. Compound 44: LC- MS (ESI) m/z: 437 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 3.85 (s, 3H), 7.65 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 8.00 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H).
[00638] Example 45
[00639] Synthesis of oxetan-3-yl 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)- 1H-1,2,3-triazole-5-carboxylate (45)
Figure imgf000214_0002
[00640] Compound 45 was synthesized by employing the procedure described for Compound 19A using oxetan-3-ol and Compound 16 using TEA as base and dichloromethane as solvent in lieu of cyclopropanol and Compound 9A using DIPEA as base and DMF as solvent, LC-MS (ESI) m/z: 438 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.52-4.55 (m, 2H), 4.81-4.85 (m, 2H), 5.53-5.59 (m, 1H), 7.45-7.48 (m, 4H), 7.68 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H). [00641] Example 46
[00642] Synthesis of 4-((6-chloroquinolin-2-yl)thio)-1H-1,2,3-triazole-5-carboxylic acid (46)
Figure imgf000215_0001
[00643] Compounds 46B, 46C, and 46 were synthesized by employing the procedures described for Compounds 35D, 8F, and 1 using Compounds 46A, 46B, and 46 in lieu of Compounds 35C, 8E, and 1E. Compound 46B: LC-MS (ESI) m/z: 455 [M+H]+. Compound 46C: LC-MS (ESI) m/z: 427 [M+H]+. Compound 46: LC-MS (ESI) m/z: 307 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.36 (d, J = 8.8 Hz, 1H), 7.72-7.81 (m, 2H), 8.08 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 13.56 (brs, 1H), 16.08 (brs, 1H).
[00644] Example 47
[00645] Synthesis of 4-((2,4'-dichloro-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (47)
Figure imgf000215_0002
[00646] Compounds 47B, 47C, 47D, and 47 were synthesized by employing the procedures described for Compounds 8B, 35D, 8F, and 1 using 4-chlorophenylboronic acid, Compounds 47A, 47B, 47C, and 47D in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A, 35C, 8E, and 1E. Compound 47B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 7.18 (d, J = 8.0 Hz, 1H), 7.33- 7.35 (m, 2H), 7.40-7.42 (m, 2H), 7.45 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H). Compound 47C: LC-MS (ESI) m/z: 514 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.36 (t, J = 6.8 Hz, 3H), 3.72 (s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 5.63 (s, 2H), 6.73-6.75 (m, 2H), 6.86-6.90 (m, 2H), 7.06-7.08 (m, 1H), 7.14-7.16 (m, 2H), 7.27-7.29 (m, 2H), 7.38-7.40 (m, 2H). Compound 47D: LC-MS (ESI) m/z: 486 [M+H]+. Compound 47: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.46-7.50 (m, 4H), 7.55-7.57 (m, 2H), 7.69 (s, 1H).
[00647] Example 48
[00648] Synthesis of 4-((3,4'-dichloro-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (48)
Figure imgf000216_0001
48D 48E 48
[00649] Compounds 48B, 48C, 48D, 48E, and 48 were synthesized by employing the procedures described for Compounds 8B, 30B, 35D, 8F, and 1 using 4-chlorophenylboronic acid, Compounds 48A using Na2CO3 as base and 1,4-dioxane as solvent, 48B using t-butyl nitrite and CuBr, 48C, 48D, and 48E in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A using Cs2CO3 as base and DME as solvent, 30A using isoamyl nitrite and CuCl2, 35C, 8E, and 1E. Compound 48B: LC-MS (ESI) m/z: 238 [M +H]+. Compound 48C: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used. Compound 48D: LC-MS (ESI) m/z: 514 [M+H]+. Compound 48E: LC-MS (ESI) m/z: 486 [M+H]+. Compound 48: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.40 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.63-7.66 (m, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 2.0 Hz, 1H), 13.55 (br, 1H), 14.75 (br, 1H).
[00650] Example 49
[00651] Synthesis of 4-((3,4-difluorophenyl)thio)-1H-1,2,3-triazole-5-carboxylic acid (49)
Figure imgf000217_0001
[00652] Compounds 49B, 49C, and 49 were synthesized by employing the procedures described for Compounds 1E, 8F, and 1 using Intermediate A, Compounds 49A, 49B, and 49C in lieu of Intermediates B, Compounds 1D, 8E, and 1E. Compound 49B: LC-MS: (ESI) m/z: 406 [M+H]+. Compound 49C: LC-MS (ESI) m/z: 400 [M+Na]+. Compound 49: LC-MS (ESI) m/z: 258 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.36 (s, 1H), 7.45-7.52 (m, 1H), 7.66 (t, J = 8.4 Hz, 1H).
[00653] Example 50
[00654] Synthesis of 4-((5,6,7,8-tetrahydronaphthalen-2-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (50)
Figure imgf000217_0002
[00655] To a solution of Compound 50A (9.66 g, 73 mmol) in CHCl3 (22 mL) was dropped ClSO3H (26 g, 0.223 mol) at -10 oC. The mixture was stirred at room temperature for 1 hour, poured into ice-water (100 mL), and extracted with dichloromethane (100 mL x 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to yield Compound 50B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.83-1.86 (m, 4H), 2.85-2.88 (m, 4H), 7.27-7.29 (m, 1H), 7.71-7.73 (m, 2H).
[00656] To a mixture of Compound 50B (1.5 g, 6.5 mmol) and Zn powder (2.5 g, 38.2 mmol) in ethanol (10 mL) was dropped concentrated HCl (10 mL) over a period of 30 minutes. After the mixture was stirred at 80 oC for 1 hour and cooled down to room temperature, it was filtered. The filtration was diluted with ethyl acetate (200 mL). The organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield Compound 50C. LC-MS (ESI) m/z: 163 [M-H]-; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.75- 1.78 (m, 4H), 2.68-2.72 (m, 4H), 3.34 (s, 1H), 6.92-6.94 (m, 1H), 7.00-7.02 (m, 2H).
[00657] Compounds 50D, 50E, and 50 were synthesized by employing the procedures described for Compounds 1E, 8F, and 1 using Intermediate A, Compounds 50C, 50D, and 50E in lieu of Intermediates B, Compounds 1D, 8E, and 1E. Compound 50D: LC-MS (ESI) m/z: 424 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.34 (t, J = 6.8 Hz, 3H), 1.72-1.73 (m, 4H), 2.53-2.56 (m, 2H), 2.66-2.68 (m, 2H), 3.76 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H), 5.51 (s, 2H), 6.63 (s, 1H), 6.75-6.78 (m, 2H), 6.83-6.91 (m, 2H), 7.12-7.15 (m, 2H). Compound 50E: LC-MS (ESI) m/z: 396 [M+H]+. Compound 50: LC-MS (ESI) m/z: 276 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.71-1.74 (m, 4H), 2.69-2.71 (m, 4H), 7.07-7.09 (m, 1H), 7.16-7.20 (m, 2H).
[00658] Example 51
[00659] Synthesis of 1-((pivaloyloxy)methyl)-4-((4'-(trifluoromethoxy)-[1,1'- biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5-carboxylic acid (51)
Figure imgf000218_0001
[00660] To a solution of Compound 16 (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) was added chloromethyl pivalate (21 mg, 0.143 mmol), triethylamine (59 mg, 0.26 mmol), and NaI (2 mg). The mixture was stirred at 50 oC for 1 hour and concentrated under vacuum. The residue was purified by preparative HPLC to furnish Compound 51. LC-MS (ESI) m/z: 496 [M+H]+.1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.11 (s, 9H), 6.15 (s, 2H), 7.46 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 6.8 Hz, 2H), 7.68 (d, J = 6.8 Hz, 2H), 7.82 (d, J = 6.8 Hz, 2H).
[00661] Example 52
[00662] Synthesis of 1-((isobutyryloxy)methyl)-4-((4'-(trifluoromethoxy)-[1,1'- biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5-carboxylic acid (52)
Figure imgf000219_0001
[00663] Compound 52 was synthesized by employing the procedure described for Compound 51 using chloromethyl isobutyrate in lieu of chloromethyl pivalate, LC-MS (ESI) m/z: 482 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.03 (s, 3H), 1.05 (s, 3H), 2.55-2.57 (m, 1H), 6.15 (s, 2H), 7.46 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 6.8 Hz, 2H), 7.68 (d, J = 6.8 Hz, 2H), 7.82 (d, J = 6.8 Hz, 2H).
[00664] Example 53
[00665] Synthesis of 4-(benzo[d]thiazol-6-ylthio)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (53)
Figure imgf000220_0001
[00666] Compounds 53B, 53C, 53D, and 53 were synthesized by employing the procedures described for Compounds 50C, 1E, 8F, and 1 using Compounds 53A, Intermediate A, 53B using NMP as solvent at 100 °C, 53C, and 53D in lieu of Compounds 50B, Intermediates B, Compounds 1D using DMF as solvent at 50 °C, 8E, and 1E. Compound 53B: LC-MS (ESI) m/z: 168 [M+H]+. Compound 53C: LC-MS (ESI) m/z: 427 [M+H]+. Compound 53D: LC-MS (ESI) m/z: 399 [M+H]+. Compound 53: LC-MS (ESI) m/z: 279 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.60 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.34 (d, J = 1.2 Hz, 1H), 9.43 (s, 1H).
[00667] Example 54
[00668] Synthesis of (pivaloyloxy)methyl 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)thio)-1H-1,2,3-triazole-5-carboxylate (54)
Figure imgf000220_0002
[00669] To a solution of Compound 33 (280 mg, 0.71 mmol) in CH3CN (20 mL) was added (chloromethanetriyl)tribenzene (198 mg, 0.71mmol) and triethylamine (143 mg, 1.42 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 54A. LC-MS (ESI) m/z: 638 [M+H]+.
[00670] Compound 54B was synthesized by employing the procedure described for Compound 8F using Compound 54A in lieu of Compound 8E, LC-MS (ESI) m/z: 622. [M-H]-.
[00671] To a solution of Compound 54B (150 mg, 0.24 mmol) in DMF (10 mL) was added chloromethyl isobutyrate (36 mg, 0.24 mmol) and Na2CO3 (50 mg, 0.48 mmol). The reaction mixture was stirred at 50 oC for 3 hour. After cooling down to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to furnish Compound 54C. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[00672] To a solution of Compound 54C (110 mg, 0.16 mmol) in dichloromethane (4 mL) was added 2,2,2-trifluoroacetic acid (1 mL) and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Compound 54. LC-MS (ESI) m/z: 496 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.19 (s, 9H), 5.99 (s, 2H), 7.35 (d, J = 6.8 Hz, 2H), 7.56 (d, J = 6.8 Hz, 2H), 7.65(d, J = 6.8 Hz, 2H), 7.73 (d, J = 6.8 Hz, 2H).
[00673] Example 55
[00674] Synthesis of (isobutyryloxy)methyl 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]- 4-yl)thio)-1H-1,2,3-triazole-5-carboxylate (55)
Figure imgf000221_0001
[00675] Compounds 55A and 55 were synthesized by employing the procedures described for Compounds 54C and 1 using chloromethyl isobutyrate and 55A in lieu of chloromethyl pivalate and 1E. Compound 55A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 55: LC-MS (ESI) m/z: 482 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.13 (s, 3H), 1.15 (s, 3H), 2.57-2.60 (m, 1H), 5.97 (s, 2H), 7.34 (d, J = 6.8 Hz, 2H), 7.51 (d, J = 6.8 Hz, 2H), 7.61 (d, J = 6.8 Hz, 2H), 7.71 (d, J = 6.8 Hz, 2H).
[00676] Example 56
[00677] Synthesis of 4-((6-chloronaphthalen-2-yl)thio)-1H-1,2,3-triazole-5-carboxylic acid (56)
Figure imgf000222_0001
[00678] To a solution of 6-bromonaphthalen-2-amine (Compound 56A) (1 g, 4.52 mmol) in H2O (5 mL) and HCl (6 N, 10 mL) was added NaNO2 (350 mg, 4.97 mmol). After the mixture was stirred at room temperature for 1 hour, to it was added a solution of CuCl (2.27 g, 20.73 mmol) in HCl (6 N, 5 mL) and stirred at room temperature for 3 hours. The reaction mixture was poured into ice water (50 mL). A solid was precipitated, filtered, and dried under vacuum to give Compound 56B. LC-MS (ESI) m/z: Non-ionizable compound under routeine conditions used.
[00679] Compounds 56C, 56D, and 56 were synthesized by employing the procedures described for Compounds 35D, 8F, and 1 using Compounds 56B, 568C, and 56D in lieu of Compounds 35C, 8E, and 1E. Compound 56C: LC-MS (ESI) m/z: 454 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.08 (t, J = 6.8 Hz, 3H), 3.59 (s, 3H), 4.13-4.20 (m, 2H), 5.66 (s, 2H), 6.72 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 1H), 7.49-7.53 (m, 1H), 7.56-7.57 (m, 1H), 7.76-7.79 (m, 2H), 7.99 (d, J = 2.0 Hz, 1H). Compound 56D: LC-MS (ESI) m/z: 426 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 3.55 (s, 3H), 5.50 (s, 2H), 6.63 (d, J = 9.2 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 1H), 7.43-7.49 (m, 2H), 7.69-7.75 (m, 2H), 7.96 (d, J = 1.6 Hz, 1H). Compound 56: LC-MS (ESI) m/z: 306 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 7.56 (d, J = 8.8 Hz, 2H), 7.91-7.98 (m, 2H), 8.10 (d, J = 8.8 Hz, 2H). [00680] Example 57
[00681] Synthesis of 4-((5,6-dichloro-2,3-dihydro-1H-inden-2-yl)thio)-1H-1,2,3- triazole-5-carboxylic 2,2,2-trifluoroacetate (57)
Figure imgf000223_0001
[00682] To a solution of 5,6-dichloro-2,3-dihydro-1H-inden-1-one (Compound 57A) (6.03 g, 30 mmol) in dichloromethane (100 mL) was added pyridinium bromide perbromide (10.5 g, 33 mmol) at 0 oC and stirred at room temperature overnight. The mixture was diluted with EtOAc (50 mL) and washed with brine (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 57B. LC-MS (ESI) m/z: 279 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.36-3.41 (m, 1H), 3.78-3.85 (m, 1H), 4.67 (dd, J = 7.2, 2.8 Hz, 1H), 7.60 (s, 1H), 7.92 (s, 1H).
[00683] To a solution of Compound 57B (500 mg, 1.79 mmol) in methanol (15 mL) was added sodium borohydride (102 mg, 2.68 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with brine (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 57C. LC-MS (ESI) m/z: 281 [M+H]+.
[00684] A mixture of Compound 57C (200 mg, 0.71 mmol), Intermediate D (208 mg, 0.71 mmol), and sodium carbonate (159 mg, 1.5 mmol) in 1-methylpyrrolidin-2-one (8 mL) was stirred at 80 oC overnight. The mixture was diluted with EtOAc (50 mL) and washed with brine (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 57D. LC-MS (ESI) m/z: 494 [M+H]+.
[00685] A mixture of Compound 57D (140 mg, 0.28 mmol) and triethylsilane (326 mg, 2.8 mmol) in TFA (2 mL) was stirred at 60 oC for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified with preparative TLC (ethyl acetate in
dichloromethane, 20% v/v) to afford Compound 57E. LC-MS (ESI) m/z: 358 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 3.00 (dd, J = 16.8, 5.2 Hz, 2H), 3.52 (dd, J = 16.8, 7.6 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 4.46-4.50 (m, 1H), 7.30 (s, 2H).
[00686] Compound 57 was synthesized by employing the procedure described for Compound 8F using Compound 57E in lieu of Compound 8E, LC-MS (ESI) m/z: 330 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 3.00 (dd, J = 16.8, 5.2 Hz, 2H), 3.52 (dd, J = 16.8, 7.6 Hz, 2H), 4.46-4.50 (m, 1H), 7.38 (s, 2H).
[00687] Example 58
[00688] Synthesis of ethyl 4-((4'-chloro-[1,1'-biphenyl]-4-yl)amino)-1H-1,2,3-triazole- 5-carboxylate (58-1) and 4-((4'-chloro-[1,1'-biphenyl]-4-yl)amino)-1H-1,2,3-triazole-5- carboxylic acid (58-2)
Figure imgf000224_0001
[00689] Compounds 58B, 58-1, and 58-2 were synthesized by employing the procedures described for Compounds 6B, 1, and 8F using Intermediate A, Compounds 58A using K3PO4 as base, 58B, and 58-1 in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 1E, and 8E. Compound 58B: LC-MS (ESI) m/z: 463 [M+H]+. Compound 58-1: LC-MS (ESI) m/z: 343.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.41 (t, J = 7.2 Hz, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.45-7.47 (m, 2H), 7.64-7.69(s, 4H), 7.77-7.79 (s, 2H), 8.19 (brs, 1H). Compound 58-2: LC-MS (ESI) m/z: 315.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.45-7.47 (m, 2H), 7.54-7.63 (s, 4H), 7.65-7.67 (s, 2H), 9.13 (brs, 1H).
[00690] Example 59
[00691] Synthesis of 4-((4-(3,4-dichlorophenyl)thiazol-2-yl)amino)-1H-1,2,3-triazole- 5-carboxylic acid (59)
Figure imgf000225_0001
[00692] A suspension of 2-bromo-1-(3,4-dichlorophenyl)ethanone (1A) (2.68 g, 10 mmol) and thiourea (912 mg, 12.0 mmol) in EtOH (20 mL) was heated at reflux for 2 hours. The mixture was concentrated and the residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to yield Compound 59A. LC-MS (ESI) m/z: 245 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 5.01 (br, 2H), 6.75 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.59 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H)
[00693] Compounds 59B, 59C, and 59 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 59A using K3PO4 as base, 59B, and 59C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 59B: LC-MS (ESI) m/z: 504 [M+H]+. Compound 59C: LC-MS (ESI) m/z: 476 [M+H]+. Compound 59: LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 4.02 (br, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.93 (d, J = 6.8 Hz, 1H), 8.19 (s, 1H), 9.57 (br, 1H).
[00694] Example 60
[00695] Synthesis of 4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1H-1,2,3-triazole- 5-carboxylic acid (60)
Figure imgf000226_0001
[00696] Compounds 60B, 60C, 60D, and 60 were synthesized by employing the procedures described for Compounds 8B, 6B, 8F, and 1 using Compounds 60A using Na2CO3 as base, Intermediate A, 60B using K3PO4 as base, 60C, and 60D in lieu of Compounds 8A using Cs2CO3 as base, 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 60B: LC-MS (ESI) m/z: 238 [M+H]+. Compound 60C: LC-MS (ESI) m/z: 497 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40 (t, J = 6.8 Hz, 3H ), 3.75 (s, 3H), 4.41 (q, J = 7.6 Hz, 2H ), 5.22 (s, 2H), 6.73 (dd, J = 2.4, 6.8 Hz, 2H), 6.82-6.89 (m, 4H), 7.16 (s, 1H), 7.38 (dd, J = 2.4, 8.8 Hz, 1H), 7.46 (dd, J = 1.6, 6.8 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H).
Compound 60D: LC-MS (ESI) m/z: 469 [M+H]+. Compound 60: LC-MS (ESI) m/z: 349
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.65-7.68 (m, 7H), 7.90 (s, 1H), 8.33 (s, 1H), 14.95 (s, 1H).
[00697] Example 61
[00698] Synthesis of ammonium 4-((2-(3,4-dichlorophenyl)thiazol-4-yl)amino)-1H- 1,2,3-triazole-5-carboxylate (61)
Figure imgf000227_0001
[00699] Compounds 61B and 61C were synthesized by employing the procedures described for Compounds 8B and 8F using Compounds 61A using KF as base and THF as solvent, and 61B in lieu of Compounds 8A using Cs2CO3 as base and DME as solvent, and 8E. Compound 61B: LC-MS (ESI) m/z: 288 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 4.00 (s, 3H), 7.55 (d, J = 8.0 Hz, 1H), 7.83 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H). Compound 61C: LC-MS (ESI) m/z: 274 [M+H]+.
[00700] To a solution of Compound 61C (2.1 g, 7.66 mmol) in t-BuOH (100 mL) was added Et3N (851 mg, 8.43 mmol) and DPPA (2.32 g, 8.43 mmol) at 0 oC. The mixture was heated at reflux overnight and evaporated under reduced pressure. The residue was diluted with CH2Cl2 (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to yield Compound 61D. LC-MS (ESI) m/z: 367 [M+Na]+.
[00701] Compound 61D (400 mg, 1.6 mmol) was dissolved in a solution of HCl/1,4- dioxane (4 N, 5 mL) and stirred at room temperature overnight. The mixture was concentrated to yield Compound 61E. LC-MS (ESI) m/z: 245 [M+H]+.
[00702] Compounds 61F, 61G, and 61 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 61E using K3PO4 as base, 61F, and 61G in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 61F: LC-MS (ESI) m/z: 504 [M+H]+. Compound 61G: LC-MS (ESI) m/z: 476 [M+H]+. Compound 61: LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 3.98 (br, 4H), 6.07 (s, 1H), 7.29 (s, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.88 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H).
[00703] Example 62
[00704] Synthesis of 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (62)
Figure imgf000228_0001
[00705] Compounds 62A, 62B, 62C, and 62 were synthesized by employing the procedures described for Compounds 8B, 6B, 2, and 1 using Compounds 60A using K2CO3 as base, Intermediate A, 62A using K3PO4 as base, 62B, and 62C in lieu of Compounds 8A using Cs2CO3 as base, 6A, 1-methylpiperazine using t-BuONa as base, 1, and 1E. Compound 62A: LC-MS (ESI) m/z: 254 [M+H]+. Compound 62B: LC-MS (ESI) m/z: 513 [M+H]+. Compound 62C: LC-MS (ESI) m/z: 485 [M+H]+. Compound 62: LC-MS (ESI) m/z: 365 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.31 (d, J = 8.4 Hz, 2H), 7.59-7.70 (m, 6H).
[00706] Example 63
[00707] Synthesis of 4-((2-(3,4-dichlorophenyl)thiazol-4-yl)(methyl)amino)-1H-1,2,3- triazole-5-carboxylic acid (63)
Figure imgf000229_0002
[00708] To a mixture of Compound 61F (250 mg, 0.5 mmol) and Cs2CO3 (326 mg, 1 mmol) in DMF (20 mL) was added MeI (142 mg, 1 mmol) and stirred at 60 oC for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to afford Compound 63A. LC-MS (ESI) m/z: 518 [M+H]+.
[00709] Compounds 63B and 63 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 63A and 63B in lieu of Compounds 8E and 1E. Compound 63B: LC-MS (ESI) m/z: 490 [M+H]+. Compound 63: LC-MS (ESI) m/z: 370
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.48 (s, 3H), 6.64 (s, 1H), 7.73-7.75(m, 2H), 7.98 (s, 1H).
[00710] Example 64
[00711] Synthesis of 4-((4-(3-chloro-4-(trifluoromethoxy)phenyl)thiazol-2-yl)amino)- 1H-1,2,3-triazole-5-carboxylic acid (64)
Figure imgf000229_0001
[00712] Compounds 64B, 64C, 64D, 64E, and 64 were synthesized by employing the procedures described for Compounds 15B, 58A, 6B, 8F, and 1 using Compounds 64A, 64B, Intermediate A, 64C using K3PO4 as base at 160 °C in a microwave oven, 64D, and 64E in lieu of Compounds 15A, 1A, 6A, 1-methylpiperazine using t-BuONa as base at 120 °C, 8E, and 1E. Compound 64B: LC-MS (ESI) m/z: 317 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.39 (s, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H).Compound 64C: LC-MS (ESI) m/z: 295 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 6.70 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 2.4Hz, 1H), 8.86 (s, 2H). Compound 64D: LC- MS (ESI) m/z: 554 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 8.8 Hz, 3H), 3.74 (s, 3H), 4.40-4.46 (m, 2H), 5.73 (s, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.10 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.68-72 (m, 1H), 7.89 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H).
Compound 64E: LC-MS (ESI) m/z: 526 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.68 (s, 3H), 5.55 (s, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H). Compound 64: LC-MS (ESI) m/z: 406 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 7.61 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 8.01 (d, J = 6.4 Hz, 1H), 8.20 (s, 1H), 9.57 (s, 1H), 13.76 (brs, 1H), 15.32 (brs, 1H).
[00713] Example 65
[00714] Synthesis of methyl 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-1H- 1,2,3-triazole-5-carboxylate (65)
Figure imgf000230_0001
[00715] Compounds 65A and 65 were synthesized by employing the procedures described for Compounds 11A and 1 using Compounds 62C using methanol and 65A in lieu of
Compounds 9A using propan-2-ol and 1E. Compound 65A: LC-MS (ESI) m/z: 499 [M+H]+. Compound 65: LC-MS (ESI) m/z: 379 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 3.98 (s, 3H), 7.32 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.69-7.71 (m, 4H).
[00716] Example 66 [00717] Synthesis of 4-((carboxymethyl)(4'-chloro-[1,1'-biphenyl]-4-yl)amino)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (66)
Figure imgf000231_0001
[00718] A mixture of Compound 58B (462 mg, 1 mmol), ethyl 2-bromoacetate (250 mg, 1.5 mmol) and Na2CO3 (160 mg, 1.5 mmol) in DMF (10 mL) was stirred at 70 oC overnight. The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to afford Compound 66A. LC-MS (ESI) m/z: 549 [M+H]+.
[00719] Compounds 66B and 66 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 66A and 66B in lieu of Compounds 8E and 1E. Compound 66B: LC-MS (ESI) m/z: 493 [M+H]+. Compound 66: LC-MS (ESI) m/z: 373
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.52 (s, 2H), 6.83 (s, 2H), 7.46-7.53 (m, 4H), 7.62-7.64 (m, 2H), 12.87 (s, 1H), 15.13 (s, 1H).
[00720] Example 67
[00721] Synthesis of 4-(((3',4'-dichloro-[1,1'-biphenyl]-3-yl)methyl)amino)-1H-1,2,3- triazole-5-carboxylic acid (67)
Figure imgf000232_0001
[00722] A mixture of Intermediate G (500 mg, 1.8 mmol) and NaH (60% suspension in oil, 216 mg, 5.4 mmol) in DMF (5 mL) was stirred at room temperature for 30 minutes. To the mixture was added 1-bromo-3-(bromomethyl)benzene (67A) (500 mg, 2.0 mmol) and was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined extracts were concentrated and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 33% v/v) to afford Compound 67B. LC-MS (ESI) m/z: 445 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.25 (t, J = 6.8 Hz, 3H), 3.74 (s, 3H), 4.20-4.26 (m, 2H), 4.59 (d, J = 6.8 Hz, 2H), 5.42 (s, 2H), 6.88-6.94 (m, 3H), 7.07-7.09 (m, 3H), 7.19(t, J = 8.0 Hz, 1H), 7.29 (s, 1H), 7.39 (d, J = 8.4Hz, 1H).
[00723] Compounds 67C, 67D, and 67 were synthesized by employing the procedures described for Compounds 4B, 1, and 8F using 3,4-dichlorophenylboronic acid, Compounds 67B using 1,4-dioxane and H2O as solvent, 67C, and 67D in lieu of (4-bromophenyl)boronic acid, Compounds 4A using toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 67C: LC-MS (ESI) m/z: 511 [M+H]+. Compound 67D: LC-MS (ESI) m/z: 391 [M+H]+. Compound 67: LC-MS (ESI) m/z: 363 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 4.57 (s, 2H), 7.40-7.65 (m, 6H), 7.78 (s, 1H).
[00724] Example 68 [00725] Synthesis of 4-(((3',4'-dichloro-[1,1'-biphenyl]-4-yl)methyl)amino)-1H-1,2,3- triazole-5-carboxylic acid (68)
Figure imgf000233_0001
[00726] Compounds 68B, 68C, 68D, and 68 were synthesized by employing the procedures described for Compounds 67B, 4B, 1, and 8F using Compounds 68A, 3,4- dichlorophenylboronic acid, 68B using 1,4-dioxane and H2O as solvent, 68C, and 68D in lieu of Compounds 67A, (4-bromophenyl)boronic acid, 4A using toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 68B: LC-MS (ESI) m/z: 445 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.25 (t, J = 7.2 Hz, 3H), 3.74 (s, 3H), 4.21-4.24 (m, 2H), 4.56 (d, J = 6.8 Hz, 2H), 5.40 (s, 2H), 6.88-6.91 (m, 3H), 7.02-7.07 (m, 4H), 7.40-7.42 (m, 2H). Compound 68C: LC-MS (ESI) m/z: 511 [M+H]+. Compound 68D: LC-MS (ESI) m/z: 391 [M+H]+. Compound 68: LC-MS (ESI) m/z: 363 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 4.54 (s, 2H), 7.48-7.56 (m, 6H), 7.77 (s, 1H).
[00727] Example 69
[00728] Synthesis of 4-((3,4-dichlorophenyl)amino)-1H-1,2,3-triazole-5-carboxylic acid (69)
Figure imgf000234_0001
[00729] Compounds 69B, 69C, and 69 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 69A using K3PO4 as base, 69B, and 69C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 69B: LC-MS (ESI) m/z: 421 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40 (t, J = 7.2 Hz, 3H), 3.77 (s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 5.21 (s, 2H), 6.64 (dd, J = 8.8, 2.2 Hz, 1H), 6.74-6.77 (m, 2H), 6.79 (d, J = 2.4 Hz, 1H), 6.83-6.86 (m, 2H), 6.94 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H). Compound 69C: LC-MS: (ESI) m/z: 393 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.69 (s, 3H), 5.31 (s, 2H), 6.56 (dd, J = 8.8, 2.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.80-6.84 (m, 2H), 7.05-7.07 (m, 2H), 7.33 (d, J = 8.8 Hz, 1H), 8.73 (brs, 1H). Compound 69: LC-MS (ESI) m/z: 273 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.50 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 13.47 (brs, 1H), 15.06 (brs, 1H).
[00730] Example 70
[00731] Synthesis of 4-((1-(4-(trifluoromethoxy)phenyl)piperidin-3-yl)amino)-1H- 1,2,3-triazole-5-carboxylic acid (70)
Figure imgf000234_0002
[00732] A mixture of tert-butyl piperidin-3-ylcarbamate (70A) (1.5 g, 7.29 mmol), 4- (trifluoromethoxy)phenylboronic acid (1.5 g, 7.29 mmol), Cu(OAc)2 (1.57 g, 8.75 mmol), and K3PO4 (3.09 g, 14.58 mmol) in DMSO (30 mL) was stirred at 80 oC overnight. The mixture was cooled down to room temperature, diluted with water (100 mL), and extracted with EtOAc (50 mL x 3). The combined extracts were concentrated under reduced pressure. The residue was purified with column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 70B. LC-MS (ESI) m/z: 361 [M+H]+.
[00733] A mixture of Compound 70B (432 mg, 1.2 mmol) and a solution of HCl in 1,4- dioxane (4 M, 10 mL) was stirred at room temperature for 2 hours. The mixture was
concentrated to give Compound 70C. LC-MS (ESI) m/z: 261 [M+H]+.
[00734] Compounds 70D, 70E, and 70 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 70C using K3PO4 as base, 70D, and 70E in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 70D: LC-MS (ESI) m/z: 520 [M+H]+. Compound 70E: LC-MS (ESI) m/z: 492 [M+H]+. Compound 70: LC-MS (ESI) m/z: 372 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.58-1.60 (m, 2H), 1.71-1.73 (m, 1H), 2.31-2.33 (m, 1H), 2.89-2.94 (m, 2H), 3.33-3.51 (m, 3H), 7.99 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H).
[00735] Example 71
[00736] Synthesis of 4-((1-(4-chlorophenyl)piperidin-4-yl)amino)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (71)
Figure imgf000235_0001
[00737] Compounds 71B, 71C, 71D, 71E, and 71 were synthesized by employing the procedures described for Compounds 70B, 70C, 6B, 8F, and 1 using 4-chlorophenylboronic acid, Compounds 71A using dichloromethane as solvent, 71B using EtOAc as solvent,
Intermediate A, 71C using K3PO4 as base, 71D, and 71E in lieu of 4- (trifluoromethoxy)phenylboronic acid, Compounds 70A using DMSO as solvent, 70B using 1,4- dioxane as solvent, 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 71B: LC-MS (ESI) m/z: 311 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.46 (s, 9H), 1.51-1.59 (m, 2H), 2.03-2.06 (m, 2H), 2.79-2.86 (m, 2H), 3.54-3.61 (m, 3H), 4.47 (br, 1H), 6.82-6.86 (m, 2H), 7.17-7.21 (m, 2H). Compound 71C: LC-MS (ESI) m/z: 211 [M+H]+. Compound 71D: LC- MS (ESI) m/z: 470 [M+H]+. Compound 71E: LC-MS (ESI) m/z: 442 [M+H]+. Compound 71: LC-MS (ESI) m/z: 322 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.59-1.62 (m, 2H), 1.97-2.00 (m, 2H), 2.80-2.86 (m, 2H), 3.51 (br, 1H), 3.62-3.66 (m, 2H), 6.96-6.99 (m, 2H), 7.20- 7.23 (m, 2H).
[00738] Example 72
[00739] Synthesis of cyclopropyl 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)amino)-1H-1,2,3-triazole-5-carboxylate 2,2,2-trifluoroacetate (72)
Figure imgf000236_0001
[00740] Compound 72 was synthesized by employing the procedure described for Compound 19A using Compound 62 in lieu of Compound 9A, LC-MS (ESI) m/z: 405 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.82-0.89 (m, 4H), 4.42-4.44 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.60-7.71 (m, 6H).
[00741] Example 73
[00742] Synthesis of 4-((1-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)-1H- 1,2,3-triazole-5-carboxylic acid (73)
Figure imgf000237_0001
[00743] Compounds 73B, 73C, 73D, 73E, and 73 were synthesized by employing the procedures described for Compounds 70B, 70C, 6B, 8F, and 1 using Compounds 73A, 73B, Intermediate A, 73C using K3PO4 as base, 73D, and 73E in lieu of Compounds 70A, 70B, 6A, 1- methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 73B: LC-MS (ESI) m/z: 347 [M+H]+. Compound 73C: LC-MS (ESI) m/z: 247 [M+H]+.1H-NMR (CD3OD, 400 MHz): d 2.14-2.22 (m, 1H), 2.44-2.53 (m, 1H), 3.34-3.45 (m, 2H), 3.56-3.62 (m, 2H), 4.00-4.05 (m, 1H), 6.64 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H). Compound 73D: LC-MS (ESI) m/z: 506
[M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.38 (t, J = 6.8 Hz, 3H), 1.82-1.89 (m, 1H), 2.01-2.09 (m, 1H), 3.04-3.07 (m, 1H), 3.18-3.39 (m, 3H), 3.77 (s, 3H), 4.23-4.28 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 5.48 (d, J = 3.2 Hz, 2H), 6.41(d, J = 9.2 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.06-7.11 (m, 4H). Compound 73E: LC-MS (ESI) m/z: 478 [M+H]+. Compound 73: LC-MS (ESI) m/z: 358 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.05-2.13 (m, 1H), 2.28-2.36 (m, 1H), 3.21-3.42 (m, 3H), 3.58-3.62 (m, 1H), 4.26 (s, 1H), 6.58(d, J = 9.2 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H).
[00744] Example 74
[00745] Synthesis of 4-((1-(4-(trifluoromethoxy)phenyl)piperidin-4-yl)amino)-1H- 1,2,3-triazole-5-carboxylic acid (74)
Figure imgf000238_0001
[00746] Compounds 74A, 74B, 74C, 74D, and 74 were synthesized by employing the procedures described for Compounds 70B, 70C, 6B, 1, and 8F using Compounds 71A, 74A using dichloromethane as solvent, Intermediate A, 74B using K3PO4 as base, 74C, and 74D in lieu of Compounds 70A, 70B using 1,4-dioxane as solvent, 6A, 1-methylpiperazine using t- BuONa as base, 1E, and 8E. Compound 74A: LC-MS (ESI) m/z: 361 [M+H]+. Compound 74B: LC-MS (ESI) m/z: 261 [M+H]+. Compound 74C: LC-MS (ESI) m/z: 520 [M+H]+. Compound 74D: LC-MS (ESI) m/z: 400 [M+H]+. Compound 74: LC-MS (ESI) m/z: 372 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.53-1.56 (m, 2H), 1.99-2.02 (m, 2H), 2.82-2.88 (m, 2H), 3.51- 3.53 (m, 1H), 3.63-3.66 (m, 2H), 7.01-7.03 (m, 2H), 7.16-7.18 (m, 2H).
[00747] Example 75
[00748] Synthesis of 4-((4'-chloro-[1,1'-biphenyl]-4-yl)(methyl)amino)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (75)
Figure imgf000238_0002
[00749] Compounds 75A, 75B, and 75 were synthesized by employing the procedures described for Compounds 63A, 1, and 8F using Compounds 58B using K2CO3 as base, 75A, and 75B in lieu of Compounds 61F using Cs2CO3 as base, 1E, and 8E. Compound 75A: LC-MS (ESI) m/z: 477 [M+H]+. Compound 75B: LC-MS (ESI) m/z: 357 [M+H]+. Compound 75: LC- MS (ESI) m/z: 329 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.28 (s, 3H), 6.77-6.79 (m, 2H), 7.44-7.46 (m, 2H), 7.51-7.53 (m, 2H), 7.61-7.63 (m, 2H).
[00750] Example 76
[00751] Synthesis of 4-((6-chloroquinolin-2-yl)amino)-1H-1,2,3-triazole-5-carboxylic acid (76)
Figure imgf000239_0001
[00752] A mixture of 2,6-dichloroquinoline (Compound 76A) (1.97 g, 10 mmol), acetamide (12 g, 200 mmol), and K2CO3 (7 g, 50 mmol) was heated at 200 oC under nitrogen for 4 hours. The reaction mixture was cooled down to room temperature, diluted with H2O (200 mL), and extracted with ethyl acetate (50 mL x 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to afford Compound 76B. LC-MS (ESI) m/z: 179 [M+H]+.
[00753] Compounds 76C, 76D, and 76 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 76B using K3PO4 as base, 76C, and 76D in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 76C: LC-MS (ESI) m/z: 438 [M+H]+. Compound 76D: LC-MS (ESI) m/z: 410 [M+H]+. Compound 76: LC-MS (ESI) m/z: 290 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.61-7.64 (m, 1H), 7.85 (brs, 1H), 7.92 (d, J = 2.4 Hz, 1H), 8.18-8.25 (m, 2H), 10.13 (brs, 1H).
[00754] Example 77 [00755] Synthesis of 4-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)-1H-1,2,3-triazole- 5-carboxylic acid (77)
Figure imgf000240_0001
[00756] Compounds 77B, 77C, and 77 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 77A using K3PO4 as base, 77B, and 77C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 77B: LC-MS (ESI) m/z: 407 [M+H]+. Compound 77C: LC-MS (ESI) m/z: 379 [M+H]+. Compound 77: LC-MS (ESI) m/z: 259 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.71-1.69 (m, 4H), 2.68-2.62 (m, 4H), 6.90 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 10.4 Hz, 1H), 7.21 (s, 1H), 8.79 (s, 1H).
[00757] Example 78
[00758] Synthesis of 4-((4-chloronaphthalen-1-yl)amino)-1H-1,2,3-triazole-5- carboxylic acid (78)
Figure imgf000240_0002
[00759] Compounds 78B, 78C, and 78 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 78A using K3PO4 as base, 78B, and 78C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 78B: LC-MS (ESI) m/z: 437 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.44 (t, J = 7.2 Hz, 3H), 3.67 (s, 3H), 4.45 (q, J = 7.2 Hz, 2H), 5.03 (s, 2H), 6.38-6.47 (m, 4H), 6.80 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.50-7.53 (m, 1H), 7.61-7.68 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H). Compound 78C: LC-MS (ESI) m/z: 409 [M+H]+.
Compound 78: LC-MS (ESI) m/z: 289 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.71 (d, J = 8.4 Hz, 1H), 7.74-7.79 (m, 2H), 8.04-8.07 (m, 1H), 8.13-8.14 (m, 1H), 8.22-8.25 (m, 1H), 9.05 (s, 1H), 13.68 (s, 1H), 15.06 (s, 1H).
[00760] Example 79 [00761] Synthesis of 4-(benzo[d]thiazol-6-ylamino)-1H-1,2,3-triazole-5-carboxylic acid (79)
Figure imgf000241_0001
[00762] Compounds 79B, 79C, and 79 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 79A using K3PO4 as base, 79B, and 79C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 79B: LC-MS: (ESI) m/z: 410 [M+H]+. Compound 79C: LC-MS (ESI) m/z: 382 [M+H]+. Compound 79: LC-MS (ESI) m/z: 262 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.67 (d, J = 10.7 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 8.43 (d, J = 11.3 Hz, 2H), 9.16 (s, 1H), 13.52 (s, 1H), 14.96 (s, 1H).
[00763] Example 80
[00764] Synthesis of 4-((3,4-difluorophenyl)amino)-1H-1,2,3-triazole-5-carboxylic acid (80)
Figure imgf000241_0002
[00765] Compounds 80B, 80C, and 80 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 80A using K3PO4 as base, 80B, and 80C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 80B: LC-MS: (ESI) m/z: 389 [M+H]+. Compound 80C: LC-MS (ESI) m/z: 361 [M+H]+. Compound 80: LC-MS (ESI) m/z: 241 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.28-7.41 (m, 2H), 7.71-7.76 (m, 1H), 8.34 (s, 1H), 13.37 (s, 1H), 14.96 (s, 1H).
[00766] Example 81
[00767] Synthesis of (pivaloyloxy)methyl 4-((4'-chloro-[1,1'-biphenyl]-4-yl)amino)- 1H-1,2,3-triazole-5-carboxylate (81)
Figure imgf000242_0001
[00768] Compound 81A was synthesized by employing the procedure described for Compound 1 using Intermediate A in lieu of Compound 1E, LC-MS (ESI) m/z: 220 [M+H]+.
[00769] To a solution of Compound 81A (2.3 g, 10.4 mmol) in CH3CN (8 mL) was added TrtCl (2.9 g, 10.4 mmol) and Et3N (2.17 g, 15.7 mmol). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 81B. LC-MS (ESI) m/z: Non-ionizable compound under routeine conditions used.
[00770] Compounds 81C, 81D, 81E, and 81 were synthesized by employing the procedures described for Compounds 6B, 8F, 54C, and 1 using Compounds 81B, 58A using K3PO4 as base, 81C, 81D, and 81E in lieu of Compounds 6A, 1-methylpiperazine using t- BuONa as base, 8E, 54B, and 1E. Compound 81C: LC-MS (ESI) m/z: 607 [M+Na]+. Compound 81D: LC-MS (ESI) m/z: 555. [M-H]-. Compound 81E: LC-MS (ESI) m/z: 669 [M-H]-.
Compound 81: LC-MS (ESI) m/z: 429 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.16 (s, 9H), 5.97 (s, 2H), 7.47 (d, J = 6.8 Hz, 2H), 7.62 (d, J = 6.8 Hz, 2H), 7.67(d, J = 6.8 Hz, 2H), 7.71 (d, J = 6.8 Hz, 2H), 8.18 (s, 1H).
[00771] Example 82 [00772] Synthesis of 4-((6-chloronaphthalen-2-yl)amino)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (82)
Figure imgf000243_0001
[00773] Compounds 82B, 82C, 82D, 82E, and 82 were synthesized by employing the procedures described for Compounds 61D, 61E, 6B, 1, and 8F using Compounds 82A, 82B, Intermediate A, 82C using K3PO4 as base, 82D, and 82E in lieu of Compounds 61C, 61E, 6A, 1- methylpiperazine using t-BuONa as base, 1E, and 8E. Compound 82B: LC-MS (ESI) m/z: 276 [M-H]-; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.51 (s, 9H), 7.43 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.81 (t, J = 8.4 Hz, 2H), 7.91 (s, 1H), 8.13 (s, 1H), 9.64 (s, 1H). Compound 82C: LC-MS (ESI) m/z: 178 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.49 (s, 2H), 6.82 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 7.23 (s, J = 8.8 Hz, 1H), 7.51-7.59 (m, 2H), 7.71 (d, J = 2.0 Hz, 1H). Compound 82D: LC-MS (ESI) m/z: 437 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40 (t, J = 8.8 Hz, 3H), 3.72 (s, 3H), 4.38-4.43 (m, 2H), 5.18 (s, 2H), 6.64 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.99 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H).
Compound 82E: LC-MS (ESI) m/z: 317 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.35 (t, J = 7.2 Hz, 3H), 4.34-4.42 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.80-7.85 (m, 2H), 7.92 (s, 1H), 8.22 (s, 1H), 8.40 (s, 1H), 15.12 (s, 1H). Compound 82: LC-MS (ESI) m/z: 289 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.42 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.82 (t, J = 8.8 Hz, 2H), 7.92 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 8.47 (s, 1H).
[00774] Example 83
[00775] Synthesis of 4-((4-(trifluoromethoxy)phenyl)amino)-1H-1,2,3-triazole-5- carboxylic acid (83)
Figure imgf000244_0001
[00776] Compounds 83B, 83C, and 83 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 83A using K3PO4 as base, 83B, and 83C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 83B: LC-MS (ESI) m/z: 437 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 0.96 (t, J = 7.2 Hz, 3H), 3.69 (s, 3H), 4.02-4.07 (m, 2H), 5.40 (s, 2H), 6.69 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 7.09-7.16 (m, 4H), 8.67 (s, 1H). Compound 83C: LC-MS (ESI) m/z: 409 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.67 (s, 3H), 5.18 (s, 2H), 6.70 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H).
Compound 83: LC-MS (ESI) m/z: 289 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.28 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 8.34 (s, 1H), 13.42 (s, 1H), 15.01 (s, 1H).
[00777] Example 84
[00778] Synthesis of 4-(3,4-dihydroisoquinolin-2(1H)-yl)-1H-1,2,3-triazole-5- c
Figure imgf000244_0002
[00779] Compounds 84B, 84C, and 84 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 84A using Cs2CO2 as base and 1,4-dioxane as solvent, 84B, and 84C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base and toluene as solvent, 8E, and 1E. Compound 84B: LC-MS (ESI) m/z: 393 [M+H]+. Compound 84C: LC-MS (ESI) m/z: 365 [M+H]+. Compound 84: LC-MS (ESI) m/z: 245 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.86-2.91 (m, 2H), 3.53-3.71 (m, 2H), 4.38-4.59 (m, 2H), 7.09-7.30 (m, 4H), 12.83 (brs, 1H), 14.78 (brs, 1H).
[00780] Example 85 [00781] Synthesis of 4-((6-bromonaphthalen-2-yl)amino)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (85)
Figure imgf000245_0001
[00782] Compounds 85A, 85B, and 85 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 56A using K3PO4 as base and DMF as solvent, 85A, and 85B in lieu of Compounds 6A, 1-methylpiperazine using t- BuONa as base and toluene as solvent, 8E, and 1E. Compound 85A: LC-MS (ESI) m/z: 481 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.40 (t, J = 7.6 Hz, 3H), 3.72 (s, 3H), 4.38-4.43 (m, 2H), 5.19 (s, 2H), 6.64 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 6.98 (s, 1H), 7.07-7.10 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H). Compound 85B: LC-MS (ESI) m/z: 453 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.30 (s, 3H), 5.20 (s, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 1.6 Hz, 1H). Compound 85: LC-MS (ESI) m/z: 333 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.53 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 8.20 (s, 1H), 8.46 (s, 1H), 13.39 (s, 1H), 15.01 (s, 1H).
[00783] Example 86
[00784] Synthesis of 4-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid (86)
Figure imgf000246_0001
[00785] To a solution of 4'-chlorobiphenyl-4-ol (86A) (200 mg, 1 mmol) in DMF (100 mL) was added sodium hydride (60% in mineral oil, 40 mg, 1 mmol) under N2 at 0 oC and stirred at for 30 minutes. To the mixture was added Intermediate A (340 mg, 1 mmol) and stirred at 90 oC for 16 hours. The mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 27% v/v) to give Compound 86B. LC- MS (ESI) m/z: 464 [M+H]+.
[00786] Compounds 86C and 86 were synthesized by employing the procedures described for Compounds 1 and 8F using Compounds 86B and 86C in lieu of Compounds 1E and 8E. Compound 86C: LC-MS (ESI) m/z: 344 [M+H]+. Compound 86: LC-MS (ESI) m/z: 316
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.15 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 8.8, 2.4 Hz, 4H).
[00787] Example 87
[00788] Synthesis of 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (87)
Figure imgf000247_0001
[00789] Compounds 87B, 87C, 87D, and 87 were synthesized by employing the procedures described for Compounds 4B, 86B, 8F, and 1 using (4- (trifluoromethoxy)phenyl)boronic acid, Compounds 87A using DME and H2O as solvent, 87B, 87C, and 87D in lieu of (4-bromophenyl)boronic acid, Compounds 4A using toluene/EtOH/H2O as solvent, 86A, 8E, and 1E. Compound 87B: LC-MS (ESI) m/z: 255 [M+H]+; 1H-NMR
(CDCl3, 400 MHz): d (ppm) 4.82 (s, 1H), 6.90-6.92 (m, 2H), 7.25-7.27 (m, 2H), 7.43-7.46 (m, 2H), 7.52-7.55 (m, 2H). Compound 87C: LC-MS (ESI) m/z: 514 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.12 (t, J = 7.2 Hz, 3H), 3.73 (s, 3H), 4.21 (q, J = 7.2 Hz, 2H), 5.38 (s, 2H), 6.76- 6.79 (m, 2H), 6.81-6.84 (m, 2H), 7.20-7.23 (m, 2H), 7.26-7.30 (m, 2H), 7.41-7.45 (m, 2H), 7.51- 7.54 (m, 2H). Compound 87D: LC-MS: (ESI) m/z: 486 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.68 (s, 3H), 5.40 (s, 2H), 6.83-6.85 (m, 2H), 6.95-6.97 (m, 2H), 7.16-7.18 (m, 2H), 7.43-7.47 (m, 2H), 7.60-7.63 (m, 2H), 7.73-7.75 (m, 2H). Compound 87: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.14-7.18 (m, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.66-7.70 (m, 2H), 7.75-7.79 (m, 2H).
[00790] Example 88
[00791] Synthesis of 4-(3,4-dichlorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid (88)
Figure imgf000247_0002
[00792] Compounds 88B, 88C, and 88 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 88A, 88B, and 88C in lieu of Compounds 86A, 8E, and 1E. Compound 88B: LC-MS (ESI) m/z: 422 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.17 (t, J = 7.2 Hz, 3H), 3.76 (s, 3H), 4.23 (q, J = 7.2 Hz, 2H), 5.38 (s, 2H), 6.58 (dd, J = 8.8, 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 6.75-6.77 (m, 2H), 7.15-7.17 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H). Compound 88C: LC-MS: (ESI) m/z: 394 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.70 (s, 3H), 5.43 (s, 2H), 6.81-6.83 (m, 2H), 7.10-7.12 (m, 1H), 7.15-7.17 (m, 2H), 7.37 (d, J = 2.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 13.24 (brs, 1H). Compound 88: LC-MS (ESI) m/z: 274 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.11 (dd, J = 8.8, 2.8 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H).
[00793] Example 89
[00794] Synthesis of 4-((6-bromonaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (89)
Figure imgf000248_0001
[00795] Compounds 89B, 89C, and 89 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 89A, 89B, and 89C in lieu of Compounds 86A, 8E, and 1E. Compound 89B: LC-MS (ESI) m/z: 482 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.03 (t, J = 7.2 Hz, 3H), 3.65 (s, 3H), 4.14 (q, J = 7.2 Hz, 2H), 5.39 (s, 2H), 6.67-6.69 (m, 2H), 6.76 (d, J = 2.8 Hz, 1H), 7.14-7.26 (m, 3H), 7.40 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H). Compound 89C: LC-MS: (ESI) m/z: 454 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.62 (s, 3H), 5.43 (s, 2H), 6.76-6.78 (m, 2H), 7.14-7.17 (m, 3H), 7.34 (dd, J = 8.8, 2.4 Hz, 1H), 7.60 (dd, J = 8.8, 2.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H). Compound 89: LC-MS (ESI) m/z: 334 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.43 (dd, J = 8.8, 2.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H).
[00796] Example 90
[00797] Synthesis of 4-((1-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (90)
Figure imgf000249_0001
[00798] The mixture of 4-(trifluoromethoxy)phenylboronic acid (1.5 g, 7.28 mmol), pyrrolidin-3-ol (Compound 90A) (0.63 g, 7.28 mmol), Cu(OAc)2 (1.57 g, 8.75 mmol), and K3PO4 (3.09 g, 14.58 mmol) in DMSO (20 mL) was stirred at 90 oC overnight. The reaction mixture was cooled down to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 40% v/v) to furnish Compound 90B. LC-MS (ESI) m/z: 248 [M+H]+.
[00799] A mixture of Compound 90B (100 mg, 0.40 mmol), Intermediate H (93 mg, 0.34 mmol), and PPh3 (132 mg, 0.51 mmol) in dry THF (5 mL) was dropped DIAD (103 mg, 0.51 mmol) at 0 oC and stirred at room temperature overnight. The mixture was concentrated to give a product, which was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to furnish Compound 90C. LC-MS (ESI) m/z: 507 [M+H]+.
[00800] Compounds 90D and 90 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 90C and 90D in lieu of Compounds 8E and 1E. Compound 90D: LC-MS (ESI) m/z: 479 [M+H]+. Compound 90: LC-MS (ESI) m/z: 359
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 2.27-2.35 (m, 2H), 3.38-3.45 (m, 3H), 3.64- 3.68 (m, 1H), 5.35 (s, 1H), 6.59 (d, J = 6.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 12.82 (s, 1H), 14.81 (s, 1H).
[00801] Example 91
[00802] Synthesis of 4-(3,5-dichlorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid (91)
Figure imgf000250_0001
[00803] Compounds 91B, 91C, and 91 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 91A, 91B, and 91C in lieu of Compounds 86A, 8E, and 1E. Compound 91B: LC-MS (ESI) m/z: 422 [M+H]+. Compound 91C: LC-MS (ESI) m/z: 392 [M-H]-. Compound 91: LC-MS (ESI) m/z: 272 [M-H]-; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.23 (d, J = 1.6 Hz, 2H), 7.42 (d, J = 1.6 Hz, 1H).
[00804] Example 92
[00805] Synthesis of 4-((4-chloronaphthalen-1-yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (92)
Figure imgf000250_0002
[00806] Compounds 92B, 92C, and 92 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 92A, 92B, and 92C in lieu of Compounds 86A, 8E, and 1E. Compound 92B: LC-MS (ESI) m/z: 438 [M+H]+. Compound 92C: LC-MS (ESI) m/z: 410 [M+H]+. Compound 92: LC-MS (ESI) m/z: 290 [M+H]+.1H-NMR (400 MHz, DMSO-d6): d (ppm) 7.11 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H).
[00807] Example 93
[00808] Synthesis of methyl 4-((6-bromonaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5- carboxylate (93)
Figure imgf000250_0003
[00809] To a solution of Compound 89C (60 mg, 0.132 mmol) in CH3CN (10 mL) and MeOH (10 mL) was added a solution of TMSCHN2 in hexane (2 M, 0.2 mL, 0.41 mmol) at 0 oC and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was used directly for next step without further purification. LC- MS (ESI) m/z: 468 [M+H] +.
[00810] Compound 93 was synthesized by employing the procedure described for Compound 1 using Compound 93A in lieu of Compound 1E, LC-MS (ESI) m/z: 348 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.76 (s, 3H), 7.44 (dd, J = 8.8, 2.4 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H).
[00811] Example 94
[00812] Synthesis of 4-(3,4-difluorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid (94)
Figure imgf000251_0001
[00813] Compounds 94B, 94C, and 94 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 94A, 94B, and 94C in lieu of Compounds 86A, 8E, and 1E. Compound 94B: LC-MS: (ESI) m/z: 801 [2M+Na]+. Compound 94C: LC-MS (ESI) m/z: 745 [2M+Na]+. Compound 94: LC-MS (ESI) m/z: 242 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 6.92-6.97 (m, 1H), 7.30-7.36 (m, 1H), 7.40-7.47 (m, 1H).
[00814] Example 95
[00815] Synthesis of 4-(2,4-dichlorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid (95)
Figure imgf000251_0002
[00816] Compounds 95B, 95C, and 95 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 95A, 95B, and 95C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 95B: LC-MS (ESI) m/z: 422 [M+H]+. Compound 95C: LC-MS (ESI) m/z: 392 [M-H]-. Compound 95: LC-MS (ESI) m/z: 272 [M-H]-; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.20 (d, J = 9.2 Hz, 1H), 7.41 (dd, J = 9.2, 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H).
[00817] Example 96
[00818] Synthesis of 4-(4-(trifluoromethoxy)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid (96)
Figure imgf000252_0001
[00819] Compounds 96B, 96C, and 96 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 96A, 96B, and 96C in lieu of Compounds 86A, 8E, and 1E. Compound 96B: LC-MS: (ESI) m/z: 438 [M+H]+. Compound 96C: LC-MS (ESI) m/z: 432 [M+Na]+. Compound 96: LC-MS (ESI) m/z: 290 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 7.17-7.19 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H).
[00820] Example 97
[00821] Synthesis of 4-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid (97)
Figure imgf000252_0002
[00822] Compounds 97B, 97C, and 97 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 97A, 97B, and 97C in lieu of Compounds 86A, 8E, and 1E. Compound 97B: LC-MS (ESI) m/z: 408[M+H]+. Compound 97C: LC-MS (ESI) m/z: 380 [M+H]+. Compound 97: LC-MS (ESI) m/z: 260 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.69-1.70 (m, 4H), 2.64 (s, 4H), 6.62 (s, 1H).6.69 (d, J = 8.4 Hz, 1H).6.97 ( 8.4 Hz, 1H).
[00823] Example 98
[00824] Synthesis of methyl 4-(3,4-dichlorophenoxy)-1H-1,2,3-triazole-5-carboxylate 2,2,2-trifluoroacetate (98)
Figure imgf000253_0001
[00825] A solution of Compound 88B (200 mg, 0.5 mmol) and concentrated H2SO4 (0.1 mL) in MeOH (5 mL) was stirred at 60 oC for 16 hours. After cooling down to room
temperature, the mixture was concentrated and purified with reverse phase chromatography using eluents (acetonitrile in water, from 0% to 100% v/v) to afford Compound 98A. LC-MS (ESI) m/z: 408 [M+H]+.
[00826] Compound 98 was synthesized by employing the procedure described for Compound 1 using Compound 98A in lieu of Compound 1E, LC-MS (ESI) m/z: 288 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 3.87 (s, 3H), 7.10 (dd, J = 8.8, 2.8 Hz, 1H), 7.37 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H).
[00827] Example 99
[00828] Synthesis of 4-(benzo[d]thiazol-6-yloxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (99)
Figure imgf000253_0002
[00829] Compounds 99B, 99C, and 99 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 99A using NMP as solvent, 99B, and 99C in lieu of 4-bromophenol using DMF as solvent, Compounds 8E, and 1E. Compound 99B: LC-MS (ESI) m/z: 411 [M+H]+. Compound 99C: LC-MS (ESI) m/z: 383
[M+H]+. Compound 99: LC-MS (ESI) m/z: 263 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.31 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 9.30 (s, 1H).
[00830] Example 100
[00831] Synthesis of 4-(2,5-dichlorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid (100)
Figure imgf000254_0001
[00832] Compounds 100B, 100C, and 100 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 100A, 100B, and 100C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 100B: LC-MS (ESI) m/z: 422
[M+H]+. Compound 100C: LC-MS (ESI) m/z: 392 [M-H]-. Compound 100: LC-MS (ESI) m/z: 274 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.31 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H).
[00833] Example 101
[00834] Synthesis of 1-(acetoxymethyl)-4-((6-bromonaphthalen-2-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (101)
Figure imgf000254_0002
[00835] Compound 101 was synthesized by employing the procedure described for Compound 51 using chloromethyl acetate and Compound 89 in lieu of chloromethyl pivalate and Compound 16, LC-MS (ESI) m/z: 406 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.09 (s, 3H), 6.15 (s, 2H), 7.37 (dd, J = 2.4, 8.8 Hz, 1H), 7.41 (d, J = 5.2 Hz, 1H), 7.60 (dd, J = 2.0, 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 8.20 (d, J = 2 Hz, 1H).
[00836] Example 102
[00837] Synthesis of 4-(3,4-dichlorophenoxy)-1-((pivaloyloxy)methyl)-1H-1,2,3- triazole-5-carboxylic acid (102)
Figure imgf000255_0001
[00838] Compound 102 was synthesized by employing the procedure described for Compound 51 using Compound 88 in lieu of Compound 16, LC-MS (ESI) m/z: 405 [M+18]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.04 (s, 9H), 5.72 (s, 2H), 6.88 (dd, J = 9.2, 2.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H).
[00839] Example 103
[00840] Synthesis of 4-(3,4-dichlorophenoxy)-1-((isobutyryloxy)methyl)-1H-1,2,3- triazole-5-carboxylic acid (103)
Figure imgf000255_0002
[00841] Compound 103 was synthesized by employing the procedure described for Compound 51 using chloromethyl isobutyrate and Compound 88 in lieu of chloromethyl pivalate and Compound 16, LC-MS (ESI) m/z: 391 [M+18]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.07 (d, J = 6.8 Hz, 6H), 2.58-2.59 (m, 1H), 6.18 (s, 2H), 7.03 (dd, J = 8.8, 2.8 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H).
[00842] Example 104
[00843] Synthesis of 1-(acetoxymethyl)-4-(3,4-dichlorophenoxy)-1H-1,2,3-triazole-5- carboxylic acid (104)
Figure imgf000256_0001
[00844] Compound 104 was synthesized by employing the procedure described for Compound 51 using chloromethyl acetate and Compound 88 in lieu of chloromethyl pivalate and Compound 16, LC-MS (ESI) m/z: 363 [M+18]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.08 (s, 3H), 6.15 (s, 2H), 7.05 (dd, J = 8.4, 2.8 Hz, 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H).
[00845] Example 105
[00846] Synthesis of acetoxymethyl 4-((6-bromonaphthalen-2-yl)oxy)-1H-1,2,3- triazole-5-carboxylate (105)
Figure imgf000256_0002
[00847] Compounds 105A, 105B, 105C, 105D, and 105 were synthesized by employing the procedures described for Compounds 1, 54A, 8F, 54C, and 54 using Compounds 89B, 105A, 105B, 105C, chloromethyl acetate, and 105D in lieu of Compounds 1E, 33, 8E, 54B, chloromethyl pivalate, and 54C. Compound 105A: LC-MS (ESI) m/z: 362 [M+H]+. Compound 105B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d 1.21 (t, J = 6.8 Hz, 3H), 4.27 (q, J = 6.8 Hz, 2H), 7.17-7.20 (m, 6H), 7.29- 7.35 (m, 11H), 7.45-7.53 (m, 2H), 7.66-7.63 (m, 1H), 7.94-7.95 (m, 1H). Compound 105C: LC- MS (ESI) m/z: 243 [M-Trt]+. Compound 105D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 105: LC-MS (ESI) m/z: 406 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.96 (s, 3H), 5.83 (s, 2H), 7.45 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 2.0 Hz, 8.8 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H).
[00848] Example 106
[00849] Synthesis of 4-((6-chloronaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (106)
Figure imgf000257_0001
[00850] A mixture of 6-bromo-2-naphthoic acid (Compound 106A) (3.00 g, 11.47 mmol), CuI (2.19 g, 11.50 mmol), and CuCl (11.70 g, 114.64 mmol) in DMF (20 mL) was stirred at 150 °C under nitrogen for 3 hours. The mixture was cooled down to room temperature and diluted with an aqueous HCl solution (3 M, 100 mL). A solid was formed, filtered, and washed with water (100 mL). It was suspended in THF (100 mL), filtered, and washed with THF (100 mL). The combined filtrates were concentrated under reduced pressure. The residue was suspended in an aqueous HCl solution (3 M, 100 mL), stirred at room temperature for 10 minutes, and filtered. The cake was washed with water (50 mL) and CH3CN (50 mL) and dried under vacuum to yield Compound 106B. LC-MS (ESI) m/z: 205 [M-H]-; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.61-7.64 (m, 1H), 7.99-8.05 (m, 2H), 8.15-8.19 (m, 2H), 8.65 (s, 1H), 13.18 (s, 1H).
[00851] A mixture of Compound 106B (3.00 g, 14.56 mmol), N,O- dimethylhydroxylamine hydrochloride (1.71 g, 17.47 mmol), Et3N (4.41 g, 43.68 mmol), and HATU (8.30 g, 21.84 mmol) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (160 mL), washed with water (100 mL) and brine (100 mL), and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 80% v/v) to yield Compound 106C. LC-MS (ESI) m/z: 250 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.31 (s, 3H), 3.56 (s, 3H), 7.59-7.62 (m, 1H), 7.71-7.74 (m, 1H), 7.97 (d, J = 8.8 Hz, 1H), 8.08-8.12 (m, 2H), 8.24 (s, 1H).
[00852] To a solution of Compound 106C (3.00 g, 12.05 mmol) in dry THF (20 mL) was added a solution of MeMgBr in Et2O (3 M, 6.4 mL, 19.28 mmol) at 0 oC and stirred at room temperature under nitrogen for 16 hours. The reaction mixture was quenched with methanol (10 mL) and an aqueous HCl solution (3 M, 50 mL), and extracted with ethyl acetate (160 mL). The extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 10% v/v) to yield Compound 106D. LC-MS (ESI) m/z: 205 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.70 (s, 3H), 7.65 (d, J = 8.8 Hz, 1H), 7.99-8.05 (m, 2H), 8.14-8.20 (m, 2H), 8.71 (s, 1H).
[00853] To a solution of Compound 106D (2.38 g, 11.67 mmol) in 1,2-dichloroethane (30 mL) was added m-CPBA (3.00 g, 17.50 mmol) at room temperature and stirred at 80 oC for 4 hours. Another portion of m-CPBA (3.00 g, 17.50 mmol) was added and stirred at 80 oC for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 20% v/v) to yield Compound 106E. LC-MS (ESI) m/z: 221 [M+H]+.
[00854] Compounds 106F, 106G, 106H, and 106 were synthesized by employing the procedures described for Compounds 8F, 86B, 8F, and 1 using Compounds 106E, 106F, 106G, and 106H in lieu of Compounds 8E, 86A, 8E, and 1E. Compound 106F: LC-MS (ESI) m/z: 179 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.11-7.14 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.71-7.77 (m, 2H), 7.88 (d, J = 2.0 Hz, 1H), 9.87 (s, 1H). Compound 106G: LC-MS (ESI) m/z: 438 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.82 (t, J = 7.2 Hz, 3H), 3.63 (s, 3H), 3.97 (q, J = 7.2 Hz, 2H), 5.48 (s, 2H), 6.78 (d, J = 8.8 Hz, 2H), 7.18-7.25 (m, 2H), 7.30-7.35 (m, 1H), 7.37-7.40 (m, 1H), 7.48-7.52 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.90-7.95 (m, 1H), 8.05 (d, J = 2.4 Hz, 1H). Compound 106H: LC-MS (ESI) m/z: 410 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.61 (s, 3H), 5.30 (s, 2H), 6.74 (d, J = 8.8 Hz, 2H), 7.04 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz.1H), 8.01 (s, 1H). Compound 106: LC-MS (ESI) m/z: 290 [M+H]+; 1H-NMR (DMSO- d6, 400 MHz,): d (ppm) 7.42 (d, J = 8.8 Hz, 1H), 7.19-7.52 (m, 2H), 7.90 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 8.06 (s, 1H).
[00855] Example 107
[00856] Synthesis of (pivaloyloxy)methyl 4-(3,4-dichlorophenoxy)-1H-1,2,3-triazole-5- carboxylate (107)
Figure imgf000259_0001
[00857] Compounds 107A, 107B, 107C, 107D, and 107 were synthesized by employing the procedures described for Compounds 1, 54A, 8F, 51, and 1 using Compounds 88B, 107A, 107B, 107C, and 107D in lieu of Compounds 1E, 33, 8E, 16, and 1E. Compound 107A: LC-MS (ESI) m/z: 302 [M+ H]+. Compound 107B: LC-MS (ESI) m/z: 566 [M+Na]+. Compound 107C: LC-MS (ESI) m/z: 538 [M+Na]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 7.08-7.12 (m, 7H), 7.37-7.43 (m, 10H), 7.58-7.60 (m, 1H), 13.50 (s, 1H). Compound 107D: LC-MS (ESI) m/z: 652 [M+Na]+. Compound 107: LC-MS (ESI) m/z: 405 [M+H2O]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.17 (s, 9H), 5.93 (s, 2H), 7.07-7.10 (m, 1H), 7.33 (s, 1H), 7.50-7.52 (m, 1H).
[00858] Example 108
[00859] Synthesis of (isobutyryloxy)methyl 4-(3,4-dichlorophenoxy)-1H-1,2,3- triazole-5-carboxylate (108)
Figure imgf000259_0002
[00860] Compounds 108A and 108 were synthesized by employing the procedures described for Compounds 51 and 1 using chloromethyl isobutyrate, Compounds 107C, and 108A in lieu of chloromethyl pivalate, Compounds 16, and 1E. Compound 108A: LC-MS (ESI) m/z: 633 [M+H2O]+. Compound 108: LC-MS (ESI) m/z: 391 [M+H2O]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.10 (d, J = 7.2 Hz, 6H), 2.46-2.54 (m, 1H), 5.84 (s, 2H), 6.87-6.90 (m, 1H), 7.06-7.07 (m, 1H), 7.41-7.43 (m, 1H).
[00861] Example 109
[00862] Synthesis of acetoxymethyl 4-(3,4-dichlorophenoxy)-1H-1,2,3-triazole-5- carboxylate (109)
Figure imgf000260_0001
[00863] Compounds 109A and 109 were synthesized by employing the procedures described for Compounds 51 and 1 using chloromethyl acetate, Compounds 107C, and 109A in lieu of chloromethyl pivalate, Compounds 16, and 1E. Compound 109A: LC-MS (ESI) m/z: 605 [M+H2O]+. Compound 109: LC-MS (ESI) m/z: 346 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 2.01 (s, 3H), 5.82 (s, 2H), 6.87-6.90 (m, 1H), 7.07-7.08 (m, 1H), 7.41-7.43 (m, 1H).
[00864] Example 110
[00865] Synthesis of cyclopropyl 4-((6-bromonaphthalen-2-yl)oxy)-1H-1,2,3-triazole- 5-carboxylate (110)
Figure imgf000260_0002
[00866] Compounds 110A and 110 were synthesized by employing the procedures described for Compounds 19A and 1 using Compounds 105C using TEA as base and dichloromethane as solvent and 110A in lieu of Compounds 9A using DIPEA as base and DMF as solvent and 1E. Compound 110A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d 0.58-0.68 (m, 4H), 4.23-4.28 (m, 1H), 7.16-7.19 (m, 6H), 7.28-7.35 (m, 11H), 7.45-7.53 (m, 2H), 7.66-7.68 (m, 1H), 7.94-7.95 (m, 1H).
Compound 110: LC-MS (ESI) m/z: 374 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.36- 0.40 (m, 2H), 0.58-0.63 (m, 2H), 4.15-4.19 (m, 1H), 7.40 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 2.0 Hz, 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H).
[00867] Example 111
[00868] Synthesis of 4-((6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (111)
Figure imgf000261_0001
[00869] To a suspend of methyltriphenylphosphonium bromide (10.7 g, 30 mmol) in dry THF (150 mL) was added t-BuOK (3.37 g, 30 mmol) and stirred at 0 oC for 15 minutes. To the mixture was added a solution of 5,6-dichloro-2,3-dihydro-1H-inden-1-one (Compound 111A) (3.0 g, 15.0 mmol) in dry THF (60 mL) in one portion at 0 oC. After stirring at 0 oC for 5 hours, to the mixture was added more methyltriphenylphosphonium bromide (10.7 g, 30 mmol) and t- BuOK (3.37 g, 30 mmol) at 0 oC and stirred at room temperature for 58 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was diluted with n- hexane (100 mL) and passed through a short silica gel column. The eluent was concentrated to give Compound 111B. LC-MS (ESI) m/z: Non-ionizable Compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.78-2.84 (m, 2H), 2.89-2.94 (m, 2H), 5.08 (t, J = 2.0 Hz, 1H), 5.42 (t, J = 2.0 Hz, 1H), 7.32 (s, 1H), 7.51 (s, 1H).
[00870] To a solution of Compound 111B (907 mg, 4.56 mmol) in 95% MeOH (20 mL) at 0 oC was added hydroxy(tosyloxy)iodobenzene (1.8 g, 4.56 mmol) and stirred at 0 oC for 30 minutes. The mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (120 mL), washed with saturated aqueous NaHCO3 solution (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 111C. The product was used directly in next step without further purification. LC- MS (ESI) m/z: 215 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.55 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 6.4 Hz, 2H), 3.54 (s, 2H), 7.23 (s, 1H), 7.34 (s, 1H).
[00871] Compounds 111D, 111E, 111F, and 111 were synthesized by employing the procedures described for Compounds 57C, 90C, 8F, and 1 using Compounds 111C, 111D, 111E, and 111F in lieu of Compounds 57B, 90B, 8E, and 1E. Compound 111D: LC-MS (ESI) m/z: 199 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.77-1.86 (m, 1H), 1.97-2.04 (m, 1H), 2.67-2.73 (m, 1H), 2.76-2.79 (m, 1H), 2.88-2.95 (m, 1H), 2.98-3.03 (m, 1H), 4.13-4.19 (m, 1H), 7.16 (s, 1H), 7.18 (s, 1H). Compound 111E: LC-MS (ESI) m/z: 476 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 1.94-2.13 (m, 2H), 2.69-2.84 (m, 3H), 2.94-2.99 (m, 1H), 3.77 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.02-5.16 (m, 2H), 5.66-5.71 (m, 1H), 6.74-6.76 (m, 2H), 6.96-6.98 (m, 2H), 7.06 (s, 1H), 7.19 (s, 1H). Compound 111F: LC-MS (ESI) m/z: 448 [M+H]+. Compound 111: LC-MS (ESI) m/z: 328 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.12-2.21 (m, 2H), 2.78-2.85 (m, 1H), 2.97-3.08 (m, 2H), 3.20-3.25 (m, 1H), 5.17 (t, J = 4.0 Hz, 1H), 7.25 (s, 1H), 7.27 (s, 1H).
[00872] Example 111-1 and 111-2
[00873] Synthesis of (R)-4-((6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (111-1) and (S)-4-((6,7-dichloro-1,2,3,4- tetrahydronaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (111-2)
Figure imgf000263_0001
[00874] To a suspend of methyltriphenylphosphonium bromide (10.7 g, 30 mmol) in dry THF (150 mL) was added t-BuOK (3.37 g, 30 mmol) and stirred at 0 oC for 15 minutes. To the mixture was added a solution of 5,6-dichloro-2,3-dihydro-1H-inden-1-one (111A) (3.0 g, 15.0 mmol) in dry THF (60 mL) in one portion at 0 oC. After stirred at 0 oC for 5 hours, to the mixture was added more methyltriphenylphosphonium bromide (10.7 g, 30 mmol) and t-BuOK (3.37 g, 30 mmol) at 0 oC and stirred at room temperature for 58 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was diluted with n-hexane (100 mL) and passed through a short silica gel column. The eluent was concentrated to give Compound 111B as a colorless oil (2.3 g, yield 75%). LC-MS (ESI) m/z: Non-ionizable Compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.78-2.84 (m, 2H), 2.89-2.94 (m, 2H), 5.08 (t, J = 2.0 Hz, 1H), 5.42 (t, J = 2.0 Hz, 1H), 7.32 (s, 1H), 7.51 (s, 1H).
[00875] To a solution of Compound 111B (907 mg, 4.56 mmol) in 95% MeOH (20 mL) at 0 oC was added hydroxy(tosyloxy)iodobenzene (1.8 g, 4.56 mmol) and stirred at 0 oC for 30 minutes. The mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (120 mL), washed with saturated aqueous NaHCO3 solution (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude Compound 111C as a yellow solid (980 mg, yield 100%). The crude product was used directly in next step without further purification. LC-MS (ESI) m/z: 215 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.55 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 6.4 Hz, 2H), 3.54 (s, 2H), 7.23 (s, 1H), 7.34 (s, 1H).
[00876] Compounds 111D, 111E, 111F, and 111 were synthesized by employing the procedures described for Compounds 57C, 90C, 8F, and 1 using Compounds 111C, 111D,
111E, and 111F in lieu of Compounds 57B, 90B, 8E, and 1E. Compound 111D: LC-MS (ESI) m/z: 199 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.77-1.86 (m, 1H), 1.97-2.04 (m, 1H), 2.67-2.73 (m, 1H), 2.76-2.79 (m, 1H), 2.88-2.95 (m, 1H), 2.98-3.03 (m, 1H), 4.13-4.19 (m, 1H), 7.16 (s, 1H), 7.18 (s, 1H). Compound 111E: LC-MS (ESI) m/z: 476 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 1.94-2.13 (m, 2H), 2.69-2.84 (m, 3H), 2.94-2.99 (m, 1H), 3.77 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.02-5.16 (m, 2H), 5.66-5.71 (m, 1H), 6.74-6.76 (m, 2H), 6.96-6.98 (m, 2H), 7.06 (s, 1H), 7.19 (s, 1H). Compound 111F: LC-MS (ESI) m/z: 448 [M+H]+. Compound 111: LC-MS (ESI) m/z: 328 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.12-2.21 (m, 2H), 2.78-2.85 (m, 1H), 2.97-3.08 (m, 2H), 3.20-3.25 (m, 1H), 5.17 (t, J = 4.0 Hz, 1H), 7.25 (s, 1H), 7.27 (s, 1H).
[00877] Compound 111 (130 mg) was separated with preparative chiral-HPLC and HPLC to furnish Compound 111-1 as a white solid (29 mg, yield 22%) and Compound 111-2 as a white solid (29 mg, yield 22%). Compound 111-1: LC-MS (ESI) m/z: 328 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.14-2.19 (m, 2H), 2.78-2.86 (m, 1H), 2.98-3.09 (m, 2H), 3.20-3.26 (m, 1H), 5.17 (brs, 1H), 7.26 (s, 1H), 7.28 (s, 1H). Chiral separation condition: n-hexane/EtOH contained 0.1% diethylamine (30/70); IE (4.6 x 250 mm, 5 µm), retention time: 7.69 min. It is a mixture as mobile phase; Compound 111-2: LC-MS (ESI) m/z: 328 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.16-2.21 (m, 2H), 2.80-2.88 (m, 1H), 3.00-3.11 (m, 2H), 3.23-3.28 (m, 1H), 5.19 (brs, 1H), 7.28 (s, 1H), 7.30 (s, 1H). Chiral separation condition: n-hexane/EtOH contained 0.1% diethylamine (30/70); IE (4.6 x 250 mm, 5 µm), retention time: 12.62 min.
[00878] Example 112
[00879] Synthesis of cyclopropyl 4-(3,4-dichlorophenoxy)-1H-1,2,3-triazole-5- carboxylate (112)
Figure imgf000265_0001
[00880] Compounds 112A and 112 were synthesized by employing the procedures described for Compounds 19A and 1 using Compounds 107C using dichloromethane as solvent and 112A in lieu of Compounds 9A using DMF as solvent and 1E. Compound 112A: LC-MS (ESI) m/z: 578 [M+Na]+. Compound 112: LC-MS (ESI) m/z: 314 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 0.64-0.65 (m, 2H), 0.75-0.77 (m, 2H), 4.31-4.33 (m, 1H), 7.03-7.06 (m, 1H), 7.31-7.32 (m, 1H), 7.51-7.53 (m, 1H).
[00881] Example 113
[00882] Synthesis of 4-(quinolin-7-yloxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2- trifluoroacetate (113)
Figure imgf000265_0002
[00883] Compounds 113B, 113C, and 113 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 113A, 113B, and 113C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 113B: LC-MS (ESI) m/z: 405
[M+H]+. Compound 113C: LC-MS (ESI) m/z: 377 [M+H]+. Compound 113: LC-MS (ESI) m/z: 257 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.52 (s, 1H), 7.53-7.62 (m, 1H), 7.65- 7.68 (m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 9.00 (d, J = 4.4 Hz, 1H).
[00884] Example 114
[00885] Synthesis of 4-(3-(trifluoromethoxy)phenoxy)-1H-1,2,3-triazole-5-carboxylic a
Figure imgf000265_0003
[00886] Compounds 114B, 114C, and 114 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 114A, 114B, and 114C in lieu of Compounds 86A, 8E, and 1E. Compound 114B: LC-MS (ESI) m/z: 438 [M+H]+. Compound 114C: LC-MS (ESI) m/z: 410 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.32 (s, 3H), 5.28 (s, 2H), 6.74-6.82 (m, 4H), 7.01-7.03 (m, 1H), 7.06-7.09 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H). Compound 114: LC-MS (ESI) m/z: 290 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.09- 7.17 (m, 3H), 7.50 (t, J = 8.4 Hz, 1H).
[00887] Example 115
[00888] Synthesis of 4-(quinolin-3-yloxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2- trifluoroacetate (115)
Figure imgf000266_0001
[00889] Compounds 115B, 115C, and 115 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 115A, 115B, and 115C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 115B: LC-MS (ESI) m/z: 405
[M+H]+. Compound 115C: LC-MS (ESI) m/z: 377 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.56 (s, 3H), 5.41 (s, 2H), 6.73 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.65 (t, J = 6.0 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.71 (d, J = 2.8 Hz, 1H). Compound 115: LC-MS (ESI) m/z: 257 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.62 (t, J = 8.4 Hz, 1H), 7.72 (t, J = 8.4 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 8.90 (d, J = 2.8 Hz, 1H).
[00890] Example 116
[00891] Synthesis of cyclopropyl 4-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)-1H-1,2,3- triazole-5-carboxylate (116)
Figure imgf000266_0002
[00892] Compound 116 was synthesized by employing the procedure described for Compound 19A using Compound 97 in lieu of Compound 9A, LC-MS (ESI) m/z: 300 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.52-1.54 (m, 2H), 1.65-1.67 (m, 2H), 1.77-1.80 (m, 4H), 2.71-2.72 (m, 4H), 4.21-4.23 (m, 1H), 6.63-6.68 (m, 2H), 6.96-6.98 (m, 1H).
[00893] Example 117
[00894] Synthesis of 4-((1,2,3,4-tetrahydronaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (117)
Figure imgf000267_0001
[00895] Compounds 117B, 117C, 117D, and 117 were synthesized by employing the procedures described for Compounds 57C, 90C, 8F, and 1 using Compounds 117A, 117B,
117C, and 117D in lieu of Compounds 57B, 90B, 8E, and 1E. Compound 117B: LC-MS (ESI) m/z: 131 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.75-1.80 (m, 1H), 2.01-2.15 (m, 1H), 2.80-2.94 (m, 2H), 2.95-2.98 (m, 1H), 3.03-3.18 (m, 1H), 4.15-4.21 (m, 1H), 7.07-7.13 (m, 4H). Compound 117C: LC-MS (ESI) m/z: 408 [M+H]+. Compound 117D: LC-MS (ESI) m/z: 380 [M+H]+. Compound 117: LC-MS (ESI) m/z: 260 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.99-2.03 (m, 1H), 2.08-2.15 (m, 1H), 2.73-2.80 (m, 1H), 2.91-2.98 (m, 2H), 3.19-3.25 (m, 1H), 5.06-5.07 (m, 1H), 7.09-7.11 (m, 4H).
[00896] Example 118
[00897] Synthesis of 4-(isoquinolin-7-yloxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2- trifluoroacetate (118)
Figure imgf000267_0002
[00898] Compounds 118B, 118C, and 118 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 118A, 118B, and 118C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 118B: LC-MS: (ESI) m/z: 405
[M+H]+. Compound 118C: LC-MS (ESI) m/z: 377 [M+H]+. Compound 118: LC-MS (ESI) m/z: 257 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.56 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 6.1 Hz, 1H), 9.50 (s, 1H).
[00899] Example 119
[00900] Synthesis of 4-((2-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (119)
Figure imgf000268_0001
[00901] Compounds 119B, 119C, 119D, and 119 were synthesized by employing the procedures described for Compounds 4B, 86B, 8F, and 1 using (4- (trifluoromethoxy)phenyl)boronic acid, Compounds 119A using 1,4-dioxane and H2O as solvent, 119B, 119C, and 119D in lieu of (4-bromophenyl)boronic acid, Compounds 4A using toluene/EtOH/H2O as solvent, 86A, 8E, and 1E. Compound 119B: LC-MS (ESI) m/z: 287 [M- H]-. Compound 119C: LC-MS (ESI) m/z: 548 [M+H]+. Compound 119D: LC-MS (ESI) m/z: 1061 [2M+Na]+. Compound 119: LC-MS (ESI) m/z: 400 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.13 (dd, J = 8.4, 2.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.43-7.48 (m, 3H), 7.55- 7.59 (m, 2H).
[00902] Example 120
[00903] Synthesis of 4-(quinolin-6-yloxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2- trifluoroacetate (120)
Figure imgf000269_0001
[00904] Compounds 120B, 120C, and 120 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 120A, 120B, and 120C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 120B: LC-MS: (ESI) m/z: 405
[M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.05 (t, J = 7.1 Hz, 3H), 3.61 (s, 3H), 4.09-4.21 (m, 2H), 5.41 (s, 2H), 6.63-6.68 (m, 2H), 6.72 (d, J = 2.4 Hz, 1H), 7.13-7.19 (m, 2H), 7.24 (dd, J = 9.0, 2.5 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 8.47 (d, J = 5.8 Hz, 1H), 9.19 (s, 1H). Compound 120C: LC-MS (ESI) m/z: 377 [M+H]+. Compound 120: LC-MS (ESI) m/z: 257 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.55-7.64 (m, 2H), 7.69 (dd, J = 8.8, 2.4 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 8.43 (d, J = 7.7 Hz, 1H), 8.91 (d, J = 2.6 Hz, 1H).
[00905] Example 121
[00906] Synthesis of 4-(isoquinolin-6-yloxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2- trifluoroacetate (121)
Figure imgf000269_0002
[00907] Compounds 121B, 121C, and 121 were synthesized by employing the procedures described for Compounds 86B, 8F, and 1 using Compounds 121A, 121B, and 121Cin lieu of Compounds 86A, 8E, and 1E. Compound 121B: LC-MS: (ESI) m/z: 405 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.05 (t, J = 7.1 Hz, 3H), 3.61 (s, 3H), 4.02-4.27 (m, 2H), 5.42 (s, 2H), 6.60-6.69 (m, 2H), 6.72 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 7.36 (d, J = 5.8 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 8.47 (d, J = 5.8 Hz, 1H), 9.19 (s, 1H). Compound 121C: LC-MS (ESI) m/z: 377 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.55 (s, 3H), 5.51 (s, 2H), 6.69 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 8.8, 2.4 Hz, 1H), 8.19 (t, J = 7.2 Hz, 1H), 8.50 (d, J = 9.1 Hz, 1H), 8.58 (d, J = 6.4 Hz, 1H), 9.75 (s, 1H). Compound 121: LC-MS (ESI) m/z: 257 [M+H]+; 1H-NMR (DMSO- d6, 400 MHz): d (ppm) 7.62 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 6.1 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 8.55 (d, J = 6.2 Hz, 1H), 9.58 (s, 1H). [00908] Example 122
[00909] Synthesis of 5-(4-(quinolin-6-yl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid (122)
Figure imgf000270_0001
[00910] Compounds 122A, 122B, and 122 were synthesized by employing the procedures described for Compounds 8B, 8F, and 1 using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinolone, Intermediate I using Na2CO3 as base and 1,4-dioxane/H2O as solvent, Compounds 122A, and 122B in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 122A: LC-MS (ESI) m/z: 481 [M+H]+. Compound 122B: LC-MS (ESI) m/z: 453 [M+H]+. Compound 122: LC-MS (ESI) m/z: 333
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.23 (dd, J = 2.0, 6.8 Hz, 2H), 7.66 (dd, J = 2.0, 6.8 Hz, 1H), 7.85 (dd, J = 1.6, 6.4 Hz, 2H), 8.11-8.15 (m, 2H), 8.34 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.96 (d, J = 4.8 Hz, 1H).
[00911] Example 123
[00912] Synthesis of 4-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (123)
Figure imgf000271_0001
[00913] To a mixture of 1,2,3,4-tetrahydroisoquinolin-6-ol (Compound 123A) (1.49 g, 10.0 mmol), acetone (3 mL, 50 mmol), and sodium cyanoborohydride (1.26 g, 20 mmol) in methanol (100 mL) was added 60 drops of acetic acid and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 123B. LC-MS (ESI) m/z: 192.
[00914] Compounds 123C, 123D, and 123 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 123B using NMP as solvent, 123C, and 123D in lieu of 4-bromophenol using DMF as solvent, Compounds 8E, and 1E. Compound 123C: LC-MS (ESI) m/z: 451. Compound 123D: LC-MS (ESI) m/z: 423.
Compound 123: LC-MS (ESI) m/z: 303 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.32 (s, 3H), 1.33 (s, 3H), 3.06 (d, J = 2.4 Hz, 2H), 3.30 (s, 1H), 3.62-3.66 (m, 2H), 4.37 (s, 1H), 6.96-7.03 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 9.64 (s, 1H).
[00915] Example 124
[00916] Synthesis of 4-(2-(3,4-dichlorophenyl)thiazol-4-yl)-1H-1,2,3-triazole-5- carboxylic acid (124)
Figure imgf000272_0001
[00917] To a solution of Compound 8B (309 mg, 1.0 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (254 mg, 1.0 mmol) in 1,4-dioxane (5 mL) were successively added Pd2(dba)3 (92 mg, 0.1 mmol), tricyclohexyl phosphine (56 mg, 0.2 mmol) and potassium acetate (196 mg, 2.0 mmol). The mixture was heated at 145 °C in a microwave reactor under nitrogen for 50 minutes. The mixture was allowed to cool down to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 124A, which was used directly for the next step. LC-MS (ESI) m/z: 274 [M-82+H]+.
[00918] Compounds 124B, 124C, and 124 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using Intermediate A, Compounds 124A using K3PO4 as base and DMF/H2O as solvent, 124B, and 124C in lieu of Compounds 4A using Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 124B: LC-MS (ESI) m/z: 489
[M+H]+. Compound 124C: LC-MS (ESI) m/z: 461 [M+H]+. Compound 124: LC-MS (ESI) m/z: 341 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.83 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.77 (s, 1H).
[00919] Example 125
[00920] Synthesis of 4-(3,4-dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid (125)
Figure imgf000273_0001
[00921] Compounds 125A, 125B, and 125 were synthesized by employing the procedures described for Compounds 8B, 8F, and 1 using Intermediate A using Na2CO3 as base and 1,4- dioxane/H2O as solvent, Compounds 125A, and 125B in lieu of Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 125A: LC-MS (ESI) m/z: 406 [M+H]+. Compound 125B: LC-MS (ESI) m/z: 378 [M+H]+. Compound 125: LC-MS (ESI) m/z: 258 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.73 (d, J = 8.4Hz, 1H), 7.97 (s, 1H), 8.31 (s, 1H).
[00922] Example 126
[00923] Synthesis of 4-(4'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (126)
Figure imgf000273_0002
[00924] Compounds 126A, 126B, and 126 were synthesized by employing the procedures described for Compounds 8B, 8F, and 1 using 4'-chlorobiphenyl-4-ylboronic acid using Na2CO3 as base and 1,4-dioxane/H2O as solvent, Compounds 126A, and 126B in lieu of Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 126A: LC-MS (ESI) m/z: 448 [M+H]+. Compound 126B: LC-MS (ESI) m/z: 420 [M+H]+. Compound 126: LC-MS (ESI) m/z: 300 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.54 (d, J = 8.8 Hz, 4H).7.78 (d, J = 8.4 Hz, 4H), 7.85-7.91 (m, 3H).
[00925] Example 127
[00926] Synthesis of 4-(4-(4-chlorophenoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid (127)
Figure imgf000274_0001
[00927] To a suspension of 4-bromophenol (Compound 87A) (5.0 g, 29 mmol), 4- chlorophenylboronic acid (6.8 g, 43.5 mmol), and 4 Å molecular sieves (2.0 g) in
dichloromethane (200 mL) was added Cu(OAc)2 (5.26 g, 29 mmol), pyridine (11.5 g, 145 mmol), and DIPEA (18.7 g, 145 mmol), stirred at room temperature for 12 hours, and filtered. The filtrate was concentrated and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 127A. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 6.86-6.88 (m, 2H), 6.91-6.94 (m, 2H), 7.28-7.30 (m, 2H), 7.42-7.44 (m, 2H).
[00928] To a solution of Compound 127A (660 mg, 2.3 mmol) in anhydrous THF (20 mL) at -78 oC under nitrogen was added a solution of n-BuLi in n-hexane (2.5 M, 1.1 mL, 2.76 mmol) and stirred at -78 oC for 30 minutes. To the solution was added triisopropyl borate (526 mg, 2.76 mmol) and stirred at -78oC for 2 hours. The mixture was quenched with H2O (10 mL), diluted with 10% aqueous HCl solution (10 mL), stirred at room temperature for additional 30 minutes, and extracted with ethyl acetate (50 mL x 3). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give Compound 127B, which was used directly in the next step. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[00929] Compounds 127C, 127D, and 127 were synthesized by employing the procedures described for Compounds 8B, 8F, and 1 using Intermediate A, Compounds 127B using toluene/DMF as solvent, 127C, and 127D in lieu of Compounds 8A, (3,4- dichlorophenyl)boronic acid using DME/H2O as solvent, 8E, and 1E. Compound 127C: LC-MS (ESI) m/z: 464 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.30 (t, J = 7.2 Hz, 3H), 3.77 (s, 3H), 4.31 (q, J = 7.2 Hz, 2H), 5.38 (s, 2H), 6.78 (m, 2H), 6.94-6.97 (m, 2H), 7.01-7.04 (m, 4H), 7.16-7.18 (m, 2H), 7.34-7.36 (m, 2H). Compound 127D: LC-MS (ESI) m/z: 436 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 3.77 (s, 3H), 5.39 (s, 2H), 6.78-6.81 (m, 2H), 6.97-7.05 (m, 6H), 7.19-7.21 (m, 2H), 7.35-7.37 (m, 2H). Compound 127: LC-MS (ESI) m/z: 316 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 7.10-7.13 (m, 4H), 7.46-7.48 (m, 2H), 7.84-7.87 (m, 2H), 13.10 (s, 1H), 15.80 (s, 1H).
[00930] Example 128
[00931] Synthesis of 4-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole- 5-carboxylic acid (128)
Figure imgf000275_0001
[00932] Compounds 128B, 128C, 128D, 128E, and 128 were synthesized by employing the procedures described for Compounds 8B, 27C, 8B, 8F, and 1 using Compounds 128A, 4- (trifluoromethoxy)phenylboronic acid using Na2CO3 as base and toluene/DMF as solvent, 128B, Intermediate A, 128C using Na2CO3 as base and toluene/DMF as solvent, 128D, and 128E in lieu of Compounds 8A, (3,4-dichlorophenyl)boronic acid using Cs2CO3 as base and DME/H2O as solvent, 27B, 8A, (3,4-dichlorophenyl)boronic acid using Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 128B: LC-MS (ESI) m/z: Non-ionizable compound under routeine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.30 (dd, J = 8.8, 1.2 Hz, 2H), 7.43 (dd, J = 6.4, 2.0 Hz, 2H), 7.56-7.60 (m, 4H). Compound 128C: LC-MS (ESI) m/z: Non- ionizable compound under routeine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm), 1.38 (s, 12H), 7.30 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H). Compound 128D: LC-MS (ESI) m/z: 498 [M+H]+. Compound 128E: LC-MS (ESI) m/z: 378 [M+H]+. Compound 128: LC-MS (ESI) m/z: 350 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.39 (d, J = 8.0 Hz, 2H), 7.75-7.82 (m, 4H), 7.97 (d, J = 8.0 Hz, 2H).
[00933] Example 129
[00934] Synthesis of 4-(3',4'-dichloro-[1,1'-biphenyl]-3-yl)-1H-1,2,3-triazole-5- carboxylic acid (129)
Figure imgf000276_0001
[00935] Compounds 129B, 129C, 129D, 129E, and 129 were synthesized by employing the procedures described for Compounds 8B, 27C, 8B, 1, and 8F using Compounds 129A using Na2CO3 as base and toluene/DMF as solvent, 129B, Intermediate A, 129C using Na2CO3 as base and toluene/DMF as solvent, 129D, and 129E in lieu of Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 27B, 8A, 4-dichlorophenyl)boronic acid using Cs2CO3 as base and DME/H2O as solvent, 1E, and 8E. Compound 129B: LC-MS (ESI) m/z: Non-ionizable compound under routeine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.33 (t, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.46-7.49 (m, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H), 7.69 (t, J = 1.6 Hz, 1H). Compound 129C: LC-MS (ESI) m/z: Non-ionizable compound under routeine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm), 1.42 (s, 12H), 7.45-7.51 (m, 3H), 7.64 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 8.00 (s, 1H). Compound 129D: LC-MS (ESI) m/z: 482 [M+H]+. Compound 129E: LC-MS (ESI) m/z: 362 [M+H]+. Compound 129: LC-MS (ESI) m/z: 334 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.57-7.63 (m, 3H), 7.74 (d, J = 8.0 Hz, 1H), 7.87-7.90 (m, 2H), 8.18 (s, 1H).
[00936] Example 130
[00937] Synthesis of 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (130)
Figure imgf000277_0001
[00938] Compounds 130B, 130C, 130D, 130E, and 130 were synthesized by employing the procedures described for Compounds 8B, 127C, 8B, 8F, and 1 using Compounds 130A using K2CO3 as base and DMF/H2O as solvent, 130B, Intermediate A, 130C using Na2CO3 as base and toluene/DMF as solvent, 130D, and 130E in lieu of Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 127B, 8A, (3,4-dichlorophenyl)boronic acid using Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 130B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.15- 7.17 (d, J = 8.0 Hz, 1H), 7.31-7.33 (m, 2H), 7.38-7.40 (m, 2H), 7.45 (dd, J = 8.0, 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H). Compound 130C: LC-MS (ESI) m/z: 267 [M+H]+. Compound 130D: LC-MS (ESI) m/z: 482 [M+H]+. Compound 130E: LC-MS (ESI) m/z: 454 [M+H]+. Compound 130: LC-MS (ESI) m/z: 334 [M+H]+; 1H-NMR (CD3OD, 500 MHz): d (ppm) 7.48-7.49 (m, 5H), 7.94-7.96 (m, 1H), 8.14 (s, 1H).
[00939] Example 131
[00940] Synthesis of 4-(3-(3,4-dichlorophenoxy)phenyl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (131)
Figure imgf000278_0001
[00941] Compounds 131B, 131C, 131D, 131E, and 131 were synthesized by employing the procedures described for Compounds 127B, 127C, 8B, 8F, and 1 using 3,4- dichlorophenylboronic acid, Compounds 131A, 131B, Intermediate A, 131C using toluene/DMF as solvent, 131D, and 131E in lieu of 4-chlorophenylboronic acid, Compounds 127A, 127B, 8A, (3,4-dichlorophenyl)boronic acid using DME/H2O as solvent, 8E, and 1E. Compound 131B: LC- MS (ESI) m/z: Non-ionizable compound under routeine conditions used. Compound 131C: LC- MS (ESI) m/z: 283 [M+H]+. Compound 131D: LC-MS (ESI) m/z: 498 [M+H]+. Compound
131E: LC-MS (ESI) m/z: 470 [M+H]+. Compound 131: LC-MS (ESI) m/z: 350 [M+H]+; 1H- NMR (CD3OD, 400 MHz): d (ppm) 6.89 (dd, J = 8.8, 2.8 Hz, 1H), 7.05 (dd, J = 8.0, 2.0 Hz, 1H), 7.10 (d, J = 3.2 Hz, 1H), 7.38-7.41 (m, 2H), 7.50-7.51 (m, 1H), 7.57-7.59 (m, 1H).
[00942] Example 132
[00943] Synthesis of 4-(6-chloroquinolin-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (132)
Figure imgf000278_0002
[00944] To a mixture of Compound 76A (198 mg, 1.0 mmol) and
tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol,) in xylene (10 mL) was added tributyltin hydride (582 mg, 2.0 mmol) and stirred at 135 oC under nitrogen for 2 hours. After the mixture was cooled down to room temperature, to it was added ethyl 5-bromo-1-(4- methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (340 mg, 1.0 mmol) and
tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol,) and stirred at 120 oC under nitrogen for 4 hours. The mixture was cooled down to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 25% v/v) to afford Compound 132A. LC-MS (ESI) m/z: 423 [M+H]+.
[00945] Compounds 132B and 132 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 132A and 131B in lieu of 8E and 1E. Compound 132B: LC-MS (ESI) m/z: 393 [M-H]-. Compound 132: LC-MS (ESI) m/z: 275
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.92 (d, J = 8.8, 2.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 8.67 (d, J = 8.8 Hz, 1H).
[00946] Example 133
[00947] Synthesis of 4-(6-chloronaphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (133)
Figure imgf000279_0001
[00948] Compounds 133A, 133B, 133C, and 133 were synthesized by employing the procedures described for Compounds 27C, 8B, 1, and 8F using Compounds 56B using DMSO as solvent, Intermediate A, 133A using Na2CO3 as base and 1,4-dioxane/ H2O as solvent, 133B, and 133C in lieu of Compounds 27B using 1,4-dioxane as solvent, 8A, 4-dichlorophenyl)boronic acid using Cs2CO3 as base and DME/H2O as solvent, 1E, and 8E. Compound 133A: LC-MS (ESI) m/z: Non-ionizable compound under routeine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm), 1.30 (s, 12H), 7.30-7.31 (m, 1H), 7.32-7.33 (m, 1H), 7.63-7.79 (m, 3H), 8.25 (s, 1H). Compound 133B: LC-MS (ESI) m/z: 422 [M+H]+. Compound 133C: LC-MS (ESI) m/z: 302 [M+H]+. Compound 133: LC-MS (ESI) m/z: 274 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.56-7.59 (m, 1H), 7.99-7.81 (m, 4H), 8.44 (s, 1H).
[00949] Example 134
[00950] Synthesis of 4-(7-chloroisoquinolin-1-yl)-1H-1,2,3-triazole-5-carboxylic acid (134)
Figure imgf000280_0001
[00951] Compound 134B was synthesized by employing the procedure described for Compound 20C using Compound 134A in lieu of 20B, LC-MS (ESI) m/z: 180 [M+H]+.
[00952] To a solution of Compound 134B (562 mg, 3.12 mmol) in dry DMF (10 mL) was added 4-methylbenzene-1-sulfonyl chloride (3.57 g, 18.73 mmol) and stirred at 80 oC overnight. The mixture was cooled down to room temperature, poured into a saturated aqueous NaHCO3 solution (150 mL), stirred at room temperature for 0.5 hour, and extracted with EtOAc (60 mL x 3). The combined extracts were washed with H2O (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 30% v/v) to afford Compound 134C. LC-MS (ESI) m/z: 180 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 6.51 = 6.8 Hz, 1H), 7.13 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 2 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 10.48 (s, 1H).
[00953] To a solution of Compound 134C (280 mg, 3.12 mmol) in dry toluene (10 mL) was added DMF (1 mL) and SOCl2 (1 mL) and stirred at 80 oC for 3 hours. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 30% v/v) to afford Compound 134D. LC-MS (ESI) m/z: 198 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 7.59 (d, J = 5.6 Hz, 1H), 7.70 (dd, J = 2.4, 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 8.34 (d, J = 1.2 Hz, 1H).
[00954] Compounds 134E, 134F, and 134 were synthesized by employing the procedures described for Compounds 132A, 8F, and 1 using Compounds 134D, 134E, and 134F in lieu of Compounds 76A, 8E, and 1E. Compound 134E: LC-MS (ESI) m/z: 423 [M+H]+. Compound 134F: LC-MS (ESI) m/z: 395 [M+H]+. Compound 134: LC-MS (ESI) m/z: 275 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 7.93 (dd, J = 1.6, 8.8 Hz, 1H), 8.08 (d, J = 5.6 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 8.98 (s, 1H).
[00955] Example 135
[00956] Synthesis of 4-(3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid (135)
Figure imgf000281_0001
[00957] Compounds 135A, 135B, and 135 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using 3-(trifluoromethoxy)phenylboronic acid, Intermediate A using 1,4-dioxane/H2O as solvent, Compounds 135A, and 135B in lieu of (4- bromophenyl)boronic acid, Compounds 4A using toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 135A: LC-MS (ESI) m/z: 422 [M+H]+. Compound 135B: LC-MS (ESI) m/z: 394 [M+H]+. Compound 135: LC-MS (ESI) m/z: 274 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.45 (d, J = 8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.90 (b, 2H).
[00958] Example 136
[00959] Synthesis of 4-(4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid (136)
Figure imgf000281_0002
[00960] Compounds 136A, 136B, and 136 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using 3-(trifluoromethoxy)phenylboronic acid, Intermediate A using 1,4-dioxane/H2O as solvent, Compounds 136A, and 136B in lieu of (4- bromophenyl)boronic acid, Compounds 4A using toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 136A: LC-MS (ESI) m/z: 422 [M+H]+. Compound 136B: LC-MS (ESI) m/z: 394 [M+H]+. Compound 136: LC-MS (ESI) m/z: 274 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.48 (d, J = 8.8 Hz, 2H), 7.95 (s, 2H).
[00961] Example 137
[00962] Synthesis of 4-(4-(cyclopentylmethoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid (137)
Figure imgf000282_0001
[00963] Compounds 137A, 137B, 137C, 137D, and 137 were synthesized by employing the procedures described for Compounds 90C, 27C, 4B, 8F, and 1 using cyclopentylmethanol, Compounds 87A using DEAD as coupling reagent, 137A, 137B, Intermediate A using 1,4- dioxane/H2O as solvent, 137C, and 137D in lieu of Compounds 90B, Intermediate H using DIAD as coupling reagent, 27B, (4-bromophenyl)boronic acid, Compounds 4A using
toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 137A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.32-1.36 (m, 2H), 1.55-1.63 (m, 4H), 1.81-1.83 (m, 2H), 2.32-2.35 (m, 1H), 3.78 (d, J = 6.4 Hz, 2H), 6.76 (dd, J = 2.4, 6.8 Hz, 2H), 7.35 (dd, J = 2.4, 6.8 Hz, 2H). Compound 137B: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.32 (s, 12H), 1.32-1.36 (m, 2H), 1.56-1.64 (m, 4H), 1.81-1.83 (m, 2H), 2.32-2.37 (m, 1H), 3.84 (d, J = 6.8 Hz, 2H), 6.88 (dd, J = 1.6, 6.4 Hz, 2H), 7.72 (dd, J = 1.6, 6.4 Hz, 2H). Compound 137C: LC-MS (ESI) m/z: 436 [M+H]+. Compound 137D: LC-MS (ESI) m/z: 408 [M+H]+. Compound 137: LC-MS (ESI) m/z: 288 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.31-1.38 (m, 2H), 1.51-1.61 (m, 4H), 1.74-1.82 (m, 2H), 2.28-2.34 (m, 1H), 3.90 (dd, J = 7.2 Hz, 2H), 7.0 (dd, J = 2.8, 6 Hz, 2H), 7.71 (dd, J = 2.8, 6 Hz, 2H).
[00964] Example 138
[00965] Synthesis of 4-(4-(cyclopentyloxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid (138)
Figure imgf000283_0001
[00966] Compounds 138A, 138B, 138C, 138D, and 138 were synthesized by employing the procedures described for Compounds 27B, 27C, 4B, 8F, and 1 using bromocyclopentane at room temperature, Compounds 87A, 138A, 138B, Intermediate A using 1,4-dioxane/H2O as solvent, 138C, and 138D in lieu of 2-bromopropane at 90 °C, Compounds 27A, 27B, (4- bromophenyl)boronic acid, 4A using toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 138A: LC-MS (ESI) m/z: 241 [M+H]+, Compound 138B: LC-MS (ESI) m/z: 289 [M+H]+.
Compound 138C: LC-MS (ESI) m/z: 422 [M+H]+. Compound 138D: LC-MS (ESI) m/z: 394 [M+H]+. Compound 138: LC-MS (ESI) m/z: 274 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.57-1.62 (m, 2H).1.70-1.74 (m, 4H), 1.91-1.96 (m, 2H), 4.84-4.87 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 8.05 (s, 2H).
[00967] Example 139
[00968] Synthesis of 4-(2-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (139)
Figure imgf000284_0001
[00969] Compounds 139A, 139B, 139C, 139D, and 139 were synthesized by employing the procedures described for Compounds 8B, 27C, 4B, 8F, and 1 using 4- (trifluoromethoxy)phenylboronic acid, Compounds 130A using K2CO3 as base and 1,4- dioxane/H2O as solvent, 139A, Intermediate A, 139B using 1,4-dioxane/H2O as solvent, 139C, and 139D in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 27B, 4A, (4-bromophenyl)boronic acid using toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 139A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 7.28-7.31 (m, 3H), 7.55 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H). Compound 139B: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used. Compound 139C: LC-MS (ESI) m/z: 532 [M+H]+. Compound 139D: LC-MS (ESI) m/z: 504 [M+H]+. Compound 139: LC-MS (ESI) m/z: 384 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.49 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 5.6 Hz, 1H), 7.92 (d, J = 8.8 Hz, 3H).
[00970] Example 140
[00971] Synthesis of 4-(3,4-dihydronaphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (140)
Figure imgf000285_0001
[00972] To a mixture of 3,4-dihydronaphthalen-2(1H)-one (Compound 140A) (1.5 g, 10.3 mmol) in THF (100 mL) was added t-BuOK (2.31 g, 20.6 mmol) at -20 °C under nitrogen and stirred at room temperature for 1 hour. To the mixture was added a solution of 1,1,1-trifluoro-N- phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (5.52 g, 15.5 mmol) in dry THF (10 mL) in one portion at -20 °C and stirred at room temperature for 4 hours. It was quenched with a saturated aqueous NH4Cl solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (petroleum ether, 100% v/v) to give Compound 140B. LC-MS (ESI) m/z: 279
[M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.71 (t, J = 7.2 Hz, 2H), 3.07 (t, J = 7.2 Hz, 2H), 6.49 (s, 1H), 7.08-7.10 (m, 1H), 7.14-7.16 (m, 1H), 7.20-7.22 (m, 2H).
[00973] Compounds 140C, 140D, 140E, and 140 were synthesized by employing the procedures described for Compounds 27C, 8B, 8F, and 1 using Compounds 140B using DMSO as solvent, Intermediate A, 140C using 1,4-dioxane/H2O as solvent, 140D, and 140E in lieu of Compounds 27B using 1,4-dioxane/H2O as solvent, 8A, (4-bromophenyl)boronic acid using toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 140C: LC-MS (ESI) m/z: 257 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.22 (s, 12H), 2.41 (t, J = 7.2 Hz, 2H), 2.76 (t, J = 7.2 Hz, 2H), 7.12-7.13 (m, 2H), 7.15-7.18 (m, 3H). Compound 140D: LC-MS (ESI) m/z: 390 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.38 (t, J = 7.2 Hz, 3H), 2.36 (t, J = 7.2 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H), 3.79 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 5.51 (s, 2H), 6.42 (s, 1H), 6.81-6.83 (m, 2H), 7.01-7.04 (m, 1H), 7.12-7.15 (m, 2H), 7.17-7.23 (m, 3H). Compound 140E: LC-MS (ESI) m/z: 362 [M+H]+. Compound 140: LC-MS (ESI) m/z: 242 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.70-2.71 (m, 2H), 2.86-2.90 (m, 2H), 7.18-7.30 (m, 5H), 13.13 (s, 1H), 15.60 (s, 1H).
[00974] Example 141
[00975] Synthesis of 4-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (141)
Figure imgf000286_0001
[00976] To a mixture of Compound 140 (40 mg, 0.17 mmol) in ethyl acetate (20 mL) was added 10% Pd/C (20 mg) and stirred at room temperature under hydrogen (1 atm) overnight. The mixture was filtered and filtration was concentrated. The residue was purified with preparative HPLC to afford Compound 141. LC-MS (ESI) m/z: 244 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.94-1.99 (m, 1H), 2.08-2.10 (m, 1H), 2.89-2.92 (m, 2H), 2.92-3.04 (m, 2H), 3.60-3.62 (m, 1H), 7.08-7.12 (m, 4H), 13.12 (s, 1H), 15.22 (s, 1H).
[00977] Example 142
[00978] Synthesis of 4-(1-isopropyl-1,2,3,4-tetrahydroquinolin-7-yl)-1H-1,2,3- t
Figure imgf000286_0002
[00979] Compounds 142B, 142C, 142D, 142E, and 142 were synthesized by employing the procedures described for Compounds 63A, 27C, 8B, 8F, and 1 using 2-iodopropane, Compounds 142A using K2CO3 as base, 142B, Intermediate A, 142C using 1,4-dioxane/H2O as solvent, 142D, and 142E in lieu of iodomethane, Compounds 61F using using Cs2CO3 as base, 27B, 8A, (4-bromophenyl)boronic acid using toluene/EtOH/H2O as solvent, 8E, and 1E.
Compound 142B: LC-MS (ESI) m/z: 254 [M+H]+. Compound 142C: LC-MS (ESI) m/z: 302 [M+H]+; 260 [M+CH3CN]+. Compound 142D: LC-MS (ESI) m/z: 435 [M+H]+. Compound 142E: LC-MS (ESI) m/z: 407 [M+H]+. Compound 142: LC-MS (ESI) m/z: 287 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.14(d, J = 6.4 Hz, 6H), 1.82-1.85 (m, 2H), 2.69 (t, J = 6 Hz, 2H), 3.15 (t, J = 6 Hz, 2H), 4.06-4.10 (m, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H).
[00980] Example 143
[00981] Synthesis of 4-(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (143)
Figure imgf000287_0001
[00982] Compounds 143B, 143C, 143D, 143E, and 143 were synthesized by employing the procedures described for Compounds 63A, 27C, 8B, 8F, and 1 using 2-iodopropane, Compounds 143A using K2CO3 as base and acetonitrile as solvent, 143B, Intermediate A, 143C using 1,4-dioxane/H2O as solvent, 143D, and 143E in lieu of iodomethane, Compounds 61F using Cs2CO3 as base, 27B, 8A, (4-bromophenyl)boronic acid using toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 143B: LC-MS (ESI) m/z: 254 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.13 (d, J = 6.4 Hz, 6H), 2.74 (t, J = 6.4 Hz, 2H), 2.85-2.93 (m, 3H), 3.65 (s, 2H), 6.99 (d, J = 8.0 Hz, 1H), 7.20-7.23 (m, 2H). Compound 143C: LC-MS (ESI) m/z: 302 [M+H]+. Compound 143D: LC-MS (ESI) m/z: 435 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.17 (d, J = 6.8 Hz, 6H), 1.28 (t, J = 6.8 Hz, 3H), 2.80 (t, J = 5.6 Hz, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.91-2.97 (m, 1H), 3.7-3.79 (m, 5H), 4.30 (q, J = 6.8 Hz, 2H), 5.31 (s, 2H), 6.77-6.79 (m, 2H), 6.89 (s, 1H), 6.95-6.99 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H). Compound 143E: LC-MS (ESI) m/z: 407
[M+H]+. Compound 143: LC-MS (ESI) m/z: 287 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.35 (d, J = 8.4 Hz, 6H), 3.10-3.37 (m, 3H), 3.65-3.71 (m, 2H), 4.46-4.47 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.60-7.70 (m, 2H), 9.72 (bs, 1H).
[00983] Example 144
[00984] Synthesis of 4-(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (144)
Figure imgf000288_0001
[00985] Compounds 144B, 144C, 144D, 144E, and 144 were synthesized by employing the procedures described for Compounds 63A, 27C, 8B, 8F, and 1 using 2-iodopropane, Compounds 144A using K2CO3 as base and acetonitrile as solvent, 144B, Intermediate A, 144C using K2CO3 as base and 1,4-dioxane/H2O as solvent, 144D, and 144E in lieu of iodomethane, Compounds 61F using Cs2CO3 as base, 27B, 8A, (4-bromophenyl)boronic acid using Cs2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 144B: LC-MS (ESI) m/z: 254 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.13 (d, J = 6.8 Hz, 6H), 2.74-2.77 (m, 2H), 2.81-2.84 (m, 2H), 2.86-2.93 (m, 1H), 3.68 (s, 2H), 6.96 (d, J = 8.0 Hz, 1H), 7.18-7.23 (m, 2H). Compound 144C: LC-MS (ESI) m/z: 302 [M+H]+. Compound 144D: LC-MS (ESI) m/z: 435 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d 1.15 (d, J = 6.8 Hz, 6H), 1.28 (t, J = 7.2 Hz, 3H), 2.81 (t, J = 6.0 Hz, 2H), 2.89-2.98 (m, 3H), 3.68 (s, 2H), 3.78 (s, 3H), 4.30 (q, J = 7.2 Hz, 2H), 5.31 (s, 2H), 6.77- 6.82 (m, 3H), 6.96-7.00 (m, 3H), 7.18 (d, J = 8.0 Hz, 1H). Compound 144E: LC-MS (ESI) m/z: 407 [M+H]+. Compound 144: LC-MS (ESI) m/z: 287 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.35 (d, J = 8.4 Hz, 6H), 3.10-3.24 (m, 2H), 3.34-3.38 (m, 1H), 3.64-3.71 (m, 2H), 4.46 (s, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.69-7.74 (m, 2H), 10.02 (bs, 1H).
[00986] Example 145
[00987] Synthesis of 4-(5-(trifluoromethoxy)pyridin-2-yl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (145)
Figure imgf000289_0001
[00988] Compounds 145B, 145C, and 145 were synthesized by employing the procedures described for Compounds 132A, 8F, and 1 using Compounds 145A, 145B, and 145C in lieu of Compounds 76A, 8E, and 1E. Compound 145B: LC-MS (ESI) m/z: 423 [M+H]+. Compound 145C: LC-MS (ESI) m/z: 395 [M+H]+. Compound 145: LC-MS (ESI) m/z: 275 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 8.21 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.67 (s, 1H).
[00989] Example 146
[00990] Synthesis of 4-(3-(4-chlorophenyl)pyrrolidine-1-carbonyl)-1H-1,2,3-triazole- 5-carboxylic acid (146)
Figure imgf000289_0002
[00991] A mixture of Intermediate J (200 mg, 0.66 mmol), Compound 146A, 3-(4- chlorophenyl)pyrrolidine, (143 mg, 0.79 mmol), HATU (380 mg, 1 mmol), and DIPEA ( 258 mg, 2 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc (50 mL), washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with preparative HPLC give Compound 146B. LC-MS (ESI) m/z: 469 [M +H]+. [00992] Compounds 146C and 146 were synthesized by employing the procedures described for Compounds 1 and 2 using Compounds 146B and Compound 146C in lieu of Compounds 1E and 1. Compound 146C: LC-MS (ESI) m/z: 349 [M+H]+. Compound 146: LC- MS (ESI) m/z: 321 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.10-2.20 (m, 1H), 2.38- 2.47 (m, 1H), 3.53-3.63 (m, 1H), 3.66-3.81 (m, 2H), 3.99-4.44 (m, 2H), 7.32-7.37 (m, 4H).
[00993] Example 147
[00994] Synthesis of 4-(5-chloroisoindoline-2-carbonyl)-1H-1,2,3-triazole-5- carboxylic acid (147)
Figure imgf000290_0001
[00995] Compounds 147B, 147C, and 147 were synthesized by employing the procedures described for Compounds 146B, 1, and 8F using Compounds 147A using DMF as solvent, 147B, and 147C in lieu of Compounds 146A using dichloromethane as solvent, 1E, and 8E. Compound 147B: LC-MS (ESI) m/z: 441 [M+H]+. Compound 147C: LC-MS (ESI) m/z: 321 [M+H]+.
Compound 147: LC-MS (ESI) m/z: 293 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.91- 4.93 (m, 2H), 5.37-5.40 (m, 2H), 7.36-7.39 (m, 1H), 7.43-7.47 (m, 1H), 7.52-7.54 (m, 1H).
[00996] Example 148
[00997] Synthesis of 4-(5-chloroindoline-1-carbonyl)-1H-1,2,3-triazole-5-carboxylic acid (148)
Figure imgf000290_0002
[00998] Compounds 148B, 148C, and 148 were synthesized by employing the procedures described for Compounds 146B, 1, and 8F using Compounds 148A, 148B, and 148C in lieu of Compounds 146A, 1E, and 8E. Compound 147B: LC-MS (ESI) m/z: 441 [M+H]+. Compound 148C: LC-MS (ESI) m/z: 321 [M+H]+. Compound 148: LC-MS (ESI) m/z: 293 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 3.11 (t, J = 8.0 Hz, 2H), 4.23-4.25 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H).
[00999] Example 149
[001000] Synthesis of 4-(3-(2,4-dichlorophenyl)pyrrolidine-1-carbonyl)-1H-1,2,3- t
Figure imgf000291_0001
Figure imgf000291_0002
[001001] Compounds 149B and 149C were synthesized by employing the procedures described for Compounds 140B and 4B using Compound 149A using LiHMDS as base at - 78 °C, 149B using Et3N as base and DMF as solvent, and 2,4-dichlorophenylboronic acid in lieu of Compound 140A using tBuOK as base at -20 °C, 4A using Na2CO3 as base and
toluene/EtOH/H2O as solvent, and (4-bromophenyl)boronic acid. Compound 149B: LC-MS (ESI) m/z: 262 [M-55]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (s, 9H), 2.85-3.00 (m, 2H), 3.78 -3.90 (m, 2H), 6.66-6.81 (m, 1H). Compound 149C: LC-MS (ESI) m/z: 258 [M-55]+.
[001002] A mixture of Compound 149C (300 mg, 1 mmol) and HCl solution in EtOAc (3 M, 5 mL) was stirred at room temperature for 16 hours. The mixture was concentrated and purified with flash column chromatography on silica gel (methanol in ethyl acetate, 10% v/v) to afford Compound 149D. LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used.
[001003] A mixture of Compound 149D (100 mg, 1 mmol) and PtO2 (50 mg) in MeOH (5 mL) was stirred at room temperature under hydrogen (1 atm.) for 16 hours. The mixture was filtered and the filtrate was concentrated to give Compound 149E. LC-MS (ESI) m/z: 216
[M+H]+.
[001004] Compounds 149F, 149G, and 149 were synthesized by employing the procedures described for Compounds 146B, 1, and 8F using Compounds 149E using dichloromethane as solvent, 149F, and 149G in lieu of Compounds 146A using DMF as solvent, 1E, and 8E.
Compound 149F: LC-MS (ESI) m/z: 503 [M+H]+. Compounds 149G: LC-MS (ESI) m/z: 383 [M+H]+. Compounds 149: LC-MS (ESI) m/z: 355 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.00-2.40 (m, 2H), 3.62-4.15 (m, 5H), 7.32-7.40 (m, 1H), 7.45-7.51 (m, 2H).
[001005] Example 150
[001006] Synthesis of 4-(3-(3,4-dichlorophenyl)pyrrolidine-1-carbonyl)-1H-1,2,3- triazole-5-carboxylic acid (150)
Figure imgf000292_0001
[001007] Compounds 150A, 150B, 150C, 150D, 150E, and 150 were synthesized by employing the procedures described for Compounds 4B, 149D, 149E, 146B, 1, and 8F using 3,4-dichlorophenylboronic acid, Compounds 149B using Et3N as base and DMF as solvent, 150A, 150B, 150C using dichloromethane as solvent, 150D, and 150E in lieu of (4- bromophenyl)boronic acid, Compounds 4A using Na2CO3 as base and toluene/EtOH/H2O as solvent, 149C, 149D, 146A using DMF as solvent, 1E, and 8E. Compound 150A: LC-MS (ESI) m/z: 258 [M-55]+. Compound 150B: LC-MS (ESI) m/z: 214 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 4.28-4.30 (m, 2H), 4.45-4.47 (m, 2H), 6.47 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H) , 7.57 (d, J = 8.0 Hz, 1H), 7.71(d, J = 2.0 Hz, 1H). Compound 150C: LC-MS (ESI) m/z: 216 [M+H]+. Compound 150D: LC-MS (ESI) m/z: 503 [M+H]+. Compound 150E: LC-MS (ESI) m/z: 383 [M+H]+. Compound 150: LC-MS (ESI) m/z: 355 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.00-2.11 (m, 1H), 2.27-2.44 (m, 1H), 3.54-4.17 (m, 5H), 7.25-7.34 (m, 1H), 7.45-7.56 (m, 2H). [001008] Example 151
[001009] Synthesis of 4-((5-chloroisoindolin-2-yl)methyl)-1H-1,2,3-triazole-5- carboxylic acid (151)
Figure imgf000293_0001
[001010] To a solution of Intermediate C-1 (3.34 g, 40 mmol) and paraformaldehyde (1.44 g, 48 mmol) in DMSO (20 mL) was added a solution of trimethylbenzylammonium hydroxide (0.668 g, 4 mmol) in DMSO (20 mL) over 10 minutes. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethylacetate/hexane (1:3 in volume, 100 mL x 3). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column
chromatography on silica gel using ethyl acetate- hexane eluent to afford Compound 151A. LC- MS (ESI) m/z: 145 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 5.49 (s, 2H), 4.97 (t, J = 1.6 Hz, 1H), 4.56 (d, J = 1.2 Hz, 2H), 3.72 (s, 3H).
[001011] A mixture of Compound 151A (340 mg, 2.36 mmol) and 1-(azidomethyl)-4- methoxybenzene (500 mg, 3.07 mmol) in toluene (15 mL) was stirred at 110 oC for 48 hours. The reaction mixture was concentrated and purified by column chromatography on silica gel using ethyl acetate- hexane as eluent to afford a Mixture 151B. LC-MS (ESI) m/z: 278 [M+H]+.
[001012] A Mixture 151B (60 mg, 0.217 mmol) and thionyl chloride (0.45 mL) in methylene chloride (10 mL) was stirred at 50 oC for 5 hours. The reaction mixture was concentrated to give 151C, which was used directly in the next step without further purification. LC-MS (ESI) m/z: 296 [M+H]+. [001013] A Mixture 151C (74 mg, 0.217 mmol), 5-chloroisoindoline (38 mg, 0.248 mmol), and K2CO3 (60 mg, 0.435 mmol) in DMF (6 mL) was stirred at 60 oC for 5 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with preparative HPLC to afford a Mixture 151D. LC- MS (ESI) m/z: 413 [M+H]+.
[001014] Mixture 151E and Compound 151 were synthesized by employing the procedures described for Compounds 8F and 1 using Mixtures 151D and 151E in lieu of Compounds 8E and 1E. Mixture 151E: LC-MS (ESI) m/z: 399. Compound 151: LC-MS (ESI) m/z: 279 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 4.80 (s, 2H), 4.81 (s, 2H), 4.97 (s, 2H), 7.38-7.40 (m, 1H), 7.42-7.46 (m, 2H).
[001015] Example 152
[001016] Synthesis of 4-(((4-chloronaphthalen-1-yl)methyl)thio)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (152)
Figure imgf000294_0001
[001017] To a mixture of 1-methylnaphthalene (Compound 152A) (1.46 g, 10 mmol) and SnCl4 (5.2 g, 20 mmol) in dichloromethane (40 mL) was added Pb(OAc)4 (4.4 g, 10 mmol) at 0 oC and stirred at room temperature overnight. The mixture was diluted with Et2O (80 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified with reverse phase chromatography using eluent (methanol in water, 60% v/v) to afford Compound 152B. LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.66 (s, 3H), 7.20-7.24 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.56-7.60 (m, 2H), 7.98 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H).
[001018] To a mixture of Compound 152B (1.76 g, 10 mmol) and N-Bromosuccinimide (1.94 g, 11 mmol) in carbon tetrachloride (40 mL) was added BPO (50 mg) at 0 oC and heated at reflux overnight. The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to afford Compound 152C. LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.93 (s, 2H), 7.45-7.51 (m, 2H), 7.65-7.69 (m, 2H), 8.16 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H).
[001019] Compounds 152D, 152E, and 152 were synthesized by employing the procedures described for Compounds 35D, 8F, and 1 using Compounds 152C, 152D, and 152E in lieu of Compounds 35C, 8E, and 1E. Compound 152D: LC-MS (ESI) m/z: 468 [M+H]+. Compound 152E: LC-MS (ESI) m/z: 440 [M+H]+. Compound 152: LC-MS (ESI) m/z: 320 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 4.85 (s, 2H), 7.58-7.65 (m, 2H), 7.71-7.74 (m, 2H), 8.23- 8.29 (m, 2H).
[001020] Example 153
[001021] Synthesis of 4-((3,5-dichlorophenyl)amino)-1H-1,2,3-triazole-5-carboxylic acid (153)
Figure imgf000295_0001
[001022] Compounds 153B, 153C, and 153 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 153A using K3PO4 as base, 153B, and 153C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 153B: LC-MS (ESI) m/z: 421 [M+H]+. Compound 153C: LC-MS (ESI) m/z: 301 [M+H]+. Compound 153: LC-MS (ESI) m/z: 273 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 6.93-6.94 (m, 1H), 7.64-7.65 (m, 2H), 9.26 (brs, 1H).
[001023] Example 154 [001024] Synthesis of 4-((2,5-dichlorophenyl)amino)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (154)
Figure imgf000296_0001
[001025] Compounds 154B, 154C, and 154 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 154A using K3PO4 as base, 154B, and 154C in lieu of Compounds 6A, 1-methylpiperazine using t-BuONa as base, 8E, and 1E. Compound 154B: LC-MS (ESI) m/z: 421 [M+H]+. Compound 154C: LC-MS (ESI) m/z: 301 [M+H]+. Compound 154: LC-MS (ESI) m/z: 273 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.01 (dd, J1 = 4.0 Hz, J2 = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.85 (s, 1H).
[001026] Example 155
[001027] Synthesis of 4-((3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)- 1H-1,2,3-triazole-5-carboxylic acid (155)
Figure imgf000296_0002
[001028] Compounds 155B, 155C, 155D, and 155 were synthesized by employing the procedures described for Compounds 4B, 6B, 1, and 8F using 4-aminophenylboronic acid, Compounds 155A, Intermediate A, 155B using K3PO4 as base, 155C, and 155D in lieu of (4- bromophenyl)boronic acid, Compounds 4A, 6A, 1-methylpiperazine using t-BuONa as base, 1E, and 8E. Compound 155B: LC-MS (ESI) m/z: 288 [M+H]+. Compound 155C: LC-MS (ESI) m/z: 547 [M+H]+. Compound 155D: LC-MS (ESI) m/z: 427 [M+H]+. Compound 155: LC-MS (ESI) m/z: 399 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 7.59-7.61 (m, 1H), 7.70-7.71 (m, 5H), 7.95-7.96 (m, 1H), 8.36 (brs, 1H), 13.40 (brs, 1H), 14.97 (brs, 1H).
[001029] Example 156
[001030] Synthesis of 4-((3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (156)
Figure imgf000297_0001
[001031] Compounds 156B, 156C, 156D, and 156 were synthesized by employing the procedures described for Compounds 8B, Intermediate I, 8F, and 1 using 4- hydroxyphenylboronic acid, Compounds 32A using K2CO3 as base and 1,4-dioxane/H2O as solvent, 156A, 156B, and 156C in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 4-bromophenol, 8E, and 1E. Compound 156B: LC-MS (ESI) m/z: 287 [M-H]-. Compound 156C: LC-MS (ESI) m/z: 548 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.13, 1.41 (t, J = 7.2 Hz, 3H), 3.73, 3.75 (s, 3H), 4.20, 4.43 (q, J = 7.2 Hz, 2H), 5.38, 5.54 (s, 2H), 6.75-6.88 (m, 4H), 7.19-7.27 (m, 3H), 7.38-7.60 (m, 4H).
Compound 156D: LC-MS (ESI) m/z: 518 [M-H]-. Compound 156: LC-MS (ESI) m/z: 400
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.15-7.19 (m, 2H), 7.63 (dd, J = 1.2, 8.8 Hz, 1H), 7.72-7.77 (m, 3H), 7.98 (d, J = 2 Hz, 1H), 13.34 (b, 1H), 15.32 (b, 1H).
[001032] Example 157
[001033] Synthesis of 4-((3'-(piperidine-1-carbonyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (157)
Figure imgf000298_0001
[001034] To a mixture of 3-bromobenzoyl chloride (Compound 157A) (1.09 g, 5 mmol) and DIPEA (3.22 g, 25 mol) in dichloromethane (10 mL) was added piperidine (2.12 g, 25 mmol) at -10 oC and stirred at room temperature for 2 hours. The mixture was washed successively with an aqueous HCl solution (1N, 20 mL), water (10 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 157B. LC-MS (ESI) m/z: 268 [M+H]+.
[001035] Compounds 157C, 157D, 157E, and 157 were synthesized by employing the procedures described for Compounds 27C, 4B, 8F, and 1 using Compounds 157B, Intermediate I, 157C using 1,4-dioxane/H2O as solvent, 157D, and 157E in lieu of Compounds 27B, 4A, (4- bromophenyl)boronic acid using toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 157C: LC-MS (ESI) m/z: 316 [M+H]+. Compound 157D: LC-MS (ESI) m/z: 541[M+H]+. Compound 157E: LC-MS (ESI) m/z: 513 [M+H]+. Compound 157: LC-MS (ESI) m/z: 393 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm)1.47-1.60 (m, 6H), 3.29 (s, 2H), 3.59 (s, 2H), 7.15 (d, J = 4.4 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.68-7.72 (m, 3H), 13.21 (s, 1H), 15.30 (s, 1H).
[001036] Example 158
[001037] Synthesis of 4-(((6-chloronaphthalen-2-yl)oxy)methyl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (158)
Figure imgf000299_0001
158D 158
[001038] To a mixture of Intermediate A (3.39 g, 10 mmol) in anhydrous THF (100 mL) was added a solution of n-BuLi in hexane (2.5 M, 4.0 mL, 10 mmol) at -78 °C under nitrogen and stirred at -78 °C for 10 minutes. To the mixture was added DMF (730 mg, 100 mmol) and stirred at -78 °C for 1 hour. It was quenched with a saturated aqueous NH4Cl solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to give Compound 158A. LC-MS (ESI) m/z: 290 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.45 (t, J = 7.2 Hz, 3H), 3.78 (s, 3H), 4.50 (q, J = 7.2 Hz, 2H), 5.86 (s, 2H), 6.84 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 8.8 Hz, 2H), 10.48 (s, 1H).
[001039] Compounds 158B, 158C, 158D, and 158 were synthesized by employing the procedures described for Compounds 57C, 90C, 8F, and 1 using Compounds 158A using EtOAc as solvent, 158B using DEAD, 106F, 158C, and 158D in lieu of Compounds 57B using MeOH as solvent, 90B using DIAD, Intermediate H, 8E, and 1E. Compound 158B: LC-MS (ESI) m/z: 292 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.45 (t, J = 7.2 Hz, 3H), 3.80-3.84 (m, 4H), 4.47 (q, J = 7.2 Hz, 2H), 4.79 (d, J = 6.8 Hz, 2H), 5.58 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H). Compound 158C: LC-MS (ESI) m/z: 452 [M+H]+. Compound 158D: LC-MS (ESI) m/z: 424 [M+H]+. Compound 158: LC-MS (ESI) m/z: 304 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.49 (s, 2H), 7.28 (dd, J = 8.8, 2.4 Hz, 1H), 7.49 (dd, J = 8.8, 2.4 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.8, 2.4 Hz, 2H), 7.98 (d, J = 2.0 Hz, 1H). [001040] Example 159
[001041] Synthesis of 4-((4-chloronaphthalen-1-yl)methoxy)-1H-1,2,3-triazole-5- carboxylic acid formate (159)
Figure imgf000300_0001
[001042] Compounds 159A, 159B, and 159 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 152C, 159A, and 159B in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 159A: LC-MS (ESI) m/z: 452
[M+H]+. Compound 159B: LC-MS (ESI) m/z: 424 [M+H]+. Compound 159: LC-MS (ESI) m/z: 302 [M-H]-; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 6.20 (s, 2H), 7.00-7.07 (m, 1H), 7.61-7.80 (m, 3H), 8.12 (s, 1H), 8.24-8.27 (m, 1H), 8.35-8.41 (m, 1H).
[001043] Example 160
[001044] Synthesis of 4-((3'-(piperidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (160)
Figure imgf000300_0002
[001045] Compound 160A was synthesized by employing the procedure described for Compound 4B using 3-formylphenylboronic acid and Intermediate I in lieu of (4- bromophenyl)boronic acid and Compound 4A, LC-MS (ESI) m/z: 458 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.93 (t, J = 7.2 Hz, 3H), 3.67 (s, 3H), 4.01-4.07 (m, 2H), 5.47 (s, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.66-7.71 (m, 3H), 7.88 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 10.08 (s, 1H).
[001046] A mixture of Compound 160A (160 mg, 0.35 mmol), piperidine (36 mg, 0.42 mol) and anhydrous magnesium sulfate (500 mg) in dichloromethane (10 mL) was stirred at 20 oC under nitrogen for 0.5 hour. To the mixture was added NaBH3CN (26 mg, 0.42 mol) and stirred at 20 °C for 15 hours. It was filtered and the filtrate was concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 60% v/v) to give Compound 160B. LC-MS (ESI) m/z: 527 [M+H]+.
[001047] Compounds 160C and 160 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 160B and 160C in lieu of Compounds 8E and 1E. Compound 160C: LC-MS (ESI) m/z: 499 [M+H]+. Compound 160: LC-MS (ESI) m/z: 379 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)1.33-1.42 (m, 1H), 1.57-1.70 (m, 3H), 1.81-1.84 (m, 2H), 2.87 (s, 2H), 3.34-3.37 (m, 2H), 4.34 (s, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 9.45 (s, 1H), 13.23 (s, 1H), 15.30 (s, 1H).
[001048] Example 161
[001049] Synthesis of 4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (161)
Figure imgf000301_0001
[001050] Compounds 161A, 161B, and 161 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using 4-(trifluoromethyl)phenylboronic acid,
Intermediate I using K2CO3 as base and 1,4-dioxane/H2O as solvent, Compounds 161A, and 161B in lieu of (4-bromophenyl)boronic acid, Compounds 4A using Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 161A: LC-MS (ESI) m/z: 498 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.13 (t, J = 7.2 Hz, 3H), 3.73 (s, 3H), 4.21 (q, J = 7.2 Hz, 2H), 5.39 (s, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H). Compound 161B: LC-MS (ESI) m/z: 492 [M+Na]+. Compound 161: LC-MS (ESI) m/z: 350 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.20 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H).
[001051] Example 162
[001052] Synthesis of 4-((3'-(cyclopentyloxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (162)
Figure imgf000302_0001
[001053] Compounds 162A, 162B, 162C, 162D, and 162 were synthesized by employing the procedures described for Compounds 27B, 27C, 8B, 8F, and 1 using bromocyclopentane, Compounds 131A, 162A, 162B, Intermediate I using Na2CO3 as base and 1,4-dioxane/H2O as solvent, 162C, and 162D in lieu of 2-bromopropane, Compounds 27A, 27B, (4- bromophenyl)boronic acid, 8A using Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 162A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 162B: LC-MS (ESI) m/z: 289 [M+H]+. Compound 162C: LC-MS (ESI) m/z: 514 [M+H]+. Compound 162D: LC-MS (ESI) m/z: 486 [M+H]+. Compound 162: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.59-1.75 (m, 6H), 1.92-1.95 (m, 2H), 4.90-4.91 (m, 1H), 6.88 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.10-7.18 (m, 4H), 7.34 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H).
[001054] Example 163 [001055] Synthesis of 4-((4'-chloro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (163)
Figure imgf000303_0001
[001056] Compounds 163A, 163B, 163C, and 163 were synthesized by employing the procedures described for Compounds 8B, Intermediate I, 8F, and 1 using 4- hydroxyphenylboronic acid, Compounds 30B using K2CO3 as base and 1,4-dioxane/H2O as solvent, 163A, 163B, and 163C in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 4-bromophenol, 8E, and 1E. Compound 163A: LC-MS (ESI) m/z: 287 [M-H]-. Compound 163B: LC-MS (ESI) m/z: 548 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.15 (t, J = 7.2 Hz, 3H), 3.73 (s, 3H), 4.21 (q, J = 7.2 Hz, 2H), 5.38 (s, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.37-7.45 (m, 4H), 7.53 (d, J = 8.4 Hz, 1H). Compound 163C: LC-MS (ESI) m/z: 518 [M-H]-. Compound 163: LC-MS (ESI) m/z: 400 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.18 (d, J = 8.8 Hz, 2H), 7.73-7.76 (m, 4H), 7.82 (s, 1H).
[001057] Example 164
[001058] Synthesis of 4-((3'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (164)
Figure imgf000304_0001
[001059] Compounds 164B, 164C, 164D, and 164 were synthesized by employing the procedures described for Compounds 27C, 4B, 8F, and 1 using Compounds 164A, 164B, Intermediate F using K3PO4 as base and DME/H2O as solvent, 164C, and 164D in lieu of Compounds 27B, (4-bromophenyl)boronic acid, 4A using Na2CO3 as base and
toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 164B: LC-MS (ESI) m/z: 288 [M+H]+. Compound 164C: LC-MS (ESI) m/z: 529 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.24-1.28 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.70-1.74 (m, 4H), 3.19-3.22 (m, 4H), 3.71 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H), 5.56 (s, 2H), 6.75 (d, J = 8.8 Hz, 2H), 6.92-6.96 (m, 2H), 7.04-7.07 (m, 3H), 7.15 (d, J = 8.8 Hz, 2H), 7.28-7.31 (m, 1H), 7.40 (d, J = 8.4 Hz, 2H). Compound 164D: LC-MS (ESI) m/z: 499 [M-H]-. Compound 164: LC-MS (ESI) m/z: 381 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.54-1.57 (m, 2H), 1.64-1.66 (m, 4H), 3.23-3.25 (m, 4H), 7.01-7.10 (m, 2H), 7.20-7.23 (m, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 13.53 (bs, 1H), 15.81 (bs, 1H).
[001060] Example 165
[001061] Synthesis of 4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (165)
Figure imgf000305_0001
[001062] Compounds 165A, 165B, 165C, and 165 were synthesized by employing the procedures described for Compounds 8B, Intermediate I, 8F, and 1 using Compounds 87A using Na2CO3 as base and 1,4-dioxane/H2O as solvent, 165A, 165B, and 165C in lieu of Compounds 8A using Cs2CO3 as base and DME/H2O as solvent, 4-bromophenol, 8E, and 1E. Compound 165A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 6.89- 6.92 (m, 2H), 7.33- 7.36 (m, 1H), 7.41-7.47 (m, 3H), 7.61 (d, J = 2.4 Hz, 1H). Compound 165B: LC-MS (ESI) m/z: 498 [M+H]+. Compound 163C: LC-MS (ESI) m/z: 470 [M+H]+. Compound 165: LC-MS (ESI) m/z: 350 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.14 (d, J = 8.8 Hz, 2H), 7.63-7.66 (m, 1H), 7.68- 7.73 (m, 3H), 7.91 (d, J = 2.0 Hz, 1H).
[001063] Example 166
[001064] Synthesis of 4-((3,4-dichlorophenyl)difluoromethyl)-1H-1,2,3-triazole-5- carboxylic acid (166)
Figure imgf000306_0001
[001065] A mixture of 3,4-dichlorobenzoic acid (Compound 166A) (6.0 g, 28.7 mmol) and sulfurous dichloride (100 mL) was heated at 80 oC for 4 hours. The reaction mixture was concentrated to give a crude Compound 166B, which was used directly for next step without further purification.
[001066] A mixture of ethyl propiolate (2.82 g, 28.8 mmol), CuI (5.97 g, 31.4 mmol), DIPEA (4.2 g, 32.6 mmol), and Compound 166B (6.0 g, 28.8 mmol) in THF (70 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under the reduced pressure. The residue was purified be column chromatography (silica gel, eluted with petroleum ether/ethyl acetate: 1/0 to 20/1) to give Compound 166C. LC-MS (ESI) m/z: 271 [M+H]+.
[001067] To Compound 166C (900 mg, 3.33 mmol) was added DAST (5 mL) and two drops of ethanol (95%). The reaction mixture was stirred at 60 oC for 16 hours. After cooled down to room temperature, to the mixture was added pentane (50 mL), followed by slowly addition of HCl solution (1%, 50 mL). The organic layers were separated, washed with water (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude Compound 166D, which was used directly for next step without further purification. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. [001068] A mixture of Compound 166D (850 mg, 2.9 mmol) and Intermediate A-2 (608 mg, 3.73 mmol) in THF (10 mL) was stirred at 60 oC for 8 hours. The reaction mixture was concentrated and purified with preparative HPLC to afford a Mixture of 166E-1 and 166E-2. LC-MS (ESI) m/z: 456 [M+H]+.
[001069] Mixture of 166F-1 and 166F-2, and Compound 166 were synthesized by employing the procedures described for Compounds 8F and 1 using Mixtures of 166E-1 and 166E-2, and 166F-1 and 166F-2 in lieu of Compounds 8E and 1E. Mixture of 166F-1 and 166F- 2: which was used directly for next step without further purification. LC-MS (ESI) m/z: 877 [2M+Na]+. Compound 166: LC-MS (ESI) m/z: 308 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.50 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H).
[001070] Example 167
[001071] Synthesis of 4-((4,4-difluorocyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (167)
Figure imgf000307_0001
[001072] Compounds 167B, 167C, and 167 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 167A, 167B, and 167C in lieu of Compounds 90B, 8E, and 1E. Compound 167B: LC-MS (ESI) m/z: 396 [M+H]+. Compound 167C: LC-MS (ESI) m/z: 368 [M+H]+. Compound 167: LC-MS (ESI) m/z: 248 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.91-2.11 (m, 8H), 4.85 (s, 1H), 12.89 (s, 1H), 14.78 (s, 1H).
[001073] Example 168
[001074] Synthesis of 4-(bicyclo[2.2.1]heptan-2-yloxy)-1H-1,2,3-triazole-5-carboxylic a
Figure imgf000307_0002
[001075] Compounds 168B, 168C, and 168 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 168A, 168B, and 168C in lieu of Compounds 90B, 8E, and 1E. Compound 168B: LC-MS (ESI) m/z: 372 [M+H]+. Compound 168C: LC-MS (ESI) m/z: 344 [M+H]+. Compound 168: LC-MS (ESI) m/z: 224 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.03 (dt, J = 13.2 Hz, 1H), 1.31 (t, J = 9.8 Hz, 3H), 1.42 (d, J = 9.9 Hz, 1H), 1.54 (dd, J = 8.3 Hz, 1H), 1.85 (t, J = 13.0 Hz, 1H), 2.02 (dd, J = 8.8 Hz, 1H), 2.21 (s, 1H), 2.57 (s, 1H), 4.90 (d, J = 9.6 Hz, 1H).
[001076] Example 169
[001077] Synthesis of 4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3 triazole-5-carboxylic acid 2,2,2-trifluoroacetate (169)
Figure imgf000308_0001
[001078] Compounds 169B, 169C, 169D, and 169 were synthesized by employing the procedures described for Compounds 27C, 4B, 1, and 8F using Compounds 169A, 169B, Intermediate F with K3CO3 as base and 1,4-dioxane/H2O as solvent, 169C, and 169D in lieu of Compounds 27B, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 169B: LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (s, 12H), 1.61-1.63 (m, 2H), 1.66-1.72 (m, 4H), 3.24-3.28 (m, 4H), 6.90 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H).
Compound 169C: LC-MS (ESI) m/z: 529 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 1.60-1.65 (m, 2H), 1.70-1.74 (m, 4H), 3.21-3.24 (m, 4H), 3.72 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.56 (s, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.06(d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.37-7.44 (m, 4H). Compound 169D: LC-MS (ESI) m/z: 409 [M+H]+. Compound 169: LC-MS (ESI) m/z: 381 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.81-1.84 (m, 2H), 2.02-2.08 (m, 4H), 2.64-2.68 (m, 4H), 7.60 (d, J = 8.4 Hz, 2H), 7.68- 7.71 (m, 4H), 7.87 (d, J = 8.4 Hz, 2H).
[001079] Example 170
[001080] Synthesis of 4-((3'-(cyclopropylmethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (170)
Figure imgf000309_0001
[001081] Compounds 170A, 170B, 170C, 170D, and 170 were synthesized by
employing the procedures described for Compounds 29B, 27C, 1, 4B, and 8F using
(bromomethyl)cyclopropane, Compounds 131A, 170A, Intermediate F, 170B, 170C with K3CO3 as base and 1,4-dioxane/H2O as solvent, and 170D in lieu of iodoethane, Compounds 29A, 27B, 1E, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, and 8E. Compound 170A: LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used. Compound 170B: LC-MS (ESI) m/z: 275 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.33-0.37 (m, 2H), 0.61-0.65 (m, 2H), 1.26-1.30 (m, 1H), 1.36 (s, 12H), 3.85 (d, J = 6.8 Hz, 2H), 7.02-7.05 (m, 1H), 7.29-7.33 (m, 2H), 7.40 (d, J = 7.6 Hz, 1H). Compound 170C: LC-MS (ESI) m/z: 328 [M+H]+. Compound 170D: LC-MS (ESI) m/z: 396 [M+H]+. Compound 170: LC-MS (ESI) m/z: 368 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.35-0.40 (m, 2H), 0.61-0.66 (m, 2H), 1.28-1.31 (m, 1H), 3.89 (d, J = 6.4 Hz, 2H), 6.92 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.15 (t, J = 2.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H).
[001082] Example 171
[001083] Synthesis of 4-(((6-chloronaphthalen-2-yl)thio)methyl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2,-trifluoroacetate (171)
Figure imgf000310_0001
[001084] Compound 171A was synthesized by employing the procedure described for Intermediate D-1 using Compounds 56B in lieu of Intermediate A, LC-MS (ESI) m/z: non- ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 2.69 (t, J = 7.2 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H), 3.69 (s, 3H), 7.41-7.48 (m, 2H), 7.69 (dd, J = 8.8 Hz, 2.4 Hz, 2H), 7.77 (d, J = 10.4 Hz, 2H).
[001085] To a solution of Compound 171A (70 mg, 0.25 mmol) in dry THF (10 mL) at -78 oC and under nitrogen was added potassium tert-butoxide (56 mg, 0.5 mmol) and stirred at -78 oC for 30 minutes, and then stirred at room temperature for 1 hour. A solution of Intermediate K (88 mg, 0.25 mmol) in dry THF (2 mL) was added. The resulting mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (methanol in CH2Cl2, 20% v/v) to afford Compound 171B. LC-MS (ESI) m/z: 440 [M+H]+.
[001086] Compound 171 was synthesized by employing the procedure described for Compound 1 using Compound 171B in lieu of Compound 1E, LC-MS (ESI) m/z: 320 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.60 (s, 2H), 7.50-7.54 (m, 2H), 7.33 (dd, J = 8.8, 3.2 Hz, 2H), 7.94 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H).
[001087] Example 172 [001088] Synthesis of 4-((6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (172)
Figure imgf000311_0001
[001089] Compounds 172A, 172B, and 172 were synthesized by employing the
procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 237D with DEAD, 172A, and 172B in lieu of Intermediate H, Compounds 90B with DIAD, 8E, and 1E. Compound 172A: LC-MS (ESI) m/z: 460 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.25 (t, J = 7.6 Hz, 3H), 1.70-1.75 (m, 1H), 1.94-1.98 (m, 1H), 2.47-2.54 (m, 1H), 2.65-2.69 (m, 1H), 2.75-2.80 (m, 2H), 3.75 (s, 3H), 3.79-3.84 (m, 1H), 4.44 (q, J = 7.2 Hz, 2H), 5.5 (d, J = 14.8 Hz, 2H), 6.66 (q, J = 2.8, 8 Hz, 1H), 6.81-6.86 (m, 3H), 7.20 (d, J = 8.8 Hz, 2H). Compound 172B: LC-MS (ESI) m/z: 432 [M+H]+. Compound 172: LC-MS (ESI) m/z: 312 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.84-1.89 (m, 1H), 2.16-2.19 (m, 1H), 2.82-2.85 (m, 3H), 3.21-3.22 (m, 1H), 3.97-3.99 (m, 1H), 7.14-7.19 (m, 2H), 13.24 (s, 1H), 15.60 (s, 1H) .
[001090] Example 173
[001091] Synthesis of 4-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (173)
Figure imgf000312_0001
[001092] Compounds 173B, 173C, 173D, 173E, 173F, and 170 were synthesized by employing the procedures described for Compounds 57B, 57C, 57D, 57E, 8F, and 1 using Compounds 173A, 173B, 173C with K3CO3 as base and DMF as solvent, 173D, 173E, and 170F in lieu of Compounds 57A, 57B, 57C with Na2CO3 as base and NMP as solvent, 57D, 8E, and 1E. Compound 173B: LC-MS (ESI) m/z: 247 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 3.38 (d, J = 18 Hz, 1H), 3.81 (dd, J = 7.6, 18.8 Hz, 1H), 4.66 (dd, J = 3.2, 7.2 Hz, 1H), 7.24-7.28 (m, 1H), 7.61-7.65 (m, 1H). Compound 173C: LC-MS (ESI) m/z: 231 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d 2.47-2.50 (m, 1H), 3.29-3.43 (m, 2H), 4.92-4.93 (m, 2H), 7.04-7.08 (m, 1H), 7.22-7.26 (m, 1H). Compound 173D: LC-MS (ESI) m/z: 462 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.44 (t, J = 7.2 Hz, 3H), 2.58-2.65 (m, 1H), 3.03-3.09 (m, 1H), 3.43 (d, J = 5.2 Hz, 1H), 3.57-3.63 (m, 1H), 3.78 (s, 3H), 4.47 (q, J = 7.2 Hz, 2H), 4.90-4.93 (m, 1H), 5.64 (s, 2H), 6.84-6.91 (m, 3H), 7.08-7.12 (m, 1H), 7.23-7.25 (m, 2H). Compound 173E: LC-MS (ESI) m/z: 446 [M+H]+.
Compound 173F: LC-MS (ESI) m/z: 418 [M+H]+. Compound 173: LC-MS (ESI) m/z: 298
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.89-2.94 (m, 2H), 3.45-3.51 (m, 2H), 4.41- 4.44 (m, 1H), 7.29-7.34 (m, 2H).
[001093] Example 174
[001094] Synthesis of 4-(((6-chloronaphthalen-2-yl)methyl)thio)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (174)
Figure imgf000313_0001
[001095] To a solution of 6-chloro-2-naphthoic acid (106B) (1.00 g, 10.00 mmol) in THF (20 mL) was added LiAlH4 (295 mg, 2.77 mmol) in several portions. The mixture was stirred at room temperature for 16 hours, quenched with water (0.3 mL), NaOH solution (15% in water, 0.3 mL), and water (0.9 mL), and filtered through Celite. The filtrate was concentrated under reduced pressure and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40% v/v) to afford Compound 174A. LC-MS (ESI) m/z: 175 [M-OH]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.66 (d, J = 6.0 Hz, 2H), 5.35 (t, J = 6.0 Hz, 1H), 7.48-7.53 (m, 2H), 7.86-7.89 (m, 2H), 7.94 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H).
[001096] To a solution of Compound 174A (190 mg, 0.99 mmol) and PPh3 (337 mg, 1.29 mmol) in dichloromethane (5 mL) was added NBS (230 mg, 1.29 mmol). The mixture was stirred at room temperature under nitrogen for 16 hours and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (tetrahydrofuran in petroleum ether, from 0% to 20% v/v) to give Compound 174B. LC-MS (ESI) m/z: non- ionizable compound under routine conditions used; 1H-NMR CDCl3, 400 MHz): d (ppm) 4.64 (s, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.81 (s, 2H).
[001097] Compounds 174C, 174D, and 174 were synthesized by employing the
procedures described for Compounds 57D, 1, and 8F using Compounds 174B with K3CO3 as base and DMF as solvent, 174C, and 174D in lieu of Compounds 57C with Na2CO3 as base and NMP as solvent, 1E, and 8E. Compound 174C: LC-MS (ESI) m/z: 468 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.31 (t, J = 7.2 Hz, 3H), 3.68 (s, 3H), 4.27-4.32 (m, 2H), 4.34 (s, 2H), 5.33 (s, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.49-7.52 (m, 2H), 7.82 (d, J = 8.8 Hz, 2H), 8.01 (s, 1H). Compound 174D: LC-MS (ESI) m/z: 348 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40 (t, J = 7.2 Hz, 3H), 4.39-4.45 (m, 2H), 4.53 (s, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.70-7.73 (m, 2H), 7.79 (s, 1H), 7.83 (s, 1H). Compound 174: LC-MS (ESI) m/z: 320 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.52 (s, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 8.01 (s, 1H).
[001098] Example 175
[001099] Synthesis of 4-((4-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (175)
Figure imgf000314_0001
[001100] To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (175A) (1.3 g, 6.1 mmol) in toluene (20 mL) was added Boc2O (1.6 g, 7.4 mmol). The reaction mixture was stirred at 110 oC overnight and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish Compound 175B. LC-MS (ESI) m/z: 255 [M-56]+.
[001101] Compounds 175C and 175D were synthesized by employing the procedures described for Compounds 27C and 4B using Compounds 175B, Intermediate F, and 175C with K3PO4 as base and 1,4-dioxane as solvent in lieu of Compounds 27B and 4A, (4- bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent. Compound 175C: LC-MS (ESI) m/z: 382 [M+Na]+. Compound 175D: LC-MS (ESI) m/z: 601 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 1.55 (s, 9H), 1.93-2.00 (m, 2H), 2.80-2.85 (m, 2H), 3.72-3.77 (m, 5H), 4.35-4.40 (m, 2H), 5.55 (d, J = 4.0 Hz, 2H), 6.76 (d, J = 14.4 Hz, 2H), 7.04-7.17 (m, 4H), 7.23 (d, J = 5.6 Hz, 1H), 7.28-7.31 (m, 1H), 7.37-7.40 (m, 2H), 7.74-7.78 (m, 1H).
[001102] A mixture of Compound 175D (560 mg, 0.93 mmol) and TFA (1 mL) in dichloromethane (4 mL) was stirred at 20 oC for 3 hours. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to give Compound 175E. LC-MS (ESI) m/z: 501 [M+H]+.
[001103] To a mixture of Compound 175E (300 mg, 0.6 mmol) and (CH2O)n (180 mg, 6 mmol) in dichloromethane (10 mL) was added TFA (0.43 mL, 3 mmol) and TES (0.74 mL, 10 mmol) and stirred at room temperature under nitrogen overnight. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 20 % to 30% v/v) to furnish Compound 175F. LC-MS (ESI) m/z: 515 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.32 (t, J = 7.2 Hz, 3H), 2.12-2.18 (m, 2H), 2.93 (t, J = 6.4 Hz, 2H), 3.11 (s, 3H), 3.46 (t, J = 5.6 Hz, 2H), 3.72 (s, 3H), 4.34-4.39 (m, 2H), 5.57 (s, 2H), 6.75 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 7.14-7.27 (m, 4H), 7.33-7.37 (m, 3H).
[001104] Compounds 175G and 175 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 175F and 175G in lieu of Compounds 8E and 1E. Compound 175G: LC-MS (ESI) m/z: 487 [M+H]+. Compound 175: LC-MS (ESI) m/z: 367 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.90 (t, J = 6.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.87 (s, 3H), 3.23 (t, J = 5.6 Hz, 2H), 6.65 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.34 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H).
[001105] Example 176
[001106] Synthesis of 4-((3,4-dichlorobenzyl)thio)-1H-1,2,3-triazole-5-carboxylic acid (176)
Figure imgf000315_0001
[001107] Compounds 176B, 176C, and 176 were synthesized by employing the procedures described for Compounds 57D, 8F, and 57E using Compounds 176A with K3CO3 as base and DMF as solvent, 176B, and 176C in lieu of Compounds 57C with Na2CO3 as base and NMP as solvent, 8E, and 57D. Compound 176B: LC-MS (ESI) m/z: 452 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.47 (t, J = 6.8 Hz, 3H), 3.80 (s, 3H), 4.03 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 5.39 (s, 2H), 6.82-6.85 (m, 3H), 7.13-7.27 (m, 4H). Compound 176C: LC-MS (ESI) m/z: 424 [M+H]+. Compound 176: LC-MS (ESI) m/z: 304 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.34 (s, 2H), 7.39 (dd, J = 8.4, 1.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H).
[001108] Example 177
[001109] Synthesis of 4-(((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (177)
Figure imgf000316_0001
[001110] Compounds 177B, 177C, 177D, and 177 were synthesized by employing the procedures described for Compounds 57D, 4B, 8F, and 57E using Compounds 177A with K3CO3 as base and DMF as solvent, 177B with K2CO3 as base and 1,4-dioxane/H2O as solvent, 177C, and 177D in lieu of Compounds 57C with Na2CO3 as base and NMP as solvent, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E and 57D. Compound 177B: LC-MS (ESI) m/z: 462 [M+H]+ ; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.46 (t, J = 6.8 Hz, 3H), 3.79 (s, 3H), 4.05 (s, 2H), 4.47 (q, J = 6.8 Hz, 2H), 5.30 (s, 2H), 6.81-6.83 (m, 2H), 6.89-6.92 (m, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 6.8 Hz, 2H). Compound 177C: LC-MS (ESI) m/z: 544 [M+H]+. Compound 177D: LC-MS (ESI) m/z: 516 [M+H]+. Compound 177: LC-MS (ESI) m/z: 396 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.38 (s, 2H), 7.42 (dd, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H),
[001111] Example 178
[001112] Synthesis of 4-(((6-chloronaphthalen-2-yl)amino)methyl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (178)
Figure imgf000317_0001
[001113] To a mixture of Intermediate K (950 mg, 2.69 mmol) in anhydrous DMF (30 mL) was added K2CO3 (557 mg, 4.04 mmol) and Compound 82C (476 mg, 2.69 mmol). The mixture was stirred at room temperature under nitrogen overnight, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 40% v/v) to furnish Compound 178A. LC-MS (ESI) m/z: 451 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.44 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.28-4.32 (m, 1H), 4.48 (q, J = 7.2 Hz, 2H), 4.64 (d, J = 7.2 Hz, 2H), 5.65 (s, 2H), 6.76-6.86 (m, 4H), 7.14 (d, J = 8.8 Hz, 2H), 7.31-7.34 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H).
[001114] Compounds 178B and 178 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 178A and 178B in lieu of Compounds 8E and 1E. Compound 178B: LC-MS (ESI) m/z: 423 [M+H]+. Compound 178: LC-MS (ESI) m/z: 303 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.72 (s, 2H), 6.61 (s, 1H), 6.90 (s, 1H), 7.17 (dd, J = 8.8, 2.0 Hz, 1H), 7.37 (dd, J = 8.8, 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 13.33 (s, 1H), 15.63 (s, 1H).
[001115] Example 179
[001116] Synthesis of 4-(((3,4-dichlorophenyl)(methyl)amino)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (179)
Figure imgf000318_0001
[001117] To a solution of 3,4-dichloroaniline (69A) (324 mg, 2.0 mmol) in MeOH (5 mL) was added MeONa (540 mg, 10.0 mmol), paraformaldehyde (120 mg, 4.0 mmol), and Molecular sieves (4 Angstroms, 200 mg). The mixture was stirred at room temperature under nitrogen overnight, and then sodium borohydride (151 mg, 4 mmol) was added. The mixture was heated at reflux for 1 hour, cooled down to room temperature, filtered through Celite, and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 179A. LC-MS (ESI) m/z: 176 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.82 (s, 3H), 3.80 (s, 1H), 6.44 (dd, J = 8.8, 2.8 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H).
[001118] Compounds 179B, 179C, and 179 were synthesized by employing the procedures described for Compounds 178A, 8F, and 1 using Compounds 179A, 179B, and 179C in lieu of Compounds 82C, 8E and 1E. Compound 179B: LC-MS (ESI) m/z: 449 [M+H]+. Compound 179C: LC-MS (ESI) m/z: 421 [M+H]+. Compound 179: LC-MS (ESI) m/z: 301 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.05 (s, 3H), 4.86 (s, 2H), 6.74 (s, 1H), 6.96 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 13.38 (s, 1H), 15.38 (s, 1H).
[001119] Example 180
[001120] Synthesis of 4-(((6-chloronaphthalen-2-yl)(methyl)amino)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (180)
Figure imgf000319_0001
[001121] Compounds 180A, 180B, 180C, and 180 were synthesized by employing the procedures described for Compounds 179A, 178A, 8F, and 1 using Compounds 82C, 180A, 180B, and 180C in lieu of Compounds 69A, 82C, 8E and 1E. Compound 180A: LC-MS (ESI) m/z: 192 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.94 (s, 3H), 3.95 (s, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.8, 2.0 Hz, 1H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.56 (dd, J = 8.4, 2.0 Hz, 2H), 7.65 (d, J = 2.4 Hz, 1H). Compound 180B: LC-MS (ESI) m/z: 465 [M+H]+. Compound 180C: LC-MS (ESI) m/z: 437 [M+H]+. Compound 180: LC-MS (ESI) m/z: 317 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 3.14 (s, 3H), 4.97 (s, 2H), 7.03 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.8, 2.0 Hz, 2H), 7.65-7.72 (m, 2H), 7.80 (s, 1H), 13.39 (s, 1H), 15.29 (s, 1H).
[001122] Example 181
[001123] Synthesis of 4-((2,4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1H-1,2,3-triazole-5- carboxylic acid (181)
Figure imgf000320_0001
[001124] Compounds 181B, 181C, 181D, and 181 were synthesized by employing the procedures described for Compounds 8B, 6B, 8F, and 1 using (4-chlorophenyl)boronic acid, Compounds 181A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, Intermediate A, 181B with K3PO4 as base, 181C, and 181D in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 6A, 1-methylpiperazine with t-BuONa as base, 8E and 1E. Compound 181B: LC-MS (ESI) m/z: 238 [M+H]+. Compound 181C: LC-MS (ESI) m/z: 497[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.05 (t, J = 14.4 Hz, 3H), 3.7 (s, 3H), 4.12 (q , J = 7.2 Hz, 2H), 5.44 (s, 2H), 6.66-6.63 (m, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.86 (t, J = 8.8Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.4 Hz, 1H), 7.39 (q, J = 1.6 Hz, 2H), 7.49 (q, J = 2 Hz, 2H), 8.8 (s, 1H). Compound 181D: LC-MS (ESI) m/z: 469 [M+H]+.
Compound 181: LC-MS (ESI) m/z: 349 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.33 (d, J = 8.4 Hz, 1H), 7.5 (q, J = 8.4 Hz, 4H), 7.63 (q , J = 1.6 Hz, 1H), 7.94 (s, 1H), 8.46 (s, 1H), 13.44 (s, 1H), 15.01 (s, 1H).
[001125] Example 182
[001126] Synthesis of 4-(((6-chloronaphthalen-2-yl)methyl)amino)-1H-1,2,3-triazole-5- carboxylic acid (182)
Figure imgf000321_0001
[001127] Compound 182A was synthesized by employing the procedure described for Compound 106C using NH4Cl with DMF as solvent in lieu of N,O-dimethylhydroxylamine hydrochloride with dichloromethane as solvent, LC-MS (ESI) m/z: 206 [M+H]+.
[001128] To a solution of Compound 182A (2.00 g, 9.75 mmol) in THF (10 mL) at room temperature was dropped a solution of BH3 in THF (1 M, 49 mL, 48.78 mmol) and stirred at 65 oC for 16 hours. After cooled down to room temperature, the mixture was quenched with water (10 mL) and methanol (10 mL), concentrated under reduced pressure. The residue was purified with reverse phase chromatography using eluent (acetonitrile in water, from 0% to 100% v/v) to afford Compound 182B. LC-MS (ESI) m/z: 175 [M-NH2]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 4.03 (s, 2H), 7.41 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 8.8 Hz, 1H), 7.72-7.81 (m, 4H).
[001129] Compounds 182C, 182D, and 182 were synthesized by employing the procedures described for Compounds 6B, 1, and 8F using Intermediate A, Compounds 182B with K3PO4 as base and DMF as solvent, 182C, and 182D in lieu of Compounds 6A, 1- methylpiperazine with t-BuONa as base and toluene as solvent, 1E and 8E. Compound 182C: LC-MS (ESI) m/z: 451 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.23 (t, J = 7.2 Hz, 3H), 3.72 (s, 3H), 4.20-4.26 (m, 2H), 4.75 (d, J = 6.8 Hz, 2H), 5.43 (s, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.76-7.79 (m, 2H), 7.98(s, 1H). Compound 182D: LC-MS (ESI) m/z: 331 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.35 (t, J = 7.2 Hz, 3H), 4.39-4.44 (m, 2H), 4.68 (s, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.72-7.80 (m, 4H). Compound 182: LC-MS (ESI) m/z: 303 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 4.65 (s, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.77-7.85 (m, 4H).
[001130] Example 183
[001131] Synthesis of 4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)-1H-1,2,3- triazole-5-carboxylic acid (183)
Figure imgf000322_0001
183D 183
[001132] Compounds 183B, 183C, 183D, and 183 were synthesized by employing the procedures described for Compounds 4B, 6B, 1, and 8F using (4- (trifluoromethyl)phenyl)boronic acid, Compounds 183A with K2CO3 as base and DMF/H2O as solvent, Intermediate A, 183B with K3PO4 as base, 183C, and 183D in lieu of (4- bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 6A, 1-methylpiperazine with t-BuONa as base, 1E and 8E. Compound 183B: LC-MS: (ESI) m/z: 238 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 6.77-6.79 (m, 2H), 7.43-7.45 (m, 2H), 7.64 (s, 4H). Compound 183C: LC-MS (ESI) m/z: 497 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 3.76 (s, 3H), 4.42 (q, J = 7.2 Hz, 2H), 5.24 (s, 2H), 6.74 (J = 8.7 Hz, 2H), 6.86 (J = 8.7 Hz, 2H), 6.92 (J = 8.4 Hz, 2H), 7.18 (s, 1H), 7.55 (J = 8.4 Hz, 2H), 7.67-7.73 (m, 4H). Compound 183D: LC-MS (ESI) m/z: 377 [M+H]+; 1H-NMR (DMSO- d6, 400 MHz): d (ppm) 1.34 (t, J = 7.2 Hz, 3H), 4.35 (q, J = 7.2 Hz, 2H), 7.68-7.73 (m, 4H), 7.76 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H), 8.30 (s, 1H). Compound 183: LC-MS (ESI) m/z: 349 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.62-7.68 (m, 4H), 7.73 (d, J = 8.4 Hz, 2H),7.85 (d, J = 8.2 Hz, 2H). [001133] Example 184
[001134] Synthesis of 4-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-1H-1,2,3-triazole-5- carboxylic acid (184)
Figure imgf000323_0001
[001135] Compounds 184B, 184C, and 184 were synthesized by employing the
procedures described for Compounds 178A, 8F, and 1 using Compounds 184A, 184B, and 184C in lieu of Compounds 82C, 8E and 1E. Compound 184B: LC-MS (ESI) m/z: 469 [M+H]+.
Compound 184C: LC-MS (ESI) m/z: 441 [M+H]+. Compound 184: LC-MS (ESI) m/z: 321 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.55-1.70 (m, 4H), 2.13-2.19 (m, 2H), 2.46- 2.49 (m, 1H), 2.99-3.02 (m, 2H), 3.86 (s, 2H), 7.23-7.25 (m, 2H), 7.31-7.33 (m, 2H).
[001136] Example 185
[001137] Synthesis of 4-(((3,4-dichlorophenyl)(ethyl)amino)methyl)-1H-1,2,3-triazole- 5-carboxylic acid (185)
Figure imgf000324_0001
[001138] To a solution of 3,4-dichloroaniline (69A) (1.62 g, 10.0 mmol) in acetone (100 mL) was added K2CO3 (4.14 g, 30.0 mmol) and acetyl chloride (1.18 g, 15.0 mmol). The mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column
chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 185A. LC-MS (ESI) m/z: 204 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.20 (s, 3H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H).
[001139] To a solution of Compound 185A (612 mg, 3.0 mmol) in anhydrous THF (30 mL) was added LiAlH4 (456 mg, 12 mmol) and stirred at 30 °C for 3 hours. The reaction mixture was quenched with Na2SO4·10H2O and stirred at room temperature for 30 minutes. The resulting suspension was filtered through Celite and the cake was washed with ethyl acetate (50 mL x 3). The combined filtrates was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 40% v/v) to furnish Compound 185B. LC-MS (ESI) m/z: 190 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.26 (t, J = 7.2 Hz, 3H), 3.12 (q, J = 7.2 Hz, 2H), 3.64 (s, 1H), 6.43 (dd, J = 8.8, 1.8 Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H).
[001140] Compounds 185C, 185D, and 185 were synthesized by employing the
procedures described for Compounds 178A, 8F, and 1 using Compounds 185B, 185C, and 185D in lieu of Compounds 82C, 8E and 1E. Compound 185C: LC-MS (ESI) m/z: 463 [M+H]+.
Compound 185D: LC-MS (ESI) m/z: 435 [M+H]+. Compound 185: LC-MS (ESI) m/z: 315 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.09 (t, J = 7.2 Hz, 3H), 3.49 (q, J = 7.2 Hz, 2H), 4.79 (s, 2H), 6.67 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 2.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H).
[001141] Example 186
[001142] Synthesis of 4-((7-chloroquinolin-3-yl)amino)-1H-1,2,3-triazole-5-carboxylic acid (186)
Figure imgf000325_0001
[001143] To a stirred solution of 7-chloroquinolin-4-ol (186A) (5 g, 27.9 mmol) in HOAc (100 mL) was added HNO3 (63%, 5.41 g, 55.8 mmol) and stirred at 125 oC overnight. After cooled down to room temperature, the mixture was concentrated under reduced pressure, the residue was diluted with EtOH (20 mL), the resulting solid was collected and dried under vacuum to afford Compound 186B. LC-MS: (ESI) m/z: 225 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.53 (dd, J = 8.8, 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 9.23 (s, 1H), 12.99 (s, 1H).
[001144] A mixture of Compound 186B (5 g, 22.32 mmol) and POCl3 (50 mL) was stirred at 115 oC overnight. The mixture was evaporated under reduced pressure and the residue was diluted with dichloromethane (50 mL) and washed with brine (30 mL x 2). The organic layer wash dried over anhydrous Na2SO4, filtered and concentrated to give a crude Compound 186C, which was used directly in next step without further purification. LC-MS (ESI) m/z: 243 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.78 (dd, J = 8.8, 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 9.29 (s, 1H). [001145] A solution of Compound 186C (4 g, 16.5 mmol) and p- toluenesulfonylhydrazine (6.1 g, 33 mmol) in CHCl3 (100 mL) was stirred at room temperature for 24 hours. The mixture was filtered. The solid was washed with cold CHCl3 and dried under vacuum to afford the hydrazino intermediate as solid. The intermediate was mixed with aqueous NaOH solution (0.5 N, 50 mL) and heated at 80 oC for 1 hour. After cooled down to room temperature, the resulting mixture was extracted with dichloromethane (30 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 186D. LC-MS (ESI) m/z: 209 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.71 (dd, J = 8.8, 2.0 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 9.04 (d, J = 2.4 Hz, 1H), 9.67 (d, J = 2.4 Hz, 1H).
[001146] To a solution of Compound 186D (200 mg, 0.96 mmol) in MeOH (10 mL) was added SnCl .
22H2O (1.25 g, 4.8 mmol) and stirred at 100 oC overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to leave a crude product, which was further purified with reverse phase chromatography using eluent (acetonitrile in water, from 0% to 20% v/v) afford Compound 186E. LC-MS (ESI) m/z: 179 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 7.28 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H),7.70-7.73 (m, 1H), 7.82 (s, 1H), 8.50(s, 1H).
[001147] Compounds 186F, 186G, and 186 were synthesized by employing the procedures described for Compounds 6B, 1, and 8F using Intermediate A, Compounds 186E with as Cs2CO3 base and DMF as solvent at 150 oC in a microwave reactor, 186F, and 186G in lieu of Compounds 6A, 1-methylpiperazine with as t-BuONa base and toluene as solvent at 120 oC, 1E and 8E. Compound 186F: LC-MS (ESI) m/z: 438 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.87 (t, J = 7.2 Hz, 3H), 3.60 (s, 3H), 4.01 (q, J = 7.2 Hz, 2H), 5.48 (s, 2H), 6.77 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 2.6 Hz, 1H), 7.46-7.49 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.6 Hz, 1H), 9.13 (s, 1H). Compound 186G: LC-MS (ESI) m/z: 318 [M+H]+. Compound 186: LC-MS (ESI) m/z: 290 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 7.50 (d, J = 8.8 Hz, 1H), 7.87-7.90 (m, 2H), 8.63 (s, 1H), 8.87 (s, 1H), 9.74 (s, 1H).
[001148] Example 187 [001149] Synthesis of 4-(((6-chloronaphthalen-2-yl)(ethyl)amino)methyl)-1H-1,2,3- triazole-5-carboxylic acid (187)
Figure imgf000327_0001
[001150] To a solution of 6-chloronaphthalen-2-amine (82C) (1.00 g, 4.69 mmol) and Et3N (1.18 g, 11.73 mmol) in THF (10 mL) was dropped neat AcCl (439 mg, 5.63 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate (160 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel
(tetrahydrofuran in petroleum ether, from 0% to 80% v/v) to afford Compound 187A. MS (ESI) m/z: 220 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.10 (s, 3H), 7.43-7.47 (m, 1H), 7.59-7.62 (m, 1H), 7.83-7.86 (m, 2H), 7.94 (s, 1H), 8.32 (s, 1H), 10.20 (s, 1H).
[001151] Compounds 187B, 187C, 187D, and 187 were synthesized by employing the procedures described for Compounds 182B, 178A, 1, and 8F using Compounds 187A, 187B, 187C, and 187D in lieu of Compounds 182A, 82C, 1E, and 8E. Compound 187B: LC-MS (ESI) m/z: 206 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.22 (t, J = 7.6 Hz, 3H), 3.08-3.15 (m, 2H), 5.99 (t. J = 5.2 Hz, 1H), 6.70 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.55-7.60 (m, 2H), 7.70 (s, 1H). Compound 187C: LC-MS (ESI) m/z: 479 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.96 (t, J = 7.2 Hz, 3H), 1.46 (t, J = 7.2 Hz, 3H), 3.18 (q, J = 7.2 Hz, 2H), 3.73 (s, 3H), 4.48 (q, J = 7.2 Hz, 2H), 4.73 (s, 2H), 5.53 (s, 2H), 6.68-6.71 (m, 2H), 6.85-6.89 (m, 2H), 7.00 (s, 1H), 7.14-7.18 (m, 1H), 7.33-7.36 (m, 1H), 7.50-7.54 (m, 2H), 7.71 (s, 1H). Compound 187D: LC-MS (ESI) m/z: 359 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.24 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H), 3.68 (q, J = 7.2 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 5.13 (s, 2H), 7.28-7.46 (m, 2H), 7.60 (d, J = 1.6 Hz, 1H), 7.68-7.77 (m, 3H).
Compound 187: LC-MS (ESI) m/z: 331 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.25 (t, J = 7.2 Hz, 3H), 3.69 (q, J = 7.2 Hz, 2H), 4.96 (s, 2H), 7.05 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.55-7.62 (m, 3H).
[001152] Example 188
[001153] Synthesis of 4-((6-chloro-3,4-dihydroquinolin-1(2H)-yl)methyl)-1H-1,2,3- triazole-5-carboxylic acid (188)
Figure imgf000328_0001
[001154] Compounds 188B, 188C, and 188 were synthesized by employing the procedures described for Compounds 178A, 1, and 8F using Compounds 188A, 188B, and 188C in lieu of Compounds 82C, 1E, and 8E. Compound 188B: LC-MS (ESI) m/z: 441 [M+H]+. Compound 188C: LC-MS (ESI) m/z: 321 [M+H]+. Compound 188: LC-MS (ESI) m/z: 293 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.87-1.88 (m, 2H), 2.67-2.68 (m, 2H), 3.34- 3.41 (m, 2H), 4.73 (m, 2H), 6.54 (brs, 1H), 6.87-6.91 (m, 2H).
[001155] Example 189
[001156] Synthesis of 4-((ethyl(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)amino)methyl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (189)
Figure imgf000329_0001
[001157] Compounds 189A, 189B, 189C, 189D, 189E, and 189 were synthesized by employing the procedures described for Compounds 185A, 4B, 185B, 178A, 8F, and 1 using Compounds 183A, (4-(trifluoromethoxy)phenyl)boronic acid, 189A with K2CO3 as base and as 1,4-dioxane/H2O solvent, 189B, 189C, 189D, and 189E in lieu of Compounds 69A, (4- bromophenyl)boronic acid, 4A with Na2CO3 as base and as toluene/EtOH/H2O solvent, 185A, 82C, 8E, and 1E. Compound 189A: LC-MS (ESI) m/z: 214 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.18 (s, 3H), 7.24 (s, 1H), 7.39-7.45 (m, 4H). Compound 189B: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.21 (s, 3H), 7.28 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.56-7.61 (m, 4H). Compound 189C: LC-MS (ESI) m/z: 282 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.30 (t, J = 7.2 Hz, 3H), 3.21 (q, J = 7.2 Hz, 2H), 3.69 (s, 1H), 6.68 (d, J = 8.4Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H). Compound 189D: LC-MS (ESI) m/z: 555 [M+H]+. Compound 189E: LC-MS (ESI) m/z: 527 [M+H]+. Compound 189: LC-MS (ESI) m/z: 407 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.13 (t, J = 7.2 Hz, 3H), 3.57 (q, J = 7.2 Hz, 2H), 4.87 (s, 2H), 6.88 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H).
[001158] Example 190
[001159] Synthesis of 4-((5,6-dichloro-2,3-dihydro-1H-inden-2-yl)amino)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (190)
Figure imgf000330_0001
[001160] Compound 190A was synthesized by employing the procedure described for Compound 57C using Compound 57A and EtOH as solvent in lieu of Compound 57B and MeOH as solvent, LC-MS (ESI) m/z: 185 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.93- 2.00 (m, 1H), 2.49-2.57 (m, 1H), 2.75-2.83 (m, 1H), 2.98-3.05 (m, 1H), 5.21 (t, J = 6.0 Hz, 1H), 7.34 (s, 1H), 7.48 (s, 1H).
[001161] To a mixture of Compound 190A (4.3 g, 21.3 mmol) in toluene (100 mL) was added MgSO4 (5.11 g, 42.6 mmol) and p-TsOH (366 mg, 2.13 mmol). The mixture was heated at reflux for 2 hours. After cooled down to room temperature, the mixture was filtered, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to give Compound 190B. LC-MS (ESI) m/z: 185 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.39-3.40 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.53 (s, 1H). [001162] To a mixture of Compound 190B (1.0 g, 5.43 mmol) in dichloromethane (60 mL) was added m-CPBA (1.40 g, 8.15 mmol) and NaHCO3 (685 mg, 8.15 mmol). The resulting mixture was stirred at room temperature under nitrogen for 16 hours, quenched with water (100 mL), and extracted with dichloromethane (50 mL x 3). The combined organic layers was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to give Compound 190C. LC-MS (ESI) m/z: 201 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.95 (dd, J = 18, 2.8 Hz, 1H), 3.18 (d, J = 18 Hz, 1H), 4.15 (t, J = 2.8 Hz, 1H), 4.22 (t, J = 2.8 Hz, 1H), 7.32 (s, 1H), 7.57 (s, 1H).
[001163] To a solution of Compound 190C (400 mg, 2 mmol) in 1,4-dioxane (100 mL) was added InCl3 (443 mg, 2 mmol) and stirred at 60 °C for 2 hours, followed by addition of
NaCNBH3 (378 mg, 6 mmol). The mixture was heated at reflux for 2 hours. After cooled down to room temperature, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to give Compound 190D. LC-MS (ESI) m/z: 185 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.89 (dd, J = 18, 2.8 Hz, 2H), 3.17 (dd, J = 18, 2.8 Hz, 2H), 4.72-4.76 (m, 1H), 7.32 (s, 2H).
[001164] Compound 190E was synthesized by employing the procedure described for Compound 90C using O-phthalimide and Compound 190D with DEAD in lieu of Intermediate H and Compound 90B with DIAD, LC-MS (ESI) m/z: 332 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.15-3.22 (m, 2H), 3.53-3.59 (m, 2H), 5.13-5.22 (m, 1H), 7.32 (s, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H).
[001165] To a mixture of Compound 190E (570 mg, 1.72 mmol) in methanol (50 mL) was added 85% N2H4 (5 mL), stirred at reflux for 16 hours, and concentrated under reduced pressure. The residue was purified with reverse phase chromatography using eluent (methanol in water (include 0.5% NH4HCO3), 80% v/v) to furnish Compound 190F. LC-MS (ESI) m/z: 202
[M+H]+.
[001166] Compounds 190G, 190H, and 190 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using Intermediate A, Compounds 190F with t-BuONa as base and DMF as solvent, 190G, and 190H in lieu of Compounds 6A, 1- methylpiperazine with K3PO4 as base and toluene as solvent, 8E, and 1E. Compound 190G: LC- MS (ESI) m/z: 461[M+H]+. Compound 190H: LC-MS (ESI) m/z: 433 [M+H]+. Compound 190: LC-MS (ESI) m/z: 313 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.91-2.97 (m, 2H), 3.23-3.29 (m, 2H), 4.37 (s, 1H), 5.36 (s, 1H), 7.51 (s, 2H).
[001167] Example 191
[001168] Synthesis of 4-((6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (191)
Figure imgf000332_0001
[001169] Compounds 191B, 191C, and 191 were synthesized by employing the procedures described for Compounds 178A, 8F, and 1 using Compounds 191A, 191B, and 191C in lieu of Compounds 82C, 8E, and 1E. Compound 191B: LC-MS (ESI) m/z: 441 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 2.67-2.70 (m, 2H), 2.82-2.85 (m, 2H), 3.50 (s, 2H), 3.77 (s, 3H), 3.91 (s, 2H), 4.45 (q, J = 7.2 Hz, 2H), 5.69 (s, 2H), 6.78-6.80 (m, 2H), 6.88-6.90 (m, 1H), 7.09-7.13 (m, 4H). Compound 191C: LC-MS (ESI) m/z: 413 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.60-2.61 (m, 2H), 2.68-2.69 (m, 2H), 3.49 (s, 2H), 3.66 (s, 3H), 4.05 (s, 2H), 5.51 (s, 2H), 6.76 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.7 Hz, 4H). Compound 191: LC-MS (ESI) m/z: 293 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.05-3.08 (m, 2H), 3.49 (s, 2H), 4.37 (s, 2H), 4.64 (s, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.29-7.31 (m, 1H), 7.34 (s, 1H).
[001170] Example 192
[001171] Synthesis of 4-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-1,2,3-triazole- 5-carboxylic acid (192)
Figure imgf000333_0001
[001172] Compounds 192B, 192C, and 192 were synthesized by employing the procedures described for Compounds 178A, 8F, and 1 using Compounds 192A, 192B, and 192C in lieu of Compounds 82C, 8E, and 1E. Compound 192B: LC-MS (m/z): 470 [M+H]+.
Compound 192C: LC-MS (m/z): 442 [M+H]+. Compound 192: LC-MS (m/z): 322 [M+H]+; 1H- NMR (CD3OD, 400 MHz): d (ppm) 3.36-3.82 (m, 8H), 4.78 (s, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H).
[001173] Example 193
[001174] Synthesis of 4-((benzyl(1-(4-chlorophenyl)piperidin-4-yl)amino)methyl)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (193)
Figure imgf000334_0001
[001175] Compounds 193B and 193C were synthesized by employing the procedures described for Compounds 70B and 175E using (4-chlorophenyl)boronic acid, Compounds 193A with pyridine as base, and 192B in lieu of (4-(trifluoromethoxy)phenyl)boronic acid, Compounds 70A with K3PO4 as base, and 175D. Compound 193B: LC-MS (ESI) m/z: 311 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.46 (s, 9H), 1.49-1.55 (m, 2H), 2.03-2.07 (m, 2H), 2.79-2.86 (m, 2H), 3.54-3.61 (m, 3H), 4.48-4.49 (m, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H). Compound 193C: LC-MS (ESI) m/z: 211 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.47- 1.55 (m, 4H), 1.90-1.94 (m, 2H), 2.74-2.80 (m, 3H), 3.58-3.62 (m, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H).
[001176] A mixture of Compound 193C (278 mg, 1.32 mmol), benzoyl chloride (228 mg, 1.62 mmol), DMAP (36 mg, 0.294 mmol) and triethylamine (297 mg, 2.94 mmol) in
dichloromethane (30 mL) was stirred at room temperature for 4 hours. The mixture was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to give compound 193D. LC-MS (ESI) m/z: 315 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.73-1.83 (m, 2H), 2.03-2.06 (m, 2H), 2.83-2.89 (m, 2H), 3.71-3.75 (m, 2H), 4.03-4.07 (m, 1H), 6.96-7.01 (m, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.44-7.48 (m, 2H), 7.51-7.56 (m, 1H), 7.83 (m, J = 7.6 Hz, 2H).
[001177] Compounds 193E, 193F, 193G, and 193 were synthesized by employing the procedures described for Compounds 182B, 178A, 1, and 8F using Compounds 193D, 193E, 193F, and 192G in lieu of Compounds 182A, 82C, 1E, and 8E. Compound 193E: LC-MS (ESI) m/z: 301 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.59-1.62 (m, 2H), 2.02-2.05 (m, 2H), 2.69-2.78 (m, 3H), 3.59-3.63 (m, 2H), 3.88 (s, 2H), 6.85 (d, J = 9.2 Hz, 2H), 7.17-7.20 (m, 2H), 7.28-7.39 (m, 5H). Compound 193F: LC-MS (ESI) m/z: 574 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.24 (t, J = 7.2 Hz, 3H), 1.71-1.81 (m, 2H), 1.94-1.97 (m, 2H), 2.64-2.70 (m, 2H), 2.84-2.90 (m, 1H), 3.65-3.68 (m, 2H), 3.78 (s, 3H), 3.80 (s, 2H), 4.05 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 5.76 (s, 2H), 6.80-6.85 (m, 4H), 7.14-7.27 (m, 9H). Compound 193G: LC-MS (ESI) m/z: 454 [M+H]+. Compound 193: LC-MS (ESI) m/z: 426 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.07-2.17 (m, 2H), 2.26-2.29 (m, 2H), 2.75-2.81 (m, 2H), 3.61-3.67 (m, 1H), 3.85-3.89 (m, 2H), 4.57 (s, 2H), 4.78 (s, 2H), 6.98 (d, J = 9.2 Hz, 2H), 7.20-7.24 (m, 2H), 7.41- 7.52 (m, 5H).
[001178] Example 194
[001179] Synthesis of 4-((benzyl(4-cyclohexylphenyl)amino)methyl)-1H-1,2,3-triazole- 5-carboxylic acid (194)
Figure imgf000335_0001
[001180] Compounds 194B, 194C, 194D, 194E, and 194 were synthesized by employing the procedures described for Compounds 193D, 182B, 178A, 1, and 2 using
Compounds 194A with THF as solvent and without DMAP, 194B, 194C, 194D, and 194E in lieu of Compounds 193C with THF as solvent and with DMAP, 182A, 82C, 1E, and 1.
Compound 194B: LC-MS (ESI) m/z: 280 [M+H]+. Compound 194C: LC-MS (ESI) m/z: 266 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.16-1.38 (m, 5H), 1.69-1.84 (m, 5H), 2.36-2.37 (m, 1H), 3.90 (s, 1H), 4.30 (s, 2H), 6.58 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 7.26-7.38 (m, 5H). Compound 194D: LC-MS (ESI) m/z: 539 [M+H]+. Compound 194E: LC-MS (ESI) m/z: 419 [M+H]+. Compound 194: LC-MS (ESI) m/z: 391 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 1.17-1.27 (m, 5H), 1.63-1.71 (m, 5H), 2.28-2.30 (m, 1H), 4.68 (s, 2H), 4.89 (s, 2H), 6.58 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 7.21-7.32 (m, 5H), 13.45 (brs, 1H), 15.38 (brs, 1H).
[001181] Example 195
[001182] Synthesis of 4-(((4-chlorophenyl)(4-(trifluoromethoxy)benzyl)amino)methyl)- 1H-1,2,3-triazole-5-carboxylic acid (195)
Figure imgf000336_0001
[001183] Compounds 195B, 195C, 195D, 195E, and 195 were synthesized by
employing the procedures described for Compounds 193D, 182B, 178A, 1, and 8F using 4- (trifluoromethoxy)benzoyl chloride, Compounds 195A without DMAP, 195B with BH .
3Me2S as reducing agent, 195C, 195D, and 195E in lieu of benzoyl chloride, Compounds 193C with DMAP, 182A with BH3 .THF as reducing agent, 82C, 1E, and 8E. Compound 195B: LC-MS (ESI) m/z: 316 [M+H]+. Compound 195C: 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.11 (s, 1H), 4.33 (s, 2H), 6.52-6.56 (m, 2H), 7.11-7.14 (m, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H). Compound 195D: LC-MS (ESI) m/z: 575 [M+H]+; 1H-NMR (CDCl3, 400 MHz): 1.27 (t, J = 7.2 Hz, 3H), 3.79 (s, 3H), 4.30 (q, J = 7.2 Hz, 2H), 4.72 (s, 2H), 4.81 (s, 2H), 5.78 (s, 2H), 6.72-6.74 (m, 2H), 6.82-6.85 (m, 2H), 7.10-7.12 (m, 4H), 7.21-7.24 (m, 4H). Compound 195E: LC-MS (ESI) m/z: 455 [M+H]+; 1H-NMR (CDCl3, 400 MHz): 1.35 (t, J = 7.2 Hz, 3H), 4.42 (q, J = 7.2 Hz, 2H), 4.70 (s, 2H), 4.94 (s, 2H), 6.69 (d, J = 8.6 Hz, 2H), 7.12-7.17 (m, 4H), 7.26 (m, 2H). Compound 195: LC-MS (ESI) m/z: 427 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 4.74 (s, 2H), 4.93 (s, 2H), 6.65 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 7.28-7.35 (m, 4H).
[001184] Example 196
[001185] Synthesis of 4-((benzyl(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)amino)methyl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (196)
Figure imgf000337_0001
[001186] Compounds 196A, 196B, 196C, 196D, 196E, and 196 were synthesized by employing the procedures described for Compounds 8B, 193D, 182B, 178A, 1, and 8F using 4- (trifluoromethoxy)phenylboronic acid, Compounds 60A with K2CO3 as base and 1,4- dioxane/H2O as solvent, 196A without DMAP, 196B, 196C, 196D, and 196E in lieu of (3,4- dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and toluene as solvent, 193C with DMAP, 182A, 82C, 1E, and 8E. Compound 196A: LC-MS (ESI) m/z: 254 [M+H]+.
Compound 196B: LC-MS (ESI) m/z: 358 [M+H]+. Compound 196C: LC-MS (ESI) m/z: 344 [M+H]+ ;1H-NMR: (CDCl3, 400 MHz): d (ppm) 4.19 (s, 1H), 4.38 (s, 2H), 6.69-6.71 (m, 2H), 7.21-7.27 (m, 3H), 7.29-7.40 (m, 6H), 7.50-7.52 (m, 2H). Compound 196D: LC-MS (ESI) m/z: 617 [M+H]+. Compound 196E: LC-MS (ESI) m/z: 497 [M+H]+. Compound 196: LC-MS (ESI) m/z: 469 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.54 (s, 2H), 4.86 (s, 2H), 6.94-6.96 (m, 2H), 7.08-7.27 (m, 7H), 7.30-7.32 (m, 4H).
[001187] Example 197
[001188] Synthesis of 4-((2,4'-dichloro-[1,1'-biphenyl]-4-yl)difluoromethyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (197)
Figure imgf000338_0001
[001189] Compounds 197B, 197C, 197D, 197E, 197F, Mixtures of 197G-1 and 197G-2, 197H-1 and 197H-2, and 197 were synthesized by employing the procedures described for Compounds 8B, 8F, 166B, 166C, 166D, Mixtures of 166E-1 and 166E-2, 8F, and 1 using (2- chloro-4-(methoxycarbonyl)phenyl)boronic acid, Compounds 197A with Na2CO3 as base and 1,4-dioxane/MeCN/H2O as solvent, 197B, 197C, 197D, 197E, 197F, Mixtures of 197G-1 and 197G-2, and 197H-1 and 197H-2 in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 8E, 166A, 166B, 166C, 166D, 8E, and 1E. Compound 197B: LC-MS (ESI) m/z: 281 [M+H]+. Compound 197C: LC-MS (ESI) m/z: 267 [M+H]+. Compound 197E: LC-MS (ESI) m/z: 347 [M+H]+. Compound 197F: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.35 (t, J = 7.1 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 7.34–7.40 (m, 2H), 7.41–7.45 (m, 3H), 7.58–7.62 (m, 1H), 7.76 (d, J = 1.4 Hz, 1H). Mixtures of 197G-1 and 197G-2: LC-MS (ESI) m/z: 532 [M+H]+. Mixtures of 197H-1 and 197H-2: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 197: LC-MS (ESI) m/z: 384 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.49– 7.59 (m, 6H), 7.75 (s, 1H).
[001190] Example 198
[001191] Synthesis of 4-(difluoro(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (198)
Figure imgf000339_0001
[001192] Compounds 198B, 198C, 198D, 198E, Mixtures of 198F-1 and 198F-2,
198G-1 and 198G-2, and 198 were synthesized by employing the procedures described for Compounds 4B, 166B, 166C, 166D, Mixtures of 166E-1 and 166E-2, 8F, and 1 using (4- (trifluoromethoxy)phenyl)boronic acid, Compounds 198A with K2CO3 as base and 1,4- dioxane/H2O as solvent, 198B, 198C, 198D, 198E, Mixtures of 198F-1 and 198F-2, and 198G-1 and 198G-2 in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 166A, 166B, 166C, 166D, 8E, and 1E. Compound 198B: LC-MS (ESI) m/z: 281 [M-H]-. Compound 198D: LC-MS (ESI) m/z: 363[M+H]+. Compound 198E: LC- MS (ESI) m/z: non-ionizable compound under routine conditions used. Mixtures of 198F-1 and 198F-2: LC-MS (ESI) m/z: 548 [M+H]+. Mixtures of 198G-1 and 198G-2: LC-MS (ESI) m/z: 1061 [2M+Na]+. Compound 198: LC-MS (ESI) m/z: 400 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.47 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H).
[001193] Example 199
[001194] Synthesis of 4-((6-chloronaphthalen-2-yl)difluoromethyl)-1H-1,2,3-triazole-5- carboxylic acid (199)
Figure imgf000340_0001
[001195] Compounds 199B, 199C, 199D, 199E-1 and 199E-2, 199F, and 199 were synthesized by employing the procedures described for Compounds 166B, 166C, 166D, Mixtures of 166E-1 and 166E-2, 8F, and 1 using Compounds 199A, 199B, 199C, 199D, 199E- 1, and 199F in lieu of Compounds 166A, 166B, 166C, 166D, 8E, and 1E. Compound 199C: LC- MS (ESI) m/z: 287 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40 (t, J = 7.2 Hz, 3H), 4.39 (q, J = 6.8 Hz, 2H), 7.55 (dd, J = 2, 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 2 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 8.12 (dd, J = 2, 8.8 Hz, 1H), 8.66 (s, 1H). Compound 199D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.32 (t, J = 7.2 Hz, 3H), 4.30 (q, J = 7.6 Hz, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.87-7.89 (m, 3H), 8.14 (s, 1H). Compound 199E-1: LC-MS (ESI) m/z: 472
[M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.18 (t, J = 6.8 Hz, 3H), 3.58 (s, 3H), 4.22 (q, J = 7.2 Hz, 2H), 5.73 (s, 2H), 6.60 (dd, J = 2, 6.4 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.25-7.26 (m, 1H), 7.44 (dd, J = 2., 8.4 Hz, 1H), 7.48-7.50 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H). Compound 199E-2: LC-MS (ESI) m/z: 472 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.26 (t, J = 7.2 Hz, 3H), 3.78 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 5.82 (s, 2H), 6.84 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.48 (dd, J = 2, 8.4 Hz, 1H), 7.68 (dd, J = 2, 8.4 Hz, 1H), 7.79-7.86 (m, 3H), 8.02 (s, 1H). Compound 199F: LC-MS (ESI) m/z: 466 [M+Na]+. Compound 199: LC-MS (ESI) m/z: 324 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.61 (dd, J = 2.8, 8.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 2.8 Hz, 2H).
[001196] Example 200
[001197] Synthesis of 4-((4'-chloro-[1,1'-biphenyl]-4-yl)difluoromethyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (200)
Figure imgf000341_0001
[001198] Compounds 200B, 200C, 200D, Mixtures of 200E-1 and 200E-2, 200F-1 and 200F-2, and 200 were synthesized by employing the procedures described for Compounds 166B, 166C, 166D, Mixtures of 166E-1 and 166E-2, 8F, and 1 using Compounds 200A, 200B, 200C, 200D, Mixtures of 200E-1 and 200E-2, and 200F-1 and 200F-2 in lieu of Compounds 166A, 166B, 166C, 166D, 8E, and 1E. Compound 200C: LC-MS (ESI) m/z: 313 [M+H]+. Compound 200D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Mixtures of 200E-1 and 200E-2: LC-MS (ESI) m/z: 498 [M+H]+. Mixtures of 200E-1 and 200E-2: LC-MS (ESI) m/z: 961 [2M+Na]+. Compound 200: LC-MS (ESI) m/z: 350 [M+H]+; 1H-NMR (DMSO- d6, 400 MHz): d (ppm) 7.53 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.77 8.4 Hz, 2H).
[001199] Example 201
[001200] Synthesis of 4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)difluoromethyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (201)
Figure imgf000342_0001
[001201] Compounds 201B, 201C, 201D, Mixtures of 201E-1 and 201E-2, 201F-1 and 201F-2, and 201 were synthesized by employing the procedures described for Compounds 166B, 166C, 166D, Mixtures of 166E-1 and 166E-2, 8F, and 1 using Compounds 201A, 201B, 201C, 201D, Mixtures of 201E-1 and 201E-2, and 201F-1 and 201F-2 in lieu of Compounds 166A, 166B, 166C, 166D, 8E, and 1E. Compound 201B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 201C: LC-MS (ESI) m/z: 347 [M+H]+. Compound 201D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used, 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.35 (t, J = 7.1 Hz, 3H), 4.31 (q, J = 7.1 Hz, 2H), 7.42 (dd, J = 8.3, 2.1 Hz, 1H), 7.50– 7.58 (m, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H). Mixtures of 201E-1 and 201E-2: LC-MS (ESI) m/z: 532 [M+H]+. Mixtures of 201E-1 and 201E-2: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 201: LC-MS (ESI) m/z: 384 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.62 (d, J = 8.2 Hz, 2H), 7.71– 7.78 (m, 2H), 7.85 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 1.6 Hz, 1H), 13.53 (s, 1H), 15.98 (s, 1H). [001202] Reference Example 202
[001203] Synthesis of 4-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (202)
Figure imgf000343_0001
[001204] Compounds 202B, 202C, 202D, and 202 were synthesized by employing the procedures described for Compounds 27C, 8B, 8F, and 1 using Compounds 202A, 202B, 202C, and 202D in lieu of Compounds 27B, 8A, 8E, and 1E. Compound 202C: LC-MS (ESI) m/z: 392 [M+H]+. Compound 202D: LC-MS (ESI) m/z: 364 [M+H]+. Compound 202: LC-MS (ESI) m/z: 244 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.74 (s, 4H), 2.74 (s, 4H), 7.12 (d, J = 7.2 Hz, 1H), 7.46 (s, 2H), 13.03(s, 1H), 15.63 (s, 1H).
[001205] Example 203
[001206] Synthesis of 4-(4'-chloro-2-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3- triazole-5-carboxylic acid (203)
Figure imgf000343_0002
[001207] Compounds 203B, 203C, 203D, 203E, and 203 were synthesized by employing the procedures described for Compounds 4B, 27C, 4B, 1, and 8F using (4- chlorophenyl)boronic acid, Compounds 203A with K2CO3 as base and 1,4-dioxane as solvent, 203B with DMSO as solvent, 203C, Intermediate A with 1,4-dioxane/H2O as solvent, 203D, and 203E in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 27B with 1,4-dioxane as solvent, (4-bromophenyl)boronic acid, 4A with toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 203B: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 7.34- 7.42 (m, 4H), 7.50-7.52 (m, 2H), 7.71-7.73 (m, 1H). Compound 203C: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used. Compound 203D: LC-MS (ESI) m/z: 532 [M+H]+. Compound 203E: LC-MS (ESI) m/z: 412 [M+H]+. Compound 203: LC-MS (ESI) m/z: 384 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 7.47-7.57 (m, 5H), 8.12-8.14 (m, 1H), 8.21 (s, 1H).
[001208] Example 204
[001209] Synthesis of (isobutyryloxy)methyl 4-(6-chloroquinolin-2-yl)-1H-1,2,3- triazole-5-carboxylate (204)
Figure imgf000344_0001
[001210] To a solution of Compound 132A (474 mg, 1.12 mmol) in TFA (5 mL) was added thioanisole (139 mg, 1.12 mmol) and stirred at 60 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 40% v/v) to afford Compound 204A. LC-MS (ESI) m/z: 303 [M+H]+.
[001211] Compounds 204B, 204C, 204D, and 204 were synthesized by employing the procedures described for Compounds 54A, 8F, 54C, and 54 using Compounds 204A, 204B, chloromethyl isobutyrate, 204C at room temperature, and 204D in lieu of Compounds 33, 8E, chloromethyl pivalate, 54B at 50 °C, and 54C. Compound 204B: LC-MS (ESI) m/z: 545
[M+H]+. Compound 204C: LC-MS (ESI) m/z: 517 [M+H]+. Compound 204D: LC-MS (ESI) m/z: 617 [M+H]+. Compound 204: LC-MS (ESI) m/z: 375 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.11 (d, J = 6.8 Hz, 6H), 2.51-2.61 (m, 1H), 5.97 (s, 2H), 7.76-7.81 (m, 1H), 8.04-8.16 (m, 3H), 8.38-8.42 (m, 1H).
[001212] Reference Example 205
[001213] Synthesis of 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (205)
Figure imgf000345_0001
[001214] Compounds 205B, 205C, and 205 were synthesized by employing the procedures described for Compounds 27C, 4B, and 1 using Compounds 205A, Intermediate A, 205B with K2CO3 as base and 1,4-dioxane as solvent, and 205C in lieu of Compounds 27B, 4A, (4- bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, and 1E. Compound 205B: LC-MS: (ESI) m/z: 263 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (s, 12H), 4.24-4.29 (m, 4H), 6.87 (d, J = 8.0 Hz, 1H), 7.27-7.33 (m, 2H). Compound 205C: LC- MS (ESI) m/z: 368 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.69 (s, 3H), 4.26-4.30 (m, 4H), 5.36 (s, 2H), 6.78-6.84 (m, 3H), 6.88-6.95 (m, 4H), 12.82 (s, 1H). Compound 205: LC- MS (ESI) m/z: 248 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.23 (s, 4H), 6.81 (d, J = 8.4 Hz, 1H), 7.74-7.76 (m, 1H), 7.96 (s, 1H).
[001215] Example 206
[001216] Synthesis of 4-(1-isopropyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (206)
Figure imgf000346_0001
[001217] To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline 175A (1.4 g, 6.6 mmol) in DMF (30 mL) was added Cs2CO3 (3.8 g, 11.7 mmol) and 2-iodopropane (7.5 g, 17.6 mmol). The mixture was stirred at 55 oC for 16 hours. After cooled down to room temperature, the mixture was diluted with water (200 mL) and extracted with ethyl acetate in petroleum ether (15% v/v) (200 mL x 3). The combined organic phase was washed with bine (150 mL x 4), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (petroleum ether) to furnish Compound 206A. LC-MS (ESI) m/z: 254 [M+H]+.
[001218] Compound 206B was synthesized by employing the procedure described for Compound 27C using Compound 206A in lieu of Compound 27B, LC-MS (ESI) m/z: 302
[M+H]+.
[001219] A mixture of Intermediate A (575 mg, 1.69 mmol), Pd(PPh3)2Cl2 (387 mg, 0.55 mmol), Compound 206B (450 mg, 1.49 mmol), and Na2CO3 (473 mg, 4.46 mmol) in water (5 mL) and 1,4-dioxane (20 mL) was heated to 90 o C for 16 hours. The mixture was cooled down to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified with preparative HPLC to afford Compound 206C. LC-MS (ESI) m/z: 435 [M+H]+.
[001220] Compounds 206D and 206 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 206C and 206D in lieu of Compounds 8E and 1E. Compound 206D: LC-MS (ESI) m/z: 407 [M+H]+. Compound 206: LC-MS (ESI) m/z: 287 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.26 (s, 3H), 1.28 (s, 3H), 1.98-2.04 (m, 2H), 2.84 (s, 2H), 3.39 (s, 2H), 4.21 (s, 1H), 7.05 (s, 1H), 7.59 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H). [001221] Example 207
[001222] Synthesis of 4-(4,5-dichloropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (207)
Figure imgf000347_0001
[001223] A mixture of 2,4,5-trichloropyridine 207A (600 mg, 3.28 mmol), 1,1,1,2,2,2- hexamethyldistannane (1.18 g, 3.61 mmol), and tetrakis(triphenylphosphine)palladium (379 mg, 0.328 mmol) in 1,4-dioxane (10 mL) was degassed with nitrogen, and then heated at 100 oC under nitrogen for 3 hours. The reaction mixture was concentrated to give a crude Compound 207B, which was used directly for next step without purification. LC-MS (ESI) m/z: 312
[M+H]+.
[001224] To a solution of the crude Compound 207B in DMA (5 mL) was added
Intermediate A (1.11 g, 3.28 mmol) and tetrakis(triphenylphosphine)palladium (379 mg, 0.328 mmol) and degassed with nitrogen, and then heated in a microwave reactor at 140 oC for 1 hour. The reaction mixture was quenched with a saturated KF solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to afford Compound 207C. LC-MS (ESI) m/z: 407 [M+H]+.
[001225] Compounds 207D and 207 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 207C and 207D in lieu of Compounds 8E and 1E. Compound 207D: LC-MS (ESI) m/z: 379 [M+H]+. Compound 207: LC-MS (ESI) m/z: 259 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 8.49 (s, 1H), 8.98 (s, 1H). [001226] Example 208
[001227] Synthesis of 4-(5-chloropyridin-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (208)
Figure imgf000348_0001
[001228] Compounds 208B, 208C, 208D, and 208 were synthesized by employing the procedures described for Compounds 207B, 207C, 8F, and 1 using Compounds 208A, 208B with 1,4-dioxane as solvent, 208C, and 208D in lieu of Compounds 207A, 207B with DMA as solvent, 8E, and 1E. Compound 208C: LC-MS (ESI) m/z: 373 [M+H]+. Compound 208D: LC- MS (ESI) m/z: 345 [M+H]+. Compound 208: LC-MS (ESI) m/z: 225 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 8.22-8.32 (m, 2H), 8.87 (s, 1H).
[001229] Example 209
[001230] Synthesis of 4-(4-(2-acetamidoethoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid (209)
Figure imgf000349_0001
[001231] Compounds 209A and 209B were synthesized by employing the procedures described for Compounds 90C and 190F using 2-(2-hydroxyethyl)isoindoline-1,3-dione, Compounds 87A with DEAD as coupling reagent, and 209A with EtOH as solvent in lieu of Compounds 90B, Intermediate H with DIAD as coupling reagent, and 190E with MeOH/H2O as solvent. Compound 209A: LC-MS (ESI) m/z: 346 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.07-4.13 (m, 2H), 4.18-4.21 (m, 2H), 6.73-6.76 (m, 2H), 7.31-7.34 (m, 2H), 7.72-7.74 (m, 2H), 7.85-7.87 (m, 2H). Compound 209B: LC-MS (ESI) m/z: 216 [M+H]+.
[001232] To a solution of Compound 209B (541 mg, 2.65 mmol) in dichloromethane (20 mL) was added Et3N (802 mg, 7.95 mmol) and acetic anhydride (541 mg, 5.3 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with diluted HCl solurion (1N, 30 mL) and saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 209C. LC-MS (ESI) m/z: 258 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.04 (s, 3H), 3.65 (t, J = 4.8 Hz, 2H), 4.00 (t, J = 4.8 Hz, 2H), 5.97 (b, 1H), 6.75-6.79 (m, 2H), 7.35-7.39 (m, 2H).
[001233] Compounds 209D, 209E, 209F, and 209 were synthesized by employing the procedures described for Compounds 27C, 4B, 8F, and 1 using Compounds 209C, Intermediate A, 209D with K2CO3 as base and 1,4-dioxane as solvent, 209E, and 209F in lieu of Compounds 27B, 4A, (4-bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 209D: LC-MS (ESI) m/z: 306 [M+H]+. Compound 209E: LC-MS (ESI) m/z: 439 [M+H]+. Compound 209F: LC-MS (ESI) m/z: 411 [M+H]+. Compound 209: LC-MS (ESI) m/z: 291 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.83 (s, 3H), 3.42 (q, J = 5.6 Hz, 2H), 4.04 (t, J = 5.7 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 7.77 (s, 2H), 8.12 (s, 1H), 12.97 (s, 1H), 15.69 (s, 1H) .
[001234] Example 210
[001235] Synthesis of 4-(7-fluoroisoquinolin-3-yl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (210)
Figure imgf000350_0001
[001236] To a solution of 6-fluoro-2,3-dihydro-1H-inden-1-one (210A) (3.0 g, 20 mmol) in ether (20 mL) was added a solution of HCl in 1,4-dioxane (4 M, 7.5 ml, 30 mmol), followed by dropping isopentyl nitrite (3.5 g, 30 mmol) at 0 oC. The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was washed with petroleum ether (50 ml) to afford Compound 210B. LC-MS (ESI) m/z: 180 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.76 (s, 2H), 7.50 (s, 1H), 7.51-7.68 (m, 2H), 12.74 (s, 1H).
[001237] A mixture of Compound 210B (2.5 g, 14 mmol) and PCl5 (4.3 g, 21 mmol) in POCl3 (20 mL) was stirred at 80 oC overnight. After cooled down to room temperature, the mixture was concentrated under reduced pressure to give a crude Compound 210C. LC-MS (ESI) m/z: 216 [M+H]+.
[001238] To a solution of Compound 210C (3.0 g, 14 mmol) in acetic acid (10 mL) was added 55% aqueous HI solution (5 mL) and stirred at 100 oC for 16 hours. The mixture was concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 solution (100 mL), extracted with ethyl acetate (50 mL x 3), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to afford Compound 210D. LC-MS (ESI) m/z: 182 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.52- 7.55 (m, 1H), 7.58-7.61 (m, 1H), 7.75 (s, 1H), 7.78-7.82 (m, 1H), 9.05 (s, 1H).
[001239] Compounds 210E, 210F, 210G, and 210 were synthesized by employing the procedures described for Compounds 207B, 207C, 1, and 8F using tributyltin hydride,
Compounds 210D with xylene as solvent at 135 °C, 210E with xylene as solvent, 210F, and 210G in lieu of 1,1,1,2,2,2-hexamethyldistannane, Compounds 207A with 1,4-dioxane as solvent at 100 °C, 207B with DMA as solvent, 1E, and 8E. Compound 210E: LC-MS (ESI) m/z: 438 [M+H]+. Compound 210F: LC-MS (ESI) m/z: 407 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 3.67 (s, 3H), 4.36 (q, J = 7.2 Hz, 2H), 5.81 (s, 2H), 6.61-6.64 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.55-7.57 (m, 1H), 7.67-7.69 (m, 1H), 7.87-7.90 (m, 1H), 8.03 (s, 1H), 9.34 (s, 1H). Compound 210G: LC-MS (ESI) m/z: 287 [M+H]+. Compound 210: LC-MS (ESI) m/z: 259 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.92-7.94 (m, 1H), 8.10-8.13 (m, 1H), 8.39 (s, 1H), 8.95 (s, 1H), 9.57 (s, 1H).
[001240] Example 211
[001241] Synthesis of 4-(6-(trifluoromethoxy)isoquinolin-3-yl)-1H-1,2,3-triazole- carboxylic acid (211)
Figure imgf000351_0001
[001242] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (5.0 g, 26.3 mmol) in THF (50 mL) was added NaH (60% suspension in oil, 1.26 g, 31.6 mmol) at 0 oC. After the mixture was stirred at 0 oC for 10 minutes, a solution of 3-(trifluoromethoxy)benzaldehyde (211A) (7.1 g, 31.6 mmol) in THF (30 mL) was added. The resulting mixture was stirred at room temperature for 12 hours, quenched with H2O (50 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers was dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 211B. LC-MS (ESI) m/z: 261 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34 (t, J = 7.2 Hz, 3H), 4.27 (q, J = 7.2 Hz, 2H), 6.45 (d, J = 16.4 Hz, 1H), 7.22-7.24 (m, 1H), 7.36-7.43 (m, 3H), 7.65 (d, J = 16.4 Hz, 1H).
[001243] To a solution of Compound 211B (6.5 g, 25 mmol) in EtOH (100 mL) was added Pd/C (10%, 1.0 g) and stirred at room temperature under hydrogen (1 atm) for 12 hours. The mixture was filtered through Celite and the filtrate was concentrated to give a crude
Compound 211C. LC-MS (ESI) m/z: 263 [M+H]+.
[001244] Compound 211D was synthesized by employing the procedure described for Compound 2 using Compound 211C with MeOH/H2O as solvent in lieu of Compound 1 with THF/H2O as solvent, LC-MS (ESI) m/z: 235 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.69 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 7.06-7.08 (m, 1H), 7.13-7.15 (m, 2H), 7.29- 7.33 (m, 1H), 9.93 (s, 1H).
[001245] The mixture of Compound 211D (8.5 g, 36 mmol) in PPA (30 mL) was stirred at 80 oC for 12 hours. The mixture was quenched with ice-water (100 mL), adjusted to pH 8 with saturated NaHCO3 solution, and extracted with ethyl acetate (100 mL x 3). The combined organic layers was dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 211E. LC-MS (ESI) m/z: 217 [M+H]+; 1H-NMR (CDCl3, 500 MHz): d (ppm) 2.73- 2.76 (m, 2H), 3.17-3.19 (m, 2H), 7.21 (dd, J = 7.2, 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H).
[001246] Compounds 211F, 211G, and 211H were synthesized by employing the procedures described for Compounds 210B, 210C, and 210D using Compounds 211E, 211F, and 211G in lieu of Compounds 210A, 210B, and 210C. Compound 211F: LC-MS (ESI) m/z: 246 [M+H]+. Compound 211G: LC-MS (ESI) m/z: 282 [M+H]+. Compound 211H: LC-MS (ESI) m/z: 248 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.46 (dd, J = 8.8, 1.6 Hz, 1H), 7.71 (s, 1H), 7.86 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 9.04 (s, 1H).
[001247] To a mixture of Compound 211H (1.5 g, 6.1 mmol) and
bis(triphenylphosphine)palladium(II) chloride (428 mg, 0.61 mmol) in triethylamine (3 mL) was added CuI (116 mg, 0.61 mmol) and heated in a sealed tube at 80 oC under nitrogen for 12 hours. After cooled down to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford a crude Compound 211I, which was used directly in next step without further purification. LC-MS (ESI) m/z: 310 [M+H]+.
[001248] To a solution of Compound 211I (1.0 g, 3.2 mmol) in MeOH (20 mL) and water (2 mL) was added KOH (896 mg, 16 mmol) and stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 6 with diluted aqueous HCl solution and extracted with ethyl acetate (100 mL x 3). The combined organic layers was dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 211J. LC-MS (ESI) m/z: 238 [M+H]+.
[001249] To a solution of Compound 211J (480 mg, 2 mmol) in THF (50 mL) at -78 oC under nitrogen was dropped a solution of n-BuLi in n-hexane (2.5 M, 1.6 mL, 4 mmol) and stirred at -78 oC for 15 minutes, followed by addition of ethyl carbonochloridate (1 mL, 10.5 mmol) dropwise. The mixture was stirred at -78 oC for 1.5 hours, quenched with saturated aqueous NH4Cl solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish Compound 211K. LC-MS (ESI) m/z: 310 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.29 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 7.45-7.57 (m, 2H), 7.96-8.01 (m, 2H), 9.19 (s, 1H).
[001250] Compounds 211L, 211M, and 211 were synthesized by employing the
procedures described for Mixture of 166E-1 and 166E-2, Compounds 1, and 8F using
Compounds 211K with EtOH as solvent at reflux, 211L, and 211M in lieu of Compounds 166D with THF as solvent at 60 oC,, 1E, and 8E. Compound 211L: LC-MS (ESI) m/z: 473 [M+H]+. Compound 211M: LC-MS (ESI) m/z: 353 [M+H]+. Compound 211: LC-MS (ESI) m/z: 325 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.82 (d, J = 8.8 Hz, 1H), 8.33 (s, 1H), 8.48 (d, J = 8.8 Hz, 1H), 8.99 (s, 1H), 9.67 (s, 1H).
[001251] Example 212
[001252] Synthesis of 4-(5,6,7,8-tetrahydroquinolin-2-yl)-1H-1,2,3-triazole-5- carboxylic acid (212)
Figure imgf000354_0001
[001253] Compounds 212B, 212C, 212D, 212E, 212F, and 212 were synthesized by employing the procedures described for Compounds 211I, 211J, 211K, Mixture of 166E-1 and 166E-2, Compounds 1, and 8F using Compounds 212A, 212B, 212C, 212D with EtOH as solvent at reflux, 212E, and 212F in lieu of Compounds 211H, 211I, 211J, 166D with THF as solvent at 60 oC, 1E, and 8E. Compound 212B: LC-MS (ESI) m/z: 230 [M+H]+. Compound 212C: LC-MS (ESI) m/z: 158 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.79-1.90 (m, 4H), 2.77 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H), 3.07 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H). Compound 212D: LC-MS (ESI) m/z: 230 [M+H]+. Compound 212E: LC-MS (ESI) m/z: 393 [M+H]+. Compound 212F: LC-MS (ESI) m/z: 273 [M+H]+. Compound 212: LC- MS (ESI) m/z: 245 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.77-1.88 (m, 4H), 2.77- 2.88 (m, 4H), 7.78 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H).
[001254] Example 213
[001255] Synthesis of 4-(6-fluoroisoquinolin-3-yl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (213)
Figure imgf000355_0001
[001256] Compounds 213B, 213C, 213D, 213E, 213F, 213G, and 213 were synthesized by employing the procedures described for Compounds 210B, 210C, 210D, 207B, 207C, 1, and 8F using Compounds 213A, 213B, 213C, tributyltin hydride, 213D with xylene as solvent at 135 °C, 213E with xylene as solvent, 213F, and 213G in lieu of Compounds 210A, 210B, 210C, 1,1,1,2,2,2-hexamethyldistannane, 207A with 1,4-dioxane as solvent, 207B with DMA as solvent, 8E, and 1E. Compound 210B: LC-MS (ESI) m/z: 180 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.87 (s, 2H), 7.15-7.22 (m, 2H), 7.91-7.94 (m, 1H), 8.88 (s, 1H). Compound 210C: LC-MS (ESI) m/z: 216 [M+H]+. Compound 210D: LC-MS (ESI) m/z: 182 [M+H]+; 1H- NMR (CD3OD, 400 MHz): d (ppm) 7.48-7.53 (m, 1H), 7.58-7.61 (m, 1H), 7.90 (s, 1H), 8.18- 8.22 (m, 1H), 9.09 (s, 1H). Compound 210E: LC-MS (ESI) m/z: 438 [M+H]+. Compound 210F: LC-MS (ESI) m/z: 407 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 3.68 (s, 3H), 4.36 (q, J = 7.2 Hz, 2H), 5.81 (s, 2H), 6.62-6.64 (m, 2H), 6.91 (d, J = 8.8 Hz, 2H), 7.45-7.51 (m, 2H), 7.97 (s, 1H), 8.07-8.11 (m, 1H), 9.35 (s, 1H). Compound 210G: LC-MS (ESI) m/z: 287 [M+H]+. Compound 210: LC-MS (ESI) m/z: 259 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.61-7.80 (m, 1H), 8.10-8.12 (m, 1H), 8.42-8.46 (m, 1H), 8.95 (s, 1H), 9.63 (s, 1H).
[001257] Example 214
[001258] Synthesis of 4-(7-(trifluoromethoxy)isoquinolin-3-yl)-1H-1,2,3-triazole-5- carboxylic acid (214)
Figure imgf000356_0001
[001259] Compounds 214B, 214C, 214D, 214E, 214F, 214G, 214H, 214I, 214J, 214K, 214L, 214M, and 214 were synthesized by employing the procedures described for Compounds 211B, 211C, 2, 211E, 210B, 210C, 210D, 211I, 211J, 211K, Mixture of 166E-1 and 166E-2, 1, and 8F using Compounds 214A, 214B, 214C with MeOH/H2O as solvent, 214D, 214E, 214F, 214G, 214H, 214I, 214J, 214K with EtOH as solvent at reflux, 214L, and 214M in lieu of Compounds 211A, 211B, 1 with THF/H2O as solvent, 211D, 210A, 210B, 210C, 211H, 211I, 211J, 166D with THF as solvent at 60 oC, 1E, and 8E. Compound 214B: LC-MS (ESI) m/z: 261 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm)1.34 (t, J = 7.2 Hz, 3H), 4.27 (q, J = 7.2 Hz, 2H), 6.41 (d, J = 16.0 Hz, 1H), 7.21-7.23 (m, 2H), 7.54-7.56 (m, 2H), 7.65 (d, J = 16.0 Hz, 1H).
Compound 214C: LC-MS (ESI) m/z: 263 [M+H]+. Compound 214D: LC-MS (ESI) m/z: 235 [M+H]+. Compound 214E: LC-MS (ESI) m/z: 217 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.68-2.70 (m, 2H), 3.07-3.10 (m, 2H), 7.34-7.37 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H). Compound 214F: LC-MS (ESI) m/z: 246 [M+H]+. Compound 214G: LC-MS (ESI) m/z: 282 [M+H]+. Compound 214H: LC-MS (ESI) m/z: 248 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.59-7.61 (m, 1H), 7.85 (s, 1H), 7.90-7.94 (m, 2H), 9.05 (s, 1H). Compound 214I: LC- MS (ESI) m/z: 310 [M+H]+. Compound 214J: LC-MS (ESI) m/z: 238 [M+H]+. Compound
214K: LC-MS (ESI) m/z: 310 [M+H]+. Compound 214L: LC-MS (ESI) m/z: 473 [M+H]+.
Compound 214M: LC-MS (ESI) m/z: 353 [M+H]+. Compound 214: LC-MS (ESI) m/z: 325 [M+H]+; 1H-NMR (DMSO-d6, 500 MHz): d (ppm) 7.97 (s, 1H), 8.35-8.43 (m, 2H), 8.97 (s, 1H), 9.65 (s, 1H).
[001260] Example 215
[001261] Synthesis of 4-(7-(trifluoromethyl)isoquinolin-3-yl)-1H-1,2,3-triazole-5- carboxylic acid (215)
Figure imgf000357_0001
[001262] Compounds 215B, 215C, 215D, 215E, 215F, 215G, 215H, 215I, 215J, and 215 were synthesized by employing the procedures described for Compounds 211E, 210B, 210C, 210D, 211I, 211J, 211K, Mixture of 166E-1 and 166E-2, 1, and 8F using Compounds 215A, 215B, 215C, 215D, 215E, 215F, 215G, 215H with EtOH as solvent at reflux, 215I, and 215J in lieu of Compounds 211D, 210A, 210B, 210C, 211H, 211I, 211J, 166D with THF as solvent at 60 oC, 1E, and 8E. Compound 215B: LC-MS (ESI) m/z: 201 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.77-2.80 (m, 2H), 3.22-3.25 (m, 2H), 7.63(d, J = 8.0 Hz, 1H), 7.84 (dd, J = 8.0, 1.2 Hz, 1H), 8.04 (s, 1H). Compound 215C: LC-MS (ESI) m/z: 230 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.96 (s, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H). Compound 215D: LC-MS (ESI) m/z: 266 [M+H]+. Compound 215E: LC-MS (ESI) m/z: 232 [M+H]+. Compound 215F: LC-MS (ESI) m/z: 294 [M+H]+; 1H-NMR (CDCl3, 500 MHz): d (ppm) 3.32 (s, 9H), 7.89-7.96 (m, 3H), 8.30 (s, 1H), 9.33 (s, 1H). Compound 215G: LC-MS (ESI) m/z: 222 [M+H]+. Compound 215H: LC-MS (ESI) m/z: 294 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.38 (t, J = 7.2 Hz, 3H), 4.35 (q, J = 7.2 Hz, 2H), 7.91-8.01 (m, 2H), 8.12 (s, 1H), 8.32 (d, J = 12 Hz, 1H), 9.35 (d, J = 13.6 Hz, 1H). Compound 215I: LC-MS (ESI) m/z: 457 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34 (t, J = 7.2 Hz, 3H), 3.68 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.85 (s, 2H), 6.62-6.64 (m, 2H), 6.90-6.94 (m, 2H), 7.92-7.99 (m, 2H), 8.11 (s, 1H), 8.39 (s, 1H), 9.50 (s, 1H). Compound 215J: LC-MS (ESI) m/z: 337 [M+H]+. Compound 215: LC-MS (ESI) m/z: 309 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 8.20 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H), 8.80 (s, 1H), 8.98 (d, J = 11.2 Hz, 1H), 9.74 (s, 1H).
[001263] Example 216
[001264] Synthesis of 4-(7-chloroquinolin-3-yl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (216)
Figure imgf000358_0001
[001265] Compounds 216A, 216B, 216C, and 216 were synthesized by employing the procedures described for Compounds 30B, 27C, 4B, and 1 using Compounds 186E with tert- butyl nitrite and CuBr2 and 1,2-dibromoethane as solvent, 216A, Intermediate A, 216B with K2CO3 as base and 1,4-dioxane/H2O as solvent, and 216C in lieu of Compounds 30A with isoamyl nitrite and CuCl2 and MeCN as solvent, 27B, 4A, (4-bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, and 1E. Compound 216A: LC-MS (ESI) m/z: 241 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.53-7.56 (m, 1H), 7.69-7.71 (m, 1H), 8.09- 8.10 (m, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H). Compound 216B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR: (CDCl3, 400 MHz): d (ppm) 1.41 (s, 12H), 7.49-7.52 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.60 (s, 1H), 9.19 (d, J = 1.6 Hz, 1H). Compound 216C: LC-MS (ESI) m/z: 395 [M+H]+. Compound 216: LC-MS (ESI) m/z: 275 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.70-7.72 (m, 1H), 8.12-8.14 (m, 2H), 8.85 (s, 1H), 9.29 (s, 1H).
[001266] Example 217
[001267] Synthesis of 4-(3-chloro-5-(cyclopropylmethoxy)phenyl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (217)
Figure imgf000359_0001
[001268] Compounds 217B, 217C, and 217D were synthesized by employing the procedures described for Compounds 27B, 27C, and 206C using (bromomethyl)cyclopropane, Compounds 217A with K2CO3 as base at 80 °C, 217B, and 217C in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base at 100 °C, 27B, and 206B. Compound 217B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.34-0.36 (m, 2H), 0.64-0.67 (m, 2H), 1.25-1.27 (m, 1H), 3.77 (d, J = 7.2 Hz, 2H), 6.84 (t, J = 1.6 Hz, 1H), 6.95 (t, J = 2.4 Hz, 1H), 7.09 (t, J = 1.6 Hz, 1H). Compound 217C: %). LC- MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.32-0.36 (m, 2H), 0.62-0.66 (m, 2H), 1.26 (s, 1H), 1.34 (s, 12H), 3.83 (d, J = 6.8 Hz, 2H), 7.01 (t, J = 1.6 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H). Compound 217D: 442 [M+H]+.
[001269] To a solution of Compound 217D (100 mg, 0.23 mmol) in CH3CN (3 mL) was added the solution of cerium ammonium nitrate (621 mg, 1.13 mmol) in H2O (2 mL) and stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 217E. LC-MS (ESI) m/z: 322 [M+H]+.
[001270] Compound 217 was synthesized by employing the procedure described for Compound 8F using Compounds 217E in lieu of Compound 8E, LC-MS (ESI) m/z: 294
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.31 (d, J = 4.4 Hz, 2H), 0.57 (d, J = 4 Hz, 2H), 1.22-1.25 (m, 1H), 3.87 (d, J = 7.2 Hz, 2H), 7.08 (s, 1H), 7.48 (m, 2H). [001271] Example 218
[001272] Synthesis of 4-(4-chloro-3-(cyclopropylmethoxy)phenyl)-1H-1,2,3-triazole-5- carboxylic acid (218)
Figure imgf000360_0001
[001273] Compounds 218B, 218C, 218D, 218E, and 218 were synthesized by
employing the procedures described for Compounds 27B, 27C, 206C, 217E, and 8F using (bromomethyl)cyclopropane, Compounds 218A with K2CO3 as base at 90 °C, 218B, 218C, 218D, and 218E in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base at 100 °C, 27B, 206B, 217D, and 8E. Compound 218B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.38-0.41 (m, 2H), 0.64-0.68 (m, 2H), 1.29-1.34 (m, 1H), 3.86 (d, J = 6.8 Hz, 2H), 6.99-7.02 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H). Compound 218C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.38-0.39 (m, 2H), 0.63-0.63 (m, 2H), 1.33-1.34 (m, 13H), 3.92 (d, J = 6.8 Hz, 2H), 7.29-7.35 (m, 3H). Compound 218D: LC-MS (ESI) m/z: 442 [M-H]+. Compound 218E: LC-MS (ESI) m/z: 320 [M-H] ¯. Compound 218: LC-MS (ESI) m/z: 294
[M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.34-0.38 (m, 2H), 0.57-0.62 (m, 2H), 1.29- 1.34 (m, 1H), 3.94 (d, J = 6.8 Hz, 2H), 7.37-7.64 (m, 3H), 13.22 (s, 1H), 15.66 (s, 1H).
[001274] Example 219
[001275] Synthesis of 4-(2-chloro-5-(cyclopropylmethoxy)phenyl)-1H-1,2,3-triazole-5- carboxylic acid (219)
Figure imgf000361_0001
[001276] Compounds 219B, 219C, 219D, 219E, and 219 were synthesized by
employing the procedures described for Compounds 27B, 27C, 206C, 217E, and 8F using (bromomethyl)cyclopropane, Compounds 219A with K2CO3 as base at 80 °C, 219B, 219C, 219D, and 219E in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base at 100 °C, 27B, 206B, 217D, and 8E. Compound 219B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.33-0.38 (m, 2H), 0.63-0.69 (m, 2H), 1.20-1.32 (m, 1H), 3.77 (d, J = 6.8 Hz, 2H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H). Compound 219C: LC-MS (ESI) m/z: 309 [M+H]+. Compound 219D: LC-MS (ESI) m/z: 442 [M+H]+. Compound 219E: LC-MS (ESI) m/z: 322 [M+H]+.
Compound 219: LC-MS (ESI) m/z: 294 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.28- 0.33 (m, 2H), 0.52-0.58 (m, 2H), 1.16-1.26 (m, 1H), 3.82 (d, J = 7.2 Hz, 2H), 6.95-7.15 (m, 2H), 7.43 (s, 1H), 13.06 (s, 1H), 15.62 (s, 1H).
[001277] Example 220
[001278] Synthesis of 4-((3'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (220)
Figure imgf000362_0001
[001279] Compounds 220A, 220B, and 220 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using Intermediate I, Compounds 164B with K2CO3 as base and DME as solvent, 220A, and 220B in lieu of Compounds 4A, (4- bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 220A: LC-MS (ESI) m/z: 513 [M+H]+. Compound 220B: LC-MS (ESI) m/z: 483 [M-H]¯. Compound 220: LC-MS (ESI) m/z: 365 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.56-1.63 (m, 2H), 1.71-1.77 (m, 4H), 3.30-3.42 (m, 4H), 7.15-7.17 (m, 3H), 7.27-7.58 (m, 3H), 7.68 (d, J = 8.4 Hz, 2H).
[001280] Example 221
[001281] Synthesis of 4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (221)
Figure imgf000362_0002
[001282] Compounds 221A, 221B, and 221 were synthesized by employing the procedures described for Compounds 4B, 1, and 8F using Intermediate I, Compounds 169B with K2CO3 as base and 1,4-dioxane/ H2O as solvent, 221A, and 221B in lieu of Compounds 4A, (4- bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 221A: LC-MS (ESI) m/z: 513 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.11 (t, J = 7.2 Hz, 3H), 1.61-1.64 (m, 2H), 1.70-1.75 (m, 4H), 3.20-3.24 (m, 4H), 3.75 (s, 3H), 4.19 (q, J = 7.2 Hz, 2H), 5.37 (s, 2H), 6.77-6.81 (m, 4H), 6.99 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.41-7.45 (m, 4H). Compound 221B: LC-MS (ESI) m/z: 393 [M+H]+. Compound 221 LC-MS (ESI) m/z: 365 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.79-1.83 (m, 2H), 2.02-2.08 (m, 4H), 3.62-2.65 (m, 4H), 7.22 (d, J = 8.8 Hz, 2H), 7.65-7.68 (m, 4H), 7.80 (d, J = 8.4 Hz, 2H).
[001283] Example 222
[001284] Synthesis of 4-(4-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenoxy)-1H- 1,2,3-triazole-5-carboxylic acid (222)
Figure imgf000363_0001
[001285] Compounds 222A, 222B, 222C, 222D, and 222 were synthesized by
employing the procedures described for Compounds 206A, 27C, 8B, 8F, and 1 using idomethane with KOtBu as base and DMF as solvent at room temperature, Compounds 222A, Intermediate I, 222B with Na2CO3 as base and 1,4-dioxane/ H2O as solvent, 222C, and 222D in lieu of 2- iodopropane with Cs2CO3 as base and DMF as solvent at 60 °C, Compounds 27B, 8A, (3,4- dichlorophenyl)boronic acid with Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E.
Compound 222A: LC-MS (ESI) m/z: 226 [M+H]+. Compound 222B: LC-MS (ESI) m/z: 274 [M+H]+. Compound 222C: LC-MS (ESI) m/z: 499 [M+H]+. Compound 222D: LC-MS (ESI) m/z: 471[M+H]+. Compound 222: LC-MS (ESI) m/z: 351 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.89-1.92 (m, 2H), 2.75 (t, J = 12.8 Hz, 2H), 2.86 (s, 3H), 3.21 (t, J = 10 Hz, 2H), 6.64 (d, , J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 7.20 (s, 1H), 7.27-7.29 (m, 1H), 7.52 (d, , J = 9.2 Hz, 2H), 15.2 (s, 1H).
[001286] Example 223
[001287] Synthesis of 4-(4-(5,6,7,8-tetrahydronaphthalen-1-yl)phenoxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (223)
Figure imgf000364_0001
[001288] To a stirred solution of 5-bromo-3,4-dihydronaphthalen-1(2H)-one (223A) (225 mg, 1 mmol) in dichloromethane (5 mL) was added BF3 .Et2O (2 mL) and triethylsilane (2 mL) and stirred at room temperature overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with dichloromethane (10 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 1% v/v) to afford Compound 223B. LC-MS: (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.75-1.89 (m, 4H), 2.75-2.81 (m, 4H), 6.94 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H).
[001289] Compounds 223C, 223D, and 223 were synthesized by employing the
procedures described for Compounds 27C, 4B, and 1 using Compounds 223B, Intermediate I, 222C with K2CO3 as base and 1,4-dioxane/ H2O as solvent, and 223D in lieu of Compounds 27B, 4A, (4-bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, and 1E. Compound 223C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (s, 12H), 1.76-1.83 (m, 4H), 2.78-2.81 (m, 2H), 3.04-3.08 (m, 2H), 7.08-7.16 (m, 2H), 7.60-7.63 (m, 1H). Compound 223D: LC-MS (ESI) m/z: 456 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.63-1.73 (m, 4H), 2.45-2.49 (m, 2H), 2.75-2.79 (m, 2H), 3.67 (s, 3H), 5.35 (s, 2H), 6.79-6.91 (m, 5H), 7.04-7.20 (m, 6H). Compound 223: LC-MS(ESI) m/z: 336 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.60-1.75 (m, 4H), 2.48-2.53 (m, 2H), 2.76-2.79 (m, 2H), 6.95 (d, J = 7.2 Hz, 1H), 7.05-7.15 (m, 4H), 7.26 (d, J = 8.8 Hz, 2H).
[001290] Example 224
[001291] Synthesis of 4-((3'-((2-oxopiperidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (224)
Figure imgf000365_0001
[001292] To a solution of piperidin-2-one (396 mg, 4 mmol) in DMF (15 mL) was added NaH (60% suspension in oil, 192 mg, 4.8 mmol) at 0 oC and stirred at 0 oC for 15 minutes, followed by addition of 1-bromo-3-(bromomethyl)benzene (67A) (1000 mg, 4 mmol). The mixture was stirred at room temperature overnight, diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 224A. LC-MS (ESI) m/z: 268 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.79-1.84 (m, 4H), 2.46-2.50 (m, 2H), 3.19-3.23 (m, 2H), 4.57 (s, 2H), 7.19-7.28 (m, 2H), 7.39-7.42 (m, 2H).
[001293] Compounds 224B, 224C, 224D, and 224 were synthesized by employing the procedures described for Compounds 27C, 4B, 1, and 8F using Compounds 224A, Intermediate I, 224B with K2CO3 as base and 1,4-dioxane/ H2O as solvent, 224C, and 224D in lieu of Compounds 27B, 4A, (4-bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 224B: LC-MS (ESI) m/z: 316 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.25 (s, 12H), 1.73-1.82 (m, 4H), 2.46-12.50 (m, 2H), 3.16-3.20 (m, 2H), 4.62 (s, 2H), 7.32-7.40 (m, 2H), 7.67 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H). Compound 224C: LC-MS (ESI) m/z: 541 [M+H]+. Compound 224D: LC-MS (ESI) m/z: 421 [M+H]+. Compound 224: LC- MS (ESI) m/z: 393 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.81-1.83 (m, 4H), 2.43- 2.46 (m, 2H), 3.31-2.33 (m, 2H), 4.66 (s, 2H), 7.19-7.26 (m, 3H), 7.42 (t, J = 7.2 Hz, 1H), 7.51- 7.54 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H).
[001294] Example 225
[001295] Synthesis of 4-((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid (225)
Figure imgf000366_0001
[001296] Compounds 225B and 225C were synthesized by employing the procedures described for Compounds 8B and 8F using Compounds 225A, Intermediate I with Na2CO3 as base and 1,4-dioxane/H2O as solvent, and 225B in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, and 8E. Compound 225B: LC- MS (ESI) m/z: 455 [M+H]+. Compound 225C: LC-MS (ESI) m/z: 427 [M+H]+.
[001297] A mixture of Compound 225C (65 mg, crude) and methyl(phenyl)sulfane (0.5 mL) in TFA (6 mL) was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified with preparative HPLC to afford Compound 225. LC-MS (ESI) m/z: 307 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.14 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.88 (q, , J = 11.6 Hz, 4H).
[001298] Example 226
[001299] Synthesis of 4-((2-isopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (226)
Figure imgf000367_0001
[001300] A mixture of isoquinolin-7-ol (226A) (306 mg, 2.11 mmol) and PtO2 (42 mg, 0.19 mmol) in acetic acid (8 mL) was stirred at room temperature under hydrogen (1 atm.) for 40 hours. The mixture was filtered through Celite and the filtrate was concentrated to give a crude Compound 226B. LC-MS (ESI) m/z: 150 [M+H]+.
[001301] Compounds 226C, 226D, 226E, and 226 were synthesized by employing the procedures described for Compounds 123B, Intermediate I, 8F, and 1 using Compounds 226B, 226C with NMP as solvent, 226D, and 224E in lieu of Compounds 123A, 4-bromophenol with DMF as solvent, 8E, and 1E. Compound 226C: LC-MS (ESI) m/z: 192 [M+H]+. Compound 226D: LC-MS (ESI) m/z: 451 [M+H]+. Compound 226E: LC-MS (ESI) m/z: 423 [M+H]+.
Compound 226: LC-MS (ESI) m/z: 303 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.44 (s, 3H), 1.45 (s, 3H), 3.19 (s, 2H), 3.42 (s, 1H), 3.68-3.75 (m, 2H), 4.43 (s, 2H), 7.02 (s, 1H), 7.09 (dd, J1 = 2.4 Hz, J1 = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H).
[001302] Example 227
[001303] Synthesis of 4-((6-chloronaphthalen-2-yl)methoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (227)
Figure imgf000368_0001
[001304] Compounds 227A, 227B, and 227 were synthesized by employing the procedures described for Compounds 90C, 217E, and 1 using Compounds 174A, 227A, and 227B in lieu of Compounds 90B, 217D, and 1E. Compound 227A: LC-MS (ESI) m/z: 452
[M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.44 (t, J = 7.2 Hz, 3H), 3.75 (s, 3H), 4.43-4.49 (m, 2H), 5.17 (s, 2H), 5.56 (s, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H).
Compound 227B: LC-MS (ESI) m/z: 332 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.41 (t, J = 7.2 Hz, 3H), 4.40-4.46 (m, 2H), 5.54 (s, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.75-7.78 (m, 2H), 7.82 (d, J = 1.6 Hz, 1H), 7.91 (s, 1H). Compound 227: LC-MS (ESI) m/z: 304 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.48 (s, 2H), 7.55 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.94-8.07 (m, 4H), 12.93 (s, 1H), 14.80 (s, 1H).
[001305] Example 228
[001306] Synthesis of 4-((3'-cyclohexyl-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid (228)
Figure imgf000369_0001
[001307] Compounds 228A, 228B, 228C, 228D, 228E, and 228 were synthesized by employing the procedures described for Compounds 8B, 8B, 141, Intermediate I, 8F, and 1 using 4-(benzyloxy)phenylboronic acid, Compounds 129A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, cyclohexenylboronic acid, 228A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 228B with MeOH as solvent at 50 °C, 228C, 228D, and 224E in lieu of (3,4- dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 4-bromophenol with DMF as solvent, 140 with EtOAc as solvent at room temperature, 4-bromophenol, 8E, and 1E. Compound 228A: 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.16 (s, 2H), 7.10 (d, J = 5.2 Hz, 2H), 7.35 (d, J = 9.6 Hz, 1H),7.41 (t, J = 5.2 Hz, 3H), 7.48 (t, J = 8.8 Hz, 3H), 7.64 (d, J = 4.8 Hz, 3H),7.80 (t, J = 3.6 Hz, 1H). Compound 228B: LC-MS (ESI) m/z: 341 [M+H]+. Compound 228C: LC-MS (ESI) m/z: 253 [M+H]+. Compound 228D: LC-MS (ESI) m/z: 512 [M+H]+. Compound 228E: LC-MS (ESI) m/z: 484 [M+H]+. Compound 228: LC-MS (ESI) m/z: 364 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.24-1.27 (m, 1H), 1.36- 1.49(m, 4H), 1.72 (d, J = 12.4 Hz, 1H), 1.79-1.84 (m, 4H), 2.54-2.60 (m, 1H), 7.13 (d, J = 9.2 Hz, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.4 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H).
[001308] Example 229
[001309] Synthesis of 1-(((cyclohexanecarbonyl)oxy)methyl)-4-(3,4- dichlorophenoxy)1H-1,2,3-triazole-5-carboxylic acid (229)
Figure imgf000370_0001
[001310] To a suspension of cyclohexanecarboxylic acid (229A) (2.0 g, 15.6 mmol), K2CO3 (8.2 g, 59.4 mmol), and Bn4NHSO4 (0.5 g, 1.5 mmol) in dichloromethane (20 mL) and water (20 mL) at 5 oC was dropped chloromethyl sulfochloridate (3.3 g, 20.3 mmol) and stirred at room temperature for 16 hours. The mixture was diluted with water (30 mL) and extracted with dichlorrmethane (30 mL x 3). The combined organic phases was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give Compound 229B.1H- NMR (CDCl3, 400 MHz): d (ppm) 1.21-1.95 (m, 10H), 2.34-2.41 (m, 1H), 5.71 (s, 2H).
[001311] Compound 229 was synthesized by employing the procedure described for Compound 51 using Compounds 229B and 88 in lieu of chloromethyl pivalate and Compound 16, LC-MS (ESI) m/z: 431 [M+18]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.25-1.34 (m, 5H), 1.42-1.44 (m, 1H), 1.65-1.74 (m, 2H), 1.84-1.88 (m, 2H), 2.37-2.42 (m, 1H), 6.20 (s, 2H), 7.13 (dd, J = 8.8, 2.8 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H).
[001312] Example 230
[001313] Synthesis of 4-((3'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (230)
Figure imgf000370_0002
[001314] Compounds 230A, 230B, 230C, and 230 were synthesized by employing the procedures described for Compounds 8B, 27B, 8F, and 1 using 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenol, Intermediate I, 1-bromo-2-methoxyethane, Compounds 230A with K2CO3 as base, 230B, and 230C in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 2-bromopropane, 27A with Cs2CO3 as base, 8E, and 1E. Compound 230A: LC-MS (ESI) m/z: 446 [M+H]+. Compound 230B: LC-MS (ESI) m/z: 504 [M+H]+. Compound 230C: LC-MS (ESI) m/z: 476 [M+H]+. Compound 230: LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.49-2.51 (m, 3H), 3.67-3.69(m, 2H), 4.16-4.18 (m, 2H), 6.91-6.94 (dd, J = 10 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.17-7.21 (m, 2H), 7.36 (t, J = 16 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 13.26 (s, 1H), 15.25 (s, 1H).
[001315] Example 231
[001316] Synthesis of 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (231)
Figure imgf000371_0001
[001317] Compounds 231B, 231C, and 231 were synthesized by employing the
procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 231A, 231B, and 231C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 231B: LC-MS (ESI) m/z: 412 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.18 (t, J = 7.2 Hz, 3H), 3.77 (s, 3H), 4.20-4.26 (m, 6H), 5.32 (s, 2H), 6.25-6.28 (m, 1H), 6.30-6.31 (m, 1H), 6.72-6.74 (m, 1H), 6.79- 6.81 (m, 2H), 7.19-7.27 (m, 2H). Compound 231C: LC-MS (ESI) m/z: 384 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.70 (s, 3H), 4.17-4.20 (m, 4H), 5.35 (s, 2H), 6.31-6.37 (m, 2H), 6.75-6.77 (m, 1H), 6.83-6.86 (m, 2H), 7.12-7.15 (m, 2H), 13.00 (s, 1H). Compound 231: LC-MS (ESI) m/z: 264 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.16-4.20 (m, 4H), 6.41-6.43 (m, 2H), 6.73-6.75 (m, 1H).
[001318] Example 232
[001319] Synthesis of 4-((3'-(cyclopropylmethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (232)
Figure imgf000372_0001
[001320] Compounds 232A, 232B, and 232 were synthesized by employing the
procedures described for Compounds 8F, 4B, and 1 using Intermediate I, Compounds 232A, 170B with K2CO3 as base and 1,4-dioxane/H2O as solvent, and 232B in lieu of Compounds 8E, 4A, (4-bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, and 1E. Compound 232A: LC-MS (ESI) m/z: 312 [M+H]+. Compound 232B: LC-MS (ESI) m/z: 380 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.37-0.39 (m, 2H), 0.66-0.69 (m, 2H), 1.25-1.28 (m, 1H), 1.36 (t, J = 7.6 Hz, 3H), 3.87 (d, J = 6.8 Hz, 2H), 4.41 (q, J = 7.6 Hz, 2H), 7.09-7.13 (m, 2H), 7.25 (d, J = 8.8 Hz, 2H).7.32-7.36 (m, 2H), 7.59 (d, J = 8.8 Hz, 2H). Compound 232: LC-MS (ESI) m/z: 352 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.35-0.40 (m, 2H), 0.60-0.66 (m, 2H), 1.26-1.30 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 6.87-6.90 (m, 1H), 7.11-7.20 (m, 4H), 7.30-7.35 (m, 1H), 7.60-7.63 (m, 2H).
[001321] Example 233
[001322] Synthesis of 4-((3'-(4-acetylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (233)
Figure imgf000372_0002
[001323] A mixture of 1-(3-bromophenyl)piperazine (233A) (480 mg, 2 mmol) and acetic anhydride (2 mL) was stirred at room temperature for 4 hours. The mixture was quenched with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield Compound 233B. LC-MS (ESI) m/z: 283 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 2.13 (s, 3H), 3.13-3.19 (m, 4H), 3.60 (t, J = 5.6 Hz, 2H), 3.75 (t, J = 5.6 Hz, 2H), 6.81-6.84 (m, 1H), 6.99-7.03 (m, 2H), 7.12 (t, J = 8.0 Hz, 1H).
[001324] Compounds 233C, 233D, 233E, and 233 were synthesized by employing the procedures described for Compounds 27B, 4B, 8F, and 1 using Compounds 233B, 233C, Intermediate I with K2CO3 as base and 1,4-dioxane/H2O as solvent, 233D, and 233E in lieu of Compounds 27A, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/ H2O as solvent, 8E, and 1E. Compound 233C: LC-MS (ESI) m/z: 331 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34 (s, 12H), 2.14 (s, 3H), 3.16-3.22 (m, 4H), 3.61 (t, J = 5.2 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 7.01-7.04 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.35-7.38 (m, 2H). Compound 233D: LC-MS (ESI) m/z: 556 [M+H]+. Compound 233E: LC-MS (ESI) m/z: 528 [M+H]+. Compound 233: LC-MS (ESI) m/z: 408 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.03 (s, 3H), 3.17 (t, J = 5.2 Hz, 2H), 3.23 (t, J = 5.2 Hz, 2H), 3.58 (s, 4H), 6.93-6.96 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.8 Hz, 3H), 7.30 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H).
[001325] Example 234
[001326] Synthesis of 4-((4'-(2-methoxyethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (234)
Figure imgf000373_0001
[001327] Compounds 234B, 234C, 234D, and 234 were synthesized by employing the procedures described for Compounds 27B, 4B, 8F, and 1 using Compounds 234A, 234B, Intermediate I with K2CO3 as base and 1,4-dioxane/H2O as solvent, 234C, and 234D in lieu of Compounds 27A, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/ H2O as solvent, 8E, and 1E. Compound 234B: LC-MS (ESI) m/z: 279 [M+H]+. Compound 234C: LC-MS (ESI) m/z: 504 [M+H]+. Compound 234D: LC-MS (ESI) m/z: 476 [M+H]+. Compound 234: LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.32 (s, 3H), 3.67 (d, J = 9.2 Hz, 2H), 4.13 (d, J = 9.2 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.59 (m, 4H), 13.2 (bs, 1H), 15.22 (bs, 1H).
[001328] Example 235
[001329] Synthesis of acetoxymethyl 4-((6-chloronaphthalen-2-yl)oxy)-1H-1,2,3- triazole-5-carboxylate (235)
Figure imgf000374_0001
[001330] Compounds 235A, 235B, 235C, 235D, and 235 were synthesized by
employing the procedures described for Compounds 1, 54A, 8F, 54C, and 54 using Compounds 106G, 235A, 235B, 235C, chloromethyl acetate with Et3N as base and adding NaI, and 235D in lieu of Compounds 1E, 33, 8E, 54B, chloromethyl pivalate with Na2CO3 as base and without NaI, and 54C. Compound 235A: LC-MS (ESI) m/z: 318 [M+H]+. Compound 235B: LC-MS (ESI) m/z: 582 [M+Na]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.20 (t, J = 7.6 Hz, 3H), 4.27 (q, J = 7.6 Hz, 2H), 7.11-7.19 (m, 6H), 7.28-7.39 (m, 12H), 7.52 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H). Compound 235C: LC-MS (ESI) m/z: 530 [M-H]¯; 1H- NMR (DMSO-d6, 400 MHz,): d (ppm) 7.11-7.14 (m, 6H), 7.37-7.44 (m, 11H), 7.52 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 13.42 (s, 1H). Compound 235D: LC-MS (ESI) m/z: 626 [M+Na]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 2.00 (s, 3H), 5.88 (s, 2H), 7.15-7.18 (m, 6H), 7.25-7.40 (m, 12H), 7.53 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H). Compound 235: LC-MS (ESI) m/z: 362 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.95 (s, 3H), 5.81 (s, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.50-7.54 (m, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H).
[001331] Example 236
[001332] Synthesis of 4-((6-(difluoromethoxy)naphthalen-2-yl)oxy)-1H-1,2,3-triazole- 5-carboxylic acid (236)
Figure imgf000375_0001
[001333] To a stirred mixture of 6-bromonaphthalen-2-ol (236A) (316 mg, 1.42 mmol) and aqueous KOH solution (25%, 1.2 g, 21.32 mmol) in acetonitrile (15 mL) was added 2-chloro- 2,2-difluoro-1-phenylethanone (1.35 g, 7.1 mmol) at 0 oC and stirred at 80 oC under nitrogen for 4 hours. After cooled down to room temperature, the mixture was extracted with ethyl acetate (50 mL x 3). The combined extracts was washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to afford Compound 236B. LC-MS (ESI) m/z: 273 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 6.39 (t, J = 73.6 Hz, 1H), 7.25-7.31 (m, 1H), 7.44-7.47 (m, 1H), 7.55-7.58 (m, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H).
[001334] Compound 236C was synthesized by employing the procedure described for Compound 27C using Compound 236B in lieu of Compound 27B, LC-MS (ESI) m/z: 321
[M+H]+.
[001335] To a solution of Compound 236C (320 mg, 1.0 mmol) in THF (20 mL) was added NaOH (40 mg, 1 mmol) and H2O2 (30%, 0.1 mL, 1 mmol). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to afford Compound 236D. LC-MS (ESI) m/z: 209 [M-H]¯.
[001336] Compounds 236E, 236F, and 236 were synthesized by employing the
procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 236D, 236E, and 236F in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 236E: LC-MS (ESI) m/z: 470 [M+H]+. Compound 236F: LC-MS (ESI) m/z: 442 [M+H]+. Compound 236: LC-MS (ESI) m/z: 322 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.33 (t, J = 73.6 Hz, 1H), 7.34-7.38 (m, 1H), 7.41-7.42 (m, 1H), 7.43-7.44 (m, 1H), 7.70 (s, 1H), 7.92-7.98 (m, 2H).
[001337] Example 237
[001338] Synthesis of 4-((6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (237)
Figure imgf000376_0001
[001339] Compounds 237B, 237C, 237D, 237E, 237F, and 237 were synthesized by employing the procedures described for Compounds 111B, 111C, 57C, 90C, 8F, and 1 using Compounds 237A, 237B, 237C, 237D, 237E, and 237F in lieu of Compounds 111A, 111B, 57B, 90B, 8E, and 1E. Compound 237B: LC-MS (ESI) m/z: Non-ionizable Compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.78-2.83 (m, 2H), 2.90-2.94 (m, 2H), 5.02 (t, J = 2.4 Hz, 1H), 5.32 (t, J = 2.4 Hz, 1H), 7.01 (q, J = 7.6, 2.4 Hz, 1H), 7.21 (q, J = 7.6, 2.4 Hz, 1H). Compound 237C: LC-MS (ESI) m/z: 183 [M+H]+. Compound 237D: LC-MS (ESI) m/z: 167 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.79-1.95 (m, 1H), 1.99-2.03 (m, 1H), 2.66-2.79 (m, 2H), 2.86-2.91 (m, 1H), 2.97-3.02 (m, 1H), 4.14-4.17 (m, 1H), 6.83-6.89 (m, 2H). Compound 237E: LC-MS (ESI) m/z: 444 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 6.8 Hz, 3H), 1.94-2.07 (m, 2H), 2.73-2.78 (m, 3H), 2.94-2.99 (m, 1H), 3.77 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 5.0 (d, J = 14.8 Hz, 1H), 5.14 (d, J = 15.2 Hz, 1H), 5.66-5.71 (m, 1H), 6.73-6.78 (m, 3H), 6.86-6.91 (m, 1H), 7.00 (d, J = 1.6 Hz, 2H). Compound 237F: LC-MS (ESI) m/z: 416 [M+H]+. Compound 237: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.99-2.08 (m, 2H), 2.49-2.51 (m, 1H), 2.71-2.97 (m, 2H), 3.15-3.36 (m, 1H), 5.02-5.09 (m, 1H), 7.16-7.21 (m, 2H), 12.81 (s, 1H), 14.76 (s, 1H) .
[001340] Example 238
[001341] Synthesis of 4-((3'-(tetrahydro-2H-pyran-4-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (238)
Figure imgf000377_0001
[001342] Compounds 238A, 238B, 238C, 238D, 238E, and 238 were synthesized by employing the procedures described for Compounds 8B, 27C, 4B, 1, 141, and 8F using 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, Compounds 129A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 238A, 238B, Intermediate I with K2CO3 as base and 1,4-dioxane/H2O as solvent, 238C, 238D, and 238E in lieu of (3,4- dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 27B, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 1E, 140, and 8E. Compound 238A: LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.48-2.52 (m, 2H), 3.92-3.96 (m, 2H), 4.32-4.35 (m, 2H), 6.14-6.16 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 2.4 Hz, 1H). Compound 238B: LC-MS (ESI) m/z: 287 [M+H]+. Compound 238C: LC-MS (ESI) m/z: 512 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.13 (t, J = 7.2 Hz, 3H), 2.57-2.60 (m, 2H), 2.75 (s, 3H), 3.98 (t, J = 5.6 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 4.35-4.38 (m, 2H), 5.39 (s, 2H), 6.19-6.21 (m, 1H), 6.78-6.85 (m, 4H), 7.23 (d, J = 8.4 Hz, 2H), 7.38-7.53 (m, 6H). Compound 238D: LC-MS (ESI) m/z: 392 [M+H]+. Compound 238E: LC-MS (ESI) m/z: 394 [M+H]+. Compound 238: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.79-1.88 (m, 4H), 2.86-2.91 (m, 1H), 3.56-3.63 (m, 2H), 4.05- 4.09 (m, 2H), 7.18-7.25 (m, 3H), 7.35-7.48 (m, 3H), 7.59-7.64 (m, 2H).
[001343] Example 239
[001344] Synthesis of (isobutyryloxy)methyl 4-((6-chloronaphthalen-2-yl)oxy)-1H- 1,2,3-triazole-5-carboxylate (239)
Figure imgf000378_0001
[001345] Compounds 239A and 239 were synthesized by employing the procedures described for Compounds 54C and 54 using Compounds 235C, chloromethyl isobutyrate with Et3N as base and adding NaI, and 239A in lieu of Compounds 54B, chloromethyl pivalate with Na2CO3 as base and without NaI, and 54C. Compound 239A: LC-MS (ESI) m/z: 654 [M+Na]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.10 (d, J = 7.2 Hz, 6H), 2.46-2.53 (m, 1H), 5.29 (s, 2H), 7.15-7.18 (m, 6H), 7.30-7.40 (m, 12H), 7.53 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H). Compound 239: LC-MS (ESI) m/z: 390 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.12 (d, J = 7.2 Hz, 6H), 2.50-2.57 (m, 1H), 5.96 (s, 2H), 7.37-7.41 (m, 2H), 7.52 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H).
[001346] Example 240
[001347] Synthesis of 1-(((1-(tert-butoxycarbonyl)piperidine-2-carbonyl)oxy)methyl)- 4-(3,4-dichlorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid (240)
Figure imgf000378_0002
[001348] Compounds 240A and 240 were synthesized by employing the procedures described for Compounds 229B and 51 using Compounds 240A, 240B with DMF as solvent, and 88 in lieu of Compounds 229A, chloromethyl pivalate with 1,4-dioxane as solvent, and 16. Compound 240A: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.24-1.27 (m, 1H), 1.30-1.47 (m, 10H), 1.68-1.71 (m, 3H), 2.22-2.24 (m, 1H), 2.90-3.02 (m, 1H), 3.91-4.06 (m, 1H), 4.78-4.94 (m, 1H), 5.66-5.82 (m, 2H). Compound 240: LC-MS (ESI) m/z: 537 [M+Na]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.16-1.23 (m, 1H), 1.37-1.43 (m, 10H), 1.61-1.68 (m, 3H), 2.14-2.17 (m, 1H), 2.84-2.92 (m, 1H), 3.88-3.92 (m, 1H), 4.78-4.80 (m, 1H), 6.22-6.32 (m, 2H), 7.16 (dd, J = 9.2, 3.2 Hz, 1H), 7.38 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 9.2 Hz, 1H).
[001349] Example 241
[001350] Synthesis of 4-((5,6-dichloro-2,3-dihydro-1H-inden-2-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (241)
Figure imgf000379_0001
[001351] Compounds 241A, 241B, and 241 were synthesized by employing the
procedures described for Compounds 90C, 8F, and 1 using Compounds 190D, 241A, and 241B in lieu of Compounds 90B, 8E, and 1E. Compound 241A: LC-MS (ESI) m/z: 462 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.45 (t, J = 7.2 Hz, 3H), 2.95 (d, J = 17.6 Hz, 2H), 3.19 (dd, J = 17.6, 4.8 Hz, 2H), 3.79 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 5.06 (s, 2H), 6.19-6.21 (m, 1H), 6.72 (d, J = 8.8Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 7.26 (s, 2H). Compound 241B: LC-MS (ESI) m/z: 434 [M+H]+. Compound 241: LC-MS (ESI) m/z: 314 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.12 (d, J = 18.8 Hz, 2H), 3.38 (dd, J = 18.8, 6.0 Hz, 2H), 5.46 (s, 1H), 7.57 (s, 2H), 12.88 (s, 1H), 14.84 (s, 1H).
[001352] Example 242
[001353] Synthesis of 4-((4'-(tetrahydro-2H-pyran-4-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (242)
Figure imgf000380_0001
[001354] Compounds 242A, 242B, 242C, 242D, 242E, and 242 were synthesized by employing the procedures described for Compounds 8B, 27C, 4B, 141, 1, and 8F using 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, Compounds 128A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 242A, 242B, Intermediate I with K2CO3 as base and 1,4-dioxane/H2O as solvent, 242C, 242D, and 242E in lieu of (3,4- dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 27B, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140, 1E, and 8E. Compound 242A: LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.47-2.52 (m, 2H), 3.94 (t, J = 5.6 Hz, 2H), 4.31-4.33 (m, 2H), 6.13-6.15 (m, 1H), 7.25-7.28 (m, 2H), 7.345-7.49 (m, 2H). Compound 242B: LC-MS (ESI) m/z: 287 [M+H]+. Compound 242C: LC-MS (ESI) m/z: 512 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.12 (t, J = 6.8 Hz, 3H), 2.56-2.58 (m, 2H), 3.75 (s, 3H), 3.97 (t, J = 5.6 Hz, 2H), 4.21 (q, J = 6.8 Hz, 2H), 4.35-4.38 (m, 2H), 5.39 (s, 2H), 6.20 (t, J = 1.6 Hz, 1H), 6.78-6.85 (m, 4H), 7.22 (d, J = 8.4 Hz, 2H), 7.46-7.53 (m, 6H). Compound 242D: LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used. Compound 242E: LC-MS (ESI) m/z: 394 [M+H]+. Compound 242: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.79-1.85 (m, 4H), 2.82-2.87 (m, 1H), 3.56-3.63 (m, 2H), 4.05-4.08 (m, 2H), 7.18-7.21 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 8.4, 2.0 Hz, 2H), 7.59-7.64 (m, 2H).
[001355] Example 243
[001356] Synthesis of 4-(((3,4-dichlorophenyl)thio)methyl)-1H-1,2,3-triazole-5- carboxylic acid (243)
Figure imgf000381_0001
[001357] A mixture of Intermediate K (248 mg, 0.7 mmol), 3,4-dichlorobenzenethiol (243A) (126 mg, 0.7 mmol) and sodium carbonate (149 mg, 1.4 mmol) in NMP (10 mL) was stirred at 100 oC overnight. After cooled down to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 243B. LC-MS (ESI) m/z: 452 [M +H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.38 (t, J = 6.8 Hz, 3H), 3.81 (s, 3H), 4.27 (s, 2H), 4.34 (q, J = 6.8 Hz, 2H), 5.62 (s, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.01-7.07 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.28-7.42 (m, 2H).
[001358] Compounds 243C and 243 were synthesized by employing the procedures described for Compounds 1 and 8F using Compounds 243B and 243C in lieu of Compounds 1E and 8E. Compound 243C: LC-MS (ESI) m/z: 332 [M+H]+. Compound 243: LC-MS (ESI) m/z: 304 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 4.52 (s, 2H), 7.27 (dd, J = 8.4, 2.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H).
[001359] Example 244
[001360] Synthesis of (isobutyryloxy)methyl 4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4- yl)thio)-1H-1,2,3-triazole-5-carboxylate (244)
Figure imgf000382_0001
[001361] Compounds 244A and 244 were synthesized by employing the procedures described for Compounds 54C and 256 using chloromethyl isobutyrate, Compounds 278B with Na2CO3 as base and DMF/THF as solvent and adding NaI, and 244A in lieu of chloromethyl pivalate, Compounds 54B with Na2CO3 as base and DMF as solvent and without NaI, and 256D. Compound 244A: LC-MS (ESI) m/z: 723 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.18 (d, J = 6.8 Hz, 6H), 1.59-1.63 (m, 2H), 1.70-1.75 (m, 4H), 2.51-2.60 (m, 1H), 3.22-3.25 (m, 4H), 5.96 (s, 2H), 6.98-7.02 (m, 8H), 7.20-7.25 (m, 5H), 7.28-7.32 (m, 4H), 7.40-7.49 (m, 6H).
Compound 244: LC-MS (ESI) m/z: 481 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.09 (d, J = 7.2 Hz, 6H), 1.58-1.70 (m, 6H), 2.57-2.65 (m, 1H), 3.31 (brs, 4H), 5.94 (s, 2H),7.11-7.27 (m, 2H), 7.51-7.64 (m, 2H), 7.63-7.69 (m, 4H).
[001362] Example 245
[001363] Synthesis of 4-((1-isopropyl-1,2,3,4-tetrahydroquinolin-7-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (245)
Figure imgf000383_0001
[001364] To a mixture of Compound 245A (500 mg, 3.36 mmol), acetone (2.12 g, 36.5 mmol) and triethylsilane (4.0 mL) in DCM (15 mL) was added TFA (2.2 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified with preparative HPLC to afford Compound 245B. LC-MS (ESI) m/z: 192 [M+H]+.
[001365] Compounds 245C, 245D, and 245 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 245B, 245C, and 245D in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 245C: LC-MS (ESI) m/z: 451 [M+H]+. Compound 245D: LC-MS (ESI) m/z: 423 [M+H]+. Compound 245: LC-MS (ESI) m/z: 303 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.11 (s, 3H), 1.13 (s, 3H), 1.80 (t, J = 4.8 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 3.08- 3.11 (m, 1H), 3.11- 3.16 (m, 2H), 4.50- 5.50 (br, 1H), 6.18 (s, 1H), 6.90 (s, 1H).
[001366] Example 246
[001367] Synthesis of 4-((3'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (246)
Figure imgf000384_0001
[001368] Compounds 246A, 246B, 246C, 246D, and 246 were synthesized by
employing the procedures described for Compounds 245B, 27C, 206C, 8F, and 1 using 1,3,5- trioxane, Compounds 233A, 246A, 246B, Intermediate I, 246C, and 246D in lieu of acetone, Compounds 245A, 27B, 206B, Intermediate A, 8E, and 1E. Compound 246A: LC-MS (ESI) m/z: 255 [M+H]+. Compound 246C: LC-MS (ESI) m/z: 528 [M+H]+. Compound 246D: LC-MS (ESI) m/z: 500 [M+H]+. Compound 246: LC-MS (ESI) m/z: 380 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.87 (s, 3H), 3.39 (s, 8H), 6.98-7.00 (m, 1H), 7.12-7.16 (m, 3H), 7.22-7.23 (m, 1H), 7.34 (t, J = 15.6 Hz, 1H), 7.66-7.68 (m, 2H).
[001369] Example 247
[001370] Synthesis of 4-((3'-cyclohexyl-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (247)
Figure imgf000385_0001
[001371] Compounds 247B, 247C, 247D, 247E, 247F, 247G, and 247 were synthesized by employing the procedures described for Compounds 4B, 141, 30B, 27C, 4B, 225, and 8F using cyclohexenylboronic acid, Compounds 247A with K2CO3 as base and 1,4-dioxane/H2O as solvent, 247B with MeOH as solvent, 247C with HBr/CuBr/isopentyl nitrite, 247D, 247E with K2CO3 as base and 1,4-dioxane/H2O as solvent, 247F, and 246D in lieu of (4- bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 30A with isoamyl nitrite/CuCl2, 27B, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 225C, and 8E. Compound 247B: LC-MS (ESI) m/z: 174 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.63-1.67 (m, 2H), 1.73-1.77 (m, 2H), 2.16-2.20 (m, 2H), 2.35-2.39 (m, 2H), 3.61 (s, 2H), 6.06-6.08 (m, 1H), 6.55-6.57 (m, 1H), 6.70-6.71 (m, 1H), 6.79-6.80 (m, 1H), 7.07-7.11 (m, 1H). Compound 247C: LC-MS (ESI) m/z: 176 [M+H]+. Compound 247D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.24-1.44 (m, 5H), 1.72-1.84 (m, 5H), 2.45-2.46 (m, 1H), 7.13-7.17 (m, 2H), 7.28-7.31 (m, 1H), 7.35 (s, 1H). Compound 247E: LC-MS (ESI) m/z: 287 [M+H]+;1H-NMR (CDCl3, 400 MHz): d (ppm) 1.26-1.29 (m, 2H), 1.30-1.32 (m, 12H), 1.36-1.49 (m, 3H), 1.81-1.88 (m, 5H), 2.51-2.53 (m, 1H), 7.29-7.31 (m, 2H), 7.62-7.66 (m, 2H).
Compound 247F: LC-MS (ESI) m/z: 528 [M+H]+. Compound 247G: LC-MS (ESI) m/z: 408 [M+H]+. Compound 247: LC-MS (ESI) m/z: 380 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.31-1.34 (m, 1H), 1.45-1.55 (m, 4H), 1.77-1.80 (m, 1H), 1.86-1.92 (m, 4H), 2.58-2.59 (m, 1H), 7.22-7.24 (m, 1H), 7.34-7.36 (m, 1H), 7.42-7.46 (m, 2H), 7.56-7.58 (m, 2H), 7.63-7.65 (m, 2H).
[001372] Example 248
[001373] Synthesis of 4-(4-(trifluoromethyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid (248)
Figure imgf000386_0001
[001374] Compounds 248B, 248C, and 248 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 248A, 248B, and 248C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 248B: LC-MS (ESI) m/z: 422
[M+H]+. Compound 248C: LC-MS (ESI) m/z: 394 [M+H]+. Compound 248: LC-MS (ESI) m/z: 274 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.23 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H).
[001375] Example 249
[001376] Synthesis of (benzoyloxy)methyl 4-((6-chloronaphthalen-2-yl)oxy)-1H-1,2,3- triazole-5-carboxylate (249)
Figure imgf000386_0002
[001377] Compounds 249A and 249 were synthesized by employing the procedures described for 54C and 54 using Compounds 235C, chloromethyl benzoate with Et3N as base and adding NaI, and 249A in lieu of Compounds 54B, chloromethyl pivalate with Na2CO3 as base and without NaI, and 54C. Compound 249A: LC-MS (ESI) m/z: 688 [M+Na]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 6.13 (s, 2H), 7.15-7.18 (m, 6H), 7.29-7.41 (m, 14H), 7.46 (d, J = 8.8 Hz, 1H), 7.55-7.59 (m, 2H), 7.66 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H). Compound 249: LC-MS (ESI) m/z: 424 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 6.03 (s, 2H), 7.07 (d, J = 2.4 Hz, 1H), 7.23-7.27 (m, 2H), 7.32-7.37 (m, 2H), 7.52-7.7.63 (m, 4H), 7.69-7.72 (m, 2H).
[001378] Example 250
[001379] Synthesis of 4-(4-(quinolin-7-yl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (250)
Figure imgf000387_0001
[001380] Compounds 250A, 250B, and 250 were synthesized by employing the procedures described for Compounds 8B, 8F, and 1 using 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinolone, Intermediate I with Na2CO3 as base and 1,4-dioxane/H2O as solvent, Compounds 8E, and 1E in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 250A: LC-MS (ESI) m/z: 481 [M+H]+. Compound 250B: LC-MS (ESI) m/z: 453 [M+H]+. Compound 250: LC-MS (ESI) m/z: 333 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.21-7.25 (m, 2H), 7.55-7.58 (m, 1H), 7.87-7.90 (m, 2H), 7.96-7.99 (m, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H).8.95-8.97 (m, 1H).
[001381] Example 251
[001382] Synthesis of (pivaloyloxy)methyl 4-((6-chloronaphthalen-2-yl)oxy)-1H-1,2,3- triazole-5-carboxylate (251)
Figure imgf000387_0002
[001383] Compounds 251A and 251 were synthesized by employing the procedures described for 54C and 54 using Compounds 235C with Et3N as base and adding NaI, and 251A in lieu of Compounds 54B with Na2CO3 as base and without NaI, and 54C. Compound 251A: LC-MS (ESI) m/z: 668 [M+Na]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.13 (s, 9H), 5.91 (s, 2H), 7.15-7.18 (m, 6H), 7.29-7.40 (m, 12H), 7.52(d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H). Compound 251: LC-MS (ESI) m/z: 426 [M+Na]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.02 (s, 9H), 5.84 (s, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.32-7.40 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 1.6 Hz, 1H).
[001384] Example 252
[001385] Synthesis of (isobutyryloxy)methyl 4-((5,6,7,8-tetrahydronaphthalen-2- yl)oxy)-1H-1,2,3-triazole-5-carboxylate (252)
Figure imgf000388_0001
[001386] To a solution of Compound 97 (180 mg, 0.695 mmol) in MeOH (20 mL) was added oxalyl dichloride (126 mg, 13.9 mmol) and stirred at room temperature under nitrogen overnight. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude Compound 252A. LC-MS (ESI) m/z: 274 [M+H]+.
[001387] Compounds 252B, 252C, 252D, and 252 were synthesized by employing the procedures described for Compounds 54A, 8F, 54C, and 1 using Compounds 252A, 252B, 252C, chloromethyl isobutyrate with Et3N as base and adding NaI, and 252D in lieu of
Compounds 33, 8E, 54B, chloromethyl pivalate with Na2CO3 as base and without NaI, and 1E. Compound 252B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 252C: LC-MS (ESI) m/z: 500 [M-H]¯. Compound 252D: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used. Compound 252: LC-MS (ESI) m/z: 360 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.10 (s, 3H), 1.11 (s, 3H), 1.76-1.79 (m, 4H), 2.51-2.54 (m, 1H), 2.68-2.70 (m, 4H), 5.88 (s, 2H), 6.66 (d, J = 2.8 Hz, 1H), 6.70 (dd, J = 2.8, 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H).
[001388] Example 253
[001389] Synthesis of 4-(3-cyclopropoxyphenoxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (253)
Figure imgf000389_0001
[001390] Compounds 253A, 253B, 253C, 253D, 253E, and 253 were synthesized by employing the procedures described for Compounds 27B, 27C, 236D, Intermediate I, 8F, and 1 using bromocyclopropane, Compounds 131A with NMP as solvent at 130 °C, 253A, 253B, 253C, 253D, and 253E in lieu of 2-bromopropane, Compounds 27A with DMF as solvent at 100 °C, 27B, 236C, 4-bromophenol, 8E, and 1E. Compound 253A: 1H-NMR: (CDCl3, 400 MHz): d (ppm) 0.75-0.79 (m, 4H), 3.68-3.72 (m, 1H), 6.93-6.96 (m, 1H), 7.07-7.10 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 2.4 Hz, 1H). Compound 253B: LC-MS (ESI) m/z: 261 [M+H]+. Compound 253C: LC-MS (ESI) m/z: 151 [M+H]+.1H-NMR: (CDCl3, 400 MHz): d (ppm) 0.76 (d, J = 4.4 Hz, 4H), 3.68-3.71 (m, 1H), 5.22 (brs, 1H), 6.42-6.45 (m, 1H), 6.56-6.58 (m, 1H), 6.61-6.64 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H). Compound 253D: LC-MS (ESI) m/z: 410 [M+H]+. Compound 253E: LC-MS (ESI) m/z: 382 [M+H]+. Compound 253: LC-MS (ESI) m/z: 262 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.62-0.66 (m, 2H), 0.73-0.78 (m, 2H), 3.81-3.85 (m, 1H), 6.60-6.63 (m, 1H), 6.75-6.85 (m, 2H), 7.24 (t, J = 8.0 Hz, 1H), 13.24 (brs, 1H), 15.21 (brs, 1H).
[001391] Example 254
[001392] Synthesis of 4-(4-chloro-3-(trifluoromethoxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (254)
Figure imgf000390_0001
[001393] Compounds 254B, 254C, and 254 were synthesized by employing the
procedures described for Compounds Intermediate I, 8F, and 1 using Compounds 254A, 254B, and 254C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 254B: LC-MS (ESI) m/z: 472 [M+H]+. Compound 254C: LC-MS (ESI) m/z: 909 [2M+Na]+. Compound 254: LC-MS (ESI) m/z: 324 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.15-7.18 (dd, J = 12 Hz, 1H), 7.39-7.40 (m, 1H), 7.67 (d, J = 8.8 Hz, 1H).
[001394] Example 255
[001395] Synthesis of 4-((4'-(2-acetamidoethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (255)
Figure imgf000390_0002
[001396] Compounds 255A, 255B, and 255 were synthesized by employing the
procedures described for Compounds 4B, 8F, and 1 using Intermediate I, Compounds 209D with K3PO4 as base and 1,4-dioxane/H2O as solvent, 255A, and 255B in lieu of Compounds 4A, (4- bromophenyl)boronic acid Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 255A: LC-MS (ESI) m/z: 531 [M+H]+. Compound 255B: LC-MS (ESI) m/z: 503 [M+H]+. Compound 255: LC-MS (ESI) m/z: 383 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.83 (s, 3H), 3.39-3.44 (m, 2H), 4.01 (t, J = 5.6 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.56-7.61 (m, 4H), 8.12 (t, J = 1.6 Hz, 1H), 13.19 (s, 1H), 15.19 (s, 1H).
[001397] Example 256
[001398] Synthesis of (isobutyryloxy)methyl 4-((6,7-dichloro-1,2,3,4- tetrahydronaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylate (256)
Figure imgf000391_0001
[001399] Compounds 256A, 256B, 256C, and 256D were synthesized by employing the procedures described for Compounds 1, 54A, 8F, and 54C using Compounds 111E, 256A, 256B, 256C, and chloromethyl isobutyrate with Et3N as base and adding NaI, in lieu of
Compounds 1E, 33, 8E, 54B, and chloromethyl pivalate with Na2CO3 as base and without NaI. Compound 256A: LC-MS (ESI) m/z: 356 [M+H]+. Compound 256B: LC-MS (ESI) m/z: 620 [M+Na]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.26 (t, J = 7.2 Hz, 3H), 1.98-2.15 (m, 2H), 2.63-2.71 (m, 1H), 2.93-3.00 (m, 3H), 4.27-4.31 (m, 2H), 4.83-4.94 (m, 1H), 7.05 (s, 1H), 7.13- 7.16 (m, 6H), 7.28-7.33 (m, 10H). Compound 256C: LC-MS (ESI) m/z: 592 [M+Na]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.91-1.96 (m, 2H), 2.63-2.67 (m, 1H), 2.70-2.78 (m, 2H), 3.00- 3.07 (m, 1H), 4.83-4.89 (m, 1H), 7.08-7.11 (m, 6H), 7.28 (s, 1H), 7.34-7.40 (m, 10H), 13.02 (s, 1H). Compound 256D: LC-MS (ESI) m/z: 692 [M+Na]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.15 (d, J = 7.2 Hz, 6H), 2.01-2.06 (m, 2H), 2.51-2.56 (m, 1H), 2.58-2.70 (m, 1H), 2.87-3.01 (m, 3H), 4.85-4.93 (m, 1H), 5.89 (s, 2H), 7.03 (s, 1H), 7.12-7.17 (m, 7H), 7.28-7.34 (m, 9H). [001400] To a solution of Compound 256D (170 mg, 0.25 mmol) in dichloromethane (5 mL) was added TFA (1.5 mL) and stirred at 20 oC for 16 hours. To the mixture was added triethylsilane (0.3 mL) and stirred at 20 oC for another 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified with reverse phase
chromatography using eluent (acetonitrile in water, from 0% to 95% v/v) to afford Compound 256. LC-MS (ESI) m/z: 428 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.05 (d, J = 7.2 Hz, 6H), 1.93-1.99 (m, 2H), 2.53-2.56 (m, 1H), 2.68-2.76 (m, 1H), 2.86-2.95 (m, 2H), 3.09-3.15 (m, 1H), 4.95-5.00 (m, 1H), 5.75 (s, 2H), 7.36 (s, 1H), 7.38 (s, 1H).
[001401] Example 257
[001402] Synthesis of 4-(4-(isoquinolin-6-yl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid (257)
Figure imgf000392_0001
[001403] Compounds 257A, 257B, and 257 were synthesized by employing the
procedures described for Compounds 4B, 8F, and 1 using isoquinolin-6-ylboronic acid,
Intermediate I with K3PO4 as base and DME/H2O as solvent, Compounds 25A, and 257B in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 257A: LC-MS (ESI) m/z: 481 [M+H]+. Compound 257B: LC- MS (ESI) m/z: 453 [M+H]+. Compound 257: LC-MS (ESI) m/z: 333 [M+H]+; 1H-NMR
(DMSO-d6, 400 MHz): d (ppm) 7.24 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.23-8.29 (m, 2H), 8.54 (d, J = 6.0 Hz, 1H), 9.38 (s, 1H).
[001404] Example 258
[001405] Synthesis of (pivaloyloxy)methyl 4-((6,7-dichloro-1,2,3,4- tetrahydronaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylate (258)
Figure imgf000393_0001
[001406] Compounds 258A and 258 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 256C with Et3N as base and adding NaI and 258A in lieu of Compounds 54B with Na2CO3 as base and without NaI and 256D.
Compound 258A: LC-MS (ESI) m/z: 706 [M+Na]+; 1H-NMR (CDCl3, 500 MHz,): d (ppm) 1.17 (s, 9H), 2.01-2.05 (m, 2H), 2.63-2.69 (m, 1H), 2.87-3.01 (m, 3H), 4.87-4.92 (m, 1H), 5.89 (s, 2H), 7.03 (s, 1H), 7.12-7.16 (m, 7H), 7.28-7.35 (m, 9H). Compound 258: LC-MS (ESI) m/z: 442 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.16 (s, 9H), 2.08-2.13 (m, 2H), 2.75-2.83 (m, 1H), 3.00-3.08 (m, 2H), 3.13-3.19 (m, 1H), 5.04-5.09 (m, 1H), 5.87 (s, 2H), 7.23 (s, 1H), 7.26 (s, 1H).
[001407] Example 259
[001408] Synthesis of 4-((3'-(2-acetamidoethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (259)
Figure imgf000393_0002
[001409] Compounds 259A, 259B, 259C, 259D, 259E, 259F, and 259 were synthesized by employing the procedures described for Compounds 90C, 190F, 209C, 27C, 4B, 8F, and 1 using 2-(2-hydroxyethyl)isoindoline-1,3-dione, Compounds 131A with DEAD as coupling reagent, 259A with EtOH as solvent, 259B, 259C, Intermediate I, 259D with K3PO4 as base and 1,4- dioxane/H2O as solvent, 259E, and 259F in lieu of Compounds 90B, Intermediate H with DIAD as coupling reagent, 190E with MeOH/H2O as solvent, 209B, 27B, 4A, (4-bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 259A: LC- MS (ESI) m/z: 346 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.11 (t, J = 5.6 Hz, 2H), 4.22 (t, J = 5.6 Hz, 2H), 6.80-6.83 (m, 1H), 7.05-7.13 (m, 3H), 7.73-7.76 (m, 2H), 7.85-7.90 (m, 2H). Compound 259B: LC-MS (ESI) m/z: 216 [M+H]+. Compound 259C: LC-MS (ESI) m/z: 258 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.02 (s, 3H), 3.64-3.68 (m, 2H), 4.03 (t, J = 4.8 Hz, 2H), 5.92 (b, 1H), 6.82-6.85 (m, 1H), 7.06-7.18 (m, 3H). Compound 259D: LC-MS (ESI) m/z: 306 [M+H]+. Compound 259E: LC-MS (ESI) m/z: 531 [M+H]+. Compound 259F: LC-MS (ESI) m/z: 503 [M+H]+. Compound 259: LC-MS (ESI) m/z: 383 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.82 (s, 3H), 3.30-3.41 (m, 2H), 4.04 (t, J = 5.6 Hz, 2H), 6.90-6.93 (m, 1H), 7.12-7.21 (m, 4H), 7.35 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 8.10 (t, J = 5.2Hz, 1H).
[001410] Example 260
[001411] Synthesis of 4-((1-(isoquinolin-6-yl)piperidin-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (260)
Figure imgf000394_0001
[001412] Compounds 260B, 260C, 260D, 260E, and 260 were synthesized by
employing the procedures described for Compounds 90C, 175E, 6B, 8F, and 1 using
Compounds 260A with DEAD as coupling reagent, 260B, 260C, 6-bromoisoquinoline with K3PO4 as base, 260D, and 260E in lieu of Compounds 90B with DIAD as coupling reagent, 175D, 1-methylpiperazine, 6A with tBuONa as base, 8E, and 1E. Compound 260B: LC-MS (ESI) m/z: 461 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.41 (t, J = 6.8 Hz, 3H), 1.45 (s, 9H), 1.51-1.60 (m, 2H), 1.82-1.90 (m, 2H), 3.07-3.14 (m, 2H), 3.65-3.75 (m, 2H), 3.78 (s, 3H), 4.39 (q, J = 14.4, 7.2 Hz, 2H), 5.20-5.25 (m, 1H), 5.29 (s, 2H), 6.83-6.86 (m, 2H), 7.20-7.22 (m, 2H). Compound 260C: LC-MS (ESI) m/z: 361 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.41 (t, J = 7.2 Hz, 3H), 1.51-1.55 (m, 2H), 1.92-1.97 (m, 2H), 2.62-2.69 (m, 2H), 3.02- 3.08 (m, 2H), 3.78 (s, 3H), 4.39 (q, J = 6.8 Hz, 2H), 5.11-5.14 (m, 1H), 5.29 (s, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H). Compound 260D: LC-MS (ESI) m/z: 488 [M+H]+.
Compound 260E: LC-MS (ESI) m/z: 460 [M+H]+. Compound 260: LC-MS (ESI) m/z: 340
[M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.77-1.80 (m, 2H), 2.06-2.10 (m, 2H), 3.50- 3.53 (m, 2H), 3.72-3.76 (m, 2H), 4.85-4.91 (m, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.49-7.53 (m, 2H), 7.88 (d, J = 9.2 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 8.98 (s, 1H).
[001413] Example 261
[001414] Synthesis of (benzoyloxy)methyl 4-((6,7-dichloro-1,2,3,4- tetrahydronaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylate (261)
Figure imgf000395_0001
[001415] Compounds 261A and 261 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 256C with Et3N as base and adding NaI and 261A in lieu of Compounds 54B with Na2CO3 as base and without NaI and 256D.
Compound 261A: LC-MS (ESI) m/z: 726 [M+Na]+; 1H-NMR (CDCl3, 500 MHz,): d (ppm) 1.96- 2.04 (m, 2H), 2.58-2.63 (m, 1H), 2.95-2.97 (m, 3H), 4.85-4.92 (m, 1H), 6.14 (s, 2H), 6.99 (s, 1H), 7.08 (s, 1H), 7.12-7.15 (m, 6H), 7.28-7.32 (m, 9H), 7.42-7.47 (m, 2H), 7.57-7.61 (m, 1H), 8.05 (d, J = 6.5 Hz, 2H). Compound 261: LC-MS (ESI) m/z: 462 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 2.04-2.09 (m, 2H), 2.68-2.76 (m, 1H), 2.94-3.03 (m, 2H), 3.09-3.15 (m, 1H), 5.03-5.09 (m, 1H), 6.12 (s, 2H), 7.16 (s, 2H), 7.48 (t, J = 8.8 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.02 8.4 Hz, 2H). [001416] Example 262
[001417] Synthesis of 4-(3-(cyclopropylmethoxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (262)
Figure imgf000396_0001
[001418] Compounds 262A, 262B, 262C, and 262 were synthesized by employing the procedures described for Compounds 236D, Intermediate I, 217E, and 8F using Compounds 170B, 262A with NMP as solvent, 262B, and 262C in lieu of Compounds 236C, 4-bromophenol with DMF as solvent, 217D, and 8E. Compound 262A: LC-MS (ESI) m/z: 165 [M+H]+.
Compound 262B: LC-MS (ESI) m/z: 424 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.32- 0.34 (m, 2H), 0.63-0.66 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H), 1.16-1.26 (m, 1H), 3.66 (d, J = 6.8 Hz, 2H), 3.77 (s, 3H), 4.21 (q, J = 7.2 Hz, 2H), 5.34 (s, 2H), 6.28 (t, J = 2.4 Hz, 1H), 6.35-6.38 (m, 1H), 6.65 (dd, J = 8.4, 2.0 Hz, 1H), 6.78-6.80 (m, 2H), 7.13-7.20 (m, 1H), 7.21-7.22 (m, 2H). Compound 262C: LC-MS (ESI) m/z: 304 [M+H]+. Compound 262: LC-MS (ESI) m/z: 276 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.32-0.37 (m, 2H), 0.58-0.63 (m, 2H), 1.21- 1.27 (m, 1H), 3.80 (d, J = 7.2 Hz, 2H), 6.62-6.72 (m, 3H), 7.23 (t, J = 8.0 Hz, 1H).
[001419] Example 263
[001420] Synthesis of 4-(4-(tetrahydro-2H-pyran-4-yl)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (263)
Figure imgf000397_0001
[001421] To a solution of 1-(benzyloxy)-4-bromobenzene (263A) (1.3 g, 5 mmol) in anhydrous THF (20 mL) was dropped a solution of n-BuLi in n-hexane (2.5 M, 2.4 mL, 6 mmol) at -78 oC under nitrogen and stirred at -78 oC for 1 hour, followed by addition of dihydro-2H- pyran-4(3H)-one (263B) (0.56 mL, 6 mmol). The mixture was stirred at -78 oC for 1.5 hours, quenched with saturated NH4Cl solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% to 100% v/v) to give Compound 263C. LC-MS (ESI) m/z: 267 [M-OH]+.
[001422] To a solution of Compound 263C (1.14 g, 4.0 mmol) in MeOH (20 mL) and THF (20 mL) was added HCl solution (3M, 2 mL) and Pd/C (10%, 57 mg). The mixture was stirred at 50 oC under H2 (1 atm.) for 15 hours. After cooled down to room temperature, the mixture was filtered through Celite and the filtrate was concentrated to give a crude Compound 263D. LC- MS (ESI) m/z: 179 [M+H]+.
[001423] Compounds 263E, 263F, and 263 were synthesized by employing the
procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 263D, 263E, and 263F in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 263E: LC-MS (ESI) m/z: 438 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.08 (t, J = 7.2 Hz, 3H), 1.72-1.75 (m, 4H), 2.68-2.76 (m, 1H), 3.49-3.55 (m, 2H), 3.77 (s, 3H), 4.06-4.10 (m, 2H), 4.15-4.21 (m, 2H), 5.34 (s, 2H), 6.73 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H). Compound 263F: LC-MS (ESI) m/z: 410 [M+H]+. Compound 263: LC-MS (ESI) m/z: 290 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.57-1.69 (m, 4H), 2.68-2.78 (m, 1H), 3.40-3.44 (m, 2H), 3.91-3.94 (m, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 13.14 (s, 1H), 15.16 (s, 1H).
[001424] Example 264
[001425] Synthesis of 4-((3,4-dichlorophenoxy)methyl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (264)
Figure imgf000398_0001
[001426] Compounds 264A, 264B, and 264 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 264A and Intermediate K-5 using DEAD as coupling reagent, 264B, and 264C in lieu of Compounds 90B and
Intermediate H using DIAD as coupling reagent, 8E, and 1E. Compound 264A: LC-MS (ESI) m/z: 436 [M+H]+. Compound 264B: LC-MS (ESI) m/z: 408 [M+H]+. Compound 264: LC-MS (ESI) m/z: 288 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.38 (s, 2H), 7.11 (dd, J 1 = 2.4 Hz, J 2 = 9.2 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H), 13.55 (s, 1H), 15.81 (s, 1H).
[001427] Example 265
[001428] Synthesis of 4-(((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)methyl)-1H- 1,2,3-triazole-5-carboxylic acid (265)
Figure imgf000399_0001
[001429] Compounds 265A, 265B, 265C, and 265 were synthesized by employing the procedures described for Compounds 90C, 8B, 8F, and 1 using Compounds 87A and
Intermediate K-5 using DEAD as coupling reagent, 4-(trifluoromethoxy)phenylboronic acid, Compounds 265A using Na2CO3 as base and MeCN/H2O as solvent, 265B, and 265C in lieu of Compounds 90B and Intermediate H using DIAD as coupling reagent, (3,4- dichlorophenyl)boronic acid, 8A using t-BuONa as base and DME/H2O as solvent, 8E, and 1E. Compound 265A: LC-MS (ESI) m/z: 446 [M+H]+. Compound 265B: LC-MS (ESI) m/z: 528 [M+H]+. Compound 265C: LC-MS (ESI) m/z: 500 [M+H]+. Compound 265: LC-MS (ESI) m/z: 380 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.41 (s, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H).
[001430] Example 266
[001431] Synthesis of 4-(((3',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (266)
Figure imgf000400_0001
[001432] Compounds 266A, 266B, and 266 were synthesized by employing the procedures described for Compounds 8B, 8F, and 1 using Compounds 265A using Na2CO3 as base and MeCN/H2O as solvent, 266A, and 266B in lieu of Compounds 8A using t-BuONa as base and DME/H2O as solvent, 8E, and 1E. Compound 266A: LC-MS (ESI) m/z: 512 [M+H]+. Compound 266B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 266: LC-MS (ESI) m/z: 364 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.41 (s, 2H), 7.12 (d, J = 8.7 Hz, 2H), 7.65 - 7.66 (m, 4H), 7.90 (d, J = 2.0 Hz, 1H), 13.36 (s, 1H), 15.57 (s, 1H).
[001433] Example 267
[001434] Synthesis of (propionyloxy)methyl 4-((6,7-dichloro-1,2,3,4-t
etrahydronaphthalen-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylate (267)
Figure imgf000401_0001
[001435] Compounds 267B, 267C, and 267 were synthesized by employing the procedures described for Compounds 229B, 54C, and 256 using Compounds 267A with NaHCO3 as base, 267B with Et3N as base and adding NaI, and 267C in lieu of Compounds 229A with K2CO3 as base, 54B with Na2CO3 as base and without NaI, and 256D. Compound 267B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.18 (t, J = 7.6 Hz, 3H), 2.42 (q, J = 7.6 Hz, 2H), 5.71 (s, 2H). Compound 267C: LC-MS (ESI) m/z: 678 [M+Na]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.12 (t, J = 7.6 Hz, 3H), 2.01-2.07 (m, 2H), 2.34 (q, J = 7.6 Hz, 2H), 2.63-2.71 (m, 1H), 2.88- 3.01 (m, 3H), 4.88-4.94 (m, 1H), 5.30 (s, 2H), 7.04 (s, 1H), 7.12-7.17 (m, 7H), 7.28-7.36 (m, 9H). Compound 267: LC-MS (ESI) m/z: 414 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.10 (t, J = 7.6 Hz, 3H), 2.09-2.14 (m, 2H), 2.35 (q, J = 7.6 Hz, 2H), 2.76-2.83 (m, 1H), 3.00- 3.08 (m, 2H), 3.14-3.3.20 (m, 1H), 5.06-5.12 (m, 1H), 5.88 (s, 2H), 7.24 (s, 1H), 7.26 (s, 1H).
[001436] Example 268
[001437] Synthesis of 4-(4-(3,3-difluorocyclobutyl)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (268)
Figure imgf000402_0001
[001438] T0 a solution of 3-(4-bromophenyl)cyclobutan-1-one (268A) (416 mg, 1.84 mmol) in dichloromethane (15 mL) at -70 oC was dropped DAST (0.58 mL, 4.62 mmol) and stirred at room temperature overnight. The mixture was quenched with water (30 mL), neutralized with saturated sodium bicarbonate solution (50 mL), and extracted with
dichloromethane (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to furnish Compound 268B. LC-MS (ESI) m/z: non- ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.59- 2.67 (m, 2H), 2.97-3.01 (m, 2H), 3.33-3.34 (m, 1H), 7.09-7.12 (m, 2H), 7.43-7.46 (m, 2H).
[001439] Compounds 268C, 268D, 268E, 268F, and 268 were synthesized by
employing the procedures described for Compounds 27C, 236D, Intermediate I, 8F, and 1 using Compounds 268B, 268C, 268D, 268E, and 268F in lieu of Compounds 27B, 236C, 4- bromophenol, 8E, and 1E. Compound 268C: LC-MS (ESI) m/z: 295 [M+H]+. Compound 268D: LC-MS (ESI) m/z: 185 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.57-2.68 (m, 2H), 2.92- 2.99 (m, 2H), 3.28-3.31 (m, 1H), 5.05 (s, 1H), 6.78-6.82 (m, 2H), 7.08-7.12 (m, 2H). Compound 268E: LC-MS (ESI) m/z: 444 [M+H]+. Compound 268F: LC-MS (ESI) m/z: 416 [M+H]+.
Compound 268: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.62- 2.71 (m, 2H), 2.95-3.01 (m, 2H), 3.28-3.41 (m, 1H), 7.03 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 9.2 Hz, 2H).
[001440] Example 269
[001441] Synthesis of 4-((3,4-dichlorobenzyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (269)
Figure imgf000403_0001
[001442] Compounds 269B and 269C were synthesized by employing the procedures described for Compounds 90C and 217E using Compounds 269A with DEAD as coupling reagent and 269B in lieu of Compounds 90B with DIAD as coupling reagent and 217D.
Compound 269B: LC-MS (ESI) m/z: 436 [M+H]+. Compound 269C: LC-MS (ESI) m/z: 316 [M+H]+.
[001443] A mixture of Compound 269C (253 mg, 0.8 mmol) and KOH (448 mg, 8 mmol) in EtOH (10 ml) and H2O (5 ml) was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified with preparative HPLC to afford Compound 269. LC-MS (ESI) m/z: 288 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.34 (s, 2H), 7.45-7.48 (m, 1H), 7.68 (d, J = 8 Hz, 1H), 7.74 (d, J = 2 Hz, 1H), 13.04 (s, 1H), 14.85 (s, 1H).
[001444] Example 270
[001445] Synthesis of 4-((1-(4-chlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (270)
Figure imgf000403_0002
[001446] To a solution of piperidin-4-ol (270A) (500 mg, 4.94 mmol) and 1-chloro-4- iodobenzene (197A) (1.18 g, 4.94 mmol) in DMF (25 mL) was added K2CO3 (2.05 g, 14.82 mmol), CuI (94 mg, 0.494 mmol), and L-proline (171mg, 1.482mmol). The mixture was stirred at 95 oC for 12 hours. After the reaction mixture was cooled down to room temperature, the precipitate was removed by filtration. The filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish Compound 270B. LC-MS (ESI) m/z: 212 [M+H]+.
[001447] Compounds 270C, 270D, and 270 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 270B with DEAD as coupling reagent, 270C, and 270D in lieu of Compounds 90B with DIAD as coupling reagent, 8E, and 1E. Compound 270C: LC-MS (ESI) m/z: 471 [M+H]+. LC-MS (ESI) m/z: 436 [M+H]+. Compound 270D: LC-MS (ESI) m/z: 443 [M+H]+. Compound 270: LC-MS (ESI) m/z: 323 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.86 (d, J = 8.8 Hz, 2H), 2.12 (t, J = 11.2 Hz, 2H), 3.18 (t, J = 19.2 Hz, 2H), 3.49-3.54 (m, 2H), 4.86 (s, 1H), 7.13 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 9.2 Hz, 2H).
[001448] Example 271
[001449] Synthesis of 4-((5,6-difluoro-2,3-dihydro-1H-inden-2-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (271)
Figure imgf000404_0001
[001450] Compounds 271A, 271B, 271C, 271D, 271E, 271F, and 271 were synthesized by employing the procedures described for Compounds 57C, 190B, 190C, 190D, 90C, 8F, and 1 using Compounds 237A, 271A, 271B, 271C, 271D with DEAD as coupling reagent, 271E, and 271F in lieu of Compounds 57B, 190B, 190C, 190D, 90B with DIAD as coupling reagent, 8E, and 1E. Compound 271A: LC-MS (ESI) m/z: 153 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d 1.93-2.01 (m, 1H), 2.49-2.57 (m, 1H), 2.73-2.81 (m, 1H), 2.97-3.04 (m, 1H), 5.19 (t, J = 6.0 Hz, 1H), 7.01 (dd, J = 7.2, 9.2 Hz, 1H), 7.18 (t, J = 8.8 Hz, 1H). Compound 271B: %). LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d 3.36 (s, 2H), 6.59-6.60 (m, 1H), 6.78-6.79 (m, 1H), 6.59 (dd, J = 7.6, 10.4 Hz, 1H), 7.23-7.27 (m, 1H). Compound 271C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d 2.93-2.97 (m, 1H), 3.15-3.19 (m, 1H), 4.14-4.16 (m, 1H), 4.21-4.22 (m, 1H), 7.03 (dd, J = 7.2, 10.0 Hz, 1H), 7.30 (dd, J = 7.6, 9.2 Hz, 1H). Compound 271D: LC-MS (ESI) m/z: 153 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d 2.86 (dd, J = 2.8, 16.0 Hz, 2H), 3.17 (dd, J = 6.0, 16.8 Hz, 2H), 4.73 (bs, 1H), 7.02 (t, J = 8.8 Hz, 2H). Compound 271E: LC-MS (ESI) m/z: 430 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.44 (t, J = 7.2 Hz, 3H), 2.89-2.94 (m, 2H), 3.13-3.19 (m, 2H), 3.77 (s, 3H), 4.42 (q, J = 7.2 Hz, 2H), 5.04 (s, 2H), 6.13- 6.16 (m, 1H), 6.69-6.71 (m, 2H), 6.92-6.97 (m, 4H). Compound 271F: LC-MS (ESI) m/z: 402 [M+H]+. Compound 271: LC-MS (ESI) m/z: 282 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.05-3.09 (m, 2H), 3.34-3.39 (m, 2H), 5.44 (bs, 1H), 7.34 (t, J = 9.2 Hz, 2H), 12.84 (bs, 1H), 14.79 (bs, 1H).
[001451] Example 272
[001452] Synthesis of 4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid and 4-(((cis)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (272)
Figure imgf000405_0001
[001453] Compounds 272C, 272D, and 272E were synthesized by employing the procedures described for Compounds 263C, 57E, and 141 using Compounds 272A, 272B, 272C with BF .
3Et2O as acid, and 272D with MeOH as solvent in lieu of Compounds 263A, 263B, 57D with TFA as acid, and 140 with EtOAc as solvent. Compound 272C: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.83- 1.88 (m, 6H), 2.01-2.04 (m, 2H), 3.44-3.47 (m, 1H), 4.62 (s, 2H), 7.17-7.19 (m, 2H), 7.29-7.34 (m, 1H), 7.34-7.39 (m, 4H), 7.49-7.52 (m, 2H). Compound 272D: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used. [001454] Compound 272E was separated with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30% v/v) to yield Compound 272E-1 and
Compound 272E-2. Compound 272E-1: LC-MS (ESI) m/z: 243 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.61-1.70 (m, 4H), 1.83-1.93 (m, 4H), 2.52-2.58 (m, 1H), 4.11-4.15 (m, 1H), 7.13-7.15 (m, 2H), 7.24-7.26 (m, 2H). Compound 272E-2: LC-MS (ESI) m/z: 243 [M-OH]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.38-1.53 (m, 4H), 1.91-1.94 (m, 2H), 2.09-2.12 (m, 2H), 2.48-2.54 (m, 1H), 3.66-3.72 (m, 1H), 7.12-7.14 (m, 2H), 7.20-7.22 (m, 2H).
Figure imgf000406_0001
[001455] Compounds 272F-1, 272G-1, and 272-1 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Compounds 272E-1, 272F-1, and 272G-1 in lieu of Compounds 90B, 1E, and 8E. Compound 272F-1: LC-MS (ESI) m/z: 520 [M+H]+; 1.42 (t, J = 7.2 Hz, 3H), 1.47-1.54 (m, 4H), 1.91-1.94 (m, 2H), 2.14-2.17 (m, 2H), 2.43- 2.47 (m, 1H), 3.79 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.07-5.12 (m, 1H), 5.30 (s, 2H), 6.86-6.88 (m, 2H), 7.12-7.14 (m, 2H), 7.17-7.20 (m, 2H), 7.24-7.26 (m, 2H). Compound 272G-1: LC-MS (ESI) m/z: 400 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.38 (t, J = 7.2 Hz, 3H), 1.66- 1.71 (m, 4H), 1.98-2.00 (m, 2H), 2.35-2.38 (m, 2H), 2.66-2.69 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.74-4.76 (m, 1H), 7.18-7.20 (m, 2H), 7.35-7.37 (m, 2H). Compound 272-1: LC-MS (ESI) m/z: 372 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.63-1.73 (m, 4H), 1.95-1.98 (m, 2H), 2.33-2.36 (m, 2H), 2.66-2.69 (m, 1H), 4.71-4.72 (m, 1H), 7.17-7.19 (m, 2H), 7.34-7.36 (m, 2H).
Figure imgf000406_0002
[001456] Compounds 272F-2, 272G-2, and 272-2 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Compounds 272E-2, 272F-2, and 272G-2 in lieu of Compounds 90B, 1E, and 8E. Compound 272F-2: LC-MS (ESI) m/z: 520 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 1.63-1.73 (m, 6H), 2.10- 2.13 (m, 2H), 2.56-2.60 (m, 1H), 3.76 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.37 (s, 2H), 5.48 (s, 1H), 6.82-6.85 (m, 2H), 7.12-7.17 (m, 4H), 7.19-7.22 (m, 2H). Compound 272G-2: LC-MS (ESI) m/z: 400 [M+H]+. Compound 272-2: LC-MS (ESI) m/z: 372 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.66-1.79 (m, 4H), 1.97-2.04 (m, 2H), 2.21-2.25 (m, 2H), 2.67-2.71 (m, 1H), 5.06 (s, 1H), 7.17-7.19 (m, 2H), 7.35-7.38 (m, 2H).
[001457] Example 273
[001458] Synthesis of 4-(4-cyclohexylphenoxy)-1H-1,2,3-triazole-5-carboxylic acid (
Figure imgf000407_0001
[001459] Compounds 273A, 273B, 273C, and 273 were synthesized by employing the procedures described for Compounds 4B, 141, 1, and 8F using cyclohexenylboronic acid, Intermediate I with K2CO3 as base and 1,4-dioxane/H2O as solvent, Compounds 273A, 273B, and 273C in lieu of (4-bromophenyl)boronic acid, Compounds 4A with tBuONa as base and toluene/EtOH/H2O as solvent, 140, 1E, and 8E. Compound 273A: LC-MS (ESI) m/z: 434
[M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.11 (t, J = 7.2 Hz, 3H), 1.64-1.68 (m, 2H), 1.76- 1.80 (m, 2H), 2.18-2.22 (m, 2H), 2.33-2.37 (m, 2H), 3.77 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 5.34 (s, 2H), 6.04-6.07 (m, 1H), 6.69-6.72 (m, 2H), 6.78-6.80 (m, 2H), 7.19-7.22 (m, 2H), 7.26-7.27 (m, 2H). Compound 273B: LC-MS (ESI) m/z: 436 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.11 (t, J = 7.2 Hz, 3H), 1.23-1.26 (m, 4H), 1.82-1.85 (m, 4H), 2.44-2.49 (m, 2H), 2.20- 2.28 (m, 1H), 3.77 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 5.34 (s, 2H), 6.68-6.72 (m, 2H), 6.77-6.81 (m, 2H), 7.08-7.10 (m, 2H), 7.19-7.22 (m, 2H). Compound 273C: LC-MS (ESI) m/z: 316
[M+H]+. Compound 273: LC-MS (ESI) m/z: 288 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.28-1.49 (m, 5H), 1.74-1.87 (m, 5H), 2.49-2.51 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H).
[001460] Example 274
[001461] Synthesis of 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methoxy)-1H- 1,2,3-triazole-5-carboxylic acid (274)
Figure imgf000408_0001
[001462] A mixture of Intermediate H (500 mg, 1.8 mmol), 1-bromo-4- (bromomethyl)benzene (274A) (497 mg, 3.6 mmol), and K2CO3 (497 mg, 3.6 mmol) in DMF (20 mL) was stirred at room temperature for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to furnish Compound 274B. LC-MS (ESI) m/z: 446 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.35 (t, J = 14.4 Hz, 3H), 3.72 (s, 3H), 4.36 (q, J = 7.2 Hz, 2H), 5.12 (s, 2H), 5.28 (s, 2H), 6.74 (d, J = 8.8 Hz, 2H), 7.00-7.04 (m, 4H), 7.37 (d, J = 8.8 Hz, 2H).
[001463] Compounds 274C, 274D, and 274 were synthesized by employing the procedures described for Compounds 4B, 217E, and 8F using 4- (trifluoromethoxy)phenylboronic acid, Compounds 274B with K3PO4 as base and DME/H2O as solvent, 274C, and 274D in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 217D, and 8E. Compound 274C: LC-MS (ESI) m/z: 528 [M+H]+. Compound 274D: LC-MS (ESI) m/z: 408 [M+H]+. Compound 274: LC-MS (ESI) m/z: 402 [M+Na]+; 1H-NMR (DMSO-d6, 500 MHz): d (ppm) 5.38 (s, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 12.93 (s, 1H), 14.84 (s, 1H).
[001464] Example 275
[001465] Synthesis of 4-((3-(4-(trifluoromethoxy)phenyl)cyclopentyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (275)
Figure imgf000409_0001
[001466] To a solution of cyclopentane-1,3-dione (275A) (300 mg, 3.06 mmol) and 2,6- lutidine (196 mg, 4.59 mmol) in DCM (10 mL) was dropped Tf2O (1.03 g, 3.67 mmol) at -70 oC. The mixture was stirred at -70 oC for 1 hour, quenched with water (80 mL), and extracted with dichloromethane (60 mL x 3). The combined organic phases was washed with diluted aqueous hydrochloric acid (2 M, 80 mL) and water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude Compound 275B. LC-MS (ESI) m/z: 231 [M+H]+.
[001467] Compounds 275C, 275D, 275E, 275F, 275G, and 275 were synthesized by employing the procedures described for Compounds 206C, 141, 57C, 90C, 1, and 8F using 4- (trifluoromethoxy)phenylboronic acid, Compounds 275B with K2CO3 as base, 275C, 275D with EtOH as solvent, 275E, 275F, and 275G in lieu of Compounds 206B, 206A with Na2CO3 as base, 140, 57B with MeOH as solvent, 90B, 1E, and 8E. Compound 275C: LC-MS (ESI) m/z: 243 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.60-2.63 (m, 2H), 3.02-3.06 (m, 2H), 6.56- 5.57 (m, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.69 (d. J = 8.8 Hz, 2H). Compound 275D: LC-MS (ESI) m/z: 245 [M+H]+. Compound 275E: LC-MS (ESI) m/z: 229 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.57-1.93 (m, 4H), 2.08-2.51 (m, 2H), 3.03-3.45 (m, 1H), 4.45-4.56 (m, 1H), 7.12-7.14 (m, 2H), 7.22-7.31 (m, 2H). Compound 275F: LC-MS (ESI) m/z: 506 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 6.8 Hz, 3H), 1.51-1.61 (m, 1H), 1.71-1.91 (m, 2H), 2.01-2.11 (m, 2H), 2.19-2.55 (m, 1H), 2.95-3.08 (m, 1H), 3.73-3.75 (s, 3H), 4.37-4.43 (m, 2H), 5.30-5.37 (m, 2H), 5.76-7.88 (m, 1H), 6.81-6.85 (m, 2H), 7.09-7.14 (m, 4H), 7.16-7.22 (m, 2H). Compound 275G: LC-MS (ESI) m/z: 386 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.39-1.43 (m, 3H), 1.61-1.72 (m, 1H), 1.91-2.18 (m, 3H), 2.26-2.72 (m, 2H), 3.11-3.40 (m, 1H), 4.37-7.76 (m, 2H), 5.27-5.36 (m, 1H), 7.13-7.16 (m, 2H), 7.25-7.36 (m, 2H). Compound 275: LC-MS (ESI) m/z: 358 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.65-2.70 (m, 1H), 1.90-2.62 (m, 5H), 3.19-3.53 (m, 1H), 5.33 (brs, 1H), 7.16-7.20 (m, 2H), 7.37-7.50 (m, 2H).
[001468] Reference Example 276
[001469] Synthesis of 4-((4'-fluoro-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (276)
Figure imgf000410_0001
[001470] Compounds 276A, 276B, and 276 were synthesized by employing the procedures described for Compounds 4B, 1, and 8F using 4-fluorophenylboronic acid,
Intermediate E with K2CO3 as base and 1,4-dioxane/H2O as solvent, Compounds 276A, and 276B in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 276A: LC-MS (ESI) m/z: 464 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 3.71 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H), 5.58 (s, 2H), 6.75 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.10-7.17 (m, 4H), 7.35 (d, J = 8.4 Hz, 2H), 7.45-7.48 (m, 2H). Compound 276B: LC-MS (ESI) m/z: 344 [M+H]+. Compound 276: LC-MS (ESI) m/z: 316 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.19 (d, J = 8.8 Hz, 2H), 7.56-7.68 (m, 6H).
[001471] Example 277
[001472] Synthesis of 4-((6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (277)
Figure imgf000411_0001
[001473] Compounds 277A, 277B, and 277 were synthesized by employing the
procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 111D with DEAD as coupling reagent, 277A, and 277B in lieu of Intermediate H, Compounds 90B with DIAD as coupling reagent, 8E, and 1E. Compound 277A: LC-MS (ESI) m/z: 492 [M+H]+. Compound 277B: LC-MS (ESI) m/z: 464 [M+H]+. Compound 277: LC-MS (ESI) m/z: 344
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.84-1.89 (m, 1H), 2.15-2.21 (m, 1H), 2.82- 2.85 (m, 3H), 3.34-3.41 (m, 1H), 3.96-4.01 (m, 1H), 7.36-7.39 (m, 2H).
[001474] Example 278
[001475] Synthesis of (benzoyloxy)methyl 4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4- yl)thio)-1H-1,2,3-triazole-5-carboxylate (278)
Figure imgf000412_0001
[001476] Compounds 278A, 278B, 278C, and 278 were synthesized by employing the procedures described for Compounds 54A, 8F, 54C, and 256 using Compounds 169D, 278A, chloromethyl benzoate, 278B with Et3N as base and DMF/THF as solvent and adding NaI, and 278C in lieu of Compounds 33, 8E, chloromethyl pivalate, 54B with Na2CO3 as base and DMF as solvent and without NaI, and 256D. Compound 278A: LC-MS (ESI) m/z: 651 [M+H]+. Compound 278B: LC-MS (ESI) m/z: 623 [M+H]+. Compound 278C: LC-MS (ESI) m/z: 757 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.52-1.64 (m, 6H), 3.73-3.76 (m, 4H), 5.30 (s, 2H), 6.98-7.04 (m, 7H), 7.21-7.30 (m, 9H), 7.36-7.60 (m, 10H), 8.08 (d, J = 7.2 Hz, 2H).
Compound 278: LC-MS (ESI) m/z: 515 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.59- 1.65 (m, 2H), 1.71-1.76 (m, 4H), 3.18-3.22 (m, 4H), 6.17 (s, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.37-7.43 (m, 6H), 7.54-7.59 (m, 1H), 7.97 (d, J = 7.2 Hz, 2H).
[001477] Example 279
[001478] Synthesis of 4-(4-(4,4-difluorocyclohexyl)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (279)
Figure imgf000413_0001
[001479] Compounds 279A, 279B, and 279C were synthesized by employing the procedures described for Compounds 4B, 141, and Intermediate I using 4,4,5,5-tetramethyl-2- (1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 263A with K2CO3 as base and 1,2-dimethoxyethane/H2O as solvent, 279A with EtOAc/MeOH as solvent, and 279B in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, and 4-bromophenol. Compound 279A: LC-MS (ESI) m/z: 323 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.92 (t, J = 6.4 Hz, 2H), 2.46 (brs, 2H), 2.63- 2.66 (m, 2H), 4.03 (s, 4H), 5.07 (s, 2H), 5.91 (t, J = 4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.32- 7.45 (m, 7H). Compound 279B: LC-MS (ESI) m/z: 235 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.62-1.78 (m, 4H), 1.82-1.86 (m, 4H), 2.46-2.52 (m, 1H), 3.98 (s, 4H), 4.72 (s, 1H), 6.75 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8 Hz, 2H). Compound 279C: LC-MS (ESI) m/z: 494 [M+H]+.
[001480] To a solution of Compound 279C (625 mg, crude) in acetone (20 mL) was added HCl solution in 1,4-dioxane (4 N, 1.3 mL, 5.2 mmol). The mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 50% v/v) to yield Compound 279D. LC-MS (ESI) m/z: 450 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.08 (t, J = 7.2 Hz, 3H), 1.82-1.93 (m, 2H), 2.17-2.21 (m, 2H), 2.48-2.52 (m, 4H), 2.96-3.02 (m, 1H), 3.75 (s, 3H), 4.17 (q, J = 7.2 Hz, 2H), 5.34 (s, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H),
[001481] Compounds 279E, 279F, and 279 were synthesized by employing the
procedures described for Compounds 268B, 8F, and 1 using Compounds 279D, 279E, and 279F in lieu of Compounds 4A, 8E, and 1E. Compound 279E: LC-MS (ESI) m/z: 472 [M+H]+.
Compound 279F: LC-MS (ESI) m/z: 444 [M+H]+. Compound 279: LC-MS (ESI) m/z: 324
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.57-1.66 (m, 2H), 1.83-2.08 (m, 6H), 2.66- 2.72 (m, 1H),) 6.99 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H).
[001482] Example 280
[001483] Synthesis of 4-(spiro[2.5]octan-6-yloxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (280)
Figure imgf000414_0001
[001484] A solution of 4-hydroxycyclohexanone (280A) (3.5 g, 3.07 mmol), TBDPSCl (10 mL, 3.68 mmol), and imidazole (3.13 g, 4.61 mmol) in dry DMF (150 mL) was stirred at 50 oC under nitrogen for 18 hours. It was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (petroleum ether) to afford Compound 280B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[001485] To a solution of methyltriphenylphosphonium bromide (54 g, 153.3 mmol) in dry THF (300 mL) was added t-BuONa (14.67 g, 153.3 mmol) and stirred at room temperature for 1 hour. To the mixture was added Compound 280B (9 g, 25.5 mmol) and stirred at room temperature for 18 hours. It was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (petroleum ether) to afford Compound. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.97 (s, 9H), 1.50-1.59 (m, 4H), 1.83-1.90 (m, 2H), 2.28-2.33 (m, 2H), 3.81-3.83 (m, 1H), 4.51 (s, 2H), 7.26-7.35 (m, 6H), 7.59- 7.61 (m, 4H).
[001486] To a solution of trifluoroacetic acid (3.9 g, 34.32 mmol) in dry
dichloromethane (100 mL) was slowly dropped diethylzine (37.74 g, 37.74 mmol) at -10 oC. After the mixture was stirred at room temperature for 30 minutes, and then Diiodomethane (9 g, 34.32 mmol) was added, followed by Compound 280C (3 g, 8.58 mmol). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated and purified with flash column chromatography on silica gel (petroleum ether) to afford Compound 280D. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.91-0.95 (m, 4H), 0.97 (s, 9H), 1.55-1.62 (m, 4H), 1.93-1.96 (m, 2H), 2.38-2.43 (m, 2H), 3.87-3.89 (m, 1H), 7.35-7.42 (m, 6H), 7.66-7.69 (m, 4H).
[001487] A solution of Compound 280D (1.6 g, 4.39 mmol) and TBAF (8.8 mL, 8.79 mmol) in dry THF (20 mL) was stirred at room temperature under nitrogen for 18 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.88-0.92 (m, 4H), 1.07- 1.42 (m, 8H), 3.55-3.56 (m, 1H).
[001488] Compounds 280F, 280G, and 280 were synthesized by employing the procedures described for Compounds 90C, 8F, and 217E using Compounds 280E, 280F, and 280G in lieu of Compounds 90B, 8E, and 217D. Compound 280F: LC-MS (ESI) m/z: 386
[M+H]+. Compound 280G: LC-MS (ESI) m/z: 358 [M+H]+. Compound 280: LC-MS (ESI) m/z: 238 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.22-0.31 (m, 4H), 1.22-1.49 (m, 4H), 1.61-1.70 (m, 2H), 1.90-1.93 (m, 2H), 4.72 (s, 1H).
[001489] Example 281
[001490] Synthesis of 4-((5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (281)
Figure imgf000416_0001
[001491] To a solution of TiCl4 (3.76 g, 20 mmol) in dichloromethane (17 mL) was added a solution of Me2Zn in toluene (1.0 M, 20 mL, 20 mmol) at -30 oC and stirred at this temperature for 20 minutes, followed by dropping of a solution of 6-methoxy-3,4- dihydronaphthalen-1(2H)-one (281A) (1.76 g, 10 mmol) in dichloromethane (8 mL). The mixture was stirred at room temperature overnight, poured into ice-water (100 mL), and extracted with ether (40 mL x 2). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound. LC-MS (ESI) m/z: 191 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.25 (s, 6H), 1.62-1.65 (m, 2H), 1.77-1.80 (m, 2H), 2.73 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H), 6.56 (d, J = 2.8 Hz, 1H), 6.72 (dd, J = 8.8, 2.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H).
[001492] To a solution of Compound 281B (1.9 g, 10 mmol) in dichloromethane (40 mL) was added a solution of BBr3 in dichloromethane (17%, 3 mL) at 0 oC. The mixture was stirred at room temperature overnight, poured into ice water (20 mL), and extracted with ether (40 mL x 2). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 281C. LC-MS (ESI) m/z: 177 [M+H]+. [001493] Compounds 281D, 281E, and 281 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 2 using Compounds 281C, 281D, and 281E with EtOH/H2O in lieu of 4-bromophenol, Compounds 8E, and 1. Compound 281D: LC-MS (ESI) m/z: 436 [M+H]+. Compound 281E: LC-MS (ESI) m/z: 316 [M+H]+. Compound 281: LC-MS (ESI) m/z: 288 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.22 (s, 6H), 1.58-1.62 (m, 2H), 1.69-1.73 (m, 2H), 2.65-2.68 (m, 2H), 6.70 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 13.15 (brs, 1H), 15.15 (brs, 1H).
[001494] Example 282
[001495] Synthesis of 4-((5-(trifluoromethoxy)-2,3-dihydro-1H-inden-2-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (282)
Figure imgf000417_0001
[001496] Compounds 282A, 282B, 282C, 282D, 282E, 282F, and 282 were synthesized by employing the procedures described for Compounds 57C, 190B, 190C, 190D, 90C, 8F, and 1 using Compounds 211E, 282A, 282B, 282C, 282D with DEAD as coupling reagent, 282E, and 282F in lieu of Compounds 57B, 190A, 190B, 190C, 90B with DIAD as coupling reagent, 8E, and 1E. Compound 282A: LC-MS (ESI) m/z: 201 [M-OH]+. Compound 282B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d 3.42 (s, 2H), 6.60-6.62 (m, 1H), 6.86-6.88 (m, 1H), 7.13-7.15 (m, 1H), 7.33-7.38 (m, 2H).
Compound 282C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 282D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d 1.64 (d, J = 4.2 Hz, 1H), 2.88-2.96 (m, 2H), 3.17-3.26 (m, 2H), 4.72-4.78 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H). Compound 282E: LC-MS (ESI) m/z: 478 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.44 (t, J = 7.2 Hz, 3H), 2.96-3.03 (m, 2H), 3.18-3.27 (m, 2H), 3.75 (s, 3H), 4.42 (q, J = 7.2 Hz, 2H), 5.01 (d, J = 3.2 Hz, 2H), 6.12-6.15 (m, 1H), 6.68-6.70 (m, 2H), 6.89-6.92 (m, 2H), 7.08-7.09 (m, 2H), 7.19-7.21 (m, 1H). Compound 282F: LC-MS (ESI) m/z: 450 [M+H]+. Compound 282: LC-MS (ESI) m/z: 330 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.09-3.17 (m, 2H), 3.36-3.45 (m, 2H), 5.47 (bs, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 12.92 (bs, 1H), 14.84 (bs, 1H).
[001497] Example 283
[001498] Synthesis of 4-(spiro[5.5]undecan-3-yloxy)-1H-1,2,3-triazole-5-carboxylic acid (283)
Figure imgf000418_0001
[001499] To a sodium ethoxide-ethanol solution, which was prepared by slowly
addition sodium (8.625 g, 375 mmol) into ethanol (600 mL) in small pieces, was added diethyl malonate 283A (30 g, 187.5 mmol) at room temperature and stirred at room temperature for 20 minutes. To the solution was added 1,5-dibromopentane (45.29 g, 196.9 mmol) and stirred at reflux for 16 hours. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with water (80 mL) and brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column
chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 10% v/v) to yield Compound 283B. LC-MS (ESI) m/z: 229 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.25 (t, J = 7.2 Hz, 6H), 1.40-1.46 (m, 2H), 1.50-1.55 (m, 4H), 1.96-1.99 (m, 4H), 4.18 (q, J = 7.2 Hz, 4H).
[001500] To a solution of Compound 283B (16 g, 70.18 mmol) in anhydrous THF (200 mL) was added dropwise LiAlH4 solution (1 M in THF, 210.5 mL, 210.5 mmol) at 0 oC. After addition the resulting mixture was stirred at room temperature under nitrogen for 3.5 hours. The mixture was quenched slowly with water (300 mL) at 0 oC and extracted with ethyl acetate (400 mL x 4). The combined organic phases were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to yield Compound 283C. LC-MS (ESI) m/z: 167 [M+Na]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1..35-1.37 (m, 4H), 1.44-1.48 (m, 6H), 2.28 (s, 2H), 3.64 (s, 4H).
[001501] A solution of anhydrous dimethyl sulfoxide (20.6 mL, 290.27 mmol) in anhydrous dichloromethane (48 mL) was dropped to a solution of oxalyl chloride (12.3 mL, 145.13 mmol) in anhydrous dichloromethane (95 mL) at -78 °C under nitrogen and stirred for 30 minutes. To the solution at -78 °C was dropped a solution of Compound 283C (9.5 g, 65.97 mmol) in anhydrous dichloromethane (95 mL) and stirred at -70 °C for 90 minutes. Triethyl amine (65.9 mL, 474.98 mmol) was slowly added and the mixture was stirred at -70 °C for 30 minutes. After it was slowly warmed to room temperature, the mixture was quenched with saturated aqueous NH4Cl solution (178 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers was washed with diluted aqueous HCl solution (2 M, 150 mL x 5) and brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to give
Compound 283D.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.43-1.47 (m, 2H), 1.50-1.56 (m, 4H), 1.92-1.95 (m, 4H), 9.53 (s, 2H).
[001502] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (32.42 g, 145.07 mmol) in anhydrous THF (160 mL) was added NaH (60% suspension in oil, 5.82 g, 145.43 mmol) in four portions at 0 oC and stirred at 0 oC for 15 minutes. To the solution was dropped a solution of Compound 283D (9.15 g, 68.57 mmol) in anhydrous THF (35 mL) and stirred at room temperature for 2 hours. It was quenched with water (60 mL) and extracted with ethyl acetate (150 mL x 2). The combined organic layers was washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 10% v/v) to yield Compound 283E. LC- MS (ESI) m/z: 281 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.29 (t, J = 7.2 Hz, 6H), 1.42- 1.45 (m, 2H), 1.50-1.54 (m, 4H), 1.65-1.68 (m, 4H), 4.19 (q, J = 7.2 Hz, 4H), 5.77 (d, J = 16 Hz, 2H), 6.94 (d, J = 16 Hz, 2H).
[001503] Compound 283F was synthesized by employing the procedure described for Compound 141 using Compound 283E with EtOH as solvent in lieu of Compound 140 with EtOAc as solvent, LC-MS (ESI) m/z: 285 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.24- 1.27 (m, 10H), 1.38-1.44 (m, 6H), 1.56-1.60 (m, 4H), 2.18-2.22 (m, 4H), 4.12 (q, J = 6.8 Hz, 4H).
[001504] To a solution of Compound 283F (8.9 g, 31.3 mmol) in anhydrous THF (150 mL) was added NaH (60% suspension in oil, 2.5 g, 62.6 mmol) at 0 oC. The solution was stirred at 0 oC for 10 minutes and heated at reflux for 16 hours. The mixture was quenched with water (50 mL), acidified to pH 6 with aqueous HCl solution (4 N), and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 283G. LC-MS (ESI) m/z: 239 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.29-1.32 (m, 7H), 1.43-1.57 (m, 8H), 2.06 (s, 2H), 2.25 (t, J = 6.4 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 12.22 (s, 1H).
[001505] To a solution of Compound 283G (5.9 g, 24.79 mmol) in 1,4-dioxane (100 mL) was added a solution of potassium hydroxide (6.94 g, 123.95 mmol) in water (8 mL) and stirred at reflux for 16 hours. It was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield Compound 283H. LC-MS (ESI) m/z: 167 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.46-1.47 (m, 10H), 1.70 (t, J = 7.2 Hz, 4H), 2.31 (t, J = 6.8 Hz, 4H),
[001506] Compounds 283I, 283J, 283K, and 283 were synthesized by employing the procedures described for Compounds 57C, 90C, 217E, and 8F using Compounds 283H, 283I, 283J, and 283K in lieu of Compounds 57B, 90B, 217D, and 8E. Compound 283I: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.07-1.14 (m, 2H), 1.20-1.26 (m, 2H), 1.43-1.47 (m, 10H), 1.59- 1.63 (m, 2H), 1.69-1.73 (m, 2H), 3.58-3.65 (m, 1H). Compound 283J: LC-MS (ESI) m/z: 428 [M+H]+. Compound 283K: LC-MS (ESI) m/z: 308 [M+H]+. Compound 283: LC-MS (ESI) m/z: 581 [2M+Na]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.07-1.22 (m, 4H), 1.36 (brs, 8H), 1.46-1.75 (m, 6H), 4.59-4.64 (m, 1H). [001507] Example 284
[001508] Synthesis of 4-(spiro[4.5]decan-8-yloxy)-1H-1,2,3-triazole-5-carboxylic acid (
Figure imgf000421_0001
[001509] Compounds 284A, 284B, 284C, 284D, 284E, 284F, 284G, 284H, 284I, 284J, and 284 were synthesized by employing the procedures described for Compounds 283B, 283C, 283D, 283E, 141, 283G, 283H, 57C, 90C, 217E, and 8F using 1,4-dibromobutane, Compounds 284A, 284B, 284C, 284D with EtOH as solvent, 284E, 284F, 284G, 284H, 284I, and 284J in lieu of 1,5-dibromopentane, Compounds 283B, 283C, 283D, 140 with EtOAc as solvent, 283F, 283G, 57B, 90B, 217D, and 8E. Compound 284A: LC-MS (ESI) m/z: 215 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.24 (t, J = 7.2 Hz, 6H), 1.67-1.70 (m, 4H), 2.16-2.20 (m, 4H), 4.18 (q, J = 7.2 Hz, 4H). Compound 284B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42-1.45 (m, 4H), 1.60-1.64 (m, 4H), 2.36 (brs, 2H), 3.61 (s, 4H). Compound 284C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.69-1.72 (m, 4H), 2.06- 2.09 (m, 4H), 9.68 (s, 2H). Compound 284D: LC-MS (ESI) m/z: 267 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.29 (t, J = 7.2 Hz, 6H), 1.70-1.74 (m, 4H), 1.77-1.80 (m, 4H), 4.19 (q, J = 7.2 Hz, 4H), 5.77 (d, J = 15.6 Hz, 2H), 6.94 (d, J = 15.6 Hz, 2H). Compound 284E: LC-MS (ESI) m/z: 271 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.25 (t, J = 7.2 Hz, 6H), 1.36- 1.39 (m, 4H), 1.59-1.63 (m, 8H), 2.22-2.27 (m, 4H), 4.11 (q, J = 7.2 Hz, 4H). Compound 284F: LC-MS (ESI) m/z: 225 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.30 (t, J = 7.2 Hz, 3H), 1.34-1.47 (m, 4H), 1.53-1.57 (m, 2H), 1.63-1.66 (m, 4H), 2.09 (s, 2H), 2.29-2.32 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 12.23 (s, 1H). Compound 284G: LC-MS (ESI) m/z: 153 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.56-1.60 (m, 4H), 1.68-1.71 (m, 4H), 1.75-1.78 (m, 4H), 2.34-2.37 (m, 4H). Compound 284H: LC-MS (ESI) m/z: 177 [M+Na]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.24-1.44 (m, 8H), 1.49-1.61 (m, 6H), 1.76-1.81 (m, 2H), 3.60-3.65 (m, 1H). Compound 284I: LC-MS (ESI) m/z: 414 [M+H]+. Compound 284J: LC-MS (ESI) m/z: 294
[M+H]+.Compound 284: LC-MS (ESI) m/z: 553 [2M+Na]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.25-1.43 (m, 6H), 1.51-1.56 (m, 8H), 1.85-1.88 (m, 2H), 4.57-4.64 (m, 1H).
[001510] Example 285
[001511] Synthesis of 4-((1-(3,5-dichlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazole- 5-carboxylic acid 2,2,2-trifluoroacetate (285)
Figure imgf000422_0001
[001512] Compounds 285B, 285C, 285D, and 285 were synthesized by employing the procedures described for Compounds 270B, 90C, 8F, and 1 using Compounds 285A, 285B with DEAD as coupling reagent, 285C, and 285D in lieu of Compounds 197A, 90B with DIAD as coupling reagent, 8E, and 1E. Compound 285B: LC-MS (ESI) m/z: 246 [M+H]+. Compound 285C: LC-MS (ESI) m/z: 505 [M+H]+. Compound 285D: LC-MS (ESI) m/z: 477 [M+H]+. Compound 285: LC-MS (ESI) m/z: 357 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.71- 1.79 (m, 2H), 2.04-2.08 (m, 2H), 3.18-3.24 (m, 2H), 3.56-3.61 (m, 2H), 4.83-5.00 (m, 1H), 6.84 (s, 1H), 6.98 (s, 2H), 12.94 (s, 1H), 14.80 (s, 1H).
[001513] Example 286 [001514] Synthesis of 4-((1-(3,4-dichlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazole- 5-carboxylic acid 2,2,2-trifluoroacetate (286)
Figure imgf000423_0001
[001515] Compounds 286B, 286C, 286D, and 286 were synthesized by employing the procedures described for Compounds 270B, 90C, 1, and 8F using Compounds 286A, 286B with DEAD as coupling reagent, 286C, and 286D in lieu of Compounds 197A, 90B with DIAD as coupling reagent, 1E, and 8E. Compound 286B: LC-MS (ESI) m/z: 246 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.49 (d, J = 4.4 Hz, 1H), 1.63-1.72 (m, 2H), 1.97-2.03 (m, 2H), 2.93-2.99 (m, 2H), 3.49-3.55 (m, 2H), 3.87-3.91 (m, 1H), 6.76 (dd, J = 8.8, 2.8 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H). Compound 286C: LC-MS (ESI) m/z: 505 [M+H]+; 1H- NMR (CDCl3, 500 MHz): d (ppm) 1.44 (t, J = 6.0 Hz, 3H), 1.74-1.77 (m, 2H), 1.99-2.03 (m, 2H), 2.97-3.03 (m, 2H), 3.29-3.34 (m, 2H), 3.77(s, 3H), 4.42 (q, J = 6.0 Hz, 2H ), 5.32 (s, 2H), 5.33-5.34 (m, 1H), 6.72 (dd, J = 7.2, 2.8 Hz, 1H), 6.82 (dd, J = 8.0 Hz, 2H), 6.94 (d, J = 2.8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H). Compound 286D: LC-MS (ESI) m/z: 385 [M+H]+. Compound 286: LC-MS (ESI) m/z: 357 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.97-2.06 (m, 2H), 2.16-2.22 (m, 2H), 3.17-3.24 (m, 2H), 3.56-3.62 (m, 2H), 4.92-4.97(m, 1H), 6.98 (dd, J = 8.8, 2.8 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H).
[001516] Example 287
[001517] Synthesis of 4-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (287)
Figure imgf000424_0001
[001518] Compounds 287B, 287C, 287D, and 287 were synthesized by employing the procedures described for Compounds 270B, 90C, 1, and 2 using Compounds 286A, 286B with DEAD as coupling reagent, 286C, and 286D with EtOH/H2O as solvent in lieu of Compounds 197A, 90B with DIAD as coupling reagent, 1E, and 1 with THF/H2O as solvent. Compound 287B: LC-MS (ESI) m/z: 246 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 2.05-2.15 (m, 4H), 3.14-3.17 (m, 4H), 3.46 (s, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H). Compound 287C: LC-MS (ESI) m/z: 505 [M+H]+. Compound 287D: LC-MS (ESI) m/z: 385 [M+H]+.
Compound 287: LC-MS (ESI) m/z: 357 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.74- 1.78 (m, 2H), 2.05-2.09 (m, 2H), 3.22-3.28 (m, 2H), 363-3.67 (m, 2H), 4.88 (s, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H).
[001519] Example 288
[001520] Synthesis of 4-(3-(cyclopropylmethoxy)-5-(trifluoromethyl)phenoxy)-1H- 1,2,3-triazole-5-carboxylic acid (288)
Figure imgf000425_0001
[001521] Compounds 288B, 288C, 288D, 288E, 288F, and 288 were synthesized by employing the procedures described for Compounds 27B, 27C, 236D, Intermediate I, 217E, and 8F using (bromomethyl)cyclopropane, Compounds 288A with K2CO3 as base, 288B, 288C, 288D, 288E, and 288F in lieu of iodoethane, Compounds 27A with Cs2CO3 as base, 27B, 236C, 4-bromophenol, 217D, and 8E. Compound 288B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.35-0.37 (m, 2H), 0.66- 0.68 (m, 2H), 1.25-1.27 (m, 1H), 3.82 (d, J = 7.2 Hz, 2H), 7.06 (s, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.32 (s, 1H). Compound 288C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 288D: LC-MS (ESI) m/z: 231 [M-H]¯. Compound 288E: LC-MS (ESI) m/z: 492 [M+H]+. Compound 288F: LC-MS (ESI) m/z: 372 [M+H]+. Compound 288: LC- MS (ESI) m/z: 344 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.30-0.34 (m, 2H), 0.54- 0.58 (m, 2H), 1.18-1.22 (m, 1H), 3.89 (d, J = 7.2 Hz, 2H), 6.94-6.95 (m, 2H), 7.04 (s, 1H), 13.30 (s, 1H), 15.32 (s, 1H).
[001522] Example 289
[001523] Synthesis of 4-(3-chloro-5-(cyclopropylmethoxy)phenoxy)-1H-1,2,3-triazole- 5-carboxylic acid 2,2,2-trifluoroacetate (289)
Figure imgf000426_0001
[001524] Compounds 289A, 289B, 289C, and 289 were synthesized by employing the procedures described for Compounds 236D, Intermediate I, 217E, and 8F using Compounds 217C, 289B, 289C, and 289D in lieu of Compounds 236C, 4-bromophenol, 217D, and 8E. Compound 289A: LC-MS (ESI) m/z: 197 [M-H]¯. Compound 289B: LC-MS (ESI) m/z: 458 [M+H]+. Compound 289C: LC-MS (ESI) m/z: 338 [M+H]+. Compound 289: LC-MS (ESI) m/z: 310 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.28-0.29 (m, 2H), 0.53-0.55 (m, 2H), 1.18-1.22 (m, 1H), 3.80 (d, J = 6.8 Hz, 2H), 6.59-6.79 (t, J = 8 Hz, 3H), 13.26 (s, 1H), 15.28 (s, 1H).
[001525] Example 290
[001526] Synthesis of 4-(3-(cyclopentylmethoxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (290)
Figure imgf000426_0002
[001527] Compounds 290B, 290C, 290D, and 290 were synthesized by employing the procedures described for Compounds 29B, Intermediate I, 217E, and 8F using
(bromomethyl)cyclopentane, Compounds 290A with K2CO3 as base, 290B, 290C, and 290D in lieu of iodoethane, Compounds 29A with Cs2CO3 as base, 4-bromophenol, 217D, and 8E.
Compound 290B: LC-MS (ESI) m/z: 193 [M+H]+. Compound 290C: LC-MS (ESI) m/z: 452 [M+H]+. Compound 290D: LC-MS (ESI) m/z: 332 [M+H]+. Compound 290: LC-MS (ESI) m/z: 304 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.28-1.73 (m, 8H), 2.23-2.28 (m, 1H), 3.78-3.80 (m, 2H), 6.52-6.73 (m, 3H) 7.19-7.23 (m, 1H).
[001528] Example 291
[001529] Synthesis of 4-((1-(2,5-dichlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazole- 5-carboxylic acid 2,2,2-trifluoroacetate (291)
Figure imgf000427_0001
[001530] Compounds 291B, 291C, 291D, and 291 were synthesized by employing the procedures described for Compounds 270B, 90C, 57E, and 8F using Compounds 291A, 291B with DEAD as coupling reagent, 291C, and 291D in lieu of Compounds 197A, 90B with DIAD as coupling reagent, 57D, and 8E. Compound 291B: LC-MS (ESI) m/z: 246 [M+H]+; 1H-NMR (CDCl3, 500 MHz): d (ppm) 1.68-1.72 (m, 2H), 1.96-1.99 (m, 2H), 2.71-2.76 (m, 2H), 3.14 (s, 1H), 3.20-3.24 (m, 2H), 3.79-3.81 (m, 1H), 6.68 (dd, J = 8.5, 2.5 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H). Compound 291C: LC-MS (ESI) m/z: 505 [M+H]+. Compound 291D: LC-MS (ESI) m/z: 385 [M+H]+. Compound 291: LC-MS (ESI) m/z: 357 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.83-1.89 (m, 2H), 2.12-2.15 (m, 2H), 2.91-2.96 (m, 2H), 3.17-3.32 (m, 2H), 4.80 (brs, 1H), 7.09-7.12 (m, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 12.88 (brs, 1H), 14.78 (brs, 1H).
[001531] Example 292
[001532] Synthesis of 4-(4-chloro-3-(cyclopropylmethoxy)phenoxy)-1H-1,2,3-triazole- 5-carboxylic acid (292)
Figure imgf000428_0001
[001533] Compounds 292A, 292B, 292C, and 292 were synthesized by employing the procedures described for Compounds 236D, Intermediate I, 217E, and 8F using Compounds 218C, 292A, 292B, and 292C in lieu of Compounds 236C, 4-bromophenol, 217D, and 8E. Compound 292A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 292B: LC-MS (ESI) m/z: 458 [M+H]+. Compound 292C: LC-MS (ESI) m/z: 338 [M+H]+. Compound 292: LC-MS (ESI) m/z: 310 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.33-0.35 (m, 2H), 0.55-0.59 (m, 2H), 1.19-1.25 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 6.59 (dd, J = 2.4, 8.4 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H),13.24 (s, 1H), 15.23 (s, 1H).
[001534] Example 293
[001535] Synthesis of 4-(2-chloro-5-(cyclopropylmethoxy)phenoxy)-1H-1,2,3-triazole- 5-carboxylic acid (293)
Figure imgf000429_0001
[001536] Compounds 293A, 293B, 293C, and 293 were synthesized by employing the procedures described for Compounds 236D, Intermediate I, 217E, and 8F using Compounds 219C, 293A, 293B, and 293C in lieu of Compounds 236C, 4-bromophenol, 217D, and 8E. Compound 293A: LC-MS (ESI) m/z: 197 [M-H]¯. Compound 293B: LC-MS (ESI) m/z: 458 [M+H]+. Compound 293C: LC-MS (ESI) m/z: 338 [M+H]+. Compound 293: LC-MS (ESI) m/z: 310 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.25-0.30 (m, 2H), 0.49-0.56 (m, 2H), 1.10-1.20 (m, 1H), 3.75 (d, J = 6.8 Hz, 2H), 6.70 (s, 1H), 6.76-6.82 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H).
[001537] Example 294
[001538] Synthesis of 4-((1,3-bis(4-chlorophenyl)propan-2-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid (294)
Figure imgf000429_0002
[001539] To a solution of DCC (2.8 g, 13.6 mmol) and DMAP (0.45 g, 3.69 mmol) in anhydrous dichloromethane was slowly added a solution of 4-chlorophenylacetic acid (294A) (2.0 g, 11.76 mmol) in anhydrous dichloromethane (80 mL). The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL), washed with brine (15 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 25% v/v) to afford Compound 294B. LC-MS (ESI) m/z: 279 [M+H]+.1H- NMR (CDCl3, 400 MHz): d (ppm) 3.71 (s, 4H), 7.08 (d, J = 8.4 Hz, 4H), 7.30 (d, J = 8.8 Hz, 4H).
[001540] Compounds 294C, 294D, 294E, and 294 were synthesized by employing the procedures described for Compounds 57C, 90C, 57E, and 2 using Compounds 291A, 291B with DEAD as coupling reagent, 291C, and 291D in lieu of Compounds 197A, 90B with DIAD as coupling reagent, 57D, and 1. Compound 294C: 263 [M+H-H2O]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.69-2.85 (m, 4H), 3.99-4.02 (m, 1H), 7.16 (d, J = 8.4 Hz, 4H), 7.29 (d, J = 8.0 Hz, 4H). Compound 294D: LC-MS (ESI) m/z: 540 [M+H]+. Compound 294E: LC-MS (ESI) m/z: 420 [M+H]+. Compound 294: LC-MS (ESI) m/z: 392 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.96 (d, J = 6 Hz, 4H), 5.05-5.08 (m, 1H), 7.25-7.31 (m, 8H), 12.85 (br, 1H), 14.67 (s, 1H).
[001541] Example 295
[001542] Synthesis of 4-(3-(cyclopropylmethoxy)-4-(trifluoromethyl)phenoxy)-1H- 1
Figure imgf000430_0001
[001543] To a solution of cyclopropylmethanol (2.22 g, 31 mmol) in THF (100 mL) at 0oC was added sodium hydride (60% dispersion in oil, 2.06 g, 51 mmol) in portions and stirred at room temperature for 30 minutes, followed by addition of 4-bromo-2-fluoro-1- (trifluoromethyl)benzeneare (295A) (5.0 g, 20.5 mmol). The mixture was stirred at room temperature for 16 hours, quenched with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases was washed with brine (50 mL), dried over sodium sulphate, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 295B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.39 (q, J = 4.9 Hz, 2H), 0.64 (q, J = 5.9 Hz, 2H), 0.81– 0.91 (m, 1H), 3.91 (t, J = 8.1 Hz, 2H), 7.03– 7.18 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H).
[001544] Compounds 295C, 295D, 295E, 295F, and 295 were synthesized by
employing the procedures described for Compounds 27C, 236D, Intermediate I, 217E, and 8F using Compounds 295B, 295C, 295D, 295E, and 295F in lieu of Compounds 27B, 236C, 4- bromophenol, 217D, and 8E. Compound 295C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.39 (q, J = 4.9 Hz, 2H), 0.57– 0.66 (m, 2H), 0.96– 0.77 (m, 1H), 1.35 (s, 12H), 3.98 (d, J = 6.5 Hz, 2H), 7.35 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H). Compound 295D: LC-MS (ESI) m/z: 233 [M+H]+. Compound 295E: LC-MS (ESI) m/z: 492 [M+H]+. Compound 295F: LC-MS (ESI) m/z: 372 [M+H]+. Compound 295: LC-MS (ESI) m/z: 344 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.34 (t, J = 5.1 Hz, 2H), 0.46– 0.61 (m, 2H), 1.20 (s, 1H), 3.96 (d, J = 6.8 Hz, 2H), 6.61 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H).
[001545] Example 296
[001546] Synthesis of 4-(1,3-diphenylpropoxy)-1H-1,2,3-triazole-5-carboxylic acid (296)
Figure imgf000432_0001
[001547] To a solution of 3-phenylpropanal (296A) (1.34 g, 10 mmol ) in anhydrous THF (15 mL) was added phenylmagnesium chloride (2.0 M in THF, 5 mL , 10 mmol ) at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with saturated NH4Cl solution (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 14% v/v) to furnish Compound 296B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.02-2.13 (m, 2H), 2.64-2.74 (m, 2H), 4.65-4.68 (m, 1H), 7.15-7.19 (m, 3H), 7.27-7.29 (m, 3H), 7.33-7.34 (m, 4H).
[001548] Compounds 296C, 296D, and 296 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Compounds 296B, 296C, and 296D in lieu of Compounds 90B, 1E, and 8E. Compound 296C: LC-MS (ESI) m/z: 472 [M+H]+. Compound 296D: LC-MS (ESI) m/z: 352 [M+H]+. Compound 296: LC-MS (ESI) m/z: 324 [M+H]+.1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.86-1.99 (m, 1H), 2.18-2.33 (m, 1H), 2.45-2.67 (m, 2H), 4.72-4.76 (m, 1H), 7.17-7.34 (m, 10H).
[001549] Example 297
[001550] Synthesis of 4-((4'-(4,4-difluoropiperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (297)
Figure imgf000433_0001
[001551] A mixture of 1-fluoro-4-nitrobenzene (297A) (1.42 g, 10 mmol), 4,4- difluoropiperidine hydrochloride (297B) (1.6 g, 10 mmol), and K2CO3 (4.14 g, 30 mmol) in DMF (80 mL) was stirred at 70 oC overnight. After cooled down to room temperature, the mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic layers was washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 297C. LC-MS (ESI) m/z: 243 [M+H]+.
[001552] To a mixture of Compound 297C (2.4 g, 10 mmol) and NH4Cl (2.65 g, 50 mmol) in THF/H2O (100 mL/25 mL) was added iron powder (2.8 g, 50 mmol). The mixture was stirred at 70 oC overnight. The mixture was filtered through Celite. The filtrate was concentrated to afford Compound 297D. LC-MS (ESI) m/z: 213 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.05-2.15 (m, 4H), 3.15 (t, J = 6.0 Hz, 4H), 3.44-3.46 (m, 2H), 6.63-6.66 (m, 2H), 6.81- 6.83 (m, 2H).
[001553] Compounds 297E, 297F, 297G, 297H, and 297 were synthesized by
employing the procedures described for Compounds 56B, 27C, 4B, 1, and 2 using Compounds 297D with HBr/CuBr, 297E, Intermediate I, 297F with K2CO3 as base and 1,4-dioxane/H2O as solvent, 297G, and 297H in lieu of Compounds 56A with HCl/CuCl, 27B, (4- bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 1E, and 1. Compound 297E: LC-MS (ESI) m/z: 276 [M+H]+. Compound 297F: LC-MS (ESI) m/z: 324 [M+H]+. Compound 297G: LC-MS (ESI) m/z: 549 [M+H]+. Compound 297H: LC-MS (ESI) m/z: 429 [M+H]+. Compound 297: LC-MS (ESI) m/z: 401 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.99-2.12 (m, 4H), 3.37-3.40 (m, 4H), 7.06-7.12 (q, J = 9.2 Hz, 4H), 7.51 (d, J = 9.2 Hz, 2H), 7.58 (d, J = 9.2 Hz, 2H), 13.24 (brs, 1H), 15.20 (brs, 1H).
[001554] Example 298
[001555] Synthesis of 4-((4-(4-(trifluoromethoxy)phenyl)cyclohexyl)methoxy)-1H- 1,2,3-triazole-5-carboxylic acid (298)
Figure imgf000434_0001
[001556] To a solution of LiHMDS (1 M in THF, 13.99 mL , 13.99 mmol ) in dry THF (20 mL) was added ethyl 4-oxocyclohexane-1-carboxylate (298A) (2.16 g , 12.72 mmol ) at -78 oC and stirred at -78 oC for 30 minitesand, followed by addition of 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (5 g , 13.99 mmol ). It was stirred at -78 oC for 30 minutes and at room temperature overnight. The mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish Compound 298B. LC-MS (ESI) m/z: 303 [M+H]+.
[001557] A mixture of Compound 298B (1.64 g, 5.43 mmol), (4- (trifluoromethoxy)phenyl) boronic acid (700 mg, 3.39 mmol), Na2CO3 (922 mg, 6.78 mmol), PPh3 (88 mg, 0.339 mmol) and Pd(OAc)2 (76 mg, 0.339 mmol) in toluene/EtOH (15 mL/5 mL) was degassed with N2 for three times and heated to 110 oC for 2 hours. After cooled down to room temperature, the mixture was diluted with H2O (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers was concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 298C. LC-MS (ESI) m/z: 315 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.16-1.30 (m, 3H), 1.83-1.87 (m, 1H), 2.16-2.20 (m, 1H), 2.41-2.49 (m, 4H), 2.58-2.62 (m, 1H), 4.13-4.18 (m, 2H), 6.08-6.16 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 6.8 Hz, 2H).
[001558] Compounds 298D, 298E, 298F, 298G, and 298 were synthesized by
employing the procedures described for Compounds 141, 283B, 90C, 1, and 8E using
Compounds 298C, 298D at -30 oC, 298E with DEAD as coupling reagent, 298F, and 298G in lieu of Compounds 140, 283B at 0 oC to room temperature, 90C with DIAD as coupling reagent, 1E, and 8E. Compound 298D: LC-MS (ESI) m/z: 317 [M+H]+. Compound 298E: LC-MS (ESI) m/z: 257 [M-OH]+. Compound 298F: LC-MS (ESI) m/z: 534 [M+H]+. Compound 298G: LC- MS (ESI) m/z: 414 [M+H]+. Compound 298: LC-MS (ESI) m/z: 386 [M+H]+.1H-NMR
(DMSO-d6, 400 MHz): d (ppm) 1.61-1.80 (m, 8H), 2.17-2.20 (m, 1H), 2.62-2.64 (m, 1H), 4.31- 4.35 (m, 2H), 7.25 (d, J = 8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 12.89 (s, 1H), 14.73 (s, 1H).
[001559] Example 299
[001560] Synthesis of 4-(((3',5'-dichloro-[1,1'-biphenyl]-4-yl)oxy)methyl)-1H-1,2,3- triazole-5-carboxylic acid (299)
Figure imgf000436_0001
[001561] Compounds 299A, 299B, and 299 were synthesized by employing the procedures described for Compounds 4B, 1, and 8E using (3,5-dichlorophenyl)boronic acid, Compounds 265A with 1,4-dioxane/EtOH as solvent, 299A, and 299B in lieu of (4- bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 299A: LC-MS (ESI) m/z: 512 [M+H]+. Compound 299B: LC-MS (ESI) m/z: 392 [M+H]+. Compound 299: LC-MS (ESI) m/z: 364 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.41 (s, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.53 (s, 1H), 7.69-7.72 (m, 4H), 13.35 (s, 1H), 15.55 (s, 1H).
[001562] Example 300
[001563] Synthesis of 4-(((3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)oxy)methyl)-1H-1,2,3-triazole-5-carboxylic acid (300)
Figure imgf000437_0001
[001564] Compounds 300A, 300B, 300C, and 300 were synthesized by employing the procedures described for Compounds 27C, 4B, 1, and 8E using Compounds 32A, 300A 265A with 1,4-dioxane/EtOH as solvent, 300B, and 300C in lieu of Compounds 27B, (4- bromophenyl)boronic acid, 4A with toluene/EtOH/H2O as solvent, 1E, and 8E. Compound
300A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34 (s, 12H), 7.31 (dd, J = 1.6, 8 Hz, 1H), 7.90 (dd, J = 1.6, 8 Hz, 1H), 7.90 (s, 1H). Compound 300B: LC-MS (ESI) m/z: 562 [M+H]+;. Compound 300C: LC-MS (ESI) m/z: 442 [M+H]+. Compound 300: LC-MS (ESI) m/z: 414 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.40 (s, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.68-7.74 (m, 3H), 7.94 (d, J = 2.4 Hz, 1H), 13.39 (s, 1H), 15.56 (s, 1H).
[001565] Example 301
[001566] Synthesis of 4-(4-(4,4-difluoropiperidin-1-yl)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (301)
Figure imgf000437_0002
[001567] A of Intermediate I (600 mg, 1.39 mmol), 4,4-difluoropiperidine
hydrochloride (297B) (439 mg, 2.78 mmol), Pd(OAc)2 (156 mg, 0.695 mmol), X-Phos (331 mg, 0.695 mmol), and Cs2CO3 (1.36 g, 4.17 mmol) in 1,4-dixoane (30 mL) was stirred at 100 oC under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 301A. LC-MS (ESI) m/z: 473 [M+H]+.
[001568] Compounds 301B and 301 were synthesized by employing the procedures described for Compounds 8E and 1 using Compounds 301A and 301B in lieu of Compounds 8E and 1E. Compound 301B: LC-MS (ESI) m/z: 445 [M+H]+. Compound 301: LC-MS (ESI) m/z: 325 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.03-2.10 (m, 4H), 3.26-3.27 (m, 4H), 7.01 (s, 4H).
[001569] Example 302
[001570] Synthesis of ((isopropoxycarbonyl)oxy)methyl 4-(((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylate (302)
Figure imgf000438_0001
[001571] Compounds 302A, 302B, 302C, and 302 were synthesized by employing the procedures described for Compounds 54A, 8F, 54C, and 256 using Compounds 271G-1, 302A, 302B, chloromethyl isopropyl carbonate with TEA as base and adding NaI, and 302C in lieu of Compounds 33, 8E, 54B, chloromethyl pivalate with Na2CO3 as base and without NaI, and
256D. Compound 302A: LC-MS (ESI) m/z: 664 [M+Na]+. Compound 302B: LC-MS (ESI) m/z: 636 [M+Na]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.49-1.63 (m, 4H), 1.87-1.90 (m, 2H), 2.22-2.25 (m, 2H), 2.57-2.63 (m, 1H), 4.48-4.55 (m, 1H), 7.15-7.18 (m, 8H), 7.29-7.33 (m, 11H). Compound 302C: LC-MS (ESI) m/z: 752 [M+Na]+. Compound 302: LC-MS (ESI) m/z: 488 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.20-1.22 (m, 6H), 1.56-1.61 (m, 4H), 1.87- 1.89 (m, 2H), 2.24-2.26 (m, 2H), 2.56-2.58 (m, 1H), 4.66-4.66 (m, 1H), 4.79-4.81 (m, 1H), 5.86 (s, 2H), 7.08-7.10 (m, 2H), 7.25-7.27 (m, 2H).
[001572] Example 303
[001573] Synthesis of ((cyclohexanecarbonyl)oxy)methyl 4-(((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylate (303)
Figure imgf000439_0001
[001574] Compounds 303A and 303 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 302B, 229B with TEA as base and adding NaI, and 303A in lieu of Compounds 54B, chloromethyl pivalate with Na2CO3 as base and without NaI, and 256D. Compound 303A: LC-MS (ESI) m/z: 776 [M+Na]+. Compound 303: LC-MS (ESI) m/z: 534 [M+Na]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.24-1.51 (m, 5H), 1.65-1.77 (m, 7H), 1.90-1.99 (m, 4H), 2.34-2.44 (m, 3H), 2.66-2.68 (m, 1H), 4.74-4.76 (m, 1H), 5.97 (s, 2H), 7.18-7.20 (m, 2H), 7.34-7.37 (m, 2H).
[001575] Example 304
[001576] Synthesis of 4-(((1s,4s)-4-(3,5-dichlorophenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (304)
Figure imgf000440_0001
[001577] Compounds 304A, 304B, 304C, and 304D were synthesized by employing the procedures described for Compounds 8B, 141, 279D, and 57C using 4,4,5,5-tetramethyl-2-(1,4- dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 285A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 304A with THF as solvent, 304B with THF as solvent, and 304C in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with tBuONa as base and DME/H2O as solvent, 140 with EtOAc as solvent, 279C with acetone as solvent, and 57B. Compound 304A: LC-MS (ESI) m/z: 285 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.89-1.93 (m, 2H), 2.46- 2.47 (m, 2H), 2.58-2.61 (m, 2H), 4.03 (s, 4H), 6.02 (t, J = 2.0 Hz, 1H), 7.20-7.21 (m, 1H), 7.25- 7.26 (m, 2H). Compound 304B: LC-MS (ESI) m/z: Non-ionizable compounds under routine condition used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.58-1.80 (m, 8H), 2.42-2.45 (m, 1H), 3.91 (s, 4H), 7.04 (d, J = 2.0 Hz, 2H), 7.11 (t, J = 2.0 Hz, 1H). Compound 304C: LC-MS (ESI) m/z: 243 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.85-1.95 (m, 2H), 2.20-2.24 (m, 2H), 2.48-2.52 (m, 4H), 2.95-3.02 (m, 1H), 7.13 (d, J = 1.2 Hz, 2H), 7.23-7.24 (m, 1H).
[001578] Compound 304D was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to furnish Compound 304D-1 and Compound 304D-2. Compound 304D-1: LC-MS (ESI) m/z: 227 [M-OH]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.21-1.44 (m, 4H), 1.74-1.78 (m, 2H), 1.92-1.95 (m, 2H), 2.37-2.41 (m, 1H), 3.48-3.52 (m, 1H), 7.08 (d, J = 2.0 Hz, 2H), 7.12-7.13 (m, 1H).
Figure imgf000441_0001
[001579] Compounds 304E, 304F, and 304 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Compounds 304D-1 with DEAD as coupling reagent, 304E, and 304F in lieu of Compounds 90B with DIED as coupling reagent, 1E, and 8E. Compound 304E: LC-MS (ESI) m/z: 504 [M+H]+. Compound 304F: LC-MS (ESI) m/z: 384 [M+H]+. Compound 304: LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.65-1.79 (m, 4H), 1.93-2.00 (m, 2H), 2.21-2.25 (m, 2H), 2.64-2.68 (m, 1H), 5.06 (s, 1H), 7.25 (s, 3H).
[001580] Example 305
[001581] Synthesis of (benzoyloxy)methyl 4-(((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylate (305)
Figure imgf000442_0001
[001582] Compounds 305A and 305 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 302B, chloromethyl benzoate with TEA as base and adding NaI, and 305A in lieu of Compounds 54B, chloromethyl pivalate with Na2CO3 as base and without NaI, and 256D. Compound 305A: LC-MS (ESI) m/z: 770 [M+Na]+. Compound 305: LC-MS (ESI) m/z: 506 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.63- 1.65 (m, 4H), 1.93-1.95 (m, 2H), 2.02-2.04 (m, 2H), 2.60-2.61 (m, 1H), 4.70-4.72 (m, 1H), 6.23 (s, 2H), 7.17-7.19 (m, 2H), 7.31-7.33 (m, 2H), 7.49-7.53 (m, 2H), 7.63-7.65 (m, 1H), 8.07-8.09 (m, 2H).
[001583] Example 306
[001584] Synthesis of 4-(4-(4-(piperidin-1-yl)cyclohexyl)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (306)
Figure imgf000443_0001
[001585] Compounds 306B, 306C, 306D, and 306 were synthesized by employing the procedures described for Compounds 160B, Intermediate I, 1, and 2 using Compounds 306A with MeOH as solvent, 306B with Na2CO3 as base, 306C, and 306D in lieu of Compounds 160A with dichloromethane as solvent, 4-bromophenol with K2CO3 as base, 1E, and 1. Compound 306B: LC-MS (ESI) m/z: 260 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.36-1.50 (m, 10H), 1.74-2.54 (m, 10H), 6.63-6.68 (m, 2H), 6.97-7.02 (m, 2H), 9.08 (s, 1H). Compound 306C: LC-MS (ESI) m/z: 519 [M+H]+. Compound 306D: LC-MS (ESI) m/z: 399 [M+H]+. Compound 306: LC-MS (ESI) m/z: 371 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.44-2.06 (m, 12.5H), 2.20-2.33 (m, 2H), 2.58-2.65 (m, 0.5H), 2.96-3.29 (m, 3H), 3.49-3.53 (m, 2H), 7.06-7.12 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H).
[001586] Example 307
[001587] Synthesis of (isobutyryloxy)methyl 4-(((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylate (307)
Figure imgf000444_0001
[001588] Compounds 307A and 307 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 302B, chloromethyl isobutyrate with TEA as base and adding NaI, and 307A in lieu of Compounds 54B, chloromethyl pivalate with Na2CO3 as base and without NaI, and 256D. Compound 307A: LC-MS (ESI) m/z: 736 [M+Na]+. Compound 307: LC-MS (ESI) m/z: 472 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.18- 1.19 (m, 6H), 1.64-1.70 (m, 4H), 1.97-1.99 (m, 2H), 2.33-2.35 (m, 2H), 2.61-2.67 (m, 2H), 4.74- 4.75 (m, 1H), 5.97 (s, 2H), 7.17-7.20 (m, 2H), 7.34-7.36 (m, 2H).
[001589] Example 308
[001590] Synthesis of 4-(((cis)-4-(3,4-dichlorophenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (308-1) and 4-(((trans)-4-(3,4-dichlorophenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (308-2)
Figure imgf000444_0002
[001591] Compounds 308B, 308C, and 308D were synthesized by employing the procedures described for Compounds 206C, 141, and 279D using 4,4,5,5-tetramethyl-2-(1,4- dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 308A, 308B with THF as solvent, and 308C with TFA as acid and dichlormethane as solvent in lieu of Compounds 206B, Intermediate A, 140 with EtOAc as solvent, and 279C with HCl as acid and acetone as solvent. Compound 308B: LC-MS: (ESI) m/z: 285 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.92 (t, J = 6.4 Hz, 2H), 2.45 (brs, 2H), 2.58-2.66 (m, 2H), 4.03 (s, 4H), 6.00-6.04 (m, 1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H). Compound 308C: LC- MS: (ESI) m/z: 287 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.65-1.90 (m, 8H), 2.48-2.58 (m, 1H), 3.99 (s, 4H), 7.05-7.10 (m, 1H), 7.32-7.37 (m, 2H). Compound 308D: LC-MS (ESI) m/z: 243 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.84-1.98 (m, 2H), 2.16-2.28 (m, 2H), 2.48-2.56 (m, 4H), 2.96-3.06 (m, 1H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H).
[001592] To a solution of Compound 308D (1.47 g, 6.05 mmol) in anhydrous THF (20 mL) was added a solution of DIBAL-H in toluene (25%, 6.05 mL) at 0 oC and stirred at room temperature for 2 hours. It was quenched with dilute HCl solution (0.5 M, 50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude Compound 308E, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 30% v/v) to yield Compound 308E-1(trans isomer) and Compound 308E-2 (cis isomer). Compound 308E-1: LC-MS (ESI) m/z: 227 [M-OH]+; retention time: 1.67 min (214 nm).1H-NMR (CDCl3, 400 MHz): d (ppm) 1.38-1.52 (m, 4H), 1.88-1.96 (m, 2H), 2.06-2.14 (m, 2H), 2.43-2.52 (m, 1H), 3.64-3.73 (m, 1H), 7.04 (dd, J = 8.0, 2.0 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H). Compound 308E-2: LC-MS (ESI) m/z: 227 [M-OH]+; retention time: 1.72 min (214 nm).1H-NMR (CDCl3, 400 MHz): d (ppm) 1.60-1.72 (m, 4H), 1.80-1.96 (m, 4H), 2.46-2.56 (m, 1H), 4.12-4.18 (m, 1H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 7.32-7.40 (m, 2H).
Figure imgf000445_0001
[001593] Compounds 308F-1, 308G-1, and 308-1 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 308E-1 with DEAD as coupling reagent, 308F-1, and 308G-1 in lieu of Compounds 90B with DIAD as coupling reagent, 8E, and 1E. Compound 308F-1: LC-MS (ESI) m/z: 504 [M+H]+. Compound 308G-1: LC-MS (ESI) m/z: 476 [M+H]+. Compound 308-1: LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 1.58-1.83 (m, 6H), 2.07 (d, J = 12.5 Hz, 2H), 2.69 (t, J = 11.5 Hz, 1H), 4.91 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 12.89 (s, 1H), 14.76 (s, 1H).
Figure imgf000446_0001
[001594] Compounds 308F-2, 308G-2, and 308-2 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 308E-2 with DEAD as coupling reagent, 308F-2, and 308G-2 in lieu of Compounds 90B with DIAD as coupling reagent, 8E, and 1E. Compound 308F-2: LC-MS (ESI) m/z: 504 [M+H]+. Compound 308G-2: LC-MS (ESI) m/z: 476 [M+H]+. Compound 308-2: LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): 1.43-1.71 (m, 4H), 1.85 (d, J = 12.1 Hz, 2H), 2.23 (d, J = 11.2 Hz, 2H), 2.64 (t, J = 11.4 Hz, 1H), 4.67 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 12.89 (s, 1H), 14.75 (s, 1H).
[001595] Example 309
[001596] Synthesis of 4-(4-chloro-3-(cyclohexylmethoxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (309)
Figure imgf000446_0002
[001597] Compounds 309A, 309B, 309C, 309D, 309E, and 309 were synthesized by employing the procedures described for Compounds 27B, 27C, 236D, Intermediate I, 217E, and 8F using Compounds 218A with K2CO3 as base, 309A, 309B, 309C, 309D, and 309E in lieu of Compounds 27A with Cs2CO3 as base, 27B, 236C, 4-bromophenol, 217D, and 8E. Compound 309A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 309B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.06-1.10 (m, 2H), 1.19-1.22 (m, 1H), 1.29-1.34 (m, 15H), 1.75- 1.79 (m, 3H), 1.89-1.93 (m, 2H), 3.86 (d, J = 6.0 Hz, 2H), 7.28-7.36 (m, 3H). Compound 309C: LC-MS (ESI) m/z: 241 [M+H]+. Compound 309D: LC-MS (ESI) m/z: 500 [M+H]+. Compound 309E: LC-MS (ESI) m/z: 380 [M+H]+. Compound 309: LC-MS (ESI) m/z: 352 [M+H]+.1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.04-1.27 (m, 5H), 1.63-1.82 (m, 6H), 3.83 (d, J = 6.4 Hz, 2H), 6.59 (dd, J = 2.8, 8.8 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 13.35 (s, 1H), 15.31 (s, 1H).
[001598] Example 310
[001599] Synthesis of 4-(((cis)-4-(4-(trifluoromethyl)phenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (310)
Figure imgf000447_0001
[001600] Compounds 310B, 310C, 310D, and 310E were synthesized by employing the procedures described for Compounds 4B, 141, 279D, and 57C using 4,4,5,5-tetramethyl-2-(1,4- dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 310A with K2CO3 as base and 1,4-dioxane/H2O as solvent, 310B, 310C with 1,4-dioxane as solvent, and 310D in lieu of (4- bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140, 279C with acetone as solvent, and 57B. Compound 310B: LC-MS (ESI) m/z: 285 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.93-1.96 (m, 2H), 2.50 (d, J = 2.8 Hz, 2H), 2.66-2.69 (m, 2H), 4.04 (s, 4H), 6.07-6.09 (m, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H). Compound 310C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.68-1.90 (m, 8H), 2.60-2.66 (m.1H), 4.00 (s, 4H), 7.35 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H). Compound 310D: LC-MS (ESI) m/z: 243 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.91-2.02 (m, 2H), 2.21-2.26 (m, 2H), 2.52-2.55 (m, 4H), 3.07-3.14 (m, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H).
[001601] Compound 310E was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 310E-1 (trans isomer) and Compound 310E-2 (cis isomer). Compound 310E-1: LC-MS (ESI) m/z: 227 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.39-1.60 (m, 4H), 1.92-1.96 (m, 2H), 2.11-2.15 (m, 2H), 2.53-2.60 (m, 1H), 3.67-3.74 (m, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H). Compound 310E- 2: LC-MS (ESI) m/z: 227 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.66-1.73 (m, 4H), 1.88-1.98 (m, 4H), 2.58-2.64 (m, 1H), 4.16 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H).
[001602] Compounds 310F, 310G, and 310 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Compounds 310E-1 with DEAD as coupling reagent, 310F, and 310G in lieu of Compounds 90B with DIAD as coupling reagent, 1E, and 8E. Compound 310F: LC-MS (ESI) m/z: 504 [M+H]+; 1H-NMR (CDCl3, 400
MHz):1.24-1.34 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.62-1.71 (m, 4H), 2.12-2.15 (m, 2H), 2.61- 2.67 (m, 1H), 3.75 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.38 (s, 2H), 5.49 (s, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.19-7.27 (m, 4H), 7.57 (d, J = 8.4 Hz, 2H). Compound 310G: LC-MS (ESI) m/z: 384 [M+H]+. Compound 310: LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (CD3OD, 400 MHz):1.67- 1.81 (m, 4H), 2.00-2.11 (m, 2H), 2.24 (d, J = 14.4 Hz, 2H), 2.72-2.79 (m, 1H), 5.07 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H).
[001603] Example 311
[001604] Synthesis of 4-(spiro[4.5]decan-8-ylthio)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (311)
Figure imgf000449_0001
[001605] Compounds 311A, 311B, and 311 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Intermediate D, Compounds 284H, 311A, and 311B in lieu of Intermediate H, Compounds 90B, 1E, and 8E. Compound 311A: LC- MS (ESI) m/z: 430 [M+H]+. Compound 311B: LC-MS (ESI) m/z: 310 [M+H]+. Compound 311: LC-MS (ESI) m/z: 282 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.31-1.40 (m, 6H), 1.47-1.55 (m, 8H), 1.91-1.93 (m, 2H), 3.52-3.54 (m, 1H).
[001606] Example 312
[001607] Synthesis of 4-(((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)methyl)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (312)
Figure imgf000449_0002
[001608] Compounds 312A, 312B, 312C, and 312 were synthesized by employing the procedures described for Compounds 243B, 4B, 1, and 8F using Compounds 21A, 312A with 1,4-dioxane/H2O as solvent, 312B, and 312C in lieu of Compounds 243A, 4A with
toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 312A: LC-MS (ESI) m/z: 462 [M+H]+. Compound 312B: LC-MS (ESI) m/z: 544 [M+H]+. Compound 312C: LC-MS (ESI) m/z: 424 [M+H]+. Compound 312: LC-MS (ESI) m/z: 396 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.53 (s, 2H), 7.43-7.47 (m, 4H), 7.63 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H).
[001609] Example 313
[001610] Synthesis of (propionyloxy)methyl 4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4- yl)thio)-1H-1,2,3-triazole-5-carboxylate 2,2,2-trifluoroacetate (313)
Figure imgf000450_0001
[001611] Compounds 313A and 313 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 267B, 278B with Et3N as base and DMF/THF as solvent and adding NaI, and 313A in lieu of chloromethyl pivalate, Compounds 54B with Na2CO3 as base and DMF as solvent and without NaI, and 256D. Compound 313A: LC-MS (ESI) m/z: 709 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.15 (t, J = 7.2 Hz, 3H), 1.59-1.65 (m, 2H), 1.70-1.76 (m, 4H), 2.35-2.42 (m, 2H), 3.22-3.24 (m, 4H), 5.96 (s, 2H), 6.98- 7.04 (m, 8H), 7.20-7.30 (m, 9H), 7.40-7.47 (m, 6H). Compound 313: LC-MS (ESI) m/z: 467 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.15 (t, J = 7.2 Hz, 3H), 1.72 (brs, 2H), 2.05- 2.10 (m, 4H), 2.37-7.43 (m, 2H), 3.48 (brs, 4H), 5.99 (s, 2H), 7.41-7.47 (m, 2H), 7.54-7.57 (m, 6H).
[001612] Example 314
[001613] Synthesis of 4-((3-(4-(trifluoromethoxy)phenyl)cyclopentyl)thio)-1H-1,2,3- triazole-5-carboxylic acid (314)
Figure imgf000451_0001
[001614] Compounds 314A, 314B, and 314 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Intermediate D, Compounds 275E, 314A, and 314B in lieu of Intermediate H, Compounds 90B, 1E, and 8E. Compound 314A: LC- MS (ESI) m/z: 522 [M+H]+. Compound 314B: LC-MS (ESI) m/z: 402 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.40 (t, J = 7.2 Hz, 3H), 1.59-1.92, 2.11-2.43 (m, 5H), 2.47-2.52, 2.66-2.73 (m, 1H), 3.17-3.23, 3.36-3.42 (m, 1H), 4.04-4.23 (m, 1H), 4.36-4.42 (m, 2H), 7.17- 7.20 (m, 2H), 7.36-7.39 (m, 2H). Compound 314: LC-MS (ESI) m/z: 374 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.62-1.89, 2.10-2.31 (m, 5H), 2.39-2.48, 2.62-2.70 (m, 1H), 3.14- 3.23, 3.37-3.45 (m, 1H), 4.03-4.20 (m, 1H), 7.16-7.19 (m, 2H), 7.35-7.39 (m, 2H).
[001615] Example 315
[001616] Synthesis of 4-(spiro[5.5]undecan-3-ylthio)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (315)
Figure imgf000451_0002
[001617] Compounds 315A, 315B, and 315 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Intermediate D, Compounds 283I, 315A, and 315B in lieu of Intermediate H, Compounds 90B, 1E, and 8E. Compound 315A: LC- MS (ESI) m/z: 444 [M+H]+. Compound 315B: LC-MS (ESI) m/z: 324 [M+H]+. Compound 315: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.15-1.21 (m, 4H), 1.35 (brs, 8H), 1.47-1.62 (m, 4H), 1.84-1.87 (m, 2H), 3.52 (brs, 1H). [001618] Example 316
[001619] Synthesis of 4-(((4-(piperidin-1-yl)naphthalen-1-yl)methyl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (316)
Figure imgf000452_0001
[001620] A mixture of 4-bromonaphthalen-1-amine (316A) (2.21 g, 10 mmol), 1,5- dibromopentane (2.51 g, 11 mmol), and potassium carbonate (1.52 g, 11 mmol) in DMF (80 mL) was stirred at 120 oC for 16 hours. After cooled down to room temperature, the mixture was diluted with ice-water (90 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phases was washed with water (100 mL) and brine (40mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 20% v/v) to afford Compound 316B. LC-MS (ESI) m/z: 290 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.56-1.70 (m, 2H), 1.83-1.88 (m, 4H), 3.03 (s, 4H), 6.92 (d, J = 8.4 Hz, 1H), 7.52-7.61 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 8.23 (t, J = 8.0 Hz, 2H).
[001621] To a mixture of Compound 316B (1.1 g, 3.8 mmol) and TEA (10 mL) in anhydrous DMF (12 mL) and MeOH (20 mL) was added Pd(OAc)2 (220 mg, 0.98 mmol) and Xantphos (1.15 g, 1.98 mmol) and stirred at 90 oC under CO (5 atm) for 24 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 15% v/v) to afford
Compound 316C. LC-MS (ESI) m/z: 270 [M+H]+.
[001622] Compounds 316D, 316E, 316F, and 316 were synthesized by employing the procedures described for Compounds 283C, 90C, 8F, and 57E using Compounds 316C, Intermediate D, 316D with DEAD as coupling reagent, 316E, and 316F in lieu of Compounds 283B, Intermediate H, 90B with DIAD as coupling reagent, 8E, and 57D. Compound 316D: LC- MS (ESI) m/z: 242 [M+H]+. Compound 316E: LC-MS (ESI) m/z: 517 [M+H]+. Compound
316F: LC-MS (ESI) m/z: 489 [M+H]+. Compound 316: LC-MS (ESI) m/z: 369 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.60 (s, 2H), 1.76-1.79 (m, 4H), 2.97 (br, 4H), 4.78 (s, 2H), 7.03-7.05 (m, 1H), 7.50-7.58 (m, 3H), 8.10-8.17 (m, 2H).
[001623] Example 317
[001624] Synthesis of ((cyclohexanecarbonyl)oxy)methyl 4-((4'-(piperidin-1-yl)-[1,1'- biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5-carboxylate 2,2,2-trifluoroacetate (317)
Figure imgf000453_0001
[001625] Compounds 317A and 317 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 229B, 278B with Et3N as base and DMF/THF as solvent and adding NaI, and 317A in lieu of chloromethyl pivalate, Compounds 54B with Na2CO3 as base and DMF as solvent, and without NaI and 256D. Compound 317A: LC-MS (ESI) m/z: 763 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.22-1.29 (m, 6H), 1.59- 1.63 (m, 2H), 1.70-1.76 (m, 6H), 1.87-1.93 (m, 2H), 2.36-2.38 (m, 1H), 3.21-3.25 (m, 4H), 5.30 (s, 2H), 6.98-7.04 (m, 8H), 7.22-7.30 (m, 9H), 7.40-7.47 (m, 6H). Compound 317: LC-MS (ESI) m/z: 521 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.11-1.35 (m, 5H), 1.55-1.80 (m, 11H), 2.32-2.41 (m, 1H), 3.34 (brs, 4H), 5.94 (s, 2H), 7.24-7.29 (m, 2H), 7.51-7.54 (m, 2H), 7.65-7.70 (m, 4H).
[001626] Example 318
[001627] Synthesis of 4-((4-chloro-3-(trifluoromethoxy)phenyl)thio)-1H-1,2,3-triazole- 5-carboxylic acid (318)
Figure imgf000454_0001
[001628] To a solution of 2-(trifluoromethoxy)aniline (318A) (2.655 mg, 15 mmol) in acetic acid (6 mL) was added NBS (2.94 g, 16.5 mmol) at 0 oC and stirred at room temperature overnight. It was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 318B. LC-MS (ESI) m/z: 256 [M +H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.89 (s, 2H), 6.67 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 8.8, 2.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H).
[001629] Compounds 318C, 318D, 318E, and 318 were synthesized by employing the procedures described for Compounds 30B, 35D, 1, and 8F using Compounds 318B with tert- butyl nitrite, 318C with Xantphos as ligand, 318D, and 318E in lieu of Compounds 30A with isoamyl nitrite, 35C with X-phos as ligand, 1E, and 8E. Compound 318C: LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.34-7.42 (m, 2H), 7.50 (s, 1H). Compound 318D: LC-MS (ESI) m/z: 488 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 3.75 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H), 5.62 (s, 2H), 6.66-6.69 (m, 1H), 6.72 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H). Compound 318E: LC-MS (ESI) m/z: 368 [M+H]+. Compound 318: LC-MS (ESI) m/z: 340 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.45 (dd, J = 8.8, 2.0 Hz, 1H), 7.56-7.59 (m, 2H).
[001630] Example 319
[001631] Synthesis of 4-((4'-(4,4-difluoropiperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (319)
Figure imgf000455_0001
[001632] Compounds 319A, 319B, and 319 were synthesized by employing the procedures described for Compounds 4B, 1, and 2 using Intermediate F, Compounds 297F with K2CO3 as base and 1,4-dioxane/H2O as solvent, 319A, and 319B in lieu of Compounds 4A, (4- bromophenyl)boronic acid with Na2CO3 as base and toluene/EtOH/H2O as solvent, 1E, and 1. Compound 319A: LC-MS (ESI) m/z: 565 [M+H]+. Compound 319B: LC-MS (ESI) m/z: 445 [M+H]+. Compound 319: LC-MS (ESI) m/z: 417 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.00-2.10 (m, 4H), 3.41 (t, J = 5.6 Hz, 4H), 7.08 (d, J = 8.8 Hz, 2H), 7.49-7.51 (m, 2H), 7.56 (d, J = 9.2 Hz, 2H), 7.63 (d, J = 9.2 Hz, 2H).
[001633] Example 320
[001634] Synthesis of 4-((5-(trifluoromethoxy)-2,3-dihydro-1H-inden-2-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (320)
Figure imgf000456_0001
[001635] Compounds 320A, 320B, 320C, 320D, 320E, and 320 were synthesized by employing the procedures described for Compounds 57B, 57C, 57D, 57E, 8F, and 1 using Compounds 211E, 320A, 320B, 320C with BF3-Et2O as acid and dichloromethane as solvent, 320D, and 320E in lieu of Compounds 57A, 57B, 57C, 57D with TFA as acid and solvent, 8E, and 1E. Compound 320A: LC-MS (ESI) m/z: 295 [M+H]+. Compound 320B: LC-MS (ESI) m/z: 279 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d 2.46 (d, J = 9.2 Hz, 1H), 3.36-3.49 (m, 2H), 4.93- 4.99 (m, 2H), 7.12-7.17 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H). Compound 320C: LC-MS (ESI) m/z: 510 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d 1.44 (t, J = 7.2 Hz, 3H), 2.65-2.71 (m, 1H), 3.08- 3.14 (m, 1H), 3.42 (d, J = 5.2 Hz, 1H), 3.59-3.65 (m, 1H), 3.77 (s, 3H), 4.47 (q, J = 7.2 Hz, 2H), 4.95-4.99 (m, 1H), 5.65 (d, J = 2.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.95 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H). Compound 320D: LC-MS (ESI) m/z: 494 [M+H]+ Compound 320E: LC-MS (ESI) m/z: 466 [M+H]+. Compound 320: LC-MS (ESI) m/z: 346 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.92-3.01 (m, 2H), 3.48-3.57 (m, 2H), 4.41-4.48 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 13.33 (bs, 1H), 15.62 (bs, 1H).
[001636] Example 321
[001637] Synthesis of 4-((4-(5-(trifluoromethoxy)pyridin-2-yl)phenyl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (321)
Figure imgf000457_0001
[001638] Compounds 321B, 321C, 321D, 321E, and 321 were synthesized by
employing the procedures described for Compounds 4B, 30B, 35D, 1, and 8F using 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, Compounds 321A with 1,4-dioxane/H2O as solvent, 321B with isopentyl nitrite and CuBr2, 321C with Xantphos as ligand, 320D, and 320E in lieu of (4-bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 30A with isoamyl nitrite and CuCl2, 35C with X-phos as ligand, 1E, and 8E. Compound 321B: LC-MS (ESI) m/z: 255 [M+H]+. Compound 321C: LC-MS (ESI) m/z: 318 [M+H]+. Compound 321D: LC-MS (ESI) m/z: 531 [M+H]+. Compound 321E: LC-MS (ESI) m/z: 411 [M+H]+. Compound 321: LC-MS (ESI) m/z: 383 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.46-7.49 (m, 2H), 7.73-7.76 (m, 1H), 7.90-7.96 (m, 3H), 8.52 (s, 1H).
[001639] Example 322
[001640] Synthesis of 4-(((3',4'-dichloro-[1,1'-biphenyl]-4-yl)thio)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (322)
Figure imgf000458_0001
[001641] Compounds 322A, 322B, and 322 were synthesized by employing the procedures described for Compounds 4B, 57E, and 8F using 3,4-dichlorophenylboronic acid, Compounds 312A with 1,4-dioxane/H2O as solvent, 322A, and 322B in lieu of (4- bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 57D, and 8E. Compound 322A: LC-MS (ESI) m/z: 528 [M+H]+; 1H-NMR: (CDCl3, 400 MHz): d (ppm) 1.31 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.26-4.28 (m, 4H), 5.61 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 7.33-7.36 (m, 3H), 7.41-7.44 (m, 2H), 7.49-7.51 (m, 1H), 7.62 (d, J = 2.0 Hz, 1H). Compound 322B: LC-MS (ESI) m/z: 408 [M+H]+. Compound 322: LC-MS (ESI) m/z: 380 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 4.62 (s, 2H), 7.43-7.46 (m, 2H), 7.54-7.59 (m, 4H), 7.78 (s, 1H).
[001642] Example 323
[001643] Synthesis of 4-((1-(3,4-dichlorophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazole- 5-carboxylic acid 2,2,2-trifluoroacetate (323)
Figure imgf000459_0001
[001644] Compounds 323A, 323B, and 323 were synthesized by employing the
procedures described for Compounds 90C, 1, and 8F using Intermediate D, Compounds 286B with DEAD as coupling reagent, 323A, and 323B in lieu of Intermediate H, Compounds 90B with DIAD as coupling reagent, 1E, and 8E. Compound 323A: LC-MS (ESI) m/z: 521 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.44 (t, J = 7.2 Hz, 3H), 1.57-1.61 (m, 2H), 1.78-1.83 (m, 2H), 2.70-2.77 (m, 2H), 3.44-3.52 (m, 3H), 3.78 (s, 3H), 4.46 (q, J = 6.0 Hz, 2H ), 5.62 (s, 2H), 6.68 (dd, J = 8.8, 2.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 1H). Compound 323B: LC-MS (ESI) m/z: 401 [M+H]+. Compound 323: LC-MS (ESI) m/z: 373 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.77-1.85 (m, 2H), 2.21-2.24 (m, 2H), 2.96-3.02 (m, 2H), 3.65-3.69 (m, 2H), 3.77-3.83 (m, 1H), 6.92 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H).
[001645] Example 324
[001646] Synthesis of 4-((1-(4-(trifluoromethoxy)phenyl)piperidin-4-yl)thio)-1H-1,2,3- triazole-5-carboxylic acid (324)
Figure imgf000460_0001
[001647] Compounds 324A, 324B, and 324 were synthesized by employing the
procedures described for Compounds 90C, 1, and 2 using Intermediate D, Compounds 287B with DEAD as coupling reagent, 324A, and 324B in lieu of Intermediate H, Compounds 90B with DIAD as coupling reagent, 1E, and 1. Compound 324A: LC-MS (ESI) m/z: 521 [M+H]+. Compound 324B: LC-MS (ESI) m/z: 401 [M+H]+. Compound 324: LC-MS (ESI) m/z: 373
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.65-1.68 (m, 2H), 2.12-2.15 (m, 2H), 3.06 (t, J = 10.4 Hz, 2H), 3.79 -3.84 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H).
[001648] Example 325
[001649] Synthesis of 4-((1-(3,5-dichlorophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazole- 5-carboxylic acid 2,2,2-trifluoroacetate (325)
Figure imgf000460_0002
325 [001650] Compounds 325A, 325B, and 325 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 285B with DEAD as coupling reagent, 325A, and 325B in lieu of Intermediate H, Compounds 90B with DIAD as coupling reagent, 8E, and 1E. Compound 325A: LC-MS (ESI) m/z: 521 [M+H]+. Compound 325B: LC-MS (ESI) m/z: 493 [M+H]+. Compound 325: LC-MS (ESI) m/z: 373 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.63-1.68 (m, 2H), 2.08-2.12 (m, 2H), 2.98- 3.03 (m, 2H), 3.72-3.75 (m, 3H), 6.84 (s, 1H), 6.95 (s, 2H), 13.34 (s, 1H), 15.52 (s, 1H).
[001651] Example 326
[001652] Synthesis of 4-((4-(3-(trifluoromethoxy)phenyl)cyclohexyl)thio)-1H-1,2,3- triazole-5-carboxylic acid (326)
Figure imgf000461_0001
[001653] Compounds 326B, 326C, 326D, 326E, 326F, 326G, and 326 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 57C, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 326A with 1,4-dioxane/H2O as solvent, 326B with MeOH as solvent, 326C with TFA as acid and dichloromethane as solvent, 326D, Intermediate D, 326E, 326F, and 326G in lieu of (4- bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and acetone as solvent, 57B, Intermediate H, 90B, 8E, and 1E. Compound 326B: LC-MS (ESI) m/z: 301 [M+H]+. Compound 326C: LC-MS (ESI) m/z: 303 [M+H]+. Compound 326D: LC-MS (ESI) m/z: 259 [M+H]+. Compound 326E: LC-MS (ESI) m/z: 243 [M-OH]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42-1.58 (m, 2H), 1.58-1.71 (m, 3H), 1.93-1.97 (m, 2H), 2.10-2.14 (m, 2H), 2.49-2.57 (m, 1H), 3.67-3.74 (m, 1H), 7.04-7.06 (m, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8 Hz, 1H). Compound 326F: LC-MS (ESI) m/z: 536
[M+H]+. Compound 326G: LC-MS (ESI) m/z: 508 [M+H]+. Compound 326: LC-MS (ESI) m/z: 388 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.71-1.80 (m, 4H), 1.98-1.99 (m, 4H), 2.65-2.72 (m, 1H), 4.13 (s, 1H), 7.18 (d, J = 7.2 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 13.25 (s, 1H), 15.52(s, 1H).
[001654] Example 327
[001655] Synthesis of 4-((4-(3-(trifluoromethyl)phenyl)cyclohexyl)thio)-1H-1,2,3- triazole-5-carboxylic acid (327)
Figure imgf000462_0001
[001656] Compounds 327B, 327C, 327D, 327E, 327F, 327G, and 327 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 57C, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 327A with 1,4-dioxane/H2O as solvent, 327B with MeOH as solvent, 327C, 327D, Intermediate D, 327E with DEAD as coupling reagent, 327F, and 327G in lieu of (4-bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 279C, 57B, Intermediate H, 90B with DIAD as coupling reagent, 8E, and 1E. Compound 327B: LC-MS (ESI) m/z: 285 [M+H]+. Compound 327C: LC-MS (ESI) m/z: 287 [M+H]+. Compound 327D: LC-MS (ESI) m/z: 243 [M+H]+. Compound 327E: LC-MS (ESI) m/z: 267 [M+Na]+. Compound 327F: LC-MS (ESI) m/z: 520 [M+H]+. Compound 327G: LC-MS (ESI) m/z: 492 [M+H]+.
Compound 327: LC-MS (ESI) m/z: 372 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.75- 1.84 (m, 4H), 1.94-2.08 (m, 4H), 2.73-2.80 (m, 1H), 4.13 (s, 1H), 7.53-7.60 (m, 4H), 13.3 (s, 1H), 15.44-15.47 (m, 1H).
[001657] Example 328
[001658] Synthesis of 4-(((3',5'-dichloro-[1,1'-biphenyl]-4-yl)thio)methyl)-1H-1,2,3- triazole-5-carboxylic acid (328)
Figure imgf000463_0001
[001659] Compounds 328A, 328B, and 328 were synthesized by employing the
procedures described for Compounds 8B, 1, and 8F using 3,5-dichlorophenylboronic acid, Compounds 312A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 328A, and 328B in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 1E, and 8E. Compound 328A: LC-MS (ESI) m/z: 528 [M+H]+. Compound 328B: LC- MS (ESI) m/z: 408 [M+H]+. Compound 328: LC-MS (ESI) m/z: 380 [M+H]+; 1H-NMR
(DMSO-d6, 400 MHz): d (ppm) 4.54 (s, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 3.6 Hz, 1H), 7.69 (s, 1H), 7.71 (s, 1H), 7.73 (d, J = 2.4 Hz, 2H).
[001660] Example 329
[001661] Synthesis of 4-(((3'-chloro-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)thio)methyl)-1H-1,2,3-triazole-5-carboxylic acid (329)
Figure imgf000464_0001
[001662] Compounds 329A, 329B, and 329 were synthesized by employing the procedures described for Compounds 8B, 1, and 8F using 3-chloro-4- (trifluoromethoxy)phenylboronic acid, Compounds 312A with Na2CO3 as base and 1,4- dioxane/H2O as solvent, 329A, and 329B in lieu of (3,4-dichlorophenyl)boronic acid,
Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 1E, and 8E. Compound 329A: LC-MS (ESI) m/z: 578 [M+H]+. Compound 329B: LC-MS (ESI) m/z: 458 [M+H]+. Compound 329: LC-MS (ESI) m/z: 430 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.54 (s, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H),
[001663] Example 330
[001664] Synthesis of 4-((1-(2,5-dichlorophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazole- 5-carboxylic acid (330)
Figure imgf000465_0001
[001665] Compounds 330A, 330B, and 330 were synthesized by employing the procedures described for Compounds 90C, 57E, and 8F using Intermediate D, Compounds 291B with DEAD as coupling reagent, 330A, and 330B in lieu of Intermediate H, Compounds 90B with DIAD as coupling reagent, 57D, and 8E. Compound 330A: LC-MS (ESI) m/z: 521
[M+H]+. Compound 330B: LC-MS (ESI) m/z: 401 [M+H]+. Compound 330: LC-MS (ESI) m/z: 373 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.88-1.93 (m, 2H), 2.23-2.27 (m, 2H), 2.83-2.89 (m, 2H), 3.32-3.38 (m, 2H), 3.77-3.80 (m, 1H), 7.01 (dd, J = 8.4, 2.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H).
[001666] Example 331
[001667] Synthesis of 4-(((cis)-4-(3,5-dichlorophenyl)cyclohexyl)thio)-1H-1,2,3- triazole-5-carboxylic acid (331)
Figure imgf000466_0001
331
[001668] Compounds 331A, 331B, and 331 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Intermediate D, Compounds 304D-1 with DEAD as coupling reagent, 331A, and 331B in lieu of Intermediate H, Compounds 90B with DIAD as coupling reagent, 1E, and 8E. Compound 331A: LC-MS (ESI) m/z: 520 [M+H]+. Compound 331B: LC-MS (ESI) m/z: 400 [M+H]+. Compound 331: LC-MS (ESI) m/z: 372 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.72-1.75 (m, 2H), 1.90-2.08 (m, 6H), 2.64- 2.66 (m, 1H), 4.20 (s, 1H), 7.24 (s, 2H), 7.26 (s, 1H).
[001669] Example 332
[001670] Synthesis of 4-(((cis)-4-(4-(trifluoromethyl)phenyl)cyclohexyl)thio)-1H-1,2,3- triazole-5-carboxylic acid (332)
Figure imgf000467_0001
[001671] Compounds 332A, 332B, and 332 were synthesized by employing the
procedures described for Compounds 90C, 1, and 8F using Intermediate D, Compounds 310E-1 with DEAD as coupling reagent, 332A, and 332B in lieu of Intermediate H, Compounds 90B with DIAD as coupling reagent, 1E, and 8E. Compound 332A: LC-MS (ESI) m/z: 520 [M+H]+. Compound 332B: LC-MS (ESI) m/z: 400 [M+H]+. Compound 332: LC-MS (ESI) m/z: 372
[M+H]+; 1H-NMR (CD3OD, 400 MHz):1.75-1.78 (m, 2H), 1.93-2.10 (m, 6H), 2.71-2.76 (m, 1H), 4.21 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H).
[001672] Example 333
[001673] Synthesis of 4-((methyl(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)amino)methyl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (333)
Figure imgf000468_0001
[001674] To a solution of 4-bromoaniline (60A) (1.71 g, 10.0 mmol) in THF (100 mL) and water (10 mL) was added K2CO3 (4.14 g, 30.0 mmol) and di-tert-butyl dicarbonate (3.27 g, 15.0 mmol). The mixture was stirred at room temperature overnight, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to afford Compound 333A. LC-MS (ESI) m/z: 216 [M-55]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.52 (s, 9H), 6.48 (brs, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H).
[001675] Compounds 333B, 333C, 333D, 333E, 333F, and 333 were synthesized by employing the procedures described for Compounds 4B, 63A, 70C, 178A, 8F, and 1 using 4- (trifluoromethoxy)phenylboronic acid, Compounds 333A with K2CO3 as base and 1,4- dioxane/H2O as solvent, 333B with K2CO3 as base at room temperature, 333C, 333D, 333E, and 333F in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 61F with Cs2CO3 as base at 60 °C, 70B, 82C, 8E, and 1E.
Compound 333B: LC-MS (ESI) m/z: 298 [M-55]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.55 (s, 9H), 6.54 (brs, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H). Compound 333C: LC-MS (ESI) m/z: 312 [M-55]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.49 (s, 9H), 3.31 (s, 3H), 7.27 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H). Compound 333D: LC-MS (ESI) m/z: 268 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.58 (brs, 1H), 2.90 (s, 3H), 6.70 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H). Compound 333E: LC-MS (ESI) m/z: 541 [M+H]+. Compound 333F: LC-MS (ESI) m/z: 513 [M+H]+.
Compound 333: LC-MS (ESI) m/z: 393 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.11 (s, 3H), 4.90 (s, 2H), 6.83 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H).
[001676] Example 334
[001677] Synthesis of 4-(3-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl)-1H-1,2,3- t
Figure imgf000469_0001
[001678] Compounds 334A, 334B, and 334 were synthesized by employing the
procedures described for Compounds 206C, 217E, and 8F using Compounds 288C, 334A, and 334B in lieu of Compounds 206B, 217D, and 8E. Compound 334A: LC-MS (ESI) m/z: 476 [M+H]+. Compound 334B: LC-MS (ESI) m/z: 356 [M+H]+. Compound 334: LC-MS (ESI) m/z: 328 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.35-0.37 (m, 2H), 0.57-0.62 (m, 2H), 1.25-1.29 (m, 1H), 3.95 (d, J = 7.2 Hz, 2H), 7.30 (s, 1H), 7.74-7.76 (m, 2H), 13.28 (s, 1H), 15.79 (s, 1H).
[001679] Example 335
[001680] Synthesis of 4-((4-chloro-3-(cyclohexylmethoxy)phenyl)sulfinyl)-1H-1,2,3- triazole-5-carboxylic acid (335)
Figure imgf000470_0001
335
[001681] Compound 335A was synthesized by employing the procedure described for Compound 35D using Compound 309A in lieu of Compound 35C, LC-MS (ESI) m/z: 516
[M+H]+.
[001682] To a solution of Compound 335A (492 mg, 0.95mmol) in CH3CN (15 mL) was added a solution of CAN (2.6 g, 6.8 mmol) in H2O (5 mL) and stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 335B. LC-MS (ESI) m/z: 412 [M+H]+.
[001683] Compound 335 was synthesized by employing the procedure described for Compound 8F using Compound 335B in lieu of Compound 8E, LC-MS (ESI) m/z: 384 [M+H]+. 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.04-1.26 (m, 5H), 1.69-1.83 (m, 6H), 3.87-3.90 (m, 2H), 7.27 (dd, J = 0.8, 8 Hz, 1H), 7.46 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H).
[001684] Example 336
[001685] Synthesis of 4-((4-chloro-3-(cyclohexylmethoxy)phenyl)thio)-1H-1,2,3- triazole-5-carboxylic acid (336)
Figure imgf000470_0002
[001686] To a mixture of Compound 335B (140 mg, 0.34 mmol) and NaI (255 mg, 1.70 mmol) in CH3CN (15 mL) was dropped neat TiCl4 (0.19 mL, 1.70 mmol) at room temperature and stirred at room temperature for 0.5 hours. The mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude Compound 336A. LC-MS (ESI) m/z: 396 [M+H]+.
[001687] Compound 336 was synthesized by employing the procedure described for Compound 8F using Compound 336A in lieu of Compound 8E, LC-MS (ESI) m/z: 368
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.03-1.26 (m, 5H), 1.63-1.81 (m, 6H), 3.84 (d, J = 6.4 Hz, 2H), 7.0 (dd, J = 1.2, 7.6 Hz, 1H), 7.24 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 13.46 (s, 1H), 15.60 (s, 1H).
[001688] Example 337
[001689] Synthesis of 4-(((cis)-4-(3-chloro-5- (trifluoromethoxy)phenyl)cyclohexyl)thio)-1H-1,2,3-triazole-5-carboxylic acid (337)
Figure imgf000471_0001
[001690] Compounds 337B, 337C, 337D, 337E, 337F, 337G, 337H, and 337 were synthesized by employing the procedures described for Compounds 56B, 8B, 141, 279D, 57C, 90C, 8F, and 1 using Compounds 337A with KI, 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec- 7-en-8-yl)-1,3,2-dioxaborolane, 337B with Na2CO3 as base and 1,4-dioxane as solvent, 337C with MeOH as solvent, 337D with TFA as acid and dichloromethane as solvent, 337E,
Intermediate D, 337F, 337G, and 337H in lieu of Compounds 56A with CuCl, (4- bromophenyl)boronic acid, 8A with Cs2CO3 as base and DME/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and acetone as solvent, 57B, Intermediate H, 90B, 8E, and 1E. Compound 337B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 7.23 (s, 1H), 7.49 (s, 1H), 7.67 (s, 1H). Compound 337C: LC-MS (ESI) m/z: 335 [M+H]+. Compound 337D: LC-MS (ESI) m/z: 337 [M+H]+.
Compound 337E: LC-MS (ESI) m/z: 293 [M+H]+. Compound 337F: LC-MS (ESI) m/z: 277 [M- OH]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40-1.51 (m, 5H), 1.93 (d, J = 12.8 Hz, 2H), 2.11 (d, J = 11.6 Hz, 2H), 2.46-2.55 (m, 1H), 3.66-3.72 (m, 1H), 6.94 (s, 1H), 7.06 (s, 1H), 7.13 (s, 1H). Compound 337G: LC-MS (ESI) m/z: 570 [M+H]+. Compound 337H: LC-MS (ESI) m/z: 542 [M+H]+. Compound 337: LC-MS (ESI) m/z: 422 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.70-1.78 (m, 4H), 1.97 (s, 4H), 2.71-2.76 (m, 1H), 4.11 (s, 1H), 7.23 (s, 1H), 7.37 (d, J = 4.8 Hz, 2H), 13.32 (s, 1H), 15.52(s, 1H).
[001691] Example 338
[001692] Synthesis of 4-((1-(3-chloro-5-(trifluoromethoxy)phenyl)piperidin-4-yl)thio)- 1H-1,2,3-triazole-5-carboxylic acid (338)
Figure imgf000472_0001
338C 338
[001693] Compounds 338A, 338B, 338C, and 338 were synthesized by employing the procedures described for Compounds 270B, 90C, 8F, and 1 using Compounds 337B with Cs2CO3 as base, Intermediate D, 338A, 338B, and 338C in lieu of Compounds 270A with K2CO3 as base, Intermediate H, 90B, 8E, and 1E. Compound 338A: LC-MS (ESI) m/z: 296 [M+H]+. Compound 338B: LC-MS (ESI) m/z: 571 [M+H]+. Compound 338C: LC-MS (ESI) m/z: 543 [M+H]+. Compound 338: LC-MS (ESI) m/z: 423 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.59-1.67 (m, 2H), 2.06-2.12 (m, 2H), 3.02 (t, J = 10.8 Hz, 2H), 3.74 (d , J = 13.2 Hz, 3H), 6.74 (s, 1H), 6.85 (s, 1H), 7.00 (s, 1H), 13.35 (s, 1H), 15.49 (s, 1H).
[001694] Example 339
[001695] Synthesis of 4-((4-(4,4-difluoropiperidin-1-yl)phenyl)thio)-1H-1,2,3-triazole- 5-carboxylic acid 2,2,2-trifluoroacetate (339)
Figure imgf000473_0001
[001696] A mixture of Compound 297E (500 mg, 1.82 mmol), Intermediate D (639 mg, 2.18 mmol), L-proline (63 mg, 0.55 mmol), CuI (34 mg, 0.182 mmol), and K2CO3 (502 mg, 3.64 mmol) in anhydrous DMF (15 mL) was stirred at 110 oC under N2 for 12 hours. After cooled down to room temperature, the mixture was diluted with ethyl acetate (200 mL), washed with water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 33% v/v) to furnish Compound 339A. LC-MS (ESI) m/z: 489 [M+H]+.
[001697] Compounds 339B and 339 were synthesized by employing the procedures described for Compounds 1 and 8F using Compounds 339A and 339B in lieu of Compounds 1E and 8E. Compound 339B: LC-MS (ESI) m/z: 369 [M+H]+. Compound 339: LC-MS (ESI) m/z: 341 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.00-2.07 (m, 4H), 3.40 (m, 4H), 7.02- 7.04 (m, 2H), 7.37-7.40 (m, 2H).
[001698] Example 340 [001699] Synthesis of 4-((4-(3-(piperidin-1-yl)phenyl)cyclohexyl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (340)
Figure imgf000474_0001
[001700] Compounds 340B, 340C, 340D, and 340E were synthesized by employing the procedures described for Compounds 8B, 141, 279D, and 57C using 4,4,5,5-tetramethyl-2-(1,4- dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 340A with Na2CO3 as base and 1,4-dioxane as solvent, 340B with MeOH as solvent, 340C with TFA as acid and
dichloromethane as solvent, and 340D in lieu of (4-bromophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and acetone as solvent, and 57B. Compound 340B: LC-MS (ESI) m/z: 300 [M+H]+.
Compound 340C: LC-MS (ESI) m/z: 302 [M+H]+. Compound 340D: LC-MS (ESI) m/z: 258 [M+H]+. Compound 340E: LC-MS (ESI) m/z: 260 [M+H]+.
[001701] To a solution of Compound 340E (450 mg, 1.74 mmol) and triethylamine (750 mg, 7.42 mmol) in dichloromethane (40 mL) was added methanesulfonyl chloride (397 mg, 3.46 mmol) and stirred at 30 oC for 3 hours. The mixture was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give Compound 340F. LC-MS (ESI) m/z: 338 [M+H]+.
[001702] Compounds 340G, 340H, and 340 were synthesized by employing the procedures described for Compounds 1E, 8F, and 1 using Intermediate D, Compounds 340F at 90 °C, 340G, and 340H in lieu of Compounds 1D, Intermediate B at 90 °C, 8E, and 1E.
Compound 340G: LC-MS (ESI) m/z: 535 [M+H]+. Compound 340H: LC-MS (ESI) m/z: 507 [M+H]+. Compound 340: LC-MS (ESI) m/z: 387 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.60-1.79 (m, 10H), 1.94-2.00 (m, 4H), 2.62-2.65 (m, 1H), 3.63-3.79 (m, 4H), 4.15 (s, 1H), 7.16-7.36 (m, 4H).
[001703] Example 341
[001704] Synthesis of 4-(((cis)4-(4-(4-methylpiperazin-1-yl)phenyl)cyclohexyl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (341)
Figure imgf000475_0001
341G 341
[001705] Compounds 341B, 341C, 341D, 341E, 341F, 341G, and 341 were synthesized by employing the procedures described for Compounds 8B, 141, 279D, 57C, 90C, 1, and 8F using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 341A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 341B with THF/MeOH as solvent, 341C with 1,4-dioxane as solvent, 341D, Intermediate D, 341E with DEAD as coupling reagent, 341F, and 341G in lieu of (4-bromophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 140 with EtOAc as solvent, 279C with acetone as solvent, 57B,
Intermediate H, 90B with DIAD as coupling reagent, 1E, and 8E. Compound 341B: LC-MS (ESI) m/z: 315 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm), 1.90-1.97 (m, 2H), 2.38 (s, 3H), 2.46 (s, 2H), 2.60-2.65 (m, 6H), 3.22-3.25(m, 4H), 4.03(m, 4H), 5.89-5.91 (m, 1H), 6.87 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H). Compound 341C: LC-MS (ESI) m/z: 317 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm), 1.68-1.77 (m, 3H), 1.84-1.87 (m, 4H), 2.46 (s, 3H), 2.73-2.76 (m, 6H), 3.26-3.29 (m, 4H), 3.99(s, 4H), 6.88 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H). Compound 341D: LC-MS (ESI) m/z: 273 [M+H]+. Compound 341E: LC-MS (ESI) m/z: 275 [M+H]+. Compound 341F: LC-MS (ESI) m/z: 550 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm), 1.44 (t, J = 7.2 Hz, 3H), 1.68-1.71 (m, 2H), 1.80-1.83 (m, 4H), 2.36-2.37 (m, 4H), 2.58- 2.61 (m, 5H), 3.20-3.23 (m, 5H), 3.77 (s, 3H), 3.92 (s, 1H), 4.42-4.48 (m, 2H), 5.62 (s, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H). Compound 341G: LC-MS (ESI) m/z: 430 [M+H]+. Compound 341: LC-MS (ESI) m/z: 402 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.69-1.72 (m, 2H), 1.86-2.07 (m, 6H), 2.54- 2.60 (m, 1H), 2.97-3.04 (m, 5H), 3.25-3.32 (m, 2H), 3.58-3.62 (s, 2H), 3.78-3.82 (m, 2H), 4.18 (br, 1H), 6.98 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H).
[001706] Example 342
[001707] Synthesis of 4-((2-chloro-4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (342)
Figure imgf000476_0001
[001708] To a suspension of 4-bromo-3-chloroaniline (341A) (3.6 g, 14.6 mmol) in aqueous HCl solution (12 N, 4 mL) and ice (7.0 g) was slowly added a solution of NaNO2 (1.0 g, 14.6 mmol) in water (7.0 mL) at 0 °C and stirred at 0 °C for 30 minutes. The diazonium salt solution was dropped into a stirred solution of potassium O-ethyl carbonodithioate (4.5 g, 28 mmol) in water (7.0 mL). The mixture was carefully warmed to 75 °C and stirred for 1.5 hours. After cooled down to room temperature, the mixture was diluted with saturated aqueous
NaHCO3 solution (40 mL) and extracted with ether (50 mL x 3). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude Compound 341B. LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.37 (t, J = 7.2 Hz, 3H), 4.63 (q, J = 7.2 Hz, 2H), 7.24-7.25 (m, 1H), 7.60-7.61 (m, 1H), 7.68 (d, J = 8.4 Hz, 1H).
[001709] To a solution of Compound 341B (3.5 g, 11.3 mmol) in EtOH (25 mL) was added KOH (3.6 g, 64.3 mmol). The mixture was stirred at reflux under nitrogen overnight and concentrated under reduced pressure. The residue was diluted with water (50 mL) and washed with ether (45 mL x 3). The aqueous layer was acidified to pH 2 with diluted aqueous H2SO4 solution (2 N) and extracted with CH2Cl2 (50 mL x 3). The combined organic layers was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 341C. LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.51 (s, 1H), 6.94 (dd, J = 8.4, 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H).
[001710] Compounds 341D, 341E, 341F, and 341 were synthesized by employing the procedures described for Compounds 1E, 4B, 8F, and 1 using Compounds 341C with Na2CO3 as base at 80 oC, 169B, 341D with K2CO3 as base and 1,4-dioxane/H2O as solvent, 341E, and 341F in lieu of Compounds 1D with K2CO3 as base at 50 oC, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 341D: LC-MS (ESI) m/z: 482 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.35 (t, J = 7.2 Hz, 3H), 3.77 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.60 (s, 2H), 6.70 (dd, J = 8.4, 2.0 Hz, 1H), 6.72 (d, J = 8.4Hz, 2H), 7.80 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H). Compound 341E: LC-MS (ESI) m/z: 563 [M+H]+. Compound 341F: LC-MS (ESI) m/z: 535 [M+H]+. Compound 341: LC-MS (ESI) m/z: 415 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.56-1.63 (m, 6H), 3.39-3.46 (m, 4H), 7.07 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4H z, 1H), 7.63 (s, 1H), 13.52 (s, 1H), 15.86 (s, 1H).
[001711] Example 343
[001712] Synthesis of 4-((2-chloro-5-(cyclopentylmethoxy)phenyl)thio)-1H-1,2,3- triazole-5-carboxylic acid (343)
Figure imgf000478_0001
[001713] Compounds 343A, 343B, 343C, and 343 were synthesized by employing the procedures described for Compounds 27B, 35D, 217E, and 8F using
(bromomethyl)cyclopentane, Compounds 219A with K2CO3 as base, 343A, 343B, and 343C in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base, 35C, 217D, and 8E. Compound 343A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 343B: LC-MS (ESI) m/z: 502 [M+H]+. Compound 343C: LC-MS (ESI) m/z: 382 [M+H]+.
Compound 343: LC-MS (ESI) m/z: 354 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.22- 1.32 (m, 2H), 1.44-1.60 (m, 4H), 1.66-1.76 (m, 2H), 2.18-2.26 (m, 1H), 3.78 (d, J = 6.8 Hz, 2H), 6.92-6.98 (m, 2H), 7.44 (d, J = 8.8 Hz, 1H).
[001714] Example 344
[001715] Synthesis of 4-((1-(4-cyanophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (344)
Figure imgf000479_0001
[001716] Compounds 344B, 344C, 344D, and 344 were synthesized by employing the procedures described for Compounds 297C, 90C, 8F, and 1 using Compounds 270A, 344A with Cs2CO3 as base at 100 oC, Intermediate D, 344B, 344C, and 344D in lieu of Compounds 297B, 397A with K2CO3 as base as base at 70 oC, Intermediate H, 90B, 8E, and 1E. Compound 344B: LC-MS (ESI) m/z: 203 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.61-1.68 (m, 2H), 1.97- 2.03 (m, 2H), 3.10-3.17 (m, 2H), 3.69-3.75 (m, 2H), 3.95-3.98 (m, 1H), 6.88 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H). Compound 344C: LC-MS (ESI) m/z: 478 [M+H]+. Compound 344D: LC-MS (ESI) m/z: 550 [M+H]+. Compound 344: LC-MS (ESI) m/z: 330 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.60-1.68 (m, 2H), 2.08-2.14 (m, 2H), 3.09-3.15 (m, 2H), 3.81- 3.88 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 13.29 (s, 1H), 15.52 (s, 1H).
[001717] Example 345
[001718] Synthesis of 4-(((cis)-4-(3,4-dichlorophenyl)cyclohexyl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (345)
Figure imgf000479_0002
[001719] Compounds 345A, 345B, and 345 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 308E-1 wit DEAD as coupling reagent, 345A, and 345B in lieu of Intermediate H, Compounds 90B wit DIAD as coupling reagent, 8E, and 1E. Compound 345A: LC-MS (ESI) m/z: 520 [M+H]+. Compound 345B: LC-MS (ESI) m/z: 492 [M+H]+. Compound 345: LC-MS (ESI) m/z: 372 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.68-1.78 (m, 2H), 1.84-2.14 (m, 6H), 2.58- 2.69 (m, 1H), 4.19 (brs, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.39-7.46 (m, 2H).
[001720] Example 346
[001721] Synthesis of 4-((1-(3-chloro-4-(trifluoromethoxy)phenyl)piperidin-4-yl)thio)- 1H-1,2,3-triazole-5-carboxylic acid (346)
Figure imgf000480_0001
[001722] Compounds 346B, 346C, 346D, and 346 were synthesized by employing the procedures described for Compounds 6B, 90C, 8F, and 1 using Compounds 270A, 346A with Ruphos as ligand and THF as solvent, Intermediate D, 346B, 346C, and 346D in lieu of 1- methylpiperazine, Compounds 6A with Xantphos as ligand and toluene as solvent, Intermediate H, 90B, 8E, and 1E. Compound 346B: LC-MS (ESI) m/z: 296 [M+H]+. Compound 346C: LC- MS (ESI) m/z: 571 [M+H]+. Compound 346D: LC-MS (ESI) m/z: 543 [M+H]+. Compound 346: LC-MS (ESI) m/z: 423 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.64-1.67 (m, 2H), 2.10 -2.13 (m, 2H), 2.98 (t, J = 10.8 Hz, 2H), 3.67-3.75 (m, 3H), 6.96 (d, J = 13 Hz, 1H), 7.13(d, J = 2.4 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 15.52 (s, 1H).
[001723] Example 347
[001724] Synthesis of 4-(((cis)-4-(4-(pyrrolidin-1-yl)phenyl)cyclohexyl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (347)
Figure imgf000481_0001
[001725] Compound 347B was synthesized by employing the procedure described for Compound 57C using Compound 347A with THF/MeOH as solvent in lieu of Compound 57B with MeOH as solvent, LC-MS (ESI) m/z: 159 [M-OH]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.39-1.65 (m, 4H), 1.95 (d, J = 13.2 Hz, 2H), 2.11 (d, J = 11.2 Hz, 2H), 2.47-2.55 (m, 1H), 3.68- 3.74 (m, 1H), 7.19-7.23 (m, 3H), 7.27-7.33 (m, 2H).
[001726] To a solution of Compound 347B (2.17 g, 12.32 mmol) in anhydous
dichloromethane (60 mL) at -8 oC was added AlCl3 (2.14 g, 16.02 mmol) in several portions and stirred for 15 minutes, followed by dropping a solution of bromine (0.56 mL, 11.09 mmol) in dichloromethane (15 mL) over 10 minutes. The mixture was stirred at -8 oC for 10 minutes and poured into a ice-water (50 mL). To the mixture was added concentrated hydrochloric acid (30 mL) and stirred at room temperature for 1 hour. The organic phase was separated and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phases was concentrated under reduced pressure. The residue was diluted with ethyl acetate (80 mL), washed with saturated EDTA solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 30% v/v) to afford Compound 347C. LC-MS (ESI) m/z: 237 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.37-1.46 (m, 4H), 1.89-1.93 (m, 2H), 2.09-2.12 (m, 2H), 2.43-2.50 (m, 1H), 3.66-3.72 (m, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H).
[001727] Compounds 347D, 347E, 347F, 347G, and 347 were synthesized by
employing the procedures described for Compounds 301A, 90C, 182B, 8F, and 57E using pyrrolidin-2-one, Compounds 347C with t-butyl Brettphos as ligand and K3PO4 as base and tBuOH/H2O as solvent, 347D, Intermediate D, 347E with borane-methyl sulfide complex as reducing agent, 347F, and 347G in lieu of Compounds 297B, Intermediate I with X-Phos as ligand and Cs2CO3 as base and 1,4-dioxane as solvent, Intermediate H, 90B, 182A with borane- THF complex as reducing agent, 8E, and 57D. Compound 347D: LC-MS (ESI) m/z: 260
[M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.41-1.57 (m, 4H), 1.89-1.94 (m, 2H), 2.08-2.13 (m, 2H), 2.14-2.20 (m, 2H), 2.46-2.52 (m, 1H), 2.61 (t, J = 7.2 Hz, 2H), 3.66-3.72 (m, 1H), 3.86 (t, J = 6.8 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 6.8 Hz, 2H). Compound 347E: LC-MS (ESI) m/z: 535 [M+H]+. Compound 347F: LC-MS (ESI) m/z: 521 [M+H]+. Compound 347G: LC-MS (ESI) m/z: 493 [M+H]+. Compound 347: LC-MS (ESI) m/z: 373 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.64-1.65 (m, 4H), 1.91-1.96 (m, 8H), 2.40 (s, 1H), 3.19 (s, 4H), 4.11 (s, 1H), 6.51 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H).
[001728] Example 348
[001729] Synthesis of 4-(((cis)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (348)
Figure imgf000482_0001
[001730] Compounds 348A, 348B, and 348 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 272E-2, Intermediate D, 348A, and 348B in lieu of Compounds 90B, Intermediate H, 8E, and 1E. Compound 348A: LC- MS (ESI) m/z: 536 [M+H]+. Compound 348B: LC-MS (ESI) m/z: 508 [M+H]+. Compound 348: LC-MS (ESI) m/z: 388 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.62-1.65 (m, 2H), 1.79- 2.02 (m, 6H), 2.54-2.61 (m, 1H), 4.09 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H
[001731] Example 349
[001732] Synthesis of 4-((4'-(2-methylpiperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (349)
Figure imgf000483_0001
[001733] Compound 349B was synthesized by employing the procedure described for Compound 297C using Compound 349A with as Cs2CO3 base and NMP as solvent at 100 oC in lieu of Compound 297B with as K2CO3 base and DMF as solvent at 70 oC, LC-MS (ESI) m/z: 221 [M+H]+.
[001734] To a mixture of Compound 349B (2.2 g, 10 mmol) and Ranny-Ni (1.0 g) in EtOH (20 mL) was dropped 85% N2H .
4H2O (3 mL) at 60 oC, and stirred at this temperature for 3 hours. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 35% v/v) to afford Compound. LC-MS (ESI) m/z: 191 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.88 (d, J = 6.8 Hz, 3H), 1.44-1.48 (m, 2H), 1.64-1.82 (m, 4H), 2.80-2.84 (m, 1H), 2.94-2.96 (m, 1H), 3.21-3.25 (m, 1H), 3.46 (brs, 2H), 6.62-6.65 (m, 2H), 6.86-6.89 (m, 2H)
[001735] Compounds 349D, 349E, 349F, 349G, and 349 were synthesized by
employing the procedures described for Compounds 30B, 27C, 4B, 57E, and 8F using
Compounds 349C with isopentyl nitrite/CuBr2 and THF as solvent, 349D, 349E, Intermediate F with 1,4-dioxane/H2O as solvent, 349F, and 349G in lieu of Compounds 30A with Isoamyl nitrite/CuCl2 and MeCN as solvent, 27B, (4-bromophenyl)boronic acid, 4A with
toluene/EtOH/H2O as solvent, 57D, and 8E. Compound 349D: LC-MS (ESI) m/z: 254 [M+H]+. Compound 349E: LC-MS (ESI) m/z: 302 [M+H]+. Compound 349F: LC-MS (ESI) m/z: 543 [M+H]+. Compound 349G: LC-MS (ESI) m/z: 423 [M+H]+. Compound 349: LC-MS (ESI) m/z: 395 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.99 (d, J = 6.8 Hz, 3H), 1.50-1.61 (m, 4H), 1.73-1.75 (m, 2H), 2.88-2.90 (m, 1H), 3.41-3.42 (m, 1H), 4.11-4.15 (m, 1H), 6.97-.99 (m, 2H), 7.48-7.64 (m, 6H).
[001736] Example 350
[001737] Synthesis of 4-(((1-(3,5-dichlorophenyl)piperidin-4-yl)thio)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (350)
Figure imgf000484_0001
[001738] Compounds 350A and 350B were synthesized by employing the procedures described for Compounds 270B and 340F using Compounds 285A and 350A in lieu of
Compounds 197A and 340E. Compound 350A: LC-MS (ESI) m/z: 246 [M+H]+. Compound 350B: LC-MS (ESI) m/z: 324 [M+H]+.
[001739] To a solution of Compound 350B (0.72 g, 2.22 mmol) in DMF (20 mL) was added KSAc (759 mg, 6.66 mmol) and stirred at 130 oC for 2 hours. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish Compound 350C. LC-MS (ESI) m/z: 304 [M+H]+.
[001740] After a suspension of LiAlH4 (23 mg, 0.2 mmol) in THF(10 mL) was stirred at 0 oC for 10 minutes, to the suspension was added Compound 350C (60 mg, 0.2 mmol) and stirred at room temperature overnight. It was quenched with 10% aqueous NaOH solution (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to furnish Compound
350D. LC-MS (ESI) m/z: 262 [M+H]+.
[001741] Compounds 350E, 350F, and 350 were synthesized by employing the
procedures described for Compounds 243B, 57E, and 8F using Compounds 350D with K2CO3 as base and DMF as solvent, 350E, and 350F in lieu of Compounds 243A with Na2CO3 as base and NMP as solvent, 57D, and 8E. Compound 350E: LC-MS (ESI) m/z: 535 [M+H]+. Compound 350F: LC-MS (ESI) m/z: 415 [M+H]+. Compound 350: LC-MS (ESI) m/z: 387 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.44-1.47 (m, 2H), 1.93-1.96 (m, 2H), 2.83-2.89 (m, 3H), 3.67-3.71 (m, 2H), 4.07 (s, 2H), 6.81 (s, 1H), 6.91-6.92 (m, 2H).
[001742] Example 351
[001743] Synthesis of 4-((3-(cyclopentyloxy)phenyl)thio)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (351)
Figure imgf000486_0001
[001744] Compounds 351A, 351B, 351C, and 351 were synthesized by employing the procedures described for Compounds 27B, 35D, 1, and 8F using bromocyclopentane,
Compounds 131A, 351A, 351B, and 351C in lieu of 2-bromopropane, Compounds 27A, 35C, 1E, and 8E. Compound 351A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.60-1.65 (m, 2H), 1.74-1.93 (m, 6H), 4.70-4.75 (m, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.01-7.06 (m, 2H), 7.11 (t, J = 8.0 Hz, 1H).
Compound 351B: LC-MS (ESI) m/z: 454 [M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.31 (t, J = 7.2 Hz, 3H), 1.41-1.45 (m, 2H), 1.71-1.81 (m, 6H), 3.76 (s, 3H), 4.36 (q, J = 7.2 Hz, 2H), 4.53-4.56 (m, 1H), 5.51 (s, 2H), 6.45 (s, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 7.02 (t, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H). Compound 351C: LC-MS (ESI) m/z: 334 [M+H]+. Compound 351: LC-MS (ESI) m/z: 306 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.58-1.63 (m, 2H), 1.64-1.82 (m, 4H), 1.86-1.95 (m, 2H), 4.77 (t, J = 6.0 Hz, 1H), 6.86-6.88 (m, 1H), 6.98-7.02 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H).
[001745] Example 352
[001746] Synthesis of 4-(((cis)-4-(4-cyanophenyl)cyclohexyl)thio)-1H-1,2,3-triazole-5- carboxylic acid (352)
Figure imgf000487_0001
[001747] Compounds 352B-1, 352B-2, 352C, 352D, and 352 were synthesized by employing the procedures described for Compounds 57C, 90C, 8F, and 1 using Compounds 352A, Intermediate D, 352B-2, 352C, and 352D in lieu of Compounds 57B, Intermediate H, 90B, 8E, and 1E. Compound 352B-1: LC-MS (ESI) m/z: 202 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.64-1.71 (m, 4H), 1.86-1.96 (m, 4H), 2.57-2.63 (m, 1H), 4.16 (s, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H). Compound 352B-2: LC-MS (ESI) m/z: 202 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.39-1.58 (m, 4H), 1.91-1.94 (m, 2H), 2.11-2.14 (m, 2H), 2.52-2.59 (m, 1H), 3.67-3.72 (m, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H).
Compound 352C: LC-MS (ESI) m/z: 477 [M+H]+. Compound 352D: LC-MS (ESI) m/z: 449 [M+H]+. Compound 352: LC-MS (ESI) m/z: 329 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.73-1.77 (m, 2H), 1.92-2.10 (m, 6H), 2.71-2.78 (m, 1H), 4.20 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H).
[001748] Example 353
[001749] Synthesis of 4-(4-chloro-3-(cyclopentylmethoxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (353)
Figure imgf000488_0001
[001750] Compounds 353A, 353B, 353C, 353D, 353E, and 353 were synthesized by employing the procedures described for Compounds 27B, 27C, 236D, Intermediate I, 217E, and 8F using (bromomethyl)cyclopentane, Compounds 218A with K2CO3 as base, 353A, 353B, 353C, 353D, and 353E in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base, 27B, 236C, 4-bromophenol, 217D, and 8E. Compound 353A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 353B: LC-MS (ESI) m/z: 337 [M+H]+. Compound 353C: LC-MS (ESI) m/z: 227 [M+H]+. Compound 353D: LC-MS (ESI) m/z: 486 [M+H]+. Compound 353E: LC-MS (ESI) m/z: 366 [M+H]+. Compound 353: LC-MS (ESI) m/z: 338 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.31-1.39 (m, 2H), 1.49-1.55 (m, 2H), 1.57-1.65 (m, 2H), 1.72-1.80 (m, 2H), 2.26-2.37 (m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 6.59 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 13.24 (s, 1H), 15.24 (s, 1H).
[001751] Example 354
[001752] Synthesis of 4-((1-(3-chloro-5-(trifluoromethoxy)phenyl)piperidin-4-yl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (354)
Figure imgf000489_0001
[001753] Compounds 354A, 354B, and 354 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 338A, 354A, and 354B in lieu of Compounds 90B, 8E, and 1E. Compound 354A: LC-MS (ESI) m/z: 555 [M+H]+. Compound 354B: LC-MS (ESI) m/z: 527 [M+H]+. Compound 354: LC-MS (ESI) m/z: 407 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.69-1.76 (m, 2H), 2.02-2.06 (m, 2H), 3.17- 3.25 (m, 2H), 3.55-3.61 (m, 2H), 4.81 (s, 1H), 6.75 (s, 1H), 6.87(s, 1H), 7.02 (s, 1H), 12.84 (s, 1H), 14.78 (s, 1H).
[001754] Example 355
[001755] Synthesis of 4-(((cis)-4-(3-chloro-5- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (355)
Figure imgf000490_0001
[001756] Compounds 355A, 355B, and 355 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 337F, 355A, and 355B in lieu of Compounds 90B, 8E, and 1E. Compound 354A: LC-MS (ESI) m/z: 554 [M+H]+. Compound 354B: LC-MS (ESI) m/z: 526 [M+H]+. Compound 354: LC-MS (ESI) m/z: 406 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.60-1.85 (m, 6H), 2.06 (d, J = 13.2 Hz, 2H), 2.75 (t, J = 12 Hz, 1H), 4.93 (s, 1H), 7.19 (s, 1H), 7.36 (d, J = 10.4 Hz, 2H), 12.95 (s, 1H), 14.79 (s, 1H).
[001757] Example 356
[001758] Synthesis of 4-(((cis)-4-(4-(pyrrolidin-1-yl)phenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (356)
Figure imgf000491_0001
[001759] Compounds 356A, 356B, 356C, and 356 were synthesized by employing the procedures described for Compounds 90C, 182B, 8F, and 57E using Compounds 347D, 356A with borane-methyl sulfide complex as reducing agent, 356B, and 356C in lieu of Compounds 90B, 182A with borane-THF complex as reducing agent, 8E, and 57D. Compound 356A: LC- MS (ESI) m/z: 519 [M+H]+. Compound 356B: LC-MS (ESI) m/z: 505 [M+H]+. Compound
356C: LC-MS (ESI) m/z: 477 [M+H]+. Compound 356: LC-MS (ESI) m/z: 357 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.52 (d, J = 10.4 Hz, 2H), 1.65-1.69 (m, 2H), 1.74-1.81 (m, 2H), 1.91-1.95 (m, 4H), 2.02-2.06 (m, 2H), 2.45 (s, 1H), 3.18-3.21 (m, 4H), 4.92 (s, 1H), 6.54 (d, J = 7.6 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H).
[001760] Example 357
[001761] Synthesis of 4-(2-chloro-5-(cyclopentylmethoxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (357)
Figure imgf000491_0002
[001762] Compounds 357A, 357B, 357C, 357D, and 357 were synthesized by employing the procedures described for Compounds 27C, 236D, Intermediate I, 217E, and 8F using Compounds 343A, 357A, 357B, 357C, and 357D in lieu of Compounds 27B, 236C, 4- bromophenol, 217D, and 8E. Compound 357A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 357B: LC-MS (ESI) m/z: 225 [M-H]¯. Compound 357C: LC-MS (ESI) m/z: 486 [M+H]+. Compound 357D: LC-MS (ESI) m/z: 366 [M+H]+. Compound 357: LC-MS (ESI) m/z: 338 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.22- 1.32 (m, 2H), 1.46-1.60 (m, 4H), 1.67-1.77 (m, 2H), 2.19-2.23 (m, 1H), 3.80 (d, J = 7.2 Hz, 2H), 6.72 (s, 1H), 6.81 (dd, J = 8.8,2.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 13.21 (s, 1H), 15.14 (s, 1H).
[001763] Example 358
[001764] Synthesis of 4-(3-chloro-5-(trifluoromethoxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (358)
Figure imgf000492_0001
[001765] Compounds 358B, 358C, and 358 were synthesized by employing the procedures described for Intermediate I, Compounds 8F, and 1 using Compounds 358A, 358B, and 358C in lieu of 4-bromophenol, Compounds 8E, and 1E. Compound 358B: LC-MS (ESI) m/z: 472
[M+H]+. Compound 358C: LC-MS (ESI) m/z: 909 [2M+Na]+. Compound 358: LC-MS (ESI) m/z: 324 [M+H]+; 1H-NMR (d-DMSO, 400 MHz): d (ppm) 7.18 (s, 1H), 7.29 (t, J = 2 Hz, 2H), 7.35 (s, 1H).
[001766] Example 359
[001767] Synthesis of 4-((1-(4-cyanophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (359)
Figure imgf000493_0001
[001768] Compounds 359A, 359B, and 359 were synthesized by employing the
procedures described for Compounds 90C, 8F, and 1 using Compounds 344B, 359A, and 359B in lieu of Compounds 90B, 8E, and 1E. Compound 359A: LC-MS (ESI) m/z: 462 [M+H]+. Compound 359B: LC-MS (ESI) m/z: 434 [M+H]+. Compound 359: LC-MS (ESI) m/z: 314
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.69-1.78 (m, 2H), 2.03-2.08 (m, 2H), 3.29- 3.35 (m, 2H), 3.66-3.71 (m, 2H), 4.86-4.87 (m, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 12.79 (s, 1H), 14.79 (s, 1H).
[001769] Example 360
[001770] Synthesis of 4-(((cis)-4-(3-chloro-4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (360)
Figure imgf000493_0002
Figure imgf000494_0001
[001771] Compounds 360A, 360B, 360C, 360D-1, 360D-2, 360E, 360F, and 360 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 308E-1, 90C, 1, and 8F using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2- dioxaborolane, Compounds 32A with K2CO3 as base and 1,4-dioxane as solvent, 360A with MeOH as solvent, 360B with TFA as acid and dichloromethane as solvent, 360C, 360D-2 with DEAD as coupling reagent, 360E, and 360F in lieu of (4-bromophenyl)boronic acid,
Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and acetone as solvent, 308D, 90B with DIAD as coupling reagent, 1E, and 8E. Compound 360A: LC-MS (ESI) m/z: 335 [M+H]+. Compound 360B: LC- MS (ESI) m/z: 337 [M+H]+. Compound 360C: LC-MS (ESI) m/z: 293 [M+H]+. Compound 360D-1: LC-MS (ESI) m/z: 278 [M+H-OH]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.64-1.70 (m, 4H), 1.82-1.92 (m, 4H), 2.51-2.56 (m, 1H), 4.15 (s, 1H), 7.14-7.16 (m, 1H), 7.25-7.27 (m, 1H), 7.34 (s, 1H). Compound 360D-2: LC-MS (ESI) m/z: 278 [M+H-OH]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.41-1.51 (m, 4H), 1.91-1.94 (m, 2H), 2.10-2.13 (m, 2H), 2.48-2.50 (m, 1H), 3.63-3.78 (m, 1H), 7.10-7.12 (m, 1H), 7.22-7.24 (m, 1H), 7.30 (s, 1H). Compound 360E: LC-MS (ESI) m/z: 554 [M+H]+. Compound 360F: LC-MS (ESI) m/z: 434 [M+H]+. Compound 360: LC- MS (ESI) m/z: 406 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.63-1.75 (m, 4H), 2.04- 2.26 (m, 4H), 2.62-2.73 (m, 1H), 5.01 (s, 1H), 7.32-7.40 (m, 2H), 7.53 (s, 1H).
[001772] Example 361 [001773] Synthesis of 4-((1-(3-chloro-4-(trifluoromethoxy)phenyl)piperidin-4-yl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (361)
Figure imgf000495_0001
[001774] Compounds 361A, 361B, and 361 were synthesized by employing the
procedures described for Compounds 90C, 8F, and 1 using Compounds 346B with DEAD as coupling reagent, 361A, and 361B in lieu of Compounds 90B with DIAD as coupling reagent, 8E, and 1E. Compound 361A: LC-MS (ESI) m/z: 555 [M+H]+. Compound 361B: LC-MS (ESI) m/z: 527 [M+H]+. Compound 361: LC-MS (ESI) m/z: 407 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.69-1.78 (m, 2H), 2.02-2.06 (m, 2H), 3.14-3.19 (m, 2H), 3.51-3.57 (m, 2H), 4.83 (s, 1H), 6.99 (d, J = 12.4 Hz, 1H), 7.15 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 14.76 (s, 1H).
[001775] Example 362
[001776] Synthesis of 4-(4-chloro-3-((4-fluorobenzyl)oxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (362)
Figure imgf000496_0001
[001777] Compounds 362A, 362B, 362C, 362D, 362E, and 362 were synthesized by employing the procedures described for Compounds 27B, 27C, 236D, Intermediate I, 217E, and 8F using 1-(bromomethyl)-4-fluorobenzene, Compounds 218A, 362A, 362B, 362C, 362D, and 362E in lieu of 2-bromopropane, Compounds 27A, 27B, 236C, 4-bromophenol, 217D, and 8E. Compound 362A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 5.23 (s, 2H), 7.18 (d, J = 8.5 Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.52 (dd, J = 8.0, 5.9 Hz, 2H). Compound 362B: LC- MS (ESI) m/z: 263 [M+H]+. Compound 362C: LC-MS (ESI) m/z: 253 [M+H]+. Compound 362D: LC-MS (ESI) m/z: 512 [M+H]+. Compound 362E: LC-MS (ESI) m/z: 392 [M+H]+. Compound 362: LC-MS (ESI) m/z: 364 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.16 (s, 2H), 6.62 (dd, J = 8.7, 2.5 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 7.24 (t, J = 8.8 Hz, 2H), 7.40 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.3, 5.8 Hz, 2H).
[001778] Example 363
[001779] Synthesis of 4-(((cis)-4-(4-carbamoylphenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (363)
Figure imgf000497_0001
363
[001780] Compounds 363A and 363B were synthesized by employing the procedures described for Compounds 90C and 1 using Compounds 352B-2 with DEAD as coupling reagent and 363A in lieu of Compounds 90B with DIAD as coupling reagent and 1E. Compound 363A: LC-MS (ESI) m/z: 461 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.26-1.31 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H), 1.67-1.73 (m, 2H), 2.05-2.14 (m, 2H), 2.62-2.66 (m, 1H), 3.77 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.36 (s, 2H), 5.47 (s, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.17-7.22 (m, 4H), 7.60 ( d, J = 8.2 Hz, 2H). Compound 363B: LC-MS (ESI) m/z: 341 [M+H]+.
[001781] To a solution of Compound 363B (140 mg, 0.41 mmol) in EtOH (10 mL) and H2O (5 mL) was added LiOH.H2O (86 mg, 2.05 mmol) and stirred at 40 oC overnight. It was concentrrated under reduced pressure and the residue was purified with preparative HPLC to afford Compound 363. LC-MS (ESI) m/z: 331 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.59 (d, J = 10.6 Hz, 2H), 1.65-1.72 (m, 2H), 1.81-1.90 (m, 2H), 2.07 (d, J = 13.7 Hz, 2H), 2.64-2.70 (m, 1H), 4.94 (s, 1H), 7.29 (d, J = 8.2 Hz, 3H), 7.78 (d, J = 8.1 Hz, 2H), 7.88 (s, 1H), 12.90 (s, 1H), 14.74 (s, 1H).
[001782] Example 364
[001783] Synthesis of 4-(((trans)-4-(4-carbamoylphenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (364)
Figure imgf000498_0001
[001784] Compounds 364A, 364B, and 364 were synthesized by employing the procedures described for Compounds 90C, 1, and 363 using Compounds 352B-1 with DEAD as coupling reagent, 364A, and 364B in lieu of Compounds 90B with DIAD as coupling reagent, 1E, and 363B. Compound 364A: LC-MS (ESI) m/z: 461 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 1.47-1.59 (m, 4H), 1.91-1.95 (m, 2H), 2.15-2.18 (m, 2H), 2.51- 2.57 (m, 1H), 3.79 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.06-5.11 (m, 1H), 5.30 (s, 2H), 6.87 (d, J = 8.7 Hz, 2H), 7.24 -7.29 (m, 4H), 7.58 ( d, J = 8.2 Hz, 2H). Compound 364B: LC-MS (ESI) m/z: 341 [M+H]+. Compound 364: LC-MS (ESI) m/z: 331 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.51-1.66 (m, 4H), 1.86 (d, J = 10.8 Hz, 2H), 2.23 (d, J = 9.9 Hz, 2H), 2.60-2.65 (m, 1H), 4.67 (s, 1H), 7.26 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.89 (s, 1H).
[001785] Example 365
[001786] Synthesis of 4-(((cis)-4-(4-cyanophenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5- carboxylic acid (365)
Figure imgf000498_0002
[001787] Compounds 365A and 365 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 353A and 365A in lieu of Compounds 8E and 1E. Compound 365A: LC-MS (ESI) m/z: 433 [M+H]+. Compound 365: LC-MS (ESI) m/z: 313 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.66-1.80 (m, 4H), 2.08-2.08 ( m, 2H), 2.22-2.26 (m, 2H), 2.73-2.79 (m, 1H), 5.06 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H).
[001788] Example 366
[001789] Synthesis of 4-((1,3-bis(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2- yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (366)
Figure imgf000499_0001
[001790] To a solution of DCC (2.23 g, 10.8 mmol) and DMAP (0.35 g, 2.91 mmol) in anhydrous dichloromethane (50 mL) was slowly added a solution of 2-(4-bromophenyl)acetic acid (366A) (2.0 g, 9.35 mmol) in anhydrous dichloromethane (80 mL). The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 25% v/v) to afford Compound 366B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.87 (s, 4H), 7.13 (d, J = 8.3 Hz, 4H), 7.49 (d, J = 8.3 Hz, 4H).
[001791] Compounds 366C, 366D, 366E, 366F, and 366 were synthesized by employing the procedures described for Compounds 8B, 57C, 90C, 217E, and 8F using 4- (trifluoromethoxy)phenylboronic acid, Compounds 366B with Na2CO3 as base and 1,4- dioxane/H2O as solvent, 366C, 366D, 366E, and 366F in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 57B, 90B, 217D, and 8E. Compound 366C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.95 (s, 4H), 7.30 (d, J = 8.0 Hz, 4H), 7.44 (d, J = 8.3 Hz, 4H), 7.63 (d, J = 8.0 Hz, 4H), 7.78 (d, J = 8.6 Hz, 4H). Compound 366D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.75 (ddd, J = 21.2, 13.6, 6.2 Hz, 4H), 3.90– 4.08 (m, 1H), 4.76 (d, J = 5.9 Hz, 1H), 7.33 (d, J = 8.2 Hz, 4H), 7.43 (d, J = 8.2 Hz, 4H), 7.59 (d, J = 8.2 Hz, 4H), 7.72– 7.83 (m, 4H). Compound 366E: LC-MS (ESI) m/z: 792 [M+H]+. Compound 366F: LC-MS (ESI) m/z: 672 [M+H]+. Compound 366: LC-MS (ESI) m/z: 644 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.06 (s, 4H), 5.17 (s, 1H), 7.38 (d, J = 8.0 Hz, 4H), 7.43 (d, J = 8.4 Hz, 4H), 7.59 (d, J = 8.0 Hz, 4H), 7.76 (d, J = 8.7 Hz, 4H), 12.98 (s, 1H), 14.78 (s, 1H).
[001792] Example 367
[001793] Synthesis of 4-((1-(5-chloro-2-(trifluoromethoxy)phenyl)piperidin-4-yl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (367)
Figure imgf000500_0001
[001794] A solution of 2-bromo-4-chloro-1-(trifluoromethoxy)benzene (367A) (2 g, 7.3 mmol), Compound 270A (3 g, 29.2 mmol), and Cs2CO3 (9.6 g, 29.4 mmol) in DMF (20 mL) were stirred at 180 oC under nitrogen in a microwave oven for 8 hours. After cooled down to room temperature, the mixture was concentrated and purified with flash column chromatography on silica (ethyl acetate in petroleum ether, from 0% to 20% v/v) to give Compound 367B. LC- MS (ESI) m/z: 296 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.67-1.76 (m, 2H), 1.99-2.05 (m, 2H), 2.80-2.87 (m, 2H), 3.29-3.35 (m, 2H), 3.84-3.88 (m, 1H), 6.89-6.97 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H).
[001795] Compounds 367C, 367D, and 367 were synthesized by employing the
procedures described for Compounds 90C, 8F, and 1 using Compounds 367B, 367C, and 367D in lieu of Compounds 90B, 8E, and 1E. Compound 367C: LC-MS (ESI) m/z: 555 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 7.2 Hz, 3H), 1.77-1.80 (m, 2H), 2.00-2.05 (m, 2H), 2.83-2.88 (m, 2H), 3.14-3.18 (m, 2H), 3.76 (s, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.29-5.33 (m, 3H), 6.84-6.97 (m, 4H), 7.11 (d, J = 8.8 Hz, 1H), 7.23-7.27 (m, 2H). Compound 367D: LC-MS (ESI) m/z: 527 [M+H]+. Compound 367: LC-MS (ESI) m/z: 407 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.82-1.90 (m, 2H), 2.12-2.16 (m, 2H), 2.92-2.98 (m, 2H), 3.22-3.26 (m, 2H), 4.84 (s, 1H), 7.03-7.06 (m, 1H), 7.10 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 8.8Hz, 1H).
[001796] Example 368
[001797] Synthesis of 4-(((cis)-4-(4-(4,4-difluoropiperidin-1- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (368)
Figure imgf000501_0001
Figure imgf000502_0001
[001798] Compounds 368A, 368B, 368C, 368D-1, 368D-2, 368E, 368F, and 368 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 57C, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 297E with 1,4-dioxane/H2O as solvent, 368A with MeOH as solvent, 368B with 1,4-dioxane as solvent, 368C, 368D-1, 368E, and 368F in lieu of (4-bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 279C with acetone as solvent, 57B, 90B, 8E, and 1E. Compound 368A: LC-MS (ESI) m/z: 336 [M+H]+;1H- NMR (CDCl3, 400 MHz): d (ppm) 1.91 (t, J = 6.4 Hz, 2H), 2.01-2.13 (m, 4H), 2.40-2.46 (m, 2H), 2.61-2.67 (m, 2H), 3.34 (t, J = 6.0 Hz, 4H), 4.01 (s, 4H), 5.90 (s, 1H), 6.86 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H). Compound 368B: LC-MS (ESI) m/z: 338 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.56-1.96 (m, 8H), 2.04-2.14 (m, 4H), 2.46-2.52 (m, 1H), 3.31 (t, J = 5.6 Hz, 4H), 3.98 (s, 4H), 6.88 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H). Compound 368C: LC-MS (ESI) m/z: 294 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.57-1.96 (m, 2H), 2.05- 2.22 (m, 6H), 2.48-2.52 (m, 4H), 2.94-2.99 (m, 1H), 3.33 (t, J = 6.0 Hz, 4H), 6.91 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H). Compound 368D-1: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.36-1.51 (m, 4H), 1.89-1.92 (m, 2H), 2.04-2.14 (m, 6H), 2.40-2.46 (m, 1H), 3.31 (t, J = 5.6 Hz, 4H), 3.65-3.70 (m, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H). Compound 368D-2: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.63-1.70 (m, 4H), 1.80-1.90 (m, 4H), 2.04-2.14 (m, 4H), 2.44-2.51 (m, 1H), 3.29-3.32 (m, 4H), 4.12 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H). Compound 368E: LC- MS (ESI) m/z: 555 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42 (t, J = 6.8 Hz, 3H), 1.66-1.74 (m, 6H), 2.06-2.15 (m, 6H), 2.52-2.53 (m, 1H), 3.33 (t, J = 5.2 Hz, 4H), 3.77 (s, 3H), 4.40 (q, J = 6.8 Hz, 2H), 5.36 (s, 2H), 5.45 (s, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H). Compound 368F: LC-MS (ESI) m/z: 527 [M+H]+. Compound 368: LC-MS (ESI) m/z: 407 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.54-1.57 (m, 2H), 1.67-1.70 (m, 2H), 1.79-1.83 (m, 2H), 2.00-2.10 (m, 6H), 2.49-2.53 (m, 1H), 3.27 (t, J = 5.6 Hz, 4H), 4.94 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H).
[001799] Example 369
[001800] Synthesis of 4-((3-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-6- yl)methoxy)-1H-1,2,3-triazole-5-carboxylic acid (369)
Figure imgf000503_0001
[001801] A mixture of 3,4-dichloroaniline (69A) (16.2 g, 0.1 mol) and furan-2,5-dione (9.8 g, 0.1 mmol) in 1,2-dichloroethane (150 mL) was stirred at 80 oC for 3 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in Ac2O (100 mL) and stirred at 100 oC for 4 hours. After cooled down to room temperature, the mixture was filtered, washed with petroleum ether (100 mL), and dried under vacuum to give Compound 369A. LC-MS (ESI) m/z: 242 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 6.88 (s, 2H), 7.28 (dd, J = 8.4, 2.4 Hz, 1H), 7.53-7.56 (m, 2H).
[001802] To a mixture of Compound 369A (10.7 g, 44.2 mmol) in toluene (130 mL) was dropped a solution of ethyl 2-diazoacetate in dichloromethane (90% wt, 5.04 g, 44.2 mmol) at room temperature and the resulting mixture was stirred at 100 oC for 3 hours. After cooled down to room temperature, the mixture was filtered, washed with petroleum ether (50 mL), and dried under vacuum to afford Compound 369B. LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.24 (t, J = 7.2 Hz, 3H), 4.13-4.26 (m, 2H), 4.65 (d, J = 11.6 Hz, 1H), 5.09 (dd, J = 11.6, 2.0 Hz, 1H), 7.35 (dd, J = 8.8, 2.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 9.71 (d, J = 2.0 Hz, 1H).
[001803] Compound 369B (1.07 g, 3 mmol) was heated at 190 oC for 1 hour. After cooled down to room temperature, the residue was dissolved in CH2Cl2 (30 mL) and evaporated under reduced pressure and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish Compound 369C. LC-MS (ESI) m/z: 328
[M+H]+.
[001804] To a solution of Compound 369C (2.38 g, 7.25 mmol) in andydrous THF (25 mL) was dropped a solution of BH3-Me2S in THF (2 M, 15 mL, 30 mmol) at 0 oC and heated at reflux overnight. After cooled down to 0 oC, the mixture was slowly quenched with methanol (25 mL) and heated at reflux for 1 hour. The mixture was evaporated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30% v/v) to afford Compound 369D. LC-MS (ESI) m/z: 258 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.06-1.12 (m, 1H), 1.35-1.38 (m, 1H), 1.64-1.65 (m, 2H), 3.24-3.27 (m, 2H), 3.50 (d, J = 9.2 Hz, 2H), 3.54-3.57 (m, 2H), 6.35 (dd, J = 8.8, 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H).
[001805] Compounds 369E, 369F, and 369 were synthesized by employing the
procedures described for Compounds 90C, 8F, and 1 using Compounds 369D, 369E, and 369F in lieu of Compounds 90B, 8E, and 1E. Compound 369E: LC-MS (ESI) m/z: 517 [M+H]+. Compound 369F: LC-MS (ESI) m/z: 489 [M+H]+. Compound 369: LC-MS (ESI) m/z: 369
[M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.29-1.34 (m, 1H), 1.85-1.87 (m, 2H), 3.23- 3.26 (m, 2H), 3.55 (d, J = 9.2 Hz, 2H), 4.26 (d, J = 7.2 Hz, 2H), 6.49 (dd, J = 8.8, 2.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H). [001806] Example 370
[001807] Synthesis of ((diethylcarbamoyl)oxy)methyl 4-(((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylate (370)
Figure imgf000505_0001
[001808] To a solution of diethylamine (3.86 g, 52.9 mmol) in THF (150 mL) was dropped chloromethyl carbonochloridate (370A) (3.38 g, 26.4 mmol) at 0 oC and stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL) and washed with H2O (100 mL). The organic layer was washed with HCl solution (1M, 50 mL) and aqueous NaHCO3 solution (100 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to give Compound 370B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[001809] Compounds 370C and 370 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 370B with TEA as base and adding NaI, 302B, and 370C in lieu of chloromethyl pivalate with Na2CO3 as base and without adding NaI, Compounds 54B, and 256D. Compound 370C: LC-MS (ESI) m/z: 765 [M+Na]+.
Compound 370: LC-MS (ESI) m/z: 501 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.11- 1.16 (m, 6H), 1.62-1.69 (m, 4H), 1.95-1.97 (m, 2H), 2.33-2.35 (m, 2H), 2.64-2.66 (m, 1H), 3.31- 3.34 (m, 4H), 4.72-4.74 (m, 1H), 5.98 (s, 2H), 7.17-7.19 (m, 2H), 7.33-7.35 (m, 2H).
[001810] Example 371
[001811] Synthesis of 2-(isobutyryloxy)ethyl 4-(((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylate (371)
Figure imgf000506_0001
[001812] To a solution of 2-bromoethanol (2.3 g, 18.9 mmol) and TEA (2.9 g, 28.3 mmol) in hexane (30 mL) at 0-5 oC was added isobutyryl chloride (371A) (2 g, 18.9 mmol) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL). The organic layer was washed with diluted aqueous HCl solution (1 N, 20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford Compound 371B. 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.20 (d, J = 6.8 Hz, 6H), 2.58-2.62 (m, 1H), 3.52 (t, J = 5.6 Hz, 2H), 4.38 (d, J = 6.0 Hz, 2H).
[001813] Compounds 371C and 371 were synthesized by employing the procedures described for Compounds 54C and 256 using Compounds 371B with TEA as base and adding NaI, 302B, and 371C in lieu of chloromethyl pivalate with Na2CO3 as base and without adding NaI, Compounds 54B, and 256D. Compound 371C: LC-MS (ESI) m/z: 750 [M+Na]+.
Compound 371: LC-MS (ESI) m/z: 486 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.15 (d, J = 7.2 Hz, 6H), 1.63-1.68 (m, 4H), 1.95-1.97 (m, 2H), 2.33-2.34 (m, 2H), 2.54-2.65 (m, 2H), 4.38-4.41 (m, 2H), 4.52-4.54 (m, 2H), 4.72-4.74 (m, 1H), 7.17-7.19 (m, 2H), 7.32-7.34 (m, 2H).
[001814] Example 372
[001815] Synthesis of 4-(2-(bis(4-chlorobenzyl)amino)ethyl)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (372)
Figure imgf000506_0002
Figure imgf000507_0001
[001816] A solution of 4-chlorobenzaldehyde (372A) (281 mg, 2.0 mmol) and (4- chlorophenyl)methanamine (372B) (283 mg, 2.0 mmol) in ethanol (10 mL) was stirred at room temperature for 2 hours, followed by addition of sodium borohydride (227 mg, 6.0 mmol). The mixture was stirred at room temperature for 2 hours, quenched with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers was dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 372C. LC-MS (ESI) m/z: 266 [M+H]+.
[001817] To a solution of (but-3-ynyloxy)(tert-butyl)dimethylsilane (372D) (6.45 g, 35.0 mmol) in anhydrous THF (80 mL) at -78 oC was added a solution of n-BuLi in n-hexane (2.5 M, 15.4 mL, 38.5 mmol) under nitrogen and stirred at -78 oC for 30 minutes followed by addition of ethylchloroformate (4.43 g, 40.8 mmol). The mixture was warmed gradually to room
temperature and stirred for 3 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to yield Compound 372E LC-MS (ESI) m/z: 279 [M+Na]+.
[001818] Compounds 372F, 372G, and 372H were synthesized by employing the procedures described for Compounds 151B, Intermediate K-5, and 18D using Compounds 372E, 372F, and 372G in lieu of Compounds 151A, Intermediate K-4, and 18C. Compound 372F: LC- MS (ESI) m/z: 420 [M+H]+. Compound 372G: LC-MS (ESI) m/z: 306 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.37 (t, J = 7.2 Hz, 3H), 2.89 (t, J = 6.0 Hz, 1H), 3.16 (t, J = 6.0 Hz, 2H), 3.79 (s, 3H), 4.00-4.07 (m, 2H), 4.34-4.40 (m, 2H), 5.83 (s, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H). Compound 372H: LC-MS (ESI) m/z: 304 [M+H]+.
[001819] A mixture of Compounds 372H (607 mg, 2.0 mmol) and 372C (300 mg, 1.13 mmol) in ethanol (10 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with a mixture of ethyl acetate (10 mL) and petroleum ether (80 mL) and stirred at room temperature for 5 minutes. The resulting solid was collected by filtration to give Compound 372I. LC-MS (ESI) m/z: 551 [M+H]+.
[001820] Compounds 372J, 372K, and 372 were synthesized by employing the procedures described for Compounds 141, 8F, and 1 using Compounds 372I with dichloromethane as solvent, 372J, and 372K in lieu of Compounds 140 with EtOAc as solvent, 8E, and 1E.
Compound 372J: LC-MS (ESI) m/z: 553 [M+H]+. Compound 372K: LC-MS (ESI) m/z: 525 [M+H]+. Compound 372: LC-MS (ESI) m/z: 405 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.01 (brs, 2H), 3.27 (brs, 2H), 3.71 (brs, 4H), 7.43 (br, 8H).
[001821] Example 373
[001822] Synthesis of 4-(((3-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-6- yl)methyl)thio)-1H-1,2,3-triazole-5-carboxylic acid (373)
Figure imgf000509_0001
[001823] Compounds 373A, 373B, 373C, and 373 were synthesized by employing the procedures described for Intermediate K, Compounds 171B, 8F, and 57E using Compounds 369D, 373A, Intermedaite D-1, 373B, and 373C in lieu of Intermediates K-5, K, Compounds 171A, 8E, and 57D. Compound 373A: LC-MS (ESI) m/z: 320 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.27-133 (m, 1H), 1.72-.175 (m, 2H), 3.23-3.26 (m, 2H), 3.38 (d, J = 11.6 Hz, 2H), 3.52 (d, J = 9.2 Hz, 2H), 6.35 (dd, J = 8.8, 2.8 Hz, 1H), 6.57 (d, J = 2.8 hz, 1H), 7.20 (d, J = 8.8 Hz, 1H). Compound 373C: LC-MS (ESI) m/z: 505 [M+H]+. Compound 373: LC-MS (ESI) m/z: 385 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.12 (s, 1H), 1.75 (s, 2H), 3.15 (d, J = 7.2 Hz, 2H), 3.19-3.21 (m, 2H), 3.49 (d, J = 9.2 Hz, 2H), 6.46 (dd, J = 8.4, 2.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H).
[001824] Example 374
[001825] Synthesis of 4-(2-((4-chlorobenzyl)((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4- yl)methyl)amino)ethyl)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (374)
Figure imgf000510_0001
[001826] Compounds 374B, 374C, 374D, 374E, 374F, and 374 were synthesized by employing the procedures described for Compounds 4B, 372C, 372I, 141, 8F, and 1 using 4- (trifluoromethoxy) phenylboronic acid, Compounds 374A with toluene/H2O as solvent, 374B, 374C, 374D with dichloromethane as solvent, 374E, and 374F in lieu of (4- bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 372A, 372C, 140 with EtOAc as solvent, 8E, and 1E. Compound 374B: LC-MS (ESI) m/z: 267 [M+H]+.
Compound 374C: LC-MS (ESI) m/z: 392 [M+H]+. Compound 374D: LC-MS (ESI) m/z: 677 [M+H]+. Compound 374E: LC-MS (ESI) m/z: 679 [M+H]+. Compound 374F: LC-MS (ESI) m/z: 651 [M+H]+. Compound 374: LC-MS (ESI) m/z: 531 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.32 (br, 2H), 3.50-4.10 (m, 2H), 4.10-4.70 (m, 4H), 7.20-7.90 (m, 12H).
[001827] Example 375 [001828] Synthesis of 4-(3-(cyclopentyloxy)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (375)
Figure imgf000511_0001
[001829] Compounds 375A, 375B, 375C, 375D, and 375 were synthesized by
employing the procedures described for Compounds 27C, 336D, Intermediate I, 217E, and 8F using Compounds 351A, 375A, 375B, 375C, and 375D in lieu of Compounds 27B, 336C, 4- bromophenol, 217D, and 8E. Compound 375A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (s, 12H), 1.59-1.64 (m, 2H), 1.76-1.93 (m, 6H), 4.79-4.83 (m, 1H), 6.95-6.99 (m, 1H), 7.24-7.36 (m, 3H).
Compound 375B: LC-MS (ESI) m/z: 177 [M-H]-; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.58- 1.63 (m, 2H), 1.77-1.88 (m, 6H), 4.69-4.74 (m, 1H), 4.90 (s, 1H), 6.37-6.39 (m, 2H), 6.44-6.48 (m, 1H), 7.09 (t, J = 8.0 Hz, 1H). Compound 375C: LC-MS (ESI) m/z: 438 [M+H]+. Compound 375D: LC-MS (ESI) m/z: 318 [M+H]+. Compound 375: LC-MS (ESI) m/z: 290 [M+H]+; 1H- NMR (CD3OD, 400 MHz,): d (ppm) 1.60-1.66 (m, 2H), 1.68-1.87 (m, 4H), 1.89-1.95 (m, 2H), 4.75-4.80 (m, 1H), 6.60-6.69 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H).
[001830] Example 376
[001831] Synthesis of 4-((3'-chloro-4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (376)
Figure imgf000512_0001
[001832] Compounds 376B, 376C, 376D, 376E, 376F, 376G, and 376 were synthesized by employing the procedures described for Compounds 297C, 186E, 56B, 27C, 4B, 1, and 8F using piperidine, Compounds 376A, 376B, 376C with CuBr2 and 48% HBr aqueous solution as acid and CH3CN as solvent, 376D, Intermediate F, 376E with K2CO3 as base and 1,4-dioxane/H2O as solvent, 376F, and 376G in lieu of Compounds 297B, 297A, 186D, 56A with CuCl and HCl as acid and water as solvent, 27B, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 376B: LC-MS (ESI) m/z: 241 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.60-1.69 (m, 2H), 1.72-1.80 (m, 4H), 3.10-3.18 (m, 4H), 7.01 (d, J = 9.0 Hz, 1H), 8.08 (dd, J = 9.0, 2.6 Hz, 1H), 8.23 (d, J = 2.6 Hz, 1H). Compound 376C: LC-MS (ESI) m/z: 211 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.53 (m, 2H), 1.71 (m, 4H), 2.66-2.99 (m, 4H), 3.50 (s, 2H), 6.55 (dd, J = 8.4, 2.6 Hz,1H), 6.73 (d, J = 2.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H). Compound 376D: LC-MS (ESI) m/z: 274 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.39-1.56 (m, 2H), 1.66 (m, 4H), 2.70-3.16 (m, 4H), 6.81 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.2 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H). Compound 376E: LC-MS (ESI) m/z: 322 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (s, 12H), 1.53-1.59 (m, 2H), 1.71- 1.77 (m, 4H), 2.98-3.03 (m, 4H), 7.00 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H). Compound 376F: LC-MS (ESI) m/z: 563 [M+H]+. Compound 376G: LC-MS (ESI) m/z: 443 [M+H]+. Compound 376: LC-MS (ESI) m/z: 415 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.58-1.70 (m, 2H), 1.74-1.85 (m, 4H), 3.01-3.16 (m, 4H), 7.25 (d, J = 8.4 Hz, 1H), 7.51- 7.60 (m, 3H), 7.63 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 2.2 Hz, 1H).
[001833] Example 377
[001834] Synthesis of 4-((((cis)-4-(3,5-dichlorophenyl)cyclohexyl)thio)methyl)-1H- 1,2,3-triazole-5-carboxylic acid (377)
Figure imgf000513_0001
[001835] Compounds 377A, 377B, 377C, 377D, 377E, and 377 were synthesized by employing the procedures described for Compounds 340F, 350C, 350D, 243B, 1, and 8F using Compounds 304D-1, 377A, 377B, 377C with Na2CO3 as base and NMP as solvent at 100 °C, 377D, and 377E in lieu of Compounds 340E, 350B, 350C, 243A with K2CO3 as base and DMF as solvent at room temperature, 1E, and 8E. Compound 377A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.50-1.62 (m, 2H), 1.66-1.78 (m, 2H), 1.98-2.01 (m, 2H), 2.28-2.31 (m, 2H), 2.47-2.57 (m, 1H), 3.04 (s, 3H), 4.65-4.75 (m, 1H), 7.07 (s, 2H), 7.21 (s, 1H). Compound 377B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 377C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 377D: LC-MS (ESI) m/z: 534 [M+H]+. Compound 377E: LC-MS (ESI) m/z: 414 [M+H]+. Compound 377: LC-MS (ESI) m/z: 386 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.58-1.82 (m, 8H), 2.58-2.63 (m, 1H), 3.17- 3.21 (m, 1H), 4.01 (s, 2H), 7.24 (s, 2H), 7.42 (s, 1H), 13.21 (bs, 1H), 15.33 (bs, 1H).
[001836] Example 378 [001837] Synthesis of 4-(2-(4-chlorophenyl)-2-hydroxy-1-phenylethoxy)-1H-1,2,3- triazole-5-carboxylic acid (378)
Figure imgf000514_0001
[001838] To a solution of 2-phenylacetic acid (378A) (1.36 g, 10 mmol) in
dichloromethane (10 mL) was added oxalyl dichloride (1.9 g, 15 mmol). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to give a crude Compound 378B, which was used directly for next step without any purification. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[001839] To a mixture of compound 378B (1.54 g, 10 mmol) and chlorobenzene (1.45 g, 13 mmol) in dichloromethane (10 mL) was added AlCl3 (1.73 g, 13 mmol). The mixture was stirred at room temperature for 3 hours, poured into water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% v/v) to afford Compound 378C. LC-MS (ESI) m/z: 231 [M+H]+.
[001840] Compounds 378D, 378E, 378F, 378G, and 378 were synthesized by employing the procedures described for Compounds 43B, 274B, 57C, 217E, and 8F using Compounds 378C, 378D with acetone as solvent at 90 °C, 378E, 378F, and 378G in lieu of Compounds 43A, 274A with DMF as solvent at room temperature, 57B, 217D, and 8E. Compound 378D: LC-MS (ESI) m/z: 309 [M+H]+. Compound 378E: LC-MS (ESI) m/z: 506 [M+H]+. Compound 378F: LC-MS (ESI) m/z: 530 [M+Na]+. Compound 378G: LC-MS (ESI) m/z: 410 [M+Na]+. Compound 378: LC-MS (ESI) m/z: 382 [M+Na]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.98-5.03 (m, 1H), 5.64-6.03 (brs, 2H), 7.11-7.36 (m, 9H), 13.0-13.2 (brs, 1H), 14.63-14.65 (m, 1H).
[001841] Example 379
[001842] Synthesis of 4-(((cis)-4-(4-(2-oxopiperidin-1-yl)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (379)
Figure imgf000515_0001
[001843] Compounds 379A, 379B, 379C, and 379 were synthesized by employing the procedures described for Compounds 301A, 90C, 269, and 256 using piperidin-2-one,
Compounds 347C K3PO4 as base and t-BuOH/water as solvent and t-butyl Brettphos as ligand, 379A with DEAD as coupling reagent, 379B with EtOH/water as solvent at room temperature, and 379C at room temperature in lieu of Compounds 297B, Intermediate I with Cs2CO3 as base and 1,4-dioxane as solvent and X-Phos as ligand, 90B with DIAD as coupling reagent, 269C with MeOH/water as solvent at 60 oC, and 256D at 50 oC. Compound 379A: LC-MS (ESI) m/z: 274 [M+H]+. Compound 379B: LC-MS (ESI) m/z: 533 [M+H]+. Compound 379C: LC-MS (ESI) m/z: 505 [M+H] +. Compound 379: LC-MS (ESI) m/z: 385 [M+H]+.1H-NMR (CD3OD, 400 MHz): d (ppm) 1.66 (d, J = 12Hz, 2H), 1.75 (t, J = 14Hz, 2H), 1.93 -2.00 (m, 4H), 2.04 -2.10 (m, 2H), 2.23 (d, J = 14Hz, 2H), 2.51(t, J = 6Hz, 2H), 2.67 (t, J = 15.2Hz, 1H), 3.65 (t, J = 5.2Hz, 2H), 5.05 (s, 1H), 7.17 (d, J = 8.8Hz, 2H), 7.36 (d, J = 8.4Hz, 2H). [001844] Example 380
[001845] Synthesis of 4-(3-(cyclohexyloxy)phenoxy)-1H-1,2,3-triazole-5-carboxylic a
Figure imgf000516_0001
[001846] Compounds 380A, 380B, 380C, and 380D were synthesized by employing the procedures described for Compounds 90C, 27C, 236D, and Intermediate I using cyclohexanol, Compounds 131A CH2Cl2 as solvent and DEAD as coupling reagent, 380A, 380B, and 380C in lieu of Compounds 90B, Intermediate H with THF as solvent and DIAD as coupling reagent, 27B, 236C, and 4-bromophenol. Compound 380A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.29-1.38 (m, 3H), 1.40- 1.55 (m, 3H), 1.76-1.80 (m, 2H), 1.93-1.98 (m, 2H), 4.18-4.25 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 7.02-7.07 (m, 2H), 7.11 (t, J = 8.0 Hz, 1H). Compound 380B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.35-1.40 (m, 15H), 1.51-1.56 (m, 3H), 1.77-1.80 (m, 2H), 1.93-1.97 (m, 2H), 4.26-4.32 (m, 1H), 6.98-7.01 (m, 1H), 7.24-7.28 (m, 1H), 7.33-7.37 (m, 2H). Compound 380C: LC-MS (ESI) m/z: 191 [M-H]¯; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.35-1.41 (m, 3H), 1.48-1.58 (m, 3H), 1.77-1.81 (m, 2H), 1.96-2.05 (m, 2H), 4.16-4.23 (m, 1H), 4.98 (s, 1H), 6.37-6.42 (m, 2H), 6.47-6.50 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H). Compound 380D: LC-MS (ESI) m/z: 452 [M+H]+. [001847] A mixture of Compound 380D (280 mg, 0.62 mmol) and 10% Pd/C (200 mg) in MeOH (20 mL) was stirred at room temperature under H2 (1 atm.) for 16 hours. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified with flash column chromatography on silica gel (tetrahydrofuran in petroleum ether, from 0% to 70% v/v) to furnish Compound 380E. LC-MS (ESI) m/z: 332 [M+H]+.
[001848] Compound 380 was synthesized by employing the procedure described for Compound 8F using Compound 380E in lieu of Compound 8E, LC-MS (ESI) m/z: 304 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.39-1.53 (m, 6H), 1.79-1.81 (m, 2H), 1.97-2.00 (m, 2H), 4.28-4.33 (m, 1H), 6.63-6.65 (m, 1H), 6.68-6.69 (m, 1H), 6.71-6.73 (m, 1H), 7.23 (t, J = 6.8 Hz, 1H).
[001849] Example 381
[001850] Synthesis of 4-(4-chloro-3-(cyclopentyloxy)phenoxy)-1H-1,2,3-triazole-5- c
Figure imgf000517_0001
Figure imgf000517_0002
381
[001851] Compounds 381A, 381B, 381C, 381D, 381E, and 381 were synthesized by employing the procedures described for Compounds 27B, 27C, 236D, Intermediate I, 217E, and 8F using bromocyclopentane, Compounds 218A, 381A, 381B, 381C with Cs2CO3 as base, 381D, and 381E in lieu of 2-bromopropane, Compounds 27A, 27B, 236C, 4-bromophenol with K2CO3 as base, 217D, and 8E. Compound 381A: LC-MS (ESI) m/z: Non-ionzable Compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.62-1.766 (m, 2H), 1.82-1.91 (m, 6H), 4.78 (t, J = 4.0 Hz, 1H), 6.98 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H). Compound 381B: LC-MS (ESI) m/z: Non-ionzable Compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34 (d, J = 4.0 Hz, 12H), 1.61-1.64 (m, 2H), 1.83-1.91 (m, 6H), 4.90-4.92 (m, 1H), 7.28-7.37 (m, 3H). Compound 381C: LC-MS (ESI) m/z: 213 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.60-1.64 (m, 2H), 1.81-1.91 (m, 6H), 4.72-4.74 (m, 1H), 6.33 (dd, J = 8.4, 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H). Compound 381D: LC-MS (ESI) m/z: 472 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.15 (t, J = 7.2 Hz, 3H), 1.58-1.63 (m, 2H), 1.76-1.81 (m, 6H), 3.76 (s, 3H), 4.21 (q, J = 7.2 Hz, 2H), 4.50-4.52 (m, 1H), 5.35 (s, 2H), 6.23 (dd, J = 8.4, 2.8 Hz, 1H), 6.29 (d, J = 2.8 Hz, 1H), 6.76-6.78 (m, 2H), 7.17-7.20 (m, 3H). Compound 381E: LC-MS (ESI) m/z: 352 [M+H]+; 1H- NMR (CDCl3, 400 MHz): d (ppm) 1.34 (t, J = 7.2 Hz, 3H), 1.60-1.64 (m, 2H), 1.81-1.91 (m, 6H), 4.10 (q, J = 7.2 Hz, 2H), 4.74-4.75 (m, 1H), 6.64 (dd, J = 8.8, 2.8 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H). Compound 381: LC-MS (ESI) m/z: 324 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.64-1.70 (m, 2H), 1.81-1.93 (m, 6H), 4.81-4.89 (m, 1H), 6.63 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1 H), 7.31(d, J = 8.8 Hz, 1H).
[001852] Example 382
[001853] Synthesis of 4-((3-(cyclohexyloxy)phenyl)thio)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (382)
Figure imgf000518_0001
[001854] Compound 382A was synthesized by employing the procedure described for Compound 35D using Compound 380A in lieu of Compound 35C, LC-MS (ESI) m/z: 468
[M+H]+; 1H-NMR (CDCl3, 400 MHz,): d (ppm) 1.26-1.42 (m, 9H), 1.73-1.78 (m, 2H), 1.83-1.89 (m, 2H), 3.76 (s, 3H), 4.05-4.10 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 5.51 (s, 2H), 6.53-6.58 (m, 2H), 6.70-6.73 (m, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.09 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H).
[001855] To a solution of Compound 382A (600 mg, 1.28 mmol) in CH3CN (15 mL) was added a solution of CAN (3.52 g, 6.42 mmol) in H2O (5 mL). The mixture was stirred at 25 oC for 5 hours, diluted with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate,
concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to furnish Compound 382B. LC-MS (ESI) m/z: 364 [M+H]+.
[001856] To a solution of Compound 382B (200 mg, 0.55 mmol) and NaI (412 mg, 2.75 mmol) in CH3CN (15 mL) was added dropwise TiCl4 (523 mL, 2.75 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with water (2 mL), and concentrated under reduced pressure. The residue was purified with reverse phase
chromatography using eluent (acetonitrile in water, from 0% to 70% v/v) to give Compound 382C. LC-MS (ESI) m/z: 348 [M+H]+.
[001857] Compound 382 was synthesized by employing the procedure described for Compound 8F using Compound 382C in lieu of Compound 8E, LC-MS (ESI) m/z: 320 [M+H]+; 1H-NMR (CD3OD, 400 MHz,): d (ppm) 1.32-1.49 (m, 6H), 1.76-1.81 (m, 2H), 1.94-1.98 (m, 2H), 4.26-4.32 (m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 7.00-7.03 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H).
[001858] Example 383
[001859] Synthesis of 4-(((1-(2,5-dichlorophenyl)piperidin-4-yl)thio)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (383)
Figure imgf000520_0001
383
[001860] Compounds 383A, 383B, 383C, 383D, 383E, and 383 were synthesized by employing the procedures described for Compounds 340F, 350C, 350D, 243B, 256, and 8F using Compounds 291B, 383A, 383B, 383C, 383D with TFA as acid and solvent, and 383E in lieu of Compounds 340E, 350B, 350C, 243A, 256D with TFA as acid and dichloromethane as solvent, and 8E. Compound 383A: LC-MS (ESI) m/z: 324 [M+H]+. Compound 383B: LC-MS (ESI) m/z: 304 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.82-1.88 (m, 2H), 2.07-2.10 (m, 2H), 2.35 (s, 3H), 2.82-2.88 (m, 2H), 3.19-3.28 (m, 2H), 3.57-3.64 (m, 1H), 6.92-7.03 (m, 2H), 7.25-7.28 (m, 1H). Compound 383C: LC-MS (ESI) m/z: 262 [M+H]+. Compound 383D: LC-MS (ESI) m/z: 535 [M+H]+. Compound 383E: LC-MS (ESI) m/z: 415 [M+H]+. Compound 383: LC- MS (ESI) m/z: 387 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.70-1.79 (m, 2H), 2.08- 2.12 (m, 2H), 2.70-2.76 (m, 2H), 2.81-2.84 (m, 1H), 3.32-3.34 (m, 2H), 4.17 (s, 2H), 7.00 (dd, J = 8.4, 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H).
[001861] Example 384
[001862] Synthesis of 4-(((1-(3,4-dichlorophenyl)piperidin-4-yl)thio)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (384)
Figure imgf000521_0001
[001863] Compounds 384A, 384B, 384C, 384D, 384E, and 384 were synthesized by employing the procedures described for Compounds 340F, 350C, 350D, 243B, 256, and 8F using Compounds 286B, 384A, 384B, 384C, 384D with TFA as both acid and solvent, and 384E in lieu of Compounds 340E, 350B, 350C, 243A, 256D with TFA as acid and dichloromethane as solvent, and 8E. Compound 384A: LC-MS (ESI) m/z: 324 [M+H]+. Compound 384B: LC-MS (ESI) m/z: 304 [M+H]+. Compound 384C: LC-MS (ESI) m/z: 262 [M+H]+. Compound 384D: LC-MS (ESI) m/z: 535 [M+H]+. Compound 384E: LC-MS (ESI) m/z: 415 [M+H]+. Compound 384: LC-MS (ESI) m/z: 387 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.52-1.55 (m, 2H), 1.93-1.98 (m, 2H), 2.72-2.78 (m, 3H), 3.49-3.52 (m, 2H), 4.05 (s, 2H), 6.77 (dd, J = 9.2, 2.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 9.2 Hz, 1H).
[001864] Example 385
[001865] Synthesis of 4-((1-(4-chlorophenyl)-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]- 4-yl)propan-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (385)
Figure imgf000522_0001
[001866] To a solution of 2-(4-bromophenyl)acetic acid (385A) (5.1g, 30 mmol) and 2-(4- chlorophenyl)acetic acid (385B) (6.45g, 30 mmol) in THF (100 mL) was added DCC (9.27g, 45 mmol) and catalytic amount of DMAP. The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 385C. LC-MS (ESI) m/z: 323 [M+H]+.
[001867] Compounds 385D, 385E, 385F, 385G, and 385 were synthesized by employing the procedures described for Compounds 4B, 57C, 90C, 1, and 8F using 4- (trifluoromethoxy)phenylboronic acid, Compounds 385C, 385D, 385E with toluene as solvent, 385F, and 385G in lieu of (4-bromophenyl)boronic acid, Compounds 4A, 57B, 90B with THF as solvent, 1E, and 8E. Compound 385D: LC-MS (ESI) m/z: 405 [M+H]+. Compound 385E: LC- MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 385F: LC- MS (ESI) m/z: 666 [M+H]+. Compound 385G: LC-MS (ESI) m/z: 546 [M+H]+. Compound 385: LC-MS (ESI) m/z: 518 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.98-2.99 (m, 4H), 5.14-5.18 (m, 1H), 7.30-7.31 (m, 4H), 7.35-7.44 (m, 4H), 7.57-7.59 (m, 2H), 7.75-7.77 (m, 2H).
[001868] Example 386
[001869] Synthesis of 4-((1-(5-chloro-2-(trifluoromethoxy)phenyl)piperidin-4-yl)thio)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (386)
Figure imgf000523_0001
[001870] Compounds 386A, 386B, and 386 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 367B, 386A, and 386B in lieu of Intermediate H, Compounds 90B, 8E, and 1E. Compound 386A: LC-MS (ESI) m/z: 571 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.44 (t, J = 7.2 Hz, 3H), 1.62-1.71 (m, 2H), 1.80-1.84 (m, 2H), 2.61-2.67 (m, 2H), 3.26-3.30 (m, 2H), 3.46-3.51 (m, 1H), 3.77 (s, 3H), 4.45 (d, J = 7.2 Hz, 2H), 5.63 (s, 2H), 6.84-6.96 (m, 4H), 7.08-7.10 (m, 1H), 7.27-7.30 (m, 2H). Compound 386B: LC-MS (ESI) m/z: 543 [M+H]+. Compound 386: LC-MS (ESI) m/z: 423 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.79-1.89 (m, 2H), 2.22-2.25 (m, 2H), 2.87- 2.93 (m, 2H), 3.38-3.42 (m, 2H), 3.75-3.80 (m, 1H), 7.04 (dd, J = 8.8, 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.19-7.22 (m, 1H).
[001871] Example 387
[001872] Synthesis of 4-((4'-chloro-2-(cyclopentylmethoxy)-[1,1'-biphenyl]-4-yl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (387)
Figure imgf000524_0001
[001873] Compounds 387B, 387C, 387D, 387E, and 387 were synthesized by employing the procedures described for Compounds 27B, 4B, Intermediate I, 1, and 8F using
(bromomethyl)cyclopentane, Compounds 387A with K2CO3 as base, (4-chlorophenyl)boronic acid, 387B with K2CO3 as base and 1,4-dioxane as solvent, 387C, 387D, and 387E in lieu of 2- bromopropane, Compounds 27A with Cs2CO3 as base, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 4-bromophenol, 1E, and 8E. Compound 387B: LC-MS (ESI) m/z: 254 [M-17+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.33 (d, J = 8.4Hz, 1H), 6.42 (d, J = 2.8Hz, 1H), 6.31-6.28 (m, 1H), 4.93 (s, 1H), 3.84 (d, J = 6.8Hz, 2H), 2.44-2.37 (m, 1H), 1.89-1.81 (m, 2H), 1.69-1.55 (m, 4H), 1.44-1.36 (m, 2H). Compound 387C: LC-MS (ESI) m/z: 286 [M-17+H]+. Compound 387D: LC-MS (ESI) m/z: 562 [M+H]+.
Compound 387E: LC-MS (ESI) m/z: 442 [M+H]+. Compound 387: LC-MS (ESI) m/z: 414 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.22-1.26 (m, 2H), 1.42-1.54 (m, 4H), 1.64- 1.66 (m, 2H), 2.19-2.22 (m, 1H), 3.83 (d, J = 6.8 Hz, 2H), 6.59-6.61 (m, 1H), 6.86 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.44-7.51 (m, 4H).
[001874] Example 388
[001875] Synthesis of 4-(4-(1-cyclohexylpiperidin-4-yl)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (388)
Figure imgf000525_0001
[001876] Compounds 388B, 388C, 388D, 388E, 388F, and 388 were synthesized by employing the procedures described for Compounds 160B, 27C, 236D, Intermediate I, 1, and 8F using cyclohexanone, Compounds 388A, 388B, 388C, 388D with Cs2CO3 as base in a microoven at 120 oC, 388E, and 388F in lieu of Compounds 160A, piperidine, 27B, 236C, 4-bromophenol with K2CO3 as base at 90 oC, 1E, and 8E. Compound 388B: LC-MS (ESI) m/z: 322 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.10-1.31 (m, 4H), 1.36-1.49 (m, 2H), 1.59-1.63 (m, 1H), 1.80-1.84 (m, 2H), 1.95-2.06 (m, 5H), 2.79-2.90 (m, 1H), 3.04-3.23 (m, 3H), 3.45-3.48 (m, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H). Compound 388C: LC-MS (ESI) m/z: 288 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.05-1.12 (m, 1H), 1.23-1.32 (m, 2H), 1.38- 1.47 (m, 2H), 1.60-1.63 (m, 1H), 1.81-2.06 (m, 8H), 2.80-2.86 (m, 1H), 3.07-3.21 (m, 3H), 3.46- 3.50 (m, 2H), 7.19 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 8.03 (s, 2H). Compound 388D: LC-MS (ESI) m/z: 260 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.08-1.11 (m, 1H), 1.22-1.31 (m, 2H), 1.37-1.45 (m, 2H), 1.59-1.63 (m, 1H), 1.08-1.97 (m, 6H), 2.01-2.04 (m, 2H), 2.67-2.71 (m, 1H), 3.03-3.18 (m, 3H), 3.42-3.46 (m, 2H), 7.19 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H), 9.31 (d, J = 6.3 Hz, 1H). Compound 388E: LC-MS (ESI) m/z: 519 [M+H]+. Compound 388F: LC-MS (ESI) m/z: 399 [M+H]+. Compound 388: LC-MS (ESI) m/z: 371
[M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.22-1.29 (m, 1H), 1.41-1.54 (m, 4H), 1.72- 1.76 (m, 1H), 1.95-1.98 (m, 4H), 2.11-2.14 (m, 4H), 2.90 (s, 1H), 3.21 (s, 3H), 3.58-3.60 (m, 2H), 7.09 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H).
[001877] Example 389
[001878] Synthesis of 4-((4'-cyano-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (389)
Figure imgf000526_0001
[001879] Compounds 389B, 389C, 389D, 389E, and 389 were synthesized by employing the procedures described for Compounds 4B, 30B, 35D, 8F, and 1 using 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzenamine, Compounds 389A with K2CO3 as base and 1,4-dioxane as solvent, 389B with tert-butyl nitrite and CuBr and dichloromethane as solvent, 389C, 389D, and 389E in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 30A with isoamyl nitrite and CuCl2 and MeCN as solvent, 35C, 8E, and 1E. Compound 389B: LC-MS (ESI) m/z: 195 [M+H]+; 1H-NMR (CDCl3, 400MHz): d (ppm) 3.86 (s, 2H), 6.77-6.79 (m, 2H), 7.43-7.45 (m, 2H), 7.61-7.69 (m, 4H). Compound 389C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.44-7.52 (m, 2H), 7.59-7.62 (m, 2H), 7.63-7.76 (m, 4H). Compound 389D: LC-MS (ESI) m/z: 471 [M+H]+. Compound 389E: LC-MS (ESI) m/z: 443 [M+H]+. Compound 389: LC-MS (ESI) m/z: 323 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 7.59 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.80-7.86 (m, 4H). [001880] Example 390
[001881] Synthesis of 4-(4-cyano-3-((4-fluorobenzyl)oxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (390)
Figure imgf000527_0001
[001882] Compounds 390A and 390B were synthesized by employing the procedures described for Compounds 27B and Intermediate I using 1-(chloromethyl)-4-fluorobenzene, Compounds 387A with K2CO3 as base and acetone as solvent at reflux, and 390A in lieu of 2- bromopropane, Compounds 27A with Na2CO3 as base and DMF as solvent at 100 oC, and 4- bromophenol. Compound 390A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 5.03 (s, 1H), 5.07 (s, 2H), 6.34 (dd, J = 2.8, 8.4 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 7.08 (t, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 5.2, 8.8 Hz, 2H). Compound 390B: LC-MS (ESI) m/z: 556 [M+H]+.
[001883] A mixture of Compound 390B (130 mg, 0.23 mmol), Zn(CN)2 (33 mg, 0.28 mmol), dppf (25 mg, 0.046 mmol), and Pd2(dba)3 (26 mg, 0.023 mmol) in DMF (3 mL) was heated in a microwave reactor at 140 oC under N2 for 1.5 hours. The mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 30% v/v) to afford Compound 390C as a yellow film (59 mg, yield 51%). LC-MS (ESI) m/z: 503 [M+H]+.
[001884] Compounds 390D and 390 were synthesized by employing the procedures described for Compounds 217E and 8F using Compounds 390C and 390D in lieu of Compounds 217D and 8E. Compound 390D: LC-MS (ESI) m/z: 383 [M+H]+. Compound 390: LC-MS (ESI) m/z: 355 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.23 (s, 2H), 6.70 (dd, J = 2.0, 8.4 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.4, 11.2 Hz, 2H), 7.50 (dd, J = 5.6, 8.4 Hz, 2H), 7.72 (d, J = 8.4, 1H). [001885] Example 391
[001886] Synthesis of 1-((cyclohexanecarbonyl)oxy)ethyl 4-(((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylate (391)
Figure imgf000528_0001
[001887] To a mixture of cyclohexanecarbonyl chloride (391A) (5.00 g, 34.25 mmol) and anhydrous ZnCl2 (232 mg, 1.72 mmol) was dropped anhydrous acetaldehyde (1.66 g, 37.67 mmol) at -20 oC and stirred at -20 oC for 2 hours. It was warmed gradually to room temperature and stirred for 16 hours. The mixture was concentrated and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to give Compound 391B.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.23-1.30 (m, 3H), 1.31-1.48 (m, 2H), 1.60-1.65 (m, 1H), 1.74-1.79 (m, 5H), 1.87-1.96 (m, 2H), 2.30-2.37 (m, 1H), 6.54 (q, J = 6.0 Hz, 1H).
[001888] Compound 391C was synthesized by employing the procedure described for Compound 51 using Compound 391B and Compound 302B with DMF as solvent in lieu of Compound 16 and chloromethyl pivalate with 1,4-dioxane as solvent, LC-MS (ESI) m/z: 790 [M+Na]+.
[001889] A suspension of Compound 391C (160 mg, 0.21 mmol), triethylsilane (0.23 mL) and 10% Pd/C (100 mg) in MeOH (20 mL) was stirred at room temperature under H2 (1 atm) for 16 hours. The mixture was filtered through Celite, concentrated, and purified with preparative HPLC to afford Compound 391. LC-MS (ESI) m/z: 1073 [2M+Na]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.24-1.49 (m, 5H), 1.60 (d, J = 8.0 Hz, 3H), 1.70-1.79 (m, 7H), 1.91-2.00 (m, 4H), 2.35-2.40 (m, 3H), 2.66-2.70 (m, 1H), 4.72-4.79 (m, 1H), 7.04-7.07 (m, 1H), 7.20 (d, J = 6.4 Hz, 2H), 7.37 (d, J = 6.4 Hz, 2H). [001890] Example 392
[001891] Synthesis of 1-((cyclohexanecarbonyl)oxy)propyl 4-(((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylate (392)
Figure imgf000529_0001
[001892] Compounds 392A, 392B, and 392 were synthesized by employing the procedures described for Compounds 391B, 51, and 391 using propionaldehyde, Compounds 392A and Compound 302B with DMF as solvent, and 392B in lieu of acetaldehyde, Compounds 16 and chloromethyl pivalate with 1,4-dioxane as solvent, and 391C. Compound 392A: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.04 (t, J = 7.2 Hz, 3H), 1.23-1.31 (m, 4H), 1.45-1.51 (m, 2H), 1.74- 1.77 (m, 2H), 1.89-1.99 (m, 2H), 2.01-2.07 (m, 2H), 2.32-2.38 (m, 1H), 8.38 (t, J = 6.0 Hz, 1H). Compound 392B: LC-MS (ESI) m/z: 804 [M+Na]+. Compound 392: LC-MS (ESI) m/z: 1101 [2M+Na]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.06 (t, J = 6.0 Hz, 3H), 1.26-1.52 (m, 5H), 1.67-1.79 (m, 7H), 1.92-2.01 (m, 6H), 2.37-2.41 (m, 3H), 2365-2.71 (m, 1H), 4.73-7.79 (m, 1H), 6.95 (t, J = 6.0 Hz, 1H), 2.20 (d, J = 6.4 Hz, 2H), 7.37 (d, J = 6.8 Hz, 2H).
[001893] Example 393
[001894] Synthesis of 4-(((trans)-4-(5-chloro-2- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (393)
Figure imgf000530_0001
[001895] Compounds 393B, 393C, 393D, and 393E were synthesized by employing the procedures described for Compounds 8B, 141, 30B, and 279D using 4,4,5,5-tetramethyl-2- (1,4- dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 393A with K2CO3 as base and 1,4-dioxane/H2O as solvent, 393B, 393C with tert-butyl nitrite, and 393D with TFA as acid and dichloromethane as solvent in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 140, 30A with isoamyl nitrite, and 279C with HCl as acid and 1,4-dioxane as solvent. Compound 393B: LC-MS (ESI) m/z: 316 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.77-1.81 (m, 2H), 2.34-2.36 (m, 2H), 2.43-2.47 (m, 2H), 3.54 (s, 2H), 3.94 (s, 4H), 5.57-5.59 (m, 1H), 6.43-6.49 (m, 2H), 6.90-6.93 (m, 1H). Compound 393C: LC-MS (ESI) m/z: 318 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.57-1.79 (m, 8H), 2.79- 2.83 (m, 1H), 3.56 (brs, 2H), 3.92 (s, 4H), 6.39-6.42 (m, 1H), 6.55-6.56 (m, 1H), 6.89-6.93 (m, 1H). Compound 393D: LC-MS (ESI) m/z: 337 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.53-1.80 (m, 8H), 2.85-2.89 (m, 1H), 3.91 (s, 4H), 7.05-7.12 (m, 2H), 7.26-7.27 (m, 1H).
Compound 393E: LC-MS (ESI) m/z: 293 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.78- 1.83 (m, 2H), 2.06-2.11 (m, 2H), 2.43-2.47 (m, 4H), 3.28-3.34 (m, 1H), 7.13-7.20 (m, 3H).
[001896] To a solution of Compound 393E (820 mg, 2.8 mmol) in anhydrous THF (20 mL) was dropped L-Selectride solution of (1 M in THF, 4.2 mL, 4.2 mmol) at -78 oC under nitrogen and stirred at -78 oC for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution (30 mL), stirred at room temperature for 0.5 hour, and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish Compounds 393F-1 and 393F-2. Compounds 393F-1: LC-MS (ESI) m/z: 277 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.57-1.61 (m, 2H), 1.68-1.73 (m, 2H), 1.82-1.93 (m, 4H), 2.87-2.95 (m, 1H), 4.16-4.17 (m, 1H), 7.14-7.19 (m, 2H), 7.35-7.36 (m, 1H). Compounds 393F-2: LC-MS (ESI) m/z: 277 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34-1.42 (m, 4H), 1.78-1.82 (m, 2H), 2.03-2.05 (m, 2H), 2.78-2.81 (m, 1H), 3.59-3.63 (m, 1H), 7.08-7.17 (m, 2H), 7.18-7.19 (m, 1H).
[001897] Compounds 393G, 393H, and 393 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 393F-1, 393G, and 393H in lieu of Compounds 90B, 8E, and 1E. Compound 393G: LC-MS (ESI) m/z: 554 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34-1.43 (m, 7H), 1.76-1.79 (m, 2H), 2.08-2.09 (m, 2H), 2.75-2.79 (m, 1H), 3.71 (s, 3H), 4.35 (q, J = 7.2 Hz, 2H), 5.00-5.02 (m, 1H), 5.23 (s, 2H), 6.78-6.81 (m, 2H), 7.08-7.20 (m, 5H). Compound 393H: LC-MS (ESI) m/z: 526 [M+H]+. Compound 393: LC- MS (ESI) m/z: 406 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.55-1.60 (m, 4H), 1.79 (m, 2H), 2.27-2.28 (m, 2H), 2.83-2.90 (m, 1H), 4.62-4.67 (m, 1H), 7.17-7.20 (m, 2H), 7.36-7.37 (m, 1H).
[001898] Example 394
[001899] Synthesis of 4-((2-chloro-4'-cyano-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole- 5-carboxylic acid (394)
Figure imgf000532_0001
[001900] Compounds 394B, 394C, 394D, and 394 were synthesized by employing the procedures described for Compounds 4B, Intermediate I, 8F, and 1 using (4- cyanophenyl)boronic acid, Compounds 394A with K2CO3 as base and DME/H2O as solvent, 394B, 394C, and 394D in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 4-bromophenol, 8E, and 1E. Compound 394B: LC-MS (ESI) m/z: 228 [M-H]¯. Compound 394C: LC-MS (ESI) m/z: 489 [M+H]+. Compound 394D: LC-MS (ESI) m/z: 459 [M-H]¯. Compound 394: LC-MS (ESI) m/z: 341 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.16 (dd, J = 8.4, 2.8 Hz, 1H), 7.39 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H).
[001901] Example 395
[001902] Synthesis of 4-(((trans)-4-(2-chloro-5- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (395)
Figure imgf000532_0002
Figure imgf000533_0001
[001903] Compounds 395B, 395C, 395D, 395E, 395F-1 and 395F-2, 395G, 395H, and 395 were synthesized by employing the procedures described for Compounds 30B, 4B, 141, 279D, 393F-1 and 393F-2, 90C, 8F, and 1 using Compounds 395A with tert-butyl nitrite, 4,4,5,5- tetramethyl-2- (1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, 395B with K2CO3 as base and 1,4-dioxane/H2O as solvent, 395C with MeOH as solvent, 393D with THF/H2O as solvent, 395E, 395F-1, 395G, and 395H, in lieu of Compounds 30A with isoamyl nitrite, (4- bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 279C with 1,4-dioxane as csolvent, 393E, 90B, 8E, and 1E. Compound 395B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.13-7.15 (m, 1H), 7.47-7.52 (m, 2H). Compound 395C: LC-MS (ESI) m/z: 335 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.90 (t, J = 6 Hz, 2H), 2.45-2.46 (m, 2H), 2.52-2.56 (m, 2H), 4.00 (s, 4H), 5.62 (brs, 1H), 7.03-7.09 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H). Compound 395D: LC-MS (ESI) m/z: 337 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.64-1.76 (m, 4H), 1.83-1.90 (m, 4H), 3.01-3.07 (m, 1H), 3.99 (s, 4H), 6.98-7.01 (m, 1H), 7.14 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H). Compound 395E: LC-MS (ESI) m/z: 293 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.79-1.90 (m, 2H), 2.24-2.27 (m, 2H), 2.53-2.57 (m, 4H), 3.46-3.54 (m, 1H), 7.05-7.09 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H). Compound 395F-1: LC-MS (ESI) m/z: 277 [M-OH]+; 1H-NMR (CDCl3, 500 MHz): d (ppm) 1.67-1.74 (m, 4H), 1.77-1.88 (m, 2H), 1.92-1.95 (m, 2H), 2.98-3.04 (m, 1H), 4.17-4.18 (m, 1H), 6.98-7.01 (m, 1H), 7.16-7.17 (m, 1H), 7.35 (d, J = 8 Hz, 1H). Compound 395F-2: LC-MS (ESI) m/z: 277 [M-OH]+; 1H-NMR (CDCl3, 500 MHz): d (ppm) 1.42-1.49 (m, 4H), 1.94-1.96 (m, 2H), 2.12-2.14 (m, 2H), 2.96-3.00 (m, 1H), 3.70 (brs, 1H), 6.99-7.01 (m, 1H), 7.072-7.078 (m, 1H), 7.36 (d, J = 7.2 Hz, 1H). Compound 395G: LC-MS (ESI) m/z: 554 [M+H]+.Compound 395H: LC-MS (ESI) m/z: 526 [M+H]+. Compound 395: LC-MS (ESI) m/z: 406 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.58-1.78 (m, 4H), 1.98-2.01 (m, 2H), 2.38-2.41 (m, 2H), 3.11-3.17 (m, 1H), 4.74-4.79 (m, 1H), 7.12-7.15 (m, 1H), 7.27-7.28 (m, 1H), 7.49 (d, J = 8.8 Hz, 1 H).
[001904] Example 396
[001905] Synthesis of 4-(((cis)-4-(2-chloro-5-(trifluoromethoxy)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (396)
Figure imgf000534_0001
[001906] Compounds 396A, 396B, and 396 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 395F-2, 396A, and 396B in lieu of Compounds 90B, 8E, and 1E. Compound 396A: LC-MS (ESI) m/z: 554 [M+H]+. Compound 396B: LC-MS (ESI) m/z: 526 [M+H]+. Compound 396: LC-MS (ESI) m/z: 406 [M+H]+; 1H- NMR (CD3OD, 400 MHz): d (ppm) 1.67-1.70 (m, 2H), 1.75-1.83 (m, 2H), 1.92-2.03 (m, 2H), 2.25-2.28 (m, 2H), 3.15-3.23 (m, 1H), 5.08 (brs, 1H), 7.10-7.13 (m, 1H), 7.31-7.32 (m, 1H), 7.47 (d, J = 8.4 Hz, 1 H).
[001907] Example 397
[001908] Synthesis of 4-((4'-carbamoyl-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid (397)
Figure imgf000535_0001
[001909] Compounds 397A and 397 were synthesized by employing the procedures described for Compounds 4B and 1 using 4-carbamoylphenylboronic acid, Intermediate I, and 397A in lieu of (4-bromophenyl)boronic acid, Compounds 4A, and 1E. Compound 397A: LC- MS (ESI) m/z: 445 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 3.68 (s, 3H), 5.43 (s, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.39 (s, 1H), 7.60- 7.73 (m, 4H), 7.95 (d, J = 8.5 Hz, 2H), 8.02 (s, 1H), 13.06 (s, 1H). Compound 397: LC-MS (ESI) m/z: 325 [M+H]+; 1H-NMR (DMSO-d6, 400MHz): d (ppm) 7.17 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.74 (d, J = 8.4 Hz, 4H), 7.95 (d, J = 8.8 Hz, 2H), 8.02 (s, 1H).
[001910] Example 398
[001911] Synthesis of 4-((4'-chloro-2-(cyclopentylmethoxy)-[1,1'-biphenyl]-4-yl)thio)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (398)
Figure imgf000535_0002
[001912] To a mixture of Compound 387C (500 mg, 1.66 mmol) and Et3N (251 mg, 2.48 mmol) in CH2Cl2 (20 ml) was added Tf2O (560 mg, 1.99 mmol) at 0 oC. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified with flash column chromatography (ethyl acetate in petroleum ether, from 0% to 3% v/v) to yield Compound 398A. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
[001913] Compounds 398B, 398C, and 398 were synthesized by employing the procedures described for Compounds 35D, 1, and 8F using Compounds 398A, 398B, and 398C in lieu of Compounds 35C, 1E, and 8E. Compound 398B: LC-MS (ESI) m/z: 578 [M+H]+. Compound 398C: LC-MS (ESI) m/z: 458 [M+H]+. Compound 398: LC-MS (ESI) m/z: 430 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.23-1.27 (m, 2H), 1.46-1.56 (m, 4H), 1.65-1.69 (m, 2H), 2.18-2.22 (m, 1H), 3.85 (d, J = 6.8 Hz, 2H), 7.05-7.07 (m, 1H), 7.21 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.46-7.48 (m, 2H), 7.52-7.55 (m, 2H).
[001914] Example 399
[001915] Synthesis of 4-(4-chloro-3-(cyclohexyloxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (399)
Figure imgf000536_0001
[001916] Compounds 399B, 399C, 399D, 399E, 399F, and 399 were synthesized by employing the procedures described for Compounds 90C, 27C, 236D, Intermediate I, 217E, and 8F using cyclohexanol, Compounds 399A, 399B, 399C, 399D, 399E, and 399F in lieu of Compounds 90B, Intermediate H, 27B, 236C, 4-bromophenol, 217D, and 8E. Compound 399B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.35-1.55 (m, 3H), 1.64-1.67 (m, 3H),1.81-1.84 (m, 2H), 1.92-1.95 (m, 2H), 4.26-4.31 (m, 1H), 7.00 (dd, J = 8.8, 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H). Compound 399C: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.26-1.41 (m, 16H), 1.62-1.66 (m, 2H), 1.81-1.84 (m, 2H), 1.92-1.95 (m, 2H), 4.38-4.39 (m, 1H), 7.30-7.36 (m, 3H). Compound 399D: LC-MS (ESI) m/z: 227 [M+H]+. Compound 399E: LC-MS (ESI) m/z: 486 [M+H]+. Compound 399F: LC-MS (ESI) m/z: 366 [M+H]+. Compound 399: LC-MS (ESI) m/z: 338 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.40-1.44 (m, 3H), 1.55-1.65 (m, 3H), 1.78-1.82 (m, 2H), 1.91-1.93 (m, 2H), 4.34-4.38 (m, 1H), 6.64 (dd, J = 8.8, 2.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 8.8 Hz, 1H).
[001917] Example 400
[001918] Synthesis of 4-(4-fluoro-3-((4-(trifluoromethoxy)benzyl)oxy)phenoxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (400)
Figure imgf000537_0001
[001919] Compounds 400B, 400C, 400D, and 400 were synthesized by employing the procedures described for Compounds 27B, Intermediate I, 217E, and 8F using 1-(chloromethyl)- 4-(trifluoromethoxy)benzene, Compounds 400A, 400B, 400C, and 400D in lieu of 2- bromopropane, Compounds 27A, 4-bromophenol, 217D, and 8E. Compound 400B: LC-MS (ESI) m/z: 303 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.97 (s, 2H), 5.23 (s, 1H), 6.23- 6.26 (m, 1H), 6.40-6.43 (m, 1H), 6.82-6.87 (m, 1H), 7.12-7.17 (m, 2H), 7.34-7.37 (m, 2H).
Compound 400C: LC-MS (ESI) m/z: 562 [M+H]+. Compound 400D: LC-MS (ESI) m/z: 442 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.21 (t, J = 6.8 Hz, 3H), 4.30 (q, J = 6.8 Hz, 2H), 4.99 (s, 2H), 6.61-6.63 (m, 1H), 6.79-6.81 (m, 1H), 6.95-7.02 (m, 1H), 7.14-7.16 (m, 2H), 7.36- 7.38 (m, 2H). Compound 400: LC-MS (ESI) m/z: 414 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.18 (s, 2H), 6.61-6.63 (m, 1H), 7.10-7.13 (m, 1H), 7.19-7.24 (m, 1H), 7.39-7.41 (m, 2H), 7.57-7.59 (m, 2H).
[001920] Example 401 [001921] Synthesis of 4-((4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (401)
Figure imgf000538_0001
[001922] Compounds 401A, 401B, and 401 were synthesized by employing the procedures described for Compounds 4B, 1, and 8F using 4-(methylsulfonyl)phenylboronic acid,
Intermediate I with K2CO3 as base and 1,4-dioxane/H2O as solvent, Compounds 401A, and 401B in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and
toluene/EtOH/H2O as solvent, 1E, and 8E. Compound 401A: LC-MS (ESI) m/z: 508 [M+H]+. Compound 401B: LC-MS (ESI) m/z: 388 [M+H]+. Compound 401: LC-MS (ESI) m/z: 360
[M+H]+; 1H-NMR (DMSO-d6, 400MHz): d (ppm) 3.26 (s, 3H), 7.20 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H).
[001923] Example 402
[001924] Synthesis of 4-((1-(2-chloro-5-(trifluoromethoxy)phenyl)piperidin-4-yl)thio)- 1H-1,2,3-triazole-5-carboxylic acid (402)
Figure imgf000539_0001
[001925] Compounds 402A, 402B, 402C, 402D, and 402 were synthesized by employing the procedures described for Compounds 6B, 340F, 340G, 8F, and 1 using 4-hydroxypiperidine, Compounds 395B with Ruphos as ligand and THF as solvent, 402A, 402B, 402C, and 402D in lieu of 1-methylpiperazine, Compounds 6A with Xantophos as ligand and toluene as solvent, 340E, 340F, 8E, and 1E. Compound 402A: LC-MS (ESI) m/z: 296 [M+H]+. Compound 402B: LC-MS (ESI) m/z: 374 [M+H]+. Compound 402C: LC-MS (ESI) m/z: 571 [M+H]+. Compound 402D: LC-MS (ESI) m/z: 543 [M+H]+. Compound 402: LC-MS (ESI) m/z: 423 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.69-1.72 (m, 2H), 2.11-2.14 (m, 2H), 2.79-2.84 (m, 2H), 3.27 (s, 1H), 3.58-3.71 (m, 2H), 7.02 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H).
[001926] Example 403
[001927] Synthesis of 4-(((trans)-4-(4-(4H-1,2,4-triazol-4-yl)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (403)
Figure imgf000540_0001
[001928] A mixture of 4-bromoaniline (403A) (1.71 g, 9.94 mmol), N'- formylformohydrazide (2.64 g, 30 mmol), and Et3N (9.74 mL, 69.9 mmol) in pyridine (50 mL) was added TMSCl (19.2 mL, 151 mmol) and stirred at 100 oC overnight. The mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried in ether (30 mL) and the resulting solid was collected by filtration to furnish Compound 403B. LC-MS (ESI) m/z: 224 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.30 (dd, J = 2, 6.8 Hz, 2H), 7.69 (dd, J = 2, 6.8 Hz, 2H), 8.47 (s, 2H).
[001929] Compounds 403C, 403D, 403E, 403F-1 and 403F-2, and 403G were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 393F-1 and 393F-2, and 340F using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 403B with 1,4-dioxane/H2O as solvent, 403C with MeOH as solvent, 403D with TFA as acid and dichloromethane as solvent, 403E, and 403F-1 in lieu of (4- bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and acetone as solvent, 393E, and 340E. Compound 403C: LC-MS (ESI) m/z: 284 [M+H]+. Compound 403D: LC-MS (ESI) m/z: 286 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.61-1.91(m, 8H), 2.31-2.65 (m, 1H), 4.00 (s, 4H), 7.31 (dd, J = 2, 6.4 Hz, 2H), 7.40 (dd, J = 2, 6.4 Hz, 2H), 8.47 (s, 2H). Compound 403E: LC-MS (ESI) m/z: 242 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.96-2.00 (m, 2H), 2.23-2.29 (m, 2H), 2.53-2.57 (m, 4H), 3.10-3.16 (m, 1H), 7.36 (dd, J = 2, 6.4 Hz, 2H), 7.43 (dd, J = 2, 6.4 Hz, 2H), 8.47 (s, 2H). Compound 403F-1: LC-MS (ESI) m/z: 244 [M+H]+; 1H-NMR: (DMSO-d6, 400 MHz): d (ppm) 1.49-1.58 (m, 4H), 1.74-1.87 (m, 4H), 2.51-2.59 (m, 1H), 3.89-3.91 (m, 1H), 7.41 (dd, J = 1.6, 6.4 Hz, 2H), 7.61 (dd, J = 2, 6.8 Hz, 2H), 9.15 (s, 2H). Compound 403F-2: LC-MS (ESI) m/z: 244 [M+H]+; 1H-NMR: (DMSO-d6, 400 MHz): d (ppm) 1.28-1.31 (m, 2H), 1.49-1.53 (m, 2H), 1.76-1.79 (m, 2H), 1.90-1.95 (m, 2H), 2.50-2.53 (m, 1H), 3.46-3.47 (m, 1H), 5.08 (s, 1H), 7.42 (dd, J = 1.6, 6.4 Hz, 2H), 7.59 (dd, J = 2, 6.4 Hz, 2H), 9.16 (s, 2H). Compound 403G: LC- MS (ESI) m/z: 322 [M+H]+.
[001930] To a solution of Compound 403G (290 mg, crude, 0.82 mmol) in DMF (10 ml) was added Intermediate H (263 mg g, 0.82 mmol) and Cs2CO3 (401 mg, 1.23 mmol). The mixture was stirred at 90 oC overnight. After cooled down to room temperature, the mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (methanol in DCM, 10% v/v) to give Compound 403H as a yellow film (190 mg, yield 46%). LC-MS (ESI) m/z: 503 [M+H]+.
[001931] Compounds 403I and 403 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 403H and 403I in lieu of Compounds 8E and 1E. Compound 403I: LC-MS (ESI) m/z: 475 [M+H]+. Compound 403: LC-MS (ESI) m/z: 355 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.51-1.59 (m, 4H), 1.85-1.88 (m, 2H), 2.20-2.49 (m, 2H), 2.65-2.67 (m, 1H), 4.70-4.72 (m, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 9.07 (s, 2H).
[001932] Example 404 [001933] Synthesis of 4-((trans)-3-(4-cyanophenyl)cyclobutoxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (404)
Figure imgf000542_0001
[001934] Compounds 404B, 404C, 404D, 404E, and 404 were synthesized by employing the procedures described for Compounds 393F-1, 90C, 390C, 8F, and 1 using Compounds
404A, 404B, 404C with Pd(PPh3)4 as catalyst at 140 oC, 404D, and 404E in lieu of Compounds 393E, 90B, 390B with Pd2(dba)3 as catalyst at 120 oC, 8E, and 1E. Compound 404B: LC-MS (ESI) m/z: 209 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.77 (d, J = 6.4 Hz, 1H), 1.94- 2.02 (m, 2H), 2.73-2.81 (m, 2H), 2.88-2.96 (m, 1H), 4.25-4.33 (m, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H). Compound 404C: LC-MS (ESI) m/z: 486 [M+H]+. Compound 404D: LC-MS (ESI) m/z: 433 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40 (t, J = 7.2 Hz, 3H), 2.42-2.46 (m, 4H), 3.39-3.48 (m, 1H), 3.78 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 4.94-5.01 (m, 1H), 5.38 (s, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.22 (d. J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H). Compound 404E: LC-MS (ESI) m/z: 405 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 2.42-2.52 (m, 4H), 3.44-3.52 (m, 1H), 3.76 (s, 3H), 5.40 (s, 2H), 5.70 (brs, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.27 (brs, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H).
Compound 404: LC-MS (ESI) m/z: 307 [M+Na]+; 1H-NMR (CD3OD, 500 MHz): d (ppm) 2.66- 2.71 (m, 2H), 2.76-2.82 (m, 2H), 3.84-3.91 (m, 1H), 5.26 (brs, 1H), 7.53 (d, J = 6.8 Hz, 2H), 7.71 (d, J = 6.8 Hz, 2H).
[001935] Example 405
[001936] Synthesis of 4-(((trans)-4-(4-(1H-1,2,4-triazol-1-yl)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (405)
Figure imgf000543_0001
[001937] Compounds 405A, 405B, and 405C were synthesized by employing the procedures described for Compounds 393F-1, 347C, and 90C using Compounds 347A, 405A, and 405B in lieu of Compounds 393E, 347B, and 90B. Compound 405A: LC-MS (ESI) m/z: 159 [M-17]+. Compound 405B: LC-MS (ESI) m/z: 237 [M-17]+. Compound 405C: LC-MS (ESI) m/z: 514 [M+H]+.
[001938] A mixture of Compound 405C (200 mg, 0.39 mmol), 1H-1,2,4-triazole (40 mg, 0.58 mmol), (1R,3R)-N1,N3-dimethylcyclohexane-1,3-diamine (11 mg, 0.08 mmol), CuI (15 mg, 0.08 mmol), and K2CO3 (74 mg, 0.54 mmol) in DMSO (5 mL) was stirred at 120 oC under nitrogen for 16 hours. The mixture was diluted with EtOAc (20 mL) and H2O (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography (MeOH in DCM, from 0% to 6% v/v) to afford Compound 405D. LC-MS (ESI) m/z: 503 [M+H]+.
[001939] Compounds 405E and 405 were synthesized by employing the procedures described for Compounds 1 and 8F using Compounds 405D and 405E in lieu of Compounds 1E and 8E. Compound 405E: LC-MS (ESI) m/z: 383 [M+H]+. Compound 405: LC-MS (ESI) m/z: 355 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.56-1.67 (m, 4H), 1.88-1.92 (m, 2H), 2.24-2.26 (m, 2H), 2.67-2.68 (m, 1H), 4.66-4.68 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 8.21 (s, 1H), 9.24 (s, 1H).
[001940] Example 406
[001941] Synthesis of 4-((2-chloro-4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (406)
Figure imgf000544_0001
[001942] Compounds 406A, 406B, 406C, and 406 were synthesized by employing the procedures described for Intermediate I, Compounds 4B, 8F, and 1 using Compounds 394A with Cs2CO3 as base, 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine, 406A with K2CO3 as base and 1,4-dioxane as solvent, 406B, and 406C in lieu of 4-bromophenol with K2CO3 as base, (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 406A: LC-MS (ESI) m/z: 466 [M+H]+. Compound 406B: LC-MS (ESI) m/z: 547 [M+H]+. Compound 406C: LC-MS (ESI) m/z: 519 [M+H]+. Compound 406: LC-MS (ESI) m/z: 399 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.69-1.72 (m, 2H), 1.85-1.86 (m, 4H), 3.37-3.39 (m, 4H), 7.11-7.14 (m, 1H), 7.26-7.29 (m, 3H), 7.36 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H).
[001943] Example 407
[001944] Synthesis of 4-((2'-chloro-4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (407)
Figure imgf000545_0001
[001945] Compounds 407B, 407C, 407D, 407E, and 407 were synthesized by employing the procedures described for Compounds 316B, 4B, Intermediate I, 8F, and 1 using Compounds 407A with Na2CO3 as base and EtOH as solvent, 407B with K2CO3 as base and DME as solvent, 407C with Cs2CO3 as base,, 407D, and 407E in lieu of Compounds 316A with K2CO3 as base and DMF as solvent, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 4-bromophenol with K2CO3 as base, 8E, and 1E. Compound 407B: LC-MS (ESI) m/z: 274 [M+H]+. Compound 407C: LC-MS (ESI) m/z: 288 [M-H]+. Compound 407D: LC-MS (ESI) m/z: 547 [M+H]+.
Compound 407E: LC-MS (ESI) m/z: 519 [M+H]+. Compound 407: LC-MS (ESI) m/z: 399
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.52-1.64 (m, 6H), 3.19-3.24 (m, 4H), 6.95- 6.99 (m, 1H), 7.02 (s, 1H), 7.08-7.12 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 7.35-7.39 (m, 2H).
[001946] Example 408
[001947] Synthesis of 4-(4-chloro-3-((4-(trifluoromethoxy)benzyl)oxy)phenoxy)-1H- 1,2,3-triazole-5-carboxylic acid (408)
Figure imgf000545_0002
[001948] Compounds 408B, 408C, 408D, and 408 were synthesized by employing the procedures described for Compounds 27B, Intermediate I, 217E, and 8F using 1-(chloromethyl)- 4-(trifluoromethoxy)benzene, Compounds 408A with K2CO3 as base and acetone as solvent, 408B with NMP as solvent, 408C, and 408D in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base and DMF as solvent, 4-bromophenol with DMF as solvent, 217D, and 8E.
Compound 408B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 5.10 (s, 2H), 6.40 (dd, J = 8.4, 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 7.20-7.26 (m, 3H), 7.47-7.51 (m, 2H). Compound 408C: LC-MS (ESI) m/z: 578 [M+H]+. Compound 408D: LC-MS (ESI) m/z: 458 [M+H]+. Compound 408: LC-MS (ESI) m/z: 430 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 5.17 (s, 2H), 6.70 (dd, J = 8.4, 2.4 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.582 (d, J = 8.4 Hz, 2H).
[001949] Example 409
[001950] Synthesis of 4-(((trans)-4-(quinolin-6-yl)cyclohexyl)oxy)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (409)
Figure imgf000546_0001
[001951] Compounds 409B, 409C, 409D, 409E, 409F, 409G, and 409 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 393F-1, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 409A with K2CO3 as base and 1,4-dioxane/H2O as solvent, 409B with THF as solvent, 409C, 409D, 409E, 409F, and 409G in lieu of (4-bromophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 279C, 393E, 90B, 8E, and 1E.
Compound 409B: LC-MS (ESI) m/z: 268 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.97- 2.00 (m, 2H), 2.53-2.54 (m, 2H), 2.78-2.91 (m, 2H), 4.05 (s, 4H), 6.18-6.20 (m, 1H), 7.35-7.38 (m, 1H), 7.75-7.76 (m, 1H), 7.82-7.85 (m, 1H), 8.01-8.03 (m, 1H), 8.10-8.12 (m, 1H), 8.84-8.86 (m, 1H). Compound 409C: LC-MS (ESI) m/z: 270 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.74-1.79 (m, 2H), 1.89-2.00 (m, 6H), 2.75-2.77 (m, 1H), 4.01 (s, 4H), 7.35-7.38 (m, 1H), 7.62-7.63 (m, 2H), 8.03 (d, J = 9.6 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 8.84-8.86 (m, 1H).
Compound 409D: LC-MS (ESI) m/z: 226 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.00- 2.11 (m, 2H), 2.31-2.35 (m, 2H), 2.55-2.63 (m, 4H), 3.19-3.27 (m, 1H), 7.38-7.42 (m, 1H), 7.62- 7.65 (m, 2H), 8.07-8.14 (m, 2H), 8.88-8.89 (m, 1H). Compound 409E: LC-MS (ESI) m/z: 228 [M+H]+; 1H-NMR (CDCl3, 500 MHz): d (ppm) 1.71-1.79 (m, 4H), 1.94-2.04 (m, 4H), 2.70-2.76 (m, 1H), 4.18 (brs, 1H), 7.26-7.38 (m, 1H), 7.63-7.65 (m, 2H), 8.04 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 6 Hz, 1H), 8.85-8.86 (m, 1H). Compound 409F: LC-MS (ESI) m/z: 487 [M+H]+. Compound 409G: LC-MS (ESI) m/z: 459 [M+H]+. Compound 409: LC-MS (ESI) m/z: 339 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.58-1.77 (m, 4H), 1.97-1.99 (m, 2H), 2.27-2.30 (m, 2H), 2.82-2.88 (m, 1H), 4.71 (brs, 1H), 7.70-7.73 (m, 1H), 7.86-7.88 (m, 1H), 7.95-7.97 (m, 1H), 8.03-8.05 (m, 1H), 8.59-8.61 (m, 1H), 8.99-9.00 (m, 1H), 14.77 (brs, 1H).
[001952] Example 410
[001953] Synthesis of 4-(((trans)-4-(quinolin-6-yl)cyclohexyl)thio)-1H-1,2,3-triazole-5- carboxylic acid 2,2,2-trifluoroacetate (410)
Figure imgf000548_0001
[001954] Compounds 410A, 410B, and 410 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 409E-1, 410A, and 410B in lieu of Intermediate H, Compounds 90B, 8E, and 1E. Compound 410A: LC-MS (ESI) m/z: 503 [M+H]+. Compound 410B: LC-MS (ESI) m/z: 475 [M+H]+. Compound 410: LC-MS (ESI) m/z: 355 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.54-1.76 (m, 4H), 1.98-2.06 (m, 2H), 2.23-2.25 (m, 2H), 2.77-2.82 (m, 1H), 3.62 (brs, 1H), 7.50-7.53 (m, 1H), 7.70-7.73 (m, 1H), 7.81 (s, 1H), 7.94-7.96 (m, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.84-8.85 (m, 1H), 15.62 (brs, 1H).
[001955] Example 411
[001956] Synthesis of 4-(((trans)-4-(2-chloro-5- (trifluoromethoxy)phenyl)cyclohexyl)thio)-1H-1,2,3-triazole-5-carboxylic acid (411)
Figure imgf000549_0001
[001957] Compounds 411A, 411B, and 411 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 395F-1, 411A, and 411B in lieu of Intermediate H, Compounds 90B, 8E, and 1E. Compound 411A: LC-MS (ESI) m/z: 570 [M+H]+. Compound 411B: LC-MS (ESI) m/z: 542 [M+H]+. Compound 411: LC-MS (ESI) m/z: 422 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.59-1.70 (m, 4H), 1.98-2.0 (m, 2H), 2.32 (brs, 2H), 3.10-3.16 (m, 1H), 3.66 (brs, 1H), 7.12-7.15 (m, 1H), 7.271-7.277 (m, 1H), 7.49 (d, J = 8.8 Hz, 1 H).
[001958] Example 412
[001959] Synthesis of 4-(((trans)-4-(4-(2-oxopyrrolidin-1-yl)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (412)
Figure imgf000550_0001
[001960] Compounds 412A, 412B, and 412 were synthesized by employing the procedures described for Compounds 301A, 8F, and 1 using pyrrolidin-2-one, Compounds 405C with t- butylbrettphos as ligand and K3PO4 as base and tert-butanol/water as solvent, 412A, and 412B in lieu of Compounds 297B and Intermediate I with X-phos as ligand and Cs2CO3 as base and 1,4- dioxane as solvent, 8E, and 1E. Compound 412A: LC-MS (ESI) m/z: 519 [M+H]+. Compound 412B: LC-MS (ESI) m/z: 491 [M+H]+. Compound 412: LC-MS (ESI) m/z: 371 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.30-1.31 (m, 2H), 1.67-1.69 (m, 4H), 1.98-2.0 (m, 2H), 2.16-2.20 (m, 2H), 2.34-2.35 (m, 2H), 2.57-2.61 (m, 3H), 3.89-3.93 (m, 2H), 7.27-7.29 (d, J = 8.4 Hz, 2H), 7.49-7.51 (d, J = 8.8 Hz, 2H).
[001961] Example 413
[001962] Synthesis of 4-((4'-sulfamoyl-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5- carboxylic acid (413)
Figure imgf000551_0001
[001963] Compounds 413A, 413B, and 413 were synthesized by employing the procedures described for Compounds 4B, 8F, and 1 using 4-sulfamoylphenylboronic acid, Intermediate H with K2CO3 as base and 1,4-dioxane as solvent, Compounds 413A, and 413B in lieu of (4- bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 413A: LC-MS (ESI) m/z: 509 [M+H]+. Compound 413B: LC- MS (ESI) m/z: 983 [2M+Na]+. Compound 413: LC-MS (ESI) m/z: 361 [M+H]+; 1H-NMR (DMSO-d6, 400MHz): d (ppm) 7.04 (d, J = 8.8 Hz, 2H), 7.36 (s, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.80-7.87 (m, 4H).
[001964] Example 414
[001965] Synthesis of 4-(((trans)-4-(4-(dimethylcarbamoyl)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (414)
Figure imgf000552_0001
[001966] To a solution of Compound 405C (600 mg, 1.17 mmol) in DMF (10 mL) was added dimethylamine (3 mL, 5.83 mmol) and Pd(PPh3)2Cl2 (164 mg, 0.234 mmol) and stirred at 120 oC under CO (4 atm) for 8 hours. After cooled down to room temperature, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to give Compound 414A. LC-MS (ESI) m/z: 507 [M+H]+.
[001967] Compounds 414B and 414 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 414A and 414B in lieu of Compounds 8E and 1E. Compound 414B: LC-MS (ESI) m/z: 479 [M+H]+. Compound 414: LC-MS (ESI) m/z: 359 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.56 -1.65 (m, 4H), 1.87 -1.91 (m, 2H), 2.25 (d, J = 8.4 Hz, 2H), 2.64 (s, 1H), 2.92 -2.96 (m, 6H), 4.68 (s, 1H), 7.32 (s, 4H).
[001968] Example 415
[001969] Synthesis of 4-(4-chloro-3-((4-(trifluoromethyl)benzyl)oxy)phenoxy)-1H- 1,2,3-triazole-5-carboxylic acid (415)
Figure imgf000553_0001
[001970] Compounds 415A, 415B, 415C, and 415 were synthesized by employing the procedures described for Compounds 27B, Intermediate I, 217E, and 8F using 1-(chloromethyl)- 4-(trifluoromethyl)benzene, Compounds 408A with K2CO3 as base and acetone as solvent, 415A with NMP as solvent, 415B, and 415C in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base and DMF as solvent, 4-bromophenol with DMF as solvent, 217D, and 8E. Compound 415A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 5.08 (brs, 1H), 5.17 (s, 2H), 6.40 (dd, J = 8.8, 2.8 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H). Compound 415B: LC-MS (ESI) m/z: 562 [M+H]+. Compound 415C: LC-MS (ESI) m/z: 442 [M+H]+. Compound 415: LC-MS (ESI) m/z: 414 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 5.24 (s, 2H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.66-7.72 (m, 4H).
[001971] Example 416
[001972] Synthesis of 4-(((trans)-4-(4-(morpholine-4-carbonyl)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (416)
Figure imgf000554_0001
[001973] Compounds 416A, 416B, and 416 were synthesized by employing the procedures described for Compounds 414A, 8F, and 1 using morpholine, Compounds 416A, and 416B in lieu of dimethylamine, Compounds 8E, and 1E. Compound 416A: LC-MS (ESI) m/z: 549
[M+H]+. Compound 416B: LC-MS (ESI) m/z: 521 [M+H]+. Compound 416: LC-MS (ESI) m/z: 401 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.55 -1.62 (m, 4H), 1.86 -1.90 (m, 2H), 2.23 (d, J = 8.8Hz, 2H), 2.62 -2.63 (m, 1H), 3.22 -3.44 (m, 4H), 3.51 -3.56 (m, 4H), 4.65 (s, 1H), 7.32 (s, 4H), 14.76 (s, 1H).
[001974] Example 417
[001975] Synthesis of 4-(((trans)-4-(4-(piperidine-1-carbonyl)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (417)
Figure imgf000555_0001
[001976] Compounds 417A, 417B, and 417 were synthesized by employing the procedures described for Compounds 414A, 8F, and 1 using piperidine, Compounds 417A, and 417B in lieu of dimethylamine, Compounds 8E, and 1E. Compound 417A: LC-MS (ESI) m/z: 547 [M+H]+. Compound 417B: LC-MS (ESI) m/z: 519 [M+H]+. Compound 417: LC-MS (ESI) m/z: 399 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.49 -1.64 (m, 10H), 1.88 (d, J = 10Hz, 2H), 2.25 (d, J = 8.8Hz, 2H), 2.63 - 2.64 (m, 1H), 3.25 - 3.29 (m, 2H), 3.52 -3.55 (m, 2H), 4.64 (s, 1H), 7.27 - 7.33 (m, 4H), 12.85 (s, 1H), 14.72 (s, 1H).
[001977] Example 418
[001978] Synthesis of 4-(((trans)-4-(4-(1H-pyrazol-1-yl)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (418)
Figure imgf000556_0001
[001979] Compounds 418A, 418B, and 418 were synthesized by employing the procedures described for Compounds 405D, 8F, and 1 using 1H-pyrazole, Compounds 418A, and 418B in lieu of 1H-1,2,4-triazole, Compounds 8E, and 1E. Compound 418A: LC-MS (ESI) m/z: 502 [M+H]+. Compound 418B: LC-MS (ESI) m/z: 474 [M+H]+. Compound 418: LC-MS (ESI) m/z: 354 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.51-1.67 (m, 4H), 1.88 (d, J = 10 Hz, 2H), 2.24 (d, J = 10 Hz, 2H), 2.60-2.66 (m, 1H), 4.63-4.71 (m, 1H), 6.50 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.72(t, J = 8.4 Hz, 3H), 8.42 (d, J = 2.8 Hz, 1H).
[001980] Example 419
[001981] Synthesis of 4-(((trans)-4-(3-chloro-4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (419)
Figure imgf000557_0001
[001982] Compounds 419A, 419B, and 419 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 360D-1 with DEAD as coupling reagent, 419A, and 419B in lieu of Compounds 90B with DIAD as coupling reagent, 8E, and 1E. Compound 419A: LC-MS (ESI) m/z: 554 [M+H]+. Compound 419B: LC-MS (ESI) m/z: 526 [M+H]+. Compound 419: LC-MS (ESI) m/z: 406 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.48-1.66 (m, 4H), 1.84-1.92 (m, 2H), 2.22-2.30 (m, 2H), 2.52-2.62 (m, 1H), 4.60-4.70 (m, 1H), 7.18-7.26 (m, 2H), 7.37 (s, 1H).
[001983] Example 420
[001984] Synthesis of 4-(((trans)-3-(4-cyanophenyl)cyclobutyl)thio)-1H-1,2,3-triazole- 5-carboxylic acid 2,2,2-trifluoroacetate (420)
Figure imgf000558_0001
[001985] Compounds 420A, 420B, and 420 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 304B with dichloromethane as solvent, 420A, and 420B in lieu of Intermediate H, Compounds 90B with THF as solvent, 8E, and 1E. Compound 420A: LC-MS (ESI) m/z: 449 [M+H]+. Compound 420B: LC-MS (ESI) m/z: 419 [M-H]¯. Compound 420: LC-MS (ESI) m/z: 301 [M+H]+; 1H- NMR (CD3OD, 400 MHz): d (ppm) 2.48-2.54 (m, 2H), 2.76-2.83 (m, 2H), 3.94-4.01 (m, 1H), 4.24-4.30 (m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H).
[001986] Example 421
[001987] Synthesis of 4-(4-cyano-3-((4-(trifluoromethoxy)benzyl)oxy)phenoxy)-1H- 1,2,3-triazole-5-carboxylic acid (421)
Figure imgf000558_0002
[001988] Compounds 421B, 421C, 421D, and 421 were synthesized by employing the procedures described for Compounds 27B, Intermediate I, 217E, and 8F using 1-(chloromethyl)- 4-(trifluoromethoxy)benzene, Compounds 421A with K2CO3 as base and acetone as solvent, 421B, 421C, and 421D in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base and DMF as solvent, 4-bromophenol, 217D, and 8E. Compound 421B: LC-MS (ESI) m/z: 310
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.24 (s, 2H), 6.48-6.51 (m, 1H), 6.62 (m, 1H), 7.42-7.44 (m, 2H), 7.51-7.53 (m, 1H), 7.58-7.60 (m, 2H), 10.68 (s, 1H). Compound 421C: LC-MS (ESI) m/z: 569 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.14 (t, J = 7.2 Hz, 3H), 3.70 (s, 3H), 4.19 (q, J = 7.2 Hz, 2H), 4.87 (s, 2H), 5.36 (s, 2H), 6.15-6.16 (m, 1H), 6.37-6.40 (m, 1H), 6.71-6.73 (m, 2H), 7.12-7.14 (m, 2H), 7.24-7.26 (m, 2H), 7.39-7.41 (m, 2H), 7.44-7.46 (m, 1H). Compound 421D: LC-MS (ESI) m/z: 449 [M+H]+. Compound 421: LC-MS (ESI) m/z: 421 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 5.29 (s, 2H), 6.70 (dd, J = 8.8, 2.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.8 Hz, 1H).
[001989] Example 422
[001990] Synthesis of 4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)thio)-1H- 1,2,3-triazole-5-carboxylic acid (422)
Figure imgf000559_0001
422
[001991] Compounds 422A, 422B, and 422 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 272E-1, 422A, and 422B in lieu of Intermediate H, Compounds 90B, 8E, and 1E. Compound 422A: LC-MS (ESI) m/z: 536 [M+H]+. Compound 422B: LC-MS (ESI) m/z: 508 [M+H]+. Compound 422: LC-MS (ESI) m/z: 388 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.55-1.72 (m, 4H), 1.95-1.98 (m, 2H), 2.27-2.30 (m, 2H), 2.62-2.68 (m, 1H), 3.60-3.63 (m, 1H), 7.18 (d, J = 8 Hz, 2H), 7.34 (d, J = 9.2 Hz, 2H).
[001992] Example 423
[001993] Synthesis of 4-(4-chloro-3-((4-cyanobenzyl)oxy)phenoxy)-1H-1,2,3-triazole-5- carboxylic acid (423)
Figure imgf000560_0001
[001994] Compounds 423A, 423B, 423C, and 423 were synthesized by employing the procedures described for Compounds 27B, Intermediate I, 217E, and 8F using 4- (chloromethyl)benzonitrile, Compounds 408A with K2CO3 as base and acetone as solvent, 423A with NMP as solvent, 423B, and 423C in lieu of 2-bromopropane, Compounds 27A with Cs2CO3 as base and DMF as solvent, 4-bromophenol with DMF as solvent, 217D, and 8E. Compound 423A: LC-MS (ESI) m/z: 260 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 5.08 (brs, 1H), 5.16 (s, 2H), 6.41 (dd, J = 8.4, 2.8 Hz, 1H), 6.47 (d, J = 2.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H). Compound 423B: LC-MS (ESI) m/z: 519 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.16 (t, J = 7.2 Hz, 3H), 3.71 (s, 3H), 4.20 (q, J = 7.2 Hz, 2H), 4.88 (s, 2H), 5.35 (s, 2H), 6.20 (d, J = 2.8 Hz, 1H), 6.35-6.37 (m, 1H), 6.75 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.24-7.27 (m, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H). Compound 423C: LC-MS (ESI) m/z: 399 [M+H]+. Compound 423: LC-MS (ESI) m/z: 371 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 5.25 (s, 2H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H).
[001995] Example 424
[001996] Synthesis of 4-(((trans)-4-(2,4-difluorophenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (424)
Figure imgf000561_0001
[001997] Compounds 424B, 424C, 424D, 424E, 424F, 424G, and 424 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 393F-1, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 424A with K3PO4 as base and DME as solvent, 424B with MeOH as solvent, 424C with TFA as acid and dichloromethane as solvent, 424D, 424E, 424F, and 424G in lieu of (4- bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and 1,4-dioxane as solvent, 393E, 90B, 8E, and 1E. Compound 424B: LC-MS (ESI) m/z: 253 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.90 (t, J = 6.8 Hz, 2H), 2.47 (s, 2H), 2.59-2.62 (m, 2H), 4.03 (s, 4H), 5.80-5.82 (m, 1H), 6.75-6.84 (m, 2H), 7.20-7.27 (m, 1H). Compound 424C: LC-MS (ESI) m/z: 255
[M+H]+. Compound 424D: LC-MS (ESI) m/z: 211 [M+H]+. Compound 424E: LC-MS (ESI) m/z: 195 [M-OH]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.57-1.73 (m, 4H), 1.83-1.92 (m, 4H), 2.82-2.89 (m, 1H), 3.73-3.91 (m, 1H), 4.16 (d, J = 7.6 Hz, 1H), 6.73-6.85 (m, 2H), 7.20-7.27 (m, 1H). Compound 424F: LC-MS (ESI) m/z: 472 [M+H]+. Compound 424G: LC-MS (ESI) m/z: 444 [M+H]+. Compound 424: LC-MS (ESI) m/z: 324 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.52-1.68 (m, 4H), 1.80-1.83 (m, 2H), 2.22-2.24 (m, 2H), 2.81-2.87 (m, 1H), 4.62 (s, 1H), 7.00-7.05 (m, 1H), 7.12-7.18 (m, 1H), 7.37-7.43 (m, 1H), 12.81 (s, 1H), 14.70 (s, 1H).
[001998] Example 425
[001999] Synthesis of 4-(((trans)-4-(4-(4H-1,2,4-triazol-3-yl)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (425)
Figure imgf000562_0001
[002000] A mixture of Compound 425A (4 g, 20 mmol) and 1,1-dimethoxy-N,N- dimethylmethanamine (20 mL) was heated at 100 oC overnight. The mixture was concentrated to give a crude Compound 425B. LC-MS (ESI) m/z: 255 [M+H]+.
[002001] To a solution of Compound 425B (5.1 g, 20 mmol) in acetic acid (50 mL) was added hydrazine hydrate (1.2 g, 23.99 mmol). The mixture was stirred at 90 oC for 3 hours and concentrated under reduced pressure. The residue was re-crystallized from ethyl acetate (100 mL) to give Compound 425C. LC-MS (ESI) m/z: 224 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 7.67-7.69 (m, 2H), 7.96-7.98 (m, 2H), 8.49-8.50 (m, 1H).
[002002] To a solution of Compound 425C (3.25 g, 14.5 mmol) in DMF (50 mL) was added NaH (696 mg, 17.4 mmol) in portions at 0 oC, followed by addition of SEMCl (2.9 g, 17.4 mmol). The mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate (200 mL), washed with water (200 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 425D. LC-MS (ESI) m/z: 354 [M+H]+.
[002003] Compounds 425E, 425F, 425G, 425H, 425I, 425J, 425K, and 425 were synthesized by employing the procedures described for Compounds 8B, 141, 279D, 393F-1, 340F, 403H, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2- dioxaborolane, Compounds 425D with K2CO3 as base and 1,4-dioxane/H2O as solvent, 425E with MeOH as solvent, 425F with TFA as acid and dichloromethane as solvent, 425G, 425H, 425I with K2CO3 as base, 425J, and 425K in lieu of (3,4-dichlorophenyl)boronic acid,
Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and 1,4-dioxane as solvent, 393E, 340E, 403G with Cs2CO3 as base, 8E, and 1E. Compound 425E: LC-MS (ESI) m/z: 414 [M+H]+. Compound 425F: LC-MS (ESI) m/z: 416 [M+H]+. Compound 425G: LC-MS (ESI) m/z: 372 [M+H]+. Compound 425H: LC-MS (ESI) m/z: 374 [M+H]+. Compound 425I: LC-MS (ESI) m/z: 452 [M+H]+. Compound 425J: LC- MS (ESI) m/z: 633 [M+H]+. Compound 425K: LC-MS (ESI) m/z: 605 [M+H]+. Compound 425: LC-MS (ESI) m/z: 355 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.57-1.66 (m, 4H), 1.89-1.92 (m, 2H), 2.25-2.27 (m, 2H), 2.60-2.70 (m, 1H), 4.61-4.70 (m, 1H), 7.34-7.44 (m, 2H), 7.92-8.01 (m, 2H), 8.58 (s, 1H), 12.80 (bs, 1H), 14.02-14.35 (m, 1H), 14.72 (s, 1H).
[002004] Example 426
[002005] Synthesis of 4-((trans)-3-(4-(piperidin-1-yl)phenyl)cyclobutoxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (426)
Figure imgf000564_0001
[002006] Compounds 426A, 426B, and 426 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using piperidine, Compounds 404C with Cs2CO3 as base and 1,4-dioxane as solvent, 426A, and 426B in lieu of 1-methylpiperazine, Compounds 6A with tBuONa as base and toluene as solvent, 8E, and 1E. Compound 426A: LC-MS (ESI) m/z: 491 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40 (t, J = 7.2 Hz, 3H), 1.57-1.71 (m, 8H), 2.38-2.46 (m, 4H), 3.11-3.13 (m, 3H), 3.78 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 5.38 (s, 2H), 5.61- 5.66 (m, 1H), 6.89 (d, J = 8.4 Hz, 4H), 7.00-7.04 (m, 2H), 7.24-7.30 (m, 2H). Compound 426B: LC-MS (ESI) m/z: 463 [M+H]+. Compound 426: LC-MS (ESI) m/z: 343 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.81-1.83 (m, 2H), 2.03-2.06 (m, 4H), 2.63-2.69 (m, 2H), 2.74- 2.81 (m, 2H), 3.62-3.65 (m, 4H), 3.81-3.89 (m, 1H), 5.22-5.28 (m, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H).
[002007] Example 427
[002008] Synthesis of 4-(((3aR,5s,6aS)-2-(3,4- dichlorophenyl)octahydrocyclopenta[c]pyrrol-5-yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (427)
Figure imgf000565_0001
[002009] Compounds 427B, 427C, 427D, 427E, 427F, and 427 were synthesized by employing the procedures described for Compounds 57C, 175E, 297C, 90C, 1, and 8F using Compounds 427A, 427B with HCl as acid and 1,4-dioxane as solvent, 1,2-dichloro-4- fluorobenzene, 427C at 100 oC, 427D, 427E, and 425F in lieu of Compounds 57B, and 175D with TFA as acid and dichloromethane as solvent, 297A, 297B at 70 oC, 90B, 1E, and 8E.
Compound 427B: LC-MS (ESI) m/z: 228 [M+H]+. Compound 427C: LC-MS (ESI) m/z: 128 [M+H]+. Compound 427D: LC-MS (ESI) m/z: 272 [M+H]+. Compound 427E: LC-MS (ESI) m/z: 531 [M+H]+. Compound 427F: LC-MS (ESI) m/z: 411 [M+H]+. Compound 427: LC-MS (ESI) m/z: 383 [M+H]+; 1H-NMR (CD3OD, 400 MHz) d (ppm) 1.90-1.96 (m, 2H), 2.28-2.35 (m, 2H), 3.07-3.08 (m, 2H), 3.19-3.22 (m, 2H), 3.31-3.36 (m, 2H), 5.29-5.30 (m, 1H), 6.55-6.58 (m, 1H), 6.74 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H).
[002010] Example 428
[002011] Synthesis of 4-(((3aR,5s,6aS)-2-(3,4- dichlorophenyl)octahydrocyclopenta[c]pyrrol-5-yl)thio)-1H-1,2,3-triazole-5-carboxylic acid (428)
Figure imgf000566_0001
[002012] Compounds 428A, 428B, 428C, and 428 were synthesized by employing the procedures described for Compounds 340F, 340G, 1, and 8F using Compounds 427D, 428A, 428B, and 428C in lieu of Compounds 340E, 340F, 1E, and 8E. Compound 428A: LC-MS (ESI) m/z: 350 [M+H]+. Compound 428B: LC-MS (ESI) m/z: 547 [M+H]+. Compound 428C: LC-MS (ESI) m/z: 427 [M+H]+. Compound 428: LC-MS (ESI) m/z: 399 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.98-2.03 (m, 2H), 2.08-2.12 (m, 2H), 3.03-3.06 (m, 2H), 3.14-3.17 (m, 2H), 3.35-3.39 (m, 2H), 4.09-4.13 (m, 1H), 6.55-6.58 (m, 1H), 6.73 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H).
[002013] Example 429
[002014] Synthesis of 4-((1-(2-chloro-5-(trifluoromethoxy)phenyl)piperidin-4-yl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (429)
Figure imgf000566_0002
[002015] Compounds 429A, 429B, and 429 were synthesized by employing the procedures described for Compounds 403H, 8F, and 1 using Compounds 402B, 428A, and 429B in lieu of Compounds 403G, 8E, and 1E. Compound 429A: LC-MS (ESI) m/z: 555 [M+H]+. Compound 429B: LC-MS (ESI) m/z: 527 [M+H]+. Compound 429: LC-MS (ESI) m/z: 407 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.85-1.87 (m, 2H), 2.12-2.15 (m, 2H), 2.90-2.96 (m, 2H), 3.2-3.24 (m, 2H), 4.8 (m, 1H), 7.01 (d, J = 12 Hz, 1H), 7.08 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H).
[002016] Example 430
[002017] Synthesis of 4-(((trans)-4-(5-chloro-2- (trifluoromethoxy)phenyl)cyclohexyl)thio)-1H-1,2,3-triazole-5-carboxylic acid (430)
Figure imgf000567_0001
[002018] Compounds 430A, 430B, and 430 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 393F-1, 430A, and 430B in lieu of Intermediate H, Compounds 90B, 8E, and 1E. Compound 430A: LC-MS (ESI) m/z: 570 [M+H]+. Compound 430B: LC-MS (ESI) m/z: 542 [M+H]+. Compound 430: LC-MS (ESI) m/z: 422 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.50-1.54 (m, 2H), 1.69 -1.75 (m, 4H), 2.20-2.23 (m, 2H), 2.88-2.89 (m, 1H), 3.61-3.63 (m, 1H), 7.35-7.41 (m, 2H), 7.60-7.61 (m, 1H).
[002019] Example 431
[002020] Synthesis of 4-(((trans)-4-(4-(1,3,4-thiadiazol-2-yl)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (431)
Figure imgf000568_0001
[002021] To a solution of 4-bromobenzohydrazide 431A (460 mg, 2.15 mmol) in toluene (12 mL) was dropped neat formic acid (1.5 g, 32.6 mmol) over 10 minute, heated in a microwave reactor at 120 oC for 90 minutes, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to furnish Compound 431B. LC-MS (ESI) m/z: 243 [M+H]+.
[002022] To a solution of Compound 431B (400 mg, 1.65 mmol) in toluene (12 mL) was added Lawesson’s reagent (1.0 g, 2.47 mmol) and heated in a microwave reactor at 90 oC for 30 minutes and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to furnish Compound 431C. LC-MS (ESI) m/z: 241 [M+H]+. [002023] Compounds 431D, 431E, 431F, 431G, 431H, 431I, 431J, and 431 were synthesized by employing the procedures described for Compounds 8B, 141, 279D, 393F-1 and 393F-2, 340F, 403H, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)- 1,3,2-dioxaborolane, Compounds 431C with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 431D with MeOH as solvent, 431E with TFA as acid and dichloromethane as solvent, 431F, 431G, 431H with K2CO3 as base, 431I, and 431J in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and 1,4-dioxane as solvent, 393E, 340E, 403G with Cs2CO3 as base, 8E, and 1E. Compound 431D: LC-MS (ESI) m/z: 301 [M+H]+. Compound 431E: LC-MS (ESI) m/z: 303 [M+H]+. Compound 431F: LC-MS (ESI) m/z: 259 [M+H]+. Compound 431G: LC-MS (ESI) m/z: 261 [M+H]+. Compound 431H: LC-MS (ESI) m/z: 339 [M+H]+. Compound 431I: LC-MS (ESI) m/z: 520 [M+H]+. Compound 431J: LC-MS (ESI) m/z: 492 [M+H]+. Compound 431: LC- MS (ESI) m/z: 372 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.53-1.69 (m, 4H), 1.88- 1.91 (m, 2H), 2.23-2.31 (m, 2H),2.65-2.70 (m, 1H), 4.67-4.69 (m, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 9.59 (s, 1H).
[002024] Example 432
[002025] Synthesis of 4-(((trans)-4-(4-(piperidin-1-yl)phenyl)cyclohexyl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (432)
Figure imgf000569_0001
[002026] Compounds 432A, 432B, 432C, 432D, and 432 were synthesized by employing the procedures described for Compounds 340F, 340G, 6B, 8F, and 1 using Compounds 405B, 432A, piperidine, 432B with 1,4-dioxane as solvent, 432C, and 432D in lieu of Compounds 340E, 340F, 1-methylpiperazine, 6A with toluene as solvent, 8E, and 1E. Compound 432A: LC- MS (ESI) m/z: 355 [M+Na]+. Compound 432B: LC-MS (ESI) m/z: 530 [M+H]+. Compound 432C: LC-MS (ESI) m/z: 535 [M+H]+. Compound 432D: LC-MS (ESI) m/z: 507 [M+H]+. Compound 432: LC-MS (ESI) m/z: 387 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.50 -1.60 (m, 6H), 1.75 (s, 4H), 1.84 (d, J = 10.8Hz, 2H), 2.20 (d, J = 8.4Hz, 2H), 3.42 (s, 6H), 7.25 (s, 4H).
[002027] Example 433
[002028] Synthesis of 4-(((trans)-4-(4-(1,3,4-oxadiazol-2-yl)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (433)
Figure imgf000570_0001
[002029] A mixture of 4-bromobenzohydrazide (431A) (5.0 g, 23.36 mmol) and triethoxymethane (50 mL) was stirred at 120^ for 12 hours and concentrated under reduced pressure. The residue was slurred in petrolumn ether (200 mL) for 15 minutes and filtered to afford Compound 433A. LC-MS (ESI) m/z: 225 [M+H]+.
[002030] Compounds 433B, 433C, 433D, 433E, 433F, 433G, and 433 were synthesized by employing the procedures described for Compounds 8B, 141, 279D, 393F-1, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 433A with K2CO3 as base and 1,4-dioxane/H2O as solvent, 433B with MeOH as solvent, 433C with TFA as acid and dichloromethane as solvent, 433D, 433E, 433F, and 433G in lieu of (3,4- dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 140 with EtOAc as solvent, 279C with HCl as acid and 1,4-dioxane as solvent, 393E, 90B, 8E, and 1E. Compound 433B: LC-MS (ESI) m/z: 285 [M+H]+. Compound 433C: LC-MS (ESI) m/z: 287 [M+H]+. Compound 433D: LC-MS (ESI) m/z: 243 [M+H]+. Compound 433E: LC-MS (ESI) m/z: 245 [M+H]+. Compound 433F: LC-MS (ESI) m/z: 504 [M+H]+. Compound 433G: LC-MS (ESI) m/z: 476 [M+H]+. Compound 433: LC-MS (ESI) m/z: 356 [M+H]+; 1H NMR (DMSO-d6, 400 MHz) d 1.44-1.65 (m, 4H), 1.85-1.89 (s, 2H), 2.18-2.22 (m, 2H), 2.66-2.69 (m, 1H), 4.68- 4.72 (m, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.95 (d, J = 7.9 Hz, 2H), 9.32 (s, 1H).
[002031] Example 434
[002032] Synthesis of 4-(((trans)-3-(4-(piperidin-1-yl)phenyl)cyclobutyl)thio)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (434)
Figure imgf000571_0001
[002033] Compounds 434A, 434B, and 434 were synthesized by employing the procedures described for Compounds 6B, 8F, and 1 using piperidine, Compounds 420A with Cs2CO3 as base and 1,4-dioxane as solvent, 434A, and 434B in lieu of 1-methylpiperazine, Compounds 6A with t-BuONa as base and toluene as solvent, 8E, and 1E. Compound 434A: LC-MS (ESI) m/z: 507 [M+H]+. Compound 434B: LC-MS (ESI) m/z: 479 [M+H]+. Compound 434: LC-MS (ESI) m/z: 359 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.77-1.83 (m, 2H), 2.00-2.06 (m, 4H), 2.48-2.54 (m, 2H), 2.74-2.82 (m, 2H), 3.59-3.62 (m, 4H), 3.93-4.01 (m, 1H), 4.24-4.30 (m, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H).
[002034] Example 435
[002035] Synthesis of 4-((spiro[4.5]decan-8-ylthio)methyl)-1H-1,2,3-triazole-5- carboxylic acid (435)
Figure imgf000572_0001
[002036] Compounds 435A, 435B, 435C, 435D, 435E, and 435 were synthesized by employing the procedures described for Compounds 340F, 350C, 350D, 243B, 256, and 8F using Compounds 284H, 435A, 435B, 435C with DMF solvent, 435D with TFA as both acid and solvent, and 435E in lieu of Compounds 340E, 350B, 350C, 243A with NMPF solvent, 256D with TFA as acid and dichloromethane as solvent, and 8E. Compound 435A: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.30-1.45 (m, 6H), 1.55-1.63 (m, 6H), 1.69-1.80 (m, 2H), 1.87-1.96 (m, 2H), 3.00 (s, 3H), 4.67-4.75 (m, 1H). Compound 435B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34-1.52 (m, 10H), 1.55-1.60 (m, 4H), 1.80-1.88 (m, 2H), 2.29 (s, 3H) 3.42-3.52 (m, 1H). Compound 435C: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.22-1.54 (m, 14H), 1.78-1.85 (m, 2H), 2.66-2.76 (m, 1H). Compound 435D: LC-MS (ESI) m/z: 444 [M+H]+. Compound 435E: LC-MS (ESI) m/z: 416 [M+H]+. Compound 435: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.17-1.37 (m, 8H), 1.41-1.57 (m, 6H), 1.72-1.84 (m, 2H), 2.54-2.68 (m, 1H), 3.97-4.07 (m, 2H), 13.17 (br, 1H), 15.26,15.64 (brs, 1H).
[002037] Example 436
[002038] Synthesis of 4-(((trans)-4-(4-(piperidin-1-yl)phenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (436)
Figure imgf000573_0001
[002039] Compounds 436A, 436B, and 436 were synthesized by employing the procedures described for Compounds 6B, 8F, and 256 using piperidine, Compounds 405C with X-phos as ligand and Cs2CO3 as base and 1,4-dioxane as solvent, 436A, and 436B with TFA as both base and solvent in lieu of 1-methylpiperazine, Compounds 6A with Xantphos as ligand and t-BuONa as base and toluene as solvent, 8E, and 256D with TFA as base and dichloromethane as solvent. Compound 436A: LC-MS (ESI) m/z: 519 [M+H]+. Compound 436B: LC-MS (ESI) m/z: 491 [M+H]+. Compound 436: LC-MS (ESI) m/z: 371 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.47 -1.64 (m, 6H), 1.76 -1.83 (m, 6H), 2.21 -2.23 (m, 2H), 2.58 -2.66 (m, 1H), 3.11 -3.18 (m, 4H), 4.64 -4.66 (m, 1H), 7.22 -7.50 (m, 4H), 14.71 (s, 1H).
[002040] Example 437
[002041] Synthesis of 4-((4-cyano-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (437)
Figure imgf000574_0001
[002042] To a solution of 2-(4-(trifluoromethoxy)phenyl)acetonitrile (437A, 32.8 g, 163 mmol) and methyl acrylate (28.1 g, 326 mmol) in THF (475 mL) at room temperature was added potassium t-butoxide (55 g, 489 mmol), and stirred at room temperature for one hour, followed by addition of water (2.4 L). The mixture was stirred at 70 °C for 2 hours and extracted with ethyl acetate (500 mL x 3). The combined extracts was dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel (eluted with ethyl acetate in petroleum ether from 5% to 35%) to afford Compound 437B. LC-MS (ESI) m/z: 284 [M+H]+; 1H-NMR (CDCl3, 400 MHz) d (ppm) 2.19-2.34 (m, 2H), 2.45-2.51 (m, 2H), 2.67-2.56 (m, 2H), 2.89-2.95 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.54-7.61 (m, 2H).
[002043] Compounds 437C, 437D, 437E, and 437 were synthesized by employing the procedures described for Compounds 57C, 90C, 8F, and 1 using Compounds 437B, 437C, 437D, and 437E in lieu of Compounds 57B, 90B, 8E, and 1E. Compound 437C: LC-MS (ESI) m/z: 286 [M+H]+; 1H-NMR (CDCl3, 400 MHz) d (ppm) 1.83-1.95 (m, 4H), 2.14-2.26 (m, 4H), 3.61-3.78 (m, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.55-7.49 (m, 2H). Compound 437D: LC-MS (ESI) m/z: 545 [M+H]+; 1H-NMR (CDCl3, 400 MHz) d (ppm) 1.44 (t, J = 7.1 Hz, 3H), 1.90-1.99 (m, 4H), 2.08-2.18 (m, 4H), 3.74 (s, 3H), 4.42 (q, J = 7.1 Hz, 2H), 5.35 (s, 2H), 5.42-5.49 (m, 1H), 6.80 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.21-7.27 (m, 2H), 7.37 (d, J = 8.8 Hz, 2H). Compound 437E: LC-MS (ESI) m/z: 517 [M+H]+. Compound 437: LC-MS (ESI) m/z: 397
[M+H]+; 1H-NMR (DMSO-d6, 400 MHz) d (ppm) 1.94-1.99 (m, 4H), 2.10-2.33 (m, 4H), 5.04 (s, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H).
[002044] Example 438 [002045] Synthesis of 4-(((trans)-4-(4-(methylsulfonyl)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (438)
Figure imgf000575_0001
[002046] To a solution of (4-bromophenyl)(methyl)sulfane (438A, 4.5 g, 22.17 mmol) in dichloromethane (100 mL) was added m-chlorobenzoperoxoic acid (11.44 g, 66.51 mmol) in several portions at 0 oC, stirred at room temperature for 16 hours, and filtered. The filtrate was washed with saturated aqueous NaHCO3 solution (60 mL x 2) and brine (60 mL), dried over anhydrous sulfate, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40% v/v) to furnish Compound 438B. LC-MS (ESI) m/z: 235 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 3.05 (s, 3H), 7.72 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H).
[002047] Compounds 438C, 438D, 438E, 438F-1 and 438F-2, 438G, 438H, and 438 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 393F-1 and 393F-2, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2- (1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2- dioxaborolane, Compounds 438B with K2CO3 as base and 1,4-dioxane/H2O as solvent, 438C, 438D with THF/MeOH as solvent, 438E, 438F-1, 438G, and 438H in lieu of (4- bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140, 279C with 1,4-dioxane as solvent, 393E, 90B, 8E, and 1E. Compound 438C: LC- MS (ESI) m/z: 295 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.94 (t, J = 6.8 Hz, 2H), 2.50 (brs, 2H), 2.65-2.69 (m, 2H), 3.04 (s, 3H), 4.03 (s, 4H), 6.13-6.15 (m, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H). Compound 438D: LC-MS (ESI) m/z: 297 [M+H]+. Compound 438E: LC-MS (ESI) m/z: 253 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.91-2.02 (m, 2H), 2.23-2.26 (m, 2H), 2.52-2.55 (m, 4H), 3.05 (s, 3H), 3.10-3.17 (m, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H). Compound 438F-1: LC-MS (ESI) m/z: 237 [M-17]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.62-1.72 (m, 4H), 1.88-1.98 (m, 4H), 2.61-2.68 (m, 1H), 3.04 (s, 3H), 4.16 (brs, 1H), 7.43 (d, J = 8 Hz, 2H), 7.86 (d, J = 8 Hz, 2H). Compound 438F-2: LC-MS (ESI) m/z: 255 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.40-1.59 (m, 4H), 1.92-1.96 (m, 2H), 2.11- 2.14 (m, 2H), 2.56-2.63 (m, 1H), 3.04 (s, 3H), 3.66-3.74 (m, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H). Compound 438G: LC-MS (ESI) m/z: 514 [M+H]+. Compound 438H: LC- MS (ESI) m/z: 486 [M+H]+. Compound 438: LC-MS (ESI) m/z: 366 [M+H]+; 1H-NMR
(CD3OD, 400 MHz): d (ppm) 1.67-1.78 (m, 4H), 2.00-2.02 (m, 2H), 2.38 (brs, 2H), 2.76-2.81 (m, 1H), 3.10 (s, 3H), 4.78 (brs, 1H), 7.55 (d, J = 8 Hz, 2H), 7.88 (d, J = 8 Hz, 2H).
[002048] Example 439
[002049] Synthesis of 4-(((trans)-4-(4-(methylsulfonyl)phenyl)cyclohexyl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (439)
Figure imgf000577_0001
[002050] Compounds 439A, 439B, and 439 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Intermediate D, Compounds 438F1, 439A, and 439B in lieu of Intermediate H, Compounds 90B, 8E, and 1E. Compound 439A: LC-MS (ESI) m/z: 530 [M+H]+. Compound 439B: LC-MS (ESI) m/z: 502 [M+H]+. Compound 439: LC-MS (ESI) m/z: 382 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.57-1.76 (m, 4H), 1.97-2.00 (m, 2H), 2.29-2.32 (m, 2H), 2.72-2.78 (m, 1H), 3.10 (s, 3H), 3.61-3.67 (m, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H).
[002051] Example 440
[002052] Synthesis of 4-(3-methoxy-3-(4-(trifluoromethoxy)phenyl)cyclobutoxy)-1H- 1,2,3-triazole-5-carboxylic acid (440)
Figure imgf000577_0002
[002053] Compound 440B was synthesized by employing the procedure described for Compounds 263C using Compounds 272A and 440A in lieu of Compounds 263A and 263B, LC-MS (ESI) m/z: 361 [M+Na]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.44-2.49 (m, 3H), 2.88-2.93 (m, 2H), 3.86-3.89 (m, 1H), 4.47 (s, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.29-7.31 (m, 1H), 7.33-7.35 (m, 4H), 7.48 (dd, J = 2.4, 6.8 Hz, 2H).
[002054] To a solution of Compound 440B (500 mg, 1.48 mmol) in THF (5 mL) was added NaH (89 mg, 2.2 mmol) at 0 oC. After stirred at 0 oC for 10 minutes, to the mixture was added CH3I (312 mg, 2.2 mmol) and stirred at room temperature overnight. The mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on silica gel (AcOEt in PE, 17% v/v) to furnish Compound 440C as a colorless film (307 mg, yield 59%). LC-MS (ESI) m/z: 375
[M+Na]+.
[002055] The mixture of Compound 440C (304 mg, 0.86 mmol) and Pd/C (10%, 150 mg) in MeOH (30 mL) was stirred under hydrogen at room temperature (1 atm.) for 12 hours. The mixture was filtered through Celite, concentrated, and purified by column chromatography on silica gel (AcOEt in PE, 50% v/v) to furnish Compound 440D. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.01 (d, J = 6.0 Hz, 1H), 2.32-2.37(m, 2H), 2.83-2.88 (m, 2H), 2.95 (s, 3H), 4.09-4.11 (m, 1H), 7.21 (d, J = 8 Hz, 2H), 7.40 (dd, J = 2.4, 6.8 Hz, 2H).
[002056] Compounds 440E, 440F, and 440 were synthesized by employing the procedures described for Compounds 90C, 8F, and 1 using Compounds 440D, 440E, and 440F in lieu of Compounds 90B, 8E, and 1E. Compound 440E: LC-MS (ESI) m/z: 522 [M+H]+. Compound 440F: LC-MS (ESI) m/z: 494 [M+H]+. Compound 440: LC-MS (ESI) m/z: 374 [M+H]+.1H- NMR (DMSO-d6, 400 MHz) d (ppm) 2.35-2.40 (m, 2H), 2.84-2.89 (m, 2H), 2.90 (s, 3H), 5.15- 5.18 (m, 1H), 7.36 (d, J = 8 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H).
[002057] Example 441
[002058] Synthesis of 4-(((trans)-4-(3-chloro-4-(piperidin-1-yl)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (441)
Figure imgf000579_0001
[002059] To a solution of piperidin-2-one (3.96 g, 40 mmol) in DMF (40 mL) was added NaH (1.6 g, 40 mmol) at 0 oC and stirred at 0 oC under N2 for 5 minutes. To the mixture was added 2-chloro-1-fluoro-4-nitrobenzene (441A, 6.96 g, 40 mmol) was added, stirred at room temperature for 15 hours, diluted with water (40 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, from 50% to 80% v/v) to furnish Compound 441B. LC-MS (ESI) m/z: 255 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.02 (s, 4H), 2.60 (s, 2H), 3.57 (d, J = 20 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 8.19 (d, J1 = 2.8 Hz, J2= 8.8 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H).
[002060] Compounds 441C, 441D, 441E, 441F, 441G, 441H, 441I, 441J, 441K, and 440 were synthesized by employing the procedures described for Compounds 186E, 56B, 8B, 141, 279D, 393F-1 and 393F-2, 90C, 182B, 8F, and 1 using Compounds 441B, 441C with aqeous HBr solution (47%) and CuBr2, 4,4,5,5-tetramethyl-2- (1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2- dioxaborolane and 441D with K2CO3 as base, 441E, 441F with TFA solution (4 M) as acid and dichloromethane as solvent, 441G, 441H, 441I, 441J, and 441K in lieu of Compounds 186D, 56A with aqeous HCl solution (47%) and CuCl, 3,4-dichlorophenylboronic acid and 8A with Cs2CO3 as base, 140, 279C with HCl as acid and 1,4-dioxane as solvent, 393E, 90B, 182A, 8E, and 1E. Compound 441C: LC-MS (ESI) m/z: 225 [M+H]+. Compound 441D: LC-MS (ESI) m/z: 288 [M+H]+. Compound 441E: LC-MS (ESI) m/z: 348 [M+H]+. Compound 441F: LC-MS (ESI) m/z: 350 [M+H]+. Compound 441G: LC-MS (ESI) m/z: 306 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.87-1.96 (m, 6H), 2.21-2.25 (m, 2H), 2.50-2.59 (m, 6H), 2.98-3.05 (m, 1H), 3.44-3.59 (m, 2H), 7.19 (s, 2H), 7.35 (s, 1H). Compound 441H: LC-MS (ESI) m/z: 308 [M+1]+. 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.37-1.54 (m, 1H), 1.65-1.68 (m, 3H), 1.81-1.95 (m, 8H), 2.49-2.58 (m, 3H), 3.44-3.59 (m, 2H), 4.13 (s, 1H), 7.14 (s, 1H), 7.26 (s, 1H), 7.34 (s, 1H).
Compound 441I: LC-MS (ESI) m/z: 567 [M+H]+. Compound 441J: LC-MS (ESI) m/z: 553 [M+H]+. Compound 441K: LC-MS (ESI) m/z: 525 [M+H]+. Compound 441: LC-MS (ESI) m/z: 405 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) d (ppm) 1.51-1.66 (m, 10H), 1.81-1.84 (m, 2H), 2.20-2.21(m, 2H), 2.53-2.56 (m, 1H), 2.86 (t, J = 5.6 Hz, 4H), 4.65 (s, 1H), 7.05 (d, J =8.4 Hz, 1H), 7.16 (dd, J1 = 1.6 Hz, J2= 8.0 Hz, 1H), 7.27 (s, 1H).
[002061] Example 442
[002062] Synthesis of 4-(((cis)-4-(3-chloro-4-(piperidin-1-yl)phenyl)cyclohexyl)thio)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (442-1) and 4-(((trans)-4-(3- chloro-4-(piperidin-1-yl)phenyl)cyclohexyl)thio)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2- t
Figure imgf000580_0001
[002063] Compounds 442A, 442B, 442C, 442-1, and 442-2 were synthesized by employing the procedures described for Compounds 90C, 182B, 8F, and 1 using Compounds 441H, 442A, 442B, and 442C in lieu of Compounds 90B, 182A, 8E, and 1E. Compound 442A: LC-MS (ESI) m/z: 583 [M+H]+. Compound 442B: LC-MS (ESI) m/z: 569 [M+H]+. Compound 442C: LC-MS (ESI) m/z: 541 [M+H]+. Compound 442-1: LC-MS (ESI) m/z: 421 [M+H]+; 1H-NMR (DMSO- d6, 400 MHz) d (ppm) 1.51-1.52 (m, 2H), 1.61-1.68 (m, 8H), 1.95 (s, 4H), 2.53-2.59 (m, 1H), 2.87 (t, J = 4.8Hz, 4H), 4.11 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 7.15 (dd, J1 = 2 Hz, J2 = 8.4 Hz, 1H), 7.22 (s, 1H). Compound 442-2: LC-MS (ESI) m/z: 421 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) d (ppm) 1.47-1.63 (m, 10H), 1.80-1.83 (m, 2H), 2.18 (s, 2H), 2.49 (s, 1H), 2.86 (s, 4H), 3.55 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 7.25 (s, 1H).
[002064] Example 443
[002065] Synthesis of 4-(((1r,4r)-4-methyl-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (443)
Figure imgf000581_0001
[002066] A mixture of Compound 437B (13.0 g, 45.95 mmol), ethylene glycol (2.9 g, 46.85 mol), and p-TSOH (111 mg, 0.643 mmol) in toluene (250 mL) was heated at reflux for 6 hours with continued removal of water by using a Dean-Stark trap. The mixture was concentrated in vacuum and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish Compound 443A. LC-MS (ESI) m/z: 328
[M+H]+. [002067] To a solution of Compound 443A (8 g, 24.45 mmol) in toluene (160 mL) was dropped a solution of diisobutylaluminum hydride in toluene (1 M, 37 mL, 37 mmol) at -78 °C and stirred at -78 °C for 2 hours. The mixture was quenched with ethyl acetate (300 mL) and water (10 mL), stirred at room temperature for 20 minutes, washed with diluted HCl solution (2 N, 200 mL) and water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a crude Compound 443B. LC-MS (ESI) m/z: 331 [M+H]+; 1H- NMR (CDCl3, 400 MHz) d (ppm) 1.66-1.77 (m, 4H), 2.08-2.17 (m, 4H), 3.93-3.97 (m, 4H), 7.22 (d, J = 8.7 Hz, 2H), 7.32-7.36 (m, 2H), 9.41 (s, 1H).
[002068] To a solution of N2H4-H2O (6.54 g, 121.2 mmol) in ethylene glycol (20 mL) was dropped Compound 443B (4 g, 12.12 mmol) and stirred at room temperature for 1 hour followed by addition of powdered KOH (2.71 g, 48.48 mmol). After heated at reflux for 4 hours, the mixture was cool down to room temperature, diluted with H2O (300 mL), and extracted with ethyl acetate (200 mL x 2). The combined extracts was washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish Compound 443C. LC-MS (ESI) m/z: 317 [M+H]+; 1H-NMR (CDCl3, 400 MHz) d (ppm) 1.22 (s, 3H), 1.51– 1.59 (m, 2H), 1.65– 1.83 (m, 4H), 2.10– 2.22 (m, 2H), 3.88– 4.01 (m, 4H), 7.15 (d, J = 8.5 Hz, 2H), 7.33– 7.43 (m, 2H).
[002069] Compounds 443D, 443E, 443F-1, 443F-2, 443G, and 443 were synthesized by employing the procedures described for Compounds 279D, 57C, 90C, 8F, and 1 using
Compounds 443C with TFA as acid and dichloromethane as solvent, 443D with EtOH as solvent, 443E with toluene as solvent, 443F-1, and 443G in lieu of Compounds 279C with HCl as acid and 1,4-dioxane as solvent, 57B with MeOH as solvent, 90B with THF as solvent, 8E, and 1E. Compound 443D: LC-MS (ESI) m/z: 273 [M+H]+; 1H-NMR (CDCl3, 400 MHz) d (ppm) 1.34 (s, 3H), 1.95– 1.99 (m, 2H), 2.24– 2.35 (m, 2H), 2.40– 2.45 (m, 4H), 7.23 (d, J = 8.5 Hz, 2H), 7.41– 7.48 (m, 2H). Compound 443E: LC-MS (ESI) m/z: 257 [M-OH]+.
Compound 443F-1: LC-MS (ESI) m/z: 534 [M+H]+; 1H-NMR (CDCl3, 400 MHz) d (ppm) 1.15 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H), 1.42 (t, J = 7.1 Hz, 4H), 1.80– 1.93 (m, 2H), 2.15– 2.29 (m, 2H), 3.76 (s, 3H), 4.40 (q, J = 7.1 Hz, 2H), 5.11– 5.25 (m, 3H), 6.71 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H). Compound 443F-2: LC-MS (ESI) m/z: 534 [M+H]+; 1H-NMR (CDCl3, 400 MHz) d (ppm) 1.19 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.63– 1.90 (m, 8H), 3.79 (s, 3H), 4.37 (q, J = 7.1 Hz, 2H), 5.34 (s, 2H), 5.09– 5.13 (m, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.27 (t, J = 4.3 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H). Compound 443G: LC-MS (ESI) m/z: 506 [M+H]+. Compound 443: LC-MS (ESI) m/z: 386 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) d (ppm) 1.18 (s, 3H), 1.47– 1.55 (m, 4H), 1.85– 2.02 (m, 2H), 2.20– 2.31 (m, 2H), 4.75 (s, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 12.85 (s, 1H), 14.72 (s, 1H).
[002070] Example 444
[002071] Synthesis of 4-(((1s,4s)-4-methyl-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (444)
Figure imgf000583_0001
[002072] Compounds 444A and 444 were synthesized by employing the procedures described for Compounds 8F and 1 using Compounds 443F-2 and 444A in lieu of Compounds 8E and 1E. Compound 444A: LC-MS (ESI) m/z: 506 [M+H]+. Compound 444: LC-MS (ESI) m/z: 386 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) d (ppm) 1.22 (s, 3H), 1.72– 2.02 (m, 8H), 4.66 (s, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.9 Hz, 2H), 12.90 (s, 1H), 14.71 (s, 1H).
[002073] Example 445
[002074] Synthesis of 4-(4-chloro-3-cyclopropoxyphenoxy)-1H-1,2,3-triazole-5- carboxylic acid (445)
Figure imgf000583_0002
[002075] Compounds 445A, 445B, 445C, 445D, 445E, and 445 were synthesized by employing the procedures described for Compounds 27B, 27C, 236D, Intermediate I, 217E, and 8F using bromocyclopropane, Compounds 218A, 445A, 445B, 445C, 445D, and 445E in lieu of 2-bromopropane, Compounds 27A, 27B, 236C, 4-bromophenol, 217D, and 8E. Compound 445A: 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.86-0.87 (m, 4H), 3.78-3.80 (m, 1H), 7.04 (dd, J = 8.4, 2.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H). Compound 445B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.85-0.87 (m, 4H), 1.36 (s, 12H), 3.89-3.90 (m, 1H), 7.35 (s, 2H), 7.66 (s, 1H). Compound 445C: LC-MS (ESI) m/z: 185 [M+H]+. Compound 445D: LC-MS (ESI) m/z: 444 [M+H]+. Compound 445E: LC-MS (ESI) m/z: 324 [M+H]+. Compound 445: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.73-0.77 (m, 2H), 0.78-0.85 (m, 2H), 3.81-3.86 (m, 1H), 6.67 (dd, J = 8.8, 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H).
[002076] Example 446
[002077] Synthesis of 4-(((trans)-4-(4-cyclopropoxyphenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (446)
Figure imgf000584_0001
[002078] Compounds 446B, 446C, 446D, 446E, 446F, 446G, and 446 were synthesized by employing the procedures described for Compounds 8B, 141, 279D, 393F-1 and 393F-2, 90C, 380E, and 8F using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2- dioxaborolane, Compounds 446A with K2CO3 as base and 1,4-dioxane/H2O as solvent, 446B, 446C with TFA as acid amd dichloromethane as solvent, 446D, 446E, 446F with THF as solvent, and 446G in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, 140, 279C with HCl as acid and 1,4-dioxane as solvent, 393E, 90B, 380D with MeOH as solvent, and 8E. Compound 446B: LC-MS (ESI) m/z: 273 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.76-0.77 (m, 4H), 1.91 (t, J = 6.4 Hz, 2H), 2.45-2.46 (m, 2H), 2.62-2.66 (m, 2H), 3.70-3.74 (m, 1H), 4.01-4.02 (m, 4H), 5.88-5.90 (m, 1H), 6.98 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H). Compound 446C: LC-MS (ESI) m/z: 275 [M+H]+.
Compound 446D: LC-MS (ESI) m/z: 231 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.76- 0.77 (m, 4H), 1.86-1.97 (m, 2H), 2.18-2.23 (m, 2H), 2.48-2.52 (m, 4H), 2.95-3.03 (m, 1H), 3.69- 3.74 (m, 1H), 7.01 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H). Compound 446E: LC-MS (ESI) m/z: 215 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.75-0.76 (m, 4H), 1.64-1.70 (m, 4H), 1.85-1.91 (m, 4H), 2.47-2.54 (m, 1H), 3.68-3.73 (m, 1H), 4.10-4.15 (m, 1H), 6.98 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H). Compound 446F: LC-MS (ESI) m/z: 492 [M+H]+. Compound 446G: LC-MS (ESI) m/z: 372 [M+H]+. Compound 446: LC-MS (ESI) m/z: 366 [M+Na]+; 1H- NMR (CD3OD, 400 MHz): d (ppm) 0.64-0.79 (m, 4H), 1.58-1.73 (m, 4H), 1.93-1.96 (m, 2H), 2.33-2.35 (m, 2H), 2.53-2.60 (m, 1H), 3.72-3.76 (m, 1H), 4.73-4.75 (m, 1H), 6.96 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H).
[002079] Example 447
[002080] Synthesis of 4-(((trans)-4-(4-fluorophenyl)cyclohexyl)oxy)-1H-1,2,3-triazole- 5-carboxylic acid (447)
Figure imgf000586_0001
[002081] Compounds 447B, 447C, 447D, 447E, 447F, 447G, and 447 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 393F-1 and 393F-2, 90C, 1, and 8F using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 447A with 1,4-dioxane/H2O as solvent, 447B, 447C with TFA as acid amd dichloromethane as solvent, 447D, 447E, 447F, and 447G in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 4A with toluene/EtOH/H2O as solvent, 140, 279C with HCl as acid and 1,4- dioxane as solvent, 393E, 90B, 1E, and 8E. Compound 447B: LC-MS (ESI) m/z: 235 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.90-1.93 (m, 2H), 2.46 (m, 2H), 2.61-2.65 (m, 2H), 4.02 (s, 4H), 5.91-5.93 (m, 1H), 6.95-7.00 (m, 2H), 7.32-7.36 (m, 2H). Compound 447C: LC-MS (ESI) m/z: 237 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.60-1.79 (m, 8H), 2.46-2.47 (m, 1H), 3.91 (s, 4H), 6.87-6.91 (m, 2H), 7.09-7.13 (m, 2H). Compound 447D: LC-MS (ESI) m/z: 193 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.81-1.87 (m, 2H), 2.11-2.15 (m, 2H), 2.42- 2.46 (m, 4H), 2.92-2.98 (m, 1H), 6.91-6.95 (m, 2H), 7.11-7.14 (m, 2H). Compound 447E: LC- MS (ESI) m/z: 177 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.55-1.63 (m, 4H), 1.74- 1.84 (m, 4H), 2.42-2.45 (m, 1H), 4.04-4.06 (m, 1H), 6.88-6.92 (m, 2H), 7.10-7.13 (m, 2H).
Compound 447F: LC-MS (ESI) m/z: 454 [M+H]+. Compound 447G: LC-MS (ESI) m/z: 426 [M+H]+. Compound 447: LC-MS (ESI) m/z: 306 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.51-1.60 (m, 4H), 1.83-1.86 (m, 2H), 2.22-2.25 (m, 2H), 2.51-2.52 (m, 1H), 4.63 (m, 1H), 6.87-6.91 (m, 2H), 7.13-7.17 (m, 2H).
[002082] Example 448
[002083] Synthesis of 4-(4-chloro-3-cyclobutoxyphenoxy)-1H-1,2,3-triazole-5- c
Figure imgf000587_0001
[002084] Compounds 448A, 448B, 448C, 448D, 448E, and 448 were synthesized by employing the procedures described for Compounds 90C, 27C, 236D, Intermediate I, 217E, and 8F using cyclobutanol, Compounds 218A, 448A, 448B, 448C, 448D, and 445E in lieu of Compounds 90B, Intermedaite H, 27B, 236C, 4-bromophenol, 217D, and 8E. Compound 448A: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.95-2.01 (m, 1H), 2.14-2.25 (m, 2H), 2.28-2.34 (m, 1H), 3.96-4.01 (m, 1H), 4.06-4.12 (m, 1H), 5.77-5.79 (m, 1H), 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H). Compound 448B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.33 (s, 12H), 1.92-2.01 (m, 1H), 2.09-2.34 (m, 3H), 3.95-4.01 (m, 2H), 5.90-5.92 (m, 1H), 7.34-7.38 (m, 2H), 7.60 (s, 1H). Compound 448C: LC-MS (ESI) m/z: 199 [M+H]+.
Compound 448D: LC-MS (ESI) m/z: 458 [M+H]+. Compound 448E: LC-MS (ESI) m/z: 338 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.21-1.26 (m, 3H), 1.68-1.90 (m, 2H), 2.11- 2.21 (m, 2H), 2.40-2.48 (m, 2H), 4.28-4.30 (m, 2H), 4.64-4.71 (m, 1H), 6.56-6.59 (m, 1H), 6.66 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.8, 2.8 Hz, 1H). Compound 448: LC-MS (ESI) m/z: 310
[M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.69-1.79 (m, 1H), 1.83-1.91 (m, 1H), 2.12- 2.22 (m, 2H), 2.42-2.49 (m, 2H), 4.66-4.79 (m, 1H), 6.64 (dd, J = 8.8, 2.8 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H).
[002085] Example 449 [002086] Synthesis of 4-(3-(4-(trifluoromethoxy)phenyl)cyclobutoxy)-1H-1,2,3-triazole- 5-carboxylic acid (449)
Figure imgf000588_0001
[002087] Compounds 449A, 449B, 449C, and 449 were synthesized by employing the procedures described for Compounds 440D, 90C, 263D, and 8F using Compounds 440B, 449A, 449B, and 449C in lieu of Compounds 440C, 90B, 263C, and 8E. Compound 449A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.04 (d, J = 6.0 Hz, 1H), 2.35 (s, 1H), 2.37-2.42 (m, 2H), 2.95-3.00 (m, 2H), 4.16-4.18 (m, 1H), 7.21 (d, J = 8 Hz, 2H), 7.47 (dd, J = 2, 6.4 Hz, 2H). Compound 449B: LC-MS (ESI) m/z: 512 [M+Na]+. Compound 449C: LC-MS (ESI) m/z: 372 [M+H]+. Compound 449: LC-MS (ESI) m/z: 344 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 2.27-2.35 (m, 1H), 2.60-2.66 (m, 1H), 2.70-2.79 (m, 1H), 2.92-2.99 (m, 1H), 3.19-3.23 (m, 0.5H), 3.76-3.81 (m, 0.5H), 5.03- 5.07 (m, 0.5H), 5.23-5.28 (m, 0.5H), 7.19-7.24 (m, 2H), 7.38-7.42 (m, 2H).
[002088] Example 450
[002089] Synthesis of 4-((4'-(1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (450)
Figure imgf000589_0001
[002090] A mixture of 1H-pyrazole (680 mg, 10 mmol), 1-bromo-4-fluorobenzene (450A, 3.50 g, 20 mmol), and K3PO4 (6.37 g, 30 mmol) in NMP (20 mL) was heated in a sealed tube at 200 °C for 2 hours. The mixture was cooled down to room temperature, quenched with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with column chromatography on silica gel (ethyl acetate in petroleum ether, 10%, v/v) to furnish Compound 450B. LC-MS (ESI) m/z: 223 [M+H]+.
[002091] Compounds 450C, 450D, 450E, and 450 were synthesized by employing the procedures described for Compounds 27C, 4B, 8F, and 1 using Compounds 450B, 450C, Intermediate I with Na2CO3 as base and 1,4-dioxane as solvent, 450D, and 450E in lieu of 2- bromopropane, Compounds 27B, (3,4-dichlorophenyl)boronic acid, 4-bromophenylboronic acid and 4A with Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 450C: LC-MS (ESI) m/z: 271 [M+H]+. Compound 450D: LC-MS (ESI) m/z: 496 [M+H]+. Compound 450E: LC-MS (ESI) m/z: 468 [M+H]+. Compound 450: LC-MS (ESI) m/z: 348 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 6.56 (t, J = 2.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 8.54 (t, J = 2.0 Hz, 1H).
[002092] Example 451
[002093] Synthesis of 4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)amino)-1H- 1,2,3-triazole-5-carboxylic acid (451)
Figure imgf000590_0001
[002094] A mixture of Compound 272J (2.6 g, 10 mmol) and NH2OH.HCl (690 mg, 10 mmol) in ethanol (20 mL) was stirred at 80 °C for 2 hours. The mixture was concentrated to afford a crude Compound 451A. LC-MS (ESI) m/z: 274 [M+H]+.
[002095] To a mixture of Compound 451A (3.7 g, 10 mmol) and Ranny-Ni (1 g) in EtOH (50 mL) was dropped a solution of N2H4 in water (85%, 5 ml) at room temperature. The mixture was stirred at room temperature for 16 hours, filtered, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 30% to 100% v/v) to afford Compound 451B. LC-MS (ESI) m/z: 260 [M+H]+.
[002096] Compounds 451C-1, 451C-2, 451D, and 451 were synthesized by employing the procedures described for Compounds 6B, 1, and 8F using Intermediate A, Compounds 451B with K3PO4 as base and NMP as solvent, 451C-1, and 451D in lieu of Compounds 6A, 1- methylpiperazine with tBuONa as base and toluene as solvent, 1E, and 8E. Compound 451C-1: LC-MS (ESI) m/z: 519 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.09-1.26 (m, 4H), 1.33- 1.38 (m, 3H), 1.74-1.82 (m, 4H), 2.33-2.37 (m, 1H), 3.11-3.14 (m, 1H), 3.72 (s, 3H), 4.31-4.35 (m, 2H), 5.39-5.41 (m, 3H), 6.82-6.85 (m, 2H), 7.04-7.19 (m, 6H). Compound 451C-2: LC-MS (ESI) m/z: 519 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42-1.46 (m, 3H), 1.50-1.72 (m, 8H), 2.48-2.52(m, 1H), 3.79-3.83 (m, 4H), 4.40-4.47 (m, 2H), 5.44 (s, 2H), 6.23-6.26 (m, 1H), 6.87 (d, J = 8.8 Hz, 2H), 7.12-7.14 (m, 4H), 7.23-7.26 (m, 2H). Compound 451D: LC-MS (ESI) m/z: 399 [M+H]+. Compound 451: LC-MS (ESI) m/z: 371 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.48-1.53 (m, 2H), 1.63-1.72 (m, 2H), 1.96-2.02 (m, 2H), 2.21-2.24 (m, 2H), 2.63-2.69 (m, 1H), 2.31-2.45 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H) 7.34-7.38 (m, 2H).
[002097] Example 452
[002098] Synthesis of 4-(((cis)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)amino)-1H- 1,2,3-triazole-5-carboxylic acid (452)
Figure imgf000591_0001
[002099] Compounds 452A, and 452 were synthesized by employing the procedures described for Compounds 1 and 8F using 451C-2 and 452A in lieu of Compounds 1E and 8E. Compound 452A: LC-MS (ESI) m/z: 399 [M+H]+. Compound 452: LC-MS (ESI) m/z: 371 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.71-1.87 (m, 6H), 2.01-2.04 (m, 2H), 2.69- 2.72 (m, 1H), 3.87(s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H).
[002100] Example 453
[002101] Synthesis of 4-((4-hydroxy-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid (453)
Figure imgf000591_0002
[002102] Compounds 453A, 453B, 453C, and 453 were synthesized by employing the procedures described for Compounds 263D, 90C, 380E, and 8F using Compounds 272C, 453A with toluene as solvent, 453B with THF as solvent, and 453C in lieu of Compounds 263C, 90B with THF as solvent, 380D with MeOH as solvent, and 8E. Compound 453A: 1H-NMR (DMSO- d6, 400 MHz): d (ppm) 1.57-1.64 (m, 5H), 1.70-1.74 (m, 3H), 3.90-3.54 (m, 1H), 4.47 (m, 1H), 4.84 (s, 1H), 7.25 (d, J = 8Hz, 2H), 7.57 (d, J = 8Hz, 2H). Compound 453B: LC-MS (ESI) m/z: 536 [M+H]+. Compound 453C: LC-MS (ESI) m/z: 416 [M+H]+. Compound 453: LC-MS (ESI) m/z: 388 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.44-1.47(m, 2H), 1.82-1.85 (m, 2H), 1.96-2.02 (m, 2H), 2.07-2.11 (m, 2H), 4.94 (s, 1H), 5.05 (s, 1H), 7.27 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.8Hz, 2H).
[002103] Example 454
[002104] Synthesis of 4-((4'-(trifluoromethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (454)
Figure imgf000592_0001
453 454
[002105] A mixture of Compound 453 (0.04 g, 0.103 mmol) and BF3-Et2O (0.035 g, 0.246 mmol) was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified with preparative HPLC to yield Compound 454. LC- MS (ESI) m/z: 370 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.96-2.00 (m, 1H), 2.06- 2.08 (m, 1H), 2.37-2.42 (m, 1H), 2.49-2.55 (m, 2H), 2.69-2.73 (m, 1H), 4.93 (s, 1H), 6.12 (s, 1H), 7.30 (d, J = 8Hz, 2H), 7.54 (d, J = 8Hz, 2H).
[002106] Example 455
[002107] Synthesis of 4-(((cis-3a,6a)-5-(4- (trifluoromethoxy)phenyl)octahydropentalen-2-yl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (455)
Figure imgf000593_0001
[002108] Compound 455A was synthesized by employing the procedure described for Compounds 263C using Compounds 272A and tetrahydropentalene-2,5(1H,3H)-dione in lieu of Compounds 263A and 263B, LC-MS (ESI) m/z: 283 [M-OH]+.
[002109] To a solution of Compound 455A (2 g, 6.66 mmol) in toluene (40 mL) was added 4-methylbenzenesulfonic acid (115 mg, 0.666 mmol) and stirred at 110 oC for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to yield Compound 455B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.06-2.12 (m, 1H), 2.36-2.37 (m, 1H), 2.50-2.63 (m, 3H), 3.06-3.18 (m, 2H), 3.61-3.66 (m, 1H), 6.04 (d, J = 3.6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H).
[002110] Compounds 455C, 455D, 455E, 455F, and 455 were synthesized by employing the procedures described for Compounds 141, 393F-1, 90C, 8F, and 1 using Compounds 455B, 455C, 455D with DEAD as coupling reagent, 455E, and 455F in lieu of Compounds 140, 393E, 90B with DIAD as coupling reagent, 8E, and 1E. Compound 455C: LC-MS (ESI) m/z: 285 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.42-1.50 (m, 2H), 2.13-2.18 (m, 2H), 2.44-2.50 (m, 2H), 2.55-2.62 (m, 2H), 2.83-2.89 (m, 2H), 3.12-3.22 (m, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H). Compound 455D: LC-MS (ESI) m/z: 269 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.50-1.66 (m, 4H), 2.05-2.11 (m, 2H), 2.27-2.34 (m, 2H), 2.54-2.60 (m, 2H), 2.97-3.06 (m, 1H), 4.37-4.40 (m, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H).
Compound 455E: LC-MS (ESI) m/z: 546 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.26- 1.28 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.65-1.71 (m, 2H), 1.96-2.02 (m, 2H), 2.25-2.32 (m, 2H), 2.59-2.65 (m, 2H), 3.00-3.09 (m, 1H), 3.79 (s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 5.27 (s, 2H), 5.75- 5.80 (m, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.20-7.24 (m, 4H). Compound 455F: LC-MS (ESI) m/z: 518 [M+H]+. Compound 455: LC-MS (ESI) m/z: 420 [M+Na]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.28-1.36 (m, 2H), 1.86-1.97 (m, 4H), 2.26-2.29 (m, 2H), 2.67-2.71 (m, 2H), 3.00-3.09 (m, 1H), 5.20-5.26 (m, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 12.95 (bs, 1H), 14.74 (bs, 1H).
[002111] Example 456
[002112] Synthesis of 4-((((trans)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)methyl)-1H-1,2,3-triazole-5-carboxylic acid (456)
Figure imgf000594_0001
[002113] To a solution of compound 272E-2 (3.76 g, 14.45 mmol) in THF (100 mL) was added 18-crown-6 (9.55 g, 36.13 mmol) and NaH (60% oil dispersion, 1.45 g, 36.13 mmol) at 0 oC and stirred at 0 oC for 20 minutes. To the solution was added 3-bromoprop-1-yne (8.59 g, 72.25 mmol) and stirred at room temperature overnight. It was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with column chromatography on silica gel (ethyl acetate in petroleum ether, from 15% to 25 %, v/v) to furnish Compound 456A. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.35-1.56 (m, 4H), 1.92-2.00 (m, 2H), 2.16-2.24 (m, 2H), 2.44 (t, J = 2.0 Hz, 1H), 2.50-2.58 (m, 1H), 3.52-3.60 (m, 1H), 4.24 (t, J = 2.0 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H).
[002114] Compounds 456B, 456C, 456D, and 456 were synthesized by employing the procedures described for Compounds 372E, 151B, 8F, and 1 using Compounds 456A, 456B, 456C with DEAD as coupling reagent, and 456D in lieu of Compounds 372D, 151A, 8E, and 1E. Compound 456B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 1.38-1.58 (m, 4H), 1.93- 2.00 (m, 2H), 2.16-2.24 (m, 2H), 2.50-2.58 (m, 1H), 3.50-3.58 (m, 1H), 4.23-4.40 (m, 2H), 4.36 (s, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H). Compound 456C: LC-MS (ESI) m/z: 534 [M+H]+. Compound 456D: LC-MS (ESI) m/z: 504 [M-H]-. Compound 456: LC-MS (ESI) m/z: 386 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.24-1.38 (m, 2H), 1.39-1.52 (m, 2H), 1.76-1.85 (m, 2H), 2.04-2.14 (m, 2H), 2.53-2.60 (m, 1H), 3.40-3.48 (m, 1H), 4.79, 4.85 (s, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 13.20 (s, 1H), 15.37,15.70 (s, 1H).
[002115] Example 457
[002116] Synthesis of 4-(((trans)-4-(4-sulfamoylphenyl)cyclohexyl)oxy)-1H-1,2,3- triazole-5-carboxylic acid (457)
Figure imgf000595_0001
Figure imgf000596_0001
[002117] Compounds 457B, 457C, and 457D were synthesized by employing the procedures described for Compounds 4B, 141, and 279D using 4,4,5,5-tetramethyl-2-(1,4- dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 457A with K2CO3 as base and 1,4-dioxane/H2O as solvent, 457B at reflux, and 457C with THF/methanol as solvent in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140 at room temperature, and 279C with HCl as acid and 1,4-dioxane as solvent. Compound 457B: LC-MS (ESI) m/z: 296 [M+H]+; 1H-NMR (DMSO-d6, 500 MHz): d (ppm) 1.83 (t, J = 6.5 Hz, 2H), 2.40 (brs, 2H), 2.55-2.58 (m, 2H), 3.92 (s, 4H), 6.17 (brs, 1H), 7.32 (s, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H). Compound 457C: LC-MS (ESI) m/z: 298 [M+H]+. Compound 457D: LC-MS (ESI) m/z: 254 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.85-196 (m, 2H), 2.05-2.09 (m, 2H), 2.26-2.29 (m, 2H), 2.55-2.63 (m, 2H), 3.13-3.19 (m, 1H), 7.28 (brs, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H).
[002118] To a mixture of Compound 457D (840 mg, 3.32 mmol), NaOH (664 mg, 16.6 mmol), K2CO3 (641 mg, 4.64 mmol), and Bu4NHSO4 (181 g, 0.532 mmol) in toluene (8 mL) was added a solution of (bromomethyl)benzene (1.361 mg, 7.96 mmol) in THF (3 mL) at 45 °C and stirred at 45 °C for 16 hours. The mixture was cooled down to room temperature and filtered. The cake was washed with THF (8 mL). The combined filtrate and washing was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified with flash column chromatography (ethyl acetate in petroleum ether, from 0% to 50% v/v) to yield Compound 457E. LC-MS (ESI) m/z: 434 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.91- 2.02 (m, 2H), 2.23-2.27 (m, 2H), 2.53-2.56 (m, 4H), 3.08-3.16 (m, 1H), 4.33 (s, 4H), 7.05-7.05 (m, 4H), 7.19-7.21 (m, 6H), 7.37 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H).
[002119] Compounds 457F-1, 457F-2, 457G, 457H, and 457 were synthesized by employing the procedures described for Compounds 393F-1, 90C, 380E, and 8F using
Compounds 457E, 457F-1, 457G with MeOH/THF as solvent at reflux, and 457H in lieu of Compounds 393E, 90B, 380D with MeOH as solvent at room temperature, and 8E. Compound 457F-1: LC-MS (ESI) m/z: 436 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.57-1.74 (m, 4H), 1.89-1.99 (m, 4H), 2.60-2.68 (m, 1H), 4.17 (brs, 1H), 4.32 (s, 4H), 7.01-7.03 (m, 4H), 7.19- 7.21 (m, 6H), 7.36 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H). Compound 457F-2: LC-MS (ESI) m/z: 436 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.41-1.55 (m, 4H), 1.94-1.97 (m, 2H), 2.12-2.15 (m, 2H), 2.55-2.63 (m, 1H), 3.69-3.74 (m, 1H), 4.08 (s, 4H), 7.01-7.03 (m, 4H), 7.18-7.21 (m, 6H), 7.32 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H). Compound 457G: LC-MS (ESI) m/z: 695 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 1.25-1.56 (m, 7H), 1.94-1.97 (m, 2H), 2.17-2.20 (m, 2H), 2.53-2.60 (m, 1H), 3.80 (s, 3H), 4.31 (s, 4H), 4.42 (q, J = 7.2 Hz, 2H), 5.06-5.14 (m, 1H), 5.30 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.01-7.03 (m, 4H), 7.18-7.21 (m, 6H), 7.26-7.26 (m, 1H), 7.27-7.30 (m, 3H), 7.75 (d, J = 8.4 Hz, 2H). Compound 457H: LC-MS (ESI) m/z: 395 [M+H]+. Compound 457: LC-MS (ESI) m/z: 367 [M+H]+.1H-NMR (CD3OD, 400 MHz): d (ppm) 1.65-1.76 (m, 4H), 1.98-2.00 (m, 2H), 2.37-2.38 (m, 2H), 2.70-2.76 (m, 1H), 4.74-4.79 (m, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H).
[002120] Example 458
[002121] Synthesis of 4-(((trans)-4-(4-(1-(2-ethyl-2-hydroxypentyl)-1H-pyrazol-3- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (458)
Figure imgf000597_0001
Figure imgf000598_0001
[002122] To a suspension of hexan-3-one (458A, 3.0 g, 30 mmol) and trimethyl sulfoxonium iodide (7.92 g, 36 mmol) in DMSO (35 mL) was added potassium tert-butoxide solution (1 M solution in THF, 33 mL, 33.0 mmol). The reaction mixture was stirred at room temperature under N2 for 16 hours and concentrated under reduced pressure. The residue was partitioned between Et2O (50 mL) and brine (50 mL). The organic layer was separated, washed with water (50 mL) and brine (50 mL), dried over MgSO4, filtered, and distillated to afford a crude Compound 458B.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.93 (t, J = 7.2 Hz, 6H), 1.36- 1.64 (m, 6H), 1.85-2.60 (m, 2H).
[002123] To a solution of Compound 405A (500 mg, 2.84 mmol) in dichloromethane (30 mL) was added AlCl3 (1.13 g, 8.52 mmol) at 0 oC and stirred at 0 oC for 20 minutes, followed by addition of acetyl chloride (266 mg, 3.41 mmol). The mixture was stirred at 0 oC for 30 minutes, pour into ice-water (50 mL), and extracted with EtOAc (50 mL x 2). The combined extracts was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (eluting with EA/PE=1:5) to afford Compound 458C. LC-MS (ESI) m/z: 219 [M+H]+.
[002124] Compound 458D was synthesized by employing the procedure described for Compound 90C using Compound 458C with toluene as solvent at 70 oC in lieu of Compound 90B with THF as solvent at room temperature, Compound 458D: LC-MS (ESI) m/z: 478
[M+H]+.
[002125] A mixture of Compound 458D (800 mg, 1.67 mmol) and DMF-DMA (20 mL) was heated at 110 oC for 48 hours. The mixture was concentrated and purified by flash column chromatography (eluting with MeOH/DCM=1:13) to afford Compound 458E. LC-MS (ESI) m/z: 533 [M+H]+.
[002126] A mixture of Compound 458E (1.5 g, 2.81 mmol) and N2H4-H2O (3 mL) in EtOH (20 mL) was tirred at 80 oC for 2 hours and concentrated. The residue was purified by flash column chromatography (eluting with MeOH/DCM=1:13) to afford Compound 458F. LC-MS (ESI) m/z: 502 [M+H]+.
[002127] A mixture of Compound 458F (200 mg, 0.40 mmol), CS2CO3 (261 mg, 0.8 mmol), Compound 458B and DMF (5 mL) was heated in a sealed tube at 60 oC for 16 hours. The mixture was diluted with EtOAc (30 mL), washed with brine (20 mL x 2), dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography (eluting with
MeOH/DCM=1:10) to afford Compound 458G. LC-MS (ESI) m/z: 616 [M+H]+.
[002128] Compounds 458H and 458 were synthesized by employing the procedures described for Compounds 1 and 8F using Compounds 458G and 458H in lieu of Compounds 1E and 8E. Compound 458H: LC-MS (ESI) m/z: 496 [M+H]+. Compound 458: LC-MS (ESI) m/z: 468 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.90-0.97 (m, 6H), 1.35-1.48 (m, 6H), 1.65-1.72 (m, 4H), 1.96-1.99 (m, 2H), 2.33-2.36 (m, 2H), 2.61-2.63 (m, 1H), 4.15 (s, 2H), 4.71- 4.74 (m, 1H), 6.60 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H).
[002129] Example 459
[002130] Synthesis of 4-(((trans)-4-(4-(1H-pyrazol-1-yl)phenyl)cyclohexyl)thio)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (459)
Figure imgf000600_0001
[002131] Compounds 459B, 459C, 459D, 459E, 459F, 459G, 459H, and 459 were synthesized by employing the procedures described for Compounds 4B, 141, 279D, 393F-1, 340F, 340G, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2- dioxaborolane, Compounds 459A with K3PO4 as base and toluene/H2O as solvent, 459B, 459C with TFA as acid amd dichloromethane as solvent, 459D, 459E, 459F, 459G, and 459H in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 4A with Na2CO3 as base and
toluene/EtOH/H2O as solvent, 140, 279C with HCl as acid and 1,4-dioxane as solvent, 393E, 340E, 340F, 8E, and 1E. Compound 459B: LC-MS (ESI) m/z: 283 [M+H]+. Compound 459C: LC-MS (ESI) m/z: 285 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.61-1.90 (m, 8H), 2.58- 2.65 (m, 1H), 4.00 (s, 4H), 6.45 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.71 (s, 1H), 7.89 (s, 1H). Compound 459D: LC-MS (ESI) m/z: 241 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.92-2.03 (m, 2H), 2.24-2.30 (m, 2H), 2.52-2.56 (m, 4H), 3.05-3.12 (m, 1H), 6.47 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.72 (s, 1H), 7.91 (s, 1H).
Compound 459E: LC-MS (ESI) m/z: 243 [M+H]+. Compound 459F: LC-MS (ESI) m/z: 321 [M+H]+. Compound 459G: LC-MS (ESI) m/z: 518 [M+H]+. Compound 459H: LC-MS (ESI) m/z: 490 [M+H]+. Compound 459: LC-MS (ESI) m/z: 370 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.53-1.66 (m, 4H), 1.88-1.90 (m, 2H), 2.21-2.24 (m, 2H), 2.60-2.66 (m, 1H), 3.58-3.59 (m, 1H), 6.51-6.52 (m, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.71-7.75 (m, 3H), 8.43 (s, 1H).
[002132] Example 460
[002133] Synthesis of 4-(((trans)-4-(4-(cyclohexylmethoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (460)
Figure imgf000601_0001
[002134] To a solution of 4-(4-hydroxyphenyl)cyclohexanone (460A, 15.00 g, 78.95 mmol) and 1H-imidazole (8.05 g, 118.42 mmol) in dichloromethane (150 mL) was added TBSCl (17.77 g, 118.42 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate (200 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 30% v/v) to furnish Compound 460B. LC-MS (ESI) m/z: 305 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.19 (s, 6H), 0.98 (m, 9H), 1.83- 1.95 (m, 2H), 2.16-2.21(m, 2H), 2.47-2.51 (m, 4H), 2.92-3.00 (m, 1H), 6.78 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H).
[002135] Compounds 460C, 460D, 460E, 460F, 460G, and 460 were synthesized by employing the procedures described for Compounds 393F-1, 90C, 280E, 27B, 380E, and 8F using Compounds 460B, 460C, 460D with THF/H2O as solvent and adding KF, 460E,
(bromomethyl)cyclohexane, 460F, and 460G in lieu of Compounds 393E, 90B, 280D with THF as solvent and without KF, 27A, 2-bromopropane, 380D, and 8E. Compound 460C: LC-MS (ESI) m/z: 289 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 0.19 (s, 6H), 0.98 (m, 9H), 1.63- 1.69 (m, 4H), 1.79-1.89 (m, 4H), 2.44-2.51 (m, 1H), 4.05-4.18 (m, 1H), 6.76 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H). Compound 460D: LC-MS (ESI) m/z: 566 [M+H]+. Compound 460E: LC-MS (ESI) m/z: 452 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz,): d (ppm) 1.31 (t, J = 7.2 Hz, 3H), 1.32-1.39 (m, 2H), 1.44-1.51 (m, 2H), 1.76-1.70 (m, 2H), 2.02-2.05 (m, 2H), 2.37-2.44 (m, 1H), 3.73 (s, 3H), 4.27-4.33 (m, 2H), 4.71-4.91 (m, 1H), 5.35 (s, 2H), 6.65 (d, J = 8.4 Hz, 2H), 6.92-7.00 (m, 4H), 7.23 (d, J = 8.8 Hz, 2H), 9.13 (s, 1H). Compound 460F: LC-MS (ESI) m/z: 548 [M+H]+. Compound 460G: LC-MS (ESI) m/z: 428 [M+H]+. Compound 460: LC-MS (ESI) m/z: 400 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.00-1.25 (m, 6H), 1.52-1.81 (m, 12H), 1.21 (m, 2H), 3.71-3.73 (m, 2H), 4.65 (m, 1H), 6.81-6.83 (m, 2H), 7.13-7.15 (m, 2H).
[002136] Example 461
[002137] Synthesis of 4-(((cis-3a,6a)-5-(4- (trifluoromethoxy)phenyl)octahydropentalen-2-yl)thio)-1H-1,2,3-triazole-5-carboxylic acid (461)
Figure imgf000602_0001
[002138] Compounds 461A, 461B, 461C, and 461 were synthesized by employing the procedures described for Compounds 340F, 340G, 1, and 8F using Compounds 459A with K3PO4 as base and toluene/H2O as solvent, 455D, 461A, 461B, and 461C in lieu of Compounds 340E, 340F, 1E, and 8E. Compound 461A: LC-MS (ESI) m/z: 382 [M+18]+. Compound 461B: LC-MS (ESI) m/z: 562 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 0.99-1.07 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.60-1.68 (m, 4H), 2.14-2.22 (m, 2H), 2.60-2.65 (m, 2H), 2.81-2.90 (m, 1H), 3.63-3.69 (m, 4H), 4.45 (q, J = 7.2 Hz, 2H), 5.62 (s, 2H), 6.84 (d, J = 8.4 Hz, 2H), 7.10-7.17 (m, 4H), 7.27 (d, J = 8.8 Hz, 2H). Compound 461C: LC-MS (ESI) m/z: 442 [M+H]+. Compound 461: LC-MS (ESI) m/z: 414 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.28-1.36 (m, 2H), 1.62-1.70 (m, 2H), 2.01-2.05 (m, 2H), 2.21-2.28 (m, 2H), 2.65-2.72 (m, 2H), 2.89-2.99 (m, 1H), 4.00-4.05 (m, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 13.25 (bs, 1H), 15.43 (bs, 1H).
[002139] Example 462
[002140] Synthesis of 4-(((trans)-4-(4-(2-cyclohexylethoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (462)
Figure imgf000603_0001
[002141] Compounds 462A, 462B, and 462 were synthesized by employing the procedures described for Compounds 27B, 380E, and 8F using Compounds 460E, (2- bromoethyl)cyclohexane, 462A, and 462B in lieu of Compounds 27A, 2-bromopropane, 380D, and 8E. Compound 462A: LC-MS (ESI) m/z: 562 [M+H]+. Compound 462B: LC-MS (ESI) m/z: 442 [M+H]+. Compound 462: LC-MS (ESI) m/z: 414 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.91-1.22 (m, 5H), 1.52-1.82 (m, 14H), 2.21 (m, 2H), 2.49 (m, 1H), 3.92-3.96 (m, 2H), 4.65 (m, 1H), 6.82-6.84 (m, 2H), 7.13-7.15 (m, 2H).
[002142] Example 463
[002143] Synthesis of 4-(((trans)-4-(4-(3-hydroxypropoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (463)
Figure imgf000604_0001
[002144] Compounds 463B, 463C, 463D, and 463 were synthesized by employing the procedures described for Compounds 340F, 27B, 380E, and 8F using Compounds 463A, 460E, 463B, 463C, and 463D in lieu of Compounds 340E, 27A, 2-bromopropane, 380D, and 8E. Compound 463B: LC-MS (ESI) m/z: 245 [M+H]+. Compound 463C: LC-MS (ESI) m/z: 600 [M+H]+. Compound 463D: LC-MS (ESI) m/z: 390 [M+H]+. Compound 463: LC-MS (ESI) m/z: 362 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.52-1.57 (m, 4H), 1.80-1.85 (m, 4H), 2.22 (m, 2H), 3.52-3.56 (m, 2H), 3.97-4.00 (m, 2H), 4.51-4.62 (m, 2H), 6.82-6.84 (m, 2H), 7.13- 7.16 (m, 2H), 12.83 (s, 1H), 14.75 (s, 1H).
[002145] Example 464
[002146] Synthesis of 4-(((trans)-4-(4-(3-isopropyl-1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (464)
Figure imgf000605_0001
[002147] A mixture of 3-isopropyl-1H-pyrazole (464A, 2 g, 18 mmol) and 3,4-dihydro-2H- pyran (3.05 g, 36 mmol) was heated in a seal tube at 120 o C for 12 hours. The reaction mixture was cooled down to room temperature, concentrated, and purified by preparative HPLC to give Compound 464B. LC-MS (ESI) m/z: 195 [M+1]+.
[002148] Compounds 464C, 464D, 464E, and 464 were synthesized by employing the procedures described for Compounds 30C-1, 8B, 1, and 8F using 2-isopropoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane, Compounds 464B without treatment of HCl, 464C, 405C with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 464D, and 464E in lieu of triisopropyl borate, Compounds 30B with treatment of HCl, (3,4-dichlorophenyl)boronic acid, 8A with Cs2CO3 as base and DME/H2O as solvent, 1E, and 8E. Compound 464C: LC-MS (ESI) m/z: 321 [M+H]+. Compound 464D: LC-MS (ESI) m/z: 628 [M+H]+. Compound 464E: LC-MS (ESI) m/z: 424 [M+H]+. Compound 464: LC-MS (ESI) m/z: 396 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.23 -1.27 (m, 6H), 1.38 -1.41 (m, 1H), 1.55 -1.65 (m, 3H), 1.80 -1.90 (m, 2H), 2.20 -2.25 (m, 2H), 2.92 -3.00 (m, 1H), 3.16 -3.29 (m, 1H), 4.64 (s, 1H), 6.15 (s, 1H), 6.41 (s, 1H), 7.20 - 7.41 (m, 3H), 7.65 (d, J = 8.4Hz, 1H), 14.71 (s, 1H).
[002149] Example 465
[002150] Synthesis of 4-(methyl((cis)-4-(4- (trifluoromethoxy)phenyl)cyclohexyl)amino)-1H-1,2,3-triazole-5-carboxylic acid (465)
Figure imgf000606_0001
[002151] To a solution of Compound 451C-2 (180 mg, 0.35 mmol) in THF (5 mL) was added NaH (60%, 70 mg, 1.7 mmol) and stirred at room temperature for 0.5 hour. To the mixture was added CH3I (241 mg, 1.7 mmol) and stirred at room temperature for 16 hours. It was quenched with water (0.2 mL) and concentrated in vacuum. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to furnish Compound 465A. LC-MS (ESI) m/z: 505 [M+H]+.
[002152] Compound 465 was synthesized by employing the procedure described for Compound 1 using Compounds 465A in lieu of Compounds 1E, LC-MS (ESI) m/z: 385
[M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.58-1.73 (m, 4H), 1.84-1.90 (m, 2H), 2.10- 2.16 (m, 2H), 2.80-2.90(m, 4H), 3.86 (d, J = 2.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H).
[002153] Example 466
[002154] Synthesis of 4-(((trans)-4-(3-(hydroxymethyl)-4-(1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (466)
Figure imgf000607_0001
[002155] Compounds 466C, 466D, 466E, 466F, 466G, 466H, 466I-1, 466I-2, 466J, 466K, and 466 were synthesized by employing the procedures described for Compounds 8B, 4B, 141, 283C, 279D, 460B, 393F-1, 90C, 1, and 8F using Compounds 466A, 466B with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2- dioxaborolane, 466C with K2CO3 as base and 1,4-dioxane/H2O as solvent, 466D, 466E, 466F with TFA as acid amd dichloromethane as solvent, 466G, 466H, 466I-1, 466J, and 466K in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with Cs2CO3 as base and DME/H2O as solvent, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, 140, 283B, 279C with HCl as acid and 1,4-dioxane as solvent, 460A, 393E, 90B, 8E, and 1E. Compound 466C: LC-MS (ESI) m/z: 365 [M+1]+.Compound 466D: LC-MS (ESI) m/z: 425 [M+1]+. Compound 466E: LC-MS (ESI) m/z: 343 [M+1]+. Compound 466F: LC-MS (ESI) m/z: 315 [M+H]+. Compound 466G: LC-MS (ESI) m/z: 271 [M+H]+. Compound 466H: LC-MS (ESI) m/z: 385 [M+H]+. Compound 466I-1: LC-MS (ESI) m/z: 387 [M+H]+; 1H-NMR (DMSO- d6, 400 MHz): d (ppm) 0.86 (s, 15H), 1.7 -1.50 (m, 3H), 1.70 -1.73 (m, 2H), 1.80 -1.90 (m, 2H), 2.46 -2.52 (m, 2H), 3.86 (s, 1H), 4.34 (s, 1H), 4.69 (s, 1H), 4.90 (s, 1H), 6.50 (s, 1H), 7.12 (s, 1H), 7.44 -7.51 (m, 2H), 7.73 (s, 1H), 12.89 (s, 1H). Compound 466I-2: LC-MS (ESI) m/z: 387 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.86 (s, 9H), 1.26 -1.33 (m, 2H), 1.40 -1.49 (m, 2H), 1.76 (d, J = 12Hz, 2H), 1.90 (d, J = 9.6Hz, 2H), 2.42 -2.48 (m, 1H), 3.43 (br, 8H), 4.63 (s, 1H), 4.89 (s, 1H), 6.50 (s, 1H), 7.13 (s, 1H), 7.42 (s, 2H), 7.74 (s, 1H), 12.89 (s, 1H).
Compound 466J: LC-MS (ESI) m/z: 646 [M+1]+. Compound 466K: LC-MS (ESI) m/z: 412 [M+1]+, Compound 466: LC-MS (ESI) m/z: 384 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.64 -1.67 (m, 4H), 1.88 -1.90 (m, 2H), 2.23 -2.32 (m, 2H), 2.53 -2.69 (m, 1H), 4.56 (s, 2H), 4.68 (s, 1H), 5.41 (s, 1H), 6.54 (s, 1H), 7.20 (d, J = 9.2Hz, 1H), 7.43 -7.48 (m, 2H), 7.72 (s, 1H).
[002156] Example 467
[002157] Synthesis of 4-(((cis)-4-(3-(hydroxymethyl)-4-(1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (467)
Figure imgf000608_0001
[002158] Compounds 467A, 467B, and 467 were synthesized by employing the procedures described for Compounds 90C, 1, and 8F using Compounds 466I-2, 467A, and 467B in lieu of Compounds 90B, 1E, and 8E. Compound 467A: LC-MS (ESI) m/z: 646 [M+H]+. Compound 467B: LC-MS (ESI) m/z: 412 [M+H]+. Compound 467: LC-MS (ESI) m/z: 384 [M+H]+.1H- NMR (DMSO-d6, 400 MHz): d (ppm) 1.62 -1.76 (m, 4H), 1.88 -1.91 (m, 2H), 2.08 -2.12 (m, 2H), 2.67-2.68 (m, 1H), 4.59 (s, 2H), 4.96 (s, 1H), 6.56 (d, J = 1.6 Hz, 1H), 7.19 -7.21 (m, 1H), 7.42 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.74 (s, 1H).
[002159] Example 468
[002160] Synthesis of 4-(((trans)-4-(4-(4-methylpiperazin-1-yl)phenyl)cyclohexyl)oxy)- 1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (468)
Figure imgf000609_0001
[002161] Compounds 468A, 468B, and 468 were synthesized by employing the procedures described for Compounds 6B, 1, and 8F using Compounds 405C with X-phos as ligand and Cs2CO3 as base and 1,4-dioxane as solvent, 468A, and 468B in lieu of Compounds 6A with Xantophos as ligand and tBuONa as base and toluene as solvent, 1E, and 8E. Compound 468A: LC-MS (ESI) m/z: 534 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm), 1.24-1.30 (m, 6H), 1.41- 4.43 (t, J = 7.2 Hz, 3H), 1.70 (s, 3H), 1.89-1.93 (m, 2H), 2.13-2.15 (m, 2H), 2.37-2.43 (m, 3H), 2.56-2.64 (m, 2H), 3.16-3.22 (m, 2H), 3.80 (s, 3H), 4.39-4.45 (m, 2H), 5.01-5.08 (m, 1H), 5.31 (s, 2H), 6.86-6.89 (m, 2H), 7.07-7.09 (m, 1H), 7.17-7.20 (m, 1H), 7.25-7.30 (m, 4H). Compound 468B: LC-MS (ESI) m/z: 414 [M+H]+. Compound 468: LC-MS (ESI) m/z: 386 [M+H]+; 1H- NMR (CD3OD, 400 MHz): d (ppm) 1.60-1.70 (m, 4H), 1.92-1.95 (m, 2H), 2.32-2.35 (m, 2H), 2.53-2.57 (m, 1H), 3.02-3.04 (m, 5H), 3.26-3.30 (m, 2H), 3.57-3.60 (m, 2H), 3.78-3.80 (m, 2H), 4.73-4.75 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H).
[002162] Example 469
[002163] Synthesis of 4-(((trans)-4-(4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (469)
Figure imgf000609_0002
[002164] To a solution of Compound 458F (0.3 g, 0.598 mmol) in anhydrous THF (3 mL) was added NaH (60% in mineral oil, 0.03 g, 0.716 mmol) and stirred at 0 oC for 10 minutes, followed by addition of 1,2-epoxy-2-methylpropane (0.129 g, 1.794 mmol). The mixture was stirred at room temperature overnight, quenched with saturated NH4Cl solution (15 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50%~100% v/v) to give Compound 469A. LC-MS (ESI) m/z: 546 [M+H]+.
[002165] Compound 469 was synthesized by employing the procedure described for Compound 1 using Compound 469A in lieu of Compound 1E, LC-MS (ESI) m/z: 426 [M+H]+. 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.07 (s, 6H), 1.55-1.62 (m, 4H), 1.85-1.88 (m, 2H), 2.23-2.24 (m, 2H), 2.58-2.60 (m, 1H), 4.0 (s, 2H), 4.64-4.73(m, 2H), 6.30 (d, J = 2 Hz, 1H), 7.26 (d, J = 8 Hz, 2H), 7.68 (d, J = 8 Hz, 3H).
[002166] Example 470
[002167] Synthesis of 4-(((trans)-4-(4-(1-(2-ethyl-2-hydroxypentyl)-1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (470)
Figure imgf000610_0001
[002168] A mixture of Compound 458D (800 mg, 1.67 mmol) and DMF-DMA (20 ml) was stirred at 110 oC for 72 hours. The mixture was concentrated and purified by flash column chromatography (eluting with MeOH/DCM=1:13) to afford a mixture of Compounds 458E and 470A. LC-MS (ESI) m/z: 533 [M+H]+ and 519 [M+H]+.
[002169] A mixture of 2-ethyl-2-propyloxirane (600 mg, 5.3 mmol) and 98% hydrazine monohydrate (45 mg, 1.59 mmol) in EtOH (10 mL) was heated in a sealed tube at 60 oC for 16 hours. After the mixture was cooled down to room temperature, to it was added the Mixture of 458E and 470A (254 mg, 0.47 mmol), stirred at 80 oC for 2 hours, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with EtOAc/PE = 4:5) to afford a mixture of Compounds 470B-1 and 470B-2. LC-MS (ESI) m/z: 616 [M+H]+ and 602 [M+H]+.
[002170] Mixture of 470C-1 and 470C-2, and Compound 470 were synthesized by employing the procedures described for Compounds 1 and 8F using Mixtures of 470B-1 and 470B-2, and 470C-1 and 470C-2 in lieu of Compounds 1E and 8E. Mixture of 470C-1 and
470C-2: LC-MS (ESI) m/z: 496 [M+H]+ and 482 [M+H]+. Compound 470: LC-MS (ESI) m/z: 468 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.71 (t, J = 7.6 Hz, 3H), 0.77 (t, J = 6.4 Hz, 3H), 1.14-1.34 (m, 6H), 1.70-1.75 (m, 4H), 2.01-2.04 (m, 2H), 2.35-2.38 (m, 2H), 2.70-2.71 (m, 1H), 4.16 (s, 2H), 4.76-4.80 (m, 1H), 6.33 (d, J = 1.6 Hz, 1H), 7.40 (s, 4H), 7.56 (d, J = 2.0 Hz, 1H).
[002171] Example 471
[002172] Synthesis of 4-(((trans)-4-(4-(1-((1-hydroxycyclohexyl)methyl)-1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (471)
Figure imgf000612_0001
[002173] Compound 471B was synthesized by employing the procedure described for Compound 458B using Compound 471A in lieu of Compound 458A, LC-MS (ESI) m/z: non- ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.48- 1.62 (m, 10H), 2.60 (s, 2H).
[002174] A mixture of Compound 471B (720 mg, crude) and tert-butyl
hydrazinecarboxylate (800 mg, 6.05 mmol) in ethanol (5 mL) was heated at 80 oC overnight. The reaction mixture was concentrated and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% to 50% v/v) to furnish Compound 471C. LC-MS (ESI) m/z: 267 [M+Na]+.
[002175] To a solution of Compound 471C (540 mg, 2.21 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to afford Compound 471D. LC-MS (ESI) m/z: 145 [M+H]+.
[002176] The mixture of Compound 471D (350 mg, 2.21 mmol) and Compound 458E (150 mg, 0.244 mmol) in ethanol (5 ml) was stirred at 80 oC for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column
chromatography on silica gel (ethyl acetate in petroleum ether, 20% to 33% v/v) to give
Compound 471E. LC-MS (ESI) m/z: 614 [M+H]+. [002177] Compounds 471F and 471 were synthesized by employing the procedures described for Compounds 1 and 8F using Compounds 471E and 471F in lieu of Compounds 1E and 8E. Compound 471F: LC-MS (ESI) m/z: 494 [M+H]+. Compound 471: LC-MS (ESI) m/z: 466 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.01-1.28 (m, 7H), 1.39-1.69 (m, 7H), 1.90-1.93 (m, 2H), 2.25-2.27 (m, 2H), 2.63-2.70 (m, 1H), 4.04 (s, 2H), 4.61-4.68 (m, 2H), 6.33 (d, J = 1.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 1.6 Hz, 1H), 12.96 (bs, 1H), 14.80 (bs, 1H).
[002178] Example 472
[002179] Synthesis of 4-(((trans)-4-(4-(3-aminopropoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (472)
Figure imgf000613_0001
[002180] Compounds 472B, 472C, 472D, 472E, and 472 were synthesized by employing the procedures described for Compounds 340F, 27B, 380E, 149D, and 8F using Compounds 472A, 460E, 472B, 472C, 472D with 1,4-dioxane/dichloromethane as solvent, and 472E in lieu of Compounds 340E, 27A, 2-bromopropane, 380D, 149C with ethyl acetate as solvent, and 8E. Compound 472B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.44 (s, 9H), 1.89-1.97 (m, 2H), 3.03 (s, 3H), 3.24-3.29 (m, 2H), 4.28 (t, J = 6.4 Hz, 2H), 4.74 (s, 1H). Compound 472C: LC-MS (ESI) m/z: 609
[M+H]+. Compound 472D: LC-MS (ESI) m/z: 389 [M-100+H]+. Compound 472E: LC-MS (ESI) m/z: 389 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.24 (t, J = 6.8 Hz, 3H), 1.47- 1.57 (m, 4H), 1.80-1.84 (m, 2H), 1.94-1.99 (m, 2H), 2.18-2.22 (m, 2H), 2.92 (t, J = 6.8 Hz, 2H), 3.11-3.21 (m, 1H), 4.01 (t, J = 6.0 Hz, 2H), 4.12-4.18 (m, 2H), 4.54 (s, 1H), 6.84 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H). Compound 472: LC-MS (ESI) m/z: 361 [M+H]+.1H-NMR (CD3OD, 400 MHz): d (ppm) 1.60-1.70 (m, 4H), 1.92-1.95 (m, 2H), 2.09-2.16 (m, 2H), 2.32- 2.35 (m, 2H), 2.54-2.60 (m, 1H), 3.15 (t, J = 7.2 Hz, 2H), 4.10 (t, J = 5.6 Hz, 2H), 4.74 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H).
[002181] Example 473
[002182] Synthesis of 4-(((trans)-4-(4-(3-(pentan-3-yl)-1H-pyrazol-5-
Figure imgf000614_0001
[002183] Compounds 473B, 473C, 473D, 473E, 473F, 473G, 473H, and 473 were synthesized by employing the procedures described for Compounds 275B, 8B, 141, 464B, 30C- 1, 8B, 8F, and 1 using Compounds 473A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 1H-pyrazol-5-ylboronic acid, 473B with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 473C, 473D with toluene as solvent and p-TsOH as acidic catalyst, 2-isopropoxy-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane, 473E without treatment of HCl, 473F, 405C with Na2CO3 as base and 1,4- dioxane/ H2O as solvent, 473G, and 473H in lieu of Compounds 275A with 2,6-lutidine as base, (3,4-dichlorophenyl)boronic acid, 8A with Cs2CO3 as base and DME/H2O as solvent, 140, 464A without acid as acidic catalyst, triisopropyl borate, 30B with treatment of HCl, (3,4- dichlorophenyl)boronic acid, 8A with Cs2CO3 as base and DME/H2O as solvent, 8E, and 1E. Compound 473B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz) d 1.08-1.18 (m, 3H), 1.66-1.80 (m, 3H), 2.37 (dt, J = 14.9, 6.8 Hz, 2H), 5.23– 5.38 (m, 1H). Compound 473C: LC-MS (ESI) m/z: 137 [M+H]+. Compound 473D: LC-MS (ESI) m/z: 139 [M+H]+. Compound 473E: LC-MS (ESI) m/z: 223 [M+H]+. Compound 473F: LC-MS (ESI) m/z: 349 [M+H]+. Compound 473G: LC-MS (ESI) m/z: 572 [M+H]+. Compound 473H: LC-MS (ESI) m/z: 544 [M+H]+. Compound 473: LC-MS (ESI) m/z: 424 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) d 0.71-0.87 (m, 6H), 1.18 (d, J = 6.2 Hz, 2H), 1.29- 1.37 (m, 1H), 1.49-1.71 (m, 5H), 1.79-1.85 (m, 2H), 2.11-2.28 (m, 2H), 2.53-2.63 (m, 1H), 3.08 (s, 1H), 4.59-4.69 (m, 1H), 6.12 (s, 0.5H), 6.40 (s, 0.5H), 7.13-7.46 (m, 3H), 7.67 (d, J = 8.2 Hz, 1H).
[002184] Example 474
[002185] Synthesis of 4-(((trans)-4-(4-(3- (methylamino)propoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2- trifluoroacetate (474)
Figure imgf000616_0001
[002186] Compounds 474B, 474C, 474D, 474E, and 474 were synthesized by employing the procedures described for Compounds 340F, 27B, 380E, 149D, and 8F using Compounds 474A, 460E, 474B, 474C, 474D with 1,4-dioxane/dichloromethane as solvent, and 474E in lieu of Compounds 340E, 27A, 2-bromopropane, 380D, 149C with ethyl acetate as solvent, and 8E. Compound 474B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.46 (s, 9H), 1.94-2.01 (m, 2H), 2.87 (s, 3H), 3.03 (s, 3H), 3.35 (t, J = 6.4 Hz, 2H), 4.28 (t, J = 6.4 Hz, 2H). Compound 474C: LC-MS (ESI) m/z: 623 [M+H]+. Compound 474D: LC-MS (ESI) m/z: 403 [M-100+H]+. Compound 474E: LC-MS (ESI) m/z: 403 [M+H]+. Compound 474: LC-MS (ESI) m/z: 375 [M+H]+.1H- NMR (CD3OD, 400 MHz): d (ppm) 1.55-1.70 (m, 4H), 1.855-1.95, 2.32-2.35 (m, 4H), 2.12-2.19 (m, 2H), 2.50-2.61 (m, 1H), 2.75 (s, 3H), 3.22 (t, J = 7.2 Hz, 2H), 4.04, 4.73 (s, 1H), 4.10 (t, J = 5.6 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H).
[002187] Example 475
[002188] Synthesis of 4-(((trans)-4-(4-(3-(2-methoxybutyl)-1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (475)
Figure imgf000617_0001
[002189] Compound 475A was synthesized by employing the procedure described for Compound 27C using Compound 405C in lieu of Compound 27B, LC-MS (ESI) m/z: 562
[M+H]+.
[002190] To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (475B, 6 g,
39.4mmol) and N,N,N’N’-tetraethyl-ethylenediamine (6.86 g, 59.1 mmol) in anhydrous THF ( 60 mL) was dropped a solution of n-BuLi in hexane (2.5 M, 23.6 mL, 59.1 mmoL) at -78oC under nitrogen and stirred at -78oC for 30 minutes, followed by addition of 1, 2-epoxybutane (4.26 g, 59.1 mmoL). The mixture was stirred at -78oC for 90 minutes, warmed gradually to room temperature, and stirred overnight. The mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers was dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to give Compound 475C. LC-MS (ESI) m/z: 225 [M+H]+.
[002191] To a stirred solution of Compound 475C (3.3 g, 14.7 mmoL) in anhydrous THF (35 mL) was added NaH (1.18 g, 29.4 mmoL, 60% in mineral oil) at 0 oC and stirred at 0 oC for 10 minutes, followed by addition of iodomethane (8.345 g, 58.8 mmoL) dropwise. The mixture was warmed gradually to room temperature, stirred under nitrogen overnight, quenched with saturated NH4Cl solution (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30%v/v) to afford Compound 475D. LC-MS (ESI) m/z: 239 [M+H]+.
[002192] A mixture of Compound 475D (2.9 g, 12.2 mmol) and TFA (6 mL) in
dichloromethane (24 mL) was stirred at room temperature overnight. The mixture was quenched with dichloromethane (30 mL), washed with saturated Na2CO3 solution (30 mL x 3) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a crude Compound 475E, which was used directly for the next step without further purification. LC-MS (ESI) m/z: 155 [M+H]+.
[002193] A mixture of Compound 475E (2.7 g crude, 17.5 mmol) and N-iodosuccinimide (8.27 g, 36.75 mmol) in dichloromethane (48 mL) was heated at reflux under nitrogen overnight. The mixture was diluted with dichloromethane (40 mL), washed with saturated sodium sulfite solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30%v/v) to give Compound 475F. LC-MS (ESI) m/z: 407 [M+H]+.
[002194] A mixture of Compound 475F (1.75 g, 4.3 mmoL) and diluted hydrochloric acid (2 N, 60 mL, 120 mmol) was heated at reflux overnight. The mixture was cooled down to room temperature, adjusted to pH 10 with potassium carbonate, and extracted with ethyl acetate (50 mL x 3). The combined organic layers was dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether, 30% v/v) to give Compound 475G. LC-MS (ESI) m/z: 281 [M+H]+.
[002195] Compounds 475H and 475 were synthesized by employing the procedures described for Compounds 4B and 1 using Compounds 475A with K2CO3 as base and 1,4- dioxane as solvent, 475G, and 475H in lieu of (4-bromophenyl)boronic acid, Compounds 4A with Na2CO3 as base and toluene/EtOH/H2O as solvent, and 1E. Compound 475H: LC-MS (ESI) m/z: 560 [M+H]+. Compound 475: LC-MS (ESI) m/z: 440 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.86 (t, J = 7.6 Hz, 3H), 1.36-1.50 (m, 2H), 1.51-1.65 (m, 4H), 1.86-1.88 (m, 2H), 2.16-2.24 (m, 2H), 2.56-2.61 (m, 1H), 2.66-2.8 (m, 3H), 3.25 (s, 3H), 4.64 (m, 1H), 6.30 (d, J = 104.4 Hz, 1H), 7.27(d, J = 8 Hz, 2H), 7.64(d, J = 8 Hz, 2H), 14.72 (s,1H).
[002196] Example 476
[002197] Synthesis of 4-(((trans)-4-(4-(1-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (476)
Figure imgf000619_0001
[002198] Compounds 476B, 476C, 476D, 476E, and 476 were synthesized by employing the procedures described for Compounds 471C, 471D, 471E, 8F, and 1 using Compounds 476A, 476B, 476C, 476D, and 476E in lieu of Compounds 471B, 471C, 471D, 8E, and 1E. Compound 476B: LC-MS (ESI) m/z: 253 [M+Na]+. Compound 476C: LC-MS (ESI) m/z: 131 [M+H]+. Compound 476D: LC-MS (ESI) m/z: 600 [M+H]+. Compound 476E: LC-MS (ESI) m/z: 572 [M+H]+. Compound 476: LC-MS (ESI) m/z: 452 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz) d 1.20-1.26 (m, 3H), 1.60-1.65 (m, 6H), 1.75 (d, J = 12.1 Hz, 1H), 1.83-1.99 (m, 4H), 2.24 (d, J = 10.5 Hz, 2H), 2.64 (t, J = 11.4 Hz, 1H), 3.92 (d, J = 9.7 Hz, 2H), 4.65-4.74 (m, 1H), 6.23 (d, J = 1.7 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.44-7.55 (m, 3H).
[002199] Example 477
[002200] Synthesis of 4-(((1-(3,5-dichlorophenyl)piperidin-4-yl)oxy)methyl)-1H-1,2,3- triazole-5-carboxylic acid (477)
Figure imgf000620_0001
[002201] Compounds 477A, 477B, 477C, 477D, 477E, and 477 were synthesized by employing the procedures described for Compounds 270B, 456A, 372E, 151B, 8F, and 1 using 1,3-dichloro-5-iodobenzene, Compounds 477A, 477B, 477C, 477D, and 477E in lieu of Compounds 197A, 272E-2, 372D, 151A, 8E, and 1E. Compound 477A: LC-MS (ESI) m/z: 246 [M+H]+. Compound 477B: LC-MS (ESI) m/z: 284 [M+H]+. Compound 477C: LC-MS (ESI) m/z: 356 [M+H]+. Compound 477D: LC-MS (ESI) m/z: 519 [M+H]+. Compound 477E: LC-MS (ESI) m/z: 491 [M+H]+. Compound 477: LC-MS (ESI) m/z: 371 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.50-1.52 (m, 2H), 1.86-1.89 (m, 2H), 2.97-3.02 (m, 2H), 3.53-3.65 (m, 3H), 4.81 (s, 2H), 6.78 (s, 1H), 6.91 (m, 2H), 13.18 (s, 1H).
[002202] Example 478
[002203] Synthesis of 4-(((trans)-4-(4-(3- (dimethylamino)propoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2- trifluoroacetate (478)
Figure imgf000621_0001
[002204] Compounds 478B, 478C, 478D, and 478 were synthesized by employing the procedures described for Compounds 340F, 27B, 380E, and 8F using Compounds 478A, 460E, 478B, 478C, and 478D in lieu of Compounds 340E, 27A, 2-bromopropane, 380D, and 8E. Compound 478B: 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.88-1.95 (m, 2H), 2.23 (s, 6H), 2.39 (t, J = 6.8 Hz, 2H), 3.02 (s, 3H), 4.30 (t, J = 6.4 Hz, 2H). Compound 478C: LC-MS (ESI) m/z: 537 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.40 (t, J = 6.8 Hz, 3H), 1.47-1.61 (m, 4H), 1.85-1.89 (m, 2H), 2.10-2.22 (m, 4H), 2.44-2.51 (m, 1H), 2.95 (s, 6H), 3.33-3.37 (m, 2H), 3.79 (s, 3H), 4.07 (t, J = 6.0 Hz, 2H), 4.36-4.42 (m, 2H), 4.94-5.01 (m, 1H), 5.36 (s, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H).
Compound 478D: LC-MS (ESI) m/z: 417 [M+H]+. Compound 478: LC-MS (ESI) m/z: 389 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.55-1.70 (m, 4H), 1.92-1.96 (m, 2H), 2.16- 2.23 (m, 2H), 2.32-2.35 (2H), 2.52-2.61 (m, 1H), 2.95 (s, 6H), 3.32-3.38 (m, 2H), 4.09 (t, J = 6.0 Hz, 2H), 4.74 (s, 1H), 6.88 (d, J = 8.4Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H).
[002205] Example 479
[002206] Synthesis of 4-(((trans)-4-(4-(1-(2-ethyl-2-hydroxybutyl)-1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (479)
Figure imgf000622_0001
[002207] To a solution of 3-methylenepentane (479A, 3.0 g, 35.71 mmol) in
dichloromethane (90 mL) was dropped a solution of 3-chloroperbenzoic acid (9.3 g, 53.56 mmol) in dichloromethane (45 ml) over 30 minutes. The reaction mixture was stirred at room temperature for 16 hours, washed with saturated sodium sulfite solution (100 mL) and saturated sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude Compound 479B.1H-NMR (CDCl3, 400 MHz): d (ppm) 0.92 (t, J = 7.6 Hz, 6H), 1.54-1.68 (m, 4H), 2.59 (s, 2H).
[002208] Compounds 479C, 479D, and 479 were synthesized by employing the procedures described for Compounds 470A, 1, and 8F using Compounds 479B, 479C, and 479D in lieu of 2-ethyl-2-propyloxirane, Compounds 1E, and 8E. Compound 479C: LC-MS (ESI) m/z: 602 [M+H]+. Compound 479D: LC-MS (ESI) m/z: 482 [M+H]+. Compound 479: LC-MS (ESI) m/z: 454 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.68 (t, J = 7.2 Hz, 6H), 1.21-1.33 (m, 4H), 1.65-1.78 (m, 4H), 1.98-2.04 (m, 2H), 2.34-2.40 (m, 2H), 2.67-2.72 (m, 1H), 4.15 (s, 2H), 4.74- 4.80 (m, 1H), 6.33 (d, J = 2.0 Hz, 1H), 7.40 (s, 4H), 7.56 (d, J = 2.0 Hz, 1H).
[002209] Example 480
[002210] Synthesis of 4-(((trans)-4-(4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (480)
Figure imgf000623_0001
[002211] Compounds 480B, 480C, 480D, 480E, and 480 were synthesized by employing the procedures described for Compounds 471C, 471D, 471E, 1, and 8F using Compounds 480A, 480B, 480C, 476D0, and 480E in lieu of Compounds 471B, 471C, 471D, 1E, and 8E.
Compound 480B: LC-MS (ESI) m/z: 227 [M+Na]+.1H-NMR (CD3OD, 400 MHz): d (ppm) 1.20 (s, 6H), 1.46 (s, 9H), 4.8 (s, 4H). Compound 480C: 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.26 (s, 6H), 2.95 (s, 2H). Compound 480D: LC-MS (ESI) m/z: 574 [M+H]+. Compound 480E: LC-MS (ESI) m/z: 454 [M+H]+. Compound 480: LC-MS (ESI) m/z: 426 [M+H]+.1H-NMR (DMSO-d6, 400 MHz): d (ppm) 0.95(s, 6H), 1.53-1.65 (m, 4H), 1.88-1.92 (m, 2H), 2.23-2.25 (m, 2H), 2.61-2.66 (m, 1H), 3.96 (s, 2H), 4.64-4.67(m, 1H), 6.32 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 8 Hz, 2H), 7.42 (d, J = 8 Hz, 2H), 7.52 (d, J = 1.6 Hz, 1H).
[002212] Example 481
[002213] Synthesis of 4-(((1-(2,5-dichlorophenyl)piperidin-4-yl)oxy)methyl)-1H-1,2,3- triazole-5-carboxylic acid 2,2,2-trifluoroacetate (481)
[002214] Compounds 481A, 481B, 481C, 481D, and 481 were synthesized by employing the procedures described for Compounds 456A, 372E, 151B, 1, and 8F using Compounds 291A, 481A, 481B, 481C, and 481D in lieu of Compounds 272E-2, 372D, 151A, 1E, and 8E.
Compound 481A: LC-MS (ESI) m/z: 284 [M+H]+. Compound 481B: LC-MS (ESI) m/z: 356 [M+H]+. Compound 481C: LC-MS (ESI) m/z: 519 [M+H]+. Compound 481D: LC-MS (ESI) m/z: 399 [M+H]+. Compound 481: LC-MS (ESI) m/z: 371 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.84-1.87 (m, 2H), 2.08-2.12 (m, 2H), 2.83-2.88 (m, 2H), 3.27-3.30 (m, 2H), 3.70-3.73 (m, 1H), 4.97 (s, 2H), 6.71 (dd, J = 8.4, 2.0 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H).
[002215] Example 482
[002216] Synthesis of 4-(((trans)-4-(4-chloro-3-cyclobutylphenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carboxylic acid (482)
Figure imgf000624_0001
[002217] Compounds 482B, 482C, 482D, 482E, 482F, 482G, and 482 were synthesized by employing the procedures described for Compounds 8B, 263C, 57E, 141, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane, Compounds 482A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 482B, cyclobutanone, 482C with BF .
3Et2O as acid, 482D, 482E with diphenyl-2-pyridylphosphine and di-tert-Butyl azodicarboxylate, 482F, and 482G in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with tBuONa as base and toluene as solvent, 263A, 263B, 57D with TFA as acid, 140, 90B with triphenylphosphane and DIAD, 8E, and 1E. Compound 482B: LC-MS (ESI) m/z: 329 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.91 (t, J = 6.8 Hz, 2H), 2.45-2.46 (m, 2H), 2.58-2.62 (m, 2H), 4.02 (s, 4H), 5.99-6.01 (m, 1H), 7.24-7.27 (m, 1H), 7.35-7.37 (m, 1H), 7.63-7.64 (m, 1H). Compound 482C: LC-MS (ESI) m/z: 303 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.63-1.73 (m, 1H), 1.92 (t, J = 6.4 Hz, 2H), 2.04-2.18 (m, 1H), 2.41-2.47 (m, 4H), 2.62-2.69 (m, 4H), 2.77 (s, 1H), 4.01- 4.02 (m, 4H), 5.96-5.97 (m, 1H), 7.21-7.23 (m, 1H), 7.26-7.29 (m, 1H), 7.37-7.38 (m, 1H).
Compound 482D: LC-MS (ESI) m/z: 263 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.77- 1.87 (m, 3H), 1.99-2.19 (m, 5H), 2.37-2.44 (m, 2H), 2.51-2.59 (m, 3H), 3.76-3.80 (m, 1H), 4.05- 4.07 (m, 1H), 5.97-5.99 (m, 1H), 7.10-7.12 (m, 1H), 7.12-7.26 (m, 1H), 7.29-7.30 (m, 1H). Compound 482E: LC-MS (ESI) m/z: 247 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.48- 1.60 (m, 3H), 1.81-2.16 (m, 10H), 2.36-2.43 (m, 2H), 2.50-2.56 (m, 1H), 3.75-3.80 (m, 1H), 4.13-4.14 (m, 1H), 6.98-7.01 (m, 1H), 7.05-7.16 (m, 1H), 7.21-7.23 (m, 1H). Compound 482F: LC-MS (ESI) m/z: 524 [M+H]+. Compound 482G: LC-MS (ESI) m/z: 496 [M+H]+. Compound 482: LC-MS (ESI) m/z: 398 [M+Na]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.63-1.89 (m, 4H), 1.95-2.10 (m, 6H), 2.17-2.44 (m, 4H), 2.60-2.65 (m, 1H), 3.75-3.82 (m, 1H), 4.73-4.78 (m, 1H), 7.04-7.06 (m, 1H), 7.21-7.23 (m, 2H).
[002218] Example 483
[002219] Synthesis of 4-(((trans)-4-(4-(((trans)-3- (hydroxymethyl)cyclohexyl)methoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (483)
Figure imgf000625_0001
[002220] To a solution of (trans)-cyclohexane-1,3-dicarboxylic acid (483A, 3 g, 17.44 mmol) in ethanol (20 mL) was dropped neat sulfurous dichloride (6.2 g, 52.32 mmol,) at room temperature, stirred at room temperature for 3 hours, and concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 solution (30 mL) and extracted with ethyl acetate (15mL x 3), the combined organic layers was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford Compound 483B. LC-MS (ESI) m/z: 251 [M+Na]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.26 (t, J = 7.6 Hz, 6H), 1.51-1.57 (m, 2H), 1.67-1.77 (m, 4H), 1.95-1.98 (m, 2H), 2.63-2.69 (m, 2H), 4.13 (q, J = 7.6 Hz, 4H).
[002221] Compounds 483C, 483D, and 483E were synthesized by employing the procedures described for Compounds 283C, 340F, and 27B using Compounds 483B, 483C, 460E, and 483D in lieu of Compounds 283B, 340E, 27A, and 2-bromopropane. Compound 483C: LC-MS (ESI) m/z: 289 [2M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.20-1.28 (m, 2H), 1.34-1.41 (m, 4H), 1.47-1.54 (m, 2H), 1.60-1.67 (m, 2H), 3.45 (d, J = 7.2 Hz, 4H).
Compound 483D: LC-MS (ESI) m/z: 323 [M+Na]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.34- 1.43 (m, 2H), 1.51-1.54 (m, 2H), 1.56-1.59 (m, 2H), 1.62-1.70 (m, 2H), 2.06-2.11 (m, 2H), 3.02 (s, 6H), 4.12-4.14 (m, 4H). Compound 483E: LC-MS (ESI) m/z: 656 [M+H]+.
[002222] To a stirred solution of Compound 483E (650 mg, crude) in t-BuOH (16 mL) was added a solution of NaOH (200 mg, 5 mmol) in H2O (2 mL) and stirred at reflux for 16 hours. After cooled down to room temperature, the mixture was acidified to pH 6 with aqueous HCl solution (2 M) and extracted with ethyl acetate (15 mL x 2). The combined organic layers was dried over anhydrous sodium sulfate, concentrated, and purified with reversed phase
chromatography (elution with MeCN in water, from 15 to 100%) to afford Compound 483F. LC- MS (ESI) m/z: 550 [M+H]+.
[002223] Compound 483 was synthesized by employing the procedure described for Compound 380E using Compound 483F in lieu of Compound 380D, LC-MS (ESI) m/z: 430 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.21-1.27 (m, 1H), 1.34-1.68 (m, 13H), 1.81- 1.83 (m, 2H), 1.96-2.02 (m, 1H), 2.21 (brs, 2H), 3.27-3.29 (m, 2H), 3.80 (d, J = 6.8 Hz, 2H), 4.36 (brs, 1H), 4.63 (brs, 1H), 6.83 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 12.80 (brs, 1H), 14.72 (brs, 1H).
[002224] Example 484
[002225] Synthesis of 4-(((trans)-4-(3-cyclobutyl-4- (trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid (484)
Figure imgf000627_0001
[002226] Compounds 484B, 484C, 484D, 484E, 484F, 484G, 484H, 484I, and 484 were synthesized by employing the procedures described for Compounds 8B, 263C, 455B, 141, 279D, 393F-1, 90C, 8F, and 1 using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2- dioxaborolane, Compounds 484A with Na2CO3 as base and 1,4-dioxane/H2O as solvent, 484B, cyclobutanone, 484C, 484D, 484E with TFA as acid and dichloromethane as solvent, 484F, 484G with diphenyl-2-pyridylphosphine and di-tert-Butyl azodicarboxylate, 484H, and 484I in lieu of (3,4-dichlorophenyl)boronic acid, Compounds 8A with tBuONa as base and toluene as solvent, 263A, 263B, 455A, 140, 279C with HCl as acid and 1,4-dioxane as solvent, 393E, 90B with triphenylphosphine and DIAD, 8E, and 1E. Compound 484B: LC-MS (ESI) m/z: 379
[M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.92 (t, J = 6.4 Hz, 2H), 2.47-2.48 (m, 2H), 2.60- 2.64 (m, 2H), 4.03 (s, 4H), 6.00-6.02 (m, 1H), 7.24 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.34 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H). Compound 484C: LC-MS (ESI) m/z: 353 [M- OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.75-1.83 (m, 1H), 1.93 (t, J = 6.4 Hz, 2H), 2.22- 2.31 (m, 1H), 2.35-2.41 (m, 3H), 2.47-2.48 (m, 1H), 2.59-2.67 (m, 4H), 4.03 (s, 4H), 5.95-5.98 (m, 1H), 7.19 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.31 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H). Compound 484D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.94 (t, J = 6.4 Hz, 2H), 2.48-2.49 (m, 2H), 2.58- 2.59 (m, 2H), 2.63-2.67 (m, 2H), 2.86-2.90 (m, 2H), 4.04 (s, 4H), 5.96-5.99 (m, 1H), 6.42 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H).
Compound 484E: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 484F: LC-MS (ESI) m/z: 313 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.84- 1.89 (m, 1H), 1.91-2.00 (m, 2H), 2.01-2.16 (m, 3H), 2.20-2.25 (m, 2H), 2.33-2.40 (m, 2H), 2.51- 2.54 (m, 4H), 3.01-3.09 (m, 1H), 3.71-3.80 (m, 1H), 7.06 (d, J = 9.6 Hz, 1H), 7.12 (d, J = 9.6 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H). Compound 484G: LC-MS (ESI) m/z: 297 [M-OH]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.66-1.90 (m, 10H), 2.10-2.20 (m, 2H), 2.32-2.38 (m, 2H), 2.53- 2.61 (m, 1H), 3.71-3.80 (m, 1H), 4.12-4.16 (m, 1H), 7.05-7.10 (m, 2H), 7.20 (s, 1H). Compound 484H: LC-MS (ESI) m/z: 574 [M+H]+.1H-NMR (CD3OD, 400 MHz): d (ppm) 1.26 (t, J = 7.2 Hz, 3H), 1.50-1.56 (m, 4H), 1.81-1.95 (m, 4H), 2.09-2.17 (m, 4H), 2.31-2.39 (m, 2H), 2.46-2.52 (m, 1H), 3.70-3.77 (m, 1H), 3.80 (s, 3H), 4.42 (q, J = 7.2 Hz, 2H), 5.04-5.12 (m, 1H), 5.30 (s, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.99 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.08 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H). Compound 484I: LC-MS (ESI) m/z: 546 [M+H]+. Compound 484: LC-MS (ESI) m/z: 448 [M+Na]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.52-1.66 (m, 4H), 1.74-1.81 (m, 1H), 1.87-1.89 (m, 2H), 1.93-2.00 (m, 1H), 2.03-2.13 (m, 2H), 2.22-2.28 (m, 4H), 2.55-2.60 (m, 1H), 3.61-3.70 (m, 1H), 4.65-4.69 (m, 1H), 7.00-7.07 (m, 2H), 7.19 (d, J = 2.0 Hz, 1H).
[002227] Example 485
[002228] Synthesis of 4-(((trans)-4-(4-(3-(2-methoxyethyl)-1H-pyrazol-5- yl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5-carboxylic acid 2,2,2-trifluoroacetate (485)
Figure imgf000629_0001
[002229] Compound 485B was synthesized by employing the procedure described for Compound 464B using Compound 485A with toluene as solvent and p-TsOH as acidic catalyst,in lieu of Compound 464A without acid as acidic catalyst, LC-MS (ESI) m/z: 203
[M+Na]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.60-1.73 (m, 3H), 1.99-2.19 (m, 3H), 3.70-3.77 (m, 1H), 4.06-4.12 (m, 1H), 5.46-5.49 (m, 1H), 6.84 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 10.0 (s, 1H).
[002230] To the solution of (methoxymethyl)triphenylphosphonium chloride (8.4 g, 24.4 mmol) in THF (20 mL) was dropped a solution of n-BuLi in hexane (2.5 M, 9.76 mL, 24.4 mmol) at 0 oC and stirred at 0 oC for 1 hour. The mixture was cooled down to -78 oC and a solution of Compound 485B (2.2 g, 12.2 mmol) in THF (10 mL) was dropped and stirred at -78 oC for 1 hour. It was warmed gradually to room temperature, stirred overnight, and quenched with saturated NH4Cl solution (20 mL), and extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL) and brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to give Compound 485C. LC-MS (ESI) m/z: 209 [M+H]+.
[002231] Compounds 485D, 485E, 485F, 485G, 485H, 485I, and 485 were synthesized by employing the procedures described for Compounds 141, 475E, 475F, 475G, 4B, 8F, and 1 using Compounds 485C, 485D with HCl as acid and EtOH as solvent, 485E with TFA as acid and dichloromethane as solvent, 485F, 475A, 485G with K2CO3 as base and 1,4-dioxane/H2O as solvent, 485H, and 485I in lieu of Compounds 140, 475D with TFA as acid and dichloromethane as solvent, 475E, 475F, (4-bromophenyl)boronic acid, 4A with Na2CO3 as base and
toluene/EtOH/H2O as solvent, 8E, and 1E. Compound 485D: LC-MS (ESI) m/z: 211 [M+H]+. Compound 485E: LC-MS (ESI) m/z: 127 [M+H]+. Compound 485F: LC-MS (ESI) m/z: 379 [M+H]+.1H-NMR (CDCl3, 400 MHz): d (ppm) 2.94 (t, J = 5.6 Hz, 2H), 3.41 (s, 3H), 3.62 (t, J = 5.6 Hz, 2H), 10.82 (s, 1H). Compound 485G: LC-MS (ESI) m/z: 253 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 2.90 (t, J = 5.6 Hz, 2H), 3.40 (s, 3H), 3.61 (t, J = 5.6 Hz, 2H), 6.22 (s, 1H). Compound 485H: LC-MS (ESI) m/z: 560 [M+H]+. Compound 485I: LC-MS (ESI) m/z: 532 [M+H]+. Compound 485: LC-MS (ESI) m/z: 412 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.51-1.66 (m, 4H), 1.86-1.90 (m, 2H), 2.22-2.25 (m, 2H), 2.55-2.64 (m, 1H), 2.81 (t, J = 7.2 Hz, 2H), 3.25 (s, 3H), 3.57 (t, J = 7.2 Hz, 2H), 4.62 (s, 1H), 6.44 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 12.73 (s, 2H), 14.71 (s, 1H).
[002232] Example 486
[002233] Synthesis of 4-((((trans)-4-(3,5-dichlorophenyl)cyclohexyl)oxy)methyl)-1H- 1,2,3-triazole-5-carboxylic acid (486)
Figure imgf000631_0001
[002234] Compounds 486A, 486B, 486C, 486D, and 486 were synthesized by employing the procedures described for Compounds 456A, 372E, 151B, 8F, and 1 using Compounds 304D- 1, 486A, 486B, 486C, and 486D in lieu of Compounds 272E-2, 372D, 151A, 8E, and 1E.
Compound 486A: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.37-1.53 (m, 4H), 1.93-1.96 (m, 2H), 2.18-2.21 (m, 2H), 2.43-2.44 (m, 1H), 2.47-2.52 (m, 1H), 3.50-3.59 (m, 1H), 4.23 (s, 2H), 7.08-7.09 (m, 2H), 7.19- 7.20 (m, 1H). Compound 486B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H-NMR (CDCCl3, 400 MHz): d (ppm) 1.33 (t, J = 7.2 Hz, 3H), 1.37-1.55 (m, 4H), 1.93-1.96 (m, 2H), 2.17-2.20 (m, 2H), 2.44-2.52 (m, 1H), 3.49-3.56 (m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.35 (s, 2H), 7.07-7.08 (m, 2H), 7.19-7.20 (m, 1H). Compound 486C: LC-MS (ESI) m/z: 518 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.37 (t, J = 7.2 Hz, 3H), 1.41-1.51 (m, 4H), 1.92-1.95 (m, 2H), 2.21-2.24 (m, 2H), 2.44-2.51 (m, 1H), 3.46-3.52 (m, 1H), 3.78 (s, 3H), 4.39 (q, J = 7.2 Hz, 2H), 4.82 (s, 2H), 5.81 (s, 2H), 6.84 (d, J = 9.2 Hz, 2H), 7.07-7.09 (m, 2H), 7.18-7.19 (m, 1H), 7.30 (d, J = 9.2 Hz, 2H). Compound 486D: LC-MS (ESI) m/z: 490 [M+H]+. Compound 486: LC-MS (ESI) m/z: 370 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.40- 1.59 (m, 4H), 1.91-1.94 (m, 2H), 2.23-2.26 (m, 2H), 2.53-2.60 (m, 1H), 3.53-3.58 (m, 1H), 4.98 (s, 2H), 7.21-7.22 (m, 2H), 7.24-7.25 (m, 1H).
[002235] Example 487 [002236] Synthesis of (4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazol-5-yl)methanol (487)
Figure imgf000632_0001
[002237] To a solution of Compound 87D (330 mg, 0.68 mmol) in THF (20 ml) was added a solution of borane in THF (1 M, 2 mL, 2.0 mmol) and stirred at 45 oC for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50% v/v) to give Compound 487A. LC-MS (ESI) m/z: 472 [M+H]+.
[002238] A mixture of Compound 487A (100 mg, 0.212 mmol) and TFA (6 mL) were stirred at 50 oC for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified with preparative HPLC to afford Compound 487. LC-MS (ESI) m/z: 352 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 4.76 (s, 2H), 7.235 (d, J = 8.0 Hz, 2H), 7.277 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 8.0 Hz, 4H).
[002239] Example 488
[002240] Synthesis of (4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazol-5-yl)methanol (488)
Figure imgf000632_0002
[002241] To a solution of Compound 272F-1 (3.0 g, 5.8 mmol) in anhydrous THF (60 mL) was dropped a solution of LiAlH4 in THF (1 M, 11.6 mL, 11.6 mmol). The mixture was stirred at room temperature under nitrogen for 2 hours, carefully quenched with diluted aqueous HCl solution (1 M, 10 mL) and H2O (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified with flash column chromatography on silica gel (THF in
dichloromethane, from 0% to 30% v/v) to yield Compound 488A. LC-MS (ESI) m/z: 478 [M+H]+; 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.48-1.53 (m, 4H), 1.92-1.94 (m, 2H), 2.18-2.27 (m, 2H), 2.50-2.52 (m, 1H), 3.33 (s, 1H), 3.78 (s, 3H), 4.41-4.44 (m, 1H), 4.71 (s, 2H), 5.24 (s, 2H), 6.85-6.87 (m, 2H), 7.12-7.19 (m, 4H), 7.24-7.26 (m, 2H).
[002242] A mixture of Compound 488A (0.2 g, 0.4 mmol) and Pd/C (10%, 0.1 g) in MeOH (10 mL) under hydrogen (1 atm.) was stirred at room temperature for 16 hours. The mixture was filtered through Celite and the filtrate was evaporated to afford Compound 488. LC-MS (ESI) m/z: 358 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.62-1.68 (m, 4H), 1.96-1.98 (m, 2H), 2.34-2.36 (m, 2H), 2.65-2.66 (m, 1H), 4.57-4.60 (m, 3H), 7.18 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H).
[002243] Example 489
[002244] Synthesis of (4-(((cis)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)thio)-1H- 1,2,3-triazol-5-yl)methanol (489)
Figure imgf000633_0001
[002245] Compounds 489A and 489 were synthesized by employing the procedures described for Compounds 487 and 488A using Compounds 348B and 489A in lieu of
Compounds 487A and 272F-1. Compound 489A: LC-MS (ESI) m/z: 416 [M+H]+. Compound 489: LC-MS (ESI) m/z: 374 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.37-1.47 (m, 2H), 1.51-1.61 (m, 2H), 1.87-1.90 (m, 2H), 2.05-2.07 (m, 2H), 2.52-2.57 (m, 1H), 3.58-3.66 (m, 1H), 4.89 (s, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H).
[002246] Example 490
[002247] Synthesis of 4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H- 1,2,3-triazole-5-carbaldehyde (490)
Figure imgf000633_0002
[002248] A mixture of Compound 488 (0.1 g, 0.3 mmol), NaHCO3 (59 mg, 0.7 mmol), and Dess-Martin periodinane (0.2 g, 0.4 g) in dichloromethane (10 mL) were stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified with preparative HPLC to yield Compound 490. LC-MS (ESI) m/z: 356 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.57-1.63 (m, 4H), 1.86-1.88 (m, 2H), 2.25-2.26 (m, 2H), 2.65-2.66 (m, 1H), 4.72-4.74 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 9.92 (s, 1H).
[002249] Example 491
[002250] Synthesis of 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3- triazole-5-carbaldehyde (491)
Figure imgf000634_0001
[002251] To a solution of Compound 487 (200 mg, 0.57 mmol) in EtOAc (20 mL) was added IBX (958 mg, 3.42 mmol) and stirred at 75 oC for 12 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified with preparative HPLC to afford
Compound 491. LC-MS (ESI) m/z: 350 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 7.28- 7.30 (d, J = 8.8Hz, 2H), 7.45 -7.47 (d, J = 8.0Hz, 2H), 7.71 -7.73 (d, J = 9.2Hz, 2H), 7.78 -7.80 (d, J = 8.8Hz, 2H), 10.01 (s, 1H).
[002252] Example 492
[002253] Synthesis of (4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3- triazol-5-yl)methanol (492)
Figure imgf000634_0002
[002254] Compound 492A was synthesized by employing the procedure described for Compound 488A using Compound 278A in lieu of Compound 272F-1, LC-MS (ESI) m/z: 609 [M+H]+.
[002255] A mixture of Compound 492A (300 mg, crude) and TES (1 mL) in TFA (5 mL) were stirred at room temperature for 4 hours. The mixture was concentrated and purified with preparative HPLC (TFA-MeCN-H2O) to afford Compound 492. LC-MS (ESI) m/z: 367 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.59 (s, 2H), 1.71 (s, 4H), 3.32 (s, 4H), 4.55 (s, 2H), 7.20 (d, J = 8.4 Hz, 4H), 7.52– 7.71 (m, 4H).
[002256] Example 493
[002257] Synthesis of (4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5- yl)methanol 2,2,2-trifluoroacetate (493-1) and (4-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)-1H- 1,2,3-triazol-5-yl)methanol 2,2,2-trifluoroacetate (493-2)
Figure imgf000635_0001
[002258] To a solution of compound Intermediate I (200 mg, 0.463 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added (3,4-dichlorophenyl)boronic acid (105 mg, 0.556 mmol), Pd(dppf)Cl2 chloride (27 mg, 0.037 mmol), and Na2CO3 (318 mg, 3.0 mmol) and stirred at 90 oC under nitrogen atmosphere for 3 hours. The reaction mixture was cooled down to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (ethyl acetate/petroleum ether, 0~38%) to give compound 165B. LC-MS (ESI) m/z: 498 [M+H]+. [002259] Compound 493A and Compounds 493-1 and 493-2 were synthesized by employing the procedures described for Compounds 487 and 488A using Compounds 165B and 493A in lieu of Compounds 487A and 272F-1. The resulting mixture of Compounds 493-1 and 493-2 was separated by procedures described herein. Compound 493A: LC-MS (ESI) m/z: 378 [M+H]+. Compound 493-1: LC-MS (ESI) m/z: 336 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.42 (d, J = 5.6Hz, 2H), 5.17 (t, J = 5.6Hz, 1H), 7.08-7.15 (m, 2H), 7.64-7.74 (m, 4H), 7.92 (d, J = 1.6Hz, 1H), 14.53 (brs, 1H). Compound 493-2: LC-MS (ESI) m/z: 302 [M+H]+; 1H- NMR (DMSO-d6, 400 MHz): d (ppm) 4.42 (d, J=4.8Hz, 2H), 5.17 (s, 1H), 7.12-7.14 (m, 2H), 7.39-7.51 (m, 2H), 7.61-7.70 (m, 4H), 14.51 (brs, 1H).
[002260] Example 494
[002261] Synthesis of (4-((1-(3,5-dichlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazol-5- yl)methanol 2,2,2-trifluoroacetate (494)
Figure imgf000636_0001
[002262] Compounds 484A and 494 were synthesized by employing the procedures described for Compounds 487 and 488A using Compounds 285C and 484A in lieu of
Compounds 487A and 272F-1. Compound 494A: LC-MS (ESI) m/z: 385 [M+H]+. Compound 494: LC-MS (ESI) m/z: 343 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.87-1.96 (m, 2H), 2.11-2.18 (m, 2H), 3.15-3.30 (m, 2H), 3.55-3.61(m, 2H), 4.57 (s, 2H), 4.75-4.82 (m, 1H), 6.77 (s, 1H), 6.91 (s, 2H).
[002263] Example 495
[002264] Synthesis of (4-((1-(3,5-dichlorophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazol- 5-yl)methanol 2,2,2-trifluoroacetate (495)
Figure imgf000636_0002
[002265] Compounds 495A and 495 were synthesized by employing the procedures described for Compounds 487 and 488A using Compounds 325A and 495A in lieu of
Compounds 487A and 272F-1. Compound 495A: LC-MS (ESI) m/z: 401 [M+H]+. Compound 495: LC-MS (ESI) m/z: 359 [M+H]+; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.62-1.71 (m, 2H), 2.00-2.04 (m, 2H), 2.85-2.92 (m, 2H), 3.22-3.32 (m, 1H), 3.65-3.70 (m, 2H), 4.72 (s, 2H), 6.76 (s, 1H), 6.85 (s, 2H).
[002266] Example 496
[002267] Synthesis of (4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol- 5-yl)methanol (496)
Figure imgf000637_0001
[002268] Compounds 496A and 496 were synthesized by employing the procedures described for Compounds 484A and 487 using Compounds 221A and 496A in lieu of
Compounds 272F-1 and 487A. Compound 496A: LC-MS (ESI) m/z: 471 [M+H]+. Compound 496: LC-MS (ESI) m/z: 351 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 1.60 (s, 2H), 1.74 (s, 4H), 3.35 (s, 4H), 4.43 (s, 2H), 7.01-7.13 (m, 4H), 7.63 (d, J = 7.7 Hz, 4H).
[002269] Example 497
[002270] Synthesis of (4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3- triazol-5-yl)methanol (497)
Figure imgf000637_0002
[002271] Compound 497A was prepared according to procedures described herein.
Compounds 497B and 497 were synthesized by employing the procedures described for
Compounds 487 and 488A using Compounds 497A and 497B in lieu of Compounds 487A and 272F-1. Compound 497B: LC-MS (ESI) m/z: 410 [M+H]+. Compound 497: LC-MS (ESI) m/z: 368 [M+H]+; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 4.49-4.61 (m, 2H), 5.26-5.67 (m, 1H), 7.19-7.26 (m, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 15.32-15.75 (m, 1H).
BIOLOGICAL EXAMPLES
[002272] The following describes ways in which the compounds described herein were tested to measure in vitro activity in enzymatic assays. A person of ordinary skill in the art would know that variations in the assay conditions could be used to determine the activity of the compounds.
[002273] Assay 1: GO Enzymatic Assay
[002274] Human GO was obtained from Novus Biologicals (NBP1-72412, Novus
Biologicals, LLC, 8100 Southpark Way, A-8 Littleton, CO 80120, USA). A coupled
fluorescence GO enzymatic assay was performed as previously described (Martin-Higueras et al., Mol Ther.24(4): 719-725 (2016)). GO was incubated with its substrate, glycolate, in 50 mM potassium phosphate buffer, pH 7. The addition of sulfonated-DCIP and 4-aminoantipyrine (Sigma Aldrich) in a coupled HRP reaction produced a chromogen that was measured at 515 nm. The enzyme assay was linear and sensitive. The enzyme was optimized and the kinetics was determined. The Km of substrate was determined to be about 50 ^M, where the tolerance of DMSO was 0.5% in both compound-treated and mock-treated samples.
[002275] Compound inhibition was determined by adding various concentrations of inhibitors in the GO enzyme assay. The IC50 value for each measured compound was generated from sigmoidal dose-response (variable slope) curves with GraphPad Prism software (GraphPad Software, Inc., San Diego, CA) using the percent inhibition of GO activity relative to DMSO control.
[002276] Assay 2: GO Cellular Assay: primary hepatocyte assay
[002277] Primary hepatocytes were used for a GO cellular assay as previously described (Martin-Higueras et al., Mol Ther.24(4): 719-725 (2016)). Hepatocytes were isolated using an in situ collagenase perfusion method from male C56BL/6 mice liver. The freshly isolated hepatocytes were cultured in six well plates with Williams E medium supplemented with 5% fetal bovine serum, 2 mM l-glutamine, 100 U/ml penicillin, 100 mg/ml streptomycin, 2.2 mUI/ml insulin and 0.3 mg/ml hydrocortisone. After 5 hours, the medium was changed to Williams E complete medium (Biochrom, Cambridge,UK) without serum and cells were treated with various concentrations of inhibitors in the presence of 5 mM glycolate. Culture medium was harvested at 72 hours after treatment, and the oxalate was quantified by using an oxalate oxidase assay kit (Trinity Biotech, Co Wicklow, Ireland) following manufacturer’s instructions. The oxalate level was also confirmed by LC-MS method. The IC50 value for each measured compound was generated from sigmoidal dose-response (variable slope) curves with GraphPad Prism software (GraphPad Software, Inc., San Diego, CA) using the percent inhibition of GO activity relative to DMSO control.
[002278] Assay 3: GO Cellular Assay: CHO-Agt Cells Assay
[002279] CHO cells (A.T.C.C. number CCl-61) and engineered CHO-Agt cells (provided by Dr. Sonia Fargue and Dr. Christopher J. Danpure, Biochem. J. (2006) 394, 409–416) were used as a screening cellular assay for primary compounds. The cells were seeded in 20,000 cell/well in 96 well plate and cultured at 37◦C under O2/CO2 (19:1) in Ham’s F12 medium (Invitrogen) supplemented with fetal calf serum (10%, v/v), L-glutamine (2 mM), penicillin (100 units/ml) and streptomycin (100 mg/ml). After overnight culture, the cells were treated with various concentrations of inhibitors in the presence of 100 uM glycolic acid in HEPES buffer, pH7.0 (Sigma-Aldrich, Cat#124737). Culture medium was harvested at 2 hours after treatment for glyoxylate analysis and cell viability was measured by Cell Titer-Glo (Fisher Scientific, Cat#. PR-G7570).
[002280] The glyoxylate was quantified using LC-MS method. An aliquot of 120 µL medium was removed from each well and protein precipitated by adding 240 µL IS (100 ng/ml 13C2-glyoxylic acid, Sigma-Aldrich, Cat#G755002). The mixture was vortex-mixed well and centrifuged at 3900 rpm for 15 min, 4°C.100 µL supernatant was then mixed with 10 µL formic acid and 100 µL 400 µM DNPH (2,4-dinitrophenylhydrazine) (Shanghai Runjie Huaxue Shiji Ltd., Cat# A0000436) and the mixture was shaken for 30 minutes. A 3 µL mixture of reaction mixture was injected for LC-MS/MS analysis. (Behnam JT, Williams EL, Brink S, Rumsby G, Danpure CJ.,“Reconstruction of human hepatocyte glyoxylate metabolic pathways in stably transformed Chinese-hamster ovary cells”, Biochem J.2006 Mar 1;394(Pt 2):409-16.)
[002281] Using the above assays, the compounds of Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6 were tested. In Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6 biological data range of IC50 values calculated from the enzymatic assays (Assay 1) are provided, where: A is < 0.1 µM;
B is 0.1 to 1.0 µM;
C is > 1.0 to 10 µM;
D is > 10 µM; and
NA is not active under the tested condition.
[002282] Using the above assays, the compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7 were tested. In Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7 biological data range of IC50 values calculated from the cellular assays (Assay 3), where:
A* is < 1 mM;
B* is 1 to 5 mM;
C* is > 5 to 10 mM;
D* is > 10 mM;
NA is not active under the tested condition.
[002283] Using the above assays, the compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7 were tested. In Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7 biological data range of IC50 values calculated from the cellular assays (Assay 2), where:
A** is < 1 mM;
B** is 1 to 5 mM;
C** is > 5 to 10 mM;
D** is > 10 mM;
NA is not active under the tested condition. Table 1
Figure imgf000640_0001
Figure imgf000641_0001
Figure imgf000642_0001
Figure imgf000643_0001
Figure imgf000644_0001
Figure imgf000645_0001
Figure imgf000646_0001
Figure imgf000647_0001
Figure imgf000648_0001
Figure imgf000649_0001
Figure imgf000650_0001
Figure imgf000651_0001
Table 2
Figure imgf000651_0002
Figure imgf000652_0001
Figure imgf000653_0001
Figure imgf000654_0001
Figure imgf000655_0001
Figure imgf000656_0001
Figure imgf000657_0001
Figure imgf000658_0001
Figure imgf000659_0001
Figure imgf000660_0001
Figure imgf000661_0001
Table 3
Figure imgf000661_0002
Table 4
Figure imgf000661_0003
Figure imgf000662_0001
Figure imgf000663_0001
Figure imgf000664_0001
Figure imgf000665_0001
Figure imgf000666_0001
Figure imgf000667_0001
Figure imgf000668_0001
Table 5
Figure imgf000668_0002
Table 6
Figure imgf000668_0003
Table 7
Figure imgf000669_0001
[002284] Primary Hyperoxaluria type I mouse model
[002285] PH1 male mice (agxt-/-) are obtained from Dr. Salido (Salido et al., Proc Natl Acad Sci USA., 103(48): 18249-18254 (2006 Nov.28)) and are housed in the“Association for Assessment and Accreditation of Laboratory Animal Care” (AAALAC) in Bulk Institute, Novato, following standards and procedures approved by the local“Institutional Animal Care and Use Committee” for ethical use of animals in experiments. Mice are fed with normal chow and drinking water, and are oral dosed with GO inhibitors at specific time intervals. Mice are individually housed in a metabolic cage for a 5~7 day acclimation period before the first oral dosing and at the time of sample collection.
[002286] Urine and plasma samples are collected every 24 hours for biomarker analysis. Biomarkers include glycolate (LC-MS), oxalate (Oxalate kit, Trinity Biotech #591-D), creatinine (Creatinine Urinary Colorimetric Assay Kit, Cayman Chemical #500701), LDH (using LDH Activity Colorimetric Assay Kit, BioVision Inc.#K726), and Ca+2.
[002287] Urine is collected every 24 hours using the metabolic cage. Urine is collected 3 days before the first oral dosing to establish baseline, and at the end of treatment. For the oxalate measurement, the urine sample is acidified by collection in a tube containing 50 ^l of 6N HCl. Any urine samples with volumes less than 1 ml and/or urine samples that are contaminated with food and/or fecal matter are excluded from collection.
[002288] Plasma is collected using lithium-heparin as anticoagulant. Plasma is ultrafiltered at 1500xg for 30 min at 4°C using a Centrisart-Iultrafiltration vial (Sartorius, Type: Vivaspin® 500 ml). Plasma is placed in the inner chamber of the vial and 20mL of 2 molar HCl per ml plasma is added into the outer chamber to ensure simultaneous acidification of the ultrafiltrate. The acidified plasma is stored at -80 °C before being delivered on dry ice for oxalate and glycolate measurement.
[002289] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following description. It should be understood, however, that the description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present description will become apparent from this detailed description.
[002290] Each publication, including patents, patent applications and published patent applications, cited herein is hereby incorporated by reference in its entirety for all purposes. Exemplary Embodiments
[002291] A1. A compound of Formula (I):
Figure imgf000671_0001
wherein:
ring C is selected from:
Figure imgf000671_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to the
carbonyl of C(O)-OR1, and the C2 carbon to L;
L is a bond, CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl, hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is C3-8 cycloalkyl, C8-11 spirocycloalkyl, 5-8 membered heterocycloalkyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thienyl, phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl, pyridyl, indolyl, benzothiazolyl, quinolinyl, isoquinolinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or tetrahydro-methanonaphthalenyl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with one or two groups
independently selected from halo, alkyl, alkoxy, cyano, hydroxy, haloalkoxy, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present and Ring A is phenyl, then Ring A is substituted with:
(i) one or two RAA groups;
(ii) 2 halo groups when L is other than O;
(iii) 2 halo groups when L is O, and R2 and R3 are not hydrogen or alkyl; (iv) one halo group when L is CH2NRL;
(v) one halo group and one group selected from the group consisting of haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, and (phenyl)alkoxy, when L is bond, O, S, or S(=O), wherein the phenyl is optionally substituted with halo, cyano, haloalkyl, or haloalkoxy; or
(vi) one cyano group and one (phenyl)alkoxy group, when L is bond or O, wherein the phenyl as part of the (phenyl)alkoxy group is optionally substituted with halo or haloalkoxy;
when Ring B is not present and Ring A is other than phenyl, then
(i) Ring A is substituted with one or two RAB groups or
(ii) Ring A is unsubstituted, wherein:
1) when Ring A is unsubstituted tetrahydroquinolinyl, then L is a bond;
2) when Ring A is unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl, then L is O; 3) when Ring A is unsubstituted tetrahydronaphthyl, then L is O, and R1 is not hydrogen or ethyl; or
4) when Ring A is unsubstituted spirocycloalkyl, then L is O, S, or CH2S; each RAA is independently alkyl; haloalkyl; haloalkoxy; cycloalkyloxy; (cycloalkyl)alkoxy; phenoxy optionally substituted with one or two halo groups; or
alkylcarbonylaminoalkoxy;
each RAB is independently halo; alkyl; hydroxy; alkoxy; haloalkyl; haloalkoxy; cycloalkyloxy;
(cycloalkyl)alkoxy; or phenoxy optionally substituted with one or two halo groups; Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is
optionally substituted with 1, 2, or 3 RB groups;
each RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl; aminosulfonyl;
alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy;
alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy; haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl;
alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy;
(cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy; heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl-one)alkyl; 5-6-membered
heterocycloalkyl-one; (heterocycloalkyl)alkyl; heterocycloalkylcarbonyl; or
5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or W; wherein W is alkyl substituted with amino, alkylamino, dialkylamino, alkylcarbonyloxy, alkoxycarbonyl, phenylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,
alkoxycarbonyloxy, cycloalkylcarbonyloxy, -N(R1A)C(O)R1B, -N(R1A)C(O)OR1B, or -N(R1A)C(O)NR1BR1C; wherein R1A, R1B, and R1C are each independently hydrogen or C1-6 alkyl;
R2 and R3 are independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl;
wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy,
alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
provided:
i. when L is S or CH2, and Ring A is phenyl other than phenyl substituted with
(cycloalkyl)alkoxy, then Ring B cannot be halo-substituted phenyl;
ii. when L is O, Ring A is phenyl, and Ring B is not present, then RAA cannot be alkyl; iii. when L is O, Ring A is phenyl substituted with 1 RAA, and Ring B is not present, then RAA cannot be meta-substituted trifluoromethyl;
iv. when L is O, Ring A is phenyl, Ring B is not present, and R1 is ethyl, then RAA cannot be trifluoromethoxy;
v. when L is bond, Ring A is other than phenyl, Ring B is not present, and R1 is H, then RAB cannot be methyl, and
vi. when L is NH, Ring A is pyridyl, indolyl, or indolinyl, and Ring B is not present, then RAB cannot be alkyl; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002292] A2. The compound of Exemplary Embodiment A1, wherein the compound is selected from from the group consisting of compounds in Table 1, Table 2, Table 3, Table 4, Table 5, or Table 6; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002293] A3. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from from the group consisting of compounds in Table 1; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002294] A4. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from from the group consisting of compounds in Table 2; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002295] A5. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from from the group consisting of compounds in Table 3; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002296] A6. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from from the group consisting of compounds in Table 4; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002297] A7. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from from the group consisting of compounds in Table 5; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002298] A8. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from from the group consisting of compounds in Table 6; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002299] A9. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from the group consisting of compounds in Table 1, Table 2, and Table 4; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof. [002300] A10. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from the group consisting of Compounds 1-168; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002301] A11. The compound of any one of Exemplary Embodiments A1-A2 or A10, wherein the compound is selected from from the group consisting of compounds: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25-1, 25-2, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58-1, 58-2, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 111-1, 111-2, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 152, 153, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166, 167, and 168; optionally as a tautomer, a single stereoisomer or mixture of
stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002302] A12. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from the group consisting of Compounds 169-375; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002303] A13. The compound of any one of Exemplary Embodiments A1-A2 or A12, wherein the compound is selected from from the group consisting of compounds: 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 185, 186, 187, 188, 189, 190, 194, 195, 196, 197, 198, 199, 200, 201, 203, 204, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272-1, 272- 2, 273, 274, 275, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 295, 297, 298, 299, 300, 301, 303, 304, 305, 306, 307, 308-1, 308-2, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 367, 368, 369, 370, 373, and 375; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002304] A14. The compound of Exemplary Embodiment A1 or A2, wherein the compound is selected from the group consisting of Compounds 376-486; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002305] A15. The compound of any one of Exemplary Embodiments A1-A2 or A14, wherein the compound is selected from from the group consisting of compounds: 376, 377, 379, 380, 381, 382, 383, 384, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442-1, 442-2, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, and 486; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002306] A16. A compound of Formula (XII):
Figure imgf000676_0001
wherein:
ring C is selected from:
Figure imgf000676_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; Z is -C(=O)H or -CH2OY; Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); -SO2NR5R6; -P(=O)(OR7)2;
-P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups; each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy;
haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11,
-N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9,
-C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14,
-SO2N(R9)2, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl,
cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
provided:
i. the compound represented by Formula (XII) is exclusive of:
a. 4-(phenylamino)-1H-1,2,3-triazole-5-carbaldehyde;
b. 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-5- carbaldehyde;
c. ethyl hydrogen (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate;
d. diethyl (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)- 1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; and
e. 1-((4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methyl)-5-methylpyrimidine- 2,4(1H,3H)-dione;
ii. when Z is -C(=O)H, L is NRL, RL is hydrogen, and Ring A is phenyl, then Ring B is present and/or the phenyl Ring A is substituted with 1, 2, or 3 RA2 groups; iii. when Z is -C(=O)H, L is CH2, and Ring A is cyclopropyl, phenyl, indole, or thiophene, then Ring B is present;
iv. when Z is -C(=O)H, L is CH2-O, and Ring A is phenyl, then Ring B is present; v. when Z is -CH2OY, Y is W, W is -P(=O)(OR7)2 or -P(=O)(OR7)(O-), R7 is ethyl, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and vi. when Z is -CH2OY, Y is hydrogen, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002307] A17. A compound of Formula (XII):
Figure imgf000679_0001
wherein:
ring C is selected from:
Figure imgf000679_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is a CF2, O, S, S(=O), C(=O), CH2-NRL, CH2-S, or Q-CH2; wherein Q is O, NRL, or S; Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); -SO2NR5R6; -P(=O)(OR7)2;
-P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-; RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups; each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy;
haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, -N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9,
-C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14,
-SO2N(R9)2, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl,
cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002308] A18. A compound of Formula (XII):
Figure imgf000681_0001
wherein:
ring C is selected from:
Figure imgf000681_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is a CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH L
2; wherein Q is O, NR , or S; Z is -CH2OY; Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); -SO2NR5R6; -P(=O)(OR7)2;
-P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups; each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy;
haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl,
alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, -N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9,
-C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14,
-SO2N(R9)2, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl,
cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002309] A19. A compound of Formula (XII):
Figure imgf000683_0001
wherein:
ring C is selected from:
Figure imgf000683_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is a CF2, O, S, S(=O), C(=O), CH2-NRL, CH2-S, or Q-CH2; wherein Q is O, NRL, or S; Z is -C(=O)H;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups; each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy;
haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl,
alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002310] A20. A compound of Formula (XII):
Figure imgf000685_0001
wherein:
ring C is selected from:
Figure imgf000685_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is a CF2, O, S, S(=O), or C(=O);
Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); -SO2NR5R6; -P(=O)(OR7)2;
-P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups; each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy;
haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11,
-N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, - C(=O)OR9, -C(=O)N(R9)2, -N(R9) 9 9
2, -SR , -S(O)R , -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14,
-SO2N(R9)2, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl,
cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002311] A21. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16, wherein:
L is a CF2, O, S, S(=O), C(=O), CH2-NRL, CH2-S, or Q-CH2; wherein Q is O, NRL, or S.
[002312] A22. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16, wherein:
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; and
Z is -CH2OY.
[002313] A23. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16, wherein:
L is a CH2, CF L
2, O, NR , S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; and
Z is -CH2OY;
provided:
i. the compound represented by Formula (XII) is exclusive of:
a. ethyl hydrogen (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; b. diethyl (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; and c. 1-((4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methyl)-5- methylpyrimidine-2,4(1H,3H)-dione;
ii. when Z is -CH2OY, Y is W, W is -P(=O)(OR7)2 or -P(=O)(OR7)(O-), R7 is ethyl, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
iii. when Z is -CH2OY, Y is hydrogen, L is CH2, and Ring A is pyrimidine-2,4- dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002314] A24. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16, wherein:
L is a CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; and Z is -CH2OY.
[002315] A25. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16, wherein:
L is a CF2, O, S, S(=O), C(=O), CH2-NRL, CH2-S, or Q-CH2; wherein Q is O, NRL, or S; and
Z is -C(=O)H;
[002316] A26. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16, wherein:
L is a CF2, O, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S;
provided:
i. the compound represented by Formula (XII) is exclusive of 4-(((tetrahydro-2H- pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-5-carbaldehyde; and
ii. when Z is -C(=O)H, L is CH2-O, and Ring A is phenyl, then Ring B is present; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002317] A27. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A26, wherein: L is a CF2, O, S, S(=O), or C(=O).
[002318] A28. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A26, wherein:
L is a O or S.
[002319] A29. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A26, wherein:
L is a O.
[002320] A30. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16 or A17, wherein:
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); -SO2NR5R6; -P(=O)(OR7)2; - P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy;
haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11, -N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9, - C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14,
-SO2N(R9)2, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl,
cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002321] A31. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16 or A17, wherein:
ring C is:
Figure imgf000691_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is O or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen;
Ring A is C5-7 cycloalkyl, 7-9 membered heterocycloalkyl, aryl, or heteroaryl; wherein Ring A is optionally substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
Ring B is C5-7 cycloalkyl, 7-9 membered heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; C1-4 alkyl; C1-4 hydroxyalkyl; C1-4
haloalkyl; C1-4 alkoxy; C1-4 aminoalkoxy; C1-4 hydroxyalkoxy; C1-4 haloalkoxy; C1-4 alkylcarbonyl; C1-4 alkoxyalkoxy; C1-4 aminocarbonyl; C3-6 cycloalkyl; 7-9 membered heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; and
R2 is independently hydrogen;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002322] A32. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16 or A17, wherein:
ring C is:
Figure imgf000691_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is O or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen;
Ring A is C5-7 cycloalkyl, piperidinyl, or phenyl; wherein Ring A is optionally
substituted with 1 or 2 RA1 groups;
each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy,
hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
Ring B is C5-7 cycloalkyl, 7-9 membered heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; C1-4 alkyl; C1-4 hydroxyalkyl; C1-4
haloalkyl; C1-4 alkoxy; C1-4 hydroxyalkoxy; C1-4 haloalkoxy; C3-6 cycloalkyl; 7-9 membered heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; and
R2 is independently hydrogen;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002323] A33. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A16 or A17, wherein:
ring C is:
Figure imgf000692_0001
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is O or S;
Z is -C(=O)H or -CH2OY;
Y is hydrogen; Ring A is C5-7 cycloalkyl, piperidinyl, or phenyl;
Ring B is C5-7 cycloalkyl, piperidynly, phenyl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently fluoro, chloro; cyano; C1-4 alkyl; C1-4 hydroxyalkyl; C1- 4 haloalkyl; C1-4 alkoxy; C1-4 hydroxyalkoxy; C1-4 haloalkoxy; C3-6 cycloalkyl; 7-9 membered heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; and
R2 is independently hydrogen;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002324] A34. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A31-A33, wherein:
L is a O.
[002325] A35. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A17, A20-A21, or A26-A34, wherein Z is -C(=O)H.
[002326] A36. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A17, A20-A21, or A26-A34, wherein Z is -CH2OY.
[002327] A37. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A18, A20-A24, A26-A34, or A36, wherein Y is hydrogen.
[002328] A38. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A18, A20-A24, A26-A34, or A36, wherein Y is W.
[002329] A39. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A38, wherein W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5; -S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); or -SO2NR5R6.
[002330] A40. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A38, wherein W is methylene substituted with R4; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is - O(C(R8)2)mO-.
[002331] A41. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A19, A21-A26, A30, or A35-A40, wherein L is a CF2, O, S, S(=O), C(=O), CH2-O, or O-CH2.
[002332] A42. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A19, A21-A26, A30, or A35-A40, wherein L is O, NH, or S.
[002333] A43. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A19, A21-A26, A30, or A35-A40, wherein L is O, NRL, or S.
[002334] A44. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A19, A21-A26, A30, or A35-A43, wherein RL is hydrogen or C1-4 alkyl.
[002335] A45. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A19, A21-A26, A30, or A35-A43, wherein RL is hydrogen.
[002336] A46. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A45, wherein Ring A is C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl.
[002337] A47. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A46, wherein Ring A is C3-7 cycloalkyl.
[002338] A48. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A46, wherein Ring A is 5-6 membered heterocycloalkyl.
[002339] A49. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A46, wherein Ring A is phenyl.
[002340] A50. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A49, wherein Ring B is present. [002341] A51. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A50, wherein Ring B is 5-6 membered heterocycloalkyl, aryl, or heteroaryl.
[002342] A52. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A51, wherein Ring B is 5-6 membered heterocycloalkyl.
[002343] A53. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A51, wherein Ring B is phenyl.
[002344] A54. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of Exemplary Embodiment A51, wherein Ring B is heteroaryl.
[002345] A55. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A54, wherein Ring B is independently substituted with 1 RB group.
[002346] A56. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A54, wherein Ring B is independently substituted with 2 RB groups.
[002347] A57. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A54, wherein Ring B is independently substituted with 3 RB groups.
[002348] A58. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A57, wherein RB is independently chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, cyclopentoxy, piperidinyl, piperidinylalkyl, or
piperidinylcarbonyl.
[002349] A59. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A58, wherein R2 and R3 are independently hydrogen.
[002350] A60. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A59, wherein Ring C is:
Figure imgf000696_0001
.
[002351] A61. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of Exemplary Embodiments A16-A59, wherein Ring C is:
Figure imgf000696_0002
.
[002352] A62. The compound of any one of Exemplary Embodiments A16-A61, wherein the compound is selected from from the group consisting of compounds in Table 7; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002353] A63. The compound of any one of Exemplary Embodiments A16-A62, wherein the compound is selected from the group consisting of Compounds 487-497; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002354] A64. The compound of any one of Exemplary Embodiments A16-A63, wherein the compound is selected from from the group consisting of compounds: 487, 488, 489, 490, 491, 492, 493-1, 493-2, 494, 495, 496, and 497; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
[002355] A65. The compound of any one of Exemplary Embodiments A16-A64, wherein the compound is selected from from the group consisting of compounds:
(4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol; (4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazol-5- yl)methanol;
(4-(((cis)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)thio)-1H-1,2,3-triazol-5- yl)methanol; 4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5- carbaldehyde;
4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5-carbaldehyde; (4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazol-5-yl)methanol;
(4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol;
(4-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol;
(4-((1-(3,5-dichlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol;
(4-((1-(3,5-dichlorophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazol-5-yl)methanol;
(4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol; and (4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazol-5-yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002356] A66. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5- yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002357] A67. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazol-5- yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002358] A68. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-(((cis)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)thio)-1H-1,2,3-triazol-5- yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002359] A69. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is 4-(((trans)-4-(4-(trifluoromethoxy)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-5- carbaldehyde; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002360] A70. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is 4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-5- carbaldehyde; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002361] A71. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazol-5- yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002362] A72. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002363] A73. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-((4'-chloro-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol;
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002364] A74. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-((1-(3,5-dichlorophenyl)piperidin-4-yl)oxy)-1H-1,2,3-triazol-5-yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002365] A75. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-((1-(3,5-dichlorophenyl)piperidin-4-yl)thio)-1H-1,2,3-triazol-5-yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002366] A76. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-((4'-(piperidin-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazol-5- yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
[002367] A77. The compound of any one of Exemplary Embodiments A16-A65, wherein the compound is (4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazol-5- yl)methanol; optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [002368] A78. A pharmaceutical composition comprising a compound of any one of Exemplary Embodiments A1-A77, optionally as a single stereosiomer, or mixtures of stereoisomers, and additionally optionally as a pharmaceutically acceptable excipient.
[002369] A79. A method of treating a disease or disorder associated with a defect in glyoxylate metabolism comprising administering to a patient suffering from such disease or disorder a compound or pharmaceutically acceptable salt thereof of any one of Exemplary Embodiments A1-A77 or the pharmaceutical composition of Exemplary Embodiment A78.
[002370] A80. A method of treating a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism comprising administering to a patient suffering from such disease or disorder a compound or pharmaceutically acceptable salt thereof of any one of Exemplary Embodiments A1-A77 or the pharmaceutical composition of Exemplary Embodiment A78.
[002371] A81. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is characterized by high oxalate content in the urine.
[002372] A82. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is characterized by a deficiency in the enzyme alanine: glyoxylate aminotransferase (AGT).
[002373] A83. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is selected from the group consisting of: hyperoxaluria, genetic or environmental vitamin B6 deficiency, genetic or environmental abnormal calcium metabolism, abnormal collagen metabolism, abnormal function of oxalate transporters, and genetic kidney disease.
[002374] A84. The method of treating of Exemplary Embodiment A83, wherein the hyperoxaluria is a primary hyperoxaluria (“PH”) or is a secondary hyperoxaluria.
[002375] A85. The method of treating of Exemplary Embodiment A84, wherein the primary hyperoxaluria (“PH”) is selected from the group consisting of: Primary hyperoxaluria type 1 (“PH1”), Primary hyperoxaluria type 2 (“PH2”), and Primary hyperoxaluria type 3 (“PH3”).
[002376] A86. The method of treating of Exemplary Embodiment A83, wherein the genetic or environmental abnormal calcium metabolism is hypercalciuria or
hyperparathyroidism. [002377] A87. The method of treating of Exemplary Embodiment A83, wherein the genetic kidney disease is Hirschsprung’s disease.
[002378] A88. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is an enteric hyperoxaluria.
[002379] A89. The method of treating of Exemplary Embodiment A88, wherein the enteric hyperoxaluria is selected from the group consisting of: fat malabsorption, steatorrhea, inflammatory bowel disease (“IBD”), pancreatic insufficiency, biliary cirrhosis, short-bowel syndrome, bariatric surgery, jejunoileal bypass, Crohn’s disease, ulcerative colitis, cystic fibrosis, high blood pressure, diabetes, obesity, absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes, and ileal dysfunction.
[002380] A90. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is a dietary hyperoxaluria.
[002381] A91. The method of treating of Exemplary Embodiment A90, wherein the dietary hyperoxaluria is associated with and/or the result of one or more of a high oxalate diet, a high protein diet, a high oxalate precursor diet, and a low calcium diet.
[002382] A92. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is an idiopathic hyperoxaluria.
[002383] A93. The method of treating of Exemplary Embodiment A92, wherein the idiopathic hyperoxaluria is undefined elevated hyperoxaluria.
[002384] A94. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is a pharmacologically induced hyperoxaluria.
[002385] A95. The method of treating of Exemplary Embodiment A94, wherein the pharmacologically induced hyperoxaluria is associated with and/or the result of ingestion of compounds that metabolize to oxylate.
[002386] A96. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is a kidney disease.
[002387] A97. The method of treating of Exemplary Embodiment A96, wherein the kidney disease is selected from the group consisting of: primary hyperoxaluria, dietary hyperoxaluria, kidney stones (nephrolithiasis), recurrent kidney stones, progressive kidney failure, nephrocalcinosis, urinary tract infections, end stage renal disease, chronic kidney disease (“CKD”), end-stage kidney disease (“ESKD”), hypertension, diabetes, urolithiasis, and systemic oxalosis.
[002388] A98. The method of treating of Exemplary Embodiment A96, wherein the kidney disease is chronic kidney disease (“CKD”) or end-stage kidney disease (“ESKD”).
[002389] A99. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is oxalate nephropathy or chronic calcium-oxalate nephropathy.
[002390] A100. The method of treating of Exemplary Embodiment A79 or A80, wherein the disease or disorder is calcium oxalate (CaOx) stone disease, calcium oxalate (CaOx) nephrolithiasis, or renal failure.
[002391] A101. A method of inhibiting the enzyme GO comprising administering to a patient suffering from such disease or disorder a compound or pharmaceutically acceptable salt thereof of any one of Exemplary Embodiments A1-A77 or the pharmaceutical composition of Exemplary Embodiment A78.
[002392] A102. The compound or pharmaceutically acceptable salt thereof of any one of Exemplary Embodiments A1-A77 or the pharmaceutical composition of Exemplary Embodiment A78, for use as a medicament.
[002393] A103. The compound or pharmaceutically acceptable salt thereof of any one of Exemplary Embodiments A1-A77 or the pharmaceutical composition of Exemplary Embodiment A78, for use in a method of treating a disease or disorder associated with a defect in glyoxylate metabolism.
[002394] A104. The compound or pharmaceutically acceptable salt thereof for use or the pharmaceutical composition for use of Exemplary Embodiment A103, wherein the disease of disorder is primary hyperoxaluria.
[002395] A105. The compound or pharmaceutically acceptable salt thereof of any one of Exemplary Embodiments A1-A77 or the pharmaceutical composition of Exemplary Embodiment A78, for use in a method of treating a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism.

Claims

WE CLAIM: 1. A compound of Formula (XII):
Figure imgf000702_0001
wherein:
ring C is selected from:
Figure imgf000702_0002
wherein the wavy lines ( ) indicate the points of attachment of the C1 carbon to Z, and the C2 carbon to L;
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; Z is -C(=O)H or -CH2OY;
Y is hydrogen or W;
W is methylene substituted with R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5;
-S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); -SO2NR5R6; -P(=O)(OR7)2;
-P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-;
RL is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, phenyl, or benzyl; wherein the C1-4 alkyl is optionally substituted with hydroxycarbonyl, alkoxycarbonyl,
hydroxycarbonylalkyl, or alkylcarbonyloxy; and the phenyl group alone or as a part of the benzyl group is optionally substituted with one or two groups selected from halo and haloalkoxy;
Ring A is cycloalkyl, C8-11 spirocycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
Ring B is present or not present; wherein:
when Ring B is present, then Ring A is optionally substituted with 1 or 2 RA1 groups; each RA1 is independently selected from halo, alkyl, alkoxy, cyano, nitro, hydroxy, hydroxyalkyl, haloalkyl, haloalkoxy, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, and cycloalkyl;
when Ring B is not present, then Ring A is optionally substituted with 1, 2, or 3 RA2 groups;
Ring B, when present, is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each is optionally substituted with 1, 2, or 3 RB groups;
each RA2 and RB is independently halo; cyano; alkyl; hydroxyalkyl; alkylsulfonyl;
aminosulfonyl; alkylaminosulfonyl; dialkylaminosulfonyl; haloalkyl; alkoxy; aminoalkoxy; alkylaminoalkoxy; dialkylaminoalkoxy; hydroxyalkoxy;
haloalkoxy; alkylcarbonyl; alkoxyalkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylaminoalkoxy; cycloalkyl; (cycloalkyl)alkyl; cycloalkyloxy; (cycloalkyl)alkoxy wherein the cycloalkyl group is optionally substituted with hydroxyalkyl; cycloalkylcarbonyl; cycloalkylcarbonyloxy;
heterocycloalkyl optionally substituted with one or two groups independently selected from halo, alkyl, and alkylcarbonyl; (5-6-membered heterocycloalkyl- one)alkyl; 5-6-membered heterocycloalkyl-one; (heterocycloalkyl)alkyl;
heterocycloalkylcarbonyl; or 5-6-membered heteroaryl optionally substituted with one group selected from alkyl, hydroxyalkyl, (hydroxycycloalkyl)alkyl, alkoxyalkyl, and hydroxycycloalkyl;
each R2 and R3 is independently hydrogen, alkyl, phenyl, benzyl, or alkoxy-substituted benzyl; wherein the alkyl is optionally substituted with halo, alkoxy, haloalkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, or heterocycloalkylcarbonyloxy optionally substituted with alkoxycarbonyl;
R4 is alkylcarbonyloxy, phenylcarbonyloxy, cycloalkylcarbonyloxy,
heterocycloalkylcarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxycarbonyloxy, -N(R10)C(O)R11,
-N(R10)C(O)OR11, -N(R10)C(O)NR12R13, -O-P(=O)(O-)2, -O-P(=O)(OR7)(O-), or -O-P(=O)(X) wherein X is -O(C(R8)2)mO-;
each R8 is independently hydrogen, halo, -CN, -OR9, -C(=O)R9,
-C(=O)OR9, -C(=O)N(R9)2, -N(R9)2, -SR9, -S(O)R9, -S(O)2R9, -OC(=O)R9, -OC(=O)OR9, -OC(=O)(N(R9)2), -N(R9)C(=O)R14, -N(R9)C(=O)OR14,
-SO2N(R9)2, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl;
each R5, R6, R7, R9, R10, R11, R12, R13, and R14 is independently hydrogen, alkyl,
cycloalkyl, aryl, arylalkyl, heterocycloalkyl, or heteroaryl; and
m is 1, 2, or 3; and
provided:
i. the compound represented by Formula (XII) is exclusive of:
a. 4-(phenylamino)-1H-1,2,3-triazole-5-carbaldehyde;
b. 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazole-5- carbaldehyde;
c. ethyl hydrogen (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate;
d. diethyl (((5-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)- 1H-1,2,3-triazol-4-yl)methoxy)methyl)phosphonate; and
e. 1-((4-(hydroxymethyl)-1H-1,2,3-triazol-5-yl)methyl)-5-methylpyrimidine- 2,4(1H,3H)-dione;
ii. when Z is -C(=O)H, L is NRL, RL is hydrogen, and Ring A is phenyl, then Ring B is present and/or the phenyl Ring A is substituted with 1, 2, or 3 RA2 groups; iii. when Z is -C(=O)H, L is CH2, and Ring A is cyclopropyl, phenyl, indole, or
thiophene, then Ring B is present;
iv. when Z is -C(=O)H, L is CH2-O, and Ring A is phenyl, then Ring B is present; v. when Z is -CH2OY, Y is W, W is -P(=O)(OR7)2 or -P(=O)(OR7)(O-), R7 is ethyl, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and vi. when Z is -CH2OY, Y is hydrogen, L is CH2, and Ring A is pyrimidine-2,4-dione, then Ring B is present and/or the pyrimidine-2,4-dione Ring A is unsubstituted or substituted with 2 RA2; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
2. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of claim 1, wherein
L is a CF2, O, S, S(=O), C(=O), CH2-NRL, CH2-S, or Q-CH2; wherein Q is O, NRL, or S.
3. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of claim 1, wherein
L is a CH2, CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; and
Z is -CH2OY.
4. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of claim 1, wherein
L is a CF2, O, NRL, S, S(=O), C(=O), CH2-Q, or Q-CH2; wherein Q is O, NRL, or S; and Z is -CH2OY.
5. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of claim 1, wherein
L is a CF2, O, S, S(=O), C(=O), CH2-NRL, CH2-S, or Q-CH2; wherein Q is O, NRL, or S; and
Z is -C(=O)H.
6. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-2, wherein Z is -C(=O)H.
7. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-2, wherein Z is -CH2OY.
8. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-4 or 7, wherein Y is hydrogen.
9. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-4 or 7, wherein Y is W.
10. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of claim 9, wherein W is methylene substituted with
R4; -C(=O)R5; -C(=O)OR5; -C(=O)NR5R6; -C(=O)SR5; -S(O)R5; -S(O)2R5; -S(O)(OR5); -S(O)2(OR5); or -SO2NR5R6.
11. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of claim 9, wherein W is methylene substituted with R4; -P(=O)(OR7)2; -P(=O)(O-)2; -P(=O)(OR7)(O-); or -P(=O)(X) wherein X is -O(C(R8)2)mO-.
12. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1 or 3-11, wherein L is a CF2, O, NRL, S, S(=O), C(=O), CH2-O, or O-CH2.
13. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1 or 3-11, wherein L is a CF2, O, S, S(=O), C(=O), CH2-O, or O-CH2.
14. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1 or 3-11, wherein L is O, NRL, or S.
15. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1 or 3-11, wherein L is O, NH, or S.
16. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-15, wherein L is O or S.
17. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-16, wherein L is O.
18. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-17, wherein Ring A is C3-7 cycloalkyl, 5-6 membered heterocycloalkyl, or phenyl.
19. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-18, wherein Ring A is C3-7 cycloalkyl.
20. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-18, wherein Ring A is 5-6 membered heterocycloalkyl.
21. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-18, wherein Ring A is phenyl.
22. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-21, wherein Ring B is present.
23. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-22, wherein Ring B is 5-6 membered heterocycloalkyl, aryl, or heteroaryl.
24. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-23, wherein Ring B is 5-6 membered heterocycloalkyl.
25. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-23, wherein Ring B is phenyl.
26. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-23, wherein Ring B is heteroaryl.
27. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-26, wherein Ring B is independently substituted with 1 RB group.
28. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-26, wherein Ring B is independently substituted with 2 RB groups.
29. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-28, wherein RB is independently halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-7 cycloalkoxy, piperidinyl,
piperidinylalkyl, or piperidinylcarbonyl.
30. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-29, wherein RB is independently chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, cyclopentoxy, piperidinyl, piperidinylalkyl, or piperidinylcarbonyl.
31. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-30, wherein R2 and R3 are independently hydrogen.
32. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-31, wherein ring C is:
Figure imgf000708_0001
.
33. The compound, single stereoisomer or mixture of stereoisomers or pharmaceutically acceptable salt of any one of claims 1-31, wherein ring C is:
Figure imgf000709_0001
.
34. A compound selected from the group consisting of compounds 487, 488, 489, 490, 491, 492, 493-1, 493-2, 494, 495, 496, and 497, or a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.
35. A pharmaceutical composition comprising a compound of any one of claims 1-34,
optionally as a single stereosiomer, or mixtures of stereoisomers, and a pharmaceutically acceptable excipient.
36. A method of treating a disease or disorder associated with a defect in glyoxylate
metabolism comprising administering to a patient suffering from such disease or disorder a compound or pharmaceutically acceptable salt thereof of any one of claims 1-34 or the pharmaceutical composition of claim 35.
37. A method of treating a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism comprising administering to a patient suffering from such disease or disorder a compound or pharmaceutically acceptable salt thereof of any one of claims 1-34 or the pharmaceutical composition of claim 35.
38. The method of treating of claim 36 or 37, wherein the disease or disorder is characterized by high oxalate content in the urine.
39. The method of treating of claim 36 or 37, wherein the disease or disorder is characterized by a deficiency in the enzyme alanine : glyoxylate aminotransferase (AGT).
40. The method of treating of claim 36 or 37, wherein the disease or disorder is selected from the group consisting of: hyperoxaluria, genetic or environmental vitamin B6 deficiency, genetic or environmental abnormal calcium metabolism, abnormal collagen metabolism, abnormal function of oxalate transporters, and genetic kidney disease.
41. The method of treating of claim 40, wherein the hyperoxaluria is a primary hyperoxaluria (“PH”) or is a secondary hyperoxaluria.
42. The method of treating of claim 41, wherein the primary hyperoxaluria (“PH”) is selected from the group consisting of: Primary hyperoxaluria type 1 (“PH1”), Primary hyperoxaluria type 2 (“PH2”), and Primary hyperoxaluria type 3 (“PH3”).
43. The method of treating of claim 40, wherein the genetic or environmental abnormal calcium metabolism is hypercalciuria or hyperparathyroidism.
44. The method of treating of claim 40, wherein the genetic kidney disease is Hirschsprung’s disease.
45. The method of treating of claim 36 or 37, wherein the disease or disorder is an enteric hyperoxaluria.
46. The method of treating of claim 45, wherein the enteric hyperoxaluria is selected from the group consisting of: fat malabsorption, steatorrhea, inflammatory bowel disease (“IBD”), pancreatic insufficiency, biliary cirrhosis, short-bowel syndrome, bariatric surgery, jejunoileal bypass, Crohn’s disease, ulcerative colitis, cystic fibrosis, high blood pressure, diabetes, obesity, absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes, and ileal dysfunction.
47. The method of treating of claim 36 or 37, wherein the disease or disorder is a dietary hyperoxaluria.
48. The method of treating of claim 47, wherein the dietary hyperoxaluria is associated with and/or the result of one or more of a high oxalate diet, a high protein diet, a high oxalate precursor diet, and a low calcium diet.
49. The method of treating of claim 36 or 37, wherein the disease or disorder is an idiopathic hyperoxaluria.
50. The method of treating of claim 36 or 37, wherein the disease or disorder is a kidney disease.
51. The method of treating of claim 50, wherein the kidney disease is selected from the group consisting of: primary hyperoxaluria, dietary hyperoxaluria, kidney stones
(nephrolithiasis), recurrent kidney stones, progressive kidney failure, nephrocalcinosis, urinary tract infections, end stage renal disease, chronic kidney disease (“CKD”), end- stage kidney disease (“ESKD”), hypertension, diabetes, urolithiasis, and systemic oxalosis.
52. The method of treating of claim 50, wherein the kidney disease is chronic kidney disease (“CKD”) or end-stage kidney disease (“ESKD”).
53. The method of treating of claim 36 or 37, wherein the disease or disorder is oxalate
nephropathy or chronic calcium-oxalate nephropathy.
54. The method of treating of claim 36 or 37, wherein the disease or disorder is calcium
oxalate (CaOx) stone disease, calcium oxalate (CaOx) nephrolithiasis, or renal failure.
55. A method of inhibiting the enzyme GO comprising administering to a patient suffering from such disease or disorder a compound or pharmaceutically acceptable salt thereof of any one of claims 1-34 or the pharmaceutical composition of claim 35.
56. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-34 or the pharmaceutical composition of claim 35, for use as a medicament.
57. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-34 or the pharmaceutical composition of claim 35, for use in a method of treating a disease or disorder associated with a defect in glyoxylate metabolism.
58. The compound or pharmaceutically acceptable salt thereof for use or the pharmaceutical composition for use of claim 57, wherein the disease of disorder is primary
hyperoxaluria.
59. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-34 or the pharmaceutical composition of claim 35, for use in a method of treating a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism.
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US17/619,818 US20230088214A1 (en) 2019-06-19 2020-06-18 Glycolate oxidase inhibitors for the treatment of disease
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